Oncolytic Combinations for the Treatment of Cancer

专利摘要:
Leukotriene (LTB 4 ) antagonists enhance the effectiveness of 2 ', 2'-difluoronucleoside anticancer agents.
公开号:KR20020069512A
申请号:KR1020027006027
申请日:2000-11-09
公开日:2002-09-04
发明作者:제롬 허버트 플레스크；로저 스튜어트 벤자민；재슨 스코트 소이어；비벌리 앤 테처；더글라스 웨이드 베이트；에드워드 씨. 알. 스미스；윌리암 토마스 맥밀렌
申请人:일라이 릴리 앤드 캄파니；
IPC主号:

专利说明:

Oncolytic Combinations for the Treatment of Cancer
[3] Leukotriene B ₄ (LTB ₄ ) is a combination of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, inflammatory bone disease, and other inflammatory conditions characterized by infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. It is a proinflammatory lipid involved in etiology. Thus, activated polymorphonuclear leukocytes release tissue degrading enzymes and reactive chemicals that cause inflammation. US Pat. No. 5,462,954 describes the treatment of psoriasis, arthritis, chronic lung disease, acute respiratory distress syndrome, shock, asthma, inflammatory bone disease, and other inflammatory conditions characterized by infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Useful phenylphenol leukotriene antagonists are disclosed. US Pat. No. 5,910,505 discloses that some phenylphenol leukotriene B ₄ (LTB ₄ ) antagonists are useful as agents for the treatment of oral squamous cell carcinoma. US Pat. No. 5,543,428 discloses a group of phenylphenol leukotriene antagonists that have the property of reversing multidrug resistance in tumor cells. The use of leukotriene antagonists includes vinblastine, vincristine, vindesine, nabelbin, donorubicin, doxorubicin, mitoxantrone, etoposide, teniposide, mitomycin C, actinomycin, taxol, topotecan, mitramycin, It will reverse drug resistance of resistant tumor cells to colchicine, puromycin, grapephytotoxin, emetine, gramicidine and ballinomycin.
[1] This application claims priority from U.S. Provisional Patent Application 60 / 164,786, filed November 11, 1999; the entire disclosure of which is incorporated herein by reference.
[2] The present invention relates to a method of treating cancer using an anticancer agent. More specifically, the present invention relates to the use of 2 ', 2'-difluoronucleoside anticancer agents in combination with leukotriene (LTB ₄ ) antagonists that enhance the effectiveness of anticancer agents.
[384] 1-6 are horizontal bar graphs showing the data of Tables 1-6 provided in “analytic example 1” herein. In each figure the vertical axis of the graph forms the source of the numbered horizontal bars, each bar being a separate treatment presented in the table above. The horizontal axis is the number of tumor growth retardation (TGD) days.
[4] <Overview of invention>
[5] The present invention provides compositions and methods useful for the treatment of cancer, particularly cancers that are not multidrug resistant. The method of the present invention comprises the use of a 2 ', 2'-difluoronucleoside anticancer agent described in US Pat. No. 5,464,826 with a leukotriene (LTB ₄ ) antagonist of Formula A, Formula I and Formula II described below do.
[6] Surprisingly, the inventors have found that the combination of a 2 ', 2'-difluoronucleoside anticancer agent with a leukotriene (LTB ₄ ) antagonist acts synergistically against cancers that are not multidrug resistant.
[7] The types of cancer that can be treated with the compositions of the invention include breast cancer, bladder cancer, colon cancer, esophageal cancer, gastric cancer, germ cell cancer, for example testicular cancer, gynecological cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, multiple Myeloma, neurological cancer, brain cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteosarcoma, soft tissue sarcoma, non-small cell lung cancer, childhood cancer and the like.
[8] <Detailed Description of the Invention>
[9] I. Definition
[10] The term "acidic group" refers to an organic group that acts as a proton donor capable of hydrogen bonding when combined as a "Z" substituent of formula (I) or a "Z2" substituent of formula (II). Exemplary acid values are carboxyl.
[11] The term "active ingredient" refers to certain 2 ', 2'-difluoronucleoside compounds and leukotriene B4 antagonist compounds generally described by formula A, and diphenyl leukotriene B4 antagonist compounds generally described by formula I and formula II. Or combinations of 2 ', 2'-difluoronucleosides and leukotriene B4 antagonists described by Formula A or Formula I and / or II, as well as a series of specific diphenyl compounds described herein, and such compounds Salts, solvates and prodrugs thereof.
[12] The term "alkenyl" means a monovalent radical of the general formula C _n H _2n , such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, 2-butenyl and 3-butenyl. do.
[13] The term "alkyl", alone or as part of another substituent, unless otherwise defined, includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl and n-hexyl; Like, monovalent straight or branched chain hydrocarbon radicals.
[14] The term "alkaryl" refers to an aryl radical substituted with an alkyl or substituted alkyl group, as follows:
[15]
[16] In the term "C ₆ -C ₂₀ alkaryl", the lower numbers below refer to the total number of carbon atoms in the radical.
[17] The term "C ₆ -C ₂₀ aralkyl" means an alkyl radical substituted with an aryl or substituted aryl group, as follows:
[18]
[19] In the term “C ₆ -C ₂₀ aralkyl”, the lower numbers below refer to the total number of carbon atoms in the radical.
[20] The term "carbocyclic group" refers to a 5, 6, 7 or 8 membered saturated, unsaturated or aromatic ring containing only carbon and hydrogen (eg benzene, cyclohexene, cyclohexane, cyclopentane).
[21] The term "cycloalkyl" refers to monovalent carbocyclic non-aromatic radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.
[22] The term "halo" means fluoro, chloro, bromo or iodo.
[23] The term “heterocyclic radical (s)” refers to a radical having a 5 membered saturated, unsaturated or aromatic ring containing 1 to 4 heteroatoms.
[24] The terms "mammal" and "mammal" include humans.
[25] The term "N-sulfonamidyl" means the following radicals:
[26]
[27] Wherein R 12 is C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₆ alkyl substituted aryl, C ₆ -C ₂₀ alkaryl or C ₆ -C ₂₀ aralkyl.
[28] The term "substituted alkyl" refers to halo, C ₁ -C ₆ alkyl, aryl, benzyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkoxy , An alkyl group further substituted with one or more radicals selected from C ₁ -C ₆ haloalkyl (eg —CF ₃ ).
[29] The term "substituted aryl" means halo, C ₁ -C ₆ alkyl, aryl, benzyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ alkoxy , Aryl group further substituted with one or more radicals selected from C ₁ -C ₆ haloalkyl (eg —CF ₃ ).
[30] The term "tetrazolyl" refers to an acidic group of the formula:
[31]
[32] The term "therapeutically effective interval" refers to (a) or (b) in the treatment of cancer from (a) when the 2 ', 2'-difluoronucleoside anticancer agent or (b) the LTB ₄ antagonist is administered to the mammal. ) Is the time to reach the limit of beneficial anticancer effects. In general, the anticancer agent and leukotriene (LTB ₄ ) antagonist are administered within each of 24 hours, more preferably within 4 hours and most preferably within 1 hour.
[33] In the practice of the present invention, the phrase "therapeutically effective combination" means the administration of (a) 2 ', 2'-difluoronucleoside anticancer agent and (b) LTB ₄ antagonist simultaneously or in any order separately. do.
[34] Anticancer agents that can be used are 2 ', 2'-difluoronucleoside compounds of the formula: and pharmaceutically acceptable salts thereof:
[35]
[36] (here,
[37] R ¹ is hydrogen or —C (═O) —R ⁵ ;
[38] R ² is a base defined by one of the following formulae:
[39] ;
[40] X is N or CR ⁴ ;
[41] R ³ is hydrogen, C ₁ -C ₄ alkyl or —C (═O) —R ⁵ ;
[42] R ⁴ is hydrogen, C ₁ -C ₄ alkyl, amino, bromo, fluoro, chloro or iodo;
[43] Each R ⁵ is independently hydrogen or C ₁ -C ₄ alkyl.
[44] In addition, compounds of the formula and pharmaceutically acceptable salts thereof may be used:
[45]
[46] (here,
[47] R ⁶ is hydrogen or C ₁ -C ₄ alkyl;
[48] R ⁷ is a base defined by one of the following formulae:
[49]
[50] ;
[51] X is N or CR ⁴ ;
[52] R ⁸ is hydrogen or C ₁ -C ₄ alkyl;
[53] R ⁴ is hydrogen, C ₁ -C ₄ alkyl, amino, bromo, fluoro, chloro or iodo;
[54] Provided that R ⁶ and R ⁸ may both be hydrogen only when X is N), and
[55]
[56] (here,
[57] R ⁶ is hydrogen or C ₁ -C ₄ alkyl;
[58] R ⁹ is being).
[59] Such compounds are disclosed in US Pat. No. 5,464,826, which is incorporated herein by reference, for a description of methods of making the compounds, formulating the compounds, and treating cancer with the compounds.
[60] Alternatively, preferred 2 ', 2'-difluoronucleoside compounds are compounds of the formula and pharmaceutically acceptable salts thereof:
[61]
[62] (here,
[63] R ¹ is hydrogen;
[64] R ² is a base defined by one of the following formulae:
[65]
[66]
[67] X is CR ⁴ ;
[68] R ³ is hydrogen;
[69] R ⁴ is hydrogen, C ₁ -C ₄ alkyl, bromo, fluoro, chloro or iodo).
[70] More preferred compounds are those wherein R ² is a base defined by the formula:
[71]
[72] Even more preferred are anticancer agents or pharmaceutically acceptable salts thereof selected from the group consisting of:
[73] (i) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose,
[74] (ii) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoroxylose,
[75] (iii) 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose, and
[76] (iv) 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose.
[77] Most preferred is gemcitabine HCl, a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl is 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (β-isomer), 2', 2'-difluoro-2'-deoxycytidine monohydro Also known as chloride or 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose.
[78] The structural formula is:
[79]
[80] The anticancer agent is generally mixed with a carrier that can act as a diluent or excipient. The anticancer agent may be administered in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups or aerosols. In addition, sterile injectable solutions may also be used.
[81] Leukotriene (LTB ₄ ) antagonists useful in the present invention include a compound of Formula (A) or a pharmaceutically acceptable base addition salt thereof:
[82]
[83] (In the above formula,
[84] R ₁ ′ is C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) thio, halo, or R ₂ ′ -Substituted phenyl;
[85] Each R ₂ ′ and R ₃ ′ are each independently hydrogen, halo, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl)-(O) _q S-, tri Fluoromethyl or di- (C ₁ -C ₃ alkyl) amino;
[86] X 'is -O-, -S-, -C (= 0) or -CH _2- ;
[87] Y 'is -O- or -CH _2- ;
[88] Or together, -X'-Y'- is -CH = CH- or -C≡C-;
[89] Z 'is a straight or branched C ₁ -C ₁₀ alkylidedenyl;
[90] A 'is a single bond, -0-, -S-, -CH = CH- or -CR _a R _b- (wherein R _a and R _b are each independently hydrogen, C ₁ -C ₅ alkyl, or R ₇ '-Substituted phenyl or together with the carbon atom to which they are attached form a C ₄ -C ₈ cycloalkyl ring;
[91] R ₄ 'is R ₆ ,
[92]
[93] ego;
[94] Each R ₆ is independently —COOH, 5-tetrazolyl, —CON (R ₉ ) ₂ or —CONHSO ₂ R ₁₀ ;
[95] Each R ₇ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, benzyl, methoxy, -WR ₆ , -TGR ₆ , (C ₁ -C ₄ alkyl) -T- (C ₁ -C ₄ alkylidenyl) -O-, or hydroxy;
[96] R ₈ is hydrogen or halo;
[97] Each R ₉ is independently hydrogen, phenyl or C ₁ -C ₄ alkyl or together with the nitrogen atom form a morpholino, piperidino, piperazino or pyrrolidino group;
[98] R ₁₀ is C ₁ -C ₄ alkyl or phenyl;
[99] R ₁₁ is R ₂ , -WR ₆ or -TGR ₆ ;
[100] Each W is a single bond or a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
[101] Each G is a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
[102] Each T is a single bond, —CH ₂ —, —O—, —NH—, —NHCO—, —C (═O) — or (O) _q S—;
[103] K is -C (= 0)-or -CH (OH)-;
[104] Each q is independently 0, 1 or 2;
[105] p is 0 or 1;
[106] t is 0 or 1;
[107] Provided that when X 'is -O- or -S-, Y' is not -O-; When A 'is -O- or -S-, R ₄ ′ is not R ₆ ; if p is 0, W is not a single bond).
[108] Preferred LTB ₄ antagonists of Formula A are those compounds wherein R ₄ ′ is selected from:
[109]
[110] Even more preferred LTB ₄ antagonist of Formula A is a compound wherein R ₄ ′ is of the formula:
[111]
[112] Some of the preferred LTB ₄ antagonist compounds, or pharmaceutically acceptable acid or salt derivatives thereof, are listed as groups (A) to (KKKK) consisting of:
[113] A) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) heptane;
[114] B) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (3-fluorophenyl) -5-hydroxyphenoxy) heptane;
[115] C) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-dimethylaminocarbonylbutyloxy) phenyl) Propionic acid;
[116] D) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
[117] E) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutyloxy) phenyl) propionic acid;
[118] F) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-methoxyphenyl) propionic acid;
[119] G) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (lH-tetrazol-5-yl ) Butyloxy) phenyl) propionic acid;
[120] H) methyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionate;
[121] I) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionic acid;
[122] J) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) phenyl) propionic acid;
[123] K) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) -6-methoxy phenyl) propionic acid;
[124] L) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionate;
[125] M) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionic acid;
[126] N) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-butyloxy) phenyl) propionic acid;
[127] O) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-methylthiobutyloxy) phenyl) propionic acid;
[128] P) 3- (2- (3- (2,4-di (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutoxy) phenyl) propionic acid;
[129] Q) 6-methyl-6- (lH-tetrazol-5-yl) -11- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) undecane;
[130] R) N, N-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
[131] S) N-methanesulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
[132] T) N-phenylsulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
[133] U) 3- (2- (3- (2-butyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
[134] V) ethyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionate;
[135] W) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionic acid;
[136] X) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (methoxycarbonyl) phenoxy ) Phenyl) propionate;
[137] Y) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4 carboxyphenoxy) phenyl) propionic acid;
[138] Z) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4 carboxyphenoxy) phenyl) propionic acid;
[139] AA) 3,3-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
[140] BB) 2-methyl-2- (lH-tetrazol-5-yl) -3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) pro Foxy) phenyl) propane;
[141] CC) 2-methyl-2- (lH-tetrazol-5-yl) -3-hydroxy-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydrate Oxyphenoxy) propoxy) phenyl) propane;
[142] DD) 3- (2- (3- (2-bromo-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
[143] EE) 3- (2- (3- (2-ethylthio-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
[144] FF) methyl 3- (2-hydroxy-3- (4-methoxycarbonylbutyl) -6- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) Propoxy) phenyl) propionate;
[145] GG) 5- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -8- (4-carboxybutyl) dihydrocoumarin;
[146] HH) 2-phenyl-4-ethyl-5- [6- (2H-tetrazol-5-yl) -6-methylheptyloxy] phenol sodium salt;
[147] II) 2- (4-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
[148] JJ) 2- (3-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
[149] KK) 2- (2-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
[150] LL) 2- (4-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
[151] MM) 2- (3-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
[152] NN) 2- (4-trifluoromethylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
[153] 00) 2- (3-dimethylaminophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
[154] PP) 3- (5- (6- (4-phenyl-5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalene-1 (2H ) -On) propanoic acid;
[155] QQ) 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetra Hydronaphthalene-1 (2H) -one) propanoic acid;
[156] RR) 3- (4- (5- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-2,3-dihydroindene- 1 (2H) -on) propanoic acid;
[157] SS) 3,3-dimethyl-5- (3- (2-carboxyethyl) -4- (3- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) phenyl)- 5-oxopentanoic acid;
[158] TT) 7- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -3,4-dihydro-8-propyl-2H- l-benzopyran-2-carboxylic acid;
[159] UU) 8-propyl-7- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy] -3,4-dihydro-2H-l-benzopyran 2-carboxylic acid;
[160] VV) 2- [3- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -2-propylphenoxy] propanoic acid;
[161] WW) 2- (4-chlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
[162] XX) 2- (3,5-dichlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
[163] YY) 3- [2- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid sodium salt;
[164] ZZ) 7-carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9H-xanthene-4-propanoic acid disodium salt monohydrate;
[165] AAA) 2- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid sodium salt hemihydrate;
[166] BBB) 3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] [1,1'-biphenyl] -4-propanoic acid disodium salt monohydrate;
[167] CCC) 5-ethyl-4- [3- [2-propyl-3- [2- (2H-tetrazol-5-yl) phenoxy] phenoxy] propoxy] [l, l'-biphenyl]- 2-ol 2 sodium salt sesquihydrate;
[168] DDD) 3- [4- [3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9-oxo-9H-xanthene]] sodium propanoate hemihydrate;
[169] EEE) 2-fluoro-6- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid disodium salt;
[170] FFF) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt;
[171] GGG) 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-ch Xanthene]] propanoic acid disodium salt trihydrate;
[172] HHH) 3- [4- [9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propane mountain;
[173] III) 3- [2- [1- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -4- (5-oxo-5-morpholinopentaneami Phenyl) propanoic acid;
[174] JJJ) 2-Fluoro-6- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid 2 sodium Salt hydrates;
[175] KKK) 4-fluoro-2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
[176] LLL) 2- [2-propyl-3- [5- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] pentoxy] phenoxy] benzoic acid;
[177] MMM) 2- [2-propyl-3- [4- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] butoxy] phenoxy] benzoic acid sesquihydrate;
[178] NNN) 2- [2- (2-methylpropyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
[179] 000) 2- [2-butyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid hydrate;
[180] PPP) 2- [2- (phenylmethyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
[181] QQQ) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] phenyl acetic acid;
[182] RRR) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid;
[183] SSS) 2-[[2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenyl] methyl] benzoic acid;
[184] TTT) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid;
[185] UUU) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfinyl] benzoic acid;
[186] VVV) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfonyl] benzoic acid hydrate;
[187] WWW) 5- [3- [2- (l-carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] 4-pentynic acid disodium salt 0.4 hydrate;
[188] XXX) l-phenyl-l- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane;
[189] YYY) 1- (4- (carboxymethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy C) hexane;
[190] ZZZ) 1- (4- (dimethylaminocarbonylmethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5- Hydroxyphenoxy) hexane;
[191] AAAA) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -E-propenoic acid;
[192] BBBB) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -2-methyl-E-propenoic acid;
[193] CCCC) 5- (2- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) ethyl) -1H-tetrazole;
[194] DDDD) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4-carboxybutyloxy) phenyl) propionic acid;
[195] EEEE) 5- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy-3,4-dihydro-2H-l-benzopyran-2-one;
[196] FFFF) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} phenyl) propanoic acid;
[197] GGGG) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -4-propylphenyl) propanoic acid sodium salt;
[198] HHHH) 3- (4- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -3-propylphenyl) propanoic acid;
[199] IIII) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -2-propylphenyl) propanoic acid;
[200] JJJJ) 3- {3- [3- (2-ethyl-5-hydroxyphenyloxy) propoxy] -2-propylphenyl} propanoic acid disodium salt; And
[201] KKKK) 2- [3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid disodium salt hemihydrate.
[202] Such leukotriene (LTB ₄ ) antagonists are well known in the art, and US patents specifically incorporated herein by reference with respect to methods of making certain leukotriene B ₄ antagonists, and descriptions of leukotriene antagonist compounds or agents that may be administered to a patient. 5,462,954, which is described in detail. Preferred compounds are described in US Pat. No. 5,462,954 as Example 66, 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4 represented by the following compound A (formula B): -(4-fluorophenyl) phenoxy] propoxy] phenoxy benzoic acid, which is also 2- [3- [3- (5-ethyl-4'-fluoro-2-hydroxybiphen-4-yljade May also be referred to as propoxy-2-propylphenoxy] benzoic acid:
[203] <Compound A (Formula B)>
[204]
[205] The second group of LTB ₄ antagonists for use as co-agents essential in the compositions and practice of the present invention is a co-pending provisional application (named “Heterocycle Substituted Diphenyl Leukotriene Antagonists” (inventor: Jason Scott Sawyer, 97 pages in total)); ELi Lilly and Company Docket No., B-13240; filing date Nov. 11, 1999; Provisional Application No. 60 / 164,786. This second group of heterocycle substituted diphenyl leukotrienes antagonists are described in more detail below.
[206] II. Additional LTB ₄ Antagonists
[207] Additional LTB ₄ antagonists which are novel heterocycle substituted diphenyl compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrug derivatives thereof, are described below:
[208]
[209] (In the above formula,
[210] X is (i) a 5 membered, substituted or unsubstituted heterocyclic radical containing 1 to 4 heteroatoms independently selected from the group consisting of sulfur, nitrogen and oxygen, or (ii) a carbocyclic group is A fused bicyclic radical fused to two adjacent carbon atoms of the heterocyclic radical (i) of the circle;
[211] Y ₁ is a single bond or a divalent bonding group containing 1 to 9 atoms;
[212] Y ₂ and Y ₃ are divalent bonding groups independently selected from the group consisting of —CH ₂ —, —O— and —S—;
[213] Z is an acidic group;
[214] R 1 is C ₁ -C ₁₀ alkyl, aryl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₂₀ aralkyl, C ₆ -C ₂₀ alk Aryl, C ₁ -C ₁₀ haloalkyl, C ₆ -C ₂₀ aryloxy or C ₁ -C ₁₀ alkoxy;
[215] R 2 is hydrogen, halogen, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, an acidic group or — (CH ₂ ) _1-7 (acidic group) )ego;
[216] R 3 is hydrogen, halogen, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ aryloxy or C ₃ -C ₈ cycloalkyl;
[217] R 4 is C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, — (CH ₂ ) _1-7 (cycloalkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, benzyl or aryl ;
[218] n is 0, 1, 2, 3, 4, 5 or 6.
[219] III. Preferred LTB ₄ antagonists include the following.
[220] III A. Preferred X Substituents
[221] "Substituted heterocyclic radicals" preferably consist of hydrogen, halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, aryl or C ₆ -C ₂₀ aryloxy It is substituted with 1 to 3 groups independently selected from.
[222] Preferred group 1 of the X substituents (symbol, "PG1-X")
[223] Preferred LTB ₄ antagonist compounds for use in the compositions of the present invention are compounds wherein X is a heterocyclic radical selected from the group consisting of substituents of the formula:
[224]
[225]
[226] Wherein R 10 is hydrogen or a C ₁ -C ₄ alkyl radical and R 11 is hydrogen, halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, aryl or C ₆ -C ₂₀ It is a radical selected from the group consisting of aryloxy. Preferred R 10 groups are hydrogen, methyl or phenyl. In addition, any of the heterocyclic radicals of the above formula can be bound to the diphenyl leukotriene antagonist of formula (I) by any monovalent bond originating on a suitable carbon or nitrogen atom in its ring structure.
[227] For example, the pyrrole radical can be bound to the diphenyl molecule by a single bond derived from any carbon atom or any nitrogen atom having less than three bonds in the heterocyclic ring.
[228] Bonding position in pyrrole:
[229]
[230] A preferred form of substituent X is a fused bicyclic radical, in which the carbocyclic group is fused to two adjacent carbon atoms in the 5-membered heterocyclic radical:
[231]
[232] III B. Preferred group 2 of the X substituents (symbol, “PG2-X”)
[233] The following heterocyclic radicals are most preferred as X substituents:
[234]
[235] III C. Excluded X Substituents
[236] The heterocyclic radical X of formula (I) is considered to have low LTB ₄ antagonist activity of the compound containing 3-bromo-1,2,4-thiadiazole, so as to form an aspect of the present invention, It does not contain such radicals.
[237] III D. Preferred Y ₁ Substituents
[238] Y ₁ is a single bond or a divalent bonding group containing 1 to 9 atoms independently selected from the group consisting of carbon, hydrogen, sulfur, nitrogen and oxygen.
[239] Preferred group 1 of the Y ₁ substituent (symbol “PG1-Y ₁ ”)
[240] Preferred LTB ₄ compounds included in the compositions of the present invention are compounds wherein Y ₁ is a divalent linking group selected from the group consisting of substituents of the formula: wherein R 13 is hydrogen, methyl or ethyl:
[241]
[242] The divalent groups can be used in the forward or reverse direction. For example, a -C (= 0) CH ₂ -group can be located in the indicated fragment of formula (I) as follows:
[243]
[244] III E. Preferred group 2 of the Y ₁ substituent (symbol, “PG2-Y ₁ ”)
[245] Most preferred divalent Y ₁ substituent is an -O- group.
[246] III F. Preferred Group 1 of the Y ₂ substituent (symbol, “PG1-Y ₂ ”) and Preferred Group 1 of the Y ₃ substituent (symbol, “PG1-Y ₃ ”)
[247] Y ₂ and Y ₃ substituents are preferably selected from the group consisting of -S- and -0-.
[248] III G. Preferred group 2 of the Y ₂ substituent (symbol, “PG2-Y ₂ ”) and preferred group 2 of the Y ₃ substituent (symbol, “PG2-Y ₃ ”)
[249] Most preferably, both Y ₂ and Y ₃ are —0- groups.
[250] Preferred group 1 of the III H. Z substituents (symbol, "PG1-Z")
[251] Z is an acidic group as previously defined. Preferred are acidic groups selected from:
[252]
[253]
[254] Wherein R 12 is C ₁ -C ₁₀ alkyl, aryl, C ₆ -C ₂₀ alkaryl or C ₆ -C ₂₀ aralkyl. Preferred R12 groups are represented by the formula:
[255]
[256] III I. Preferred group 2 of the Z substituents (symbol, "PG2-Z")
[257] Very preferred are acidic groups which are -5-tetrazolyl, N-acyl sulfonamide, -SO ₃ H and carboxyl.
[258] Preferred group 3 of the III J. Z substituent (symbol, "PG3-Z")
[259] Carboxyl is the most preferred Z substituent.
[260] III. Preferred group 1 of the n variable (symbol, "PG1-n")
[261] For the divalent linking group-(CH ₂ ) n-, the most preferred integer values of n are 1, 2 and 3.
[262] III. Preferred group 2 of the n variable (symbol, "PG2-n")
[263] For the divalent linking group-(CH ₂ ) n-, the most preferable integer value of n is 1.
[264] Preferred group 1 of the III M. R1 substituent (symbol "PG1-R1")
[265] Preferred R 1 groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and 2-propenyl, with n-propyl being most preferred.
[266] III N. Preferred Group 1 of the R2 substituent (symbol, "PG1-R2") and Preferred Group 1 of the R3 substituent (symbol, "PG1-R3")
[267] Preferred groups R2 and R3 are independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, halo and -CF ₃ , most preferably R2 and R3 are hydrogen.
[268] III O. Preferred Group 1 of the R4 substituent (symbol, "PG1-R4")
[269] Preferred R4 substituents are ethyl, propyl and isopropyl.
[270] III P. Combination of Substituents of Compounds of Formula (I)
[271] As defined above, substituents of formula (I) are defined as "Z,""X,""n,""R1,""R2,""R3,""R4,""Y1,""Y2" and It is defined as "Y3". In addition, as previously described, within each defined substituent of Formula (I) there are "preferred" and "most preferred" subgroups that define the various substituents to be used in the definition of the LTB ₄ antagonist of the present invention. These preferred subgroups are defined by names such as "PG1-R4" as cited above. It is often advantageous to use a combination of preferred groups, or combinations of preferred groups with the general definition of the variables shown in formula (I).
[272] Suitable combinations of substituents are shown in the following three tables (ie R-Table, Y-Table and XZn-Table).
[273] The following R-table is used to select combinations of common and preferred configurations of the variables R1, R2, R3 and R4 for substitution of formula (I):
[274] <R-Table>
[275] R variable combination code Select R1 R2 machine selection R3 device selection R4 machine selection R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-R1 R2 R3 PG1-R4 R11 PG1-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1 PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16 PG1-R1 PG1-R2 PG1-R3 PG1-R4
[276] Thus, for example, the substituent combination "R14" is derived from the preferred set "PG1-R1" of variable R1, ie methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and 2-propenyl. Selected; The R2 substituent is selected from the preferred set of variables "PG1-R2", ie hydrogen, methyl, ethyl, methoxy, ethoxy, halo and -CF ₃ ; R3 has a range defined in formula (I); Suitable substituents for R 4 represent a combinatorial selection of substituents in formula (I), selected from the preferred group “PG 1 -R 4” with the preferred set of variables, ethyl, propyl and isopropyl.
[277] The following "Y-table" is used to select a wide range of preferred configurations of the variables Y1, Y2 and Y3 for substitution of formula (I):
[278] <Y-Table>
[279] Y variable combination code Y1 group selection Y2 group selection Y3 machine selection Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3
[280] The following "XZn-table" is used to select a wide range of preferred configurations of the variables X, Z and n for substitution of formula (I):
[281] <XZn-Table>
[282] XZn Variable Combination Code Select X Z group selection n integer selection XZn01 X Z n XZn02 X Z PG1-n XZn03 X Z PG2-n XZn04 X PG1-Z n XZn05 X PG2-Z n XZn06 X PG3-Z n XZn07 X PG1-Z PG1-n XZn08 X PG2-Z PG1-n XZn09 X PG3-Z PG1-n XZn10 X PG1-Z PG2-n XZn11 X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-n XZn15 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-X PG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n
[283] How to use the table:
[284] Any of each of the 16 combinations of the R substituents shown in the R-table can be used in combination with any of each of the 27 combinations of the Y substituents shown in the Y-table, and these are 24 combinations of the XZn substituents shown in the XZn-table. It can be used with any of. For example, the combinatorial selection of substituents "R07, Y21, XZn03" defines a substituent set selection for a subset of formula (I) useful in the practice of the compositions and methods of the present invention.
[285] III Q. Additional preferred LTB ₄ antagonists are described by the formula (II):
[286]
[287] (In the above formula,
[288] X2 is a heterocyclic radical selected from:
[289]
[290] R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
[291] R 22 is hydrogen, n-butyl, sec-butyl, fluoro, chloro, -CF ₃ or tert-butyl;
[292] Z2 is carboxyl, tetrazolyl, N-sulfonamidyl).
[293] Preferred Compounds of the Invention
[294] III R. Specific compounds preferred as LTB ₄ antagonist components of the compositions and methods of the present invention are represented by compounds of the formula: and all acids, salts, solvates and prodrug derivatives thereof:
[295]
[296]
[297]
[298]
[299]
[300]
[301] (C20):
[302]
[303] III S. Highly preferred LTB ₄ antagonists are the following compounds and all acids, salts, solvates and prodrug derivatives thereof:
[304]
[305]
[306] IV. Process for the preparation of LTB ₄ antagonist compounds of the compositions and methods of the present invention
[307] General schemes applicable to the synthesis of LTB ₄ antagonist compounds of formula (I) (but not representative of specific examples) are shown below. Numerous references and chemical abstract registration numbers (eg, RN 152609-60-4) are provided as additional assistants for preparing the reagents used to practice the synthetic schemes of the present invention.
[308] LTB of the Compositions and Methods of the Invention ₄Schemes of antagonist compounds
[309] The following scheme shows the preparation of the 4-substituted oxazole LTB ₄ receptor antagonist of Example (1):
[310]
[311]
[312] Known chloride 26 may be alkylated with benzyl bromide to produce chloride 28. Acetophenone (32) is produced by reaction with a known ester (30) with a suitable base as a catalyst. Oxidation with bis (trifluoroacetoxy) iodobenzene gives alpha-hydroxy ketone (34), which is cyclized with triflic acid anhydride and formamide to give 4-substituted oxazole (36). can do. Debenzylation with boron trifluoride etherate and ethanethiol yields oxazole (38), which is hydrolyzed and protonated to produce Example (1).
[313] The following scheme shows the preparation of the 5 (4) -substituted imidazole LTB ₄ receptor antagonist of Example (2):
[314]
[315] Trimethylsilyl enol ether of acetophenone (32) is formed and treated with N-chlorosuccinimide followed by tetra-n-butylammonium fluoride to produce chloroketone (40). Treatment of (40) with 2-benzyl-2-thioshudorea and base yields imidazole (42), which is treated with boron trifluoride etherate and ethanethiol to produce imidazole (44). By hydrolysis and protonation reaction, Example (2) is obtained as hydrochloride.
[316] The following scheme shows the preparation of the 4-substituted thiazole LTB ₄ receptor antagonist of Example (3):
[317]
[318] Chloroketone 40 is treated with thioformamide and magnesium carbonate to obtain thiazole 46, which is debenzylated with boron trifluoride etherate and ethanethiol to produce thiazole 48. Example (3) is obtained by hydrolysis and protonation reaction.
[319] The following scheme shows the preparation of the 5 (3) -substituted pyrazole LTB ₄ receptor antagonist of Example (4):
[320]
[321] Acetophenone (32) is treated with N, N-dimethylformamide dimethyl acetal to obtain enon (50), which is hydrolyzed, protonated, and heated with hydrazine hydrate to produce pyrazole (52). The resulting pyrazole is debenzylated with boron trifluoride etherate and ethanethiol to give Example (4).
[322] The following scheme shows the preparation of the 5-substituted isoxazole LTB ₄ receptor antagonist of Example (5):
[323]
[324] Enion 50 is treated with hydroxylamine to obtain isoxazole 54, which is debenzylated with boron trifluoride etherate and ethanethiol to produce isoxazole 56. Example (5) is obtained by hydrolysis and protonation reaction.
[325] The following scheme shows the preparation of the 5 (4) -substituted 1,2,3-triazole LTB ₄ receptor antagonist of Example (6):
[326]
[327] Known phenol 30 is alkylated with known chloride 58 to produce aryl bromide 60. (60) is treated with tri-n-butylethynyltin and palladium catalyst to produce alkyne 62. (62) is heated with trimethylsilyl azide to give triazole (64), which is debenzylated with boron trifluoride etherate and ethanethiol to give triazole (66). Example (6) is obtained by hydrolysis and protonation reaction.
[328] The following scheme depicts the preparation of the 1-substituted pyrrole LTB ₄ receptor antagonist of Example (7):
[329]
[330] 4-ethylbenzene-1,3-diol (68) is treated with potassium nitrosodisulfonate followed by 3-pyrroline, benzyl bromide and base to produce pyrrole (70). Alkylation with 1-bromo-3-chloropropane yields chloride 72 which is used to alkylate phenol 30 to produce pyrrole 74. Debenzylation with boron trifluoride etherate and ethanethiol give Example (7).
[331] The following scheme shows the preparation of the 5-substituted 1,2,4-thiadiazole LTB ₄ receptor antagonist of Example (8):
[332]
[333] 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane is added to the bromide 60 with a palladium catalyst to produce boronic acid ester 76. 3-Bromo-5-chloro-1,2,4-thiadiazole is added to (76) with a palladium catalyst to produce ester (78). Example (8) is obtained by debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation.
[334] The following scheme shows the preparation of the 2-substituted thiophene LTB ₄ receptor antagonist of Example (9):
[335]
[336] Boronic acid ester 76 is added palladium catalyst to 2-bromothiophene and then debenzylated with boron trifluoride etheride and ethanethiol to produce thiophene 80. Example (9) is obtained by hydrolysis and salt formation.
[337] The following scheme shows the preparation of the 4-substituted pyrazole LTB ₄ receptor antagonist of Example (10):
[338]
[339] Boronic acid ester 76 is added to p-dium catalyst to 1-methyl-4-iodopyrazole to produce pyrazole 82. Debenzylated with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation reaction to obtain Example (10).
[340] The following scheme shows the preparation of the 2-substituted thiazole LTB ₄ receptor antagonist of Example (11):
[341]
[342] Boronic acid ester 76 is added palladium catalyst to 2-bromothiazole to produce thiazole 84. Debenzylation with boron trifluoride etherate and ethanethiol yields thiazole 86. Example (11) is obtained by hydrolysis and protonation reaction.
[343] The following scheme shows the preparation of the 4-substituted isoxazole LTB ₄ receptor antagonist of Example (12):
[344]
[345] Boronic acid ester 76 is added to 3,5-dimethyl-4-iodoisoxazole with a palladium catalyst to produce isoxazole 88. Debenzylated with trimethylsilyl iodide, followed by hydrolysis and salt formation to obtain Example (12).
[346] The following scheme shows the preparation of the 2-substituted furan LTB ₄ receptor antagonist of Example (13):
[347]
[348] The bromide 60 is debenzylated with boron tribromide to give phenol 90 which is treated with tert-butyldimethylsilyl chloride and imidazole to produce silyl ether 92. (92) is added palladium catalyst to furan-2-boronic acid to produce furan 94. Example (13) is obtained by hydrolysis and salt formation.
[349] The following scheme shows the preparation of the 3-substituted furan LTB ₄ receptor antagonist of Example (14):
[350]
[351] (92) is added a palladium catalyst to furan-3-boronic acid to produce furan 96. Example (14) is obtained by hydrolysis and salt formation.
[352] The following scheme shows the preparation of the 3-substituted tetrahydrofuran LTB ₄ receptor antagonist of Example (15):
[353]
[354] Bromine 60 is added to the furan-3-boronic acid with a palladium catalyst to produce furan 98. Hydrogenation on a palladium catalyst produces tetrahydrofuran 100. Example (15) is obtained by hydrolysis and salt formation.
[355] The following scheme shows the preparation of the 2-substituted pyrrolidine LTB ₄ receptor antagonist of Example (16):
[356]
[357] The bromide 60 is added palladium catalyst to N-boc pyrrole-2-boronic acid to produce pyrrole 102. Hydrogenation over a palladium catalyst produces pyrrolidine 104. Hydrolysis and salt formation produce pyrrolidine 106. Treatment with hydrochloric acid affords Example (16) as hydrochloride.
[358] The following scheme shows the preparation of the 3-substituted thiophene LTB ₄ receptor antagonist of Example (17):
[359]
[360] Bromide 58 is added to thiophene-3-boronic acid with a palladium catalyst to produce thiophene 108. Known phenols (110) are alkylated with (108) using a base as a catalyst to produce thiophenes (112). Debenzylation with boron tribromide produces thiophene 114. Example (17) is obtained by hydrolysis and protonation reaction.
[361] The following scheme shows the preparation of the 5-substituted 1,2,3,4-thiatriazole LTB ₄ receptor antagonist of Example (18):
[362]
[363] References to the formation of dithio acids: N. C. Gonnella et al. Syn. Commun. 1979, 17
[364] Reference for the formation of 5-substituted 1,2,3,4-thiatriazoles from dithio acids: S. I. Ikeda et al., Synthesis 1990, 415
[365] Phenol 30 was alkylated with 1-bromo-3-chloropropane to give chloride 116, which was treated with known aldehydes and bases, and then benzylated with benzyl bromide and bases to give aldehydes 120. Create The aldehyde 120 is treated with 1,2-ethanedithiol to produce thioacetals. The resulting thioacetal is treated with a base to produce thio acid. Treatment with piperidine yields piperidinium salt 122. By teaching of Ikeda, the disclosure of which is incorporated herein by reference, (122) is treated with 2-chloropyridinium methyl iodide followed by azide ion to 1,2,3,4-thiatriazole Get 124. Debenzylated with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation to yield the product of Example (18).
[366] The following scheme shows the preparation of the 4-substituted 1,2,3-thiadiazole LTB ₄ receptor antagonist of Example (19):
[367]
[368] Acetophenone 32 is treated with ethyl carbazate to produce hydrazone 128. Intermediate 1,2,3-thiadiazole (130) is obtained using thionyl chloride by the method of Thomas et al., The disclosure of which is incorporated herein by reference, which is used as boron trifluoride etherate and ethanethiol. After debenzylation, the product of Example (19) is obtained by hydrolysis and protonation.
[369] The following scheme shows the preparation of the 3-substituted 1,2,5-thiadiazole LTB ₄ receptor antagonist of Example (20):
[370]
[371] Alkyne 62 is treated with trithiazyl trichloride by the method of Thomas et al., The disclosure of which is incorporated herein by reference, to produce thiadiazole 132. The product of Example (20) is obtained by debenzylation with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation.
[372] The following scheme shows the preparation of the 2-substituted 1,3,4-thiadiazole LTB ₄ receptor antagonist of Example (21):
[373]
[374] Boronic acid ester 76 is added palladium catalyst to 2-bromo-1,3,4-thiadiazole to produce ester 134. Debenzylated with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation reaction to obtain the product of Example (21).
[375] The following scheme shows the preparation of the 5-substituted isothiazole LTB ₄ receptor antagonist of Example (22):
[376]
[377] Bromide 58 is added to pmethyldium catalyst in 3-methylisothiazole-5-boronic acid to produce isothiazole 136. Phenol 30 is alkylated with (136) using a base as a catalyst to produce isothiazole (138). Debenzylated with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation reaction to obtain the product of Example (22).
[378] The following scheme shows the preparation of the 2-substituted oxazole LTB ₄ receptor antagonist of Example (23):
[379]
[380] Boronic acid ester 76 is added to palladium catalyst to 2-bromooxazole to produce oxazole 140. Debenzylated with boron trifluoride etherate and ethanethiol, followed by hydrolysis and protonation reaction to obtain the product of Example (23).
[381] The following scheme shows the preparation of the 3-substituted thiophene LTB ₄ receptor antagonist of Example (24):
[382]
[383] Thiophene 114 is reduced in the presence of triethylsilane and trifluoroacetic acid by the method of Kursanov et al., The disclosure of which is incorporated herein by reference, to produce thiophan 142. The product of Example (24) is obtained by hydrolysis and protonation.
[385] V. Preparation Examples 1-17
[386] Example 1
[387] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[388] A. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone
[389]
[390] Known Compound: RN # 156005-61-7
[391] R. W. Harper et al., J. Med. Chem. 1994, 37 (15), 2411-20
[392] 26.1 g (102 mmol) of 1- [2-hydroxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone in 300 ml of N, N-dimethylformamide, 33.4 g (103 mmol) cesium carbonate And a mixture of 12.2 ml (103 mmol) of benzyl bromide at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed four times with water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The resulting oil was triturated with ethyl acetate and hexanes, left for 18 hours and then cooled at 0 ° C. for 3 hours. The resulting precipitate was recovered by vacuum filtration to give 24.3 g (69%) of the title compound as white crystals: mp 60-61 ° C. ¹ H NMR (CDC1 ₃ ) δ7.68 (s, 1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4.13 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 2.56 (s, 3H), 2.55 (q, J = 7 Hz, 2H), 2.26 (quintet, J = 6 Hz, 2H), 1.16 (t, J = 7 Hz , 3H); Accurate mass calcd. For TOF MS ES ⁺ C ₂₀ H ₂₄ ClO ₃ (p + 1): m / z = 347.1414. Found: 347.1402; IR (CHCl ₃ , cm ⁻¹ ) 1659, 1602, 1266.
[393] Anal for C ₂₀ H ₂₃ ClO ₃ : C, 69.26; H, 6.68. Found: C, 69.30; H, 6.52.
[394] B. Preparation of 2- {3- [3- (4-acetyl-5-benzyloxy-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[395]
[396] A mixture of 7.27 g (21.0 mmol) of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] ethanone and 3.14 g (23.1 mmol) of sodium iodide in 100 ml of 2-butanone Heated at reflux for 18 hours. The mixture was cooled to rt, filtered and concentrated in vacuo. The residue was dissolved in 100 ml of N, N-dimethylformamide, 6.0 g (21 mmol) of 2- (3-hydroxy-2-propylphenoxy) benzoic acid methyl ester and 3.2 g of potassium carbonate (23) at room temperature for 15 hours. mmol). The mixture was diluted with ethyl acetate and washed four times with water and once with saturated sodium chloride solution. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 9.2 g (72%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.88 (d, J = 9 Hz, 1H), 7.69 (s, 1H), 7.38 (m, 6H), 7.12 (d, J = 8 Hz, 1H), 7.07 (d , J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.44 (d, J = 9 Hz, 1H ), 5.14 (s, 2H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 7 Hz, 2H), 2.57 (q, J = 7 Hz, 2H), 2.56 (s , 3H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.15 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H ); IR (CHCl ₃ , cm ⁻¹ ) 2965, 1726, 1602, 1461.
[397] Anal for C ₃₇ H ₄₀ 0 ₇ : C, 74.48; H, 6.76. Found: C, 74.39; H, 6.77.
[398] C. Preparation of 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2-hydroxyacetyl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[399]
[400] 5.31 g (8.89 mmol) of 2- {3- [3- (4-acetyl-5-benzyloxy-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 50 ml of acetonitrile and water 10 ml of the mixture was treated with 1.4 ml (18 mmol) of trifluoroacetic acid and 7.65 g (17.8 mmol) of [bis (trifluoroacetoxy) iodo] benzene. The resulting mixture was heated at reflux for 4 h and then concentrated in vacuo. The residue was dissolved in methylene chloride and washed once with water. The aqueous layer was extracted twice with fresh methylene chloride. The combined organic layers were washed three times with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 20% ethyl acetate / 80% hexanes) to give 1.68 g (31%) of the title compound as a brown oil. ¹ H NMR (CDC1 ₃ ) δ7.92 (s, 1H), 7.88 (d, J = 9 Hz, 1H), 7.40 (m, 6H), 7.12 (d, J = 9 Hz, 1H), 7.05 (d , J = 9 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.43 (d, J = 8 Hz, 1H ), 5.15 (s, 2H), 4.65 (s, 2H), 4.22 (m, 4H), 3.83 (s, 3H), 2.65 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.89 (t, J = 8 Hz, 3H); Accurate mass calcd. For TOS MS ES + C ₃₇ H ₄₁ 0 ₈ (p + 1): m / z = 613.2801. Found: 613.2833.
[401] D. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[402]
[403] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2-hydroxyacetyl) phenoxy] propoxy} -2-propylphenoxy in 20 ml of methylene chloride cooled to −78 ° C. To a solution of 1.39 g (2.27 mmol) of benzoic acid methyl ester was added 0.57 ml (3.4 mmol) of triflic acid anhydride and 0.40 ml (3.4 mmol) of 2,6-lutidine. The resulting mixture was stirred for 1 hour and then poured into ether and water. The organic layer was separated, washed once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 9 ml of a 2: 1 mixture of formamide / N, N-dimethylformamide and heated in a sealed tube at 120 ° C. for 4 hours. The mixture was cooled to rt and diluted with ethyl acetate. The mixture was washed four times with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 89 mg (6%) of the title product as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ7.92 (s, 1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J = 8 Hz, 1H), 7.00 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J = 8 Hz , 1H), 5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H), 2.61 (m, 4H), 2.26 (quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 7 Hz, 2H), 1.15 (t, J = 8 Hz, 3H), 0.84 (t, J = 8 Hz, 3H).
[404] E. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[405]
[406] 89 mg of 2- {3- [3- (5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 2 ml of ethanethiol A solution of (0.14 mmol) was treated with 0.27 ml (2.2 mmol) of boron trifluoride etherate for 4 hours at room temperature. The solution was poured into ether, washed once with water, once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate / 85% hexanes) to give 34 mg (45%) of the title product as a light brown oil. ¹ H NMR (CDC1 ₃ ) δ 7.99 (d, J = 1 Hz, 1H), 7.90 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 2 Hz, 1H), 7.38 (t , J = 7 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 9 Hz, 1H), 7.06 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H) , 6.70 (d, J = 9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.58 (q, J = 8 Hz, 2H), 2.33 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.91 (t, J = 8 Hz, 3H); MS ES + m / e = 532 (p + 1).
[407] F. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[408]
[409] 89 mg of 2- {3- [3- (2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 2 ml of methanol ( 0.14 mmol) was added 0.28 ml of a 1 M lithium hydroxide solution and the resulting mixture was warmed at 60 ° C. for 3.5 h. The mixture was cooled to rt and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to ˜4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 27 mg (92%) of the title compound as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.78 (dd, J = 8.1 Hz, 1H) , 7.64 (s, 1H), 7.47 (t, J = 8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J = 8 Hz, 2H), 6.56 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 4.20 (t, J = 6 Hz, 2H), 4.12 (t, J = 6 Hz, 2H); 2.54 (m, 4H), 2.24 (quintet, J = 6 Hz, 2H), 1.43 (hextet, J = 8 Hz, 2H), 1.10 (t, J = 8 Hz, 3H), 0.80 (t, J = 8 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₀ H ₃₂ N0 ₇ (p + 1): m / z = 518.2179. Found: 518.2206; IR (KBr, cm ⁻¹ ) 2961, 1696, 1460, 1222.
[410] Anal for C ₃₀ H ₃₁ NO ₇ : C, 69.62; H, 6.04; N, 2.71. Found: C, 68.71; H, 5. 82; N, 2.65.
[411] Example 2
[412] Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H-imidazol-4-yl) -phenoxy] propoxy} -2-propylphenoxy) benzoic acid hydrochloride
[413] A. Preparation of 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[414]
[415] 2- {3- [3- (4-acetyl-5-benzyloxy-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 50 ml of tetrahydrofuran cooled to −78 ° C. To a solution of 3.04 g (5.09 mmol) was added 11.2 ml (11.2 mmol) of a solution of 1 M lithium hexamethyldisilazide in tetrahydrofuran. After stirring for 20 minutes, 2.6 ml (20 mmol) of trimethylsilyl chloride were added and the mixture was warmed to 0 ° C and stirred for 30 minutes. The mixture was evaporated in vacuo and the residue dissolved in hexane. The resulting solution was filtered and concentrated in vacuo. The residue was dissolved in 50 ml of tetrahydrofuran, cooled to 0 ° C. and treated with 750 mg (5.6 mmol) N-chlorosuccinimide. The mixture was warmed to room temperature, stirred for 30 minutes and then heated at reflux for 2 hours. The mixture was cooled to room temperature and treated with 4 ml of water and 6 ml of a solution of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran. After stirring for 15 minutes, the mixture was diluted with ether, washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 1.94 g (60%) of the title compound as a white solid. ¹ H NMR (CDC1 ₃ ) δ 7.89 (d, J = 8 Hz, 1H), 7.77 (s, 1H), 7.40 (m, 6H), 7.12 (d, J = 9 Hz, 1H), 7.06 (d , J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.49 (s, 1H), 6.43 (d, J = 8 Hz, 1H ), 5.15 (s, 2H), 4.68 (s, 2H), 4.20 (q, J = 6 Hz, 4H), 3.82 (s, 3H), 2.65 (t, J = 7 Hz, 2H), 2.59 (q , J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); _{^{TOF MS ES + C 37 H 4O}} ClO 7 Exact Mass calculated for (p + 1): m / z = 631.2463. Found: 631.2470; IR (CHC1 ₃ , cm ⁻¹ ) 2964, 1720, 1603, 1461.
[416] Anal for C ₃₇ H ₃₉ Cl0 ₇ : C, 70.41; H, 6.23. Found: C, 70.04; H, 5.97.
[417] B. 2- (3- {3- [5-benzyloxy-4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethylphenoxy] propoxy} -2-propylphenoxy Preparation of benzoic acid methyl ester
[418]
[419] 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid in 20 ml of N, N-dimethylformamide A mixture of 800 mg (1.27 mmol) of methyl ester, 313 mg (1.52 mmol) of 2-benzyl-2-thioshudorea hydrochloride, 77 mg (0.51 mmol) of sodium iodide and 700 mg (5.06 mmol) of potassium carbonate was added at 80 ° C. 6 Treated for hours. The mixture was cooled down, diluted with diethyl ether and washed once with water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate / 70% hexanes) to give 376 mg (40%) of the title compound as a yellow amorphous solid. ¹ H NMR (CDC1 ₃ ) δ 7.89 (d, J = 8 Hz, 1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J = 9 Hz, 1H), 7.06 (d , J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H ), 5.07 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 4.10 (s, 2H), 3.83 (s, 3H), 2.63 (m , 4H), 2.31 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.18 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H ); Exact mass calcd. For TOF MS ES ⁺ C ₄₅ H ₄₇ N ₂ 0 ₆ S (p + 1): m / z = 743.3155. Found: 743.3142; IR (CHCI ₃ , cm ⁻¹ ) 2963, 1720, 1602, 1453.
[420] Anal for C ₄₅ H ₄₆ N ₂ 0 ₆ S: C, 72.75; H, 6. 24; N, 3.77. Found: C, 72.69; H, 6. 17; N, 3.56.
[421] C. 2- (3- {3- [4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-5-hydroxyphenoxy] propoxy} -2-propylphenoxy Preparation of benzoic acid methyl ester
[422]
[423] 2- (3- {3- [5-benzyloxy-4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethylphenoxy] propoxy} -2- in 7 ml of ethanethiol A solution of 360 mg (0.49 mmol) of propylphenoxy) benzoic acid methyl ester was treated with boron trifluoride etherate at room temperature for 3.5 hours. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 20% ethyl acetate / 80% hexanes) to give 154 mg (48%) of the title compound as an orange oil. ¹ H NMR (CDC1 ₃ ) δ 7.85 (d, J = 8 Hz, 1H), 7.36 (t, J = 7 Hz, 1H), 7.20 (m, 7H), 7.12 (s, 1H), 7.05 (m , 3H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.54 (s, 1H), 6.41 (d, J = 8 Hz, 1H), 4.20 (s , 2H), 4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz , 2H), 1.53 (hextet, J = 8 Hz, 2H), 1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 8 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₈ H ₄₁ N ₂ 0 ₆ S (p + 1): m / z = 653.2685. Found: 653.2669.
[424] _{Anal for} C ₃₈ H ₄ O N ₂ 0 ₆ S: C, 69.92; H, 6. 18; N, 4.29. Found: C, 69.44; H, 6. 25; N, 3.99.
[425] D. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H-imidazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid hydrochloride
[426]
[427] 2- (3- {3- [4- (2-benzylsulfanyl-3H-imidazol-4-yl) -2-ethyl-5-hydroxyphenoxy] propoxy} -2-propyl in 3 ml of methanol A solution of 154 mg (0.235 mmol) of phenoxy) benzoic acid methyl ester was treated with 1 N lithium hydroxide solution at 60 ° C. for 3.5 hours. The mixture was cooled to rt and concentrated in vacuo. The solution was diluted with water and the pH adjusted to 4. The aqueous solution was extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 3 ml of ethanol and treated with 1 ml of 0.2 N sodium hydroxide solution and 75 mg of Raney nickel at 75 ° C. for 4 hours. The mixture was cooled to rt, filtered through Celite (tradename) and the filtrate was concentrated in vacuo. The residue was diluted with water and the pH adjusted to 2 with 1 N hydrochloric acid. The resulting precipitate was recovered by vacuum filtration to give 27 mg (21%) of the title compound. Exact mass calculated for TOF MS ES ⁺ C ₃₀ H ₃₃ N ₂ 0 ₆ (p + 1): m / z = 517.2339. Found: 517.2340.
[428] Example 3
[429] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[430] A. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[431]
[432] 500 mg of 2- (3- {3- [5-benzyloxy-4- (2-chloroacetyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester in 10 ml of dioxane ( 0.792 mmol), 20 ml (8.0 mmol) of thioformamide and magnesium carbonate were heated at reflux for 2 hours. The mixture was cooled to rt and diluted with diethyl ether and 0.2 M sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 254 mg (50%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ8.91 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 8.1 Hz, 1H), 7.84 (d, J = 1 Hz, 1H), 7.40 (m , 6H), 7.08 (m, 2H), 6.80 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J = 8 Hz , 1H), 5.16 (s, 2H), 4.21 (t, J = 6 Hz, 4H), 3.83 (s, 3H), 2.68 (m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.21 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Exact mass calculation for TOF MS ES ⁺ C ₃₈ H ₄₀ N0 ₆ S (p + 1): m / z = 638.2576. Found: 638.2579. IR (CHCl ₃ , cm ⁻¹ ) 2964, 1719, 1563, 1461.
[433] B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[434]
[435] 243 mg of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 7 ml of ethanethiol (0.366 mmol) was treated with boron trifluoride etherate for 4 hours at room temperature. The mixture was diluted with diethyl ether, washed once with water and once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate / 85% hexanes) to give 131 mg (65%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 8.88 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 1 Hz, 1H), 7.44 (d, J = 1 Hz, 1H), 7.38 (m , 2H), 7.08 (m, 2H), 6.81 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz , 1H), 4.21 (t, J = 6 Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz , 2H), 1.19 (t, J = 8 Hz, 3H), 0.91 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOF MS ES ⁺ C ₃₁ H ₃₄ NO ₆ S (p + 1): m / z = 548.2107. Found: 548.2085.
[436] C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[437]
[438] 130 mg of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 4 ml of methanol ( 0.236 mmol) was treated with 1 M lithium hydroxide solution at 60 ° C. for 3 hours. The mixture was cooled to rt, concentrated in vacuo and diluted with water. The solution was adjusted to pH ˜4 and extracted three times with methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in a minimum amount of methylene chloride and hexane was added until the solution was cloudy. The mixture was concentrated slowly in vacuo to give 96 mg (76%) of the title compound. ¹ H NMR (CDC1 ₃ ) δ8.90 (s, 1H), 8.23 (dd, J = 8.1 Hz, 1H), 7.41 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.82 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.54 (s, 1H), 4.25 (t, J = 6 Hz , 2H), 4.22 (t, J = 6 Hz, 2H), 2.59 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.50 (hextet, J = 8 Hz, 2H), 1.19 (t , J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H); Exact mass calculation for TOFMS ES ⁺ C ₃₀ H ₃₂ NO ₆ S (p + 1): m / z = 534.1950. Found: 534.1957. IR (CHCl ₃ , cm ⁻¹ ) 2965, 1738, 1454.
[439] Anal for C ₃₀ H ₃₁ NO ₆ S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.19; H, 5.72; N, 2.53.
[440] Example 4
[441] Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid
[442] A. Preparation of 2- (3- {3- [5-benzyloxy-4- (3-dimethylaminoacryloyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[443]
[444] 3.07 g of 2- (3- {3- [4-acetyl-5-benzyloxy-2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester in 3 ml of N, N-dimethylformamide 5.04 mmol) and 0.9 ml (7 mmol) of dimethylformamide dimethylacetal were heated at 110-120 ° C. for 35 hours. The mixture was cooled to rt and diluted with a mixture of ethyl acetate and 1 N hydrochloric acid. The organic layer was separated, washed twice with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate / 70% hexanes to ethyl acetate) to give 2.1 g (63%) of the title compound as a yellow oil. Accurate mass calcd. For TOF MS ES + C ₄₀ H ₄₆ N0 ₇ (p + 1): m / z = 652.3274. Found: 652.3270. IR (CHCI ₃ , cm ⁻¹ ) 2965, 1720, 1605. Anal. For C ₄₀ H ₄₅ NO ₇ : C, 73.71; H, 6.96; N, 2.15. Found: C, 73.72; H, 6. 95; N, 2.18.
[445] B. Preparation of 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid
[446]
[447] 2- (3- {3- [5-benzyloxy-4- (3-dimethylaminoacryloyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 550 in 30 ml of methanol A solution of mg (0.843 mmol) was treated with 1 M lithium hydroxide solution at 60 ° C. for 3 hours. The mixture was cooled to rt and diluted with ethyl acetate and 0.5 M hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 15 ml of methanol and treated with 4 ml of water and 0.50 ml (7.7 mmol) of hydrazine monohydrate at reflux for 3 hours. The mixture was diluted with ethyl acetate and 1 N hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (30% ethyl acetate / 69% hexane / 1% acetic acid) to give 350 mg (65%) of the title compound as an acetate salt. Some of this material was free basified with sodium bicarbonate to obtain analytical samples. ¹ H NMR (CDC1 ₃ ) δ8.20 (dd, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.38 (m, 5H), 7.15 (m, 2H), 6.78 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.61 (d, J = 8 Hz, 1H), 6.58 (s, 1H), 6.55 (bs, 1H), 5.18 (s, 2H), 4.22 (t, J = 6 Hz, 2H), 4.17 (t, J = 6 Hz, 2H), 2.58 (m, 4H), 2.30 (quintet, J = 6 Hz, 2H), 1.47 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₇ H ₃₉ N ₂ 0 ₆ (p + 1): m / z = 607.2808. Found: 607.2831. IR (CHCI ₃ , cm ⁻¹ ) 2965, 1739, 1604, 1454.
[448] Anal for C ₃₇ H ₃₈ N ₂ 0 ₆ : C, 73.25; H, 6. 31; N, 4.62. Found: C, 73.31; H, 6. 30; N, 4.62.
[449] C. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid
[450]
[451] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (2H-pyrazol-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid 300 in 2.5 ml of ethanethiol A solution of mg (0.490 mmol) was treated with 2 ml of boron trifluoride etheride for 3 hours at room temperature, 1 ml of additional boron trifluoride etheride was added, and further stirred for 1 hour. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate / 85% hexanes to 60% ethyl acetate / 40% hexanes) to give 60 mg (24%) of the title compound as a white solid. ¹ H NMR (CDC1 ₃ ) δ8.23 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.42 (t, J = 7 Hz, 1H), 7.30 (s, 1H), 7.19 (d , J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.69 (d, J = 8 Hz, 1H), 6.61 (s, 1H) ), 6.60 (d, J = 8 Hz, 1H), 6.54 (s, 1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.48 (hextet , J = 8 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.86 (t, J = 7 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₀ H ₃₃ N ₂ 0 ₆ (P + 1): m / z = 517.2339. Found: 517.2334. IR (CHCI ₃ , cm ⁻¹ ) 2965, 1738, 1454.
[452] Anal for C ₃₀ H ₃₂ N ₂ 0 ₆ : C, 69.75; H, 6. 24; N, 5.42. Found: C, 69.73; H, 6. 33; N, 5.25.
[453] Example 5
[454] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[455] A. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[456]
[457] 2- (3- {3- [5-benzyloxy-4- (3-dimethylaminoacryloyl) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester in 4 ml of methanol 280 A mixture of mg (0.43 mmol), 75 mg (1.1 mmol) of hydroxylamine hydrochloride and 1 ml of water was heated at reflux for 2 hours. The mixture was cooled to rt and diluted with diethyl ether and water. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 202 mg (76%) of the title compound as a white solid. ¹ H NMR (CDC1 ₃ ) δ8.20 (d, J = 20 Hz, 1H), 7.88 (dd, J = 9, 2 Hz, 1H), 7.79 (s, 1H), 7.40 (m, 7H), 7.08 (m, 2H), 6.68 (d, J = 8 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H) , 4.21 (t, J = 6 Hz, 4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H) , 1.20 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOF MS ES ⁺ C ₃₈ H ₄₀ NO ₇ (p + 1): m / z = 622.2805. Found: 622.2817. IR (CHC1 ₃ , cm ⁻¹ ) 2964, 1720, 1461.
[458] Anal for C ₃₈ H ₃₉ N0 ₇ : C, 73.41; H, 6. 32; N, 2.25. Found: C, 73.20; H, 6. 34; N, 2.27.
[459] B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[460]
[461] 180 mg of 2- {3- [3- (5-benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 5 ml of ethanethiol (0.289 mmol) of the solution was treated with 1.5 ml of boron trifluoride etheride at room temperature for 2 hours, and additional 0.5 ml of boron trifluoride etheride was added and stirred for 1 hour more. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate / 85% hexanes) to give 94 mg (61%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ8.28 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8.2 Hz, 1H), 7.38 (t, J = 8 Hz, lH), 7.36 (s, 1H ), 7.08 (t, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.62 (m, 4H), 2.34 (quintet , J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Exact mass calcd. For TOFMS ES ⁺ C ₃₁ H ₃₄ NO ₇ (p + 1): m / z = 532.2335. Found: 532.2335. IR (CHCI ₃ , cm ⁻¹ ) 2964, 1715, 1601, 1461.
[462] Anal for C ₃₁ H ₃₃ NO ₇ : C, 70.04; H, 6. 26; N, 2.63. Found: C, 70.13; H, 6. 35; N, 2.63.
[463] C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[464]
[465] 94 mg of 2- {3- [3- (2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 3 ml of methanol ( 0.18 mmol) was added 1 ml of 1 M lithium hydroxide solution and the resulting mixture was warmed at 60 ° C. for 3 hours. The mixture was cooled to rt and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to ˜4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 12 mg (13%) of the title compound as a greyish-white amorphous solid. ¹ H NMR (CDC1 ₃ ) δ8.26 (s, 1H), 8.20 (dd, J = 8.1 Hz, 1H), 7.49 (t, J = 6 Hz, 1H), 7.36 (s, 1H), 7.18 (d , J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 7.02 (bs, 1H), 6.80 (d, J = 8 Hz, 1H), 6.69 (d, J = 8 Hz, 1H ), 6.60 (d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.46 (s, 1H), 4.22 (t, J = 6 Hz, 2H), 4.19 (t, J = 6 Hz, 2H ), 2.57 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.47 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H), 0.85 (t, J = 7 Hz, 3H); Exact mass calculated for TOS MS ES ⁺ C ₃₀ H ₃₂ NO ₇ (p + 1): m / z = 518.2179. Found: 518.2175. Anal for C ₃₀ H ₃₁ NO ₇ : C, 69.62; H, 6.04; N, 2.71. Found: C, 69.57; H, 6. 15; N, 2.74.
[466] Example 6
[467] 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) Preparation of benzoic acid
[468] A. Preparation of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[469]
[470] 1.19 g (3.11 mmol), 2- (3-hydroxy-2-propylphenoxy, 5-benzyloxy-4-bromo-1- (3-chloropropoxy) -2-ethylbenzene in 20 ml of 2-butanone A mixture of 0.89 g (3.1 mmol) of benzoic acid methyl ester, 1.29 g (9.34 mmol) of potassium carbonate, 0.52 g (3.1 mmol) of potassium iodide and 2 ml of methyl sulfoxide was heated at reflux for 48 hours. The mixture was cooled to rt, diluted with diethyl ether and washed once with water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 6% ethyl acetate / 94% hexanes) to give 1.34 g (68%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ7.91 (dd, J = 8.2 Hz, 1H), 7.50 (d, J = 7 Hz, 2H), 7.38 (m, 5H), 7.15 (d, J = 8 Hz, 1H ), 7.10 (d, J = 8 Hz, 1H), 6.83 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.48 (d, J = 8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.68 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.31 (quintet, J = 6 Hz, 2H), 1.58 (hextet, J = 6 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H).
[471] B. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-ethynylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[472]
[473] 1.50 g of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 25 ml of N, N-dimethylformamide (2.37 mmol), a mixture of 0.82 ml (2.8 mmol) of tri-n-butylethynyltin and 1.0 g (0.95 mmol) of tetrakis (triphenylphosphine) palladium (o) are purged with argon and in a sealed tube Heated at 120 ° C. for 24 hours. The mixture was cooled to rt and filtered. The filtrate was diluted with ethyl acetate, washed four times with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 532 mg (39%) of the title compound as a brown oil. ¹ H NMR (CDC1 ₃ ) δ 7.88 (dd, J = 8, 2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m, 6H), 7.10 (d, J = 8 Hz, 1H) , 7.05 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.43 (m, 2H), 5.16 (s, 2H) , 4.17 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 1H), 2.64 (t, J = 8 Hz, 2H) , 2.53 (q, J = 7 Hz, 2H), 2.27 (quintet, J = 6 Hz, 2H), 1.53 (m, 2H), 1.13 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); Exact mass calculation for TOF MS ES ⁺ C ₃₇ H ₃₉ 0 ₆ (p + 1): m / z = 579.2747. Found: 579.2739.
[474] C. 2- (3- {3- [5-benzyloxy-2-ethyl-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy Preparation of benzoic acid methyl ester
[475]
[476] 517 mg (0.893 mmol) of 2- {3- [3- (5-benzyloxy-2-ethyl-4-ethynylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester and trimethylsilyl azide 3.0 A mixture of ml (18 mmol) was heated in toluene in a sealed tube at 130 ° C. for 120 hours. The mixture was cooled to rt and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes to 50% ethyl acetate / 50% hexanes) to give 347 mg (88% based on recovered starting material) as a brown solid. ¹ H NMR (CDC1 ₃ ) δ8.10 (bs, 1H), 7.89 (dd, J = 8.2 Hz, 1H), 7.76 (s, 1H), 7.40 (m, 7H), 7.10 (d, J = 8 Hz , 1H), 7.05 (d, J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.62 (s, 1H), 6.43 (d , J = 8 Hz, 1H), 5.18 (s, 2H), 4.21 (m, 4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.21 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Exact mass calculation for TOF MS ES ⁺ C ₃₇ H ₄₀ N ₃ 0 ₆ (p + 1): m / z = 622.2917. Found: 622.2946. IR (CHCI ₃ , cm ⁻¹ ) 3400, 1721, 1602, 1453.
[477] Anal for C ₃₇ H ₃₉ N ₃ 0 ₆ : C, 71.48; H, 6. 32; N, 6.76. Found: C, 70.28; H, 6.07; N, 6.54.
[478] D. 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy Preparation of benzoic acid methyl ester
[479]
[480] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2 in 9 ml of ethanethiol A solution of 330 mg (0.531 mmol) of propylphenoxy) benzoic acid methyl ester was treated with 2.0 ml (16 mmol) of boron trifluoride etheride for 1 hour at room temperature, followed by 1 hour with 1.0 ml of additional boron trifluoride etheride. Treated during. The mixture was diluted with diethyl ether and water. The organic layer was washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate / 70% hexanes to 50% ethyl acetate / 50% hexanes) to give 180 mg (63%) of the title compound as a brown solid. ¹ H NMR (CDC1 ₃ ) δ 7.97 (s, 1H), 7. 88 (dd, J = 8.2 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.59 (s , 1H), 6.43 (d, J = 8 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₀ H ₃₄ N ₃ 0 ₆ (p + 1): m / z = 532.2447. Found: 532.2466. IR (CHCI ₃ , cm ⁻¹ ) 2964, 1718, 1453.
[481] Anal for C ₃₀ H ₃₃ N ₃ 0 ₆ : C, 67.78; H, 6. 26; N, 7.90. Found: C, 66.80; H, 6.02; N, 7.53.
[482] E. 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2-propylphenoxy Preparation of benzoic acid
[483]
[484] 2- (3- {3- [2-ethyl-5-hydroxy-4- (3H- [1,2,3] triazol-4-yl) phenoxy] propoxy} -2- in 5 ml of methanol A solution of 160 mg (0.30 mmol) of propylphenoxy) benzoic acid methyl ester was treated with 1.5 ml of a 1 N lithium hydroxide solution at 60 ° C. for 3.5 hours. The mixture was cooled to rt, diluted with water and the pH adjusted to ˜4. The resulting mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 134 mg (86%) of the title compound as a brown solid. ¹ H NMR (DMSO-d) δ 14.98 (bs, 1H), 12.80 (bs, 1H), 10.02 (bs, 1H), 8.17 (bs, 1H), 7.77 (dd, J = 7.2 Hz, 1H), 7.60 (bs, 1H), 7.47 (t, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.57 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 4.22 (t, J = 6 Hz, 2H), 4.15 ( t, J = 6 Hz, 2H), 2.54 (m, 4H), 2.25 (quintet, J = 6 Hz, 2H), 1.45 (hextet, J = 8 Hz, 2H), 1.11 (t, J = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H); Exact mass calculation for TOF MS ES ⁺ C ₂₉ H ₃₂ N ₃ 0 ₆ (p + 1): m / z = 518.2291. Found: 518.2302. IR (CHCI ₃ , cm ⁻¹ ) 2965, 1738, 1454.
[485] Anal for C ₂₉ H ₃₁ N ₃ 0 ₆ : C, 67.30; H, 6.04; N, 8.12. Found: C, 67.15; H, 5.98; N, 7.93.
[486] Example 7
[487] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrole-1-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[488] A. Preparation of 5-benzyloxy-2-ethyl-4-pyrrole-1-yl-phenol
[489]
[490] To a mixture of 40.0 g (149 mmol) of potassium nitrosodisulfonate and 10 g of potassium hydrogen phosphate in 1.2 ml of water at room temperature, 10.0 g (2.37 mmol) of 4-ethylbenzene-1,3-diol and potassium hydrogen phosphate in 150 ml of water 10.5 g of solution was added. The mixture was stirred for 15 minutes and the pH was adjusted to ˜3. The solution was extracted three times with diethyl ether. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in 70 ml of acetonitrile and treated with 12 ml of 65% 3-pyrroline at room temperature. The resulting mixture was stirred for 1 h, concentrated in vacuo, dissolved in ethyl acetate and hexanes and filtered over a short column of silica gel. The resulting solution was concentrated in vacuo. The residue was dissolved in 10 ml of N, N-dimethylformamide and treated with 0.85 ml (7.1 mmol) of benzyl bromide and 960 mg (6.9 mmol) of potassium carbonate for 15 hours at room temperature. The mixture was diluted with ethyl acetate, washed four times with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, ethyl acetate / hexane gradient) to give 316 mg (2%) of the title compound. Exact mass calculated for TOF MS ES ⁺ C ₁₉ H ₂₀ NO ₂ (p + 1): m / z = 294.1494. Found: 294.1471.
[491] B. Preparation of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] -1 H-pyrrole
[492]
[493] 316 mg (1.08 mmol) of 5-benzyloxy-2-ethyl-4-pyrrole-1-yl-phenol, 223 mg (1.62 mmol) of potassium carbonate and 1-bromo-3 in 5 ml of N, N-dimethylformamide A mixture of 0.16 ml (1.6 mmol) of chloropropane was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and water, washed four times with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 5% ethyl acetate / 95% hexanes) to give 314 mg (79%) of the title compound as a colorless oil. Accurate mass calcd. For TOF MS ES ⁺ C ₂₂ H ₂₅ NClO ₂ (p + 1): m / z = 370.1574. Found: 370.1548.
[494] C. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-pyrrole-1-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[495]
[496] Of 310 mg (0.85 mmol) of 1- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] -1H-pyrrole and 140 mg (0.94 mol) of sodium iodide in 5 ml of 2-butanone The mixture was heated at reflux for 6 hours. The mixture was cooled to rt, filtered and concentrated in vacuo. The residue was dissolved in 7 ml of N, N-dimethylformamide, 242 mg (0.85 mmol) of 2- (3-hydroxy-2-propylphenoxy) benzoic acid methyl ester and 129 g (93) of potassium carbonate for 15 hours at room temperature. mmol). The mixture was diluted with ethyl acetate and water, washed four times with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 5% ethyl acetate / 95% hexanes) to give 196 mg (37%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.86 (dd, J = 8.2 Hz, 1H), 7.37 (dt, J = 8.2 Hz, 1H), 7.30 (m, 5H), 7.07 (m, 3H), 6.84 (m , 2H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.58 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 6.29 (m , 2H), 4.92 (s, 2H), 4.17 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.65 (t, J = 8 Hz , 2H), 2.58 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 7 Hz, 3H ), 0.80 (t, J = 7 Hz, 3H); Exact mass calculation for TOF MS ES ⁺ C ₃₉ H ₄₂ N0 ₆ (p + 1): m / z = 620.3012. Found: 620.3021.
[497] D. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrole-1-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[498]
[499] 195 mg of 2- {3- [3- (5-benzyloxy-2-ethyl-4-pyrrole-1-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 5 ml of ethanethiol ( 0.315 mmol) was treated with 1.3 ml (9.5 mmol) of boron trifluoride etherate for 2.5 hours at room temperature. The mixture was diluted with diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 39 mg (23%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.89 (d, J = 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.07 (m, 2H), 6.98 (s, 1H), 6.68 (m , 3H), 6.65 (d, J = 8 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 6.35 (m, 2H), 5.04 (bs, 1H), 4.19 (m, 2H), 3.83 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (m, 2H), 1.14 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOF MS ES ⁺ C ₃₂ H ₃₆ NO ₆ (P + 1): m / z = 530.2543. Found: 530.2516.
[500] Example 8
[501] 2- (3- {3- [4- (3-bromo- [1,2,4] thiadiazol-5-yl) -2-ethyl-5-hydroxyphenoxy] propoxy} -2- Propylphenoxy) benzoic acid
[502] A. 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) Preparation of Phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[503]
[504] 8.30 g (13.1 mmol) of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 80 ml of deoxygenated toluene ), A mixture of 5.2 ml (39 mmol) of triethylamine and 320 mg (0.39 mmol) of PdCl ₂ (dppf) in 4,4,5,5-tetramethyl- [1,3,2] dioxa in tetrahydrofuran Treated with 20 ml (20 mmol) of a 1 M solution of borolane and heated at room temperature for 6 hours. The mixture was filtered through a shot column of silica gel and the filtrate was concentrated in vacuo. The residue was chromatographed (silica gel, 35% ethyl acetate / 65% hexanes) to give a dark oil, which was further chromatographed (silica gel, 30% ethyl acetate / 70% hexanes) to give 7.70 g (84%) of the title compound. . ¹ H NMR (CDC1 ₃ ) δ 7.86 (dd, J = 8.2 Hz, 1H), 7.60 (d, J = 8 Hz, 2H), 7.47 (s, 1H), 7.34 (m, 3H), 7.24 (t , J = 8 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.47 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s, 2H), 4.18 (m, 4H), 3.81 (s, 3H), 2.64 (t , J = 8 Hz, 2H), 2.56 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J = 8 Hz, 2H), 1.34 (s, 12H ), 1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOF MS ES ⁺ C ₄₁ H ₅₃ NBO ₈ (p + NH ₄ ): m / z = 698.3864. Found: 698.3889. IR (CHCI ₃ , cm ⁻¹ ) 2964, 1720, 1604, 1453.
[505] Anal for C ₄₁ H ₄₉ BO ₈ : C, 72.35; H, 7. 26. Found: C, 72.30; H, 7.12.
[506] B. 2- (3- {3- [5-benzyloxy-4- (3-bromo- [1,2,4] thiadiazol-5-yl) -2-ethylphenoxy] propoxy}- Preparation of 2-propylphenoxy) benzoic acid methyl ester
[507]
[508] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane in 10 ml of deoxygenated toluene -2-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 310 mg (0.46 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole 120 mg (0.60 mmol), cesium carbonate 300 mg (0.92 mmol) and 20 mg (0.024 mmol) PdCl ₂ (dppf) were heated at 100 ° C. for 15 h. The mixture was diluted with a solution of 35% ethyl acetate / 65% hexanes and filtered through a shot column of silica gel. The filtrate was concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate / 70% hexanes) to give 232 mg (70%) of the title compound. ¹ H NMR (CDC1 ₃ ) δ8.13 (s, 1H), 7.87 (dd, J = 8.2 Hz, 1H), 7.44 (m, 2H), 7.37 (m, 4H), 7.08 (t, dJ = 8.1 Hz , 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.55 (s, 1H), 6.43 (d , J = 8 Hz, 1H), 5.28 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.19 (t, J = 6 Hz, 2H), 3.81 (s, 3H), 2.62 (m , 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H ); MS ES ⁺ m / e 717, 719.
[509] C. 2- (3- {3- [4- (3-Bromo- [1,2,4] thiadiazol-5-yl) -2-ethyl-5-hydroxyphenoxy] propoxy}- Preparation of 2-propylphenoxy) benzoic acid
[510]
[511] 2- (3- {3- [5-benzyloxy-4- (3-bromo- [1,2,4] thiadiazol-5-yl) -2-ethylphenoxy] prop in 4 ml of ethanethiol A solution of 230 mg (0.31 mmol) of Foxy} -2-propylphenoxy) benzoic acid methyl ester was treated with 0.32 ml (2.5 mmol) of boron trifluoride etheride for 6 hours at room temperature, and additional boron trifluoride etherate was added. And stirring was continued for 7 hours. The reaction mixture was diluted with water, concentrated in vacuo and extracted with diethyl ether. The residue was dissolved in 5 ml of methanol and treated with 2 ml of 1 N lithium hydroxide solution at 65 ° C. for 1 hour. The mixture was concentrated in vacuo, the residue was diluted with water and the pH adjusted to ˜3 with 1 N hydrochloric acid. The resulting precipitate was recovered by vacuum filtration and dissolved in dilute basic aqueous solution. Reverse phase chromatography (1: 1 acetonitrile / water) gave 43 mg (23%) of the title compound as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 7.85 (s, 1H), 7.80 (dd, J = 8.2 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 3H), 6.83 (d, J = 9 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.62 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 2.55 (m, 4H) , 2.27 (quintet, J = 5 Hz, 2H), 1.44 (hextet, J = 8 Hz, 2H), 1.13 (t, J = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H); MS ES ⁺ m / e 551 (p + NH ₄ ⁺ -Br); IR (KBr, cm ⁻¹ ) 2900, 1696, 1603, 1461.
[512] Anal for C ₂₉ H ₂₉ BrN ₂ 0 ₆ S: C, 56.77; H, 4.76; N, 4.56. Found: C, 56.63; H, 4.72; N, 3.98.
[513] Example 9
[514] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt
[515] A. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[516] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane in 10 ml of deoxygenated toluene -2-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 300 mg (0.44 mmol), 2-bromothiophene 110 mg (0.66 mmol), cesium carbonate 300 mg (2.17 mmol) and PdCl A mixture of ₂ (dppf) 20 mg (0.024 mmol) was heated at 105 ° C. for 66 hours. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in methylene chloride and filtered through a shot column of silica gel. The filtrate was concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate / 70% hexanes) to give an oil which was dissolved in 4 ml of ethanethiol and treated with 0.44 ml (3.4 mmol) of boron trifluoride etheride for 3 hours at room temperature. The mixture was diluted with water and extracted with diethyl ether. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, hexanes to 30% ethyl acetate / 70% hexanes) to give 120 mg (50%) of the title compound as a yellow film. ¹ H NMR (CDC1 ₃ ) δ 7.85 (dd, J = 8.2 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.15 (d, J = 7 Hz, 1H), 7.03-7.15 (m , 5H), 6.80 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.51 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.44 (bs , 1H), 4.18 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.54 (quintet, J = 6 Hz , 2H), 1.52 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); MS ES ^- m / e 545 (p-1).
[517] B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt
[518]
[519] 120 mg of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 3 ml of methanol ( 0.22 mmol) was treated with 0.5 ml of 1 N lithium hydroxide solution for 1 hour at room temperature followed by 0.75 ml of additional 1 N lithium hydroxide solution for 18 hours. The mixture was heated at 50 ° C. and then concentrated in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed once with water and concentrated in vacuo. The residue was diluted with 0.22 ml of 1 N sodium hydroxide solution, diethyl ether and toluene. The mixture was concentrated in vacuo, dissolved in methylene chloride and concentrated in vacuo to yield 120 mg (98%) of the title compound as a green film. ¹ H NMR (DMSO-d ₆ ) δ7.71 (d, J = 8 Hz, 1H), 7.42 (m, 2H), 7.31 (m, 2H), 7.10 (m, 2H), 6.99 (m, 1H) , 6.76 (t, J = 7 Hz, 2H), 6.52 (s, 1H), 6.30 (d, J = 8 Hz, 1H), 4.16 (t, J = 7 Hz, 2H), 4.07 (t, J = 7 Hz, 2H), 2.50 (m, 4H), 2.20 (m, 2H), 1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H), 0.77 (t, J = 7 Hz, 3H) ; MS ES + m / e 533 (p + 1-Na ⁺ ). IR (CHCI ₃ , cm ⁻¹ ) 2900,1738, 1604, 1454.
[520] Example 10
[521] Of 2- (3- {3- [2-ethyl-5-hydroxy-4- (1-methyl-1H-pyrazol-4-yl) -phenoxy] propoxy} -2-propylphenoxy) benzoic acid Produce
[522] A. Preparation of 4-iodo-1-methylpyrazole (known compound: RN 39806-90-1)
[523]
[524] To a solution of 1.3 g (6.8 mmol) of 4-iodopyrazole in 10 ml of dioxane was added 0.42 ml (6.8 mmol) of iodomethane and the resulting mixture was stirred at room temperature for 96 hours. The mixture was concentrated in vacuo, the residue mixed with methylene chloride and filtered. The filtrate was concentrated in vacuo to give 1.35 g (95%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.47 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H).
[525] B. 2- (3- {3- [5-benzyloxy-2-ethyl-4- (1-methyl-1H-pyrazol-4-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid Preparation of Methyl Ester
[526] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane in 35 ml of deoxygenated toluene 2-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 1.00 g (1.47 mmol), 4-iodo-1-methylpyrazole 450 mg (2.16 mmol), cesium carbonate 1.20 g ( 3.62 mmol) and 72 mg (0.088 mmol) of PdCl ₂ (dppf) were heated at 100 ° C. for 24 h. Additional about 30 mg of 4-iodo-1-methylpyrazole and about 30 mg of PdCl ₂ (dppf) were added and heating continued at 100 ° C. for 40 hours. The mixture was cooled to rt, concentrated in vacuo, diluted with methylene chloride and filtered through a short plug of silica gel. The filtrate was concentrated in vacuo. The residue was chromatographed (silica gel, 35% ethyl acetate / 65% hexanes to 65% ethyl acetate / 35% hexanes) to give 710 mg (76%) of the title compound. ¹ H NMR (CDC1 ₃ ) δ 7.86 (dd, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.37 (m, 6H), 7.28 (s, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.56 (s , 1H), 6.42 (d, J = 8 Hz, 1H), 5.08 (s, 2H), 4.18 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.85 (s , 3H), 3.81 (s, 3H), 2.63 (t, J = 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.55 (hextet , J = 8 Hz, 2H), 1.23 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H).
[527] C. 2- (3- {3- [2-ethyl-5-hydroxy-4- (1-methyl-1H-pyrazol-4-yl) -phenoxy] propoxy} -2-propylphenoxy) Preparation of benzoic acid
[528]
[529] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (1-methyl-1H-pyrazol-4-yl) phenoxy] propoxy} -2-propylphenoxy in 5 ml of ethanethiol A solution of 710 mg (1.12 mmol) of benzoic acid methyl ester was treated with 1.42 ml (11.2 mmol) of boron trifluoride etheride for 20 hours at room temperature. The reaction mixture was diluted with water, concentrated in vacuo and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated twice with hexane and the residue was dissolved in 5 ml of methanol. This solution was treated with 5 ml of 1 N lithium hydroxide solution at ˜95 ° C. for 2 hours. The mixture was concentrated in vacuo, the residue diluted with water, washed twice with diethyl ether and the aqueous layer acidified with 1N hydrochloric acid. The resulting solution was extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 10% methanol / 90% methylene chloride) gave 338 mg (57%) of the title compound as a brown foam. ¹ H NMR (DMS0-d ₆ ) δ 12.85 (bs, 1H), 9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48 (dt, J = 8.2 Hz, 1H) , 7.44 (s, 1H), 7.18 (t, J = 8 Hz, 1H), 7.13 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.77 (d, J = 9 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (t, J = 6 Hz, 2H), 4.08 (t, J = 6 Hz, 2H), 3.85 (s, 3H), 2.50 (m, 4H), 2.24 (quintet, J = 5 Hz, 2H), 1.45 (hextet, J = 8 Hz, 2H), 1.09 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H); MS ES ⁺ m / e 531 (p + 1); IR (KBr, cm ⁻¹ ) 2961, 1697, 1602, 1460, 1222.
[530] Anal for C ₃₁ H ₃₄ N ₂ 0 ₆ : C, 70.17; H, 6. 46; N, 5.28. Found: C, 69.27; H, 6.08; N, 4.63.
[531] Example 11
[532] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[533] A. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[534]
[535] 2- (3- {3- [5-benzyloxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane in 35 ml of deoxygenated toluene 2-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 960 mg (1.41 mmol), 0.25 ml (2.8 mmol) 2-bromothiazole, 1.15 g (3.52 mmol) cesium carbonate and PdCl 35 mg (0.040 mmol) of ₂ (dppf) was heated at 60 ° C. for 16 h and then at 100 ° C. for 7 h. Additional 0.13 ml of 2-bromothiazole and about 30 mg of PdCl ₂ (dppf) were added and heating continued at 100 ° C. for 72 hours. The mixture was cooled to rt, concentrated in vacuo, diluted with methylene chloride and filtered through a short plug of silica gel. The filtrate was concentrated in vacuo. The residue was chromatographed (silica gel, hexanes to 35% ethyl acetate / 65% hexanes) to give 282 mg (31%) of the title compound. ¹ H NMR (CDC1 ₃ ) δ8.20 (s, 1H), 7.86 (dd, J = 8.1 Hz, 1H), 7.82 (d, J = 3 Hz, 1H), 7.49 (d, J = 7 Hz, 2H ), 7.35 (m, 4H), 7.23 (d, J = 3 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.65 (d, J = 9 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H ), 3.81 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19 (t, J = 7 Hz, 3H ), 0.88 (t, J = 7 Hz, 3H).
[536] B. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[537]
[538] 282 mg of 2- {3- [3- (5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 3 ml of ethanethiol (0.442 mmol) was treated with 0.56 ml (4.4 mmol) of boron trifluoride etherate for 3 hours at room temperature. The reaction mixture was diluted with water, concentrated in vacuo and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, ethyl acetate / hexanes) gave 107 mg (44%) of the title compound. ¹ H NMR (CDC1 ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.80 (d, J = 4 Hz, 1H), 7.35 (dt, J = 8.2 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J = 9.2 Hz, 1H), 7.05 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J = 9 Hz, 1H), 4.24 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 3.81 (s, 3H), 2.63 (t, J = 7 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.34 (quintet, J = 6 Hz, 2H), 1.52 ( hextet, J = 8 Hz, 2H), 1.17 (t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H); MS ES ⁺ m / e 548 (p + 1).
[539] C. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid
[540]
[541] 107 mg (0.196 mmol) of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester It was dissolved in 3 ml of a 1: 1 solution of methanol / dioxane and treated with 1 ml of 1 N lithium hydroxide solution at 60 ° C. for 2 hours. The mixture was concentrated in vacuo, the residue diluted with water, washed twice with diethyl ether and the aqueous layer acidified with 1N hydrochloric acid. The resulting solution was extracted twice with methylene chloride and the combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was triturated (hexanes) to give 72 mg (69%) of the title compound as a brown powder. ¹ H NMR (CDC1 ₃ ) δ8.22 (dd, J = 8.2 Hz, 1H), 7.70 (d, J = 4 Hz, 1H), 7.41 (dt, J = 8.2 Hz, 1H), 7.35 (s, 1H ), 7.18 (m, 3H), 6.82 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H), 6.62 (d, J = 9 Hz, 1H), 6.55 (s, 1H ), 4.22 (t, J = 6 Hz, 2H), 4.21 (t, J = 6 Hz, 2H), 2.57 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.49 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.86 (t, J = 7 Hz, 3H); MS ES ⁺ m / e 534 (p + 1); IR (KBr, cm ⁻¹ ) 2957, 1695, 1599, 1457.
[542] Anal for C ₃₀ H ₃₁ NO ₆ S: C, 67.52; H, 5.86; N, 2.62. Found: C, 67.44; H, 5.95; N, 2.55.
[543] Example 12
[544] 2- (3- {3- [4- (3,5-dimethylisoxazol-4-yl) -2-ethyl-5-hydroxyphenoxy] propoxy} -2-propylphenoxy) benzoic acid sodium salt Produce
[545]
[546] 2- (3- {3- [5-hydroxy-2-ethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane in 10 ml of deoxygenated toluene 2-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester 305 mg (0.448 mmol), 3,5-dimethyl-4-iodoisoxazole 110 mg (0.493 mmol), cesium carbonate 293 A mixture of mg (0.899 mmol) and 15 mg (0.018 mmol) of PdCl ₂ (dppf) was heated at 95 ° C. for 10 hours. Additional 110 mg of 3,5-dimethyl-4-iodoisoxazole, 260 mg of cesium carbonate and about 15 mg of PdCl ₂ (dppf) were added and heating was continued at 110 ° C. for 20 hours. The mixture was cooled to rt, concentrated in vacuo, diluted with methylene chloride and filtered over a short plug of silica gel with 20% ethyl acetate / 80% hexanes. The filtrate was concentrated in vacuo. The resulting colorless oil was dissolved in 4 ml of methylene chloride, cooled to 0 ° C. and treated with 0.40 ml (2.7 mmol) of iodotrimethylsilane. The resulting mixture was warmed to room temperature and stirred for 18 hours. 0.70 ml of additional iodotrimethylsilane was added and stirring continued for 72 hours. The mixture was poured into dilute sodium trisulfate solution. The organic layer was separated, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting foam was dissolved in 5 ml of a 1: 1 mixture of tetrahydrofuran / 1 N hydrochloric acid and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and treated with 1 equivalent of 1 N sodium hydroxide solution in ether. The resulting mixture was concentrated in vacuo to give 59 mg (23%) of the title compound as a greyish white solid. ¹ H NMR (DMSO-d ₆ ) δ 7.40 (dd, J = 9.2 Hz, 1H), 7.13 (dt, J = 8.2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H), 6.68 (d, J = 9 Hz, 1H), 6.65 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 6.21 (d, J = 8 Hz, 1H), 4.19 (t, J = 6 Hz , 2H), 4.01 (t, J = 6 Hz, 2H), 2.66 (t, J = 8 Hz, 2H), 2.48 (q, J = 8 Hz, 2H), 2.24 (s, 3H), 2.17 (quintet , J = 6 Hz, 2H), 2.07 (s, 3H), 1.49 (hextet, J = 8 Hz, 2H), 1.07 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₂ H ₃₆ N0 ₇ (p + 1): m / z = 546.2492. Found: 546.2514; IR (KBr, cm ⁻¹ ) 3400, 1605, 1460.
[547] Example 13
[548] Preparation of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt
[549] A. Preparation of 2- {3- [3- (4-bromo-2-ethyl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[550]
[551] Of 2.50 g (3.95 mmol) of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 40 ml of methylene chloride The solution was cooled to -70 ° C and treated with 0.25 ml (2.6 mmol) of boron tribromide. After 25 minutes, the mixture was poured into cold water and the resulting mixture was extracted with methylene chloride. The combined organic extracts were washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo to give 1.1 g (52%) of the title compound as a pale yellow oil. ¹ H NMR (CDC1 ₃ ) δ 7.89 (d, J = 9 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 9 Hz, 1H ), 7.08 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.68 (d, J = 9 Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 9 Hz, 1H), 5.40 (s, 1H), 4.18 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); MS ES ^- m / z = 541 (M-H), 543 (M-H + 2).
[552] B. Preparation of 2- (3- {3- [4-bromo-5- (tert-butyldimethylsilanyloxy) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[553]
[554] Of 1.00 g (1.84 mmol) of 2- {3- [3- (4-bromo-2-ethyl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 20 ml of methylene chloride The solution was treated with 0.19 g (2.8 mmol) of imidazole and 0.388 g (2.57 mmol) of tert-butyldimethylsilyl chloride for 2 hours at room temperature. The mixture is poured into water, the organic layer is separated, washed once with water, once with saturated sodium chloride solution, filtered through a shot pad of silica gel and concentrated in vacuo to give 1.1 g (91%) of the title compound as a colorless oil. Obtained as. ¹ H NMR (CDC1 ₃ ) δ 7.88 (d, J = 9 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.22 (s 1H), 7.12 (d, J = 9 Hz, 1H) , 7.08 (d, J = 2 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H), 6.45 (d, J = 9 Hz, 1H), 6.40 (s, 1H), 4.20 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 (t, J = 7 Hz, 3H), 1.03 (s , 9H), 0.89 (t, J = 7 Hz, 3H), 0.23 (s, 6H).
[555] C. Preparation of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[556]
[557] Methyl 2- (3- {3- [4-bromo-5- (tert-butyldimethylsilanyloxy) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoate in 20 ml of tetrahydrofuran A mixture of 1.05 g (1.60 mmol) of ester, 0.358 g (3.20 mmol) of furan-2-boronic acid, 0.185 g (0.160 mmol) of tetrakis (triphenylphosphine) palladium (O) and 8 ml of an aqueous 2 M sodium carbonate solution was refluxed. Heat at temperature for 18 hours. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 0.8 g (94%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ7.90 (d, J = 9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J = 8 Hz, 1H), 7.21 (s, 1H), 7.13 (s , 1H), 7.10 (d, J = 9 Hz, 1H), 7.07 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H ), 6.52 (m, 3H), 6.44 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J = 8 Hz, 2H), 2.59 (q , J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.91 (t, J = 7 Hz, 3H); ^{MS ES - m / z = 589} (p + AcO -).
[558] Anal for C ₃₂ H ₃₄ 0 ₇ : C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15.
[559] D. Preparation of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt
[560]
[561] 250 mg (0.47 mmol) of 2- {3- [3- (2-ethyl-4-furan-2-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester It was dissolved in 4 ml of furan and treated with 2 ml of 1 N lithium hydroxide solution at 50 ° C. for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed once with mole and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and shaken with 1 N hydrochloric acid. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was dissolved in diethyl ether and treated with 0.32 ml of 1 N aqueous sodium hydroxide solution. The mixture was concentrated in vacuo, sequentially azeotropic with diethyl ether, chloroform and diethyl ether and dried to give 168 mg (66%) of the title compound as a cream solid. ¹ H NMR (DMSO-d ₆ ) δ 7.56 (s, 1H), 7.44 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 7.13 (m, 1H), 6.97 (m, 2H) , 6.77 (d, J = 2 Hz, 1H), 6.65 (m, 4H), 6.48 (d, J = 2 Hz, 1H), 6.24 (d, J = 9 Hz, 1H), 4.15 (t, J = 6 Hz, 2H), 3.96 (t, J = 6 Hz, 2H), 2.66 (t, J = 8 Hz, 2H), 2.42 (q, J = 7 Hz, 2H), 2.13 (quintet, J = 6 Hz , 2H), 1.48 (hextet, J = 8 Hz, 2H), 1.09 (t, J = 7 Hz, 3H), 0.84 (t, J = 7 Hz, 3H); Exact mass calculated for TOF MS ES ⁺ C ₃₁ H ₃₃ 0 ₇ (P + 1): m / z = 517.2226. Found: 517.2230. IR (KBr, cm ⁻¹ ) 3400, 2961, 1599, 1460.
[562] Example 14
[563] Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4-furan-3-yl-phenoxy] propoxy} -2-propylphenoxy) benzoic acid
[564] A. Preparation of 2- {3- [3- (2-ethyl-4-furan-3-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[565]
[566] Methyl 2- (3- {3- [4-bromo-5- (tert-butyldimethylsilanyloxy) -2-ethylphenoxy] propoxy} -2-propylphenoxy) benzoate in 30 ml of tetrahydrofuran A mixture of 2.10 g (3.19 mmol) of ester, 0.722 g (6.45 mmol) of furan-3-boronic acid, 0.37 g (0.32 mmol) of tetrakis (triphenylphosphine) palladium (O) and 16 ml of an aqueous 2 M sodium carbonate solution was refluxed. Heated at temperature for 48 hours. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate / 85% hexanes) to give 0.29 g (17%) of the title compound as a yellow oil. Exact mass calculation for TOF MS ES ⁺ C ₃₂ H ₃₅ 0 ₇ (P + 1): m / z = 531.2383. Found: 531.2396.
[567] B. Preparation of 2- {3- [3- (2-ethyl-4-furan-3-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid sodium salt
[568]
[569] 170 mg (0.32 mmol) of 2- {3- [3- (2-ethyl-4-furan-3-yl-5-hydroxyphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester It was dissolved in 4 ml of furan and 1 ml of methanol and treated with 4 ml of 1 N lithium hydroxide solution at 50 ° C. for 2 hours. The mixture was concentrated in vacuo, the residue was acidified with hydrochloric acid and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 2% methanol / 98% chloroform) to give 45 mg of material, which was then chromatographed (silica gel, 1% methanol / 99% chloroform) to give 25 mg (155) of the title compound as an oil. Exact mass calculated for TOF MS ES ⁺ C ₃₁ H ₃₃ 0 ₇ (P + 1): m / z = 517.226. Found: 517.2230.
[570] Example 15
[571] Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid sodium salt hemihydrate
[572] A. Preparation of 2- {3- [3- (5-benzyloxy-2-ethyl-4-furan-3-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester
[573]
[574] 3.00 g (4.73 mmol) of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 40 ml of tetrahydrofuran , A mixture of 1.06 g (9.47 mmol) of furan-3-boronic acid, 0.54 g (0.47 mmol) of tetrakis (triphenylphosphine) palladium (O) and 20 ml of an aqueous 2 M sodium carbonate solution was heated at 100 ° C. for 48 hours. . The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 1.9 g (65%) of the title compound as a yellow oil. ¹ H NMR (CDC1 ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s, 1H), 7.05 (m, 2H), 6.80 (d, J = 9 Hz, 1H), 6.76 (d, J = 2 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J = 9 Hz , 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J = 8 Hz, 2H), 2.62 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 8 Hz, 2H), 1.20 (t, J = 7 Hz, 3H), 0.92 (t, J = 7 Hz, 3H); MS ES ⁺ m / z = 621 (p + 1); IR (CHC1 ₃ , cm ^-1 ) 3000, 1727, 1603, 1461.
[575] B. Preparation of 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid methyl ester
[576]
[577] 1.8 g of 2- {3- [3- (5-benzyloxy-2-ethyl-4-furan-3-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 40 ml of ethyl acetate ( 2.9 mmol) was treated with 0.39 g of palladium on 10% carbon and hydrogenated at 45 ° C., 48 psi for 72 hours. The mixture was cooled to rt, filtered through celite and the filtrate was concentrated in vacuo to give 1.2 g (77%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.57 (dt, J = 8.2 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J = 9 Hz, 1H), 6.44 (d, J = 9 Hz, 1H), 6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H), 4.02 (dd, J = 12.3 Hz, 1H), 3.88 (dd, J = 12.8 Hz, 1H), 3.84 (s, 3H ), 3.73 (q, J = 9 Hz, 1H), 3.45 (m, 1H), 2.64 (t, J = 8 Hz, 2H), 2.53 (q, J = 7 Hz, 2H), 2.38 (m, 1H ), 2.28 (quintet, J = 6 Hz, 2H), 1.99 (m, 1H), 1.55 (hextet, J = 8 Hz, 2H), 1.15 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); ^{MS ES - m / z = 593} (p + CH 3 COO -); IR (CHCl ₃ , cm ⁻¹ ) 2963, 1719, 1589, 1461.
[578] Anal for C ₃₂ H ₃₈ 0 ₇ : C, 71.89; H, 7.16. Found: C, 71.41; H, 7.06.
[579] C. 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy) benzoic acid sodium salt hemihydrate Produce
[580]
[581] 2- (3- {3- [2-ethyl-5-hydroxy-4- (tetrahydrofuran-3-yl) phenoxy] propoxy} -2-propylphenoxy in 10 ml of tetrahydrofuran and 5 ml of methanol A solution of 0.92 g (1.7 mmol) of benzoic acid methyl ester was treated with 10 ml of a 1 M lithium hydroxide solution at 55 ° C. for 2 hours. The mixture was cooled to rt and stirred for 18 h more. The mixture was concentrated in vacuo and the residual aqueous mixture was washed once with diethyl ether. The aqueous layer was acidified with concentrated sulfuric acid and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting colorless oil was dissolved in diethyl ether and treated with 1.72 ml of 1 N sodium hydroxide solution. The resulting biphasic mixture was diluted with chloroform and concentrated in vacuo. Diethyl ether was added and concentrated in vacuo. The resulting white foam was dried in vacuo at room temperature for 60 hours to give 0.78 g (84%) of the title compound: mp 67-71 ° C. ¹ H NMR (DMSO-d ₆ ) δ7.62 (dd, J = 8.2 Hz, 1H), 7.30 (dt, J = 8.2 Hz, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.73 (d, J = 9 Hz, 1H), 6.70 (d, J = 9 Hz, 1H), 6.53 (s, 1H), 6.34 (d, J = 9 Hz, 1H), 4.15 (t, J = 6 Hz , 2H), 4.04 (t, J = 6 Hz, 2H), 3.95 (m, 1H), 3.88 (m, 1H), 3.75 (q, J = 9 Hz, 1H), 3.49 (m, 2H), 2.60 (t, J = 8 Hz, 2H), 2.45 (q, J = 7 Hz, 2H), 2.15 (m, 3H), 1.90 (m, 1H), 1.48 (hextet, J = 8 Hz, 2H), 1.06 (t, J = 7 Hz, 3H), 0.83 (t, J = 7 Hz, 3H); MS ES ^- m / z = 519 (p-Na ⁺ ); IR (CHCl ₃ , cm ⁻¹ ) 2964, 1783, 1604, 1461.
[582] Anal for C ₃₁ H ₃₅ NaO ₇ .0.5 H ₂ O: C, 67.50; H, 6.58. Found: C, 67.76; H, 6.68.
[583] Example 16
[584] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid hydrochloride hydrate
[585] A. 2- (2-benzyloxy-5-ethyl-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrole-1-carboxyl Preparation of Acid Tert-Butyl Ester
[586]
[587] 3.00 g (4.73 mmol) of 2- {3- [3- (5-benzyloxy-4-bromo-2-ethylphenoxy) propoxy] -2-propylphenoxy} benzoic acid methyl ester in 60 ml of tetrahydrofuran , A mixture of 1.99 g (9.43 mmol) of N-boc pyrrole-2-boronic acid, 0.54 g (0.47 mmol) of tetrakis (triphenylphosphine) palladium (O) and 25 ml of an aqueous 2 M sodium carbonate solution at reflux for 40 hours. Heated during. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once with water and once with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate / 90% hexanes) to give 2.6 g (76%) of the title compound as a solid. ¹ H NMR (CDC1 ₃ ) δ 7.88 (dd, J = 8.2 Hz, 1H), 7.15-7.40 (m, 7H), 7.08 (m, 3H), 6.82 (d, J = 9 Hz, 1H), 6.68 (d, J = 9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 6.23 (t, J = 4 Hz, 1H), 6.12 (m, 1H), 4.95 (s, 2H), 4.20 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 2.66 (t, J = 8 Hz, 2H), 2.60 (q, J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 8 Hz, 2H), 1.28 (s, 9H), 1.18 (t, J = 7 Hz , 3H), 0.93 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOS MS ES ⁺ C ₄₄ H ₅₃ N ₂ 0 ₈ (p + NH ₄ ⁺ ): m / z = 737.3802. Found: 737.3804; IR (CHC1 ₃ , cm ^-1 ) 2964, 1730, 1461.
[588] Anal for C ₄₄ H ₄₉ NO ₈ : C, 73.41; H, 6. 86; N, 1.94. Found: C, 73.76; H, 6.76; N, 2.04.
[589] B. 2- (5-ethyl-2-hydroxy-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrolidine-1- Preparation of Carboxylic Acid Tert-Butyl Ester
[590]
[591] 2- (2-benzyloxy-5-ethyl-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] propoxy} phenyl) pyrrole-1 in 40 ml of ethyl acetate A solution of 0.98 g (1.4 mmol) of carboxylic acid tert-butyl ester was treated with 0.98 g of palladium on 10% carbon and hydrogenated at 45 ° C., 25 hours at 48 psi, 20 hours at room temperature, then 19 hours at 45 ° C. It was. The mixture was cooled to rt, filtered through celite and the filtrate was concentrated in vacuo to give 0.76 g (88%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.87 (dd, J = 8.2 Hz, 1H), 7.37 (dt, J = 8.2 Hz, 1H), 7.10 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.91 (s, 1H), 6.81 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.47 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 5.09 (m, 1H), 4.18 (d, J = 6 Hz, 2H), 4.14 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 3.45 (m, 2H ), 2.64 (t, J = 8 Hz, 2H), 2.54 (m, 3H), 2.25 (m, 5H), 2.06 (m, 1H), 1.54 (hextet, J = 8 Hz, 2H), 1.43 (s , 9H), 1.15 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H).
[592] C. 2- (4- {3- [3- (2-carboxyphenoxy) -2-propylphenoxy] propoxy} -5-ethyl-2-hydroxyphenyl) pyrrolidine-1-carboxylic acid Preparation of tert-butyl ester lithium salt hydrate
[593]
[594] 2- (5-ethyl-2-hydroxy-4- {3- [3- (2-methoxycarbonylphenoxy) -2-propylphenoxy] in 4 ml of a 1: 1 mixture of methanol / tetrahydrofuran] A solution of 0.114 g (0.18 mmol) of propoxy} phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester was treated with 4 ml of a 1 M lithium hydroxide solution for 18 hours at room temperature. The mixture was concentrated in vacuo and the residue dissolved in water. The resulting mixture was extracted with ethyl acetate. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo. The residue was diluted with diethyl ether, concentrated in vacuo and dried to give 90 mg (78%) of the title compound. MS ES ⁺ m / z = 620 (p + 1-Li ⁺ ); IR (KBr, cm ⁻¹ ) 2964, 1672, 1603, 1416.
[595] Anal for C ₃₆ H ₄₄ NO ₈ LiH ₂ 0: C, 67.17; H, 7. 20; N, 2.18. Found: C, 66.72; H, 6. 99; N, 2.27.
[596] D. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid hydrochloride hydrate
[597]
[598] 2- (4- {3- [3- (2-carboxyphenoxy) -2-propylphenoxy] propoxy} -5-ethyl-2-hydroxyphenyl) pyrrolidine in 5 ml of anhydrous diethyl ether Gas HCl was bubbled into a solution of 0.100 g (0.16 mmol) of 1-carboxylic acid tert-butyl ester lithium salt hydrate. The resulting mixture was stirred for 1 hour. The mixture was concentrated in vacuo. The residue was chromatographed (SCX cation exchange resin, 1: 1 tetrahydrofuran / methanol to dilute ammonia / methanol) to give a brown solid. This material was dissolved in ether and treated with gaseous HCl. This mixture was concentrated in vacuo to give 48 mg (52%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ 12.80 (bs, 1H), 10.12 (s, 1H), 9.34 (bs, 1H), 8.36 (bs, 1H), 7.79 (dd, J = 9.2 Hz, 1H) , 7.47 (dt, J = 8.2 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 7.12 (d, J = 9 Hz, 1H), 7.07 (s, 1H), 6.80 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.58 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.56 (m, 1H), 4.20 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.25 (m, 2H), 2.50 (m, 5H), 1.90-2.60 (m, 5H), 1.44 (hextet, J = 8 Hz, 2H), 1.08 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H); Accurate mass calcd. For TOS MS ES ⁺ C ₃₁ H ₃₈ NO ₆ (p + 1): m / z = 520.2699. Found: 520.2672.
[599] Example 17
[600] Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-3-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid hydrate
[601] A. Preparation of 3- [2-benzyloxy-4- (3-chloropropoxy) -5-ethylphenyl] thiophene
[602]
[603] Known Compounds:
[604] Sawyer et al., J. Med. Chem. 1995, 38, 4411.
[605] 1.90 g (5.30 mmol) of 4- (benzyloxy) -5-bromo-2- (3-chloropropoxy) ethylbenzene in 16 ml of toluene, 2.00 g (15.9 mmol) of 3-thiophenboronic acid, tetrakis ( A mixture of 312 mg (0.270 mmol) of triphenylphosphine) palladium (O), 4 ml of 2 M aqueous sodium carbonate solution and 4 ml of n-propanol was refluxed for 4 hours. The mixture was cooled to rt, diluted with diethyl ether, washed once with water and once with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 5% ethyl acetate / 95% hexanes) to give 1.54 g (80%) of the title compound as a white solid. ¹ H NMR (CDC1 ₃ ) δ 7.58 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.45-7.30 (m, 7H), 6.62 (s, 1H), 5.13 (s, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.29 (quintet, J = 6.0 Hz , 2H), 1.24 (t, J = 7.5 Hz, 3H); MS FD m / e 386 (p); IR (CHCI ₃ , cm ⁻¹ ) 2969, 1613, 1501, 1138.
[606] Anal for C ₂₂ H ₂₃ 0 ₂ C1S: C, 68.29; H, 5.99. Found: C, 68.53; H, 6.00.
[607] B. Preparation of 2- [2-propyl-3- [3- [5- (benzyloxy) -2-ethyl-4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile
[608]
[609] 1.25 g (3.23 mmol), 3- (2-cyano) 4- (benzyloxy) -2- (3-chloropropoxy) -5- (thiophen-3-yl) ethylbenzene in 10 ml of 2-butanone A mixture of 0.82 g (3.2 mmol) of phenoxy) -2-propylphenol, 0.21 g (1.3 mmol) of potassium iodide, 1.12 g (8.08 mmol) of potassium carbonate and 2 ml of methyl sulfoxide was refluxed for 60 hours. The mixture was cooled to rt, diluted with ether and washed with water. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was chromatographed (silica gel, 5% ethyl acetate / 95% hexanes) to give 1.31 g (67%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.45-7.25 (m , 8H), 7.20 (t, J = 8.2 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H ), 6.64 (s, 1H), 6.63 (d, J = 6.4 Hz, 1H), 5.11 (s, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H ), 2.65 (m, 4H), 2.36 (quintet, J = 5.9 Hz, 2H), 1.58 (hextet, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H); MS FD m / e 603 (p); IR (CHC1 ₃ , cm ⁻¹ ) 2967, 2250, 1613, 1501. Anal. For C ₃₈ H ₃₇ NO ₄ S: C, 75.59; H, 6. 18; N, 2.32. Found: C, 74.65; H, 6. 21; N, 2.57.
[610] C. Preparation of 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] benzonitrile
[611]
[612] 2- [2-propyl-3- [3- [5- (benzyloxy) -2-ethyl-4- (thiophen-3-yl) phenoxy] propoxy in 25 ml of methylene chloride cooled to −78 ° C. To a solution of 900 mg (1.49 mmol) of] phenoxy] benzonitrile was added 2.99 ml (2.99 mmol) of a 1 M boron tribromide solution in methylene chloride over 2 minutes. The resulting dark purple solution was stirred for 30 minutes and warmed to room temperature. The mixture was diluted with water and shaken. The organic layer was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 25% ethyl acetate / 75% hexanes) gave 400 mg (52%) of the title compound as a colorless oil. ¹ H NMR (CDC1 ₃ ) δ 7.84 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H ), 7.42 (t, J = 7.1 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 7.20 (s, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.85 (s, 1H ), 6.89 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H, -OH), 4.26 ( t, J = 6.0 Hz, 4H), 2.72 (q, J = 7.4 dHz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.39 (quintet, J = 6.1 Hz, 2H), 1.54 (hextet, J = 7.7 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H).
[613] D. Preparation of 2- {3- [3- (2-ethyl-5-hydroxy-4-thiophen-3-yl-phenoxy) propoxy] -2-propylphenoxy} benzoic acid hydrate
[614]
[615] 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (thiophen-3-yl) phenoxy] propoxy] phenoxy] in 6 ml of 2: 1 methanol / water] A solution of 400 mg (0.780 mmol) of benzonitrile was treated with 4.0 ml of an aqueous 12.5 M sodium hydroxide solution at reflux for 36 hours. The mixture was cooled to rt, diluted with water and extracted once with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined methylene chloride layers were dried (magnesium sulfate), filtered and concentrated in vacuo to give a brown solid: mp 90-95 ° C. (dec). ¹ H NMR (CDC1 ₃ ) δ8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.36 (d, J = 3 Hz, 1H), 7.24 (d, J = 4.9 Hz, 1H), 7.19 (m, 2H), 7.09 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 5.38 (bs, 1H, -OH), 4.26 (t, J = 6.2 Hz, 2H), 4.21 ( t, J = 7.1 Hz, 2H), 2.60 (m, 4H), 2.36 (quintet, J = 5.8 Hz, 2H), 1.51 (hextet, J = 7.1 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); MS FD m / e 532 (p); IR (KBr, cm ⁻¹ ) 3200 (br), 2961, 1697, 1457, 1110. Anal. For C ₃₁ H ₃₂ 0 ₆ SH ₂ 0: C, 67.62; H, 6.22. Found: C, 67.34; H, 5.87.
[616] The LTB ₄ antagonists and anticancer agents described above used in the compositions and methods of the present invention are often advantageously used in the form of salt derivatives which are additional aspects of the present invention. When the compounds of the present invention have acidic group (s) or other reactive groups, salts that are more water soluble and / or physiologically suitable than the parent compound in its acid form may be formed. Representative pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. Sodium salt is particularly preferred. Salts are conveniently prepared from the free acid by treating the acid form in solution with a base or exposing the acid to an ion exchange resin. For example, the acidic group Z in formula (I) may be selected as —CO ₂ H and may form salts by reaction with a suitable base (eg, NaOH, KOH) to produce the corresponding sodium or potassium salts. .
[617] Inorganic and organic base additions of compounds of the invention, such as ammonium, quaternary ammonium, and relatively nontoxic, such as amine cations derived from a nitrogenous base having a basic enough salt to form a salt with the LTB ₄ antagonist compound of the invention Salts are included within the definition of pharmaceutically acceptable salts (see, eg, SM Berge et al., “Pharmaceutical Salts,” J. Phar. Sci. , 66: 1-19 (1977)). Some compounds of the present invention may have one or more chiral centers and, therefore, may exist in optically active forms. All such stereoisomers and mixtures thereof are construed as being included in the present invention. For the purpose of specific stereoisomers, methods well known in the art, for example, using stereospecific reactions with starting materials containing asymmetric centers and already separated, or generating mixtures of stereoisomers It can manufacture by the method of separating by a well-known method. For example, the racemic mixture can be reacted with a single enantiomer of any other compound. This changes the racemic form into a mixture of diastereomers. The diastereomers then have different melting points, different boiling points and different solubilities and can therefore be separated by conventional means such as crystallization.
[618] The prodrugs of LTB ₄ antagonists and anticancer compounds used in the present invention have a chemically or metabolically cleavable group and result in a compound of the present invention which is pharmaceutically active in vivo by solvolysis or under physiological conditions. Derivatives. Derivatives of the compounds of the invention have activity in both acid and base derivative forms, but acid derivative forms often provide the advantages of solubility, histocompatibility or delayed release in mammals (Bundgard, H., Design of Prodrugs, 7 -9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by the reaction of a parent acid compound with a suitable alcohol, or amides prepared by the reaction of a parent acid compound with a suitable amine. Single aliphatic or aromatic esters derived from acidic groups present on the compounds of the invention are preferred prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl and N, N-diethylglycolamido.
[619] Esters of carboxylic acids are preferred prodrugs of the compounds of the compositions of the present invention.
[620] Methyl ester prodrugs can be prepared by reacting the acid form of the compound of formula (I) in a medium such as methanol with an acid or base esterification catalyst (eg, NaOH, H ₂ SO ₄ ). Ethyl ester prodrugs are prepared in a similar manner using ethanol instead of methanol.
[621] N, N-diethylglycolamido ester prodrug is used to prepare the sodium salt of a compound of formula (I) (in a medium such as dimethylformamide) in 2-chloro-N, N-diethylacetamide Available from Drich Chemical Corporation; can be prepared by reacting with Product No. 25,099-6).
[622] The morpholinylethyl ester prodrug is obtained from the sodium salt of the compound of formula (I) (in a medium such as dimethylformamide) from 4- (2-chloroethyl) morpholine hydrochloride (Aldrich Chemical Corporation, Milwaukee, WI) Yes, can be prepared by reacting with product number: C4,220-3).
[623] Preferred LTB ₄ compounds and anticancer compounds of the present invention are compounds wherein the acid, salt and prodrug derivatives thereof are carboxylic acids, sodium salts and ester prodrugs, respectively.
[624] The composition of the present invention is a combination of a therapeutically effective amount of the leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of the anticancer agent. The compositions may be formulated with conventional excipients, diluents or carriers, compressed into tablets, formulated in convenient oral elixirs or solutions, or administered by the intravenous intravenous route. The compound may be administered transdermally and may be formulated as a sustained release formulation or the like.
[625] In another embodiment, the present invention relates to a method for treating a patient suffering from non-multidrug resistant cancer disease comprising separately administering a therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and an anticancer agent. When administered separately, leukotriene (LTB ₄ ) antagonists and anticancer agents may be administered on different schedules. As long as the time between the two administrations falls within the therapeutically effective interval, one may be administered before the other. The therapeutically effective interval is the period from when (a) the anticancer agent or (b) the LTB ₄ antagonist is administered to a human to the limit of the beneficial effect of the combination of (a) and (b) in the treatment of cancer. The method of administering leukotriene (LTB ₄ ) antagonist and anticancer agent may vary. Thus, one drug can be administered orally and the other drug can be administered intravenously. One of the products may be administered in a continuous infusion and the other may be provided in a separate formulation. It is particularly important that the anticancer agent be provided in a manner known to optimize its performance.
[626] Pharmaceutical Compositions of the Invention
[627] Preferably the compounds of the present invention or pharmaceutical compositions containing these compounds are unit dosage forms for mammalian administration. The unit dosage form may be a capsule, IV bag, tablet or vial. The amount of active ingredient in a unit dose of the composition is a therapeutically effective amount and can vary depending on the particular treatment involved. It will be appreciated that it may be necessary to make customary changes in dosage depending on age and the condition of the patient. The dosage will also depend on the route of administration.
[628] The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.
[629] Pharmaceutical compositions of the invention may be used in a pharmaceutically acceptable carrier or pharmaceutical composition for treating a therapeutically effective amount of an anticancer agent (eg, 2 ′, 2′-difluoronucleoside) and an LTB ₄ antagonist (eg, Formula A, Formula I, II) or Prepared by combining (eg mixing) with a diluent. The present pharmaceutical compositions are prepared by known methods using well known and readily available ingredients.
[630] In preparing the compositions of the present invention, the active ingredient will usually be contained in a carrier which may be mixed with the carrier, diluted by the carrier or in the form of a capsule, sachet, paper or other container. When the carrier acts as a diluent, it may be a solid, frozen solid or paste, semisolid, or liquid acting as a vehicle, or it may contain, for example, tablets, pills, powders, containing up to 10% by weight of active compound, Lozenges, elixirs, suspensions, emulsions, solutions, syrups, injections, aerosols (solid or liquid media) or ointments. The compounds of the present invention are preferably formulated prior to administration.
[631] In pharmaceutical compositions, any suitable carrier known in the art may be used. In such compositions, the carrier may be a solid, liquid, or a mixture of solids and liquids. For example, for intravenous injection, the compounds of the present invention may contain about 0.05 to about 5.0 mg / ml of sugar and / or buffer in sterile water, sterile physiological fluids, or aqueous 4% dextrose / 0.5% sodium citrate solution. Can be dissolved in sterile water or physiological fluids.
[632] Solid compositions include powders, tablets, and capsules. The solid carrier can be one or more materials that can also serve as flavors, lubricants, solubilizers, suspending agents, binders, disintegrants and encapsulating materials.
[633] Tablets for oral administration include calcium carbonate, sodium carbonate, lactose, phosphoric acid, with disintegrants such as corn, starch or alginic acid, and / or binders such as gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. It may contain a suitable excipient such as calcium.
[634] In powders, the carrier is a finely divided solid mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[635] Advantageously, a composition containing a compound of formula (I) preferably contains about 5 to about 500 mg of each dosage unit (about 5 to 50 mg for parenteral or inhaled administration, about 25 for oral or rectal administration). To 500 mg) in the form of dosage units containing the active ingredient. Of course, it will be readily appreciated that the amount of the compound of formula (I) to be administered in practice will be determined by the attending physician in light of all relevant circumstances, but the dosage of about 0.5 to about 300 mg / kg per day, preferably 0.5 To 20 mg / kg of active ingredient may be administered.
[636] The powders and tablets preferably contain about 1 to about 99% by weight of the active ingredient, which is a novel compound of the present invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melt wax and cocoa butter.
[637] Sterile solutions include suspending agents, emulsions, syrups and elixirs.
[638] The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvents or mixtures thereof. "Pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other ingredients in the composition and should not be harmful to its recipient.
[639] The active ingredient can also be dissolved in a suitable organic solvent such as aqueous propylene glycol. Other compositions can be prepared by dispersing the finely divided active component in starch or aqueous sodium carboxymethyl cellulose solution or a suitable oil.
[640] The following pharmaceutical compositions 1 to 22 are exemplary only and are not intended to limit the scope of the invention. "Active ingredient" refers to a 2 ', 2'-difluoronucleoside or a compound of formula A, formula (I) or (II), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
[641] In one embodiment, the composition of the present invention is a combination of a therapeutically effective amount of said leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of a 2 ', 2'-difluoronucleoside anticancer agent. The compositions may be formulated with conventional excipients, diluents or carriers, compressed into tablets, formulated in convenient oral elixirs or solutions, or administered by the intravenous intravenous route. The compound may be administered transdermally and may be formulated as a sustained release formulation or the like.
[642] In another embodiment, the 2 ', 2'-difluoronucleoside anticancer agent is formulated independently of the leukotriene (LTB ₄ ) antagonist and administered separately. The anticancer agent may be formulated with conventional excipients, diluents or carriers and administered by intravenous infusion. On the other hand, the anticancer agent may be formulated in a liquid suitable for oral administration. The anticancer agent can also be administered orally in a compressed tablet. If the anticancer agent and the leukotriene (LTB ₄ ) antagonist are administered separately, the anticancer agent may be administered before, after or during the administration of the leukotriene (LTB ₄ ) antagonist. If anticancer agents are administered separately from leukotriene (LTB ₄ ) antagonists, they should be administered within a therapeutically effective interval.
[643] This is the treatment of human patients the method according to the invention leukotrienes (LTB ₄₎ antagonists and includes both the administration of a combination of anticancer drugs, and leukotrienes (LTB ₄₎ separate administration of the antagonist and anti-cancer agents. When administered separately, the leukotriene (LTB ₄ ) antagonist is, for example, 1-10% by weight of the activity in tablets, lozenges, sublingual tablets, sachets, capsules, elixirs, gels, suspensions, aerosols, for example suitable substrates. Oral and rectal routes, topical, in the form of ointments, soft and hard gelatin capsules containing the compound, suppositories, injections and suspensions in physiologically acceptable media, and sterile packaging powders absorbed on support materials for the preparation of injections , Parenteral (eg, injection, and continuous or discontinuous intraarterial infusion). Advantageously for this purpose, the composition has a formula (I) of about 5 to about 500 mg (about 5 to 50 mg for parenteral or inhaled administration and about 25 to 500 mg for oral or rectal administration). Or in the form of dosage units containing a compound of formula (II). Of course, it will be readily understood that the amount of the compound of formula (I) to be administered in practice will be determined by the attending physician in light of all relevant circumstances including the disease to be treated, the choice of compound to be administered and the choice of route of administration. Doses of about 0.5 to about 300 mg / kg per day, preferably 0.5 to 20 mg / kg of active ingredient, may be administered, and thus the preferred range of administration is not intended to limit the scope of the invention.
[644] Compositions useful for the separate administration of a leukotriene (LTB ₄ ) antagonist are generally ingestible carriers or ampoules mixed with the carrier, diluted by the carrier, or in the form of capsules, sachets, cachets, paper or other containers. It will consist of one or more compounds selected from compounds of Formula A and Formula I contained by the same disposable container. The carrier or diluent can be a solid, semisolid or liquid which acts as a vehicle, excipient or medium for the active therapeutic substance. Some examples of diluents or carriers that may be used in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, Calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starch, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, theobroma oil, peanut oil, alginate, tragacanth, gelatin , Syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate, oleyl alcohol, and trichloromonofluoro Propellants such as methane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, lubricants may be incorporated to prevent the attachment and bonding of the powdered components on the dies and punches of the tablet press. For this purpose, for example aluminum stearate, magnesium or calcium, talc or mineral oil can be used.
[645] Preferred formulations of the invention are capsules, tablets, suppositories, injections, creams and ointments. Inhalation preparations such as aerosols, and oral preparations are particularly preferred.
[646] The following formulation examples can use any of the above leukotriene (LTB ₄ ) antagonists as active ingredient. The examples are illustrative only and are not intended to limit the scope of the invention.
[647] Formulation Example 1
[648] Hard gelatin capsules were prepared using the following ingredients:
[649] Volume (mg / capsule)
[650] 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)
[651] Propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid250
[652] Starch 200
[653] Magnesium Stearate 10
[654] The ingredients were mixed and filled into 460 mg doses of hard gelatin capsules.
[655] Formulation Example 2
[656] Tablets were prepared using the following ingredients:
[657] Volume (mg / tablet)
[658] 1- (4- (carboxymethoxy) phenyl) -1- (lH-tetrazol-5-yl)-
[659] 6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane250
[660] Microcrystalline Cellulose 400
[661] Fumed Silicon Dioxide 10
[662] Magnesium Stearate 5
[663] The components were mixed and compression molded of 665 mg weight tablets each.
[664] Formulation Example 3
[665] An aerosol solution was prepared containing the following ingredients:
[666] weight%
[667] 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluoro
[668] Phenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propanoic acid0.25
[669] Ethanol 30.00
[670] Propellant 11 (trichlorofluoromethane)
[671] Propellant 12 (dichlorodifluoromethane)
[672] Propellant 114 (dichlorotetrafluoroethane)
[673] The active compound was dissolved in ethanol and the solution was added to propellant 11 cooled to −30 ° C. and transferred to the filling apparatus. The required amount was supplied to the vessel and further charged with propellants 12 and 114 which were premixed by cold-filling or press-filling. The valve unit was then fitted to the vessel.
[674] Formulation Example 4
[675] Tablets containing 60 mg of active ingredient each were prepared as follows:
[676] 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl)
[677] Phenoxy] propoxy] phenoxy] benzoic acid sodium salt 60 mg
[678] Starch45 mg
[679] Microcrystalline Cellulose35 mg
[680] Polyvinylpyrrolidone (10% aqueous solution) 4 mg
[681] Sodium Carboxymethyl Starch4.5 mg
[682] Magnesium Stearate0.5 mg
[683] Talc1 mg
[684] 150 mg total
[685] The active ingredient, starch and cellulose are no. Passed through a 45 mesh U. S. sieve (355 μm) and mixed well. The polyvinylpyrrolidone solution was mixed with the resulting powder and then No. Passed through a 14 mesh U. S. sieve (1.4 mm). The resulting granules were dried at 50 to 60 ° C. and No. Passed through an 18 mesh U. S. sieve (1.00 mm). No. in advance Sodium carboxymethyl starch, magnesium stearate and talc, which were passed through a 60 mesh U. S. sieve (250 μm), were added to the granules, mixed, and then compressed into a tablet press to obtain tablets each weighing 150 mg.
[686] Formulation Example 5
[687] Capsules containing 80 mg of medicament each were prepared as follows:
[688] 5- [3- [2- (l-carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluoro
[689] Phenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentinic acid 80 mg
[690] Starch59 mg
[691] Microcrystalline Cellulose59 mg
[692] Magnesium stearate2 mg
[693] 200 mg total
[694] The active ingredient, cellulose, starch and magnesium stearate are mixed, Passed through a 45 mesh U. S. sieve (355 μm) and filled into a 200 mg dose of hard gelatin capsules.
[695] Formulation Example 6
[696] Suppositories containing 225 mg of active ingredient each are prepared as follows:
[697] 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy)
[698] Propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalene-
[699] 1 (2H) -one) propanoic acid 225 mg
[700] Total up to 2,000 mg of unsaturated or saturated fatty acid glycerides
[701] Active ingredient No. Passed through a 60 mesh U. S. sieve (250 μm) and suspended in pre-melted fatty acid glycerides using a minimum amount of heat. The mixture was poured into a suppository mold of nominal 2 g capacity and cooled.
[702] Formulation Example 7
[703] Suspensions containing 50 mg of medicament each 5 ml dose were prepared as follows:
[704] 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxy
[705] Phenoxy] propoxy] phenoxy] benzoic acid 50 mg
[706] Sodium Carboxymethyl Cellulose50 mg
[707] Per 1 g
[708] Methyl Paraben0.05 mg
[709] Propyl Paraben0.03 mg
[710] Appropriate amount of spices
[711] Coloring agent
[712] Add up to 5 ml of purified water
[713] No. It was passed through a 45 mesh U. S. sieve (355 μm) and mixed with sodium carboxymethyl cellulose, sugar and an amount of water to form a suspending agent. Parabens, flavors and colorants were dissolved and diluted by the addition of a certain amount of water with stirring. Sufficient water was added until the required volume was obtained.
[714] Formulation Example 8
[715] Hard gelatin capsules were prepared using the following ingredients:
[716] Volume (mg / capsule)
[717] 1- (4-amino-5-methyl-2oxo-1H-pyrimidin-1-yl) -2-desoxy
[718] -2,2'-difluororibose250
[719] Starch Anhydrous 200
[720] Magnesium Stearate 10
[721] The ingredients were mixed and filled into 460 mg doses of hard gelatin capsules.
[722] Formulation Example 9
[723] Tablets were prepared using the following ingredients:
[724] Volume (mg / tablet)
[725] 1- (2-oxo-4-amino-1 H-pyrimidin-1-yl) -2-desoxy
[726] -2,2'-difluororibose250
[727] Microcrystalline Cellulose 400
[728] Fumed Silicon Dioxide 10
[729] Stearic Acid 5
[730] The ingredients were mixed and compression molded of 665 mg weight tablets each.
[731] Formulation Example 10
[732] The erosol solution was prepared using the following ingredients:
[733] weight%
[734] 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy
[735] -2,2'-difluororibose0.25
[736] Ethanol29.75
[737] Propellant 22 (Chlorodifluoromethane) 70.00
[738] The active compound was mixed with ethanol and the mixture was added to an amount of propellant 22 cooled to −30 ° C. and transferred to the filling apparatus. The required amount was placed in a stainless steel container and diluted with the remaining propellant. The valve unit was fitted to the container.
[739] Formulation Example 11
[740] Tablets containing 60 mg of active ingredient each were prepared as follows:
[741] 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy
[742] -2,2'-difluororibose60 mg
[743] Starch45 mg
[744] Microcrystalline Cellulose35 mg
[745] Polyvinylpyrrolidone (10% aqueous solution) 4 mg
[746] Sodium Carboxymethyl Starch4.5 mg
[747] Magnesium Stearate0.5 mg
[748] Talc1 mg
[749] Difluoronucleosides, starch and cellulose were No. Pass through a 45 mesh U. S. sieve and mix well. The polyvinylpyrrolidone solution was mixed with the resulting powder and then No. Passed through a 45 mesh U. S. sieve. The resulting granules were dried at 50 to 60 ° C. and No. Passed through an 18 mesh U. S. sieve. No. in advance Sodium carboxymethyl starch, magnesium stearate and talc, which were passed through a 60 mesh U. S. sieve, were added to the granules, which were mixed and then compressed with a tablet press to obtain tablets each weighing 150 mg.
[750] Formulation Example 12
[751] Capsules containing 80 mg of medicament each were prepared as follows:
[752] 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy
[753] -2,2'-difluoroxylose80 mg
[754] Starch59 mg
[755] Microcrystalline Cellulose59 mg
[756] Magnesium stearate2 mg
[757] The active ingredient, cellulose, starch and magnesium stearate are mixed, It was passed through a 45 mesh U. S. sieve and filled into a 200 mg dose of hard gelatin capsule.
[758] Formulation Example 13
[759] Suppositories containing 225 mg of nucleosides each were prepared as follows:
[760] 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy
[761] -2,2'-difluororibose225 mg
[762] Add up to 2 g of saturated fatty acid glycerides
[763] Nucleoside to No. Passed through a 60 mesh U. S. sieve and suspended in pre-melted saturated fatty acid glycerides using a minimum amount of heat. The mixture was poured into a suppository mold of nominal 2 g capacity and cooled.
[764] Formulation Example 14
[765] Suspensions containing 50 mg of medicament each 5 ml dose were prepared as follows:
[766] 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy
[767] -2,2'-difluororibose50 mg
[768] Sodium Carboxymethyl Cellulose50 mg
[769] Syrup1.25 ml
[770] Benzoic acid solution0.10 ml
[771] Appropriate amount of spices
[772] Coloring agent
[773] Add up to 5 ml of purified water
[774] Formulation Example 15
[775] Intravenous formulations were prepared as follows:
[776] 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy
[777] -2,2'-difluororibose100 mg
[778] 1000 ml of isotonic saline
[779] A solution of these components was administered intravenously to a mammal in need of treatment from a diseased neoplastic tumor at a rate of 1 ml / min.
[780] Formulation Example 16
[781] Hard gelatin capsules were prepared using the following ingredients:
[782] Volume (mg / capsule)
[783] 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)
[784] Propoxy) -6- (4-carboxyphenoxy) phenyl) propanoic acid250
[785] 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride 250
[786] Starch 200
[787] Magnesium Stearate 10
[788] The ingredients were mixed and filled into 710 mg doses of hard gelatin capsules.
[789] Formulation Example 17
[790] Tablets were prepared using the following ingredients:
[791] Volume (mg / tablet)
[792] 1- (4- (carboxymethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6-
[793] (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane250
[794] 2 ', 2'-difluoro-2'-deoxycytidine monochloride 250
[795] Microcrystalline Cellulose 400
[796] Fumed Silicon Dioxide 10
[797] Magnesium Stearate 5
[798] The ingredients were mixed and each 915 mg weight tablet was compression molded.
[799] Formulation Example 18
[800] The eosol solution was prepared using the following ingredients:
[801] weight%
[802] 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluoro
[803] Phenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propanoic acid0.25
[804] 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride0.25
[805] Ethanol 30.00
[806] Propellant 11 (trichlorofluoromethane) 10.00
[807] Propellant 12 (dichlorodifluoromethane)
[808] Propellant 114 (dichlorotetrafluoroethane)
[809] The active compound was dissolved in ethanol and the solution was added to propellant 11 cooled to −30 ° C. and transferred to the filling apparatus. The required amount was supplied to the vessel and further charged with propellants 12 and 114 which were premixed by cold-filling or press-filling. The valve unit was fitted to the container.
[810] Formulation Example 19
[811] Tablets containing 60 mg of active ingredient each were prepared as follows:
[812] 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluoro
[813] Phenyl) phenoxy] propoxy] phenoxy] benzoic acid sodium salt 60 mg
[814] 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride60 mg
[815] Starch45 mg
[816] Microcrystalline Cellulose35 mg
[817] Polyvinylpyrrolidone (10% aqueous solution) 4 mg
[818] Sodium Carboxymethyl Starch4.5 mg
[819] Magnesium Stearate0.5 mg
[820] Talc1 mg
[821] Total 210 mg
[822] The active ingredient, starch and cellulose are no. Passed through a 45 mesh U. S. sieve (355 μm) and mixed well. The polyvinylpyrrolidone solution was mixed with the resulting powder and then No. Passed through a 14 mesh U. S. sieve (1.4 mm). The resulting granules were dried at 50 to 60 ° C. and No. Passed through an 18 mesh U. S. sieve (1.00 mm). No. in advance Sodium carboxymethyl starch, magnesium stearate and talc, which were passed through a 60 mesh U. S. sieve (250 µm), were added to the granules, mixed, and then compressed into a tablet press to obtain tablets each weighing 210 mg.
[823] Formulation Example 20
[824] Capsules containing 80 mg of medicament each were prepared as follows:
[825] 5- [3- [2- (l-carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluoro
[826] Phenyl) -5-hydroxyphenoxy] propoxy] phenyl] -4-pentinic acid 80 mg
[827] 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride80 mg
[828] Starch59 mg
[829] Microcrystalline Cellulose59 mg
[830] Magnesium stearate2 mg
[831] 280 mg total
[832] The active ingredient, cellulose, starch and magnesium stearate are mixed, Passed through a 45 mesh U. S. sieve (355 μm) and filled into a 280 mg dose of hard gelatin capsule.
[833] Formulation Example 21
[834] Suppositories containing 225 mg of active ingredient each are prepared as follows:
[835] 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy)
[836] Propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalene
[837] -1 (2H) -one) propanoic acid225 mg
[838] 2 ', 2'-difluoro-2'-deoxycytidine monochloride225 mg
[839] Total up to 2,000 mg of unsaturated or saturated fatty acid glycerides
[840] Active ingredient No. Passed through a 60 mesh U. S. sieve (250 μm) and suspended in pre-melted fatty acid glycerides using a minimum amount of heat. The mixture was poured into a suppository mold of nominal 2 g capacity and cooled.
[841] Formulation Example 22
[842] Suspensions containing 50 mg of medicament each 5 ml dose were prepared as follows:
[843] 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl)-
[844] 5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid 50 mg
[845] 2 ', 2'-difluoro-2'-deoxycytidine monohydrochloride50 mg
[846] Sodium Carboxymethyl Cellulose50 mg
[847] Per 1 g
[848] Methyl Paraben0.05 mg
[849] Propyl Paraben0.03 mg
[850] Appropriate amount of spices
[851] Coloring agent
[852] Add up to 5 ml of purified water
[853] No. Suspensions were prepared by passing through a 45 mesh U. S. sieve (355 μm) and mixing with sodium carboxymethyl cellulose, sugars and an amount of water. Parabens, flavors and colorants were dissolved and diluted by the addition of a certain amount of water with stirring. Sufficient water was added until the required volume was obtained.
[854] Pharmaceutical Compositions of the Invention
[855] The pharmaceutical composition of the present invention comprises an essential component of (a) LTB ₄ antagonist and (b) anticancer agent.
[856] When the pharmaceutical composition of the invention is prepared in injectable form, it comprises (a) LTB ₄ antagonist, (b) anticancer agent and (c) injectable liquid carrier. Pharmaceutically acceptable carriers are those well known in the art of pharmacy, such as sterile water, sterile water containing saline, and sterile water containing sugar and / or saline.
[857] Ratios and Amounts of Components in Compositions of the Invention
[858] Essential ingredients (a) LTB ₄ antagonist and (b) anticancer compound are present in the formulation in such a proportion that the dose of the formulation provides a pharmaceutically effective amount of each component to the patient to be treated. In general, the weight ratio of LTB ₄ antagonist to anticancer agent is from 1: 100 to 100: 1, preferably from 10: 1 to 1:10, most preferably from 1: 4 to 4: 1.
[859] Leukotriene (LTB ₄ ) antagonists are generally administered before, during or after administration of the 2 ′, 2′-difluoronucleoside anticancer agent. If leukotriene (LTB ₄ ) antagonists are administered after 2 ', 2'-difluoronucleoside anticancer agents, they should be administered within therapeutically effective intervals.
[860] Analytical Example 1
[861] Nude mouse xenograft trials used to evaluate anticancer agents of the invention are well known and are described in Beverly A Teicher, Editor, Anticancer Drug Development Guide , Humana Press, Totowa, NJ, 1997, pp. 75-124 (ISBN 0 -89603-461-5); The disclosures of which are incorporated herein by reference in their entirety. Xenograft testing is described in more detail as follows:
[862] Male or female nude mice (CharlesRiver) selected to be suitable for cancer sex were treated with systemic gamma irradiation (450 rads). After 24 hours, human LNCaP and DU-145 prostate carcinomas, Panc-1 and BxPC-3 pancreatic carcinomas, and H460 and Calu-6 non-small cell lungs, prepared from the cancer donor's brie (5 × 10 ⁶ cells) Carcinoma (all carcinomas available from the American Type Culture Collection, Manassas, VA) were implanted subcutaneously in the hind limbs of mice. Mice were treated with 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] from day 4 after cancer cell transplantation. Benzoic acid (Formula IV) was administered orally at a dose of 30, 100, 200 or 300 mg / kg per day. Gemcitabine (60 mg / kg) was administered intraperitoneally.
[863] Cancer response was monitored by cancer volume measurements performed twice per week over 60-90 days. Body weight was measured as a general measure of toxicity. Mice were separated into untreated controls and multiple treatment groups with 5 mice in each group.
[864] Data was analyzed by measuring the average cancer volume for the control group and each treatment group over the course of the experiment and the cancer growth delay was calculated as the difference in the number of days up to 1000 mm ³ for the treatment group versus the control arm.
[865] Mouse Xenograft Test Results: Growth Delay of Prostate Cancer ⁽¹⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-1.20.30 Formula IV100-2.00.30 Formula IV200-2.20.30 GEM-6012.20.50 Formula IV + GEM306043.23.00 Formula IV + GEM1006051.23.50
[866] (1) = LNCaP prostate carcinoma
[867] Formula IV = LTB ₄ antagonist, 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid
[868] GEM = gemcitabine hydrochloride, 2 ', 2'-difluoronucleoside anticancer agent, Elililyl Campanile
[869] LNCaP = LNCaP Prostate Carcinoma
[870] Dose = mg / kg mouse weight
[871] TGD = mean cancer growth delay (days)
[872] sem = standard error of the mean
[873] Mouse Xenograft Test Results: Growth Delay of Prostate Cancer ⁽²⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-5.80.50 Formula IV100-7.70.60 Formula IV300-12.71.00 GEM-609.60.80 Formula IV + GEM306015.61.40 Formula IV + GEM1006025.22.20
[874] (2) = DU-145 prostate carcinoma
[875] Mouse Xenograft Test Results: Delayed Growth of Pancreatic Cancer ⁽³⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-7.40.50 Formula IV100-21.62.00 Formula IV300-30.23.20 GEM-6017.11.50 Formula IV + GEM306022.91.90 Formula IV + GEM1006027.02.30
[876] (3) = BxPC3 pancreatic cancer
[877] Mouse Xenograft Test Results: Delayed Growth of Pancreatic Cancer ⁽⁴⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-10.21.40 Formula IV100-16.72.00 Formula IV200-19.42.40 GEM-607.700.80 Formula IV + GEM306018.21.50 Formula IV + GEM1006023.32.30 Formula IV + GEM2006029.13.00
[878] (4) = Panc-1 pancreatic cancer
[879] Mouse Xenograft Test Results: Growth Delay of Non-Small Cell Lung Cancer ⁽⁵⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-10.91.00 Formula IV100-13.21.20 Formula IV200-13.91.30 GEM-609.30.90 Formula IV + GEM306020.22.00 Formula IV + GEM1006021.32.20 Formula IV + GEM2006032.03.10
[880] (5) = person H460 NSCLC
[881] Mouse Xenograft Test Results: Growth Delay of Non-Small Cell Lung Cancer ⁽⁶⁾ processDosage Formula IVDosageTGDTGD, sem Formula IV30-7.40.60 Formula IV100-10.00.80 Formula IV200-17.91.60 GEM-6014.01.20 Formula IV + GEM306017.41.60 Formula IV + GEM1006022.52.00
[882] (4) = Calu-6 carcinoma
[883] Detailed description of the drawings:
[884] 1 to 6 show the data of Tables 1 to 6 above. Figures show the increased effectiveness in delaying cancer growth of the combination treatment of (i) Formula IV and (ii) gemcitabine hydrochloride compared to the use of individual agents (i) or (ii).
[885] 1 shows various treatments for LNCaP prostate carcinoma.
[886] Bars (1), (2) and (3) show delayed cancer growth following the single use of the LTB ₄ antagonist Formula IV at doses of 30, 100 and 200 mg / kg, respectively.
[887] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[888] Bars (5) and (6) show delayed cancer growth with the combination of Formula IV (dosages of 30 and 100 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively.
[889] 2 shows various treatments for DU-145 prostate carcinoma.
[890] Bars (1), (2) and (3) show delayed cancer growth following the single use of LT IV ₄ antagonist Formula IV at doses of 30, 100 and 300 mg / kg, respectively.
[891] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[892] Bars (5) and (6) show delayed cancer growth with the combination of Formula IV (dosages of 30 and 100 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively.
[893] 3 shows various treatments for BxPC3 pancreatic carcinoma.
[894] Bars (1), (2) and (3) show delayed cancer growth following the single use of LT IV ₄ antagonist Formula IV at doses of 30, 100 and 300 mg / kg, respectively.
[895] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[896] Bars (5) and (6) show delayed cancer growth with the combination of Formula IV (dosages of 30 and 100 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively.
[897] 4 shows various treatments for Panc-1 pancreatic carcinoma.
[898] Bars (1), (2) and (3) show delayed cancer growth following the single use of LT IV ₄ antagonist Formula IV at doses of 30, 100 and 200 mg / kg, respectively.
[899] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[900] Bars (5), (6) and (7) show delayed cancer growth due to the combination of Formula IV (dosages of 30, 100 and 200 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively. Indicates.
[901] 5 shows various treatments for human H460 non-small cell lung carcinoma.
[902] Bars (1), (2) and (3) show delayed cancer growth following the single use of LT IV ₄ antagonist Formula IV at doses of 30, 100 and 200 mg / kg, respectively.
[903] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[904] Bars (5), (6) and (7) show delayed cancer growth due to the combination of Formula IV (dosages of 30, 100 and 200 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively. Indicates.
[905] 6 shows various treatments for Calu-6 non-small cell lung carcinoma.
[906] Bars (1), (2) and (3) show delayed cancer growth following the single use of LT IV ₄ antagonist Formula IV at doses of 30, 100 and 200 mg / kg, respectively.
[907] Bar (4) shows the delay of cancer growth for the single use of the anticancer gemcitabine hydrochloride at a dose of 60 mg / kg.
[908] Bars (5) and (6) show delayed cancer growth with the combination of Formula IV (dosages of 30 and 100 mg / kg) and gemcitabine hydrochloride (dosage of 60 mg / kg), respectively.

权利要求:
Claims (40)
[1" claim-type="Currently amended] A composition comprising a therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of a 2 ′, 2′-difluoronucleoside anticancer agent.
[2" claim-type="Currently amended] A therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of a 2 ′, 2′-difluoronucleoside anticancer agent, wherein the anticancer compound is a therapeutic agent of a compound of the formula and a pharmaceutically acceptable salt thereof An effective amount of the composition.

(here,
R ¹ is hydrogen;
R ² is a base defined by one of the following formulae:

;
X is CR ⁴ ;
R ³ is hydrogen;
R ⁴ is hydrogen, C ₁ -C ₄ alkyl, bromo, fluoro, chloro or iodo)
[3" claim-type="Currently amended] The composition of claim 2, wherein R ² is a base defined by the formula

[4" claim-type="Currently amended] The composition of claim 2 wherein the anticancer agent is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:
(i) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose,
(ii) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoroxylose,
(iii) 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose, and
(iv) 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose.
[5" claim-type="Currently amended] The composition of claim 2 wherein the anticancer agent is gemcitabine hydrochloride.
[6" claim-type="Currently amended] 6. The composition of claim 1, wherein the leukotriene (LTB ₄ ) antagonist is of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof. 7.
<Formula I>

(In the above formula,
X is (i) a 5 membered, substituted or unsubstituted heterocyclic radical containing 1 to 4 heteroatoms independently selected from the group consisting of sulfur, nitrogen and oxygen, or (ii) a carbocyclic group is A fused bicyclic radical, fused to two adjacent carbon atoms of the original heterocyclic radical (i);
Y ₁ is a single bond or a divalent bonding group containing 1 to 9 atoms;
Y ₂ and Y ₃ are divalent bonding groups independently selected from the group consisting of —CH ₂ —, —O— and —S—;
Z is an acidic group;
R 1 is C ₁ -C ₁₀ alkyl, aryl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₂₀ aralkyl, C ₆ -C ₂₀ alk Aryl, C ₁ -C ₁₀ haloalkyl, C ₆ -C ₂₀ aryloxy or C ₁ -C ₁₀ alkoxy;
R2 is hydrogen, halogen, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, acidic group or-(CH ₂ ) _1-7- (acidic Group);
R 3 is hydrogen, halogen, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₆ -C ₂₀ aryloxy or C ₃ -C ₈ cycloalkyl;
R 4 is C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl,-(CH ₂ ) _1-7- (C ₃ -C ₄ cycloalkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkoxy Nil, benzyl or aryl;
n is 0, 1, 2, 3, 4, 5 or 6)
[7" claim-type="Currently amended] 7. The composition of claim 6, wherein X is a heterocyclic radical selected from the group consisting of substituents of the formula:


Wherein R 10 is hydrogen or a C ₁ -C ₄ alkyl radical and R 11 is hydrogen, halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, aryl or C ₆ -C ₂₀ radicals selected from the group consisting of aryloxy)
[8" claim-type="Currently amended] 7. A compound according to claim 6 wherein the R1, R2, R3 and R4 groups for substitution of formula (I) are selected from the following variables encoded by R01 to R16 and the Y1, Y2 and Y3 groups for substitution of formula (I) are Y01 To Y27, wherein the X and Z groups for substitution of formula (I), and the variable n are selected from the following variables encoded by XZn01 to XZn24.
R variable combination code Select R1 R2 machine selection R3 device selection R4 machine selection R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-R1 R2 R3 PG1-R4 R11 PG1-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1 PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16 PG1-R1 PG1-R2 PG1-R3 PG1-R4
Y variable combination code Y1 group selection Y2 group selection Y3 machine selection Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3
XZn Variable Combination Code Select X Z group selection n integer selection XZn01 X Z n XZn02 X Z PG1-n XZn03 X Z PG2-n XZn04 X PG1-Z n XZn05 X PG2-Z n XZn06 X PG3-Z n XZn07 X PG1-Z PG1-n XZn08 X PG2-Z PG1-n XZn09 X PG3-Z PG1-n XZn10 X PG1-Z PG2-n XZn11 X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-n XZn15 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-X PG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n
[9" claim-type="Currently amended] 7. The composition of claim 6, wherein the leukotriene B ₄ antagonist is of formula (II), or a salt, solvate or prodrug thereof.
<Formula II>

(In the above formula,
X2 is a heterocyclic radical selected from:

R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
R 22 is hydrogen, n-butyl, sec-butyl, fluoro, chloro, -CF ₃ or tert-butyl;
Z2 is an acidic group selected from the group consisting of carboxyl, tetrazolyl and N-sulfonamidyl)
[10" claim-type="Currently amended] 10. The composition of claim 9, wherein the leukotriene antagonist is a compound selected from: or an acid, salt, solvate or prodrug derivative thereof.






[11" claim-type="Currently amended] 10. The composition of claim 9, wherein the leukotriene antagonist is a compound selected from: or an acid, salt, solvate or prodrug derivative thereof.


[12" claim-type="Currently amended] The composition according to any one of claims 1 to 5, wherein the leukotriene (LTB ₄ ) antagonist is a compound of formula (A), or a pharmaceutically acceptable base addition salt thereof.
<Formula A>

(In the above formula,
R ₁ ′ is C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) thio, halo, or R _2- Substituted phenyl;
Each R ₂ ′ and R ₃ ′ are each independently hydrogen, halo, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl)-(O) _q S-, tri Fluoromethyl or di- (C ₁ -C ₃ alkyl) amino;
X 'is -O-, -S-, -C (= 0) or -CH _2- ;
Y 'is -O- or -CH _2- ;
Or together, -X'-Y'- is -CH = CH- or -C≡C-;
Z 'is a straight or branched C ₁ -C ₁₀ alkylidedenyl;
A 'is a single bond, -0-, -S-, -CH = CH- or -CR _a R _b- (wherein R _a and R _b are each independently hydrogen, C ₁ -C ₅ alkyl, or R ₇ -Substituted phenyl or together with the carbon atom to which they are attached form a C ₄ -C ₈ cycloalkyl ring;
R ₄ 'is R ₆ ,


ego;
Each R ₆ is independently —COOH, 5-tetrazolyl, —CON (R ₉ ) ₂ or —CONHSO ₂ R ₁₀ ;
Each R ₇ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, benzyl, methoxy, -WR ₆ , -TGR ₆ , (C ₁ -C ₄ alkyl) -T- (C ₁ -C ₄ alkylidenyl) -O-, or hydroxy;
R ₈ is hydrogen or halo;
Each R ₉ is independently hydrogen, phenyl or C ₁ -C ₄ alkyl or together with the nitrogen atom form a morpholino, piperidino, piperazino or pyrrolidino group;
R ₁₀ is C ₁ -C ₄ alkyl or phenyl;
R ₁₁ is R ₂ ′, —WR ₆ or —TGR ₆ ;
Each W is a single bond or a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
Each G is or a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
Each T is a single bond, —CH ₂ —, —O—, —NH—, —NHCO—, —C (═O) — or (O) _q S—;
K is -C (= 0)-or -CH (OH)-;
Each q is independently 0, 1 or 2;
p is 0 or 1;
t is 0 or 1;
Provided that when X 'is -O- or -S-, Y' is not -O-; When A 'is -O- or -S-, R ₄ ′ is not R ₆ ; if p is 0, W is not a single bond)
[13" claim-type="Currently amended] The composition of claim 12, wherein R ₄ ′ is selected from the following formula:

[14" claim-type="Currently amended] The composition of claim 13, wherein R ₄ ′ is of the formula:

[15" claim-type="Currently amended] The composition of claim 12, wherein the LTB ₄ antagonist compound, or a pharmaceutically acceptable acid, prodrug or salt derivative thereof, is selected from the groups (A) to (KKKK) consisting of:
A) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) heptane;
B) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (3-fluorophenyl) -5-hydroxyphenoxy) heptane;
C) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-dimethylaminocarbonylbutyloxy) phenyl) Propionic acid;
D) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
E) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutyloxy) phenyl) propionic acid;
F) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-methoxyphenyl) propionic acid;
G) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (lH-tetrazol-5-yl ) Butyloxy) phenyl) propionic acid;
H) methyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionate;
I) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionic acid;
J) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) phenyl) propionic acid;
K) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) -6-methoxy phenyl) propionic acid;
L) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionate;
M) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionic acid;
N) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-butyloxy) phenyl) propionic acid;
O) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-methylthiobutyloxy) phenyl) propionic acid;
P) 3- (2- (3- (2,4-di (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutoxy) phenyl) propionic acid;
Q) 6-methyl-6- (lH-tetrazol-5-yl) -11- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) undecane;
R) N, N-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
S) N-methanesulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
T) N-phenylsulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
U) 3- (2- (3- (2-butyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
V) ethyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionate;
W) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionic acid;
X) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (methoxycarbonyl) phenoxy ) Phenyl) propionate;
Y) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4 carboxyphenoxy) phenyl) propionic acid;
Z) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4 carboxyphenoxy) phenyl) propionic acid;
AA) 3,3-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
BB) 2-methyl-2- (lH-tetrazol-5-yl) -3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) pro Foxy) phenyl) propane;
CC) 2-methyl-2- (lH-tetrazol-5-yl) -3-hydroxy-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydrate Oxyphenoxy) propoxy) phenyl) propane;
DD) 3- (2- (3- (2-bromo-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
EE) 3- (2- (3- (2-ethylthio-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
FF) methyl 3- (2-hydroxy-3- (4-methoxycarbonylbutyl) -6- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) Propoxy) phenyl) propionate;
GG) 5- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -8- (4-carboxybutyl) dihydrocoumarin;
HH) 2-phenyl-4-ethyl-5- [6- (2H-tetrazol-5-yl) -6-methylheptyloxy] phenol sodium salt;
II) 2- (4-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
JJ) 2- (3-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
KK) 2- (2-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
LL) 2- (4-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
MM) 2- (3-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
NN) 2- (4-trifluoromethylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
00) 2- (3-dimethylaminophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
PP) 3- (5- (6- (4-phenyl-5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalene-1 (2H ) -On) propanoic acid;
QQ) 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetra Hydronaphthalene-1 (2H) -one) propanoic acid;
RR) 3- (4- (5- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-2,3-dihydroindene- 1 (2H) -on) propanoic acid;
SS) 3,3-dimethyl-5- (3- (2-carboxyethyl) -4- (3- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) phenyl)- 5-oxopentanoic acid;
TT) 7- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -3,4-dihydro-8-propyl-2H- l-benzopyran-2-carboxylic acid;
UU) 8-propyl-7- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy] -3,4-dihydro-2H-l-benzopyran 2-carboxylic acid;
VV) 2- [3- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -2-propylphenoxy] propanoic acid;
WW) 2- (4-chlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
XX) 2- (3,5-dichlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
YY) 3- [2- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid sodium salt;
ZZ) 7-carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9H-xanthene-4-propanoic acid disodium salt monohydrate;
AAA) 2- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid sodium salt hemihydrate;
BBB) 3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] [1,1'-biphenyl] -4-propanoic acid disodium salt monohydrate;
CCC) 5-ethyl-4- [3- [2-propyl-3- [2- (2H-tetrazol-5-yl) phenoxy] phenoxy] propoxy] [l, l'-biphenyl]- 2-ol 2 sodium salt sesquihydrate;
DDD) 3- [4- [3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9-oxo-9H-xanthene]] sodium propanoate hemihydrate;
EEE) 2-fluoro-6- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid disodium salt;
FFF) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt;
GGG) 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-ch Xanthene]] propanoic acid disodium salt trihydrate;
HHH) 3- [4- [9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propane mountain;
III) 3- [2- [1- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -4- (5-oxo-5-morpholinopentaneami Phenyl) propanoic acid;
JJJ) 2-Fluoro-6- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid 2 sodium Salt hydrates;
KKK) 4-fluoro-2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
LLL) 2- [2-propyl-3- [5- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] pentoxy] phenoxy] benzoic acid;
MMM) 2- [2-propyl-3- [4- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] butoxy] phenoxy] benzoic acid sesquihydrate;
NNN) 2- [2- (2-methylpropyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
000) 2- [2-butyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid hydrate;
PPP) 2- [2- (phenylmethyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
QQQ) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] phenyl acetic acid;
RRR) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid;
SSS) 2-[[2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenyl] methyl] benzoic acid;
TTT) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid;
UUU) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfinyl] benzoic acid;
VVV) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfonyl] benzoic acid hydrate;
WWW) 5- [3- [2- (l-carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] 4-pentynic acid disodium salt 0.4 hydrate;
XXX) l-phenyl-l- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane;
YYY) 1- (4- (carboxymethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy C) hexane;
ZZZ) 1- (4- (dimethylaminocarbonylmethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5- Hydroxyphenoxy) hexane;
AAAA) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -E-propenoic acid;
BBBB) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -2-methyl-E-propenoic acid;
CCCC) 5- (2- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) ethyl) -1H-tetrazole;
DDDD) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4-carboxybutyloxy) phenyl) propionic acid;
EEEE) 5- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy-3,4-dihydro-2H-l-benzopyran-2-one;
FFFF) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} phenyl) propanoic acid;
GGGG) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -4-propylphenyl) propanoic acid sodium salt;
HHHH) 3- (4- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -3-propylphenyl) propanoic acid;
IIII) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -2-propylphenyl) propanoic acid;
JJJJ) 3- {3- [3- (2-ethyl-5-hydroxyphenyloxy) propoxy] -2-propylphenyl} propanoic acid disodium salt; And
KKKK) 2- [3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid disodium salt hemihydrate.
[16" claim-type="Currently amended] 6. The compound of claim 1, 2 or 5, wherein the leukotriene (LTB ₄ ) antagonist is a compound of formula B, namely 2- [2-propyl-3- [3- [2-ethyl-5] -Hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid or a pharmaceutically acceptable salt thereof.
<Formula B>

[17" claim-type="Currently amended] The composition of claim 1, wherein the anticancer agent is a therapeutically effective amount of a 2 ′, 2′-difluoronucleoside anticancer agent of the formula: and a pharmaceutically acceptable salt thereof.

(here,
R ¹ is hydrogen or —C (═O) —R ⁵ ;
R ² is a base defined by one of the following formulae:

;
X is N or CR ⁴ ;
R ³ is hydrogen, C ₁ -C ₄ alkyl or —C (═O) —R ⁵ ;
R ⁴ is hydrogen, C ₁ -C ₄ alkyl, amino, bromo, fluoro, chloro or iodo;
Each R ⁵ is independently hydrogen or C ₁ -C ₄ alkyl)
[18" claim-type="Currently amended] 13. The composition of claim 1, 2, 3, 6 or 12 wherein the weight ratio of LTB ₄ antagonist to anticancer agent is from 1: 100 to 100: 1.
[19" claim-type="Currently amended] 13. A composition according to claim 1, 2, 3, 6 or 12 in the form of an injection solution.
[20" claim-type="Currently amended] Use of a composition comprising a leukotriene (LTB ₄ ) antagonist and an anticancer agent according to any one of claims 1 to 10 and 12 to 17 in the manufacture of a medicament for the treatment of cancer in a mammal.
[21" claim-type="Currently amended] A method of treating cancer in a patient comprising administering to the mammalian patient a therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of a 2 ′, 2′-difluoronucleoside anticancer agent.
[22" claim-type="Currently amended] The method of claim 21, wherein the anticancer compound is a therapeutically effective amount of a compound of the formula: and a pharmaceutically acceptable salt thereof.

(here,
R ¹ is hydrogen;
R ² is a base defined by one of the following formulae:

X is CR ⁴ ;
R ³ is hydrogen;
R ⁴ is hydrogen, C ₁ -C ₄ alkyl, bromo, fluoro, chloro or iodo)
[23" claim-type="Currently amended] The method of claim 22, wherein R ² is a base defined by the formula:

[24" claim-type="Currently amended] The method of claim 23, wherein the anticancer agent is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:
(i) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose,
(ii) 1- (4-amino-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluoroxylose,
(iii) 1- (2,4-dioxo-1H, 3H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose, and
(iv) 1- (4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl) -2-desoxy-2 ', 2'-difluororibose.
[25" claim-type="Currently amended] The method of claim 22, wherein the anticancer agent is gemcitabine hydrochloride.
[26" claim-type="Currently amended] 26. The method of any one of claims 21-25, wherein the leukotriene (LTB ₄ ) antagonist is of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
<Formula I>

(In the above formula,
X is (i) a 5 membered, substituted or unsubstituted heterocyclic radical containing 1 to 4 heteroatoms independently selected from the group consisting of sulfur, nitrogen and oxygen, or (ii) a carbocyclic group is A fused bicyclic radical fused to two adjacent carbon atoms of the heterocyclic radical (i) of the circle;
Y ₁ is a single bond or a divalent bonding group containing 1 to 9 atoms;
Y ₂ and Y ₃ are divalent bonding groups independently selected from the group consisting of —CH ₂ —, —O— and —S—;
Z is an acidic group;
R 1 is C ₁ -C ₁₀ alkyl, aryl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₂₀ aralkyl, C ₆ -C ₂₀ alk Aryl, C ₁ -C ₁₀ haloalkyl, C ₆ -C ₂₀ aryloxy or C ₁ -C ₁₀ alkoxy;
R2 is hydrogen, halogen, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, acidic group or-(CH ₂ ) _1-7- (acidic Group);
R 3 is hydrogen, halogen, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₆ -C ₁₀ aryloxy or C ₃ -C ₈ cycloalkyl;
R 4 is C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl,-(CH ₂ ) _1-7- (C ₃ -C ₄ cycloalkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkoxy Nil, benzyl or aryl;
n is 0, 1, 2, 3, 4, 5 or 6)
[27" claim-type="Currently amended] 27. The method of claim 26, wherein X is a heterocyclic radical selected from the group consisting of substituents of the formula:



Wherein R 10 is hydrogen or a C ₁ -C ₄ alkyl radical and R 11 is hydrogen, halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, aryl or C ₆ -C ₂₀ radicals selected from the group consisting of aryloxy)
[28" claim-type="Currently amended] 27. A compound according to claim 26, wherein the R1, R2, R3 and R4 groups for substitution of formula (I) are selected from the following variables encoded by R01 to R16, and the Y1, Y2 and Y3 groups for substitution of formula (I) are Y01 To Y27, wherein the X and Z groups for substitution of formula (I), and the variable n are selected from the following variables, coded XZn01 to XZn24.
R variable combination code Select R1 R2 machine selection R3 device selection R4 machine selection R01 R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-R1 R2 R3 PG1-R4 R11 PG1-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1 PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16 PG1-R1 PG1-R2 PG1-R3 PG1-R4
Y variable combination code Y1 group selection Y2 group selection Y3 machine selection Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3
XZn Variable Combination Code Select X Z group selection n integer selection XZn01 X Z n XZn02 X Z PG1-n XZn03 X Z PG2-n XZn04 X PG1-Z n XZn05 X PG2-Z n XZn06 X PG3-Z n XZn07 X PG1-Z PG1-n XZn08 X PG2-Z PG1-n XZn09 X PG3-Z PG1-n XZn10 X PG1-Z PG2-n XZn11 X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-n XZn15 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-X PG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n
[29" claim-type="Currently amended] 27. The method of claim 26, wherein the leukotriene B ₄ antagonist is of formula (II), or a salt, solvate or prodrug thereof.
<Formula II>

(In the above formula,
X2 is a heterocyclic radical selected from:

R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
R 22 is hydrogen, n-butyl, sec-butyl, fluoro, chloro, -CF ₃ or tert-butyl;
Z2 is an acidic group selected from the group consisting of carboxyl, tetrazolyl and N-sulfonamidyl)
[30" claim-type="Currently amended] 27. The method of claim 26, wherein the leukotriene antagonist is a compound selected from: or acid, salt, solvate or prodrug thereof.






[31" claim-type="Currently amended] 27. The method of claim 26, wherein the leukotriene antagonist is a compound selected from: or acid, salt, solvate or prodrug thereof.


[32" claim-type="Currently amended] 26. The method of any one of claims 21-25, wherein the leukotriene (LTB ₄ ) antagonist is a compound of formula (A), or a pharmaceutically acceptable base addition salt thereof.
<Formula A>

(In the above formula,
R ₁ ′ is C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) thio, halo, or R _2- Substituted phenyl;
Each R ₂ ′ and R ₃ ′ are each independently hydrogen, halo, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl)-(O) _q S-, tri Fluoromethyl or di- (C ₁ -C ₃ alkyl) amino;
X 'is -O-, -S-, -C (= 0) or -CH _2- ;
Y 'is -O- or -CH _2- ;
Or together, -X'-Y'- is -CH = CH- or -C≡C-;
Z 'is a straight or branched C ₁ -C ₁₀ alkylidedenyl;
A 'is a single bond, -0-, -S-, -CH = CH- or -CR _a R _b- (wherein R _a and R _b are each independently hydrogen, C ₁ -C ₅ alkyl, or R ₇ -Substituted phenyl or together with the carbon atom to which they are attached form a C ₄ -C ₈ cycloalkyl ring;
R ₄ 'is R ₆ ,


ego;
Each R ₆ is independently —COOH, 5-tetrazolyl, —CON (R ₉ ) ₂ or —CONHSO ₂ R ₁₀ ;
Each R ₇ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, benzyl, methoxy, -WR ₆ , -TGR ₆ , (C ₁ -C ₄ alkyl) -T- (C ₁ -C ₄ alkylidenyl) -O-, or hydroxy;
R ₈ is hydrogen or halo;
Each R ₉ is independently hydrogen, phenyl or C ₁ -C ₄ alkyl or together with the nitrogen atom form a morpholino, piperidino, piperazino or pyrrolidino group;
R ₁₀ is C ₁ -C ₄ alkyl or phenyl;
R ₁₁ is R ₂ ′, —WR ₆ or —TGR ₆ ;
Each W is a single bond or a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
Each G is or a divalent straight or branched chain hydrocarbyl radical having 1 to 8 carbon atoms;
Each T is a single bond, —CH ₂ —, —O—, —NH—, —NHCO—, —C (═O) — or (O) _q S—;
K is -C (= 0)-or -CH (OH)-;
Each q is independently 0, 1 or 2;
p is 0 or 1;
t is 0 or 1;
Provided that when X 'is -O- or -S-, Y' is not -O-; When A 'is -O- or -S-, R ₄ ′ is not R ₆ ; if p is 0, W is not a single bond)
[33" claim-type="Currently amended] The method of claim 32, wherein R ₄ ′ is selected from the following formula:

[34" claim-type="Currently amended] The method of claim 32, wherein R ₄ ′ is of the formula:

[35" claim-type="Currently amended] 33. The method of claim 32, wherein the LTB ₄ antagonist compound, or a pharmaceutically acceptable acid, prodrug or salt derivative thereof is selected from the group (A) to (KKKK) consisting of:
A) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) heptane;
B) 2-methyl-2- (lH-tetrazol-5-yl) -7- (2-ethyl-4- (3-fluorophenyl) -5-hydroxyphenoxy) heptane;
C) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-dimethylaminocarbonylbutyloxy) phenyl) Propionic acid;
D) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
E) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutyloxy) phenyl) propionic acid;
F) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-methoxyphenyl) propionic acid;
G) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (lH-tetrazol-5-yl ) Butyloxy) phenyl) propionic acid;
H) methyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionate;
I) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy)-(l-butenyl)) phenyl) propionic acid;
J) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) phenyl) propionic acid;
K) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyl) -6-methoxy phenyl) propionic acid;
L) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionate;
M) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6-hydroxyphenyl) propionic acid;
N) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-butyloxy) phenyl) propionic acid;
O) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-methylthiobutyloxy) phenyl) propionic acid;
P) 3- (2- (3- (2,4-di (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4-carboxybutoxy) phenyl) propionic acid;
Q) 6-methyl-6- (lH-tetrazol-5-yl) -11- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) undecane;
R) N, N-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
S) N-methanesulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
T) N-phenylsulfonyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionamide;
U) 3- (2- (3- (2-butyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
V) ethyl 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionate;
W) 3- (2- (4- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) butyloxy) phenyl) propionic acid;
X) methyl 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4- (methoxycarbonyl) phenoxy ) Phenyl) propionate;
Y) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -6- (4 carboxyphenoxy) phenyl) propionic acid;
Z) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4 carboxyphenoxy) phenyl) propionic acid;
AA) 3,3-dimethyl-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
BB) 2-methyl-2- (lH-tetrazol-5-yl) -3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) pro Foxy) phenyl) propane;
CC) 2-methyl-2- (lH-tetrazol-5-yl) -3-hydroxy-3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydrate Oxyphenoxy) propoxy) phenyl) propane;
DD) 3- (2- (3- (2-bromo-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
EE) 3- (2- (3- (2-ethylthio-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) propionic acid;
FF) methyl 3- (2-hydroxy-3- (4-methoxycarbonylbutyl) -6- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) Propoxy) phenyl) propionate;
GG) 5- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -8- (4-carboxybutyl) dihydrocoumarin;
HH) 2-phenyl-4-ethyl-5- [6- (2H-tetrazol-5-yl) -6-methylheptyloxy] phenol sodium salt;
II) 2- (4-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
JJ) 2- (3-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
KK) 2- (2-methylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
LL) 2- (4-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
MM) 2- (3-methoxyphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol sodium salt;
NN) 2- (4-trifluoromethylphenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
00) 2- (3-dimethylaminophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 2 sodium salt;
PP) 3- (5- (6- (4-phenyl-5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetrahydronaphthalene-1 (2H ) -On) propanoic acid;
QQ) 3- (5- (6- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-1,2,3,4-tetra Hydronaphthalene-1 (2H) -one) propanoic acid;
RR) 3- (4- (5- (4- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) -2-carboxymethyl-2,3-dihydroindene- 1 (2H) -on) propanoic acid;
SS) 3,3-dimethyl-5- (3- (2-carboxyethyl) -4- (3- (4-fluorophenyl) -5-hydroxy-2-ethylphenoxy) propoxy) phenyl)- 5-oxopentanoic acid;
TT) 7- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -3,4-dihydro-8-propyl-2H- l-benzopyran-2-carboxylic acid;
UU) 8-propyl-7- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy] -3,4-dihydro-2H-l-benzopyran 2-carboxylic acid;
VV) 2- [3- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -2-propylphenoxy] propanoic acid;
WW) 2- (4-chlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
XX) 2- (3,5-dichlorophenyl) -4-ethyl-5- [6-methyl-6- (2H-tetrazol-5-yl) heptyloxy] phenol 1 sodium salt;
YY) 3- [2- [3-[(5-ethyl-2-hydroxy [l, l'-biphenyl] -4-yl) oxy] propoxy] -1-dibenzofuran] propanoic acid sodium salt;
ZZ) 7-carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9H-xanthene-4-propanoic acid disodium salt monohydrate;
AAA) 2- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid sodium salt hemihydrate;
BBB) 3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] [1,1'-biphenyl] -4-propanoic acid disodium salt monohydrate;
CCC) 5-ethyl-4- [3- [2-propyl-3- [2- (2H-tetrazol-5-yl) phenoxy] phenoxy] propoxy] [l, l'-biphenyl]- 2-ol 2 sodium salt sesquihydrate;
DDD) 3- [4- [3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] -9-oxo-9H-xanthene]] sodium propanoate hemihydrate;
EEE) 2-fluoro-6- [2-propyl-3- [3- (2-ethyl-5-hydroxy-4-phenylphenoxy) propoxy] phenoxy] benzoic acid disodium salt;
FFF) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid sodium salt;
GGG) 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-ch Xanthene]] propanoic acid disodium salt trihydrate;
HHH) 3- [4- [9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -9H-xanthene]] propane mountain;
III) 3- [2- [1- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] -4- (5-oxo-5-morpholinopentaneami Phenyl) propanoic acid;
JJJ) 2-Fluoro-6- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid 2 sodium Salt hydrates;
KKK) 4-fluoro-2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
LLL) 2- [2-propyl-3- [5- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] pentoxy] phenoxy] benzoic acid;
MMM) 2- [2-propyl-3- [4- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] butoxy] phenoxy] benzoic acid sesquihydrate;
NNN) 2- [2- (2-methylpropyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
000) 2- [2-butyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid hydrate;
PPP) 2- [2- (phenylmethyl) -3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid;
QQQ) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] phenyl acetic acid;
RRR) 2- [2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid;
SSS) 2-[[2-propyl-3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenyl] methyl] benzoic acid;
TTT) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] thiophenoxy] benzoic acid;
UUU) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfinyl] benzoic acid;
VVV) 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenylsulfonyl] benzoic acid hydrate;
WWW) 5- [3- [2- (l-carboxy) ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] propoxy] phenyl] 4-pentynic acid disodium salt 0.4 hydrate;
XXX) l-phenyl-l- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane;
YYY) 1- (4- (carboxymethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy C) hexane;
ZZZ) 1- (4- (dimethylaminocarbonylmethoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- (2-ethyl-4- (4-fluorophenyl) -5- Hydroxyphenoxy) hexane;
AAAA) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -E-propenoic acid;
BBBB) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) -2-methyl-E-propenoic acid;
CCCC) 5- (2- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) phenyl) ethyl) -1H-tetrazole;
DDDD) 3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) -4- (4-carboxybutyloxy) phenyl) propionic acid;
EEEE) 5- [3- [4- (4-fluorophenyl) -2-ethyl-5-hydroxyphenoxy] propoxy-3,4-dihydro-2H-l-benzopyran-2-one;
FFFF) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} phenyl) propanoic acid;
GGGG) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -4-propylphenyl) propanoic acid sodium salt;
HHHH) 3- (4- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -3-propylphenyl) propanoic acid;
IIII) 3- (3- {3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenyloxy] propoxy} -2-propylphenyl) propanoic acid;
JJJJ) 3- {3- [3- (2-ethyl-5-hydroxyphenyloxy) propoxy] -2-propylphenyl} propanoic acid disodium salt; And
KKKK) 2- [3- [3- [2-ethyl-5-hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] benzoyl] benzoic acid disodium salt hemihydrate.
[36" claim-type="Currently amended] 26. The method of claim 21, 22 or 25, wherein the leukotriene (LTB ₄ ) antagonist is a compound of formula B, i.e. 2- [2-propyl-3- [3- [2-ethyl-5 -Hydroxy-4- (4-fluorophenyl) phenoxy] propoxy] phenoxy] benzoic acid and a pharmaceutically acceptable salt thereof.
<Formula B>

[37" claim-type="Currently amended] The method of claim 21, wherein the anticancer agent is a therapeutically effective amount of a 2 ′, 2′-difluoronucleoside anticancer agent of the formula and a pharmaceutically acceptable salt thereof.

(here,
R ¹ is hydrogen or —C (═O) —R ⁵ ;
R ² is a base defined by one of the following formulae:

;
X is N or CR ⁴ ;
R ³ is hydrogen, C ₁ -C ₄ alkyl or —C (═O) —R ⁵ ;
R ⁴ is hydrogen, C ₁ -C ₄ alkyl, amino, bromo, fluoro, chloro or iodo;
Each R ⁵ is independently hydrogen or C ₁ -C ₄ alkyl)
[38" claim-type="Currently amended] Administering to a mammalian patient a therapeutically effective amount of a leukotriene (LTB ₄ ) antagonist and a therapeutically effective amount of a 2 ', 2'-difluoronucleoside anticancer agent, wherein the anticancer agent is gemcitabine hydrochloride and the leukotriene (LTB ₄₎ ) The antagonist is a compound of formula (B) or a pharmaceutically acceptable salt thereof, the method of treating cancer in said patient.

[39" claim-type="Currently amended] The method of claim 21, 22 or 38, wherein the weight ratio of LTB ₄ antagonist to anticancer agent is from 1: 100 to 100: 1.
[40" claim-type="Currently amended] The method of claim 21, 22 or 23, wherein the combined dose of LTB ₄ antagonist and anticancer agent is 0.5 to about 300 mg / kg per day.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-11-11|Priority to US16478699P

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1999-11-11|Priority to US60/164,786

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2000-11-09|Application filed by 일라이 릴리 앤드 캄파니

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2000-11-09|Priority to PCT/US2000/031039

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2002-09-04|Publication of KR20020069512A

优先权:

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申请号 | 申请日 | 专利标题

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US16478699P| true| 1999-11-11|1999-11-11|

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US60/164,786|1999-11-11|

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PCT/US2000/031039|WO2001034137A2|1999-11-11|2000-11-09|Oncolytic combinations for the treatment of cancer|