JPH0681727B2 - Platelet adhesion inhibitor - Google Patents

Description

TECHNICAL FIELD The present invention relates to a platelet adhesion inhibitor.

DISCLOSURE OF THE INVENTION General Formula [In the formula, R represents an unsaturated heterocyclic residue having 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. On the heterocycle, an oxo group; a thio group; a phenyl group; A phenyl group having 1 to 3 substituents selected from; a cycloalkyl group; a phenylthio group; a lower alkyl group; 1 to 2 substituents selected from the group consisting of an amino group, a lower alkylamino group and a carboxyl group Lower alkyl group;
Amino group; hydroxyl group; cyano group; carboxyl group; lower alkoxycarbonyl group; phenyl lower alkyl group that may have a hydroxyl group as a substituent on the phenyl ring; and fluorine group that may have a lower alkyl group as a substituent on the phenyl ring. It may have 1 to 3 substituents selected from the group consisting of an enylsulfonyl group; a lower alkoxy-substituted phenyl lower alkyl group; a lower alkylthio group; a lower alkenyl group; a lower alkoxy group and a pyridyl group. R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group. R ² represents a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, a lower alkoxy group or a hydroxyl group. Z is an oxygen atom, a sulfur atom, (R ³ represents a hydrogen atom or a lower alkyl group) or a group —NH—. A represents a lower alkylene group. X represents an oxygen atom, a sulfur atom, a group —SO— or a group —SO ₂ —. n represents 0 or 1. The carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton represent a single bond or a double bond. ] The carbostyril derivative represented by: It can be used during artificial dialysis or implantation of artificial organs.

Each group represented by the above general formula (1) is as follows.

Examples of the lower alkyl group include methyl, ethyl, propyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

As the halo lower alkyl group, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-chlorobutyl, 3 ,
1 to 1 halogen atom as a substituent such as 4-dichlorobutyl, 3-fluoropentyl, 2,3,4-trifluoropentyl, 2,3-dichlorohexyl, and 6,6-dibromohexyl groups.
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms and having 3 carbon atoms.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the lower alkylamino group include methylamino, ethylamino, propylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, dipentylamino, dihexyl. A linear or branched alkyl group having 1 to 6 carbon atoms as a substituent such as amino, N-methyl-Nn-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexylamino group. An amino group having 1 or 2 groups can be exemplified.

As the lower alkoxy group, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as pentyloxy and hexyloxy groups.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and other cycloalkyl groups having 3 to 8 carbon atoms.

Examples of the lower alkyl group having 1 to 2 substituents selected from the group consisting of an amino group, a lower alkylamino group and a carboxyl group include aminomethyl, 2-methylaminoethyl,
1-ethylaminoethyl, 3-propylaminopropyl, 4-tert-butylaminobutyl, 1,1-dimethyl-
2-pentylaminoethyl, 5-hexylaminopentyl, 6-dimethylaminohexyl, dimethylaminomethyl, 2-diethylaminoethyl, 1-di-n-propylaminoethyl, 3-di-n-butylaminopropyl, 4
-Dipentylaminobutyl, 1,1-dimethyl-2-dihexylaminoethyl, 5- (N-methyl-N-n-butylamino) pentyl, 6- (N-methyl-N-pentylamino) hexyl, 2-methyl -3- (N-ethyl-N
-Hexylamino) propyl, carboxymethyl, 2-
Carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 1,1-dimethyl-2-carboxyethyl, 5-carboxypentyl, 6
-Carboxyhexyl, 2-methyl-3-carboxypropyl, 2-amino-2-carboxyethyl, 1-dimethylamino-1-carboxymethyl, 3-amino-2-
A straight chain or branched chain having 1 to 6 carbon atoms having 1 to 2 substituents selected from the group consisting of a straight chain or branched chain alkylamino group having 1 to 6 carbon atoms such as carboxypropyl group and a carboxy group. The alkyl group can be exemplified.

Examples of the lower alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups. It can be illustrated.

As the phenyl lower alkyl group, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl Examples thereof include a phenylalkyl group in which the alkyl moiety such as -3-phenylpropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

As the lower alkoxy-substituted phenyl lower alkyl group,
3-methoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 1- (4-ethoxyphenyl) ethyl, 3
-(2-propoxyphenyl) propyl, 4- (3-butoxyphenyl) butyl, 1,1-dimethyl-2- (4-
Pentyloxyphenyl) ethyl, 5- (4-hexyloxyphenyl) pentyl, 6- (3,4,5-trimethoxyphenyl) hexyl, 2-methyl-3- (2,5-dimethoxyphenyl) A straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms having 1 to 3 carbon atoms on the phenyl ring such as a propyl group as a substituent and an alkyl moiety having 1 to 6 carbon atoms A phenylalkyl group which is an alkyl group can be exemplified.

Examples of the lower alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, te
Examples thereof include linear or branched alkylthio groups having 1 to 6 carbon atoms such as rt-butylthio, pentylthio and hexylthio groups.

Examples of the lower alkenyl group include a linear or branched alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups. .

A lower alkyl group on the phenyl ring, a halo lower alkyl group,
1 is a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group and a lower alkoxy group.
As the phenyl group having 3 to 3, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,
4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,5-dibromophenyl, 3,
4,5-trichlorophenyl, 2-methylphenyl, 3-
Methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-
Isopropylphenyl, 4-hexylphenyl, 3,4-
Dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl Enyl, 4-ethoxyphenyl,
4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-methoxy-3-chlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl,
2,4-diaminophenyl, 2-methylaminophenyl,
3-methylaminophenyl, 4-methylaminophenyl, 2-ethylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 4-isopropylaminophenyl, 4-hexylaminophenyl, 3 , 4-dimethylaminophenyl, 2- (dimethylamino) phenyl, 3- (dimethylamino) phenyl, 4- (dimethylamino) phenyl, 2- (diethylamino) phenyl,
3- (N-methyl-N-ethylamino) phenyl, 4-
(N-methyl-N-isopropylamino) phenyl, 4
-(N-isopropyl-N-hexylamino) phenyl, 2- (di-n-butylamino) phenyl, 2-trifluoromethylphenyl, 3- (3-chloropropyl)
Phenyl, 4- (2-fluoroethyl) phenyl, 2-
(4-chlorobutyl) phenyl, 3- (3-bromopentyl) phenyl, 2- (iodomethyl) phenyl, 4-
On the phenyl ring such as (2,3-dichlorohexyl) phenyl and 3- (2,2,2-trifluoroethyl) phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom 1 to 6 linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, an amino group, 1 to 3 carbon atoms
A phenyl having 1 to 2 substituents selected from the group consisting of an amino group having 1 or 2 straight-chain or branched-chain alkyl groups of 6 and a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms A group can be illustrated.

Examples of the unsaturated heterocyclic residue having 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 1,2,4-triazolyl, imidazolyl, 1,2,3,5- Tetrazolyl, 1,2,3,4-tetrazolyl, pyrrolyl, benzimidazolyl, 1,3,4-triazolyl, imidazolinyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, 1,3,4-oxadiazolyl, 1,3 , 4-thiadiazolyl, thienyl, furyl, pyranyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, 3H-
Examples thereof include indolyl, indolizinyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pyrrolinyl, pyrazolinyl, indolinyl and isoindolinyl groups.

Selected from the group consisting of an oxo group, a thio group, a phenyl group on the heterocycle, a lower alkyl group, a halo lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group, a carboxy group and a lower alkoxy group on the phenyl ring. 1 to 2 substituents having 1 to 2 substituents selected from the group consisting of a phenyl group, a cycloalkyl group, a phenylthio group, a lower alkyl group, an amino group, a lower alkylamino group, a carboxy group and a carboxyl group. Lower alkyl group, amino group, hydroxyl group, cyano group, carboxyl group, lower alkoxycarbonyl group, phenyl lower alkyl group which may have a hydroxyl group as a substituent on the phenyl ring, and lower alkyl group as a substituent on the phenyl ring Phenylsulfonyl group, lower alkoxy substituted phenyl lower alkyl group, low Examples of the heterocyclic residue having 1 to 3 substituents selected from the group consisting of an alkylthio group, a lower alkenyl group, a lower alkoxy group and a pyridyl group include 2-phenylthiopyrrolyl, 2-methylimidazolyl, 2 -Ethylimidazolyl, 2-propylimidazolyl, 4-n-butylimidazolyl, 4-pentylimidazolyl, 4-hexylimidazolyl, 2-phenylimidazolyl, 2-phenylthioimidazolyl, 2-phenylthio-1,3,5-triazolyl , 3-phenylthio-1,
2,4-triazolyl, 1-phenylimidazolyl, 1-
Ethylimidazolyl, 5-methylimidazolyl, 5-methoxybenzimidazolyl, 1-ethylbenzimidazolyl, 6-ethoxybenzimidazolyl, 7-propoxybenzimidazolyl, 4-n-butoxybenzimidazolyl, 5-pentyloxybenzimidazolyl, 6-
Hexyloxybenzimidazolyl, 1-phenyl-1,
3,4-triazolyl, 1-phenyl-1,2,3,4-tetrazolyl, 1- (3-pyridyl) imidazolyl, 1- (2-
Methylphenyl) imidazolyl, 1- (2-methoxyphenyl) imidazolyl, 1- (4-methylphenyl) imidazolyl, 1- (3-ethylphenyl) imidazolyl, 1- (4-propylphenyl) imidazolyl, 1-
(2-n-butylphenyl) imidazolyl, 1- (3-
Pentylphenyl) imidazolyl, 1- (4-hexylphenyl) imidazolyl, 1- (3-ethoxyphenyl) imidazolyl, 1- (4-methoxyphenyl) imidazolyl, 1- (4-propoxyphenyl) imidazolyl, 1- (2-n-butoxyphenyl) imidazolyl,
1- (3-pentyloxyphenyl) imidazolyl, 1
-(4-hexyloxyphenyl) imidazolyl, 1-
Allylimidazolyl, 1- (2-butenyl) imidazolyl, 1- (3-butenyl) imidazolyl, 1- (1-methylallyl) imidazolyl, 1- (2-pentenyl) imidazolyl, 1- (2-hexenyl) imidazolyl, 1
-Benzylimidazolyl, 1- (2-phenylethyl)
Imidazolyl, 1- (1-phenylethyl) imidazolyl, 1- (3-phenylpropyl) imidazolyl, 1-
(4-phenylbutyl) imidazolyl, 1- (6-phenylhexyl) imidazolyl, 1- (5-phenylpentyl) imidazolyl, 1-ethyl-1,3,4-triazolyl, 4-ethyl-1,3,4-triazolyl , 1-methyl-
1,3,4-triazolyl, 4-propyl-1,3,4-triazolyl, 1-benzyl-1,3,4-triazolyl, 4-benzyl-1,3,4-triazolyl, 1- (2-phenylethyl) ) -1,3,4-triazolyl, 3-methylpyrazolyl,
4-ethylpyrazolyl, 3-propylpyrazolyl, 3-
n-butylpyrazolyl, 1-ethylpyrrolyl, 1-methylpyrrolyl, 1-propylpyrrolyl, 1-n-butylpyrrolyl, 1-allylbenzimidazolyl, 1- (2-butenyl) benzimidazolyl, 1- (3-butenyl) benzimidazolyl , 1- (1-methylallyl) benzimidazolyl, 1- (2-pentenyl) benzimidazolyl, 1- (2-hexenyl) benzimidazolyl, 1-
(2-trifluoromethylphenyl) imidazolyl, 1
-(4-chlorophenyl) imidazolyl, 1- (4-hydroxyphenyl) imidazolyl, 1- (4-dimethylaminophenyl) imidazolyl, 1- (3,4-difluoromethylphenyl) imidazolyl, 1- (3, 4,5-trichlorophenyl) imidazolyl, 1- [4- (2-fluoroethyl) phenyl] imidazolyl, 1- [4- (2,
3-dichlorohexyl) phenyl] imidazolyl, 1-
[3- (3-chloropropyl) phenyl] imidazolyl, 1- (2-aminophenyl) imidazolyl, 1-
(2-Ethylaminophenyl) imidazolyl, 1- (4
-Isopropylaminophenyl) imidazolyl, 1-
[4- (N-methyl-N-hexylamino) phenyl]
Imidazolyl, 2-cyclohexyl-1,3,4-oxadiazolyl, 2-cyclopropyl-1,3,4-oxadiazolyl, 2-cycloheptyl-1,3,4-oxadiazolyl, 2-cyclooctyl-1,3,4 -Oxadiazolyl,
1-cyclohexylimidazolyl, 1-cyclopentyl-1,3,4-triazolyl, 1-cyclopropyl-benzimidazolyl, 2-methylthioimidazolyl, 4-ethylthioimidazolyl, 2-propylthioimidazolyl,
4-n-butylthioimidazolyl, 4-pentylthioimidazolyl, 2-hexylthioimidazolyl, 1-ethyl-5,6-dimethoxy-benzimidazolyl, 2-phenyl-3,4-dimethylpyrrolyl, 1,2,3 -Trimethylimidazolyl, 2,4-dichloro-1,2,4-triazolyl, 2,4,
5-trichloropyridyl, 3,4,5-trimethoxypyridyl, 2- (2-amino-2-carboxyethyl) imidazolyl, 2-methyl-3-dimethylaminomethylimidazolyl, 2-carboxymethyl-3-methylimidazolyl, 3-methyl-5-pyrazolonyl, 3-methyl-4-
Hydroxypyrazolyl, 4-amino-5-cyanoimidazolyl, 4-methyl-5-ethoxycarbonylimidazolyl, 4-methyl-5-carboxyimidazolyl, 1-
[2- (3,4-dihydrophenyl) ethyl] -1,2,3,4-
Tetrazolyl, 1- (3-pyridyl) -5-thio-1,2,
3,4-tetrazolyl, 1-phenyl-5-thio-1,2,3,4
An oxo group, a thio group, a phenyl group, or a lower alkyl group on the phenyl ring on the heterocycle such as tetrazolyl, 1- (4-phenylsulfonyl) pyrrolyl, or 1- (4-carboxyphenyl) imidazolyl group; A halo lower alkyl group, the above halogen atom, a hydroxyl group, an amino group, the above lower alkylamino group, a carboxy group and a phenyl group having 1 to 3 substituents selected from the group consisting of the above lower alkoxy group, the above cycloalkyl group, and a phenylthio group. Group, the above lower alkyl group, amino group, the above lower alkylamino group, and the above lower alkyl group having 1 to 2 substituents selected from the group consisting of a carboxyl group, an amino group, a hydroxyl group, a cyano group, a carboxyl group, the above lower group Alkoxycarbonyl group, a phenyl lower group which may have a hydroxyl group as a substituent on the above phenyl ring. A kill group, a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring, a lower alkoxy-substituted phenyl lower alkyl group, the lower alkylthio group, the lower alkenyl group, the lower alkoxy group and a pyridyl group. The above heterocyclic residue having 1 to 3 substituents selected from the group consisting of can be exemplified.

Examples of the lower alkylene group include carbon such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene groups. Examples thereof include linear or branched alkylene groups of formulas 1 to 6.

As the phenyl lower alkyl group which may have a hydroxyl group as a substituent on the phenyl ring, in addition to the phenyl lower alkyl group, 3-hydroxybenzyl, 2- (3,
4-dihydroxyphenyl) ethyl, 1- (4-hydroxyphenyl) ethyl, 3- (2-hydroxyphenyl) propyl, 4- (3-hydroxyphenyl) butyl, 1,1-dimethyl-2- ( 4-hydroxyphenyl)
Ethyl, 5- (4-hydroxyphenyl) pentyl, 6
-(3,4,5-trihydroxyphenyl) hexyl, 2-
A linear or branched alkyl having 1 to 6 carbon atoms in the alkyl moiety, which may have 1 to 3 hydroxyl groups on the phenyl ring such as methyl-3- (2,5-dihydroxyphenyl) propyl group. Examples thereof include a phenylalkyl group.

As the phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl, 4
-Methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl, 2-pentylphenylsulfonyl, 3,4-dimethylphenylsulfonyl, 2,5-dimethylphenyl 1 to 1 carbon atoms as a substituent on a phenyl ring such as sulfonyl or 3,4,5-trimethylphenylsulfonyl
A phenylsulfonyl group which may have 1 to 3 linear or branched alkyl groups of 6 can be exemplified.

The lower alkylsulfonyloxy group has 1 to 6 carbon atoms such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy and hexylsulfonyloxy groups. A straight chain or branched chain alkyl sulfonyloxy group can be illustrated.

The side chain -ZA- (X) nR may be substituted at any of the 3-position, 4-position, 5-position, 6-position, 7-position and 8-position of the carbostyryl skeleton.

The carbostyril derivative represented by the above general formula (1) can be produced by various methods, and a preferred example thereof is produced according to the method shown in the following reaction scheme.

Reaction formula-1 [In the formula, R, R ¹ , R ² , A, X, n, and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above. Za represents an oxygen atom, a sulfur atom or a group —NH—. X ¹ represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. The lower alkanesulfonyloxy group represented by X ¹ is specifically methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexane. Examples thereof include a sulfonyloxy group, and specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, and 2-methylphenylsulfonyloxy.
Methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy group and the like can be exemplified, and specific examples of the aralkylsulfonyloxy group include Include benzylsulfonyloxy, 2-phenylethylsulfonyloxy,
4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group Etc. can be illustrated.

The reaction between the compound of general formula (2) and the compound of general formula (3) can be carried out in a suitable solvent or without solvent in the presence of a basic compound. As the basic compound, conventionally known compounds can be widely used, and examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and silver carbonate, sodium, potassium and the like. Alkali metals, alcoholates such as sodium methylate and sodium ethylate, triethylamine, pyridine, N, N-dimethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4,3,0] nonene- 5 (DB
N), 1,8-diazabicyclo [5,4,0] undecene-7 (D
BU), 1,4-diazabicyclo [2,2,2] octane (DABC
Examples thereof include organic bases such as O). As the solvent, any inert one that does not adversely affect the reaction can be used, for example, alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, ethers such as diglyme. , Ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl An aprotic polar solvent such as phosphoric acid triamide (HMPA) may, for example, be mentioned. The reaction may be carried out in the presence of a metal iodide such as sodium iodide and potassium iodide. The ratio of the compound (2) to the compound (3) used in the above reaction is not particularly limited and may be appropriately selected from a wide range, but the latter is usually equimolar to 5 times the molar amount with respect to the former, preferably. It is preferable to use equimolar to 2 times the molar amount. The reaction temperature of the above reaction is not particularly limited, but is usually room temperature to about 200 ° C, preferably about 50 to 150 ° C,
Generally, the reaction is completed in about 5 minutes to 30 hours.

Reaction formula-2 [In the formula, R, R ¹ , R ² , Z, A, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. X ² and X ³ each represent X ¹ or a group —YH. Here, X ¹ is the same as above and Y represents an oxygen atom or a sulfur atom. However, when X ² is X ¹ , X ³ is a group —YH, and when X ² is a group —YH.
X ³ shall represent X ¹ . The reaction of the compound of general formula (4) with the compound of general formula (5) can be carried out under the same reaction conditions as the reaction between the compound of general formula (2) and the compound of general formula (3). .

Reaction formula-3 [In the formula, R ¹ , R ² , Z, A, X ¹ , and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above.

Represents an unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, respectively. However, the heterocyclic ring contains at least one nitrogen atom. Further, on the heterocycle, an oxo group, a thio group, a phenyl group, and a lower alkyl group, a halo lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group, a carboxy group and a lower alkoxy group on the phenyl ring. A phenyl group having 1 to 3 substituents selected from the group, a cycloalkyl group,
Lower alkyl group having 1 to 2 substituents selected from the group consisting of phenylthio group, lower alkyl group, amino group, lower alkylamino group and carboxyl group, amino group, hydroxyl group, cyano group, carboxyl group, lower alkoxycarbonyl group , A phenyl lower alkyl group which may have a hydroxyl group as a substituent on a phenyl ring, a phenylsulfonyl group which may have a lower alkyl group as a substituent on a phenyl ring, a lower alkoxy-substituted phenyl lower alkyl group, a lower alkylthio group It may have 1 to 3 substituents selected from the group consisting of a lower alkenyl group, a lower alkoxy group and a pyridyl group.

The reaction of the compound of general formula (6) with the compound of general formula (7) is carried out in the presence or absence of a basic compound, preferably in the presence of a basic compound, in a suitable solvent. As the basic compound, conventionally known compounds can be widely used, and examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal hydroxides such as sodium methylate, sodium ethylate, potassium methylate and potassium ethylate. Examples thereof include alkali metal amides such as alcoholate, sodium amide and potassium amide, alkali metal such as sodium and potassium, alkali metal hydrides such as sodium hydroxide and potassium hydride, DBU and the like. The amount of the basic compound used is not particularly limited and may be appropriately selected within a wide range, but is usually equimolar to excess amount, preferably equimolar to 3 with respect to the compound (6).
It is preferable to use a double molar amount. As the solvent, a commonly used inert solvent can be widely used, for example, lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, cyclohexanone, ketones such as acetophenone, Aromatic hydrocarbons such as benzene, toluene, xylene, methyl acetate,
Examples thereof include esters such as ethyl acetate, DMF, HMPA, acetonitrile and the like. The reaction may be carried out in the presence of a metal iodide such as sodium iodide and potassium iodide.
The ratio of the compound (6) to the compound (7) used in the above reaction is not particularly limited and may be appropriately selected from a wide range, but the latter is usually equimolar to excess amount, preferably equimolar to the former. It is preferable to use about 2 times the molar amount. The above-mentioned reaction proceeds normally at about 0 to 200 ° C, preferably at room temperature to about 150 ° C, and is generally completed in about 10 minutes to 24 hours.

In the above reaction, Z is When using a compound (6) having the formula (1), first, the compound (6) is reacted with a dihydroxy lower alkylene such as ethylene glycol or propylene glycol to give Z (W represents a lower alkylene group) and protected, and then reacted with the compound (7), followed by deprotection to give Z. A compound of general formula (1c)

Here, the protection reaction is carried out in the presence of an acid in a suitable solvent. Examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, organic acids such as p-toluenesulfonic acid, pyridine p-toluenesulfonate, acetic acid and propionic acid. As the solvent, lower alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, aromatic hydrocarbons such as benzene, toluene and xylene, n-hexane, Examples thereof include aliphatic hydrocarbons such as n-octane, alkanoic acids such as acetic acid propionate, acetonitrile, and mixed solvents thereof. The amount of dihydroxy lower alkylenes to be used is usually at least an equimolar amount, preferably an equimolar to 5-fold molar amount with respect to the compound (6). The reaction is usually about 0 to 150 ° C., preferably 0 to 100.
The reaction proceeds suitably at 0 ° C., and generally the reaction is completed in about 0.5 to 10 hours.

Further, the deprotection reaction is carried out in the presence of an acid in a suitable solvent or without solvent. As the acid, any of the acids used in the above protection reaction can be used. The amount of the acid used is usually at least an equimolar amount with respect to the raw material compound, and preferably a large excess amount. As the solvent, in addition to the solvent used in the above protection reaction,
Water, DMF, DMSO, etc. can be mentioned. The reaction proceeds normally at about −30 to 200 ° C., preferably at −30 to 100 ° C., and is generally completed in about 0.5 to 12 hours.

Reaction formula-4 [In the formula, R, R ¹ , R ² , A, X, n, and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above. The reduction of the compound of the general formula (1d) is carried out by a reduction method using a hydrogenating / reducing agent, a catalytic reduction method or the like.

When the reduction method using a hydrogenating / reducing agent is adopted, examples of the hydrogenating / reducing agent include sodium borohydride, lithium aluminum hydride and the like, and preferably sodium borohydride. The hydrogenating / reducing agent is usually used in an amount of at least an equimolar amount, preferably an equimolar to 3-fold molar amount with respect to the compound (1d). The reduction reaction with a hydrogenating / reducing agent is, for example, water, methanol, ethanol, lower alcohols such as isopropanol, tetrahydrofuran, ethers such as diethyl ether, DMF and the like or a mixed solvent thereof, usually at −60 ° C. to 100 ° C., Preferably -30 to 70
The reaction is carried out at about C, and the reaction is generally completed in about 10 minutes to 3 hours. When lithium aluminum hydride is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether or tetrahydrofuran.

When the catalytic reduction method is adopted, a catalyst for catalytic reduction which is usually used, such as platinum oxide, palladium black, palladium carbon, Raney-Nitzkel, etc., is used as the reduction catalyst.
The amount of catalyst used is usually about 0 for compound (1d).
It is recommended that the weight is 2 to 0.5 times. This catalytic reduction may be carried out in a solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and diethyl ether, etc., usually in a hydrogen atmosphere at 1 to 10 atm, preferably 1 to 3 atm. It is done by shaking. The reduction is usually carried out at -30 ° C to the boiling point of the solvent, preferably 0 ° C to around room temperature.

Reaction formula-5 [In the formula, R ¹ , R ² , Z, A, X, n, and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above. X ⁴ represents a halogen atom.

Represents an unsaturated heterocyclic residue having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, respectively. However, the heterocyclic ring contains at least one nitrogen atom. Further, on the heterocycle, an oxo group, a thio group, a phenyl group, and a lower alkyl group, a halo lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group, a carboxy group and a lower alkoxy group on the phenyl ring. A phenyl group having 1 to 3 substituents selected from the group, a cycloalkyl group,
Lower alkyl group having 1 to 2 substituents selected from the group consisting of phenylthio group, lower alkyl group, amino group, lower alkylamino group and carboxyl group, amino group, hydroxyl group, cyano group, carboxyl group, lower alkoxycarbonyl group , A phenyl lower alkyl group which may have a hydroxyl group as a substituent on a phenyl ring, a phenylsulfonyl group which may have a lower alkyl group as a substituent on a phenyl ring, a lower alkoxy-substituted phenyl lower alkyl group, a lower alkylthio group It may have 1 to 3 substituents selected from the group consisting of a lower alkenyl group, a lower alkoxy group and a pyridyl group. -Bb- is -NH-
−Bc− is Indicates. Here, R ⁴ is a phenyl group, a lower alkyl group on the phenyl ring, a halo lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkylamino group, a carboxy group,
And a substituent selected from the group consisting of lower alkoxy groups
Three phenyl groups, cycloalkyl groups, phenylthio groups, lower alkyl groups, phenyl lower alkyl groups that may have a hydroxyl group as a substituent on the phenyl ring, and lower alkyl groups that may have a substituent on the phenyl ring. A lower alkyl group having 1 to 2 substituents selected from the group consisting of a phenylsulfonyl group, a lower alkenyl group, a lower alkylamino group and a carboxy group as a substituent, a lower alkoxycarbonyl group, a lower alkoxy-substituted phenyl lower alkyl group Alternatively, it represents a pyridyl group. The reaction between the compound of general formula (1f) and the compound of general formula (8) is carried out in a suitable solvent, for example, in the presence of a basic compound. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, sodium hydroxide, potassium hydroxide and the like. Examples of the solvent include ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, and DM.
F, DMSO, HMPA and the like can be mentioned. If necessary, copper halides such as copper iodide, metal iodides such as sodium iodide and potassium iodide, and copper powder may be added to the reaction system of the reaction. The use ratio of the compound (1f) and the compound (8) is not particularly limited and may be appropriately selected from a wide range, but usually the latter is at least about equimolar amount to the former, preferably equimolar to 3 times. It is advisable to use a molar amount. The reaction is usually about 0 to 100 ° C, preferably 0 to 70 ° C.
The reaction proceeds suitably at around 0 ° C, and the reaction is generally completed in about 5 minutes to 12 hours.

Reaction formula-6 [In the formula, R ¹ , R ² , Z, A, and 3 of the carbostyryl skeleton
The carbon bond at the 4th and 4th positions is the same as above. R ⁵ is a group -COR ⁶ or a group -CSR ⁶ (R ⁶ is a phenyl group, a lower alkyl group on the phenyl ring, a halo lower alkyl group, a halogen atom, a hydroxyl group,
A phenyl group having 1 to 3 substituents selected from the group consisting of an amino group, a lower alkylamino group, a carboxy group and a lower alkoxy group, a cycloalkyl group, a phenylthio group,
On a lower alkyl group, an amino group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a phenyl ring having 1 to 2 substituents selected from the group consisting of a lower alkyl group, an amino group, a lower alkylamino group and a carboxyl group. A phenyl lower alkyl group which may have a hydroxyl group as a substituent, a phenyl sulfonyl group which may have a lower alkyl group as a substituent on a phenyl ring, a lower alkoxy substituted phenyl lower alkyl group, a lower alkylthio group,
A lower alkenyl group, a lower alkoxy group or a pyridyl group is shown. Bd represents an oxygen atom or a sulfur atom. For the reaction between the compound of general formula (9) and the compound of general formula (10), known reaction conditions for amide bond formation can be easily applied. In the present invention, instead of the compound (9), a compound whose carboxyl group is activated may be used. As a typical method, for example, (a) mixed acid anhydride method, that is, a method of reacting a carboxylic acid (9) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with a hydrazine derivative (10), (B) Active ester method, that is, carboxylic acid (9) is converted into p-nitrophenyl ester, N-
A method in which an active ester such as hydroxysuccinimide ester or 1-hydroxybenzotriazole ester is reacted with a hydrazine derivative (10), or (c) a carbodiimide method, that is, a carboxylic acid (9) is treated with a hydrazine derivative (10) in dicyclohexyl. As a method of condensing in the presence of an activator such as carbodiimide or carbonyldiimidazole, and (d) other methods, carboxylic acid (9) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and a hydrazine derivative ( 10), a reaction of a hydrazine derivative (10) with an ester of a carboxylic acid (9) and a lower alcohol at high temperature and high pressure, an acid halide of the carboxylic acid (9), that is, a carboxylic acid halide, a hydrazine derivative Examples thereof include a method of reacting (10). Of these, the mixed acid anhydride method is preferred.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The mixed acid anhydride is obtained by an ordinary Schottuten-Baumann reaction, and the compound of the general formula (11) is produced by reacting it with a hydrazine derivative (10) without usually isolating it.

The Schottuten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, any of the compounds commonly used in the Schottuten-Baumann reaction can be used, and examples thereof include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine and DB.
Examples thereof include organic bases such as N, DBU and DABCO, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The Schautzen-Baumann reaction is usually carried out at −20 to 100 ° C., preferably 0 to 50 ° C., and the reaction time is generally about 5 minutes to 10 hours.

The reaction between the mixed acid anhydride obtained above and the compound (10) is generally carried out in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used,
For example, methylene chloride, chloroform, halogenated hydrocarbons such as dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate, Aprotic polar solvents such as DMF, DMSO, HMPA and the like can be mentioned. The reaction is usually carried out at -20 to 150 ° C, preferably 10 to 50 ° C, and the reaction time is generally about 5 minutes to 10 hours.

The compound (9), the alkylhalocarboxylic acid and the compound (10) used in the above reaction are usually used in equimolar proportions. You may use -1.5 times mol.

The reaction for obtaining the compound of the general formula (1h) by cyclizing the compound of the general formula (11) can be carried out according to various conventionally known cyclization reactions. For example, a method by heating, a ring using a dehydrating agent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, acetyl chloride, p-toluenesulfonic acid, benzenesulfonic acid, thionyl chloride, concentrated sulfuric acid, hydrochloric acid, acetic anhydride, and polyphosphoric acid. Chemical methods and the like can be exemplified. When adopting the cyclization method by heating, high boiling point hydrocarbons and high boiling point ethers such as tetraphosphoric acid diphenyl ether, diethylene glycol dimethyl ether, decalin, tetralin, toluene, xylene, mesitylene, chlorobenzene, bromobenzene, etc. Using a solvent, a heating condition of usually about 100 to 250 ° C, preferably 150 to 200 ° C can be adopted. When the cyclization method using a dehydrating agent is adopted, it is particularly preferable to use polyphosphoric acid as the dehydrating agent. Polyphosphoric acid is usually equimolar to a large excess amount with respect to compound (11), preferably 10
~ 20 times the amount is good, and the reaction is usually 100 ~ 250
It is carried out at about C and is generally completed in about 5 minutes to 6 hours.

The compound (9) used as a starting material in the above Reaction Scheme-6 is a known compound, and a part of the compound (10) is a known compound, but also includes novel compounds, and these novel compounds are known to be known compounds. It is produced in the same manner, for example, by the method shown in the following reaction formula-7.

Reaction formula-7 [In the formula, R ⁵ is the same as above. The reaction of the compound of the general formula (12) with the compound of the general formula (13) is carried out by reacting the compound (9) with the compound (1
It is produced under the same reaction conditions as the reaction with (0).

Reaction formula-8 [In the formula, R ¹ , R ² , Z, A, and 3 of the carbostyryl skeleton
The carbon bond at the 4th and 4th positions is the same as above. R ⁷ represents a lower alkyl group. The reaction between the compound of general formula (14) and the compound of general formula (15) is carried out without solvent or in a suitable solvent. Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, high boiling point solvents such as ethers such as dimethoxyethane, diphenyl ether and dioxane. Compound (14) and Compound (15)
As for the usage ratio of the above, the latter is usually equimolar to a large excess amount, preferably about 2 to 50 times the molar amount of the former. The above reaction is usually 50 to 250 ° C, preferably 80 to 200 ° C.
Then, it is completed in about 1 to 40 hours.

Reaction formula-9 [In the formula, R, R ¹ , R ² , Z, A, X and n are the same as defined above. The dehydrogenation reaction of the compound of the general formula (1j) is carried out by a conventional method by subjecting it to a dehydrogenation reaction using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include 2,3-
Benzoquinones such as dichloro-5,6-dicyanobenzoquinone (DDQ) and chloranil (2,3,5,6-tetrachlorobenzoquinone), metal catalysts such as selenium dioxide and palladium carbon, N-bromosuccinimide, bromine and the like Examples include brominating agents. The amount of the oxidizing agent to be used is, for example, when a benzoquinone or a brominating agent is used as the oxidizing agent, it is usually equimolar to 5 times the molar amount of the compound (1j),
It is preferable to use an equimolar to 2-fold molar amount of the oxidizing agent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. And alcohols such as butanol, amyl alcohol and hexanol, and aprotic polar solvents such as DMF, DMSO and HMPA. The above reaction is usually at room temperature to
Appropriately proceeds at about 300 ° C, preferably about 50 to 200 ° C,
Generally, it is completed in about 1 to 48 hours.

The catalytic reduction of the compound of the general formula (1k) is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method. As the catalyst, conventionally known ones can be widely used, for example, platinum wire, platinum plate, platinum sponge, platinum black, platinum catalyst such as platinum oxide, colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium-barium sulfate, Palladium barium carbonate, palladium carbon, palladium silica gel, palladium catalysts such as colloidal palladium, rhodium with asbestos, iridium, colloidal rhodium, ruthenium catalysts, platinum group catalysts such as colloidal iridium, reducing nickel, nickel oxide, lane nickel, lacquer nickel, nickel formate Nickel catalyst produced by thermal decomposition of nickel, nickel catalyst such as boride nickel, reduced cobalt, Raney cobalt, cobalt catalyst such as Urushibara cobalt, reduced iron, iron catalyst such as Raney iron, reduced copper, Raney copper, copper such as Ullmann copper Catalyst, and even zinc-like Include other metal catalysts.
As the solvent used, methanol, ethanol, lower alcohols such as isopropanol, water, acetic acid, methyl acetate, acetic acid esters such as ethyl acetate, ethylene glycol diethyl ether, diethyl ether, tetrahydrofuran, ethers such as dioxane, benzene, Examples thereof include aromatic hydrocarbons such as toluene and xylene, cycloalkanes such as cyclopentane and cyclohexane, and n-alkanes such as n-hexane and n-pentane.
The above reaction is usually carried out under hydrogen pressure or atmospheric pressure or under pressure, preferably 1
It is carried out at -20 atm, usually at room temperature to the boiling point of the solvent, preferably at room temperature to 100 ° C.

Reaction formula-10 [In the formula, R, R ² , Z, A, X, n, X ⁴ and the carbon-carbon bonds at the 3-position and 4-position of the carbostyryl skeleton are the same as above.
R ¹ ′ represents a lower alkyl group or a phenyl lower alkyl group. The reaction of the compound of the general formula (1) with the compound of the general formula (16) can be carried out under the same reaction conditions as the reaction of the compound (1f) with the compound (8) in the aforementioned Reaction formula-5. In the reaction, the compound (1) having a group —NH— in the heterocyclic residue of R may react with the compound (16) at the same time, but this compound is easily separated from the compound (1m). can do.

Reaction formula-11 [In the formula, R, R ¹ , R ² , A, X, n, and the carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton are the same as above. The reaction of the compound of general formula (1n) with hydroxylamine (17) is carried out in a suitable solvent in the presence or absence of a basic compound. Examples of the basic compound used here include sodium hydroxide, potassium hydroxide, sodium carbonate, inorganic bases such as potassium carbonate, piperidine,
Examples thereof include organic bases such as pyridine, triethylamine, DBN, DBU, DABCO and the like. As the solvent, for example, water, alcohols such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol dimethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, dichloroethane, Halogenated hydrocarbons such as chloroform and carbon tetrachloride, DM
Examples thereof include polar solvents such as F, DMSO and HMPA. The compound ((1n) and hydroxylamine (17) are usually used in an amount of at least equimolar to the former, preferably equimolar to 5 times the molar amount of the former. Suitably progresses at ˜150 ° C., preferably 0˜100 ° C., and generally finishes in about 10 minutes to 10 hours.

Reaction formula-12 [In the formula, R, R ¹ , R ² , R ³ , A, X, n, X ⁴ and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as described above. The halogenation reaction of the compound of general formula (1p) is carried out in the presence of a halogenating agent, in a suitable solvent or without solvent. As the halogenating agent, hydrochloric acid, hydrohalic acid such as hydrobromic acid, N, N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride,
Examples thereof include thionyl chloride. The amount of such a halogenating agent used is at least equimolar to the compound (1p), and usually in a large excess amount. Examples of the solvent include ethers such as dioxane, tetrahydrofuran and diethyl ether, and halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. The above-mentioned reaction suitably proceeds normally at -20 to 150 ° C, preferably -20 to 80 ° C, and is generally completed in about 10 minutes to 6 hours.

The reaction of the compound of general formula (1q) with the compound of general formula (18) is carried out in the presence or absence of a basic compound, in a suitable solvent or without solvent. Examples of the basic compound used include sodium hydroxide, potassium hydroxide,
Sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Examples thereof include inorganic bases such as potassium hydrogen carbonate, sodium amide and sodium hydride, alcohols such as sodium methylate and sodium ethylate, organic bases such as triethylamine, pyridine and N, N-dimethylaniline. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropanol,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether,
Ethers such as tetrahydrofuran and dioxane, n-
Examples thereof include aliphatic hydrocarbons such as hexane, octane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, polar solvents such as acetone, acetonitrile, DMF, DMSO and HMPA, and mixed solvents thereof. The ratio of the compound (1q) to the compound (18) used is preferably such that the latter is at least equimolar to the former, usually in a large excess amount. The above reaction is usually 0 to 150 ° C, preferably 0 to 100
The process proceeds suitably at 0 ° C and is generally completed in about 10 minutes to 10 hours.

Reaction formula-13 [In the formula, R, R ¹ , R ² , Z, A, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction of oxidizing the compound of general formula (1s) to obtain the compound of general formula (1t), the reaction of oxidizing the compound of general formula (1s) to obtain the compound of general formula (1u), and the general formula (1t) The reaction of oxidizing the compound of formula (1) to obtain the compound of general formula (1u) is carried out in the presence of an oxidizing agent in a suitable solvent. As the oxidizing agent used here, any conventionally known one can be used as long as it can oxidize a sulfido group to a sulfoxide group or a sulfone group, for example, performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid. Acid, peracids such as m-chloroperbenzoic acid and o-carbonylbenzoic acid, hydrogen peroxide, dichromic acid, sodium dichromate, dichromate such as potassium dichromate, permanganate, permanganate sodium,
Examples thereof include permanganate salts such as potassium permanganate. Examples of the solvent include water, organic acids such as formic acid, acetic acid and trifluoroacetic acid, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and dichloromethane, and mixed solvents thereof.
The above-mentioned reaction proceeds normally at -20 to 40 ° C, preferably -20 ° C to around room temperature, and is generally completed in about 0.5 to 50 hours.

When the compound (1s) is oxidized to obtain the compound (1t),
The above-mentioned oxidizing agent is usually used in an amount of at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound (1s).

When the compound (1s) is oxidized to obtain the compound (1u),
The oxidizing agent is usually used in an amount of at least 2 times, preferably 2 to 4 times the molar amount of the compound (1s).

When the compound (1t) is obtained by oxidizing the compound (1t),
The above-mentioned oxidizing agent is usually used in an amount of at least equimolar, preferably equimolar to 4 times the molar amount of the compound (1t).

Reaction formula-14 [In the formula, R, R ¹ , R ² , A, X, n, X ⁴ and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are the same as above. The reaction between the compound of general formula (19) and the compound of general formula (20) is generally called the Friedel-Crafts reaction, and is carried out in the presence of a Lewis acid in a suitable solvent. Examples of the Lewis acid here include aluminum chloride, zinc chloride, ferric chloride, stannic chloride, boron tribromide,
Examples thereof include boron trifluoride and concentrated sulfuric acid. The amount of such a Lewis acid used is usually an equimolar to 6-fold molar amount, preferably an equimolar to 4-fold molar amount, relative to the compound (19). Examples of the solvent include aromatic hydrocarbons such as carbon disulfide, nitrobenzene and chlorobenzene,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane and the like can be mentioned. The ratio of the compound (19) to the compound (20) used is usually at least equimolar to the former, preferably equimolar to 4-fold molar. The above reaction normally proceeds suitably at 0 to 120 ° C., preferably at 0 to 70 ° C., and is generally completed in about 0.5 to 6 hours.

The compound (6) used as a starting material in the above Reaction scheme-3 and the compound (9) used as a starting material in the above Reaction scheme-6 can also be produced, for example, by the method shown below.

Reaction formula-15 [In the formula, R, R ¹ , R ² , R ³ , A, X ¹ , and X ⁴ , and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as described above. ] The reduction reaction of the compound of the general formula (6a) is carried out by the above-mentioned compound (1d)
It can be carried out under the same reaction conditions as the reduction reaction of.

The halogenation reaction of the compound of general formula (6b) can be performed under the same reaction conditions as the halogenation reaction of the compound (1p).

The reaction of the compound of the general formula (6d) with the compound (18) can be carried out under the same reaction conditions as the reaction of the compound (1q) with the compound (18). In the reaction, the compound (6d)
X in the compound (6d) in which X ^{1 of} is substituted with a group R ³ O-
Compounds in which ¹ and X ⁴ are each substituted with the group R ³ O— are formed, and these compounds can be easily separated from the compound (6e).

The reaction of the compound of general formula (6a) with hydroxylamine (17) is carried out by reacting the compound (1q) with hydroxylamine (17)
It can be carried out under the same reaction conditions as the reaction with. In addition, in the reaction, a compound in which X ¹ of the compound (6a) reacts with the hydroxylamine (17) is produced, but the compound can be easily separated from the compound (6c).

Reaction formula-16 [In the formula, R ¹ , R ² , Z, X ¹ , X ⁴ and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are the same as described above. R ⁸ and R ⁹ represent a lower alkyl group. A'represents a lower alkylene group. The reaction between the compound of general formula (6f) and the compound of general formula (23) is carried out in a suitable solvent. Here, examples of the compound (23) include cyanides such as potassium cyanide, sodium cyanide, silver cyanide, copper cyanide, and calcium cyanide. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropanol, and mixed solvents thereof. The compound (1f) and the compound (23) are usually used in a proportion of at least equimolar, preferably equimolar to 1.5 times the molar amount of the former. The reaction is
Usually, the reaction proceeds suitably at room temperature to 150 ° C, preferably around 50 to 120 ° C, and is generally completed in about 30 minutes to 10 hours.

The hydrolysis reaction of the compound of the general formula (24) is carried out by hydrohalic acid such as hydrochloric acid and hydrobromic acid, mineral acid such as sulfuric acid and phosphoric acid, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, and carbonic acid. It is carried out in a suitable solvent or without solvent in the presence of a hydrolysis catalyst such as an alkali metal carbonate or hydrogen carbonate such as sodium, potassium carbonate or sodium hydrogen carbonate. Examples of the solvent used include water, methanol,
Examples thereof include alcohols such as ethanol and mixed solvents thereof. The reaction is usually 50 to 150 ° C., preferably 70 to 1
The process proceeds suitably at around 00 ° C, and generally ends in about 1 to 24 hours. Thus, the compound of general formula (9a) is obtained.

The reaction of compound (6f) with the compound of general formula (21) is carried out in the presence of a basic compound in a suitable solvent. Examples of the basic compound used include calcium carbonate,
Sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate and sodium ethylate, amines such as triethylamine, tripropylamine, pyridine, quinoline and the like can be mentioned. . Examples of the solvent used include ethers such as dioxane, tetilahydrofuran, ethylene glycol dimethyl ether and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol and isopropanol, and DMF. , DMSO, HMPA
Examples thereof include polar solvents and the like. The reaction advantageously proceeds by allowing an alkali metal iodide such as potassium iodide or sodium iodide to exist in the reaction system. Compound (6f)
The compound (19) is usually used in an equimolar to large excess amount, preferably an equimolar to 5-fold molar amount, and more preferably an equimolar to 1.2-fold molar amount with respect to the former. Good. The reaction is usually room temperature to 200 ° C., preferably 60 to 120.
The process proceeds suitably at around 0 ° C and is generally completed in about 1 to 24 hours.

The hydrolysis reaction of the compound of general formula (22) can be carried out under the same reaction conditions as the hydrolysis reaction of the compound (24). Thus, the compound of general formula (9b) can be obtained.

For the reaction of the compound (9a) or the compound (9b) with the compound of the general formula (25), ordinary conditions for esterification reaction are applied,
For example, (1) a method in a suitable solvent in the presence of a dehydrating agent, (2) a method in a suitable solvent in the presence of an acid or basic compound, and the like can be mentioned.

Examples of the solvent used in the above method (1) include dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, dimethoxyethane, DMF, DMSO, HMPA, etc. A polar solvent etc. can be illustrated.
Examples of the dehydrating agent used include dicyclohexylcarbodiimide and carbonyldiimidazole. The amount of such dehydrating agent used is compound (9a)
Alternatively, it is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of (9b). The ratio of the compound (9a) or (9b) to the compound (25) used is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of the former. The reaction is usually at room temperature to 1
The process suitably proceeds at 50 ° C, preferably around 50 to 100 ° C, and is generally completed in about 1 to 10 hours.

Examples of the acid used in the method (2) include hydrochloric acid gas, sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and naphthalenesulfonic acid. Examples thereof include organic acids such as p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic acid anhydride and trifluoromethanesulfonic acid anhydride, thionyl chloride and acetone dimethyl acetal. Furthermore, an acidic ion exchange resin can also be used.
Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. it can. The reaction can be carried out without a solvent, but it is advantageously carried out using the solvent exemplified in the above method (1). Further, the reaction advantageously proceeds when a desiccant such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorus pentoxide and the like is used. The amount of the compound (25) to be used is usually a large excess amount when no solvent is used, and is usually an equimolar to 5 times molar amount, preferably an equimolar to 2 times molar amount for the group in the presence of the solvent. Good to use. The reaction normally proceeds suitably at about -20 to 200 ° C, preferably at about 0 to 150 ° C and is generally completed in about 1 to 20 hours.

The reduction reaction of compound (9a), compound (9b), compound (26) or compound (28) is carried out in a suitable solvent in the presence of a hydrogenating / reducing agent. Examples of the reducing agent used include sodium borohydride, lithium aluminum hydride, diborane and the like. The amount of the reducing agent used is usually at least equimolar, preferably equimolar to 3 times the molar amount of the compound to be treated. Especially when using lithium aluminum hydride as a reducing agent,
It is preferred to use an equal weight to the compound to be treated. Examples of the solvent used include water, lower alcohols such as methanol, ethanol and isopropanol, and ethers such as tetrahydrofuran, diethyl ether and diglyme. Especially when using lithium aluminum hydride or diborane as a reducing agent, diethyl ether, tetrahydrofuran,
It is preferable to use an anhydrous solvent such as diglyme. The reaction normally proceeds suitably at -60 to 50 ° C, preferably -30 ° C to around room temperature, and is generally completed in about 10 minutes to 5 hours.

The halogenation of the compound of the general formula (27) or the compound of the general formula (29) can be carried out under the same reaction conditions as the halogenation reaction of the compound (1p).

The desired compound (6) or compound (9) can be produced by sequentially repeating the reaction of the above reaction formula-16.

The carbostyril derivative represented by the general formula (1) can form a salt with a pharmacologically acceptable acid. Examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid,
Examples thereof include organic acids such as oxalic acid, succinic acid, maleic acid, fumaric acid, acetic acid, malic acid, citric acid, and lactic acid.

Further, among the carbostyril derivatives of the general formula (1), the compound having an acidic group can form a salt with a pharmacologically acceptable base. Examples of such a base include hydroxides of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide.

The compound of the present invention naturally contains optical isomers and stereoisomers.

The compound of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
Etc. In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Disintegrating agents such as sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., sucrose, stearin, cocoa butter, disintegrating inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate,
Moisturizers such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid,
Examples of the lubricant include purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, excipients such as kaolin and talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrating agent such as laminaranthantene. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterilized and isotonic with blood. When molding these solutions, emulsions and suspensions, use all diluents commonly used in this field. Examples thereof include water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation,
Ordinary solubilizing agents, buffering agents, soothing agents and the like may be added. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation. When forming into a paste, cream or gel, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent.

The amount of the compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight in the entire composition. Is good.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, liquids,
In the case of suspensions, emulsions, granules and capsules, it is orally administered. In the case of an injection, it may be administered alone or mixed with an ordinary replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of the disease, etc., but the amount of the compound of the general formula (1) which is the active ingredient is usually 1 kg per day. About 0.06 to 100 mg is recommended for each preparation.
It can be administered in 2 to 4 divided doses daily.

Examples Formulation examples, reference examples, examples, and pharmacological tests are listed below.

Formulation Example 1 Preparation of tablets Amount (g) 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 5 Lactose (Japanese Pharmacopoeia) 50 Corn starch (Japanese Pharmacopoeia) 25) Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium stearate (Japanese Pharmacopoeia) 1 A compound of the above-mentioned present invention, lactose, corn starch and crystalline cellulose are thoroughly mixed to give methylcellulose. Granulate with a 5% aqueous solution of 1., pass through a 200 mesh sieve, carefully dry, and tablet this by a conventional method to prepare 1000 tablets.

Formulation Example 2 Preparation of Capsule Preparation Content (g) 6- {3- [1- (3-pyridyl) -2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 1
0 Lactose (Japanese Pharmacopoeia) 80 Starch (Japanese Pharmacopoeia) 30 Talc (Japanese Pharmacopoeia) 5 Magnesium stearate (Japanese Pharmacopoeia) 1 Sufficiently powder the above ingredients into a uniform mixture. After stirring, the mixture is filled into a gelatin capsule for oral administration having a desired size to prepare 1000 capsules.

Formulation Example 3 Preparation of injectable formulation Cobalt amount (g) 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 1 Polyethylene glycol (molecular weight: 4000) (Japanese Pharmacopoeia) ) 0.3 Sodium chloride (Japanese Pharmacopoeia) 0.9 Polyoxyethylenesorbitan monooleate (Japanese Pharmacopoeia) 0.4 Sodium metabisulfite 0.1 Methyl-paraben (Japanese Pharmacopoeia) 0.18 Propyl-paraben (Japanese Pharmacopoeia) 0.02 Injection Distilled water 100 (ml) The parabens, sodium metabisulfite and sodium chloride are dissolved in about half the amount of distilled water at 80 ° C. with stirring, the solution is cooled to 40 ° C., and the compound of the present invention, Polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution and distilled water for injection is added to the solution to make the final volume. The amount is adjusted and sterilized by sterilizing with an appropriate filter paper to prepare an injection.

Reference Example 1 6- (4-chlorobutyryl) -3,4-sihydrocarbostyril 10 g (39.7 mmol) was dissolved in benzene 300 ml,
To this, 7.4 g (120 mmol) of ethylene glycol and 300 mg of p-toluenesulfonic acid are added, and the mixture is heated under reflux in Dean Stark for 6 hours while dehydrating. After cooling, the mixture is neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. After washing with water and drying over magnesium sulfate, the solvent is concentrated. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 40: 1) to give 1
0.5 g of 6- (1-ethylenedioxy-4-chlorobutyl) -3,4-dihydrocarbostyril is obtained.

Reference Example 2 Methylcyclohexylcarboxylate 28g and 85% NH ₂ NH
The ₂ · H ₂ O15g was dissolved in isopropyl alcohol 50 ml, 10
Heat to reflux for hours. After concentration, water is added to collect the precipitated crystals, which are washed with water and recrystallized from water to obtain 20 g of colorless needle crystals of cyclohexanecarbohydrazide. Melting point 155.5-15
6,5 ° C Example 1 6- (3-Bromopropoxy) -3,4-dihydrocarbostyril 2.0 g (7.0 mmol), 2-methylimidazole 2.
2 g (7.7 mmol) and DBU 1.3 ml (8.4 mmol) are added to isopropanol 80 ml and heated under reflux for 20 hours. After concentrating, water is added to the residue and extracted with chloroform. Wash with water, dry over sodium sulfate, and then concentrate. The obtained residue is purified by silica gel column chromatography (eluent; dichloromethane: methanol = 20: 1) and then ethanol-
Recrystallized from n-hexane to give 1.0 g of 6- [3- (2-
Methyl-1-imidazolyl) propoxy] -3,4-dihydrocarbostyril is obtained.

White powder mp.141.5-142.5 ° C Example 2 6-mercapto-3,4-dihydrocarbostyril 2.4 g (1
3.4 mol), 1- (3-bromopropyl) -1,2,4-triazole 3.3 g (17.4 mmol) and DBU 2.6 ml (17.4 mmol)
Is added to 60 ml of isopropanol and heated under reflux for 2 hours.
After completion of the reaction, the mixture is concentrated and the residue is extracted with chloroform. Wash with water, saturated aqueous sodium hydrogen carbonate, and water in that order,
Dry over sodium sulfate. After concentrating the solvent, the resulting residue was subjected to silica gel column chromatography (eluent;
After purification with dichloromethane: methanol = 20: 1), the crystals were recrystallized from ethanol-n-hexane to give 2.5 g of 6- [3
-(1H-1,2,4-triazol-1-yl) propylthio] -3,4-dihydrocarbostyril is obtained.

mp.114.5-115.5 ° C. colorless needle-like crystals Using the appropriate starting materials, the compounds shown in Table 1 below are obtained in the same manner as in Examples 1 and 2.

Example 69 6- (1-ethylenedioxy-4-chlorobutyl) -3,
4-Dihydrocarbostyril 10.5 g (35.5 mmol) was dissolved in dimethylformamide 170 ml and sodium iodide 10.
6g (71mmol), 1H-1,2,4-triazole 5.4g (78.1m
Mol) and DBU 6.5 ml (46.2 mmol) were added, and the mixture was heated to 80 ° C
Heat and stir for hours. The solvent is concentrated under reduced pressure, and the residue is extracted with chloroform. Wash with water, dry over magnesium sulfate, and concentrate. The obtained residue was subjected to silica gel column chromatography (eluent; chloroform: methanol = 4).
After purification with 0: 1), it was recrystallized from ethanol-n-hexane to give 8.0 g of 6- [1-ethylenedioxy-4- (1H-1,2,4-triazole-1) as colorless granular crystals. -Yl) butyl] -3,4-dihydrocarbostyril is obtained. Next, the 6- [1-ethylenedioxy-4- (1H-
1,2,4-triazol-1-yl) butyl] -3,4-dihydrocarbostyryl 1 g (3.0 mmol) in DMF 10 ml solution 5
Add 3 ml of hydrochloric acid and stir at room temperature for 2 hours. After concentrating the solvent, the obtained residue is chloroform: methanol = 3: 1.
Extract with. Wash with water, dry over magnesium sulfate, and then concentrate the solvent. Recrystallization from chloroform-ethanol gives 6- [4- (1H-1,2,4-triazol-1-yl) butyryl] -3,4-dihydrocarbostyril.

Colorless needle crystals mp. 194.0-195.0 ° C Using the appropriate starting materials, in the same manner as in Example 69, Examples 5, 7-12, 14, 18-20, 26, 28, 34, 36, 37, 41. ,
The compounds of 43 to 51, 169, 170 and the compounds shown in Table 2 below are obtained.

Example 85 6-α-chloroacetyl-3,4-dihydrocarbostyril 2.24 g (10 mmol), 1-phenyl-2-mercaptoimidazole 1.94 g (11 mmol) and DBU 1.75 ml (12 mmol)
Is added to 80 ml of isopropanol and heated under reflux for 10 minutes.
After cooling, the precipitated crystals are taken and washed with isopropanol. Recrystallized from ethanol to give 6- [2- (1-phenyl-
2-Imidazolyl) thioacetyl] -3,4-dihydrocarbostyril is obtained.

Pale yellow needle mp. 209.0 to 210.0 ° C Example 86 6- (2-Bromobutyryl) -3,4-dihydrocarbostyril 2.0 g (6.8 mmol), 1-phenyl-2-mercaptoimidazole 1.4 g (8.1 m Mol) and DBU 1.1 ml (8.1 mmol) are added to isopropanol 60 ml and heated under reflux for 3 hours. After completion of the reaction, the solvent is concentrated, and the obtained residue is extracted with chloroform. After washing with water and drying over sodium sulfate, the solvent is concentrated. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 20: 1) and recrystallized from chloroform-n-hexane to give 2 g of 6- [2- (1-phenyl- 2-
Imidazolyl) thiobutyryl] -3,4-dihydrocarbostyril is obtained.

Colorless needle crystals mp.82.0-84.5 ° C Using the appropriate starting materials in the same manner as in Examples 85 and 86, Examples 3, 13, 15-17, 21-25, 27, 29-33, 35, 38 described above.
~ 40, 42, 52-65, 175-202 and the compounds shown in Table 3 below are obtained.

Example 141 6- [3- (2-imidazolyl) thiopropoxy] -3,
To a solution of 4-dihydrocarbostyril 2g (6.6mmol) in DMF (50ml) was added potassium hydroxide (520mg, 7.9mmol) and the mixture was allowed to stand at room temperature.
Stir for 0 minutes. Next, 1.5 ml (19.8 mmol) of ethyl bromide was added dropwise under ice cooling and the mixture was stirred at 40 to 50 ° C for 10 minutes. The solvent is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. After washing with water and drying over sodium sulfate, the solvent is concentrated. The obtained residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: ethyl acetate =
10: 1: 20) and then recrystallized from ethanol-n-hexane to give 1.2 g of 6- [3- (1-ethyl-2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril. To get Colorless needle crystals mp. 120.5-121.0 ° C Using the appropriate starting materials and in the same manner as in Example 108, Examples 3, 13, 15, 25, 29, 30, 31, 32, 35, 38-40, 4
2, 55-65, 85-103, 107, 109-110, 112-137, 173-
179, 182, 185-188, 190-191, 195-199 and 202 compounds are obtained.

Example 142 6- [2- (1-Phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 2 g (5.5 mmol) in a DMF: methanol = 3: 1 mixed solution (80 ml) was added with sodium borohydride (208 mg) (5.5 mmol) is added, and the mixture is heated with stirring at 50 to 60 ° C. for 1 hour. After concentrating the solvent, the residue is 1N-hydrochloric acid 50.
Pour into ml. After alkalinizing with 1N-sodium hydroxide, the precipitated crystals are taken, washed with water and dried. Recrystallize from ethanol to give 1.5 g of 6- [1-hydroxy-2- (1-
Phenyl-2-imidazolyl) thioethyl] -3,4-dihydrocarbostyril is obtained.

Yellow needle crystals mp.

Example 143 N'-Cyclohexycarbonyl-4- [6- (1,2-dihydro-2-oxoquinolyloxy)] butyrohydrazide (3 g) was added with polyphosphoric acid (120 g), and the oil bath temperature was adjusted to 190-210 ° C. Heat for 10 minutes with occasional stirring. After cooling, the reaction solution is poured into 400 ml of ice water and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (chloroform: methanol = 20: 1). Recrystallized from chloroform-petroleum ether to give 6- [3-
(2-cyclohexyl-1,3,4-oxadiazole-5
0.4 g of -yl) propoxy] carbostyril is obtained. mp16
0 to 161.5 ° C. The compounds of Examples 4 and 150 to 166 above are obtained in the same manner as in Example 143 using appropriate starting materials.

Example 144 6- [3- (1,2,4-triazol-1-yl) propoxy] -3,4-dihydrocarbostyril 2 g (7.35 mmol)
Sodium hydride (60% oily) 350mg in 20ml DMF solution of
Add (8.8 mmol) and heat at 60 ° C for 30 minutes. Then, under ice cooling, 0.6 ml (8.1 mmol) of ethyl bromide is added dropwise.
After stirring at room temperature for 3 hours, water is added to the reaction mixture and the mixture is extracted with chloroform. After washing with water and drying over sodium sulfate,
The solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 30: 1) and recrystallized from ethyl acetate-n-hexane to give 1.8 g of 1-ethyl-6- [3. -(1,2,4-Triazol-1-yl) propoxy] -3,4-dihydrocarbostyril is obtained.

Colorless needle crystals mp. 97.0-98.0 ° C Using the appropriate starting materials, the compounds of Examples 44 and 100 are obtained in the same manner as in Example 144.

Example 145 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 3.63 g (10 mmol) and hydroxylamine hydrochloride 1.09 g (15 mmol) are added to ethanol 100 ml and water 20 ml. 2.0 g (50 mmol) of sodium hydroxide powder is added with vigorous stirring, and the mixture is stirred at room temperature for 30 minutes. After the reaction is complete, add 5
After neutralization with 8% hydrochloric acid, the mixture is extracted with chloroform: methanol = 8: 1, dried over magnesium sulfate, and the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 20: 1),
Recrystallize from ethanol to give 3.34 g of 6- [1-hydroxyimino-2- (1-phenyl-2-imidazolyl).
Thioethyl] -3,4-dihydrocarbostyril is obtained.

White powder mp 201.0-202.0 ° C Example 146 6- [1-hydroxy-2- (1-phenyl-2-imidazolyl) thioethyl] -3,4-dihydrocarbostyril 3.0 g (8,17 mmol) Thionyl chloride 9 at -10 ° C
50 ml of methanol is added dropwise after stirring for 30 minutes at the same temperature. Then, stir at room temperature for 30 minutes. After the reaction,
The reaction solution is made alkaline with sodium hydrogen carbonate and extracted with chloroform. After drying over magnesium sulfate, the solvent is distilled off. Recrystallized from ethanol to give 1.5g of 6-
[1-Methoxy-2- (1-phenyl-2-imidazolyl) thioethyl] -3,4-dihydrocarbostyril is obtained.

Colorless prism mp. 193.0 to 194.0 ° C Example 147 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 4.47 g (12.3 m
Mol) was dissolved in 200 ml of chloroform and 45 ml of acetic acid, and 3.0 g (15.0 mmol) of m-chloroperbenzoic acid was added under ice cooling.
Stir for 1 hour at the same temperature. After completion of the reaction, the mixture is made alkaline with sodium hydrogen carbonate and extracted with chloroform. The crystals precipitated from the chloroform layer were collected and washed with ethanol to give 4.0 g of 6- [2- (1-phenyl-
2-Imidazolyl) sulfinylacetyl] -3,4-dihydrocarbostyril is obtained.

White powder mp.195 ° C. (decomposition) Using appropriate starting materials, compounds of Examples 191, 193, 196, and 199 to 200 described below are obtained in the same manner as in Example 147.

Example 148 6- [2- (1-phenyl-2-imidazolyl) sulfinylacetyl] -3,4-dihydrocarbostyril 3.79 g
(10 mmol) is dissolved in a mixed solution of 240 ml of acetic acid and 100 ml of water,
5.06 g (32 mmol) of potassium permanganate was added, and the mixture was stirred at room temperature for 2 days. After the reaction is completed, chloroform is added to the reaction solution and the mixture is filtered through Celite. The solution is washed with water and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1), and then ethanol-
Recrystallize from chloroform to give 0.6 g of 6- [2- (1-
Phenyl-2-imidazolyl) sulfonylacetyl]-
Obtain 3,4-dihydrocarbostyril.

Light yellow granular mp. 199 to 201 ° C Using the appropriate starting materials, the compounds of Examples 194 to 195, 197 and 201 to 202 described below are obtained in the same manner as in Example 148.

Example 149 2- (1-phenyl-2-imidazolyl) thioacetyl chloride 23.3 g (0.096 mol) and aluminum chloride 1
In a solution of 2.8 g (0.096 mol) of carbon disulfide in 60 ml of solution, at room temperature and with stirring, 3.4-dihydrocarbostyril 3.5 g (0.024 mol)
Is added little by little. After the addition is complete, heat to reflux for 2.5 hours. Decant carbon disulfide and pour the residue into ice water. The precipitated crystals are collected, washed with water and recrystallized from ethanol to obtain 17 g of 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril.

Pale yellow needles mp.
The compounds of 173-184, 186-189 and 191-202 are obtained.

The compounds shown in Table 4 below are obtained in the same manner as in Examples 1 and 2 using appropriate starting materials.

Using the appropriate starting materials, the same procedure as in Example 69
The compounds given in the table are obtained.

The compounds shown in Table 6 below are obtained in the same manner as in Examples 85 and 86 using appropriate starting materials.

Pharmacological test method The platelet adhesion inhibition rate was measured using the Salzman glass bead method.

The test compound is suspended in gum arabic and 100 mg / kg / 5 ml is applied to a 6-week-old Wistar male rat (body weight 150 to 200 g).
Oral administration, and after about 3 hours, the abdomen was opened under ether anesthesia, and a fixed-time blood suction device (made by Ikusho Shoinki Co., Ltd.) was passed through the abdominal descending vena cava via a glass bead column (made by Ikusho Shoin Kikai).
Blood was collected at a rate of 1 ml / min. A 1% gum arabic solution was orally administered to the control group, and blood was collected in the same manner. The collected blood was immediately transferred to a plastic bottle containing EDTA (manufactured by Toa Medical Electronics Co., Ltd., Sysmex SB-41) and rotatively mixed with a rolling mixer (manufactured by Thermal Science Industry). The number of platelets in the blood was counted by an automatic hemocytometer (ELT-8, manufactured by Ortho Diagnostics) and the platelet adhesion rate was calculated by the following formula.

The platelet adhesion inhibition rate was calculated from the following formula.

Test compound No. 16- [3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropoxy] -3,4-dihydrocarbostyril 26- [3- (2- Cyclohexyl-1,3,4-oxadiazol-5-yl) propoxy] -3,4-dihydrocarbostyryl 36- [3- (1-imidazolyl) propoxy] carbostyryl hydrochloride 4 6- [3- (2-Cyclohexyl-1,3,4-oxadiazol-5-yl) propoxy] carbostyryl 5 6- [3- (1,2,4-triazol-1-yl) propoxy] -3,4-dihydro Carbostyryl 6 6- [3- (1,2,3,4-tetrazol-1-yl)
Propoxy] -3,4-dihydrocarbostyril 7 6- [3- (2-methyl-1-imidazolyl) propoxy] -3,4-dihydrocarbostyril 8 6- [3- (1,2,4-triazole- 1-yl) propoxy] carbostyryl 9 6- [3- (2-methyl-1-imidazolyl) propoxy] carbostyryl 10 6- [3- (1,2,4,5-tetrazol-1-yl)
Propoxy] carbostyril 11 6- [3- (1,2,3,4-tetrazol-1-yl)
Propoxy] carbostyril 12 6- [3- (1-phenyl-2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 13 6- [3- (1-imidazolyl) propoxy] -3,
4-Dihydrocarbostyril 14 6- [3- (1-phenyl-1,3,4-triazol-2-yl) thiopropoxy] -3,4-dihydrocarbostyril 15 6- [3- (2-imidazolyl) Thiopropoxy]
-3,4-Dihydrocarbostyryl 16 6- [3- (1-ethyl-2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 17 8-[3- (1,2,4-triazole-1) -Yl) propoxy] -3,4-dihydrocarbostyril 18 7- [3- (1,2,4-triazol-1-yl) propoxy] -3,4-dihydrocarbostyril 19 5- [3- (1 , 2,4-Triazol-1-yl) propoxy] -3,4-dihydrocarbostyril 20 6- [3- (5-methyl-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 21 6- [3 -(5-Methoxybenzimidazole-2
-Yl) thiopropoxy] -3,4-dihydrocarbostyryl monohydrate 22 6- [3- (5-phenyl-2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyryl 1/2 oxalic acid Salt 23 7- [3- (1,3,4-triazol-2-yl) thiopropoxy] -3,4-dihydrocarbostyril 24 6- [3- (1-Ethyl-benzimidazole-2
-Yl) thiopropoxy] -3,4-dihydrocarbostyryl hemihydrate 25 7- [2- (1,2,4-triazol-1-yl) ethoxy] -3,4-dihydrocarbostyril 26 7- [3- (2-thiazolinyl) thiopropoxy]
-3,4-Dihydrocarbostyril 27 7- [4- (1,2,4-triazol-1-yl) butoxy] -3,4-dihydrocarbostyril 28 7- [3- (1-benzyl-2- Imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 29 7- [3- (1-allyl-2-imidazolyl) thiopropoxy] -3,4-dihydrocarbostyril 30 7- [3- (1-ethyl- 1,3,4-triazole-
2-yl) thiopropoxy] -3,4-dihydrocarbostyril 31 7- [3- (1-ethyl-1,2,4-triazole-
3-yl) thiopropoxy] -3,4-dihydrocarbostyryl 32 7- [3- (2-pyridyl) thiopropoxy] -3,
4-Dihydrocarbostyril 33 7- [5- (1,2,4-triazol-1-yl) pentyloxy] -3,4-dihydrocarbostyril 34 6- [4- (1,2,4-triazole- 1-yl) butyryl] -3,4-dihydrocarbostyril 35 6- {3- [1- (2-methylphenyl) -2-imidazolyl] thiopropoxy} -3,4-dihydrocarbostyril 36 6- [2- (1,2,4-Triazol-1-yl) ethoxy] -3,4-dihydrocarbostyril 37 6- [4- (1,2,4-triazol-1-yl) butoxy] -3,4-dihydro Carbostyril 38 6- {3- [1- (3-pyridyl) -2-imidazolyl] thiopropoxy} -3,4-dihydrocarbostyril 39 6- {3- [1- (2-methoxyphenyl) -2 −
Imidazolyl] thiopropoxy} -3,4-dihydrocarbostyril 40 6- {3- [1- (4-methylphenyl) -2-imidazolyl] thiopropoxy} -3,4-dihydrocarbostyril 41 6-{[3- (1,2,4-triazol-1-yl)
Propyl] amino} -3,4-dihydrocarbostyril 42 6-{[3- (1,2,4-triazol-1-yl)
Propyl] thio} -3,4-dihydrocarbostyryl 43 6- [2- (1,2,4-triazol-1-yl) acetyl] -3,4-dihydrocarbostyril 44 6- [2- (1- Phenyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyryl 45 6- [2- (1-phenyl-2-imidazolyl) thioacetyl] carbostyril 46 6- [2- (1-imidazolyl) acetyl] -3 ,Four
-Dihydrocarbostyryl bromohydrogenate 47 6- [2- (3-methyl-1-pyrazolyl) acetyl] -3,4-dihydrocarbostyril 48 6- [2- (2-methylthio-4-methyl-1) -Imidazolyl) acetyl] -3,4-dihydrocarbostyril 49 6- [1-hydroxy-2- (1-phenyl-2-)
Imidazolyl) thioethyl] -3,4-dihydrocarbostyril 50 6- [2- (1-ethyl-2-imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 51 6- [2- (1-allyl-2- Imidazolyl) thioacetyl] -3,4-dihydrocarbostyril 52 6- [1-hydroxy-4- (1-phenyl-2-)
Imidazolyl) thiobutyl] -3,4-dihydrocarbostyril 53 6- [1-hydroxy-3- (1-phenyl-2-)
Imidazolyl) thiopropyl] -3,4-dihydrocarbostyril 54 6- {2- [1- (3-trifluoromethylphenyl) -2-imidazolyl] thioacetyl} -3,4-dihydrocarbostyril 55 6- {2 -[1- (2-Methylphenyl) -2-imidazolyl] thioacetyl} -3,4-dihydrocarbostyril 56 6- [2- (1-phenyl-2-imidazolyl) thiobutyryl] -3,4-dihydrocarbostyryl 57 7- [3- (1,2,4-triazol-1-yl) propoxy] carbostyril

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 401/06 233 7602-4C 249 7602-4C 401/12 207 7602-4C 213 7602-4C 231 7602 -4C 233 7602-4C 235 7602-4C 239 7602-4C 249 7602-4C 257 7602-4C 401/14 233 7602-4C 257 7602-4C 405/14 215 7602-4C 413/12 215 7602-4C 417/12 215 9051-4C (56) Reference JP-A 56-46810 (JP, A) JP-A 56-49378 (JP, A) JP-A 57-159778 (JP, A) JP-A 50-142576 (JP , A) JP 54-30183 (JP, A) JP 55-35019 (JP, A) JP 57-9780 (JP, A) JP 57-183761 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula, R represents an unsaturated heterocyclic residue having 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. On the heterocycle, an oxo group; a thio group; a phenyl group; A phenyl group having 1 to 3 substituents selected from; a cycloalkyl group; a phenylthio group; a lower alkyl group; 1 to 2 substituents selected from the group consisting of an amino group, a lower alkylamino group and a carboxyl group Lower alkyl group;
Amino group; hydroxyl group; cyano group; carboxyl group; lower alkoxycarbonyl group; phenyl lower alkyl group that may have a hydroxyl group as a substituent on the phenyl ring; and fluorine group that may have a lower alkyl group as a substituent on the phenyl ring. It may have 1 to 3 substituents selected from the group consisting of an enylsulfonyl group; a lower alkoxy-substituted phenyl lower alkyl group; a lower alkylthio group; a lower alkenyl group; a lower alkoxy group and a pyridyl group. R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group. R ² represents a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, a lower alkoxy group or a hydroxyl group. Z
Is an oxygen atom, a sulfur atom, (R ³ represents a hydrogen atom or a lower alkyl group) or a group —NH—. A represents a lower alkylene group. X represents an oxygen atom, a sulfur atom, a group —SO— or a group —SO ₂ —. n represents 0 or 1. The carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton represent a single bond or a double bond. ] A platelet adhesion inhibitor characterized by containing a carbostyril derivative represented by or a salt thereof as an active ingredient.