Dibenzocycloheptene compound

专利摘要:
The present invention is general formula (I) (In the formula, R 1 : hydrogen atom, halogen atom, etc., R 2 : hydrogen atom, halogen atom, etc., 5-member containing 1 to 3 hetero atoms selected from A: nitrogen atom, oxygen atom and sulfur atom, etc. Or a heteroaromatic cyclic group such as a 6-membered heteroaromatic cyclic group or the like preferably has a halogen atom, a nitro atom, or the like as a substituent, such as B: -CH = CH-, -CH 2 O-, Y: optionally a halogeno, etc. Z: an optionally protected carboxyl group, such as C 1 -C 10 alkylene, etc., m: an integer of 1-4, n: an integer of 1-3, : Represents a single bond or a double bond) Dibenzocycloheptene compound or a pharmacologically acceptable salt thereof, and as an active ingredient, an asthma agent, an antiallergic agent having not only a potent leukotriene D 4 antagonist, but also a leukotriene C 4 antagonist and a leukotriene E 4 antagonist Disclosed are pharmaceutical compositions useful as agents or anti-inflammatory agents.
公开号:KR20040030700A
申请号:KR10-2003-7016811
申请日:2002-06-27
公开日:2004-04-09
发明作者:구로키요시아키；우에노히토시；가쯔베데쯔시；가와구치데쯔오；오카나리에이지；다나카이찌로；다나카마사유키；하기하라마사히꼬
申请人:우베 고산 가부시키가이샤；
IPC主号:

专利说明:

Dibenzocycloheptene compound {DIBENZOCYCLOHEPTENE COMPOUND}
[2] As a compound having a leukotriene D ₄ antagonism similar to the present invention and having a structure similar to that of the compound of the present invention, for example, a compound described in WO-94 / 19345 is known, and as a compound having a partially similar structure, , 5- [3- [3- (2-quinolinylmethoxy) phenoxy] propyl] -1 H-tetrazole (RG7152; J. Med. Chem., 33 , 1186 (1990)), 5-[[2 - [[4- (2-quinolinyl -dihydroxy-20) phenoxy] methyl] phenyl] methyl] -1H- tetrazole (RG12525; J / Med.Chem, 33 , 1194 (1990).), WO95 / 18107 discloses Compounds described in the above are known.
[1] In addition to potent leukotriene D ₄ antagonism, the present invention has leukotriene C ₄ antagonism and leukotriene E ₄ antagonism, and is useful for dibenzocycloheptene compounds, or pharmacologically acceptable salts thereof, which are useful as anti-asthmatic, anti-allergic and anti-inflammatory agents. It is about.
[3] The present invention is a novel dibenzocycloheptane as a result of long-term studies on the synthesis and pharmacological action of a compound having not only a strong leukotriene D ₄ antagonist but also an antagonistic action against leukotriene C ₄ and leukotriene E ₄ . The present invention has been accomplished by discovering that the compounds have excellent leukotriene D ₄ antagonism, leukotriene C ₄ and leukotriene E ₄ antagonism not only have a good balance, but also have high safety and good oral absorption and persistence of action.
[4] Summary of the Invention
[5] The present invention is represented by general formula (I)
[6]
[7] Wherein R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a carboxyl group, a 1H-tetrazol-5-yl group, a C ₁ -C ₄ alkyl group, a fluoro C _1- C ₄ alkyl group, hydroxy C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₁ -C ₄ alkoxy group, fluoro C ₁ -C ₄ alkoxy group, C _1- C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group or C ₁ -C ₄ alkylsulfonyl group, R ² represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C ₁ -C ₄ alkyl group or C ₁ -C ₄ alkoxy, A is a 5- or 6-membered heteroaromatic ring group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom or a heteroaromatic ring group and a benzene ring condensed Heteroaromatic condensed cyclic group, heteroaromatic cyclic group or heteroaromatic condensed cyclic group is a substituent, halogen atom, nitro group, Cyano group, C ₁ -C ₄ alkyl group, fluoro C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, fluoro C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio or C ₃ -C ₄ may have a substituent (s) selected from an alkylene group, wherein B is of the formula —CH═CH—, —CH ₂ O—, —CH ₂ CH ₂ —, —CH ₂ S—, —OCH ₂ —, or —SCH _2- , X represents an oxygen atom, a sulfur atom, a methylene group or the formula = CH-, and Y has a substituent (s) selected from a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ alkoxy group A C ₁ -C ₁₀ alkylene group or a formula (a) group;
[8]
[9] Wherein o and p each represent an integer of 0 to 2, q represents an integer of 1 to 4, z is a carboxyl group which can be protected; a 1H-tetrazol-5-yl group; formula -NH-SO ₂ -R ³ ; Or formula -CO-NH-SO ₂ -R ³
[10] Wherein R ³ is a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group or a substituent, and a halogen atom, a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy Phenyl group which may have a group, a fluoro C ₁ -C ₄ alkoxy group, a nitro group or a cyano group,
[11] m represents an integer of 1 to 4, when m is 2 or more, R ¹ may be different from each other, n is an integer of 1 to 3, and when n is 2 or more, a plurality of R ² may be different from each other; ,
[12] Represents a single bond or a double bond.
[13] It relates to a dibenzocycloheptene compound and a pharmacologically acceptable salt thereof.
[14] Best Mode for Carrying Out the Invention
[15] In the compound represented by the above general formula (I), examples of the halogen atom of R ^{1 include} a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably. For example, a fluorine atom or a chlorine atom can be mentioned.
[16] As the C ₁ -C ₄ alkyl group of R ¹ , for example, a straight or branched C ₁ -C ₄ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl group is mentioned. And preferably methyl, ethyl, propyl or isopropyl groups, more preferably methyl or ethyl groups, particularly more preferably methyl groups.
[17] Fluoro C ₁ -C ₄ alkyl groups of R ¹ , such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl , A linear or branched C ₁ -C ₄ alkyl group substituted by 1 to 3 at a fluorine atom such as 3-fluoropropyl or 4-fluorobutyl group, preferably fluoromethyl, difluoromethyl, Trifluoromethyl or 2-fluoroethyl groups, more preferably fluoromethyl, difluoromethyl or trifluoromethyl groups, particularly more preferably difluoromethyl or trifluoromethyl groups.
[18] As a hydroxy C ₁ -C ₄ alkyl group of R ¹ , for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 2-hydroxy Linear or branched C ₁ -C ₄ alkyl groups substituted with hydroxy groups such as hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl or 4-hydroxybutyl groups, preferably hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl or 2-hydroxypropyl group, more preferably, hydroxymethyl, 1-hydroxyethyl , 1-hydroxy-1-methylethyl or 1-hydroxypropyl group, particularly preferably hydroxymethyl or 1-hydroxy-1-methylethyl group.
[19] As a C ₂ -C ₄ alkenyl group of R ¹ , for example, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, Linear or branched C ₂ -C ₄ alkenyl groups such as 2-methyl-1-propenyl or 2-methyl-2-propenyl group, preferably vinyl, 1-propenyl, allyl, 1 -Butenyl, 2-butenyl or 2-methyl-1-propenyl groups, more preferably vinyl, 1-propenyl or allyl groups, and even more preferably vinyl groups.
[20] C ₂ -C ₄ alkynyl groups of R ¹ , for example straight C ₂ -C ₄ such as ethynyl, 1-propynyl, propargyl, 1-butynyl, 2-butynyl or 3-butynyl groups Alkynyl groups are mentioned, Preferably an ethynyl, 1-propynyl or 1-butynyl group, More preferably, ethynyl or 1-propynyl, Especially more preferably, an ethynyl group is mentioned.
[21] C ₁ -C ₄ alkoxy of R ¹ , for example linear or branched C such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or t-butoxy groups _1- C ₄ alkoxy group, preferably methoxy, ethoxy, propoxy or isopropoxy group, more preferably methoxy or ethoxy group, and even more preferably methoxy group.
[22] As a fluoro C ₁ -C ₄ alkoxy group of R ¹ , for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2 Linear or branched C ₁ -C ₄ alkoxy groups substituted by 1 to 3 at fluorine atoms such as -fluoropropoxy, 3-fluoropropoxy or 4-fluorobutoxy groups, preferably Fluoromethoxy, difluoromethoxy, trifluoromethoxy or 2-fluoroethoxy groups, more preferably fluoromethoxy, difluoromethoxy or trifluoromethoxy groups, particularly more preferably difluoromethoxy Or a trifluoromethoxy group.
[23] C ₁ -C ₄ alkylthio groups of R ¹ , for example, straight or branched groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio or t-butylthio groups Terrestrial C ₁ -C ₄ alkylthio groups, preferably methylthio, ethylthio, propylthio or isopropylthio groups, more preferably methylthio or ethylthio groups, and even more preferably methylthio groups Can be mentioned.
[24] As a C ₁ -C ₄ alkylsulfinyl group of R ¹ , for example methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or t-butyl Linear or branched C ₁ -C ₄ alkylsulfinyl groups such as sulfinyl groups, preferably methylsulfinyl, ethylsulfinyl, propylsulfinyl or isopropylsulfinyl groups, more preferably methylsulfinyl Or an ethylsulfinyl group, particularly preferably a methylsulfinyl group.
[25] C ₁ -C ₄ alkylsulfonyl groups of R ¹ , for example methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or t-butyl Linear or branched C ₁ -C ₄ alkylsulfonyl groups such as sulfonyl groups, preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl groups, more preferably methylsulfonyl Or an ethylsulfonyl group, particularly preferably a methylsulfonyl group.
[26] Especially as R <^1> in general formula (I), Preferably, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a carboxyl group, 1H- tetrazole- 5-yl group, methyl group, ethyl group, propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group , 1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, 2-methyl- 1-propenyl group, ethynyl group, 1-propynyl group, 1-butynyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, methylthio group, ethylthio group, propylthio group, isopropylthio group, methylsul Pinyl group, ethyl sulfinyl group, propyl sulfinyl group, isopropyl sulfinyl group, methyl sulfonyl group, ethyl sulfonyl group, propyl sulfonyl group, or isopropyl sulfonyl group.
[27] More preferably, a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a 1H-tetrazol-5-yl group, a methyl group, an ethyl group, a fluoromethyl group, a difluoromethyl group, Trifluoromethyl group, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, vinyl group, 1-propenyl group, allyl group, ethynyl group, 1-propynyl group , 1-butynyl group, methoxy group, ethoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, ethylthio group, methylsulfinyl group, ethylsulfinyl group, methylsulfonyl group or ethyl Sulfonyl group, and even more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, a formyl group, a 1H-tetrazol-5-yl group, a methyl group, a difluoromethyl group and a trifluoromethyl group , Hydroxymethyl group, 1-hydroxy-1-methyl Tyl group, vinyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, methylsulfinyl group or methylsulfonyl group, particularly preferably hydrogen atom, fluorine atom, chlorine atom, cyano group And trifluoromethyl group, hydroxymethyl group, 1-hydroxy-1-methylethyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylsulfinyl group or methylsulfonyl group.
[28] In the general formula (I), the halogen atom of R ^2, C ₁ -C ₄ alkyl group and C ₁ -C ₄ alkoxy groups are the same as mentioned for the R ^1, R ² as preferably a hydrogen atom, a fluorine atom, a chlorine Atoms, bromine atoms, nitro groups, cyano groups, methyl groups, ethyl groups, propyl groups, isopropyl groups, methoxy groups, ethoxy groups, propoxy or isopropoxy groups, more preferably hydrogen atoms, fluorine atoms, chlorine atoms, Nitro group, cyano group, methyl group, ethyl group, methoxy group or ethoxy, even more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or methoxy, and even more preferably a hydrogen atom are mentioned.
[29] In general formula (I), the 5-membered or 6-membered heteroaromatic ring group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom of A or a heteroaromatic ring group and a benzene ring are condensed. Heteroaromatic condensed cyclic groups "include, for example, 5-membered aromatic cyclic groups such as furan, thiophene, oxazole, thiazole, imidazole, pyrazole or thiadiazole group; 6-membered heteroaromatic ring groups such as pyridine, pyrimidine, pyridazine or pyrazine group; Or heteroaromatic condensed cyclic groups such as benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, quinoline, quinazoline or quinoxaline group, and preferably oxazole, thiazole, imidazole, Pyrazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, benzoxazole, benzothiazole, benzimidazole, quinoline, quinazoline or quinoxaline group, more preferably thiazole, thiadiazole, pyridine , Pyrimidine, benzoxazole, benzothiazole, quinoline or quinazoline group, particularly preferably pyridine, benzothiazole or quinoline group.
[30] The hetero aromatic ring group or heteroaromatic fused ventilation may have a substituent (s), the substituent (s) include, for example, a halogen atom, shown in the same manner as R ^1; shown in the same manner as R _¹ C ¹ -C ₄ alkyl group; A fluoro C ₁ -C ₄ alkyl group as represented by R ¹ ; A fluoro C ₁ -C ₄ alkoxy group represented the same as R ₁ ; A C ₁ -C ₄ alkylthio group as represented by R ¹ ; Nitro group; Cyano group; Or C ₃ -C ₄ alkylene groups such as trimethylene and tetramethylene groups, wherein the alkylene groups combine with adjacent carbon atoms on the heteroaromatic ring to form a 5-membered ring or a 6-membered ring, and preferably fluorine Atom, chlorine atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl , Methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, methylthio, ethylthio, propylthio, isopropylthio, trimethylene Or a tetramethylene group, more preferably a fluorine atom, a chlorine atom, nitro, cyano, methyl, ethyl, isopropyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy , Fluoromethok , Difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, trimethylene or tetramethylene group, even more preferably fluorine atom, chlorine atom, nitro, cyano, methyl, isopropyl, t-butyl, di Fluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio or tetramethylene groups, and particularly preferably fluorine atom, chlorine atom, trifluoromethyl or tetramethylene group. .
[31] The number of substituents on the heteroaromatic ring group or the heteroaromatic condensed ring group is 1 to 4, preferably 1 to 2 pieces.
[32] As A in general formula (I), specifically, preferably, 2-oxazolyl, 2-thiazolyl, 2- or 4-imidazolyl, 3-pyrazolyl, 1,3,4-thiadiazole- 2-yl, 2-pyridyl, 2- or 4-pyrimidinyl, 3-pyridazinyl, 2-pyrazinyl, 2-benzooxazolyl, 2-benzothiazolyl, 2-benzoimidazolyl, quinoline- 2-yl, quinazolin-2-yl, quinoxalin-2-yl, 4-methyl-2-thiazolyl, 4-ethyl-2-thiazolyl, 4-isopropyl-2-thiazolyl, 4-t- Butyl-2-thiazolyl, 4-trifluoromethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazole -2-yl, 5-isopropyl-1,3,4-thiadiazol-2-yl, 5-t-butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl -1,3,4-thiadiazol-2-yl, 5,6-difluoro-2-pyridyl, 5,6-dichloro-2-pyridyl, 5,6-dimethyl-2-pyridyl, 5,6-diethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 6-methylthio-2-pyridyl, 5H-6,7-dihydrocyclopenta [b] pyridine-2 -Day, 5,6,7,8-te Trihydroquinolin-2-yl, 5,6-difluoro-2-pyrimidinyl, 5,6-dichloro-2-pyrimidinyl, 5,6-dimethyl-2-pyrimidinyl, 6-trifluoro Chloromethyl-2-pyrimidinyl, 5H-6,7-dihydrocyclopenta [d] pyrimidin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, 6-fluoro 2-benzooxazolyl, 5-fluoro-2-benzooxazolyl, 5,6-difluoro-2-benzooxazolyl, 6-chloro-2-benzooxazolyl, 5-chloro-2-benzooxa Zolyl, 5,6-dichloro-2-benzooxazolyl, 5-chloro-6-fluoro-2-benzooxazolyl, 5-methyl-2-benzooxazolyl, 5-cyano-2-benzooxazolyl, 5-trifluoromethyl-2-benzooxazolyl, 5-methylthio-2-benzooxazolyl, 6-fluoro-2-benzthiazolyl, 5-fluoro-2-benzothiazolyl, 5,6- Difluoro-2-benzothiazolyl, 6-chloro-2-benzothiazolyl, 5-chloro-2-benzothiazolyl, 5,6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro 2-benzothiazolyl, 5-meth -2-benzothiazolyl, 5-cyano-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-methylthio-2-benzothiazolyl, 5-fluoroquinoline-2- 1, 6-fluoroquinolin-2-yl, 6-fluoroquinolin-2-yl, 7-fluoroquinolin-2-yl, 5-chloro-2-quinolin-2-yl, 6-chloroquinoline-2 -Yl, 7-chloroquinolin-2-yl, 7-methylquinolin-2-yl, 7-trifluoromethylquinolin-2-yl, 7-methoxyquinolin-2-yl, 7-difluoromethoxyquinoline -2-yl, 7-trifluoromethoxyquinolin-2-yl, 5,7-difluoroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 5,7-dichloroquinoline- 2-yl, 6,7-dichloroquinolin-2-yl, 5-chloro-7-fluoroquinolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 7-chloro-5-fluoro Roquinolin-2-yl, 7-chloro-6-fluoroquinolin-2-yl, 7-chloro-6-cyano-quinolin-2-yl, 7-cyano-6-fluoroquinolin-2-yl , 6-fluoro-7-trifluoromethylquinolin-2-yl, 5,6,7-t Rifluoroquinolin-2-yl, 5-fluoroquinazolin-2-yl, 6-fluoroquinazolin-2-yl, 7-fluoro-quinazolin-2-yl, 5-chloroquinazolin-2 -Yl, 6-chloroquinazolin-2-yl, 7-chloroquinazolin-2yl, 7-methylquinazolin-2-yl, 7-trifluoromethylquinazolin-2-yl, 7-methoxyquina Zolin-2-yl, 7-difluoromethoxyquinazolin-2-yl, 7-trifluoromethoxyquinazolin-2-yl, 5,7-difluoroquinazolin-2-yl, 6,7- Difluoroquinazolin-2-yl, 5,7-dichloroquinazolin-2-yl, 6,7-dichloroquinazolin-2yl, 5-chloro-7-fluoroquinazolin-2-yl, 6- Chloro-7-fluoroquinazolin-2-yl, 7-chloro-5-fluoroquinazolin-2-yl, 7-chloro-6-fluoroquinazolin-2-yl, 7-chloro-6-cya Noquinazolin-2-yl, 7-cyano-6-fluoroquinazolin-2-yl, 6-fluoro-7-trifluoromethylquinazolin-2-yl or 5,6,7-trifluoro Roquinazolin-2-yl group,
[33] More preferably 2-thiazolyl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 2-pyrimidinyl, 2-benzooxazolyl, 2-benzothiazolyl, quinoline-2- 1, quinazolin-2-yl, 4-methyl-2-thiazolyl, 4-isopropyl-2-thiazolyl, 4-t-butyl-2-thiazolyl, 4-trifluoromethyl-2-thiazolyl , 5-methyl-1,3,4-thiadiazol-2-yl, 5-isopropyl-1,3,4-thiadiazol-2-yl, 5-t-butyl-1,3,4- Thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5,6-di-fluoro-2-pyridyl, 5,6-dichloro-2 -Pyridyl, 5,6-dimethyl-2-pyridyl, 5H-6,7-dihydrocyclopenta [b] pyridin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6-difluoro-2-pyrimidinyl, 5,6-dichloro-2-pyrimidinyl, 5,6-dimethyl-2-pyrimidinyl, 6-trifluoromethyl-2-pyrimidinyl , 5H-6,7-dihydrocyclopenta [d] pyrimidin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, 6-fluoro-2-benzooxazolyl, 5 Fluorine Ro-2-benzooxazolyl, 5,6-difluoro-2-benzooxazolyl, 6-chloro-2-benzooxazolyl, 5-chloro-2-benzooxazolyl, 5,6-dichloro-2- Benzooxazolyl, 5-chloro-6-fluoro-2-benzooxazolyl, 5-methyl-2-benzooxazolyl, 5-cyano-2-benzooxazolyl, 5-trifluoromethyl-2-benzo Oxazolyl, 5-methyl-thio-2-benzooxazolyl, 6-fluoro-2-benzothiazolyl, 5-fluoro-2-benzothiazolyl, 5,6-difluoro-2-benzothiazolyl , 6-chloro-2-benzothiazolyl, 5-chloro2-benzothiazolyl, 5,6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro-2-benzothiazolyl, 5-methyl -2-benzothiazolyl, 5-cyano-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-methylthio-2-benzothiazolyl, 5-fluoroquinoline-2- 1, 6-fluoroquinolin-2-yl, 7-fluoroquinolin-2-yl, 5-chloroquinolin-2-yl, 6-chloro-quinolin-2-yl, 7-chloroquinolin-2-yl, 7-methylquinolin-2-yl, 7-trifluoromethylquinolin-2-yl, 7-methoxyquinolin-2-yl, 7-difluoromethoxyquinolin-2-yl, 7-trifluoromethoxyquinolin-2-yl, 5,7- Difluoroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 5,7-dichloroquinolin-2-yl, 6,7-dichloroquinolin-2-yl, 5-chloro7-fluoro Roquinolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 7-chloro-5-fluoroquinolin-2-yl, 7-chloro-6-fluoroquinolin-2-yl, 7 -Chloro-6-cyanoquinolin-2-yl, 7-cyano-6-fluoroquinolin-2-yl, 6-fluoro-7-trifluoromethylquinolin-2-yl, 5,6,7 -Trifluoroquinolin-2-yl, 5-fluoroquinazolin-2-yl, 6-fluoroquinazolin-2yl, 7-fluoroquinazolin-2-yl, 5-chloro-quinazolin-2 -Yl, 6-chloroquinazolin-2-yl, 7-chloroquinazolin-2-yl, 7-methylquinazolin-2-yl, 7-trifluoromethylquinazolin-2-yl, 7-methoxy Quinazolin-2-yl, 7-difluoromethoxyquinazolin-2-yl, 7- Trifluoromethoxyquinazolin-2-yl, 5,7-difluoroquinazolin-2-yl, 6,7-difluoroquinazolin-2-yl, 5,7-dichloroquinazolin-2-yl , 6,7-dichloroquinazolin-2-yl, 5-chloro-7-fluoroquinazolin-2-yl, 6-chloro-7-fluoroquinazolin-2yl, 7-chloro-5-fluoro Quinazolin-2-yl, 7-chloro-6-fluoroquinazolin-2-yl, 7-chloro-6-cyanoquinazolin-2-yl, 7-cyano-6-fluoroquinazolin-2 -Yl, 6-fluoro-7-trifluoromethylquinazolin-2-yl or 5,6,7-trifluoroquinazolin-2-yl group;
[34] Even more preferably, 2-pyridyl, 2-benzothiazolyl, quinolin-2-yl, 5,6-difluoro-2-pyridyl, 5,6-dichloro-2-pyridyl, 5,6 -Dimethyl-2-pyridyl, 5,6,7,8-tetrahydroquinolin-2-yl, 6-fluoro-2-benzothiazolyl, 5-fluoro-2-benzothiazolyl, 5,6- Difluoro-2-benzothiazolyl, 6-chloro-2-benzothiazolyl, 5-chloro-2-benzothiazolyl, 5,6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro -2-benzothiazolyl, 5-methyl-2-benzothiazolyl, 5-cyano-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-methylthio-2-benzothia Zolyl, 5-fluoroquinolin-2-yl, 6-fluoroquinolin-2-yl, 7-fluoroquinolin-2yl, 5-chloroquinolin-2-yl, 6-chloroquinolin-2-yl, 7 -Chloroquinolin-2-yl, 7-methylquinolin-2-yl, 7-trifluoromethylquinolin-2-yl, 7-methoxyquinolin-2-yl, 7-difluoromethoxyquinolin-2-yl , 7-trifluoromethoxyquinolin-2- , 5,7-difluoroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 5,7-dichloroquinolin-2-yl, 6,7-dichloroquinolin-2-yl, 5 -Chloro-7-fluoroquinolin-2-yl, 6-chloro-7-fluoroquinolin-2yl, 7-chloro-5-fluoroquinolin-2-yl, 7-chloro-6-fluoroquinoline- 2-yl, 7-chloro-6-cyanoquinolin-2-yl, 7-cyano-6-fluoroquinolin-2yl, 6-fluoro-7-trifluoromethylquinolin-2-yl or 5 And 6,7-trifluoroquinolin-2-yl groups,
[35] Especially preferably, 5,6,7,8-tetrahydroquinolin-2-yl, 7-fluoroquinolin-2-yl, 7-chloroquinolin-2-yl, 6,7-difluoroquinoline-2 -Yl, 6,7-dichloroquinolin-2-yl or 7-chloro-6-fluoroquinolin-2-yl.
[36] In general formula (I), B is, for example, a formula: -CH = CH-, a formula: -CH ₂ O-, a formula: -CH ₂ CH _2- , a formula: -CH ₂ S-, a formula: -OCH ₂ Or formula: -SCH _2- , preferably formula: -CH = CH-, formula: -OCH ₂ -or formula: -CH ₂ O-.
[37] In said general formula (I), X is an oxygen atom, a sulfur atom, a methylene group, or a formula: = CH-, Preferably it is an oxygen atom or a sulfur atom.
[38] Examples of the C ₁ -C ₁₀ alkylene group of Y in the general formula (I) include a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene Linear C ₁ -C ₁₀ alkylene groups, preferably C ₁ -C ₆ alkylene groups, and more preferably C ₁ -C ₄ alkylene groups.
[39] Especially preferably, a methylene, ethylene, or trimethylene group is mentioned.
[40] The alkylene group may have a substituent, and as the substituent, a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ alkoxy group are the same as mentioned above in R ¹ .
[41] Substituents for the alkylene group of Y are preferably a fluorine atom, a chlorine atom, methyl, ethyl, propyl, methoxy, ethoxy or propoxy group, more preferably a fluorine atom, methyl, ethyl or methoxy group Especially preferably, a fluorine atom or a methyl group is mentioned.
[42] As group represented by Formula (a) of Y, Preferably, group which is o = 0, p = 0, and q = 1 (henceforth (a-1) group), o = 0, p = 1, and q = Groups having 1 group (hereinafter referred to as (a-2)), o = 0, p = 1, and q = 2 groups (hereinafter referred to as (a-3)), o = 1, p = 0 and groups with q = 1 (hereinafter referred to as (a-4)), o = 1, p = 1 and groups with q = 1 (hereinafter referred to as (a-5)), o = 1, p = 1 and q A group of = 2 (hereinafter referred to as (a-6) group), a group of o = 1, p = 1 and q = 3 (hereinafter referred to as (a-7) group), more preferably (a-4) The group, the group (a-5) or the group (a-6), the group more preferably (a-5) is mentioned.
[43] As a preferable group of Y in General formula (I), Specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, fluoromethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-methoxyethylene, 2-methoxyethylene, 1-fluoromethylene, 2-fluorotrimethylene, 3-fluorotrimethylene, 1,1-difluorotrimethylene, 2,2-difluoro Rotrimethylene, 3,3-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 2, 2-diethyltrimethylene, 2-methoxytrimethylene, 3-methoxytrimethylene, 2,2-dimethoxytrimethylene, 3,3-dimethoxytrimethylene, (a-1) group, (a-2 ), (A-3 ), (A-4), (a-5) or (a-6) groups, and more preferably methylene, ethylene, trimethylene, fluoromethylene, difluoromethylene, 1-fluoro Rhoethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 1-fluorotrimethylene, 2-fluorotree Methylene, 3-fluorotrimethylene, 1,1-difluorotrimethylene, 2,2-difluorotrimethylene, 3,3-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1 -Dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, (a-4) group, (a-5) group or (a-6) group, even more preferably methylene, Ethylene, trimethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2- Methylethylene, 2,2-difluorotrime Methylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene or (a-5) groups, particularly preferably methylene And ethylene, trimethylene, ethylidene, 1-methylethylene, 2-methylethylene or (a-5) groups.
[44] In a group of the formula -NH-SO ₂ -R ³ represented by Z or a formula -CO-NH-SO ₂ -R ³ , a C ₁ -C ₄ alkyl group of R ³ ; a fluoro C ₁ -C ₄ alkyl group; Or a halogen atom, a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group or a fluoro C ₁ -C ₄ alkoxy group which is a substituent on the phenyl group, respectively, as mentioned above in R ¹ Is the same as
[45] R ³ is preferably methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, phenyl, (o-, m-, or p-) fluorophenyl, (o-, m- or p-) chlorophenyl, (o-, m- or p-) methylphenyl, (o-, m- or p-) ethylphenyl, ( o-, m- or p-) (trifluoromethyl) phenyl, (o-, m- or p-) methoxyphenyl, (o-, m- or p-) ethoxyphenyl, (o-, m Or p-) (difluoromethoxy) phenyl, (o-, m- or p-) (trifluoromethoxy) phenyl, (o-, m- or p-) nitrophenyl or (o-, m- Or p-) cyanophenyl groups, more preferably methyl, ethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, phenyl, (o- or p- ) Fluorophenyl, (o- or p-) chlorophenyl, (o- or p-) methylphenyl, (o- or p-)-(trifluoromethyl) phenyl, (o- or p-) methoxyphenyl , (o- or p-) (difluoromethoxy) Nyl, (o- or p-) (trifluoromethoxy) -phenyl, (o- or p-) nitrophenyl or (o- or p-) cyanophenyl groups, even more preferably methyl, ethyl, trifluoro Romethyl, phenyl, p-fluorophenyl, p-chlorophenyl, (o- or p-)-methylphenyl, p- (trifluoromethyl) phenyl, (o- or p-) methoxyphenyl, p- ( Difluoromethoxy) phenyl, p- (trifluoromethoxy) -phenyl, p-nitrophenyl or p-cyanophenyl groups, particularly preferably methyl, trifluoromethyl, phenyl, o-methylphenyl or p-methylphenyl groups Can be mentioned.
[46] As a preferable group of Z in General formula (I), Specifically, carboxy, 1H- tetrazol-5-yl, methanesulfonylamino, ethanesulfonylamino, trifluoromethanesulfonylamino, phenylsulfonylamino, p-fluorophenylsulfonylamino, p-chlorophenylsulfonylamino, o-methylphenylsulfonylamino, p-methylphenylsulfonylamino, p-trifluoromethylphenylsulfonylamino, o-methoxyphenylsulfonylamino, p-methoxyphenylsulfonylamino, p-difluoromethoxyphenylsulfonylamino, p-trifluoromethoxyphenylsulfonylamino, p-nitrophenylsulfonylamino, p-cyanophenylsulfonylamino, methanesulfur Ponylaminocarbonyl, ethanesulfonylaminocarbonyl, trifluoromethanesulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, p-fluorophenylsulfonylaminocarbonyl, p-chlorophenylsulfonylaminocarbonyl, o-methylphenylsulfonylaminocarbonyl, p-methylphenylsulfonylaminocarbonyl, p-trifluoromethylphenylsulfonylaminocarbonyl, o-methoxyphenylsulfonylaminocarbonyl, p-methoxyphenylsulfonylaminocarbonyl, p-difluoromethoxyphenyl Sulfonylaminocarbonyl, p-trifluoromethoxyphenylsulfonylaminocarbonyl, p-nitrophenylsulfonylaminocarbonyl or p-cyanophenylsulfonylaminocarbonyl group.
[47] More preferably, carboxy, 1H-tetrazol-5-yl, methanesulfonylamino, trifluoromethanesulfonylamino, phenylsulfonylamino o-methylphenylsulfonylamino, p-methylphenylsulfonylamino, methanesulfonyl Aminocarbonyl, trifluoromethanesulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, o-methylphenylsulfonylaminocarbonyl or p-methylphenylsulfonylaminocarbonyl group, even more preferably carboxy, methanesulfonylamino , Trifluoromethanesulfonylamino, methanesulfonylaminocarbonyl or trifluoromethanesulfonylaminocarbonyl group, and particularly preferably a carboxyl group.
[48] Incidentally, when Z is a carboxyl group, the carboxyl group can be protected with a protecting group. The protecting group is not particularly limited as long as it can be easily deprotected in vivo and converted into a carboxyl group, for example, the same C ₁ -C ₄ alkyl group as defined in R ¹ ; C ₇ such as benzyl, phenylethyl or phenylpropyl groups. -C ₁₀ aralkyl group; acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, 1-acetoxybutyl, propanoyloxymethyl, 1-propanoyloxyethyl, butanoyloxymethyl, 1-buta C ₁ -substituted with a C ₂ -C ₅ alkanoyloxy group such as noyloxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, 1-pivaloyloxypropyl or 1-pivaloyloxybutyl group C ₄ alkyl group; methoxycarbonyloxymethyl, 1- (methoxycarbonyl) oxyethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, propoxycarbonyloxymethyl, oxymethylcarbon Bonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxyme , 1- (butoxycarbonyloxy) ethyl, t- butoxycarbonyloxy-methyl or 1- (t- butoxycarbonyloxy) ethyl group such as (C ₁ -C ₄ alkoxy) carbonyloxy substituted by C _1- C ₄ alkyl group; N, N-di (C ₁ -C ₄ alkyl) amino, such as N, N-dimethylaminocarbonylmethyl, 2- (N, N-dimethylaminocarbonyl) ethyl or N, N-diethylaminocarbonylmethyl group C ₁ -C ₄ alkyl group substituted with a carbonyl group; 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-piperidinoethyl, 2- (4-methyl N, N-di (C ₁ -C ₄ alkyl) amino group or 5- to 6-membered ring which may contain oxygen atoms such as) -piperidinoethyl, 3-piperidinopropyl or 2-morpholinoethyl group C ₁ -C ₄ alkyl group substituted with an amino group; Or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group.
[49] As the protecting group of a carboxyl group, preferably a C ₁ -C ₄ alkyl group; a benzyl group; C ₂ -C ₅ alkanoyl C ₁ -C ₂ alkyl group substituted with ilrok time; (C ₁ -C ₄ alkoxy) carbonyl group substituted by hydroxy C ₁ -C ₂ alkyl group; Or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group,
[50] More preferably, there is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl or 1-pivaloyloxyethyl group.
[51] In said general formula (I), m is an integer of 1-4, Preferably m is 1, 2 or 3, Especially preferably, it is 1 or 2. When m is 2 or more, R ¹ may be different from each other.
[52] In said general formula (I), n is an integer of 1-3, Preferably n is 1 or 2, Especially preferably, it is 1. When n is 2 or more, R ² may be different from each other.
[53] In the compound (I) of the present invention, optical isomers (including diastereomers) exist due to asymmetric carbon atoms in the molecule, or geometric isomers exist due to double bonds, and each of these isomers is also included in the present invention. do.
[54] In addition, the compound (I) of the present invention may be converted into a pharmacologically acceptable salt as necessary. Such pharmacologically acceptable salts include, for example, acid addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodine, sulfates or phosphates; Acid addition salts of organic acids such as trifluoroacetate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartarate or citrate; sodium salts, potassium salts Metal salts of carboxylic acids, such as calcium salts, magnesium salts, manganese salts, iron salts or aluminum salts; Or pharmacologically acceptable salts such as salts with organic bases such as ammonium salts, triethylamine salts, guanidiene salts, hydrazine salts, quineine salts, or cinconine salts.
[55] In addition, the compound (I) of the present invention may also exist as a hydrate.
[56] In the dibenzocyclopeptene compound having the general formula (I) of the present invention, Preferably,
[57] (1) R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a carboxyl group, 1H-tetrazol-5- Diary, methyl group, ethyl group, propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, hydroxy methyl group, 1-hydroxy ethyl group, 2-hydroxy ethyl group, 1 -Hydroxy-1-methylethyl group, 1-hydroxy propyl group, 2-hydroxy propyl group, vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, 2-methyl-1- Propenyl group, ethynyl group, 1-propynyl group, 1-butynyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2- Fluoroethoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfinyl, ethyl Dibenzocycloheptene compound selected from sulfinyl group, propyl sulfinyl group, isopropyl sulfinyl group, methyl sulfonyl group, ethyl sulfonyl group, propyl sulfonyl group and isopropyl sulfonyl group,
[58] (2) R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a 1H-tetrazol-5-yl group, a methyl group, an ethyl group , Fluoromethyl group, difluoromethyl group, trifluoromethyl group, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, vinyl group, 1-propenyl group, Allyl group, ethynyl group, 1-propynyl group, 1-butynyl group, methoxy group, ethoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, ethylthio group, methylsulfinyl group , Dibenzocyclopeptene compound selected from ethyl sulfinyl group, methyl sulfonyl group and ethyl sulfonyl group,
[59] (3) R ¹ of the compound represented by formula (I) is hydrogen atom, fluorine atom, chlorine atom, nitro group, cyano group, formyl group, 1H-tetrazol-5-yl group, methyl group, difluoromethyl group, trifluor Among rhomethyl group, hydroxy methyl group, 1-hydroxy-1-methylethyl group, vinyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, methylsulfinyl group and methylsulfonyl group Dibenzocycloheptene compound selected,
[60] (4) R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a trifluoromethyl group, a hydroxy methyl group, a 1-hydroxy-1-methylethyl group, an ethynyl group, or a methoxy Dibenzocycloheptene compound selected from season, difluoromethoxy group, trifluoromethoxy group, methylsulfinyl group and methylsulfonyl group,
[61] (5) R ² of the compound represented by formula (I) is hydrogen atom, fluorine atom, chlorine atom, bromine atom, nitro group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, pro Dibenzocycloheptene compound selected from aoxy group and isopropoxy group,
[62] (6) a dibenzocycloheptene compound in which R ² of the compound represented by formula (I) is selected from hydrogen atom, fluorine atom, chlorine atom, nitro group, cyano group, methyl group, ethyl group, methoxy group and ethoxy,
[63] (7) a dibenzocycloheptene compound in which R ² of the compound represented by formula (I) is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and a methoxy group;
[64] (8) a dibenzocycloheptene compound wherein R ² of the compound represented by formula (I) is a hydrogen atom;
[65] (9) A of the compound represented by formula (I) is 2-thiazolyl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 2-pyrimidinyl, 2-benzooxazolyl, 2 -Benzothiazolyl, quinolin-2-yl, quinazolin-2-yl, 4-methyl-2-thiazolyl, 4-isopropyl-2-thiazolyl, 4-t-butyl-2-thiazolyl, 4- Trifluoromethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-isopropyl-1,3,4-thiadiazol-2-yl, 5-t -Butyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5,6-difluoro-2-pyridyl , 5,6-dichloro-2-pyridyl, 5,6-dimethyl-2-pyridyl, 5H-6,7-dihydrocyclopenta [b] pyridin-2-yl, 5,6,7,8- Tetrahydroquinolin-2-yl, 5,6-difluoro-2-pyrimidinyl, 5,6-dichloro-2-pyrimidinyl, 5,6-dimethyl-2-pyrimidinyl, 6-trifluoro Romethyl-2-pyrimidinyl, 5H-6,7-dihydrocyclopenta [d] -pyrimidin-2-yl, 5,6,7,8-tetrahydroquinazolin-2-yl, 6-fluoro Rho-2-benzoxazole Reel, 5-fluoro-2-benzooxazolyl, 5,6-difluoro-2-benzooxazolyl, 6-cyclo-2-benzooxazolyl, 5-chloro-2-benzooxazolyl, 5,6 -Dichloro-2-benzooxazolyl, 5-cyclo-6-fluoro-2-benzooxazolyl, 5-methyl-2-benzooxazolyl, 5-cyano-2-benzooxazolyl, 5-trifluoro Methyl-2-benzooxazolyl, 5-methylthio-2-benzooxazolyl, 6-fluoro-2-benzothiazolyl, 5-fluoro-2-benzothiazolyl, 5,6-difluoro-2 -Benzothiazolyl, 6-chloro-2-benzothiazolyl, 5-chloro-2-benzothiazolyl, 5,6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro-2-benzothia Zolyl, 5-methyl-2-benzothiazolyl, 5-cyano-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-methylthio-2-benzothiazolyl, 5-fluoro Roquinolin-2-yl, 6-fluoroquinolin-2-yl, 7-fluoroquinolin-2-yl, 5-chloroquinolin-2-yl, 6-chloroquinolin-2-yl, 7-chloroquinoline 2-yl, 7-methyl Nolin-2-yl, 7-trifluoromethylquinolin-2yl, 7-methoxyquinolin-2-yl, 7-difluoromethoxyquinolin-2-yl, 7-trifluoromethoxyquinolin-2-yl , 5,7-difluoroquinolin-2-yl, 6,7-difluoroquinolin-2yl, 5,7-dichloroquinolin-2-yl, 6,7-dichloroquinolin-2-yl, 5- Chloro-7-fluoroquinolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 7-chloro-5-fluoroquinolin-2-yl, 7-chloro-6-fluoroquinoline- 2-yl, 7-chloro-6-cyanoquinolin-2-yl, 7-cyano-6-fluoroquinolin-2-yl, 6-fluoro-7-trifluoromethylquinolin-2-yl, 5,6,7-trifluoroquinolin-2-yl, 5-fluoroquinazolin-2-yl, 6-fluoroquinazolin-2-yl, 7-fluoroquinazolin-2-yl, 5 -Chloroquinazolin-2-yl, 6-chloroquinazolin-2-yl, 7-chloroquinazolin-2-yl, 7-methylquinazolin-2-yl, 7-trifluoromethylquinazolin-2- 1,7-methoxyquinazolin-2-yl, 7-difluoromethoxyquina Lin-2-yl, 7-trifluoromethoxyquinazolin-2-yl, 5,7-difluoroquinazolin-2-yl, 6,7-difluoroquinazolin-2-yl, 5,7 -Dichloroquinazolin-2-yl, 6,7-dichloroquinazolin-2-yl, 5-chloro-7-fluoroquinazolin-2-yl, 6-chloro-7-fluoroquinazolin-2-yl , 7-chloro-5-fluoroquinazolin-2-yl, 7-chloro-6-fluoroquinazolin-2-yl, 7-chloro-6-cyanoquinazolin-2-yl, 7-cyano Dibenzo selected from -6-fluoroquinazolin-2-yl, 6-fluoro-7-trifluoromethylquinazolin-2-yl and 5,6,7-trifluoroquinazolin-2-yl groups Cycloheptene compounds,
[66] (10) A of the compound represented by formula (I) is 2-pyridyl, 2-benzothiazolyl, quinolin-2-yl, 5,6-dimethyl-2-pyridyl, 5,6,7,8- Tetrahydroquinolin-2-yl, 6-fluoro-2-benzothiazolyl, 5-fluoro-2-benzothiazolyl, 5,6-difluoro-2-benzothiazolyl, 6-chloro-2- Benzothiazolyl, 5-chloro-2-benzothiazolyl, 5,6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro-2-benzothiazolyl, 5-methyl-2-benzothiazolyl , 5-cyano-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-methylthio-2-benzothiazolyl, 5-fluoroquinolin-2-yl, 6-fluoro Quinolin-2-yl, 7-fluoroquinolin-2-yl, 5-chloroquinolin-2-yl, 6-chloroquinolin-2-yl, 7-chloroquinolin-2-yl, 7-methylquinoline-2- 1,7-trifluoromethylquinolin-2-yl, 7-methoxyquinolin-2-yl, 7-difluoromethoxyquinolin-2-yl, 7-trifluoromethoxyquinolin-2-yl, 5, 7-difluoroquinolin-2-yl, 6,7- Difluoroquinolin-2-yl, 5,7-dichloroquinolin-2-yl, 6,7-dichloroquinolin-2-yl, 5-chloro-7-fluoroquinolin-2-yl, 6-chloro-7 -Fluoroquinolin-2-yl, 7-chloro-5-fluoroquinolin-2-yl, 7-chloro-6-fluoroquinolin-2-yl, 7-chloro-6-cyanoquinolin-2-yl , 7-cyano-6-fluoroquinolin-2-yl, 6-fluoro-7-trifluoromethylquinolin-2-yl and 5,6,7-trifluoroquinolin-2-yl group Dibenzocycloheptene compound,
[67] (11) A of the compound represented by formula (I) is 5,6,7,8-tetrahydroquinolin-2-yl, 7-fluoroquinolin-2-yl, 7-chloroquinolin-2-yl, 6, Dibenzocycloheptene compound selected from 7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro-6-fluoroquinolin-2-yl group,
[68] (12) a dibenzocycloheptene compound, wherein B of the compound represented by formula (I) is formula -CH = CH, formula -OCH _2-, or formula -CH ₂ O-;
[69] (13) a dibenzocycloheptene compound wherein X of the compound represented by formula (I) is an oxygen atom or a sulfur atom,
[70] (14) Y of the compound represented by formula (I) is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, fluoromethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1 -Difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, 1-ethylethylene, 2-ethyl Ethylene, 1-methoxyethylene, 2-methoxyethylene, 1-fluorotrimethylene, 2-fluorotrimethylene, 3-fluoromethylene, 1,1-difluorotrimethylene, 2,2-difluorotrimethylene, 3,3-difluorotrimethylene-1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 2,2-di Ethyltrimethylene, 2-methoxytrimethylene, 3-methoxytrimethylene, 2,2-dimethoxytrimethylene, 3,3-dimethoxytrimethylene, (a-1) group, (a-2) group, (a-3), (a-4), (a-5) and dibenzocycloheptene compound selected from (a-6) groups,
[71] (15) Y of the compound represented by formula (I) is methylene, ethylene, trimethylene, fluoromethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethyledene, 1-methylethylene, 2-methylethylene, 1-fluorotrimethylene, 2-fluorotrimethylene, 3-fluorotrimethylene, 1,1-difluorotrimethylene, 2,2-difluorotrimethylene, 3,3-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3- Dibenzocycloheptene compound selected from dimethyltrimethylene, (a-4) group, (a-5) group and (a-6) group,
[72] (16) Y of the compound represented by formula (I) is methylene, ethylene, trimethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2- Difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 2,2-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2 Dibenzocycloheptene compound selected from -dimethyltrimethylene, 3,3-dimethyltrimethylene and (a-5) group,
[73] (17) a dibenzocycloheptene compound in which Y of the compound represented by formula (I) is selected from methylene, ethylene, trimethylene, ethylidene, 1-methylethylene, 2-methylethylene, and (a-5) groups,
[74] (18) Z of the compound represented by formula (I) is carboxy, 1H-tetrazol-5-yl, methanesulfonylamino, ethanesulfonylamino, trifluoromethanesulfonylamino, phenylsulfonylamino, p-fluoro Rophenylsulfonylamino, p-chlorophenylsulfonylamino, o-methylphenylsulfonylamino, p-methylphenylsulfonylamino, p-trifluoromethylphenylsulfonylamino, o-methoxyphenylsulfonylamino, p-meth Methoxyphenylsulfonylamino, p-difluoromethoxyphenylsulfonylamino, p-trifluoromethoxyphenylsulfonylamino, p-nitrophenylsulfonylamino, p-cyanophenylsulfonylamino, methanesulfonylaminocar Carbonyl, ethanesulfonylaminocarbonyl, trifluoromethanesulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, p-fluorophenylsulfonylaminocarbonyl, p-chlorophenylsulfonylaminocarbonyl, o-methylphenyl Sulfonylaminocarbonyl, p-methylphenylsulfonyl Nocarbonyl, p-trifluoromethylphenylsulfonylaminocarbonyl, o-methoxyphenylsulfonylaminocarbonyl, p-methoxyphenylsulfonylaminocarbonyl, p-difluoromethoxyphenylsulfonylaminocarbonyl di- selected from p-trifluoromethoxyphenylsulfonylaminocarbonyl, p-trifluoromethoxyphenylsulfonylaminocarbonyl, p-nitrophenylsulfonylaminocarbonyl and p-cyanophenylsulfonylaminocarbonyl group Benzocycloheptene compound,
[75] (19) Z of the compound represented by formula (I) is carboxy, 1H-tetrazol-5-yl, methanesulfonylamino, trifluoromethanesulfonylamino, phenylsulfonylamino, o-methylphenylsulfonylamino, p Di-methylphenylsulfonylamino, methanesulfonylaminocarbonyl, trifluoromethanesulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, o-methylphenylsulfonylaminocarbonyl and p-methylphenylsulfonylaminocarbonyl group Benzocycloheptene compound,
[76] (20) Z of the compound represented by formula (I) is dibenzocycloheptene selected from carboxy, methanesulfonylamino, trifluoromethanesulfonylamino, methanesulfonylaminocarbonyl and trifluoromethanesulfonylaminocarbonyl groups compound,
[77] (21) A dibenzocycloheptene compound wherein Z of the compound represented by formula (I) is a carboxyl group,
[78] (22) when Z of the compound represented by formula (I) is a carboxyl group, the protecting group is a C ₁ -C ₄ alkyl group; a benzyl group; a C ₁ -C ₂ alkyl group substituted with a C ₂ -C ₅ alkanoyloxy group; A C ₁ -C ₂ alkyl group substituted with a (C ₁ -C ₄ alkoxy) carbonyloxy group; And a (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl group, a dibenzocycloheptene compound,
[79] (23) When Z of the compound represented by formula (I) is a carboxyl group, the protecting group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl and Dibenzocycloheptene compound selected from 1-pivaloyloxyethyl group,
[80] (24) a dibenzocycloheptene compound wherein m of the compound represented by formula (I) is 1,2 or 3;
[81] (25) a dibenzocycloheptene compound wherein m of the compound represented by formula (I) is 1 or 2,
[82] (26) a dibenzocycloheptene compound wherein n is 1 or 2 of the compound represented by formula (I),
[83] For 27 expression of the compounds represented by (I) wherein n is 1, dibenzo-cycloheptene compounds, dibenzo-cycloheptene compounds, up the net in a desired order of for R ¹ in (1) (4), R ² More preferred in order of (5) to (8), more preferred in order of (9) to (11) for A, more preferred in order of (14) to (17) for Y, Z It is more preferable in order of (18) to (21), and when Z is a carboxyl group, it is more preferable in order of this protecting group (22) to (23), and for m in order of (24) to (25) It is more preferable, and about n is more preferable in order of (26)-(27).
[84] Moreover, as a dibenzocycloheptene compound which has the said general formula (I), the dibenzocycloheptene compound containing two or more compounds of said (1)-(27) is preferable.
[85] For example, the following can be mentioned.
[86] (28) R ¹ of the compound represented by formula (I) is hydrogen atom, fluorine atom, chlorine atom, nitro group, cyano group, formyl group, 1H-tetrazol-5-yl group, methyl group, difluoromethyl group, trifluor Among rhomethyl group, hydroxymethyl group, 1-hydroxy-1-methylethyl group, vinyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, methylsulfinyl group and methylsulfonyl group R ² is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and a methoxy group, and A is 5,6,7,8-tetrahydroquinolin-2-yl, 7-fluoroquinolin-2-yl , 7-chloroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro-6-fluoroquinolin-2-yl , B is formula -CH = CH-, formula -OCH ₂ - or a group represented by the formula -CH ₂ O-, and and X is selected from oxygen atom or sulfur atom, Y is methylene, ethylene, trimethylene, Fluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 2,2 -Difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene and (a-5) groups, Z is a carboxy, methanesulfonylamino, trifluoromethanesulfonylamino, methanesulfonylaminocarbonyl and trifluoromethanesulfonylaminocarbonyl group, m is 1 or 2, n is 1,
[87] (29) R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a trifluoromethyl group, a hydro group methyl group, a 1-hydroxy-1-methylethyl group, an ethynyl group, or a methoxy group , Difluoromethoxy group, trifluoromethoxy group, methylsulfinyl group and methylsulfonyl group, R ² is a hydrogen atom, A is 5,6,7,8-tetrahydroquinolin-2-yl, 7 -Fluoroquinolin-2-yl, 7-chloroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro-6-fluoro A quinolin-2-yl group, wherein B is a formula -CH = CH-, a formula -OCH ₂ -or a formula -CH ₂ O-, X is an oxygen atom or a sulfur atom, Y is methylene, ethylene, trimethylene, A compound selected from ethylidene, 1-methylethylene, 2-methylethylene and (a-5) groups, Z is a carboxyl group, m is 1 or 2, n is 1,
[88] As a preferable compound in compound (I), the compound of the following Table 1 can be illustrated concretely.
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154] Additionally, the abbreviations in the table above are
[155] t-Bu: t-butyl group, BT: 2-benzothiazolyl group, Tet: 1H-tetrazol-5-yl group, Ph: phenyl group, Py: 2-pyridyl group, Q: quinolin-2-yl group, T: 2-thiazolyl group and TQ: 2,5,6,7,8-tetrahydroquinolin-2-yl group,
[156] _{-OCH 2 C (CH 2 CH 2} ) -CH 2 COOH or _{-SCH 2 C (CH 2 CH 2} ) CH 2 C in _{CH 2 COOH (CH 2 CH 2} ) CH 2 portion, o = 1, p = Equation (a) with 1 and q = 1, wherein CH ₂ C (CH ₂ CH ₂ ) CH ₂ moiety in —SCH ₂ C (CH ₂ CH ₂ ) COOH is o = 1, p = 0, and q Formula (a) of = 1 is shown. In addition, in the said Table 1, the number in general formula (I) shows the position number of a substituent.
[157] As a more preferable compound, Compound No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 24, 25, 27, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 47, 49, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 78, 79, 87, 89, 92, 94, 97, 99, 102, 103, 104, 105, 106, 107, 110, 112, 118, 121, 122, 123, 124, 128, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 149, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 170, 179, 184, 185, 190, 191, 196, 197, 202, 203, 220, 223, 224, 241, 243, 244, 245, 246, 247, 248, 249, 250, 251, 257, 264, 273, 274, 275, 277, 280, 281, 282, 283, 284, 285, 288, 296, 298, 299, 300, 301, 302, 303, 304, 305, 306, 308, 309, 310, 311, 312, 313, 314, 315, 319, 320, 327, 329, 331, 332, 333, 334, 335, 336, 337, 340, 348, 351, 366, 368, 371, 372, 373, 374, 375, 376, 378, 379, 387, 392, 393, 394, 396, 397, 400, 420, 421, 426, 427, 429, 432,433, 435, 453, 454, 455, 456, 471, 472, 473, 474, 475, 476, 477, 478, 479, 481, 482, 483, 484, 485, 486, 487, 494, 495, 497, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 517, 519, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 546, 548, 549, 557, 558, 559, 562, 564, 567, 569, 572, 573, 574, 575, 576, 577, 580, 582, 588, 591, 592, 593, 594, 598, 606, 608, 609, 610, 611, 612, 613, 614, 615, 616, 619, 627, 629, 630, 631, 632, 633, 634, 635, 636, 637, 640, 649, 654, 655, 660, 661, 666, 667, 672, 673, 690, 693, 694, 711, 713, 714, 715, 716, 717, 718, 719, 720, 721, 727, 734, 743, 744, 745, 747, 750, 751, 752, 753, 754, 755, 758, 766, 768, 769, 770, 771, 772, 773, 774, 775, 776, 778, 779, 780, 781, 782, 783, 784, 785, 789, 790, 797, 799, 801, 802, 803, 804, 805, 806, 807, 810, 818, 821, 836, 838, 841, 842, 843, 844, 845, 846, 848, 849, 857, 862, 863, 864, 866, 867, 870, 890, 891, 896, 897, 899, 902, 903, 905, 923, 924, 925, 926, 941, 942, 943, 944, 945, 946, 947, 948, 949, 951, 952, 953, 954, 955, 956, 957, 964, 965, 967, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 987, 989, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1016, 1018, 1019, 1027, 1029, 1032, 1034, 1037, 1039, 1042, 1043, 1044, 1045, 1046, 1047, 1050, 1052, 1058, 1061, 1062, 1063, 1064, 1068, 1076, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1089, 1097, 1099, 1100, 1101,1102, 1103, 1104, 1105, 1106, 1107, 1110, 1119, 1124, 1125, 1130, 1131, 1136, 1137, 1142, 1143, 1160, 1163, 1164, 1181, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1197, 1204, 1213, 1214, 1215, 1217, 1220, 1221, 1222, 1223, 1224, 1225, 1228, 1236, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1259, 1260, 1267, 1269, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1280, 1288, 1291, 1306, 1308, 1311, 1312, 1313, 1314, 1315, 1316, 1318, 1319, 1327, 1332, 1333, 1334, 1336, 1337, 1340, 1360, 1361, 1366, 1367, 1369, 1372, 1373, 1375, 1393, 1394, 1395, 1396, 1411 , 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1434, 1435, 1437, 1443, 1444, 1445, 1446, 1447, 1448, 1449 , 1450, 1451, 1452, 1453, 1454, 1457, 1459, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482 , 1483, 1484, 1486, 1488, 1489, 1497, 1499, 1502, 1504, 1507, 1509, 1512, 1513, 1514, 1515, 1516, 1517, 1520, 1522, 1528, 1531, 1532, 1533, 1534, 1538 , 1546, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1559, 1567, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1580, 1589, 1594, 1595 , 1600, 1601, 1606, 1607, 1612, 1613, 1630, 1633, 1634, 1651, 1653, 1654, 1655, 1656, 1657, 1658, 1659, 1660, 1661, 1667, 1674, 1683, 1684, 1685, 1687 , 1690, 1691, 1692, 1693, 1694, 1695, 1698, 1706, 1708, 1709, 1710, 1711, 1712, 1713, 1714, 1715, 1716, 1718, 1719, 1720, 1721, 1722, 1723, 1724, 1725 , 1729, 1730, 1737, 1739, 1741, 1742,1743, 1744, 1745, 1746, 1747, 1750, 1758, 1761, 1776, 1778, 178 1, 1782, 1783, 1784, 1785, 1786, 1788, 1789, 1797, 1802, 1803, 1804, 1806, 1807, 1810, 1830, 1831, 1836, 1837, 1839, 1842, 1843, 1845, 1863, 1864, 1865, 1866, 1884, 1885, 1886, 1888, 1894, 1903, 1907, 1911, 1915, 1921, 1925, 1931, 1932, 1934, 1940, 1949, 1953, 1961, 1967, 1971, 1976, 1978, 1980, 1982, 1984, 1988, 1990, 1994, 1995, 1996, 2000, 2001, 2002, 2004, 2006, 2007, 2008, 2012, 2013, 2014, 2018, 2019, 2020, 2024, 2028, 2031, 2034, 2037, 2040, 2043, 2046, 2049, 2052, 2055, 2058, 2061, 2064, 2067, 2070, 2073, 2076, 2079, 2082, 2085, 2088, 2091, 2094, 2097 or 2100.
[158] More preferably, compound no. 1, 2, 3, 4, 6, 7, 8, 9, 11, 14, 15, 17, 35, 37, 38, 40, 41, 42, 43, 47, 49, 55, 57, 60, 62, 63, 64, 65, 66, 67, 70, 72, 73, 74, 78, 79, 87, 89, 92, 94, 97, 102, 104, 105, 106, 110, 121, 122, 123, 136, 138, 141, 143, 144, 145, 149, 157, 159, 162, 163, 164, 165, 166, 170, 191, 197, 202, 203, 220, 224, 241, 243, 246, 247, 248, 249, 251, 257, 275, 280, 282, 283, 284, 288, 296, 298, 301, 303, 304, 305, 306, 308, 311, 312, 313, 314, 315, 320, 327, 332, 334, 335, 336, 340, 351, 366, 371, 372, 373, 374, 375, 376, 379, 387, 393, 394, 400, 420, 421, 426, 427, 432, 433, 453, 456, 471, 473, 474, 476, 477, 478, 479, 481, 484, 485, 487, 505, 507, 508, 510, 511, 512, 513, 517, 519, 525, 527, 530, 532, 533, 534, 535, 536, 537, 540, 542, 543, 544, 548, 549, 557, 558, 559, 562, 564, 567, 572, 574,575, 576, 580, 591, 592, 593, 606, 608, 611, 613, 614, 615, 619, 627, 629, 632, 633, 634, 635, 636, 640, 661, 667, 672, 673, 690, 694, 711, 713, 716, 717, 718, 719, 721, 727, 745, 750, 752, 753, 754, 758, 766, 768, 771, 773, 774, 775, 776, 778, 781, 782, 783, 784, 785, 790, 797, 802, 804, 805, 806, 810, 821, 836, 841, 842, 843, 844, 845, 846, 849, 857, 863, 864, 870, 890, 891, 896, 897, 902, 903, 923, 926, 941, 943, 944, 946, 947, 948, 949, 951, 954, 955, 957, 975, 977, 978, 980, 981, 982, 983, 987, 989, 995, 997, 1000, 1002, 1003, 1004, 1005, 1006, 1007, 1010, 1012, 1013, 1014, 1018, 1019, 1027, 1029, 1032, 1034, 1037, 1042, 1044, 1045, 1046, 1050, 1061, 1062, 1063, 1076, 1078, 1081, 1083, 1084, 1085, 1089, 1097, 1099, 1102, 1103, 1104, 1105, 1106, 1110, 1131, 1137, 1142, 1143, 1160, 1164, 1181, 1183, 1186, 1187, 1188, 1189, 1191, 1197, 1215, 1220, 1222, 1223, 1224, 1225, 1228, 1236, 1238, 1241, 1243, 1244, 1245, 1246, 1248, 1251, 1252, 1253, 1254, 1255, 1260, 1267, 1272, 1274, 1275, 1276, 1280, 1291, 1306, 1311, 1312, 1313, 1314, 1315, 1316, 1319, 1327, 1333, 1334, 1340, 1360, 1361, 1366, 1367, 1372, 1373, 1393, 1396, 1411, 1413, 1414, 1416, 1417, 1418, 1419, 1421, 1424, 1425, 1427, 1445, 1447, 1448, 1450, 1451, 1452, 1453, 1457, 1459, 1465, 1467, 1470, 1472, 1473, 1474, 1475, 1476, 1477, 1480, 1482, 1483, 1484, 1488, 1489, 1497, 1499, 1502, 1504, 1507, 1512, 1514, 1515, 1516, 1520, 1531, 1532, 1533, 1546, 1548, 1551, 1553, 1554, 1555, 1559, 1567, 1569, 1572, 1573, 1574, 1575, 1576, 1580, 1601, 1607, 1612, 1613,1630, 1634, 1651, 1653, 1656, 1657, 1658, 1659, 1661, 1667, 1685, 1690, 1692, 1693, 1694, 1695, 1698, 1706, 1708, 1711, 1713, 1714, 1715, 1716, 1718, 1721, 1722, 1723, 1724, 1725, 1730, 1737, 1742, 1744, 1745, 1746, 1750, 1761, 1776, 1781, 1782, 1783, 1784, 1785, 1786, 1789, 1797, 1803, 1804, 1810, 1830, 1831, 1836, 1837, 1842, 1843, 1863, 1866, 1885, 1886, 1888, 1894, 1907, 1911, 1915, 1921, 1931, 1932, 1934, 1953, And compounds of 1961, 1967 or 1971.
[159] Even more preferably Compound No. 1, 2, 3, 4, 6, 8, 9, 11, 15, 17, 38, 40, 41, 42, 43, 47, 62, 63, 64, 72, 73, 74, 79, 87, 89, 92, 94, 97, 104, 106, 110, 121, 136, 143, 144, 145, 149, 157, 163, 164, 165, 166, 191, 197, 203, 220, 247, 248, 249, 251, 257, 282, 283, 284, 303, 312, 313, 314, 315, 334, 372, 373, 374, 375, 393, 394, 421, 427, 433, 471, 473, 474, 476, 477, 478, 479, 481, 485, 487, 505, 508, 510, 511, 512, 513, 517, 532, 533, 534, 535, 542, 543, 544, 549, 557, 558, 559, 562, 564, 567, 574, 576, 580, 591, 606, 613, 614, 615, 619, 627, 633, 634, 635, 636, 661, 667, 673, 690, 717, 718, 719, 721, 727, 752, 753, 754, 773, 782, 783, 784, 785, 804, 842, 843, 844, 845, 863, 864, 891, 897, 903, 941, 943, 944, 946, 948, 949, 951, 955, 957, 978, 980, 981, 982, 983, 987, 1002, 1003, 1004, 1012, 1013, 1014, 1019, 1027, 1029, 1032, 1034, 1037, 1044, 1046, 1050, 1061, 1076, 1083, 1084, 1085, 1089, 1097, 1103, 1104, 1105, 1106, 1131, 1137, 1143, 1160, 1187, 1188, 1189, 1191, 1197, 1222, 1223, 1224, 1243, 1252, 1253, 1254, 125 5, 1274, 1312, 1313, 1314,1315, 1333, 1334, 1361, 1367, 1373, 1411, 1413, 1414, 1416, 1418, 1419, 1421, 1425, 1427, 1448, 1450, 1451, 1452, 1453, 1457, 1472, 1473, 1474, 1482, 1483, 1484, 1489, 1497, 1499, 1502, 1504, 1507, 1514, 1516, 1520, 1531, 1546, 1553, 1554, 1555, 1559, 1567, 1573, 1574, 1575, 1576, 1601, 1607, 1613, 1630, 1657, 1658, 1659, 1661, 1667, 1692, 1693, 1694, 1713, 1722, 1723, 1724, 1725, 1744, 1782, 1783, 1784, 1785, 1803, And compounds of 1804, 1831, 1837, 1843, 1885, 1886, 1894, 1907, or 1921.
[160] Particularly preferably,
[161] Compound no. 1; [3-[(E) -2- (6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
[162] Compound no. 4; 3- {3-[(E) -2- (6,7-Difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5yl] oxy} 2-methylpropionic acid,
[163] Compound no. 8; 3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] Thio} propionic acid,
[164] Compound no. 9; 3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] Thio} -2-methylpropionic acid,
[165] Compound no. 471; [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl-5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
[166] Compound no. 473; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Oxy} propionic acid,
[167] Compound no. 474; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Oxy} -2-methylpropionic acid,
[168] Compound no. 476; [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetic acid ,
[169] Compound no. 477; 2-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Thio} propionic acid,
[170] Compound no. 478; 3-{[3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Thio} propionic acid,
[171] Compound no. 487; 3-{[3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Thiomethyl} -cyclopropane acetic acid,
[172] Compound no. 505; [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5 -Yl] oxyacetic acid,
[173] Compound no. 510; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclo Heptene-5-yl] thio} -propionic acid,
[174] Compound no. 535; [3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cycloheptene-5- Oxyacetic acid,
[175] Compound no. 542; 3-{[3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cycloheptene -5-yl] thio} -propionic acid,
[176] Compound no. 549; 3-{[3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -8-chloro-5H-dibenzo [a, d] cycloheptene -5-yl] thio} -propionic acid,
[177] Compound no. 557; [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5- Oxyacetic acid,
[178] Compound no. 558; 2-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Oxy} propionic acid,
[179] Compound no. 559; 3-{[3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cycloheptene -5-yl] oxy} propionic acid,
[180] Compound no. 562; [3-[(E) -2- (7-Chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cycloheptene-5- Thioacetic acid,
[181] Compound no. 564; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cycloheptene -5-yl] thio} propionic acid,
[182] Compound no. 613; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d ] Cyclohepten-5-yl] thio} propionic acid,
[183] Compound no. 718; 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -methoxy-5H-dibenzo [a, d] cyclohepten-5-yl] Thio} propionic acid,
[184] Compound no. 1411; [3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
[185] Compound no. 1416; [3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetic acid,
[186] Compound no. 1418; 3-{[3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionic acid,
[187] Compound no. 1885; 3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cycloheptene-5 -Yl] thio} propionic acid, or
[188] Compound no. 1921; 3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a , d] cyclohepten-5-yl] thio} propionic acid.
[189] The compound represented by the general formula (I) of the present invention can be prepared by, for example, the preparation method A, B, C, D, E or L shown below.
[190] Preparation A
[191]
[192] Recipe B
[193]
[194] Recipe C
[195]
[196] Preparation D
[197]
[198] Preparation E
[199]
[200] Recipe L
[201]
[202] In the above scheme, R ¹ , R ² , R ³ , A, B, X, Y, Z, m and n have the same as above, L is a halogen atom, a C ₁ -C ₄ alkylsulfonyloxy group, fluoro C ₁ -C ₄ alkylsulfonyloxy group or phenylsulfonyloxy group which may be substituted (wherein the substituent is a C ₁ -C ₄ alkyl group or halogen atom), R ⁴ is a C ₁ -C ₄ alkyl group or may be substituted A phenyl group (wherein the substituent is a C ₁ -C ₄ alkyl group or a halogen atom), Tet represents a 1H-tetrazol-5-yl group, and Hal represents a halogen atom.
[203] Production method A is a method for producing compound (I).
[204] Step A1 of Preparation A is a step of synthesizing Compound (III) obtained by halogenating or sulfonylating Compound (II).
[205] Halogenation of compound (II) is carried out by reacting compound (II) with a halogenating agent in the presence or absence of a solvent (preferably in the presence of a solvent).
[206] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; Aromatic hydrocarbons such as benzene, toluene, and the like; or aliphatic hydrocarbons such as heptane, hexane, cyclohexane, and the like, and preferably halogenated hydrocarbons.
[207] Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and the like. Preferably, thionyl chloride or phosphorus oxychloride is preferable. The amount of the halogenating agent used is usually 1 to 10 times the molar amount, preferably 1 to 2 times the molar amount relative to the amount of the compound (II).
[208] The reaction is usually carried out in a temperature range of -20 to 100 ° C, preferably -10 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours is preferable.
[209] Sulfonylation of compound (II) is carried out by reacting compound (II) with a sulfonylating agent in a solvent in the presence of a base.
[210] The solvent used does not inhibit the reaction and is not particularly limited as long as it can dissolve the starting material to some extent, for example, the same solvent as that used in the halogenation reaction (eg, halogenated hydrocarbons, aromatic hydrocarbons or aliphatic hydro). Carbons), and preferably halogenated hydrocarbons.
[211] As sulfonylating agents, for example, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl bromide, toluenesul Phenyl bromide etc. are mentioned, Preferably methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, etc. are preferable. The usage-amount of a sulfonylating agent is 1 to 10 times molar amount normally with respect to the quantity of compound (II), Preferably it is 1-3 to molar amounts.
[212] Examples of the base include amines such as triethylamine, tributyl amine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine and the like, preferably triethylamine, diisopropylethylamine or Pyridine is good. The amount of base used is usually 1 to 10 times molar amount, preferably 1 to 2 times molar amount relative to the amount of sulfonylating agent.
[213] The reaction is usually carried out in a temperature range of -10 to 100 ° C, preferably 0 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and is usually 5 minutes to 10 hours, preferably 30 minutes to 5 hours.
[214] In addition, Compound (III) may be separated and purified from the reaction mixture according to a conventional method, but the crude product obtained by concentrating the reaction mixture may be used in the following process.
[215] Process A2 can be carried out by reacting compound (III) and compound (IV) in a solvent in the presence of a base or without a base.
[216] The amount of compound (IV) to be used is usually 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount relative to compound (III).
[217] The solvent which is commonly used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, N, N Aprotic polar solvents such as dimethylacetamide, hexamethylphosphonic acid triamide and the like; Halogenated hydrocarbons such as chloride, chloroform, 1,2-dichloroethane and the like; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; Nitriles such as acetonitrile and the like; Esters such as ethyl acetate and the like; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or the like, or a mixed solvent of the above solvents. Preferably, an aprotic polar solvent, a terter, or a mixed solvent of the above solvents is used. Can be mentioned.
[218] Examples of the base used may include alkali metal hydrides such as sodium hydride, lithium hydride and the like; Alkali metal amides such as sodium amide and the like; Amines such as triethylamine, tributyl amine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine and the like; Or alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and the like, and amines or alkali metal hydrides are preferable. The amount of the base used may vary depending on the type of the starting compound, and is generally 1 to 10 times molar amount, preferably 1 to 5 times molar amount, relative to compound (IV). In addition, in the present reaction, the use of a base is not essential.
[219] The reaction is usually carried out in a temperature range of -50 to 150 ° C, preferably -10 to 100 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 10 hours, preferably 30 minutes to 5 hours.
[220] Step A3 is a step of separately obtaining compound (I), and is particularly preferably used when X is a sulfur atom. This process is carried out by reacting compound (II) and compound (IV) in a solvent in the presence of an acid catalyst.
[221] The amount of the compound (IV) to be used is usually 1 to 5 times the molar amount, preferably 1 to 2 times the molar amount relative to the compound (II).
[222] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like; ratios such as N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, N, N-dimethylacetamide, hexamethylphosphonic acid triamide and the like Protic polar solvents; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and the like, and halogenated hydrocarbons are preferable.
[223] As the acid catalyst to be used, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like; Organic acids such as methanesulfonic acid, trifluoroacetic acid and the like; Lewis acids such as boron trifluoride-diethyl ether complex, zinc chloride, tin tetrachloride, aluminum chloride, and the like, are preferred, and organic acids or boron trifluoride-diethyl ether complexes are preferred. The amount of the catalyst to be used is usually 0.1 to 50 times the molar amount, preferably 1 to 10 times the molar amount with respect to the compound (II). When an organic acid is used, the amount of the catalyst can also be used in a significant excess as a solvent.
[224] The reaction is usually carried out in a temperature range of -10 ° C to 100 ° C, preferably 0 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
[225] Additionally, in compound (I), a compound in which Z is a carboxyl group (hereinafter referred to as compound Ic) is prepared directly by using compound (IV) in which Z is a carboxyl group, or compound (IV) in which Z is a protected carboxyl group. (The protecting group is preferably a C ₁ -C ₄ alkyl group), and then, once Z reaches a compound (I) which is a protected carboxyl group, the protecting group is hydrolyzed by conventional methods under acidic or alkaline conditions. It can synthesize | combine by making it.
[226] In compound (I), compound (Ic) in which Z is a carboxyl group can be easily introduced with a desired protecting group by a known method. (See, eg, W. Greene and P.G.H.Wult, "Protective Group in Organic Synthesis" 2nd Ed., John Wiley & Sons, p. 224).
[227] Production method B is a method for producing compound (Ia) wherein X is a sulfur atom in compound (I).
[228] The reaction for obtaining the compound (VI) from the compound (II) or the compound (III) of the step B1 and the thiocarboxylic acid (V) is carried out except that a thiocarboxylic acid (V) is used instead of the compound (IV). Can be carried out in the same manner as described in Process A2 or Process A3 of Production Method A above.
[229] In step B2, compound (VII) can be synthesized by hydrolyzing compound (VI) under alkaline conditions in a conventional manner.
[230] Step B3 can be carried out by reacting compound (VII) and compound (VIII) in a solvent in the presence of a base. The reaction can be carried out in the same manner as described in A2 above, except for using compound (VII) instead of compound (II) and using compound (VIII) instead of compound (IV).
[231] The amount of compound (VIII) to be used is usually 1 to 10 times molar amount, preferably 1 to 5 times molar amount, relative to compound (VII).
[232] Production method C is a method for producing compound (Ib) wherein Z is a 1H-tetrazol group in compound (I), and in step C1, a reaction for obtaining compound (X) from compound (II) or compound (III) and compound (IX) Silver can be carried out in the same form as the method described in A, except that compound (IX) is used instead of compound (IV).
[233] In step C2, compound (Ib) can be synthesized by reacting compound (X) with an azide compound in a solvent.
[234] As an azide compound used, For example, alkali metal azide, such as sodium azide, potassium azide, lithium azide, etc .; Alkaline earth metal azides such as calcium azide and magnesium azide; Or organic tin azide such as trimethyl tin azide, tributyl tin azide, triphenyltin azide and the like. The usage-amount of an azide compound is 1-10 times molar quantity normally with respect to compound (X), Preferably 1-5 times molar amount is good. In the reaction, azide compounds are used alone or Lewis acids such as, for example, aluminum chloride, stanic chloride, zinc chloride, titanium chloride, boron trifluoride-diethyl ether complex, and the like; Ammonium salts such as ammonium chloride, tetramethylammonium chloride and the like; Sulfonic acids such as methanesulfonic acid and ethanesulfonic acid; Alkali metal chlorides such as lithium chloride and the like; Or you may use in combination with amine salts, such as triethylamine hydrochloride.
[235] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, N, N Aprotic polar solvents such as dimethylacetamide and the like; Ethers such as tetrahydrofuran, dimethoxyethane, diethoxyethane, dioxane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Or aliphatic hydrocarbons such as hexane, petroleum ether and the like.
[236] The reaction is usually carried out at a temperature range of 0 to 200 캜, preferably 50 to 150 캜. The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 72 hours, preferably 3 hours to 48 hours.
[237] Formulation D is a method for preparing a compound (Id) wherein Z is CO-NH-SO ₂ -R ³ in compound (I). Step D1 is a method of reacting compound (Ic) and compound (XI) in the presence of a condensing agent (step D1a), or after introducing compound (Ic) into its reactive derivative (step D1b), the reactive derivative and the compound A method of reacting (XI) in the presence of a base (step D1c) is included.
[238] Examples of the condensing agent used in Step D1a include N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N, N'-carbonyldiimidazole (CDI), diphenylphosphoic acid azide, hexafluorophosphoic acid benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium (BOP), hexafluorophosphonic acid Benzotriazol-1-yloxy-tris-pyrrolidinophosphonium (PyBOP), hexafluorophosphonic acid 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro Nium (HBTU), tetrafluoroboric acid 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (TBTU), and the like, and preferably DCC or EDC is mentioned. The amount of the condensing agent used is usually 1 to 5 times molar amount, preferably 1 to 3 times molar amount, relative to compound (Ic).
[239] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxyethane, dioxane and the like. ; Nitriles such as acetonitrile; Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylacetamide and the like; Or halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like, and these may be used alone or as a mixed solvent.
[240] The reaction is usually carried out in a temperature range of -20 to 100 ° C, preferably 0 to 50 ° C. The reaction time may vary depending on the reaction temperature, and typically 30 minutes to 24 hours, preferably 1 hour to 10 hours.
[241] Examples of the reactive derivative of the compound (Ic) in the step D1b include, for example, an acid halide derivative of the compound (Ic) such as an acid bromide compound or an acid chloride compound of the compound (Ic); Or reactive amide derivatives such as compound (Ic) and imidazole, 3,5-dimethylpyrazole or triazole and compound (Ic), and the like, and preferably acid halide derivatives.
[242] Acid halide compounds of compound (Ic) may be prepared according to conventional methods, for example compound (Ic) may be prepared in a solvent (e.g., halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc.). It can be synthesized by reacting with a halogenating agent (eg, thionyl chloride, thionyl bromide, phosphorus pentachloride, etc.).
[243] In addition, activated amide derivatives of compound (Ic) can be prepared according to conventional methods, for example in the case of imidazolidated compounds of compound (Ic), in solvents (eg diethyl ether, tetra Ethers such as hydrofuran, dimethoxyethane, dimethoxyethane, dioxane and the like; nitriles such as acetonitrile and the like; N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, N, N-dimethylacet Aprotic polar solvents such as amides; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc.) and the like (Ic) can be synthesized by reacting the compound (Ic) with 1,1'-carbonyldiimidazole. have.
[244] The reactive derivatives of compound (Ic) can be used after production, without separation, as in the next step D1c.
[245] The amount of the compound (XI) used in the reaction of the reactive derivative of the compound (Ic) and the compound (XI) in the step D1c is usually 1 to 10-fold molar amount, preferably 1 to 5, relative to the compound (Ic). Double molar amount is good.
[246] Examples of the base to be used include, for example, triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0]- Amines such as 7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene, and the like, and triethylamine, tributylamine or diisopropyretylamine are preferable. have. The amount of the base used is usually 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount with respect to the compound (Ic).
[247] The reaction is usually carried out at a temperature in the range of 0 to 150 ° C, preferably 10 to 100 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
[248] In addition, compound (Id) may be prepared by a method via compound (XII).
[249] Step D2 is a method for obtaining compound (XII) by amidating a carboxyl group of compound (Ic), and can be carried out using a method known in the art as appropriate. For example, compound (XII) can be easily produced by reacting ammonia with the reactive derivative of compound (Ic).
[250] Step D3 is carried out by reacting compound (XII) and compound (XIII) in a solvent in the presence of a base.
[251] The amount of compound (XIII) used is usually 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount relative to compound (XII).
[252] As the solvent and the base to be used, the same ones as those used in the above step D1 can be used, and the reaction can also be carried out under the same conditions as the step D1.
[253] Formulation E is a method for producing compound (Ie) wherein Z is -NH-SO ₂ -R ³ group in compound (I).
[254] In step E1, the method of obtaining compound (XV) from compound (II) or compound (III) and compound (XIV) is the same as that of Method A except that compound (XIV) is used instead of compound (IV). It can be performed by the same method.
[255] Step E2 is carried out by reacting compound (XV) and compound (XIII) in a solvent in the presence of a base.
[256] The amount of compound (XIII) used is usually 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount relative to compound (XV).
[257] As the solvent used, the same solvent as mentioned in the above step D1 can be used, and halogenated hydrocarbons or aprotic polar solvents are preferable.
[258] As the base to be used, the same base as mentioned in the step D1 can be used, and the amount of the base used is usually 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount with respect to the compound (XIV). In addition, in this reaction, the base can also be used in excess in combination with the solvent.
[259] The reaction is usually carried out in a temperature range of -20 to 100 ° C, preferably 0 to 50 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 10 hours, preferably 30 minutes to 5 hours is preferable.
[260] Formulation L is a compound (I) wherein X is a methylene group and B is -CH = CH- in compound (I), and a compound (Ig) wherein X is methylene group and B is -CH ₂ O- in compound (I). ) Is a manufacturing method.
[261] Process L1 is carried out in the same manner as in Process F1, except that Compound (XXXVIII) is used instead of Compound (XVI), and Process L2 is used except that Compound (XXXIX) is used instead of Compound (XVII). Is carried out in the same manner as the following step F2.
[262] Step L3 is carried out in the same manner as in Step G1 of Preparation G below, except that Compound (XXXVIII) is used instead of Compound (XVI).
[263] In each of the above reactions, the desired compound to be produced can be collected from the reaction mixture according to a conventional method. For example, if insolubles are present, the insolubles are removed by filtration, then the solvents are removed, or the solvents are removed under reduced pressure, and water is added to the residue to remove water insoluble organic solvents such as ethyl acetate. It is possible to obtain by removing the solvent, if necessary, after drying with anhydride sodium sulfate and the like, and if necessary, by purification by conventional methods such as recrystallization, column chromatography and the like.
[264] The compounds of formula (I) of the invention can also be converted to pharmacologically acceptable salts by treatment with acids or bases according to conventional methods. For example, inert solvents (preferably ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, diethoxyethane, dioxane, etc .; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc .; methylene chloride, chloroform Halogenated hydrocarbons such as water or the like; or water), the desired salt is obtained by reacting with a desired acid or base, removing the solvent or otherwise precipitation to obtain crystals. It can also be separated as a salt directly from the reaction mixture of the final reaction process.
[265] Furthermore, in compounds of general formula (I), optical isomers (including diastereomers) due to asymmetric carbons and / or geometric (E, Z) isomers due to unsaturated carbons are present. Each of these isomers may be prepared by subjecting the racemic isomer or geometric isomer mixture to conventional optical decomposition methods (fractional crystallization, optical resolution column chromatography, or diastereoisomers, etc.) or separation methods (recrystallization, column chromatography, etc.). It can isolate | separate by processing by. For example, in the case of separating the optical isomers, the compound (I) of the racemate is reacted with an optically activated sulfonic acid compound (such as (S) or (R) -camphor-10-sulfonic acid, etc.) in the diastereomeric salt. One is obtained, if necessary, after further purification, and the resulting diastereomeric salt is decomposed according to conventional methods to obtain an optically active substance. In addition, even when the reaction is carried out by using the optically decomposed or separated raw material compound, the desired optical isomer or geometric isomer can be obtained.
[266] Compounds (IV), (V), (VIII), (IX), (XI), (XIII), (XIV) used as starting materials in the above production methods A, B, C, D, E or L and their The external subsidiary materials are each known compounds or can be easily prepared according to known methods. In addition, compounds (II) and (XXXVIII) can be prepared by appropriately selecting one of the preparation methods F, G, H, I, J, K, N, O and P shown below or using a combination of two or more thereof. .
[267] Recipe F
[268]
[269] Preparation G
[270]
[271] Manufacturing method H
[272]
[273] Preparation I
[274]
[275] Preparation J
[276]
[277] Recipe K
[278]
[279] Recipe M
[280]
[281] Recipe N
[282]
[283] Recipe O
[284]
[285] Recipe P
[286]
[287] Wherein R ¹ , R ² , A, Hal, m and n are the same as above, Tf represents a trifluoromethanesulfonyl group, and W represents a methoxy group or a halogen atom (preferably a bromine atom or an iodine atom) And R ⁵ represents a C ₁ -C ₄ alkyl group.
[288] Production method F is a method for producing compound (IIa).
[289] Step F1 is a step of synthesizing a trifrating compound (XVI) in which a compound (XVII) is triflated.
[290] Trifration of compound (XVI) is carried out by reacting compound (XVI) with a triflate agent in a solvent in the presence of a base.
[291] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like Ryu; Aromatic hydrocarbons such as benzene, toluene and the like; Or aliphatic hydrocarbons such as heptane, hexane, cyclohexane, and the like, and halogenated hydrocarbons are preferable.
[292] Examples of the triphthalating agent include trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride. The use amount of the triflate is 1 to 10 times the molar amount, preferably 1 to 2 times the molar amount relative to the compound (XVI).
[293] Examples of the base include amines such as triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine and the like, and preferably triethylamine and diisopropylethyl. Amines or pyridine are preferred. The amount of the base used is preferably 1 to 10 times the molar amount, and preferably 1 to 2 times the molar amount relative to the triflate.
[294] The reaction is usually carried out in a temperature range of -20 to 100 ° C, preferably -10 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 10 hours, preferably 30 minutes to 5 hours.
[295] Process F2 is carried out by reacting compound (XVII) and compound (XVIII) in a solvent in the presence of a catalyst (palladium catalyst) and a base in an inert gas atmosphere such as nitrogen, helium or argon.
[296] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrroli Polar solvents such as toxin, dimethyl sulfoxide and the like, or acetonitrile, and the like, and preferably N, N-dimethylformamide is preferable.
[297] Examples of the base include amines such as triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine, and the like, and triethylamine is preferable. The amount of the base used is preferably 1 to 10 times the molar amount, and preferably 1 to 2 times the molar amount based on the compound (XVII).
[298] Instead of amines, quaternary amines such as tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like can be used in combination.
[299] Examples of the palladium catalyst include palladium acetate, palladium acetate-triphenylphosphine, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, and the like, and preferably palladium acetate-triphenyl Phosphine or tetrakis (triphenylphosphine) palladium is preferred. The amount of the palladium catalyst to be used is preferably 0.01 to 1 times the molar amount, preferably 0.01 to 0.3 times the molar amount relative to compound (XVII).
[300] In addition, lithium chloride or lithium bromide can coexist in the reaction.
[301] The reaction is usually carried out in a temperature range of 0 to 200 ° C, preferably 50 to 150 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
[302] The reduction reaction from compound (XIX) to compound (IIa) in step F3 can be carried out by using a reducing agent in a solvent.
[303] Examples of the reducing agent include sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and the like, and lithium borohydride is preferable.
[304] The solvent used may be, for example, alcohols such as methanol, ethanol, propanol, butanol and the like; Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Nitriles such as acetonitrile and the like; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like; Water or a mixed solvent of the above solvents, preferably tetrahydrofuran or a mixed solvent with tetrahydrofuran.
[305] The reaction is usually carried out in a temperature range of -10 to 150 캜, preferably 0 to 100 캜. The reaction time may vary depending on the reaction temperature and the like, and typically 10 minutes to 10 hours, preferably 30 minutes to 6 hours.
[306] Step F4 is another method for preparing the compound (XIX), by using compound (XX) (preferably as bromine atom or iodine atom as Hal) instead of compound (XVII) as the starting compound, Under the same conditions as
[307] Production method G is a method for producing compound (IIb).
[308] Step G1 is carried out by reacting compound (XVI) and compound (XXI) in a solvent in the presence of a base, using compound (XVI) instead of compound (III), and compound (XXI) instead of compound (IV). Is carried out in the same manner as in Process A2, except that
[309] The reduction reaction from compound (XXII) to compound (IIb) in step G2 is carried out by using a reducing agent in a solvent. Except for using compound (XXII) instead of compound (XIX), it is carried out in the same manner as in Step F3.
[310] The manufacturing method H is a manufacturing method of a compound (XXIX), and includes the manufacturing method of a compound (XX: W = halogen atom) and the following compound (XXXVI: W = methoxy group).
[311] Preparation H is known in the art, such as Helv. Chim. It may be readily prepared with reference to the conventional known methods described in Acta, 48 , 1240 (1965) or USP 1, 207, 404.
[312] Process H1 is carried out by dehydrating condensation of compound (XXIII) and compound (XXIV) under solvent (preferably between 100 and 250 ° C.), using diphenyl ether as solvent-free or solvent in the presence of a base such as, for example, sodium acetate. Is performed.
[313] The process for obtaining compound (XXXVI) by reducing the compound (XXV) of step H2 is carried out using a reduction method (USP 1,207,404) or hydrogen iodide / red phosphorus using hydrogen in the presence of a Raney-nickel catalyst. The reduction method (Helv. Chi, Acta, 48. 1240 (1965)) used is suitably carried out, and the latter reduction method is preferred when W is a halogen atom.
[314] The step of dehydrating compound (XXVI) of step H3 to obtain compound (XXVII) is carried out by reacting compound (XXVI) in or without solvent and in the presence of a catalyst (dehydrating agent).
[315] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; Benzene and carbon disulfide are mentioned, Preferably halogenated hydrocarbons are preferable.
[316] As a catalyst used, For example, inorganic acids, such as a sulfuric acid, phosphoric acid, polyphosphoric acid, etc .; Acid anhydrides such as methanesulfonic anhydride, trifluoroacetic anhydride and the like; Lewis acids such as boron trifluoride-diethyl ether complex, aluminum chloride, zinc chloride, and the like, preferably polyphosphoric acid, methanesulfonic anhydride, trifluoroacetic anhydride or boron trifluoride-diethyl ether complex good. In addition, a mixture of trifluoroacetic anhydride and boron triprolide-diethyl ether complex can be suitably used. The amount of the catalyst used is preferably 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount based on the compound (XXVI).
[317] The reaction is usually carried out in a temperature range of 0 to 150 ° C, preferably 0 to 100 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 10 hours, preferably 30 minutes to 5 hours.
[318] For example, when polyphosphoric acid etc. are used excessively as a catalyst, it is not necessary to add a solvent in particular. In this case, the amount used is 5 to 100 times molar amount, preferably 10 to 30 times molar amount relative to compound (XXVI).
[319] The reaction is usually carried out at a temperature range of 0 to 250 ° C, preferably 100 to 200 ° C. The reaction time may vary depending on the reaction temperature, and typically 10 minutes to 12 hours, preferably 30 minutes to 5 hours.
[320] The step of obtaining compound (XXVIII) by bromination of compound (XXVII) of step H4 is carried out by a conventional known method, such as a method of performing a reaction under light irradiation using N-bromine succinate imide as a brominating agent or azobis It is readily carried out by a method of reacting in the presence of radical initiators such as isobutyronitrile (AIBN), benzoyl peroxide (BPO) and the like. The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like. And preferably 1,2-dichloroethane.
[321] When reacting under light irradiation, a mercury lamp is preferably used as the light source. The N-bromosuccinimide used is usually 1 to 2.5 times molar amount, preferably 1 to 1.1 times molar amount, relative to compound (XXVII). The reaction temperature is usually 0 to 80 ° C, preferably 30 to 60 ° C.
[322] The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 12 hours, preferably 3 hours to 8 hours.
[323] When reacting in the presence of a radical initiator such as azobisisobutyronitrile (AIBN), benzoyl peroxide (BPO), etc., the amount of the radical initiator to be used is usually 0.001 to 0.1 times the molar amount, preferably with respect to the compound (XXVII). The molar amount of 0.01 to 0.05 times is good. The N-bromosuccinimide used is usually 1 to 4 times molar amount, preferably 1 to 1.1 times molar amount, relative to compound (XXVII).
[324] The reaction is usually carried out in a temperature range of 50 to 100 ° C., preferably 60 to 80 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 30 minutes to 12 hours, preferably 1 hour to 6 hours.
[325] Dehydrogen bromide of compound (XXVIII) of step H5 to obtain compound (XXIX) comprises compound (XXVIII) as a base (preferably triethylamine or 1,5-diazabicyclo [4.3.0]). It is carried out by treatment with -5-nonene (DBN).
[326] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Esters such as methyl acetate, ethyl acetate and the like; Nitriles such as acetonitrile, propionitrile and the like, and the like, and preferably 1,2-dichloroethane, toluene, ethyl acetate or acetonitrile is preferable.
[327] The amount of base used is 1 to 150 times molar amount, preferably 1 to 15 times molar amount, relative to compound (XXVIII).
[328] The reaction is usually carried out in a temperature range of 0 to 150 ° C, preferably 60 to 120 ° C. The reaction time may vary depending on the reaction temperature and the like, and typically 30 minutes to 12 hours, preferably 1 hour to 3 hours.
[329] Formulation I is another method for preparing compound (XXVI) of formula H.
[330] The bromination reaction of compound (XXX) in step (I1) is carried out in the same manner as in step H4, except that compound (XXX) is used instead of compound (XXVII).
[331] Process I2 is carried out by reacting compound (XXXI) with triphenylphosphine in a solvent.
[332] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Esters such as methyl acetate, ethyl acetate and the like; Nitriles such as acetonitrile, propionitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like; Ketones such as acetone, methyl ethyl ketone and the like; Or dimethyl sulfoxide, preferably ethyl acetate or acetonitrile.
[333] The amount of the triphenylphosphine to be used is 1 to 2 times the molar amount, preferably 1 to 1.5 times the molar amount relative to the compound (XXXI).
[334] The reaction is usually carried out in a temperature range of 0 to 150 ° C, preferably 60 to 100 ° C. The reaction may vary depending on the reaction temperature and the like, and typically 30 minutes to 12 hours, preferably 1 hour to 3 hours.
[335] The reaction between the compound (XXXII) and the compound (XXXIII) in step I3 is a so-called witting reaction, which is carried out by appropriately selecting common known conditions.
[336] The amount of the compound (XXXIII) used is usually 1 to 10 times the molar amount, and preferably 1 to 1.5 times the molar amount relative to the compound (XXXII).
[337] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane and the like; Ethers such as diethyl ether, tetra hydrofuran, dioxane, dimethoxyethane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Esters such as methyl acetate, ethyl acetate and the like; Nitriles such as acetonitrile, propionitrile and the like; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like; Dimethyl sulfoxide or a mixed solvent of the solvent may be mentioned. In addition, a mixed solvent of the solvent and water may also be used.
[338] Bases used are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; Alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-boxoxide and the like; Alkali metal hydrides such as sodium hydride, potassium hydride and the like; Alkyl lithiums such as methyl lithium, butyl lithium and the like; Metal amides such as sodium amide, lithium diisopropylamide; Organic amines such as triethylamine, diisopropylethylamine, tripropylamine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), and the like. The amount of base used is usually 1 to 5 times molar amount, preferably 1 to 2 times molar amount, relative to compound (XXXII).
[339] The reaction is usually carried out at a temperature range of 0 to 150 ° C, preferably 15 to 80 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 24 hours, preferably 1 hour to 6 hours.
[340] In addition, this process generally yields a mixture of cis and trans geometric isomers and can be used in the next process in the form of a mixture.
[341] The hydrolysis reaction of the carboxyl group of the compound of Process I4 (XXXIV) can be carried out in typical alkali hydrolysis reactions using, for example, sodium hydroxide or potassium hydroxide or in W. Green and P.G.H. Wult, also carried out by the method described in "Protective Group in Organic Synthesis" 2nd Ed., John Wiley & Sons, p 229.
[342] The reduction reaction of the compound (XXXV) in step I5 is carried out by a catalytic hydrogenation reaction or a reduction reaction using hydroiodic acid / red phosphorus, and when W is a halogen atom, a reduction reaction by hydroiodic acid / red phosphorus is preferable. .
[343] In the catalytic hydrogenation reaction, compound (XXVI) can be synthesized by catalytic reduction of compound (XXXV) with hydrogen in the presence of a catalyst in a solvent.
[344] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, alcohols such as methanol, ethanol and the like; And ethers such as tetrahydrofuran, dioxane, and the like, and alcohols are preferable.
[345] Examples of the catalyst to be used include palladium-carbon, platinum-carbon, platinum black, rhodium-carbon or Raney nickel, and preferably palladium-carbon.
[346] In the catalytic hydrogenation reaction, the hydrogen partial pressure is generally 1 atm to 10 atm, preferably 1 atm to 5 atm.
[347] The reaction is usually carried out in a temperature range of 0 to 100 ° C, preferably 20 to 80 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 15 minutes to 72 hours, preferably 30 minutes to 48 hours.
[348] In the case of the reduction reaction with iodide acid / red phosphorus, the solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, water, acetic acid or propionic acid, and preferably Acetic acid is good. Hydrogen iodide to be used is 3 to 15 times the molar amount, preferably 4 to 8 times the molar amount relative to the compound (XXXV).
[349] The red phosphorus used is preferably 1 to 10 times the molar amount, preferably 2 to 5 times the molar amount relative to the compound (XXXV). The addition method can be divided once or several times.
[350] The reaction is usually carried out at a temperature range of 90 to 150 ° C, preferably 100 to 130 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 48 hours, preferably 6 hours to 24 hours.
[351] Production method J is a method for preparing compound (XVI) by demethylating compound (XXXVI). Demethylation of compound (XXXVI) can be carried out by conventional known methods (see, eg, W. Greene and PGHWult, "Protective Group in Organic SYnthesis" 2nd Ed., John Wiley & Sons, p146) such as hydrobromic acid or hydroiodic acid. The method used, or the method using boron tribromide and trimethylsilane iodine, etc. are performed suitably.
[352] Production method K is a method for preparing compound (XVIII), and known conventional methods such as J. Org. This is readily accomplished by using the method described in Chem., 61 , 3398 (1996).
[353] Preparation M is another method for preparing compound (XXVI).
[354] Step M1 is a method for producing compound (XXXV ') by condensation reaction of compound (XXX) with compound (XXXIII) in the presence of a base.
[355] The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, for example, alcohols such as methanol, ethanol, propanol, butanol, t-butanol and the like; Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; And amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, and the like. Preferably, N, N-dimethylformamide is preferable.
[356] The amount of the compound (XXXIII) used is usually 1 to 1.5 times the molar amount, and preferably 1 to 1.2 times the molar amount relative to the compound (XXX).
[357] Bases used include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like; Or alkali metal hydrides such as sodium hydride, potassium hydride and the like, and preferably sodium t-butoxide. The amount used is usually 1 to 2 times the molar amount, preferably 1 to 1.5 times the molar amount relative to the compound (XXX).
[358] The reaction is usually carried out in a temperature range of 0 to 100 ° C, preferably 10 to 40 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 24 hours, preferably 3 hours to 12 hours.
[359] Process M2 is a hydrogenation reaction of olefins and can be carried out in the same manner as Process I5 of Preparation I.
[360] Preparation N is another method for preparing compound (XXIX).
[361] Step N1 is a step of obtaining compound (XXXX) by reacting compound (XXVII) with N-brosuccinimide under light irradiation, preferably under irradiation with a mercury lamp light source.
[362] The solvent used is not particularly limited as long as the starting material can be dissolved to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like. And preferably 1,2-dichloroethane. The amount of N-bromosuccinimide used is usually 1.8 to 2.5 times the molar amount, and preferably 2.0 to 2.1 times the molar amount relative to compound (XXVII).
[363] The reaction is usually carried out in a temperature range of 0 to 80 ° C, preferably 30 to 60 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 1 hour to 12 hours, preferably 3 hours to 8 hours.
[364] Process N2 is a process for converting an olefin from vicinal dibromide to an olefin, and is easily carried out by the method described, for example, in Synth., Comm., 26 , 3791 (1996).
[365] The manufacturing method O is a manufacturing method of the intermediate compound (XXXXX) with respect to implementation compound (If) and (Ig) of the compound represented by X = methylene group among the compound represented by General formula (I).
[366] Step O1 is a step of producing compound (XXXXIII) by reacting an acetylene compound (XXXXII) with compound (XXXXI).
[367] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like are preferable.
[368] The amount of the acetylene compound (XXXXII) used is usually 1 to 2 times the molar amount, and preferably 1 to 1.5 times the mole amount relative to the compound (XXXXI).
[369] The reaction is usually carried out in a temperature range of 0 to 100 ° C, preferably 0 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 12 hours, preferably 30 minutes to 6 hours.
[370] The process for preparing compound (XXXXIV) from compound (XXXXIII) in step O2 is carried out by rearrangement in the presence of an acid catalyst in a solvent.
[371] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, alcohols such as methanol, ethanol, propanol and butanol; Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Nitriles such as acetonitrile and the like; And mixed solvents of amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and water with water, preferably methanol, ethanol, tetrahydrofuran or N, N A mixed solvent of dimethylformamide and water is preferred.
[372] As the acid catalyst to be used, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like; Or organic acids such as methanesulfonic acid, trifluoroacetic acid, and the like, preferably trifluoroacetic acid. The amount of the catalyst used is 1 to 100-fold molar amount, preferably 1 to 50-fold molar amount with respect to compound (XXXXIII).
[373] The reaction is usually carried out in a temperature range of 0 to 100 ° C, preferably 0 to 30 ° C. The reaction time may vary depending on the reaction temperature and the like, and usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
[374] Step O3 is a step of obtaining compound (XXXXVI) by reacting compound (XXXXIV) with compound (XXXXV) in a solvent in the presence of a base.
[375] The amount of the compound (XXXXV) used is preferably 1 to 10 times the molar amount, and preferably 1 to 5 times the molar amount relative to the compound (XXXXIV).
[376] Examples of the base to be used include alkali metal hydrides such as sodium hydride, lithium hydride and the like; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; Alkyl lithiums such as methyl lithium, butyl lithium and the like; Metal amides such as sodium amide, lithium diisopropyl amide, and the like, and alkali metal hydrides are preferable. The amount of the base used is preferably 1 to 5 times the molar amount, and preferably 1 to 2 times the molar amount relative to the compound (XXXXV).
[377] The solvent used does not inhibit the reaction and is not particularly limited as long as the starting material can be dissolved to some extent, for example, aromatic hydrocarbons such as benzene, toluene and the like; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, dimethoxyethane and the like; Or aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like, and ethers are preferred.
[378] The reaction is usually carried out in a temperature range of -50 to 100 ° C, preferably -10 to 50 ° C. The reaction time may vary depending on the reaction temperature and the like, and typically 15 minutes to 12 hours, preferably 30 minutes to 5 hours.
[379] In step O4, compound (XXXVVII) can be synthesized by catalytic reduction of compound (XXXVI) with hydrogen in the presence of a base in a solvent, and is carried out in the same manner as the catalytic hydrogenation of step I5.
[380] Process O5 is a conversion to olefins by a dehydrogenation reaction, for example, is carried out in the same manner as in Preparation N, except that Compound (XXXXVII) is used instead of Compound (XXVII).
[381] Step O6 is demethylation of a methoxy group and hydrolysis of an ester group.
[382] For example, except that the compound (XXXVIII) is used instead of the compound (XXXVI), demethylation of the methyl group and hydrolysis of the ester group are simultaneously achieved by the same method as in Preparation J.
[383] Process O7 is a manufacturing process by esterification of carboxyl groups and can be easily converted by conventional known methods (see, eg, W. Green and PGH Wult, “Protective Group in Organic Synthesis” 2nd Ed., John Wiley) & Sons, p 229).
[384] Preparation P is another method for preparing compound (XVIII).
[385] Step P1 is a step of producing compound (XXXXXI) by reacting compound (XXI) with triphenylphosphine, and step P2 is step (2) to prepare compound (XVIII) by reacting compound (XXXXXI) with formaldehyde in the presence of a base. It is a process to do it.
[386] Process P1 is carried out in the same manner as process I2, except that compound (XXI) is used instead of compound (XXXI).
[387] Step P2 is carried out in the same manner as in step I3, except that compound (XXXXXI) is used instead of compound (XXXII) and formaldehyde is used instead of compound (XXXIII).
[388] The compounds represented by formula (I) of the present invention have potent leukotriene antagonism and are very useful as anti-asthmatic, anti-allergic and anti-inflammatory agents.
[389] When the compound (I) of the present invention and its pharmacologically acceptable salts are used as a therapeutic or prophylactic agent for the above-mentioned disease, tablets, It is administered parenterally (preferably orally) by oral or injection by capsule, granule, powder or syrup.
[390] These formulations include excipients (e.g., sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol, etc .; starch derivatives such as corn starch, potato starch, α-starch, textine, carboxymethyl starch, and the like; crystalline cellulose, low-substituted hydride). Cellulose derivatives such as oxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internally crosslinked sodium carboxymethylcellulose, etc .; gum arabic; dextran; flulan; hard anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate Silicate derivatives, such as metasilicates; phosphate derivatives, such as calcium phosphate; carbonate derivatives, such as calcium carbonate; sulfate derivatives, such as calcium sulfate), binders (e.g. Disintegrating agents (e.g., excipients; chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, etc .; crosslinked polyvinyl pyrrolidone), lubricants (e.g. talc; metal stearic acid; calcium stearate) Stearates, such as magnesium stearate, colloidal silica; waxes such as non-gum, spermaceti, etc .; boronic acid; glycols; carboxylic acids, such as fumaric acid, adipic acid, etc .; sodium carboxylates, such as sodium benzoate; Sulfates such as sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate and the like; starch derivatives such as excipients), stabilizers (e.g., methyl paraben, Parahydroxybenzoates such as propyl paraben, etc .; chlorobutanol, benzyl alcohol Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol, cresol, etc .; trimerosal; acetic anhydride; sorbic acid, etc .; and copulation agents (e.g., commonly used sweeteners, acidulants, flavors, etc.), It is prepared by a known method using an additive including an excipient, a solvent for injection (e.g., water, ethanol, slyserine and the like) and the like. The amount may vary depending on symptoms, age, and the like, and in the case of oral administration, the lower limit is 1 mg (preferably 5 mg) once a day, the upper limit is 1000 mg (preferably 500 mg). 0.1 mg (preferably 1 mg) of ash and 500 mg (preferably 300 mg) of the upper limit need to be administered to adults 1 to 6 times per day according to symptoms.
[391] In the following, the present invention is described in detail by showing test examples and examples, but the scope of the present invention is not limited thereto.
[392] Test Example 1
[393] Leukotriene D ₄ receptor binding test
[394] <Receptor Sample Preparation>
[395] As receptor samples, lung membrane fractions from guinea pigs were used. The preparation of the membrane fraction was performed according to the method of Ahn et al. (Eur. J. Pharmacol., 127 , 153-155 (1986)). The lungs of Hartley male guinea pigs (weight 400-500 g, Nippon SLC Co.) were extracted and perfused with physiological saline, and then 10 mM PIPES, 10 mM MgCl ₂ and 10 mM CaCl ₂ buffer (pH 7.5) were added. , The mixture was homogenized. The homogenate was centrifuged at 70,000 x g for 10 minutes to obtain a membrane fraction.
[396] <Leukotriene D ₄ Receptor Binding Test>
[397] The leukotriene D ₄ (LTD ₄ ) receptor binding test is performed according to the method of Aharony et al. (J. Pharmacol. Expl. Ther., 243 , 921-926 (1987)). To 0.42 mg of the receptor sample, 10 mM PIPES, 10 mM MgCl ₂ and 10 mM CaCl ₂ buffer (pH 7.5) were added, and 480 μl, dimethyl sulfoxide of [ ³ H] LTD ₄ (NEN Life Science Products Co.) and the test compound. 10 μl of the solution was added and incubated at 25 ° C. for 30 minutes. This was filtered on glass fiber filter paper (Whatman Co., CF / C) using a cell harvester (Brandel Co., M-30R). The filter paper was washed with 10 mM Tris and 100 mM NaCl buffer (pH 7.5), to which 5 ml of liquid scintillator (NACALAI TESQUE INC., Clrearsol I) was added, and in a liquid scintillator analyzer (Packard Co., 2000CA) Radioactivity was measured. If obtain the dissociation constants (Kd) for LTD ₄ include, ^[3 H] LTD ₄ was 0.03 to 0.5nM using, non-radioactive St. LTD ₄ was added to 1㎕. [ ³ H] LTD ₄ used 0.2 nM to obtain the binding inhibition constant (Ki) of the test compound. The Kd and Ki methods other than ben net ^{(Bennett) (2 nd ed.} Neurotransmitter Receptor Binding,, edited by HI Yamamura et al., Pp. 61-89, Raven Press (1985)) was calculated according to.
[398]
[399] Compound A; 3- [2- (7-chloro-6-fluoroquinolin-2-yl) methoxy-6,11-dihydrobenze [b, e] oxepin-11-yl] thiopropionic acid (see WO 94/193445 publication)
[400] Test Example 2
[401] Leukotriene D ₄ -induced airway constriction test
[402] The airway stenosis reaction was measured by changing the Konzett and Rosler method (Arch. Exp. Pathol. Pharmakol., 195 , pp. 71-74 (1940)). Hartley male guinea pigs (400-500 g body weight, Nippon SLC Co.) were anesthetized with pentobarbital (50 mg.kg, sc), and then a cannula was inserted into the trachea (Harvard Co., Model 683). Artificial respiration was performed. The internal pressure of the airway was measured by a differential pressure transducer (Nihon Koden, TP-603T) connected to the airway cannula and used as an indicator of airway narrowing.
[403] LTD ₄ (0.03, 0.06, 0.13, 0.25, 0.5, 1 and 2 μg / kg, Sigma) was administered intravenously at 5 minute intervals at low doses from the cannula inserted into the total jugular vein, causing airway stenosis and causing intratracheal pressure The increase amount of was measured. Test compounds were suspended in 0.5% aqueous sodium carboxymethyl cellulose solution or dissolved in 30% aqueous propylene glycol solution and administered orally 24 hours before LTD ₄ administration. Animals were fasted 24 hours prior to administration of the test compound. The 50% response dose (ED50) was obtained from the dose response curve of LTD _{4 and} the dose of test compound required to double shift the dose response curve of the control to the high dose side was calculated by the following equation, LTD ₄ inhibitory activity.
[404] LTD ₄ inhibitory activity = (amount of compound administered) / (ED ₅₀ of the group to which the compound was administered) / ED _{50-1 of the} control group}
[405]
[406] Compound A; 3- [2- (7-chloro-6-fluoroquinolin-2-yl) -methoxy-6,11-dihydrobenzene [b, e] oxepin-11-yl] thiopropionic acid (WO 94/193445 publication)
[407] Formulation Example 1
[408] refine
[409] 30.0 mg of compound of Example 7
[410] Lactose
[411] Corn Starch 25.0
[412] Magnesium Stearate 1.0
[413] 200 mg
[414] The powder of the above formula was mixed and tableted by tablet press to prepare 200 mg of tablet per tablet.
[415] This tablet can be sugar-coated or coated as necessary.
[416] Example 1
[417] Methyl [3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetate Methyl ester of compound 1)
[418] 1.19 g (2.99 mmol) of 3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol After cooling 10 ml of tetrahydrofuran at 0 ° C., 0.85 ml (5.98 mmol) of triethenylamine and 0.30 ml (3.89 mmol) of methanesulfonyl chloride were added, followed by 1 hour at 0 ° C., and further at room temperature. Stirred for time.
[419] After completion of the reaction, the solvent was removed from the reaction solution under reduced pressure. The residue was dissolved in 15 ml of N, N-dimethylformamide, then 0.54 g (5.98 mmol) of methyl glycolate was added and stirred overnight at room temperature.
[420] After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: hexane / ethyl acetate = 2/1 (volume ratio)) to give 0.38 g of the title compound as a yellow solid.
[421] EI-MS (m / z); 469 (M ⁺ ).
[422] CI-MS (m / z); 470 (M ⁺ +1).
[423] Example 2
[424] [3-[(E) -2- {6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid (Compound Compound 1 )
[425] 0.38 g (0.81) of [3-[(E) -2- {6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetate mmol) was dissolved in a mixed solution of 15 ml of methanol and 5 ml of tetrahydrofuran, 2.4 ml (1,2 mmol) of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 5 hours.
[426] After completion of the reaction, the reaction solution was adjusted to pH 6.5 using dilute acetic acid aqueous solution, and then concentrated under reduced pressure. Water was added to the residue, and the precipitated solid was collected by filtration. The solid was subjected to silica gel column chromatography (solvent: chloroform / methanol = 9/1 (volume ratio)) to give 0.21 g of the title compound as a yellow solid.
[427] FAB-MS (m / z); 456 (M ⁺ +1).
[428] ¹ H-NMR (δ, DMSO-d ₆ ); 4.14 (s, 2H), 4.93 (s, 1H), 7.18-7.67 (m, 9H), 7.89-8.07 (m, 5H), 8.37 (d, J = 8.5 Hz, 1H).
[429] Example 3
[430] Sodium [3-[(E) -2- (6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetate (Compound Compound 1, sodium salt)
[431] 0.20 g (0.44) of [3-[(E) -2- {6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid mmol) was dissolved in a mixed solution of 15 ml of tetrahydrofuran and 5 ml of methanol, 0.44 ml (0.44 mmol) of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 1 hour.
[432] After completion of the reaction, the reaction solution was concentrated, ethanol was added to the residue, and the precipitated solid was collected by filtration to give 0.14 g of the title compound as a pale yellow solid.
[433] m.p .; 213 to 227 ° C.
[434] FAB-MS (m / z); 478 (M ⁺ +1).
[435] ¹ H-NMR (δ, DMSO-d ₆ ); 3.81 (s, 2H), 5.03 (s, 1H), 7.15-7.65 (m, 9H), 7.89-8.06 (m, 5H), 8.37 (d, J = 8.8 Hz, 1H).
[436] Example 4
[437] Sodium 3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio } Propionate (sodium salt of Compound 8)
[438] (a) 0.33 g (0.83 mmol) of 3-[(E) -2- {6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol ) Was dissolved in a mixed solution of 0.4 ml of trifluoroacetic acid and 40 ml of methylene chloride, 0.08 ml (0.92 mmol) of 3-mercaptopropionic acid was added, and stirred at room temperature for 3 hours.
[439] After completion of the reaction, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (eluent: chloroform / methanol = 19/1 (volume ratio)) to give 3-{[(E) -2- {6,7 0.17 g (0.35 mmol) of -difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionic acid was obtained as a brown solid.
[440] (b) 3-{[(E) -2- {6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cycloheptene obtained in Example 4 (a) -5-yl] thio} propionic acid was dissolved in a mixed solution of 10 ml of tetrafidrofuran and 20 ml of methanol, 0.35 ml (0.35 mmol) of 1N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour.
[441] After completion of the reaction, the reaction solution was concentrated, the residue was washed with diethyl ether and dried under reduced pressure to give 0.14 g of the title compound as pale yellow.
[442] m.p .; 213 to 216 ° C.
[443] FAB-MS (m / z); 508 (M ⁺ +1).
[444] ¹ H-NMR (δ, DMSO-d ₆ ); 1.90-2.10 (m, 2H), 2.30-2.45 (m, 2H), 5.48 (s, 1H), 7.00 (s, 2H), 7.20-7.60 (m, 6H), 7.33 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 16.4 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H) , 7.80-8.20 (m, 3H), 7.87 (d, J = 16.1 Hz, 1H), 8.04 (dd, J = 9.0 Hz, 2.2 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H).
[445] The reaction was carried out in the same manner as in Example 4 to obtain the compound of Examples 5 to 9 below.
[446] Example 5
[447] Sodium 3-{[3- (7-chloro-6-fluoroquinolin-2-yl) -methoxy-5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionate (completion compound 718 sodium salts)
[448] Appearance; Pale yellow solid
[449] m.p .; 229 to 232 ° C.
[450] ¹ H-NMR (δ, DMSO-d ₆ ); 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 5.38 (s, 1H), 5.41 (s, 2H), 6.83 (d, J = 12.0 Hz, 1H), 6.90 (d, J = 12.2Hz, 1H), 7.00 (dd, J = 8.5Hz, 2.7Hz, 1H), 7.20-7.55 (m, 6H), 7.75 (d, J = 8.5Hz, 1H), 8.05 (d, J = 9.8Hz , 1H), 8.29 (d, J = 7.3 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H).
[451] Example 6
[452] Sodium 3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio } -2- (S) -methylpropionate (sodium salt of Example Compound 9)
[453] Appearance; Pale yellow solid
[454] m.p .; 240 to 249 ° C.
[455] FAB-MS (m / z); 522 (M ⁺ +1).
[456] ¹ H-NMR (δ, DMSO-d ₆ ); 0.89 (d, J = 6.6 Hz, 3H), 2.10-2.89 (m, 2H), 2.51-2.58 (m, 1H), 5.45 (s, 1H), 7.00 (s, 2H), 7.31-7.49 (m, 5H), 7.54 (d, J = 16.4 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.86-7.98 (m, 2H), 7.98 ( d, J = 3.9 Hz, 1H), 8.04 (dd, J = 11.0 Hz, 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H).
[457] Example 7
[458] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] Thio} propionate (sodium salt of Compound 478)
[459] Appearance; Yellow solid
[460] m.p .; 228 to 238 ° C.
[461] FAB-MS (m / z); 524 (M ⁺ +1).
[462] ¹ H-NMR (δ, DMSO-d ₆ ); 1.96-2.01 (m, 2H), 2.34-2.37 (m, 2H), 5.48 (s, 1H), 7.00 (s, 2H), 7.29-7.50 (m, 5H), 7.55 (d, J = 16.4 Hz, 1H), 7.66 (dd, J = 8.8Hz, 1.5Hz, 1H), 7.88 (d, J = 16.4Hz, 1H), 7.89 (d, J = 1.5Hz, 1H), 8.00 (d, J = 8.8Hz , 1H), 8.01 (d, J = 10.0 Hz, 1H), 8.23 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H).
[463] Example 8
[464] Sodium 3-{[3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionate (Sodium Salt of Conducting Compound 1418)
[465] Appearance; Orange solid
[466] m.p .; 193 to 203 ° C.
[467] FAB-MS (m / z); 506 (M ⁺ +1).
[468] ¹ H-NMR (δ, DMSO-d ₆ ); 2.02-2.08 (m, 2H), 2.35-2.41 (m, 2H), 5.49 (s, 1H), 7.00 (s, 2H), 7.29-7.49 (m, 5H), 7.53-7.61 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.86-7.94 (m, 3H), 7.99-8.03 (m, 2H), 8.41 (d, J = 8.5 Hz, 1H).
[469] Example 9
[470] Sodium salt 3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5- Yl] thio} propionate (sodium salt of Execution Compound 1885)
[471] Appearance; pale yellow solid
[472] m.p .; 175 to 185 ° C.
[473] FAB-MS (m / z); 508 (M ⁺ +1).
[474] ¹ H-NMR (δ, DMSO-d ₆ ); 1.76-1.85 (m, 4H), 2.08-2.13 (m, 2H), 2.35-2.40 (m, 2H), 2.74-2.84 (m, 4H), 5.44 (s, 1H), 6.97 (s, 2H), 7.28-7.46 (m, 8H), 7.54-7.59 (m, 2H), 7.78 (s, 1H).
[475] The reaction was carried out in the same manner as in Examples 1 to 3 to obtain the compounds of Examples 10 to 13 below.
[476] Example 10
[477] Sodium 3-{[3- (E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cycloheptene-yl] oxy} -2 -(R) -methylpropionate (sodium salt of Example Compound 4)
[478] Appearance; yellow solid
[479] ¹ H-NMR (δ, DMSO-d ₆ ); 0.74, 1.20 (each b, total 3H), 2.44 (b, 1H), 3.53, 3.77 (each b, total 2H), 4.68, 5.55 (each s, total 1H), 7.00-7.70 (m, 9H), 7.87 -8.07 (m, 5H), 8.37 (d, J = 8.8 Hz, 1H).
[480] Example 11
[481] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetate ( Sodium salt of embodiment compound 471)
[482] Appearance; Yellow solid
[483] ¹ H-NMR (δ, DMSO-d ₆ ); 3.81 (bs, 2H), 5.04 (bs, 1H), 7.15 (bs, 2H), 7.26-7.66 (m, 7H), 7.90-8.02 (m, 4H), 8.22 (d, J = 7.3 Hz, 1H) , 8.38 (d, J = 8.6 Hz, 1 H).
[484] Example 12
[485] Sodium 3-{[3- (E) -2- (7-cyclo-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxy} Propionate (sodium salt of Execution Compound 473)
[486] Appearance; Yellow solid
[487] ¹ H-NMR (δ, DMSO-d ₆ ); 2.37 (bs, 2H), 3.72, 3.82 (each bs, 2H total), 4.70 (bs, 1H), 7.18 (bs, 2H), 7.28-7.66 (m, 8H), 7.88-8.04 (m, 4H), 8.27 (d, J = 7.1 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H).
[488] Example 13
[489] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] -cyclohepten-5-yl] Oxy} -2- (R) -methylpropionate (sodium salt of Execution Compound 474)
[490] Appearance; Yellow solid
[491] ¹ H-NMR (δ, DMSO-d ₆ ); 0.73, 1.20, 1.52 (each b, total 3H), 2.45 (b, 1H), 3.33-3.86 (each m, 2H), 4.68, 5.55 (each s, total 1H), 7.19-7.63 (m, 9H), 7.88-8.27 (m, 5H), 8.38 (d, J = 8.8 Hz, 1H).
[492] The reaction was carried out in the same manner as in Example 4, to obtain a compound of Examples 14 to 16 below.
[493] Example 14
[494] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetate ( Sodium salt of embodiment compound 476)
[495] Appearance; Orange solid
[496] ¹ H-NMR (δ, DMSO-d ₆ ); 2.61 (d, J = 13.7 Hz, 2H), 2.66 (d, J = 13.7 Hz, 2H), 5.63 (s, 1H), 6.98 (s, 2H), 7.31 (td, J = 9.0 Hz, 2.0 Hz, 1H), 7.33-7.42 (m, 3H), 7.45 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 16.4 Hz, 1H), 7.67 (dd, J = 8.1 Hz, 1.5 Hz, 1H) , 7.75 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 16.1 Hz, 1H), 7.98 (d, J = 9.8 Hz, 1H), 8.02 (d, J = 10.0 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H).
[497] Example 15
[498] Sodium 2-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] -cyclohepten-5-yl] Thio} propionate {sodium salt of compound 477)
[499] Appearance; Pale yellow solid
[500] ¹ H-NMR (δ, DMSO-d ₆ ); 1.10-1.14 (m, 3H), 2.68-2.76 (m, 3H), 5.67 (d, J = 6.4 Hz, 1H), 6.98 (s, 2H), 7.23-7.54 (m, 6H), 7.67 (dd, J = 8.1Hz, 1.5Hz, 1H), 7.31-7.90 (m, 2H), 7.98 (d, J = 7.6Hz, 1H), 8.01 (d, J = 9.8Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H).
[501] Example 16
[502] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio Methyl} -cyclopropaneacetate (sodium salt of Example Compound 487)
[503] Appearance; Pale yellow solid
[504] ¹ H-NMR (δ, DMSO-d ₆ ); 0.15 (bs, 2H), 0.33 (bs, 2H), 1.95 (d, J = 14.2 Hz, 1H), 2.06 (d, J = 14.2 Hz, 1H), 2.43 (d, J = 13.4 Hz, 1H), 2.60 (d, J = 13.4 Hz, 1H), 5.69 (s, 1H), 7.00 (s, 2H), 7.31 (td, J = 7.3 Hz, 1.2 Hz, 1H), 7.34-7.42 (m, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.55-7.61 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 16.4 Hz, 1H), 7.96-8.03 (m , 3H), 8.26 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H).
[505] The reaction was carried out in the same manner as in Examples 1 to 3 to obtain the compound of Example 17.
[506] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5- Sun] oxy-acetate (sodium salt of Execution Compound 505)
[507] Appearance; Pale yellow solid
[508] ¹ H-NMR (δ, DMSO-d ₆ ); 3.79 (bs, 2H), 5.08 (bs, 1H), 7.06-7.35 (m, 3H), 7.40-7.55 (m, 4H), 7.62-7.72 (m, 1H), 7.92-7.97 (m, 1H), 7.93 (d, J = 16.4 Hz, 1H), 8.00 (d, J = 9.8 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.38 ( d, J = 8.8 Hz, 1H).
[509] The reaction was carried out in the same manner as in Example 4, to obtain a compound of Example 18.
[510] Example 18
[511] Sodium 3-{[3- (E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio) -propionate (sodium salt of Execution Compound 510)
[512] Appearance; Pale yellow solid
[513] ¹ H-NMR (δ, DMSO-d ₆ ); 1.96-2.01 (m, 2H), 2.36-2.42 (m, 2H), 5.56 (s, 1H), 7.06-7.20 (m, 3H), 7.33 (d, J = 6.6 Hz, 1H), 7.41 (td, J = 13.4 Hz, 5.5 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 16.4 Hz, 1H), 7.67 (dd, J = 9.4 Hz, 1.5 Hz, 1H), 7.83-7.89 (m, 2H), 7.96 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 9.7 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H).
[514] The reaction was carried out in the same manner as in Examples 1 to 3 to obtain the compound of Example 19.
[515] Example 19
[516] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cyclohepten-5-yl ] Oxyacetate (Sodium Salt of Conducting Compound 535)
[517] Appearance; Pale yellow solid
[518] ¹ H-NMR (δ, DMSO-d ₆ ); 3.79 (s, 2H), 5.07 (s, 1H), 7.35-7.51 (m, 6H), 7.66 (bs, 2H), 7.90-8.03 (m, 4H), 8.23 (d, J = 7.3 Hz, 1H) , 8.38 (d, J = 8.5 Hz, 1H).
[519] The reaction was carried out in the same manner as in Example 4, to obtain a compound of Examples 20 to 21.
[520] Example 20
[521] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -9-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} -propionate (sodium salt of Example Compound 542)
[522] Appearance; Yellow solid
[523] ¹ H-NMR (δ, DMSO-d ₆ ); 1.97-2.09 (m, 2H), 2.41-2.46 (m, 2H), 5.56 (s, 1H), 7.20 (d, J = 12.5 Hz, 1H), 7.26 (d, J = 12.5 Hz, 1H), 7.36 -7.52 (m, 4H), 7.56 (d, J = 16.4 Hz, 1H), 7.69 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 7.88 (d, J = 16.4 Hz, 1H), 7.91 (d , J = 1.5Hz, 1H), 7.98 (d, J = 8.8Hz, 1H), 8.02 (d, J = 9.8Hz, 1H), 8.23 (d, J = 7.3Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H).
[524] Example 21
[525] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -8-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} -propionate (sodium salt of Compound 549)
[526] Appearance; Yellow solid
[527] ¹ H-NMR (δ, DMSO-d ₆ ); 1.96-2.01 (m, 2H), 2.35-2.40 (m, 2H), 5.54 (s, 1H), 6.98 (d, J = 12.0 Hz, 1H), 7.07 (d, J = 12.2 Hz, 1H), 7.43 (dd, J = 8.3Hz, 2.2Hz, 1H), 7.47 (d, J = 8.1Hz, 1H), 7.50-7.58 (m, 2H), 6.68 (d, J = 7.8Hz, 1H), 7.84-7.90 (m, 2H), 7.98 (d, J = 8.8Hz, 1H), 8.02 (d, J = 9.8Hz, 1H), 8.02 (d, J = 7.8Hz, 1H), 8.39 (d, J = 8.8Hz , 1H).
[528] The reaction was carried out in the same manner as in Examples 1 to 3 to obtain the compounds of Examples 22 to 25 below.
[529] Example 22
[530] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5-yl ] Oxyacetate (Sodium Salt of Conducting Compound 557)
[531] Appearance; Pale yellow solid
[532] ¹ H-NMR (δ, DMSO-d ₆ ); 3.06 (d, J = 15.0 Hz, 1H), 3.12 (d, J = 15.0 Hz, 1H), 6.52 (s, 1H), 7.07 (d, J = 12.0 Hz, 1H), 7.11 (d, J = 12.5 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.48-7.58 (m, 4H), 7.78-7.82 (m, 2H), 7.94 (d, J = 16.4 Hz, 1H), 7.99-8.02 (m, 2H), 8.22 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H).
[533] Example 23
[534] Sodium 2- (R)-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5 -Yl] oxy} propionate (sodium salt of Compound 558)
[535] Appearance; Yellow solid
[536] ¹ H-NMR (δ, DMSO-d ₆ ); 0.84-0.86, 1.46-1.50 (each m, total 1H), 3.00-3.04, 3.75-3.79 (each m, total 1H), 5.01, 5.95 (each s, total 1H), 7.03, 7.15 (each s, total 1H ), 7.20-8.01 (m, 11H), 8.04 (d, J = 10.0 Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.37 (dd, J = 8.8 Hz, 2.4 Hz, 1H).
[537] Example 24
[538] Sodium 2- (S)-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl-5H-dibenzo [a, d] cyclohepten-5- Yl} oxy} propionate (sodium salt of Compound 558)
[539] Appearance; Pale yellow solid
[540] ¹ H-NMR (δ, DMSO-d ₆ ); 0.82-0.84, 1.44-1.48 (each m, total 1H), 3.33-3.42, 3.69-3.78 (each m, total 1H), 5.00, 5.94 (each s, total 1H), 7.03, 7.15 (each s, total 1H ), 7.20-7.99 (m, 11H), 8.04 (d, J = 10.0 Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.37 (dd, J = 8.8 Hz, 2.4 Hz, 1H).
[541] Example 25
[542] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] oxy} -propionate (sodium salt of Compound 559)
[543] Appearance; Pale yellow solid
[544] ¹ H-NMR (δ, DMSO-d ₆ ); 1.86-1.92 (m, 2H), 3.09-3.22 (m, 2H), 6.26 (s, 1H), 7.08 (d, J = 12.0 Hz, 1H), 7.13 (d, J = 12.2 Hz, 1H), 7.38 (t, J = 7.6Hz, 1H), 7.51 (dd, J = 7.8Hz, 1.2Hz, 1H), 7.53-7.62 (m, 3H), 7.80 (dd, J = 8.1Hz, 1.5Hz, 1H), 7.92 (s, 1H), 7.95 (d, J = 16.4 Hz, 1H), 7.99-8.03 (m, 2H), 8.22 (d, J = 7.3 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H ).
[545] The reaction was carried out in the same manner as in Example 4, obtaining the compounds of Examples 26 to 28.
[546] Example 26
[547] Sodium [3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5-yl ] Thioacetate (Sodium Salt of Conducting Compound 562)
[548] Appearance; Orange solid
[549] ¹ H-NMR (δ, DMSO-d ₆ ); 2.77 (d, J = 13.4 Hz, 1H), 2.85 (d, J = 13.7 Hz, 1H), 6.17 (s, 1H), 7.04 (d, J = 12.0 Hz, 1H), 7.08 (d, J = 12.0 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.1 Hz, 1H), 7.47-7.58 (m, 3H), 7.72 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.91 (d, J = 16.4 Hz, 1H), 7.98-8.03 (m, 2H), 8.22 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H ).
[550] Example 27
[551] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} -propionate (sodium salt of Execution Compound 564)
[552] Appearance; Yellow solid
[553] ¹ H-NMR (δ, DMSO-d ₆ ); 1.93-2.07 (m, 2H), 2.49-2.55 (m, 2H), 6.02 (s, 1H), 7.06 (d, J = 12.2 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 7.32 (t, J = 7.6Hz, 1H), 7.42 (dd, J = 7.8Hz, 1.2Hz, 1H), 7.51 (d, J = 8.1Hz, 1H), 7.52-7.62 (m, 2H), 7.75 (dd , J = 8.1Hz, 1.5Hz, 1H), 7.82 (d, J = 1.5Hz, 1H), 7.92 (d, J = 16.4Hz, 1H), 7.99-8.03 (m, 2H), 8.22 (d, J = 7.3 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H).
[554] Example 28
[555] Sodium 3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl) -9-trifluoromethyl-5H-dibenzo [a, d] cyclo Heptene-5-yl] thio} propionate (sodium salt of Execution Compound 613)
[556] Appearance; Pale yellow solid
[557] FAB-MS (m / z): 492 (M ⁺ +1).
[558] ¹ H-NMR (δ, DMSO-d ₆ ); 1.99-2.09 (m, 2H), 2.43-2.53 (m, 2H), 5.65 (s, 1H), 7.69-7.30 (m, 2H), 7.50-7.59 (m, 3H), 7.67-7.74 (m, 2H ), 7.85-8.03 (m, 5H), 8.23 (d, J = 7.3 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H).
[559] The reaction was carried out in the same manner as in Examples 1 to 3 to obtain the compound of Example 29.
[560] Example 29
[561] Sodium [3-[(E) -2- (7-chloroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetate (Sodium salt of Example Compound 1411 )
[562] Appearance; Orange solid
[563] ¹ H-NMR (δ, DMSO-d ₆ ); 3.80 (bs, 2H), 5.04 (bs, 1H), 7.16 (bs, 2H), 7.27-7.66 (m, 8H), 7.92-8.02 (m, 4H), 8.04 (d, J = 2.2 Hz, 1H) , 8.40 (d, J = 8.5 Hz, 1H).
[564] The reaction was carried out in the same manner as in Example 4, obtaining the compounds of Examples 30 to 31 below.
[565] Example 30
[566] Sodium [3- (E) -2- (7-chloroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetate (sodium salt of Example Compound 1416)
[567] Appearance; Pale yellow solid
[568] FAB-MS (m / z); 492 (M ⁺ +1).
[569] ¹ H-NMR (δ, DMSO-d ₆ ); 2.65 (d, J = 13.9 Hz, 2H), 2.68 (d, J = 13.9 Hz, 2H), 5.64 (s, 1H), 6.98 (s, 2H), 7.22-7.46 (m, 5H), 7.53 (d , J = 16.4Hz, 1H), 7.59 (dd, J = 8.8Hz, 2.2Hz, 1H), 7.67 (dd, J = 8.1Hz, 1.5Hz, 1H), 7.77 (d, J = 1.5Hz, 1H) , 7.87-8.04 (m, 4H), 8.41 (d, J = 8.5 Hz, 1H).
[570] Example 31
[571] Sodium 3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionate (sodium salt of Execution Compound 1921)
[572] Appearance; Pale yellow solid
[573] FAB-MS (m / z): 544 (M ⁺ +1).
[574] ¹ H-NMR (δ, DMSO-d ₆ ); 1.75-1.85 (m, 4H), 2.00-2.05 (m, 2H), 2.42-2.47 (m, 2H), 2.72-2.87 (m, 4H), 5.60 (s, 1H), 7.14-7.32 (m, 4H ), 7.44-7.47 (m, 2H), 7.53-7.61 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.81-7.83 (m, 2H).
[575] Reference Example 1
[576] (a) 7-chloro-2-vinyl quinoline
[577] J. Org. The title compound was obtained by the method described in Chem., 61 , 3398 (1996).
[578] Appearance; Ocher solid
[579] ¹ H-NMR (δ, DMSO-d ₆ ); 5.69 (dd, J = 11.0 Hz, 1.0 Hz, 1H), 6.31 (dd, J = 17.6 Hz, 0.7 Hz, 1H), 7.00 (dd, J = 17.8 Hz, 11.0 Hz, 1H), 7.45 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 8.06-8.10 (m, 2H).
[580] (b) 3-trifluoromethanesulfonyloxy-5H-dibenzo [a, d] -cyclohepten-5-one
[581] 0.23 g (1.0 mmol) of 3-hydroxy-5H-dibenzo [a, d] cyclohepten-5-one was dissolved in 30 ml of methylene chloride and allowed to cool, followed by 0.33 ml (2.0 mmol) of trifluoromethanesulfonic acid. 0.27 ml (2.0 mmol) of triethylamine was added and stirred under ice-cooling for 4 hours.
[582] After completion of the reaction, the reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (eluent: chloroform) to give 0.30 g of the title compound as a brown oily product.
[583] CI-MS (m / z); 355 (M ⁺ +1).
[584] EI-MS; 354 (M ⁺ ).
[585] ¹ H-NMR (δ, DMSO-d ₆ ); 7.31 (d, J = 12.2 Hz, 1H), 7.37 (d, J = 12.2 Hz, 1H), 7.50-8.40 (m, 7H).
[586] (c) 3-[(E) -2- (7-chloroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5one
[587] 3-trifluoromethanesulfonyloxy-5H-dibenzo [a, d] cyclohepten-5-one0.89 g (2.5 mmol) and 7-chloro-2-vinyl quinoline 0.48 g (2.5 mmol) After dissolving in 30 ml of dimethylformamide, 100 mg (0.5 mmol) of palladium acetate, 420 mg (1.6 mmol) of triphenylphosphine and 2.1 g (24 mmol) of lithium bromide were added thereto to obtain a nitrogen atmosphere. Then 5.0 ml (36 mmol) of triethylamine were added and stirred at 120 ° C. for 10 hours under a nitrogen atmosphere.
[588] After completion of the reaction, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (eluent: toluene / ethyl acetate = 9/1 (volume ratio) to give 0.53 g of the title compound as a pale brown solid.
[589] CI-MS (m / z); 394 (M ⁺ +1).
[590] ¹ H-NMR (d, DMSO-d ₆ ); 7.28 (s, 2H), 7.59-7.69 (m, 3H), 7.78-7.83 (m, 3H), 7.97-8.06 (m, 4H), 8.13-8.20 (m, 2H), 8.38 (s, 1H), 8.44 (d, J = 9.3 Hz, 1 H).
[591] (d) 3-[(E) -2- (7-chloroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol
[592] 0.53 g (1.3 mmol) of 3-[(E) -2- (7-chloroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-one with 40 ml of tetrahydrofuran It was dissolved in a mixture of 10 ml of methanol, 0.11 g (2.6 mmol) of sodium borohydride was added, and stirred at room temperature for 3 hours.
[593] After completion of the reaction, water was added to the reaction solution, the pH was adjusted to about 2.0 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to give 0.33 g of the title compound as ocher.
[594] CI-MS (m / z); 396 (M ⁺ +1).
[595] ¹ H-NMR (δ, DMSO-d ₆ ); 5.10 (d, J = 3.4 Hz, 1H), 6.20 (s, 1H), 7.18 (s, 2H), 7.26 (td, J = 8.8 Hz, 1.2 Hz, 1H), 7.37-7.52 (m, 4H), 7.59 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.64 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.91-8.04 (m, 5H) , 8.40 (d, J = 8.3 Hz, 1H).
[596] Reference Example 2
[597] The reaction was carried out in the same manner as in Reference Example 1 (a), to obtain a compound of Reference Example 2 (a).
[598] (a) 7-chloro-6-fluoro-2-vinyl quinoline
[599] Appearance; Yellow solid
[600] CI-MS (m / z); 208 (M ⁺ +1).
[601] EI-MS; 207 (M ⁺ ).
[602] ¹ H-NMR (δ, DMSO-d ₆ ); 5.73 (dd, J = 11.0 Hz, 1.0 Hz, 1H), 6.43 (dd, J = 17.6 Hz, 1.0 Hz, 1H), 6.98 (dd, J = 17.8 Hz, 11.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 9.8 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H).
[603] The reaction was carried out in the same manner as in Reference Example 1 (c), to obtain a compound of Reference Example 2 (b).
[604] (b) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5one
[605] Appearance; Pale yellow solid
[606] ¹ H-NMR (δ, DMSO-d ₆ ); 7.29 (s, 2H), 7.63-7.70 (m, 2H), 7.78-7.84 (m, 3H), 8.00-8.05 (m, 3H), 8.13-8.21 (m, 2H), 8.23 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H).
[607] The reaction was carried out in the same manner as in Reference Example 1 (d), to obtain a compound of Reference Example 2 (c).
[608] (c) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol
[609] Appearance; Yellow solid
[610] ¹ H-NMR (δ, DMSO-d ₆ ); 5.09 (d, J = 3.9 Hz, 1H), 6.20 (s, 1H), 7.18 (s, 2H), 7.26 (td, J = 7.3 Hz, 1.2 Hz, 1H), 7.37-7.50 (m, 4H), 7.60 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 7.93 (d, J = 16.4 Hz, 1H), 7.98-8.02 (m, 3H), 8.21 ( d, J = 7.3 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H).
[611] Reference Example 3
[612] The reaction was carried out in the same manner as in Reference Example 1 (a), to obtain a compound of Reference Reference 3 (a).
[613] (a) 6,7-difluoro-2-vinylquinoline
[614] Appearance; Pale yellow solid
[615] CI-MS (m / z); 192 (M ⁺ +1).
[616] EI-MS; 191 (M ⁺ ).
[617] ¹ H-NMR (δ, DMSO-d ₆ ); 5.69 (dd, J = 11.0 Hz, 1.0 Hz, 1H), 6.39 (dd, J = 17.6 Hz, 1.0 Hz, 1H), 6.93 (dd, J = 8.1 Hz, 3.9 Hz, 1H), 6.95 (dd, J = 17.6 Hz, 11.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 9.0 Hz, 2.2 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H).
[618] The reaction was carried out in the same manner as in Reference Example 1 (c), to obtain a compound of Reference Example 3 (b).
[619] (b) 3-[(E) -2- (6,7-difluoroquinolin-2-yl) ethenyl) -5H-dibenzo [a, d] cyclohepten-5-one
[620] Appearance; Brown solid
[621] CI-MS (m / z); 396 (M ⁺ +1).
[622] EI-MS; 395 (M ⁺ ).
[623] ¹ H-NMR (δ, DMSO-d ₆ ); 7.29 (s, 2H), 7.50-7.90 (m, 7H), 7.95-8.30 (m, 5H), 8.41 (d, J = 8.5 Hz, 1H).
[624] The reaction was carried out in the same manner as in Reference Example 1 (d), to obtain a compound of Reference Example 3 (c).
[625] (c) 3-[(E) -2- (6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol
[626] Appearance; Brown solid
[627] CI-MS (m / z); 398 (M ⁺ +1).
[628] EI-MS; 397 (M ⁺ ).
[629] ¹ H-NMR (δ, DMSO-d ₆ ); 5.09 (s, 1H), 7.18 (s, 2H), 7.20-7.70 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.43 (d , J = 7.8Hz, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.76 (d, J = 7.6Hz, 1H), 7.80-8.20 (m, 4H), 7.93 (d, J = 16.6Hz , 1H), 8.36 (d, J = 8.5 Hz, 1H).
[630] Reference Example 4
[631] (a) 5,6,7,8-tetrahydro-2-vinylquinoline
[632] 14.7 g (65 mmol) of (5,6,7,8-tetrahydroquinolin-2-yl) methyl bromide was dissolved in 300 ml of acetonitrile and refluxed for 2 hours by adding 25.5 g (97.5 mmol) of triphenylphosphine. . After cooling in an ice-bath, the precipitate was collected by filtration and washed with diethyl ether to give (5,6,7,8-tetrahydroquinolin-2-yl) methyltriphenylphosphonium bromide as a pale yellow solid. Then, the obtained solid was dissolved in 250 ml of chloroform, and 9.50 g (117 mmol) of 37% formaldehyde and 8.10 g (76 mmol) aqueous solution of sodium carbonate (20 ml) were added and stirred at room temperature for 2 hours.
[633] After completion of the reaction, water was added to the reaction solution and extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated. The residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 (volume ratio) to give 6.01 g of the title compound as a yellow oil.
[634] CI-MS (m / z); 160 (M ⁺ +1).
[635] EI-MS; 159 (M ⁺ ).
[636] ¹ H-NMR (δ, CDCl ₃ ); 1.85 (m, 4H), 2.75 (dd, J = 17.6 Hz, 1.0 Hz, 2H), 2.91 (dd, J = 8.1 Hz, 3.9 Hz, 2H), 5.41 (dd, J = 10.7 Hz, 1.2 Hz, 1H ), 6.06 (dd, J = 17.6 Hz, 1.2 Hz, 1H), 6.75 (dd, J = 17.6 Hz, 10.7 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H).
[637] The reaction was carried out in the same manner as in Reference Example 1 (c), to obtain a compound of Reference Example 4 (b).
[638] (b) 3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-one
[639] Appearance; Pale yellow solid
[640] ¹ H-NMR (δ, CDCl ₃ ); 1.81-1.95 (m, 4H), 2.79 (t, J = 6.1, 2H), 2.96 (t, J = 6.4 Hz, 2H), 7.05 (s, 2H), 7.15-7.37 (m, 4H), 7.52- 7.64 (m, 4H), 7.81-7.85 (m, 1H), 8.23-8.26 (m, 1H), 8.40 (d, J = 2.0 Hz, 1H).
[641] The reaction was carried out in the same manner as in Reference Example 1 (d), to obtain a compound of Reference Example 4 (c).
[642] (c) 3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-ol
[643] Appearance; Pale yellow solid
[644] ¹ H-NMR (δ, CDCl ₃ ); 1.80-2.00 (m, 4H), 2.77 (m, 2H), 2.95 (m, 2H), 5.45 (s, 1H), 7.09 (s, 1H), 7.20-7.70 (m, 10H), 7.89 (s, 1H).
[645] Reference Example 5
[646] (a) 3- (7-chloro-6-fluoroquinolin-2-yl) methoxy-5H-dibenzo [a, d] cyclohepten-5one
[647] 0.37 g (1.4 mmol) of 2-bromomethyl-7-chloro-6-fluoroquinoline and 0.30 (1.4 mmol) of 3-hydroxy-5H-dibenzo [a, d] cyclohepten-5-one are N, It was dissolved in 30 ml of N-dimethylformamide, 0.37 g (2.8 mmol) of potassium carbonate was added and stirred at room temperature for 6 hours.
[648] After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to give 0.47 g of the title compound as a dark brown solid.
[649] CI-MS (m / z); 416 (M ⁺ +1).
[650] EI-MS; 415 (M ⁺ ).
[651] ¹ H-NMR (δ, DMSO-d ₆ ); 5.53 (s, 2H), 7.13 (d, J = 12.2 Hz, 1H), 7.21 (d, J = 12.2 Hz, 1H), 7.51 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 7.55-7.90 ( m, 6H), 8.00-8.35 (m, 2H), 8.31 (d, J = 7.3 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H).
[652] (b) 3- (7-chloro-6-fluoroquinolin-2-yl) methoxy-5H-dibenzo [a, d] cyclohepten-5-ol
[653] 3- (7-chloro-6-fluoroquinolin-2-yl) methoxy-5H-dibenzo [a, d] cyclohepten-5one is added to 3-[(E) -2- (6,7-di The reaction was carried out in the same manner as in Reference Example 1 (d), except that fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-one was used instead. The title compound was obtained.
[654] Appearance; Brown solid
[655] CI-MS (m / z); 418 (M ⁺ +1).
[656] EI-MS; 418 (M ⁺ ).
[657] ¹ H-NMR (δ, DMSO-d ₆ ); 5.38 (s, 1H), 5.41 (s, 2H), 6.80-7.90 (m, 9H), 7.95-8.35 (m, 3H), 8.42 (d, J = 8.8 Hz, 1H).
[658] Reference Example 6
[659] (a) 2-methoxycarbonylbenzyltriphenylphosphonium bromide
[660] 86.32 g (377 mmol) of methyl 2- (bromomethyl) benzoate and 98.84 g (377 mmol) of triphenylphosphine were dissolved in 300 ml of acetonitrile and heated to reflux for 2 hours.
[661] After completion of the reaction, 700 ml of diethyl ether was added to the reaction solution. The precipitated white precipitate was collected by filtration and washed with diethyl ether. The precipitate was dried under reduced pressure to give 117.42 g of the title compound as a light brown solid.
[662] CI-MS (m / z); 410 (M ⁺ -Br).
[663] ¹ H-NMR (δ, DMSO-d ₆ ); 3.46 (s, 3H), 5.53 (d, J = 15.4 Hz, 2H), 7.30-7.40 (m, 1H), 7.45-7.63 (m, 8H), 7.65-7.80 (m, 6H), 7.82-7.95 ( m, 4H).
[664] (b) methyl 2- [2- (4-methoxyphenyl) ethenyl] benzoate
[665] 4.91 g (10 mmol) of 2-methoxycarbonylbenzyltriphenylphosphonium bromide and 1.77 g (13 mmol) of 4-methoxybenzaldehyde were dissolved in 50 ml of acetonitrile, followed by 1,5-diazabicyclo [4.3.0 2.48 g (20 mmol) of] -5-nonene was added and heated to reflux for 5 hours.
[666] After completion of the reaction, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (eluent: toluene) to give 1.25 g of the title compound (E, Z mixture) as a pale yellow oil.
[667] CI-MS (m / z); 269 (M ⁺ +1).
[668] EI-MS; 268 (M ⁺ ).
[669] Cis isomer (Z isomer)
[670] ¹ H-NMR (δ, DMSO-d ₆ ); 3.79 (s, 3H), 3.87 (s, 3H), 6.74 (d, J = 9.0 Hz, 1H), 6.90-7.00 (m, 2H), 7.10-7.73 (m, 5H), 7.75-7.95 (m, 2H).
[671] Trans isomer (E isomer)
[672] ¹ H-NMR (δ, DMSO-d ₆ ); 3.69 (s, 3H), 3.87 (s, 3H), 6.56 (d, J = 12.2 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 12.2 Hz, 1H), 6.90-7.00 (m, 2H), 7.10-7.73 (m, 3H), 7.75-7.95 (m, 2H).
[673] (c) 2- [2- (4-methoxyphenyl) ethenyl] benzoic acid
[674] To a 2 ml solution of methanol solution containing 1.20 g (4.5 mmol) of methyl 2- [2- (4-methoxyphenyl) ethenyl] benzoic acid, 1.5 g (26.7 mmol) aqueous potassium hydroxide solution (20 ml) was added and 6 hours Heated to reflux.
[675] After completion of the reaction, the reaction solution was cooled and adjusted to pH = 3 by adding 1N aqueous hydrochloric acid solution to the reaction solution. The resulting white precipitate was collected by filtration, washed with water and dried under reduced pressure to yield 1.12 g of the title compound (E, Z mixture) as a white solid.
[676] Cis isomer (Z isomer)
[677] ¹ H-NMR (δ, DMSO-d ₆ ); 3.78 (s, 3H), 6.53 (d, J = 12.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 12.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.15-7.60 (m, 3H), 7.70-7.95 (m, 2H), 12.93 (br, 1H).
[678] Trans isomer (E isomer)
[679] ¹ H-NMR (δ, DMSO-d ₆ ); 3.69 (s, 3H), 6.74 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 16.1 Hz, 1H), 7.15-7.60 (m, 4H), 7.70-7.95 (m, 2H), 12.93 (br, 1H).
[680] (d) 2- [2- (4-methoxyphenyl) ethyl] benzoic acid
[681] 0.10 g of 10% palladium-activated carbon was added to a 20 ml solution of methanol containing 0.20 g (1.3 mmol) of 2- [2- (4-methoxyphenyl) ethenyl] benzoic acid, followed by stirring at room temperature under hydrogen atmosphere (atmospheric pressure). Stir for hours.
[682] After completion of the reaction, 10% palladium activated carbon was removed from the reaction solution using Celite (trade name), and the filtrate was concentrated to give 0.18 g of the title compound as a pale yellow solid.
[683] CI-MS (m / z); 257 (M ⁺ +1).
[684] EI-MS; 256 (M ⁺ ).
[685] ¹ H-NMR (δ, DMSO-d ₆ ); 2.70-2.80 (m, 2H), 3.10-3.20 (m, 2H), 3.67 (s, 3H), 6.80-6.90 (m, 2H), 7.10-7.20 (m, 2H), 7.22-7.35 (m, 2H ), 7.40-7.50 (m, 1 H), 7.75-7.85 (m, 1 H), 12.88 (br, 1 H).
[686] (e) 3-methoxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one
[687] To 50 ml of methylene chloride containing 1.80 g (7.0 mmol) of 2- [2- (4-methoxyphenyl) ethyl] benzoic acid, 1.83 ml (13 mmol) of trifluoroacetic anhydride and 0.8 ml (6.3 mmol) of boron trifluoride ethyl ether complex mmol) was added and stirred at room temperature for 5 hours.
[688] After completion of the reaction, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (eluent: toluene) to give 0.65 g of the title compound as a yellow oil.
[689] CI-MS (m / z); 239 (M ⁺ +1).
[690] EI-MS; 238 (M ⁺ ).
[691] ¹ H-NMR (δ, DMSO-d ₆ ); 3.12 (s, 4H), 3.79 (s, 3H), 7.12 (dd, J = 8.3 Hz, 2.9 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 2.9 Hz, 1H), 7.51 (dd, J = 7.3 Hz, 1.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H).
[692] (f) 3-methoxy-5H-dibenzo [a, d] cyclohepten-5-one
[693] N-bromosuccinic acid in a 20 ml solution of 1,2-dichloroethane containing 0.65 g (2.7 mmol) of 3-methoxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one 0.80 g (4.5 mmol) of imide and 0.14 g (0.6 mmol) of benzoyl peroxide were added and heated to reflux for 3 hours.
[694] After completion of the reaction, 100 ml of chloroform was added to the reaction solution and washed with 50 ml of 1N sodium hydroxide aqueous solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate chloride and concentrated. The residue was dissolved in 50 ml of 1.2-dichloroethane, 50 ml of triethylamine was added and heated to reflux for 2 hours.
[695] After completion of the reaction, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (eluent: toluene / ethyl acetate = 9/1 (volume ratio) to give 0.57 g of the title compound as a brown solid.
[696] CI-MS (m / z); 237 (M ⁺ +1).
[697] EI-MS; 236 (M ⁺ ).
[698] ¹ H-NMR (δ, DMSO-d ₆ ); 3.90 (s, 3H), 7.12 (d, J = 12.2 Hz, 1H), 7.22 (d, J = 12.2 Hz, 1H), 7.38 (dd, J = 8.5 Hz, 2.9 Hz, 1H), 7.55-7.68 ( m, 2H), 7.70-7.80 (m, 3H), 8.13 (d, J = 7.6 Hz, 1H).
[699] (g) 3-hydroxy-5H-dibenzo [a, d] cyclohepten-5-one
[700] 2.03 g (8.6 mmol) of 3-methoxy-5H-dibenzo [a, d] cyclohepten-5-one are dissolved in 100 ml of acetic acid, 20 ml of 48% hydrobromic acid is added to the reaction solution and heated to reflux for 10 hours. I was.
[701] After completion of the reaction, the reaction solution was poured into 200 ml of ice water, and the resulting solid was collected by filtration, washed with water and dried under reduced pressure to give 1.48 g of the title compound as a dark brown solid.
[702] CI-MS (m / z); 223 (M ⁺ +1).
[703] EI-MS; 222 (M ⁺ ).
[704] ¹ H-NMR (δ, DMSO-d ₆ ); 7.04 (d, J = 12.0 Hz, 1H), 7.12 (d, J = 12.0 Hz, 1H), 7.19 (dd, J = 8.5 Hz, 2.9 Hz, 1H), 7.50-7.64 (m, 3H), 7.67- 7.80 (m, 2 H), 8.11 (d, J = 7.6 Hz, 1 H).
[705] Reference Example 7
[706] (a) 3- (4-methoxybenzylidene) phthalide
[707] 22.28 g (150 mmol) of phthalic anhydride, 25.0 g (150 mmol) of 4-methoxyphenyl acetate and 2.0 g (24 mmol) of sodium acetate were mixed and stirred at 220 ° C. for 8 hours.
[708] After completion of the reaction, ethanol was added to the reaction solution, insolubles were removed by filtration, and the filtrate was concentrated. The residue obtained was subjected to silica gel column chromatography (eluent: toluene / ethyl acetate = 9/1 (volume ratio) to give 13.15 g of the title compound as a yellow solid.
[709] CI-MS (m / z); 253 (M ⁺ +1).
[710] EI-MS; 252 (M ⁺ ).
[711] ¹ H-NMR (δ, DMSO-d ₆ ); 3.81 (s, 3H), 6.90 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.87 (t, J = 7.3 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H).
[712] (b) 2- [2- (4-methoxyphenyl) ethyl] benzoic acid
[713] 16.6 ml (119 mmol) of triethylamine and Raney Nickel (manufactured by Kawaken Finechemical, developed nickel catalyst NTD-65, 24 ml) in a 280 ml solution of ethanol containing 20.0 g (79.3 mmol) of 3- (4-methoxybenzylidene) phthalide Was added and stirred at 80 ° C. for 2.5 hours under hydrogen pressurization (10 atm).
[714] After completion of the reaction, the catalyst was removed by filtration from the reaction solution using Celite (trade name) and the filtrate was concentrated. The obtained residue was dissolved in 200 ml of methylene chloride, washed sequentially with 100 ml of 1N aqueous hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to give 17.2 g of the title compound as a white solid. The obtained compound was the same as in Reference Example 6 (d).
[715] Reference Example 8
[716] (a) 2- [2- (4-bromophenyl) ethenyl] -3-fluorobenzoic acid
[717] 11.6 g (121 mmol) of sodium t-butoxide was suspended in 200 ml of N, N-dimethylformamide, 20.2 g (120 mmol) of 3-fluoro-2-methylbenzoate and 22.3 g of p-bromobenzaldehyde ( 120 mmol) was dissolved in 100 ml of dimethylformamide dropwise at a temperature of 5 ° C. for 1 hour or more. After completion of the dropping, the mixture was stirred at 10 ° C. for 1 hour, and further stirred at room temperature overnight.
[718] After completion of the reaction, 1.0 liter of water was added to the reaction solution, and adjusted to pH 3 with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and then washed under reduced pressure to give 25.3 g of the titled compound as a pale yellow solid.
[719] ¹ H-NMR (δ, CDCl ₃ ); 7.06 (dd, J = 16.9 Hz, 1.7 Hz, 1H), 7.38-7.61 (m, 7H), 7.67 (dd, J = 7.1 Hz, 1.7 Hz, 1H), 13.28 (b, 1H).
[720] (b) 2- [2- (4-chromophenyl) ethyl] -3-fluorobenzoic acid
[721] 6.2 g (199.4 mmol) moistened with 25.3 g (78.8 mmol) of 2- [2- (4-bromophenyl) ethenyl] -3-fluorobenzoic acid, 60 ml of 57% hydroiodic acid and 150 ml of acetic acid were added thereto for 10 hours. Heated to reflux. After cooling, red phosphorus was further added and heated to reflux. Addition of red phosphorus was carried out twice.
[722] After the completion of the reaction, 1.0L of water was added to the reaction solution, and the precipitated solid was recovered by filtration, water was added and adjusted to pH 12 with aqueous sodium hydroxide solution, and then the insolubles were filtered off. The filtrate was adjusted to pH 3 with concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give 23.9 g of the title compound as a colorless solid.
[723] ¹ H-NMR (δ, CDCl ₃ ); 2.76-2.81 (m, 2H), 3.15-3.20 (m, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.35-7.39 (m, 2H), 7.47 (d, J = 8.3 Hz, 2H) , 7.65-7.68 (m, 1 H), 13.4 (b, 1 H).
[724] (c) 3-bromo-9-fluoro-10,11-dihydro = 5H-dibenzo [a, d] -cyclohepten-5-one
[725] To 25.8 g (80 mmol) of 2- [2- (4-bromophenyl) ethyl] -3-fluorobenzoic acid, 550 g of polyphosphoric acid was added and stirred at 170 ° C. for 3 hours. After cooling to 80 ° C., water was added and allowed to cool to room temperature under stirring.
[726] After completion of the reaction, the reaction solution was extracted with chloroform. The extract was washed sequentially with water, aqueous sodium hydroxide solution and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated and subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 (volume ratio)) to give 18.6 g of the title compound as a brown solid.
[727] CI-MS (m / z); 305 (M ⁺ +1).
[728] ¹ H-NMR (δ, CDCl ₃ ); 3.11-3.23 (m, 4H), 7.17 (d, J = 8.5 Hz, 1H), 7.19-7.34 (m, 2H), 7.55 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.99 (m, J = 2.2 Hz, 1H).
[729] (d) 3,10,11-tribromo-9-fluoro-5H-dibenzo [a, d] cyclohepten-5-one
[730] 18.1 g (59.2 mmol) of 3-bromo-9-fluoro-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one and 21.4 g (120.2) N-bromosuccinic acid imide mmol) was added 120 ml of 1,2-dichloroethane and stirred under a mercury lamp irradiation at 40 ° C. for 6 hours.
[731] After completion of the reaction, chloroform was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 28.9 g of the title compound as a yellow solid.
[732] ¹ H-NMR (δ, CDCl ₃ ); 5.70 (d, J = 5.6 Hz, 1H), 6.14 (d, J = 5.9 Hz, 1H), 7.27-7.38 (m, 2H), 7.46-7.53 (m, 1H), 7.69 (dd, J = 8.3 Hz , 2.2 Hz, 1H), 7.89-7.92 (m, 1H), 8.17 (d, J = 2.2 Hz, 1H).
[733] (e) 3-bromo-9-fluoro-5H-dibenzo [a, d] cyclohepten-5-one
[734] After dissolving 8.9 g (20 mmol) of 3,10,11-tribromo-9-fluoro-5H-dibenzo [a, d] cyclohepten-5-one in 50 ml of N, N-dimethylformamide, After cooling, 14.4 g of sodium hydrosulfite and 18.5 g of sodium hydrogen carbonate were added and stirred at 40 ° C. for 2 hours.
[735] After the completion of the reaction, warm water was added to the reaction solution and stirred until it reached room temperature, and then the precipitated solid was recovered by filtration. The filtrate was washed with water and dried under reduced pressure to give 5.1 g of the title compound as a yellow solid.
[736] ¹ H-NMR (δ, CDCl ₃ ); 7.08 (d, J = 12.5 Hz, 1H), 7.34-7.44 (m, 3H), 7.47-7.54 (m, 1H), 7.48 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 7.93-7.96 (m , 1H), 8.29 (d, J = 2.2 Hz, 1H).
[737] (f) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5 -On
[738] 2.7 g (13 mmol) of 7-chloro-6-fluoro-2-vinyl quinoline and 3.0 g (10 mmol) of 3-bromo-9-fluoro-5H-dibenzo [a, d] cyclohepten-5-one Was dissolved in 30 ml of N, N-dimethylformamide, and then 1.0 g (4.6 mmol) of palladium acetate (II), 0.52 g (4.6 mmol) of triphenylphosphine and 2.2 ml (16 mmol) of triethylamine were added thereto, followed by argon atmosphere. Under stirring at 100 ° C. for 4 h.
[739] After completion of the reaction, the reaction solution was allowed to cool to room temperature, and then stirred by addition of 50 ml of ethanol, and the precipitated solid was recovered by filtration. The product obtained by the filtration was washed with ethanol to give 2.2 g of the title compound as a pale yellow brown solid.
[740] CI-MS (m / z); 430 (M ⁺ +1).
[741] EI-MS (m / z); 429 (M ⁺ ).
[742] ¹ H-NMR (δ, DMSO-d ₆ ); 7.40 (s, 2H), 7.66-7.71 (m, 2H), 7.67 (d, J = 16.1 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.91-7.94 (m, 1H), 8.02 (d, J = 16.1 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 9.8 Hz, 1H), 8.20 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H).
[743] (g) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5 -All
[744] 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5-one 2.20 After g (5.1 mmol) was suspended in 153 ml of tetrahydrofuran, 100 mg (4.6 mmol) of lithium borohydride was added under ice-cooling, and then allowed to come to room temperature and stirred for 1 hour.
[745] After completion of the reaction, the reaction solution was ice-cooled, 50 ml of saturated aqueous sodium hydrogen carbonate solution was poured into portions, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. After the mixture was added to the organic layer, the mixture was washed with water and washed once more with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 1.52 g of the title compound as a yellow solid.
[746] CI-MS (m / z); 432 (M ⁺ +1).
[747] EI-MS (m / z); 431 (M ⁺ ).
[748] ¹ H-NMR (δ, DMSO-d ₆ ); 5.09 (bs, 1H), 6.36 (bs, 1H), 7.09-7.16 (m, 1H), 7.24 (dd, J = 11.5 Hz, 1.5 Hz, 1H), 7.32 (d, J = 11.7 Hz, 1H), 7.44-7.52 (m, 3H), 7.59 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.1 Hz, 1.9 Hz, 1H), 7.93 (d, J = 16.1 Hz, 1H), 7.99- 8.03 (m, 3H), 8.22 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H).
[749] Reference Example 9
[750] The reaction was carried out in the same manner as in Reference Example 8 (a-g), to obtain a compound of Reference Example 9 (a-g).
[751] (a) 2- [2- (4-bromophenyl) ethenyl] -3-chlorobenzoic acid
[752] Appearance; White solid
[753] ¹ H-NMR (δ, CDCl ₃ ); 6.72 (d, J = 16.6 Hz, 1H), 7.31-7.44 (m, 2H), 7.51-7.61 (m, 4H), 7.66-7.70 (m, 2H), 13.25 (b, 1H).
[754] (b) 2- [2- (4-bromophenyl) ethyl] -3-chlorobenzoic acid
[755] Appearance; White solid
[756] CI-MS (m / z); 341 (M ⁺ +1).
[757] ¹ H-NMR (δ, CDCl ₃ ); 2.77-2.83 (m, 2H), 3.22-3.27 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.5 Hz , 1H), 7.66 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.75 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 13.28 (b, 1H).
[758] (c) 3-bromo-9-chloro-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one
[759] Appearance; Tan solid
[760] CI-MS (m / z); 323 (M ⁺ +1).
[761] ¹ H-NMR (δ, CDCl ₃ ); 3.13-3.17 (m, 2H), 3.31-3.35 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.52-7.56 (m, 2H) , 7.62 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 7.97 (d, J = 2.2 Hz, 1 H).
[762] (d) 3,10,11-tribromo-9-chloro-5H-dibenzo [a, d] cyclohepten-5-one
[763] Appearance; Pale yellow solid
[764] ¹ H-NMR (δ, CDCl ₃ ); 5.78 (d, J = 5.9 Hz, 1H), 6.35 (d, J = 5.9 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.65 ( dd, J = 7.8Hz, 1.2Hz, 1H), 7.70 (dd, J = 8.3Hz, 2.2Hz, 1H), 7.92 (dd, J = 7.8Hz, 1.5Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H)
[765] (e) 3-bromo-9-chloro-5H-dibenzo [a, d] cyclohepten-5-one
[766] Appearance; Pale yellow solid
[767] CI-MS (m / z); 321 (M ⁺ +1).
[768] EI-MS (m / z); 320 (M ⁺ ).
[769] ¹ H-NMR (δ, CDCl ₃ ); 7.10 (d, J = 12.5 Hz, 1H), 7.39-7.48 (m, 2H), 7.59 (d, J = 12.7 Hz, 1H), 7.70-7.74 (m, 2H), 7.97 (dd, J = 8.1 Hz , 1.2 Hz, 1 H), 8.18 (d, J = 1.7 Hz, 1 H).
[770] (f) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cyclohepten-5- On
[771] Appearance; Greenish yellow solid
[772] CI-MS (m / z); 448 (M ⁺ +1).
[773] EI-MS (m / z); 445 (M ⁺ ).
[774] ¹ H-NMR (δ, DMSO-d ₆ ); 7.52 (d, J = 12.5Hz, 1H), 7.56 (d, J = 12.7Hz, 1H), 7.62-7.69 (m, 2H), 8.82 (d, J = 8.3Hz, 1H), 7.91-8.05 (m , 5H), 8.18-8.25 (m, 3H), 8.42 (d, J = 9.0 Hz, 1H).
[775] (g) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5 -All
[776] Appearance; Orange solid
[777] CI-MS (m / z); 448 (M ⁺ +1).
[778] ¹ H-NMR (δ, DMSO-d ₆ ); 5.05 (bs, 1H), 6.45 (bs, 1H), 7.37-7.52 (m, 7H), 7.67 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 16.1 Hz, 1H), 7.90-8.02 (m, 2H), 8.21 (d, J = 7.3 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H)
[779] Reference Example 10
[780] The reaction was carried out in the same manner as in Reference Example 8 (a-e), to obtain a compound of Reference Example 10 (a-e).
[781] (a) 2- [2- (4-bromophenyl) ethenyl] -3-iodinebenzoic acid
[782] Appearance; Pale yellow solid
[783] CI-MS (m / z): 428 (M ⁺ +1).
[784] EI-MS (m / z): 429 (M ⁺ ).
[785] ¹ H-NMR (δ, CDCl ₃ ); 6.51 (d, J = 16.6 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 16.4 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.59 ( d, J = 8.5 Hz, 1H), 7.69 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 8.07 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 13.28 (b, 1H).
[786] (b) 2- [2- (4-bromophenyl) ethyl] -3-iodinebenzoic acid
[787] Appearance; White solid
[788] CI-MS (m / z); 431 (M ⁺ +1).
[789] ¹ H-NMR (δ, CDCl ₃ ); 2.75-2.83 (m, 2H), 3.20-3.25 (m, 2H), 7.09 (t, J = 7.8Hz, 1H), 7.24 (d, J = 8.3Hz, 1H), 7.52 (d, J = 8.3Hz , 1H), 7.78 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 8.06 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 13.3 (b, 1 H).
[790] (c) 3-bromo-9-iodine-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one
[791] Appearance; Yellow solid
[792] CI-MS (m / z); 413 (M ⁺ +1).
[793] ¹ H-NMR (δ, CDCl ₃ ); 3.13-3.17 (m, 2H), 3.31-3.33 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.1 Hz , 2.2 Hz, 1H), 7.75 (dd, J = 7.8 Hz, 1.5 Hz, 1H), 7.98-8.01 (m, 2H).
[794] (d) 3,10,11-tribromo-9-iodine-5H-dibenzo [a, d] cyclohepten-5-one
[795] Appearance; Yellow solid
[796] ¹ H-NMR (δ, CDCl ₃ ); 5.80 (d, J = 5.9 Hz, 1H), 6.17 (d, J = 6.1 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.71 ( dd, J = 8.3 Hz, 2.2 Hz, 1H), 8.10 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H).
[797] (e) 3-bromo-9-iodine-5H-dibenzo [a, d] cyclohepten-5-one
[798] CI-MS (m / z); 413 (M ⁺ +1).
[799] ¹ H-NMR (δ, CDCl ₃ ); 7.05 (d, J = 12.5Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.35-7.42 (m, 2H), 7.72 (dd, J = 8.3Hz, 2.2Hz, 1H), 8.00 ( dd, J = 8.1 Hz, 1.0 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.21 (dd, J = 7.8 Hz, 1.2 Hz, 1H).
[800] (f) 3-bromo-9-trifluoromethyl-5H-dibenzo [a, d] cyclohepten-5-one
[801] 6.2 g (15.1 mmol) of 3-bromo-9-iodine-5H-dibenzo [a, d] cyclohepten-5-one obtained in Reference Example 10 (e) and 1.15 g (0.60 mmol) of copper iodide (I) Was suspended in 28 ml of N, N-dimethylformamide and 11.61 g (60.4 mmol) of fluorosulfonyl (difluoro) methyl acetate was added and stirred for 21 h at 80 ° C. under argon atmosphere.
[802] After completion of the reaction, after cooling to room temperature, the reaction solution was diluted with ethyl acetate and the precipitated solution was filtered off to remove the filtrate, and the filtrate was washed sequentially with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated and subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 (volume ratio)) to give 4.0 g of the title compound as a pale yellow solid.
[803] CI-MS (m / z); 355 (M ⁺ +1).
[804] EI-MS (m / z); 354 (M ⁺ ).
[805] ¹ H-NMR (δ, DMSO-d ₆ ); 7.14 (d, J = 12.5Hz, 1H), 7.39-7.43 (m, 2H), 7.61 (t, J = 8.3Hz, 1H), 7.75 (dd, J = 8.3Hz, 2.2Hz, 1H), 7.99 ( d, J = 7.8 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H).
[806] The reaction was carried out in the same manner as in Reference Example 8 (f), to obtain a compound of Reference Example 10 (g).
[807] (g) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] cycloheptene -5-on
[808] Appearance; Yellow solid
[809] CI-MS (m / z); 482 (M ⁺ +1).
[810] EI-MS (m / z); 479 (M ⁺ ).
[811] ¹ H-NMR (δ, DMSO-d ₆ ); 7.35 (dd, J = 12.5 Hz, 1.7 Hz, 1H), 7.50 (d, J = 12.7 Hz, 1H), 7.67 (d, J = 16.4 Hz, 1H), 7.79-7.87 (m, 2H), 7.97- 8.04 (m, 3H), 8.16-8.24 (m, 5H), 8.42 (d, J = 8.8 Hz, 1H).
[812] The reaction was carried out in the same manner as in Reference Example 8 (g), to obtain a compound of Reference Example 10 (h).
[813] (h) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] cycloheptap -5-all
[814] Appearance; Pale yellow solid
[815] CI-MS (m / z): 482 (M ⁺ +1).
[816] ¹ H-NMR (δ, DMSO-d ₆ ); 5.05 (bs, 1H), 6.53 (bs, 1H), 7.32-7.69 (m, 7H), 7.94 (d, J = 16.4 Hz, 1H), 7.99-8.02 (m, 3H), 8.10 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.79 (d, J = 8.8 Hz, 1H).
[817] Reference Example 11
[818] The reaction was carried out in the same manner as in Reference Example 8 (f), to obtain a compound of Reference Example 11 (a).
[819] (a) 3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] Cycloheptene-5-one
[820] Appearance; Brown solid
[821] CI-MS (m / z); 432 (M ⁺ +1).
[822] ¹ H-NMR (δ, DMSO-d ₆ ); 1.74-1.92 (m, 4H), 2.72-2.87 (m, 4H), 7.31 (dd, J = 12.7 Hz, 2.2 Hz, 1H), 7.36-7.53 (m, 4H), 7.66-7.83 (m, 3H) , 8.07 (dd, J = 8.0 Hz, 1.7 Hz, 1H), 8.11-8.21 (m, 3H).
[823] The reaction was carried out in the same manner as in Reference Example 8 (g), to obtain a compound of Reference Example 11 (b).
[824] (b) 3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] Cycloheptene-5-ol
[825] Appearance; Gray solid
[826] CI-MS (m / z); 434 (M ⁺ +1).
[827] ¹ H-NMR (δ, DMSO-d ₆ ); 1.75-1.85 (m, 4H), 2.72-2.86 (m, 4H), 5.03 (bs, 1H), 6.46 (bs, 1H), 7.27 (d, J = 16.1 Hz, 1H), 7.33-7.46 (m, 4H), 7.54-7.67 (m, 3H), 7.94 (s, 1H), 8.08 (d, J = 7.3 Hz, 1H).
[828] Reference Example 12
[829] (a) 2-chloro-6-methylbenzoic acid
[830] To a solution in which 42.5 g (0.43 mol) of copper chloride (I) was suspended in 700 ml of acetonitrile, 39.9 g (0.39 mol) of t-butyl nitrile was added and heated to 55 ° C. 40.0 g (0.26 mol) of 2-amino-6-methylbenzoic acid was decomposed and added to the solution. After stirring at 60 ° C. for 3 hours, it was allowed to cool to room temperature.
[831] After completion of the reaction, the reaction solution was poured into a mixed solution of 1.5 L of concentrated hydrochloric acid and 1.5 L of water and extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous magnesium sulfate. The concentrate concentrated under reduced pressure was recrystallized in cyclohexane to give 21.8 g of the title compound as a beige solid.
[832] CI-MS (m / z); 171 (M ⁺ +1).
[833] ¹ H-NMR (δ, CDCl ₃ ); 2.45 (s, 3H), 7.15 (t, J = 4.2 Hz, 1H), 7.26-7.28 (m, 2H), 9.94 (bs, 1H).
[834] (b) 2-chloro-6-methylbenzoate methyl
[835] After dissolving 1.8 g (10.6 mmol) of 2-chloro-6-methylbenzoic acid in 10 ml of N, N-dimethylformamide, 1.49 g (10.8 mmol) of potassium carbonate and 2.7 ml of methyl iodine were added, and the mixture was kept at room temperature for 3 hours. Stirred.
[836] After completion of the reaction, water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 (volume ratio) to give 1.69 g of the title compound as a pale yellow solid.
[837] CI-MS (m / z); 171 (M ⁺ +1).
[838] ¹ H-NMR (d, CDCl ₃ ); 2.32 (s, 3H), 3.95 (s, 3H), 7.10 (t, J = 4.3 Hz, 1H), 7.22-7.23 (m, 2H).
[839] (c) methyl 2-chloro-6-bromomethylbenzoate
[840] To 20.0 g (108 mmol) of methyl 2-chloro-6-methylbenzoate and 19.3 g (108 mmol) of N-bromosuccinic acid imide, 100 ml of 1,2-dichloroethane was added and subjected to a mercury lamp irradiation at 50 ° C. for 5 hours. Stirred.
[841] After completion of the reaction, chloroform was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure, hexane was added and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give 27.6 g of the title compound as a pale yellow solid.
[842] ¹ H-NMR (δ, CDCl ₃ ); 4.00 (s, 3 H), 4.50 (s, 2 H), 7.32-7.39 (m, 3 H).
[843] (d) 3-chloro-2-methoxycarbonylbenzyltriphenylphosphonium bromide
[844] To 27.6 g of methyl 2-chloro-6-bromomethylbenzoate and 39.0 g of triphenylphosphine was added 200 ml of acetonitrile and stirred at 80 ° C. for 3 hours.
[845] After completion of the reaction, the reaction solution was concentrated under reduced pressure and diethyl ether was added. The precipitated solid was collected by filtration and dried under reduced pressure to give 44.6 g of the title compound as a beige solid.
[846] ¹ H-NMR (δ, CDCl ₃ ); 3.66 (s, 3 H), 5.62 (d, J = 2.0 Hz, 2 H), 7.32-7.39 (m, 18 H).
[847] (e) methyl 6- [2- (4-bromophenyl) ethynel] -2-chlorobenzoate
[848] 150 ml of acetonitrile was added to 44.6 g (84.9 mmol) of 3-chloro-2-methoxycarbonylbenzyltriphenylphosphonium bromide and 16.7 g (90.4 mmol) of 4-bromobenzaldehyde, followed by 1,5-diaza. Bicyclo [4,3,0] -5-nonene was added dropwise.
[849] After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the insolubles were removed by filtration. The filtrate was washed sequentially with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure and subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 (volume ratio) to give 27.6 g of the title compound as a colorless liquid.
[850] ¹ H-NMR (δ, CDCl ₃ ); 3.95, 4.08 (each s, 3H total), 6.61 (dd, J = 12.2 Hz, 2.2 Hz, 1H), 6.97-7.17 (m, 3H), 7.28-7.58 (m, 6H).
[851] The reaction was carried out in the same manner as in Reference Example 8 (b), to obtain a compound of Reference Example 12 (f).
[852] (f) 6- [2- (4-bromophenyl) ethyl] -2-chlorobenzoic acid
[853] Appearance; White solid
[854] CI-MS (m / z); 339 (M ⁺ +1).
[855] ¹ H-NMR (δ, CDCl ₃ ); 2.84-2.98 (m, 4H), 6.99-7.06 (m, 2H), 7.26-7.29 (m, 3H), 7.35-7.39 (m, 2H).
[856] (g) 3-bromo-6-chloro-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one
[857] Appearance; Beige solid
[858] CI-MS (m / z): 323 (M ⁺ +1).
[859] ¹ H-NMR (δ, CDCl ₃ ); 3.06-3.11 (m, 2H), 3.16-3.20 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 6.8 Hz, 1.7 Hz, 1H), 7.26-7.31 (m , 2H), 7.54 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H).
[860] The reaction was carried out in the same manner as in Reference Example 8 (d), to obtain a compound of Reference Example 12 (h).
[861] (h) 3,11-dibromo-6-chloro-10-hydro-5H-dibenzo [a, d] cyclohepten-5-one
[862] Appearance; Tan foamy solid
[863] ¹ H-NMR (δ, CDCl ₃ ); 3.37 (dd, J = 14.9Hz, 6.6Hz, 1H), 3.74 (dd, J = 14.9Hz, 2.4Hz, 1H), 5.56-5.74 (m, 1H), 7.19 (dd, J = 7.3Hz, 1.2Hz , 1H), 7.33-7.43 (m, 3H), 7.68 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H).
[864] (i) 3-bromo-6-chloro-5H-dibenzo [a, d] cyclohepten-5-one
[865] 33.0 g of 3,11-dibromo-6-chloro-10-hydro-5H-dibenzo [a, d] cyclohepten-5-one obtained in Reference Example 12 (h) was dissolved in 300 ml of ethyl acetate, and 150 ml of ethylamine was added and heated and stirred at 80 ° C. for 90 minutes.
[866] After completion of the reaction, the reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. After ethyl acetate was added to the residue, 5% potassium hydrogen sulfate aqueous solution, saturated potassium hydrogen sulfate aqueous solution, saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution were sequentially washed. The organic layer was dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: toluene) to give 8.91 g of the title compound as a brown solid.
[867] CI-MS (m / z); 321 (M ⁺ +1).
[868] ¹ H-NMR (δ, CDCl ₃ ); 6.98 (d, J = 12.0 Hz, 1H), 7.04 (d, J = 12.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.41-7.47 (m, 2H), 7.57 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.68 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H).
[869] The reaction was carried out in the same manner as in Reference Example 8 (f), to obtain a compound of Reference Example 12 (j).
[870] (j) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5- On
[871] Appearance; Tan solid
[872] ¹ H-NMR (δ, DMSO-d ₆ ); 7.25 (d, J = 12.0 Hz, 1H), 7.30 (d, J = 12.2 Hz, 1H), 7.62-7.77 (m, 5H), 8.00-8.04 (m, 4H), 8.13 (dd, J = 8.3 Hz , 2.0 Hz, 1H), 8.22 (d, J = 7.3 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H).
[873] The reaction was carried out in the same manner as in Reference Example 8 (g), to obtain a compound of Reference Example 12 (k).
[874] (k) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -detenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5- Come
[875] Appearance; Beige solid
[876] ¹ H-NMR (δ, DMSO-d ₆ ); 5.19 (d, J = 3.7 Hz, 1H), 6.49-6.53 (m, 2H), 7.10 (d, J = 11.7 Hz, 1H), 7.15 (d, J = 12.0 Hz, 1H), 7.35 (t, J = 7.8Hz, 1H), 7.48-7.56 (m, 3H), 7.59 (d, J = 2.4Hz, 1H), 7.70 (dd, J = 8.1Hz, 1.5Hz, 1H), 7.85 (s, 1H), 7.95 (d, J = 16.4 Hz, 1H), 7.97-8.03 (m, 3H), 8.22 (d, J = 7.3 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H).
[877] Reference Example 13
[878] (a) 3-bromo-8-chloro-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one
[879] The title compound was obtained as a by-product of Reference Example 12 (g).
[880] Appearance; Beige solid
[881] CI-MS (m / z): 323 (M ⁺ +1).
[882] ¹ H-NMR (δ, CDCl ₃ ); 3.16 (s, 4H), 7.12 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.55 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H).
[883] The reaction was carried out in the same manner as in Reference Example 8 (d), to obtain a compound of Reference Example 13 (b).
[884] (b) 3,10,11-tribromo-8-chloro-5H-dibenzo [a, d] cyclohepten-5-one
[885] Appearance; Tan solid
[886] ¹ H-NMR (δ, CDCl ₃ ); 5.66 (d, J = 5.6 Hz, 1H), 5.70 (d, J = 5.6 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.47 ( dd, J = 8.3Hz, 2.0Hz, 1H), 7.69 (dd, J = 8.1Hz, 2.2Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 8.23 (d, J = 2.2Hz, 1H ).
[887] The reaction was carried out in the same manner as in Reference Example 8 (e), to obtain a compound of Reference Example 13 (c).
[888] (c) 3-bromo-8-chloro-5H-dibenzo [a, d] cyclohepten-5-one
[889] Appearance; beige solid
[890] ¹ H-NMR (δ, CDCl ₃ ); 6.96 (d, J = 12.1 Hz, 1H), 7.03 (d, J = 12.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 8.3 Hz, 2.0 Hz, 1H) , 7.53 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H ).
[891] The reaction was carried out in the same manner as in Reference Example 8 (f), to obtain a compound of Reference Example 13 (d).
[892] (d) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethynyl] -8-chloro-5H-dibenzo [a, d] cyclohepten-5- On
[893] Appearance; Yellowish-brown solid
[894] ¹ H-NMR (δ, DMSO-d ₆ ); 7.25 (d, J = 12.0 Hz, 1H), 7.35 (d, J = 12.2 Hz, 1H), 7.66 (d, J = 6.4 Hz, 1H), 7.71 (dd, J = 8.5 Hz, 2.2 Hz, 1H) , 7.84 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.99-8.04 (m, 3H), 8.15 (d, J = 8.8 Hz, 1H), 8.19-8.24 ( m, 2H), 8.38 (d, J = 1.7 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H).
[895] The reaction was carried out in the same manner as in Reference Example 8 (g), to obtain a compound of Reference Example 13 (e).
[896] (e) 3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -8-chloro-5H-dibenzo [a, d] cyclohepten-5- Come
[897] Appearance; Orange solid
[898] ¹ H-NMR (δ, DMSO-d ₆ ); 5.08 (d, J = 4.2 Hz, 1H), 6.32 (b, 1H), 7.15 (d, J = 11.5 Hz, 1H), 7.24 (d, J = 11.7 Hz, 1H), 7.44-7.52 (m, 4H ), 7.66 (dd, J = 8.1 Hz, 2.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 16.4 Hz, 1H), 7.99-8.02 (m, 3H), 8.21 (d, J = 7.3 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H).
[899] The compound represented by (I) of the present invention or a pharmacologically acceptable salt thereof has, in addition to potent leukotriene D ₄ antagonism, leukotriene C ₄ antagonism and leukotriene E ₄ antagonism, and are very useful as anti-asthmatic, anti-allergic and anti-inflammatory agents. useful.

权利要求:
Claims (25)
[1" claim-type="Currently amended] Formula (I)

Wherein R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a carbamoyl group, a formyl group, a carboxyl group, a 1H-tetrazol-5-yl group, a C ₁ -C ₄ alkyl group, a fluoro C _1- C ₄ alkyl group, hydroxy C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₁ -C ₄ alkoxy group, fluoro C ₁ -C ₄ alkoxy group, C _1- A C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group or a C ₁ -C ₄ alkylsulfonyl group,
R ² represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy,
A represents a 5-membered or 6-membered heteroaromatic ring group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom or a heteroaromatic condensed cyclic group in which a heteroaromatic ring group and a benzene ring are condensed. The aromatic ring group or heteroaromatic condensed ring group is a substituent, and a halogen atom, a nitro group, a cyano group, a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a fluoro C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio or C ₃ -C ₄ alkylene which may have a group,
B is formula _{-CH = CH-, -CH 2 O-,} -CH 2 CH 2 -, -CH 2 S-, -OCH 2 - or -SCH ₂ - represents the,
X represents an oxygen atom, a sulfur atom, a methylene group or the formula = CH-,
Y is a substituent, a C ₁ -C ₁₀ alkylene group or a group of formula (a) which may have a halogen atom, a C ₁ -C ₄ alkyl group and a C ₁ -C ₄ alkoxy group

In the formula, o and p are each an integer of 0 to 2, q is an integer of 1 to 4,
z is a carboxyl group which may be protected; a 1H-tetrazol-5-yl group; formula -NH-SO ₂ -R ³ ; Or the formula -CO-NH-SO ₂ -R ³ ,
Wherein R ³ is a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group or a substituent (s), a halogen atom, a C ₁ -C ₄ alkyl group, a fluoro C ₁ -C ₄ alkyl group, a C _1- A phenyl group which may have a C ₄ alkoxy group, a fluoro C ₁ -C ₄ alkoxy group, a nitro group or a cyano group.
m is an integer of 1 to 4, when m is 2 or more, R ¹ may be different from each other, n is an integer of 1 to 3, when n is 2 or more, R ² may be different from each other,
Represents a single bond or a double bond,
Dibenzocycloheptene compounds and pharmacologically acceptable salts thereof.
[2" claim-type="Currently amended] 2. A compound according to claim 1, wherein R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, a formyl group, a 1H-tetrazol-5-yl group, a methyl group, difluoro Methyl group, trifluoromethyl group, hydroxymethyl group, 1-hydroxy-1-methylethyl group, vinyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, methylsulfinyl group and A dibenzocycloheptene compound selected from methylsulfonyl group or a pharmacologically acceptable salt thereof.
[3" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a trifluoromethyl group, a hydroxymethyl group, a 1-hydroxy-1-methylethyl group, or ethoxy A dibenzocycloheptene compound selected from the group consisting of a silyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylsulfinyl group and a methylsulfonyl group, or a pharmacologically acceptable salt thereof.
[4" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 3, wherein R ² of the compound represented by formula (I) is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and a methoxy group or a pharmacologically acceptable thereof. Possible salts.
[5" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, wherein R ² of the compound represented by formula (I) is a hydrogen atom.
[6" claim-type="Currently amended] A compound according to any one of claims 1 to 5, wherein A of the compound represented by formula (I) is 2-pyridyl, 2-benzothiazolyl, quinolin-2-yl, 5,6-difluoro-2 -Pyridyl, 5,6-dichloro-2-pyridyl, 5,6-dimethyl-2-pyridyl, 5,6,7,8-tetrahydroquinolin-2-yl, 6-fluoro-2-benzo Thiazolyl, 5-fluoro-2-benzothiazolyl, 5,6-difluoro-2-benzothiazolyl, 6-chloro-2-benzothiazolyl, 5-chloro-2-benzothiazolyl, 5, 6-dichloro-2-benzothiazolyl, 5-chloro-6-fluoro-2-benzothiazolyl, 5-methyl-2-benzothiazolyl, 5-cyano-2-benzothiazolyl, 5-trifluoro Romethyl-2-benzothiazolyl, 5-methylthio-2-benzothiazolyl, 5-fluoroquinolin-2-yl, 6-fluoroquinolin-2-yl, 7-fluoroquinolin-2-yl, 5-chloroquinolin-2-yl, 6-chloroquinolin-2-yl, 7-chloroquinolin-2-yl, 7-methylquinolin-2-yl, 7-trifluoromethoxyquinolin-2-yl, 7- Methoxyquinolin-2-yl, 7-diflu Romethoxyquinolin-2-yl, 7-trifluoromethoxyquinolin-2-yl, 5,7-difluoroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 5,7- Dichloroquinolin-2-yl, 6,7-dichloroquinolin-2-yl, 5-chloro-7-fluoroquinolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 7-chloro- 5-fluoroquinolin-2-yl, 7-chloro-6-fluoroquinolin-2-yl, 7-chloro-6-cyanoquinolin-2-yl, 7-cyano-6-fluoroquinoline-2 A dibenzocycloheptene compound selected from -yl, 6-fluoro-7-trifluoromethylquinolin-2-yl and 5,6,7-trifluoroquinolin-2-yl groups or a pharmacologically acceptable salt thereof.
[7" claim-type="Currently amended] The compound of any one of claims 1 to 5, wherein A of the compound represented by formula (I) is 5,6,7,8-tetrahydroquinolin-2-yl, 7-fluoroquinolin-2-yl, Dibenzo selected from 7-chloroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro-6-fluoroquinolin-2-yl groups Cycloheptene compounds or pharmacologically acceptable salts.
[8" claim-type="Currently amended] The dibenzocyclo according to any one of claims 1 to 7, wherein B of the compound represented by formula (I) is formula: -CH = CH-, formula: -OCH ₂ -or formula: -CH ₂ O-. Heptene compound or a pharmacologically acceptable salt thereof.
[9" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof, wherein X of the compound represented by formula (I) is an oxygen atom or a sulfur atom.
[10" claim-type="Currently amended] The compound according to any one of claims 1 to 9, wherein Y of the compound represented by formula (I) is methylene, ethylene, trimethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1, 1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 2,2-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, A dibenzocycloheptene compound selected from 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene and (a-5) group or a pharmacologically acceptable salt thereof.
[11" claim-type="Currently amended] The compound according to any one of claims 1 to 9, wherein Y of the compound represented by formula (I) is methylene, ethylene, trimethylene, ethyledene, 1-methylethylene, 2-methylethylene and (a-5) groups. A dibenzocycloheptene compound selected from among the pharmacologically acceptable salts thereof.
[12" claim-type="Currently amended] The compound of any one of claims 1 to 11, wherein Z of the compound represented by formula (I) is carboxyl, methanesulfonylamino, trifluoromethanesulfonylamino, methanesulfonylaminocarbonyl and trifluoro A dibenzocycloheptene compound selected from metasulfonylaminocarbonyl group, or a pharmacologically acceptable salt thereof.
[13" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt thereof, wherein Z of the compound represented by formula (I) is a carboxyl group.
[14" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 13, or a pharmacologically acceptable salt thereof, wherein m of the compound represented by formula (I) is 1 or 2.
[15" claim-type="Currently amended] The dibenzocycloheptene compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, wherein n of the compound represented by formula (I) is 1.
[16" claim-type="Currently amended] 2. A compound according to claim 1, wherein R ¹ of the compound represented by formula (I) is a hydrogen atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, a formyl group, a 1H-tetrazol-5-yl group, a methyl group, difluoro Methyl group, trifluoromethyl group, hydroxymethyl group, 1-hydroxy-1-methylethyl group, vinyl group, ethynyl group, methoxy group, difluoromethoxy group, trifluoromethoxy group, methylthio group, methylsulfinyl group and Methyl sulfonyl group, R ² is selected from hydrogen atom, fluorine atom, chlorine atom, methyl group and methoxy group, A is 5,6,7,8-tetrahydroquinolin-2-yl, 7-fluoroquinoline -2-yl, 7-chloroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro-6-fluoroquinolin-2- Diary, B is a formula: -CH = CH-,-formula: -OCH ₂ -or a formula: -CH ₂ O-, X is an oxygen atom or a sulfur atom, Y is methylene, ethylene, tri Methylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 1,1-difluoroethylene, 2,2-difluoroethylene, ethylidene, 1-methylethylene, 2-methylethylene, 2,2-difluorotrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene and (a-5) Z is selected from carboxy, methanesulfonylamino, trifluoromethanesulfonylamino, metalsulfonylaminocarbonyl and trifluoromethanesulfonylaminocarbonyl groups, m is 1 or 2 and n is 1 Phosphorus dibenzocycloheptene compound or a pharmacologically acceptable salt thereof.
[17" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a trifluoromethyl group, a hydroxymethyl group, a 1-hydroxy-1-methylethyl group, or ethoxy. It is selected from a niyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, a methylsulfinyl group, and a methylsulfonyl group, R <^2> is a hydrogen atom and A is 5,6,7,8-tetrahydroquinoline-2 -Yl, 7-fluoroquinolin-2-yl, 7-chloroquinolin-2-yl, 6,7-difluoroquinolin-2-yl, 6,7-dichloroquinolin-2-yl and 7-chloro- Is selected from a 6-fluoroquinolin- ₂ -yl group, wherein B is a formula: CH═CH—, —formula: —OCH ₂ — or formula: —CH ₂ O—, X is an oxygen atom or a sulfur atom, and Y is Dibenzocycloheptene selected from methylene, ethylene, trimethylene, ethylidene, 1-methylethylene, 2-methylethylene and (a-5) groups, Z is a carboxy group, m is 1 or 2 and n is 1 Compound or Pharmacologically acceptable salts thereof.
[18" claim-type="Currently amended] The compound according to claim 1, wherein the compound represented by general formula (I) is
[3-[(E) -2- (6,7-difluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
3- {3-[(E) -2- (6,7-Difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5yl] oxy} -2 Methylpropionic acid,
3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} Propionic Acid,
3-{[3-[(E) -2- (6,7-difluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} 2-methylpropionic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl-5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxy } Propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxy} 2-methylpropionic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetic acid,
2-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio } Propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio } Propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio Methyl} -cyclopropane acetic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cyclohepten-5-yl ] Oxyacetic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-fluoro-5H-dibenzo [a, d] cycloheptene- 5-yl] thio} -propionic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cyclohepten-5-yl] Oxyacetic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} -propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -8-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} -propionic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5-yl] Oxyacetic acid,
2-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxy } Propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] oxy} propionic acid,
[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5-yl] Thioacetic Acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -6-chloro-5H-dibenzo [a, d] cyclohepten-5 -Yl] thio} propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d] cyclo Heptene-5-yl] thio} propionic acid,
3-{[3-[(E) -2- (7-chloro-6-fluoroquinolin-2-yl) -methoxy-5H-dibenzo [a, d] cyclohepten-5-yl] thio} Propionic Acid,
[3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] oxyacetic acid,
[3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thioacetic acid,
3-{[3-[(E) -2- (7-chloroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl] thio} propionic acid,
3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -5H-dibenzo [a, d] cyclohepten-5-yl ] Thio} propionic acid, and / or
3-{[3-[(E) -2- (5,6,7,8-tetrahydroquinolin-2-yl) -ethenyl] -9-trifluoromethyl-5H-dibenzo [a, d ] Cyclohepten-5-yl] thio} propionic acid, or a pharmacologically acceptable salt thereof.
[19" claim-type="Currently amended] A pharmaceutical composition comprising the dibenzocycloheptene compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient.
[20" claim-type="Currently amended] The pharmaceutical composition according to claim 19, wherein the medical composition is a composition for preventing or treating asthma, allergic diseases and / or inflammatory diseases.
[21" claim-type="Currently amended] Use of a dibenzocycloheptene compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof for the preparation of a medical composition.
[22" claim-type="Currently amended] Use according to claim 21, wherein the medical composition is a composition for the prevention or treatment of asthma, allergic diseases and / or inflammatory diseases.
[23" claim-type="Currently amended] A method for preventing or treating a disease comprising administering to a warm blooded animal a pharmacologically effective amount of the dibenzocycloheptene compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof.
[24" claim-type="Currently amended] The method of claim 23, wherein the disease is asthma, allergic disease and / or inflammatory disease.
[25" claim-type="Currently amended] The method of claim 23 or 24, wherein the warm-blooded animal is a human.

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US7799916B2|2010-09-21|Process for the preparation of 5-|butyl]-1-piperazinyl)benzofuran-2-carboxamide

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ES2385892T3|2012-08-02|Process to produce solifenacin or its salt

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EP0544821B1|1995-01-11|Indole derivatives as antiallergy and antiinflammatory agents

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US8674121B2|2014-03-18|Process for the production of benzofurans

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JP2852659B2|1999-02-03|Piperazine derivatives and their salts

同族专利:

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公开号 | 公开日

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CN1240684C|2006-02-08|

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JPWO2003002539A1|2004-10-14|

---

EP1408033A1|2004-04-14|

---

CZ20033519A3|2004-06-16|

---

CN1531528A|2004-09-22|

---

WO2003002539A1|2003-01-09|

---

CA2452105A1|2003-01-09|

---

HU0400322A2|2004-12-28|

---

US7309718B2|2007-12-18|

---

US20040180884A1|2004-09-16|

---

EP1408033A4|2004-11-24|

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:
2001-06-27|Priority to JP2001193859

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2001-06-27|Priority to JPJP-P-2001-00193859

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2002-06-27|Application filed by 우베 고산 가부시키가이샤

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2002-06-27|Priority to PCT/JP2002/006469

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2004-04-09|Publication of KR20040030700A

优先权:

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申请号 | 申请日 | 专利标题

---

JP2001193859|2001-06-27|

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JPJP-P-2001-00193859|2001-06-27|

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PCT/JP2002/006469|WO2003002539A1|2001-06-27|2002-06-27|Dibenzocycloheptene compound|