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    • 专利摘要:
    A compound of the formula (I):   wherein X1 and X2 are the same or different and eachis a bond or a spacer having 1 to 20 atom(s) in the mainchain;   one of R1 and R2 is a cycle group havingsubstituent(s) selected from 1) an optionally substitutedcarboxy-C1-6 alkoxy group and 2) an optionally substitutedcarboxy-C1-6 aliphatic hydrocarbon group, wherein the cyclegroup optionally has additional substituent(s), and theother is an optionally substituted cycle group or ahydrogen atom; and   R3, R4 and R5 are the same or different and each is ahydrogen atom or a substituent, or R4 may link togetherwith R3 or R5 to form an optionally substituted ring;   provided that when R3 is a hydrogen atom, R4 is ahydrogen atom and R5 is methyl, X2-R2 is not 4-cyclohexylphenyl;when R3 is 4-methoxyphenyl, R4 is a hydrogen atom and R5 is methyl, X2-R2 is not 4-methoxyphenyl;and when R1 or R2 is a hydrogen atom, theadjacent X1 or X2 is not a C1-7 alkylene;or a salt thereof exhibits a protein tyrosine phosphataseinhibitory action and is useful as a prophylactic ortherapeutic agent for diabetes or the like.
    公开号:EP1284260A1
    申请号:EP01932153
    申请日:2001-05-21
    公开日:2003-02-19
    发明作者:Takahiro Matsumoto；Nozomi Katayama；Hiroshi Mabuchi
    申请人:Takeda Chemical Industries Ltd；
    IPC主号:A61K-31
    专利说明:
    [0001] The present invention relates to a pyrrole compoundhaving a protein tyrosine phosphatase (hereinaftersometimes to be abbreviated as PTP) inhibitory action,which is useful as a drug such as a prophylactic ortherapeutic agent of diabetes and the like.
    [0002] The present invention also relates to a proteintyrosine phosphatase inhibitor containing a pyrrolecompound.
    [0003] The present invention further relates to aprophylactic or therapeutic agent of diabetes containing apyrrole compound. Background Art
    [0004] As compounds having a protein tyrosine phosphataseinhibitory action, the following compounds are known. 1) WO99/46244 discloses a compound of the formula:
    [0005] However, none of the above-mentioned pyrrole compounds is reported to be a protein tyrosine phosphatase inhibitoror a prophylactic or therapeutic agent of diabetes.
    [0006] Therefore, there is a strong demand for development ofa pyrrole compound which has protein tyrosine phosphataseinhibitory action and useful as a medicament such as aprophylactic or therapeutic agent for diabetes and the like. Disclosure of the Invention
    [0007] The present invention relates to (1) a novel compound characterized by the chemicalstructure wherein at least one of the substituent on thenitrogen atom of pyrrole ring and the substituent on thecarbon atom constituting the pyrrole ring and adjacents tothe nitrogen atom, has a cycle group substituted with acarboxy-C1-6 alkoxy group and/or a carboxy-C1-6 aliphatichydrocarbon group; which is the compound of the formula:
    [0008] The "spacer having 1 to 20 atom(s) in the main chain"which is represented by X1 or X2, means a divalent group in which 1 to 20 atom(s) is(are) ranged in the main chain.The number of the "atom(s) in the main chain" is counted soas to be the least number.
    [0009] The "spacer having 1 to 20 atom(s) in the main chain"includes, for example, a divalent group consisting of 1 to5 (preferably 1 to 3) groups selected from -O-; -S-; -CO-;-SO-; -SO2-; -NR6- (R6 is a hydrogen atom, an optionallysubstituted (e.g., halogenated) C1-6 alkyl, an optionallysubstituted (e.g., halogenated) C1-6 alkyl-carbonyl or anoptionally substituted (e.g., halogenated) C1-6alkylsulfonyl); and an optionally substituted divalent C1-6aliphatic hydrocarbon group and the like.
    [0010] The "optionally halogenated C1-6 alkyl"represented byR6 includes, for example, C1-6 alkyl optionally having 1 to5, preferably 1 to 3 halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine and the like) at thesubstitutable position(s), and the examples include methyl,chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl,butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl,hexyl, 6,6,6-trifluorohexyl and the like.
    [0011] The "optionally halogenated C1-6 alkyl-carbonyl"represented by R6 includes, C1-6 alkyl-carbonyl optionally having 1 to 5, preferably 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like) at thesubstitutable position(s), and the examples include, forexample, acetyl, monochloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyland the like.
    [0012] The " optionally halogenated C1-6 alkylsulfonyl"represented by R6 includes, C1-6 alkylsulfonyl optionallyhaving 1 to 5, preferably 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like) at thesubstitutable position(s), and the examples include, forexample, methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl and the like.
    [0013] The "divalent C1-6 aliphatic hydrocarbon group" of the"optionally substituted divalent C1-6 aliphatic hydrocarbongroup" includes, for example, (1) C1-6 alkylene (e.g., -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-,-(CH2)5-, -(CH2)6-, -CH(CH3)-, -C(CH3)2-, -(CH(CH3))2-,-(CH2)2C(CH3)2-, -(CH2)3C(CH3)2- and the like) ; (2) C2-6 alkenylene (e.g., -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-,-CH=CH-CH2-CH2-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-,-CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2- and the like); (3) C2-6 alkynylene (e.g., -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2-and the like) and the like.
    [0014] The "substituent" of the "optionally substituteddivalent C1-6 aliphatic hydrocarbon group" includes, forexample, halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like), hydroxy group and the like. Thenumber of the "substituent" is, for example, 1 to 5,preferably 1 to 3.
    [0015] Preferable examples of the "spacer having 1 to 20atom(s) in the main chain" include, (1) C1-20 alkylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like)(e.g., -CH2-, -(CH2)2-, -(CH2)3-, -CH(OH)(CH2)2-, -(CH2)4-,-(CH2)5-, -(CH2)6-, -CHCH3-, -C (CH3)2-, -CH (CF3)-, -(CH(CH3))2-,-(CF2)2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2-, -(CH2)7-, -(CH2)8-,-(CH2)9-, -(CH2)10-, -(CH2)11-, -(CH2)12-, -(CH2)13-, -(CH2)14-,-(CH2)15-, -(CH2)16-, -(CH2)17-, -(CH2)18-, -(CH2)19-, -(CH2)20-and the like); (2) C2-20 alkenylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like)(e.g., -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH=CH-CH2-CH2-,-CH2-CF=CH-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-,-CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2- and the like); (3) C2-20 alkynylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like) (e.g., -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2- and the like) ; (4) -(CH2)w1aO(CH2)w2a-, -(CH2)w1aS(CH2)w2a-, -(CH2)w1aCO(CH2)w2a-,-(CH2)w1aSO(CH2)w2a-, -(CH2)w1aSO2(CH2)w2a-, -(CH2)w1aNR6(CH2)w2a-; (5) -(CH2)w3aCO-, -(CH2)w3aCONR6(CH2)w4a-, -(CH2)w3aNR6CO(CH2)w4a-,-(CH2) w 3aSO2NR6(CH2) w 4a-, -(CH2) w 3aNR6SO2(CH2) w 4a-, -(CH2)w3aCOO(CH2)w4a-; (6) -(CH2)w5aNR6CONR6b(CH2)w6a-; (wherein R6 has the same meaning as above; R6b has the samemeaning as R6; w1a and w2a are each an integer of 0 to 19and w1a+w2a is 0 to 19; w3a and w4a are each an integer of0 to 18 and w3a+w4a is 0 to 18; w5a and w6a are each aninteger of 0 to 17 and w5a+w6a is 0 to 17) and the like.
    [0016] Among the above-mentioned "spacer having 1 to 20atom(s) in the main chain", the following "spacer having 1to 8 atom(s) in the main chain" are preferred. (1) C1-8 alkylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like)(e.g., -CH2-, -(CH2)2-, -(CH2)3-, -CH(OH)-(CH2)2-, -(CH2)4-,-(CH2)5-, -(CH2)6-, -CHCH3-, -C(CH3)2-, -CH(CF3), -(CH(CH3))2-,-(CF2)2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2- and the like) ; (2) C2-8 alkenylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like)(e.g., -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH=CH-CH2-CH2-,-CH2-CF=CH-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-,-CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2- and the like); (3) C2-8 alkynylene optionally having 1 to 3 substituent(s)(preferably, halogen atom, hydroxy group and the like)(e.g., -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2- and the like); (4)- (CH2)w1O(CH2)w2-, -(CH2)w1S(CH2)w2-, -(CH2)w1CO(CH2)w2-,-(CH2)w1SO(CH2)w2-, -(CH2)w1SO2(CH2)w2-, -(CH2)w1NR6(CH2)w2-; (5) -(CH2)w3CO-, -(CH2)w3CONR6(CH2)w4-, -(CH2)w3NR6CO (CH2)w4-,-(CH2)w3SO2NR6(CH2)w4-, -(CH2)w3NR6SO2(CH2)w4-, -(CH2)w3COO(CH2)w4-; (6) -(CH2)w5NR6CONR6b(CH2)w6-; (R6 has the same meaning as above; R6b has the same meaningas R6; w1 and w2 are each an integer of 0 to 5 and w1+w2 is0 to 7; w3 and w4 are each an integer of 0 to 4 and w3+w4is 0 to 6; w5 and w6 are each an integer of 0 to 3 andw5+w6 is 0 to 5) and the like.
    [0017] The "spacer having 1 to 20 atom(s) in the main chain"is preferably C1-20 alkylene (preferably C1-8 alkylene) or C2-20alkenylene (preferably C2-8 alkenylene) and the like, eachof which optionally has 1 to 3 substituent(s) (preferably,halogen atom, hydroxy group and the like).
    [0018] Preferably, X1 or X2 is a bond or C1-20 alkylene(preferably C1-8 alkylene) optionally having 1 to 3substituent(s) (preferably, halogen atom, hydroxy group andthe like) . More preferably, X1 or X2 is a bond or C1-8alkylene.
    [0019] Preferably, in the formula (I) or (II), X1 and X2 are the same or different and each is a bond or a C1-8 alkylene.
    [0020] The "cycle group" of the "cycle group havingsubstituent(s) selected from 1) an optionally substitutedcarboxy-C1-6 alkoxy group and 2) an optionally substitutedcarboxy-C1-6 aliphatic hydrocarbon group, wherein the cyclegroup optionally has additional substituent(s)" and the"optionally substituted cycle group" represented by R1, R2,R1a or R2a includes an aromatic hydrocarbon group, anaromatic heterocycle group, a non-aromatic cyclichydrocarbon group, a non-aromatic heterocycle group and thelike.
    [0021] The preferred aromatic hydrocarbon group is, forexample, C6-14aryl and the like. The C6-14 aryl includes,for example, phenyl, naphthyl, anthryl, phenanthryl,acenaphthylenyl, biphenylyl and the like.
    [0022] The aromatic heterocycle group includes, for example,a 5- to 7-membered aromatic monocyclic heterocycle oraromatic fused heterocycle group containing 1 to 4heteroatom(s) selected from an oxygen atom, a sulfur atomand a nitrogen atom as a ring-constituting atom, besidescarbon atoms. The aromatic fused heterocycle groupincludes, for example, a group formed by fusion of the 5-to7-membered aromatic monocyclic heterocycle group with a6-membered ring containing 1 or 2 nitrogen atom(s), benzenering or a 5-membered ring containing one sulfur atom and the like.
    [0023] The aromatic heterocycle group includes, for example,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-1-yl,tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl,4-quinazolyl, 2-quinoxalyl, 2-benzoxazolyl, 2-benzothiazolyl,benzimidazol-1-yl, benzimidazol-2-yl,indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl,lH-pyrrolo[2,3-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl,lH-imidazo[4,5-c]pyridin-2-yl,1H-imidazo[4,5-b]pyrazin-2-yl and the like.
    [0024] Preferable non-aromatic cyclic hydrocarbon group isnon-aromatic cyclic hydrocarbon group having 3 to 10 carbonatoms. The non-aromatic cyclic hydrocarbon group includes,for example, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10cycloalkadienyl and the like.
    [0025] The C3-10 cycloalkyl includes, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[3.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl,tricyclo[3.3.1.13,7]decyl and the like.
    [0026] The C3-10 cycloalkenyl includes, cyclopropenyl,cyclobutenyl, cyclopentenyl (e.g., 2-cyclopenten-1-yl, 3-cyclopenten-1-yl),cyclohexenyl (e.g., 2-cyclohexen-1-yl,3-cyclohexen-1-yl), cycloheptenyl, cyclooctenyl and thelike.
    [0027] The C4-10 cycloalkadienyl includes cycloheptadienyl,cyclopentadienyl (e.g., 2,4-cyclopentadien-1-yl),cyclohexadienyl (e.g., 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl)and the like.
    [0028] The non-aromatic cyclic hydrocarbon group includes2,3-dihydro-1H-inden-2-yl and the like, in addition to thegroups as mentioned above.
    [0029] The non-aromatic heterocycle group includes, forexample, a 5- to 7- membered non-aromatic monocyclicheterocycle group or non-aromatic fused heterocycle groupcontaining 1 to 4 heteroatom(s) selected from an oxygenatom, a sulfur atom and a nitrogen atom as a ring-constitutingatom, besides carbon atoms. The non-aromaticfused heterocycle group includes, for example, a groupformed by fusing the 5- to 7- membered non-aromatic monocyclic heterocycle group together with a 6-memberedring containing 1 or 2 nitrogen atom(s), benzene ring or a5-membered ring containing one sulfur atom and the like.
    [0030] The non-aromatic heterocycle group includes, forexample, 1-pyrrolidinyl, piperidino, morpholino,thiomorpholino, 1-piperazinyl, hexamethyleneimin-1-yl,oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl,2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl,2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yland the like.
    [0031] The "cycle group" is preferably an aromatichydrocarbon group, and more preferably C6-14 aryl such asphenyl, naphthyl, biphenylyl and the like. Among thesegroups, phenyl is preferable.
    [0032] The "substituent" which may be possessed by the "cyclegroup" represented by R1, R2, R1a or R2a includes, forexample, halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like), nitro, cyano, optionally substitutedC1-8 (preferably C1-6) aliphatic hydrocarbon group,optionally substituted C6-14 aryl, optionally substituted C7-19aralkyl, optionally substituted C3-10 cycloalkyl, hydroxy,optionally substituted C1-12 (preferably C1-6) alkoxy,optionally substituted C6-14 aryloxy, optionally substitutedC7-19 aralkyloxy, optionally substituted C3-10 cycloalkyloxy,mercapto, optionally substituted C1-6 alkylthio, optionally substituted C6-14 arylthio, optionally substituted C7-19aralkylthio, optionally substituted C3-10 cycloalkylthio,amino, mono-C1-6 alkylamino, di-C1-6 alkylamino, optionallysubstituted heterocycle group, acyl, acylamino, acyloxy andthe like.
    [0033] The number of the above-mentioned substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of thesubstituents is not less than 2, the substituents may bethe same or different.
    [0034] The "C1-8 aliphatic hydrocarbon group" of the"optionally substituted C1-8 aliphatic hydrocarbon group"includes, for example, C1-8 (preferably C1-6) alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl, octyl and thelike), C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 2-butenyland the like), C2-6 alkynyl (e.g., ethynyl,propargyl, 2-butynyl and the like) and the like.
    [0035] The "C6-14 aryl"of the "optionally substituted C6-14aryl" includes one exemplified as the "cycle group".
    [0036] The "C7-19 aralkyl" of the "optionally substituted C7-19aralkyl" includes, for example, benzyl, phenethyl,diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl and the like.
    [0037] The "C3-10 cycloalkyl" of the "optionally substituted C3-10 cycloalkyl" includes one exemplified as the "cyclegroup".
    [0038] The "C1-12 alkoxy" of the "optionally substituted C1-12(preferably C1-6) alkoxy" includes, for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,decyloxy, undecyloxy, dodecyloxy and the like.
    [0039] The "C6-14 aryloxy" of the "optionally substituted C6-14aryloxy" includes, for example, phenyloxy, 1-naphthyloxy,2-naphthyloxy and the like.
    [0040] The "C7-19 aralkyloxy" of the "optionally substitutedC7-19 aralkyloxy" includes, for example, benzyloxy,phenethyloxy, diphenylmethyloxy, triphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy,3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy,6-phenylhexyloxy and the like.
    [0041] The "C3-10 cycloalkyloxy" of the "optionally substitutedC3-10 cycloalkyloxy" includes, for example, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
    [0042] The "C1-6 alkylthio" of the "optionally substituted C1-6alkylthio" includes, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio,pentylthio, hexylthio and the like.
    [0043] The "C6-14 arylthio" of the "optionally substituted C6-14arylthio" includes, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
    [0044] The "C7-19 aralkylthio" of the "optionally substitutedC7-19 aralkylthio" includes, for example, benzylthio,phenethylthio, diphenylmethylthio, triphenylmethylthio, 1-naphthylmethylthio,2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio,5-phenylpentylthio and the like.
    [0045] The "C3-10 cycloalkylthio" of the "optionallysubstituted C3-10 cycloalkylthio" includes, for example,cyclopropylthio, cyclobutylthio, cyclopentylthio,cyclohexylthio and the like.
    [0046] The "mono-C1-6 alkylamino" includes, for example,methylamino, ethylamino, propylamino, isopropylamino,butylamino and the like.
    [0047] The "di-C1-6 alkylamino" includes, for example,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino and the like.
    [0048] The "heterocycle group" of the "optionally substitutedheterocycle group" includes "aromatic heterocycle group"and "non-aromatic heterocycle group" exemplified as the"cycle group".
    [0049] The "substituent" of the "optionally substituted C1-8aliphatic hydrocarbon group", "optionally substituted C6-14aryl", "optionally substituted C7-19 aralkyl", "optionallysubstituted C3-10 cycloalkyl", "optionally substituted C1-12 alkoxy", "optionally substituted C6-14 aryloxy", "optionallysubstituted C7-19 aralkyloxy", "optionally substituted C3-10cycloalkyloxy", "optionally substituted C1-6 alkylthio","optionally substituted C6-14 arylthio", "optionallysubstituted C7-19 aralkylthio", "optionally substituted C3-10cycloalkylthio" and "optionally substituted heterocyclegroup" include, for example, halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), nitro, cyano,optionally halogenated C1-6 alkyl, C6-14 aryl, hydroxy,optionally halogenated C1-6 alkoxy, mercapto, optionallyhalogenated C1-6 alkylthio, amino, mono-C1-6 alkylamino, di-C1-6alkylamino, formyl, carboxy, carbamoyl, thiocarbamoyl,optionally halogenated C1-6alkyl-carbonyl, C1-6 alkoxy-carbonyl,mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,optionally halogenated C1-6 alkylsulfonyl, formylamino,optionally halogenated C1-6 alkyl-carboxamide, C1-6 alkoxy-carboxamide,C1-6 alkylsulfonylamino, C1-6 alkyl-carbonyloxy,C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6alkyl-carbamoyloxy, heterocycle group, C3-10 cycloalkyloptionally substituted with C1-6 alkyl and the like.
    [0050] The number of the above-mentioned substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of thesubstituents is not less than 2, the substituents may bethe same or different.
    [0051] The "optionally halogenated C1-6 alkyl", "optionally halogenated C1-6 alkyl-carbonyl" and "optionally halogenatedC1-6alkylsulfonyl" include those exemplified as R6.
    [0052] The "C6-14 aryl" includes one exemplified as the "cyclegroup".
    [0053] The "optionally halogenated C1-6 alkoxy" includes, forexample, C1-6 alkoxy optionally having 1 to 5, preferably 1to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine,iodine and the like) and the like. The examples thereofinclude, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,isobutoxy, sec-butoxy, pentyloxy, hexyloxyand the like.
    [0054] The "optionally halogenated C1-6 alkylthio" includes,for example, C1-6 alkylthio optionally having 1 to 5,preferably 1 to 3 halogen atom(s) (e.g., fluorine, chlorine,bromine, iodine and the like) and the like. The examplesthreof include, for example, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio,butylthio, 4,4,4-trifluorobutylthio, sec-butylthio, tert-butylthio,pentylthio, hexylthio and the like.
    [0055] The "mono-C1-6 alkylamino" and "di-C1-6 alkylamino"include those exemplified as the "substituent" for R1 andthe like.
    [0056] The "C1-6 alkoxy-carbonyl" includes, for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
    [0057] The "mono-C1-6 alkyl-carbamoyl" includes, for example,methylcarbamoyl, ethylcarbamoyl and the like.
    [0058] The "di-C1-6alkyl-carbamoyl" includes, for example,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyland the like.
    [0059] The "optionally halogenated C1-6 alkyl-carboxamide"include, for example, C1-6 alkyl-carboxamide optionallyhaving 1 to 5, preferably 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like) and thelike. The examples thereof include, for example, acetamide,trifluoroacetamide, propanamide, butanamide and the like.
    [0060] The "C1-6 alkoxy-carboxamide" includes, for example,methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide,butoxycarboxamide and the like.
    [0061] The "C1-6 alkylsulfonylamino" includes, for example,methylsulfonylamino, ethylsulfonylamino and the like.
    [0062] The "C1-6 alkyl-carbonyloxy" includes, for example,acetoxy, propanoyloxy and the like.
    [0063] The "C1-6 alkoxycarbonyloxy" includes, for example,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like.
    [0064] The "mono-C1-6 alkyl-carbamoyloxy" includes, forexample, methylcarbamoyloxy, ethylcarbamoyloxy and the like.
    [0065] The "di-C1-6 alkyl-carbamoyloxy" includes, for example, dimethylcarbamoyloxy, diethylcarbamoyloxy and the like.
    [0066] The "heterocycle group" includes, the "aromaticheterocycle group" and "non-aromatic heterocycle group"exemplified as the "cycle group".
    [0067] The "C3-10 cycloalkyl" of "C3-10 cycloalkyl optionallysubstituted with C1-6 alkyl" includes one exemplified as the"cycle group". The "C1-6 alkyl" of the "C3-10 cycloalkyloptionally substituted with C1-6 alkyl" includes, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like.
    [0068] The "acyl" includes, for example, an acyl of theformula : -CO-R7, -CO-OR7, -CO-NR7R8, -CS-NR7R8, -SO2-R7a, -SO-R7a[wherein R7 is (i) a hydrogen atom, (ii) an optionallysubstituted hydrocarbon group, or (iii) an optionallysubstituted heterocycle group; R7a is (i) an optionallysubstituted hydrocarbon group, or (ii) an optionallysubstituted heterocycle group; R8 is a hydrogen atom or aC1-6 alkyl; R7 and R8 may form an optionally substitutednitrogen-containing heterocycle together with the adjacentnitrogen atom] and the like.
    [0069] The "hydrocarbon group" of the "optionally substitutedhydrocarbon group"represented by R7 or R7a includes, forexample, hydrocarbon group having 1 to 19 carbon atom(s)(e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyland the like) and the like. Among these, the following a) to f) are preferred. a) C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike) ; b) C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 2-butenyland the like); c) C2-6 alkynyl (e.g., ethynyl, propargyl, 2-butynyl and thelike) ; d) C3-10 cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like); e) C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl,2-anthryl and the like); and f) C7-19 aralkyl (e.g., benzyl, phenethyl, diphenylmethyl,triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyland the like).
    [0070] The "hydrocarbon group" is preferably C1-6 alkyl, C6-14aryl, C7-19 aralkyl and the like.
    [0071] The "substituent" of the "optionally substitutedhydrocarbon group" includes one exemplified as the"substituent" of the "optionally substituted C1-8 aliphatichydrocarbon group" and the like.
    [0072] The number of the above-mentioned substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of thesubstituents is not less than 2, the substituents may be the same or different.
    [0073] The "optionally substituted heterocycle group"represented by R7 or R7a includes the "optionallysubstituted heterocycle group" exemplified as the"substituent" of R1 or R2.
    [0074] The "C1-6 alkyl" represented by R8 includes oneexemplified as the "C1-8 aliphatic hydrocarbon group".
    [0075] The "nitrogen-containing heterocycle" of the"optionally substituted nitrogen-containing heterocycle"formed by R7, R8 and the adjacent nitrogen atom include,for example, a 5- to 7-membered nitrogen-containingheterocycle containing at least one nitrogen atom(s)besides carbon atoms and optionally containing 1 to 3heteroatom(s) selected from a nitrogen atom, a sulfur atomand an oxygen atom, and the like. The "nitrogen-containingheterocycle" is preferably piperidine, morpholine,thiomorpholine, piperazine, pyrrolidine and the like.
    [0076] The "substituent" of the "optionally substitutednitrogen-containing heterocycle" includes one exemplifiedas the "substituent" of the "optionally substituted C1-8aliphatic hydrocarbon group" and the like.
    [0077] The number of the above-mentioned substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of thesubstituents is not less than 2, the substituents may bethe same or different.
    [0078] The "acyl" is preferably formyl, carboxy, carbamoyl,optionally halogenated C1-6 alkyl-carbonyl (e.g., acetyl andthe like), C1-6 alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl andthe like), C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl,2-naphthoyl and the like), C6-14 aryloxy-carbonyl (e.g.,phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyland the like), C7-19 aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, phenethyloxycarbonyl and thelike), heterocyclic carbonyl (e.g., nicotinoyl and thelike), mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl and the like), di-C1-6 alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyland the like), C6-14 arylcarbamoyl (e.g., phenylcarbamoyl,naphthylcarbamoyl and the like), heterocyclic carbamoyl(e.g., 2-pyridinylcarbamoyl, 2-quinolylcarbamoyl and thelike), optionally halogenated C1-6alkylsulfonyl (e.g.,methylsulfonyl and the like), C6-14 arylsulfonyl (e.g.,phenylsulfonyl and the like) and the like.
    [0079] The "acylamino" includes, for example, an amino mono-or di-substituted with the "acyl", and preferably includes,an acylamino of the formula :-NR9-COR10, -NR9-COOR10a, -NR9-SO2R10a,-NR9-CONR10aR10b [wherein R9 is a hydrogen atom or aC1-6 alkyl; R10 has the same meaning as R7; R10a has the samemeaning as R7a; R10b has the same meaning as R8] and the like.
    [0080] The "C1-6 alkyl" represented by R9 includes oneexemplified as the "C1-8aliphatic hydrocarbon group".
    [0081] The "acylamino" is preferably formylamino, optionallyhalogenated C1-6 alkyl-carboxamide (e.g., methylcarboxamide,trifluoromethylcarboxamide, pentylcarboxamide and the like),C6-14 aryl-carboxamide (e.g., phenylcarboxamide and the like),C7-19 aralkyl-carboxamide (e.g., benzylcarboxamide and thelike), heterocyclic carboxamide (e.g., benzothiophen-2-ylcarboxamideand the like), optionally halogenated C1-6alkoxy-carboxamide (e.g., methoxycarboxamide,ethoxycarboxamide, propoxycarboxamide, butoxycarboxamideand the like), C6-14 arylaminocarbonylamino (e.g.,phenylaminocarbonylamino and the like), optionallyhalogenated C1-6 alkylsulfonylamino (e.g.,methylsulfonylamino, trifluoromethylsulfonylamino,ethylsulfonylamino and the like), C6-14 arylsulfonylamino(e.g., phenylsulfonylamino and the like) and the like.
    [0082] The "acyloxy" includes, for example, an oxysubstituted with one "acyl", preferably, an acyloxy of theformula :-O-COR11, -O-COOR11, -O-CONHR11 [wherein R11 has thesame meaning as R7] and the like.
    [0083] The "acyloxy" is preferably optionally halogenated C1-6alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy and thelike), C6-14 aryl-carbonyloxy (e.g., benzoyloxy and the like),optionally halogenated C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, trifluoromethoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxyand the like), mono-C1-6 alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy and the like), di-C1-6alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), C6-14 aryl-carbamoyloxy(e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy and thelike), heterocyclic carbonyloxy (e.g., nicotinoyloxy andthe like) and the like.
    [0084] The "substituent" possessed by the "cycle group"represented by R1, R2, R1a or R2a is, preferably, 1) halogen atom (preferably fluorine, chlorine, bromine andthe like); 2) optionally substituted C1-8 aliphatic hydrocarbon group(preferably, C1-8 alkyl or C2-6 alkenyl each optionally having1 to 3 substituent(s) selected from C3-10 cycloalkyloptionally substituted with C1-6 alkyl, halogen atom,carboxy and C1-6 alkoxy-carbonyl, and the like); 3) optionally substituted C1-12 alkoxy (preferably C1-12 alkoxyoptionally having 1 to 4 substituent(s) selected from C3-10cycloalkyl optionally substituted with C1-6 alkyl, carboxy,C6-14 aryl and halogen atom, and the like); 4) optionally substituted C6-14 aryloxy (preferably phenoxyand the like); 5) optionally substituted C3-10 cycloalkyl (preferably C3-10 cycloalkyl optionally substituted with C1-6 alkyl and thelike); 6) C7-19 aralkyl (preferably benzyl and the like); 7) heterocycle group (preferably 2-benzoxazolyl and thelike); and the like.
    [0085] The "substituent" possessed by the "cycle group"represented by R1, R2, R1a or R2a is, more preferably, 1) halogen atom (preferably, fluorine, chlorine, bromineand the like); 2) optionally substituted C1-6 aliphatic hydrocarbon group(preferably C1-6 alkyl or C2-6 alkenyl each optionally having1 to 3 substituent(s) selected from a halogen atom, carboxyand C1-6 alkoxy-carbonyl, and the like); 3) optionally substituted C1-6 alkoxy (preferably C1-6 alkoxyoptionally having 1 to 3 substituent(s) selected fromcarboxy and C6-14 aryl, and the like); 4) optionally substituted C6-14 aryloxy (preferably phenoxyand the like); and the like.
    [0086] With regard to the "cycle group" represented by R1, R2,R1a or R2a, "R1 or R2" and "R1a or R2a" have "the substituentselected from 1) optionally substituted carboxy-C1-6 alkoxygroup and 2) optionally substituted carboxy C1-6 aliphatichydrocarbon group".
    [0087] The "optionally substituted carboxy-C1-6 alkoxy group"includes the group in which the "optionally substituted C1-6 alkoxy group" exemplified as the "substituent" of the"cycle group" represented by R1, etc. is furthersubstituted with the "optionally substituted carboxy".
    [0088] The "substituent" of the "optionally substitutedcarboxy" includes an optionally substituted hydrocarbongroup, an optionally substituted heterocycle group and thelike.
    [0089] The "optionally substituted hydrocarbon group" and"optionally substituted heterocycle group" include thoseexemplified as R7.
    [0090] The "optionally substituted carboxy-C1-6 alkoxy group"is preferably carboxy-C1-6 alkoxy group (e.g., carboxy-methoxy,carboxy-ethoxy and the like); C1-6 alkoxy-carbonyl-C1-6alkoxy group (e.g., methoxy-carbonyl-methoxy, ethoxy-carbonyl-methoxy,tert-butoxy-carbonyl-methoxy, methoxy-carbonyl-ethoxy,ethoxy-carbonyl-ethoxy, tert-butoxy-carbonyl-ethoxyand the like); carboxy-(C6-14 arylsubstituted) C1-6 alkoxy group (e.g., carboxy-(phenyl) methoxy,carboxy-(phenyl)ethoxy and the like); C1-6 alkoxy-carbonyl-(C6-14aryl substituted)C1-6 alkoxy group (e.g., methoxy-carbonyl-(phenyl)methoxy,ethoxycarbonyl-(phenyl)methoxy,tert-butoxycarbonyl-(phenyl)methoxy, methoxy-carbonyl(phenyl)ethoxy,ethoxycarbonyl(phenyl)ethoxy, tert-butoxycarbonyl(phenyl)ethoxyand the like);carboxy(heterocycle substituted)C1-6 alkoxy group (e.g., carboxy-(indol-3-yl)methoxy, carboxy-(indol-3-yl)ethoxy andthe like); C1-6 alkoxy-carbonyl-(heterocycle substituted)C1-6alkoxy group (e.g., methoxycarbonyl-(indol-3-yl)methoxy,ethoxycarbonyl-(indol-3-yl)methoxy, tert-butoxycarbonyl-(indol-3-yl)methoxy,methoxycarbonyl-(indol-3-yl)ethoxy,ethoxycarbonyl-(indol-3-yl)ethoxy, tert-butoxycarbonyl-(indol-3-yl)ethoxyand the like) and the like. Among these,carboxy-(C6-14 aryl substituted)C1-6 alkoxy group, C1-6 alkoxy-carbonyl-(C6-14aryl substituted)C1-6 alkoxy group arepreferable, specifically, carboxy-(phenyl)ethoxy, methoxycarbonyl-(phenyl)ethoxy, ethoxycarbonyl-(phenyl)ethoxy andthe like are preferable.
    [0091] The "optionally substituted carboxy-C1-6 aliphatichydrocarbon group" includes the group in which the"optionally substituted C1-6 aliphatic hydrocarbon group"exemplified as the "substituent" which may be possessed bythe "cycle group" represented by R1, etc., is furthersubstituted with the "optionally substituted carboxy".
    [0092] The "substituent" of the "optionally substitutedcarboxy" includes optionally substituted hydrocarbon group,optionally substituted heterocycle group and the like.
    [0093] The "optionally substituted hydrocarbon group" and"optionally substituted heterocycle group" include thoseexemplified as R7.
    [0094] The "optionally substituted carboxy-C1-6 aliphatic hydrocarbon group" is preferably carboxy-C1-6 alkyl group(e.g., carboxymethyl, carboxyethyl and the like); C1-6alkoxy-carbonyl-C1-6 alkyl group (e.g., methoxy-carbonyl-methyl,ethoxy-carbonyl-methyl, tert-butoxy-carbonyl-methyl,methoxy-carbonyl-ethyl, ethoxy-carbonyl-ethyl, tert-butoxy-carbonyl-ethyland the like); carboxy-C2-6 alkenyl group(e.g., carboxy-vinyl and the like); C1-6 alkoxy-carbonyl-C2-6alkenyl group (e.g., methoxy-carbonyl-vinyl, ethoxy-carbonyl-vinyl,tert-butoxy-carbonyl-vinyl and the like)and the like.
    [0095] In the formula (I), R1 or R2 is preferably a C6-14 arylsubstituted with a carboxy-(C6-14 aryl-substituted)C1-6 alkoxygroup or a C1-6 alkoxy-carbonyl-(C6-14 aryl-substituted)C1-6alkoxy group.
    [0096] Further, in the formula (I), it is preferred that oneof R1 and R2 is a C6-14 aryl substituted with a carboxy-(C6-14aryl-substituted)C1-6 alkoxy group or a C1-6 alkoxy-carbonyl-(C6-14aryl-substituted)C1-6alkoxy group and the other is anoptionally substituted C6-14 aryl.
    [0097] Moreover, in the formula (I), it is preferred that R2is a C6-14 aryl substituted with a carboxy-(C6-14 aryl-substituted)C1-6alkoxy group or a C1-6 alkoxy-carbonyl-(C6-14aryl-substituted)C1-6alkoxy group and R1 is an optionallysubstituted C6-14 aryl.
    [0098] The "substituent" represented by R3, R4 or R5 includes, optionally substituted hydrocarbon group, optionallysubstituted heterocycle group, halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), nitro, cyano,hydroxy, optionally halogenated C1-6 alkoxy, mercapto,optionally halogenated C1-6 alkylthio, amino, mono-C1-6alkylamino, di-C1-6 alkylamino, formyl, carboxy, carbamoyl,thiocarbamoyl, optionally halogenated C1-6 alkyl-carbonyl,C1-6 alkoxy-carbonyl, mono-C1-10 alkyl(preferably C1-6 alkyl)-carbamoyl,di-C1-6 alkyl-carbamoyl, optionally halogenatedC1-6 alkylsulfonyl, formylamino, optionally halogenated C1-6alkyl-carboxamide, C1-6 alkoxy-carboxamide, C1-6alkylsulfonylamino, C1-6 alkyl-carbonyloxy, C1-6 alkoxy-carbonyloxy,mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxyand the like.
    [0099] The number of the above-mentioned substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of thesubstituents is not less than 2, the substituents may bethe same or different.
    [0100] The "optionally substituted hydrocarbon group" and"optionally substituted heterocycle group" include thoseexemplified as R7.
    [0101] The "optionally halogenated C1-6 alkoxy", "optionallyhalogenated C1-6 alkylthio", "C1-6 alkoxy-carbonyl", "mono-C1-6alkyl-carbamoyl", "di-C1-6 alkyl-carbamoyl", "optionallyhalogenated C1-6 alkyl-carboxamide", "C1-6 alkoxy-carboxamide", "C1-6 alkylsulfonylamino", "C1-6 alkyl-carbonyloxy", "C1-6alkoxy-carbonyloxy", "mono-C1-6 alkyl-carbamoyloxy", "di-C1-6alkyl-carbamoyloxy" include those exemplified as the"substituent" of the "optionally substituted C1-8 aliphatichydrocarbon group".
    [0102] The "optionally halogenated C1-6 alkyl-carbonyl" and"an optionally halogenated C1-6 alkylsulfonyl" include thoseexemplified as R6.
    [0103] The "mono-C1-6 alkylamino" and "di-C1-6alkylamino"include those exemplified as the "substituent" of R1, etc.
    [0104] R3, R4 and R5 are preferably hydrogen atom orhydrocarbon group, and more preferably, hydrogen atom, C1-6alkyl (preferably methyl, ethyl, propyl and the like), C6-14aryl (preferably phenyl and the like) and the like.
    [0105] Especially, R3 and R4 are preferably hydrogen atom. R5is especially preferably C1-6 alkyl (preferably methyl andthe like).
    [0106] R4 may link together with R3 or R5 to form a"optionally substituted ring".
    [0107] The "ring" of the "optionally substituted ring"includes benzene ring, C3-8 cycloalkene, C4-8 cycloalkadiene,5- to 8- membered aromatic heterocycle, 5- to 8- memberednon-aromatic heterocycle and the like.
    [0108] The C3-8 cycloalkene includes, for example,cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like.
    [0109] The C4-10 cycloalkadiene includes, for example,cycloheptadiene, cyclopentadiene, cyclohexadiene and thelike.
    [0110] The 5- to 8- membered aromatic heterocycle includes a5- to 8- membered aromatic monocyclic heterocyclecontaining 1 to 3 heteroatom(s) selected from an oxygenatom, a sulfur atom and a nitrogen atom as a ring-constitutingatom, besides carbon atoms.
    [0111] The 5- to 8- membered aromatic heterocycle includes,for example, thiophene, furan, pyrrole, imidazole, pyrazole,thiazole, isothiazole, oxazole, isoxazole, pyridine,pyrazine, pyrimidine, pyridazine and the like.
    [0112] The 5- to 8- membered non-aromatic heterocycleincludes a 5- to 8- membered non-aromatic monocyclicheterocycle containing 1 to 3 heteroatom(s) selected froman oxygen atom, a sulfur atom and a nitrogen atom as aring-constituting atom, besides carbon atoms.
    [0113] The 5- to 8- membered non-aromatic heterocycleincludes, for example, pyrroline, pyrazoline and the like.
    [0114] Among the above-mentioned "ring", benzene ring ispreferred.
    [0115] The "substituent" of the "optionally substituted ring"includes one exemplified as the "substituent" of the"optionally substituted C1-8 aliphatic hydrocarbon group". The "optionally substituted ring" is preferably benzenering.
    [0116] The preferred example of the compound of formula (I)(hereinafter sometimes abbreviated as compound (I))includes, for example, the following compounds.
    [0117] A compound whereinX1 and X2 are same or different and each is a bond or a C1-8alkylene;one of R1 and R2 (preferably R2) is a C6-14 aryl (preferablyphenyl) substituted with a carboxy-(C6-14 aryl-substituted)C1-6alkoxy group or a C1-6 alkoxy-carbonyl-(C6-14aryl-substituted)C1-6 alkoxy group [referably, carboxy-(phenyl)ethoxy,methoxycarbonyl-(phenyl)ethoxy,ethoxycarbonyl-(phenyl)ethoxy],and the other (preferably R1) is a C6-14 aryl (preferablyphenyl) optionally having 1 or 2 substituent(s) selectedfrom the following: 1) a halogen atom (preferably, fluorine, chlorine, bromineand the like); 2) a C1-8 alkyl or a C2-6 alkenyl each optionally having 1 to3 substituent(s) selected from a C3-10 cycloalkyl optionallysubstituted with a C1-6 alkyl, a halogen atom, carboxy and aC1-6 alkoxy-carbonyl; 3) a C1-12 alkoxy optionally having 1 to 4 substituent(s)selected from a C3-10 cycloalkyl optionally substituted with a C1-6 alkyl, carboxy, a C6-14 aryl and a halogen atom; 4) a C6-14 aryloxy (preferably, phenoxy and the like); 5) a C3-10 cycloalkyl optionally substituted with a C1-6alkyl; 6) a C7-19 aralkyl (preferably, benzyl and the like); and 7) a heterocycle group (preferably 2-benzoxazolyl and thelike); R3 and R4 are each a hydrogen atom; andR5 is a C1-6 alkyl (preferably methyl and the like).
    [0118] The salts of the compound (I) or (II) include, forexample, a salt with inorganic base, organic base,inorganic acid, organic acid or the like.
    [0119] The preferred example of the salt with inorganic baseincludes, for example, an alkaline metal salt such assodium salt, potassium salt and the like; an alkaline earthmetal salt such as calcium salt, magnesium salt, bariumsalt and the like; alminium salt; ammonium salt and thelike.
    [0120] The preferred example of the salt with organic baseincludes, for example, a salt with trimethylamine,triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamineor the like.
    [0121] The preferred example of the salt with inorganic acidincludes, for example, a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoricacid or the like.
    [0122] The preferred example of the salt with organic acid,for example, a salt with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid or the like; and a salt with basic oracidic amino acid.
    [0123] The preferred example of the salt with basic aminoacid includes, for example, a salt with arginine, lysine,ornithine or the like. The preferred example of the saltwith acidic amino acid includes, for example, a salt withaspartic acid, glutamic acid or the like.
    [0124] Among these salts, a pharmaceutically acceptable saltis preferable, and an alkaline metal salt such as sodiumsalt is more preferable.
    [0125] The compound (I), (II) and salts thereof (hereinaftersometimes abbreviated as the present compound) may be ananhydrate or a hydrate. The hydrate may have 0.5 to 3water molecule(s).
    [0126] The present compound may be labeled with isotope (e.g.,3H, 14C, 35S, 125I and the like) .
    [0127] When the present compound contains an optical isomer,a stereoisomer, a position isomer or a rotational isomer thereof, they are encompassed in the present compound andeach may be isolated by a synthesis and separationprocedure known per se. For example, when the presentcompound contains an optical isomer thereof, the opticalisomer resolved from the compound is also encompassed inthe present compound.
    [0128] The optical isomer is produced by a method known perse. Specifically, the optical isomer is obtained by usingan optically active intermediate, or by optical resolutionof the mixture of a final racemate product by aconventional method.
    [0129] The present compound is preferably optically active.
    [0130] As the optical resolution method, a method known perse, for example, the following fractional recrystallizationmethod, chiral column method, diastereomer method and thelike are used. 1) Fractional recrystallization method
    [0131] A salt of racemate with an optically acytive compound(e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaricacid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine,cinchonine, (-)-cinchonidine, brucine andthe like) is formed, which is separated by fractionalrecrystallization method, and a free optical isomer isobtained by neutralization step where desired. 2) Chiral column method
    [0132] A racemate or a salt thereof is applied to a columnfor separation of an optical isomer (chiral column) toallow separation. In the case of liquid chromatography,for example, a mixture of a optical isomer was added to achiral column such as ENANTIO-OVM (manufactured by TOSOHCorporation) or CHIRAL series (manufactured by Daicel) andthe like, and developed with water, various buffers (e.g.,phosphate buffer), an organic solvent (e.g., ethanol,methanol, isopropanol, acetonitrile, trifluoroacetic acid,diethylamine and the like) or a mixture thereof to separatethe optical isomers. In the case of gas chromatography,for example, the separation was performed using a chiralcolumn such as CP-Chirasil-DeX CB (GL SCIENCES, Inc.) andthe like. 3) Diastereomer method
    [0133] A racemate mixture is converted to a diastereomermixture by chemical reaction with an optically activereagent, which is prepared into a homogenous substance by aconventional separation method (e.g., fractionrecrystallization, chromatography method and the like), andsubjected to a chemical treatment such as hydrolysisreaction and the like to cut off the optically activereagent moiety, whereby an optical isomer is obtained. Forexample, when the present compound has hydroxy or primaryor secondary amino in the molecule, the compound and an optically active organic acid (e.g., MTPA [α-methoxy α-(trifluoromethyl)-phenylaceticacid], (-)-menthoxy aceticacid and the like) may be subjected to a condensationreaction to give an ester form or amide form diastereomer,respectively. When the present compound has a carboxylicacid group, the compound and an optically active amine oralcohol reagent are subjected to a condensation reaction togive an amide form or ester form diastereomer. Thediastereomer thus separated is converted to an opticalisomer of the original compound by acid hydrolysis or basehydrolysis reaction.
    [0134] The present compound may be used as a prodrug.
    [0135] A prodrug of the present compound is a compound thatconverts to the present compound due to the reaction ofenzyme, gastric acid and the like under the physiologicalcondition in vivo, i.e. a compound that converts to thepresent compound by enzymatic oxidation, reduction,hydrolysis and the like, and a compound that converts tothe present compound by hydrolysis and the like due togastric acid. The prodrug of the present compound includesa compound wherein an amino group of the present compoundis acylated, alkylated or phosphorylated [e.g., a compoundwherein an amino group of the present compound iseicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated,pivaloyloxymethylated, tert-butylated and the like]; acompound wherein a hydroxy group of the present compound isacylated, alkylated, phosphorylated or borated (e.g., acompound wherein a hydroxy group of the present compound isacetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumalylated, alanylated,dimethylaminomethylcarbonylated or the like); a compoundwherein a carboxyl group of the present compound isesterified or amidated [e.g., a compound wherein a carboxylgroup of the present compound is ethyl esterified, phenylesterified, carboxymethyl esterified, dimethylaminomethylesterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified, methylamidated andthe like]and the like. These compounds may be producedfrom the present compound according to a method known perse.
    [0136] A prodrug the present compound may be a compound thatconverts to the present compound under the physiologicalcondition described in Pharmaceutical research anddevelopment, vol. 7, Molecule Design, 163-198, HirokawaShoten (1990).
    [0137] The present compound may be prepared by the following [Production method 1], [Production method 2] or a similarmethod thereto.
    [0138] The compound (IIIa), (IVa), (V), (IIIb), (IVb), (IIIc),(VI) used as a starting compound, may be used as a salt.Such salt includes one exemplified as the salt of thecompound (I) or (II). [Production method 1]
    [0139] The compound (Ia) which is a compound of the formula(I) wherein R1 is "a cycle group having an optionallysubstituted carboxy-C1-6 alkoxy group, and wherein the cyclegroup optionally has additional substituent(s)" may beprepared by, for example, the following [Method A]. [Method A]
    [0140]
    [0141] The "cycle group" represented by A includes the "cyclegroup" exemplified in R1 or R2.
    [0142] The "C1-6 alkyl" represented by R includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl and the like. Among these, methyl ispreferred.
    [0143] The "optionally substituted carboxy C1-6 alkoxy group"represented by Y includes the "optionally substitutedcarboxy-C1-6 alkoxy group" exemplified in R1 or R2.
    [0144] In this method, compound (IIIa) is firstly subjectedto alkyl elimination reaction to give compound (IVa).
    [0145] The alkyl elimination reaction is carried out bycontacting with an acid in a solvent that does notadversely influence the reaction, according to a typicalmethod.
    [0146] The solvent that does not adversely influence thereaction includes, for example, halogenated hydrocarbonssuch as chloroform, methylene chloride and the like. Theamount of the solvent to be used is 1 to 100 fold-volume ofcompound (IIIa).
    [0147] The acid includes, for example, boron tribromide,hydrogen bromide and the like.
    [0148] The amount of the acid to be used is preferably from 1to 10 molar equivalent per compound (IIIa).
    [0149] The reaction temperature is generally from about -50to about 150°C.
    [0150] The reaction time is generally from about 0.5 to about20 hours.
    [0151] The thus-obtained compound (IVa) may be isolated andpurified by a known separation and purification means, suchas concentration, concentration under reduced pressure,solvent extraction, crystallization, recrystallization,phase transfer, chromatography and the like. Alternatively,the compound (IVa) may be used in the next reaction without isolation.
    [0152] The compound (IVa) is then reacted with compound (V)to give compound (Ia).
    [0153] This reaction may be carried out according to a methodknown per se, for example, the method described inSynthesis, page 1 (1981) and the like or a similar methodthereto.
    [0154] That is, this reaction is carried out in a solventthat does not adversely influence the reaction, in thepresence of organic phosphorous compound and anelectrophilic agent.
    [0155] The organic phosphorous compound includes, for example,triphenylphosphine, tributylphosphine and the like.
    [0156] The electrophilic agent includes, for example, diethylazodicarboxylate, diisopropyl azodicarboxylate,azodicarbonyldipiperazine and the like.
    [0157] Each of the amounts of the organic phosphorouscompound and the electrophilic agent is preferably fromabout 1 to about 5 molar equivalent per compound (IVa).
    [0158] The solvent that does not adversely influence thereaction includes, for example, ethers such as diethylether,tetrahydrofuran, dioxane and the like; halogenatedhydrocarbons such as chloroform, methylene chloride and thelike; aromatic hydrocarbons such as benzene, toluene,xylene and the like; amides such as N,N-dimethylformamide; sulfoxides such as dimethylsulfoxide and the like, and thelike. Two or more of these solvents may be used uponmixing at a suitable ratio. The amount of the solvent tobe used is, for example, from 1 to 100 fold-volume percompound (IVa).
    [0159] The reaction temperature is generally from about -50to about 150°C, preferably from about -10 to about 100°C.
    [0160] The reaction time is generally from about 0.5 to about20 hours.
    [0161] The thus-obtained compound (Ia) may be isolated andpurified by a known separation and purification method,such as concentration, concentration under reduced pressure,solvent extraction, crystallization, recrystallization,phase transfer, chromatography and the like.
    [0162] The compound (Ia) obtained by the [Method A] issubjected to hydrolysis reaction where desired, to givecompound (Iaa) wherein a carboxy of the "optionallysubstituted carboxy-C1-6 alkoxy group" represented by Y isfree.
    [0163] The hydrolysis reaction is carried out in a water-containingsolvent in the presence of an acid or a base,according to a typical method.
    [0164] The acid includes, for example, hydrochloric acid,sulfuric acid, acetic acid, hydrobromic acid and the like.
    [0165] The base includes, for example, an alkaline metal carbonate salt such as potassium carbonate, sodiumcarbonate and the like; an alkaline metal alkoxide such assodium methoxide and the like; an alkaline metal hydroxidesuch as potassium hydroxide, sodium hydroxide, lithiumhydroxide, and the like.
    [0166] The amount of the acid or base to be used is generallyexcess to compound (Ia). The amount of the acid to be usedis preferably from about 2 to about 50 equivalents percompound (Ia). The amount of the base to be used ispreferably from about 1.2 to about 5 equivalents percompound (Ia).
    [0167] The water-containing solvent includes, for example, amixture of water with one or more solvents selected fromalcohols such as methanol, ethanol; ethers such astetrahydrofuran, dioxane, diethylether; dimethylsulfoxide,acetone and the like. The amount of the solvent to be usedis, for example, 1 to 100 fold-volume per compound (Ia).
    [0168] The reaction temperature is generally from about -20to about 150°C, preferably about -10 to about 100°C.
    [0169] The reaction time is generally from about 0.1 to about20 hours.
    [0170] The thus-obtained compound (Iaa) may be isolated andpurified by a known separation and purification method,such as concentration, concentration under reduced pressure,solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
    [0171] The compound (IIIa) used as a starting compound in the[Method A] may be prepared according to a method known perse, for example, the method described in Chemistry ofHeterocyclic Compounds, vol. 48, Part 1, pp. 105-294(1990); Journal of Medicinal Chemistry, vol. 40, pp. 1619-1633(1997) and the like or a similar method thereto.
    [0172] Also, the compound (V) used as a starting compound inthe [Method A] may be prepared according to a method knownper se.
    [0173] The compound (Ib) which is a compound of the formula(I) wherein R2 is "a cycle group having an optionallysubstituted carboxy-C1-6 alkoxy group wherein the cyclegroup optionally has additional substituent(s)" may beprepared by the following [Method B]. [Method B]
    [0174]
    [0175] This method is carried out similarly to the [Method A].
    [0176] The compound (Ib) obtained by [Method B] may besubjected to a hydrolysis reaction where desired, to givecompound (Ibb) wherein a carboxy of the "optionallysubstituted carboxy-C1-6 alkoxy group" represented by Y isfree.
    [0177] The hydrolysis reaction is carried out in a similarmanner in the case of the compound (Iaa).
    [0178] The thus-obtained compound (Ibb) may be isolated andpurified by a known separation and purification method,such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,phase transfer, chromatography and the like.
    [0179] The compound (IIIb) used as a starting compound of the[Method B] may be produced by a method known per se, forexample, the method described in Chemistry of HeterocyclicCompounds, vol. 48, Part 1, pp. 105-294 (1990); Journal ofMedicinal Chemistry, vol. 40, pp. 1619-1633 (1997) and thelike or a similar method thereto. [Production method 2]
    [0180] The compound (Ic) which is a compound of the formula(I) wherein one of R1 and R2 is "a cycle group having anoptionally substituted carboxy-C1-6 aliphatic hydrocarbongroup wherein the cycle group optionally has additionalsubstituent(s)" may be prepared by, for example, thefollowing method.
    [0181] The halogen atom represented by Z includes fluorine,chlorine, bromine and the like. Z is preferably bromineand the like.
    [0182] The "optionally substituted carboxy-C1-6 aliphatichydrocarbon group"represented by Y1 includes the"optionally substituted carboxy-C1-6 aliphatic hydrocarbongroup" exemplified in R1 or R2.
    [0183] In this method, compound (IIIc) is reacted withcompound (VI) to give compound (Ic).
    [0184] This reaction is carried out in a solvent that doesnot adversely influence the reaction, in the presence of abase, a phosphine compound and a palladium compound.
    [0185] The base includes, for example, an alkaline metalcarbonate salt such as potassium carbonate, sodiumcarbonate and the like; an alkaline metal acetic acid saltsuch as sodium acetate and the like; an organic base suchas triethylamine, tributylamine and the like, and the like.
    [0186] The amount of the base to be used is preferably fromabout 1 to about 5 molar equivalent per compound (IIIc).
    [0187] The phosphine compound includes, for example, tris(2-methylphenyl)phosphine,triphenylphosphine and the like.
    [0188] The palladium compound includes, for example,palladium(II) acetate, palladium(II) chloride, palladiumcarbon, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)dichloropalladium(II), bis(benzylideneacetone)palladium and the like.
    [0189] Each of the amounts of the phosphine compound andpalladium compound to be used is preferably about 0.02 toabout 5 molar equivalent per compound (IIIc).
    [0190] The solvent that does not adversely influence thereaction includes, for example, ethers such as diethylether,tetrahydrofuran, dioxane and the like; halogenatedhydrocarbons such as chloroform, methylene chloride and thelike; aromatic hydrocarbons such as benzene, toluene,xylene and the like; amides such as N,N-dimethylformamideand the like; sulfoxides such as dimethylsulfoxide and thelike, acetonitrile and the like. Two or more of thesesolvents may be used upon mixing at a suitable ratio. Theamount of the solvent to be used is, for example, from 1 to100 fold-volume per compound (IIIc).
    [0191] The reaction temperature is generally from about -50to about 250°C, preferably from about -10 to about 200°C.
    [0192] The reaction time is generally from about 0.5 to about100 hours.
    [0193] The thus-obtained compound (Ic) may be isolated andpurified by a known separation and purification method,such as concentration, concentration under reduced pressure,solvent extraction, crystallization, recrystallization,phase transfer, chromatography and the like.
    [0194] The compound (Ic) obtained by the [Production method 2] may be subjected to a hydrolysis reaction where desired,to give compound (Icc) wherein a carboxy of the "optionallysubstituted carboxy-C1-6 aliphatic hydrocarbon group"represented by Y1 is free.
    [0195] The hydrolysis reaction is carried out in a similarmanner in the case of the compound (Iaa).
    [0196] The thus-obtained compound (Icc) may be isolated andpurified by a known separation and purification method,such as concentration, concentration under reduced pressure,solvent extraction, crystallization, recrystallization,phase transfer, chromatography and the like.
    [0197] The compound (IIIc) used as a starting compound in the[Production method 2] may be prepared according to a methodknown per se, for example, the method described inChemistry of Heterocyclic Compounds, vol. 48, Part 1, pp.105-294 (1990); Journal of Medicinal Chemistry, vol. 40, pp.1619-1633 (1997) and the like or a similar method thereto.
    [0198] Also, the compound (VI) used as a starting compound inthe [Production method 2] may be prepared according to amethod known per se.
    [0199] In each of the above-mentioned reactions, when thestarting compound has amino, carboxy, hydroxy or carbonylas a substituent, a protective group generally used inpeptide chemistry may be introduced in the substituent. Inthis case, the protective group is removed after reaction where desired, to give the object compound.
    [0200] The protective group of amino includes, for example,formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl and thelike), C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl and the like), benzoyl,C7-10 aralkyl-carbonyl (e.g., benzylcarbonyl and the like),C7-14 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyland the like), trityl, phthaloyl,N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like), C2-6 alkenyl (e.g., 1-allyland the like) and the like. These groups areoptionally substituted with 1 to 3 of a halogen atom (e.g.,fluorine, chlorine, bromine, iodine and the like), C1-6alkoxy (e.g., methoxy, ethoxy, propoxy and the like), nitroand the like.
    [0201] The protective group of carboxy includes, for example,C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl and the like), C7-11 aralkyl (e.g., benzyl and thelike), phenyl, trityl, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like), C2-6 alkenyl (e.g., 1-allyland the like) and the like. These groups areoptionally substituted with 1 to 3 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine and the like), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy and the like) andnitro and the like.
    [0202] The protective group of hydroxy includes, for example,C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl and the like), phenyl, trityl, C7-10 aralkyl (e.g.,benzyl and the like), formyl, C1-6 alkyl-carbonyl (e.g.,acetyl, propionyl and the like), benzoyl, C7-10 aralkyl-carbonyl(e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl,2-tetrahydrofuranyl, silyl (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like),C2-6 alkenyl (e.g., 1-allyl and the like) and the like.These groups are optionally substituted with 1 to 3 of ahalogen atom (e.g., fluorine, chlorine, bromine, iodine andthe like), C1-6 alkyl (e.g., methyl, ethyl, n-propyl and thelike), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy and thelike), nitro and the like.
    [0203] The protective group of carbonyl includes, for example,cyclic acetal (e.g., 1,3-dioxane and the like), an acyclicacetal (e.g., di-C1-6 alkylacetal and the like) and the like.
    [0204] The removing of the above-mentioned protective groupsmay be carried out according to a method known per se, forexample the method described in Protective Groups inOrganic Synthesis, John Wiley and Sons (1980) and the like.For example, a method using an acid, a base, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride,palladium acetate, trialkylsilyl halide (e.g.,trimethylsilyl iodide, trimethylsilyl bromide and the like)and the like, reduction method and the like are used.
    [0205] The present compound shows low toxicity and can beused as an agent for preventing or treating variousdiseases mentioned below in mammals (e.g., human, mouse,rat, rabbit, dog, cat, cattle, horse, swine, simian and thelike), as such or by admixing with a pharmacologicallyacceptable carrier and the like to give a pharmaceuticalcomposition.
    [0206] Here, various organic or inorganic carriersconventionally used as materials for pharmaceuticalpreparations are used as a pharmacologically acceptablecarrier, which are added as excipient, lubricant, binder,disintegrant for solid preparations; and solvent,dissolution aids, suspending agent, isotonicity agent,buffer, soothing agent and the like for liquid preparations.Where necessary, additive for pharmaceutical preparationssuch as preservative, antioxidant, coloring agent,sweetening agent and the like can be used.
    [0207] Preferable examples of the excipient include lactose,saccharose, D-mannitol, D-sorbitol, starch, pregelatinizedstarch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gumarabic, dextrin, pullulan, light silicic anhydride,synthetic aluminum silicate, magnesium aluminatemetasilicate and the like.
    [0208] Preferable examples of the lubricant include magnesiumstearate, calcium stearate, talc, colloidal silica and thelike.
    [0209] Preferable examples of the binder includepregelatinized starch, sucrose, gelatin, gum arabic,methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, saccharose,D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and the like.
    [0210] Preferable examples of the disintegrant includelactose, saccharose, starch, carboxymethylcellulose,calcium carboxymethylcellulose, sodium croscarmellose,sodium carboxymethyl starch, light silicic anhydride, low-substitutedhydroxypropylcellulose and the like.
    [0211] Preferable examples of the solvent include water forinjection, physiological brine, Ringer's solution, alcohol,propylene glycol, polyethylene glycol, sesame oil, corn oil,olive oil, cottonseed oil and the like.
    [0212] Preferable examples of the dissolution aids includepolyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, Tris aminomethane,cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate, sodium acetate and the like.
    [0213] Preferable examples of the suspending agent includesurfactants such as stearyltriethanolamine, sodium laurylsulfate, lauryl aminopropionate, lecithin, benzalkoniumchloride, benzethonium chloride, monostearic glyceride andthe like; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and the like;polysorbates, polyoxyethylene hydrogenated castor oil andthe like.
    [0214] Preferable examples of the isotonicity agent includesodium chloride, glycerol, D-mannitol, D-sorbitol, glucoseand the like.
    [0215] Preferable examples of the buffer include phosphatebuffer, acetate buffer, carbonate buffer, citrate buffer,and the like.
    [0216] Preferable examples of the soothing agent includebenzyl alcohol and the like.
    [0217] Preferable examples of the preservative include p-oxybenzoicacid esters, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid, sorbic acid and thelike.
    [0218] Preferable examples of the antioxidant include sulfite,ascorbate and the like.
    [0219] Preferable examples of the coloring agent includewater-soluble edible tar pigment (e.g., foodcolors such asFood Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5,Food Color Blue Nos. 1 and 2 and the like, water insolublelake pigment (e.g., aluminum salt of the aforementionedwater-soluble edible tar pigment and the like), naturalpigments (e.g., beta carotene, chlorophyll, red iron oxideetc.) and the like.
    [0220] Preferable examples of the sweetening agent includesaccharin sodium, dipotassium glycyrrhetinate, aspartame,stevia and the like.
    [0221] The dosage form of the pharmaceutical composition maybe, for example, oral agents such as tablets, capsules(including soft capsules and micro capsules), granules,powders, syrups, emulsions, suspensions and the like; orparenteral agents such as injections (e.g., subcutaneousinjections, intravenous injections, intramuscularinjections, intraperitoneal injections and the like),external agents (e.g., nasal preparations, transdermalpreparations, ointments and the like), suppositories (e.g.,rectal suppositories, vaginal suppositories and the like),pellets, infusion and the like. These may be administeredsafely via oral or parenteral route. The pharmaceutical composition may be sustained-release preparations.
    [0222] The pharmaceutical composition can be producedaccording to a method conventionally used in the field ofpharmaceutical preparation, such as the method described inJapan Pharmacopoeia and the like. The specific productionmethods of the pharmaceutical preparation are described indetail in the following.
    [0223] For example, an oral agent is produced by adding, tothe active ingredient, excipient (e.g., lactose, sucrose,starch, D-mannitol and the like), disintegrant (e.g.,calcium carboxymethylcellulose and the like), binder (e.g.,pregelatinated starch, gum arabic, carboxymethylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone and the like),lubricant (e.g., talc, magnesium stearate, polyethyleneglycol 6000 and the like) and the like, compression-moldingthe mixture, and where necessary, coating the same using acoating base for masking of taste, enteric property orsustained release according to a method known per se.
    [0224] Examples of the coating base include a sugar-coatingbase, a water-soluble film coating base, an enteric filmcoating base, a sustained release film coating base and thelike.
    [0225] As a sugar-coating base, sucrose may be used, alongwith one or two species selected from talc, precipitatedcalcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like.
    [0226] As a water-soluble film coating base, for example,cellulose polymers such as hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,methylhydroxyethylcellulose and the like; syntheticpolymers such as polyvinyl acetal diethylaminoacetate,aminoalkyl methacrylate copolymer E [Eudragit E, tradename,Rohm Pharma], polyvinylpyrrolidone and the like;polysaccharides such as pullulan and the like; and the likeare used.
    [0227] As a enteric film coating base, for example, cellulosepolymers such as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, acetic phthalic cellulose andthe like; acrylic acid polymers such as methacrylic acidcopolymer L [Eudragit L, tradename, Rohm Pharma],methacrylic acid copolymer LD [Eudragit L-30D55, trademark,Rohm Pharma], methacrylic acid copolymer S [Eudragit S,trademark, Rohm Pharma] and the like; naturally occurringsubstance such as shellac and the like; and the like areused.
    [0228] As a sustained release film coating base, for example,cellulose polymers such as ethylcellulose and the like;acrylic acid polymers such as aminoalkyl methacrylatecopolymer RS [Eudragit RS, trademark, Rohm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [EudragitNE, tradename, Rohm Pharma] and the like, and the like areused.
    [0229] Two or more kinds of the above-mentioned coating basesmay be mixed in an appropriate ratio for use. In addition,a light shielding agent such as titanium oxide, ironsesquioxide and the like may be used during coating.
    [0230] An injection is produced by dissolving, suspending oremulsifying an active ingredient in an aqueous solvent(e.g., distilled water, physiological saline, Ringer'ssolution and the like) or an oily solvent (e.g., plant oilsuch as olive oil, sesame oil, cottonseed oil, corn oil andthe like, propylene glycol and the like) and the like,together with a dipersing agent (e.g., polysorbate 80,polyoxyethylene hydrogenated castor oil 60 and the like),polyethylene glycol, carboxymethylcellulose, sodiumalginate and the like), preservative (e.g., methylparaben,propylparaben, benzyl alcohol, chlorobutanol, phenol andthe like), isotonicity agent (e.g., sodium chloride,glycerol, D-mannitol, D-sorbitol, glucose and the like) andthe like. In this step, dissolution aids (e.g., sodiumsalicylate, sodium acetate and the like), stabilizers (e.g.,human serum albumin and the like), soothing agents (e.g.,benzyl alcohol and the like) and the like may be used ondemand.
    [0231] The present compound has superior PTP inhibitoryaction and is useful as a prophylactic or therapeutic agentof diseases caused by PTP.
    [0232] The PTP includes, cytoplasmic-type PTP, receptor-typePTP, dual specificity phosphatase of which substrateincludes phosphorylated serine/threonine in addition tophosphorylated tyrosine, low molecular weight (LWN)-PTP andthe like.
    [0233] The cytoplasmic-type PTP includes, for example, PTP-1B,T-cell PTP (TC-PTP), rat brain PTP, STEP, PTPMEG1, PTPH1,PTPD1, PTPD2, FAP-1/BAS, PTP1C, SH-PTP2, SHP-2, PTP1D, SHP-1and the like.
    [0234] The receptor-type PTP includes, for example, CD45,CD45/LCA, LAR, PTP α, PTP β, PTP δ, PTP ε, PTP ζ, PTP µ,PTP κ, PTPσ, SAP-1, PTP-U2/GLEPP1, DEP-1, OST-PTP and thelike.
    [0235] The dual specificity phosphatase includes, for example,MAPK phosphatase, PAC-1, rVH6, KAP, VH-1, VHR, cdc25 andthe like.
    [0236] The present compound has a superior inhibitory action,especially to PTP-1B, among these PTPs.
    [0237] The "diseases caused by PTP" includes, for example,diabetes (e.g., insulin-dependent diabetes (type Idiabetes), insulin-independent diabetes (type II diabetes),gestational diabetes and the like), impaired glucose tolerance (IGT), tumor (e.g., pulmonary cancer, kidneycancer, pancreatic cancer, breast cancer, ovary cancer,leukemia, prostate cancer, skin cancer and the like),autoimmune disease, immunodeficiency, allergic disease(e.g., asthma and the like), born disease (e.g.,osteoporosis and the like), infectious disease (e.g.,respiratory infection, urinary tract infection, digestiveinfection, skin soft tissue infection, lower limb infectionand the like), arthritic disease (e.g., chronic rheumatoidarthritis, osteoarthritis and the like) and the like.
    [0238] Among these diseases, the present compound is usefulas a prophylactic and therapeutic agent of diabetes such asinsulin-dependent diabetes (type I diabetes), insulin-independentdiabetes (type II diabetes), gestationaldiabetes, impaired glucose tolerance (IGT) and the like.
    [0239] For diagnostic criteria of diabetes, Japan DiabetesSociety reported new diagnostic criteria in 1999.
    [0240] According to this report, diabetes is a conditionshowing any of a fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 126mg/dl, a 75 g oral glucose tolerance test (75 g OGTT) 2 hlevel (glucose concentration of intravenous plasma) of notless than 200 mg/dl, a non-fasting blood glucose level(glucose concentration of intravenous plasma) of not lessthan 200 mg/dl. A condition not falling under the above-mentioned diabetes, and which is not, "a condition showinga fasting blood glucose level (glucose concentration ofintravenous plasma) of less than 110 mg/dl and a 75 g oralglucose tolerance test (75 g OGTT) 2 h level (glucoseconcentration of intravenous plasma) of less than 140mg/dl" (normal type), is called a "borderline type".
    [0241] In addition, ADA (American Diabetes Association)reported new diagnostic criteria of diabetes in 1997 andWHO in 1998.
    [0242] According to these reports, diabetes is a conditionshowing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 126mg/dl or a 75 g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of not lessthan 200 mg/dl.
    [0243] According to the above-mentioned reports, impairedglucose tolerance is a condition showing a 75 g oralglucose tolerance test 2 h level (glucose concentration ofintravenous plasma) of not less than 140 mg/dl and lessthan 200 mg/dl. Furthermore, according to the report ofADA, a condition showing a fasting blood glucose level(glucose concentration of intravenous plasma) of not lessthan 110 mg/dl and less than 126 mg/dl is called IFG(Impaired Fasting Glucose). According to the report of WHO,among the IFG (Impaired Fasting Glucose), only a condition showing a 75g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of less than140 mg/dl is called IFG (Impaired Fasting Glycemia).
    [0244] The present compound can be also used as aprophylactic and therapeutical agent of diabetes,borderline type, impaired glucose tolerance, IFG (ImpairedFasting Glucose) and IFG (Impaired Fasting Glycemia), asdetermined according to the above-mentioned new diagnosticcriteria. Moreover, the present compound can preventprogress of borderline type, impaired glucose tolerance,IFG (Impaired Fasting Glucose) or IFG (Impaired FastingGlycemia) into diabetes.
    [0245] The present compound can be also used as aprophylactic or therapeutic agent of, for example,hyperlipidemia (e.g., hypertriglyceridemia,hypercholesterolemia, low HDL lipemia and the like);diabetic complications [e.g, neuropathy, nephropathy,retinopathy, cataract, macroangiopathy, osteopenia,hyperosmolar diabetic coma, diabetic gangrene, xerostomia,acoustic hypesthesia, cerebrovascular disorder, peripheralblood circulation disorder and the like]; obesity; cachexia(e.g., cancerous cachexia, tuberculous cachexia, diabeticcachexia, blood disease cachexia, endocrine diseasecachexia, infectious disease cachexia or cachexia due toaquired immunodeficiency syndrome); fatty liver; hypertension; polycystic ovary syndrome; kidney disease(e.g., diabetic nephropathy, glomerular nephritis,glomerulosclerosis, nephritic syndrome, hypertensivenephrosclerosis, end stage kidney disease and the like);muscular dystrophy; myocardial infarction; angina pectoris;cerebral infarction; Syndrome X; hyperinsulinemia-inducedsensory disorder; irritable bowel syndrome; acute orchronic diarrhea; inflammatory diseases (e.g., chronicrheumatoid arthritis, spondylitis deformans, arthritisdeformans, lumber pain, gout, postoperative traumaticinflammation, remission of tumentia, neuralgia,pharyngolaryngitis, cystitis, hepatitis, pneumonia,pancreatitis and the like); arterial sclerosis (e.g.,atherosclerosis and the like) and the like.
    [0246] The present compound may also used as an insulinsensitizer; an insulin sensitivity enhancer; anantithrombotic agent; an agent for suppressing progress ofimpaired glucose tolerance into diabetes and the like.
    [0247] The present compound may also used for amelioration ofsymptom such as abdominal pain, nausea, vomition,epigastric discomfort and the like accompanied with pepticulcer, acute or chronic gastritis, biliary tract dyskinesia,cholecystitis and the like.
    [0248] The present compound may also used, based on itsability of controlling (stimulating or suppressing) appetite, as for example, a therapeutic agent for leannessand cibophobia (increasing body weight of the subjectsuffering from leanness or cibophobia) or a therapeuticagent for obesity.
    [0249] Although the dose of the present compound variesdepending on the administration subject, administrationroute, target disease, condition and the like, for example,it is desirable that the present compound as an activeingredient is generally administered in a single dose ofabout 0.01-100 mg/kg body weight, preferably about 5-100mg/kg body weight 1 to 3 times a day, for oraladministration to an adult diabetic patients.
    [0250] The present compound can be used in combination withtherapeutic agents such as a therapeutic agent of diabetes,a therapeutic agent of diabetic complications, anantihyperlipemia agent, an antihypertensive agent, anantiobestic agent, a diuretic, a chemotherapeutic agent,immunotherapeutic agent and the like (hereinafter to bereferred to as a combination drug) for the purpose ofenhancing the effect.
    [0251] The timing of administration of the present compoundand a combination drug is not limited. These may besimultaneously administered or administered in a staggeredtimes to an administration subject. The dose of thecombination drug can be appropriately determined based on the dose clinically employed. The proportion of thepresent compound and combination drug can be appropriatelydetermined depending on the administration subject,administration route, target disease, condition,combination and the like. When, for example, theadministration subject is human, a combination drug is usedin an amount of 0.01-100 parts by weight per 1 part byweight of the present compound.
    [0252] Examples of the therapeutic agent of diabetes includeinsulin preparations (e.g., animal insulin preparationsextracted from pancreas of cattle, swine; human insulinpreparations synthesized by genetic engineering techniquesusing Escherichia coli or yeast); insulin sensitizers otherthan the present compound (e.g., pioglitazone orhydrochloride thereof, troglitazone, rosiglitazone ormaleate thereof, GI-262570, JTT-501, MCC-555, YM-440, KRP-297,CS-011 and the like), α-glucosidase inhibitors (e.g.,voglibose, acarbose, miglitol, emiglitate and the like),biguanides (e.g., phenformin, metformin, buformin and thelike), insulin secretagogues (e.g., sulfonylureas such astolbutamide, glibenclamide, gliclazide, chlorpropamide,tolazamide, acetohexamide, glyclopyramide, glimepiride andthe like; repaglinide, senaglinide, nateglinide,mitiglinide, GLP-1 and the like), amyrin agonists (e.g.,pramlintide and the like), protein tyrosine phosphatase inhibitors other than the present compound (e.g., vanadicacid and the like), β3 agonists (e.g., CL-316243, SR-58611-A,UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 andthe like) and the like.
    [0253] Examples of the therapeutic agent of diabeticcomplications include aldose reductase inhibitors (e.g.,Tolrestat, Epalrestat, Zenarestat, Zopolrestat, Minalrestat,Fidarestat, SK-860, CT-112 and the like), neurotrophicfactors (e.g., NGF, NT-3, BDNF and the like), PKCinhibitors (e.g., LY-333531 and the like), AGE inhibitors(e.g., ALT946, pimagedine, pyratoxanthine, N-phenacylthiazoliumbromide (ALT766) and the like), activeoxygen scavengers (e.g., thioctic acid and the like),cerebral vasodilators (e.g., tiapride, mexiletine and thelike), and the like.
    [0254] Examples of the antihyperlipemia agent include HMG-CoAreductase inhibitors (e.g., cerivastatin, pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin,itavastatin and sodium salts thereof and the like),squalene synthase inhibitors or fibrate compounds having atriglyceride lowering action (e.g., bezafibrate, clofibrate,simfibrate, clinofibrate and the like) and the like.
    [0255] Examples of the antihypertensive agent includeangiotensin converting enzyme inhibitors (e.g., captopril,enalapril, alacepril, delapril, llsinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril and thelike), angiotensin II antagonists (e.g., candesartancilexetil, losartan, eprosartan, valsartan, termisartan,irbesartan, tasosartan and the like), calcium antagonists(e.g., nicardipine hydrochloride, manidipine hydrochloride,nisoldipine, nitrendipine, nilvadipine and the like) andthe like.
    [0256] Examples of the antiobestic agent include centralantiobestic agents (e.g., Dexfenfluramine, fenfluramine,phentermine, Sibutramine, amfepramone, dexamphetamine,Mazindol, phenylpropanolamine, clobenzorex and the like),pancreatic lipase inhibitors (e.g., orlistat and the like),β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085, AZ40140 and the like), peptideanorexiants (e.g., leptin, CNTF (Ciliary NeurotropicFactor) and the like), cholecystokinin agonists (e.g.,lintitript, FPL-15849 and the like) and the like.
    [0257] Examples of the diuretic include xanthine derivatives(e.g., sodium salicylate theobromine, calcium salicylatetheobromine and the like), thiazide preparations (e.g.,ethiazide, cyclopenthiazide, trichloromethiazide,hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide,methyclothiazide and the like), antialdosterone agents(e.g., spironolactone, triamterene and the like), carbonate dehydrating enzyme inhibitors (e.g., acetazolamide and thelike), chlorobenzenesulfonamide agents (e.g., chlortalidone,mefruside, indapamide and the like), azosemide, isosorbide,etacrynic acid, piretanide, bumetanide, furosemide and thelike.
    [0258] Examples of the chemotherapeutic agent includealkylation agents (e.g., cyclophosphamide, ifosfamide andthe like), metabolic antagonists (e.g., methotrexate, 5-fluorouraciland the like), anti-cancer antibiotics (e.g.,mitomycin, adriamycin and the like), plant-derived anti-canceragents (e.g., vincristin, vindesine, taxol and thelike), cisplatin, carboplatin, etopoxide and the like. Ofthese, furtulon and neofurtulon which are 5-fluorouracilderivatives and the like are preferable.
    [0259] Examples of the immunotherapeutic agent includemicroorganism or bacterial components (e.g., muramyldipeptide derivative, picibanil and the like),polysaccharides having immunity potentiating activity (e.g.,lentinan, sizofiran, krestin and the like), cytokinesobtained by genetic engineering techniques (e.g.,interferon, interleukin (IL) and the like), colonystimulating factors (e.g., granulocyte colony stimulatingfactor, erythropoietin and the like) and the like, withpreference given to IL-1, IL-2, IL-12 and the like.
    [0260] Furthermore, drugs having a cachexia-improving action established in animal models and clinical situations, suchas cyclooxygenase inhibitors (e.g., Indometacin and thelike) [Cancer Research, vol. 49, 5935-5939, 1989],progesterone derivatives (e.g., Megesterol acetate)[Journal of Clinical Oncology, vol. 12, 213-225, 1994],glucosteroid (e.g., dexamethasone and the like),metoclopramide agents, tetrahydrocannabinol agents (ibid.),fat metabolism improving agents (e.g., eicosapentaenoicacid and the like) [British Journal of Cancer, vol. 68,314-318, 1993], growth hormones, IGF-1, or antibodies to acachexia-induced factor such as TNF-α, LIF, IL-6,Oncostatin M and the like, can be used in combination withthe present compound.
    [0261] The combination drug is preferably an insulinpreparation, an insulin sensitizer, an α-glucosidaseinhibitor, a biguanide, an insulin secretagogue (preferablya sulfonylurea) or the like.
    [0262] Two or more of the above-mentioned combination drugscan be used in combination in an appropriate ratio.Preferable combinations in the case of using two or morecombination drugs are, for example, as shown in thefollowing. 1) an insulin sensitizer and an insulin preparation; 2) an insulin sensitizer and an insulin secretagogue(preferably sulfonylurea); 3) an insulin sensitizer and α-glucosidase inhibitor; 4) an insulin sensitizer and a biguanide; 5) an insulin sensitizer, an insulin preparation and abiguanide; 6) an insulin sensitizer, an insulin preparation and aninsulin secretagogue (preferably sulfonylurea); 7) an insulin sensitizer, an insulin preparation and α-glucosidaseinhibitor; 8) an insulin sensitizer, an insulin secretagogue(preferably sulfonylurea) and a biguanide; 9) an insulin sensitizer, an insulin secretagogue(preferably sulfonylurea) and α-glucosidase inhibitor; and 10) an insulin sensitizer, a biguanide and α-glucosidaseinhibitor.When the present compound is used in combination witha combination drug, the amount thereof can be reducedwithin a safe range in consideration of counteraction ofthese agents. Particularly, the doses of an insulinsensitizer, an insulin secretagogue (preferably asulfonylurea) and a biguanide can be reduced as comparedwith the normal dose. Therefore, an adverse effect whichmay be caused by these agents can be prevented safely. Inaddition, the dose of the therapeutic agent of diabeticcomplications, antihyperlipemia agent and antihypertensiveagent can be reduced whereby an adverse effect which may be caused by these agents can be prevented effectively.
    [0263] The present invention is explained in more detail bythe following Examples, Formulation Examples andExperimental Examples. These do not limit the presentinvention and the present invention can be modified withinthe range that does not deviate from the scope of theinvention.
    [0264] In the following Examples, the "room temperature" is 0to 30°C. Unless otherwise mentioned, the "%" means percentby weight.
    [0265] The infrared spectrum was measured by diffusereflection method using Fourier transform type infraredspectrometer.
    [0266] The abbreviations used in this specification mean thefollowing. S: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDCl3: deuterated chloroform DMSO-d6: deuterated dimethylsulfoxide DMSO: dimethylsulfoxide THF: tetrahydrofuran DMF: N,N-dimethylformamide 1H-NMR: proton nuclear magnetic resonance(generally, free form was measured in CDCl3.) IR: infrared absoption spectrum
    [0267] In the present specification, when a base, an aminoacid and the like are represented by abbreviations, theseabbreviations are based on the abbreviations by IUPAC-IUBCommision on Biochemical Nomenclature or conventionalabbreviations in the art. With regard to amino acids, whenan optical isomer exists, it represents L form unlessotherwise mentioned.
    [0268] In the following Test Examples, gene engineeringmethods such as cloning method, base sequencing method andthe like, are carried out according to a known method (e.g.,the method described in Molecular Cloning, Sambrook et al.,Cold Spring Harbor Lab. Press (1989) and the like).
    [0269] The sequence numbers of the sequence listing of thepresent specification mean the following sequences. [SEQ ID NO : 1]
    [0270] The base sequence of primer 1 used in Test Example 1. [SEQ ID NO : 2]
    [0271] The base sequence of primer 2 used in Test Example 1. [SEQ ID NO : 3]
    [0272] The base sequence of PTP-1B cDNA (1322 bp) describedin Test Example 1. [SEQ ID NO : 4]
    [0273] The base sequence of primer 3 used in Test Example 1. [SEQ ID NO : 5]
    [0274] The base sequence of primer 4 used in Test Example 1. [SEQ ID NO : 6]
    [0275] The base sequence of PCR reaction product (976 bp)described in Test 'Example 1. [SEQ ID NO : 7]
    [0276] The amino acid sequence of PTP-1B enzyme active domaindescribed in Test Example 1. [SEQ ID NO : 8]
    [0277] The base sequence of PTP-1B cDNA fragment inserted topET32a(+) described in Test Example 1. ExamplesExample 1Ethyl (2R)-2-{4-[1-(4-bromophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-propanol
    [0278] To an aqueous solution of 2,2-dimethyl-1,3-propanediol(100 g, 960 mmol) (200 ml) was added concentratedhydrochloric acid (20 ml) and 2,3-dihydrofuran (66.1 ml,874 mmol) and the mixture was stirred at room temperaturefor 12 hours. The reaction solution was adjusted to pH 9with aqueous 5 N sodium hydroxide and extracted withchloroform. The extract was dried over magnesium sulfateanhydride and the solvent was removed under reducedpressure. The residue was distilled under reduced pressureto give the object compound as an oily substance. 126 g(yield: 82.9%)1H-NMR (CDCl3) δ; 0.73 (3H, s), 1.19 (3H, s), 1.67-1.81 (4H,m), 2.49 (1H, bs), 3.41-3.65 (6H, m), 4.48 (1H, t, J = 4.4Hz).IR (KBr) cm-1; 2932, 2853, 1471, 1394, 1142, 1041, 980, 926. (2) 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-propanal
    [0279] To a solution of oxalyl chloride (16.6 ml, 190 mmol)in methylene chloride (75 ml) was added dropwisedimethylsulfoxide (29.8 ml, 420 mmol) at -78°C over 15minutes. The mixture was stirred for 15 minutes and addeddropwise a solution of 3-(5,5-dimethyl-1,3-dioxane-2-yl)-1-propanol(30.0 g, 172 mmol) in methylene chloride (300 ml)over 35 minutes, and the mixture was stirred at -78°C for 1hour. Then, to the obtained mixture was added triethylamine (83.5 ml, 600 mmol) and the mixture wasstirred at -70°C for 1 hour, then the temperature of themixture was raised to room temperature, and the mixture wasstirred at room temperature for 2 hours. The reactionsolution was poured into water and extracted with methylenechloride. The extracts were collected and washed withsaturated aqueous sodium bicarbonate and dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 9:1) togive the object compound as an oily substance. 17.0 g(yield: 52.0%)1H-NMR (CDCl3) δ; 0.72 (3H, s), 1.17 (3H, s), 1.94-2.01 (2H,m), 2.55-2.63 (2H, m), 3.41 (2H, d, J = 11.0 Hz), 3.59 (2H,d, J = 11.0 Hz), 4.51 (1H, t, J = 4.0 Hz), 9.77 (1H, s).IR (KBr) cm-1; 2957, 2847, 1725, 1472, 1395, 1140, 1105,1041, 1017, 972, 928. (3) 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-(4-methoxyphenyl)-1-propanol
    [0280] To a suspension of magnesium (440 mg, 18.1 mmol) inTHF (10 ml) was added a drop of 1,2-dibromoethane, and asolution of 4-bromoaniline (2.17 ml, 17.4 mmol) in THF (10ml) was added dropwise to the mixture. The reactionsolution was stirred at 70°C for 1 hour and cooled to -70°C. Then, 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-propanal (2 g,11.6 mmol) was added to the solution. The obtained mixturewas stirred at -70°C for 2 hours and at room temperaturefor 1 hour. The mixture was poured into 10% aqueousammonium chloride and extracted with ethyl acetate. Theextracts were collected, washed with water and dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate =3:1) togive the object compound as an oily substance. 1.36 g(yield: 41.8%)1H-NMR (CDCl3) δ; 0.72 (3H, s), 1.19 (3H, s), 1.71-1.95 (4H,m), 2.58 (1H, d, J = 3.6 Hz), 3.42 (2H, d, J = 11.0 Hz),3.61 (2H, d, J = 11.0 Hz), 3.80 (3H, s), 4.47 (1H, t, J =4.0 Hz), 4.63-4.71 (1H, m), 6.86 (2H, d, J = 8.4 Hz), 7.27(2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3399, 2955, 2851, 1613, 1514, 1470, 1395,1248, 1177, 1134, 1036, 980, 833. (4) 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-(4-methoxyphenyl)-1-propanone
    [0281] To a solution of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-methoxyphenyl)-1-propanol(1.18 g, 4.21 mmol) inmethylene chloride (50 ml) was added pyridiniumchlorochromate (1.36 g, 6.32 mmol) and the mixture was stirred at room temperature for 3 hours, and the solventwas removed under reduced pressure. The residue waspurified by silica gel column chromatography (ether) togive the object compound as a solid. 1.10 g (yield: 94.0%)1H-NMR (CDCl3) δ; 0.72 (3H, s), 1.19 (3H, s), 2.03-2.13 (2H,m), 3.10 (2H, t, J = 7.8 Hz), 3.43 (2H, d, J = 10.2 Hz),3.60 (2H, d, J = 10.2 Hz), 3,87 (3H, s), 4.56 (1H, t, J =4.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 2955, 1678, 1601, 1510, 1258, 1171, 1132,1030, 995, 837. (5) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-1H-pyrrole
    [0282] A solution of 3-(5,5-dimethyl-1,3-dioxane-2-yl)-1-(4-methoxyphenyl)-1-propanone(1.00 g, 3.59 mol), 4-bromoaniline(679 mg, 3.95 mmol) and p-toluenesulfonic acidmonohydrate (51.5 mg, 0.271 mmol) in toluene (50 ml) wasrefluxed for 20 hours under heating. The solvent wasremoved under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane:ethylacetate = 20:1) to give the object compound as a solid.960 mg (yield: 81.4%)1H-NMR (CDCl3) δ; 3.78 (3H, s), 6.34-6.35 (2H, m), 6.77 (2H,d, J = 8.8 Hz), 6.86-7.07 (5H,m), 7.43 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1507, 1491, 1246, 1030, 831, 714.Elementary analysis for C17H14NBrO    Calculated: C, 62.21; H, 4.30; N, 4.27.   Found: C, 62.14; H, 4.22; N, 4.28. (6) 4-[1-(4-Bromophenyl)-1H-pyrrol-2-yl]phenol
    [0283] To a solution of 1-(4-bromophenyl)-2-(4-methoxyphenyl)-1H-pyrrole(960 mg, 2.93 mmol) in methylenechloride (30 ml) was added boron tribromide (1.11 ml, 11.7mmol) at 0°C . The mixture was stirred at 0°C for 30minutes and at room temperature for 2 hours, and thereaction solution was poured into ice water. The organiclayer was separated, washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 3:1) to give the object compound asa solid. 512 mg (yield: 55.6%)1H-NMR (CDCl3) δ; 4.91 (1H' s), 6.34-6.35 (2H, m), 6.70 (2H,d, J = 8.8 Hz), 6.86-7.06 (5H, m), 7.43 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3200, 1491, 1240, 833, 826,721.Elementary analysis for C16H12NBrO   Calculated: C, 61.17; H, 3.85; N, 4.46.   Found: C, 61.16; H, 3.81; N, 4.16. (7) Ethyl (S)-2-hydroxy-3-phenylpropanoate
    [0284] (S)-Phenylalanine (25.0 g, 151 mmol) was suspended in chloroform (100 ml). Concentrated hydrochloric acid (15ml) was added to the suspension, stirred at roomtemperature for 30 minutes, and the produced crystals werefiltered out. The crystals were dissolved into 5% sulfuricacid (450 ml). To the obtained mixture, an aqueoussolution of sodium nitrite (20.6 g, 298 mmol) (120 ml) wasadded dropwise at 0°C over 3 hours. The reaction solutionwas extracted with ether and the extract was dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. To the residue were added p-toluenesulfonicacid monohydrate (243 mg, 12.8 mmol) andethanol (250 ml) and the mixture was refluxed for 12 hoursunder heating, and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 10: 1) to give theobject compound as a solid. 4.86 g (yield: 13.6 %)1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.4 Hz), 2.77 (1H, d, J= 6.2 Hz), 2.97 (1H, dd, J = 14, 6.6 Hz), 3.14 (1H, dd, J =14, 4.4 Hz), 4.22 (2H, q, J = 7.4 Hz), 4.39-4.48 (1H, m),7.20-7.35 (5H, m).IR (KBr) cm-1; 3445, 2982, 1732, 1496, 1454, 1271, 1202,1096, 1030, 747, 700.[α]D 25.5-21.2° (c4.37, benzene),lit [α]D 24-22.6 (c4.33, benzene) (8) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0285] To a solution of 4-[1-(4-bromophenyl)-1H-pyrrol-2-yl]phenol(1.20 g, 3.82 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(888 mg, 4.58 mmol) and triphenylphosphine(1.20 g, 4.58 mmol) in toluene (10 ml) was added diethylazodicarboxylate (40%, 2.00 g, 4.58 mmol) and the mixturewas stirred at 80°C for 1.5 hours, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =20:1) to give the object compound as a solid. 860 mg(yield: 46.0%)1H-NMR (CDCl3) δ; 1.66 (3H, t, J = 7.0 Hz), 3.21-3.24 (2H,m), 4.16 (2H, q, J = 7.0 Hz), 4.75 (1H, t, J = 5.8 Hz),6.32 (2H, t, J = 2.6 Hz), 6.70 (2H, d, J = 8.8 Hz), 6.86(1H, t, J = 2.6 Hz), 6.85-7.01 (4H, m), 7.26-7.29 (5H, m),7.41 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1750, 1505, 1493, 1238, 1184, 1071, 1032,833, 702.[α]D 24 +16.0° (c 0.54, chloroform) Example 2(2R)-2-{4-[1-(4-Bromophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0286] To a mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (280 mg, 0.571 mmol) obtained in Example 1 in THF (2 ml)-methanol(1 ml) was added an aqueous 5 N sodium hydroxide(0.685 ml, 3.43 mmol) and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was dilutedwith ethyl acetate and neutralized with 1 N hydrochloricacid. The organic layer was separated and washed withwater. The organic layer was dried over magnesium sulfateanhydride and the solvent was removed under reducedpressure to give the object compound as an oily substance.240 mg (yield: 90.9%)1H-NMR (CDCl3) δ; 3.26 (2H, d, J = 7.0 Hz), 4.81 (1H, t, J= 7.0 Hz), 6.33 (2H, d, J = 2.4 Hz), 6.70 (2H, d, J = 8.8Hz), 6.86 (1H, t, J = 2.4 Hz), 6.99 (4H, d, J = 8.8 Hz),7.26-7.29 (5H, m), 7.41 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3031, 1725, 1491, 1234, 831.[α]D 27 +4.1° (c 0.42, chloroform) Example 3Ethyl (2E)-3-[4-(1-{4-[(1E)-3-ethoxy-3-oxo-1-propenyl]phenyl}-5-methyl-1H-pyrrol-2-yl)phenyl]-2-propenoate(1) 1-(4-Bromophenyl)-1,4-pentanedione
    [0287] A suspension of 4-bromobenzaldehyde (25.0 g, 135 mmol),triethylamine (29.3 ml, 210 mmol), methyl vinyl ketone (8.74 ml, 105 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (5.30 g, 21.0 mmol) in ethanol (50 ml)was stirred at 77°C for 20 hours and the solvent wasremoved under reduced pressure. 2 N hydrochloric acid wasadded to the residue and the mixture was extracted withethyl acetate. The extracts were collected and washed withsaturated aqueous sodium bicarbonate, dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure. To the residue was addeddiisopropylether to give the object compound as crystals.10.8 g (yield: 31.4%)Melting point: 76-77°C (hexane-ethyl acetate)1H-NMR (CDCl3) δ; 2.26 (3H, s), 2.89 (2H, t, J = 6.0 Hz),3.23 (2H, t, J = 6.0 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.85(2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1707, 1676, 1586, 1410, 1318, 1071, 995, 847,828, 750.Elementary analysis for C11H11OBr   Calculated: C, 51.79; H, 4.35.   Found: C, 51.82; H, 4.44. (2) 1,2-Bis(4-bromophenyl)-5-methyl-1H-pyrrole
    [0288] A solution of 1-(4-bromophenyl)-1,4-pentanedione (2.55g, 10.0 mol), 4-bromoaniline (1.72 g, 10.0 mmol) and p-toluenesulfonicacid monohydrate (144 mg, 0.755 mmol) in toluene (50 ml) was refluxed for 20 hours under heating.The solvent was removed under reduced pressure, and theresidue was purified by silica gel column chromatography(hexane) to give the object compound as a solid. 3.43 g(yield: 87.7%)1H-NMR (CDCl3) δ: 2.12 (3H, s), 6.08 (1H, d, J = 3.4 Hz),6.34 (1H, d, J = 3.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.10(2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.50 (2H, d,J = 8.8 Hz).IR (KBr) cm-1; 1508, 1489, 1410, 1319, 1071, 1009, 833, 766,733, 559.Elementary analysis for C17H13NBr2    Calculated: C, 52.21; H, 3.35; N, 3.58.   Found: C, 52.20; H, 3.33; N, 3.53. (3) Ethyl (2E)-3-[4-(1-{4-[(1E)-3-ethoxy-3-oxo-1-propenyl]phenyl}-5-methyl-1H-pyrrol-2-yl)phenyl]-2-propenoate
    [0289] A solution of 1,2-bis(4-bromophenyl)-5-methyl-1H-pyrrole(2.00 g, 5.115 mmol), ethyl acrylate (1.39 ml, 12.8mmol), tris(2-methylphenyl)phosphine (125 mg, 0.410 mmol).,palladium acetate (23.0 mg, 0.102 mmol) and triethylamine(1.78 ml, 12.8 mmol) in DMF (4 ml) was stirred at 100 °Cfor 18 hours under nitrogen atmospheric current. Theobtained mixture was poured into water and extracted with ethyl acetate. The extract was colleted and washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate:hexane = 85:15) to give the object compound as asolid. 2.00 g (yield: 91.3%)1H-NMR (CDCl3) δ; 1.27-1.38 (6H, m), 2.16 (3H, s), 4.21-4.33(4H, m), 6.12 (1H, d, J = 3.4 Hz), 6.28-6.48 (3H, m),7.04 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.30(2H, d, J = 8.4 Hz), 7.52-7.73 (4H, m).IR (KBr) cm-1; 2980, 1713, 1636, 1603, 1514, 1310, 1267,1204, 1179, 1040, 982, 839, 768, 731.Elementary analysis for C27H27NO4 0.1 H2O   Calculated: C, 75.19; H, 6.36; N, 3.24.   Found:C, 74.99; H, 6.27; N, 3.19. Example 4(2E)-3-[4-(1-{4-[(1E)-2-Carboxyethenyl]phenyl}-5-methyl-1H-pyrrol-2-yl)phenyl]-2-propenoicacid
    [0290] To a mixed solution of ethyl (2E)-3-[4-(1-{4-[(1E)-3-ethoxy-3-oxo-1-propenyl]phenyl}-5-methyl-1H-pyrrol-2-yl)phenyl]-2-propenoate(429 mg, 1.00 mmol) obtained inExample 3 in THF (4 ml)-methanol (2 ml) was added anaqueous 5 N sodium hydroxide(1.20 ml, 6 mmol), and themixture was stirred at room temperature for 12 hours and diluted with ethyl acetate. The solution was neutralizedwith 1 N hydrochloric acid and the the organic layer wasseparated. The organic layer was washed with water, driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure to give the object compoundas a solid. 300 mg (yield: 80.4%)1H-NMR (CDCl3) δ; 2.16 (3H, s), 6.11 (1H, s), 6.27-6.48 (3H,m), 7.04 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.0 Hz),7.30 (2H, d, J = 8.4 Hz), 7.53-7.72 (4H, m).IR (KBr) cm-1; 2982, 1688, 1628, 1601, 1520, 1426, 1310,1279, 1209, 1186, 990, 839, 738.Elementary analysis for C23H19NO4 0.5 H2O   Calculated: C, 72.24; H, 5.27; N, 3.66.   Found: C, 72.48; H, 4.99; N, 3.25. Example 5Ethyl (2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-1,4-pentanedione
    [0291] A solution of p-anisaldehyde (18.4 g, 135 mmol),triethylamine (29.3 ml, 210 mmol), methyl vinyl ketone(8.74 ml, 105 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide (5.30 g, 21.0 mmol) in ethanol (50ml) was stirred at 77°C for 20 hours and the solvent wasremoved under reduced pressure. To the residue was added 2 N hydrochloric acid and extracted with ethyl acetate. Theextracts were collected, washed with saturated aqueoussodium bicarbonate and dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 1:1) to give theobject compound as an oily substance. 10.8 g (yield:49.8%)1H-NMR (CDCl3) δ; 2.26 (3H, s), 2.87 (2H, t, J = 6.4 Hz),3.24 (2H, t, J = 6.4 Hz), 3.88 (3H, s), 6.92 (2H, d, J =8.8 Hz), 7.96 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1717, 1676, 1599, 1508, 1250, 1173, 1030,835. (2) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0292] A solution of 1-(4-methoxyphenyl)-1,4-pentanedione(3.00 g, 14.5 mol), 4-bromoaniline (2.50 g, 14.5 mmol) andp-toluenesulfonic acid monohydrate (208 mg, 1.09 mmol) intoluene (100 ml) was refluxed for 12 hours under heating.The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 20:1) to give the object compoundas an oily substance. 3.21 g (yield: 64.7%)1H-NMR (CDCl3) δ; 2.12 (3H, s), 3.75 (3H, s), 6.06 (1H, d, J = 3.2 Hz), 6.25 (1H, d, J = 3.2 Hz), 6.72 (2H, d, J = 8.8Hz), 6.93-7.05 (4H, m), 7.47 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1528, 1489, 1391, 1246, 1034, 766. (3) 4-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0293] To a solution of 1-(4-bromophenyl)-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole(2.10 g, 6.14 mmol) inmethylene chloride (45 ml) was added boron tribromide (2.33ml, 24.6 mmol) at 0°C. The mixture was stirred at 0°C for15 minutes and at room temperature for 0.5 hour, and thereaction solution was poured into ice water. The organiclayer was separated, washed with saturated aqueous sodiumbicarbonate, dried over magnesium sulfate anhydride andsolvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 9:1) to give the object compound as a solid.1.82 g (yield: 90.0%)1H-NMR (DMSO-d6) δ; 2.12 (3H, s), 4.73 (1H, s), 6.06 (1H, d,J = 3.6 Hz), 6.24 (1H, d J = 3.6 Hz), 6.63 (1H, d, J = 8.8Hz), 6.92 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz),7.47 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3378, 1524, 1489, 1393, 1262, 1211, 1173,833, 768, 737.Elementary analysis for C17H14NOBr   Calculated: C, 62.21; H, 4.30; N, 4.27.    Found: C, 62.05; H, 4.31; N, 4.19. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0294] To a solution of 4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.00 g, 3.04 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(886 mg, 4.56 mmol) andtriphenylphosphine (1.20 g, 4.56 mmol) in toluene (50 ml)was added diethyl azodicarboxylate (40%, 1.99 g, 4.56 mmol),and the mixture was stirred at 80°C for 3.5 hours and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 20:1) to give the object compoundas a solid. 440 mg (yield: 28.8%)1H-NMR (CDCl3) δ; 1.15 (3H, t, J = 7.4 Hz), 2.11 (3H, s),3.18-3.22 (2H, m), 4.14 (2H, q, J = 7.4 Hz), 4.68-4.74 (1H,m), 6.04 (1H, d, J = 3.8 Hz), 6.22 (1H, d, J = 3.8 Hz),6.63 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.97(2H, d, J = 8.4 Hz), 7.15-7.28 (5H, m), 7.45 (2H, d, J =8.4 Hz).IR (KBr) cm-1; 1753, 1736, 1524, 1489, 1238, 1184, 1071,833, 739, 700.[α]D 25 +13.6° (c 0.770, chloroform)Elementary analysis for C28K26NO3Br   Calculated: C, 66.67; H, 5.20; N, 2.78.    Found: C, 66.63; H, 5.23; N, 2.75. Example 6(2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0295] To a mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(340 mg, 0.674 mmol) obtained in Example 5in THF (4 ml)-methanol (2 ml) was added 5 N aqueous sodiumhydroxide (0.404 ml, 2.02 mmol), and the mixture wasstirred at room temperature for 1 hour. The reactionsolution was diluted with ethyl acetate and water, andneutralized with 1 N hydrochloric acid. The organic layerwas separated and washed with water. The organic layer wasdried over magnesium sulfate anhydride and the solvent wasremoved under reduced pressure to give the object as anoily substance. 282 mg (yield: 87.9%)1H-NMR (CDCl3) δ; 2.10 (3H, s), 3.23 (2H, d, J = 6.6 Hz),4.76 (1H, t, J = 6.6 Hz), 6.05 (1H, d, J = 3.2 Hz), 6.22(1H, d, J = 3.2 Hz), 6.63 (2H, d, J = 8.8 Hz), 6.90 (2H, d,J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.27 (5H, bs), 7.45(2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3063, 1730, 1522, 1489, 1236, 1181, 1071,833, 735, 700.[α]D 25-1.97° (c 1.70, chloroform) Example 7Ethyl (2R)-2-{2,6-dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 3,5-Dibromo-4-hydroxybenzaldehyde
    [0296] To a solution of 4-hydroxybenzaldehyde (11.0 g, 90.0mmol) and sodium acetate (22.9 g, 279 mmol) in acetic acid(150 ml) was added dropwise a solution of bromine (30.2 g,190 mmol) in acetic acid (50 ml) at room temperature, andthe reaction solution was stirred at room temperature for 1hour and the solvent was removed under reduced pressure.To the residue was added hexane and the obtained crystalswere filtered out, washed with water and subjected to airdrying to give the object compound as crystals. 24.5 g(yield: 97.2 %)1H-NMR (CDCl3) δ; 6.42 (1H, bs), 8.00 (2H, s), 9.80 (1H, s).IR (KBr) cm-1; 3148, 1674, 1580, 1549, 1476, 1381, 1304,1201, 1121, 874, 741, 658. (2) 3,5-Dibromo-4-methoxybenzaldehyde
    [0297] To a solution of 3,5-dibromo-4-hydroxybenzaldehyde(5.00 g, 17.9 mmol) in DMF (100 ml) were added potassiumcarbonate (3.22 g, 23.3 mmol) and iodomethane (1.45 ml,23.3 mmol), and the mixture was stirred at room temperaturefor 10 hours. The obtained mixture was poured into water and extracted with ethyl acetate. The extracts werecollected, washed with water and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure to give the object compound as a solid.5.10 g (yield: 97.0%)1H-NMR (CDCl3) δ; 3.97 (3H, s), 8.03 (2H, s), 9.80 (1H, s).IR (KBr) cm-1; 1707, 1694, 1547, 1470, 1368, 1264, 1190,987, 747, 731.Elementary analysis for C8H6O2Br3    Calculated: C, 32.69; H, 2.06.   Found: C, 32.69; H, 2.02. (3) 1-(3,5-Dibromo-4-methoxyphenyl)-1,4-pentanedione
    [0298] A mixed solution of 3, 5-dibromo-4-methoxybenzaldehyde(5.00 g, 17.0 mmol), methyl vinyl ketone (1.10 ml, 13.2mmol), triethylamine (3.69 ml, 26.4 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (667 mg, 2.64mmol) in ethanol (20 ml) was stirred at 77°C for 8 hours,and the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 4:1) to isolate the object compoundas a solid. 3.31 g (yield: 68.8 %)1H-NMR (CDCl3) δ; 2.25 (3H, s), 2.89 (2H, t, J = 6.0 Hz),3.18 (2H, t, J = 6.0 Hz), 3.94 (3H, s), 8.12 (2H, s).IR (KBr) cm-1; 1717, 1690, 1381, 1260, 1163, 995, 737. (4) 1-(4-Bromophenyl)-2-(3,5-dibromo-4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0299] A solution of 1-(3,5-dibromo-4-methoxyphenyl)-1,4-pentanedione(3.00 g, 8.24 mmol), 4-bromoaniline (1.42 g,8.24 mmol) and p-toluenesulfonic acid monohydrate (118 mg,0.619 mmol) in toluene (100 ml) was refluxed for 20 hoursunder heating and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to isolate theobject compound as an oily substance. 2.86 g (yield:69.4%)1H-NMR (CDCl3) δ; 2.11 (3H, s), 3.83 (3H, s), 6.07 (1H, d,J = 3.4 Hz), 6.32 (1H, d, J = 3.4 Hz), 7.02 (2H, d, J =8.4 Hz), 7.14 (2H, s), 7.55 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 1591, 1491, 1462, 1408, 1250, 1069, 1001,835, 747, 733. (5) 2,6-Dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0300] To a solution of 1-(4-bromophenyl)-2-(3,5-dibromo-4-methoxyphenyl)-5-methyl-1H-pyrrole(2.60 g, 5.20 mmol) inmethylene chloride (50 ml) was added boron tribromide (1.97ml, 20.8 mmol) at 0°C, and the mixture was stirred at 0°Cfor 1 hour. The obtained mixture was poured into ice water and extracted with ethyl acetate. The extracts werecollected and washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 10:1) to isolate the objectcompound as a solid. 2.40 g (yield: 95.2 %)1H-NMR (CDCl3) δ; 2.11 (3H, s), 5.73 (1H, s), 6.06 (1H, d,J = 3.8 Hz), 6.27 (1H, d J = 3.8 Hz), 7.01 (2H, d, J =8.8 Hz), 7.11 (2H, s), 7.54 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3490, 1508, 1491, 1458, 1412, 1318, 1159,1069, 833, 747, 733.Elementary analysis for C17H12NOBr3    Calculated: C, 42.01; H, 2.49; N, 2.88.   Found: C, 42.05; H, 2.54; N, 2.83. (6) Ethyl (2R)-2-{2,6-dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0301] To a solution of 2,6-dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol(500 mg, 1.03 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (300 mg, 1.55 mmol) andtriphenylphosphine (405 mg, 1.55 mmol) in toluene (5 ml)was added diisopropyl azodicarboxylate (0.305 ml, 1.55mmol) at room temperature. The obtained mixture wasstirred at room temperature for 1 hour and at 80°C for 1 hour, and the solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to isolate theobject compound as a solid. 670 mg (yield: 98.2%)1H-NMR (CDCl3) δ; 1.06 (3H, t, J = 7.2 Hz), 2.11 (3H, s),3.37-3.42 (2H, m), 3.98-4.09 (2H, m), 4.84-4.91 (1H, m),6.07 (1H, d, J = 3.6 Hz), 6.33 (1H, d, J = 3.6 Hz), 7.01(2H, d, J = 8.8 Hz), 7.14 (2H, s), 7.23-7.29 (5H, m), 7.54(2H, d, J = 8.8 Hz),.IR (KBr) cm-1; 1746, 1491, 1445, 1408, 1242, 1069, 1015,835, 747, 731, 700.[α]D 20 28.8° (c 0.550, chloroform) Example 8(2R)-2-{2,6-Dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0302] To a mixed solution of ethyl (2R)-2-{2,6-dibromo-4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(400 mg, 0.604 mmol) obtained in Example 7in THF (4 ml)-methanol (2 ml) was added 1N aqueous sodiumhydroxide (1.21 ml, 1.21 mmol) and the mixture was stirredat room temperature for 3 hours. The obtained mixture wasneutralized with 1 N hydrochloric acid and extracted withethyl acetate. The extracts were collected, washed withwater and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure to give theobject compound as an oily substance. 269 mg (yield:70.4%)1H-NMR (CDCl3) δ; 2.11 (3H, s), 3.37 (2H, d, J = 7.0 Hz),5.08 (1H, t, J = 7.0 Hz), 6.07 (1H, d, J = 3.4 Hz), 6.33(1H, d, J = 3.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.11 (2H, s),7.22-7.26 (5H, m), 7.55 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3065, 1725, 1493, 1445, 1410, 1240, 1069,835, 733,700.[α] D 21 17.9° (c 1.48, chloroform)Elementary analysis for C26H20NO3Br3 0.5 H2O   Calculated: C, 48.55; H, 3.29; N, 2.18.   Found: C, 48.66; H, 3.51; N, 1.97. Example 9Ethyl (2R)-2-({4'-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-yl}oxy)-3-phenylpropanoate(1) Methyl 4-(4'-methoxyphenyl)benzoate
    [0303] A mixed solution of 4-(4'-hydroxyphenyl)benzoic acid(10.0 g, 4.67 mmol), iodomethane (19.9 g, 14.0 mmol) andN,N-dimethylformamide (80 ml) was stirred at 60°C for 3hours. To the obtained mixture was added ethyl acetate(200 ml) and water (150 ml), the mixture was stirred andthe organic layer was separated. The organic layer waswashed with 5% aqueous potassium hydrogen sulfate and water, and dried over sodium sulfate anhydride. The solvent wasconcentrated under reduced pressure and the object compound(10.5 g) was obtained from the residue as colorlesscrystals. Melting point: 177-178°C1H-NMR (CDCl3) δ; 3.86 (3H, s), 3.94 (3H, s), 7.00 (2H, d,J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.62 (2H, d, J =8.4 Hz), 8.08 (2H, d, J = 8.4 Hz). (2) 4-(4'-methoxyphenyl)benzylalcohol
    [0304] Methyl 4-(4'-methoxyphenyl)benzoate (3.0 g, 12.3 mmol)was added in portions to a suspension of lithium alminiumhydride (0.94 g, 25.0 mmol) in tetrahydrofuran (40 ml) atroom temperature for 20 minutes with stirring. Thereaction solution was refluxed for 2 hours under heatingand cooled to 0°C. To the residue was added water (1 ml)and 1 N aqueous sodium hydroxide (3 ml), the insolublematter was filtered out and the filtrate was concentratedunder reduced pressure. The object compound (1.2 g) wasobtained from the residue as colorless crystals.Melting point: 163-164°C1H-NMR (CDCl3) δ; 3.86 (3H, s), 4.73 (2H, s), 7.48 (2H, d,J = 8.8 Hz), 7.37-7.58 (6H, m). (3) 4'-Methoxy[1,1'-biphenyl]-4-carbaldehyde
    [0305] A mixed solution of 4-(4'-methoxyphenyl)benzylalcohol (1.20 g, 5.60 mmol), manganese dioxide (2.0 g) andtetrahydrofuran (25 ml) was stirred at room temperature for72 hours. The reaction solution was filtered and thefiltrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate: tetrahydrofuran = 5: 1: 1) to givethe object compound (1.1 g) as colorless crystals. Meltingpoint: 99-100°C1H-NMR (CDCl3) δ; 3.87 (3H, s), 7.01 (2H, d, J = 8.8 Hz),7.60 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.2 Hz), 7.93(2H, d, J = 8.2 Hz), 10.04 (1H, s). (4) 1-(4'-Methoxy[1,1'-biphenyl]-4-yl)-1,4-pentanedione
    [0306] A mixed solution of 4'-methoxy[1,1'-biphenyl]-4-carbaldehyde(1.08 g, 5.09 mmol), methyl vinyl ketone (277mg, 3.96 mmol), triethylamine (1.10 ml, 7.91 mmol) and 3-ethyl-5-(2-hydroxyethyl-4-methylthiazolium bromide (200 mg,0.791 mmol) in ethanol (6 ml) was stirred at 77°C for 4days, and the solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 5:1) to isolate theobject compound as a solid. 510 mg (yield: 45.9 %)1H-NMR (CDCl3) δ; 2.27 (3H, s), 2.91 (2H, t, J = 6.2 Hz),3.30 (2H, t, J = 6.2 Hz), 3.86 (3H, s), 7.00 (2H, d, J =9.2 Hz), 7.56-7.67 (4H, m), 8.02 (2H, d, J = 8.6 Hz). IR (KBr) cm-1; 1709, 1674, 1601, 1260, 818, 743. (5) 1-(4-Bromophenyl)-2-(4'-methoxy[1,1'-biphenyl]-4-yl)-5-methyl-1H-pyrrole
    [0307] A solution of 1-(4'-methoxy[1,1'-biphenyl]-4-yl)-1,4-pentanedione(500 mg, 1.77 mmol), 4-bromoaniline (306 mg,1.77 mmol) and p-toluenesulfonic acid monohydrate (25.3 mg,0.133 mmol) in toluene (30 ml) was refluxed for 12 hoursunder heating and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to isolate theobject compound as a solid. 430 mg (yield: 58.1%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 3.83 (3H, s), 6.10 (1H, d,J = 3.2 Hz), 6.37 (1H, d J = 3.2 Hz), 6.93 (2H, d, J =8.8 Hz), 7.04-7.10 (4H, m), 7.36 (2H, d, J = 8.4 Hz), 7.46-7.53(4H, m).IR (KBr) cm-1; 1609, 1507, 1489, 1248, 1040, 822, 766, 733. (6) 4'-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-ol
    [0308] To a solution of 1-(4-bromophenyl)-2-(4'-methoxy[1,1'-biphenyl]-4-yl)-5-methyl-1H-pyrrole(418 mg, 1.00 mmol) inmethylene chloride (30 ml) was added boron tribromide(0.378 ml, 4.00 mmol) at 0°C , and the mixture was stirredat 0°C for 1 hour. The obtained mixture was poured into ice water and extracted with ethyl acetate. The extractswere collected, washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. To theresidue was added hexane and the mixture was filtrated togive the object compound as a solid. 400 mg (yield: 99.0%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 4.92 (1H, bs), 6.11 (1H, d,J = 3.2 Hz), 6.38 (1H, d J = 3.2 Hz), 6.86 (2H, d, J = 8.4Hz), 7.04-7.53 (10H, m).IR (KBr) cm-1; 3406, 1508, 1489, 1258, 1175, 908, 824, 768,733. (7) Ethyl (2R)-2-({4'-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-yl)oxy)-3-phenylpropanoate
    [0309] To a solution of 4'-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-ol(380 mg, 0.941 mmol),ethyl (S)-2-hydroxy-3-phenylpropanoate (274 mg, 1.41 mmol)and triphenylphosphine (370 mg, 1.41 mmol) in toluene (7ml) was added 1,1'-(azodicarbonyl)dipiperidine (356 mg,1.41 mmol) at room temperature. The obtained mixture wasstirred at room temperature for 30 minutes and at 80°C for2 hours, diluted with ethyl acetate and washed with water.The organic layer was separated and dried over magnesiumsulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 30:1) toisolate the object compound as an oily substance. 184 mg(yield: 33.7%)1H-NMR (CDCl3) δ; 1.19 (3H, t, J = 7.4 Hz), 2.14 (3H, s),3.24 - 3.28 (2H, m), 4.18 (2H, q, J = 7.4 Hz), 4.78-4.84(1H, m), 6.10 (1H, d, J = 3.2 Hz), 6.37 (1H, d, J = 3.2 Hz),6.86 (2H, d, J = 8.8 Hz), 7.03-7.52 (15H, m).IR (KBr) cm-1; 1752, 1732, 1609, 1507, 1489, 1238, 1181,822, 733.[α]D 21 11.0° (c 0.600, chloroform) Example 10(2R)-2-({4'-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-yl}oxy)-3-phenylpropanoicacid
    [0310] To a mixed solution of ethyl (2R)-2-({4'-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl][1,1'-biphenyl]-4-yl}oxy)-3-phenylpropanoateobtained in Example 9 (184 mg,0.317 mmol) in THF (2 ml) and methanol (1 ml) was added anaqueous solution of 1N potassium hydroxide (0.951 ml, 0.951mmol) and the mixture was stirred at room temperature for 3hours. The obtained mixture was neutralized with 1 Nhydrochloric acid and extracted with ethyl acetate. Theextracts were collected, washed with water and dried overmagnesium sulfate anhydride, and the solvent was removed under reduced pressure. To the residue was added hexaneand the mixture was filtrated to give the object compoundas a solid. 150 mg (yield: 85.7%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 3.30 (2H, d, J = 6.0 Hz),4.89 (1H, t, J = 6.0 Hz), 6.10 (1H, d, J = 3.2 Hz), 6.37(1H, d, J = 3.2 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.03-7.52(15H, m).IR (KBr) cm-1; 3430, 1728, 1607, 1505, 1487, 1240, 1179,1071, 824, 735.[α] D 21-4.12° (c 1.06, chloroform)Elementary analysis for C32H26NO3Br·H2O   Calculated: C, 67.37; H, 4.95; N, 2.46.   Found: C, 67.56; H, 5.02; N, 2.42. Example 11tert-Butyl (E)-3-[4-(1-{4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl}-1H-pyrrol-2-yl)phenyl]-2-propenoate(1) 1-(4-Bromophenyl)-3-(1,3-dioxolan-2-yl)-1-propanone
    [0311] To a suspension of magnesium (4.10 g, 165 mmol) in THF(100 ml) was added dropwise a solution of 2-(2-bromoethyl)-1,3-dioxane(27.2 g, 150 mmol) in THF (100 ml) at roomtemperature over 15 minutes. The obtained solution wasstirred at room temperature for 30 minutes and to themixture was added dropwise a solution of 4-bromobenzaldehyde(18.5 g, 100 mmol) in THF (100 ml) at -70°C. The obtained solution was stirred at -70 to -20°Cfor 1.5 hours and added a solution of 10% ammonium chloride(300 ml). The temperature of the mixture was raised toroom temperature and the mixture was extracted with ethylacetate. The extract was washed with water, dried overmagnesium sulfate anhydride and concentrated under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 5: 1) to give theobject compound as crystals. 2.46 g (yield: 8.6%)Melting point: 71-72°C (hexane-ethyl acetate)1H-NMR (CDCl3) δ; 2.10-2.17 (2H, m), 3.08 (2H, t, J = 7.4Hz), 3.84-4.01 (4H, m), 5.00 (1H, t, J = 4.4 Hz), 7.60 (2H,d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 2877, 1684, 1585, 1396, 1138, 1070, 1032,812, 799.Elementary analysis for C12H13O3Br   Calculated: C, 50.55; H,4.60.   Found: C, 50.57; H, 4.52. (2) 1,2-Bis(4-bromophenyl)-1H-pyrrole
    [0312] A solution of 1-(4-bromophenyl)-3-(1,3-dioxolan-2-yl)-1-propanone(500 mg, 1.75 mol), 4-bromoaniline (332 mg,1.93 mmol) and p-toluenesulfonic acid monohydrate (25.0 mg,0.132 mmol) in toluene (50 ml) was refluxed for 20 hoursunder heating and the mixture was concentrated under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 9: 1) to givethe object compound as a solid. 450 mg (yield: 68.2%).1H-NMR (CDCl3) δ; 6.34-6.44 (2H, m), 6.90-7.05 (5H, m),7.35 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J =8.8 Hz).IR (KBr) cm-1; 1489, 1071, 1009, 829, 725, 714.Elementary analysis for C16H11NBr   Calculated: C, 50.96; H, 2.94; N, 3.71.   Found: C, 50.73; H, 2.75; N, 3.52. (3) tert-Butyl (E)-3-[4-(1-{4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl}-1H-pyrrol-2-yl)phenyl]-2-propenoate
    [0313] A solution of 1,2-bis(4-bromophenyl)-1H-pyrrole (1.82g, 4.83 mmol), t-butyl ester acrylate (1.77 ml, 12.1 mmol),tris(2-methoxyphenyl)phosphine (118 mg, 0.387 mmol),palladium acetate (21.7 mg, 0.0967 mmol) and triethylamine(1.69 ml, 12.1 mmol) in DMF (4 ml) was stirred at 100 °Cfor 21 hours under nitrogen atmosphere. The obtainedmixture was poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with water anddried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =2: 1) to give the object compound as a solid. 1.76 g(yield: 77.2%). 1H-NMR (CDCl3) δ; 1.52 (9H, s), 1.53 (9H, s), 6.30 (1H, d,J = 16.2 Hz), 6.34 (1H, d, J = 16.2 Hz), 6.37-6.40 (1H, m),6.49-6.52 (1H, m), 6.96-6.98 (1H, m), 7.10-7.61 (10H, m).IR (KBr) cm-1; 2978, 1705, 1634, 1605, 1516, 1456, 1368,1325, 1209, 1154, 982, 835,731, 720. Example 12(E)-3-[4-(1-{4-[(E)-3-Hydroxy-3-oxo-1-propenyl]phenyl}-1H-pyrrol-2-yl)phenyl]-2-propenoicacid
    [0314] To a solution of tert-butyl (E)-3-[4-(1-{4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl}-1H-pyrrol-2-yl)phenyl]-2-propenoateobtained in Example 11 (800 mg,1.70 mmol) in dichloromethane (10 ml) was addedtrifluoroacetic acid (10 ml), the mixture was stirred atroom temperature for 1 hour and the solvent was removedunder reduced pressure. To the residue was added water,neutralized with 1N aqueous sodium hydroxide and themixture was filtrated to give crude crystals. The crystalswere recrystallized from THF and ethyl acetate. 193 mg(yield: 31.6%)Melting point: >300°C1H-NMR (DMSO-d6) δ; 6.35-6.59 (4H, m), 7.12-7.25 (5H, m),7.50-7.76 (6H, m).IR (KBr) cm-1; 2976, 1682, 1630, 1603, 1514, 1427, 1318,1282, 1221, 1186, 992, 945, 839, 723. Elementary analysis for C22H17NO4·0.5H2O   Calculated: C, 71.73; H, 4.93; N, 3.80.   Found: C, 71.95; H, 4.88; N, 3.55. Example 13tert-Butyl 3-(4-{1-[4-(3-tert-butoxy-3-oxopropyl)phenyl]-1H-pyrrol-2-yl}phenylpropanoate
    [0315] To a solution of tert-butyl (E)-3-[4-(1-{4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl}-1H-pyrrol-2-yl)phenyl]-2-propenoateobtained in Example 11 (471 mg,1.00 mmol) in methanol (40 ml) was added 10% palladiumcarbon (50 mg), and the mixture was stirred at roomtemperature for 12 hours under hydrogen atmosphere. Theobtained solution was filtered and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 10: 1) togive the object compound as an oily substance. 249 mg(yield: 52.4%)1H-NMR (CDCl3) δ; 1.40 (9H, s), 1.41 (9H, s), 2.43-2.58 (4H,m), 2.72-2.94 (4H, m), 6.31-6.42 (2H, m), 6.87-7.16 (9H, m).IR (KBr) cm-1; 2976, 1732, 1520, 1368, 1148, 847, 716. Example 143-(4-{1-[4-(2-Carboxyethyl)phenyl]-1H-pyrrol-2-yl}phenyl)propanoicacid
    [0316] To a solution of tert-butyl 3-(4-(1-[4-(3-tert-butoxy-3-oxopropyl)phenyl]-1H-pyrrol-2-yl}phenylpropanoate(249 mg,0.524 mmol) obtained in Example 13 in methylene chloride (4ml) was added trifluoroacetic acid (2 ml) at 0°C, and themixture was stirred at room temperature for 1 hour and thesolvent was removed under reduced pressure. To the residuewas added water, and the mixture was neutralized with 1Naqueous sodium hydroxide and extracted with ethyl acetate.The extracts were collected , washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure to give the object compoundas an oily substance. 170 mg (yield: 98.3%)1H-NMR (CDCl3) δ; 2.57-2.69 (4H, m), 2.80-2.96 (4H, m),6.34-6.41 (2H, m), 6.92-7.11 (9H, m).IR (KBr) cm-1; 3031, 1709, 1518, 1418, 1287, 1209, 1184,910, 839, 731. Example 15Ethyl (2R)-2-{4-[1-(4-([(1R)-1-benzyl-2-ethoxy-2-oxoethyl]oxy}phenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 3-(1,3-Dioxane-2-yl)-1-(4-methoxyphenyl)-1-propanone
    [0317] To a suspension of magnesium (4.10 g, 165 mmol) in THF(100 ml) was added dropwise a solution of 2-(2-bromoethyl)-1,3-dioxane(27.2 g, 150 mmol) in THF (100 ml) at room temperature over 15 minutes. The obtained solution wasstirred at room temperature for 30 minutes. To thissolution was added dropwise a solution of 4-anisaldehyde(13.6 g, 100 mmol) in THF (100 ml) at -70°C. The obtainedsolution was stirred at -70 to -20°C for 4 hours and atroom temperature for 1 hour, and a solution of 10% ammoniumchloride was added and extracted with ethyl acetate. Theextract was washed with water, dried over magnesium sulfateanhydride and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 4: 1) to give the object compoundas an oily substance. 2.86 g (yield: 12.1%)1H-NMR (CDCl3) δ; 2.08-2.18 (2H, m), 3.07 (2H, t, J = 7.6Hz), 3.83-4.00 (7H, m), 5.00 (1H, t, J = 4.4 Hz), 6.93 (2H,d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 2944, 2880, 1682, 1601, 1510, 1260, 1510,1260, 1171, 1030, 835. (2) 1,2-Bis (4-methoxyphenyl)-1H-pyrrole
    [0318] A solution of 3-(1,3-dioxane-2-yl)-1-(4-methoxyphenyl)-1-propanone(700 mg, 3.26 mol), 4-anisidine(402 mg, 3.26 mmol) and p-toluenesulfonic acid monohydrate(42.5 mg, 0.223 mmol) in toluene (70 ml) was refluxed for20 hours under heating and the solution was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) togive the object compound as a solid. 481 mg (yield: 58.2%)1H-NMR (CDCl3) δ; 3.77 (3H, s), 3.81 (3H, s), 6.32-6.34 (2H,m), 6.73-6.86 (5H, m), 7.04-7.11 (4H, m).IR (KBr) cm-1; 2930, 1514, 1464, 1248, 1177, 1036, 833, 714.Elementary analysis for C18H17NO2    Calculated: C, 77.40; H, 6.13; N, 5.01.   Found: C, 77.21; H, 6.05; N, 4.92. (3) 4-[2-(4-Hydroxyphenyl)-1H-pyrrol-1-yl]phenol
    [0319] To a solution of 1,2-bis(4-methoxyphenyl)-1H-pyrrole(1.40 g, 5.02 mmol) in methylene chloride (40 ml) was addedboron tribromide (3.80 ml, 40.2 mmol) at 0°C . Theobtained solution was stirred at 0°C for 30 minutes andpoured into ice water. The organic layer was separated,washed with saturated aqueous sodium bicarbonate and driedover magnesium sulfate anhydride. The solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 3:1) togive the object compound as a solid. 1.20 g (yield: 95.2%)1H-NMR (DMSO-d6) δ; 6.18-6.19 (2H, m), 6.61 (2H, d, J = 8.8Hz), 6.72 (2H, d, J = 8.8 Hz), 6.85-6.96 (5H, m), 9.35 (1H,s), 9.57 (1H, s).IR (KBr) cm-1; 3274, 1516, 1254, 1227, 1196, 835, 820, 718,557. Elementary analysis for C16H13NO2 0.4 H2O   Calculated: C, 74.35; H, 5.38; N, 5.42.   Found: C, 74.66; H, 5.32; N, 5.19. (4) Ethyl (2R)-2-{4-[1-(4-{[(1R)-1-benzyl-2-ethoxy-2-oxoethyl]oxy}phenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0320] To a solution of 4-[2-(4-hydroxyphenyl)-1H-pyrrol-1-yl]phenol(1.00 g, 3.98 mmol), (S)-2-hydroxy-3-phenylpropanoicacid ethyl ester (2.32 g, 11.9 mol) andtriphenylphosphine (3.12 g, 11.9 mol) in toluene (10 ml)was added dropwise diethyl azodicarboxylate (40%, 5.18 g,11.9 mmol) at room temperature. The reaction solution wasstirred at room temperature for 10 minutes and 80°C for 5hours, and the solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 9: 1) to give theobject compound as an oily substance. 233 mg (yield: 9.7%)1H-NMR (CDCl3) δ; 1.10-1.22 (6H, m), 3.20-3.25 (4H, m),4.09-4.21 (4H, m), 4.69-4.79 (2H, m), 6.28 (1H, d, J = 2.6Hz), 6.65 (2H, d, J = 8.8 Hz), 6.74 (2H, d, J = 8.8 Hz),6.80 (1H, t, J = 2.6 Hz), 6.94-7.02 (4H, m), 7.26-7.30 (10H,m).IR (KBr) cm-1; 1751, 1726, 1512, 1240, 1184, 1084, 1032,835, 735, 700. Example 16(2R)-2-{4-[1-(4-{[(1R)-1-Carboxy-2-phenylethyl]oxy}phenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0321] To a mixed solution of ethyl (2R)-2-{4-[1-(4-{[(1R)-1-benzyl-2-ethoxy-2-oxoethyl]oxy}phenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 15 (233mg, 0.386 mmol) in THF (2 ml)-methanol (1 ml) was added 5 Naqueous sodium hydroxide (0.463 ml, 2.32 mmol). Theobtained solution was stirred at room temperature for 12hours, neutralized with 1 N hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate layer was washedwith water, dried over magnesium sulfate anhydride and thesolvent was removed under reduced pressure to give theobject compound as an oily substance. 187 mg (yield:88.6%)1H-NMR (CDCl3) δ; 3.24-3.28 (4H, m), 4.73-4.82 (2H, m),6.30 (2H, s), 6.66 (2H, d, J = 8.8 Hz), 6.73 (2H, d, J =9.2 Hz), 6.83-6.94 (5H, m), 7.24-7.30 (10H, m).IR (KBr) cm-1; 3063, 1730, 1508, 1238, 1181, 1084, 910, 835,733, 700.[α]D 25 26.0° (c 0.625, chloroform)Elementary analysis for C34H29NO6 1.5·H2O   Calculated: C, 71.07; H, 5.61; N, 2.44.   Found: C, 71.02; H, 5.89; N, 2.24. Example 17Ethyl (2R)-2-{4-[2-(4-bromophenyl)-1H-pyrrol-1-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-bromophenyl)-1-(4-methoxyphenyl)-1H-pyrrole
    [0322] A solution of 1-(4-bromophenyl)-3-(1,3-dioxolan-2-yl)-1-propanone(500 mg, 1.75 mol), 4-anisidine (238 mg, 1.93mmol) and p-toluenesulfonic acid monohydrate (25.0 mg,0.132 mmol) in toluene (50 ml) was refluxed for 20 hourswith heating and the solution was concentrated underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 20: 1) togive the object compound as a solid. 412 mg (yield: 71.8%).1H-NMR (CDCl3) δ; 3.82 (3H, s), 6.31-6.43 (2H, m), 6.83-6.89(3H, m), 6.98 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J =8.8 Hz), 7.31 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 1514, 1250, 833, 729.Elementary analysis for C17H14NBrO   Calculated: C, 62.21; H, 4.30; N, 4.27.   Found: C, 62.10; H, 4.28; N, 4.26. (2) 4-[2-(4-Bromophenyl)-1H-pyrrol-1-yl]phenol
    [0323] To a solution of 2-(4-bromophenyl)-1-(4-methoxyphenyl)-1H-pyrrole(3.00 g, 9.14 mmol) in methylenechloride (100 ml) was added boron tribromide (3.46 ml, 36.6 mmol) at 0°C, and the mixture was stirred at 0°C for 10minutes and at room temperature for 0.5 hour. The obtainedsolution was poured into ice water and extracted with ethylacetate. The extracts were collected and washed withsaturated aqueous sodium bicarbonate, dried over magnesiumsulfate anhydride,, solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 3:1) to isolate theobject compound as a solid. 2.80 g (yield: 97.6%)1H-NMR (CDCl3) δ; 4.89 (1H, bs), 6.31-6.43 (2H, m), 6.78(2H, d, J = 8.8 Hz), 6.87-7.07 (5H, m), 7.32 (2H, d, J =8.4 Hz).IR (KBr) cm-1; 3191, 1514, 1487, 1458, 1236, 837, 826, 729. (3) Ethyl (2R)-2-{4-[2-(4-bromophenyl)-1H-pyrrol-1-yl]phenoxy}-3-phenylpropanoate
    [0324] To a solution of 4-[2-(4-bromophenyl)-1H-pyrrol-1-yl]phenol(2.10 g, 6.68 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.56 g, 8.02 mmol) and triphenylphosphine(2.10 g, 8.02 mmol) in toluene (10 ml) was added diethylazodicarboxylate (40%, 3.79 g, 8.02 mmol), and the mixturewas stirred at 80°C for 4 hours and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 20: 1) togive the object compound as a solid. 1.10 g (yield: 33.5%) 1H-NMR (CDCl3) δ; 1.18 (3H, t, J = 7.0 Hz), 3.25 (2H, d, J= 6.8 Hz), 4.18 (2H, q, J = 7.0 Hz), 4.78 (1H, t, J = 6.8Hz), 6.30-6.41 (2H, m), 6.78 (2H, d, J = 8.8 Hz), 6.84-6.86(1H, m), 6.94 (2H, d, J = 8.4 Hz), 7.02 (2H, d, J = 8.8 Hz),7.26-7.32 (7H, m).IR (KBr) cm-1; 1750, 1512, 1487, 1240, 1190, 1074, 831, 721,700.[α]D 24 +18.5° (c 0.425, chloroform)Elementary analysis for C27H24NO3Br   Calculated: C, 66.13; H, 4.93; N, 2.86.   Found: C, 66.20; H, 5.06; N, 2.72. Example 18(2R)-2-{4-[2-(4-bromophenyl)-1H-pyrrol-1-yl]phenoxy}-3-phenylpropanoicacid
    [0325] To a mixed solution of ethyl (2R)-2-{4-[2-(4-bromophenyl)-1H-pyrrol-1-yl]phenoxy}-3-phenylpropanoate(200 mg, 0.408 mmol) obtained in Example 17 in THF (2 ml)-methanol(1 ml) was added an aqueous solution of 1 Npotassium hydroxide (0.245 ml, 1.22 mmol), and the mixturewas stirred at room temperature for 1 hour. The reactionsolution was diluted with ethyl acetate and neutralizedwith 1 N hydrochloric acid, and the organic layer wasseparated. The organic layer was washed with water anddried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure to give the object compoundas an oily substance. 178 mg (yield: 94.2%)1H-NMR (CDCl3) δ; 3.28-3.31 (2H, m), 4.82-4.88 (1H, m),6.29-6.42 (2H, m), 6.79 (2H, d, J = 8.8 Hz), 6.84-6.86 (1H,m), 6.94 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 8.8 Hz),7.26-7.32 (7H, m).IR (KBr) cm-1; 3032, 1730, 1510, 1238, 1073, 831, 731.[α]D 27 +8.76° (c 0.515, chloroform) Example 19Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-1,4-hexanedione
    [0326] A mixed solution of p-anisaldehyde (10.0 g, 73.4 mmol),ethylvinylketone (5.68 ml, 57.0 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.88 g, 11.4mmol) and triethylamine (15.9 ml, 114 mmol) in ethanol (100ml) was stirred at 77°C for 20 hours, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =9:1) to isolate the object compound as a solid. 4.40 g(yield: 35.2%)1H-NMR (CDCl3) δ; 1.10 (3H, t, J = 7.4 Hz), 2.56 (2H, q, J= 7.4 Hz), 2.84 (2H, t, J = 6.2 Hz), 3.25 (2H, t, J = 6.2Hz), 3.87 (3H, s), 6.93 (2H, d, J = 9.2 Hz), 7.97 (2H, d, J = 9.2 Hz).IR (KBr) cm-1; 1715, 1676, 1601, 1510, 1262, 1240, 1171,1115, 1026, 839.Elementary analysis for C13H16O3    Calculated: C, 70.89; H, 7.32.   Found: C, 70.96; H, 7.21. (2) 1-(4-Bromophenyl)-2-ethyl-5-(4-methoxyphenyl)-1H-pyrrole
    [0327] A solution of 1-(4-methoxyphenyl)-1,4-hexanedione(4.00 g, 18.2 mmol), 4-bromoaniline (3.12 g, 18.2 mmol) andp-toluenesulfonic acid monohydrate (260 mg, 1.37 mmol) intoluene (150 ml) was refluxed for 20 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 30:1) to isolate the objectcompound as a solid. 6.25g (yield: 96.5%)1H-NMR (CDCl3) δ; 1.14 (3H, t, J = 7.8 Hz), 2.44 (2H, q, J= 7.8 Hz), 3.75 (3H, s), 6.09 (1H, d, J = 3.6 Hz), 6.28(1H, d J = 3.6 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.97 (2H, d,J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8Hz) .IR (KBr) cm-1; 1524, 1489, 1248, 1034, 833.Elementary analysis for C19H18NOBr   Calculated: C, 64.06; H, 5.09; N, 3.93.    Found: C, 64.11; H, 5.16; N, 3.94. (3) 4-[1-(4-Bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenol
    [0328] To a solution of 1-(4-bromophenyl)-2-ethyl-5-(4-methoxyphenyl)-1H-pyrrole(5.50 g, 15.4 mmol) in methylenechloride (200 ml) was added boron tribromide (5.84 ml, 61.8mmol) at 0°C. The obtained solution was stirred at 0°C for1 hour, poured into ice water and extracted with ethylacetate. The extracts were collected and washed withsaturated aqueous sodium bicarbonate and dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 5:1) toisolate the object compound as an oily substance. 5.01g(yield: 94.9%)1H-NMR (CDCl3) δ; 1.14 (3H, t, J = 7.6 Hz), 2.44 (2H, q, J= 7.6 Hz), 5.03 (1H, s), 6.09 (1H, d, J = 3.2 Hz), 6.27 (1H,d J = 3.2 Hz), 6.63 (2H, d, J = 8.4 Hz), 6.91 (2H, d, J =8.4 Hz), 7.01 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 2969, 1526, 1489, 1223, 831. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0329] To a solution of 4-[1-(4-bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenol(738 mg, 2.16 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (628 mg, 3.24 mmol) andtriphenylphosphine (850 mg, 3.24 mmol) in toluene (8 ml)was added 1,1'-(azodicarbonyl)dipiperidine (817 mg, 3.24mmol) at room temperature. The obtained solution wasstirred at room temperature for 1 hour and at 80°C for 2hours, diluted with ethyl acetate and washed with water.The organic layer was separated and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 30:1) toisolate the object compound as an oily substance. 535 mg(yield: 47.8%)1H-NMR (CDCl3) δ; 1.09-1.18 (6H, m), 2.42 (2H, q, J = 7.6Hz), 3.18-3.22 (2H, m), 4.15 (2H, q, J = 6.6 Hz), 4.71 (1H,t, J = 6.8 Hz), 6.07 (1H, d, J = 3.6 Hz), 6.25 (1H, d, J =3.6 Hz), 6.62 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz),6.99 (2H, d, J = 8.8 Hz), 7.22-7.30 (5H, m), 7.45 (2H, d, J= 8.8 Hz).IR (KBr) cm-1; 1753, 1736, 1520, 1489, 1240, 1182, 1069,835.[α]D 21 14.4° (c 1.06, chloroform) Example 20(2R)-2-{4-[1-(4-bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0330] To a mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-ethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 19 (425 mg, 0.820mmol) in THF (6 ml)-methanol (3 ml) was added an aqueoussolution of 1N potassium hydroxide (2.46 ml, 2.46 mmol) andthe mixture was stirred at room temperature for 1 hour.The obtained solution was neutralized with 1 N hydrochloricacid and extracted with ethyl acetate. The extracts werecollected, washed with water and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure to give the object compound as an oilysubstance. 360 mg (yield: 89.6%)1H-NMR (CDCl3) δ; 1.12 (3H, t, J = 7.6 Hz), 2.42 (2H, q, J= 7.6 Hz), 3.24 (2H, d, J = 6.6 Hz), 4.78 (1H, t, J = 6.6Hz), 6.08 (1H, d, J = 3.6 Hz), 6.27 (1H, d, J = 3.6 Hz),6.64 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.99(2H, d, J = 8.8 Hz), 7.25-7.28 (5H, m), 7.46 (2H, d, J =8.8 Hz).IR (KBr) cm-1; 3031, 1725, 1518, 1489, 1238, 1069, 835. Example 21Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-Phenyl-2-propen-1-ol
    [0331] To a solution of 1 N vinylmagnesium bromide in THF (100 ml)was added dropwise benzaldehyde (9.15 ml, 90.0mmol) at 0°C. The obtained solution was stirred at 0°C for2 hours, and an aqueous solution of 1 N ammonium chloride(200 ml) was added to the mixture. The reaction solutionwas stirred at room temperature for 1 hour and extractedwith ethyl acetate. The extracts were collected, washedwith water and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure to give theobject compound as an oily substance. 11.8g (yield: 97.5%)1H-NMR (CDCl3) δ; 1.97 (1H, d, J = 3.6 Hz), 5.17-5.23 (2H,m), 5.36 (1H, d, J = 15.8 Hz), 5.98-6.14 (1H, m), 7.24-7.41(5H, m).IR (KBr) cm-1; 3291, 1493, 1454, 1024, 990, 928, 762, 700. (2) 1-Phenyl-2-propen-1-one
    [0332] To a solution of oxalyl chloride (9.11 ml, 104 mmol)in methylene chloride (114 ml) was added dimethylsulfoxide(15.0 ml, 211 mmol) at -60°C, then to the mixture was added1-phenyl-2-propen-1-ol (11.8 g, 87.9 mmol). The obtainedsolution was stirred at -60°C for 30 minutes, and to themixture was added dropwise triethylamine (47.8 ml, 343mmol) at -60°C. The temperature of the reaction solutionwas raised to room temperature and the solution was pouredinto water. The organic layer was separated and dried overmagnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30:1) toisolate the object compound as an oily substance. 2.10 g(yield: 18.1%)1H-NMR (CDCl3) δ; 5.94 (1H, dd, J = 1.8, 8.6 Hz), 6.44 (1H,dd, J = 1.8, 17.2 Hz), 7.17 (1H, dd, J = 8.6, 17.2 Hz),7.39-7.52 (3H, m), 7.91-7.98 (2H, m).IR (KBr) cm-1; 1672, 1597, 1449, 1404, 1233, 968, 910, 745,729, 698. (3) 1-(4-Methoxyphenyl)-4-phenyl-1,4-butanedione
    [0333] 1-(4-Methoxyphenyl)-4-phenyl-1,4-butanedione wassynthesized from 1-phenyl-2-propen-1-one as a solid,according to the similar manner to that of Example 19(1).yield: 16.4%1H-NMR (CDCl3) δ; 3.43-3.45 (4H, m), 3.88 (3H, s), 6.96 (2H,d, J = 7.2 Hz), 7.44-7.59 (3H, m), 8.01-8.07 (4H, m).IR (KBr) cm-1; 1678, 1601, 1510, 1262, 1231, 1171, 1030,993, 835, 766, 691. (4) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-phenyl-1H-pyrrole
    [0334] 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-phenyl-1H-pyrrolewas isolated from 1-(4-methoxyphenyl)-4-phenyl-1,4-butanedioneas a solid, according to the similar manner to that of Example 19(2). yield: 63.2%1H-NMR (CDCl3) δ; 3.78 (3H, s), 6.39 (1H, d, J = 3.6 Hz),6.45 (1H, d J = 3.6 Hz), 6.75 (2H, d, J = 9.2 Hz), 6.87 (2H,d, J = 8.8 Hz), 6.94-7.26 (7H, m), 7.35 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1491, 1248, 831, 756. (5) 4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenol
    [0335] 4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-bromophenyl)-2-(4-methoxyphenyl)-5-phenyl-1H-pyrroleas a solid, according to the similarmanner to that of Example 19(3). yield: 18.2%1H-NMR (CDCl3) δ; 4.71 (1H, s), 6.38 (1H, d, J = 3.6 Hz),6.44 (1H, d J = 3.6 Hz), 6.68 (2H, d, J = 8.8 Hz), 6.84-7.26(9H, m), 7.35 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3395, 1599, 1491, 1262, 1173, 831, 758. (6) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0336] Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesized from 4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenolas a solid,according to the similar manner to that of Example 19(4).yield: 62.7%1H-NMR (CDCl3) δ; 1.16 (3H, t, J = 7.4 Hz), 3.20-3.26 (2H,m), 4.15 (2H, q, J = 7.4 Hz), 4.71-4.78 (1H, m), 6.36 (1H, d, J = 3.6 Hz), 6.43 (1H, d, J = 3.6 Hz), 6.67 (2H, d, J =8.8 Hz), 6.72-7.35 (16H, m).IR (KBr) cm-1; 1732, 1491, 1236, 833, 758, 698. Example 22(2R)-2-{4-[1-(4-Bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0337] (2R)-2-{4-[1-(4-Bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized as asolid, from ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example21, according to the similar manner to that of Example 20.yield: 72.5%1H-NMR (CDCl3) δ; 3.25-3.28 (2H, m), 4.80-4.86 (1H, m),6.37 (1H, d, J = 3.6 Hz), 6.43 (1H, d, J = 3.6 Hz), 6.69(2H, d, J = 9.2 Hz), 6.82-7.36 (16H, m).IR (KBr) cm-1; 3393, 1725, 1491, 1238, 1225, 833, 756, 698.[α]D 23-1.86° (c 1.06, chloroform)Elementary analysis for C31H24NBrO30.7H2O   Calculated: C, 67.40; H, 4.75; N, 2.27.   Found: C, 67.57; H, 4.658; N, 2.54. Example 23Ethyl (2R)-2-{4-[1-(4-bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-3-methyl 1,4-pentanedione
    [0338] A mixed solution of p-anisaldehyde (10.0 g, 73.4 mmol),3-methyl-3-buten-2-one (4.79 g, 57.0 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.88 g, 11.4mmol) and triethylamine (15.9 ml, 114 mmol) in ethanol (8ml) was stirred at 77°C for 12 hours and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =7:1) to isolate the object compound as an oily substance.1.61 g (yield: 12.9 %)1H-NMR (CDCl3) δ; 1.19 (3H, d, J = 7.0 Hz), 2.30 (3H, s),2.90 (2H, dd, J = 17.6, 4.4 Hz), 3.15-3.34 (1H, m), 3.48(1H, dd, J = 17.6, 8.8 Hz), 3.86 (3H, s), 6.92 (2H, d, J =8.8 Hz), 7.93 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1713, 1674, 1601, 1510, 1262, 1169, 1030,835. (2) 1-(4-Bromophenyl)-5-(4-methoxyphenyl)-2,3-dimethyl-1H-pyrrole
    [0339] A solution of 1-(4-methoxyphenyl)-3-methyl-1,4-pentanedione(1.60 g, 7.26 mmol), 4-bromoaniline (1.25 g,7.26 mmol) and p-toluenesulfonic acid monohydrate (104 mg,0.545 mmol) in toluene (50 ml) was refluxed for 48 hoursunder heating and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 30:1) to isolate theobject compound as an oily substance. 630 mg (yield:24.3%)1H-NMR (CDCl3) δ; 2.04 (3H, s), 2.11 (3H, s), 3.75 (3H, s),6.15 (1H, s), 6.70 (2H, d J = 8.8 Hz), 6.93-7.01 (4H, m),7.46 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1528, 1489, 1246, 1034, 833, 804. (3) 4-[1-(4-Bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenol
    [0340] To a solution of 1-(4-bromophenyl)-5-(4-methoxyphenyl)-2,3-dimethyl-1H-pyrrole(610 mg, 1.71 mmol)in methylene chloride (30 ml) was added boron tribromide(0.647 ml, 6.84 mmol) at 0°C. The obtained solution wasstirred at 0°C for 1 hour, poured into ice water andextracted with ethyl acetate. The extracts were collectedand washed with saturated aqueous sodium bicarbonate anddried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =6:1) to isolate the object compound as an oily substance.358 mg (yield: 61.2 %)1H-NMR (CDCl3) δ; 2.10 (3H, s), 2.11 (3H, s), 4.94 (1H, bs),6.15 (1H, s), 6.63 (2H, d J = 8.8 Hz), 6.90 (2H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3338, 1530, 1489, 1262, 1171, 835. (4) Ethyl (2R)-2-{4-[1-(4-Bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0341] To a solution of 4-[1-(4-bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenol(342 mg, 1.00 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(291 mg, 1.50 mmol) andtriphenylphosphine (393 mg, 1.50 mmol) in toluene (5 ml)was added 1,1'-(azodicarbonyl)dipiperidine (378 mg, 1.50mmol) at room temperature. The obtained solution wasstirred at room temperature for 1 hour and at 80°C for 4hours, diluted with ethyl acetate and washed with water.The organic layer was separated and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 30:1) toisolate the object compound as an oily substance. 299 mg(yield: 57.7%)1H-NMR (CDCl3) δ; 1.14 (3H, t, J = 7.0 Hz), 2.05 (3H, s),2.09 (3H, s), 3.18-3.22 (2H, m), 4.12 (2H, q, J = 7.0 Hz),4.67-4.74 (1H, m), 6.13 (1H, s), 6.62 (2H, d, J = 8.8 Hz),6.88 (2H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.26-7.29(5H, m), 7.44 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1755, 1732, 1526, 1489, 1238, 1182, 1069,835.[α]D 24 9.9553° (c 0.510, chloroform) Example 24(2R)-2-{4-[1-(4-Bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0342] To the mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenyl)-4,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 23 (280 mg, 0.540mmol) in THF (6 ml)-methanol (3 ml) was added 1N aqueouspotassium hydroxide (1.62 ml, 1.62 mmol) . The obtainedsolution was stirred at room temperature for 1 hour,neutralized with 1 N hydrochloric acid and extracted withethyl acetate. The extracts were collected, washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure to give theobject compound as an oily substance. 237 mg (yield:89.5%)1H-NMR (CDCl3) δ; 2.02 (3H, s), 2.09 (3H, s), 3.24 (2H, d,J = 5.6 Hz), 4.77 (1H, t, J = 5.6 Hz), 6.14 (1H, s), 6.63(2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.96 (2H, d,J = 8.8 Hz), 7.26-7.29 (5H, m), 7.45 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3450, 1728, 1526, 1489, 1236, 1068, 835, 735,700.[α] D 24-4.93° (c 1.06, chloroform) Example 25Ethyl (2R)-2-{4-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-2-methyl-1,4-pentanedione
    [0343] 1-(4-Methoxyphenyl)-2-methyl-1,4-pentanedione wassynthesized from 3-penten-2-one as an oily substance,according to the similar manner to that of Example 23(1).yield: 16.0%1H-NMR (CDCl3) δ; 1.29 (3H, d, J = 6.6 Hz), 2.17 (3H, s ),2.49-2.71 (2H, m), 3.09-3.22 (1H, m), 3.87 (3H, s), 6.94(2H, d, J = 8.8 Hz), 7.97 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1715, 1672, 1599, 1512, 1252, 1175, 1032,837. (2) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrrole
    [0344] 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrrolewas synthesized from 1-(4-methoxyphenyl)-2-methyl-1,4-pentanedioneas an oily substance, according to thesimilar manner to that of Example 23 (2). yield: 13.0%1H-NMR (CDCl3) δ; 2.11 (6H, s) , 3.76 (3H, s), 5.97 (3H, s) ,6.74 (2H, d J = 8.6 Hz), 6.90-6.96 (4H, m), 7.40 (2H, d, J= 8.6 Hz).IR (KBr) cm-1; 1528, 1491, 1246, 1177, 833, 810. (3) 4-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenol
    [0345] 4-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-methoxyphenyl)-2-methyl-1,4-pentanedioneas an oily substance, according tothe similar manner to that of Example 23 (3). yield: 66.6%1H-NMR (CDCl3) δ; 2.10 (6H, s), 4.83 (1H, bs), 5.96 (1H, s),6.66 (2H, d, J = 8.8 Hz), 6.85-6.94 (4H, m), 7.40 (2H, d,J = 8.8 Hz).IR (KBr) cm-1; 3389, 1530, 1491, 1387, 1262, 1171, 835, 819,800, 733. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0346] Ethyl (2R)-2-{4-[1-(4-bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[1-(4-bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenolas an oily substance, according to the similarmanner to that of Example 23 (4). yield: 74.2%1H-NMR (CDCl3) δ; 1.13 (3H, t, J = 7.2 Hz), 2.08 (3H, s),2.09 (3H, s), 3.19-3.23 (2H, m), 4.14 (2H, q, J = 7.2 Hz),4.70-4.76 (1H, m), 5.95 (1H, s), 6.66 (2H, d, J = 8.8 Hz),6.83-7.30 (9H, m), 7.38 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1753, 1734, 1526, 1493, 1236, 1182, 1071,737, 700.[α]D 25 10.3° (c 0.640, chloroform) Example 26(2R)-2-{4-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0347] (2R)-2-{4-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized fromethyl (2R)-2-{4-[1-(4-bromophenyl)-3,5-dimethyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 25, asan oily substance, according to the similar manner to thatof Example 24. yield: 84.9%1H-NMR (CDCl3) δ; 2.08 (3H, s), 2.09 (3H, s), 3.25 (2H, d,J = 6.6 Hz), 4.08 (1H, t, J = 6.6 Hz), 5.96 (1H, s), 6.67(2H, d, J = 8.4 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.26-7.28(5H, m), 7.39 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3061, 1728, 1526, 1493, 1238, 1071, 909, 833,731, 700.[α]D 26-8.50° (c 1.01, chloroform) Example 27Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-2-propyl-1,4-pentanedione
    [0348] 1-(4-Methoxyphenyl)-2-propyl-1,4-pentanedione wassynthesized from 3-hepten-2-one as an oily substance,according to the similar manner to that of Example 23(1).yield: 12.8% 1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.0 Hz), 1.22-1.49 (4H,m), 2.17 (3H, s), 2.54-2.72 (2H, m), 3.07-3.21 (1H, m),3.87 (3H, s), 6.95 (2H, d, J = 8.8 Hz), 7.98 (2H, d, J =8.8 Hz).IR (KBr) cm-1; 1713, 1669, 1601, 1510, 1254, 1169, 1032,835. (2) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-propyl-1H-pyrrole
    [0349] 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-propyl-1H-pyrrolewas synthesized from 1-(4-methoxyphenyl)-2-propyl-1,4-pentanedioneas an oily substance, accordingto the similar manner to that of Example 23(2). yield:12.2%1H-NMR (CDCl3) δ; 0.93 (3H, t, J = 7.4 Hz), 1.53-1.64 (2H,m), 2.12 (3H, s), 2.41 (2H, t, J = 7.4 Hz), 3.76 (3H, s),6.74 (2H, d, J = 8.8 Hz), 6.90-6.96 (4H, m), 7.39 (2H, d,J = 8.4 Hz).IR (KBr) cm-1; 1528, 1491, 1246, 1177, 1071, 1036, 1007,833, 814. (3) 4-[1-(4-Bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenol
    [0350] 4-[1-(4-Bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-propyl-1H-pyrrole as an oilysubstance, according to the similar manner to that ofExample 23(3). yield: 71.7%1H-NMR (CDCl3) δ; 0.92 (3H, t, J = 7.2 Hz), 1.52-1.64 (2H,m), 2.12 (3H, s), 2.40 (2H, t, J = 7.4 Hz), 4.79 (1H, s),6.00 (1H, s), 6.66 (2H, d J = 8.4 Hz), 6.87-6.94 (4H, m),7.39 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3420, 1530, 1491, 1262, 835, 822. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0351] Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[1-(4-bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenolas an oily substance, according to the similarmanner to that of Example 23(4). yield: 64.1%1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.4 Hz), 1.12 (3H, t, J= 7.0 Hz), 1.47-1.62 (2H, m), 2.10 (3H, s), 2.38 (3H, t, J= 7.4 Hz), 3.19-3.23 (2H, m), 4.14 (2H, q, J = 7.0 Hz),4.70-4.77 (1H, m), 5.98 (1H, s), 6.66 (2H, d, J = 8.8 Hz),6.85-6.91 (4H, m), 7.26-7.31 (5H, m), 7.36 (2H, d, J = 8.6Hz).IR (KBr) cm-1; 1755, 1732, 1526, 1493, 1236, 1181, 1071,833, 700.[α]D 24 7.64° (c 0.845, chloroform) Example 28(2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0352] (2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesizedfrom ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained inExample 27, as an oily substance, according to the similarmanner to that of Example 24. yield: 93.1%1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.0 Hz), 1.51-1.63 (2H,m), 2.10 (3H, s), 2.38 (3H, t, J = 7.4 Hz), 3.25 (2H, d, J= 6.6 Hz), 4.80 (1H, t, J = 6.6 Hz), 5.98 (1H, s), 6.67 (2H,d, J = 8.8 Hz), 6.88 (4H, d, J = 8.8 Hz), 7.26-7.28 (5H, m),7.37 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3065, 1728, 1526, 1491, 1236, 1179, 1071,833, 735, 700.[α]D 21-8.44° (c 1.25, chloroform) Example 29Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-2-phenyl-1,4-pentanedione
    [0353] 1-(4-Methoxyphenyl)-2-phenyl-1,4-pentanedione wassynthesized from benzalacetone as an oily substance, according to the similar manner to that of Example 23(1).yield: 16.6%1H-NMR (CDCl3) δ; 2.19 (3H, s ), 2.73 (1H, dd, J = 4.4,17.4 Hz), 3.59 (1H, dd, J = 10.2, 17.4 Hz), 3.81 (3H, s),5.07 (1H, dd, J = 4.4, 10.2 Hz), 6.86 (2H, d, J = 8.8 Hz),7.16-7.28 (5H, m), 7.95 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1715, 1672, 1601, 1574, 1510, 1248, 1169,1028, 842, 702. (2) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrrole
    [0354] 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrrolwas synthesized from 1-(4-methoxyphenyl)-2-phenyl-1,4-pentanedioneas a solid, according to thesimilar manner to that of Example 23(2). yield: 56.6%1H-NMR (CDCl3) δ; 2.15 (3H, s) , 3.75 (3H, s), 6.29 (1H, s),6.97 (2H, d J = 8.6 Hz), 6.89-6.99 (4H, m), 7.08-7.26 (5H,m), 7.42 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1508, 1491, 1298, 1177, 1034, 833, 762.Elementary analysis for C24H20NOBr   Calculated: C, 82.91; H, 4.82; N, 3.35.   Found: C, 69.15; H, 4.97; N, 3.20. (3) 4-[1-(4-Bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenol
    [0355] 4-[1-(4-Bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-bromophenyl)-2-(4-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrroleas a solid,according to the similar manner to that of Example 23(3).yield: 83.1%1H-NMR (CDCl3) δ; 2.15 (3H, s), 4.76 (1H, bs), 6.28 (1H, s),6.60 (2H, d, J = 8.8 Hz), 6.87 (2H, d J = 8.8 Hz), 6.96(2H, d J = 8.8 Hz), 7.10-7.26 (5H, m), 7.42 (2H, d, J =8.8 Hz).IR (KBr) cm-1; 3281, 1534, 1508, 1491, 1370, 1260, 1171,1005, 835, 762, 698.Elementary analysis for C23H18NOBr·0.6H2O   Calculated: C, 66.55; H, 4.66; N, 3.37.   Found: C, 66.43; H, 4.37; N, 3.17. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0356] Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[1-(4-bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenolas an oily substance, according to the similarmanner to that of Example 23(4). yield: 37.1%1H-NMR (CDCl3) δ; 1.11 (3H, t, J = 7.4 Hz), 2.13 (3H, s),3.18-3.22 (2H, m), 4.13 (2H, q, J = 7.4 Hz), 4.69-4.75 (1H,m), 6.26 (1H, s), 6.60 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.09-7.30 (10H, m),7.40 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1755, 1732, 1532, 1508, 1491, 1281, 1236,1181, 1071, 1030, 1007, 843, 762, 700.[α]D 25 8.30° (c 0.615, chloroform) Example 30(2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0357] (2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesizedfrom ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained inExample 29, as an oily substance, according to the similarmanner to that of Example 24. yield: 88.8%1H-NMR (CDCl3) δ; 2.13 (3H, s), 3.25 (2H, d, J = 6.8 Hz),4.79 (1H, t, J = 6.8 Hz), 6.26 (1H, s), 6.60 (2H, d, J =8.4 Hz), 6.86 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4Hz),7.06-7.27 (10H, m), 7.40 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3063, 1728, 1508, 1491, 1236, 909, 841, 762,733, 698.[α]D 25-17.2° (c 1.08, chloroform) Example 31Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-(1H-indol-3-yl)propanoate(1) Ethyl 2-hydroxy-3-(1H-indol-3-yl)propanoate
    [0358] A solution of 2-hydroxy-3-(1H-indol-3-yl)propanoicacid (1.00 g, 4.87 mmol) and p-toluenesulfonic acidmonohydrate (180 mg, 0.944 mmol) in ethanol (50 ml) wasrefluxed for 12 hours under heating and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =3:1) to isolate the object compound as a solid. 1.00 g(yield: 87.7%)1H-NMR (CDCl3) δ; 1.23 (3H, t, J = 7.2 Hz), 2.80 (1H, d, J= 6.4 Hz), 3.13-3.35 (2H, m), 4.07-4.24 (2H, m), 4.46-4.55(1H, m), 7.07-7.26 (4H, m), 7.34 (2H, d, J = 7.0 Hz), 7.62(2H, d, J = 7.8 Hz), 8.08 (1H, bs).IR (KBr) cm-1; 3341, 1726, 1281, 1215, 1096, 1026, 741. (2) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-(1H-indol-3-yl)propanoate
    [0359] To a solution of 4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol(400 mg, 1.22 mmol), ethyl 2-hydroxy-3-(1H-indol-3-yl)propanoate(424 mg, 1.82 mmol) andtriphenylphosphine (477 mg, 1.82 mmol) in toluene (4 ml)was added 1,1'-(azodicarbonyl)dipiperidine (459 mg, 1.82mmol) at room temperature. The obtained solution wasstirred at room temperature for 1 hour and at 80°C for 4 hours, diluted with ethyl acetate and with water. Theorganic layer was separated and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 30:1) toisolate the object compound as an oily substance. 124 mg(yield: 18.7%)1H-NMR (CDCl3) δ; 1.12 (3H, t, J = 7.2 Hz), 2.10 (3H, s),3.38 (2H, d, J = 6.2 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.79(1H, t, J = 6.2 Hz), 6.04 (1H, d, J = 3.2 Hz), 6.22 (1H, d,J = 3.2 Hz), 6.65 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.4 Hz), 7.10-7.42 (4H, m), 7.45 (2H,d, J = 8.4 Hz), 7.67 (1H, d, J = 7.0 Hz), 8.03 (1H, bs).IR (KBr) cm-1; 3411, 1738, 1524, 1489, 1233, 1184, 1071,835, 743. Example 32(2R)-2-{4-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-(1H-indol-3-yl)propanoicacid
    [0360] To a mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenyl}-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-(1H-indol-3-yl)propanoateobtained in Example 31 (124 mg, 0.228 mmol)in THF (2 ml)-methanol (1 ml) was added 1N aqueouspotassium hydroxide (0.685 ml, 0.685 mmol). The obtainedsolution was stirred at room temperature for 1 hour, neutralized with 1 N hydrochloric acid and extracted withethyl acetate. The extracts were collected , washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure to give theobject compound as a solid. 80.6 mg (68.6%)1H-NMR (CDCl3) δ; 2.10 (3H, s), 3.41 (2H, d, J = 6.2 Hz),4.85 (1H, t, J = 6.2 Hz), 6.05 (1H, d, J = 3.4 Hz), 6.24(1H, d, J = 3.4 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.90-7.35(8H, m), 7.45 (2H, d, J = 8.4 Hz), 7.64 (1H, d, J = 7.0 Hz),7.97 (1H, bs).IR (KBr) cm-1; 3416, 3056, 1725, 1522, 1489, 1231, 1071,909, 833, 737. Example 33Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-1,4-heptanedione
    [0361] 1-(4-Methoxyphenyl)-1,4-heptanedione was synthesizedfrom 1-hexen-3-one as an oily substance, according to thesimilar manner to that of Example 19(1). yield: 20.2%1H-NMR (CDCl3) δ; 0.94 (3H, t, J = 7.6 Hz), 1.59-1.71 (2H,m), 2.52 (2H, t, J = 7.2 Hz), 2.84 (2H, t, J = 6.2 Hz),3.24 (2H, t, J = 6.2 Hz), 3.87 (3H, s), 6.93 (2H, d, J =8.8 Hz), 7.97 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1713, 1678, 1601, 1510, 1260, 1171, 1026, 833. (2) 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-propyl-1H-pyrrole
    [0362] 1-(4-Bromophenyl)-2-(4-methoxyphenyl)-5-propyl-1H-pyrrolewas synthesized from 1-(4-methoxyphenyl)-1,4-heptanedioneas a solid, according to the similar manner tothat of Example 19(2). yield: 74.1%1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 7.2 Hz), 1.46-1.58 (2H,m), 2.40 (2H, t, J = 7.0 Hz), 3.75 (3H, s), 6.08 (1H, d, J= 3.2 Hz), 6.27 (1H, d J = 3.2 Hz), 6.71 (2H, d, J = 8.8Hz), 6.92-7.06 (4H, m), 7.48 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1522, 1489, 1248, 1034, 833, 766. (3) 4-[1-(4-Bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenol
    [0363] 4-[1-(4-Bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-bromophenyl)-2-(4-methoxyphenyl)-5-propyl-1H-pyrroleas a solid, according to the similarmanner to that of Example 19(3). yield: 88.0%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.2 Hz), 1.43-1.59 (2H,m), 2.40 (2H, t, J = 8.0 Hz), 4.60 (1H, s), 6.08 (1H, d, J= 3.4 Hz), 6.26 (1H, d J = 3.4 Hz), 6.63 (2H, d, J = 8.8Hz), 6.91 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.4 Hz),7.47 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3376, 1522, 1489, 1260, 1173, 833, 770, 733. (4) Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0364] Ethyl (2R)-2-{4-[1-(4-bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesized from 4-[1-(4-bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenolas a solidaccording to the similar manner to that of Example 19 (4).yield: 23.4%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.2 Hz), 1.14 (3H, t, J= 7.4 Hz), 1.45-1.55 (2H, m), 2.38 (2H, t, J = 7.6 Hz),3.18-3.22 (2H, m), 4.14 (2H, q, J = 7.4 Hz), 4.68-4.74 (1H,m), 6.06 (1H, d, J = 3.8 Hz), 6.25 (1H, d, J = 3.8 Hz),6.63(2H, d, J = 8.8Hz), 6.89 (2H, d, J = 8.8 Hz), 6.99 (2H, d,J = 8.8 Hz), 7.26-7.28 (5H, m), 7.46 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1753, 1732, 1520, 1489, 1238, 1182, 1071,835, 766, 735.[α]D 22 17.0° (c 0.645, chloroform) Example 34(2R)-2-{4-[1-(4-Bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0365] (2R)-2-{4-[1-(4-Bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized fromethyl (2R)-2-{4-[1-(4-bromophenyl)-5-propyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 33, as a solid, according to the similar manner to that of Example20. yield: 93.2%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.2 Hz), 1.45-1.56 (2H,m), 2.38 (2H, t, J = 8.0 Hz), 3.24 (2H, d, J = 6.8 Hz),4.79 (1H, t, J = 6.8 Hz), 6.07 (1H, d, J = 3.8 Hz), 6.26(1H, d, J = 3.8 Hz), 6.64 (2H, d, J = 8.8 Hz), 6.91 (2H, d,J = 8.8 Hz), 6.99 (2H, d,J = 8.8 Hz), 7.26-7.28 (5H, m),7.47 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 2957, 1726, 1520, 1489, 1236, 1071, 833, 768.[α] D 22-2.76° (c 1.07, chloroform) Example 35Ethyl (2R)-2-[4-(1-phenyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 2-(4-Methoxyphenyl)-1-phenyl-1H-pyrrole
    [0366] A solution of 3-(5,5-dimethyl-1,3-dioxane-2-yl)-1-(4-methoxyphenyl)-1-propanone(2.00 g, 7.19 mmol), aniline(0.655 ml, 7.19 mmol) and p-toluenesulfonic acidmonohydrate (103 mg, 0.543 mmol) in toluene (100 ml) wasrefluxed for 48 hours under heating and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =20:1) to isolate the object compound as a solid. 1.17 g(yield: 65.4%)1H-NMR (CDCl3) δ; 3.76 (3H, s), 6.34-6.36 (2H, m), 6.75 (2H, d, J = 8.8 Hz), 6.91 (1H, t, J = 2.2 Hz), 7.05 (2H, d, J =8.8 Hz), 7.13-7.32 (5H, m).IR (KBr) cm-1; 1613, 1597, 1498, 1464, 1246, 1177, 1034,833, 764, 714, 698. (2) 4-(1-Phenyl-1H-pyrrol-2-yl)phenol
    [0367] To a solution of 2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole(1.00 g, 4.02 mmol) in methylene chloride (30 ml)was added boron tribromide (1.52 ml, 16.1 mmol) at 0°C.The obtained solution was stirred at 0°C for 0.5 hours andat room temperature for 0.5 hours, poured into ice waterand extracted with ethyl acetate. The extracts werecollected and washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 9:1) to isolate the object compoundas a solid. 880 mg (yield: 93.0%)1H-NMR (DMSO-d6) δ; 4.89 (1H, s), 6.34 (2H, d, J = 2.2 Hz),6.67 (2H, d J = 8.4 Hz), 6.91 (1H, d J = 2.2 Hz), 7.00 (2H,d, J = 8.8 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.25-7.36 (3H, m).IR (KBr) cm-1; 3364, 1597, 1500, 1464, 1258, 1219, 1171,835, 764, 716, 698. (3) Ethyl (2R)-2-[4-(1-Phenyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0368] To a solution of 4-(1-phenyl-1H-pyrrol-2-yl)phenol(750 mg, 3.19 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(930 mg, 4.79 mmol) and triphenylphosphine (1.26 g, 4.79mmol) in toluene (5 ml) was added diethyl azodicarboxylate(40%, 2.08 g, 4.79 mmol). The obtained solution wasstirred at 80°C for 12 hours and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 20: 1) togive the object compound as a solid. 590 mg (yield: 45.0%)1H-NMR (CDCl3) δ; 1.11 (3H, t, J = 7.2 Hz), 3.18-3.22 (2H,m), 4.11 (2H, q, J = 7.2 Hz), 4.69-4.76 (1H, m), 6.29-6.33(2H, m), 6.67 (2H, d, J = 8.8 Hz), 6.87 (1H, t, J = 2.6 Hz),6.98 (2H, d, J = 8.8 Hz), 7.08-7.31 (10H, m).IR (KBr) cm-1; 1755, 1732, 1597, 1549, 1504, 1464, 1454,1285, 1238, 1181, 1084, 1034, 833, 766, 700.[α]D 25 15.7° (c 0.810, chloroform) Example 36(2R)-2-[4-(1-Phenyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0369] To a mixed solution of ethyl (2R)-2-[4-(1-phenyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateobtained in Example35 (400 mg, 0.973 mmol) in THF (4 ml)-methanol (2 ml) wasadded 5 N aqueous sodium hydroxide (0.584 ml, 2.92 mmol) and the mixture was stirred at room temperature for 1 hour.The reaction solution was diluted with ethyl acetate andwater, and neutralized with 1 N hydrochloric acid, and theorganic layer was separated. The organic layer was washedwith water and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure to give theobject compound as an oily substance. 299 mg (yield:80.2%)1H-NMR (CDCl3) δ; 3.25 (2H, d, J = 6.6 Hz), 4.79 (1H, t, J= 6.6 Hz), 6.33 (2H, d, J = 2.2 Hz), 6.68 (2H, d, J = 8.8Hz), 6.90 (1H, t, J = 2.2 Hz), 7.00 (2H, d, J = 8.8 Hz),7.10-7.30 (10H, m).IR (KBr) cm-1; 3063, 1726, 1499, 1236, 1179, 1084, 833, 700.[α] D 25-0.982° (c 0.855, chloroform) Example 37Ethyl (2R)-2-{4-[1-(4-methylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Methoxyphenyl)-1-(4-methylphenyl)-1H-pyrrole
    [0370] 2-(4-Methoxyphenyl)-1-(4-methylphenyl)-1H-pyrrole wassynthesized from p-toluidine as a solid, according to thesimilar manner to that of Example 35(1). 860 mg (yield:60.6%)1H-NMR (CDCl3) δ; 2.35 (3H, s), 3.77 (3H, s), 6.33-6.34 (2H,m), 6.75 (2H, d, J = 8.6 Hz), 6.87-6.90 (1H, m), 7.02-7.14 (6H, m).IR (KBr) cm-1; 1516, 1506, 1462, 1246, 1175, 1032, 824, 712,559.Elementary analysis for C18H17NO   Calculated: C, 82.85; H, 6.51; N, 5.32.   Found: C, 81.98; H, 6.30; N, 5.25. (2) 4-[1-(4-Methylphenyl)-1H-pyrrol-2-yl]phenol
    [0371] 4-[1-(4-Methylphenyl)-1H-pyrrol-2-yl]phenol wassynthesized from 2-(4-methoxyphenyl)-1-(4-methylphenyl)-1H-pyrroleas a solid, according to the similar manner to thatof Example 35(2). 525 mg (yield: 72.8%)1H-NMR (CDCl3) δ; 2.35 (3H, s), 4.64 (1H, s), 6.33 (2H, d J= 1.8 Hz), 6.67 (2H, d J = 8.8 Hz), 6.88 (1H, t, J = 1.8Hz), 6.99-7.13 (6H, m).IR (KBr) cm-1; 3377, 1516, 1507, 1464, 1339, 1258, 1173,835, 825, 715. (3) Ethyl (2R)-2-{4-[1-(4-methylphenyl)-1H-pyrrol-2-yl}phenoxy}-3-phenylpropanoate
    [0372] Ethyl (2R)-2-{4-[1-(4-methylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesized from 4-[1-(4-methylphenyl)-1H-pyrrol-2-yl]phenolas a solid,according to the similar manner to that of Example 35(3).yield: 21.0% 1H-NMR (CDCl3) δ; 1.15 (3H, t, J = 7.4 Hz), 2.34 (3H, s),3.20-3.23 (2H, m), 4.15 (2H, q, J = 7.4 Hz), 4.71-4.77 (1H,m), 6.31 (2H, t, J = 2.2 Hz), 6.68 (2H, d, J = 8.8 Hz),6.86 (1H, t, J = 2.2 Hz), 6.97-7.11 (6H, m), 7.11-7.28 (5H,m).IR (KBr) cm-1; 1755, 1732, 1516, 1505, 1238, 1184, 1086,1032, 826, 714, 700.[α]D 23 16.8° (c 0.545, chloroform) Example 38(2R)-2-{4-[1-(4-Methylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0373] (2R)-2-{4-[1-(4-Methylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized from ethyl (2R)-2-{4-[1-(4-methylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 37, as an oilysubstance, according to the similar manner to that ofExample 36. yield: 97.7%1H-NMR (CDCl3) δ; 2.34 (2H, s), 3.25 (2H, d, J = 5.8 Hz),4.79 (1H, t, J = 5.8 Hz), 6.33 (2H, t, J = 2.6 Hz), 6.78(2H, d, J = 9.2 Hz), 6.87 (1H, t, J = 2.6 Hz), 6.99-7.12(6H, m), 7.22-7.31 (5H, m).IR (KBr) cm-1; 3032, 1726, 1516, 1504, 1235, 1179, 1084,824, 716, 700.[α]D 23 0.742° (c 2.32, chloroform) Example 39Ethyl (2R)-2-{4-[1-(4-chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole
    [0374] 1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole wassynthesized from p-chloroaniline as a solid, according tothe similar manner to that of Example 35(1). yield: 50.9%1H-NMR (CDCl3) δ; 3.78 (3H, s), 6.35 (2H, d, J = 2.4 Hz),6.78 (2H, d, J = 9.0 Hz), 6.88 (1H, t, J = 2.4 Hz), 7.03-7.11(4H, m), 7.28 (2H, d, J = 9.4 Hz).IR (KBr) cm-1; 1495, 1248, 1032, 833, 712.Elementary analysis for C17H14NOCl   Calculated: C, 71.96; H, 4.97; N, 4.94.   Found: C, 71.96; H, 5.07; N, 4.87. (2) 4-[1-(4-Chlorophenyl)-1H-pyrrol-2-yl]phenol
    [0375] 4-[1-(4-Chlorophenyl)-1H-pyrrol-2-yl]phenol wassynthesized from 1-(4-chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrroleas a solid, according to the similar manner to thatof Example 35(2). yield: 69.9%1H-NMR (CDCl3) δ; 4.68 (1H, s), 6.33 (2H, d J = 2.2 Hz),6.70 (2H, d J = 8.8 Hz), 6.87 (1H, t, J = 2.2 Hz), 7.00 (2H,d, J = 8.8 Hz), 7.08 (2H, d, J = 9.2 Hz), 7.28 (2H, d, J =9.2 Hz). IR (KBr) cm-1; 3179, 1495, 1240, 826, 729. (3) Ethyl (2R)-2-{4-[1-(4-chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0376] Ethyl (2R)-2-{4-[1-(4-chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesized from 4-[1-(4-chlorophenyl)-1H-pyrrol-2-yl]phenolas a solid,according to the similar manner to that of Example 35(3).yield: 37.6%1H-NMR (CDCl3) δ; 1.16 (3H, t, J = 7.4 Hz), 3.20-3.24 (2H,m), 4.16 (2H, q, J = 7.4 Hz), 4.71-4.78 (1H, m), 6.33 (2H,t, J = 2.6 Hz), 6.70 (2H, d, J = 9.2 Hz), 6.86 (1H, t, J =2.6 Hz), 6.96-7.09 (4H, m), 7.24-7.29 (7H, m).IR (KBr) cm-1; 1753, 1732, 1495, 1238, 1184, 1092, 833, 700.[α]D 24 18.8° (c 0.675, chloroform) Example 40(2R)-2-{4-[1-(4-Chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0377] (2R)-2-{4-[1-(4-Chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized from ethyl (2R)-2-{4-[1-(4-chlorophenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 39, as an oilysubstance, according to the similar manner to that ofExample 36. yield: 92.6% 1H-NMR (CDCl3) δ; 3.26 (2H, d, J = 5.4 Hz), 4.81 (1H, t, J= 5.4 Hz), 6.33 (2H, t, J = 2.2 Hz), 6.70 (2H, d, J = 8.8Hz), 6.86 (1H, t, J = 2.2 Hz), 6.96-7.09 (4H, m), 7.23-7.31(7H, m).IR (KBr) cm-1; 3029, 1732, 1495, 1236, 1092, 833, 715.[α]D 23 6.97° (c 3.92, chloroform) Example 41Ethyl (2R)-2-{4-[1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Methoxyphenyl)-2-(4-trifluoromethylphenyl)-1H-pyrrole
    [0378] 1-(4-Methoxyphenyl)-2-(4-trifluoromethylphenyl)-1H-pyrrolewas synthesized from 4-trifluoromethyl aniline as asolid, according to the similar manner to that of Example35(1). yield: 61.4%1H-NMR (CDCl3) δ; 3.77 (3H, s), 6.38 (2H, d, J = 2.2 Hz),6.79 (2H, d, J = 8.8 Hz), 6.93 (1H, t, J = 2.2 Hz), 7.05(2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.57 (2H, d,J = 8.4 Hz).IR (KBr) cm-1; 1615, 1508, 1325, 1248, 1171, 1127, 1109,1069, 847, 835, 714.Elementary analysis for C18H14NOF3    Calculated: C, 68.13; H, 4.45; N, 4.41.   Found: C, 68.26; H, 4.50; N, 4.27. (2) 4-[1-(4-Trifluorophenylphenyl)-1H-pyrrol-2-yl]phenol
    [0379] 4-[1-(4-Trifluorophenylphenyl)-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-methoxyphenyl)-2-(4-trifluoromethylphenyl)-1H-pyrroleas a solid, according tothe similar manner to that of Example 35(2). yield: 90.4%1H-NMR (CDCl3) δ; 4.77 (1H, s), 6.37 (2H, d J = 2.6 Hz),6.71 (2H, d J = 8.8 Hz), 6.92-7.02 (3H, m), 7.24 (2H, d, J= 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3300, 1617, 1508, 1325, 1252, 1165, 1128,1107, 1069, 849, 835, 718. (3) Ethyl (2R)-2-{4-[1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0380] Ethyl (2R)-2-{4-[1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[1-(4-trifluorophenylphenyl)-1H-pyrrol-2-yl]phenolas a solid, according to the similar manner to that ofExample 35(3). yield: 36.0%1H-NMR (CDCl3) δ; 1.16 (3H, t, J = 7.0 Hz), 3.21-3.24 (2H,m), 4.15 (2H, q, J = 7.0 Hz), 4.17-4.78 (1H, m), 6.35 (2H,s), 6.71 (2H, d, J = 8.8 Hz), 6.92-7.00 (3H, m), 7.20-7.29(7H, m), 7.55 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 1755, 1732, 1615, 1506, 1325, 1167, 1127,1069, 847, 700. [α]D 23 16.5° (c 0.705, chloroform) Example 42(2R)-2-{4-[1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0381] (2R)-2-{4-[1-(4-Trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized fromethyl (2R)-2-{4-[1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 41, asan oily substance, according to a similar manner to that ofExample 36. yield: 90.9%1H-NMR (CDCl3) δ; 3.25-3.28 (2H, m), 4.79-4.85 (1H, m),6.35 (2H, d, J = 2.6 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.93(1H, t, J = 2.6 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.20-7.32(7H, m), 7.56 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3029, 1728, 1507, 1325, 1238, 1169, 1127,1069, 847, 700.[α] D 21 4.97° (c 4.67, chloroform) Example 43Ethyl (2R)-2-{4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1-(4-Chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0382] 1-(4-Chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole was synthesized from p-chloroaniline as a solid,according to the similar manner to that of Example 5(2).yield: 45.0%1H-NMR (CDCl3) δ; 2.12 (3H, s), 3.75 (3H, s), 6.07 (1H, d,J = 3.2 Hz), 6.25 (1H, d, J = 3.2 Hz), 6.71 (2H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz),7.32 (2H, d, J = 8.8 Hz),.IR (KBr) cm-1; 1526, 1493, 1246, 1179, 1092, 1034, 835, 766. (2) 4-[1-(4-Chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0383] 4-[1-(4-Chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenolwas synthesized from 1-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrroleas a solid, according tothe similar manner to that of Example 5(3). yield: 93.5%1H-NMR (CDCl3) δ; 2.12 (3H, s), 4.78 (1H, s), 6.06 (1H, d J= 3.4 Hz), 6.24 (1H, d J = 3.4 Hz), 6.63 (2H, d J = 8.8 Hz),6.92 (1H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.32(2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3335, 1526, 1493, 1393, 1264, 1092, 835, 768. (3) Ethyl (2R)-2-(4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0384] Ethyl (2R)-2-{4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenol as a solid, according to the similar manner to that ofExample 5(4). yield: 14.8%1H-NMR (CDCl3) δ; 1.15 (3H, t, J = 7.2 Hz), 2.11 (3H, s),3.18-3.22 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 4.68-4.74 (1H,m), 6.05 (1H, d, J = 3.2 Hz), 6.22 (1H, d, J = 3.2 Hz),6.63 (2H, d, J = 9.0 Hz), 6.90 (2H, d, J = 9.0 Hz), 7.03(2H, d, J = 8.4 Hz), 7.22-7.33 (7H, m).IR (KBr) cm-1; 1755, 1732, 1524, 1495, 1238, 1184, 1092,837, 764, 700.[α]D 23 18.1° (c 0.525, chloroform) Example 44(2R)-2-{4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0385] (2R)-2-{4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesized fromethyl (2R)-2-{4-[1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 43, asan oily substance, according to the similar manner to thatof Example 6. yield: 89.7%1H-NMR (CDCl3) δ; 2.11 (3H, s), 3.24 (2H, d, J = 5.4 Hz),4.78 (1H, t, J = 5.4 Hz), 6.05 (1H, d, J = 3.6 Hz), 6.23(1H, d, J = 3.6 Hz), 6.64 (2H, d, J = 8.8 Hz), 6.92 (2H, d,J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.26-7.33 (7H, m).IR (KBr) cm-1; 3130, 1719, 1522, 1493, 1238, 1092, 910, 837, 735, 700. Example 45Ethyl (2R)-2-{4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Methoxyphenyl)-5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrole
    [0386] 2-(4-Methoxyphenyl)-5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrolewas synthesized from 4-trifluoromethylanilineas a solid, according to the similarmanner to that of Example 5(2). yield: 38.6%1H-NMR (CDCl3) δ; 2.15 (3H, s), 3.75 (3H, s), 6.10 (1H, d,J = 3.6 Hz), 6.27 (1H, d, J = 3.6 Hz), 6.71 (2H, d, J =8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz),7.62 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1615, 1526, 1327, 1248, 1169, 1128, 1069,1034, 851, 835, 768. (2) 4-[5-Methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenol
    [0387] 4-[5-Methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenolwas synthesized from 2-(4-methoxyphenyl)-5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrroleas a solid,according to the similar manner to that of Example 5(3).yield: 90.8% 1H-NMR (CDCl3) δ; 2.15 (3H, s) , 4.81 (1H, s) , 6.09 (1H, d J= 3.2 Hz), 6.26 (1H, d J = 3.2 Hz), 6.63 (2H, d J = 8.8 Hz),6.90 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.61(2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3306, 1615, 1526, 1327, 1169, 1128, 1069,851, 839, 770. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0388] Ethyl (2R)-2-{4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoatewas synthesizedfrom 4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenolas a solid, according to the similar manner tothat of Example 5(4). yield: 27.0%1H-NMR (CDCl3) δ; 1.13 (3H, t, J = 7.0 Hz), 2.13 (3H, s),3.18-3.22 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 4.67-4.74 (1H,m), 6.08 (1H, d, J = 3.2 Hz), 6.24 (1H, d, J = 3.2 Hz),6.63 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.20-7.27(7H, m), 7.60 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 1753, 1738, 1524, 1327, 1238, 1169, 1127,1069, 851.[α]D 22 14.6° (c 0.620, chloroform) Example 46(2R)-2-{4-[5-Methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid
    [0389] (2R)-2-(4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was synthesizedfrom ethyl (2R)-2-{4-[5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained inExample 45, as an oily substance, according to the similarmanner to that of Example 6. yield: 94.9%1H-NMR (CDCl3) δ; 2.13 (3H, s), 3.22-3.25 (2H, m), 4.74-4.80(1H, m), 6.08 (1H, d, J = 3.4 Hz), 6.25 (1H, d, J =3.4 Hz), 6.64 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz),7.20-7.30 (7H, m), 7.60 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 3030, 1726, 1524, 1327, 1238, 1169, 1128,1069, 851, 768, 700. Example 47Ethyl (2R)-2-[4-(1-benzyl-5-methyl)-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 1-Benzyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0390] 1-Benzyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole wassynthesized from benzylamine as an oily substance,according to the similar manner to that of Example 5(2).yield: 64.6%1H-NMR (CDCl3) δ; 2.13 (3H, s), 3.78 (3H, s), 5.08 (2H, s),6.02 (1H, d, J = 3.0 Hz), 6.15 (1H, d, J = 3.0 Hz), 6.82(2H, d, J = 8.4 Hz), 6.91 (2H, d, J = 7.0 Hz), 7.16-7.34 (5H, m).IR (KBr) cm-1; 1526, 1287, 1246, 1177, 1032, 837, 760, 731,696. (2) 4-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)phenol
    [0391] 4-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)phenol wassynthesized from 1-benzyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 5(3). yield: 87.5%1H-NMR (CDCl3) δ; 2.13 (3H, s), 4.95 (1H, s), 5.07 (2H, s),6.01 (1H, d J = 3.2 Hz), 6.14 (1H, d J = 3.2 Hz), 6.73 (2H,d J = 8.4 Hz), 6.90 (1H, d, J = 8.0 Hz), 7.13 (2H, d, J =8.4 Hz), 7.17-7.34 (3H, m).IR (KBr) cm-1; 3367, 1526, 1481, 1400, 1262, 1229, 1173,839, 760, 729, 696. (3) Ethyl (2R)-2-[4-(1-benzyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0392] To a solution of 4-(1-benzyl-5-methyl-1H-pyrrol-2-yl)phenol(500 mg, 1.90 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(553 mg, 2.85 mmol) and triphenylphosphine(748 mg, 2.85 mmol) in toluene (5 ml) was added 1,1'-(azodicarbonyl)dipiperidine(719 mg, 2.85 mmol). Theobtained solution was stirred at room temperature for 0.5hours and at 80°C for 3 hours and the solvent was removed under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 20: 1) togive the object compound as an oily substance. 487 mg(yield: 58.3%)1H-NMR (CDCl3) δ; 1.17 (3H, t, J = 7.4 Hz), 2.11 (3H, s),3.20-3.24 (2H, m), 4.15 (2H, q, J = 7.4 Hz), 4.71-4.77 (1H,m), 5.05 (2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.12 (1H, d, J= 3.4 Hz), 6.74 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.0Hz), 7.12 (2H, d, J = 8.8 Hz), 7.19-7.33 (8H, m).IR (KBr) cm-1; 1750, 1730, 1530, 1240, 1180, 1020, 840, 760,740, 700.[α]D 24 15.1° (c 0.690, chloroform) Example 48(2R)-2-[4-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0393] (2R)-2-[4-(1-Benzyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid was synthesized from ethyl (2R)-2-[4-(1-benzyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateobtained in Example 47, as an oilysubstance, according to the similar manner to that ofExample 6. yield: 92.5%1H-NMR (CDCl3) δ; 2.11 (3H, s), 3.25 (2H, d, J = 7.0 Hz),4.79 (1H, t, J = 7.0 Hz), 5.05 (2H, s), 6.00 (1H, d, J =3.2 Hz), 6.12 (1H, d, J = 3.2 Hz), 6.75 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.24-7.33(8H, m),.IR (KBr) cm-1; 3031, 1728, 1524, 1238, 1181, 1082, 837, 758,731, 698.[α]D 26 1.03° (c 1.04, chloroform) Example 49Ethyl (2S)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) Ethyl (R)-2-hydroxy-3-phenylpropanoate
    [0394] The object compound was obtained from (R)-phenylalanineas a solid, according to the similar mannerto that of Example 1(7). yield: 63.5%1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.4 Hz), 2.77 (1H, d, J= 6.2 Hz), 2.97 (1H, dd, J = 14, 6.6 Hz), 3.14 (1H, dd, J =14, 4.4 Hz), 4.22 (2H, q, J = 7.4 Hz), 4.39-4.48 (1H, m),7.20-7.35 (5H, m).IR (KBr) cm-1; 3445, 2982, 1732, 1496, 1454, 1271, 1202,1096, 1030, 747, 700.[α]D 25 +21.2° (c4.00, benzene) (2) Ethyl (2S)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0395] To a solution of 4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenol(400 mg, 1.22 mmol), ethyl (R)-2-hydroxy-3-phenylpropanoate (353 mg, 1.82 mmol) andtriphenylphosphine (477 g, 1.82 mmol) in toluene (4 ml) wasadded 1,1'-(azodicarbonyl)dipiperidine (459 mg, 1.82 mmol).The obtained solution was stirred at 80°C for 3 hours anddiluted with ethyl acetate. The obtained solution waswashed with water, dried over magnesium sulfate anhydride,,solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 30: 1) to give the object compoundas a solid. 286 mg (yield: 46.5%)1H-NMR (CDCl3) δ; 1.15 (3H, t, J = 7.4 Hz), 2.11 (3H, s),3.18-3.22 (2H, m), 4.14 (2H, q, J = 7.4 Hz), 4.68-4.74 (1H,m), 6.04 (1H, d, J = 3.8 Hz), 6.22 (1H, d, J = 3.8 Hz),6.63 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.97(2H, d, J = 8.4 Hz), 7.15-7.28 (5H, m), 7.54 (2H, d, J =8.4 Hz).IR (KBr) cm-1; 1753, 1736, 1524, 1489, 1238, 1184, 1071,833, 700.[α]D 24-14.5° (c 0.770, chloroform) Example 50(2S)-2-{4-[1-(4-Bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0396] To a mixed solution of ethyl (2S)-2-{4-[1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate obtained in Example 49 (256 mg, 0.508mmol) in THF (4 ml)-methanol (2 ml) was added 1 N aqueouspotassium hydroxide (1.52 ml) and stirred at roomtemperature for 1 hour. The reaction solution was dilutedwith ethyl acetate and water and neutralized with 1 Nhydrochloric acid, and the organic layer was separated.The organic layer was washed with water, dried overmagnesium sulfate anhydride,, solvent was removed underreduced pressure to give the object compound as an oilysubstance. 230 mg (yield: 95.4%)1H-NMR (CDCl3) δ; 2.10 (3H, s), 3.23 (2H, d, J = 6.6 Hz),4.76 (1H, t, J = 6.6 Hz), 6.05 (1H, d, J = 3.2 Hz), 6.22(1H, d, J = 3.2 Hz), 6.63 (2H, d, J = 8.8 Hz), 6.90 (2H, d,J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.27 (5H, bs), 7.45(2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1730, 1522, 1489, 1236, 1181, 1071, 833, 735,700.[α]D 24 1.61° (c 1.70, chloroform) Example 51Ethyl (2R)-2-(4-{1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 1-[2-(4-Bromophenyl)ethyl]-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0397] A solution of 1-(4-methoxyphenyl)-1,4-pentanedione (3.20 g, 15.5 mol), 2-(4-bromophenyl)ethylamine (3.74 g,18.7 mmol) and p-toluenesulfonic acid monohydrate (150 mg,0.871 mmol) in toluene (100 ml) was refluxed for 20 hourswith heating. The insoluble matter was filtered out andthe filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 8:1) to give the object compoundas an oily substance.3.93 g (yield: 68.0%)1H-NMR (CDCl3) δ; 2.21 (3H, s), 2.67 (2H, t, J = 7.6 Hz),3.85 (3H, s), 4.04 (2H, t, J = 7.6 Hz), 5.91 (1H, d, J =3.4 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.72 (2H, d, J = 8.2 Hz),6.91 (2H, d, J = 9.0 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.30(2H, d, J = 8.2 Hz).IR (KBr) cm-1; 1613, 1526, 1487, 1285, 1246, 1175, 1036,1011, 837, 760. (2) 4-[1-[2-(4-Bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl]phenol
    [0398] To a solution of 1-[2-(4-bromophenyl)ethyl]-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole(3.46 g, 9.34 mmol) inmethylene chloride (40 ml) was added boron tribromide (9.35g, 37.3 mmol) at 0°C. The mixture was stirred at 0°C for 1hour, and the reaction solution was poured into ice waterand extracted with methylene chloride. The organic layers were collected, washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 3:1) to give the object compound asa solid. 3.33 g (yield: 100%)1H-NMR (CDCl3) δ; 2.21 (3H, s), 2.67 (2H, t, J = 7.6 Hz),4.03 (2H, t, J = 7.6 Hz), 4.95 (1H, s), 5.91 (1H, d, J =3.8 Hz), 6.01 (1H, d J = 3.8 Hz), 6.72 (2H, d J = 8.8 Hz),6.84 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.30(2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3378, 2922, 1524, 1487, 1399, 1308, 1264,1171, 1073, 1011, 912, 837. (3) Ethyl (2R)-2-(4-{1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0399] To a solution of 4-[1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl]phenol(3.00 g, 8.42 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (1.96 g, 10.1 mmol) andtriphenylphosphine (2.65 g, 10.1 mmol) in toluene (30 ml)was added diethyl azodicarboxylate (1.76 g, 10.1 mmol) andrefluxed for 20 hours under heating. The insoluble matterwas filtered out and the filtrate was diluted with ethylacetate. The obtained solution was washed with water anddried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =8: 1) to give the object compound as an oily substance.2.40 g (yield: 54.0%)1H-NMR (CDCl3) δ; 1.21 (3H, t, J = 7.4Hz), 2.20 (3H, s),2.64 (2H, t, J = 6.8 Hz), 3.27 (2H, d, J = 7.0 Hz), 4.00(2H, t, J = 6.8 Hz), 4.14 (2H, q, J = 7.4Hz), 4.82 (1H, t,J = 7.0 Hz), 5.89 (1H, d, J = 3.2 Hz), 5.98 (1H, d, J =3.2 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.83 (2H, d, J = 8.6 Hz),7.13 (2H, d, J = 8.6 Hz), 7.20-7.40 (7H, m). Example 52(2R)-2-(4-{1-[2-(4'-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0400] To a mixed solution of ethyl (2R)-2-(4-{1-[2-(4-bromophenyl)ethan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateobtained in Example 51 (2.40 g, 4.51 mmol)in THF (10 ml)-ethanol (40 ml) was added 5 N aqueous sodiumhydroxide (6.00 ml, 30.0 mmol) and stirred at 50°C for 2hours. The reaction solution was neutralized with 1 Nhydrochloric acid and extracted with ethyl acetate. Theextracts were collected, washed with water and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate) to give the object compound as an oily substance. 2.01 g (yield: 89.0%)1H-NMR (CDCl3) δ; 2.20 (3H, s), 2.63 (2H, t, J = 7.2 Hz),3.32 (2H, d, J = 7.0 Hz), 4.01 (2H, t, J = 7.2 Hz), 4.89(1H, t, J = 7.0 Hz), 5.90 (1H, d, J = 3.6 Hz), 5.97 (1H, d,J = 3.6 Hz), 6.64 (2H, d, J = 8.4 Hz), 6.84 (2H, d, J = 8.4Hz), 7.12 (2H, d, J = 8.8 Hz), 7.20-7.40 (7H, m).IR (KBr) cm-1; 3031, 2932, 1725, 1524, 1487, 1402, 1233,1073, 1013, 910, 735. Example 53Ethyl (2R)-2-{4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Methoxyphenyl)-5-methyl-1-(3-phenoxybenzyl)-1H-pyrrole
    [0401] A solution of 1-(4-methoxyphenyl)-1,4-pentanedione(2.62 g, 12.7 mol), 3-phenoxybenzylamine hydrochloric acidsalt (3.59 g, 15.2 mmol) and p-toluenesulfonic acidmonohydrate (120 mg, 0.697 mmol) in toluene (100 ml) wasrefluxed for 20 hours under heating. The insoluble matterwas filtered out and the filtrate was concentrated underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 8:1) to givethe object compound as crystals. 2.57 g (yield: 55.0%)Melting point: 100-101°C1H-NMR (CDCl3) δ; 2.15 (3H, s), 3.79 (3H, s), 5.04 (2H, s), 5.99 (1H, d, J = 3.4 Hz), 6.11 (1H, d, J = 3.4 Hz), 6.55-6.65(2H, m), 6.75-6.90 (3H, m), 6.90-7.00 (2H, m), 7.05-7.40(6H, m).IR (KBr) cm-1; 1613, 1584, 1526, 1487, 1443, 1287, 1248,1211, 1179, 1034.Elementary analysis for C25H23NO2    Calculated: C, 81.27; H, 6.27; N, 3.79.   Found: C, 81.28; H, 6.46; N, 3.71. (2) 4-[1-(3-Phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0402] 4-[1-(3-Phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenolwas obtained from 2-(4-methoxyphenyl)-5-methyl-1-(3-phenoxybenzyl)-1H-pyrroleas an oily substance, accordingto the similar manner to that of Example 51(2). yield:100%1H-NMR (CDCl3) δ; 2.15 (3H, s), 5.03 (2H, s), 4.95 (1H, s) ,5.99 (1H, d, J = 3.2 Hz), 6.10 (1H, d J = 3.2 Hz), 6.61 (2H,d J = 8.8 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.80-6.90 (1H, m),6.90-7.00 (2H, m), 7.0-7.20 (3H, m), 7.20-7.40 (3H, m).IR (KBr) cm-1; 3412, 1613, 1584, 1526, 1487, 1445, 1250,1211, 839, 760. (3) Ethyl (2R)-2-{4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0403] Ethyl (2R)-2-{4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate was obtained from4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenol as anoily substance, according to the similar manner to that ofExample 51(3). yield: 66.0%1H-NMR (CDCl3) δ; 1.17 (3H, t, J = 7.0 Hz), 2.13 (3H, s),3.21-3.25 (2H, m), 4.17 (2H, q,J = 7.0Hz), 4.72-4.79 (1H,m), 5.00 (2H, s), 5.97 (1H, d,J = 3.4 Hz), 6.08 (1H, d,J =3.4 Hz), 6.57-7.36 (18H, m). Example 54(2R)-2-{4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0404] (2R)-2-{4-[1-(3-Phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid was obtained from ethyl(2R)-2-{4-[1-(3-phenoxybenzyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateobtained in Example 53, asan oily substance, according to the similar manner to thatof Example 52. yield: 80.0%1H-NMR (CDCl3) δ; 2.12 (3H, s), 3.20-3.30 (2H, m), 4.70-4.90(1H, m), 4.97 (2H, s), 5.90-6.00 (1H, m), 6.00-6.10(1H, m), 6.50-6.65 (2H, m), 6.70-6.90 (3H, m), 6.90-7.00(2H, m), 7.00-7.20 (3H, m), 7.20-7.40 (8H, m).IR (KBr) cm-1; 3034, 2932, 1726, 1584, 1524, 1487, 1445,1244, 1084, 909, 758. Example 55Ethyl (2R)-2-[4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 1-Dodecyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0405] A solution of 1-(4-methoxyphenyl)-1,4-pentanedione(3.00 g, 14.5 mol), dodecylamine (3.24 g, 17.5 mmol) and p-toluenesulfonicacid (150 mg, 0.871 mmol) in toluene (100ml) was refluxed for 10 hours under heating using Dean-Stark'sapparatus. The insoluble matter was filtered outand the filtrate was concentrated under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 8:1) to give theobject compound as an oily substance.4.01 g (yield: 78 %)1H-NMR (200 MHz, CDCl3) d; 0.88 (3H, t, J = 6.4 Hz), 1.05-1.40(18H, m), 1.40-1.60 (2H, m), 2.30 (3H, s), 3.80 (2H, t,J = 8.0 Hz), 3.84 (3H, s), 5.92 (1H, d, J = 3.2 Hz), 6.02(1H, d, J = 3.2 Hz), 6.92 (2H, d, J = 8.4 Hz), 7.28 (2H, d,J = 8.4 Hz).IR (KBr) cm-1; 2926, 2853, 1613, 1526, 1466, 1246, 1175,1036, 835, 754. (2) 4-(1-Dodecyl-5-methyl-1H-pyrrol-2-yl)phenol
    [0406] To a solution of 1-dodecyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrol(4.01 g, 11.3 mmol) in methylene chloride (100 ml) was added boron tribromide (11.3 g, 45.0 mmol) at0°C . The mixture was stirred at 0°C for 1 hour, pouredinto ice water and extracted with methylene chloride. Theorganic layers were collected, washed with saturatedaqueous sodium bicarbonate and dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 4: 1) to give theobject compound as an oily substance. 2.97 g (yield: 77 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.40 (18H,m), 1.40-1.65 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 8.0Hz), 4.87 (1H, s), 5.91 (1H, d, J = 3.6 Hz), 6.01 (1H, d, J= 3.6 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 3397, 2924, 2853, 1615, 1526, 1468, 1262,1171, 837, 756. (3) Ethyl (2R)-2-[4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0407] To a solution of 4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenol(2.97 g, 8.70 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.86 g, 9.58 mmol) and triphenylphosphine(2.51 g, 9.57 mmol) in toluene (120 ml) was added diethylazodicarboxylate (1.67 g, 9.57 mmol) and the mixture wasrefluxed for 20 hours under heating. The insoluble matter was filtered out and the filtrate was diluted with ethylacetate. The obtained solution was washed with water anddried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =8: 1) to give the object compound as an oily substance.1.49 g (yield: 33 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.30 (21H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.26 (2H, d, J = 7.2Hz), 3.76 (2H, t, J = 7.6 Hz), 4.19 (2H, q, J = 7.0 Hz),4.81 (1H, t, J = 7.2 Hz), 5.90 (1H, d, J = 3.0 Hz), 5.98(1H, d, J = 3.0 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.15-7.40(7H, m). Example 56(2R)-2-[4-(1-Dodecyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0408] To a solution of ethyl (2R)-2-[4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateobtained inExample 55 (1.49 g, 2.88 mmol) in ethanol (30 ml) was added5 N aqueous sodium hydroxide (3.00 ml, 15.0 mmol) and themixture was stirred at room temperature for 1 hour. Thereaction solution was neutralized with 1 N hydrochloricacid and extracted with ethyl acetate. The extracts werecollected, washed with water and dried over magnesium sulfate anhydride. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate) to give the object compoundas an oily substance. 1.15 g (yield: 82 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.00-1.40 (18H,m), 1.40-1.65 (2H, m), 2.28 (3H, s), 3.31 (2H, d, J = 5.8Hz), 3.76 (2H, t, J = 8.0 Hz), 4.89 (1H, t, J = 5.8 Hz),5.90 (1H, d, J = 3.6 Hz), 5.98 (1H, d, J = 3.6 Hz), 6.86(2H, d, J = 8.8 Hz), 7.20-7.40 (7H, m).IR (KBr) cm-1; 2924, 2853, 1728, 1524, 1238, 1179, 1084,835, 754. Example 57Ethyl (2R)-2-[4-(5-methyl-1-octyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0409] The object compound was obtained according to thesimilar manner to that of Example 55. (1) 2-(4-Methoxyphenyl)-5-methyl-1-octyl-1H-pyrrole
    [0410] Oily substance (yield: 78 %)1H-NMR (CDCl3) δ; 0.86 (3H, t, J = 6.6 Hz), 1.05-1.30 (10H,m), 1.40-1.65 (2H, m), 2.30 (3H, s), 3.80 (2H, t, J = 8.0Hz), 3.84 (3H, s), 5.92 (1H, d, J = 3.6 Hz), 6.02 (1H, d, J= 3.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 2928, 2855, 1613, 1526, 1481, 1285, 1246, 1175, 1034, 835, 754. (2) 4-(5-Methyl-1-octyl-1H-pyrrol-2-yl)phenol
    [0411] Oily substance (yield: 95 %)1H-NMR (CDCl3) δ; 0.86 (3H, t, J = 6.6 Hz), 1.05-1.35 (10H,m), 1.40-1.60 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 7.8Hz), 4.94 (1H, s), 5.92 (1H, d, J = 3.6 Hz), 6.01 (1H, d, J= 3.6 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 3366, 2928, 1615, 1526, 1481, 1468, 1262,1171, 837, 758. (3) Ethyl (2R)-2-[4-(5-methyl-1-octyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0412] Oily substance (yield: 34 %)1H-NMR (CDCl3) δ; 0.86 (3H, t, J = 6.6 Hz), 1.19 (3H, t, J= 7.6 Hz), 1.10-1.40 (10H, m), 1.40-1.60 (2H, m), 2.28 (3H,s), 3.26 (2H, d, J = 6.6 Hz), 3.76 (2H, t, J = 7.6 Hz),4.19 (2H, q, J = 6.6 Hz), 4.80 (1H, t, J = 6.6 Hz), 5.90(1H, d, J = 3.2 Hz), 5.98 (1H, d, J = 3.2 Hz), 6.84 (2H, d,J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.20-7.40 (5H, m). Example 58(2R)-2-[4-(5-Methyl-1-octyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0413] The object compound was obtained from the compoundobtained in Example 57, according to the similar manner tothat of Example 56.Oily substance (yield: 88 %)1H-NMR (CDCl3) δ; 0.85 (3H, t, J = 6.4 Hz), 1.00-1.40 (10H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.30 (2H, d, J = 6.0Hz), 3.76 (2H, t, J = 7.8 Hz), 4.88 (1H, t, J = 6.0 Hz),5.90 (1H, d, J = 3.6 Hz), 5.99 (1H, d, J = 3.6 Hz), 6.86(2H, d, J = 8.8 Hz), 7.20-7.40 (7H, m).IR (KBr) cm-1; 2924, 2855, 1728, 1524, 1236, 1179, 1084,835, 756, 700. Example 59Ethyl (2R)-2-[4-(5-methyl-1-nonyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0414] The object compound was obtained according to thesimilar manner to that of Example 55. (1) 2-(4-Methoxyphenyl)-5-methyl-1-nonyl-1H-pyrrole
    [0415] Oily substance (yield: 74 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.05-1.35 (12H,m), 1.45-1.65 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 8.0Hz), 3.84 (3H, s), 5.92 (1H, d, J = 3.2 Hz), 6.01 (1H, d, J= 3.2 Hz), 6.92 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4Hz).IR (KBr) cm-1; 2928, 2855, 1613, 1526, 1466, 1285, 1246, 1175, 1034, 835, 754. (2) 4-(5-Methyl-1-nonyl-1H-pyrrol-2-yl)phenol
    [0416] Oily substance (yield: 100 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.10-1.40 (12H,m), 1.45-1.65 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 7.8Hz), 4.92 (1H, s), 5.92 (1H, d, J = 3.4 Hz), 6.01 (1H, d, J= 3.4 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 3345, 2926, 2855, 1615, 1526, 1481, 1262,1171, 837, 758. (3) Ethyl (2R)-2-[4-(5-methyl-1-nonyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0417] Oily substance (yield: 33 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.4 Hz), 1.05-1.40 (15H,m), 1.40-1.65 (2H, m), 2.28 (3H, s), 3.26 (2H, d, J = 6.6Hz), 3.76 (2H, t, J = 7.8 Hz), 4.19 (2H, q, J = 7.2 Hz),4.81 (1H, t, J = 6.6 Hz), 5.90 (1H, d, J = 3.6 Hz), 5.98(1H, d, J = 3.6 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.15-7.40(7H, m). Example 60(2R)-2-[4-(5-Methyl-1-nonyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0418] The object compound was obtained from the compoundobtained in Example 59, according to the similar manner tothat of Example 56.Oily substance (yield: 91 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.00-1.40 (12H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.31 (2H, d, J = 6.0Hz), 3.76 (2H, t, J = 7.4 Hz), 4.89 (1H, t, J = 6.0 Hz),5.91 (1H, d, J = 3.4 Hz), 5.99 (1H, d, J = 3.4 Hz), 6.86(2H, d, J = 8.8 Hz), 7.20-7.40 (7H, m).IR (KBr) cm-1; 3031, 2926, 2855, 1728, 1524, 1238, 1179,1086, 835, 756, 700. Example 61Ethyl (2R)-2-[4-(1-decyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0419] The object compound was obtained according to thesimilar manner to that of Example 55. (1) 1-Decyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0420] Oily substance (yield: 79 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.10-1.35 (16H,m), 2.30 (3H, s), 3.80 (2H, t, J = 8.0 Hz), 3.84 (3H, s),5.92 (1H, d, J = 3.4 Hz), 6.01 (1H, d, J = 3.4 Hz), 6.92(2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 2926, 2855, 1613, 1526, 1481, 1466, 1285,1246, 1175, 1034, 835, 756. (2) 4-(1-Decyl-5-methyl-1H-pyrrol-2-yl)phenol
    [0421] Oily substance (yield: 81 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.05-1.40 (16H,m), 2.30 (3H, s), 3.79 (2H, t, J = 8.0 Hz), 4.78 (1H, s),5.92 (1H, d, J = 3.6 Hz), 6.01 (1H, d, J = 3.6 Hz), 6.84(2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3331, 2926, 2855, 1615, 1526, 1481, 1262,1171, 837, 758. (3) Ethyl (2R)-2-[4-(1-decyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0422] Oily substance (yield: 38 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.00-1.40 (17H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.26 (2H, d, J = 6.6Hz), 3.76 (2H, t, J = 8.0 Hz), 4.19 (2H, q, J = 7.0 Hz),4.81 (1H, t, J = 6.6 Hz), 5.90 (1H, d, J = 3.4 Hz), 5.98(1H, d, J = 3.4 Hz), 6.84 (2H, d, J = 8.4 Hz), 7.21 (2H, d,J = 8.4 Hz), 7.20-7.40 (5H, m). Example 62(2R)-2-[4-(1-Decyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0423] The object compound was obtained from the compoundobtained in Example 61, according to the similar manner to that of Example 56.Oily substance (yield: 68 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.4 Hz), 1.05-1.60 (16H,m), 2.28 (3H, s), 3.31 (2H, d, J = 6.2 Hz), 3.76 (2H, t, J= 7.8 Hz), 4.88 (1H, t, J = 6.2 Hz), 5.90 (1H, d, J = 3.2Hz), 5.99 (1H, d, J = 3.2 Hz), 6.86 (2H, d, J = 8.4 Hz),7.20-7.40 (7H, m).IR (KBr) cm-1; 3031, 2926, 2855, 1728, 1524, 1481, 1238,1179, 1084, 835, 756. Example 63Ethyl (2R)-2-[4-(1-undecyl-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0424] The object compound was obtained according to thesimilar manner to that of Example 55. (1) 2-(4-Methoxyphenyl)-5-methyl-1-undecyl-1H-pyrrole
    [0425] Oily substance (yield: 79 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.35 (16H,m), 1.40-1.65 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 7.8Hz), 3.84 (3H, s), 5.92 (1H, d, J = 3.4 Hz), 6.01 (1H, d, J= 3.4 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 2924, 2853, 1615, 1526, 1464, 1285, 1246,1175, 1036, 835, 756. (2) 4-(5-Methyl-1-undecyl-1H-pyrrol-2-yl)phenol
    [0426] Oily substance (yield: 94 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.40 (16H,m), 1.40-1.60 (2H, m), 2.30 (3H, s), 3.79 (2H, t, J = 7.8Hz), 4.89 (1H, s), 5.92 (1H, d, J = 3.2 Hz), 6.09 (1H, d, J= 3.2 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 2922, 2855, 1526, 1466, 1262, 1171, 837, 758. (3) Ethyl (2R)-2-[4-(5-methyl-1-undecyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0427] Oily substance (yield: 37 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.35 (19H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.26 (2H, d, J = 6.6Hz), 3.76 (2H, t, J = 7.8 Hz), 4.19 (2H, q, J = 7.2 Hz),4.81 (1H, t, J = 6.6 Hz), 5.90 (1H, d, J = 3.2 Hz), 5.98(1H, d, J = 3.2 Hz), 6.84 (2H, d, J = 8.8 Hz), 7.21 (2H, d,J = 8.8 Hz), 7.20-7.40 (5H, m). Example 64(2R)-2-[4-(5-Methyl-1-undecyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0428] The object compound was obtained from the compoundobtained in Example 63, according to the similar manner tothat of Example 56. Oily substance (yield: 89 %)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.05-1.40 (16H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.29 (2H, d, J = 5.8Hz), 3.75 (2H, t, J = 8.0 Hz), 4.87 (1H, t, J = 5.8 Hz),5.90 (1H, d, J = 3.2 Hz), 5.97 (1H, d, J = 3.2 Hz), 6.85(2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.25-7.40(5H, m).IR (KBr) cm-1; 2924, 2853, 1728, 1524, 1481, 1238, 1179,1084, 835, 756, 700. Example 65Ethyl (2R)-2-[4-(5-methyl-1-tridecyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0429] The object compound was obtained according to thesimilar manner to that of Example 55. (1) 2-(4-Methoxyphenyl)-5-methyl-1-tridecyl-1H-pyrrole
    [0430] Oily substance (yield: 92 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.10-1.40 (20H,m), 1.40-1.60 (2H, m), 2.30 (3H, s), 3.80 (2H, t, J = 8.0Hz), 3.84 (3H, s), 5.92 (1H, d, J = 3.2 Hz), 6.02 (1H, d, J= 3.2 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.8Hz).IR (KBr) cm-1; 2924, 2853, 1603, 1526, 1466, 1246, 1173,1036, 835, 754. (2) 4-(5-Methyl-1-tridecyl-1H-pyrrol-2-yl) phenol
    [0431] Oily substance (yield: 94 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.40 (20H,m), 1.40-1.65 (2H, m), 2.29 (3H, s), 3.78 (2H, t, J = 7.8Hz), 5.91 (1H, d, J = 4.2 Hz), 6.01 (1H, d, J = 4.2 Hz),6.84 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3391, 2924, 2853, 1613, 1526, 1466, 1260,1171, 837, 756. (3) Ethyl (2R)-2-[4-(5-methyl-1-tridecyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0432] Oily substance (yield: 34 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.10-1.40 (23H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.26 (2H, d, J = 6.6Hz), 3.76 (2H, t, J = 7.8 Hz), 4.19 (2H, q, J = 7.2 Hz),4.81 (1H, t, J = 6.6 Hz), 5.90 (1H, d, J = 3.2 Hz), 5.98(1H, d, J = 3.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.21 (2H, d,J = 8.6 Hz), 7.20-7.40 (5H, m). Example 66(2R)-2-[4-(5-Methyl-1-tridecyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0433] The object compound was obtained from the compoundobtained in Example 65, according to the similar manner tothat of Example 56. Oily substance (yield: 52 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.10-1.40 (20H,m), 1.40-1.60 (2H, m), 2.28 (3H, s), 3.30 (2H, d, J = 5.2Hz), 3.76 (2H, t, J = 8.0 Hz), 4.88 (1H, t, J = 5.2 Hz),5.90 (1H, d, J = 3.0 Hz), 5.98 (1H, d, J = 3.0 Hz), 6.86(2H, d, J = 8.8 Hz), 7.20-7.40 (7H, m).IR (KBr) cm-1; 2926, 2853, 1725, 1597, 1524, 1236, 1179,1084, 909, 837, 754. Example 67Ethyl (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) Ethyl (E)-3-(4-butylphenyl)acrylate
    [0434] To a solution of 4-butylbenzaldehyde (9.91 g, 61.1mmol) and triethyl phosphonoacetate (13.8 g, 61.5 mmol) inN,N-dimethylformamide (120 ml) was added sodium hydride(60% oily, 2.46 g, 61.5 mmol) at 0°C and the mixture wasstirred at 0°C for 1 hour. The reaction solution waspoured into ice water and extracted with ethyl acetate.The extract was washed with water and saturated brine,dried over magnesium sulfate anhydride and concentratedunder reduced pressure to give the object compound as anoily substance. 14.2 g (yield: 100%)1H-NMR (200 MHz, CDCl3) δ; 0.93 (3H, t, J = 7.2 Hz), 1.20-1.70(7H, m), 2.63 (2H, t, J = 8.0 Hz), 4.26 (2H, q, J = 7.2 Hz), 6.40 (1H, d, J = 16.2 Hz), 7.20 (2H, d, J = 8.0Hz), 7.45 (2H, d, J = 8.0 Hz), 7.67 (1H, d, J = 16.2 Hz).IR (KBr) cm-1; 2932, 1713, 1636, 1310, 1267, 1208, 1173,1038, 984, 826. (2) Ethyl 3-(4-butylphenyl)propanoate
    [0435] To a solution of ethyl (E)-3-(4-butylphenyl)acrylate(14.2 g, 61.1 mmol) in tetrahydrofuran (120 ml) was added10% palladium carbon (4.00 g) and the mixture washydrogenated. The reaction solution was filtrated and thefiltrate was concentrated under reduced pressure to givethe object compound as an oily substance. 14.3 g (yield:100%)1H-NMR (200 MHz, CDCl3) δ; 0.92 (3H, t, J = 7.4 Hz), 1.23(3H, t, J = 7.0 Hz), 1.20-1.65 (4H, m), 2.56 (2H, t, J =6.0 Hz), 2.60 (2H, t, J = 8.0 Hz), 2.92 (2H, t, J = 8.0 Hz),4.13 (2H, q, J = 7.0 Hz), 7.10 (4H, s).IR (KBr) cm-1; 2957, 2930, 1738, 1514, 1466, 1372, 1252,1179, 1159, 1040, 820, 735. (3) 3-(4-Butylphenyl)propanol
    [0436] To a solution of ethyl 3-(4-butylphenyl)propanoate(3.48 g, 14.9 mmol) in tetrahydrofuran (30 ml) was addedlithium aluminium hydride (394 mg, 10.4 mmol) at 0°C andthe mixture was stirred for 1 hour. To the reaction mixture was added 1N hydrochloric acid and the mixture wasextracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over magnesium sulfateanhydride and concentrated under reduced pressure to givethe object compound as an oily substance. 2.86 g (yield:100%)1H-NMR (200 MHz, CDCl3) δ; 0.92 (3H, t, J = 7.2 Hz), 1.20-1.65(4H, m), 1.80-2.00 (2H, m), 2.58 (2H, t, J = 7.8 Hz),2.68 (2H, t, J = 7.8 Hz), 3.68 (2H, t, J = 6.6 Hz), 7.10(4H, s).IR (KBr) cm-1; 3299, 2955, 2857, 1738, 1514, 1454, 1377,910, 777. (4) 3-(4-Butylphenyl)propyl methanesulfonate
    [0437] To a solution of 3-(4-butylphenyl)propanol (2.86 g,14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in ethylacetate (30 ml) was added methanesulfonyl chloride (1.70 g,14.9 mmol) and the mixture was stirred at room temperaturefor 2 hours. The reaction solution was washed with waterand saturated brine, dried over magnesium sulfate anhydrideand concentrated under reduced pressure to give the objectcompound as an oily substance. 4.02 g (yield: 100%)1H-NMR (200 MHz, CDCl3) δ; 0.92 (3H, t, J = 7.2 Hz), 1.20-1.70(4H, m), 1.95-2.15 (2H, m), 2.58 (2H, t, J = 7.8 Hz),2.72 (2H, t, J = 7.8 Hz), 2.99 (3H, s), 4.23 (2H, t, J = 6.4 Hz), 7.10 (4H, s).IR (KBr) cm-1; 2957, 2928, 1732, 1514, 1354, 1175, 974, 930,829. (5) N-[3-(4-Butylphenyl)propan-1-yl]phthalimide
    [0438] To a solution of 3-(4-butylphenyl)propylmethanesulfonate (4.02 g, 14.9 mmol) in N,N-dimethylformamide(40 ml) was added potassium phthalimide(2.76 g, 14.9 mmol) and the mixture was stirred at 80°C for3 hours. The reaction solution was poured into ice waterand extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over magnesiumsulfate anhydride and concentrated under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 3:1) to give theobject compound as an oily substance. 4.48 g (yield: 94%)1H-NMR (200 MHz, CDCl3) δ; 0.91 (3H, t, J = 7.2 Hz), 1.20-1.45(2H, m), 1.45-1.60 (2H, m), 1.95-2.10 (2H, m), 2.53(2H, t, J = 7.6 Hz), 2.66 (2H, t, J = 7.6 Hz), 3.74 (2H, t,J = 7.2 Hz), 7.00-7.15 (4H, m), 7.70 (2H, dd, J = 5.8 and2.8 Hz), 7.83 (2H, dd, J = 5.8 and 2.8 Hz).IR (KBr) cm-1; 2955, 2932, 1773, 1715, 1466, 1397, 1370,1022, 720. (6) 3-(4-Butylphenyl)propylamine hydrochloric acid salt
    [0439] To a solution of N-[3-(4-butylphenyl)propan-1-yl]phthalimide(4.48 g, 13.9 mmol) in ethanol (40 ml) wasadded hydrazine monohydrate (1.03 g, 20.6 mmol) andrefluxed for 2 hours under heating. The reaction solutionwas filtrated and the filtrate was concentrated underreduced pressure. To the residue was added 5N aqueoussodium hydroxide and the mixture was extracted with ethylacetate. The extract was washed with saturated brine,dried over magnesium sulfate anhydride and concentratedunder reduced pressure. The residue was dissolved inethanol (50 ml) and concentrated hydrochloric acid (3.0 ml)was added to the mixture, and the mixture was stirred atroom temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to give the objectcompound as a colorless crystal. The compound was thenwashed with diethylether. 1.89 g (yield: 60%)1H-NMR (200 MHz, DMSO-d6) δ; 0.89 (3H, t, J = 7.6 Hz), 1.31(2H, tq, J = 7.6 and 7.6 Hz), 1.53 (2H, tt, J = 7.6 and 7.6Hz), 1.83 (2H, tt, J = 7.6 and 7.6 Hz), 2.50-2.65 (4H, m),2.65-2.85 (2H, m), 7.11 (4H, s), 7.80-8.10 (2H, m).IR (KBr) cm-1; 2934, 2066, 1597, 1472, 1152, 974, 826, 754. (7) 1-[3-(4-Butylphenyl)propan-1-yl]-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole
    [0440] A solution of 3-(4-butylphenyl)propylamine hydrochloric acid salt (1.70 g, 7.46 mmol), 1-(4-methoxyphenyl)-1,4-pentanedione(1.53 g, 7.42 mmol) and p-toluenesulfonicacid monohydrate (70.0 mg, 0.407 mmol) intoluene (20 ml) was refluxed for 20 hours under heating andthe solvent was removed under reduced pressure. Theresidue was silica gel chromatography (hexane:ethyl acetate= 8: 1) to give the object compound as an oily substance.1.28 g (yield: 48 %)1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.2 Hz), 1.20-1.45 (2H,m), 1.45-1.65 (2H, m), 1.75-1.95 (2H, m), 2.24 (3H, s),2.44 (2H, t, J = 7.6 Hz), 2.56 (2H, t, J = 7.6 Hz), 3.83(2H, t, J = 7.6 Hz), 3.84 (3H, s), 5.91 (1H, d, J = 4.0 Hz),6.02 (1H, d, J = 4.0 Hz), 6.88 (2H, d, J = 8.8 Hz), 6.94(2H, d, J = 8.2 Hz), 7.04 (2H, d, J = 8.2 Hz), 7.24 (2H, d,J = 8.8 Hz).IR (KBr) cm-1; 2955, 2930, 1613, 1526, 1464, 1285, 1246,1175, 1034, 835. (8) 4-{1-[3-(4-Butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenol
    [0441] To a solution of 1-[3-(4-butylphenyl)propan-1-yl]-2-(4-methoxyphenyl)-5-methyl-1H-pyrrole(1.28 g, 3.54 mmol)in methylene chloride (20 ml) was added boron tribromide(3.55 g, 14.2 mmol) at 0°C . The mixture was stirred at0°C for 2 hours, and the reaction solution was poured into ice water and extracted with dichloromethane. The extractwas washed with saturated aqueous sodium bicarbonate, driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate =3:1) to give the object compound as an oily substance. 880mg (yield: 72%)1H-NMR (CDCl3) δ; 0.92 (3H, t, J = 7.2 Hz), 1.25-1.45 (2H,m), 1.45-1.65 (2H, m), 1.75-1.95 (2H, m), 2.24 (3H, s),2.44 (2H, t, J = 7.6 Hz), 2.56 (2H, t, J = 7.6 Hz), 3.82(2H, t, J = 7.6 Hz), 4.90 (1H, s), 5.91 (1H, d, J = 3.2 Hz),6.01 (1H, d, J = 3.2 Hz), 6.81 (2H, d, J = 8.8 Hz), 6.94(2H, d, J = 8.0 Hz), 7.05 (2H, d, J = 8.0 Hz), 7.19 (2H, d,J = 8.8 Hz).IR (KBr) cm-1; 3411, 2955, 2930, 1615, 1526, 1400, 1260,1171, 837, 818, 758. (9) Ethyl (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0442] A solution of 4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenol(880 mg, 2.53 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (492 mg, 2.53 mmol),triphenylphosphine (665 mg, 2.54 mmol) and diethylazodicarboxylate (442 mg, 2.54 mmol) in toluene (30 ml) wasrefluxed for 20 hours under heating. The residue was poured into water, extracted with ethyl acetate, washedwith saturated brine and dried over magnesium sulfateanhydride. The solvent was removed under reduced pressureand the residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 8: 1) to give theobject compound as an oily substance. 440 mg (yield: 33%)1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.2 Hz), 1.19 (3H, t, J= 7.0 Hz), 1.25-1.40 (2H, m), 1.50-1.65 (2H, m), 1.70-1.90(2H, m), 2.22 (3H, s), 2.41 (2H, t, J = 7.2 Hz), 2.55 (2H,t, J = 7.2 Hz), 3.26 (2H, d, J = 6.4 Hz), 3.80 (2H, t, J =7.8 Hz), 4.19 (2H, q, J = 7.0 Hz), 4.81 (1H, t, J = 6.4 Hz),5.89 (1H, d, J = 3.2 Hz), 5.98 (1H, d, J = 3.2 Hz), 6.82(2H, d, J = 8.4 Hz), 6.93 (2H, d, J = 8.0 Hz), 7.04 (2H, d,J = 8.0 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.20-7.40 (5H, m). Example 68Sodium (2R)-2-(4-{1-[3-(4-Butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0443] To a solution of ethyl (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(440 mg, 0.840 mmol) in ethanol (10 ml)was added 5 N aqueous potassium hydroxide (0.80 ml, 4.00mmol) and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 1Naqueous hydrochloric acid, extracted with ethyl acetate,washed with saturated aqueous NaCl and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (ethyl acetate) to give the object compoundas an oily substance. 336 mg, (81%)1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 7.2 Hz), 1.20-1.40 (2H,m), 1.45-1.65 (2H, m), 1.70-1.95 (2H, m), 2.21 (3H, s),2.41 (2H, t, J = 7.8 Hz), 2.55 (2H, t, J = 7.6 Hz), 3.30(2H, d, J = 6.2 Hz), 3.80 (2H, t, J = 7.6 Hz), 4.89 (1H, t,J = 6.2 Hz), 5.89 (1H, d, J = 3.2 Hz), 5.98 (1H, d, J = 3.2Hz), 6.83 (2H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.0 Hz),7.04 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.25-7.40(5H, m).IR (KBr) cm-1; 3031, 2928, 1728, 1522, 1481, 1236, 1177,1084, 837, 758, 700. (2) Sodium (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0444] Ethanol (30 ml) and a solution of 1N sodium hydroxidein ethanol (2.74 ml) were added to (2R)-2-(4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (1.51 g, 3.05 mmol) and the mixturewas concentrated. To the residue was added diisopropylether to give the object compound as a solid.1.06 g (yield 67.0%)1H-NMR (DMSO-d6) δ; 0.88 (3H, t, J = 7.0 Hz), 1.18-1.86 (6H,m), 2.14 (3H, s), 2.32-2.51 (4H, m), 2.91-3.16 (2H, m),3.76 (2H, t, J = 7.2 Hz), 4.29-4.33 (1H, m), 5.75 (1H, d, J= 3.8 Hz), 5.79 (1H, d, J = 3.8 Hz), 6.73 (2H, d, J = 8.8Hz), 6.93-7.33 (11H, m).IR (KBr) cm-1; 2930, 1615, 1520, 1399, 1238, 1059, 1030,829, 760,700. Example 69Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) Ethyl (2E)-3-(4-pentylphenyl)propenoate
    [0445] To a solution of 4-pentylbenzaldehyde (25 g, 142 mmol)and ethyl diethylphosphonoacetate (30 ml, 150 mmol) in THFwas added sodium hydride (60%, 6 g, 150 mmol), and themixture was stirred at room temperature for 12 hours andpoured into ice water. The reaction mixture was extractedwith ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate anhydride,and the solvent was removed under reduced pressure to givethe object compound as an oily substance. 39.6 g, (yield100%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (7H, m), 1.58 (2H, m), 2.61 (2H, t, J = 7.8 Hz), 4.27 (2H, q, J = 7.0 Hz), 6.38(1H, d, J = 15.8 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.43 (2H, d,J = 8.0 Hz),7.66 (1H, d, J = 15.8 Hz). (2) Ethyl (2E)-3-(4-pentylphenyl)propanoate
    [0446] To a solution of ethyl (2E)-3-(4-pentylphenyl)propenoate (39.6 g, 142 mmol) in ethanol (300 ml) was added10% palladium carbon (4 g) and the mixture was stirredunder hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 30.7 g (yield 100%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (7H, m), 1.58 (2H, m),2.60 (4H, q, J = 7.8 Hz), 2.90 (2H, t, J = 7.8 Hz), 4.14(2H, q, J = 7.0 Hz),7.10 (4H, s), (3) 3-(4-Pentylphenyl)propanol
    [0447] To a solution of ethyl (2E)-3-(4-pentylphenyl)propanoate(37.3 g, 142 mmol) in THF (300 ml)was added lithium aluminium hydride (5.3 g, 142 mmol) at0°C and the mixture was stirred at room temperature for 30minutes. The reaction mixture was poured into ice and theinsoluble matter was filtered out. The filtrate wasconcentrated to give the object compound as an oilysubstance. 37.6 g (yield 100%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (5H, m), 1.60 (2H, m), 1.88 (2H, m), 2.66 (4H, m), 3.66 (2H, t, J = 6.6Hz),7.10(4H, s). (4) 3-(4-Pentylphenyl)propyl mesylate
    [0448] To a solution of 3-(4-pentylphenyl)propanol (30.8 g,149 mmol) and triethylamine (22 ml, 155 mmol) in THF (300ml) was added mesyl chloride (11.6 ml, 150 mmol) at 0°C,and the mixture was stirred at room temperature for 30minutes. The reaction mixture was poured into ice andextracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfateanhydride, and the organic layer was concentrated to givethe object compound as an oily substance. 42.4 g, (yield100%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (5H, m), 1.60 (2H, m),2.05 (2H, m), 2.57 (2H, t, J = 7.2 Hz), 2.71 (2H, t, J =7.2 Hz), 2.93 (3H, s), 4.21 (2H, t, J = 6.6 Hz),7.10 (4H,s). (5) N-3-(4-Pentylphenyl)propyl phthalimide
    [0449] A solution of 3-(4-pentylphenyl)propyl mesylate (42.4g, 149 mmol) and potassium phthalimide (27.6 g, 149 mmol)in DMF (200 ml) was stirred at 80°C for 3 hours. Thereaction solution was poured into ice water and extractedwith ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride,and the organic layer was concentrated. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 5: 1) to give the object compound as an oilysubstance. 41.1 g, (yield 82%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (5H, m), 1.61 (2H, m),2.05 (2H, m), 2.52 ( 2H, t, J = 7.2 Hz), 2.66 ( 2H, t, J =7.2 Hz), 3.74 (2H, t, J = 7.0. Hz), 7.13 (4H, m), 7.64-7.85(4H, m). (6) 3-(4-Pentylphenyl)propylamine
    [0450] A solution of N-3-(4-pentylphenyl)propylphthalimide(41.1 g, 123 mmol) and hydrazinemonohydrate (9.0 ml, 185mmol) in ethanol (300 ml) was refluxed for 3 hours. Thereaction mixture was dissolved in 5N aqueous sodiumhydroxide and extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried overmagnesium sulfate anhydride, and the organic layer wasconcentrated to give the object compound as an oilysubstance. 13.5 g, (yield 53%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (5H, m),1.60 (2H, m),1.78 (2H, m), 1.99 (2H, s), 2.76-2.52 (5H, m),.7.09 (4H, s). (7) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrole
    [0451] A solution of 3-(4-pentylphenyl)propylamine (1.8 g,8.8 mmol) and 1-(4-benzyloxyphenyl)-1,4-pentanedione (2.43g, 8.7 mmol) and p-toluenesulfonic acid monohydrate (200mg) in toluene (30 ml) was refluxed for 12 hours underheating and the solvent was removed under reduced pressure.The residue was silica gel chromatography (hexane:ethylacetate = 9: 1) to give the object compound as an oilysubstance. 2.99 g, (yield 75%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz), 5.06 (2H, s),5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz),7.56-6.89(13H, m). (8) 4-[5-Methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenol
    [0452] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrole(2.99 g, 6.6 mmol) inethanol (60 ml) was added 10%palladium carbon (300 mg) andthe mixture was stirred under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.28g, (yield 54%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56 (2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz),5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.78-7.00 (4H, m),7.05 (2H, d, J = 8.0 Hz),7.20 (2H, d, J = 8.6 Hz). (9) Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0453] A solution of 4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenol(1.3 g, 3.6 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.05 g, 5.4 mmol), 1,1'-(azodicarbonyl)dipiperidine(1.36 g, 5.4 mmol) andtriphenylphosphine (1.42 g, 5.4 mmol) in toluene (40 ml)was stirred at 80°C for 12 hours. The reaction solutionwas poured into water and extracted with ethyl acetate, andthe extract was washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 15:1) to givethe object compound as an oily substance. 250 mg, (yield13%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (7H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 4.00-3.86 (4H, m), 4.20(2H, q, J = 7.2 Hz), 4.81 (1H, t, J = 7.2 Hz), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.87-6.70 (6H, m),7.19-7.34 (7H, m). Example 70Sodium (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0454] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(230 mg, 0.43 mmol) in THF (5 ml) andmethanol (2.5 ml) was added 1N aqueous potassium hydroxide(1.3 ml, 1.3 mmol) and the mixture was stirred at roomtemperature for 1 hour. The reaction solution wasneutralized with 1N hydrochloric acid, extracted with ethylacetate, washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (ethyl acetate) to give the objectcompound as an oily substance. 145 mg, (yield 66%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.81(1H, t, J = 7.2 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m). (2) Sodium (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0455] To a solution of (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (135 mg, 0.27 mmol) in ethanol (5 ml)was added 1N sodium hydroxide-ethanol (245 ml, 0.25 mmol)and the mixture was concentrated. To the residue was addedhexane to give the object compound as a solid. 25 mg,(18%)1H-NMR (DMSO) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.13 (3H, s), 2.37 (2H, m), 2.56 (2H, m),3.27 (2H, m), 3.76 (2H, m), 4.31 (1H, m), 5.78 (2H,m),6.70-7.34 (13H, m).Elementary analysis for C34H38NO3-2.0H2O   Calculated: C, 71.93; H, 7.46; N, 2.47.   Found: C, 72.12; H, 7.03; N, 2.31. Example 71Ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) Ethyl (2E)-3-(4-heptylphenyl)propenoate
    [0456] The object compound was obtained from 4-heptylbenzaldehydeas an oily substance, according to thesimilar manner to that of Example 69(1). yield: 29%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (11H, m), 1.58 (2H, m),2.61 (2H, t, J = 7.8 Hz), 4.27 (2H, q, J = 7.0 Hz), 6.38 (1H, d, J = 15.8 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.43 (2H, d,J = 8.4 Hz),7.66 (1H, d, J = 16.2 Hz). (2) Ethyl (2E)-3-(4-heptylphenyl)propanoate
    [0457] The object compound was obtained from ethyl (2E)-3-(4-heptylphenyl)propenoateas an oily substance, according tothe similar manner to that of Example 69(2). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (11H, m), 1.58 (2H, m),2.60 (4H, q, J = 7.8 Hz), 2.90 (2H, t, J = 7.8 Hz), 4.14(2H, q, J = 7.0 Hz),7.10 (4H, s). (3) 3-(4-Heptylphenyl)propanol
    [0458] The object compound was obtained from ethyl (2E)-3-(4-heptylphenyl)propanoateas an oily substance, according tothe similar manner to that of Example 69(3). yield: 96%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.60 (2H, m),1.88 (2H, m), 2.66 (4H, m), 3.66 (2H, t, J = 6.6Hz),7.10(4H, s). (4) 3-(4-Heptylphenyl)propyl mesylate
    [0459] The object compound was obtained from 3-(4-heptylphenyl)propanolas an oily substance, according tothe similar manner to that of Example 69(4). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.60 (2H, m),2.05 (2H, m), 2.57 (2H, t, J = 7.2 Hz), 2.71 (2H, t, J = 7.2 Hz), 2.93 (3H, s), 4.21 (2H, t, J = 6.6 Hz),7.10 (4H,s). (5) N-3-(4-Pentylphenyl)propylphthalimide
    [0460] The object compound was obtained from 3-(4-heptylphenyl)propylmesylate as an oily substance,according to the similar manner to that of Example 69(5).yield: 85%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.61 (2H, m),2.05 (2H, m), 2.52 ( 2H, t, J = 7.2 Hz), 2.66 ( 2H, t, J =7.2 Hz), 3.74 (2H, t, J = 7.0. Hz), 7.13 (4H, m), 7.64-7.85(4H, m). (6) 3-(4-Heptylphenyl)propylamine
    [0461] The object compound was obtained from N-3-(4-pentylphenyl)propylphthalimideas an oily substance,according to the similar manner to that of Example 69(6).yield: 94%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.60 (2H, m),1.78 (2H, m), 1.99 (2H, s), 2.52-2.76 (5H, m),7.09 (4H, s). (7) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrole
    [0462] The object compound was obtained from 3-(4-heptylphenyl)propylamineas an oily substance, according to the similar manner to that of Example 69(7). yield: 63%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s) , 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz), 5.06 (2H, s),5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz),6.89-7.56(13H, m). (8) 4-[5-Methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenol
    [0463] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-(4-heptylphenylpropyl)-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 69(8). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.78-7.00 (4H, m),7.05 (2H, d, J = 8.0 Hz),7.20 (2H, d, J = 8.6 Hz). (9) Ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0464] The object compound was obtained from 4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 69(8). yield: 47% 1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (11H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s) , 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 4.00-3.86 (4H, m), 4.20(2H, q, J = 7.2 Hz), 4.81 (1H, t, J = 7.2 Hz), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.70-6.87 (6H,m),7.19-7.34 (7H, m). Example 72Sodium (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0465] The object compound was obtained from ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 70(1). yield: 92%1H-NMR (CDCl3) v; 0.88 (3H, m), 1.26 (8H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.81(1H, t, J = 7.2 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m). (2) Sodium (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0466] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid as a solid, according to the similarmanner to that of Example 70(2). yield: 23%1H-NMR (DMSO) δ; 0.84 (3H, m), 1.24 (6H, m), 1.51 (2H, m),1.72 (2H, s), 2.14 (3H, s), 2.34 (2H, m), 3.05 (4H, m),3.77 (2H, m), 4.34 (2H, m), 5.03 (1H, m), 5.80 (2H, m),6.74-7.30 (13H, m).Elementary analysis for C36H42NO3    Calculated: C, 77.25; H, 7.56; N, 2.50   Found: C, 76.91; H, 7.43; N, 2.34. Example 73Ethyl (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) Ethyl (2E)-3-(4-hexylphenyl)propenoate
    [0467] The object compound was obtained from 4-hexylbenzaldehydeas an oily substance, according to thesimilar manner to that of Example 69(1). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.58 (2H, m),2.61 (2H, t, J = 7.8 Hz), 4.27 (2H, q, J = 7.0 Hz), 6.38(1H, d, J = 15.8 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.43 (2H, d,J = 8.4 Hz), 7.66 (1H, d, J = 15.8 Hz).IR (KBr) cm-1; 2955, 2930, 2857, 1714, 1637, 1466, 1271,1172, 1034, 981, 825. (2) Ethyl (2E)-3-(4-hexylphenyl)propanoate
    [0468] The object compound was obtained from ethyl (2E)-3-(4-hexylphenyl)propenoateas an oily substance, according tothe similar manner to that of Example 69(2). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.58 (2H, m),2.60 (4H, q, J = 7.8 Hz), 2.90 (2H, t, J = 7.8 Hz), 4.14(2H, q, J = 7.0 Hz), 7.10 (4H, s).IR (KBr) cm-1; 2957, 2930, 2856, 1738, 1456, 1273, 1176,1028, 970, 823. (3) 3-(4-Hexylphenyl)propanol
    [0469] The object compound was obtained from ethyl (2E)-3-(4-hexylphenyl)propanoateas an oily substance, according tothe similar manner to that of Example 69(3). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),1.88 (2H, m), 2.66 (4H, m), 3.66 (2H, t, J = 6.6Hz), 7.10(4H, s),IR (KBr) cm-1; 2955, 2872, 1514, 1456, 1338, 1045, 914, 806. (4) 3-(4-Hexylphenyl)propyl mesylate
    [0470] The object compound was obtained from 3-(4-hexylphenyl)propanolas an oily substance, according to thesimilar manner to that of Example 69(4). yield: 84%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),2.05 (2H, m), 2.57 (2H, t, J = 7.2 Hz), 2.71 (2H, t, J = 7.2 Hz), 2.99 (3H, s), 4.21 (2H, t, J = 6.6 Hz), 7.10 (4H,s) .IR (KBr) cm-1; 2955, 2857, 1514, 1466, 1354, 1175, 927, 828. (5) 2-(4-Hexylphenylpropyl)-1H-isoindol-1,3-(2H)-dione
    [0471] The object compound was obtained from 3-(4-hexylphenyl)propylmesylate as an oily substance, accordingto the similar manner to that of Example 69(5). yield: 94%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.61 (2H, m),2.05 (2H, m), 2.52 (2H, t, J = 7.2 Hz), 2.66 ( 2H, t, J =7.2 Hz), 3.74 (2H, t, J = 7.0. Hz), 7.13 (4H, m),7.64-7.85(4H, m).IR (KBr) cm-1; 2928, 2855, 1714, 1468, 1397, 1022, 719. (6) 3-(4-Hexylphenyl)propylamine
    [0472] The object compound was obtained from 2-(4-hexylphenylpropyl)-1H-isoindol-1,3-(2H)-dioneas an oilysubstance, according to the similar manner to that ofExample 69(6). yield: 81%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),1.78 (2H, m), 1.99 (2H, s), 2.52-2.76 (5H, m),7.09 (4H, s).IR (KBr) cm-1; 2928, 2854, 1514, 1466, 1379, 1315, 912, 742. (7) 1-(4-Hexylphenylpropyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0473] The object compound was obtained from 3-(4-hexylphenyl)propylamineas an oily substance, according tothe similar manner to that of Example 69(7). yield: 55%1H-NMR (CDCl3) δ; 0.88 (3H, m) , 1.26 (6H, m) , 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz), 5.06 (2H, s),5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz),6.89-7.56(13H, m).IR (KBr) cm-1; 2928, 2857, 1524, 1466, 1242, 912, 742. (8) 4-[1-(4-Hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0474] The object compound was obtained from 1-(4-hexylphenylpropyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance,according to the similar manner to that of Example 69(8).yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.82 (2H, t, J = 7.8 Hz), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.78-7.00 (4H, m),7.20 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.6 Hz).IR (KBr) cm-1; 2928, 2855, 1526, 1466, 1261, 1170, 837, 762. (9) Ethyl (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0475] The object compound was obtained from 4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 69(9). yield: 57%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.20(2H, q, J = 7.2 Hz), 4.81 (1H, t, J = 7.2 Hz), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.70-6.87 (6H,m),7.19-7.34 (7H, m).IR (KBr) cm-1; 2930, 2855, 1755, 1522, 1481, 1238, 1180,1084, 835, 756. Example 74Sodium (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0476] The object compound was obtained from ethyl (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 70(1).yield: 99%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m), 1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.81(1H, t, J = 7.2 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.70-6.87 (6H, m),7.19-7.34 (7H, m).IR (KBr) cm-1; 2928, 2855, 1726, 1521, 1481, 1236, 1179,1084, 835, 756. (2) Sodium (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0477] The object compound was obtained from (2R)-2-([4-[1-(4-hexylphenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 70(2). yield: 53%1H-NMR (DMSO) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.13 (3H, s), 2.37 (2H, m), 2.56 (2H, m),3.27 (2H, m), 3.76 (2H, m), 4.31 (1H, m), 5.78 (2H, m),6.70-7.34 (13H, m).Elementary analysis for C35H40NO3Na-0.5H2O   Calculated: C, 75.78; H, 7.45; N, 2.53.   Found: C, 75.53; H, 7.22; N, 2.57. Example 75Ethyl (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 3-(4-Pentylphenyl)propanoic acid
    [0478] To a solution of ethyl 3-(4-pentylphenyl)propanoate(26.6 g, 107 mmol) in THF (100 ml) and methanol (50ml) wasadded 5N aqueous sodium hydroxide (50 ml) and the mixturewas stirred at room temperature for 2 hours. The reactionsolution was neutralized with 1N hydrochloric acid,extracted with ethyl acetate, washed with saturated brineand dried over magnesium sulfate anhydride. The solventwas removed under reduced pressure and the residue waspurified by silica gel column chromatography (ethylacetate) to give the object compound as a solid. 13.9 g,(yield 83%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 2.6 Hz), 1.26 (4H, m),1.64 (2H, m), 2.53-2.71 (4H, m), 2.94 (2H, t, J = 7.0Hz),7.11 (4H, s).IR (KBr) cm-1; 2928, 2857, 1699, 1441, 1288, 1224, 1020,943, 820. (2) 1,1-Dimethylethyl-2-(4-pentylphenyl)ethylcarbamate
    [0479] A solution of 3-(4-pentylphenyl)propanoic acid (19.6 g,89 mmol), triethylamine (12.4 ml, 89 mmol) anddiphenylphosphorylazide (19.1 ml, 89 m mmol) in t-BuOH (175ml) was stirred at 80°C for 12 hours. To the reactionmixture was poured saturated aqueous sodium bicarbonate andthe mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate= 20:1) to givethe object compound as an oily substance. 5.8 g, (yield22%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.22-1.58 (15H, m), 2.57(2H, m), 2.75 (2H, t, J = 7.2 Hz), 3.34 (2H, m),7.11 (4H,s) .IR (KBr) cm-1; 2928, 2857, 1709, 1514, 1366, 1171. (3) 3-(4-Pentylphenyl)ethylamine hydrochloride
    [0480] A solution of 1,1-dimethylethyl-2-(4-pentylphenyl)ethylcarbamate(5.75 g, 19.7 mmol) and asolution of 4N hydrogen chloride in ethyl acetate (20 ml,80 mmol) in ethyl acetate (200 ml) was stirred for 3 hours.The reaction mixture was concentrated to give the objectcompound as a solid. 1.4 g, (yield 31%)1H-NMR (DMSO) δ; 0.86 (3H, m), 1.29 (4H, m), 1.55 (2H, m),2.51 (2H, m), 2.94 (4H, m), 7.16 (4H, m),8.23 (1H, s). (4) 1-(4-Pentylphenylethyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0481] A solution of 3-(4-pentylphenyl)ethylaminehydrochloride (1.4 g, 6.20 mmol), 1-(4-benzyloxyphenyl)-1,4-pentanedione(1.7 g, 6.02 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (40 ml) was refluxedfor 12 hours under heating and the solvent was removedunder reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate = 20:1) to givethe object compound as an oily substance. 2.29 g (yield87%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),2.12 (3H, s), 2.55-2.66 (4H, m), 2.92 (2H, t, J = 8.4 Hz),4.97 (2H, s), 6.06 (1H, d, J = 3.4 Hz), 6.25 (1H, d, J =3.4 Hz),6.76-7.41 (13H, m).IR (KBr) cm-1; 3034, 2928, 2856, 1734, 1524, 1454, 1240,912, 742. (5) 4-[1-(4-Pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0482] To a solution of 1-(4-pentylphenylethyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole(2.29 g, 5.54mmol) in ethanol (150 ml) was added 10% palladium carbon(200 mg) and the mixture was stirred under hydrogenatmosphere. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 1.82 g, (yield 100%.)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.62 (2H, m),2.12 (3H, s), 2.65 (4H, m), 2.92 (2H, t, J = 8.4 Hz), 6.04(1H, d, J = 3.4 Hz), 6.24 (1H, d, J = 3.4 Hz), 6.50 (2H, d, J = 6.6 Hz), 6.93-7.30 (6H, m).IR (KBr) cm-1; 2930, 2857, 1713, 1516, 1437, 1264, 1173,835, 760. (6) Ethyl (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0483] A solution of 4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.82 g, 5.2 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.0 g, 5.1 mmol), 1,1'-(azodicarbonyl)dipiperidine(1.29 g, 5.1 mmol) andtriphenylphosphine (1.34 g, 5.1 mmol) in toluene (5 ml) wasstirred at 80°C for 12 hours. The reaction solution waspoured into water and extracted with ethyl acetate. Theextract was washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 20:1) to givethe object compound as an oily substance. 660 mg, (yield23%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.66 (2H, m),2.10 (3H, s), 2.65 (4H, m), 3.20 (2H, m), 4.15 (2H, q, J =7.2 Hz), 4.69 (1H, t, J = 7.2 Hz), 6.02 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.59 (2H, d, J = 6.6 Hz), 6.87-7.28(11H, m).IR (KBr) cm-1; 2930, 2857, 1736, 1522, 1483, 1236, 1182, 1084, 835, 760. Example 76Sodium (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0484] To a mixed solution of ethyl (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(660 mg, 1.26 mmol) in THF (15 ml) andmethanol (7 ml) was added 1N aqueous potassium hydroxide(4.0 ml, 4.0 mmol) and the mixture was stirred for 1 hourat room temperature. The reaction solution was neutralizedwith 1N hydrochloric acid, extracted with ethyl acetate,washed with saturated brine and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (ethyl acetate) to give the object compoundas an oily substance. 615 mg, (yield 98%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.66 (2H, m),2.10 (3H, s), 2.65 (4H, m), 3.20 (2H, m), 4.69 (1H, t, J =7.2 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.22 (1H, d, J = 3.4 Hz),6.59 (2H, d, J = 6.6 Hz),6.87-7.28 (11H, m).IR (KBr) cm-1; 2930, 2859, 1717, 1520, 1392, 1238, 1181,1084, 835, 760. (2) Sodium (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0485] To a solution of (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid(615 mg, 1.24 mmol) in ethanol (10 ml) was added 1N sodiumhydroxide-ethanol (1. 21 ml, 1.21 mmol) and the mixture wasconcentrated. To the residue was added hexane to give theobject compound as a solid. 500 mg, (yield 62%)1H-NMR (DMSO) δ; 0.85 (3H, m), 1.25 (4H, m), 1.51 (2H, m),2.09 (3H, s), 2.49 (2H, m), 2.65 (2H, m), 2.92-3.18 (2H, m),3.93 (2H, m), 4.35 (1H, m), 5.73, (1H, d, J = 3.2 Hz), 5.83(1H, d, J = 3.6 Hz), 6.76-7.34 (13H, m).Elementary analysis for C33H36NO3Na-1.0H2O   Calculated: C, 73.39; H, 7.15; N, 2.61.   Found: C, 73.77; H, 6.89; N, 2.56. Example 77Ethyl (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 3-(4-Hexylphenyl)propanoic acid
    [0486] The object compound was obtained from ethyl 3-(4-pentylphenyl)propanoateas an oily substance, according tothe similar manner to that of Example 75(1). yield: 96%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 2.6 Hz), 1.26 (6H, m), 1.64 (2H, m), 2.53-2.71 (4H, m), 2.94 (2H, t, J = 7.0Hz),7.11 (4H, s).IR (KBr) cm-1; 2928, 2857, 1699, 1441, 1288, 1224, 1020,943, 820. (2) 1,1-Dimethylethyl 2-(4-hexylphenyl)ethylcarbamate
    [0487] The object compound was obtained from 3-(4-hexylphenyl)propanoicacid as an oily substance, accordingto the similar manner to that of Example 75(2). yield: 30%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.58-1.22 (17H, m), 2.57(2H, m), 2.75 (2H, t, J = 7.2 Hz), 3.34 (2H, m),7.11 (4H,s) .IR (KBr) cm-1; 2928, 2857, 1709, 1514, 1366, 1171. (3) 3-(4-Hexylphenyl)ethylamine hydrochloride
    [0488] The object compound was obtained from 1,1-dimethylethyl2-(4-hexylphenyl)ethylcarbamate as a solid,according to the similar manner to that of Example 75(3).yield: 36%1H-NMR (DMSO) δ; 0.86 (3H, m), 1.29 (6H, m), 1.55 (2H, m),2.51 (2H, m), 2.94 (4H, m), 7.16 (4H, m), 8.23 (1H, s). (4) 1-(4-Hexylphenylethyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0489] The object compound was obtained from 3-(4-hexylphenyl)ethylamine hydrochloride as an oily substance,according to the similar manner to that of Example 75(4).yield: 65%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),2.12 (3H, s), 2.55-2.66 (4H, m), 2.92 (2H, t, J = 8.4 Hz),4.97 (2H, s), 6.06 (1H, d, J = 3.4 Hz), 6.25 (1H, d, J =3.4 Hz), 6.76-7.41 (13H, m).IR (KBr) cm-1; 3034, 2928, 2856, 1734, 1524, 1454, 1240,912, 742. (5) 4-[1-(4-Hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0490] The object compound was obtained from 1-(4-hexylphenylethyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 75(5). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.62 (2H, m) ,2.12 (3H, s), 2.65 (4H, m), 2.92 (2H, t, J = 8.4 Hz), 6.04(1H, d, J = 3.4 Hz), 6.24 (1H, d, J = 3.4 Hz), 6.50 (2H, d,J = 6.6 Hz), 6.93-7.30 (6H, m).IR (KBr) cm-1; 2930, 2857, 1713, 1516, 1437, 1264, 1173,835, 760. (6) Ethyl (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0491] The object compound was obtained from 4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 75(5). yield: 47%1H-NMR (CDCl3) δ; 0.88 (3H, m) , 1.26 (11H, m) , 1.66 (2H, m) ,2.10 (3H, s), 2.65 (4H, m), 3.20 (2H, m), 4.15 (2H, q, J =7.2 Hz), 4.69 (1H, t, J = 7.2 Hz), 6.02 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.59 (2H, d, J =6.6 Hz), 6.87-7.28(1,1H, m) .IR (KBr) cm-1; 2930, 2857, 1736, 1522, 1483, 1236, 1182,1084, 835, 760. Example 78Sodium (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0492] The object compound was obtained from ethyl (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 76(1).yield: 99%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m), 1.66 (2H, m),2.10 (3H, s), 2.65 (4H, m), 3.20 (2H, m), 4.69 (1H, t, J =7.2 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.22 (1H, d, J = 3.4 Hz), 6.59 (2H, d, J = 6.6 Hz),6.87-7.28 (11H, m).IR (KBr) cm-1; 2930, 2859, 1717, 1520, 1392, 1238, 1181,1084, 835, 760. (2) Sodium (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0493] The object compound was obtained from (2R)-2-([4-[1-(4-hexylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 76(2). yield: 94%1H-NMR (DMSO) δ; 0.85 (3H, m), 1.25 (6H, m), 1.51 (2H, m),2.09 (3H, s), 2.49 (2H, m), 2.65 (2H, m), 3.18-2.92 (2H, m),3.93 (2H, m), 4.35 (1H, m), 5.73 (1H, d, J = 3.2 Hz), 5.83(1H, d, J = 3.6 Hz), 6.76-7.34 (13H, m).Elementary analysis for C34H38NO3Na   Calculated: C, 76.81; H, 7.20; N, 2.63.   Found: C, 76.73; H, 7.35; N, 2.50. Example 79Ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-Heptylphenylbenzylalcohol
    [0494] To a solution of lithium aluminium hydride (3.5 g, 91 mmol)in THF (50 ml) was added a solution of 4-heptylbenzoic acid(10.0 g, 45.4 mmol) in THF (200 ml) at 0°C and refluxed for 3 hours. The reaction mixture was cooled to 0°C, water (10ml) was added carefully to the reaction mixture, then 1Naqueous sodium hydroxide (30 ml) was added to the mixture.The insoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 8.38 g, (yield 89 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.2 Hz), 1.35 (8H, m),1.56 (2H, m), 2.60 (2H, t, J = 7.4 Hz), 4.64 (2H, s),7.27(2H, d,J = 8.0 Hz), 7.16 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 2930, 1458, 1202, 1016, 742. (2) 4-Heptylphenylmethyl mesylate
    [0495] To a solution of 4-heptylphenylbenzylalcohol (8.38 g,40.6 mmol) and triethylamine (7.7 ml, 55 mmol) in THF (100ml) was added mesylchloride (3.8 ml, 49 mmol) at 0°C andthe mixture was stirred at room temperature for 30 minutes.The reaction mixture was poured into ice and extracted withethyl acetate. The organic layer was washed with saturatedbrine and dried over magnesium sulfate anhydride. Theorganic layer was concentrated to give the object compoundas an oily substance. 12.8 g, (yield 100 %)1H-NMR (CDCl3) δ; 0.88 (3H, m) , 1.35 (8H, m), 1.56 (2H, m) ,2.86 (3H, s), 5.21 (2H, s),7.26 (4H, m).IR (KBr) cm-1; 2932, 1354, 1175, 925, 820. (3) 2-(4-Heptylphenylmethyl)-1H-isoindol-1,3-(2H)-dione
    [0496] A solution of 4-heptylphenylmethyl mesylate (11.5 g,40.6 mmol) and potassium phthalimide (7.6 g, 40.6 mmol) inDMF (60 ml) was stirred at 80°C for 3 hours. The reactionmixture was poured into ice-water and extracted with ethylacetate. The organic layer was washed with saturated brineand dried over magnesium sulfate anhydride, and the organiclayer was concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 5: 1) togive the object compoundas crystals. 12.7 g, (yield 93%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m), 1.61 (2H, m),2.55 ( 2H, t, J = 7.2 Hz), 4.81 (2H, s), 7.11-7.36 (4H, m),7.64-7.85 (4H, m).IR (KBr) cm-1; 2928, 1712, 1392, 1348, 1101, 937, 715. (4) 4-Heptylphenylmethylamine
    [0497] A solution of 2-(4-heptylphenylmethyl)-1H-isoindole-1,3-(2H)-dione(12.7 g, 38 mmol) and hydrazinemonohydrate(3.7 ml, 76 mmol) in ethanol (200 ml) was refluxed for 3hours. The reaction mixture was dissolved in 5N aqueoussodium hydroxide and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and driedover magnesium sulfate anhydride. The organic layer wasconcentrated to give the object compound as an oilysubstance. 7.44 g, (yield 96%) 1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m), 1.56 (2H, m),2.17 (2H, s), 2.58 (2H, d, J = 7.2 Hz), 3.02 (2H, s),7.15(4H, s).IR (KBr) cm-1; 2928, 1485, 1310, 1019, 818, 744. (5) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrole
    [0498] A solution of 4-heptylphenylmethyl amine (2.05 g, 10.0mmol), 1-(4-benzyloxyphenyl)-1,4-pentanedione (2.8 g, 9.9mmol) and p-toluenesulfonic acid monohydrate (100 mg) intoluene (40 ml) was refluxed for 12 hours under heating andthe solvent was removed under reduced pressure. Theresidue was silica gel chromatography (hexane:ethyl acetate= 20: 1) to give the object compound as an oily substance.2.47 g, (yield 55%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.29 (8H, m), 1.57 (2H, m),2.13 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 5.04 (2H, s), 5.06(2H, s), 6.01 (1H, d, J = 3.3 Hz), 6.14 (1H, d, J = 3.3 Hz),6.81-7.56 (13H, m).IR (KBr) cm-1; 2928, 2857, 1528, 1454, 1240, 1020, 835, 750. (6) 4-[5-Methyl-1-(4-heptylphenylmethyl)-1H-pyrrol-2-yl]phenol
    [0499] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrole(2.47 g, 5.47 mmol) in ethanol (200 ml) was added 10% palladium carbon (300 mg)and the mixture was stirred under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.98 g, (yield 100%).1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.28 (8H, m), 1.58 (2H, m),2.13 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.89 (1H, s), 5.04(2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.15 (1H, d, J = 3.4 Hz),6.72-6.84 (4H, m), 7.07-7.26 (4H, m).IR (KBr) cm-1; 2930, 2857, 1526, 1400, 1259, 1020, 839, 760. (7) Ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0500] A solution of 4-[5-methyl-1-(4-heptylphenylmethyl)-1H-pyrrol-2-yl]phenol(1.98 g, 5.5 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.2 g, 6.2 mmol), 1,1'-(azodicarbonyl)dipiperidine(1.56 g, 6.2 mmol) andtriphenylphosphine (1.63 g, 6.2 mmol) in toluene (5 ml) wasstirred at 80°C for 12 hours. The reaction solution waspoured into water and extracted with ethyl acetate. Theextract was washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (hexane: ethyl acetate = 20:1) to givethe object compound as an oily substance. 1.03 g, (yield 32%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 7.30-7.07 (9H, m), 1.26(11H, m), 1.58 (2H, m) , 2.11 (3H, s), 2.56 (2H, t, J = 3.2Hz), 3.22 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 4.75 (1H, t, J= 7.2 Hz), 5.01 (2H, s), 5.99 (1H, d, J = 3.4 Hz), 6.11 (1H,d, J = 3.4 Hz),6.74-6.81 (4H, m).IR (KBr) cm-1; 2930, 2857, 1755, 1523, 1238, 1182, 1030,837, 760. Example 80Sodium (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0501] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1.03 g, 1.76 mmol) in THF (15 ml) andmethanol (7 ml) was added 1N aqueous potassium hydroxide(5.3 ml, 5.3 mmol) and the mixture was stirred for 1 hourat room temperature. The reaction solution was neutralizedwith 1N aqueous hydrochloric acid, extracted with ethylacetate, washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (ethyl acetate) to give the object compound as an oily substance. 969 mg, (yield 99%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (8H, m) , 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.81(1H, t, J = 7.2 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m). (2) Sodium (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0502] To a solution of (2R)-2-{4-[5-methyl-1-(4-heptylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (969 mg, 1.74 mmol) in ethanol (10 ml)was added 1N sodium hydroxide-ethanol solution (1.71 ml,1.71 mmol) and the mixture was concentrated. To theresidue was added hexane to give the object compound as asolid. 740 mg, (yield 80%)1H-NMR (DMSO) δ; 0.84 (3H, m), 1.25 (8H, m), 1.52 (2H, m),2.03 (3H, s), 2.50 (2H, m), 3.14-2.86 (2H, m), 4.25 (1H, dd,J = 9.2 Hz J = 2.8 Hz), 5.03 (2H, s), 5.87 (1H, d, J = 3.0Hz), 5.94 (1H, d, J = 3.0 Hz), 6.70 (4H, t, J = 9.2 Hz),7.00-7.29 (9H, m). Example 81Ethyl (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4'-Ethyl-1,1'-biphenyl-4-methylalcohol
    [0503] The object compound was obtained from 4'-ethyl-4-biphenylcarboxylicacid as a solid, according to thesimilar manner to that of Example 79(1). yield: 100%1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.8 Hz), 1.71 (1H, m),2.68 (2H, q, J = 7.8 Hz), 4.73 (2H, d, J = 5.4 Hz), 7.26-7.62(8H, m) .IR (KBr) cm-1; 3270, 2926, 2851, 1449, 1001, 800. (2) 4'-Ethyl-1,1'-biphenyl-4-methyl mesylate
    [0504] The object compound was obtained from 4'-ethyl-1,1'-biphenyl-4-methylalcoholas a solid, according to thesimilar manner to that of Example 79(2). yield: 100%1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.8 Hz), 1.71 (1H, m),2.68 (2H, q, J = 7.8 Hz), 3.00 (3H, s), 5.28 (2H, s),7.23-7.60(8H, m).IR (KBr) cm-1; 3025, 2924, 2851, 1449, 1354, 1175, 929, 816. (3) 2-(4'-Ethyl-1,1'-biphenyl-4-methyl)-1H-isoindole-1,3(2H)-dione
    [0505] The object compound was obtained from 4'-ethyl-1,1'-biphenyl-4-methylmesylate as a solid, according to thesimilar manner to that of Example 79(3). yield: 61%1H-NMR (CDCl3) δ; 1.26 (3H, t, J = 7.5 Hz), 2.68 (2H, q, J= 7.5 Hz), 4.88 (2H, s), 7.24-7.87 (12H, m). IR (KBr) cm-1; 3029, 2968, 2880, 1717, 1500, 1397, 1346,1091, 943, 715. (4) 3-(4'-Ethyl-1,1'-biphenyl-4-methyl)methylamine
    [0506] The object compound was obtained from 2-(4'-ethyl-1,1'-biphenyl-4-methyl)-1H-isoindol-1,3(2H)-dioneas asolid, according to the similar manner to that of Example79(4). yield: 100%1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.4 Hz), 1.63 (2H, s),2.68 (2H, q, J = 7.8 Hz), 3.91 (2H, s), 7.25-7.58 (8H, m).IR (KBr) cm-1; 2961, 2870, 1498, 1456, 1400, 1327, 931, 806. (5) 2-(4-Benzyloxyphenyl)-1-(4'-ethyl-1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrrole
    [0507] The object compound was obtained from 3-(4'-ethyl-1,1'-biphenyl-4-methyl)methylamineas a solid, according tothe similar manner to that of Example 79(5). yield: 58%1H-NMR (CDCl3) δ; 1.26 (3H, t, J = 6.9 Hz), 2.17 (3H, s),2.68 (2H, q, J = 7.8 Hz), 5.04 (2H, s), 5.13 (2H, s), 6.04(1H, d, J = 3.4 Hz), 6.15 (1H, d, J = 3.4 Hz), 6.93, (4H,m), 7.26-7.52 (13H, m).IR (KBr) cm-1; 3030, 2964, 2864, 1609, 1523, 1242, 1175,1020, 812. (6) 4-[1-(4'-Ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0508] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4'-ethyl-1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrrolas a solid, according to the similarmanner to that of Example 79(6). yield: 100%1H-NMR (CDCl3) δ; 1.27 (3H, t, J = 7.8 Hz), 2.17 (3H, s),2.70 (2H, q, J = 7.8 Hz), 5.11 (2H, s), 6.04 (1H, d, J =3.6 Hz), 6.16 (1H, d, J = 3.3 Hz), 6.75 (2H, d, J = 8.7 Hz),6.96 (2H, d, J = 8.1 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.26(2H, d, J = 6.3 Hz), 7.49 (4H, m).IR (KBr) cm-1; 3023, 2968, 2930, 2870, 1525, 1400, 1260,1171, 840, 760. (7) Ethyl (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0509] The object compound was obtained from 4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenolasa solid, according to the similar manner to that of Example79(7). yield: 37%1H-NMR (CDCl3) δ; 1.33-1.12 (6H, m), 2.15 (3H, s), 2.70 (2H,q, J = 7.6 Hz), 3.23 (2H, m), 4.16 (2H, q, J = 7.2 Hz),4.74 (1H, t, J = 7.2 Hz), 5.09 (2H, s), 6.00 (1H, d, J =3.8 Hz), 6.13 (1H, d, J = 3.6 Hz), 6.74 (2H, d, J = 8.8 Hz),6.92 (2H, d, J = 8.6 Hz), 7.14-7.52 (13H, m).IR (KBr) cm-1; 3030, 2967, 2899, 1751, 1522, 1280, 1240, 1084, 1030, 837, 760. Example 82Sodium (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4'-Ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-prrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0510] The object compound was obtained from ethyl (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 80(1).yield: 96%1H-NMR (CDCl3) δ; 1.27 (3H, t, J = 7.8 Hz), 2.15 (3H, s),2.70 (2H, q, J = 7.6 Hz), 3.23 (2H, m), 4.74 (1H, t, J =7.2 Hz), 5.09 (2H, s), 6.00 (1H, d, J = 3.8 Hz), 6.13 (1H,d, J = 3.6 Hz), 6.74 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J =8.6 Hz), 7.14-7.52 (13H, m).IR (KBr) cm-1; 3028, 2964, 2855, 1725, 1524, 1238, 1084,812, 733. (2) Sodium (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0511] The object compound was obtained from (2R)-2-{4-[1-(4'-ethyl-1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid as a solid, according tothe similar manner to that of Example 80(1). yield: 99%1H-NMR (DMSO) δ; 1.20 (3H, t, J = 7.6 Hz), 2.07 (3H, s),2.65, (2H, q, J = 7.6 Hz), 3.14-2.93 (2H, m), 4.34 (1H, dd,J = 9.2 Hz J = 3.0 Hz), 5.11 (2H, s), 5.91 (1H, d, J = 3.2Hz), 5.98 (1H, d, J = 3.6 Hz), 6.70 (2H, d, J = 8.8 Hz),6.88 (2H, d, J = 8.0 Hz), 7.05-7.28 (9H, m), 7.56 (4H, m).Elementary analysis for C35H32NO3Na-1.5H2O   Calculated: C, 74.45; H, 6.25; N, 2.48.   Found: C, 74.03; H, 5.90; N, 2.09. Example 83Ethyl (2R)-2-[(4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoate(1) 4'-Propyl-1,1'-biphenyl-4-methylalcohol
    [0512] The object compound was obtained from 4'-propyl-4-biphenylcarboxylic acid as a solid, according to thesimilar manner to that of Example 79(1). yield: 100%1H-NMR (CDCl3) δ; 0.98 (3H, t, J = 7.2 Hz), 1.67 (2H, m),2.63 (2H, t, J = 8.1 Hz), 3.49 (1H, s), 4.73 (2H, s), 7.19(2H, d, J = 8.0 Hz), 7.24-7.60 (8H, m).IR (KBr) cm-1; 3248, 2953, 2870, 1491, 1400, 1049, 1013, 800. (2) 4'-Propyl-1,1'-biphenyl-4-methyl mesylate
    [0513] The object compound was obtained from 4'-propyl-1,1'-biphenyl-4-methylalcohol as a solid, according to thesimilar manner to that of Example 79(2). yield: 100%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 7.2 Hz), 1.67 (2H, t, J= 7.6 Hz), 2.63 (2H, t, J = 7.4 Hz), 3.00 (3H, s), 5.28 (2H,s), 7.23-7.60 (8H, m).IR (KBr) cm-1; 2955, 2930, 2870, 1498, 1352, 1173, 1005,914, 804. (3) 2-(4'-Propyl-1,1'-biphenyl-4-methyl)-1H-isoindol-1,3-(2H)-dione
    [0514] The object compound was obtained from 4'-propyl-1,1'-biphenyl-4-methylmesylate as a solid, according to thesimilar manner to that of Example 79(3). yield: 24%1H-NMR (CDCl3) δ; 0.96 (3H, t, J = 7.2 Hz), 1.65 (2H, m),2.61 (2H, t, J = 7.2 Hz), 4.89 (2H, s), 7.22-7.89 (12H, m).IR (KBr) cm-1; 3209, 2959, 2870, 1720, 1397, 1308, 1089,939, 714. (4) 3-(4'-Propyl-1,1'-biphenyl-4-methyl)methylamine
    [0515] The object compound was obtained from 2-(4'-propyl-1,1'-biphenyl-4-methyl)-1H-isoindol-1,3(2H)-dioneas asolid, according to the similar manner to that of Example79(4). yield: 71%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 7.4 Hz), 1.70 (2H, m),2.63 (2H, t, J = 7.4 Hz), 3.91 (2H, s),7.23-7.61 (8H, m). IR (KBr) cm-1; 2959, 2870, 1558, 1498, 1398, 1305, 801. (5) 2-(4-Benzyloxyphenyl)-1-(4'-propyl-1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrrole
    [0516] The object compound was obtained from 3-(4'-propyl-1,1'-biphenyl-4-methyl)methylamineas a solid, according tothe similar manner to that of Example 79(5). yield: 56%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 6.9 Hz), 1.63 (2H, m),2.17 (3H, s), 2.62 (2H, t, J = 6.9 Hz), 5.04 (2H, s), 5.12(2H, s), 6.03 (1H, d, J = 4.2 Hz), 6.17 (1H, d, J = 3.3Hz),6.89-7.52 (17H, m).IR (KBr) cm-1; 3037, 2959, 2870, 1524, 1240, 1024, 835, 758. (6) 4-[5-Methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-5-methyl-1H-pyrrol-2-yl]phenol
    [0517] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4'-propyl-1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrrolas a solid, according to the similarmanner to that of Example 79(6). yield: 100%1H-NMR (CDCl3) δ; 0.96 (3H, t, J = 7.4 Hz), 1.67 (2H, q, J= 7.4Hz), 2.17 (3H, s), 2.62 (2H, t, J = 7.4 Hz), 5.11 (2H,s), 6.03 (1H, d, J = 3.4 Hz), 6.16 (1H, d, J = 3.2 Hz),6.75 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.2 Hz), 7.15-7.53(8H, m).IR (KBr) cm-1; 3024, 2959, 2870, 1526, 1400, 1260, 1170, 839, 796. (7) Ethyl (2R)-2-[(4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoate
    [0518] The object compound was obtained from 4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-5-methyl-1H-pyrrol-2-yl]phenolas a solid, according to the similar manner tothat of Example 79(7). yield: 52%1H-NMR (CDCl3) δ; 0.96 (3H, t, J = 7.4 Hz), 1.16 (3H, t, J= 7.2 Hz), 1.69 (2H, q, J = 7.4Hz), 2.15 (3H, s), 2.65 (2H,t, J = 7.4 Hz), 3.24 (2H, m), 4.17 (2H, q, J = 7.2 Hz),4.74 (1H, t, J = 7.2 Hz), 5.08 (2H, s), 6.01 (1H, d, J =3.4 Hz), 6.14 (1H, d, J = 3.4 Hz), 6.75 (2H, d, J = 8.8 Hz),6.97 (2H, d, J = 8.2 Hz), 7.14-7.52 (13H, m).IR (KBr) cm-1; 3088, 2959, 2870, 1752, 1524, 1240, 1186,1082, 912, 742. Example 84Sodium (2R)-2-[(4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoate(1) (2R)-2-[(4-[5-Methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl]oxy]-3-phenylpropanoic acid
    [0519] The object compound was obtained from ethyl (2R)-2-[(4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl]methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoateas an oily substance, according to the similar manner to that ofExample 80(1). yield: 94%1H-NMR (CDCl3) δ; 0.96 (3H, t, J = 7.4 Hz), 1.69 (2H, q, J= 7.4Hz), 2.15 (3H, s), 2.65 (2H, t, J = 7.4 Hz), 3.24 (2H,m), 4.74 (1H, t, J = 7.2 Hz), 5.08 (2H, s), 6.01 (1H, d, J= 3.4 Hz), 6.14 (1H, d, J = 3.4 Hz), 6.75 (2H, d, J = 8.8Hz), 6.97 (2H, d, J = 8.2 Hz), 7.14-7.52 (13H, m).IR (KBr) cm-1; 3028, 2961, 2870, 1723, 1524, 1238, 912, 743. (2) Sodium (2R)-2-[(4-(5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoate
    [0520] The object compound was obtained from (2R)-2-[(4-[5-methyl-1-[(4'-propyl-1,1'-biphenyl-4-yl)methyl]-1H-pyrrol-2-yl]phenyl)oxy]-3-phenylpropanoicacid as a solid,according to the similar manner to that of Example 80(2).yield: 87%1H-NMR (DMSO) δ; 0.90 (3H, t, J= 7.4 Hz), 1.60 (2H, m),2.07 (3H, s), 2.65 (2H, m), 2.93-3.14 (2H, m), 4.30 (1H, dd,J = 9.2 Hz J = 3.0 Hz), 5.12 (2H, s), 5.91 (1H, d, J = 3.2Hz), 5.98 (1H, d, J = 3.6 Hz), 6.70 (2H, d, J = 8.8 Hz),6.89 (2H, d, J = 8.0 Hz),7.04-7.58 (13H, m).Elementary analysis for C36H34NO3Na-1.5H2O   Calculated: C, 74.72; H, 6.44; N, 2.42.   Found: C, 74.23; H, 6.06; N, 1.92. Example 85Ethyl (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) Ethyl (2E)-3-(4'-propyl-1,1'-phenyl)propenoate
    [0521] The object compound was obtained from 4'-propylphenylbenzaldehydeas an oily substance, according tothe similar manner to that of Example 69(1). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.4 Hz), 1.32 (5H, m),1.58 (2H, m), 1.70 (2H, q, J = 7.6 Hz), 2.63 (2H, t, J =7.8 Hz), 4.29 (2H, q, J = 7.0 Hz), 6.41 (1H, m), 7.26 (2H,m), 7.60 (6H, m), 7.74 (1H, s).IR (KBr) cm-1; 2961, 2932, 2872, 1738, 1633, 1269, 1175,1030, 912, 743. (2) Ethyl (2E)-3-(4'-propyl-1,1'-phenyl)propanoate
    [0522] The object compound was obtained from ethyl (2E)-3-(4'-propyl-1,1'-phenyl)propenoateas an oily substance,according to the similar manner to that of Example 69(2).yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (3H, m), 1.58 (2H, m),2.60 (4H, q, J = 7.8 Hz), 2.99 (2H, t, J = 7.8 Hz), 4.15(4H, m), 7.25 (4H, m), 7.48 (4H, m).IR (KBr) cm-1; 2959, 2930, 2870, 1736, 1499, 1271, 1179,1028, 970, 804. (3) 3-(4'-Propyl-1,1'-phenyl)propanol
    [0523] The object compound was obtained from ethyl (2E)-3-(4'-propyl-1,1'-phenyl)propanoateas an oily substance,according to the similar manner to that of Example 69(3).yield: 100%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 7.4 Hz), 1.66 (2H, m),1.92 (2H, m), 2.62 (2H, t, J = 7.4 Hz), 2.75 (2H, t, J =7.4 Hz), 3.71 (2H, t, J = 6.6Hz), 7.25 (4H, m),7.48 (4H, m).IR (KBr) cm-1; 2928, 2870, 1499, 1454, 1377, 1059, 794. (4) 3-(4'-Propyl-1,1'-phenyl)propyl mesylate
    [0524] The object compound was obtained from 3-(4'-propyl-1,1'-phenyl)propanolas an oily substance, according to thesimilar manner to that of Example 69(4). yield: 69%1H-NMR (CDCl3) δ; 7.50 (4H, s), 0.97 (3H, t, J = 7.4 Hz),1.66 (2H, m), 2.04 (2H, m), 2.62 (2H, t, J = 7.2 Hz), 2.78(2H, t, J = 7.2 Hz), 2.99 (3H, s), 4.25 (2H, t, J = 6.6Hz),7.22 (4H, m) .IR (KBr) cm-1; 2955, 2870, 1498, 1466, 1348, 1172, 956, 804. (5) 2-(4'-Propyl-1,1'-phenylpropyl)-1H-isoindol-1,3-(2H)-dione
    [0525] The object compound was obtained from 3-(4'-propyl-1,1'-phenyl)propylmesylate as an oily substance, according to the similar manner to that of Example 69(5). yield: 86%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 7.4 Hz), 1.65 (2H, m),2.07 (2H, m), 2.65 ( 2H, t, J = 7.2 Hz), 2.76 ( 2H, t, J =7.2 Hz), 3.76 (2H, t, J = 7.0. Hz), 7.20-7.85 (12H, m).IR (KBr) cm-1; 2955, 2870, 1713, 1498, 1397, 1055, 912, 742. (6) 3-(4'-Propyl-1,1'-phenyl)propylamine
    [0526] The object compound was obtained from 2-(4'-propyl-1,1'-phenylpropyl)-1H-isoindol-1,3-(2H)-dioneas an oilysubstance, according to the similar manner to that ofExample 69(6). yield: 94%1H-NMR (CDCl3) δ; 0.93 (3H, t, J = 7.4 Hz), 1.62 (2H, m),1.73 (2H, m), 1.95 (2H, s), 2.81-2.57 (4H, m), 3.49 (1H, s),3.69 (2H, t, J = 7.0. Hz), 7.24 (4H, m),7.50 (4H, m).IR (KBr) cm-1; 2930, 2870, 1572, 1499, 1377, 1338, 1057,802. (7) 1-(4'-propyl-1,1'-phenylpropyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0527] The object compound was obtained from 3-(4'-propyl-1,1'-phenyl)propylamineas an oily substance, according tothe similar manner to that of Example 69(7). yield: 31%1H-NMR (CDCl3) δ; 0.96 (3H, t, J = 7.4 Hz), 1.67 (2H, m) ,2.27 (3H, s), 2.52 (2H, t, J = 3.2 Hz), 2.62 (2H, t, J =3.2 Hz), 5.01 (2H, s), 5.92 (1H, d, J = 3.4 Hz), 6.02 (1H, d, J = 3.4 Hz),6.92-7.51 (17H, m).IR (KBr) cm-1; 2955, 2930, 2868, 1522, 1423, 1252, 1026,833, 734. (8) 4-[1-(4'-Propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0528] The object compound was obtained from 1-(4'-propyl-1,1'-phenylpropyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance,according to the similar manner to that of Example 69(8).yield: 100%1H-NMR (CDCl3) δ; 0.97 (3H, t, J = 7.4 Hz), 1.66 (2H, m),2.36 (3H, s), 2.51 (2H, t, J = 3.2 Hz), 2.63 (2H, t, J =3.2 Hz), 3.76 (2H, t, J = 7.8 Hz), 5.91 (1H, d, J = 3.4 Hz),6.01 (1H, d, J = 3.4 Hz), 6.77 (2H, d, J = 8.0 Hz), 7.28(6H, m),7.51 (4H, m).IR (KBr) cm-1; 2959, 2930, 2868, 1526, 1499, 1400, 1264,1169, 837, 760. (9) Ethyl (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0529] The object compound was obtained from 4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 69(9). yield: 30% 1H-NMR (CDCl3) δ; 0.97 (3H, m), 1.20 (3H, m), 1.60 (2H, m),2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56 (2H, t, J =3.2 Hz), 3.27 (2H, m), 4.20 (2H, q, J = 7.2 Hz), 5.91 (1H,d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.87-6.70 (6H,m),7.19-7.34 (7H, m).IR (KBr) cm-1; 2959, 2870, 1752, 1522, 1466, 1240, 1182,1084, 912, 743. Example 86Sodium (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4'-Propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0530] The object compound was obtained from ethyl (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 70(1).yield: 98%1H-NMR (CDCl3) δ; 0.97 (3H, m), 1.60 (2H, m), 2.22 (3H, s),2.47 (2H, t, J = 3.2 Hz), 2.56 (2H, t, J = 3.2 Hz), 3.27(2H, m), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz),6.70-6.87 (6H, m),7.19-7.34 (7H, m).IR (KBr) cm-1; 3030, 2930, 2868, 1726, 1522, 1496, 1240,1182, 833, 756. (2) Sodium (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0531] The object compound was obtained from (2R)-2-([4-[1-(4'-propyl-1,1'-phenylpropyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, accordingto the similar manner to that of Example 70(2). yield: 60%1H-NMR (DMSO) δ; 0.91 (3H, m), 1.60 (2H, m), 1.78 (2H, m),2.19 (3H, s), 2.58 (2H, m), 3.04 (2H, m), 3.46 (2H, m),3.80 (2H, m), 4.43 (1H, m), 5.78 (2H, m),6.74-7.58 (17H, m). Example 87Ethyl (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 1-(4-Pentylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]-phenyl]-1H-pyrrole
    [0532] A solution of 4-pentylphenylamine (1.0 g, 6.2 mmol),1-(4-benzyloxyphenyl)-1,4-pentanedione (1.7 g, 6.02 mmol)and p-toluenesulfonic acid monohydrate (100 mg) in toluene(40 ml) was refluxed for 12 hours under heating and thesolvent was removed under reduced pressure. The residuewas purified by silica gel chromatography (hexane:ethylacetate = 20:1) to give the object compound as an oilysubstance. 1.76 g, (yield: 69%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.32 (4H, m),1.63 (2H, m), 2.13 (3H, s), 2.62 (2H, t, J = 7.4 Hz), 4.79 (2H, s), 6.05 (1H, d, J = 3.3 Hz), 6.26 (1H, d, J = 3.3 Hz),6.73-7.56 (13H, m).IR (KBr) cm-1; 2928, 2858, 1522, 1392, 1240, 1026, 833, 760. (2) 4-[1-(4-Pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0533] To a solution of 1-(4-pentylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole(1.76 g, 4.3 mmol)in ethanol (150 ml) was added 10% palladium carbon (200 mg)and the mixture was stirred under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.38 g, (yield: 100%).1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.30 (4H, m),1.58 (2H, m), 2.12 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 6.05(1H, d, J = 3.4 Hz), 6.25 (1H, d, J = 3.4 Hz), 6.60 (2H, m),6.90-7.25 (6H, m).IR (KBr) cm-1; 2928, 2857, 1514, 1395, 1261, 1172, 835, 762. (3) Ethyl (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0534] A solution of 4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.37 g, 4.3 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.0 g, 5.1 mmol), 1,1'-(azodicarbonyl)dipiperidine(1.29 g, 5.1 mmol) andtriphenylphosphine (1.34 g, 5.1 mmol) in toluene (5 ml) was stirred at 80°C for 12 hours. The mixrture was poured intowater, extracted with ethyl acetate, washed with saturatedbrine and dried over magnesium sulfate anhydride. Thesolvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 20:1) to give the object compoundas an oily substance. 670 mg, (yield: 31%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.13 (3H, t, J= 7.4 Hz), 1.26 (4H, m), 1.58 (2H, m), 2.10 (3H, s), 2.61(2H, t, J = 7.2 Hz), 3.19 (2H, m), 4.12 (2H, q, J = 7.0 Hz),4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.22(1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1755, 1520, 1236, 1182, 1036,833, 760. Example 88Sodium (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl] oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0535] To a mixed solution of ethyl (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(670 mg, 1.35 mmol) in THF (15 ml) andmethanol (7 ml) was added 1N aqueous potassium hydroxide(4.0 ml, 4.0 mmol) and the mixture was stirred for 1 hour at room temperature. The mixture was neutralized with 1Nhydrochloric acid, extracted with ethyl acetate, washedwith saturated brine and dried over magnesium sulfateanhydride. The solvent was removed under reduced pressureand the residue was purified by silica gel columnchromatography (ethyl acetate) to give the object compoundas an oily substance. 621 mg, (yield: 99%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.26 (4H, m),1.58 (2H, m), 2.10 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 3.19(2H, m), 4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1726, 1518, 1238, 1181, 1084,833, 760. (2) Sodium (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0536] To a solution of (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid(621 mg, 1.33 mmol) in ethanol (10 ml) was added 1N sodiumhydroxide-ethanol solution (1.3 ml, 1.3 mmol) and themixture was concentrated. To the residue was added hexaneto give the object compound as a solid. 460 mg, (yield:71%)1H-NMR (DMSO) δ; 0.85 (3H, m), 1.26 (4H, m), 1.56 (2H, m),2.00 (3H, s), 2.59 (2H, m), 2.86-3.14 (2H, m), 4.25 (1H, dd, J = 9.2 Hz J = 2.8 Hz), 5.94 (1H, d, J = 3.0 Hz), 6.09 (1H,d, J = 3.2 Hz), 6.50 (4H, d, J = 8.8 Hz), 6.80 (4H, d, J =8.8 Hz), 7.00-7.29 (9H, m).Elementary analysis for C31K32NO3Na   Calculated: C, 74.98; H, 6.88; N, 2.73.   Found: C, 75.61; H, 6.77; N, 2.69. Example 89Ethyl (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 1-(4-Hexylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0537] The object compound was obtained from 4-hexylphenylamineas an oily substance, according to thesimilar manner to that of Example 87(1). yield: 71%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.32 (6H, m),1.63 (2H, m), 2.13 (3H, s), 2.62 (2H, t, J = 7.4 Hz), 4.79(2H, s), 6.05 (1H, d, J = 3.3 Hz), 6.26 (1H, d, J = 3.3Hz),6.73-7.56 (13H, m).IR (KBr) cm-1; 2928, 2858, 1522, 1392, 1240, 1026, 833, 760. (2) 4-[1-(4-Hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0538] The object compound was obtained from 1-(4-hexylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance, according to the similar manner to that of Example 87(2). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.30 (6H, m),1.58 (2H, m), 2.12 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 6.05(1H, d, J = 3.4 Hz), 6.25 (1H, d, J = 3.4 Hz), 6.60 (2H, m),6.90-7.25 (6H, m).IR (KBr) cm-1; 2928, 2857, 1514, 1395, 1261, 1172, 835, 762. (3) Ethyl (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0539] The object compound was obtained from 4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 87(3). yield: 46%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.13 (3H, t, J= 7.4 Hz), 1.26 (6H, m), 1.58 (2H, m), 2.10 (3H, s), 2.61(2H, t, J = 7.2 Hz), 3.19 (2H, m), 4.12 (2H, q, J = 7.0 Hz),4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.22(1H, d, J = 3.4 Hz), 6.58 (2H, m), 6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1755, 1520, 1236, 1182, 1036,833, 760. Example 90Sodium (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoic acid
    [0540] The object compound was obtained from ethyl (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 88(1). yield: 99%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.26 (6H, m),1.58 (2H, m), 2.10 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 3.19(2H, m), 4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1726, 1518, 1238, 1181, 1084,833, 760. (2) Sodium (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0541] The object compound was obtained from (2R)-2-([4-[1-(4-hexylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as an oily substance, according to thesimilar manner to that of Example 88(2). yield: 87%1H-NMR (DMSO) δ; 0.85 (3H, m), 1.26 (6H, m), 1.56 (2H, m),2.00 (3H, s), 2.59 (2H, m), 3.14-2.86 (2H, m), 4.25 (1H, dd,J = 9.2 Hz J = 2.8 Hz), 5.94 (1H, d, J = 3.0 Hz), 6.09 (1H,d, J = 3.2 Hz), 6.50 (4H, d, J = 8.8 Hz), 6.80 (4H, d, J =8.8 Hz),7.00-7.29 (9H, m).Elementary analysis for C32H34NO3Na-0.5H2O   Calculated: C, 74.98; H, 6.88; N, 2.73.    Found: C, 75.61; H, 6.77; N, 2.69. Example 91Ethyl (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 1-(4-Heptylphenyl)-2-methyl-5-[4-[(phenylmethyl)-oxy]phenyl]-1H-pyrrole
    [0542] The object compound was obtained from 4-heptylphenylamineas an oily substance, according to thesimilar manner to that of Example 87(1). yield: 66%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.32 (8H, m),1.63 (2H, m), 2.13 (3H, s), 2.62 (2H, t, J = 7.4 Hz), 4.79(2H, s), 6.05 (1H, d, J = 3.3 Hz), 6.26 (1H, d, J = 3.3Hz),6.73-7.56 (13H, m).IR (KBr) cm-1; 2928, 2858, 1522, 1392, 1240, 1026, 833, 760. (2) 4-[1-(4-Heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0543] The object compound was obtained from 1-(4-heptylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 87(2). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.30 (8H, m),1.58 (2H, m), 2.12 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 6.05(1H, d, J = 3.4 Hz), 6.25 (1H, d, J = 3.4 Hz), 6.60 (2H,m),6.90-7.25 (6H, m). IR (KBr) cm-1; 2928, 2857, 1514, 1395, 1261, 1172, 835, 762. (3) Ethyl (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0544] The object compound was obtained from 4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 87(3). yield: 41%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.13 (3H, t, J= 7.4 Hz), 1.26 (8H, m), 1.58 (2H, m), 2.10 (3H, s), 2.61(2H, t, J = 7.2 Hz), 3.19 (2H, m), 4.12 (2H, q, J = 7.0 Hz),4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.22(1H, d, J = 3.4 Hz), 6.58 (2H, m), 6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1755, 1520, 1236, 1182, 1036,833, 760. Example 92Sodium (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoicacid
    [0545] The object compound was obtained from ethyl (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 88(1). yield: 98%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.26 (8H, m),1.58 (2H, m), 2.10 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 3.19(2H, m), 4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1726, 1518, 1238, 1181, 1084,833, 760. (2) Sodium (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0546] The object compound was obtained from (2R)-2-([4-[1-(4-heptylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 88(2). yield: 73%1H-NMR (DMSO) δ; 0.85 (3H, m), 1.26 (8H, m), 1.56 (2H, m),2.00 (3H, s), 2.59 (2H, m), 3.14-2.86 (2H, m), 4.25 (1H, dd,J = 9.2 Hz J = 2.8 Hz), 5.94 (1H, d, J = 3.0 Hz), 6.09 (1H,d, J = 3.2 Hz), 6.50 (4H, d, J = 8.8 Hz), 6.80 (4H, d, J =8.8 Hz), 7.00-7.29 (9H, m). Example 93Ethyl (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 1-(4-Octylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0547] The object compound was obtained from 4-octylphenylamineas an oily substance, according to thesimilar manner to that of Example 87(1). yield: 71%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.32 (10H, m),1.63 (2H, m) , 2.13 (3H, s), 2.62 (2H, t, J = 7.4 Hz), 4.79(2H, s), 6.05 (1H, d, J = 3.3 Hz), 6.26 (1H, d, J = 3.3 Hz),6.73-7.56 (13H, m).IR (KBr) cm-1; 2928, 2858, 1522, 1392, 1240, 1026, 833, 760. (2) 4-[1-(4-Octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0548] The object compound was obtained from 1-(4-octylphenyl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 87(2). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.30 (10H, m),1.58 (2H, m), 2.12 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 6.05(1H, d, J = 3.4 Hz), 6.25 (1H, d, J = 3.4 Hz), 6.60 (2H, m),6.90-7.25 (6H, m).IR (KBr) cm-1; 2928, 2857, 1514, 1395, 1261, 1172, 835, 762. (3) Ethyl (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0549] The object compound was obtained from 4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that of Example 87(3). yield: 40%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.13 (3H, t, J= 7.4 Hz), 1.58 (2H, m), 1.26 (10H, m) , 2.10 (3H, s), 2.61(2H, t, J = 7.2 Hz), 3.19 (2H, m), 4.12 (2H, q, J = 7.0 Hz),4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.22(1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1755, 1520, 1236, 1182, 1036,833, 760. Example 94Sodium (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(4-Octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid
    [0550] The object compound was obtained from ethyl (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 88(1). yield: 99%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.26 (10H, m),1.58 (2H, m), 2.10 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 3.19(2H, m), 4.69 (1H, t, J = 6.5 Hz), 6.03 (1H, d, J = 3.4 Hz),6.22 (1H, d, J = 3.4 Hz), 6.58 (2H, m),6.89-7.29 (11H, m).IR (KBr) cm-1; 2928, 2857, 1726, 1518, 1238, 1181, 1084,833, 760. (2) Sodium (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0551] The object compound was obtained from (2R)-2-([4-[1-(4-octylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 88(2). yield: 87%1H-NMR (DMSO) δ; 0.85 (3H, m), 1.26 (10H, m), 1.56 (2H, m),2.00 (3H, s), 2.59 (2H, m), 2.86-3.14 (2H, m), 4.25 (1H, dd,J = 9.2 Hz J = 2.8 Hz), 5.94 (1H, d, J = 3.2 Hz), 6.09 (1H,d, J = 3.2 Hz), 6.50 (4H, d, J = 8.8 Hz), 6.80 (4H, d, J =8.8 Hz),7.00-7.29 (9H, m). Example 95Ethyl (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoate(1) 2-Methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrole
    [0552] The object compound was obtained fromadamantylmethylamine as an oily substance, according to thesimilar manner to that of Example 87(1). yield: 44%1H-NMR (CDCl3) δ; 1.00-1.82 (15H, m), 2.07 (2H, s), 2.34(3H, s), 5.12 (2H, s), 5.96 (1H, d, J = 3.2 Hz), 6.04 (1H,d, J = 3.2 Hz), 7.00 (2H, d, J = 7.0 Hz), 7.27 (2H, d, J =6.6Hz), 7.34-7.47 (5H, m).IR (KBr) cm-1; 2901, 2845, 1524, 1452, 1244, 1024, 912, 835, 735. (2) 4-[5-Methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrole1H-pyrrol-2-yl]phenol
    [0553] The object compound was obtained from 2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrroleas an oily substance, according to thesimilar manner to that of Example 87(2). yield: 100%1H-NMR (CDCl3) δ; 1.00-1.82 (15H, m), 1.80 (2H, s), 2.31(3H, s), 2.61 (2H, t, J = 7.2 Hz), 5.93 (1H, d, J = 3.4 Hz),6.01 (1H, d, J = 3.4 Hz), 6.80 (2H, d, J = 7.0 Hz),7.16-7.22(2H, m).IR (KBr) cm-1; 2905, 2849, 1524, 1450, 1223, 1101, 912, 742. (3) Ethyl (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoate
    [0554] The object compound was obtained from 4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrole-1H-pyrrol-2-yl]phenolas an oily substance, according to the similarmanner to that of Example 87(3). yield: 49%1H-NMR (CDCl3) δ; 1.82-1.00 (18H, m), 1.78 (2H, s), 2.30(3H, s), 3.27 (2H, m), 4.17 (2H, q, J = 7.0 Hz), 4.82 (1H,t, J = 6.5 Hz), 5.91 (1H, d, J = 3.4 Hz), 5.97 (1H, d, J =3.4 Hz), 6.80 (2H, d, J = 7.0 Hz), 7.17-7.33 (7H, m).IR (KBr) cm-1; 2903, 2849, 1755, 1734, 1524, 1481, 1226, 1180, 1032, 837, 760. Example 96Sodium (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoate(1) (2R)-2-(4-[5-Methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoicacid
    [0555] The object compound was obtained from ethyl (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 88(1).yield: 98%1H-NMR (CDCl3) δ; 1.00-1.82 (15H, m), 1.78 (2H, s), 2.30(3H, s), 3.27 (2H, m), 4.82 (1H, t, J = 6.5 Hz), 5.91 (1H,d, J = 3.4 Hz), 5.97 (1H, d, J = 3.4 Hz), 6.80 (2H, d, J =7.0 Hz), 7.17-7.33 (7H, m).IR (KBr) cm-1; 2905, 2850, 1728, 1522, 1236, 1178, 1080,837, 760. (2) Sodium (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoate
    [0556] The object compound was obtained from (2R)-2-(4-[5-methyl-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-1H-pyrrol-2-yl]phenyl)oxy)-3-phenylpropanoicacid as a solid, accordingto the similar manner to that of Example 88(2). yield: 95% 1H-NMR (DMSO) δ; 1.00-1.78 (15H, m), 2.00 (3H, s), 2.86-3.14(2H, m), 4.31 (1H, dd, J = 9.2 Hz J = 2.8 Hz), 5.78(2H, s), 6.74 (2H, d, J = 7.6 Hz), 7.05-7.31 (7H, m).Elementary analysis for C31H34NO3Na-1.5H2O   Calculated: C, 71.79; H, 7.19; N, 2.70.   Found: C, 71.94; H, 7.16; N, 2.55. Example 97Ethyl (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) 1-(2,3-Dihydro-1H-inden-2-yl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole
    [0557] The object compound was obtained from 2,3-dihydro-1H-inden-2-ylamineas an oily substance, according to thesimilar manner to that of Example 87(1). yield: 44%1H-NMR (CDCl3) δ; 2.34 (3H, s), 3.39 (4H, m), 5.12 (2H, s),5.96 (1H, d, J = 3.4 Hz), 6.04 (1H, d, J = 3.4 Hz), 7.00(2H, d, J = 7.0 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.34-7.47(5H, m).IR (KBr) cm-1; 2901, 2845, 1524, 1452, 1244, 1024, 912, 835,735. (2) 4-[1-(2,3-Dihydro1H-inden-2-yl)-5-methyl-1H-pyrrole-1H-pyrrol-2-yl]phenol
    [0558] The object compound was obtained from 1-(2,3-dihydro-1H-inden-2-yl)-2-methyl-5-[4-[(phenylmethyl)oxy]phenyl]-1H-pyrrole as an oily substance, according to the similarmanner to that of Example 87(2). yield: 100%1H-NMR (CDCl3) δ; 2.24 (3H, s), 3.39 (4H, m), 5.21 (1H, m),5.98 (1H, d, J = 3.6 Hz), 6.02 (1H, d, J = 3.6 Hz), 6.83(2H, d, J = 8.7 Hz),7.19-7.29 (6H, m).IR (KBr) cm-1; 2928, 1526, 1485, 1388, 1261, 1170, 839, 745. (3) Ethyl (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0559] The object compound was obtained from 4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrole-1H-pyrrol-2-yl]phenolas an oily substance, according to the similarmanner to that of Example 87(3). yield: 40%1H-NMR (CDCl3) δ; 1.20 (3H, m), 2.22 (3H, s), 3.23 - 3.39(4H, m), 4.19 (2H, q, J = 7.0 Hz), 4.77 (1H, t, J = 6.5 Hz),5.18 (1H, m), 5.98 (1H, d, J = 3.6 Hz), 6.02 (1H, d, J =3.6 Hz), 6.83 (2H, d, J = 8.7 Hz),7.19-7.34 (11H, m).IR (KBr) cm-1; 2978, 1753, 1522, 1483, 1389, 1238, 1030,837, 747. Example 98Sodium (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate(1) (2R)-2-([4-[1-(2,3-Dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoic acid
    [0560] The object compound was obtained from ethyl (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 88(1).yield: 97%1H-NMR (CDCl3) δ; 2.22 (3H, s), 3.23-3.39 (4H, m), 4.77 (1H,t, J = 6.9 Hz), 5.18 (1H, m), 5.98 (1H, d, J = 3.6 Hz),6.02 (1H, d, J = 3.6 Hz), 6.83 (2H, d, J = 8.4 Hz),7.19-7.34(11H, m).IR (KBr) cm-1; 3030, 2928, 1725, 1521, 1238, 912, 745. (2) Sodium (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate
    [0561] The object compound was obtained from (2R)-2-([4-[1-(2,3-dihydro-1H-inden-2-yl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoicacid as a solid, accordingto the similar manner to that of Example 88(1). yield: 92%1H-NMR (DMSO) δ; 2.00 (3H, s), 3.14-2.86 (2H, m), 4.31 (1H,dd, J = 9.2 Hz J = 2.8 Hz), 5.78 (2H, s), 6.74 (2H, d, J =7.6 Hz), 7.05-7.31 (7H, m). Example 99Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-Pentylphenylbenzylalcohol
    [0562] To a solution of lithium aluminium hydride (3.95 g,104 mmol) in THF (50 ml) was added a solution of 4-pentylbenzoicacid (10.0 g, 52 mmol) in THF (200 ml) andthe mixture was refluxed at 0°C for 3 hours. The reactionmixture was cooled to 0°C, water (10 ml) was addedcarefully to the reaction mixture, then 1N aqueous sodiumhydroxide (30 ml) was added to the mixture. The insolublematter was filtered out and the filtrate was concentratedto give the object compound as an oily substance. 8.76 g,(yield 94 %)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.2 Hz), 1.35 (4H, m),1.56 (2H, m), 2.60 (2H, t, J = 7.4 Hz), 4.64 (2H, s), 7.16(2H, d, J = 8.0 Hz),7.27 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 2930, 1458, 1202, 1016, 742. (2) 4-Pentylphenylmethyl mesylate
    [0563] To a solution of 4-pentylphenylbenzylalcohol (8.76 g,49.0 mmol) and triethylamine (7.7 ml, 55 mmol) in THF (100ml) was added mesyl chloride (3.95 ml, 51 mmol) at 0°C andthe mixture was stirred at room temperature for 30 minutes.The reaction mixture was poured into ice, extracted withethyl acetate, the organic layer was washed with saturatedbrine and dried over magnesium sulfate anhydride. Theorganic layer was concentrated to give the object compound as an oily substance. 13.8 g, (yield 100 %)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.35 (4H, m) , 1.56 (2H, m) ,2.86 (3H, s), 5.21 (2H, s),7.26 (4H, m).IR (KBr) cm-1; 2932, 1354, 1175, 925, 820. (3) 2-(4-Pentylphenylmethyl)-1H-isoindol-1,3-(2H)-dione
    [0564] A solution of 4-pentylphenylmethyl mesylate (6.97 g,27.2 mmol) and potassium phthalimide (5.03 g, 27.2 mmol) inDMF (40 ml) was stirred at 80°C for 3 hours. The reactionmixture was poured into ice water and extracted with ethylacetate. The organic layer was washed with saturated brineand dried over magnesium sulfate anhydride, and the organiclayer was concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 5: 1) togive the object compound as crystals. 7.03 g, (yield 84%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.61 (2H, m),2.55 (2H, t, J = 7.2 Hz), 4.81 (2H, s), 7.11-7.36 (4H, m),7.64-7.85 (4H, m).IR (KBr) cm-1; 2928, 1712, 1392, 1348, 1101, 937, 715. (4) 4-Pentylphenylmethyl amine
    [0565] A solution of 2-(4-pentylphenylmethyl)-1H-isoindol-1,3-(2H)-dione(7.03 g, 23 mmol) and hydrazinemonohydrate(1.7 ml, 35 mmol) in ethanol (100 ml) was refluxed for 3hours. The reaction mixture was dissolved into 5N aqueous sodium hydroxide and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and driedover magnesium sulfate anhydride. The organic layer wasconcentrated to give the object compound as an oilysubstance. 4.02 g, (yield 99%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.56 (2H, m),2.17 (2H, s), 2.58 (2H, d, J = 7.2 Hz), 3.02 (2H, s),7.15(4H, s).IR (KBr) cm-1; 2928, 1485, 1310, 1019, 818, 744. (5) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrole
    [0566] A solution of 4-pentylphenylmethylamine (2.0 g, 11.3mmol), 1-(4-benzyloxyphenyl)-1,4-pentanedione (3.2 g, 11.2mmol) and p-toluenesulfonic acid monohydrate (100 mg) intoluene (30 ml) was refluxed for 12 hours under heating andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel chromatography(hexane:ethyl acetate = 20:1) to give the object compoundas an oily substance. 3.09 g, (yield 65%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.29 (4H, m), 1.57 (2H, m),2.13 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 5.04 (2H, s), 5.06(2H, s), 6.01 (1H, d, J = 3.3 Hz), 6.14 (1H, d, J = 3.3Hz),6.81-7.56 (13H, m).IR (KBr) cm-1; 2928, 2857, 1528, 1454, 1240, 1020, 835, 750. (6) 4-[5-Methyl-1-(4-pentylphenylmethyl)-1H-pyrrol-2-yl]phenol
    [0567] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrole(3.09 g, 7.3 mmol) inethanol (200 ml) was added 10% palladium carbon (400 mg)and the mixture was stirred under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 2.45 g, (yield 100%).1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.28 (4H, m), 1.58 (2H, m),2.13 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.89 (1H, s), 5.04(2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.15 (1H, d, J = 3.4 Hz),6.72-6.84 (4H, m), 7.07-7.26 (4H, m).IR (KBr) cm-1; 2930, 2857, 1526, 1400, 1259, 1020, 839, 760. (7) Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0568] A solution of 4-[5-methyl-1-(4-pentylphenylmethyl)-1H-pyrrol-2-yl]phenol(1.5 g, 4.5 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.3 g, 6.75 mmol), 1,1'-(azodicarbonyl)dipiperidine(1.7 g, 6.75 mmol) andtriphenylphosphine (1.8 g, 6.75 mmol) in toluene (7 ml) wasstirred at 80°C for 12 hours. The reaction solution waspoured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 15:1) to givethe object compound as an oily substance. 1.12 g, (yield49%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (7H, m), 1.58 (2H, m),2.11 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.22 (2H, m), 4.15(2H, q, J = 7.2 Hz), 4.75 (1H, t, J = 7.2 Hz), 5.01 (2H, s),5.99 (1H, d, J = 3.4 Hz), 6.11 (1H, d, J = 3.4 Hz), 6.74-6.81(4H, m),7.07-7.30 (9H, m).IR (KBr) cm-1; 2930, 2857, 1755, 1523, 1238, 1182, 1030,837, 760. Example 100Sodium (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0569] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1.12 g, 2.20 mmol) in THF (20 ml) andmethanol (10 ml) was added 1N aqueous potassium hydroxide(6.6 ml, 6.6 mmol) and the mixture was stirred for 1 hourat room temperature. The reaction solution was neutralized with 1N aqueous hydrochloric acid, extracted with ethylacetate, washed with saturated brine and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure and the residue was purified by silica gelcolumn chromatography (ethyl acetate) to give the objectcompound as an oily substance. 1.00 g, (yield 94%)1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (2H, s), 2.22 (3H, s), 2.47 (2H, t, J = 3.2 Hz), 2.56(2H, t, J = 3.2 Hz), 3.27 (2H, m), 3.86-4.00 (4H, m), 4.81(1H, t, J = 7.2 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m). (2) Sodium (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0570] To a solution of (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (1.00 g, 2.08 mmol) in ethanol (20 ml)was added 1N sodium hydroxide-ethanol solution (2.04 ml,2.04 mmol) and the mixture was concentrated. To theresidue was added hexane to give the object compound as asolid. 730 mg, (yield 70%)1H-NMR (DMSO) δ; 0.84 (3H, m), 1.25 (4H, m), 1.52 (2H, m),2.03 (3H, s), 2.50 (2H, m), 3.14-2.86 (2H, m), 4.25 (1H, dd,J = 9.2 Hz J = 2.8 Hz), 5.03 (2H, s), 5.87 (1H, d, J = 3.0Hz), 5.94 (1H, d, J = 3.2 Hz), 6.70 (4H, t, J = 9.2 Hz), 7.00-7.29 (9H, m).Elementary analysis for C32H34NO3Na-0.5H2O   Calculated: C, 74.98; H, 6.88; N, 2.73.   Found: C, 75.27; H, 6.54; N, 2.56. Example 101Ethyl (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-Hexylphenylmethylalcohol
    [0571] The object compound was obtained from 4-hexylbenzoicacid as an oily substance, according to the similar mannerto that of Example 99(1). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.2 Hz), 1.35 (6H, m),1.60 (2H, m), 2.60 (2H, t, J = 7.4 Hz), 4.64 (2H, s), 7.16(2H, d, J = 8.0 Hz), 7.27 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 2928, 1458, 1201, 1012, 810. (2) 3-(4-Hexylphenyl)propyl mesylate
    [0572] The object compound was obtained from 4-hexylphenylmethylalcohol as an oily substance, accordingto the similar manner to that of Example 99(2). yield:100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.60 (2H, m),2.93 (3H, s), 5.21 (2H, s), 7.20-7.35 (4H, m).IR (KBr) cm-1; 2928, 2857, 1466, 1354, 1174, 928, 824. (3) 2-(4-Hexylphenylmethyl)-1H-isoindol-1,3-(2H)-dione
    [0573] The object compound was obtained from 3-(4-hexylphenyl)propylmesylate as an oily substance, accordingto the similar manner to that of Example 99(3). yield: 98%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.56 (2H, m),2.55 ( 2H, t, J = 7.2 Hz), 4.00 (2H, s), 7.10-7.34 (4H, m),7.66-7.85 (4H, m).IR (KBr) cm-1; 2928, 2855, 1717, 1458, 1392, 1346, 1082,937, 715. (4) 3-(4-Hexylphenyl)methylamine
    [0574] The object compound was obtained from 2-(4-hexylphenylmethyl)-1H-isoindol-1,3-(2H)-dioneas an oilysubstance, according to the similar manner to that ofExample 99(4). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.28 (6H, m), 1.55 (2H, m),1.99 (2H, s), 2.58 (2H, t, J = 7.2 Hz), 3.81 (2H, s),7.12(4H, m).IR (KBr) cm-1; 2926, 2854, 1483, 1371, 1309, 1019, 818. (5) 2-(4-Benzyloxyphenyl)-1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrole
    [0575] The object compound was obtained from 3-(4-hexylphenyl)methylamineas an oily substance, according to the similar manner to that of Example 99(5). yield: 66%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.58 (2H, m) ,2.13 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 5.04 (2H, s), 5.05(2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.14 (1H, d, J = 3.4 Hz),6.80-7.44 (13H, m).IR (KBr) cm-1; 2928, 2854, 1523, 1242, 912, 743. (6) 4-[1-(4-Hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0576] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4-hexylphenylmethyl)-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 99(6). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.58 (2H, m),2.12 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.75 (1H, s), 5.04(2H, s), 6.01 (1H, d, J = 3.4 Hz), 6.13 (1H, d, J = 3.4 Hz),6.70-6.83 (4H, m), 7.07-7.26 (4H, m).IR (KBr) cm-1; 2928, 2857, 1525, 1261, 840, 760. (7) Ethyl (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0577] The object compound was obtained from 4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 99(7). yield: 41% 1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.57 (2H, m),2.11 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.23 (2H, m), 4.15(2H, q, J = 7.2 Hz), 4.74 (1H, t, J = 7.2 Hz), 5.01 (2H, s),5.99 (1H, d, J = 3.4 Hz), 6.11 (1H, d, J = 3.4 Hz), 6.73-7.06(4H, m),7.10-7.30 (9H, m).IR (KBr) cm-1; 2928, 2855, 1753, 1523, 1238, 1182, 1028,837, 758. Example 102Sodium (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0578] The object compound was obtained from ethyl (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 100(1). yield: 99%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.58 (2H, m),2.11 (3H, s), 2.56 (2H, t, J = 3.2 Hz), 3.25 (2H, m), 4.80(1H, t, J = 7.2 Hz), 5.02 (2H, s), 5.99 (1H, d, J = 3.4 Hz),6.11 (1H, d, J = 3.4 Hz), 6.75-6.81 (4H, m), 7.07-7.30 (9H,m).IR (KBr) cm-1; 2930, 2856, 1728, 1524, 1238, 912, 748. (2) Sodium (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0579] The object compound was obtained from (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 100(2). yield: 77%1H-NMR (DMSO) δ; 0.84 (3H, m), 1.25 (6H, m), 1.51 (2H, m),2.03 (3H, s), 2.50 (2H, m), 2.87-3.15 (2H, m), 4.25 (1H, dd,J = 9.6 Hz J = 3.2 Hz), 5.03 (2H, s), 5.87 (1H, d, J = 3.4Hz), 5.94 (1H, d, J = 3.2 Hz), 6.75 (4H, t, J = 8.0 Hz),7.04-7.29 (9H, m).Elementary analysis for C33H36NO3Na-0.5H2O   Calculated: C, 75.26; H, 7.08; N, 2.66.   Found: C, 75.01; H, 6.74; N, 2.44. Example 103Ethyl (2R)-2-{4-[1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-Cyclohexylphenylmethyl alcohol
    [0580] The object compound was obtained from 4-cyclohexylbenzoic acid as an oily substance, according to the similarmanner to that of Example 99(1). yield: 100%1H-NMR (CDCl3) δ; 1.22-1.89 (10H, m), 2.54 (1H, m), 4.65(2H, s), 7.19 (2H, d, J = 8.0 Hz),7.29 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 3270, 2926, 2851, 1449, 1001, 800. (2) 3-(4-Cyclohexylphenyl)methyl mesylate
    [0581] The object compound was obtained from 4-cyclohexylphenylmethylalcohol as an oily substance,according to the similar manner to that of Example 99(2).yield: 100%1H-NMR (CDCl3) δ; 1.22-1.89 (10H, m), 2.54 (1H, m), 2.93(3H, s), 5.21 (2H, s), 7.20-7.35 (4H, m).IR (KBr) cm-1; 3025, 2924, 2851, 1449, 1354, 1175, 929, 816. (3) 2-(4-Cyclohexylphenylmethyl)-1H-isoindol-1,3-(2H)-dione
    [0582] The object compound was obtained from 3-(4-cyclohexylphenyl)methylmesylate as an oily substance,according to the similar manner to that of Example 99(3).yield: 96%1H-NMR (CDCl3) δ; 1.22-1.83 (10H, m), 2.45 (1H, m), 4.01(2H, s), 7.13-7.65 (4H, m), 7.67-7.88 (4H, m).IR (KBr) cm-1; 3057, 2926, 2851, 1717, 1392, 1346, 1084 939,716. (4) 3-(4-Cyclohexylphenyl)methylamine
    [0583] The object compound was obtained from 2-(4-cyclohexylphenylmethyl)-1H-isoindol-1,3-(2H)-dioneas anoily substance, according to the similar manner to that ofExample 99(4). yield: 88%1H-NMR (CDCl3) δ; 1.48 (5H, m) , 1.77 (5H, m), 2.13 (2H, s), 2.48 (1H, m), 3.81 (2H, s),7.21 (4H, m).IR (KBr) cm-1; 2922, 2851, 1448, 1383, 1319, 912, 825, 743. (5) 2-(4-Benzyloxyphenyl)-1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrole
    [0584] The object compound was obtained from 3-(4-cyclohexylphenyl)methylamineas an oily substance,according to the similar manner to that of Example 99(5).yield: 60%1H-NMR (CDCl3) δ; 1.21-1.83 (10H, m), 2.13 (3H, s), 2.46(1H, m), 5.04 (2H, s), 5.05 (2H, s), 6.00 (1H, d, J = 3.4Hz), 6.14 (1H, d, J = 3.4 Hz), 6.81-7.44 (13H, m).IR (KBr) cm-1; 2924, 2851, 1522, 1242, 1020, 835, 733. (6) 4-[1-(4-Cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0585] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 99(6). yield: 100%1H-NMR (CDCl3) δ; 1.33-1.49 (5H, m), 1.71-1.86 (5H, m),2.12 (3H, s), 2.45 (1H, m), 5.04 (2H, s), 6.01 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz), 6.73-6.84 (4H, m),7.10-7.18(4H, m) .IR (KBr) cm-1; 2926, 2851, 1524, 1446, 1260, 1171, 840, 762. (7) Ethyl (2R)-2-{4-[1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0586] The object compound was obtained from 4-[1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenolasan oily substance, according to the similar manner to thatof Example 99(7). yield: 40%1H-NMR (CDCl3) δ; 1.61-1.85 (13H, m), 2.11 (3H, s), 2.45(1H, m), 3.23 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 4.74 (1H,t, J = 7.2 Hz), 5.01 (2H, s), 5.99 (1H, d, J = 3.4 Hz),6.11 (1H, d, J = 3.4 Hz), 6.73-7.08 (4H, m),7.12-7.30 (9H,m).IR (KBr) cm-1; 2928, 2851, 1755, 1521, 1280, 1181, 1030,837, 760. Example 104Sodium (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0587] The object compound was obtained from ethyl (2R)-2-{4-[1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 100(1).yield: 95% 1H-NMR (CDCl3) δ; 1.24-1.88 (10H, m), 2.11 (3H, s), 2.46(1H, m), 3.25 (2H, m), 4.80 (1H, t, J = 7.2 Hz), 5.01 (2H,s), 5.99 (1H, d, J = 3.4 Hz), 6.11 (1H, d, J = 3.4 Hz),6.75-6.82 (4H, m),7.09-7.29 (9H, m).IR (KBr) cm-1; 2926, 2851, 1726, 1522, 1236, 912, 743. (2) Sodium (2R)-2-{4-[1-(4-hexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0588] The object compound was obtained from (2R)-2-{4-[1-(4-cyclohexylphenylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 100(2). yield: 96%1H-NMR (DMSO) δ; 1.33 (5H, m), 1.73 (5H, m), 2.03 (3H, s),2.42 (1H, m), 2.87-3.15 (2H, m), 4.25 (1H, dd, J = 9.2 Hz J= 3.0 Hz), 5.03 (2H, s), 5.87 (1H, d, J = 3.4 Hz), 5.94 (1H,d, J = 3.4 Hz), 6.75 (4H, t, J = 8.6 Hz), 7.01-7.29 (9H, m).Elementary analysis for C33H34NO3Na-H2O   Calculated: C, 74.27; H, 6.80; N, 2.62.   Found: C, 74.02; H, 6.74; N, 2.42. Example 105Ethyl (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 1,1'-Biphenyl-4-methylalcohol
    [0589] The object compound was obtained from 4-phenylbenzoic acid as an oily substance, according to the similar mannerto that of Example 99(1). yield: 100%1H-NMR (CDCl3) δ; 1.22-1.89 (10H, m), 2.54 (1H, m), 4.65(2H, s), 7.19 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 3270, 2926, 2851, 1449, 1001, 800. (2) 1,1'-Biphenyl-4-methyl mesylate
    [0590] The object compound was obtained from 1,1'-biphenyl-4-methylalcohol as an oily substance, according to thesimilar manner to that of Example 99(2). yield: 100%1H-NMR (CDCl3) δ; 1.22-1.89 (10H, m), 2.54 (1H, m), 2.93(3H, s), 5.21 (2H, s), 7.20-7.35 (4H, m).IR (KBr) cm-1; 3025, 2924, 2851, 1449, 1354, 1175, 929, 816. (3) 2-(1,1'-Biphenyl-4-methyl)-1H-isoindol-1,3-(2H)-dione
    [0591] The object compound was obtained from 1,1'-biphenyl-4-methylmesylate as an oily substance, according to thesimilar manner to that of Example 99(3). yield: 96%1H-NMR (CDCl3) δ; 1.22-1.83 (10H, m), 2.45 (1H, m), 4.01(2H, s), 7.13-7.65 (4H, m),7.67-7.88 (4H, m).IR (KBr) cm-1; 3057, 2926, 2851, 1717, 1392, 1346, 1084 939,716. (4) 3-(1,1'-Biphenyl-4-methyl)methylamine
    [0592] The object compound was obtained from 2-(1,1'-biphenyl-4-methyl)-1H-isoindol-1,3-(2H)-dione as an oilysubstance, according to the similar manner to that ofExample 99(4). yield: 88%1H-NMR (CDCl3) δ; 1.48 (5H, m), 1.77 (5H, m), 2.13 (2H, s),2.48 (1H, m), 3.81 (2H, s), 7.21 (4H, m).IR (KBr) cm-1; 2922, 2851, 1448, 1383, 1319, 912, 825, 743. (5) 2-(4-Benzyloxyphenyl)-1-(1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrrole
    [0593] The object compound was obtained from 3-(1,1'-biphenyl-4-methyl)methylamineas an oilysubstance,according to the similar manner to that ofExample 99(5). yield: 60%1H-NMR (CDCl3) δ; 1.21-1.83 (10H, m), 2.13 (3H, s), 2.46(1H, m), 5.04 (2H, s), 5.05 (2H, s), 6.00 (1H, d, J = 3.4Hz), 6.14 (1H, d, J = 3.4 Hz), 6.81-7.44 (13H, m).IR (KBr) cm-1; 2924, 2851, 1522, 1242, 1020, 835, 733. (6) 4-[1-(1,1'-Biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0594] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(1,1'-biphenyl-4-methyl)-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 99(6). yield: 100%1H-NMR (CDCl3) 5; 1.33-1.49 (5H, m), 1.86-1.71 (5H, m), 2.12 (3H, s), 2.45 (1H, m), 5.04 (2H, s), 6.01 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz), 6.73-6.84 (4H, m), 7.10-7.18(4H, m).IR (KBr) cm-1; 2926, 2851, 1524, 1446, 1260, 1171, 840, 762. (7) Ethyl (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0595] The object compound was obtained from 4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 99(7). yield: 40%1H-NMR (CDCl3) δ; 1.61-1.85 (13H, m), 2.11 (3H, s), 2.45(1H, m), 3.23 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 4.74 (1H,t, J = 7.2 Hz), 5.01 (2H, s), 5.99 (1H, d, J = 3.4 Hz),6.11 (1H, d, J = 3.4 Hz), 6.73-7.08 (4H, m), 7.12-7.30 (9H,m).IR (KBr) cm-1; 2928, 2851, 1755, 1521, 1280, 1181, 1030,837, 760. Example 106Sodium (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(1,1'-Biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0596] The object compound was obtained from ethyl (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate as an oily substance,according to the similar manner to that of Example 100(1).yield: 95%1H-NMR (CDCl3) δ; 1.24-1.88 (10H, m), 2.11 (3H, s), 2.46(1H, m), 3.25 (2H, m), 4.80 (1H, t, J = 7.2 Hz), 5.01 (2H,s), 5.99 (1H, d, J = 3.4 Hz), 6.11 (1H, d, J = 3.4 Hz),6.75-6.82 (4H, m), 7.09-7.29 (9H, m).IR (KBr) cm-1; 2926, 2851, 1726, 1522, 1236, 912, 743. (2) Sodium (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0597] The object compound was obtained from (2R)-2-{4-[1-(1,1'-biphenyl-4-ylmethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 100(2). yield: 96%1H-NMR (DMSO) δ; 2.07 (3H, s), 2.87-3.15 (2H, m), 4.30 (1H,dd, J = 9.2 Hz J = 3.0 Hz), 5.12 (2H, s), 5.91 (1H, d, J =3.2 Hz), 5.98 (1H, d, J = 3.6 Hz), 6.70 (2H, d, J = 8.8 Hz),6.90 (2H, d, J = 8.0 Hz), 7.04-7.44 (10H, m), 7.61 (4H, t,J = 7.8 Hz).Elementary analysis for C33H28NO3Na-1.5H2O   Calculated: C, 73.86; H, 5.82; N, 2.61.   Found: C, 74.15; H, 6.06; N, 2.39. Example 107Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-Aminobenzylamino-t-butylcarbamate
    [0598] Di t-butylcarbonate (113 ml, 495 mmol) was addeddropwise to a solution of 4-aminobenzylamine (60.4 g, 495mmol) in THF (300 ml) at 0°C. The mixture was stirred atroom temperature for 1 hour, and the mixture was pouredinto water and extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride,dried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure to give the object compound.This compound was recrystallized from ethanol-ether. solid110 g, (yield 99%)1H-NMR (CDCl3) δ; 1.35 (9H, s), 3.90 (2H, s), 4.91 (2H, s),6.50 (2H, d, J = 8.4 Hz), 6.87 (2H, d, J = 8.4 Hz),7.16 (1H,s). (2) 4-[Heptylylamino]benzylamino-t-butylcarbamate
    [0599] Heptanoyl chloride (25g, 168 mmol) was added dropwiseto a solution of 4-aminobenzylamino-t-butylcarbamate (35.5g, 160 mmol) in THF (500 ml) at 0°C. The mixture wasstirred at room temperature for 1 hour, and the mixture waspoured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodiumchloride and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure to give theobject compound. This compound was recrystallized fromethanol-ether. solid 41.8 g, (yield 78%)1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.35 (17H, m), 2.32 (2H, t,J = 7.6 Hz), 4.25 (2H, d, J = 6.0 Hz), 7.2 (1H, s), 7.22(2H, d, J = 8.4 Hz),7.46 (2H, d, J = 8.4 Hz). (3) 4-[Heptylyl(cyclohexyl)amino]benzylamino-t-butylcarbamate
    [0600] To a solution of 4-[heptylylamino]benzylamino-t-butylcarbamate(5.0 g, 15 mmol) in THF (60 ml) and DMF (60ml) was added sodium hydride (600 mg, 15 mmol) and themixture was stirred at room temperature for 1 hour. To asolution was added cyclohexylmethyl bromide (2.1 ml, 15mmol) and the mixture was stirred at 80°C for 24 hours. Tothe reaction solution was added water and the mixture wasextracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride and dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate = 7:1) to give theobject compound as an oily substance. 580 mg, (yield 9%)1H-NMR (CDCl3) δ; 1.01-2.00 (33H, m), 2.03 (2H, t, J = 7.6 Hz), 3.54 (2H, d, J = 4.8 Hz), 4.37-4.15 (2H, dd, J = 33.6Hz, J = 6.0 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J =8.4 Hz). (4) 4-[Heptylyl(cyclohexyl)amino]benzylamine
    [0601] To a solution of 4-[heptylyl(cyclohexyl)amino]-benzylamino-t-butylcarbamate(580 mg, 1.36 mmol) in ethylacetate (20 ml) was added 4N hydrogen chloride-ethylacetate solution (10 ml, 40 mmol) and the mixture wasstirred at room temperature for 1 hour. The solvent wasremoved under reduced pressure to give the object compoundas a solid. 540 mg, (yield 100%)1H-NMR (DMSO) δ; 0.78-1.60 (21H, m), 1.96 (1H, m), 2.56 (2H,m), 3.52 (2H, d, J = 7.0 Hz), 4.04 (2H, d, J = 5.2 Hz),7.30-7.64 (4H, m),8.57 (2H, s). (5) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-[heptylyl(cyclohexyl)aminophenylmethyl]]-1H-pyrrole
    [0602] A solution of 4-[heptylyl(cyclohexyl)amino]benzylamine(540 mg, 1.47 mmol), 1-(4-benzyloxyphenyl)-1,4-pentanedione(410 mg, 1.45 mmol) and p-toluenesulfonic acid monohydrate(50 mg) in toluene (10 ml) was refluxed for 12 hours underheating and the solvent was removed under reduced pressure.The residue was purified by silica gel chromatography(hexane:ethyl acetate = 9: 1) to give the object compound as an oily substance. 370 mg, (yield 44%)1H-NMR (CDCl3) δ; 0.79-1.67 (22H, m), 1.96 (2H, t, J = 7.4Hz), 2.16 (3H, s), 3.52 (2H, d, J = 7.4 Hz), 5.05 (2H, s),5.10 (2H, s), 6.03 (1H, d, J = 3.2 Hz), 6.15 (1H, d, J =3.2 Hz), 6.89-7.44 (13H, m).IR (KBr) cm-1; 2924, 2853, 1659, 1524, 1396, 1242, 1020,835, 758. (6) 4-[5-Methyl-1-[4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl]]phenol
    [0603] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[4-[heptylyl(cyclohexyl)aminophenylmethyl]]-1H-pyrrole(370 mg,0.64 mmol) in ethanol (20 ml) was added 10% palladiumcarbon (40 mg) and the mixture was stirred under hydrogenatmosphere. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 310 mg, (yield 100%)1H-NMR (CDCl3) δ; 0.98-1.66 (22H, m), 1.97 (2H, t, J = 8.0Hz), 2.17 (3H, s), 3.53 (2H, t, J = 7.8 Hz), 5.10 (2H, s),6.02 (1H, d, J = 3.4 Hz), 6.14 (1H, d, J = 3.4 Hz),6.78-7.28(8H, m).IR (KBr) cm-1; 2926, 2853, 1634, 1512, 1448, 1402, 1269, 839,758. (7) Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0604] A solution of 4-[5-methyl-1-[4-[heptylyl(cyclohexyl)-aminophenylmethyl]-1H-pyrrol-2-yl]]phenol(300 mg, 0.62mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (180 mg,0.925 mmol), 1,1'-(azodicarbonyl)dipiperidine (234 mg,0.925 mmol) and triphenylphosphine (243 mg, 0.925 mmol) intoluene (1 ml) was stirred at 80°C for 12 hours. Themixture was poured into water, extracted with ethyl acetate,washed with saturated brine and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 9:1) to give theobject compound as an oily substance. 117 mg, (yield 28%)1H-NMR (CDCl3) δ; 0.83-1.66 (25H, m), 1.96 (2H, t, J = 8.0Hz), 2.14 (3H, s), 3.22 (2H, m), 3.53 (2H, d, J = 7.5 Hz),4.20 (2H, q, J = 7.2 Hz), 4.76 (1H, t, J = 7.2 Hz), 5.07(2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.13 (1H, d, J = 3.4Hz),6.75-7.30 (13H, m).IR (KBr) cm-1; 2926, 1753, 1657, 1523, 1398, 1240, 1182,1030, 912, 837, 743. Example 108Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-(4-[5-Methyl-1-(4-[heptylyl(cyclohexyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0605] To a solution of ethyl (2R)-2-(4-[5-methyl-1-(4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(117 mg, 0.18 mmol) in THF(2 ml) and methanol (1 ml) was added 1N aqueous potassiumhydroxide (0.6 ml, 0.6 mmol) and the mixture was stirredfor 1 hour at room temperature. The reaction solution wasneutralized with 1N aqueous hydrochloric acid, extractedwith ethyl acetate, washed with saturated brine and driedover magnesium sulfate anhydride. The solvent was removedunder reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate) to givethe object compound as an oily substance. 111 mg, (yield97%)1H-NMR (CDCl3) δ; 0.83-1.66 (22H, m), 1.96 (2H, t, J = 8.0Hz), 2.14 (3H, s), 3.22 (2H, m), 3.53 (2H, d, J = 7.5 Hz),4.76 (1H, t, J = 7.2 Hz), 5.07 (2H, s), 6.00 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz),6.75-7.30 (13H, m).IR (KBr) cm-1; 2926, 2853, 1743, 1615, 1523, 1450, 1242,1180, 1082, 835, 758. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(cyclohexyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0606] To a solution of (2R)-2-{4-[5-methyl-1-(4-[heptylyl(cyclohexyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid (111 mg, 0.17 mmol) inethanol (1 ml) was added 1N sodium hydroxide-ethanolsolution (0.165 ml, 0.165 mmol) and the mixture wasconcentrated. To the residue was added isopropylether togive the object compound as a solid. 79 mg, (yield 71%)1H-NMR (DMSO) δ; 0.75-1.36 (18H, m), 1.58 (4H, m), 1.88 (2H,m), 2.05 (3H, s), 3.15-2.88 (2H, m), 3.45 (2H, d, J = 7.0Hz), 4.35 (1H, m), 5.09 (2H, s), 5.89 (1H, d, J = 3.2 Hz),5.95 (1H, d, J = 3.2 Hz), 6.69 (2H, d, J = 8.8 Hz), 6.85(2H, d, J = 8.0 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.14-7.29(7H, m).Elementary analysis for C41H49N2O4Na-1.5H2O   Calculated: C, 72.01; H, 7.66; N, 4.10.   Found: C, 72.22; H, 7.39; N, 3.86. Example 109Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-Aminobenzylamino-t-butylcarbamate
    [0607] Di t-butyl carbonate (113 ml, 495 mmol) was addeddropwise to a solution of 4-aminobenzylamine (60.4 g, 495mmol) in THF (300 ml) at 0°C. The mixture was stirred atroom temperature for 1 hour, poured into water andextracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride, dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure to give the object compound. Thiscompound was recrystallized from ethanol-ether. Solid 110g, (yield 99%)1H-NMR (CDCl3) δ; 1.35 (9H, s), 3.90 (2H, s), 4.91 (2H, s),6.50 (2H, d, J = 8.4 Hz), 6.87 (2H, d, J = 8.4 Hz),7.16 (1H,s). (2) 4-[Heptylylamino]benzylamino-t-butylcarbamate
    [0608] Heptanoyl chloride (25g, 168 mmol) was added dropwiseto a solution of 4-aminobenzylamino-t-butylcarbamate (35.5g, 160 mmol) in THF (500 ml) at 0°C. The mixture wasstirred at room temperature for 1 hour, poured into waterand extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure to give the object compound.This compound was recrystallized from ethanol-ether. Solid41.8 g, (yield 78%) 1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.35 (17H, m), 2.32 (2H, t,J = 7.6 Hz), 4.25 (2H, d, J = 6.0 Hz), 7.2 (1H, s), 7.22(2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz). (3) 4-[Heptylyl(propyl)amino]benzylamino-t-butylcarbamate
    [0609] To a solution of 4-[heptylylamino]benzylamino-t-butylcarbamate(5.0 g, 15 mmol) in THF (60 ml) and DMF (60ml) was added sodium hydride (532 mg, 13.3 mmol) and themixture was stirred at room temperature for 1 hour. To themixture was added iodopropane (1.3 ml, 13.2 mmol) and themixture was stirred at 80°C for 24 hours. To the reactionsolution was added water and the mixture was extracted withethyl acetate. The organic layer was washed with saturatedaqueous sodium chloride, dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate = 7:1) to give theobject compound as an oily substance. 2.68 g, (yield 54%)1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.19 (6H, m), 1.50 (13H, m),2.03 (2H, t, J = 7.6 Hz), 3.61 (2H, m), 4.38 (2H, d, J =5.8 Hz), 4.92 (1H, s), 7.22 (2H, d, J = 8.4 Hz),7.46 (2H, d,J = 8.4 Hz). (4) 4-[Heptylyl(propyl)amino]benzylamine
    [0610] To a solution of 4-[heptylyl(propyl)amino]benzylamino-t-butylcarbamate (2.68 g, 7.1 mmol) in ethyl acetate (100ml) was added 4N hydrogen chloride-ethyl acetate solution(40 ml, 160 mmol)and the mixture was stirred at roomtemperature for 1 hour. An aqueous 8N NaOH was poured intothe mixture to adjust the pH to 14 and the mixture wasextracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride, dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure to give the object compound as anoily substance. 2.2 g, (yield 100%)1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.23-1.49 (8H, m), 1.73 (2H,s), 2.05 (2H, t, J = 8.6 Hz), 3.63 (2H, m), 3.92 (2H, s),7.10 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz). (5) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-[heptylyl(propyl)aminophenylmethyl]]-1H-pyrrole
    [0611] A solution of 4-[heptylyl(propyl)amino]phenylmethylamine (1.96 g, 7.1 mmol), 1-(4-benzyloxyphenyl)-1,4-pentanedione(1.98 g, 7.02 mmol), p-toluenesulfonic acidmonohydrate (200 mg) in toluene (40 ml) was refluxed for 12hours under heating and the solvent was removed underreduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate = 9:1) to give theobject compound as an oily substance. 2.55 g, (yield 69%)1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.23-1.49 (6H, m), 1.73 (4H, s), 2.00 (2H, t, J = 7.4 Hz), 2.16 (3H, s), 3.61 (2H, m),5.05 (2H, s), 5.12 (2H, s), 6.03 (1H, d, J = 3.2 Hz), 6.15(1H, d, J = 3.2 Hz), 6.89-7.40 (13H, m). (6) 4-[5-Methyl-1-[4-[heptylyl(propyl)aminophenylmethyl]-1H-pyrrol-2-yl]]phenol
    [0612] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-[heptylyl(propyl)amino])-1H-pyrrole(2.55 g, 4.9 mmol) inethanol (50 ml) was added 10% palladium carbon (250 mg) andthe mixture was stirred under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 2.2 g, (yield 100%)1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (6H, m), 1.50 (4H, m),1.98 (2H, t, J = 8.0 Hz), 2.15 (3H, s), 3.61 (2H, t, J =7.8 Hz), 5.10 (2H, s), 6.02 (1H, d, J = 3.4 Hz), 6.14 (1H,d, J = 3.4 Hz), 6.78-7.00 (4H, m), 7.05 (2H, d, J = 8.0 Hz),7.20 (2H, d, J = 8.6 Hz). (7) Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0613] A solution of 4-[5-methyl-1-(4-[heptylyl(propyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenol(2.1 g, 4.9 mmol),ethyl (S)-2-hydroxy-3-phenylpropanoate (1.43 g, 7.35 mmol), 1,1'-(azodicarbonyl)dipiperidine (1.86g, 7.35 mmol) andtriphenylphosphine (1.93 g, 7.35 mmol) in toluene (10 ml)was stirred at 80°C for 12 hours. The mixture was pouredinto water, extracted with ethyl acetate, washed withsaturated brine and dried over magnesium sulfate anhydride.The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 5:1) to give the object compound asan oily substance. 1.44 g, (yield 48%)1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (7H, m), 1.60 (2H, m) ,1.87 (4H, m), 2.14 (3H, s), 3.21 (2H, m), 3.57-3.78 (4H, m),4.20 (2H, q, J = 7.2 Hz), 4.76 (1H, t, J = 7.2 Hz), 5.07(2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.13 (1H, d, J = 3.4Hz),6.75-7.28 (13H, m).IR (KBr) cm-1; 2928, 1775, 1658, 1523, 1398, 1238, 1082,835, 758. Example 110Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-[heptylyl(propyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0614] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate (2.15 g, 3.38 mmol) in THF(30 ml) and methanol (15 ml) was added 1N aqueous potassiumhydroxide (10.1 ml, 10.1 mmol) and the mixture was stirredfor 1 hour at room temperature. The reaction solution wasneutralized with 1N aqueous hydrochloric acid, extractedwith ethyl acetate, washed with saturated brine and driedover magnesium sulfate anhydride. The solvent was removedunder reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate) to givethe object compound as an oily substance. 2.03 g, (yield98%)1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (4H, m), 1.60 (2H, m),1.87 (4H, m), 2.14 (3H, s), 3.21 (2H, m), 3.57-3.78 (4H, m),4.76 (1H, t, J = 7.2 Hz), 5.07 (2H, s), 6.00 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz), 6.75-7.28 (13H, m).IR (KBr) cm-1; 2930, 1732, 1616, 1523, 1240, 1082, 835, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0615] To a solution of (2R)-2-{4-[5-methyl-1-(4-[heptylyl(propyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid (2.0 g, 3.29 mmol) inethanol (20 ml) was added 1N sodium hydroxide-ethanol solution (3 ml, 3.0 mmol) and the mixture was concentrated.To the residue was added isopropylether to give the objectcompound as a solid. 977 mg, (yield 75%)1H-NMR (DMSO) δ; 0.78 (6H, m), 1.08 (6H, m), 1.33 (2H, m),1.88 (2H, m), 2.04 (3H, s), 2.85-3.14 (4H, m), 3.51 (2H, t,J = 6.6 Hz), 4.24 (1H, t, J = 7.2 Hz), 5.10 (2H, s), 5.89(1H, d, J = 3.4 Hz), 5.97 (1K, d, J = 3.4 Hz), 6.67 (2H, d,J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8Hz),7.14-7.23 (7H, m) . Example 111Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)-aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-[Heptylyl(pentyl)amino]benzylamino-t-butylcarbamate
    [0616] The object compound was obtained from iodopentane asan oily substance, according to the similar manner to thatof Example 109(3). yield: 94%1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.19 (10H, m), 1.50 (13H,m), 2.03 (2H, t, J = 7.6 Hz), 3.61 (2H, m), 4.38 (2H, d, J= 5.8 Hz), 4.92 (1H, s), 7.22 (2H, d, J = 8.4 Hz),7.46 (2H,d, J = 8.4 Hz). (2) 4-[Heptylyl(pentyl)amino]benzylamine
    [0617] The object compound was obtained from 4-[heptylyl(pentyl)amino]benzylamino-t-butylcarbamate as anoily substance, according to the similar manner to that ofExample 109(4). yield: 100%1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.23-1.49 (12H, m), 1.73(2H, s), 2.05 (2H, t, J = 8.6 Hz), 3.63 (2H, m), 3.92 (2H,s), 7.10 (2H, d, J = 8.4 Hz),7.34 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 2926, 1651, 1404, 1263, 1140, 845, 727. (3) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrole
    [0618] The object compound was obtained from 4-[heptylyl(pentyl)amino]benzylamineas an oily substance,according to the similar manner to that of Example 109(5).yield: 72%1H-NMR (CDCl3) δ; 0.89 (6H, m), 1.23-1.49 (10H, m), 1.73(4H, s), 2.00 (2H, t, J = 7.4 Hz), 2.16 (3H, s), 3.61 (2H,m), 5.05 (2H, s), 5.12 (2H, s), 6.03 (1H, d, J = 3.2 Hz)6.15 (1H, d, J = 3.2 Hz),6.89-7.40 (13H, m).IR (KBr) cm-1; 2930, 1655, 1523, 1242, 1020, 835, 758. (4) 4-[5-Methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenol
    [0619] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrole as an oily substance, according to the similar manner to that of Example 109(6).yield: 100%1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (10H, m), 1.50 (4H, m),1.98 (2H, t, J = 8.0 Hz), 2.15 (3H, s), 3.61 (2H, t, J =7.8 Hz), 5.10 (2H, s), 6.02 (1H, d, J = 3.4 Hz), 6.14 (1H,d, J = 3.4 Hz), 6.78-7.00 (4H, m), 7.05 (2H, d, J = 8.0Hz),7.20 (2H, d, J = 8.6 Hz).IR (KBr) cm-1; 2928, 1633, 1512, 1269, 1020, 839, 760. (5) Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0620] The object compound was obtained from 4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenolas an oily substance, according to the similarmanner to that of Example 109(7). yield: 59%1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (11H, m), 1.60 (2H, m),1.87 (4H, m), 2.14 (3H, s), 3.21 (2H, m), 3.57 - 3.78 (4H,m), 4.20 (2H, q, J = 7.2 Hz), 4.76 (1H, t, J = 7.2 Hz),5.07 (2H, s), 6.00 (1H, d, J = 3.4 Hz), 6.13 (1H, d, J =3.4 Hz),6.75-7.28 (13H, m).IR (KBr) cm-1; 2928, 1738, 1658, 1512, 1398, 1240, 1097,837, 700. Example 112Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0621] The object compound was obtained from ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateas an oilysubstance, according to the similar manner to that ofExample 110(1). yield: 98%1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (8H, m), 1.60 (2H, m),1.87 (4H, m), 2.14. (3H, s), 3.21 (2H, m), 3.57-3.78 (4H, m),4.76 (1H, t, J = 7.2 Hz), 5.07 (2H, s), 6.00 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz), 6.75-7.28 (13H, m).IR (KBr) cm-1; 2930, 1732, 1616, 1523, 1240, 1082, 835, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0622] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-[heptylyl(pentyl)aminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid as a solid, accordingto the similar manner to that of Example 110(2). yield:72% 1H-NMR (DMSO) δ; 0.78 (6H, m), 1.08 (10H, m), 1.33 (2H, m),1.88 (2H, m), 2.04 (3H, s), 2.85-3.14 (4H, m), 3.51 (2H, t,J = 6.6 Hz), 4.24 (1H, t, J = 7.2 Hz), 5.10 (2H, s), 5.89(1H, d, J = 3.4 Hz), 5.97 (1H, d, J = 3.4 Hz), 6.67 (2H, d,J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8Hz),7.14-7.23 (7H, m). Example 113Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-[Heptylylamino]benzylamine
    [0623] To a solution of 4-[heptanoylamide]benzylamino-t-butylcarbamate(3.5 g, 10.5 mmol) in ethyl acetate (100 ml)was added 4N hydrogen chloride-ethyl acetate solution (20ml, 80 mmol) and the mixture was stirred at roomtemperature for 1 hour. 8N aqueous sodium hydroxide waspoured into the solution to adjust the pH to 14 and themixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride anddried over magnesium sulfate anhydride,and the solvent wasremoved under reduced pressure to give the object compoundas an oily substance. 2.47 g, (yield 100%)1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.35 (6H, m), 1.67 (2H, t,J = 7.0 Hz), 2.32 (2H, t, J = 7.6 Hz), 3.82 (2H, s), 7.22(2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz). (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrole
    [0624] The object compound was obtained from 4-[heptylylamino]benzylamineas an oily substance, accordingto the similar manner to that of Example 109(5). yield:50%Oily substance 1.75 g, (50%)1H-NMR (CDCl3) δ; 0.89 (3H, m), 1.23-1.49 (4H, m), 1.73 (4H,s), 2.00 (2H, t, J = 7.4 Hz), 2.16 (3H, s), 3.61 (2H, m),5.05 (2H, s), 6.03 (1H, d, J = 3.2 Hz), 6.15 (1H, d, J =3.2 Hz), 6.89-7.40 (13H, m). (3) 4-[5-Methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenol
    [0625] The object compound was obtained from 2-(4-benzyloxyphenyl]-5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 109(6). yield: 100%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (6H, m), 1.98 (2H, t,J = 8.0 Hz), 2.12 (3H, s), 2.37 (2H, t, J = 7.4 Hz), 5.02(2H, s), 6.02 (1H, d, J = 3.4 Hz), 6.14 (1H, d, J = 3.4 Hz),6.72-6.88 (4H, m), 7.12 (2H, d, J = 8.0 Hz),7.49 (2H, d, J= 8.6 Hz). (4) Ethyl (2R)-2-{4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0626] The object compound was obtained from 4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenolas anoily substance, according to the similar manner to that ofExample 109(7). yield: 33%1H-NMR (CDCl3) δ; 0.88 (3H, m), 1.26 (9H, m), 1.51 (2H, m),2.01 (3H, s), 3.14 (2H, m), 3.61-3.78 (4H, m), 4.08 (2H, q,J = 7.2 Hz), 4.65 (1H, t, J = 7.2 Hz), 4.91 (2H, s), 5.91(1H, d, J = 3.4 Hz), 6.02 (1H, d, J = 3.4 Hz),6.64-7.35(13H, m).IR (KBr) cm-1; 2928, 1738, 1621, 1522, 1238, 1082, 835, 758. Example 114Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0627] The object compound was obtained from 4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenolas anoily substance, according to the similar manner to that ofExample 110(1). yield: 93%1H-NMR (CDCl3) δ; 0.88 (6H, m), 1.26 (4H, m), 1.60 (2H, m), 1.87 (4H, m), 2.14 (3H, s), 3.21 (2H, m), 3.57-3.78 (4H, m),4.76 (1H, t, J = 7.2 Hz), 5.07 (2H, s), 6.00 (1H, d, J =3.4 Hz), 6.13 (1H, d, J = 3.4 Hz),6.75-7.28 (13H, m).IR (KBr) cm-1; 2930, 1732, 1616, 1523, 1240, 1082, 835, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0628] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-[heptylylaminophenylmethyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 110(2). yield: 95%1H-NMR (DMSO) δ; 0.78 (3H, m), 1.08 (4H, m), 1.33 (2H, m),1.88 (2H, m), 2.04 (3H, s), 2.85-3.14 (4H, m), 4.24 (1H, t,J = 7.2 Hz), 5.10 (2H, s), 5.89 (1H, d, J = 3.4 Hz), 5.97(1H, d, J = 3.4 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.86 (2H, d,J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.14-7.23 (7H,m), 9.95 (1H, s). Example 115Ethyl (2R)-2-(4-{[2-(4-bromophenyl)-1H-indol-1-yl]methyl}phenoxy)-3-phenylpropanoate(1) 1-(4-Bromophenyl)-1-ethanone N-phenylhydrazone
    [0629] A solution of p-bromoacetophenone (5.00 g, 25.1 mmol),phenylhydrazone (2.71 g, 25.1 mmol) and p-toluenesulfonic acid monohydrate (358 mg, 1.88 mmol) in toluene (100 ml)was refluxed for 12 hours under heating, and the mixturewas poured into water and extracted with ethyl acetate.The extract was washed with water and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure. To the residue was added hexane and the mixturewas filtered to give the object compound as a solid. 6.68g (yield: 92.0%)1H-NMR (CDCl3) δ; 2.21 (3H, s), 5.27 (2H, s), 6.86-6.93 (1H,m), 7.15-7.36 (5H, m), 7.49 (2H, d, J = 8.4 Hz), 7.66 (2H,d, J = 8.4 Hz).IR (KBr) cm-1; 1603, 1485, 1252, 1152, 1080, 1007, 829, 812,754, 694. (2) 2-(4-Bromophenyl)-1H-indole
    [0630] A mixture of 1-(4-bromophenyl)-1-ethanone N-phenylhydrazone(6.50 g, 22.5 mmol) and polyphosphoric acid(40 g) was stirred at 190°C for 10 minutes. The mixturewas poured into 1 N aqueous sodium hydroxide (400 ml) andextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. To the residuewas added hexane and the mixture was filtered to give theobject compound as a solid. 5.76 g (yield: 94.1%)1H-NMR (CDCl3) δ; 6.82 (1H, s), 7.09-7.65 (8H, m), 8.30 (1H, bs).IR (KBr) cm-1; 3432, 1432, 1348, 1300, 1007, 829, 793, 748. (3) 2-(4-Bromophenyl)-1-(4-methoxybenzyl)-1H-indole
    [0631] To a solution of 2-(4-bromophenyl)-1H-indole (2.00 g,7.35 mmol) in toluene (16 ml) were added 50% aqueous sodiumhydroxide (8 ml), tetra n-butylammonium hydrogensulfate(126 mg, 0.372 mmol) and p-methoxybenzylchloride (1.49 ml,11.0 mmol) and the mixture was stirred at room temperaturefor 3 hours. The mixture was poured into water andextracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 30:1) to give the object compoundas a solid. 670 mg (yield: 23.3%)1H-NMR (CDCl3) δ; 3.77 (3H, s), 5.28 (2H, s), 6.63 (1H, s),6.80 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.11-7.69(8H, m) .IR (KBr) cm-1; 1613, 1512, 1460, 1346, 1248, 1175, 1011,831, 789, 752, 737. (4) 4-{[2-(4-Bromophenyl]-1H-indol-l-yl]methyl}phenol
    [0632] To a solution of 2-(4-bromophenyl)-1-(4-methoxybenzyl)-1H-indole(640 mg, 1.63 mmol) in methylene chloride (40 ml) was added boron tribromide (0.617 ml, 6.53mmol) at 0°C and the mixture was stirred at 0°C for 1 hour.The mixture was poured into ice water and extracted withethyl acetate. The extract was washed with saturatedaqueous sodium bicarbonate and dried over magnesium sulfateanhydride. The solvent was removed under reduced pressureto give the object compound as an oily substance.610 mg (yield: 98.9%)1H-NMR (CDCl3) δ; 4.90 (1H, s) , 5.27 (2H, s) , 6.63 (1H, s),6.72 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.13-7.69(8H, m) .IR (KBr) cm-1; 3299, 1615, 1514, 1346, 1240, 1173, 1011,829, 789, 748, 735. (5) Ethyl (2R)-2-(4-{[2-(4-bromophenyl)-1H-indol-1-yl]methyl}phenoxy)-3-phenylpropanoate
    [0633] To a solution of 4-{[2-(4-bromophenyl)-1H-indol-1-yl]methyl}phenol(600 mg, 1.59 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(617 mg, 3.17 mmol) andtriphenylphosphine (831 mg, 3.17 mmol) in toluene (6 ml)was added 1,1'-(azodicarbonyl)dipiperidine (799 m g, 3.17mmol), and the mixture was stirred at 80°C for 12 hours andpoured into water. The mixture was extracted with ethylacetate and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate = 30: 1) to give the object compoundas an oily substance. 650 mg (yield: 73.7%)1H-NMR (CDCl3) δ; 1.16 (3H, t, J = 7.0 Hz), 3.19 - 3.23 (2H,m), 4.15 (2H, q, J = 7.4 Hz), 4.68-4.75 (1H, m), 5.24 (2H,s), 6.61 (1H, s), 6.72 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J= 8.8 Hz), 7.11-7.73 (13H, m).IR (KBr) cm-1; 1753, 1510, 1460, 1346, 1240, 1178, 1073,1011, 831, 748, 700.[α]D 26 10.2° (c 0.700, chloroform) Example 116(2R)-2-(4-{[2-(4-Bromophenyl)-1H-indol-1-yl]methyl}phenoxy)-3-phenylpropanoicacid
    [0634] To a mixed solution of ethyl (2R)-2-(4-{[2-(4-bromophenyl)-1H-indol-1-yl]methyl}phenoxy)-3-phenylpropanoate(630 mg, 1.14 mmol) in THF (8 ml) andmethanol (4 ml) was added 1N aqueous potassium hydroxide(3.41 ml, 3.41 mmol) and the mixture was stirred for 1 hourat room temperature. The reaction solution was neutralizedwith 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with water and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure to give the object compound as an oily substance.550 mg (yield: 91.7%) 1H-NMR (CDCl3) δ; 3.25 (2H, m), 4.75-4.81 (1H, m), 5.24 (2H,s), 6.62 (1H, s), 6.72 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J= 8.8 Hz), 7.08-7.67 (13H, m).IR (KBr) cm-1; 3031, 1732, 1508, 1456, 1238, 1177, 831, 789,735, 700.[α]D 27 7.87° (c 1.20,chloroform) Example 117Ethyl (2R)-2-{4-[1-(4-bromophenethyl)-4-(decylaminocarbonyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) Ethyl 2-acetyl-4-(4-methoxyphenyl)-4-oxobutanoate
    [0635] To a solution of ethyl acetoacetate (14.2 g, 109 mmol)and sodium ethoxide (7.43 g, 109 mmol) in ethanol (200 ml)was added portionwise 4-methoxyphenacylbromide (25.0 g, 109mmol) under ice-cooling. The mixture was stirred at roomtemperature for 4 hours. The insoluble matter was filteredout and the solvent was removed under reduced pressure togive the object compound as an oily substance. 29.4 g(yield: 97.0%)1H-NMR (CDCl3) δ; 1.29 (3H, t, J = 7.0 Hz), 2.44 (3H, s),3.47 (1H, dd, J = 6.0, 18.2 Hz), 3.68 (1H, dd, J = 8.0,18.2 Hz), 3.85-4.00 (4H, m), 4.22 (2H, q, J = 7.0 Hz), 6.94(2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 1740, 1717, 1674, 1601, 1262, 1171, 1028, 835. (2) Ethyl 1-(4-bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate
    [0636] A solution of ethyl 2-acetyl-4-(4-methoxyphenyl)-4-oxobutanoate(13.9 g, 50.0 mmol), 2-(4-bromophenyl)ethylamine(10.0 g, 50.0 mmol) and p-toluenesulfonicacid monohydrate (714 mg, 3.75 mmol) intoluene (100 ml) was refluxed for 12 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 7:1) to give the object compound asa solid. 15.0 g (yield: 67.9%)1H-NMR (CDCl3) δ; 1.34 (3H, t, J = 7.2 Hz), 2.52 (3H, s),2.67 (2H, t, J = 7.0 Hz), 3.86 (3H, s), 4.05 (2H, t, J =7.0 Hz), 4.27 (2H, q, J = 7.2 Hz), 6.47 (1H, s), 6.68 (2H,d, J = 8.4 Hz), 6.91 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J =8.8 Hz), 7.29 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 1696, 1493, 1211, 1177, 1069, 837, 812, 775. (3) 1-(4-Bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylicacid
    [0637] To a mixed solution of ethyl 1-(4-bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate(11.2 g,25.3 mmol) in THF (40 ml) and methanol (80 ml) was added 4N aqueous sodium hydroxide (25.7 ml, 101 mmol) and themixture was stirred at 90°C for 4 hours. To the reactionsolution was added 8 N aqueous sodium hydroxide (38.1 ml,305 mmol) and the mixture was stirred at 90°C for 8 hours.The mixture was cooled with ice, neutralized withconcentrated hydrochloric acid and extracted with ethylacetate. The extract was washed with water, dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure to give the object compound as asolid. 10.3 g (yield: 98.1%)1H-NMR (CDCl3) δ; 2.52 (3H, s), 2.68 (2H, t, J = 7.8 Hz),3.86 (3H, s), 4.07 (2H, t, J = 7.8 Hz), 6.54 (1H, s), 6.69(2H, d, J = 8.0 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.17 (2H, d,J = 8.8 Hz), 7.31 (2H, d, J = 8.0 Hz).IR (KBr) cm-1; 3007, 1653, 1568, 1497, 1456, 1252, 1179,810. (4) 1-(4-Bromophenethyl)-N-decyl-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide
    [0638] To a solution of 1-(4-bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylicacid (2.00g, 4.83 mmol) in DMF (10 ml) were added n-decylamine (838mg, 5.33 mmol), diethyl cyanophosphate (946 mg, 5.80 mmol)and triethylamine (0.673 ml, 4.83 mmol), and the mixturewas stirred for 1 hour at room temperature. To the reaction solution were added n-decylamine (838 mg, 5.33mmol), diethyl cyanophosphate (946 mg, 5.80 mmol) andtriethylamine (0.673 ml, 4.83 mmol) and the mixture wasstirred room temperature for 2 hours. The mixture waspoured into water and extracted with ethyl acetate. Theextract was washed successively with 1N hydrochloric acid,water and saturated aqueous sodium bicarbonate and driedover magnesium sulfate anhydride, and solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 4: 1) togive the object compound as a solid. 2.16 g (80.9%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.23-1.67 (16H,m), 2.60 (3H, s), 2.68 (2H, t, J = 7.6 Hz), 3.33-3.43 (2H,m), 3.86 (3H, s), 4.02 (2H, t, J = 7.6 Hz), 5.73 (1H, t, J= 5.6 Hz), 6.11 (1H, s), 6.69 (2H, d, J = 8.4 Hz), 6.90 (2H,d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J =8.4 Hz).IR (KBr) cm-1; 3335, 1626, 1570, 1537, 1491, 1275, 1248,1175, 835, 810, 772. (5) 1-(4-Bromophenethyl)-N-butyl-5-(4-hydroxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide
    [0639] To a solution of 1-(4-bromophenethyl)-N-decyl-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide(2.10 g,3.79 mmol) in methylene chloride (40 ml) was added boron tribromide (1.51 ml, 16.0 mmol) at 0°C and the mixture wasstirred at 0°C for 1 hour. The reaction solution waspoured into ice water and extracted with ethyl acetate.The extract was washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride.The solvent was removed under reduced pressure to give theobject compound as a solid. 1.58 g (yield: 77.0%)1H-NMR (CDCl3) δ; 0.94 (3H, t, J = 7.0 Hz), 1.23-1.64 (4H,m), 2.59 (3H, s), 2.67 (2H, t, J = 7.4 Hz), 3.36-3.46 (2H,m), 4.02 (2H, t, J = 7.4 Hz), 5.77 (1H, t, J = 5.6 Hz),6.11 (1H, s), 6.47 (1H, s), 6.69 (2H, d, J = 8.4 Hz), 6.88(2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.29 (2H, d,J = 8.4 Hz).IR (KBr) cm-1; 3123, 2959, 1615, 1574, 1543, 1489, 1269,1223, 839, 812, 770, 735. (6) Ethyl (2R)-2-{4-[1-(4-bromophenethyl)-4-(decylaminocarbonyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0640] To a solution of 1-(4-bromophenethyl)-N-butyl-5-(4-hydroxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide(1.75 g,3.24 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (945 mg,4.87 mmol) and triphenylphosphine (1.28 g, 4.87 mmol) intoluene (20 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.23 g, 4.87 mmol) and the mixture was stirred at 80°C for 12 hours. The reaction solution was poured into water andextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 1.67g(yield: 72.0%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.8 Hz), 1.18-1.60 (19H,m), 2.58 (3H, s), 2.65 (2H, t, J = 7.0 Hz), 3.26-3.42 (4H,m), 4.01 (2H, t, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz),4.79-4.86 (1H, m), 5.70 (1H, bs), 6.07 (1H, s), 6.64 (2H, d,J = 8.4 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8Hz), 7.22-7.35 (7H, m) .IR (KBr) cm-1; 3331, 1750, 1634, 1572, 1539, 1489, 1275,1240, 1181, 1073, 1011, 837, 808, 700.[α]D 26 3.04° (c 0.750, chloroform) Example 118(2R)-2-{4-[1-(4-Bromophenethyl)-4-(decylaminocarbonyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0641] To a mixed solution of ethyl (2R)-2-{4-[1-(4-bromophenethyl)-4-(decylaminocarbonyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1.60 g, 2.23 mmol) in THF(20 ml) and methanol (10 ml) was added 1N aqueous potassiumhydroxide (6.69 ml, 6.69 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue wasrecrystallized from ethyl acetate and diisopropylether togive the object compound. 663 mg (yield: 43.3%)Melting point 132-133°C1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.8 Hz), 1.25-1.56 (16H,m), 2.54-2.63 (5H, m), 3.31-3.42 (4H, m), 3.96 (2H, t, J =7.4 Hz), 4.83-4.89 (1H, m), 5.73 (1H, bs), 6.03 (1H, s),6.59 (2H, d, J = 8.4 Hz), 6.81 (2H, d, J = 8.8 Hz), 6.99(2H, d, J = 8.8 Hz), 7.20-7.35 (7H, m).IR (KBr) cm-1; 3031, 2926, 1742, 1572, 1543, 1489, 1277,1242, 1178, 1073, 1011, 835, 812, 700.[α]D 26 -2.32° (c 1.12, chloroform)Elementary analysis for C39H47N2O4Br   Calculated: C, 68.11; H, 6.89; N, 4.07.   Found: C, 67.92; H, 6.86; N, 4.03. Example 119Ethyl (2R)-2-(4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate(1) Ethyl (2E)-3-[1,1'-biphenyl]propenoate
    [0642] To a solution of [1,1'-biphenyl]-2-carbaldehyde (18.5 g, 102 mmol) and ethyl diethylphosphonoacetate (27.5 g, 123mmol) in THF (200 ml) was added sodium hydride (60%, 4.90 g,123 mmol) and the mixture was stirred at room temperaturefor 12 hours. The reaction solution was poured into icewater, acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The extract was washed with water anddried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.17.8 g (yield: 69.2%)1H-NMR (CDCl3) δ; 1.28 (3H, t, J = 7.4 Hz), 4.20 (2H, q, J= 7.4 Hz), 6.40 (1H, d, J = 15.8 Hz), 7.26-7.48 (9H, m),7.73 (1H, d, J = 15.8 Hz).IR (KBr) cm-1; 1715, 1634, 1476, 1314, 1269, 1196, 1177,1036, 768, 745, 702. (2) Ethyl 3-[1,1'-biphenyl]-2-ylpropanoate
    [0643] To a solution of ethyl (E)-3-[1,1'-biphenyl]-2-ylpropenoate(17.8 g, 70.6 mmol) in ethanol (400 ml) wasadded 10 % palladium carbon (4 g) and the mixture wasstirred under hydrogen atmosphere (0.48 MPa) for 16 hours.The insoluble matter was removed and the filtrate wasconcentrated to give the object compound as an oilysubstance. 14.3 g (yield: 79.9%) 1H-NMR (CDCl3) δ; 1.18 (3H, t, J = 7.0 Hz), 2.41 (2H, t, J= 7.4 Hz), 2.94 (2H, t, J = 7.4 Hz), 4.04 (2H, q, J = 7.0Hz), 7.22-7.45 (9H, m).IR (KBr) cm-1; 1732, 1480, 1179, 1159, 750, 704. (3) 3-[1,1'-Biphenyl]-2-ylpropanol
    [0644] To a suspension of lithium aluminium hydride (4.27 g,112 mmol) in tetrahydrofuran (200 ml) was added dropwise asolution of ethyl 3-[1,1'-biphenyl]-2-ylpropanoate (14.3 g,56.2 mmol) in tetrahydrofuran (50 ml) and the mixture wasrefluxed for 2 hours under heating. To the residue wereadded water (5 ml) and 1 N aqueous sodium hydroxide (15 ml)under ice-cooling and the mixture was stirred at roomtemperature for 1 hour. The insoluble matter was removedand the filtrate was concentrated to give the objectcompound as an oily substance. 11.7 g (yield: 98.3%)1H-NMR (CDCl3) δ; 1.04 (1H, t, J = 5.4 Hz), 1.64-1.78 (2H,m), 2.69 (2H, t, J = 7.6 Hz), 3.45-3.51 (2H, m), 7.20-7.47(9H, m).IR (KBr) cm-1; 3300, 1480, 1451, 1057, 1039, 1009, 750, 702. (4) 3-[1,1'-Biphenyl]-2-ylpropanal
    [0645] To a solution of oxalyl chloride (9.60 ml, 110 mmol)in methylene chloride (200 ml) was added dropwise asolution of dimethylsulfoxide (11.6 ml, 146 mmol) in methylene chloride (30 ml) at -78°C and the mixture wasstirred at -78°C for 10 minutes. To the mixture was addeddropwise a solution of 3-[1,1'-biphenyl]-2-ylpropanol (11.7g, 55.2 mmol) in methylene chloride (30 ml) at -78°C, andthe mixture was stirred at -78 to -45°C for 2 hours. Tothe obtained mixed solution was added triethylamine (55.7ml, 400 mmol) at -45°C and the mixture was stirred at 0°Cfor 2 hours. To the obtained mixed solution was addedsaturated aqueous ammonium chloride (200 ml) and themixture was stirred at room temperature for 1 hour. Theorganic layer was separated, washed with water and driedover magnesium sulfate anhydride. The solvent was removedunder reduced pressure to give the object compound as anoily substance. 11.1 g (yield: 95.7%)1H-NMR (CDCl3) δ; 2.54 (2H, t, J = 8.4 Hz), 2.95 (2H, t, J= 8.4 Hz), 7.23-7.46 (9H, m), 9.63 (1H, s).IR (KBr) cm-1; 1723, 1480, 750, 704. (5) 7-[1,1'-Biphenyl]-2-yl-2,5-heptanedione
    [0646] A mixture of 3-[1,1'-biphenyl]-2-ylpropanal (11.1 g,52.9 mmol), methyl vinyl ketone (3.70 g, 52.9 mmol),triethylamine (14.7 ml, 106 mmol), 3-ethyl-5-(2-hydroxyethyl-4-methylthiazolium bromide (2.09 g, 8.28 ml)and ethanol (12 ml) was stirred at 77°C for 48 hours, andthe solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate = 4: 1) to give the object compoundas an oily substance. 6.20 g (yield: 41.9%)1H-NMR (CDCl3) δ; 2.15 (3H, s), 2.48-2.93 (8H, m), 7.19-7.45(9H, m) .IR (KBr) cm-1; 1713, 1480, 1364, 1171, 1092, 754, 704. (6) 2-(2-[1,1'-Biphenyl]-2-ylethyl)-1-(4-phenoxyphenethyl)-5-methyl-1H-pyrrole
    [0647] A solution of 7-[1,1'-biphenyl]-2-yl-2,5-heptanedione(3.00 g, 10.7 mmol), 2-(4-methoxyphenyl)ethylamine (1.62 g,10.7 mmol) and p-toluenesulfonic acid monohydrate (153 mg,0.803 mmol) in toluene (100 ml) was refluxed for 12 hoursunder heating and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to give theobject compound as an oily substance. 2.53 g (yield:59.8%)1H-NMR (CDCl3) δ; 2.07 (3H, s), 2.51-2.69 (4H, m), 2.86-2.95(2H, m), 3.68 (2H, t, J = 7.6 Hz), 3.79 (3H, s), 5.68(1H, d, J = 3.6 Hz), 5.74 (1H, d, J = 3.6 Hz), 6.80 (2H, d,J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.20-7.37 (9H, m).IR (KBr) cm-1; 1512, 1480, 1418, 1300, 1248, 1036, 750, 704. (7) 4-{2-[2-(2-[1,1'-Biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol
    [0648] To a solution of 2-(2-[1,1'-biphenyl]-2-ylethyl)-1-(4-phenoxyphenethyl)-5-methyl-1H-pyrrole(2.50 g, 6.32 mmol)in methylene chloride (100 ml) was added boron tribromide(2.39 ml, 25.3 mmol) at 0°C and the mixture was stirred at0°C for 1 hour. To the reaction solution was poured icewater and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodiumbicarbonate and dried over magnesium sulfate anhydride.The solvent was removed under reduced pressure to give theobject compound as an oily substance. 2.40 g (yield:99.6%)1H-NMR (CDCl3) δ; 2.06 (3H, s), 2.51-2.95 (6H, m), 3.66 (2H,t, J = 7.6 Hz), 4.74 (1H, bs), 5.68 (1H, d, J = 3.2 Hz),5.72 (1H, d, J = 3.2 Hz), 6.73 (2H, d, J = 8.6 Hz), 6.84(2H, d, J = 8.6 Hz), 7.21-7.38 (9H, m).IR (KBr) cm-1; 3393,1615, 1514,1480,1437,1223,828,750,704. (8) Ethyl (2R)-2-(4-{2-[2-(2-(1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0649] To a solution of 4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(2.40 g, 6.30mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.84 g, 9.45mmol) and triphenylphosphine (2.48 g, 9.45 mmol) in toluene(10 ml) was added 1,1'-(azodicarbonyl)dipiperidine (2.38 g, 9.45 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water, extracted withethyl acetate and dried over magnesium sulfate anhydride.The solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 30: 1) to give the object compoundas an oily substance. 1.40 g (yield: 39.9%)1H-NMR (CDCl3) δ; 1.17 (3H, t, J = 7.0 Hz), 2.04 (3H, s),2.51-2.64 (4H, m), 2.85-2.94 (2H, m), 3.21-3.29 (2H, m),3.63 (2H, t, J = 7.4 Hz), 4.15 (2H, q, J = 7.0 Hz), 4.72-4.79(1H, m), 5.67 (1H, d, J = 3.2 Hz), 5.71 (1H, d, J =3.2 Hz), 6.74 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8Hz),6.92-7.29 (14H, m).IR (KBr) cm-1;1852,1732,1510,1298,1240,1182,1113,1084,1030,750,702. Example 120Sodium (2R)-2-(4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl)ethyl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{2-[2-(2-[1,1'-Biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoicacid
    [0650] To a mixed solution of ethyl (2R)-2-(4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate(1.40 g, 2.51 mmol) inTHF (30 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (7.53 ml, 7.53 mmol) and themixture was stirred for 1 hour at room temperature. Thereaction solution was neutralized with 1N hydrochloric acidand extracted with ethyl acetate. The extract was washedwith water, dried over magnesium sulfate anhydride,and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 3:1) to give the object compound asan oily substance. 994 mg (yield: 74.7%)1H-NMR (CDCl3) δ; 2.04 (3H, s), 2.49-2.93 (6H, m), 3.26 (2H,d, J = 7.0 Hz), 3.63 (2H, t, J = 7.6 Hz), 4.83 (1H, t, J =7.0 Hz), 5.67 (1H, d, J = 3.6 Hz), 5.72 (1H, d, J = 3.6 Hz),6.74 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz),7.19-7.29(14H, m).IR (KBr) cm-1; 3063, 1728, 1510, 1236, 750, 702. (2) Sodium (2R)-2-(4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0651] Ethanol (15 ml) and a solution of 1N sodium hydroxidein ethanol (1.69 ml) were added to (2R)-2-(4-{2-[2-(2-[1,1'-biphenyl]-2-ylethyl)-5-methyl-1H-pyrrol-1-yl]ethyl)phenoxy)-3-phenylpropanoicacid (994 mg, 1.88mmol) and the mixture was concentrated. To the residue wasadded ether to give the object compound as a solid. 940 mg(yield: 68.1%) 1H-NMR (DMSO-d6) δ; 2.02 (3H, s), 2.48-2.58 (4H, m), 2.75-3.15(4H, m), 3.62 (2H, t, J = 8.0 Hz), 4.23-4.29 (1H, m),5.44 (1H, d, J = 3.2 Hz), 5.54 (1H, d, J = 3.2 Hz), 6.65(2H, d, J = 8.4 Hz), 6.84 (2H, d, J = 8.4 Hz),7.13-7.42(14H, m).IR (KBr) cm-1; 3027, 1609, 1508, 1416, 1233,1053,910,750,733,702.[α]D 26 14.1° (c 1.16,chloroform) Example 121Ethyl (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl)phenoxy)-3-phenylpropanoate(1) Ethyl (2E)-3-(2-fluoro-6-trifluoromethylphenyl)propenoate
    [0652] To a solution of 2-fluoro-6-trifluoromethylbenzaldehyde (10.0 g, 52.0 mmol) and ethyldiethylphosphonoacetate (14.0 g, 62.4 mmol) in THF (100 ml)was added sodium hydride (60%, 2.50 g, 62.4 mmol) and themixture was stirred at room temperaturefor 12 hours. Thereaction solution was poured into ice water, acidified with1N hydrochloric acid and extracted with ethyl acetate. Theextract was washed with water, dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to give theobject compound as an oily substance. 12.1 g (yield:89.0%)1H-NMR (CDCl3) δ; 1.35 (3H, t, J = 7.4 Hz), 4.29 (2H, q, J= 7.4 Hz), 6.62 (1H, d, J = 16.2 Hz), 7.27-7.56 (3H, m),7.79 (1H, d, J = 16.2 Hz).IR (KBr) cm-1; 1723, 1466, 1321, 1254, 1190, 1169, 1132,1038, 984, 912, 804,758. (2) Ethyl 3-(2-fluoro-6-trifluoromethylphenyl)propanoate
    [0653] To a solution of ethyl (2E)-3-(2-fluoro-6-trifluoromethylbiphenyl)propenoate (12.0 g, 45.8 mmol) inethanol (200 ml) was added 10 % palladium carbon (1.2g) andthe mixture was stirred under hydrogen atmosphere for 4hours. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 11.8 g (yield: 97.5%)1H-NMR (CDCl3) δ; 1.27 (3H, t, J = 7.0 Hz), 2.57 (2H, t, J= 8.0 Hz), 3.14 (2H, t, J = 8.0 Hz), 4.17 (2H, q, J = 7.0Hz), 7.20-7.48 (3H, m).IR (KBr) cm-1; 1738, 1470, 1319, 1252, 1169, 1127, 889, 802. (3) 3-(2-Fluoro-6-trifluoromethylphenyl)-1-propanol
    [0654] To a suspension of lithium aluminium hydride (3.39 g,89.3 mmol) in tetrahydrofuran (100 ml) was added dropwise a solution of ethyl 3-(2-fluoro-6-trifluoromethylphenyl)propanoate(11.8 g, 44.7 mmol) intetrahydrofuran (50 ml) and the solution was refluxed for 2hours under heating. To the residue was added water (3.5ml) and 1 N aqueous sodium hydroxide solution (10.5 ml)under ice-cooling and the mixture was stirred at roomtemperature for 1 hour. The insoluble matter was filteredout and the filtrate was concentrated to give the objectcompound as an oily substance. 9.51 g (yield: 95.9%)1H-NMR (CDCl3) δ; 1.79-1.93 (2H, m), 2.84-2.95 (2H, m),3.66-3.77 (2H, m) , 7.12-7.46 (3H, m).IR (KBr) cm-1; 3328, 1470, 1319, 1250, 1169, 1125, 1059,1036, 798. (4) 3-(2-Fluoro-6-trifluoromethylphenyl)-1-propanal
    [0655] To a solution of oxalyl chloride (7.47 ml, 85.6 mmol)in methylene chloride (100 ml) was added dropwise asolution of dimethylsulfoxide (9.00 ml, 114 mmol) inmethylene chloride (10 ml) at -78°C and the mixture wasstirred at -78°C for 10 minutes. To the mixed solution wasadded dropwise a solution of 3-(2-fluoro-6-trifluoromethylphenyl)-1-propanol(9.51 g, 42.8 mmol) inmethylene chloride (20 ml) at-78°C and the mixture wasstirred at from -78 to -45°C for 2 hours. To the obtainedmixed solution was added triethylamine (43.3 ml, 311 mmol) at -45°C and the mixture was stirred at 0°C for 2 hours.To the obtained mixed solution was added saturated aqueousammonium chloride solution (200 ml) and the mixture wasstirred at room temperature for 1 hour. The organic layerwas separated, washed with water and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure to give the object compound as an oily substance.9.10 g (yield: 96.6%)1H-NMR (CDCl3) δ; 2.74 (2H, t, J = 8.4 Hz), 3.13 (2H, t, J= 8.4 Hz), 7.14-7.48 (3H, m), 9.84 (1H, s).IR (KBr) cm-1; 1725,1470, 1319, 1250, 1169, 1123, 1032, 801. (5) 7-(2-Fluoro-6-trifluoromethylphenyl)-2,5-heptanedione
    [0656] A mixture of 3-(2-fluoro-6-trifluoromethylphenyl)-1-propanal(9.10 g, 41.4 mmol), methyl vinyl ketone (2.90 g,41.4 mmol), triethylamine (11.5 ml, 82.8 mmol), 3-ethyl-5-(2-hydroxyethyl-4-methylthiazoliumbromide (1.63 g, 6.47ml) and ethanol (9 ml) was stirred at 77°C for 48 hours andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 9: 1) to give the object compoundas an oily substance. 2.60 g (yield: 25.0%)1H-NMR (CDCl3) δ; 2.21 (3H, s), 2.66-3.11 (8H, m), 7.19-7.46(3H, m).IR (KBr) cm-1; 1715, 1470, 1319, 1252, 1167, 1125, 802, 743, 727. (6) 2-(2-Fluoro-6-trifluoromethylphenethyl)-1-(4-methoxyphenethyl)-5-methyl-1H-pyrrole
    [0657] A solution of 7-(2-fluoro-6-trifluoromethylphenyl)-2,5-heptanedione(2.50 g, 9.92 mmol), 2-(4-methoxyphenyl)-ethylamine(1.50 g, 9.92 mmol) and p-toluenesulfonic acidmonohydrate (142 mg, 0.745 mmol) in toluene (100 ml) wasrefluxed for 12 hours under heating and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.2.43 g (yield: 60.4%)1H-NMR (CDCl3) δ; 2.17 (3H, s), 2.67-3.13 (6H, m), 3.78 (3H,s), 3.96 (3H, s), 5.84 (1H, d, J = 3.6 Hz), 5.93 (1H, d, J= 3.6 Hz), 6.82 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8Hz), 7.25-7.48 (3H, m).IR (KBr) cm-1; 1613,1514,1464, 1420,1318, 1302, 1250, 1167,1146, 1125, 1036, 885, 826, 801, 752, 727. (7) 4-{2-[2-(2-Fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-l-yl]ethyl}phenol
    [0658] To a solution of 2-(2-fluoro-6-trifluoromethylphenethyl)-1-(4-phenoxyphenethyl)-5-methyl-1H-pyrrole(2.33 g, 5.77 mmol) in methylene chloride (100 ml) was added boron tribromide (2.17 ml, 23.0 mmol) at 0°Cand the mixture was stirred at 0°C for 1 hour. Thereaction solution was poured into ice water and extractedwith ethyl acetate. The extract was washed with saturatedaqueous sodium bicarbonate and dried over magnesium sulfateanhydride. The solvent was removed under reduced pressureto give the object compound as an oily substance. 2.20 g(yield: 97.3%)1H-NMR (CDCl3) δ; 2.16 (3H, s), 2.67-3.13 (6H, m), 3.96 (2H,t, J = 8.0 Hz), 4.75 (1H, bs), 5.84 (1H, d, J = 2.8 Hz),5.93 (1H, d, J = 2.8 Hz), 6.75 (2H, d, J = 8.4 Hz), 6.96(2H, d, J = 8.4 Hz), 7.26 - 7.49 (3H, m).IR (KBr) cm-1; 3453, 1514, 1464, 1318, 1250, 1167, 1125,801, 748. (8) Ethyl (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0659] To a solution of 2-(2-fluoro-6-trifluoromethylphenethyl)-1-(4-phenoxyphenethyl)-5-methyl-1H-pyrrole(2.20 g, 5.62 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.64 g, 8.43 mmol) and triphenylphosphine(2.21 g, 8.43 mmol) in toluene (40 ml) was added 1,1'-(azodicarbonyl)dipiperidine(2.12 g, 8.43 mmol) and themixture was stirred at 80°C for 12 hours. The reaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 1.02 g(yield: 31.9%)1H-NMR (CDCl3) δ; 1.33 (3H, t, J = 7.4 Hz), 2.14 (3H, s),2.68-2.84 (4H, m), 3.04-3.12 (2H, m), 3.21-3.29 (2H, m),3.89-3.93 (2H, m), 4.26 (2H, q, J = 7.4 Hz), 4.72-4.79 (1H,m), 5.83 (1H, d, J = 3.0 Hz), 5.92 (1H, d, J = 3.0 Hz),6.76 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz),7.21-7.48(8H, m).IR (KBr) cm-1; 1753, 1736, 1510, 1318, 1250, 1184, 1167,1125, 1030, 885, 802, 748, 700. Example 122Sodium (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{2-[2-(2-Fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoicacid
    [0660] To a mixed solution of ethyl (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate (1.02 g, 18.0 mmol) inTHF (20 ml) and methanol (10 ml) was added 1N aqueouspotassium hydroxide solution (5.39 ml, 5.39 mmol) and themixture was stirred for 1 hour at room temperature. Thereaction solution was neutralized with 1N hydrochloric acidand extracted with ethyl acetate. The extract was washedwith water and dried over magnesium sulfate anhydride,andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 3:1) to give the object compound asan oily substance. 533 mg (yield: 54.9%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 2.66-3.11 (6H, m), 3.27 (2H,d, J = 6.2 Hz), 3.93 (2H,t, J = 8.4 Hz), 4.82 (1H, t, J =6.2 Hz), 5.83 (1H, d, J = 3.0 Hz), 5.92 (1H, d, J = 3.0 Hz),6.76 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz),7.19-7.48(8H, m).IR (KBr) cm-1; 3034, 1725, 1510, 1318, 1238, 1167, 1127,801, 756, 700. (2) Sodium (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0661] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.889 ml) were added to (2R)-2-(4-{2-[2-(2-fluoro-6-trifluoromethylphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl)phenoxy)-3-phenylpropanoic acid (533 mg, 0.988mmol) and the mixture was concentrated. Diisopropyletherwas added to the residue to give the object compound as asolid. 165 mg (yield: 33.1%)1H-NMR (DMSO-d6) δ; 2.12 (3H, s), 2.69-3.14 (6H, m), 3.37-3.64(2H, m), 3.78-3.93 (2H, m), 4.25-4.29 (1H, m), 5.68(1H, d, J = 2.4 Hz), 5.72 (1H, d, J = 2.4 Hz), 6.66 (2H, d,J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz),7.15-7.58 (8H, m).IR (KBr) cm-1; 2971, 1609, 1508, 1464, 1418, 1318, 1235,1167, 1125,1069, 885, 801, 750, 700.[α]D 24 9.86° (c 0.221,chloroform) Example 123Ethyl (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoate(1) Ethyl (2E)-3-[3-(1,1,2,2-trifluoroethoxy)phenyl]propenoate
    [0662] To a solution of 3-(1,1,2,2-trifluoroethoxy)benzaldehyde(21.4 g, 116 mmol) and ethyldiethylphosphonoacetate (25.9 g, 116 mmol) in THF (200 ml)was added sodium hydride (60%, 4.64 g, 116 mmol) and themixture was stirred at room temperature for 12 hours. Thereaction solution was poured into ice water, acidified with1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 9:1) to give theobject compound as an oily substance. 19.7 g (yield:69.9%)1H-NMR (CDCl3) δ; 1.34 (3H, t, J = 7.0 Hz), 4.27 (2H, q, J= 7.0 Hz), 5.65-6.21 (1H, m), 6.45 (1H, d, J = 16.2 Hz),7.27-7.45 (4H, m), 7.65 (1H, d, J = 16.2 Hz).IR (KBr) cm-1; 1715, 1644, 1582,1487, 1447, 1370, 1304,1277,1196,1119,1036,982,851,802,762,679. (2) Ethyl 3-[3-(1,1,2,2-trifluoroethoxy)phenyl]propanoate
    [0663] To a solution of ethyl (2E)-3-[3-(1,1,2,2-trifluoroethoxy)phenyl]propenoate(19.6 g, 67.1 mmol) inethanol (500 ml) was added 10 % palladium carbon (1.2 g)and the mixture was stirred under hydrogen atmosphere for 4hours. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 17.7 g (yield: 89.8%)1H-NMR (CDCl3) δ; 1.23 (3H, t, J = 7.0 Hz), 2.62 (2H, t, J= 7.4 Hz), 2.97 (2H, t, J = 7.4 Hz), 4.13 (2H, q, J = 7.0Hz), 5.62-6.18 (1H, m), 7.06-7.34 (4H, m).IR (KBr) cm-1; 1732,1615, 1588, 1489, 1449, 1375, 1304,1281, 1198, 1121, 801, 760, 693. (3) 3-[3-(1,1,2,2-Trifluoroethoxy)phenyl]-1-propanol
    [0664] To a suspension of lithium aluminium hydride (4.54 g,120 mmol) in tetrahydrofuran (200 ml) was added dropwise asolution of ethyl 3-[3-(1,1,2,2-trifluoroethoxy)phenyl]propanoate(17.6 g, 59.8 mmol) intetrahydrofuran (100 ml) and the mixture was refluxed for 2hours under heating. To the residue were added water (5ml) and 1 N aqueous sodium hydroxide solution (15 ml) underice-cooling and the mixture was stirred at room temperaturefor 1 hour. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 15.0 g (yield: 99.3%)1H-NMR (CDCl3) δ; 1.32 (1H, t, J = 5.2 Hz), 1.83-1.97 (2H,m), 2.74 (2H, t, J = 8.4 Hz), 3.64-3.75 (2H, m), 5.62-6.18(1H, m), 7.03-7.34 (4H, m).IR (KBr) cm-1; 3310, 1613,1588, 1489,1449, 1304,1281,1198,1121, 802,758,694. (4) 3-[3-(1,1,2,2-Trifluoroethoxy)phenyl]propanal
    [0665] To a solution of oxalyl chloride (10.3 ml, 118 mmol)in methylene chloride (100 ml) was added dropwise asolution of dimethylsulfoxide (12.4 ml, 157 mmol) inmethylene chloride (10 ml) at -78°C and the mixture wasstirred at -78°C for 10 minutes. To the mixed solution was added dropwise a solution of 3-[3-(1,1,2,2-trifluoroethoxy)phenyl]-1-propanol(14.9 g, 59.1 mmol) inmethylene chloride (20 ml) at-78°C and the mixture wasstirred at from -78 to -45°C for 2 hours. To the obtainedmixed solution was added triethylamine (59.7 ml, 429 mmol)at -45°C and the mixture was stirred at 0°C for 2 hours.To the obtained mixed solution was added saturated aqueousammonium chloride solution (200 ml) and the mixture wasstirred at room temperature for 1 hour. The organic layerwas separated, washed with water and dried over magnesiumsulfate anhydride. The solvent was removed under reducedpressure to give the object compound as an oily substance.14.5 g (yield: 98.0%)1H-NMR (CDCl3) δ; 2.80 (2H, t, J = 7.4 Hz), 2.98 (2H, t, J= 7.4 Hz), 5.62-6.18 (1H, m), 7.05-7.35 (4H, m), 9.83 (1H,s) .IR (KBr) cm-1; 1726, 1304, 1280, 1199, 1123, 802, 758, 693. (5) 7-[3-(1,1,2,2-Trifluoroethoxy)phenyl]-2,5-heptanedione
    [0666] A mixture of 3-[3-(1,1,2,2-trifluoroethoxy)phenyl]propanal (14.5 g, 70.7 mmol), methyl vinyl ketone (4.96 g,70.7 mmol), triethylamine (19.7 ml, 141 mmol), 3-ethyl-5-(2-hydroxyethyl-4-methylthiazolium bromide (2.79 g, 11.0ml) and ethanol (15 ml) was stirred at 77°C for 12 hoursand the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate = 7:1) to give the object compound asan oily substance. 10.7 g (yield: 47.3%)1H-NMR (CDCl3) δ; 2.19 (3H, s), 2.61-2.97 (8H, m), 5.62-6.19(1H, m), 7.03-7.33 (4H, m).IR (KBr) cm-1; 1715, 1613, 1588, 1489, 1448, 1304, 1281,1196,1119, 802, 760, 694. (6) 4-(2-{2-Methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenol
    [0667] A solution of 7-[3-(1,1,2,2-trifluoroethoxy)phenyl]-2,5-heptanedione(3.00 g, 9.38 mmol), tyramine (1.28 g,9.38 mmol) and p-toluenesulfonic acid monohydrate (133 mg,0.701 mmol) in toluene (100 ml) was refluxed for 12 hoursunder heating and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 9:1) to give theobject compound as an oily substance. 2.77 g (yield:70.1%)1H-NMR (CDCl3) δ; 2.16 (3H, s), 2.59-2.95 (6H, m), 3.88 (2H,t, J = 7.4 Hz), 4.78 (1H, bs), 5.64-6.19 (3H, m), 6.73 (2H,d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.02-7.34 (4H, m).IR (KBr) cm-1; 3345, 1514,1300,1198, 1123, 829, 758. (7) Ethyl (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl)ethyl)phenoxy]-3-phenylpropanoate
    [0668] To a solution of 4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenol(2.70 g, 6.41 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.87 g, 9.62 mmol) and triphenylphosphine (2.52 g, 9.62mmol) in toluene (100 ml) was added 1,1'-(azodicarbonyl)dipiperidine(2.43 g, 9.62 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 1.00 g(yield: 26.1%)1H-NMR (CDCl3) δ; 1.17 (3H, t, J = 7.2 Hz), 2.12 (3H, s),2.64-2.95 (6H, m), 3.21-3.25 (2H, m), 3.85 (2H, t, J = 7.6Hz), 4.15 (2H, q, J = 7.2 Hz), 4.71-4.78 (1H, m), 5.63-6.19(3H, m), 6.74 (2H, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.4 Hz),7.03-7.32 (9H, m).IR (KBr) cm-1; 1752, 1613, 1586, 1510, 1300, 1279, 1236,1196, 1119, 1030, 754, 700. Example 124Sodium (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoicacid
    [0669] To a mixed solution of ethyl (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl}phenoxy}-3-phenylpropanoate(980 mg, 1.64 mmol) inTHF (20 ml) and methanol (10 ml) was added 1N aqueouspotassium hydroxide solution (4.92 ml, 4.92 mmol) and themixture was stirred for 1 hour at room temperature. Thereaction solution was neutralized with 1N hydrochloric acidand extracted with ethyl acetate. The extract was washedwith water and dried over magnesium sulfate anhydride, andthe solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 3:1) to give the object compound asan oily substance. 920 mg (yield: 98.5%)1H-NMR (CDCl3) δ; 2.12 (3H, s), 2.62 - 2.94 (6H, m), 3.26(2H, d, J = 6.6 Hz), 3.85 (2H, t, J = 8.0 Hz), 4.82 (1H, t,J = 6.6 Hz), 5.62-6.18 (3H, m), 6.75 (2H, d, J = 8.4 Hz),6.91 (2H, d, J = 8.4 Hz), 7.02-7.32 (9H, m).IR (KBr) cm-1; 3034, 1732, 1510, 1300, 1233, 1198, 1121,758, 700. (2) Sodium (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoate
    [0670] To a solution of (2R)-2-[4-(2-{2-methyl-5-[3-(1,1,2,2-tetrafluoroethoxy)phenethyl]-1H-pyrrol-1-yl}ethyl}phenoxy}-3-phenylpropanoicacid (920 mg, 1.62 mmol) were addedethanol (10 ml) and a solution of 1N sodium hydroxide inethanol (1.45 ml), and the mixture was concentrated.Diisopropylether was added to the residue to give theobject compound as a solid. 852 mg (yield: 88.9%)1H-NMR (DMSO-d6) δ; 2.09 (3H, s), 2.61-3.15 (8H, m), 3.81(2H, t, J = 8.0 Hz), 4.24-4.31 (1H, m), 5.62-5.68 (2H, m),6.57-7.40 (14H, m).IR (KBr) cm-1; 2924, 1611, 1508, 1416, 1302, 1233, 1198,1121, 756, 700.[α]D 25 13.7° (c 0.540, chloroform) Example 125Ethyl (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl}phenoxy)-3-phenylpropanoate(1) Ethyl (2E)-3-(1-naphthyl)propenoate
    [0671] To a solution of 1-naphtaldehyde (30.0 g, 192 mmol)and ethyl diethylphosphonoacetate (51.6 g, 230 mmol) in THF(400 ml) was added sodium hydride (60%, 9.20 g, 230 mmol) and the mixture was stirred at room temperature for 12hours. The reaction solution was poured into ice water,acidified with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =10:1) to give the object compound as an oily substance.37.7 g (yield: 86.9%)1H-NMR (CDCl3) δ; 1.38 (3H, t, J = 7.0 Hz), 4.32 (2H, q, J= 7.0 Hz), 6.53 (1H, d, J = 15.8 Hz), 7.45-7.92 (9H, m),8.20 (1H, d, J = 7.4 Hz) ,8.53 (1H, d, J = 15.8 Hz).IR (KBr) cm-1; 1713, 1634, 1306, 1265, 1254, 1179, 1042,978, 799, 775. (2) Ethyl 3-(1-naphthyl)propanoate
    [0672] To a solution of ethyl (2E)-3-(1-naphthyl)propenoate(37.6 g, 166 mmol) in ethanol (500 ml) was added 10 %palladium carbon (4 g) and the mixture was stirred underhydrogen atmosphere for 5 hours. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 37.7 g (yield:99.7%)1H-NMR (CDCl3) δ; 1.24 (3H, t, J = 8.2 Hz), 2.75 (2H, t, J= 7.6 Hz), 3.42 (2H, t, J = 7.6 Hz), 4.15 (2H, q, J = 8.2 Hz), 7.36-8.05 (7H, m).IR (KBr) cm-1; 1732, 1464, 1372,1177, 1036, 799, 777. (3) 3-(1-Naphthyl)-1-propanol
    [0673] To a suspension of lithium aluminium hydride (12.5 g,329 mmol) in tetrahydrofuran (500 ml) was added dropwise asolution of ethyl 3-(1-naphthyl)propanoate (37.6 g, 165mmol) in tetrahydrofuran (100 ml) and the mixture wasrefluxed for 4 hours under heating. To the residue wereadded water (13 ml) and 1 N aqueous sodium hydroxidesolution (39 ml) under ice-cooling and the mixture wasstirred at room temperature for 1 hour. The insolublematter was filtered out and the filtrate was concentratedto give the object compound as an oily substance. 29.6 g(yield: 96.4%)1H-NMR (CDCl3) δ; 1.95-2.10 (2H, m), 3.18 (2H, t, J = 8.0Hz), 3.71-3.79 (2H, m), 7.15-8.09 (7H, m).IR (KBr) cm-1; 3297, 1597,1508, 1460, 1397,1057,1009,777. (4) 3-(1-Naphthyl)-1-propanal
    [0674] To a solution of oxalyl chloride (27.0 ml, 312 mmol)in methylene chloride (500 ml) was added dropwise asolution of dimethylsulfoxide (32.9 ml, 415 mmol) inmethylene chloride (50 ml) at -78°C and the mixture wasstirred at -78°C for 10 minutes. To the mixed solution was added dropwise a solution of 3-(1-naphthyl)-1-propanol(29.0 g, 156 mmol) in methylene chloride (100 ml) at -78°C,and the mixture was stirred at -78°C for 15 minutes and at-45°C for 1 hour. To the obtained mixed solution was addedtriethylamine (158 ml, 1133 mmol) at -45°C and the mixturewas stirred at 0°C for 20 minutes. To the obtained mixedsolution was added saturated aqueous ammonium chloridesolution (500 ml) and the mixture was stirred roomtemperature for 1 hour. The organic layer was separated,washed with water and dried over magnesium sulfateanhydride. The solvent was removed under reduced pressureto give the object compound as an oily substance. 28.0 g(yield: 97.6%)1H-NMR (CDCl3) 5; 2.92 (2H, t, J = 8.4 Hz), 3.42 (2H, t, J= 8.4 Hz), 7.32 - 8.01 (7H, m), 9.89 (1H, s).IR (KBr) cm-1; 1725, 1395,791, 777. (5) 7-(1-Naphthyl)-2,5-heptanedione
    [0675] A mixture of 3-(1-naphthyl)-1-propanal (28.0 g, 152mmol), methyl vinyl ketone (10.7 g, 152 mmol),triethylamine (42.3 ml, 304 mmol), 3-ethyl-5-(2-hydroxyethyl-4-methylthiazolium bromide (5.96 g, 23.6 ml)and ethanol (28 ml) was stirred at 77°C for 2 days, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethyl acetate = 9: 1) to give the object compoundas an oily substance. 12.6 g (yield: 32.6%)1H-NMR (CDCl3) δ; 2.20 (3H, s), 2.64-2.76 (4H, m), 2.92 (2H,t, J = 7.2 Hz), 3.37 (2H, t, J = 7.2 Hz), 7.26-8.01 (7H, m).IR (KBr) cm-1; 1713, 1397, 1362,1168, 1098, 799, 779. (6) 4-(2-{2-Methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl)phenol
    [0676] A solution of 7-(1-naphthyl)-2,5-heptanedione (3.00 g,11.8 mmol), tyramine (1.62 g, 11.8 mmol) and p-toluenesulfonicacid monohydrate (168 mg, 0.882 mmol) intoluene (100 ml) was refluxed for 12 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 9:1) to give the object compound asan oily substance. 2.18 g (yield: 52.2%)1H-NMR (CDCl3) δ; 2.17 (3H, s), 2.75-2.89 (4H, m), 3.41 (2H,t, J = 8.0 Hz), 3.85 (2H, t, J = 8.0 Hz), 4.95 (1H, s),5.88 (1H, d, J = 3.2 Hz), 6.01 (1H, d, J = 3.2 Hz),6.70 (2H,d, J = 8.4 Hz), 6.84 (2H, d, J = 8.4 Hz), 7.32-8.06 (7H, m).IR (KBr) cm-1; 3362,1613, 1595,1514,1441,1418,1395,1360,1298,1260,1219,1173, 828, 781,756,733. (7) Ethyl (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl)-1H-pyrrol-1-yl}ethyl}phenoxy]-3-phenylpropanoate
    [0677] To a solution of 4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl)phenol(2.10 g, 5.92mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.73 g, 8.89mmol) and triphenylphosphine (2.33 g, 8.89 mmol) in toluene(20 ml) was added 1,1'-(azodicarbonyl)dipiperidine (2.24 g,8.89 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.960 mg (yield: 30.5%)1H-NMR (CDCl3) δ; 1.16 (3H, t, J = 7.4 Hz), 2.14 (3H, s),2.72 (2H, t, J = 7.6Hz), 2.86 (2H, t, J = 7.6Hz), 3.20-3.29(2H, m), 3.40 (2H, t, J = 7.6Hz), 3.82 (2H, t, J = 7.6 Hz),4.07 (2H, q, J = 7.4 Hz), 4.70-4.76 (1H, m), 5.86 (1H, d, J= 3.4 Hz), 6.00 (1H, d, J = 3.4 Hz),6.71 (2H, d, J = 8.8Hz),6.85 (2H, d, J = 8.8 Hz), 7.21-8.06 (12H, m).IR (KBr) cm-1; 1752, 1510,1298, 1238, 1188, 1084, 1028, 781,748, 700. Example 126Sodium (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(2-{2-Methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoicacid
    [0678] To a mixed solution of ethyl (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl}phenoxy}-3-phenylpropanoate(960 mg, 1.81 mmol) in THF (20 ml) andmethanol (10 ml) was added 1N aqueous potassium hydroxidesolution (5.42 ml, 5.42 mmol) and the mixture was stirredfor 1 hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =3:1 ) to give the object compound as an oily substance.880 mg (yield: 96.5%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 2.71 (2H, t, J = 7.0 Hz),2.84 (2H, t, J = 9.2Hz), 3.25 (2H, d, J = 6.2 Hz), 3.39 (2H,t, J = 9.2Hz), 3.82 (2H, t, J = 7.0 Hz), 4.79 (1H, t, J =6.2 Hz), 5.86 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J = 3.4Hz),6.72 (2H, d, J = 8.6Hz), 6.85 (2H, d, J = 8.6 Hz),7.18-8.05 (12H, m).IR (KBr) cm-1; 3032, 1728, 1510, 1236, 1181, 1084, 781, 733,700. (2) Sodium (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl)phenoxy]-3-phenylpropanoate
    [0679] Ethanol (8 ml) and a solution of 1N sodium hydroxidein ethanol (1.49 ml) were added to (2R)-2-[4-(2-{2-methyl-5-[2-(1-naphthyl)ethyl]-1H-pyrrol-1-yl}ethyl}phenoxy}-3-phenylpropanoicacid (835 mg, 1.66 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid.711 mg (yield: 90.8%)1H-NMR (DMSO-d6) δ; 2.11 (3H, s), 2.61 (2H, t, J = 7.8 Hz),2.83 (2H, t, J = 7.0Hz), 2.95-3.17 (2H, m), 3.31 (2H, t, J= 7.0 Hz),3.79 (2H, t, J = 7.8 Hz), 4.24-4.30 (1H, m), 5.68(1H, d, J = 3.4 Hz), 5.82 (1H, d, J = 3.4 Hz),6.65 (2H, d,J = 8.4Hz), 6.83 (2H, d, J = 8.4 Hz), 7.08-8.08 (12H, m).IR (KBr) cm-1; 1615, 1510, 1416, 1232, 1059,1017,779, 747.[α]D 26 15.6° (c 0.515, methanol) Example 127Ethyl (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate(1) Ethyl (2E)-3-(2-trifluoromethylphenyl) propenoate
    [0680] The object compound was obtained from 2-trifluoromethylbenzaldehyde as an oily substance,according to the similar manner to that of Example 125(1).yield: 96.9% 1H-NMR (CDCl3) δ; 1.35 (3H, t, J = 7.4 Hz), 4.29 (2H, q, J= 7.4 Hz), 6.41 (1H, d, J = 15.8 Hz), 7.48-7.73 (4H, m),8.02-8.11 (1H, m).IR (KBr) cm-1; 1717, 1642, 1315, 1292, 1277, 1163, 1126,1038, 980. (2) Ethyl 3-(2-trifluoromethylphenyl)propanoate
    [0681] The object compound was obtained from ethyl (2E)-3-(2-trifluoromethylphenyl)propenoateas an oily substance,according to the similar manner to that of Example 125(2).yield: 87.5%1H-NMR (CDCl3) δ; 1.25 (3H, t, J = 7.2 Hz), 2.62 (2H, t, J= 7.4 Hz), 3.14 (2H, t, J = 7.4 Hz), 4.15 (2H, q, J = 7.2Hz), 7.27-7.65 (4H, m).IR (KBr) cm-1; 1736, 1316, 1177, 1154, 1119, 1061, 1040,758, 652. (3) 3-(2-Trifluoromethylphenyl)-1-propanol
    [0682] The object compound was obtained from ethyl 3-(2-trifluoromethylphenyl)propanoateas an oily substance,according to the similar manner to that of Example 125(3).yield: 96.4%1H-NMR (CDCl3) δ; 1.40 (1H, t, J = 5.6 Hz), 1.82-1.97 (2H,m), 2.89 (2H, t, J = 8.4 Hz), 3.68-3.78 (2H, m), 7.18-7.64(4H, m). IR (KBr) cm-1; 3303, 1314, 1157, 1117, 1061, 1032, 768. (4) 3-(2-Trifluoromethylphenyl)propanal
    [0683] The object compound was obtained from 3-(2-trifluoromethylphenyl)-1-propanolas an oily substance,according to the similar manner to that of Example 125(4).yield: 96.6%1H-NMR (CDCl3) δ; 2.79 (2H, t, J = 8.0 Hz), 3.14 (2H, t, J= 8.0 Hz), 7.16-7.65 (4H, m), 9.83 (1H, s).IR (KBr) cm-1; 1725, 1608, 1454, 1314, 1161, 1119, 1061,1038, 770. (5) 7-(2-Trifluoromethylphenyl)-2,5-heptanedione
    [0684] The object compound was obtained from 3-(2-trifluoromethylphenyl)propanalas an oily substance,according to the similar manner to that of Example 125(5).yield: 41.3%1H-NMR (CDCl3) δ; 2.20 (3H, s), 2.63-3.12 (8H, m), 7.27-7.64(4H, m).IR (KBr) cm-1; 1713, 1314, 1163, 1118, 1061, 1038, 770, 654. (6) 1-(4-Methoxyphenethyl)-2-methoxy-5-(2-trifluoromethylphenethyl)-1H-pyrrole
    [0685] The object compound was obtained from 7-(2-trifluoromethylphenyl)-2,5-heptanedioneas an oily substance, according to the similar manner to that ofExample 125(6). yield: 44.5%1H-NMR (CDCl3) δ; 2.17 (3H, s), 2.66-3.14 (6H, m), 3.78 (3H,s), 3.90 (2H, t, J = 7.4 Hz), 5.84 (1H, d, J = 3.2 Hz),5.90 (1H, d, J = 3.2 Hz), 6.81 (2H, d, J = 8.4 Hz), 6.96(2H, d, J = 8.4 Hz), 7.25-7.66 (4H, m).IR (KBr) cm-1; 1611, 1512, 1314, 1248, 1119, 1038, 826, 738,754. (7) 4-{2-[2-Methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl)phenol
    [0686] The object compound was obtained from 1-(4-methoxyphenethyl)-2-methoxy-5-(2-trifluoromethylphenethyl)-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 125(7). yield: 96.6%1H-NMR (CDCl3) δ; 2.15 (3H, s), 2.66-3.13 (6H, m), 3.88 (2H,t, J = 7.8 Hz), 4.95 (1H, bs), 5.83-5.91 (2H, m), 6.74 (2H,d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.26-7.65 (4H, m).IR (KBr) cm-1; 3306, 1611, 1514, 1314, 1121, 1038, 828, 768. (8) Ethyl (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0687] The object compound was obtained from 4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenol as an oily substance, according to the similar manner tothat of Example 125(8). yield: 25.2%1H-NMR (CDCl3) δ; 1.17 (3H, t, J = 7.6 Hz), 2.13 (3H, s),2.67-2.80 (4H, m), 3.04-3.12 (2H, m), 3.21-3.25 (2H, m),3.86 (2H, t, J = 8.0 Hz), 4.15 (2H, q, J = 7.6 Hz), 4.71-4.78(1H, m), 5.82 (1H, d, J = 3.2 Hz), 5.89 (1H, d, J =3.2 Hz), 6.74 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz),7.15-7.65 (9H, m).IR (KBr) cm-1; 1755, 1732, 1510, 1314, 1238, 1181, 1119,1038, 768, 748, 700.[α]D 27 10.9° (c 0.525, chloroform) Example 128Sodium (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{2-[2-Methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoicacid
    [0688] The object compound was obtained from ethyl (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 126(1).yield: 98.5%1H-NMR (CDCl3) δ; 2.13 (3H, s), 2.66-2.80 (4H, m), 3.04-3.12(2H, m), 3.26 (2H, t, J = 6.6 Hz), 3.82 (2H, t, J = 7.8 Hz), 4.81 (1H, t, J = 6.6 Hz), 5.82 (1H, d, J = 3.4 Hz),5.89 (1H, d, J = 3.4 Hz), 6.75 (2H, d, J = 8.8 Hz), 6.93(2H, d, J = 8.8 Hz), 7.22-7.65 (9H, m).IR (KBr) cm-1; 2928, 1730, 1510, 1314, 1233, 1117, 1038,766, 754, 700.[α]D 28 3.65° (c 1.12, chloroform) (2) Sodium (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoate
    [0689] The object compound was obtained from (2R)-2-(4-{2-[2-methyl-5-(2-trifluoromethylphenethyl)-1H-pyrrol-1-yl]ethyl}phenoxy)-3-phenylpropanoicacid as a solid,according to the similar manner to that of Example 126(2).yield: 77.8%1H-NMR (DMSO-d6) δ; 2.11 (3H, s), 2.65- 2.73 (4H, m), 2.90-3.16(4H, m), 3.82 (2H, t, J = 7.4 Hz), 4.24-4.31 (1H, m),5.65 (1H, d, J = 3.6 Hz), 5.69 (1H, d, J = 3.6 Hz), 6.66(2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.12-7.68(9H, m).IR (KBr) cm-1; 1613, 1508, 1416, 1314, 1233, 1118, 1061,1038, 767, 700. Example 129Ethyl (2R)-2-{4-[1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-{2-[2-(4-Benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol
    [0690] A solution of 1-(4-benzyloxyphenyl)-1,4-pentanedione(3.00 g, 10.6 mmol), tyramine (1.46 g, 10.6 mmol) and p-toluenesulfonicacid monohydrate (151 mg, 0.792 mmol) intoluene (100 ml) was refluxed for 12 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 8:1) to give the object compound asan oily substance. 3.00 g (yield: 73.7%)1H-NMR (CDCl3) δ; 2.22 (3H, s), 2.67 (2H, t, J = 7.4 Hz),4.00 (2H, t, J = 7.4 Hz), 4.72 (1H, s), 5.11 (2H, s), 5.91(1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.65 (2H, d,J = 8.8 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8Hz),7.24-7.49 (7H, m).IR (KBr) cm-1; 3389, 1613, 1514, 1242, 1175, 1024, 833, 739,698. (2) 2-(4-Benzyloxyphenyl)-1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrole
    [0691] A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(1.50 g, 3.91 mmol), 1-bromododecane(1.41 ml, 5.87 mmol) and potassium carbonate(811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80°C for 4 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas washed with water, dried over magnesium sulfateanhydride and solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to give theobject compound as an oily substance. 1.28 g (yield:59.3%)1H-NMR (CDC13) δ; 0.88 (3H, t,J = 6.6 Hz), 1.22-1.43 (18H,m), 1.69-1.79 (2H, m), 2.23 (3H, s), 2.69 (2H, t, J = 7.8Hz), 3.90 (2H, t, J = 6.6 Hz),3.99 (2H, t, J = 7.8 Hz),5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.00 (2H, d, J = 8.8 Hz),7.24-7.50 (7H, m).IR (KBr) cm-1; 1523, 1512, 1175, 1026, 835, 756, 698. (3) 4-[1-(4-Dodecyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0692] To a solution of 2-(4-benzyloxyphenyl)-1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrole(1.23 g, 2.23mmol) in ethanol (40 ml) and tetrahydrofuran (20 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred under hydrogen atmosphere for 2 hours. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oily substance. 1.02 g (yield: 99.0%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.18-1.42 (18H,m), 1.68-1.79 (2H, m), 2.23 (3H, s), 2.68 (2H, t, J = 7.6Hz), 3.90 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 7.6 Hz),5.91 (1H, d, J = 3.4 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.72-6.87(6H, m), 7.72 (2H, d, J = 8.6 Hz).IR (KBr) cm-1; 3405, 1526, 1512, 1468, 1246, 1177, 837, 821,756. (4) Ethyl (2R)-2-{4-[1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0693] To a solution of 4-[1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.00 g, 2.17 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (631 mg, 3.25 mmol) andtriphenylphosphine (852 mg, 3.25 mmol) in toluene (10 ml)was added 1,1'-(azodicarbonyl)dipiperidine (820 mg, 3.25mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.471 mg (yield: 34.1%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.16-1.38 (21H, m), 1.72-1.79 (2H, m), 2.22 (3H, s), 2.66 (2H, t, J = 7.4Hz), 3.26-3.30 (2H, m), 3.89 (2H, t, J = 6.6 Hz), 3.97 (2H,t, J = 7.4 Hz), 4.20 (2H, q, J = 7.4 Hz), 4.79-4.86 (1H, m),5.89 (1H, d, J = 3.8 Hz), 6.00 (1K, d, J = 3.8 Hz), 6.70-6.88(6H, m), 7.20-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1244, 1179, 1032, 837, 756,700. Example 130Sodium (2R)-2-{4-[1-(4-dodecyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0694] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(461 mg, 0.722 mmol) in THF (10 ml) andmethanol (5 ml) was added 1N aqueous potassium hydroxidesolution (2.16 ml, 2.16 mmol) and the mixture was stirredfor 1 hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance. 360 mg (yield: 81.6%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.18-1.47 (18H,m), 1.71-1.79 (2H, m) , 2.21 (3H, s), 2.64 (2H, t, J = 6.2Hz), 3.31 (2H, d, J = 5.8 Hz), 3.85-4.01 (4H, m), 4.90 (1H,t, J = 5.8 Hz), 5.89 (1H, d, J = 3.2 Hz), 5.99 (1H, d, J =3.2 Hz), 6.69-6.88 (6H, m), 7.19-7.31 (7H, m).IR (KBr) cm-1; 2926, 1728, 1512, 1244, 1177, 835, 756. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0695] Ethanol (3 ml) and a solution of 1N sodium hydroxidein ethanol (0.480 ml) were added to (2R)-2-{4-[5-methyl-1-(4-dodecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (325 mg, 0.533 mmol) and the mixturewas concentrated. To the residue was added ether to givethe object compound as a solid. 160 mg (yield: 52.8%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 7.0 Hz), 1.07-1.41(18H, m), 1.61-1.75 (2H, m), 2.11 (3H, s), 2.50-2.69 (2H,m), 3.24-3.02 (2H, m), 3.80-3.99 (4H, m), 4.31-4.36 (1H, m),5.73 (1H, d, J = 3.2 Hz), 5.80 (1H, d, J = 3.2 Hz), 6.70-6.80(6H, m), 7.10-7.30 (7H, m).IR (KBr) cm-1; 1614, 1512, 1408, 1244, 1177, 1055, 1030,829, 758, 700.[α]D 25 2.96° (c 0.540, methanol) Example 131Ethyl (2R)-2-{4-[l-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-heptyloxyphenethyl)-1H-pyrrole
    [0696] The object compound was obtained from 1-bromoheptaneas an oily substance, according to the similar manner tothat of Example 129(2). yield: 84.6%1H-NMR (CDCl3) δ; 0.89 (3H, t,J = 7.0 Hz), 1.22-1.43 (8H,m), 1.69-1.79 (2H, m), 2.24 (3H, s), 2.69 (2H, t, J = 8.0Hz), 3.90 (2H, t, J = 6.6 Hz), 4.00 (2H, t, J = 8.0 Hz),5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),6.99 (2H, d, J = 8.8 Hz),7.24-7.50 (7H, m).IR (KBr) cm-1; 1613, 1524, 1512, 1244, 1175, 1024, 835, 754,737, 698. (2) 4-[1-(4-Heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0697] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-(4-heptyloxyphenethyl)-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 129(3). yield: 97.6%1H-NMR (CDCl3) δ; 0.89 (3H, t,J = 6.6 Hz), 1.21-1.45 (8H,m), 1.69-1.79 (2H, m), 2.23 (3H, s), 2.68 (2H, t, J = 7.6 Hz), 3.90 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 7.6 Hz),5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J = 3.2 Hz), 6.72-6.80(6H, m), 7.22 (2H, d, J = 8.6 Hz).IR (KBr) cm-1; 3312, 1613, 1512, 1470, 1400, 1246, 1177,837, 826, 758. (3) Ethyl (2R)-2-(4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0698] The object compound was obtained from 4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 129(4). yield: 47.1%1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.6 Hz), 1.16-1.39 (11H,m), 1.71-1.79 (2H, m), 2.22 (3H, s), 2.65 (2H, t, J = 6.8Hz), 3.25-3.29 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.4 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.4 Hz), 6.00(1H, d, J = 3.4 Hz), 6.70-6.88 (6H, m), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1479, 1277, 1244, 1179,1028, 835, 756. Example 132Sodium (2R)-2-{4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0699] The object compound was obtained from ethyl (2R)-2-{4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 130(1). yield: 72.9%1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 7.0 Hz), 1.22-1.43 (8H,m), 1.71-1.79 (2H, m), 2.22 (3H, s), 2.65 (2H, t, J = 8.0Hz), 3.32 (2H, d, J = 6.2 Hz), 3.86-4.01 (4H, m), 4.91 (1H,t, J = 6.2 Hz), 5.90 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J =3.4 Hz), 6.70-6.88 (6H, m), 7.20-7.32 (7H, m).IR (KBr) cm-1; 1728, 1512, 1242, 835, 756, 700. (2) Sodium (2R)-2-{4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0700] The object compound was obtained from (2R)-2-{4-[1-(4-heptyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 130(2). yield: 69.8 %1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 7.0 Hz), 1.08-1.41 (8H,m), 1.58-1.73 (2H, m), 2.11 (3H, s), 2.52 - 2.65 (2H, m),2.94-3.21 (2H, m), 3.85-3.91 (4H, m), 4.35-4.40 (1H, m),5.74 (1H, d, J = 3.2 Hz), 5.81 (1H, d, J = 3.2 Hz), 6.72-6.85(6H, m), 7.11-7.34 (7H, m).IR (KBr) cm-1; 1615, 1512, 1406, 1244, 1057, 1030, 829, 758,700,563, 532.[α]D 25 2.85° (c 0.580, methanol) Example 133Ethyl (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-nonyloxyphenethyl)-1H-peel
    [0701] The object compound was obtained from 1-bromononane as anoily substance, according to the similar manner to that ofExample 129(2). yield: 87.4%1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.8 Hz), 1.16-1.53 (12H,m), 1.72-1.79 (2H, m), 2.24 (3H, s), 2.69 (2H, t, J = 7.8Hz), 3.90 (2H, t, J = 6.6 Hz), 4.00 (2H, t, J = 7.8 Hz),5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.04 (1H, d, J =3.2 Hz), 6.74 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.00 (2H, d, J = 8.8 Hz),7.25-7.49 (7H, m).IR (KBr) cm-1; 1613, 1524, 1512, 1244, 1175, 1026, 835, 754,737. (2) 4-[5-Methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenol
    [0702] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 129(3). yield: 96.6%1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.21-1.42 (12H, m), 1.71-1.79 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 7.2Hz), 3.90 (2H, t, J = 6.2 Hz), 3.99 (2H, t, J = 7.2 Hz),5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J = 3.2 Hz), 6.72-6.87(6H, m), 7.22 (2H, d, J = 8.2 Hz).IR (KBr) cm-1; 3385, 1615, 1512, 1470, 1399, 1244, 1177,837, 824, 758. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0703] The object compound was obtained from 4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 129(4). yield: 54.8%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.16-1.39 (15H,m), 1.72-1.79 (2H, m), 2.22 (3H, s), 2.66 (2H, t, J = 8.4Hz), 3.26-3.29 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.4 Hz), 4.79-4.86 (1H, m), 5.90 (1H, d, J = 3.4 Hz), 6.00(1H, d, J = 3.4 Hz), 6.70-6.88 (6H, m), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732,1512, 1481, 1244, 1179, 1032, 835,756, 700. Example 134Sodium (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid
    [0704] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as an oily substance, according to thesimilar manner to that of Example 130(1). yield: 86.8%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.22-1.41 (12H,m), 1.71-1.78 (2H, m), 2.21 (3H, s), 2.64 (2H, t, J = 7.0Hz), 3.31 (2H, d, J = 6.2 Hz), 3.85-4.00 (4H, m), 4.89 (1H,t, J = 6.2 Hz), 5.89 (1H, d, J = 3.8 Hz), 6.00 (1H, d, J =3.8 Hz), 6.69-6.88 (6H, m), 7.19-7.31 (7H, m).IR (KBr) cm-1; 1728, 1512, 1242, 1177, 1086, 1032, 835, 758,700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0705] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 130(2). yield: 82.1%1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 6.6 Hz), 1.19-1.33(12H, m), 1.65-1.71 (2H, m), 2.11 (3H, s), 2.54-2.68 (2H,m), 2.96-3.23 (2H, m), 3.84-3.91 (4H, m), 4.33-4.39 (1H, m),5.73 (1H, d, J = 3.2 Hz), 5.81 (1H, d, J = 3.2 Hz), 6.70-6.85(6H, m), 7.10-7.35 (7H, m).IR (KBr) cm-1; 1615, 1512, 1406, 1244, 1175, 1055, 1032, 839, 758.[α]D 24 1.88° (c 0.525, methanol) Example 135Ethyl (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrole
    [0706] The object compound was obtained from 1-bromohexane asan oily substance, according to the similar manner to thatof Example 129(2). yield: 70.5%1H-NMR (CDCl3) δ; 0.90 (3H, t,J = 6.6 Hz), 1.27-1.48 (6H,m), 1.69-1.79 (2H, m), 2.24 (3H, s), 2.69 (2H, t, J = 7.4Hz), 3.90 (2H, t, J = 6.2 Hz), 4.00 (2H, t, J = 7.4 Hz),5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.74 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.00 (2H, d, J = 8.8 Hz),7.03-7.50 (7H, m).IR (KBr) cm-1; 1613, 1524, 1246, 1175, 1026, 835, 756, 737,698. (2) 4-[1-(4-Hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0707] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrroleas an oily substance, according to the similar manner to that of Example 129(3). yield: 97.0%1H-NMR (CDCl3) δ; 0.908 (3H, t,J = 6.6 Hz), 1.25-1.47 (6H,m) , 1.68-1.79 (2H, m), 2.23 (3H, s), 2.68 (2H, t, J = 7.8Hz), 3.87-4.02 (4H, m), 5.91 (1H, d, J = 3.2 Hz), 6.02 (1H,d, J = 3.2 Hz), 6.72-6.87 (6H, m), 7.21 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3407, 1613, 1526, 1512, 1244, 1177, 1030,837, 822, 758. (3) Ethyl (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0708] The object compound was obtained from 4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 129(4). yield: 53.3%1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 6.0 Hz), 1.16-1.48 (9H,m), 1.69-1.79 (2H, m), 2.22 (3H, s), 2.66 (2H, t, J = 7.6Hz), 3.26-3.30 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.0 Hz), 4.79-4.86 (1H, m) , 5.90 (1H, d, J = 3.6 Hz), 6.00(1H, d, J = 3.6 Hz), 6.71-6.92 (6H, m), 7.18-7.32 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1244, 1179, 1086, 1032,835, 756, 700. Example 136Sodium (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0709] The object compound was obtained from ethyl (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 130(1). yield: 78.9%1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 6.2 Hz), 1.26-1.42 (6H,m), 1.68-1.78 (2H, m), 2.21 (3H, s), 2.64 (2H, t, J = 8.8Hz), 3.31 (2H, d, J = 6.2 Hz), 3.86-4.00 (4H, m), 4.90 (1H,t, J = 6.2 Hz), 5.89 (1H, d, J = 3.6 Hz), 5.99 (1H, d, J =3.6 Hz), 6.69-6.88 (6H, m), 7.19-7.33 (7H, m).IR (KBr) cm-1; 2934, 1728, 1512, 1244, 835, 758, 700. (2) Sodium (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0710] The object compound was obtained from (2R)-2-{4-[1-(4-hexyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 130(2). yield: 96.2%1H-NMR (DMSO-d6) δ; 0.88 (3H, t, J = 6.2 Hz), 1.25-1.39 (6H,m), 1.64-1.72 (2H, m), 2.11 (3H, s), 2.55-2.68 (2H, m),2.95-3.20 (2H, m), 3.84-3.91 (4H, m), 4.35-4.39 (1H, m),5.73 (1H, d, J = 3.2 Hz), 5.81 (1H, d, J = 3.2 Hz), 6.70-6.84(6H, m), 7.10-7.34 (7H, m).IR (KBr) cm-1; 1615, 1512, 1406, 1308, 1244, 1177, 1057, 1032, 829, 758, 700.[α]D 25 1.73° (c 0.700, methanol) Example 137Ethyl (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenethyl)-5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrole
    [0711] A solution of 4-{2-[2-(4-benzyloxyphenethyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(1.00 g, 2.61 mmol), 1-bromooctane(0.541 ml, 3.13 mmol) and potassium carbonate(433 mg, 3.13 mmol) in DMF (10 ml) was stirred at 80°C for4 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas washed with water, dried over magnesium sulfateanhydride and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to give theobject compound as an oily substance. 1.03 g (yield:79.8%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.10-1.56 (10H,m), 1.69-1.79 (2H, m), 2.24 (3H, s), 2.69 (2H, t, J = 7.4Hz), 3.90 (2H, t, J = 6.6 Hz),4.00 (2H, t, J = 7.4 Hz),5.11 (2H, s), 5.92 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.74 (2H, d, J = 8.4 Hz), 6.82 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz),7.26-7.49 (7H, m).IR (KBr) cm-1; 1610, 1512, 1246, 1180, 1025, 830. (2) 4-[5-Methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenol
    [0712] To a solution of 2-(4-benzyloxyphenethyl)-5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrole(980 mg, 1.98 mmol) inethanol (20 ml) and tetrahydrofuran (10 ml) was added 10%palladium carbon (100 mg) and the mixture was stirred underhydrogen atmosphere for 2 hours. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 800 mg (yield:99.6%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 7.0 Hz), 1.21-1.51 (10H,m), 1.69-1.79 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 7.6Hz), 3.87-4.03 (4H, m), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H,d, J = 3.2 Hz), 6.72-6.89 (6H, m), 7.72 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 2930, 1512, 1246, 1175, 837, 758. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0713] To a solution of 4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenol(800 mg, 1.98 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(779 mg, 4.00 mmol) andtriphenylphosphine (1.05 g, 4.00 mmol) in toluene (10 ml) was added 1,1'-(azodicarbonyl)dipiperidine (1.01 g, 4.00mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.420 mg (yield: 36.5%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.16-1.51 (13H,m), 1.71-1.79 (2H, m), 2.22 (3H, s), 2.66 (2H, t, J = 7.4Hz), 3.25-3.29 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.2 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.2 Hz), 6.00(1H, d, J = 3.2 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1244, 1179, 1032, 835, 758,700. Example 138Sodium (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0714] To a mixed solution of ethyl (2R)-2-(4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(410 mg, 0.704 mmol) in THF (10 ml) and methanol (5 ml) was added 1N aqueous potassium hydroxidesolution (2.11 ml, 2.11 mmol) and the mixture was stirredfor 1 hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) to givethe object compound as an oily substance. 303 mg (yield:77.5%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.22-1.52 (10H,m), 1.71-1.79 (2H, m), 2.22 (3H, s), 2.65 (2H, t, J = 7.2Hz), 3.32 (2H, d, J = 6.4 Hz), 3.86-4.01 (4H, m), 4.90 (1H,t, J = 6.4 Hz), 5.90 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J =3.4 Hz), 6.70-6.88 (6H, m), 7.20-7.32 (7H, m).IR (KBr) cm-1; 3032, 1728, 1512, 1242, 1177, 833, 756, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0715] Ethanol (2 ml) and a solution of 1N sodium hydroxidein ethanol (0.451 ml) were added to (2R)-2-{4-[5-methyl-1-(4-octyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (278 mg, 0.501 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid. 227 mg (yield: 87.3%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 6.4 Hz), 1.12-1.51(10H, m), 1.59-1.66 (2H, m), 2.11 (3H, s), 2.20-2.71 (6H,m), 2.93-3.18 (2H, m), 3.85-3.91 (4H, m), 4.29-4.41 (1H, m),5.74 (1H, d, J = 3.4 Hz), 5.81 (1H, d, J = 3.4 Hz), 6.71-6.86(6H, m), 7.11-7.34 (7H, m).IR (KBr) cm-1; 2928, 1615, 1512, 1242, 1175, 1055, 1030,839, 758, 700. Example 139Ethyl (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenethyl)-5-methyl-1-(4-decyloxyphenethyl)-1H-pyrrole
    [0716] The object compound was obtained from 1-bromodecane asan oily substance, according to the similar manner to thatof Example 137(1). yield: 85.9%1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.10-1.56 (14H,m), 1.69-1.81 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 6.6Hz), 3.87-4.03 (4H, m), 5.11 (2H, s), 5.91 (1H, d, J = 3.4Hz), 6.03 (1H, d, J = 3.4 Hz), 6.74 (2H, d, J = 8.8 Hz),6.82 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.2 Hz),7.25-7.45(7H, m).IR (KBr) cm-1; 1512, 1470, 1456, 1246, 1175, 1024, 833, 754,735, 698. (2) 4-[1-(4-Decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0717] The object compound was obtained from 2-(4-benzyloxyphenethyl)-5-methyl-1-(4-decyloxyphenethyl)-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 137(2). yield: 95.0%1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.4 Hz), 1.06-1.42 (14H,m), 1.68-1.79 (2H, m), 2.23 (3H, s), 2.68 (2H, t, J = 8.0Hz), 3.87-4.02 (4H, m), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H,d, J = 3.2 Hz), 6.72-6.88 (6H, m), 7.21 (2H, d, J = 8.6 Hz).IR (KBr) cm-1; 3378, 1615, 1512, 1470, 1246, 1177, 837, 822,758. (3) Ethyl (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0718] The object compound was obtained from 4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenolas anoily substance, according to the similar manner to that ofExample 137(3). yield: 34.4%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.16-1.46 (17H,m), 1.72-1.79 (2H, m), 2.22 (3H, s), 2.656 (2H, t, J = 6.8Hz), 3.25-3.30 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.0 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.4 Hz), 6.00(1H, d, J = 3.4 Hz), 6.70-6.87 (6H, m), 7.19-7.34 (7H, m). IR (KBr) cm-1; 1755, 1732, 1512, 1244, 1179, 1030, 835, 756,700. Example 140Sodium (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0719] The object compound was obtained from ethyl (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 138(1). yield: 88.7%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.21-1.48 (14H,m), 1.71-1.80 (2H, m), 2.21 (3H, s), 2.64 (2H, t, J = 6.2Hz), 3.31 (2H, d, J = 6.2 Hz), 3.86-4.01 (4H, m), 4.90 (1H,t, J = 6.2 Hz), 5.90 (1H, d, J = 3.6 Hz), 6.00 (1H, d, J =3.6 Hz), 6.69-6.89 (6H, m), 7.20-7.31 (7H, m).IR (KBr) cm-1; 2930, 1728, 1512, 1242, 1177, 835, 754. (2) Sodium (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0720] The object compound was obtained from (2R)-2-{4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 138(2). yield: 82.5% 1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 7.0 Hz), 1.08-1.48(14H, m), 1.58-1.77 (2H, m), 2.11 (3H, s), 2.51-2.68 (2H,m), 2.93-3.20 (2H, m), 3.79-4.00 (4H, m), 4.32-4.36 (1H, m),5.73 (1H, d, J = 3.6 Hz), 5.81 (1H, d, J = 3.6 Hz), 6.71-6.81(6H, m), 7.10-7.30 (7H, m).IR (KBr) cm-1; 2924, 1615, 1512, 1404, 1244, 1177, 1055,1030, 839, 829, 756, 700.[α]D 26 1.81° (c 0.510, methanol) Example 141Ethyl (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrole
    [0721] A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(1.50 g, 3.91 mmol), 1-bromoundecane(1.31 ml, 5.87 mmol) and potassium carbonate(811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80°C for4 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas washed with water and dried over magnesium sulfateanhydride, and the solvent was removed under reducedpressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to give theobject compound as an oily substance. 1.80 g (yield: 85.7%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.26-1.46 (16H,m), 1.68-1.79 (2H, m), 2.23 (3H, s), 2.69 (2H, t, J = 7.6Hz), 3.90 (2H, t, J = 6.6 Hz),4.00 (2H, t, J = 7.6 Hz),5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.00 (2H, d, J = 8.8 Hz),7.25-7.50 (7H, m).IR (KBr) cm-1; 1611, 1524, 1512, 1468, 1454, 1246, 1175,1026, 835, 756, 735, 698. (2) 4-[5-Methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenol
    [0722] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrole(1.70 g, 3.16 mmol) inethanol (60 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 1.29 g (yield:91.5%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.9 Hz), 1.26-1.43 (16H,m), 1.70-1.78 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 7.8Hz), 3.90 (2H, t, J = 6.6 Hz), 3.98 (2H, t, J = 7.8 Hz),5.90 (1H, d, J = 3.3 Hz), 6.02 (1H, d, J = 3.3 Hz), 6.72-6.87(4H, m), 7.16-7.25 (4H, m). IR (KBr) cm-1; 3408, 1613, 1512, 1468, 1246, 1177, 837, 824,758. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0723] To a solution of 4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenol(1.29 g, 2.88mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (838 mg, 4.32mmol) and triphenylphosphine (1.13 g, 4.32 mmol) in toluene(1 ml) was added 1,1'-(azodicarbonyl)dipiperidine (1.09 mg,3.25 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.710 mg (yield: 39.4%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.16-1.47 (19H,m), 1.68-1.79 (2H, m), 2.22 (3H, s), 2.66 (2H, t, J = 7.8Hz), 3.25-3.29 (2H, m), 3.86-4.00 (4H, m), 4.20 (2H, q, J =7.4 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.2 Hz), 6.00(1H, d, J = 3.2 Hz), 6.70-6.89 (6H, m), 7.18-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1613, 1512, 1244, 1179, 1030,835, 756, 700. Example 142Sodium (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0724] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(700 mg, 1.12 mmol) in THF (25 ml) andmethanol (12 ml) was added 1N aqueous potassium hydroxidesolution (5 ml, 5 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride,and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.520 mg (yield: 77.8%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.23-1.45 (16H,m), 1.71-1.78 (2H, m), 2.22 (3H, s), 2.65 (2H, t, J = 7.4Hz), 3.32 (2H, d, J = 5.8 Hz), 3.86-4.01 (4H, m), 4.90 (1H,t, J = 5.8 Hz), 5.89 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J =3.4 Hz), 6.69-6.88 (6H, m), 7.20-7.33 (7H, m).IR (KBr) cm-1; 2924, 1728, 1512, 1244, 1176, 835, 758, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0725] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.724 ml) were added to (2R)-2-{4-[5-methyl-1-(4-undecyloxyphenethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (480 mg, 0.804 mmol) and the mixturewas concentrated. To the residue was added hexane to givethe object compound as a solid. 375 mg (yield: 83.9%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 7.0 Hz), 1.15-1.39(16H, m), 1.61-1.73 (2H, m), 2.11 (3H, s), 2.56-2.68 (2H,m), 2.95-3.20 (2H, m), 3.84-3.91 (4H, m), 4.33-4.42 (1H, m),5.73 (1H, d, J = 3.2 Hz), 5.81 (1H, d, J = 3.2 Hz), 6.70-6.84(6H, m), 7.10-7.34 (7H, m).IR (KBr) cm-1; 1613, 1582, 1512, 1468, 1454, 1406, 1310,1244, 1177, 1055, 1030, 835, 758, 700.[α]D 25 3.33° (c 0.565, methanol) Example 143Ethyl (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrole
    [0726] The object compound was obtained from 3-phenylpropylbromideas an oily substance, according to the similar manner to that of Example 141(1). yield: 91.8%1H-NMR (CDCl3) δ; 1.96-2.15 (2H, m), 2.23 (3H, s), 2.65-2.84(4H, m), 3.88-4.04 (4H, m), 5.11 (2H, s), 5.91 (1H, d,J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.73 (2H, d, J = 8.8Hz), 6.82 (2H, d, J = 8.8 Hz), 6.99 (2H, d, J = 8.8Hz),7.15-7.45 (12H, m).IR (KBr) cm-1; 1611, 1524, 1454, 1309, 1279, 1246, 1175,1026, 835, 750, 698. (2) 4-{5-Methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenol
    [0727] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 141(2). yield: 99.3%1H-NMR (CDCl3) δ; 1.96-2.15 (2H, m), 2.23 (3H, s), 2.64-2.83(4H, m), 3.88-4.03 (4H, m), 5.91 (1H, d, J = 3.2 Hz),6.02 (1H, d, J = 3.2 Hz), 6.71-6.87 (6H, m), 7.15-7.33 (7H,m).IR (KBr) cm-1; 3314, 1613, 1512, 1246, 1177, 1036, 837, 756,700. (3) Ethyl (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0728] The object compound was obtained from 4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenolas anoily substance, according to the similar manner to that ofExample 141(3). yield: 39.5%1H-NMR (CDCl3) δ; 1.19 (3H, t, J = 7.0 Hz), 2.01-2.15 (2H,m), 2.22 (3H, s), 2.66 (2H, t, J = 7.6 Hz), 2.80 (2H, t, J= 8.0 Hz), 3.25-3.29 (2H, m), 3.88-4.00 (4H, m), 4.19 (2H,q, J = 7.0 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.4 Hz),6.00 (1H, d, J = 3.4 Hz), 6.70-6.88 (6H, m), 7.15-7.36 (12H,m).IR (KBr) cm-1; 1755, 1732, 1512, 1481, 1454, 1244, 1179,1032, 835, 754, 700. Example 144Sodium (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0729] The object compound was obtained from ethyl (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 142(1).yield: 99.5%1H-NMR (CDCl3) δ; 2.01-2.14 (2H, m), 2.21 (3H, s), 2.65 (2H, t, J = 7.4 Hz), 2.79 (2H, t, J = 8.0 Hz), 3.31 (2H, d, J =5.6 Hz), 3.87-4.01 (4H, m), 4.90 (1H, t, J = 5.6 Hz), 5.89(1H, d, J = 3.2 Hz), 6.00 (1H, d, J = 3.2 Hz), 6.69-6.88(6H, m), 7.15-7.32 (12H, m).IR (KBr) cm-1; 3028, 1733, 1512, 1244, 1177, 835, 754, 700. (2) Sodium (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0730] The object compound was obtained from (2R)-2-(4-{5-methyl-1-[4-(3-phenylpropoxy)phenethyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 142(1). yield: 93.2%1H-NMR (DMSO-d6) δ; 1.92-2.06 (2H, m), 2.11 (3H, s), 2.54-2.77(4H, m), 2.94-3.19 (2H, m), 3.86-3.92 (4H, m), 4.31-4.37(1H, m), 5.73 (1H, d, J = 3.4 Hz), 5.81 (1H, d, J =3.4 Hz), 6.72-6.86 (6H, m), 7.10-7.33 (12H, m).IR (KBr) cm-1; 1615, 1512, 1410, 1244, 1177, 1036, 839, 754,700.[α]D 26 2.40° (c 0.665, methanol) Example 145Ethyl (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl}phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrole
    [0731] The object compound was obtained from cyclohexylmethylbromide as an oily substance, according to the similarmanner to that of Example 141(1). yield: 67.6%1H-NMR (CDCl3) δ; 0.85-1.88 (11H, m), 2.24 (3H, s), 2.69(2H, t, J = 7.6 Hz), 3.70 (2H, d, J = 6.2 Hz), 3.99 (2H, t,J = 7.6 Hz), 5.11 (2H, s), 5.91 (1H, d, J = 3.2 Hz), 6.03(1H, d, J = 3.2 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.82 (2H, d,J = 8.8 Hz), 7.00 (2H, d, J = 9.2 Hz),7.24-7.50 (7H, m).IR (KBr) cm-1; 1613, 1524, 1512, 1481, 1468, 1453, 1244,1174, 1026, 835, 754, 698. (2) 4-[1-(4-Cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0732] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrolas an oily substance, according to the similarmanner to that of Example 141(2). yield: 98.6%1H-NMR (CDCl3) δ; 0.98-1.87 (11H, m), 2.24 (3H, s), 2.68(2H, t, J = 7.6 Hz), 3.70 (2H, d, J = 6.2 Hz), 3.98 (2H, t,J = 7.6 Hz), 5.91 (1H, d, J = 3.2 Hz), 6.02 (1H, d, J = 3.2Hz), 6.73-7.30 (8H, m).IR (KBr) cm-1; 3401, 1613, 1526, 1512, 1244, 1221, 1175,1026, 837, 758. (3) Ethyl (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0733] The object compound was obtained from 4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenolas an oily substance, according to the similar manner tothat of Example 141(3). yield: 59.0%1H-NMR (CDCl3) δ; 0.95-1.88 (14H, m), 2.22 (3H, s), 2.66(2H, t, J = 7.8 Hz), 3.25-3.29 (2H, m), 3.69 (2H, t, J =6.2 Hz), 3.96 (2H, t, J = 7.8 Hz), 4.20 (2H, q, J = 7.0 Hz),4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.6 Hz), 6.00 (1H, d, J= 3.6 Hz), 6.70-6.92 (6H, m), 7.18-7.36 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1279, 1244, 1179, 1028,835, 756, 700. Example 146Sodium (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0734] The object compound was obtained from (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as an oily substance,according to the similar manner to that of Example 142(1).yield: 59.4%1H-NMR (CDCl3) δ; 0.88-1.88 (11H, m), 2.22 (3H, s), 2.65 (2H, t, J = 7.4 Hz), 3.31 (2H, d, J = 6.2 Hz), 3.69 (2H, t,J = 6.4 Hz), 3.97 (2H, t, J = 7.4 Hz), 4.90 (1H, t, J = 6.2Hz), 5.90 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J = 3.4 Hz),6.69-6.88 (6H, m), 7.19-7.34 (7H, m).IR (KBr) cm-1; 3029, 1728, 1512, 1244, 1177, 1084, 1028,910, 835, 756, 735, 700. (2) Sodium (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0735] The object compound was obtained from (2R)-2-{4-[1-(4-cyclohexylmethoxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 142(2). yield: 98.9%1H-NMR (DMSO-d6) δ; 0.96-1.83 (11H, m), 2.11 (3H, s), 2.61(2H, t, J = 7.5 Hz), 3.00-3.22 (2H, m), 3.69 (2H, d, J =6.3 Hz), 3.91 (2H, t, J = 7.5 Hz), 4.37-4.41 (1H, m), 5.73(1H, d, J = 3.3 Hz), 5.81 (1H, d, J = 3.3 Hz), 6.70-6.83(6H, m), 7.10-7.34 (7H, m).IR (KBr) cm-1; 1615, 1512, 1410, 1244, 1028, 829, 758, 700.[α]D 25 -26.3° (c 0.610, methanol) Example 147Ethyl (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 4-[2-(4-Benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol
    [0736] A solution of 1-(4-benzyloxyphenyl)-1,4-pentanedione(10.0 g, 35.4 mmol), p-aminophenol (3.86 g, 35.4 mmol) andp-toluenesulfonic acid monohydrate (504 mg, 2.64 mmol) intoluene (300 ml) was refluxed for 12 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 7:1) to give the object compound asa solid. 6.11 g (yield: 48.5%)1H-NMR (CDCl3) δ; 2.10 (3H, s) , 4.95 (1H, s) , 4.98 (2H, s),6.05 (1H, d, J = 3.6 Hz), 6.24 (1H, d, J = 3.6 Hz), 6.75-6.83(4H, m), 6.96-7.04 (4H, m),7.30-7.42 (5H, m).IR (KBr) cm-1; 3034, 1516, 1240, 1179, 1015, 839, 764, 735,698. (2) 2-(4-Benzyloxyphenyl)-1-(4-decyloxyphenyl)-5-methyl-1H-pyrrole
    [0737] A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.50 g, 4.22 mmol), 1-bromoundecane(1.31 ml, 6.33 mmol) and potassium carbonate (874 mg, 6.33mmol) in DMF (15 ml) was stirred at 80°C for 4 hours. Thereaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate anhydride and solventwas removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate = 30:1) to give the object compound as an oilysubstance. 1.78 g (yield: 85.2%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.19-1.55 (16H,m), 1.72-1.83 (2H, m), 2.11 (3H, s), 3.95 (2H, t, J = 6.6Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.2 Hz), 6.25 (1H, d, J= 3.2 Hz), 6.73-7.40 (9H, m).IR (KBr) cm-1; 1609, 1514, 1485, 1470,1456, 1395, 1289, 1244,1177, 1040, 1026, 835, 760, 735, 698. (3) 4-[1-(4-Decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0738] To a solution of 2-(4-benzyloxyphenyl)-1-(4-decyloxyphenyl)-5-methyl-1H-pyrrole(1.70 g, 3.43 mmol) inethanol (60 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 1.30 g (yield:93.5%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 6.6 Hz), 1.21-1.48 (14H,m), 1.75-1.82 (2H, m), 2.10 (3H, s), 3.94 (2H, t, J = 6.2Hz), 6.04 (1H, d, J = 3.2 Hz), 6.23 (1H, d, J = 3.2 Hz),6.60 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 6.94(2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3358, 1613, 1514, 1470, 1289, 1246, 1169, 1107, 1040, 835, 760. (4) Ethyl (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0739] To a solution of 4-[1-(4-decyloxyphenethyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.30 g, 3.21 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(934 mg, 4.81 mmol) andtriphenylphosphine (1.26 g, 4.81 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (1.21 g, 4.81mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.880 mg (yield: 47.0%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.6 Hz), 1.10-1.46 (17H,m), 1.57-1.83 (2H, m), 2.09 (3H, s), 3.94 (2H, t, J = 6.6Hz), 4.14 (2H, q, J = 7.0 Hz), 4.66-4.73 (1H, m), 6.02 (1H,d, J = 3.4 Hz), 6.22 (1H, d, J = 3.4 Hz), 6.61 (2H, d, J =8.8 Hz), 6.83 (2H, d, J = 9.2 Hz), 6.92 (2H, d, J = 9.2 Hz),7.01 (2H, d, J = 8.8 Hz), 7.20-7.29 (5H, m).IR (KBr) cm-1; 1755, 1734, 1514, 1287, 1244, 1182, 1084,1038, 835, 758, 700. Example 148Sodium (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0740] To a mixed solution of ethyl (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(870 mg, 1.49 mmol) in THF (30 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution(8 ml, 8 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.760 mg (yield: 92.0%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.6 Hz), 1.22-1.44 (14H,m), 1.72-1.82 (2H, m), 2.08 (3H, s), 3.22 (2H, d, J = 6.2Hz), 3.93 (2H, t, J = 6.6 Hz), 4.76 (1H, t, J = 6.2 Hz),6.02 (1H, d, J = 3.2 Hz), 6.22 (1H, d, J = 3.2 Hz), 6.62(2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.94 (2H, d,J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.26 (5H, s). IR (KBr) cm-1; 3032, 1730, 1514, 1287, 1244, 1181, 1084,835, 760, 700. (2) Sodium (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0741] Ethanol (7 ml) and a solution of 1N sodium hydroxidein ethanol (1.14 ml) were added to (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (700 mg, 1.26 mmol) and the mixturewas concentrated. To the residue was added ether to givethe object compound as a solid. 441 mg (yield: 67.1%)1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 7.0 Hz), 1.14-1.48(14H, m), 1.65-1.78 (2H, m), 1.99 (3H, s), 2.86-3.12 (2H,m), 3.95 (2H, t, J = 6.2 Hz), 4.18-4.28 (1H, m), 5.91 (1H,d, J = 3.2 Hz), 6.06 (1H, d, J = 3.2 Hz), 6.54 (2H, d, J =8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz),7.02 (2H, d, J = 8.8 Hz), 7.11-7.28 (5H, m).IR (KBr) cm-1; 1615, 1514, 1397, 1289, 1244, 1181, 1169,1042, 835, 762, 700.[α]D 25 -1.61° (c 0.730, methanol) Example 149Ethyl (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy}phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrole
    [0742] A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(1.50 g, 3.91 mmol), 1-bromo-6-phenylhexane(1.42 g, 5.87 mmol) and potassium carbonate(811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80°C for12 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas washed with water and dried over magnesium sulfateanhydride, and solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 30:1) to give theobject compound as an oily substance. 1.43 g (yield:67.1%)1H-NMR (CDCl3) δ; 1.22-1.79 (8H, m), 2.24 (3H, s), 2.57-2.72(4H, m), 3.86-4.03 (4H, m), 5.11 (2H, s), 5.91 (1H, d,J = 3.2 Hz), 6.03 (1H, d, J = 3.2 Hz), 6.73 (2H, d, J = 8.4Hz), 6.82 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.0Hz),7.15-7.49 (12H, m).IR (KBr) cm-1; 1611, 1524, 1512, 1244, 1175, 752, 689. (2) 4-[5-Methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenol
    [0743] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrole(1.35 g, 2.48 mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred for 4 hours under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.10 g (yield: 98.2%)1H-NMR (CDCl3) δ; 1.31-1.79 (8H, m), 2.23 (3H, s), 2.57-2.72(4H, m), 3.86-4.02 (4H, m), 5.91 (1H, d, J = 3.6 Hz),6.02 (1H, d, J = 3.6 Hz), 6.71-6.87 (6H, m), 7.15-7.31 (7H,m).IR (KBr) cm-1; 2934, 1613, 1512, 1246, 1177, 837, 752, 700. (3) Ethyl (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0744] To a solution of 4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenol(1.10 g,2.42 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (706 mg,3.64 mmol) and triphenylphosphine (954 mg, 3.64 mmol) intoluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(918 mg, 3.64 mmol) and the mixture was stirred at 80°C for12 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas dried over magnesium sulfate anhydride and the solventwas removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethylacetate = 10: 1) to give the object compound as an oilysubstance. 710 mg (yield: 39.4%)1H-NMR (CDCl3) δ; 1.16-1.79 (11H, m), 2.22 (3H, s), 2.58-2.69(4H, m), 3.25-3.29 (2H, m), 3.85-3.99 (4H, m), 4.20(2H, q, J = 7.0 Hz), 4.79-4.86 (1H, m), 5.89 (1H, d, J =3.2 Hz), 6.00 (1H, d, J = 3.2 Hz), 6.69-6.92 (6H, m), 7.13-7.34(12H, m).IR (KBr) cm-1; 1753, 1736, 1512, 1480, 1454, 1244, 1179,1113, 1084, 1030, 835, 754, 700. Example 150Sodium (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]-ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0745] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(760 mg, 1.21 mmol) in THF (30 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution (7 ml, 7 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.561 mg (yield: 77.1%)1H-NMR (CDCl3) δ; 1.42-1.86 (8H, m), 2.21 (3H, s), 2.57-2.69(4H, m), 3.31 (2H, d, J = 6.0 Hz), 3.85-4.00 (4H, m),4.88 (1H, t, J = 6.0 Hz), 5.89 (1H, d, J = 3.4 Hz), 6.00(1H, d, J = 3.4 Hz), 6.69-6.88 (6H, m), 7.13-7.34 (12H, m).IR (KBr) cm-1; 2932, 1728, 1512, 1242, 1177, 835, 756, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0746] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.748 ml) were added to (2R)-2-{4-[5-methyl-1-(2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (500 mg, 0.831 mmol) andthe mixture was concentrated. To the residue was addedhexane to give the object compound as a solid. 436 mg(yield: 93.6%)1H-NMR (DMSO-d6) δ; 1.34-1.68 (8H, m), 2.11 (3H, s), 2.49-2.62(4H, m), 2.95-3.25 (2H, m), 3.84-3.95 (4H, m), 4.33-4.39(1H, m), 5.73 (1H, d, J = 3.4 Hz), 5.81 (1H, d, J =3.4 Hz), 6.70-6.85 (6H, m), 7.10-7.35 (12H, m). IR (KBr) cm-1; 1613, 1512, 1408, 1244, 1177, 1053, 1030,839, 758, 698.[α]D 28 -22.8° (c 1.18, methanol) Example 151Ethyl (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-Pentylcyclohexylmethanol
    [0747] To a suspension of lithium aluminium hydride (9.56 g,252 mmol) in tetrahydrofuran (400 ml) was added dropwise asolution of 4-n-pentylcyclohexanecarboxylic acid (25.0 g,126 mmol) in tetrahydrofuran (100 ml) and refluxed for 2hours under heating. To the residue were added water (10ml) and 1 N aqueous sodium hydroxide solution (30 ml) underice-cooling and the mixture was stirred at room temperaturefor 1 hour. The insoluble matter was filtered out and thefiltrate was concentrated to give the object compound as anoily substance. 19.0 g (yield: 81.9%)1H-NMR (CDCl3) δ; 0.85-1.80 (21H, m), 3.45 (2H, d, J = 6.0Hz).IR (KBr) cm-1; 3277, 1448, 1071, 1038, 986. (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrole
    [0748] To a solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol(970 mg, 2.53 mmol), 4-pentylcyclohexylmethanol(699 mg, 3.79 mmol) andtriphenylphosphine (994 mg, 3.79 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (956 mg, 3.79mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as a solid. 1.11 g(yield: 79.9%)1H-NMR (CDCl3) δ; 0.85-1.91 (21H, m), 2.24 (3H, s), 2.69(2H, t, J = 7.8 Hz), 3.70 (2H, d, J = 6.2 Hz), 3.99 (2H, t,J = 7.8 Hz), 5.11 (2H, s), 5.92 (1H, d, J = 3.2 Hz), 6.03(1H, d, J = 3.2 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.82 (2H, d,J = 8.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.24-7.50 (7H, m).IR (KBr) cm-1; 1613, 1524, 1512, 1466, 1454, 1310, 1281,1244, 1175, 1026, 835, 754, 735, 698. (3) 4-(5-Methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]-ethyl}-1H-pyrrol-2-yl)phenol
    [0749] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrole (1.01 g, 1.84 mmol) in ethanol (60 ml) and tetrahydrofuran(30 ml) was added 10% palladium carbon (200 mg) and themixture was stirred under hydrogen atmosphere for 5 hours.The insoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 840 mg (yield: 99.3%)1H-NMR (CDCl3) δ; 0.86-1.90 (21H, m), 2.24 (3H, s), 2.68(2H, t, J = 7.8 Hz), 3.70 (2H, d, J = 6.3 Hz), 3.98 (2H, t,J = 7.8 Hz), 5.91 (1H, d, J = 3.3 Hz), 6.01 (1H, d, J =3.3 Hz), 6.74 (2H, d, J = 8.7 Hz), 6.81-6.87 (4H, m), 7.21(2H, d, J = 9.0 Hz).IR (KBr) cm-1; 3268, 1613, 1512, 1468, 1449, 1246, 1177,1032, 837, 824, 756. (4) Ethyl (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0750] To a solution of 4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenol(830 mg, 1.81 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(526 mg, 2.71 mmol) and triphenylphosphine (711 mg, 2.71mmol) in toluene (1 ml) was added 1,1'-(azodicarbonyl)dipiperidine(684 mg, 2.71 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 560 mg(yield: 48.7%)1H-NMR (CDCl3) δ; 0.85-1.91 (24H, m), 2.23 (3H, s), 2.66(2H, t, J = 8.0 Hz), 3.25-3.29 (2H, m), 3.69 (2H, d, J =6.2 Hz), 3.96 (2H, t, J = 8.0 Hz), 4.20 (2H, q, J = 7.0 Hz),4.79-4.86 (1H, m), 5.89 (1H, d, J = 3.2 Hz), 6.00 (1H, d, J= 3.2 Hz), 6.69-6.89 (6H, m), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1481, 1468, 1454, 1279,1244, 1179, 1088, 1032, 835, 758. Example 152Sodium (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0751] To a mixed solution of ethyl (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(550 mg, 0.865 mmol) in THF(20 ml) and methanol (10 ml) was added 1N aqueous potassium hydroxide solution (15 ml, 15 mmol) and the mixture wasstirred for 1 hour at room temperature. The reactionsolution was neutralized with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 1: 1) to give the object compoundas an oily substance. 342 mg (yield: 65.0%)1H-NMR (CDCl3) δ; 0.85-1.90 (21H, m), 2.22 (3H, s), 2.64(2H, t, J = 8.2 Hz), 3.31 (2H, d, J = 5.6 Hz), 3.69 (2H, d,J = 6.6 Hz), 3.96 (2H, t, J = 8.2 Hz), 4.89 (1H, t, J = 5.6Hz), 5.89 (1H, d, J = 3.2 Hz), 5.99 (1H, d, J = 3.2 Hz),6.68-6.87 (6H, m), 7.19-7.31 (7H, m).IR (KBr) cm-1; 2921, 1728, 1512, 1244, 1177, 1032, 835, 756,700. (2) Sodium (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0752] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.489 ml) were added to (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid (330 mg, 0.543 mmol) andthe mixture was concentrated. To the residue was added diisopropylether to give the object compound as a solid.256 mg (yield: 83.1%)1H-NMR (DMSO-d6) δ; 0.83-1.85 (21H, m), 2.11 (3H, s), 2.55-2.69(2H, m), 2.93-3.18 (2H, m), 3.69 (2H, d, J = 6.6 Hz),3.84-3.97 (2H, m), 4.30-4.36 (1H, m), 5.73 (1H, d, J = 3.4Hz), 5.80 (1H, d, J = 3.4 Hz), 6.70-6.85 (6H, m), 7.10-7.33(7H, m).IR (KBr) cm-1; 1613, 1512, 1408, 1244, 1034, 839, 758, 700.[α]D 26 2.35° (c 0.580, methanol) Example 153Ethyl (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 3-[2-(4-Benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol
    [0753] A solution of 1-(4-benzyloxyphenyl)pentan-1,4-dione(5.00 g, 17.7 mmol), 3-amino-1-propanol (1.33 g, 17.7 mmol)and p-toluenesulfonic acid monohydrate (253 mg, 1.33 mmol)in toluene (100 ml) was refluxed for 12 hours under heatingusing Dean-Stark's apparatus, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 4:1) togive the object compound as a solid. 4.50 g (yield: 79.1%)1H-NMR (CDCl3) δ; 1.66-1.79 (2H, m), 2.32 (3H, s), 3.39-3.47(2H, m), 4.03 (2H, d, J = 7.4 Hz), 5.09 (2H, s), 5.94 (1H, d, J = 3.4 Hz), 6.04 (1H, d, J = 3.4 Hz), 7.00 (2H, d,J = 8.8 Hz), 7.27-7.49 (7H, m).IR (KBr) cm-1; 2937, 1609, 1524, 1242, 1175, 1024, 835, 756,698. (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-[3-(4-octyloxyphenyl)propyl]-1H-pyrrole
    [0754] To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol), 4-octylphenol(642 mg, 3.11 mmol) and triphenylphosphine (1.22 g, 4.67mmol) in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.18 g, 4.67 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride, and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30:1) togive the object compound as an oily substance. 1.23 g(yield: 77.4%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.18-1.61 (12H,m), 1.88-2.00 (2H, m), 2.30 (3H, s), 2.52 (2H, t, J = 8.0Hz), 3.71 (2H, d, J = 6.0 Hz), 4.09 (2H, t, J = 7.6 Hz),5.06 (2H, s), 5.92 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J =3.4 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.92-7.05 (4H, m), 7.24-7.49 (7H, m).IR (KBr) cm-1; 1611, 1524, 1510, 1468, 1454, 1383, 1312,1281, 1244, 1175, 1024, 833, 756, 698. (3) 4-{5-Methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenol
    [0755] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[3-(4-octyloxyphenyl)propyl]-1H-pyrrole(1.15 g, 2.26 mmol) inethanol (60 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred underhydrogen atmosphere for 6 hours. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 930 mg (yield:98.1%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.21-1.28 (10H,m), 1.49-1.62 (2H, m), 1.89-1.97 (2H, m), 2.30 (3H, s),2.52 (2H, t, J = 7.4 Hz), 3.72 (2H, t, J = 7.4 Hz), 4.07(2H, t, J = 7.4 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.02 (1H, d,J = 3.4 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3424, 1613, 1524, 1510, 1242, 1175, 837, 756. (4) Ethyl (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl)phenoxy)-3-phenylpropanoate
    [0756] To a solution of 4-{5-methyl-1-[3-(4-octylphenoxy)-propyl]-1H-pyrrol-2-yl}phenol (930 mg, 2.22 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (644 mg, 3.32 mmol) andtriphenylphosphine (870 mg, 3.32 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (839 mg, 3.32mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.610 mg (yield: 46.2%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.4 Hz), 1.15-1.33 (13H,m), 1.47-1.61 (2H, m), 1.88-1.95 (2H, m), 2.28 (3H, s),2.52 (2H, t, J = 8.0 Hz), 3.24-3.29 (2H, m), 3.70 (2H, t, J= 5.6 Hz), 4.05 (2H, t, J = 7.2 Hz), 4.19 (2H, q, J = 7.4Hz), 4.76-4.79 (1H, m), 5.90 (1H, d, J = 3.6 Hz), 6.00 (1H,d, J = 3.6 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J =8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.19-7.33 (7H, m).IR (KBr) cm-1; 1753, 1736, 1524, 1510, 1242, 1179, 1086,1032, 835, 756, 700. Example 154Sodium (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0757] To a mixed solution of ethyl (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(600 mg, 1.01 mmol) in THF (20 ml) andmethanol (10 ml) was added 1N aqueous potassium hydroxidesolution (5 ml, 5 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1:1) to give the object compound as an oily substance. 414mg (yield: 72.3%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.22-1.30 (10H,m), 1.49-1.61 (2H, m), 1.89-1.94 (2H, m), 2.29 (3H, s),2.51 (2H, t, J = 7.2 Hz), 3.30 (2H, d, J = 5.8 Hz), 3.69(2H, t, J = 5.8 Hz), 4.05 (2H, t, J = 7.2 Hz), 4.85 (1H, t,J = 5.8 Hz), 5.90 (1H, d, J = 3.2 Hz), 6.00 (1H, d, J = 3.2Hz), 6.64 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.01 (2H, d, J = 8.8 Hz), 7.16-7.33 (7H, m).IR (KBr) cm-1; 3031, 1730, 1510, 1456, 1242, 1177, 1084,833, 756, 700. (2) Sodium (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl)phenoxy)-3-phenylpropanoate
    [0758] Ethanol (4 ml) and a solution of 1N sodium hydroxidein ethanol (0.634 ml) were added to (2R)-2-(4-{5-methyl-1-[3-(4-octylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (400 mg, 0.705 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid.226 mg (yield: 60.4%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 6.6 Hz), 1.19-1.32(10H, m), 1.43-1.59 (2H, m), 1.78-1.89 (2H, m), 2.21 (3H,s), 2.47 (2H, t, J = 7.2 Hz), 2.96-3.21 (2H, m), 3.69 (2H,t, J = 5.8 Hz), 3.99 (2H, t, J = 7.8 Hz), 4.33-4.40 (1H, m),5.75 (1H, d, J = 3.8 Hz), 5.81 (1H, d, J = 3.8 Hz), 6.66(2H, d, J = 8.4 Hz), 6.78 (2H, d, J = 8.4 Hz), 7.00 (2H, d,J = 8.4 Hz), 7.10-7.35 (7H, m).IR (KBr) cm-1; 1613, 1512, 1404, 1240, 1177, 1044, 827, 764,700.[α]D 25 10.2° (c 0.540, methanol) Example 155Ethyl (2R)-2-(4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 3-[2-(4-Benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol
    [0759] A solution of 1-(4-benzyloxyphenyl)pentane-1,4-dione(2.00 g, 7.08 mmol), 3-aminophenol (773 mg, 7.08 mmol) andp-toluenesulfonic acid monohydrate (100 mg, 0.528 mmol) intoluene (100 ml) was refluxed for 12 hours under heatingand the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:ethyl acetate = 4:1) to give the object compound asan oily substance. 1.81 g (yield: 72.1%)1H-NMR (CDCl3) δ; 2.14 (3H, s), 4.98 (2H, s), 6.05 (1H, d,J = 3.2 Hz), 6.25 (1H, d, J = 3.2 Hz), 6.60-6.97 (5H, m),7.01 (2H, d, J = 8.8 Hz), 7.18-7.42 (6H, m).IR (KBr) cm-1; 3422, 1599, 1524, 1229, 1179, 1018, 871, 766,696. (2) 2-(4-Benzyloxyphenyl)-1-(3-decyloxyphenyl)-5-methyl-1H-pyrrole
    [0760] A solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.80 g, 5.07 mmol), 1-bromoundecane(1.58 ml, 7.60 mmol) and potassium carbonate (1.05 g, 7.06mmol) in DMF (15 ml) was stirred at 80°C for 12 hours. Thereaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride, andsolvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 30:1) to give the object compound as an oily substance. 1.90 g (yield: 75.7%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.22-1.43 (14H,m), 1.55-1.74 (2H, m), 2.15 (3H, s), 3.84 (2H, t, J = 6.6Hz), 4.98 (2H, s), 6.05 (1H, d, J = 3.6 Hz), 6.25 (1H, d, J= 3.6 Hz), 6.67-7.42 (13H, m).IR (KBr) cm-1; 1605, 1523, 1489, 1454, 1391, 1283, 1242,1225, 1196, 1177, 760. (3) 4-[1-(3-Decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0761] To a solution of 2-(4-benzyloxyphenyl)-1-(3-decyloxyphenyl)-5-methyl-1H-pyrrole(1.80 g, 3.63 mmol) inethanol (60 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 3hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 1.40 g (yield:95.2%)1H-NMR (CDCl3) δ; 0.88 (3H, t,J = 7.4 Hz), 1.21-1.44 (14H,m), 1.64-1.74 (2H, m), 2.14 (3H, s), 3.84 (2H, t, J = 6.6Hz), 6.05 (1H, d, J = 3.4 Hz), 6.24 (1H, d, J = 3.4 Hz),6.59-7.26 (8H, m).IR (KBr) cm-1; 3285, 1595, 1526, 1489, 1456, 1265, 1219,1196, 1171, 835, 762. (4) Ethyl (2R)-2-{4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0762] To a solution of 4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol(1.40 g, 3.45 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.00 g, 5.18 mmol) andtriphenylphosphine (1.36 g, 5.18 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (1.31 g, 5.18mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.1.00 g (yield: 49.8%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.8 Hz), 1.09-1.42 (17H,m), 1.63-1.78 (2H, m), 2.12 (3H, s), 3.17-3.21 (2H, m),3.83 (2H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.0 Hz), 4.67-4.73(1H, m), 6.03 (1H, d, J = 3.8 Hz), 6.22 (1H, d, J =3.8 Hz), 6.60-7.33 (13H, m).IR (KBr) cm-1; 1757, 1732, 1605, 1601, 1524, 1489, 1283,1227, 1184, 1084, 1032, 835, 760, 698. Example 156Sodium (2R)-2-{4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(3-Decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0763] To a mixed solution of ethyl (2R)-2-{4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(960 mg, 1.65 mmol) in THF (30 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution (8 ml, 8 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.658 mg (yield: 72.0%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.22-1.42 (14H,m), 1.67-1.74 (2H, m), 2.12 (3H, s), 3.22 (2H, d, J = 6.2Hz), 3.84 (2H, t, J = 6.6 Hz), 4.76 (1H, t, J = 6.2 Hz),6.03 (1H, d, J = 3.4 Hz), 6.242 (1H, d, J = 3.4 Hz), 6.61-7.26(13H, m).IR (KBr) cm-1; 3065, 1728, 1605, 1522, 1489, 1283, 1229,1084, 833, 760, 698. (2) Sodium (2R)-2-{4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0764] Ethanol (6 ml) and a solution of 1N sodium hydroxide in ethanol (1.02 ml) were added to (2R)-2-{4-[1-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (630 mg, 1.14 mmol) and the mixturewas concentrated. To the residue was added ether to givethe object compound as a solid. 357 mg (yield: 60.7%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 6.8 Hz), 1.21-1.41(14H, m), 1.58-1.69 (2H, m), 2.03 (3H, s), 2.85-3.13 (2H,m), 3.91 (2H, t, J = 6.6 Hz), 4.16-4.23 (1H, m), 5.93 (1H,d, J = 3.2 Hz), 6.08 (1H, d, J = 3.2 Hz), 6.51-7.29 (13H,m) .IR (KBr) cm-1; 1613, 1524, 1474, 1406, 1227, 1061, 1030,829, 764, 700.[α]D 25 4.55° (c 0.530, methanol) Example 157Ethyl (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(6-phenylhexyloxy)-phenyl]-1H-pyrrole
    [0765] A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.50 g, 4.22 mmol), 1-bromo-6-phenylhexane(1.53 g, 6.33 mmol) and potassium carbonate(874 mg, 6.33 mmol) in DMF (15 ml) was stirred at 80°C for12 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfateanhydride and solvent was removed under reduced pressure.The residue was purified by silica gel columnchromatography (hexane:ethyl acetate = 20:1) to give theobject compound as an oily substance. 1.74 g (yield:79.4%)1H-NMR (CDCl3) δ; 1.22-1.83 (8H, m), 2.10 (3H, s), 2.63 (2H,t, J = 7.4 Hz), 3.94 (2H, t, J = 6.2 Hz), 4.98 (2H, s),6.04 (1H, d, J = 3.2 Hz), 6.25 (1H, d, J = 3.2 Hz), 6.74-7.42(18H, m).IR (KBr) cm-1; 1607, 1514, 1289, 1244, 1177, 1026, 835, 750,698. (2) 4-[5-Methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenol
    [0766] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrole(1.35 g, 2.48mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred for 4 hours under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.10 g (yield: 98.2%)1H-NMR (CDCl3) δ; 1.31-1.79 (8H, m), 2.23 (3H, s), 2.57-2.72(4H, m), 3.86-4.02 (4H, m), 5.91 (1H, d, J = 3.6 Hz), 6.02 (1H, d, J = 3.6 Hz), 6.71-6.87 (6H, m), 7.15-7.31 (7H,m).IR (KBr) cm-1; 2934, 1613, 1512, 1246, 1177, 837, 752, 700. (3) Ethyl (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0767] To a solution of 4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenol(1.30 g,3.05 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (890 mg,4.58 mmol) and triphenylphosphine (1.20 g, 4.58 mmol) intoluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.15 g, 4.58 mmol) and the mixture was stirred at 80°C for12 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas dried over magnesium sulfate anhydride and the solventwas removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 30: 1) to give the object compound as an oilysubstance. 830 mg (yield: 45.5%)1H-NMR (CDCl3) δ; 1.14 (3H, t, J = 7.4 Hz), 1.22-1.83 (8H,m), 2.08 (3H, s), 2.63 (2H, t, J = 8.0 Hz), 3.17-3.21 (2H,m), 3.93 (2H, t, J = 7.0 Hz), 4.12 (2H, q, J = 7.4 Hz),4.66-4.73 (1H, m), 6.02 (1H, d, J = 3.4 Hz), 6.21 (1H, d, J= 3.4 Hz), 6.62 (2H, d, J = 9.2 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 9.2 Hz), 7.01 (2H, d, J = 8.8 Hz),7.17-7.30 (10H, m).IR (KBr) cm-1; 1755, 1732, 1514, 1287, 1246, 1184, 1111,1084, 1032, 835, 760, 700. Example 158Sodium (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0768] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(800 mg, 1.33 mmol) in THF (20 ml) andmethanol (10 ml) was added 1N aqueous potassium hydroxidesolution (7 ml, 7 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.602 mg (yield: 79.0%)1H-NMR (CDCl3) δ; 1.38-1.83 (8H, m), 2.08 (3H, s), 2.63 (2H,t, J = 7.5 Hz), 3.21-3.23 (2H, m), 3.92 (2H, t, J = 6.6 Hz), 4.73-4.77 (1H, m), 6.02 (1H, d, J = 3.6 Hz), 6.22 (1H, d, J= 3.6 Hz), 6.62 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0Hz), 6.94 (2H, d, J = 9.0 Hz), 7.01 (2H, d, J = 9.0 Hz),7.15-7.30 (10H, m).IR (KBr) cm-1; 3027, 1723, 1514, 1244, 835, 758, 698. (2) Sodium (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0769] Ethanol (6 ml) and a solution of 1N sodium hydroxidein ethanol (0.900 ml) were added to (2R)-2-{4-[5-methyl-1-[4-(6-phenylhexyloxy)phenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (573 mg, 1.00 mmol) and the mixturewas concentrated. To the residue was added hexane to givethe object compound as a solid. 449 mg (yield: 83.8%)1H-NMR (DMSO-d6) δ; 1.31-1.74 (8H, m), 1.99 (3H, s), 2.59(2H, t, J = 7.5 Hz), 2.90-3.12 (2H, m), 3.94 (2H, t, J =6.6 Hz), 4.22-4.26 (1H, m), 5.91 (1H, d, J = 3.6 Hz), 6.06(1H, d, J = 3.6 Hz), 6.55 (2H, d, J = 8.7 Hz), 6.79 (2H, d,J = 8.7 Hz), 6.89 (2H, d, J = 8.7 Hz), 7.02 (2H, d, J = 8.7Hz), 7.09-7.30 (10H, m).IR (KBr) cm-1; 1613, 1514, 1404, 1244, 1053, 1028, 833, 764,698. Example 159Ethyl (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)-phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrole
    [0770] To a solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.50 g, 4.22 mmol), 4-pentylcyclohexylmethanol(776 mg, 4.22 mmol) andtriphenylphosphine (1.66 g, 6.33 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (1.56 g, 6.33mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =20: 1) to give the object compound as an oily substance.1.53 g (yield: 69.5%)1H-NMR (CDCl3) δ; 0.85-1.94 (21H, m), 2.10 (3H, s), 3.75(2H, d, J = 6.2 Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.2 Hz),6.24 (1H, d, J = 3.2 Hz), 6.75-7.42 (13H, m).IR (KBr) cm-1; 1609, 1514, 1289, 1244, 1177, 1640, 1026,833, 758, 735, 696. (2) 4-(5-Methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl)-1H-pyrrol-2-yl)phenol
    [0771] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrole(1.43 g, 2.74mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred for 4 hours under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 1.12 g (yield: 94.9%)1H-NMR (CDCl3) δ; 0.85-1.93 (21H, m), 2.10 (3H, s), 2.73(2H, t, J = 7.4 Hz), 6.04 (1H, d, J = 3.4 Hz), 6.24 (1H, d,J = 3.4 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8Hz), 6.94 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3291, 1613, 1514, 1466, 1244, 1171, 1040,833, 760. (3) Ethyl (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0772] To a solution of 4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenol(1.10g, 2.55 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (742mg, 3.82 mmol) and triphenylphosphine (1.00 g, 3.82 mmol)in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(963 mg, 3.82 mmol) and themixture was stirred at 80°C for 12 hours. The reaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 620 mg(yield: 43.4%)1H-NMR (CDCl3) δ; 0.86-1.93 (24H, m), 2.08 (3H, s), 3.17-3.21(2H, m), 3.74 (2H, d, J = 6.2 Hz), 4.14 (2H, q, J =7.0 Hz), 4.66-4.73 (1H, m), 6.02 (1H, d, J = 3.4 Hz), 6.21(1H, d, J = 3.4 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.82 (2H, d,J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8Hz), 7.21-7.29 (5H, m).IR (KBr) cm-1; 1755, 1734, 1514, 1287, 1244, 1182, 1084,1040, 835, 698. Example 160Sodium (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(5-Methyl-1-[4-(4-pentylcyclohexylmethoxy)-phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0773] To a mixed solution of ethyl (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(600 mg, 0.987 mmol) in THF (20 ml) and methanol (10 ml) was added 1N aqueous potassium hydroxidesolution (5 ml, 5 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.523 mg (yield: 91.4%)1H-NMR (CDCl3) δ; 0.86-1.92 (21H, m), 2.08 (3H, s), 3.20(2H, d, J = 5.0 Hz), 3.72 (2H, d, J = 6.2 Hz), 4.74 (1H, t,J = 5.0 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.21 (1H, d, J = 3.4Hz), 6.60 (2H, d, J = 8.4 Hz), 6.79-7.02 (6H, m), 7.24-7.26(5H, m).IR (KBr) cm-1; 3031, 1728, 1514, 1287, 1244, 1181, 1082,1042, 835, 758, 700. (2) Sodium (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0774] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.786 ml) were added to (2R)-2-[4-(5-methyl-1-[4-(4-pentylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid (500 mg, 0.874 mmol) and the mixture was concentrated. To the residue was addedhexane to give the object compound as a solid. 445 mg(yield: 94.3%)1H-NMR (DMSO-d6) δ; 0.83-1.88 (21H, m), 1.99 (3H, s), 2.88-3.13(2H, m), 3.75 (2H, d, J = 5.8 Hz), 4.19-4.25 (1H, m),5.89 (1H, d, J = 3.2 Hz), 6.04 (1H, d, J = 3.2 Hz), 6.54(2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz), 6.87 (2H, d,J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.07-7.28 (5H, m).IR (KBr) cm-1; 1613, 1514, 1399, 1244, 1181, 1042, 1030,833, 764, 700.[α]D 25-2.81° (c 0.580, methanol) Example 161Ethyl (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-Butylcyclohexylmethanol
    [0775] To a suspension of lithium aluminium hydride (10.3 g,272 mmol) in tetrahydrofuran (400 ml) was added dropwise asolution of 4-n-butylcyclohexane carboxylic acid (25.0 g,136 mmol) in tetrahydrofuran (100 ml) and the mixture wasrefluxed for 4 hours under heating. To the residue wereadded water (10 ml) and 1 N aqueous sodium hydroxidesolution (30 ml) under ice-cooling and the mixture wasstirred at room temperature for 1 hour. The insolublematter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 18.9 g(yield: 81.1%)1H-NMR (CDCl3) δ; 0.89-1.80 (19H, m), 3.42-3.48 (2H, m).IR (KBr) cm-1; 3250, 1449, 1073, 1036. (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(4-butylcyclohexylmethoxy)phenyl]-1H-pyrrole
    [0776] The object compound was obtained from 4-butylcyclohexylmethanolas an oily substance, according tothe similar manner to that of Example 159(1). yield: 53.1%1H-NMR (CDCl3) δ; 0.87-1.92 (19H, m), 2.10 (3H, s), 3.74(2H, d, J = 6.3 Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.2 Hz),6.24 (1H, d, J = 3.2 Hz), 6.74-7.06 (8H, m), 7.29 - 7.42(5H, m).IR (KBr) cm-1; 1609, 1514, 1466, 1454, 1289, 1244, 1177,1040, 1026, 835, 758, 735, 696. (3) 4-(1-[4-(4-Butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenol
    [0777] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(4-butylcyclohexylmethoxy)phenyl]-1H-pyrroleas an oilysubstance, according to the similar manner to that ofExample 159(2). yield: 95.1%1H-NMR (CDCl3) δ; 0.86-1.93 (19H, m), 2.10 (3H, s), 3.74 (2H, d, J = 6.2 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.23 (1H, d,J = 3.4 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8Hz), 6.94 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3275, 1613, 1514, 1466, 1246, 1171, 1040,833, 762. (4) Ethyl (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0778] The object compound was obtained from 4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenolas an oily substance, according to the similarmanner to that of Example 159(3). yield: 50.5%1H-NMR (CDCl3) δ; 0.86-1.93 (22H, m), 2.08 (3H, s), 3.17-3.21(2H, m), 3.73 (2H, d, J = 6.3 Hz), 4.14 (2H, q, J =7.2 Hz), 4.68-4.72 (1H, m), 6.01 (1H, d, J = 3.3 Hz), 6.21(1H, d, J = 3.3 Hz), 6.62 (2H, d, J = 9.0 Hz), 6.83 (2H, d,J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0Hz), 7.20-7.29 (5H, m).IR (KBr) cm-1; 1755, 1734, 1514, 1285, 1244, 1182, 1084,1040, 835. Example 162Sodium (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(1-[4-(4-Butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0779] The object compound was obtained from ethyl (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 160(1).yield: 54.3%1H-NMR (CDCl3) δ; 0.89-1.93 (19H, m), 2.08 (3H, s), 3.21(2H, d, J = 5.8 Hz), 3.73 (2H, d, J = 6.2 Hz), 4.74 (1H, t,J = 5.8 Hz), 6.02 (1H, d, J = 3.6 Hz), 6.21 (1H, d, J = 3.6Hz), 6.62 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 9.2 Hz),6.92-7.03 (4H, m), 7.26 (5H, s).IR (KBr) cm-1; 3029, 1732, 1609, 1514, 1287, 1244, 1181,1042, 835, 760, 700. (2) Sodium (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0780] The object compound was obtained from (2R)-2-[4-(1-[4-(4-butylcyclohexylmethoxy)phenyl]-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 160(2). yield: 80.0%1H-NMR (DMSO-d6) δ; 0.88-1.88 (19H, m), 1.99 (3H, s), 2.85-3.11(2H, m), 3.77 (2H, d, J = 6.2 Hz), 4.18-4.23 (1H, m),5.91 (1H, d, J = 3.4 Hz), 6.06 (1H, d, J = 3.4 Hz), 6.53 (2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 6.89 (2H, d,J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.11-7.27 (5H, m).IR (KBr) cm-1; 1613, 1514, 1399, 1289, 1244, 1044, 835, 764,700.[α]D 27 -2.80° (c 0.560, methanol) Example 163Ethyl (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 4-Propylcyclohexylmethanol
    [0781] The object compound was obtained from 4-n-propylcyclohexanecarboxylic acid as an oily substance,according to the similar manner to that of Example 161(1).yield: 79.0%1H-NMR (CDCl3) δ; 0.84-1.80 (17H, m), 3.42-3.48 (2H, m).IR (KBr) cm-1; 3300, 1449, 1071, 1034, 1001, 970. (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrole
    [0782] The object compound was obtained from 4-propylcyclohexylmethanolas an oily substance, according tothe similar manner to that of Example 159(1). yield: 77.0%1H-NMR (CDCl3) δ; 0.85-1.93 (17H, m), 2.10 (3H, s), 3.75(2H, d, J = 6.2 Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.4 Hz), 6.24 (1H, d, J = 3.4 Hz), 6.73-6.87 (4H, m), 6.98-7.07 (4H,m), 7.30-7.39 (5H, m).IR (KBr) cm-1; 1609, 1514, 1466, 1454, 1287, 1244, 1040,1026, 833, 760, 735, 696. (3) 4-(5-Methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenol
    [0783] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrroleas an oilysubstance, according to the similar manner to that ofExample 159(2). yield: 97.6%1H-NMR (CDCl3) δ; 0.85-1.93 (17H, m), 2.10 (3H, s), 3.75(2H, d, J = 6.0 Hz), 6.04 (1H, d, J = 3.2 Hz), 6.23 (1H, d,J = 3.2 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8Hz), 6.95 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3300, 1514, 1466, 1289, 1246, 1171, 835, 762. (4) Ethyl (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0784] The object compound was obtained from 4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenolas an oily substance, according to the similar manner tothat of Example 159(3). yield: 29.8% 1H-NMR (CDCl3) δ; 0.86-1.93 (20H, m), 2.08 (3H, s), 3.17-3.21(2H, m), 3.74 (2H, d, J = 6.2 Hz), 4.14 (2H, q, J =7.4 Hz), 4.66-4.73 (1H, m), 6.02 (1H, d, J = 3.8 Hz), 6.21(1H, d, J = 3.8 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.82 (2H, d,J = 8.8 Hz), 6.91-7.02 (4H, m), 7.26-7.29 (5H, m).IR (KBr) cm-1; 1753, 1736, 1514, 1287, 1244, 1182, 1084,1040, 835, 760, 700. Example 164Sodium (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(5-Methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoic acid
    [0785] The object compound was obtained from ethyl (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoateas an oilysubstance, according to the similar manner to that ofExample 160(1). yield: 93.1%1H-NMR (CDCl3) δ; 0.85-1.92 (17H, m), 2.08 (3H, s), 3.22(2H, d, J = 5.8 Hz), 3.74 (2H, d, J = 6.2 Hz), 4.76 (1H, t,J = 5.8 Hz), 6.03 (1H, d, J = 3.4 Hz), 6.22 (1H, d, J = 3.4Hz), 6.62 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz),6.93-7.03 (4H, m), 7.26 (5H, s).IR (KBr) cm-1; 3031, 1728, 1514, 1287, 1244, 1181, 1084,1042, 835, 758, 735, 700. (2) Sodium (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0786] The object compound was obtained from (2R)-2-[4-(5-methyl-1-[4-(4-propylcyclohexylmethoxy)phenyl]-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 160(2). yield: 91.9%1H-NMR (DMSO-d6) δ; 0.83-1.88 (17H, m), 1.99 (3H, s), 2.86-3.11(2H, m), 3.77 (2H, d, J = 6.2 Hz), 4.17-4.22 (1H, m),5.91 (1H, d, J = 3.4 Hz), 6.06 (1H, d, J = 3.4 Hz), 6.53(2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 6.89 (2H, d,J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.08-7.24 (5H, m).IR (KBr) cm-1; 1613, 1514, 1397, 1244, 1044, 1030, 835, 762,700.[α]D 27 -5.36° (c 0.645, methanol) Example 165Ethyl (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrole
    [0787] To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol), 4-benzylphenol(572 mg, 3.11 mmol) and triphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.18 g, 4.67 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 1.21 g(yield: 79.6%)1H-NMR (CDCl3) δ; 1.87-2.00 (2H, m), 2.30 (3H, s), 3.70 (2H,t, J = 5.6 Hz), 3.90 (2H, s), 4.09 (2H, t, J = 7.8 Hz),5.04 (2H, s), 5.92 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz),7.04 (2H, d, J = 8.8 Hz), 7.14-7.47 (12H, m).IR (KBr) cm-1; 1611, 1522, 1510, 1281, 1244, 1175, 1026,835, 756, 731, 698. (2) 4-{1-[3-(4-Benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol
    [0788] To a solution of 2-(4-benzyloxyphenyl)-1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrole(1.15 g, 2.26mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred for 4 hours under hydrogen atmosphere. The insoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 920 mg (yield: 98.0%)1H-NMR (CDCl3) δ; 1.86-1.99 (2H, m), 2.30 (3H, s), 3.69 (2H,t, J = 5.8 Hz), 3.90 (2H, s), 4.08 (2H, t, J = 7.0 Hz),5.91 (1H, d, J = 3.2 Hz), 6.00 (1H, d, J = 3.2 Hz), 6.61-6.70(4H, m), 7.03-7.34 (9H, m).IR (KBr) cm-1; 3399, 1613, 1526, 1510, 1244, 1175, 839, 760,729, 698. (3) Ethyl (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0789] To a solution of 4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol(910 mg, 2.29 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (667 mg, 3.44 mmol) andtriphenylphosphine (901 mg, 3.44 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (867 mg, 3.44mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.680 mg (yield: 51.5%) 1H-NMR (CDCl3) δ; 1.18 (3H, t, J = 7.2 Hz), 1.87-1.97 (2H,m), 2.28 (3H, s), 3.23-3.27 (2H, m), 3.69 (2H, t, J = 6.0Hz), 3.90 (2H, s), 4.05 (2H, t, J = 7.6 Hz), 4.17 (2H, q, J= 7.2 Hz), 4.75-4.81 (1H, m), 5.89 (1H, d, J = 3.2 Hz),6.00 (1H, d, J = 3.2 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.81(2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.14-7.32(12H, m).IR (KBr) cm-1; 1755, 1732, 1611, 1510, 1480, 1454, 1242,1179, 1084, 1030, 837, 760, 729, 698. Example 166Sodium (2R)-2-(4-(1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{1-[3-(4-Benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0790] To a mixed solution of ethyl (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(660 mg, 1.15 mmol) in THF (30 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution (6 ml, 6 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate =1:1) to give the object compound as an oily substance. 584mg (yield: 92.8%)1H-NMR (CDCl3) δ; 1.87-1.97 (2H, m), 2.28 (3H, s), 3.28 (2H,d, J = 6.0 Hz), 3.68 (2H, t, J = 5.4 Hz), 3.90 (2H, s),4.05 (2H, t, J = 7.6 Hz), 4.83 (1H, t, J = 6.0 Hz), 5.90(1H, d, J = 3.8 Hz), 6.00 (1H, d, J = 3.8 Hz), 6.64 (2H, d,J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8Hz), 7.14-7.32 (12H, m).IR (KBr) cm-1; 3029, 1726, 1611, 1510, 1242, 1177, 1084,837, 760, 698. (2) Sodium (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0791] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.900 ml) were added to (2R)-2-(4-{1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (546 mg, 1.00 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid.447 mg (yield: 87.3%)1H-NMR (DMSO-d6) δ; 1.87-1.86 (2H, m), 2.20 (3H, s), 2.93-3.20(2H, m), 3.69 (2H, t, J = 5.6 Hz), 3.90 (2H, s), 3.99(2H, t, J = 7.2 Hz), 4.29-4.35 (1H, m), 5.76 (1H, d, J =3.2 Hz), 5.81 (1H, d, J = 3.2 Hz), 6.68-6.79 (4H, m), 7.04-7.34 (14H, m).IR (KBr) cm-1; 1615, 1510, 1404, 1242, 1177, 1055, 1030,839, 762, 727, 698.[α]D 29 5.93° (c 0.650, methanol) Example 167Ethyl (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrole
    [0792] The object compound was obtained from 4-hexylphenol asan oily substance, according to the similar manner to thatof Example 165(1). yield: 79.3%1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.4 Hz), 1.22-1.34 (6H,m), 1.48-1.59 (2H, m), 1.88-1.98 (2H, m), 2.31 (3H, s),2.52 (2H, t, J = 7.2 Hz), 3.71 (2H, t, J = 6.0 Hz), 4.09(2H, t, J = 7.8 Hz), 5.06 (2H, s), 5.91 (1H, d, J = 3.6Hz), 6.03 (1H, d, J = 3.6 Hz), 6.66 (2H, d, J = 8.8 Hz),6.95 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.25-7.49(7H, m).IR (KBr) cm-1; 1611, 1524, 1510, 1468, 1454, 1242, 1175,1024, 833, 756, 698. (2) 4-{1-[3-(4-Hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol
    [0793] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 165(2). yield: 99.0%oily substance 99.0%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.22-1.34 (6H,m), 1.49-1.62 (2H, m), 1.87-2.00 (2H, m), 2.30 (3H, s),2.53 (2H, t, J = 7.8 Hz), 3.72 (2H, t, J = 6.6 Hz), 4.08(2H, t, J = 7.4 Hz), 5.92 (1H, d, J = 3.2 Hz), 6.03 (1H, d,J = 3.2 Hz), 6.67 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.4Hz), 7.04 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3380, 1613, 1510, 1472, 1385, 1242, 1175,1051, 837, 758. (3) Ethyl (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0794] The object compound was obtained from 4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenolas anoily substance, according to the similar manner to that ofExample 165(3). yield: 48.8%1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 6.6 Hz), 1.15-1.33 (9H,m), 1.49-1.58 (2H, m), 1.88-1.94 (2H, m), 2.28 (3H, s),2.52 (2H, t, J = 7.8 Hz), 3.24-3.28 (2H, m), 3.70 (2H, t, J= 5.8 Hz), 4.05 (2H, t, J = 7.6 Hz), 4.19 (2H, q, J = 7.2Hz), 4.76-4.79 (1H, m), 5.90 (1H, d, J = 3.8 Hz), 6.00 (1H, d, J = 3.8 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J =8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1738, 1611, 1510, 1480, 1454, 1279,1179, 1084, 1034, 835, 758, 700. Example 168Sodium (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{1-[3-(4-Hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl)phenoxy)-3-phenylpropanoicacid
    [0795] The object compound was obtained from ethyl (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 166(1).yield: 86.0%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.26-1.34 (6H,m), 1.48-1.58 (2H, m), 1.79-1.89 (2H, m), 2.28 (3H, s),2.52 (2H, t, J = 8.0 Hz), 3.29 (2H, d, J = 6.2 Hz), 3.69(2H, t, J = 5.8 Hz), 4.05 (2H, t, J = 7.4 Hz), 4.83 (1H, t,J = 6.2 Hz), 5.89 (1H, d, J = 3.4 Hz), 5.99 (1H, d, J = 3.4Hz), 6.65 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.01 (2H, d, J = 8.8 Hz), 7.21-7.36 (7H, m).IR (KBr) cm-1; 3063, 1728, 1611, 1510, 1480, 1238, 1177,1084, 833, 758, 700. (2) Sodium (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0796] The object compound was obtained from (2R)-2-(4-{1-[3-(4-hexylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 166(2). yield: 86.4%1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 6.6 Hz), 1.19-1.36 (6H,m), 1.43-1.59 (2H, m), 1.78-1.89 (2H, m), 2.22 (3H, s),2.48 (2H, t, J = 7.6 Hz), 2.98 - 3.23 (2H, m), 3.69 (2H, t,J = 5.2 Hz), 4.01 (2H, t, J = 7.4 Hz), 4.35 - 4.39 (1H, m),5.75 (1H, d, J = 3.4 Hz), 5.81 (1H, d, J = 3.4 Hz), 6.66(2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.4 Hz), 6.99 (2H, d,J = 8.4 Hz), 7.10-7.35 (7H, m).IR (KBr) cm-1; 1615, 1510, 1410, 1238, 1177, 1053, 828, 760,700.[α]D 27 5.55° (c 0.615, methanol) Example 169Ethyl (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrole
    [0797] The object compound was obtained from 4-butylphenol asan oily substance, according to the similar manner to thatof Example 165(1). yield: 86.5% 1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 6.8 Hz), 1.22-1.62 (4H,m), 1.88 - 1.98 (2H, m), 2.31 (3H, s), 2.53 (2H, t, J = 7.2Hz), 3.71 (2H, t, J = 5.8 Hz), 4.09 (2H, t, J = 7.8 Hz),5.06 (2H, s), 5.92 (1H, d, J = 3.2 Hz), 6.03 (1H, d, J =3.2 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.93-7.06 (4H, m), 7.25-7.49(7H, m).IR (KBr) cm-1; 1611, 1524, 1510, 1480, 1468, 1454, 1381,1310, 1281, 1242, 1175, 1024, 833, 747, 696. (2) 4-{1-[3-(4-Butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol
    [0798] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 165(2). yield: 98.5%1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 6.9 Hz), 1.21-1.60 (4H,m), 1.84-1.97 (2H, m), 2.30 (3H, s), 2.53 (2H, t, J = 7.5Hz), 3.72 (2H, t, J = 6.6 Hz), 4.07 (2H, t, J = 6.3 Hz),5.91 (1H, d, J = 3.3 Hz), 6.02 (1H, d, J = 3.3 Hz), 6.67(2H, d, J = 8.4 Hz), 6.82 (2H, d, J = 8.4 Hz), 7.03 (2H, d,J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz).IR (KBr) cm-1; 3331, 1613, 1526, 1510, 1470, 1439, 1387,1240, 1175, 1121, 837, 758, 723, 542. (3) Ethyl (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0799] The object compound was obtained from 4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenolas anoily substance, according to the similar manner to that ofExample 165(3). yield: 38.7%1H-NMR (CDCl3) δ; 0.92 (3H, t, J = 6.2 Hz), 1.19 (3H, t, J= 7.0 Hz), 1.27-1.59 (4H, m), 1.88-1.95 (2H, m), 2.29 (3H,s), 2.53 (2H, t, J = 7.6 Hz), 3.24 - 3.29 (2H, m), 3.70 (2H,t, J = 6.0 Hz), 4.05 (2H, t, J = 7.0 Hz), 4.22 (2H, q, J =7.0 Hz), 4.76-4.82 (1H, m), 5.90 (1H, d, J = 3.8 Hz), 6.00(1H, d, J = 3.8 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.82 (2H, d,J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1510, 1480, 1456, 1242, 1179,1084, 1030, 833, 760. Example 170Sodium (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0800] The object compound was obtained from ethyl (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 166(1).yield: 68.8% 1H-NMR (CDCl3) δ; 0.91 (3H, t, J = 6.6 Hz), 1.29-1.60 (4H,m), 1.87-1.95 (2H, m), 2.29 (3H, s), 2.52 (2H, t, J = 8.1Hz), 3.29-3.31 (2H, m), 3.69 (2H, t, J = 5.7 Hz), 4.05 (2H,t, J = 7.8 Hz), 4.84-4.88 (1H, m), 5.90 (1H, d, J = 3.9 Hz),5.91 (1H, d, J = 3.9 Hz), 6.65 (2H, d, J = 8.7 Hz), 6.82(2H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.7 Hz), 7.18-7.33(7H, m).IR (KBr) cm-1; 3032, 1728, 1512, 1481, 1279, 1240, 1177,1084, 833, 758, 700. (2) Sodium (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0801] The object compound was obtained from (2R)-2-(4-{1-[3-(4-butylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 166(2). yield: 72.9%1H-NMR (DMSO-d6) δ; 0.89 (3H, t, J = 7.2 Hz), 1.23-1.55 (4H,m), 1.78-1.88 (2H, m), 2.21 (3H, s), 2.84 (2H, t, J = 7.5Hz), 2.96-3.19 (2H, m), 3.69 (2H, t, J = 6.0 Hz), 4.00 (2H,t, J = 6.9 Hz), 4.31-4.35 (1H, m), 5.76 (1H, d, J = 3.3 Hz),5.81 (1H, d, J = 3.3 Hz), 6.68 (2H, d, J = 8.7 Hz), 6.77(2H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.7 Hz), 7.11-7.33(7H, m).IR (KBr) cm-1; 1615, 1512, 1410, 1312, 1240, 1177, 1053,828, 760, 700. [α]D 27 10.7° (c 0.510, methanol) Example 171Ethyl (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrole
    [0802] The object compound was obtained from 4-(4-propylcyclohexyl)phenolas an oily substance, according tothe similar manner to that of Example 165(1). yield: 80.2%1H-NMR (CDCl3) δ; 0.86-1.97 (18H, m), 2.30-2.45 (4H, m),3.71 (2H, t, J = 5.6 Hz), 4.09 (2H, t, J = 7.8 Hz), 5.06(2H, s), 5.92 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.4 Hz),6.67 (2H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.06(2H, d, J = 8.8 Hz), 7.24-7.49 (7H, m).IR (KBr) cm-1; 1611, 1524, 1468, 1454, 1381, 1312, 1283,1244, 1177, 1024, 828, 756, 737, 696. (2) 4-{5-Methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl}phenol
    [0803] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-{3-[4-(4-propylcyclohexyl)-phenoxy]propyl}-1H-pyrroleas an oily substance, accordingto the similar manner to that of Example 165(2). yield: 98.1%1H-NMR (CDCl3) δ; 0.86-1.96 (18H, m), 2.29-2.39 (4H, m),3.72 (2H, t, J = 7.0 Hz), 4.07 (2H, t, J = 7.8 Hz), 5.91(1H, d, J = 3.4 Hz), 6.02 (1H, d, J = 3.4 Hz), 6.68 (2H, d,J = 8.8 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8Hz), 7.21 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3397, 1613, 1512, 1470, 1447, 1400, 1385,1244, 1177, 1051, 837, 828; 758, 725, 544. (3) Ethyl (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0804] The object compound was obtained from 4-{5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl}phenolas an oily substance, according to the similarmanner to that of Example 165(3). yield: 42.8%1H-NMR (CDCl3) δ; 0.86-1.95 (21H, m), 2.29-2.39 (4H, m),3.24-3.28 (2H, m), 3.70 (2H, t, J = 5.8 Hz), 4.04 (2H, t, J= 6.8 Hz), 4.19 (2H, q, J = 6.6 Hz), 4.76-4.82 (1H, m),5.90 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J = 3.4 Hz), 6.67(2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz), 7.05 (2H, d,J = 8.8 Hz), 7.20-7.34 (7H, m).IR (KBr) cm-1; 1755, 1732, 1512, 1281, 1244, 1179, 1084,1032, 829, 756, 700. Example 172Sodium (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)-phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)-phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0805] The object compound was obtained from ethyl (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy] -3-phenylpropanoate as an oilysubstance, according to the similar manner to that ofExample 166(1). yield: 71.3%1H-NMR (CDCl3) δ; 0.87-1.97 (18H, m), 2.29-2.39 (4H, m),3.30 (2H, d, J = 5.8 Hz), 3.69 (2H, t, J = 6.0 Hz), 4.04(2H, t, J = 7.0 Hz), 4.85 (1H, t, J = 5.8 Hz), 5.90 (1H, d,J = 3.2 Hz), 6.00 (1H, d, J = 3.2 Hz), 6.66 (2H, d, J = 8.8Hz), 6.81 (2H, d, J = 8.8 Hz), 7.05 (2H, d, J = 8.8 Hz),7.21-7.33 (7H, m).IR (KBr) cm-1; 3031, 1728, 1512, 1480, 1281, 1236, 1179,1084, 829, 758, 700. (2) Sodium (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0806] The object compound was obtained from (2R)-2-[4-(5-methyl-1-{3-[4-(4-propylcyclohexyl)-phenoxy]propyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoic acid as a solid,according to the similar manner to that of Example 166(2).yield: 85.7%1H-NMR (DMSO-d6) δ; 0.84-1.79 (18H, m), 2.21-2.42 (4H, m),2.92-3.18 (2H, m), 3.69 (2H, t, J = 5.8 Hz), 3.99 (2H, t, J= 7.0 Hz), 4.28-4.34 (1H, m), 5.76 (1H, d, J = 3.2 Hz),5.81 (1H, d, J = 3.2 Hz), 6.66-6.78 (4H, m), 7.03-7.34 (9H,m).IR (KBr) cm-1; 1613, 1512, 1404, 1236, 1179, 1055, 1030,828, 758, 700.[α]D 28 8.07° (c 0.665, methanol) Example 173Ethyl (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (4-Methylcyclohexyl)methyl methanesulfonate
    [0807] To a solution of 4-pentylcyclohexylmethanol (776 mg,4.22 mmol) and triethylamine (3.77 ml, 27.1 mmol) in ethylacetate (50 ml) was added dropwise methanesulfonyl chloride(2.08 ml, 27.1 mmol) and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was pouredinto water and the mixture was extracted with ethyl acetate.The extract was washed with water and dried over magnesiumsulfate anhydride, and the solvent was removed under reduced pressure to give the object compound as a solid.6.77 g (yield: 95.2%)1H-NMR (CDCl3) δ; 0.85-1.82 (21H, m), 3.00 (3H, s), 4.02(2H, d, J = 6.2 Hz).IR (KBr) cm-1; 1462, 1449, 1346, 1335, 1171, 980, 955, 864,849, 530. (2) 2-(4-Benzyloxyphenyl)-5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrole
    [0808] To a suspension of sodium hydride (60%, 137 mg, 3.43mmol) in THF (5 ml) was added dropwise a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol) in THF (2 ml) and the mixture wasstirred at room temperature for 1 hour under nitrogenatmosphere. To the mixture was added dropwise a solutionof (4-methyl cyclohexyl)methyl methanesulfonate (1.06 g,4.06 mmol) in THF (1 ml), then added tetra n-butylammoniumbromide (5.0 mg, 0.0156 mmol), and the mixture was stirredat room temperature for 12 hours. The reaction solutionwas poured into water and the mixture was extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance. 740 mg (yield: 48.7%)1H-NMR (CDCl3) δ; 0.80-1.82 (23H, m), 2.31 (3H, s), 3.04(2H, d, J = 6.4 Hz), 3.22 (2H, t, J = 5.8 Hz), 3.97 (2H, t,J = 7.4 Hz), 5.08 (2H, s), 5.92 (1H, d, J = 3.8 Hz), 6.03(1H, d, J = 3.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.03-7.49(7H, m).IR (KBr) cm-1; 1611, 1524, 1466, 1454, 1377, 1310, 1279,1242, 1175, 1127, 1111, 1026, 833, 754, 735, 696, 667. (3) 4-{5-Methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl}phenol
    [0809] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrole(730 mg, 1.50mmol) in ethanol (20 ml) and tetrahydrofuran (20 ml) wasadded 10% palladium carbon (200 mg) and the mixture wasstirred for 4 hours under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as an oilysubstance. 585 mg (yield: 98.3%)1H-NMR (CDCl3) δ; 0.84-1.81 (23H, m), 2.30 (3H, s), 3.06(2H, d, J = 6.2 Hz), 3.22 (2H, t, J = 5.8 Hz), 3.95 (2H, t,J = 7.8 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.01 (1H, d, J =3.4 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3297, 1615, 1526, 1468, 1449, 1402, 1373,1265, 1225, 1127, 837, 756. (4) Ethyl (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0810] To a solution of 4-{5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl}phenol(575mg, 1.44 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (420mg, 2.17 mmol) and triphenylphosphine (569 mg, 2.17 mmol)in toluene (1 ml) was added 1,1'-(azodicarbonyl)dipiperidine(547 mg, 2.17 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 310 mg(yield: 37.5%)1H-NMR (CDCl3) δ; 0.85-1.75 (26H, m), 2.29 (3H, s), 3.07(2H, d, J = 6.6 Hz), 3.16-3.29 (4H, m), 3.92 (2H, t, J =7.2 Hz), 4.19 (2H, q, J = 7.0 Hz), 4.77-4.83 (1H, m), 5.89(1H, d, J = 3.4 Hz), 5.99 (1H, d, J = 3.4 Hz), 6.83 (2H, d,J = 8.4 Hz), 7.20-7.33 (7H, m).IR (KBr) cm-1; 1755, 1736, 1524, 1481, 1454, 1372, 1277,1238, 1182, 1111, 1084, 1032, 835, 756, 700. Example 174Sodium (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-(4-{1-[5-Methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0811] To a mixed solution of ethyl (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(300 mg, 0.523 mmol) in THF(10 ml) and methanol (10 ml) was added 1N aqueous potassiumhydroxide solution (3 ml, 3 mmol) and the mixture wasstirred for 1 hour at room temperature. The reactionsolution was neutralized with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 1:1) to give the object compound asan oily substance. 237 mg (yield: 82.9%)1H-NMR (CDCl3) δ; 0.85-1.75 (23H, m), 2.29 (3H, s), 3.07(2H, d, J = 5.8 Hz), 3.20 (2H, t, J = 6.2 Hz), 3.30 (2H, d,J = 5.8 Hz), 4.87 (1H, t, J = 5.8 Hz), 4.19 (2H, q, J = 7.0Hz), 4.77-4.83 (1H, m), 5.90 (1H, d, J = 3.4 Hz), 6.00 (1H, d, J = 3.4 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.23-7.33 (7H, m).IR (KBr) cm-1; 2921, 1732, 1524, 1481, 1454, 1233, 1109,1084, 756, 700. (2) Sodium (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0812] To (2R)-2-(4-{1-[5-methyl-1-[3-(4-pentylcyclohexylmethoxy)propyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (210 mg, 0.384 mmol) were addedethanol (5 ml) and a solution of 1N sodium hydroxide inethanol (0.346 ml) and the mixture was concentrated.Diisopropylether was added to the residue to give theobject compound as a solid. 140 mg (yield: 71.4%)1H-NMR (DMSO-d6) δ; 0.78-1.75 (23H, m), 2.21 (3H, s), 2.93-3.17(6H, m), 3.88 (2H, t, J = 6.6 Hz), 4.30-4.36 (1H, m),5.75 (1H, d, J = 3.4 Hz), 5.80 (1H, d, J = 3.4 Hz), 6.76(2H, d, J = 8.8 Hz), 7.09-7.33 (7H, m).IR (KBr) cm-1; 1615, 1522, 1481, 1454, 1410, 1231, 1111,1065, 1036, 843, 758, 700, 561.[α]D 24 9.07° (c 0.590, methanol) Example 175Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Pentylcyclohexylmethyl)-1H-isoindol-1,3-(2H)-dione
    [0813] To a suspension of potassium phthalimide (3.70 g, 20.0mmol) in DMF (50 ml) was added (4-methylcyclohexyl)methylmethanesulfonate (5.25 g, 20.0 mmol) and the mixture wasstirred at 80°C for 3 hours. The reaction solution waspoured into water and the mixture was extracted with ethylacetate. The extract was washed with water and dried overmagnesium sulfate anhydride. The solvent was removed underreduced pressure to give the object compound as a solid.5.90 g (yield: 94.2%)1H-NMR (CDCl3) δ; 0.83-1.74 (21H, m) , 3.53 (2H, d, J = 6.8Hz), 7.69-7.87 (4H, m).IR (KBr) cm-1; 1703, 1466, 1433, 1400, 1364, 1063, 1036,920, 720, 530. (2) 2-(4-Pentylcyclohexyl)methylamine
    [0814] To a solution of 2-(4-pentylcyclohexylmethyl)-1H-isoindol-1,3-(2H)-dione(5.70 g, 18.2 mmol) in ethanol (100ml) was added hydrazine monohydrate (1.31 ml, 27.0 mmol)and the mixture was refluxed for 12 hours under heating.The insoluble matter was filtered out and the filtrate wasconcentrated. The residue was dissolved into 5 N aqueoussodium hydroxide solution (100 ml) and extracted with ethylacetate. The extract was washed with water and dried overmagnesium sulfate anhydride, and the solvent was removed under reduced pressure to give the object compound as anoily substance. 3.06 g (yield: 91.9%)1H-NMR (CDCl3) δ; 0.84-1.78 (21H, m), 2.51 (2H, d, J = 6.2Hz).IR (KBr) cm-1; 3368, 1537, 1485, 1426, 1339, 1327. (3) 2-(4-Benzyloxyphenyl)-5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrole
    [0815] A solution of 1-(4-benzyloxyphenyl)pentane-1,4-dione(2.00 g, 7.08 mmol), 2-(4-pentylcyclohexyl)ethylamine (1.30g, 7.08 mmol) and p-toluenesulfonic acid monohydrate (101mg, 0.523 mmol) in toluene (100 ml) was refluxed for 12hours under heating using Dean-Stark's apparatus, and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography(hexane:ethyl acetate = 30:1) to give the object compoundas an oily substance. 770 mg (yield: 25.3%)1H-NMR (CDCl3) δ; 0.65-1.63 (21H, m), 2.28 (3H, s), 3.72(2H, d, J = 6.8 Hz), 5.09 (2H, s), 5.91 (1H, d, J = 3.2 Hz),5.99 (1H, d, J = 3.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.02-7.49(7H, m).IR (KBr) cm-1; 1611, 1524, 1481, 1454, 1381, 1242, 1175,1022, 835, 754, 735, 696. (4) 4-[5-Methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenol
    [0816] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrole(770 mg, 1.79 mmol) inethanol (10 ml) and tetrahydrofuran (10 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 600 mg (yield:98.5%)1H-NMR (CDCl3) δ; 0.65-1.62 (21H, m), 2.28 (3H, s), 3.71(2H, d, J = 7.0 Hz), 5.91 (1H, d, J = 3.4 Hz), 5.99 (1H, d,J = 3.4 Hz), 6.83 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0Hz).IR (KBr) cm-1; 3291, 1615, 1526, 1479, 1449, 1400, 1360,1260, 1217, 1188, 1171, 837, 818, 758. (5) Ethyl (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0817] To a solution of 4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenol(600 mg, 1.76mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (514 mg, 2.65mmol) and triphenylphosphine (694 mg, 2.65 mmol) in toluene(2 ml) was added 1,1'-(azodicarbonyl)dipiperidine (668 mg,2.65 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.850 mg (yield: 72.0%)1H-NMR (CDCl3) δ; 0.63-1.60 (24H, m), 2.26 (3H, s), 3.24-3.29(2H, m), 3.69 (2H, d, J = 7.0 Hz), 4.19 (2H, q, J =7.0 Hz), 4.79-4.86 (1H, m), 5.90 (1H, d, J = 3.4 Hz), 5.96(1H, d, J = 3.4 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.17-7.33(7H, m).IR (KBr) cm-1; 1755, 1734, 1524, 1481, 1454, 1281, 1238,1181, 1086, 1032, 837, 754, 698. Example 176Sodium (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-Methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0818] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(850 mg, 1.65 mmol) in THF (30 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution (8 ml, 8 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.573 mg (yield: 71.2%)1H-NMR (CDCl3) δ; 0.63-1.57 (21H, m), 2.27 (3H, s), 3.31(2H, d, J = 5.0 Hz), 3.69 (2H, d, J = 7.0 Hz), 4.89 (1H, t,J = 5.0 Hz), 5.90 (1H, d, J = 3.2 Hz), 5.97 (1H, d, J = 3.2Hz), 6.83 (2H, d, J = 8.8 Hz), 7.19-7.34 (7H, m).IR (KBr) cm-1; 3061, 1728, 1524, 1481, 1454, 1308, 1281,1236, 1084, 835, 756, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0819] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (1.01 ml) were added to (2R)-2-{4-[5-methyl-1-(4-pentylcyclohexylmethyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (550 mg, 1.13 mmol) and the mixturewas concentrated. To the residue was added hexane to givethe object compound as a solid. 470 mg (yield: 91.4%)1H-NMR (DMSO-d6) δ; 0.61-1.53 (21H, m), 2.20 (3H, s), 2.93-3.17(2H, m), 3.71 (2H, d, J = 7.0 Hz), 4.29-4.35 (1H, m), 5.75 (2H, s), 6.76 (2H, d, J = 8.8 Hz), 7.05-7.33 (7H, m).IR (KBr) cm-1; 1615, 1524, 1414, 1235, 1059, 1030, 837, 756,698.[α]D 28 3.97° (c 0.680, methanol) Example 177Ethyl (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-octyloxyphenyl)-5-methyl-1H-pyrrole
    [0820] A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.00 g, 2.82 mmol), 1-bromooctane(0.584 ml, 3.38 mmol) and potassium carbonate (466 mg, 3.38mmol) in DMF (20 ml) was stirred at 80°C for 4 hours. Thereaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride, and thesolvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 30:1) to give the object compound as an oilysubstance. 1.03 g (yield: 78.0%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.6 Hz), 1.29-1.55 (10H,m), 1.75-1.83 (2H, m), 2.10 (3H, s), 3.95 (2H, t, J = 6.2Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.2 Hz), 6.25 (1H, d, J= 3.2 Hz), 6.77 (2H, d, J = 9.2 Hz), 6.85 (2H, d, J = 9.2 Hz), 7.33-7.42 (5H, m).IR (KBr) cm-1; 1609, 1514, 1470, 1545, 1395, 1289, 1246,1177, 1040, 1026, 835, 760, 735, 698. (2) 4-[5-Methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenol
    [0821] To a solution of 2-(4-benzyloxyphenyl)-1-(4-octyloxyphenyl)-5-methyl-1H-pyrrole(950 mg, 2.03 mmol) inethanol (20 ml) and tetrahydrofuran (20 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 3hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 752 mg (yield:98.0%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 7.4 Hz), 1.21-1.96 (12H,m), 2.10 (3H, s), 3.94 (2H, t, J = 6.2 Hz), 6.04 (1H, d, J= 3.6 Hz), 6.23 (1H, d, J = 3.6 Hz), 6.61 (2H, d, J = 8.8Hz), 6.85 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz),7.04 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3339, 1514, 1472, 1246, 1171, 1040, 835, 762. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0822] To a solution of 4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenol(740 mg, 1.96 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(570 mg, 2.94 mmol) and triphenylphosphine (770 mg, 2.94 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (741 mg, 2.94mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.420 mg (yield: 39.6%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.6 Hz), 1.14 (3H, t, J= 7.4 Hz), 1.26-1.56 (10H, m), 1.72-1.83 (2H, m), 2.09 (3H,s), 3.17-3.21 (2H, m), 3.94 (2H, t, J = 6.6 Hz), 4.14 (2H,q, J = 7.4 Hz), 4.66-4.73 (1H, m), 6.02 (1H, d, J = 3.6 Hz),6.21 (1H, d, J = 3.6 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.83(2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.01 (2H, d,J = 8.8 Hz), 7.21-7.29 (5H, m).IR (KBr) cm-1; 1755, 1734, 1514, 1483, 1456, 1287, 1244,1182, 1084, 1038, 835, 760, 700. Example 178Sodium (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0823] To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl}phenoxy}-3-phenylpropanoate(410 mg, 0.739 mmol) in THF (15 ml) and methanol (8 ml) wasadded 1N aqueous potassium hydroxide solution (4 ml, 4mmol) and the mixture was stirred for 1 hour at roomtemperature. The reaction solution was neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. Theextract was washed with water and dried over magnesiumsulfate anhydride, and the solvent was removed underreduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate = 1: 1) to givethe object compound as an oily substance. 278 mg (yield:71.5%)1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.9 Hz), 1.24-1.46 (10H,m), 1.74-1.83 (2H, m), 2.09 (3H, s), 3.21-3.24 (2H, m),3.94 (2H, t, J = 6.6 Hz), 4.75-4.79 (1H, m), 6.03 (1H, d, J= 3.6 Hz), 6.23 (1H, d, J = 3.6 Hz), 6.62 (2H, d, J = 9.0Hz), 6.84 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz),7.01 (2H, d, J = 9.0 Hz), 7.22-7.30 (5H, m).IR (KBr) cm-1; 2926, 1728, 1514, 1287, 1244, 835, 758, 700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0824] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.444 ml) were added to (2R)-2-{4-[5-methyl-1-(4-octyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (260 mg, 0.493 mmol) and the mixturewas concentrated. To the residue was added hexane to givethe object compound as a solid. 227 mg (yield: 93.0%)1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 6.6 Hz), 1.28-1.41(10H, m), 1.68-1.73 (2H, m), 1.99 (3H, s), 2.87-3.10 (2H,m), 3.95 (2H, t, J = 6.3 Hz), 4.19-4.23 (1H, m), 5.92 (1H,d, J = 3.3 Hz), 6.07 (1H, d, J = 3.3 Hz), 6.53 (2H, d, J =8.7 Hz), 6.79 (2H, d, J = 8.7 Hz), 6.91 (2H, d, J = 8.7 Hz),7.03 (2H, d, J = 8.7 Hz), 7.10-7.27 (5H, m).IR (KBr) cm-1; 1611, 1514, 1396, 1244, 1181, 1169, 1043,1030, 835, 764.[α]D 30 -2.52° (c 0.530, methanol) Example 179Ethyl (2R)-2-(4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrole
    [0825] To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol), 4-n-amylphenol(766 mg, 4.67 mmol) and triphenylphosphine (1.22 g, 4.67mmol) in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.18 g, 4.67 mmol) and themixture was stirred at 80°C for 12 hours. The reaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30:1) togive the object compound as an oily substance. 1.25 g(yield: 86.2%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.22-1.64 (6H,m), 1.88-1.98 (2H, m), 2.30 (3H, s), 2.52 (2H, t, J = 7.8Hz), 3.71 (2H, d, J = 5.8 Hz), 4.09 (2H, t, J = 7.4 Hz),5.06 (2H, s), 5.92 (1H, d, J = 3.6 Hz), 6.03 (1H, d, J =3.6 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz),7.03 (2H, d, J = 8.8 Hz), 7.19-7.49 (7H, m).IR (KBr) cm-1; 1611, 1522, 1510, 1466, 1454, 1309, 1279,1244, 1175, 1024, 833, 756, 737, 698. (2) 4-{5-Methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenol
    [0826] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrole(1.17 g, 2.50 mmol) inethanol (50 ml) and tetrahydrofuran (50 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 921 mg (yield: 97.7%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.21-1.33 (4H,m), 1.49-1.60 (2H, m), 1.87-2.00 (2H, m), 2.30 (3H, s),2.52 (2H, t, J = 7.6 Hz), 3.72 (2H, t, J = 7.0 Hz), 4.08(2H, t, J = 7.4 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.03 (1H, d,J = 3.4 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.80 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3380, 1610, 1510, 1470, 1242, 1180, 837, 760. (3) Ethyl (2R)-2-(4-{5-methyl-1-(3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0827] To a solution of 4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenol(910 mg, 2.41mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (701 mg, 3.61mmol) and triphenylphosphine (946 mg, 3.61 mmol) in toluene(5 ml) was added 1,1'-(azodicarbonyl)dipiperidine (910 mg,3.61 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.770 mg (yield: 57.9%) 1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.9 Hz), 1.18 (3H, t, J= 6.9 Hz), 1.26 - 1.36 (4H, m), 1.52-1.59 (2H, m), 1.89-2.05(2H, m), 2.29 (3H, s), 2.52 (2H, t, J = 7.8 Hz), 3.24-3.29(2H, m), 3.70 (2H, t, J = 5.7 Hz), 4.05 (2H, t, J =7.5 Hz), 4.18 (2H, q, J = 6.9 Hz), 4.77-4.81 (1H, m), 5.90(1H, d, J = 3.3 Hz), 6.00 (1H, d, J = 3.3 Hz), 6.65 (2H, d,J = 8.4 Hz), 6.82 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.4Hz), 7.20-7.33 (7H, m).IR (KBr) cm-1; 1755, 1734, 1522, 1512, 1480, 1279, 1242,1179, 1084, 1032, 835, 756, 700. Example 180Sodium (2R)-2-(4-(5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0828] To a mixed solution of ethyl (2R)-2-(4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(750 mg, 1.35 mmol) in THF (20 ml) andmethanol (20 ml) was added 1N aqueous potassium hydroxidesolution (7 ml, 7 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.672 mg (yield: 94.6%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.26-1.33 (4H,m), 1.53-1.62 (2H, m), 1.87-1.94 (2H, m), 2.29 (3H, s),2.51 (2H, t, J = 7.8 Hz), 3.30 (2H, d, J = 6.2 Hz), 3.69(2H, t, J = 5.6 Hz), 4.05 (2H, t, J = 8.6 Hz), 4.85 (1H, t,J = 6.2Hz), 5.90 (1H, d, J = 3.2 Hz), 6.00 (1H, d, J = 3.2Hz), 6.65 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz),7.01 (2H, d, J = 8.8Hz), 7.20-7.33 (7H, m).IR (KBr) cm-1; 3061, 1728, 1512, 1481, 1242, 1084, 835, 758,700. (2) Sodium (2R)-2-(4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0829] Ethanol (6 ml) and a solution of 1N sodium hydroxidein ethanol (1.10 ml) were added to (2R)-2-(4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (640 mg, 1.22 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid.499 mg (yield: 82.9%)1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 7.0 Hz), 1.22-1.29 (4H, m), 1.453-1.56 (2H, m), 1.77-1.90 (2H, m), 2.21 (3H, s),2.48 (2H, t, J = 8.0 Hz), 2.95-3.22 (2H, m), 3.69 (2H, t, J= 6.0 Hz), 4.00 (2H, t, J = 7.0 Hz), 4.31-4.37 (1H, m),5.75 (1H, d, J = 3.2 Hz), 5.82 (1H, d, J = 3.2 Hz), 6.67(2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz), 7.01 (2H, d,J = 8.8Hz), 7.14-7.35 (7H, m).IR (KBr) cm-1; 1615, 1512, 1481, 1410, 1240, 1177, 1035,835, 758, 700.[α]D 27 7.45° (c 0.530, methanol) Example 181Ethyl (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrole
    [0830] To a solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol(1.00 g, 2.81 mmol), 5-phenyl-1-pentanol(692 mg, 4.22 mmol), triphenylphosphine (1.11 g, 4.22 mmol)in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.06 g, 4.22 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as a solid. 1.18 g (yield: 83.7%)1H-NMR (CDCl3) δ; 1.43-1.86 (6H, m), 2.10 (3H, s), 2.65 (2H,t, J = 7.8 Hz), 3.95 (2H, t, J = 6.6 Hz), 4.97 (2H, s),6.04 (1H, d, J = 3.6 Hz), 6.24 (1H, d, J = 3.6 Hz), 6.73-7.40(18H, m).IR (KBr) cm-1; 1610, 1514, 1451, 1397, 1290, 1244, 1180,1040, 1020, 845, 750, 710. (2) 4-{5-Methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenol
    [0831] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrole(1.11 g, 2.21 mmol)in ethanol (50 ml) and tetrahydrofuran (50 ml) was added10% palladium carbon (200 mg) and the mixture was stirredfor 4 hours under hydrogen atmosphere. The insolublematter was filtered out and the filtrate was concentratedto give the object compound as an oily substance. 891 mg(yield: 98.0%)1H-NMR (CDCl3) δ; 1.49-1.87 (6H, m), 2.10 (3H, s), 2.65 (2H,t, J = 7.8 Hz), 3.94 (2H, t, J = 6.6 Hz), 6.04 (1H, d, J =3.6 Hz), 6.23 (1H, d, J = 3.6 Hz), 6.61 (2H, d, J = 8.4 Hz),6.84 (2H, d, J = 8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.03(2H, d, J = 8.4 Hz), 7.17-7.28 (5H, m).IR (KBr) cm-1; 3397, 1613, 1512, 1397, 1289, 1246, 1171, 835, 764, 700. (3) Ethyl (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0832] To a solution of 4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenol(880 mg, 2.14mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (622 mg, 3.21mmol) and triphenylphosphine (810 mg, 3.21 mmol) in toluene(3 ml) was added 1,1'-(azodicarbonyl)dipiperidine (809 mg,3.21 mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.530 mg (yield: 42.1%)1H-NMR (CDCl3) δ; 1.13 (3H, t, J = 6.8 Hz), 1.22-1.87 (6H,m), 2.09 (3H, s), 2.66 (2H, t, J = 7.6 Hz), 3.17 - 3.21 (2H,m), 3.94 (2H, t, J = 6.2 Hz), 4.13 (2H, q, J = 6.8 Hz),4.66 - 4.73 (1H, m), 6.02 (1H, d, J = 3.2 Hz), 6.22 (1H, d,J = 3.2 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8Hz), 6.93 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz),7.18-7.33 (10H, m). IR (KBr) cm-1; 1753, 1734, 1514, 1287, 1244, 1182, 1084,1032, 837, 760, 700. Example 182Sodium (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0833] To a mixed solution of ethyl (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(520 mg, 0.884 mmol) in THF (20 ml) andmethanol (20 ml) was added 1N aqueous potassium hydroxidesolution (5 ml, 5 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride, and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.336 mg (yield: 67.9%)1H-NMR (CDCl3) δ; 1.47-1.86 (6H, m), 2.08 (3H, s), 2.65 (2H,t, J = 7.6 Hz), 3.22 (2H, d, J = 6.2 Hz), 3.93 (2H, t, J =6.6 Hz), 4.76 (1H, t, J = 6.2 Hz), 6.03 (1H, d, J = 3.2 Hz),6.23 (1H, d, J = 3.2 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.01 (2H, d,J = 8.8 Hz), 7.18-7.32 (10H, m).IR (KBr) cm-1; 3029, 1726, 1514, 1287, 1244, 1181, 1169,1084, 835, 760, 735, 700. (2) Sodium (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0834] Ethanol (6 ml) and a solution of 1N sodium hydroxidein ethanol (0.508 ml) were added to (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (316 mg, 0.565 mmol) and the mixturewas concentrated. Diisopropylether was added to theresidue to give the object compound as a solid. 267 mg(yield: 90.2%)1H-NMR (DMSO-d6) δ; 1.44-1.79 (6H, m), 1.99 (3H, s), 2.61(2H, t, J = 7.6 Hz), 2.85-3.12 (2H, m), 3.95 (2H, t, J =6.6 Hz), 4.18-4.24 (1H, m), 5.91 (1H, d, J = 3.6 Hz), 6.06(1H, d, J = 3.6 Hz), 6.53 (2H, d, J = 8.8 Hz), 6.79 (2H, d,J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8Hz), 7.09-7.31 (10H, m).IR (KBr) cm-1; 1613, 1514, 1404, 1244, 1181, 1053, 1028,833, 766, 748, 700. Example 183Ethyl (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[4-(4-phenylbutoxy)-phenyl]-1H-pyrrole
    [0835] The object compound was obtained from 4-phenyl-1-butanolas an oily substance, according to the similarmanner to that of Example 181 (1). yield: 86.9%1H-NMR (CDCl3) δ; 1.81-1.86 (4H, m), 2.10 (3H, s), 2.70 (2H,t, J = 7.0 Hz), 3.97 (2H, t, J = 5.8 Hz), 4.97 (2H, s),6.04 (1H, d, J = 3.2 Hz), 6.24 (1H, d, J = 3.2 Hz), 6.76(2H, d, J = 8.8 Hz), 6.84 (2H, d, J = 8.8 Hz), 6.96-7.40(14H, m).IR (KBr) cm-1; 1609, 1514, 1454, 1395, 1289, 1244, 1175,1026, 835, 739, 698. (2) 4-{5-Methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenol
    [0836] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 181 (2). yield: 98.2%1H-NMR (CDCl3) δ; 1.79-1.86 (4H, m), 2.10 (3H, s), 2.70 (2H,t, J = 7.0 Hz), 3.96 (2H, t, J = 5.8 Hz), 6.04 (1H, d, J =3.4 Hz), 6.23 (1H, d, J = 3.4 Hz), 6.60 (2H, d, J = 8.8 Hz),6.84 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 7.19-7.33 (5H, m).IR (KBr) cm-1; 3300, 1613, 1512, 1454, 1537, 1397, 1289,1244, 1171, 835, 764, 700. (3) Ethyl (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0837] The object compound was obtained from 4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenolas an oilysubstance, according to the similar manner to that ofExample 181 (3). yield: 39.8%1H-NMR (CDCl3) δ; 1.13 (3H, t, J = 7.2 Hz), 1.82-1.85 (4H,m), 2.08 (3H, s), 2.70 (2H, t, J = 6.9 Hz), 3.17-3.20 (2H,m), 3.96 (2H, t, J = 6.0 Hz), 4.13 (2H, q, J = 7.2 Hz),4.67-4.72 (1H, m), 6.01 (1H, d, J = 3.3 Hz), 6.22 (1H, d, J= 3.3 Hz), 6.61 (2H, d, J = 8.7 Hz), 6.82 (2H, d, J = 8.7Hz), 6.92 (2H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.7 Hz),7.17-7.32 (10H, m).IR (KBr) cm-1; 1752, 1734, 1514, 1483, 1287, 1244, 1182,1084, 1032, 835, 760, 700. Example 184Sodium (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl)phenoxy)-3-phenylpropanoicacid
    [0838] The object compound was obtained from ethyl (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 182(1).yield: 74.3%1H-NMR (CDCl3) δ; 1.81-1.85 (4H, m), 2.08 (3H, s), 2.70 (2H,t, J = 7.0 Hz), 3.22 (2H, d, J = 5.8 Hz), 3.95 (2H, t, J =6.0 Hz), 4.75 (1H, t, J = 5.8 Hz), 6.03 (1H, d, J = 3.2 Hz),6.23 (1H, d, J = 3.2 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.82(2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.01 (2H, d,J = 8.8 Hz), 7.16-7.36 (10H, m).IR (KBr) cm-1; 3031, 1728, 1514, 1287, 1244, 1181, 1084,835, 758, 700. (2) Sodium (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0839] The object compound was obtained from (2R)-2-(4-{5-methyl-1-[4-(4-phenylbutoxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 182(2). yield: 89.3%1H-NMR (DMSO-d6) δ; 1.74 (4H, bs), 1.98 (3H, s), 2.65 (2H,t, J = 7.0 Hz), 2.84-3.10 (2H, m), 3.98 (2H, t, J = 6.0 Hz),4.16-4.21 (1H, m), 5.91 (1H, d, J = 3.4 Hz), 6.06 (1H, d, J= 3.42 Hz), 6.52 (2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz),7.11-7.32 (10H, m).IR (KBr) cm-1; 1615, 1514, 1399, 1244, 1181, 1169, 1049,1030, 835, 766, 750, 700.[α]D 28-5.33° (c 0.545, methanol) Example 185Ethyl (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol
    [0840] To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol), 4-n-heptylphenol(897 mg, 4.67 mmol) and triphenylphosphine(1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(1.18 g, 4.67 mmol) and themixture was stirred at 80°C for 12 hours. The reactionsolution was poured into water and the mixture wasextracted with ethyl acetate. The extract was dried overmagnesium sulfate anhydride and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30: 1) togive the object compound as an oily substance. 1.20 g(yield: 80.0%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 7.0 Hz), 1.22-1.28 (8H, m), 1.49-1.61 (2H, m), 1.91-2.01 (2H, m), 2.30 (3H, s),2.52 (2H, t, J = 8.0 Hz), 3.71 (2H, t, J = 5.8 Hz), 4.09(2H, t, J = 7.2 Hz), 5.06 (2H, s), 5.92 (1H, d, J = 3.2 Hz),6.03 (1H, d, J = 3.2 Hz), 6.66 (2H, d, J = 8.8 Hz), 6.91-7.49(11H, m).IR (KBr) cm-1; 1611, 1524, 1510, 1468, 1454, 1383, 1310,1281, 1244, 1175, 1053, 1024, 833, 756, 735, 698. (2) 4-{1-[3-(4-Heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol
    [0841] To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-[3-(4-heptylphenoxy)propyl]-1H-pyrrole(1.14 g, 2.37 mmol) inethanol (30 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 911 mg (yield:94.8%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.21-1.28 (8H,m), 1.51-1.61 (2H, m), 1.87 - 1.97 (2H, m), 2.30 (3H, s),2.52 (2H, t, J = 7.6 Hz), 3.71 (2H, t, J = 7.0 Hz), 4.07(2H, t, J = 7.4 Hz), 5.91 (1H, d, J = 3.6 Hz), 6.02 (1H, d,J = 3.6 Hz), 6.67 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3407, 1613, 1512, 1470, 1385, 1242, 1175, 1051, 837, 758. (3) Ethyl (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0842] To a solution of 4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenol(910 mg, 2.22 mmol), ethyl(S)-2-hydroxy-3-phenylpropanoate (673 mg, 3.47 mmol) andtriphenylphosphine (910 mg, 3.47 mmol) in toluene (3 ml)was added 1,1'-(azodicarbonyl)dipiperidine (876 mg, 3.47mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30:1) to give the object compound as an oily substance.490 mg (yield: 30.8%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.15-1.33 (11H,m), 1.51-1.60 (2H, m), 1.88-1.94 (2H, m), 2.29 (3H, s),2.52 (2H, t, J = 8.0Hz), 3.24-3.28 (2H, m), 3.70 (2H, t, J= 5.8 Hz), 4.05 (2H, t, J = 7.2 Hz), 4.19 (2H, q, J = 7.0Hz), 4.76-4.82 (1H, m), 5.90 (1H, d, J = 3.8 Hz), 6.00 (1H,d, J = 3.8 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.82 (2H, d, J =8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.19-7.34 (7H, m).IR (KBr) cm-1; 1753, 1736, 1611, 1510, 1242, 1179, 1084, 1032, 835, 756, 700. Example 186Sodium (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{1-[3-(4-Heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0843] To a mixed solution of ethyl (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(480 mg, 0.825 mmol) in THF (15 ml) andmethanol (15 ml) was added 1N aqueous potassium hydroxidesolution (3 ml, 3 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =1:1) to give the object compound as an oily substance. 353mg (yield: 77.3%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 6.6 Hz), 1.23-1.30 (8H,m), 1.48-1.62 (2H, m), 1.84-1.95 (2H, m), 2.28 (3H, s),2.51 (2H, t, J = 7.8 Hz), 3.29 (2H, d, J = 6.2 Hz), 3.70(2H, t, J = 5.8 Hz), 4.04 (2H, t, J = 7.0 Hz), 4.84 (1H, t,J = 6.2Hz), 5.89 (1H, d, J = 3.6 Hz), 5.99 (1H, d, J = 3.6 Hz), 6.64 (2H, d, J = 8.8 Hz), 6.81 (2H, d, J = 8.8 Hz),7.01 (2H, d, J = 8.8Hz), 7.20-7.30 (7H, m) .IR (KBr) cm-1; 3032, 1728, 1510, 1240, 1177, 1084, 835, 758,700. (2) Sodium (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0844] Ethanol (6 ml) and a solution of 1N sodium hydroxidein ethanol (0.536 ml) were added to (2R)-2-(4-{1-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid (330 mg, 0.596 mmol) and the mixturewas concentrated. To the residue was addeddiisopropylether to give the object compound as a solid.212 mg (yield: 68.6%)1H-NMR (DMSO-d6) δ; 0.85 (3H, t, J = 7.0 Hz), 1.18-1.35 (8H,m), 1.44-1.58 (2H, m), 1.66-1.91 (2H, m), 2.21 (3H, s),2.47 (2H, t, J = 7.6 Hz), 2.92-3.19 (2H, m), 3.69 (2H, t, J= 5.8 Hz), 3.99 (2H, t, J = 7.6 Hz), 4.29-4.35 (1H, m),5.76 (1H, d, J = 3.2 Hz), 5.82 (1H, d, J = 3.2 Hz), 6.66-6.99(4H, m), 7.03-7.34 (9H, m).IR (KBr) cm-1; 1613, 1512, 1470, 1404, 1242, 1177, 1042,829, 764, 700.[α]D 27 10.3° (c 0.585, methanol) Example 187Ethyl (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-5-methyl-1-[3-(4-nonylphenoxy)-propyl]-1H-pyrrole
    [0845] The object compound was obtained from 4-n-nonylphenolas an oily substance, according to the similar manner tothat of Example 185(1). yield: 95.6%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.23-1.30 (12H,m), 1.51-1.60 (2H, m), 1.88-1.98 (2H, m), 2.31 (3H, s),2.52 (2H, t, J = 8.0 Hz), 3.71 (2H, t, J = 5.8 Hz), 4.09(2H, t, J = 7.2 Hz), 5.06 (2H, s), 5.92 (1H, d, J = 3.4 Hz),6.03 (1H, d, J = 3.4 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.70-7.06(4H, m), 7.25-7.49 (7H, m).IR (KBr) cm-1; 1611, 1524, 1510, 1468, 1454, 1309, 1279,1244, 1175, 1026, 833, 696. (2) 4-{5-Methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenol
    [0846] The object compound was obtained from 2-(4-benzyloxyphenyl)-5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrroleas an oily substance, according to the similarmanner to that of Example 185(2). yield: 95.3%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.22-1.29 (12H,m), 1.49-1.59 (2H, m), 1.87-1.97 (2H, m), 2.30 (3H, s),2.52 (2H, t, J = 7.6 Hz), 3.72 (2H, t, J = 5.8 Hz), 4.07 (2H, t, J = 7.42 Hz), 5.91 (1H, d, J = 3.4 Hz), 6.02 (1H, d,J = 3.4 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.81 (2H, d, J = 8.4Hz), 7.04 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.8 Hz).IR (KBr) cm-1; 3387, 1613, 1526, 1510, 1468, 1439, 1387,1310, 1242, 1175, 837, 758. (3) Ethyl (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0847] The object compound was obtained from 4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenolas an oilysubstance, according to the similar manner to that ofExample 185 (3). yield: 27.2%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.15-1.37 (15H,m), 1.51-1.61 (2H, m), 1.88-1.95 (2H, m), 2.29 (3H, s),2.52 (2H, t, J = 8.0Hz), 3.24 - 3.28 (2H, m), 3.70 (2H, t,J = 6.2 Hz), 4.05 (2H, t, J = 7.8 Hz), 4.19 (2H, q, J = 7.0Hz), 4.76-4.82 (1H, m), 5.90 (1H, d, J = 3.4 Hz), 6.00 (1H,d, J = 3.4 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.82 (2H, d, J =8.8 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.21-7.34 (7H, m).IR (KBr) cm-1; 1755, 1736, 1524, 1510, 1279, 1240, 1179,1084, 1032, 835, 756, 700. Example 188Sodium (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl)phenoxy)-3-phenylpropanoate(1) (2R)-2-(4-{5-Methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid
    [0848] The object compound was obtained from ethyl (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoateas an oily substance,according to the similar manner to that of Example 186(1).yield: 70.9%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.23-1.30 (12H,m), 1.49-1.59 (2H, m), 1.86-1.92 (2H, m), 2.28 (3H, s),2.51 (2H, t, J = 8.0Hz), 3.28 (2H, d, J = 6.6 Hz), 3.77 (2H,t, J = 5.6 Hz), 4.04 (2H, t, J = 7.0 Hz), 4.84 (1H, t, J =6.6 Hz), 5.90 (1H, d, J = 3.2 Hz), 5.99 (1H, d, J = 3.2 Hz),6.64 (2H, d, J = 8.4 Hz), 6.81 (2H, d, J = 8.8 Hz), 7.01(2H, d, J = 8.8 Hz), 7.20-7.30 (7H, m).IR (KBr) cm-1; 3031, 1728, 1510, 1242, 1177, 1084, 833, 700. (2) Sodium (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate
    [0849] The object compound was obtained from (2R)-2-(4-{5-methyl-1-[3-(4-nonylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoicacid as a solid, according tothe similar manner to that of Example 186(2). yield: 67.4%1H-NMR (DMSO-d6) δ; 0.85 (3H, t, J = 6.6 Hz), 1.18-1.31(12H, m), 1.45-1.57 (2H, m), 1.75-1.89 (2H, m), 2.21 (3H, s), 2.47 (2H, t, J = 7.6 Hz), 2.93-3.19 (2H, m), 3.69 (2H,t, J = 6.0 Hz), 3.99 (2H, t, J = 7.0 Hz), 4.29-4.39 (1H, m),5.76 (1H, d, J = 3.4 Hz), 5.81 (1H, d, J = 3.4 Hz), 6.67(2H, d, J = 8.4 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.99-7.34(9H, m).IR (KBr) cm-1; 1615, 1584, 1512, 1472, 1454, 1404, 1309,1227, 1179, 1053, 829, 762, 700.[α]D 27 7.97° (c 0.530, methanol) Example 189Ethyl (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-decylphenyl)-5-methyl-1H-pyrrole
    [0850] A solution of 1-(4-benzyloxyphenyl)pentane-1,4-dione(2.00 g, 7.08 mmol), 4-n-decylaniline (1.65 mg, 7.08 mmol)and p-toluenesulfonic acid monohydrate (101 mg, 0.523 mmol)in toluene (100 ml) was refluxed for 12 hours under heatingusing Dean-Stark's apparatus and the solvent was removedunder reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 30:1) togive the object compound as an oily substance. 2.79 g(yield: 82.1%)1H-NMR (CDCl3) δ; 0.87 (3H, t, J = 7.0 Hz), 1.20-1.34 (14H,m), 1.55-1.66 (2H, m), 2.13 (3H, s), 2.62 (2H, t, J = 7.8 Hz), 4.97 (2H, s), 6.05 (1H, d, J = 3.2 Hz), 6.24 (1H, d, J= 3.2 Hz), 6.75 (2H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8Hz), 7.03 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz),7.33-7.41 (5H, m).IR (KBr) cm-1; 1611, 1522, 1454, 1393, 1281, 1240, 1177,1038, 1026, 833, 760, 735, 696. (2) 4-[1-(4-Decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0851] To a solution of 2-(4-benzyloxyphenyl)-1-(4-decylphenyl)-5-methyl-1H-pyrrole(2.77 g, 5.77 mmol) inmethanol (40 ml) and tetrahydrofuran (40 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 4hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give theobject compound as an oily substance. 2.10 g (yield:93.3%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.21-1.31 (14H,m), 1.54-1.68 (2H, m), 2.11 (3H, s), 2.61 (2H, t, J = 8.0Hz), 6.05 (1H, d, J = 3.2 Hz), 6.24 (1H, d, J = 3.2 Hz),6.59 (2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.02(2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz).IR (KBr) cm-1; 3328, 1615, 1514, 1485, 1437, 1397, 1262,1171, 835, 760. (3) Ethyl (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0852] To a solution of 4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenol(2.08 g, 5.34 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(1.56 g, 8.00 mmol) andtriphenylphosphine (2.10 g, 8.00 mmol) in toluene (6 ml)was added 1,1'-(azodicarbonyl)dipiperidine (2.02 g, 8.00mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.1.64 g (yield: 54.3%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.13 (3H, t, J= 7.2 Hz), 1.17-1.34 (14H, m), 1.53 - 1.65 (2H, m), 2.10(3H, s), 2.60 (2H, t, J = 7.8 Hz), 3.17-3.21 (2H, m), 4.13(2H, q, J = 7.2 Hz), 4.66-4.73 (1H, m), 6.03 (1H, d, J =3.4 Hz), 6.22 (1H, d, J = 3.4 Hz), 6.60 (2H, d, J = 9.2 Hz),6.91 (2H, d, J = 9.2 Hz), 7.00 (2H, d, J = 8.6 Hz), 7.13(2H, d, J = 8.6 Hz), 7.21-7.36 (5H, m).IR (KBr) cm-1; 1755, 1736, 1520, 1238, 1182, 1084, 1036,833, 762, 745, 698. Example 190Sodium (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0853] To a mixed solution of ethyl (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1.62g, 2.86 mmol) in THF (60 ml) andmethanol (60 ml) was added 1N aqueous potassium hydroxidesolution (10 ml, 10 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water and driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) to givethe object compound as an oily substance. 1.10 g (yield:71.4%)1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.22-1.29 (14H,m), 1.54-1.66 (2H, m), 2.10 (3H, s), 2.61 (2H, t, J = 8.4Hz), 3.21 (2H, d, J = 6.2 Hz), 4.75 (1H, t, J = 6.2 Hz),6.03 (1H, d, J = 3.2 Hz), 6.23 (1H, d, J = 3.2 Hz), 6.60(2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.00 (2H, d,J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.26 (5H, bs).IR (KBr) cm-1; 3393, 1728, 1522, 1236, 1181, 1084, 833, 760,700. (2) Sodium (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0854] Ethanol (10 ml) and a solution of 1N sodium hydroxidein ethanol (1.76 ml) were added to (2R)-2-{4-[1-(4-decylphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (1.05 g, 1.95 mmol) and the mixturewas concentrated. Diisopropylether was added to theresidue to give the object compound as a solid. 802 mg(yield: 81.4%)1H-NMR (DMSO-d6) δ; 0.86 (3H, t, J = 6.6 Hz), 1.18-1.33(14H, m), 1.52-1.64 (2H, m), 2.01 (3H, s), 2.59 (2H, t, J =7.6 Hz), 2.86-3.16 (2H, m), 4.19-4.24 (1H, m), 5.92 (1H, d,J = 3.8 Hz), 6.07 (1H, d, J = 3.8 Hz), 6.52 (2H, d, J = 8.8Hz), 6.77 (2H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.0Hz),7.08-7.27 (7H, m).IR (KBr) cm-1; 1615, 1520, 1395, 1235, 1059, 1032, 831, 762,700. Example 191Ethyl (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrole
    [0855] A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.00 g, 2.82 mmol), 1-bromoheptane(0.543 ml, 3.38 mmol) and potassium carbonate (466 mg, 3.38mmol) in DMF (20 ml) was stirred at 80°C for 4 hours. Thereaction solution was poured into water and the mixture wasextracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate anhydride and solventwas removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 30:1) to give the object compound as an oilysubstance. 840 g (yield: 65.6%)1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 7.0 Hz), 1.22-1.46 (8H,m), 1.72-1.83 (2H, m), 2.10 (3H, s), 3.95 (2H, t, J = 6.6Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.2 Hz), 6.24 (1H, d, J= 3.2 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8Hz), 6.96-7.07 (4H, m), 7.33-7.40 (5H, m).IR (KBr) cm-1; 1609, 1514, 1483, 1468, 1454, 1393, 1289,1244, 1177, 1040, 1026, 835, 760, 735, 698. (2) 4-[1-(4-Heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol
    [0856] To a solution of 2-(4-benzyloxyphenyl)-1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrole(820 mg, 1.81 mmol) inethanol (30 ml) and tetrahydrofuran (30 ml) was added 10%palladium carbon (200 mg) and the mixture was stirred for 3hours under hydrogen atmosphere. The insoluble matter wasfiltered out and the filtrate was concentrated to give the object compound as an oily substance. 650 mg (yield:98.9%)1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 6.6 Hz), 1.28-1.43 (8H,m), 1.69-1.79 (2H, m), 2.10 (3H, s), 3.95 (2H, t, J = 6.6Hz), 6.04 (1H, d, J = 3.6 Hz), 6.23 (1H, d, J = 3.6 Hz),6.61 (2H, d, J = 8.4 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.94(2H, d, J = 8.4 Hz), 7.04 (2H, d, J = 9.2 Hz).IR (KBr) cm-1; 3403, 1613, 1514, 1472, 1437, 1246, 1171,1040, 835, 762. (3) Ethyl (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0857] To a solution of 4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol(640 mg, 1.76 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate(513 mg, 2.64 mmol) andtriphenylphosphine (692 mg, 2.64 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (666 mg, 2.64mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate =30: 1) to give the object compound as an oily substance.240 mg (yield: 25.2%) 1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 6.2 Hz), 1.14 (3H, t, J= 7.0 Hz), 1.35-1.55 (8H, m), 1.76-1.83 (2H, m), 2.09 (3H,s), 3.17-3.21 (2H, m), 3.94 (2H, t, J = 6.6 Hz), 4.14 (2H,q, J = 7.0 Hz), 4.66-4.73 (1H, m), 6.02 (1H, d, J = 3.6 Hz),6.21 (1H, d, J = 3.6 Hz), 6.61 (2H, d, J = 8.8 Hz), 6.83(2H, d, J = 8.4 Hz), 6.93 (2H, d, J = 8.4 Hz), 7.01 (2H, d,J = 8.8 Hz), 7.25-7.27 (5H, m).IR (KBr) cm-1; 1755, 1734, 1514, 1483, 1287, 1182, 1084,1038, 835, 760, 700. Example 192Sodium (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-[1-(4-Heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0858] To a mixed solution of ethyl (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(235 mg, 0.435 mmol) in THF (7 ml) andmethanol (7 ml) was added 1N aqueous potassium hydroxidesolution (2 ml, 2 mmol) and the mixture was stirred for 1hour at room temperature. The reaction solution wasneutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate =1: 1) to give the object compound as an oily substance.210 mg (yield: 94.2%)1H-NMR (CDCl3) δ; 0.90 (3H, t, J = 7.0 Hz), 1.22-1.41 (8H,m), 1.74-1.81 (2H, m), 2.08 (3H, s), 3.20 (2H, d, J = 5.4Hz), 3.92 (2H, t, J = 6.2 Hz), 4.74 (1H, t, J = 5.4 Hz),6.02 (1H, d, J = 3.6 Hz), 6.21 (1H, d, J = 3.6 Hz), 6.60(2H, d, J = 8.4 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.93 (2H, d,J = 8.4 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.25-7.26 (5H, m).IR (KBr) cm-1; 2930, 1728, 1514, 1287, 1244, 1181, 1084,1042, 835, 760, 700. (2) Sodium (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0859] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.333 ml) were added to (2R)-2-{4-[1-(4-heptyloxyphenyl}-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid (190 mg, 0.371 mmol) and the mixturewas concentrated. Diisopropylether was added to theresidue to give the object compound as a solid. 135 mg(yield: 75.8%)1H-NMR (DMSO-d6) δ; 0.89 (3H, t, J = 6.6 Hz), 1.22-1.48 (8H,m), 1.69-1.79 (2H, m), 1.99 (3H, s), 2.87-3.13 (2H, m),3.95 (2H, t, J = 6.2 Hz), 4.18-4.24 (1H, m), 5.91 (1H, d, J= 3.4 Hz), 6.06 (1H, d, J = 3.4 Hz), 6.54 (2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz),7.02 (2H, d, J = 8.8 Hz), 7.11-7.29 (5H, m).IR (KBr) cm-1; 1611, 1514, 1404, 1289, 1244, 1181, 1169,1042, 1030, 836, 764, 700.[α]D 29 -2.41° (c 0.595, methanol) Example 193Ethyl (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) 2-(4-Benzyloxyphenyl)-1-(4-nonyloxyphenyl)-5-methyl-1H-pyrrole
    [0860] The object compound was obtained from 1-bromononane asan oily substance, according to the similar manner to thatof Example 191(1). yield: 70.6%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 7.0 Hz), 1.20-1.46 (12H,m), 1.72-1.83 (2H, m), 2.10 (3H, s), 3.95 (2H, t, J = 6.6Hz), 4.98 (2H, s), 6.04 (1H, d, J = 3.6 Hz), 6.24 (1H, d, J= 3.6 Hz), 6.76 (2H, d, J = 9.0 Hz), 6.85 (2H, d, J = 9.0Hz), 6.96-7.07 (4H, m), 7.30-7.42 (5H, m).IR (KBr) cm-1; 1609, 1514, 1468, 1454, 1289, 1246, 1177,1040, 1026, 835, 760, 735, 698. (2) 4-[5-Methyl-1-(4-nonyloxyphenyl]-1H-pyrrol-2-yl]phenol
    [0861] The object compound was obtained from 2-(4-benzyloxyphenyl)-1-(4-nonyloxyphenyl)-5-methyl-1H-pyrrole as an oily substance, according to the similar manner tothat of Example 191(2). yield: 97.7%1H-NMR (CDCl3) δ; 0.88 (3H, t, J = 6.6 Hz), 1.21-1.36 (12H,m), 1.66-1.78 (2H, m), 2.10 (3H, s), 3.94 (2H, t, J = 7.6Hz), 6.04 (1H, d, J = 3.2 Hz), 6.23 (1H, d, J = 3.2 Hz),6.61 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.96(2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 9.2 Hz), 6.96-7.07(4H, m).IR (KBr) cm-1; 3400, 1610, 1514, 1472, 1244, 1171, 835. (3) Ethyl (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0862] The object compound was obtained from 4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenolas an oilysubstance, according to the similar manner to that ofExample 191(3). yield: 24.8%1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 7.2 Hz), 1.14 (3H, t, J= 7.2 Hz), 1.24-1.46 (12H, m), 1.74-1.84 (2H, m), 2.08 (3H,s), 3.17-3.21 (2H, m), 3.94 (2H, t, J = 6.6 Hz), 4.14 (2H,q, J = 7.2 Hz), 4.67-4.72 (1H, m), 6.02 (1H, d, J = 3.3 Hz),6.22 (1H, d, J = 3.3 Hz), 6.61 (2H, d, J = 9.0 Hz), 6.83(2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.01 (2H, d,J = 9.0 Hz), 7.19-7.33 (5H, m).IR (KBr) cm-1; 1755, 1736, 1514, 1483, 1287, 1244, 1182,1084, 1038, 835, 758, 698. Example 194Sodium (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate(1) (2R)-2-{4-(5-Methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid
    [0863] The object compound was obtained from ethyl (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl]-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoateas an oily substance, according to thesimilar manner to that of Example 192(1). yield: 66.9%1H-NMR (CDCl3) δ; 0.89 (3H, t, J = 6.8 Hz), 1.23-1.43 (12H,m), 1.74-1.81 (2H, m), 2.08 (3H, s), 3.13-3.22 (2H, m),3.91 (2H, t, J = 5.8 Hz), 4.69-4.75 (1H, m), 6.02 (1H, d, J= 3.2 Hz), 6.20 (1H, d, J = 3.2 Hz), 6.58 (2H, d, J = 9.2Hz), 6.80-7.02 (6H, m), 7.23-7.26 (5H, m).IR (KBr) cm-1; 3034, 1728, 1514, 1287, 1244, 1084, 835, 760,700. (2) Sodium (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate
    [0864] The object compound was obtained from (2R)-2-{4-[5-methyl-1-(4-nonyloxyphenyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoicacid as a solid, according to the similarmanner to that of Example 192(2). yield: 80.4%1H-NMR (DMSO-d6) δ; 0.87 (3H, t, J = 6.6 Hz), 1.21-1.42 (12H, m), 1.65-1.76 (2H, m), 1.99 (3H, s), 2.85-3.11 (2H,m), 3.95 (2H, t, J = 6.2 Hz), 4.15-4.20 (1H, m), 5.91 (1H,d, J = 3.4 Hz), 6.06 (1H, d, J = 3.4 Hz), 6.53 (2H, d, J =8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz),7.03 (2H, d, J = 8.8 Hz), 7.11-7.27 (5H, m).IR (KBr) cm-1; 1613, 1514, 1397, 1289, 1246, 1171, 1049,833, 760, 700. Example 195Ethyl (2R)-2-[4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) 2-(2-{3-[2-(4-Benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propoxy}phenyl)-1,3-benzoxazole
    [0865] To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol(1.00 g, 3.11 mmol), 2-(2-hydroxyphenyl)benzoxazole(986 mg, 4.67 mmol) andtriphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml)was added 1,1'-(azodicarbonyl)dipiperidine (1.18 g, 4.67mmol) and the mixture was stirred at 80°C for 12 hours.The reaction solution was poured into water and the mixturewas extracted with ethyl acetate. The extract was driedover magnesium sulfate anhydride and the solvent wasremoved under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate = 7:1) to give the object compound as an oily substance. 950mg (yield: 59.4%)1H-NMR (CDCl3) δ; 2.05-2.10 (2H, m), 2.30 (3H, s), 3.92 (2H,t, J = 5.6 Hz), 4.29 (2H, t, J = 7.4 Hz), 4.93 (2H, s),5.91 (1H, d, J = 3.2 Hz), 6.01 (1H, d, J = 3.2 Hz), 6.74(2H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.4 Hz), 7.07 (1H, t,J = 7.6 Hz), 7.18-7.54 (11H, m), 7.74-7.79 (1H, m), 8.09-8.14(11H, m).IR (KBr) cm-1; 1615, 1524, 1454, 1385, 1309, 1283, 1267,1244, 1175, 1026, 835, 750, 698. (2) 4-(1-{3-[2-(1,3-Benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenol
    [0866] To a solution of 2-(2-{3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propoxy}phenyl)-1,3-benzoxazole(930mg, 1.81 mmol) in methanol (40 ml) and tetrahydrofuran (40ml) was added 10% palladium carbon (200 mg) and the mixturewas stirred for 4 hours under hydrogen atmosphere. Theinsoluble matter was filtered out and the filtrate wasconcentrated to give the object compound as a solid. 730mg (yield: 98.4%)1H-NMR (CDCl3) δ; 1.93-2.11 (2H, m), 2.28 (3H, s), 3.83(2H, t, J = 6.0 Hz), 4.22 (2H, t, J = 6.8 Hz), 5.91 (1H, d,J = 3.4 Hz), 5.98 (1H, d, J = 3.4 Hz), 6.54 (2H, d, J = 8.0Hz), 6.83 (1H, d, J = 8.4 Hz), 7.03-7.56 (7H, m), 7.75-7.80 (1H, m), 8.05-8.10 (1H, m).IR (KBr) cm-1; 3063, 1613, 1584, 1549, 1526, 1493, 1483,1545, 1387, 1312, 1269, 1244, 1169, 1038, 910, 839, 750. (3) Ethyl (2R)-2-[4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0867] To a solution of 4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenol(710 mg,1.73 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (504 mg,2.59 mmol) and triphenylphosphine (679 mg, 2.59 mmol) intoluene (2 ml) was added 1,1'-(azodicarbonyl)dipiperidine(654 mg, 2.59 mmol) and the mixture was stirred at 80°C for12 hours. The reaction solution was poured into water andthe mixture was extracted with ethyl acetate. The extractwas dried over magnesium sulfate anhydride, and the solventwas removed under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate = 30:1) to give the object compound as an oilysubstance. 390 mg (yield: 37.5%)1H-NMR (CDCl3) δ; 1.20 (3H, t, J = 7.4 Hz), 1.98-2.05 (2H,m), 2.27 (3H, s), 3.18-3.26 (2H, m), 3.91 (2H, t, J = 5.8Hz), 4.15 (2H, q, J = 7.4 Hz), 4.22 (2H, t, J = 7.4 Hz),4.70-4.77 (1H, m), 5.89 (1H, d, J = 3.2 Hz), 5.98 (1H, d, J= 3.2 Hz), 6.68 (2H, d, J = 8.4 Hz), 6.87 (1H, d, J = 8.0 Hz), 7.04 (1H, t, J = 7.2 Hz), 7.14-7.55 (11H, m), 7.74-7.79(1H, m), 8.00-8.05 (1H, m).IR (KBr) cm-1; 1752, 1732, 1613, 1524, 1481, 1454, 1309,1269, 1240, 1187, 1084, 1033, 750, 700. Example 196Sodium (2R)-2-[4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(1) (2R)-2-[4-(1-{3-[2-(1,3-Benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid
    [0868] To a mixed solution of ethyl (2R)-2-[4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate(380 mg, 0.633 mmol) in THF(15 ml) and methanol (15 ml) was added 1N aqueous potassiumhydroxide solution (3 ml, 3 mmol) and the mixture wasstirred for 1 hour at room temperature. The reactionsolution was neutralized with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed withwater and dried over magnesium sulfate anhydride and thesolvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate) to give the object compound as an oily substance.206 mg (yield: 56.9%) 1H-NMR (CDCl3) δ; 2.05-2.10 (2H, m), 2.33 (3H, s), 3.26-3.72(2H, m), 3.47-3.87 (2H, m), 4.07-4.35 (2H, m), 4.67-4.73(1H, m), 5.88 (1H, d, J = 3.4 Hz), 5.93 (1H, d, J =3.4 Hz), 6.11 (2H, d, J = 8.4 Hz), 6.76-6.82 (3H, m), 7.04(1H, t, J = 7.0 Hz), 7.26-7.54 (10H, m), 7.93-7.98 (1H, m).IR (KBr) cm-1; 3032, 1730, 1613, 1524, 1495, 1481, 1454,1240, 1181, 1084, 1042, 910, 837, 750, 700. (2) Sodium (2R)-2-[4-(1-(3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl)-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate
    [0869] Ethanol (5 ml) and a solution of 1N sodium hydroxidein ethanol (0.299 ml) were added to (2R)-2-[4-(1-{3-[2-(1,3-benzoxazol-2-yl)phenoxy]propyl}-5-methyl-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoicacid (190 mg, 0.332 mmol) andthe mixture was concentrated. Diisopropylether was addedto the residue to give the object compound as a solid. 162mg (yield: 91.0%)1H-NMR (DMSO-d6) δ; 1.85-1.94 (2H, m), 2.17 (3H, s), 2.93-3.18(2H, m), 3.91-3.99 (2H, m), 4.12-4.18 (2H, m), 4.32-4.39(1H, m), 5.74 (1H, d, J = 3.2 Hz), 5.81 (1H, d, J =3.2 Hz), 6.68 (2H, d, J = 8.4 Hz), 7.04-7.99 (15H, m).IR (KBr) cm-1; 1613, 1524, 1481, 1454, 1416, 1310, 1269,1236, 1034, 839, 750, 700.[α]D 30 13.2° (c 0.580, methanol) Formulation Example 1 (1) Compound of Example 1 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg (5) Magnesium stearate 0.4 mg (6) Calcium carboxymethyl cellulose 20 mg total 120 mg
    [0870] (1) to (6) are mixed and compressed with a tabletingmachine according to a conventional method to give a tablet. Formulation Example 2 (1) Compound of Example 52 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg (5) Magnesium stearate 0.4 mg (6) Calcium carboxymethyl cellulose 20 mg total 120 mg
    [0871] (1) to (6) are mixed and compressed with a tabletingmachine according to a conventional method to give a tablet. Test Example 1(1) Cloning of PTP1B gene and purification of protein
    [0872] Based on the sequence of human PTP-1B registered inGenbank (M31724) database, primer 1 and primer 2 weresynthesized, and PTP1B cDNA was amplified from humanskeletal muscle cDNA library (Clonetech, Inc. HL5002a)according to PCR method using these primers. The cycle ofreactions at 98°C for 10 seconds, at 58°C for 30 secondsand at 72°C for 90 seconds was repeated 35 cycles. The PCRreaction product (1322 bp) was cloned to pT7 Blue-T vector(Novagen, Inc.) to identify the base sequence.
    [0873] Human PTP 1B cDNA (1322 bp) (100 ng) was amplifiedwith primer 3 and primer 4 in order to express 1-321 aminoacid region encoding enzyme active domain of PTP1B. ThePCR reaction product (976 bp) was cloned to pT7 Blue-Tvector (Novagen, Inc.) to identify the base sequence.
    [0874] The pT7 Blue-T vector-human PTP1B cDNA (976 bp) wascleaved with restriction enzymes NdeI and SalI (TakaraShuzo Co., Ltd.) and subjected to electrophoresis using0.7% agarose gel, and a 969 bp fragment was excised andpurified. The fragment was introduced into pET32a (+)vector (Novagen, Inc.) cleaved with restriction enzymesNdeI and XhoI (Takara Shuzo Co., Ltd.), to constitute avector pET32a(+)-human PTP1B cDNA (969 bp), which expressesPTP1B (321 amino acid) with 6 histidine residues binded toa C-terminal thereof under a control of T7 lac promotor.
    [0875] E.coli BL21 DE3 pLysS (Novagen, Inc.) was transformedwith the pET32a(+)-human PTP 1B cDNA (969 bp) to give anampicillin (50 µg/ml) resistant bacterium. This was shakecultured at 37°C using 5L of 2xYT medium (ampicillin (50µg/ml)). When OD600nm reached to 0.5, IPTG (Isopropyl b-D-Thiogalactoside)was added to the culture medium so as tobe 1 mM in order to induce the expression of protein, andthis medium was further cultured at 37°C overnight. Thebacterium was collected by centrifugation (8000 rpm, 10minutes, 4°C).
    [0876] The bacterium was suspended in lysis buffer (50 ml)(20 mM Tris HCl (pH 8.0), 0.5 M NaCl 1 mM PMSF, 5 mMbenzamidine, Lysozyme 5 mg) and crushed by sonication. Tothe supernatant after centrifuging (12000 rpm, 10 minutes,4°C) was added imidazole so as to be 50 mM and the mixturewas mixed with His Bind resin (Novagen, Inc.) binded withNi ion (4°C, overnight). The mixture was washed with 200ml of (20mM Tris HCl (pH 8.0), 0.5 M NaCl, 1 mM PMSF, 5 mMbenzamidine, 50 mM imidazole), eluted with (20 mM Tris HCl(pH 8.0), 0.5 M NaCl, 1 mM PMSF, 5 mM benzamidine, 400 mMimidazole) and concentrated by centrifugation usingUltrafree-15 Biomax-50 (MILLIPORE Corp.)(11 mg/ml, 4ml).The purified protein (PTP1B) was identified by Westernblotting method using SDS-PAGE, coomassie Blue stain andanti-PTP1B antibody (UBI Inc.). (2) Measurement of PTP1B inhibitory activity
    [0877] The PTP1B inhibitory activity of the test compound wasevaluated by measuring the ability of the test compound todephosphorylate p-nitrophenylphosphate (pNPP) (a change ofthe absorbance at 405 nm).
    [0878] To a buffer for measurement of the activity (0.1 Msodium acetate (pH 6.5), 1 mM EDTA, 10 mM DTT) (10 ml) wasadded PTP1B enzyme solution (2 µl) and the mixture wasadded to each well of a 96-well microtiter plate (100 µleach). A solution of the test compound in DMSO (10 µl) and2 mM pNPP/ the buffer for measurement of the activity (90µl) were then added to each well, and the absorbance at 405nm was measured. After keeping at 37°C for 1 hour, theabsorbance was measured again to evaluate a change of theabsorbance. Regarding the change of the absorbance in theabsence of the test compound as 100%, the concentration ofthe compound necessary for 50% inhibition (IC50 value) wascalculated.
    [0879] The results are as follows. Test compound IC50 value (µM) Compound of Example 2 0.89 Compound of Example 4 6.48 Compound of Example 6 0.5Compound of Example 8 0.38 Compound of Example 10 0.34 Compound of Example 12 3.1 Compound of Example 14 5.87 Compound of Example 16 0.41 Compound of Example 18 1.01 Compound of Example 20 0.53 Compound of Example 22 0.71 Compound of Example 24 0.32 Compound of Example 26 0.42 Compound of Example 28 0.48 Compound of Example 30 0.72 Compound of Example 32 2.1 Compound of Example 34 1.1 Compound of Example 36 1.43 Compound of Example 38 1.6 Compound of Example 40 1.2 Compound of Example 42 4.9 Compound of Example 44 0.33 Compound of Example 46 0.40 Compound of Example 48 0.36 Compound of Example 50 0.94 Compound of Example 52 0.31 Compound of Example 54 0.31 Compound of Example 56 0.13 Compound of Example 58 0.34 Compound of Example 60 0.36 Compound of Example 62 0.21 Compound of Example 64 0.23 Compound of Example 66 0.17 Compound of Example 94 0.09 Industrial Applicability
    [0880] The compound (I), (II) and a salt thereof have asuperior protein phosphatase inhibitory action and areuseful as a prophylactic or therapeutic agent for diabetesand the like.





    权利要求:
    Claims (19)
    [1] A compound of the formula:
    [2] The compound according to claim 1, wherein X1 andX2 are the same or different and each is a bond or a spacerhaving 1 to 8 atom(s) in the main chain; and one of R1 andR2 is a cycle group having substituent(s) selected from 1)an optionally substituted carboxy-C1-6 alkoxy group and 2)an optionally substituted carboxy-C1-6 aliphatic hydrocarbongroup, wherein the cycle group optionally has additionalsubstituent(s), and the other is an optionally substitutedcycle group.
    [3] The compound according to claim 1, wherein R1 or R2is a C6-14 aryl substituted with a carboxy-(C6-14 aryl-substituted)C1-6alkoxy group or a C1-6 alkoxy-carbonyl-(C6-14aryl-substituted)C1-6 alkoxy group.
    [4] The compound according to claim 1, wherein one ofR1 and R2 is a C6-14 aryl substituted with a carboxy-(C6-14aryl-substituted) C1-6 alkoxy group or a C1-6 alkoxy-carbonyl-(C6-14aryl-substituted)C1-6 alkoxy group, and theother is an optionally substituted C6-14 aryl.
    [5] The compound according to claim 1, wherein X1 andX2 are the same or different and each is a bond or a C1-8alkylene.
    [6] The compound according to claim 1, wherein R3, R4 and R5 are the same or different and each is a hydrogenatom or a hydrocarbon group.
    [7] The compound according to claim 1, wherein each R3and R4 is a hydrogen atom.
    [8] The compound according to claim 1, wherein R5 is aC1-6 alkyl.
    [9] A prodrug of the compound according to claim 1.
    [10] A pharmaceutical composition comprising thecompound according to claim 1 or a prodrug thereof.
    [11] The pharmaceutical composition according to claim10, which is a protein tyrosine phosphatase inhibitor.
    [12] The pharmaceutical composition according to claim10, which is a prophylactic or therapeutic agent ofdiabetes.
    [13] A protein tyrosine phosphatase inhibitorcomprising a compound of the formula:
    [14] The inhibitor according to claim 13, wherein X1and X2 are the same or different and each is a bond or aspacer having 1 to 8 atom(s) in the main chain; and one ofR1a and R2a is a cycle group having substituent(s) selectedfrom 1) an optionally substituted carboxy-C1-6 alkoxy groupand 2) an optionally substituted carboxy-C1-6 aliphatichydrocarbon group, wherein the cycle group optionally hasadditional substituent(s), and the other is an optionallysubstituted cycle group.
    [15] A prophylactic or therapeutic agent of diabetescomprising a compound of the formula:
    [16] The agent according to claim 15, wherein X1 and X2are the same or different and each is a bond or a spacerhaving 1 to 8 atom(s) in the main chain; and one of R1a andR2a is a cycle group having substituent(s) selected from 1)an optionally substituted carboxy-C1-6 alkoxy group and 2) an optionally substituted carboxy-C1-6 aliphatic hydrocarbongroup, wherein the cycle group optionally has additionalsubstituent(s), and the other is an optionally substitutedcycle group.
    [17] A method for preventing or treating diabetes in amammal in need thereof, which comprises administering tosaid mammal an effective amount of a compound of theformula
    [18] Use of a compound of the formula
    [19] A method for preparing a compound of the formula:   wherein A is a cycle group and the other symbols inthe formula have the same meanings as claim 1 or a saltthereof, which comprises reacting a compound of theformula:   wherein the symbols in the formula have the samemeanings as aboveor a salt thereof with a compound of the formula:H-Y   wherein Y is an optionally substituted carboxy-C1-6alkoxy group.
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    同族专利:
    公开号 | 公开日
    AU5878401A|2001-12-03|
    US20030144338A1|2003-07-31|
    CA2410338A1|2001-11-29|
    EP1284260A4|2004-03-31|
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