JPS6059912B2 - carbostyril derivatives - Google Patents

Description

[Detailed description of the invention]

The present invention relates to carbostyril derivatives. The compound of the present invention is a new compound, and has the general formula [wherein R
1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and 2 to 4 carbon atoms.
R2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a phenylalkoxy group; R3 is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 4 carbon atoms; R4 is an alkyl group having 3 to 8 carbon atoms; Cycloalkyl group, phenyl group, cycloalkylalkyl group or 2-(3●4
-dimethoxyphenyl)ethyl group. The cycloalkyl group and phenyl group include lower alkyl group, lower alkoxy group, halogen atom, lower alkanoylamino group, lower alkanoyloxy group, lower alkoxycarbonyl group, lower alkanoyl group, lower alkylcarbamoyl group, lower alkylamino group, nitro One or two of the same or different substituents selected from the group consisting of a carboxy group, a hydroxyl group, an aminosulfonyl group, a carbamoyl group, and an amino group may be substituted. R5 is a hydrogen atom,
It represents an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl group, or a cycloalkylalkyl group. m represents an integer of 1 to 3. l and n are the same or different and represent 0 or an integer from 1 to 7, but the sum of l and n does not exceed 7. However, R4 is an unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a phenyl group having no substituent, or an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen as a substituent. represents a phenyl group having one or two atoms, hydroxyl group, or alkanoylamino group having 2 to 4 carbon atoms, and R5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 8 carbon atoms; And if 0≦1+n≦5, R
1, at least one of R2 and R3 does not represent a hydrogen atom, and R4 represents a cycloalkylalkyl group, 0≦l+n≦3, and an aminocarbonylalkoxy group is present at the 6th position of the lubostyryl skeleton. When bonded, at least one of R1, R2, R3 and R5 does not represent a hydrogen atom. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] and its salts. The compound of the present invention has platelet aggregation inhibiting action, anti-inflammatory action, anti-ulcer action, vasodilatory action, and phosphodiesterase (PDE) inhibiting action, and is a preventive or therapeutic agent for thrombosis, arteriosclerosis, hypertension, asthma, etc. It is useful as an anti-inflammatory agent and anti-ulcer agent. In the above general formula [1], specific examples of the alkyl group having 1 to 4 carbon atoms represented by R1 and R3 include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
Examples include Sec-butyl and tert-butyl groups, and specific examples of the alkyl group having 1 to 8 carbon atoms represented by R5 include n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, Examples include isohexyl, 2-ethylbutyl, n-heptyl, 3-methylhexyl, and n-octyl groups. Specific examples of the alkenyl group having 2 to 4 carbon atoms represented by R1 include vinyl, allyl, isopropenyl, and 2-butenyl groups. Examples of the phenylalkyl group represented by R1 and R5 include a phenylalkyl group in which a linear or branched alkylene group having 1 to 4 carbon atoms and a phenyl group are bonded, and specifically, benzyl, 2- Examples include phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1●1-dimethyl-2-phenylethyl, and the like. Specific examples of the halogen atom represented by R2 include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. Examples of the phenylalkoxy group represented by R2 include a phenylalkoxy group in which the phenylalkyl group and an oxygen atom are bonded,
Specifically, benzyloxy, 2-phenylethoxy, 1
Examples include -phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, and 1●1-dimethyl-2-phenylethoxy. Specific examples of the cycloalkyl group having 3 to 8 carbon atoms represented by R4 and R5 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. R
Examples of the cycloalkyl group having 3 to 8 carbon atoms having a substituent represented by 4 include methyl, ethyl, n-propyl, isopropyl, n-butyl, Ter
Alkyl groups such as t-butyl group, alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy group, halogen atoms such as chlorine atom, bromine atom, iodine atom, fluorine atom, acetylamino, propionylamino , alkanoylamino groups such as butyrylamino and isobutyrylamino groups, alkanoyloxy groups such as acetyloxy, propionyloxy, butyryloxy, and isobutyryloxy groups, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl groups, etc. alkoxycarbonyl group, alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl group, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N●N-diethylcarbamoyl, Alkylcarbamoyl groups such as N-methyl-N-propylcarbamoyl group, N4eN-dimethylamino, NIN-diethylami8N●N-dipropylamino8N-ethylamino, N-
Isopropylamino, N-methyl-N-ethylamino,
Substituted with one or two of the same or different substituents selected from the group consisting of alkylamino groups such as N-N-dibutylamino groups, nitro groups, carboxy groups, hydroxyl groups, aminosulfonyl groups, carbamoyl groups, and amino groups. I can list things. Examples of phenyl having a substituent represented by R4 include phenyl groups substituted with one or two of the above substituents. Examples of the cycloalkylalkyl group represented by R4 and R5 include a cycloalkylalkyl group in which a cycloalkyl group having 3 to 8 carbon atoms and a linear or branched alkylene group having 1 to 4 carbon atoms are bonded. Specifically, 4-cyclohexylbutyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, cyclopentylmethyl, 2-cyclohexylethyl, 2-cyclohexylpropyl, 2-cycloheptylethyl, 3- Examples include cyclobutylpropyl, 1,1-dimethyl-2-cyclohexylethyl, and 1-methyl-2-cyclopentylethyl. Representative compounds of the present invention are listed below. ○6-(3-[N-cyclohexyl-N-(2-phenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl○6-(3-
[N-cyclohexyl-N-(4-phenylbutyl)aminocarbonyl]propoxy)carbostyryl or 3
●4-dihydrocarbostyryl 06-[4-(N-cyclohexyl-N-benzylaminocarbonyl)butoxy]carbostyryl or 3●4-dihydrocarbostyryl 05-(2-[N-cyclohexyl-N-(2-phenylethyl) Aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○5-[3-
(N-cyclohexyl-N-benzylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 06-[3-(N-benzylanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○4 -(0-chlorop-nitroanilinocarbonylmethoxy)carbostyryl or 3.4
-dihydrocarbostyryl○6-[3-(0-carboxyanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-[3-(0-
Ethoxycarbonylanilinocarbonyl)propoxy]
Carbostyril or 3●4-dihydrocarbostyril 0
6-[4-(N-benzyl-0-ethoxycarbonylanilinocarbonyl)butoxy]carbostyryl or 3●
4-dihydrocarbostyryl 05-[3-(p-aminosulfonylanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 06-[3
-(N-ethyl-p-aminosulfonylanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl06-[3-(N-methyl-0-carbamoylanilinocarbonyl)propoxy]carbostyryl or 3●4- Dihydrocarbostyryl○5-(3-
[N-(3-cyclopropyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 05-(3-[N-(cyclohexylmethyl)aminocarbonyl]propoxy)carbostyryl. or 3
・4-dihydrocarbostyryl 06-(3-[N-methyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(2-methyl-3-[N-aryl N-(3-cyclohexylpropyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl01-ethyl-6-[3-(N-ethyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl or 3,4 -dihydrocarbostyryl 06-(3-[N-phenyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 01-aryl-5-(3-[N-methyl-N- (3-cycloheptylpropyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06.8
-dichloro-5-(3-[N-methyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 08
-bromo6-(3-[N-arylN-(3-cyclobutylpropyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 08-
Hydroxy-5-(3-[N-ethyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○5
-[2-Methyl-3-(0-carbamoylanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl○6-(1-[0-(N-methylcarbamoyl)anilinocarbonyl]ethoxy)carbostyryl or 3,4-dihydrocarbostyryl○5-[1
-(0-carboxyanilinocarbonyl)ethoxy]carbostyryl or 3●4-dihydrocarbostyryl○6
-[1-(2-Hydroxy-6-methylanilinocarbonyl)propoxy]carbostyril or 3,4-dihimocarbostyril○6-[2-methyl-3-(N-ethylanilinocarbonyl)propoxy]carbostyril or 3,4-dihydrocarbostyryl 06-[1-methyl-3-(N-allylanilinocarbonyl)propoxy]
Carbostyril or 3●4-dihydrocarbostyril 0
5-[2-Methyl-3-(N-methylanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○1-Methyl-5-(0-ethoxyanilinocarbonylmethoxy)carbostyryl or 3,4- Dihydrocarbostyryl 01-aryl 5-[1-(p
-methoxyanilinocarbonyl)ethoxy]carbostyril or 3●4-dihydrocarbostyryl01-ethyl-6-[3-(N-methylanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl01-benzyru6 -[3-(N●N-diphenylaminocarbonyl)propoxy]carbostyryl or 3
●4-dihydrocarbostyryl 01-methyl-6-[3
-(N-methyl-m-methoxyanilinocarbonyl)propoxy]cal, bostyryl or 2●4-dihydrocarbostyrinole01-allyl6-[2-methyl-3-(
p-acetaminoanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 01
-Methyl-6-[3-(0-chloroanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○6-[1-(N-methyl-N-cyclohexylaminocarbonyl)ethoxy]carbostyril or 3. 4-dihydrocarbostyryl○6-[2-methyl-3-(N-allyl-N-cyclobutylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl○6-[2-methyl-3-(N-methyl- N-cyclohexylaminocarbonyl)propoxy]
Carbostyril or 3,4-dihydrocarbostyril 0
6-[2-Methyl-3-(N-phenyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl06-[2-methyl-3-(N-benzyl-N-cyclohexylaminocarbonyl)propoxy] Carbostyryl or 3,4-dihydrocarbostyryl 06-[1-(N-methyl-N-
cycloheptylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 06-[
3-(N-ethyl-N-cyclohexylaminocarbonyl)-3-methylpropoxy]carbostyryl or 3.
4-dihydrocarbostyryl○6-[2-isopropyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl06-[2-butyl-3-(N-aryl-N -cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl ○6-[4-
Methyl-5-(N-propyl-N-cyclohexylaminocarbonyl)heptyloxy]carbostyryl or 3
・4-dihydrocarbostyryl 06-[1-methyl-3
-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○5-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4 -dihydrocarbostyryl○5
-[2-Methyl-3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl○5-[1-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril or 3,4-dihydrocarbostyryl○7-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril or 3,4-dihydrocarbostyryl○7-[2-methyl-3-(N- Allyl N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl○8-[2-methyl-3-(N-
Ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 08-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05 -Chloro-6-(N-methyl-N-cyclohexylaminocarbonylmethoxy)carbostyryl or 3●4-dihydrocarbostyryl05-chloro-6-[(2-methoxy5
-methylphenyl)anilinocarbonylmethoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-
Chloro-6-[3-(N-methylanilinocarbonyl)
propoxy]carbostyryl or 3●4-dihydrocarbostyryl 05-chloro-6-[3-(N-methyl-N
-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-
Chloro-6-[3-(N-ethyl-0-methylanilinocarbonyl)propoxy]carbostyryl or 3,4-
Dihydrocarbostyryl 05-bromo6-[3-(N
-Methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl05-iodo6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 05-Fluoru6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4
-dihydrocarbostyryl 05-chloro-6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-chloro-6-[4-(N-
Ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl or 3●4-dihydrocarbostyryl 05-chloro-6-[1-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○ 5-chloro-6-[3-methyl-5-(N-methyl-N-cyclohexylaminocarbonyl)pentyloxy]carbostyryl or 3●4-dihydrocarbostyryl 05,6,7-
Trichloro-8-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05,6,7-tribromo-8-[3-(N-methylanilinocarbonyl)
propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05,6,7-trichloro-8-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05・6.7-Trichlore 8-[
5-(N-ethyl-N-cyclohexylamino)pentyloxy]carbostyryl or 3,4-dihydrocarbostyryl 08-bromo 5-[3-(N-methyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 08-bromo 5-[3-(2,3-dichloroanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 08-bromo 5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]
Carbostyril or 3,4-dihydrocarbostyril 0
8-fluorou 5-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 08-chlorou6-
[3-(N-propyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl08-bromo6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)proboxy] Carbostyryl or 3,4-dihydrocarbostyryl 08-iodo-5-(3-[N-2-
(3,4-dimethoxyphenyl)ethylaminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06●8-dichloro-5-[3-(N-
ethylanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 06●8-dichloro-5-[3-(p-acetylaminoanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyrinole 06・8-dibromo 5-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05.8-dichloro-6-[3-
(N-methyl-N-cyclohexylaminocarbonyl)
Propoxy] carbostyril or 3●4-dihydrocarbostyryl 06●8-dichloro-7-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○8-chloro-7-[ 3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl ○5,7-dichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3 ●4
-dihydrocarbostyryl 05,8-dibromo6-
3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○5,7,8-trichloro-6-[3-
(N-methyl-N-cyclohexylaminocarbonyl)
Propoxy] Carbostyryl or 3●4-dihydrocarbostyryl○8-Hydroxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]
Carbostyryl or 3,4-dihydrocarbostyryl○
8-hydroxy-5-[3-(N-ethylanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl08-hydroxy-6-[2-methyl-3-(N-ethyl-N-cyclohexylaminocarbonyl) propoxy]carbostyryl or 3,4-dihydrocarbostyryl 08-benzyloxy-6-[3
-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 08-(2-phenylbutoxy)-6-[
3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl05-hydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4 -dihydrocarbostyryl○5-(benzyloxy)-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]
Carbostyryl or 3,4-dihydrocarbostyryl
~○7-Hydroxy-6-[3
-(N-methyl-■-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl○5,8-dihydroxy-6-[3-(
N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○6,8-dihydroxy-5-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4- Dihydrocarbostyryl ○ 1-Methyl-6-゛[3-(N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 01-benzyl-6
-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 01-(4-phenylbutyl)-5
-[3-(N-ethyl-N-cyclohexylpropylaminocarbonyl)propoxy]carbostyryl or 3●
4-dihydrocarbostyryl 01-(2-butenyl)-
6-[3-(N-methyldiN-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○1-allyl 5-[3-(N-
Ethyl-N-cyclohexylaminocarbonyl)-3-
Methylpropoxy]carbostyryl or 3●4-dihydrocarbostyryl○1-benzyl-5-[3-methyl-5-(N-methyl-N-cyclohexylamino)pentyloxy]carbostyryl or 3,4-dihydrocarbostyryl○1- Ethyl 5●67-Trichlororu 81 [
3-(N-ethyl-N-cyclohexylamino)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 06,8-dichloro-1-methyl-5-[4-(N
-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl or 3,4-dihydrocarbostyryl○8-hydroxy-1-ethyl-5-[3-(N-
Methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl08-benzyloxy-1-methyl-5-[3-(
N-Methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○1-Methyl-5-chloro-6-[3-(N-
Methyl-N-phenylaminocarbonyl)propoxy]
Carbostyril or 3,4-dihydrocarbostyril 0
1-isopropyl-6-[3-(N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl ○1-benzyru6
-[3-Methyl-5-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05,8-dibromo1-methyl-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl) ) propoxy] carbostyryl or 3●4-dihydrocarbostyryl 05-hydroxy-1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy] carbostyril or 3●4-dihydrocarbostyryl○7-hydroxy 1-Allyl-6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05,8-dihydroxy-1-methyl-6-[3-(N-methyl-N-cyclohexylamino) carbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 01-methyl-7-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl○1- Benzyl-8-[2-methyl-3-(N-propyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-fluoro-1
-Allyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl05-chloro-1-ethyl-6-[2-methyl-3-(N-methyl-N-cyclohexyl) (aminocarbonyl)propoxy]carbostyryl or 3◆4-dihydrocarbostyryl○6,8-dichloro-1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl ○5-(1
-[N-ethyl-N-(3-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3.
4-dihydrocarbostyryl 05-[3-(N-4-methoxycyclohexylaminocarbonyl)propoxy]
Carbostyril or 3●4-dihydrocarbostyril○
5-(3-[N-methyl-(4-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N
-Methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl○5-(3-[N-ethyl-N-
(4-Butylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N-methyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4 -dihydrocarbostyryl 06
-(3-[N-methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-[3-(
N-4-Methoxycyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 4-dihydrocarbostyryl 05-(3-[N-methyl-N-(4-butyryloxycyclohebutyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06
-(2-Methyl-3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl○5-
(3-[N-methyl-N-(4-isopropylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl06-(2-hydroxy-3-[N-methyl-N-(2-methylcyclohexyl) 01-Methyl-6-(3-[N-methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 01-Allyl-6-(3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl01-Benzyru-6-[3-(N-4-ethoxycyclo heptylaminocarbonyl)propoxy]carbostyryl or 3●4
-dihydrocarbostyryl 08-hydroxy-5-(1
-(N-methyl-N-(3-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3●
4-dihydrocarbostyryl 05,6,8-trichloro-6-(3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl ○6-
(3-[N-methyl-N-(2-hydroxy-5-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6
-(3-[N-ethyl-N-(4-nitrocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N-
Methyl-N-(2-carboxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-
Dihydrocarbostyryl 05-(3-[N-aryl-N
-(2-Ethoxycarbonylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N-ethyl-N-
(2-N-methylcarbamoylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-
Dihydrocarbostyryl○5-(3-[N-methyl-N
-(2-N●N-diethylcarbamoylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl06-(3-[N-ethyl-N-(2-carbamoylcyclohexyl)aminocarbonyl]propoxy)carbostyryl Styril or 3.4-
Dihydrocarbostyryl○5-(3-[N-methyl-N
-(4-bromocyclohexyl)aminocarbonyl]propokyl. c) Carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N-methyl-N-(4-chlorocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl. boss chiril 0
6-(3-[N-methyl-N-(3,4-dimethoxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(
3-[N-arylN-(4-aminosulfonylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3
-[N-methyl-N-(3-acetylcyclohexyl)
Aminocarbonyl]propoxy)carbostyryl or 3
・4-dihydrocarbostyryl○6-(3-[N-methyl-N-(4-acetylaminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-
Dihydrocarbostyryl 05-(3-[N-ethyl-N
-(4-butyrylaminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3-[N-methyl-N-(4
-N-N-dimethylaminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3-[N-methyl-N-(
2,6-dimethylcyclohexyl)aminocarbonyl]
propoxy) carbostyryl or 3,4-dihydrocarbostyryl 06-(3-[N-ethyl-N-(2,5-dimethoxycyclohexyl)aminocarbonyl]propoxy) carbostyril or 3,4-dihydrocarbostyryl ○6-( 3-[N-methyl-N-(2,5-dichlorocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06
-(3-[N-methyl-N-(4-acetylaminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3
-[N-cyclohexylmethyl-(2-chlorocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3-[
N-methyl-N-(2-aminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-
Dihydrocarbostyryl 06-(3-[N-(3-cyclohexylbutyl)-N-(4-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl ○6-(3-[N- (
3-cycloheptylpropyl)-N-cyclohexylaminocarbonyl]propoxy)carbostyryl or 3.
4-dihydrocarbostyryl 06-(3-[3-(2-
cyclohexylethyl)-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyrinole06-(3-[N-(2-cyclohexylethyl) −
N-cyclohexylaminocarbonyl]-2-methylpropoxy) carbostyryl or 3●4-dihydrocarbostyryl○6-(3-[N-(2-cyclohexylethyl)anilinocarbonylpropoxy)carbostyryl or 3,4-dihydro Carbostyryl○6-[2-hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl05-[2-hydroxy-3-(
N-ethyl-p-methylanilinocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl Q6-[2-hydroxy-3-(N-methylanilinocarbonyl)propoxy]carbostyryl or 3●4-
Dihydrocarbostyryl○6-[2-hydroxy-3-
(p-chloroanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl01-ethyl-6-[2-hydroxy-3-(N-methyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,41-dihydrocarbostyryl 06-
(3-[N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06-(3-[N
-Methyl-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06-(3-[
N-aryl N-(2-3″・4′-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06-(3-
[N-Benzy-N-(2-3″・4′-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○6-(
3-[N-phenyl-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 05
-(3-[N-ethyl-N-(2-3″・4-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 06
-(2-methyl-3-[N-ethyl-N-(2-3″・
4″-dimethoxyphenylethyl)aminocarbonyl]
propoxy) carbostyril or 3,4-dihydrocarbostyryl 06-(2-hydroxy-3-[N-methyl-N-(2-3″·4″-dimethoxyphenylethyl)
Aminocarbonyl]propoxy)carbostyryl or 3
●4-dihydrocarbostyryl○5-chloro6-(3
-[N-methyl-N-(2-3″●4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 05-(
4-[N-methyl-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl 91-
Methyl-6-(3-[N-methyl-N-(2-3″●4
″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3,4-dihydrocarbostyryl○8-Hydroxy-5-(3-[N-methyl-N-(2-3′●4-dimethoxyphenylethyl)aminocarbonyl ]Propoxy) carbostyril or 3●4
-dihydrocarbostyryl○1-aryl7-(3-[
N-methyl-N-(2-3'●4'-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl06-(3-
[N-octyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3.
4-dihydrocarbostyryl 06-(3-[N-heptyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3●4-dihydrocarbostyryl 06-(3-[N-heptyl-N-
(4-N-N-dimethylaminocyclohexyl)aminocarbonyl]propoxy)carbostyryl or 3,4-
Dihydrocarbostyryl○6-(3-[N-octyl-N-(2-chlorocyclohexyl)aminocarbonyl]
propoxy) carbostyryl or 3,4-dihydrocarbostyryl○6-(3-[N-octyl-N-cyclohexylaminocarbonyl)-2-methylpropoxy]carbostyryl or 3,4-dihydrocarbostyryl○6
-[3-(N-heptylanilinocarbonyl)-2-methylpropoxy]carbostyryl or 3●4-dihydrocarbostyryl01-methyl-6-[3-(N-octyl-N-cyclohexylaminocarbonyl)propoxy] Carbostyryl or 3,4-dihydrocarbostyryl 05-chloro-6-[3-(N-heptyl-N-cyclohexylaminocarbonyl)propoxy] carbostyril or 3●4-dihydrocarbostyryl 06-[3-
(N-octyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 06-(3-[N-heptylanilinocarbonyl)propoxy]carbostyryl or 3,4-dihydrocarbostyryl 05-[ 3-(N-heptyl N-
cyclohexylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl 06-[
3-(N-octyl-N-cyclooctylaminocarbonyl)propoxy]carbostyryl or 3●4-dihydrocarbostyryl The compound of the present invention can be produced by various methods, typically using the following reaction scheme. The methods shown in Reaction Scheme-1 and Reaction Scheme-2 can be mentioned. The carbon-carbon bonds at the 3rd and 4th positions are the same as above. ) General formula [2] used as a starting material in the present invention
The hydroxycarbostyryl derivative represented by the formula [3], the carboxyalkoxycarbostyryl derivative represented by the general formula [4], and the amine represented by the general formula [5] are all known compounds, or It is a new compound and is produced by the method shown in Reaction Scheme-5 to Reaction Scheme-11 below. The method shown by Reaction Scheme-1 is a method in which a hydroxycarbostyryl derivative represented by the general formula [2] and a haloamide represented by the general formula [3] are subjected to a conventional dehydrohalogenation reaction. Examples of the halogen atoms in the haloamide include bromine, chlorine, and iodine. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenating agent. A wide range of known basic compounds can be used, for example,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium bicarbonate, potassium bicarbonate, and silver carbonate; alkali metals such as sodium and potassium; alcoholates such as sodium methylate and sodium ethylate; and organic bases such as triethylamine, pyridine, and N-N-dimethylaniline. Examples include bases. The reaction can be carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol; Ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, NI
N-dimethylformamide, dimethyl sulfoxide,
Examples include aprotic polar solvents such as hexamethylphosphoric triamide. The reaction also involves sodium iodide,
It is advantageous to carry out in the presence of a metal iodide such as potassium iodide. The ratio of the hydroxycarbostyryl derivative [2] and the haloamide [3] in the above method is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in an equimolar to 5 times molar ratio to the former. , preferably in an equimolar to twice molar amount. Further, the reaction temperature is not particularly limited, but is usually room temperature to 200°C.
It is carried out at a temperature of preferably 50 to 150°C. The reaction time is usually 1~3C$! 1f, preferably 1 to 1 hour. The method shown by Reaction Scheme-2 is a method in which a carboxyalkoxycarbostyryl derivative represented by the general formula [4] and an amine represented by the general formula [5] are reacted in a conventional amide bond-forming reaction. In the present invention, a compound whose carboxyl group is activated may be used instead of the compound of general formula [4]. As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. For example, (a) mixed acid anhydride method, that is, a method in which carboxylic acid [4] is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is then reacted with amine [5]; (2) active ester method, that is, carboxylic acid A method of converting [4] into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting this with amine [5]; (c) carbodiimide method, that is, carboxylic acid [ 4] is subjected to dehydration condensation of amine [5] in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Other methods include converting carboxylic acid [4] to carboxylic acid [4] in the presence of a dehydrating agent such as acetic anhydride. A method of reacting an anhydride with an amine [5], a method of reacting an ester of a carboxylic acid [4] and a lower alcohol with an amine [5] under high pressure and high temperature, an acid halide of a carboxylic acid [4], that is, a carboxylic acid Examples include a method in which acid halide is reacted with amine [5]. Among these, the mixed acid anhydride method is preferred. The alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate,
Examples include isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound of the present invention is produced by reacting it with the amine [5] without isolation. The Schotten-Baumann reaction is carried out in the presence of a basic compound. The basic compounds used are those commonly used in the Schotten-Baumann reaction, such as organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, and N-methylmorpholine, potassium carbonate, sodium carbonate, and potassium hydrogen carbonate. , inorganic bases such as sodium hydrogen carbonate. The reaction is carried out at -20 to 100'C, preferably 0 to 50C, and the reaction time is 5 minutes to 1 hour, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine [5] is carried out at -20 to 150'C, preferably 10 to 50'C, and the reaction time is 5 minutes to 1
It is carried out under conditions of 0 hours, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, and specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, N-N-
Examples include aprotic polar solvents such as dimethylformamide (DMF), dimethylsulfoxide, and hexamethylphosphoric triamide. Carboxylic acid [4] in this method
], the alkyl halocarboxylic acid and the amine [5] are usually used in equivalent molar ratios, but the ratio of the alkyl halocarboxylic acid and the amine [5] to the carboxylic acid [4] is 1 to 1.
．． It may be used in a 5-fold molar amount. The compound of the present invention can also be produced by the methods shown in Reaction Scheme-3 and Reaction Scheme-4 below. That is, the compound of general formula [1b] is produced by dehydrogenating the compound of general formula [1a], and the compound of general formula [1a]
The compound is produced by reducing the compound of general formula [1b]. Moreover, the compound of general formula [1d] is the compound of general formula [1d]
1C] and the compound of general formula [6] by dehydrohalogenation reaction. (In the above formula, R1'' represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a phenylalkyl group. R1, R2, R3, R4, R5, Mll, Nlx, and carbostyryl) The carbon bonds at the 3rd and 4th positions of the skeleton are the same as above.However, R2 of the compound [1b] used as the starting material for the reduction reaction in Reaction Scheme-3 is a hydrogen atom or a hydroxyl group.) Reaction Scheme- In 3, the dehydrogenation of the compound of general formula [1a] is achieved by subjecting it to a dehydrogenation reaction using an oxidizing agent in a suitable solvent by a conventional method.The oxidizing agent used is 2.・3-Dichlororo5●6
- benzoquinones such as dicyanopenzoquinone (hereinafter abbreviated as DDQ), chloranil (2,3,5,6-tetrachlorobenzoquinone), selenium dioxide, palladium on carbon,
Examples include metal catalysts such as palladium black, platinum oxide, and Raney nickel, and brominating agents such as N-promosuccinimide and bromine. Examples of solvents include ethers such as dioxane, tetrahydrofuran, 2-methoxyethanol, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. , alcohols such as butanol, amyl alcohol, and hexanol, and aprotic polar solvents such as N-N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. As the reaction conditions for this reaction, the reaction temperature is room temperature to 300°C.
, preferably 50 to 200°C, reaction time is 1 hour to 2 days, preferably 1 to 2 (inversion) periods, and the proportion of the oxidizing agent is, when benzoquinones or brominating agents are used, The amount is equimolar to 5 times mole, preferably equimolar to 2 times mole, relative to compound [1a], and when a metal catalyst is used, a commonly used catalyst amount may be used. Reaction formula-3
In this case, the catalytic reduction of compound [1b] is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method. The catalysts used include all known catalysts, such as platinum wire, platinum plate, platinum sponge, platinum black, platinum oxide, colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium-barium sulfate, Palladium catalysts such as palladium-barium carbonate, palladium on carbon, palladium silica gel, colloidal palladium, platinum group catalysts such as rhodium with asbestos, iridium, colloidal rhodium, ruthenium catalysts, colloidal iridium, reduced nickel, nickel oxide, Raney nickel,
Nickel catalysts such as Urushihara nickel, nickel catalysts produced by thermal decomposition of nickel formate, nickel boride, cobalt catalysts such as reduced cobalt, Raney cobalt, Urushihara cobalt,
Examples include iron catalysts such as reduced iron, Raney iron, copper catalysts such as reduced copper, Raney copper, Ullmann copper, and other metal catalysts such as zinc. Solvents used include lower alcohols (methanol, ethanol, isopropanol, etc.), water, acetic acid, acetic acid esters (methyl acetate, ethyl acetate, etc.), ethylene glycol, ethers (diethyl ether, tetrahydrofuran, dioxane, etc.), aromatic Examples include group hydrocarbons (benzene, toluene, xylene, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), and n-alkanes (n-hexane, n-pentane, etc.). The reaction conditions are
Usually, it is suitable to carry out the reaction under normal or increased hydrogen pressure, preferably 1 to 2 leakage pressure, and at room temperature to the boiling point of the solvent, preferably room temperature to 100C. In reaction scheme-4, compound [1
C] and compound [6] is carried out by reacting compound [1C] in the form of an alkali metal salt with compound [6]. The reaction for obtaining the corresponding alkali metal salt from compound [1C] is carried out in the presence of an alkali metal compound. Examples of the alkali metal compounds used here include metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium metal, and sodium azide. This reaction is generally carried out in a solvent, and the solvents used at this time include, for example, benzene solvents such as benzene, toluene, and xylene; ether solvents such as diethyl ether, 1,2-dimethoxyethylene, and dioxane; Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide, and it is particularly preferable to use the above-mentioned aprotic polar solvents. The amount of the alkali metal compound to be used is usually from 1 mole to 5 times the mole of compound [1C], particularly preferably from 1 mole to 3 times the mole of compound [1C]. Although the reaction temperature is appropriately selected, the reaction usually proceeds over a wide range of 0'C to 200C, preferably room temperature to 501C. This reaction yields a compound in which the nitrogen site at position 1 of compound [1C] is substituted with an alkali metal. The reaction to obtain compound [1d] from the alkali metal salt of compound [1C] obtained above and compound [6] is a condensation reaction, which can be easily carried out by a conventional method, but is generally carried out in a dimethylformamide solvent, for example. The reaction proceeds most preferably at room temperature. The amount of compound [6] to be used is appropriately selected within a wide range, but it is generally recommended to use an equimolar to 5 times the mole, particularly an equimolar to 3 times the mole of the alkali metal salt of the compound [1C]. is preferred. In addition, the present invention is not limited to the above-mentioned two-step operation; for example, general formula [1C]
Of course, it is also possible to carry out the reaction by allowing each compound represented by [6] and the alkali metal compound to exist simultaneously in the reaction system, and in this case as well, the reaction of the present invention can be carried out through the same reaction route as above. compound can be obtained. Among the compounds represented by the general formula [2] used as starting materials in the present invention, compounds in which R2 represents a halogen atom [? ] is the general formula [2] as shown in reaction scheme 15 below.
Among the compounds represented by R2, it is easily produced by halogenating a compound [(] (known compound) in which R2 is a hydrogen atom. (!R. In the formula, x represents a halogen atom. R1, m and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above.) The halogenation reaction of the compound [nod] can be advantageously carried out using a known halogenating agent. Examples include fluorine, chlorine, bromine, iodine, xenon difluoride, sulfuryl chloride, sodium hypochlorite, hypochlorous acid, hypobromous acid, bleaching powder, etc. The amount of the halogenating agent used depends on the compound [?] Depending on the number of halogen atoms to be introduced, the appropriate selection may be made from a wide range of options. When one halogen atom is introduced, the compound [?
], usually equimolar to twice the molar amount, preferably equimolar to
1j times the molar amount, when introducing two halogen atoms, usually 1.5f8 mol to large excess amount, preferably 2 to 3 times the molar amount, and when introducing three halogen atoms, usually It is advisable to use a 2.5-fold molar to large excess amount, preferably a 3- to 5-fold molar amount. Such halogenation reaction is usually preferably carried out in a suitable solvent. Examples of the solvent include water, methanol, ethanol, chloroform, carbon tetrachloride, acetic acid, and mixed solvents thereof. The reaction temperature is not particularly limited and may be appropriately selected within a wide range, but usually -
The temperature is preferably about 20 to 10 degrees, preferably 0 to room temperature, and the reaction is completed within about 3 to 1 hour. General formula [Haruka] which is a raw material for producing the compound of the present invention
Compounds in which m is 1 among the compounds [? ] can also be easily produced by the method shown in Reaction Formula-6 below. (In the above formula, R6 represents an alkyl group.R1, The hydroxy-halogenocarbostyryl derivative represented by the general formula [λ] is produced by halogenating the derivative and then hydrolyzing the obtained acyloxy-halogenocarbostyryl derivative represented by the general formula [8]. The reaction conditions for the halogen*÷ conversion reaction may be the same as those described above, and the reaction conditions for the hydrolysis reaction may be the same as those shown below. Furthermore, among the compounds represented by the general formula [4], compounds in which R2 represents a halogen atom, a hydroxyl group, or a phenylalkoxy group are new compounds, for example, the following reaction scheme-7
Manufactured by the method shown below. (In the above formula, R2'' represents a halogen atom, a hydroxyl group, or a phenylalkoxy group, R7 represents an organic residue, and x represents a halogen atom. R1, R3, Mll.sn and 3 of the carbostyryl skeleton)
The carbon-carbon bond at position and 4-position is the same as above. ), that is, the general formula [?
] The general formula for hydroxycarbostyryl derivatives represented by

By reacting the ester derivative represented by [9], the ester carbostyryl derivative represented by the general formula [ψ] is obtained, and by hydrolyzing the obtained compound of the general formula [ψ], the carbostyryl derivative represented by the general formula [ψ] is A carboxyalkoxycarbostyryl derivative represented by formula [4b] is produced. Compound〔? ] and compounds

The reaction with [9] is carried out under the usual reaction conditions for dehydrohalogenation reaction. Various basic compounds are used as the dehydrohalogenating agent, and specific examples include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; Examples include alkali metals such as sodium and potassium, and organic bases such as triethylamine, pyridine, and N●N-dimethylaniline. Such a reaction can be carried out without a solvent or in the presence of a solvent. A wide range of solvents that do not participate in the reaction can be used, including alcohols such as methanol, ethanol, and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, and benzene, toluene, xylene, and chlorobenzene. Solvents such as aromatic hydrocarbons, acetone, ketones such as methyl ethyl ketone, etc. can be advantageously used. Compound〔? ]
and compound

The proportion of [9] to be used is not particularly limited and may be appropriately selected from a wide range, but it is generally advisable to use the latter in an equimolar to 5-fold molar amount, preferably in an equimolar to 2-fold molar amount to the former. The reaction temperature is not particularly limited and is appropriately selected from a wide range, but it is generally preferred to carry out the reaction at room temperature to 20°C, preferably 50 to 150°C, and usually 1.
The reaction is completed within about 1 m. Hydrolysis reactions of compounds are usually carried out in the presence of a catalyst. As the catalyst used at this time, any catalyst used in normal hydrolysis reactions can be used, and typical examples include basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, sulfuric acid, hydrochloric acid, and nitric acid. Examples include mineral acids such as, acetic acid, organic acids such as aromatic sulfonic acid, and the like. The amount of the catalyst to be used is not particularly limited and may be appropriately selected from a wide range. Such hydrolysis reaction may be carried out according to conventional methods, but it generally proceeds advantageously in a solvent. As the solvent used at this time, a wide range of solvents that do not participate in the reaction can be used.
For example, water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, and mixed solvents thereof can be advantageously used. The reaction temperature is not particularly limited and may be appropriately selected from a wide range, but the reaction is usually carried out at room temperature to 200C, preferably 50 to 150'C. The reaction generally ends in about 5 minutes to 1 Vf. The amine represented by the general formula [5] used as a starting material in the present invention can be produced by various methods, for example, the following reaction scheme-8, reaction scheme-9 and reaction scheme-10.
It is easily produced by the method shown in . (In the above formula, R4'' represents a phenyl group or phenylalkyl group with or without a substituent, R4'' represents a cyclohexyl group or a cyclohexylalkyl group with or without a substituent, and X is a (Represents a halogen atom. R4 and R5 are the same as above.) According to Reaction Scheme-8, the amine represented by the general formula [5] is a known amine represented by the general formula [10] and the general formula [11]. It is easily produced by dehydrohalogenation reaction with a known halogen compound represented by the formula [5] in the presence of a basic compound.According to reaction scheme-9, the amine represented by the general formula [5] is It is easily produced by dehydrohalogenating a known amine represented by the formula [12] and a known halogen compound represented by the general formula [13] in the presence of a basic compound.These reactions are carried out as described above. General formula [2
] The dehalogenation reaction between the compound of formula [3] and the compound of general formula [3] may be carried out in the same manner as the dehalogenation reaction. According to reaction scheme-10, the general formula [? ] The cyclohexylamine derivative or cyclohexylalkylamine derivative represented by the general formula [S]
It is easily produced by reducing the benzene nucleus of a known compound represented by Although general nuclear hydrogenation reactions are widely used to reduce benzene nuclei, a method using catalytic reduction is particularly advantageous. Catalytic reduction is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method. Catalysts that can be used include platinum catalysts such as platinum black, platinum oxide, and colloidal platinum, palladium catalysts such as palladium black, palladium carbon, and colloidal palladium, rhodium catalysts such as rhodium with asbestos, rhodium alumina, ruthenium catalysts, Raney nickel, and nickel oxide. Conventional catalysts for nuclear hydrogenation reactions, such as nickel catalysts and cobalt catalysts, are used. The catalysts used include lower alcohols (methanol, ethanol, isopropanol, etc.), water, acetic acid, acetic acid ester, ethylene glycoL-
ethers (tetrahydrofuran, dioxane, etc.), and cycloalkanes (cyclohexane, cyclopentane, etc.). The reaction is carried out under hydrogen pressure (preferably 1 to 100 atmospheres), and the reaction temperature is room temperature to 1
0 (generation), reaction time is 1. It is preferable to set it as 2 hours to 2 days. General formula [3] used as a starting material in the present invention
The haloamide represented by the formula [5] can be produced by various methods, for example, as shown in the following reaction scheme-11.
It is easily produced by reacting the amine represented by ] with a known halocarboxylic acid represented by the general formula JO4. Reaction Scheme-11 (In the above formula, R3, R4, R5, 1, n and Just do it. Further, in the present invention, a compound whose carboxyl group is activated may be used instead of compound [14]. General formula [1]
Among the compounds of the present invention represented by the following, compounds in which R1 is a hydrogen atom and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are double bonds, are lactam lactamyl lactate as shown in the following reaction scheme-12. tautomers ([1e] and [1f] can be taken. Reaction scheme-12 (In the above formula, R2, R3, R4, R5, Mll and n are the same as above.) General formula [ Among the compounds represented by [1], those having an acidic group can easily form salts with pharmacologically acceptable basic compounds.Specifically, such basic compounds include sodium hydroxide, potassium hydroxide, Metal hydroxides such as lithium hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, metal carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium methylate, potassium ethylate, etc. Examples include inorganic basic compounds such as alkali metal alcoholates, alkali metals such as sodium and potassium, and organic basic compounds such as mol 1 holine, piperazine, piperidine, diethylamine, and aniline.In addition, compounds represented by the general formula [1] Among them, compounds having a basic group can easily form salts with ordinary pharmacologically acceptable acids.Specifically, such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid; acetic acid, p
-Toluenesulfonic acid, ethanesulfonic acid? Examples include organic acids such as honic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. The compound of the present invention thus obtained is commonly used;
It is easily isolated and purified using standard separation methods. Examples of such separation means include precipitation methods, extraction methods, recrystallization methods, column chromatography, preparative thin layer chromatography, and the like. The compounds of the present invention can be administered to animals and humans as such or together with conventional formulations and carriers. The dosage unit form is not particularly limited and can be appropriately selected and used as required. Examples of such dosage unit forms include oral preparations such as tablets, tablets, granules, oral solutions, and parenteral preparations such as injections. The amount of the active ingredient to be administered is not particularly limited and can be appropriately selected from a wide range, but in order to achieve the desired effect, it is preferably 0.06 to 10 WL9 per 1 kg of body weight per day. It is also preferred that the dosage unit form contains 1 to 500 m9 of the active ingredient. 1 In the present invention, oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing two compounds of the present invention with an inert pharmaceutical filler or diluent,
Filled into hard gelatin capsules, soft capsules, etc.
Syrups or elixirs are produced by mixing the compound of the present invention with sweeteners such as sucrose, preservatives such as methyl and propylvarapenes, colorants, seasonings, and the like. Moreover, parenteral preparations are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline. A solution having the desired clarity, stability and suitability for parenteral use is about 1
It is prepared by dissolving ~500 m9 of the active ingredient in water and an organic solvent and in polyethylene glycol with a molecular weight of 200-5000. Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol. Furthermore, the above liquid preparation contains bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, as well as isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers, etc. as necessary. Good too. To further increase stability, parenterally administered drugs may be frozen after filling and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use. Preparation of tablets Each 5 m9 of 6-(3-[N-methyl-N-(4-
10 for oral use containing acetoxycyclohexyl)aminocarbonyl]propoxy)carbostyril
Compressed tablets are prepared according to the following recipe. 6-(3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy)carbostyryl, lactose, cornstarch and crystalline cellulose were thoroughly mixed and granulated with a 5% aqueous solution of methylcellulose.
Pass through a 0 mesh sieve and carefully dry. The dried granules are passed through a 200 mesh screen, mixed with magnesium stearate and pressed into tablets. Preparation of capsules each containing 10119 6-(3-[N-methyl-N-(
100 2-piece hard gelatin capsules for oral use containing 4-acetoxycyclohexyl)aminocarbonyl]propoxy)carbostyril are prepared according to the following formulation. - The above ingredients are finely powdered, thoroughly stirred to obtain a homogeneous mixture, and then filled into gelatin capsules for oral administration having the desired dimensions. Preparation of Injection A sterile aqueous solution suitable for parenteral administration is prepared according to the following recipe. -〒〒〒While stirring the rosepens, sodium metabisulfite and sodium chloride,
It was dissolved in about half the amount of distilled water above at ℃. The resulting solution was cooled to 40°C and 6-(37[N-methyl-N-(4
-acetoxycyclohexyl)aminocarbonyl]propoxy)carbostyryl, then polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved in the solution. The solution was then adjusted to the final volume by adding distilled water for injection and sterilized by sterile filtration using a suitable filter vapor. Examples of the production of starting material compounds for producing the compounds of the present invention are listed below as reference examples. Reference example 1 5-hydroxy-3●4-dihydrocarbostyryl 24
Suspend y in 200 ml of acetic acid and 300 ml of chloroform. This suspension was brought to 40-50C and under stirring, sulfuryl chloride 3
Add 6 ml dropwise and stir at the same temperature for 1 hour. Pour the reaction solution into ice water and collect the precipitate. Recrystallization from methanol gives colorless flaky crystals of 5-hydroxy-6●8-dichloro-3●4-dihydrocarbostyryl 20y. Melting point 2
46-248C Reference Example 2 6-hydroxy-3●4-dihydrocarbostyryl 20
Suspend fI in 100 ml of acetic acid and 200 ml of chloroform. This suspension was heated to 40 to 50°C, and while stirring, sulfuryl chloride 2
8ml was added dropwise and stirred at the same temperature for 1 hour. Pour the reaction solution into ice water and collect the precipitate. Recrystallization from methanol gives white needle-like crystals of 6-hydroxy-5●7●8-trichloro3●4-dihydrocarbostyryl 3.5y.
Melting point 25rc (decomposition) Reference example 3 8-hydroxy-3,4-dihydrocarbostyryl 24
Dissolve f in 200 ml of acetic acid and 200 ml of chloroform. This solution was heated to 40-50'C and under stirring, sulfuryl chloride 3
Add 6 ml dropwise and stir at the same temperature for 1 hour. Pour the reaction solution into ice water and collect the precipitate. Recrystallization from methanol yields white powdery crystals of 8-hydroxy-5●6●7-trichloro-3,4-dihydrocarbostyryl 25f.
Melting point 267-26 (generation) (decomposition) The following compound was obtained in the same manner as in Reference Examples 1-3 above. do. To this solution were added 3.8 g of ethyl bromoacetate and 3.8 fI of potassium carbonate, and the mixture was stirred under reflux for 4 hours. The reaction solution was poured into ice water, the precipitate was collected and recrystallized from methanol to give colorless needle-like crystals of 5-ethoxycarbonylmethoxy-8-
3.8f of bromo-3,4-dihydrocarbostyryl is obtained. Melting point: 215-216°C The following compound is obtained in the same manner as in Reference Example 6 above. -3●Dissolve 3.6f of 4-dihydrocarbostyryl in 150ml of ethanol, and 50ml of water containing 5f of potassium hydroxide.
1 solution and refluxed for 5 hours. The solvent is distilled off and the residue is dissolved in water. The mixture is acidified with hydrochloric acid, and the precipitate is collected and recrystallized from aqueous ethanol to obtain 2.5 f of 5-carboxymethoxy-8-bromo-3,4-dihydrocarbostyryl in the form of colorless needles. Melting point 255-256C (decomposition) The following compound was obtained in the same manner as in Reference Example 14 above. Reference Example 17f of p-methylaminophenol, 20ml of triethylamine and 9y of 5% rhodium alumina are added to 200ml of sitz methanol, and the mixture is shaken and hydrogenated at a hydrogen pressure of 3 to 4 atmospheres and a temperature of 60 to 700 ml for an hour. After the reaction, the catalyst is removed, the mother liquor is concentrated to dryness, 500 ml of chloroform and 2007 n1 of 5% NaOH water are added to the residue to separate the layers, and the chloroform layer is washed with water and concentrated. The residue is distilled under reduced pressure. Boiling point of colorless solid: 123-129°C (22
Lol! 4-methylaminocyclohexanol 1 of THg)
Get 1y. Reference Example 23 To 50 ml of DMF were added 2-aminocyclohexanol 19y1 isopropyl iodide 20f and potassium carbonate 15fI, and the mixture was heated at 80 to 9 CfC.
Stir for an hour. After the reaction, it is concentrated, and the residue is dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate (Na2SO,). The drying agent was removed, the mother liquor was concentrated, the residue was crystallized from petroleum ether, and the resulting crystals were recrystallized from ethanol. Colorless crystals of 2-isopropylaminocyclohexanol 8f are obtained. Melting point? -55 to C Reference Example 24 26 ml of N-methylaminocyclohexylamine was added to 400 ml of ethyl acetate, and under stirring under external ice cooling, 25 ml of 4-chlorobutyl chloride and 33.5 ml of triethylamine were added.
mt was added dropwise at the same time while keeping the internal temperature at 10 to 20°C. The mixture was added dropwise in two batches, and then stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution to separate the layers, and the organic layer was mixed with water, saturated potassium carbonate aqueous solution (K2CO3 water), 10% hydrochloric acid,
Wash sequentially with water and dry with Na2sO4. The sodium sulfate was removed, and the mother liquor was concentrated and distilled under reduced pressure to obtain 41.5y of N-(4-chlorobutyryl)-N-methylcyclohexyl 1 amine as a colorless liquid. Melting point 133-136℃ (
2] MHg) Production examples of the compounds of the present invention are listed below as Examples. Example 1 5-(3-carboxy 2-methylpropoxy)-3●
Add 1.3 f of 4-dihydrocarbostyryl and 0.8 ml of triethylamine to 50 ml of DMF, and add 0.65 ml of isobutyl chloroformate at an internal temperature of 0 to 10°C while stirring under external ice cooling.
Drip 1. After dropping, the mixture was stirred at the same temperature for 3 minutes, and 0.7 f of N-ethylcyclohexylamine was added dropwise thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in 200 ml of chloroform, washed with dilute hydrochloric acid, K2CO3 water, and water in that order.
Dry at 2sO. The desiccant was removed, the mother liquor was concentrated, and the residue was recrystallized from ligroin-benzene to give colorless needle crystals of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3. - Obtain 0.8f of 4-dihydrocarbostyryl. Melting point 114-115
．． 5°C Example 2 1.3y of 6-(3-carboxy-2-methylpropoxy)carbostyryl and 0.8ml of triethylamine were added to D
r! Add 50 ml of 1F to dissolve, and gradually add 0.65 ml of isobutyl chloroformate dropwise while stirring while cooling with external ice. After the dropwise addition, stirred at room temperature three times, and added N-methyl-2-
Add 0.8 ml of methylcyclohexylamine dropwise and stir for 3 hours. After the reaction, the solvent is distilled off, and the residue is dissolved in 300 ml of chloroform, washed with dilute hydrochloric acid, dilute K2CO3 water, and water, and dried over Na2sO. The desiccant was removed, and the residue was recrystallized from benzene-ligroin to form colorless needle-like crystals of 6-
0.4y of (3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy)carbostyryl is obtained. Melting point 146-149°C Example 3 1-Methyl-6-(3-
2.6y of 4-dihydrocarbostyryl (carboxypropoxy)-3●4-dihydrocarbostyryl and 1.8ml of pyridine were added, and under external ice cooling and stirring, 1.0ml of methyl promoformate was brought to an internal temperature of 5 to 15°C.
Drip while maintaining the temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, then 1.2y of N-methylcyclohexylamine was added, and the mixture was further stirred for 3 hours. The reaction solution was poured into 200 ml of saturated saline solution, and the precipitated crystals were removed from the furnace and washed with water. The obtained crude crystals were recrystallized from ligroin to obtain colorless needle-like crystals of 1-methyl-6-[3-(N-cyclohexyl)-N-methylaminocarbonylpropoxy].
-3,4-dihydrocarbostyryl 2.1y is obtained. Melting point: 104.5 to 106.5-C Example 4 To 50 ml of dimethylformamide, 2.6 f of 6-(3-carboxy-2-methylpropoxy) carbostyril and 1.4 f of potassium carbonate were added, and under external ice-cooling stirring, chlorophyll was added. 1.1 ml of isobutyl acid is added dropwise while maintaining the internal temperature at 10 to 20°C. After dropping and stirring at 30-40C for 2 hours, N-methyl-2
- Add 1.6 mt of methylcyclohexylamine and stir for an additional 2 hours at the same temperature. The reaction solution was poured into 200 ml of saturated saline, and the precipitated crystals were collected and washed with water. The obtained crude crystals were recrystallized from benzene-ligroin to give colorless needle crystals of 6-(3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy)carbostyryl 0.9y. get. Melting point 146-14
CfC Example 5 5-(3-carboxy-2-methylpropoxy)-3●4-dihydrocarbostyryl 2 in 200 ml of ethyl acetate
．． 6y and 1.6 ml of triethylamine were added, and 1.0 ml of ethyl chloroformate was heated to 10° C. under external ice-cooling and stirring.
Add dropwise while keeping the temperature at ~20°C. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and then 1.4 V of N-ethylcyclohexylamine was added and stirred for 1 hour. Water is added to the reaction solution to separate the layers, and the organic layer is washed successively with a dilute aqueous NaOH solution, dilute hydrochloric acid, and water, and dried over Na2sO. After removing the inorganic substances and concentrating the mother liquor, the residue was recrystallized from ligroin-benzene to give colorless needle crystals of 5-[3-[N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]- 3,4-dihydrocarbostyryl 1.5
Get y. Melting point: 114-115.5°C Examples 1-5 above
The reaction was carried out in the same manner as above to obtain the compounds shown in Table 1 below. In addition, each compound in Table 1 is represented by the symbol shown in the following general formula [1-1]. Reactions were carried out in the same manner as in Examples 1 to 5 above to obtain the compounds shown in Table 2 below. In addition, each compound in Table 2 is represented by the symbol shown in the following general formula [1-2]. Example 62 6-(3-
[N-benzyl-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)-3.
4-dihydrocarbostyryl is obtained. The compound is identified by the following physicochemical properties. O properties: colorless oily O silica gel thin layer chromatography (silica gel 60F'-25 manufactured by silica gel Nimerk)
4” Developing solvent: Chloroform-methanol (■/V)=
8:1) Rf=0.650 elemental analysis value (C3OH34N
2O5) Calculated value (%) C7l. 69H6.82N
5.57 Actual value (%) C7l. 84H6.75N5.2
9O nuclear magnetic resonance spectroscopy (NMR) δCOCl3
=1.9-3.1ppm (10H..m), 3.4pp
m(2H,.t), 3.7-4.0ppm(8H,.m
), 4.4ppm (DJ2H), 6.4-6.7ppm
(6H1m), 6.9-7.3ppm (7H..m),
9.3ppm (1H1br) However, the above 6.9 to 7.3p
The pm signal overlaps with the CHCI3 proton signal. o Infrared absorption spectrum analysis (IR) ν♀early ((1-1)=3220, 3002, 2S0,
2?0, 1670, Tsuwa, 1595, 15001145
0, 1360, 124 to 1157, 1013s960s
85 to 80 to 740 Example Katsu 5-Kuroro 6-(3-
5.0y1 of carbostyril (carboxypropoxy), 2.97 ml of triethylamine were added to 100 ml of DMF', and 2.33 ml of isobutyl chloroformate was added dropwise to the mixture while keeping the internal temperature at 0 to 100 C while stirring with external ice cooling. After the addition, the mixture was stirred at room temperature for 1 hour, and 2.8 g of N-n-butylcyclohexylamine was added dropwise thereto, followed by stirring at room temperature for 3 hours. After the reaction, the solvent was distilled off and the residue was dissolved in chloroform 60
Dissolve in 0ml and wash with dilute hydrochloric acid, K2CO3 water, and water.
Dry with Na2sO. Remove the desiccant and concentrate the mother liquor. The residue was recrystallized from ethanol to give colorless needle crystals.
-chloro6-[3-(N-cyclohexyl N-n-
Butylaminocarbonyl)propoxy]carbostyryl 2.5y is obtained. Melting point: 178.5-179.5°C The reaction was carried out in the same manner as in the above Example to obtain the compounds shown in Table 3 below. In addition, each compound in Table 3 is represented by the symbol shown in the following general formula [1-3]. Example 83 6-[3-(p-nitrophenoxycarbonyl)-2-
Dissolve 3.8 f of carbostyril [methylpropoxy] in 40 ml of dimethylformamide, add 1.6 ml of N-methyl-2-methylcyclohexylamine, and add 60 to 70 g of
Stir in tank C for 1 full hour. After the reaction, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (silica gel Niwako C-20 eluent: chloroformimethanol (V/V) = 20:1
), the crude crystals were recrystallized from benzene-ligroin to give colorless needle-like crystals of 6-(3-[N-methyl-N-(2-
1.6y of methylcyclohexyl)aminocarbonyl]-2-methylpropoxy)carbostyryl is obtained. Melting point 1
46-149'C Compounds shown in Tables 4 to 6 below were obtained in the same manner as in Example 83 above. In addition, each compound in Table 4 is represented by the symbol shown in the above general formula [1-1], each compound in Table 5 is represented by the symbol shown in the above general formula [1-2], and each compound in Table 6 is shown by the symbol shown in the above general formula [1-2]. Each compound has the general formula [1
-3] respectively. Example 119 2.9f of 5-(6-carboxyhexyloxy)-3,4-dihydrocarbostyryl and N in 100ml of DMF
Add and dissolve 1.9 f of benzylcyclohexylamine, and gradually dropwise dropwise add a solution of 2.1 g of N-N''-dicyclohexylcarbodiimide dissolved in 7 rLl of N-N''-dicyclohexylcarbodiimide in 7 rLl of DMFL at room temperature while stirring. After the dropwise addition, stir at room temperature for 5 hours. After the reaction, Remove insoluble matter and concentrate the mother liquor. Dissolve the concentrated residue in chloroform and apply it to silica gel thin layer chromatography [solvent: chloroformimethanol (8:1)] to scrape off the part with an Rf value of 0.8. From the silica gel. After extraction with chloroform and distilling off the chloroform, the residue was recrystallized from benzene-ligroin to obtain colorless needle-like crystals of 5-[6-(N-cyclohexyl-N-benzylaminocarbonyl)hexyloxy].
1.1 g of -3,4-dihydrocarbostyril is obtained. Melting point: 49-57C Compounds shown in Tables 7-9 below are obtained in the same manner as in Example 119 above. In Table 7, each compound is represented by the symbol shown in the general formula [1-1], and in Table 8, each compound is represented by the symbol shown in the general formula [1-1].
-2] and each compound in Table 9 shall be represented by the symbol shown in the general formula [1-3]. Example 152 2.7 y of 6-(3-ethoxycarbonyl-2-methylpropoxy)carbostyryl, 0.5 y of sodium ethylate, and 5 ml of N-methyl-2-methylcyclohexylamine were added to 100 ml of ethanol, and the mixture was heated to 1 m atm in an autoclave. React at 140-150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform 20
After dissolving in 0 mt and washing with 1% K2CO3 aqueous solution, diluted hydrochloric acid, and water in this order, and drying with Na2sO4, the solvent was distilled off. After purification with nimethanol (V/V=20:1)**, the crude crystals were recrystallized from benzene-ligroin to obtain colorless needle-like crystals of 6-(3-[N-methyl-N-(
2-methylcyclohexyl)aminocarbonyl]-2-
1.0y of carbostyril (methylpropoxy) is obtained. Melting point: 146-149°C The reaction was carried out in the same manner as in Example 152 to obtain the following compounds No. 10-1. Each compound in the first cough is represented by the symbol shown in the general formula [1-1], each compound in Table 11 is represented by the symbol shown in the general formula [1-2], and each compound in the first method is represented by the symbol shown in the general formula [1-1]. is the general formula [1-
They shall be indicated by the symbols shown in 3). Example 182 5-(3-carboxy2-methylpropoxy)-3.
4-dihydrocarbostyryl 2.6y to methylene chloride 2
After adding 2 ml of pyridine, 1.4 y of thionyl chloride was added dropwise with stirring while maintaining the internal temperature at 0 to 20°C. After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and then 2 ml of N-ethylcyclohexylamine was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. The reaction solution was thoroughly washed with an aqueous K2CO3 solution, washed with water and diluted hydrochloric acid, and dried over Na2sO4, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (silica gel Niwako C-2001 eluent: chloroformimethanol (V/V) = 20:1
) and then recrystallized from ligroin-benzene to give colorless needle crystals of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3●4-dihydro 0.69 of carbostyril is obtained. Melting point: 114-115.5°C Compounds No. 13 to 1 below are obtained in the same manner as in Example 182 above. In Table B, each compound is represented by the symbol shown in the general formula [1-1], and in Table 14, each compound is represented by the symbol shown in the general formula [1-1].
1-2], and each compound in the first bale is represented by the symbol shown in the general formula [1-3]. Example 211 1.75 g of 1-methyl-6-hydroxycarbostyryl and ml of K2CO in 50 ml of DMF. 8fI. ．． KIO
．． Add 5f of N-methyl-N at 60-70°C with stirring.
-(4-chlorobutyryl)cyclohexylamine 2.8
Gradually drip fI. After the dropwise addition, the mixture was stirred at the same temperature for 4 hours and the solvent was distilled off. Dissolve the residue in 200 ml of chloroform and add dilute hydrochloric acid and 1% NaO.
Wash with H water, water and dry with Na2sO4. After removing the drying agent, the mother liquor is concentrated and the residue is crystallized from petroleum ether. The obtained crystals are recrystallized from benzene-ligroin to obtain colorless needle-like crystals of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]carbostyryl 0.6y. Melting point 118.5-119
．． 5yC Example 212 In 50ml of dimethyl sulfoxide, 3.4y1 of 1-methyl-6-hydroxy-3,4-dihydrocarbostyryl
0.9f of potassium hydroxide, 3.2g of sodium iodide and 5.0y of N-methyl-N-(4-chlorobutyryl)cyclohexylamiso are added and stirred at 70-80°C for 4.5 hours. After the reaction is completed, the reaction solution is poured into 400 TrLt of saturated saline, and the precipitated crystals are taken out and washed with water. The obtained crude crystals were recrystallized from ligroin to give colorless needle-like crystals of 1-methyl-6-[3-
(N-cyclohexyl-N-methylaminocarbonyl)
Propoxy]-3,4-dihydrocarbostyryl 3.1
′ is obtained. Melting point: 104.5-106.5°C Example 213 To 30 ml of dioxane, 1.6 fI of 5-hydroxy-3●4-dihydrocarbostyryl 1 0.8 V of pyridine 1 iodide power i month. 8f and N-ethyl-N-(4-chloro-3-methylbutyryl)-cyclohexylamine 3.1f
and reflux for 1 hour while stirring. After the reaction is completed, the reaction solution is poured into 200 ml of saturated saline solution, and the precipitated crystals are collected. The crude crystals were dissolved in 50 ml of chloroform, and the organic layer was washed with 1N NaOH (50 ml x 2), water, and then with Na2SO, the solvent was distilled off, and the resulting residue was recrystallized from ligroin-benzene. 0.9y of colorless needle-like crystals of 5-[3-(N-ethyl-N-cyclohexylaminocarbonyl)-2-methylpropoxy 3●4-dihydrocarbostyryl are obtained. Melting point 114-1
15.5°C Example 214 After adding 0.5' of sodium metal under ice cooling to 50 TnL of methanol and dissolving it, 3.4 fI of 1-methyl-6-hydroxy-3●4-dihydrocarbostyryl was added, and 3.4 fI of sodium iodide was added. 4. Add 5.0' of 2y and N-methyl-N-(4-chlorobutyryl)cyclohexylamine and stir. Reflux for an hour. After the reaction is completed, the reaction solution is poured into 400 ml of saturated brine, and the precipitated crystals are washed with water. The obtained crude crystals were recrystallized from ligroin to give colorless needle-like crystals of 1-methyl-6-[3-(N-
Cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl 2.9V is obtained. Melting point 104.5-106.5°C Example 215 6-hydroxycarbostyryl 1 in 30 ml ethanol
．． 6y1 sodium ethylate 0.7f1 sodium iodide 1.6f and N-ethyl-N-(4-chloro3-
Methylbutyryl)-2-methylcyclohexylamine 3
．． 3y was added and the mixture was refluxed for 5 hours while stirring. After the reaction is completed, the reaction solution is poured into 200 ml of saturated saline, and the precipitated crystals are taken out and washed with water. The obtained crude crystals were recrystallized from benzene-ligroin to give 6-(3-[N-methyl-N-(
2-Methylcyclohexyl)aminocarbonyl]-2
-Methylpropoxy) carbostyril 1.4f is obtained. Melting point 146-149'C Example 216 6-hydroxycarbostyryl 1.6 in DMF3Omt
V. ．． K2C0d. Add 1.6f of 4f1 sodium iodide and 3.3y of N-ethyl-N-(4-chloro-3-methylbutyryl)-2-methylcyclohexylamine, and stir at 70-80°C for 4 hours. After the reaction is completed, the reaction solution is poured into 200 ml of saturated saline, and the precipitated crystals are taken out and washed with water. The obtained crude crystals were recrystallized from benzene-ligroin to give 6-(3-[N-methyl-N-
(2-methylcyclohexyl)aminocarbonyl]-2
-Methylpropoxy) carbostyril 1.4y is obtained.
Melting point 146-14CfC Same as Examples 211-216 above, No. 16-1 below.
The compounds shown in Table 8 are obtained. In the first bale, each compound is represented by the symbol shown in the general formula [1-1], and in the first bale, each compound is represented by the symbol shown in the general formula [1-1].
-2] and each compound in the first bale is represented by the symbol shown in the general formula [1-3]. Example 286 6- was prepared in the same manner as in Example 216 using appropriate starting materials.
(3-[N-benzyl-N-(2-3″・4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)
-3●4-dihydrocarbostyril is obtained. The compound is identified by the following physicochemical properties. O properties: colorless oily O silica gel thin layer chromatography (silica gel 60F'-25 manufactured by silica gel Nimerk)
4” Developing solvent: Chloroform-methanol (■/V)=
8:1) Rf=0.650 elemental analysis value (C3OH3,N
2O,) Calculated value (%) C7l. 69H6.82N
5.57 Actual value (%) C7l. 84H6.75N5.2
9O nuclear magnetic resonance spectroscopy (NMR) δCOCl3
=1.9-3.1ppm (10H..m), 3.4pp
m(2H,.t), 3.7-4.0ppm(8H,.m
), 4.4ppm (D, s2H), 6.4-6.7pp
m (6H1m) ~ 6.9″7.3ppm (7H.sm)
, 9.3 ppm (1H..br.) However, the above 6.9 to 7
．． The 3 ppm signal overlaps with the CHCl3 proton signal. O infrared absorption spectroscopy (IR),.
* ν♀=(Cm-1)=3220, 3002, 294
0, 2840, 1670, 1638, 1595, 150
011450, 1360, 124 to 1157, 1013
850 to s96, 740 to 80 Example 2876-(3-
3.3y of [N-methyl-N-(2-methylcyclohexylaminocarbonyl]-2-methylpropoxy)-3,4-dihydrocarbostyryl and 3.4y of 90% DDQ were added to 100ml of dioxane, and the mixture was stirred for 9.5 hours. Reflux and then cool. After the reaction was completed, the solvent was distilled off, the resulting residue was dissolved in chloroform, the organic layer was washed with a saturated solution of NaHCO, then with water, dried over Na2sO4, and treated with activated carbon.
The solvent was distilled off, the residue was isolated and purified by silica gel column chromatography (silica gel Niwakou C-200s eluent: chloroformimethanol (V/V) = 10:1), and then the crude crystals were purified from benzene-ligroin. Crystallization gives colorless needle-like crystals of 6-(3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy)carbostyryl 1.2y. melting point 14
6 to 149 Le C The following No. 1
The compounds in Table 9 are obtained. In the first cough, each compound is represented by the symbol shown in the general formula [1-2]. In addition, the above Example 28
The following compounds are obtained in the same manner as in 7. Example 307 1-Methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl 2
．． 8y was added to 50 mt of methanol, 0.1f of palladium black was added thereto, and the mixture was reacted at 50° C. for 8 hours under a hydrogen pressure of 2.5 atm. After the reaction, the catalyst is separated and the solution is concentrated to dryness. The residue is recrystallized from ligroin to obtain colorless needle-like crystals of 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl 1.9y. Melting point 104.5-106.5℃
1 Example 3085-[3-(
N-cyclohexyl-N-ethylaminocarbonyl)-
2-methylpropoxy]carbostyryl 2.4' to 20
% ethanol aqueous solution, and add 10
% palladium on carbon is added, and the mixture is reacted for 15 hours at room temperature under a hydrogen pressure of 2 atm. After the reaction is completed, the catalyst is separated and the liquid is concentrated to dryness under reduced pressure. The resulting residue was recrystallized from ligroin-benzene to give colorless needle-like crystals of 5-[3-(N-''cyclohexyl-N-
ethylaminocarbonyl)-2-methylpropoxy]-
1.5y of 3,4-dihydrocarbostyryl is obtained. Melting point: 114-115.5°C The following second cough compound is obtained in the same manner as in Examples 307-308 above. In addition, each compound in the second cough is represented by the symbol shown in the above general formula [1-1]. In addition, the above Example 30
The following compound is obtained in the same manner as 7 and 308. 6-[3-[N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl was added to 1.7f8DMF50ml and dissolved, and 0.3y of sodium hydride was added under stirring at room temperature. After hydrogen generation is complete, 1 ml of methyl iodide is added dropwise, and the mixture is stirred at room temperature for 3 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is dissolved in 200 ml of chloroform. K the chloroform layer
Wash with 2CO3 water, water, and dry with Na2sO4. The desiccant was removed, the mother liquor was concentrated, and the residue was recrystallized from ligroin to give colorless needle-like crystals of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-.
0.9 g of 3,4-dihydrocarbostyryl is obtained. Melting point: 104.5-106.5°C Example 325 3.4f of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl was dissolved in 100ml of dimethylformamide, and 0.3f of potassium hydride was added. and stir at room temperature until hydrogen evolution has stopped. Next, 10 ml of a dimethylformamide solution to which 1.9 y of methyl bromide had been added was added dropwise with stirring, and the mixture was further stirred at 50° C. for 1 hour. The reaction solution was concentrated under reduced pressure to about 30 ml, the solution was poured into saturated brine, and the precipitated crystals were recrystallized from benzene-ligroin to give colorless needle-like crystals of 1-methyl-6-
[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl 2.1y is obtained. Melting point 118.5-119.5C Treated in Example 32 above 32
The following compound is obtained in the same manner as in 5. The following compound is obtained in the same manner as in Example 1 above. The following compound is obtained in the same manner as in Example 216 above. The following compound is obtained in the same manner as in Example 1 above. Examples 336 to 338 The following compounds were obtained in the same manner as in Example 1 above. 06-[3-(N-butyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyril melting point 1
54-156℃ ○6-(3-[N-cyclohexyl N-(2-3″・
4″-dimethoxyphenylethyl)aminocarbonyl]
Propoxy)-3,4-dihydrocarbostyryl melting point 8
0 to 83° C. 7-chloro6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril melting point 191.5 to 193° C. The results of pharmacological tests on the compounds of the present invention are listed below. Pharmacological Test 1> Platelet aggregation inhibitory effect was evaluated using an AG-■ type aggregometer (AregOmeter) [Bryst OnMa Manufacturing Co., Ltd.
nufacturingCO. (manufactured by )]. The blood sample collected from the rabbit was a mixture of sodium citrate and whole blood at a mixing ratio of 1:9 (volume ratio). The sample was centrifuged at 1000 rpm to obtain serum with a high platelet concentration [Plateletrichplasma].
(PRP)]. The obtained PRP was separated, and the remaining blood sample was further centrifuged at 3000r″Pm to obtain serum with a low platelet concentration [PlateIetpOOrp
lasma (PPP)]. The number of platelets contained in the PRP was determined using the Bretcher Cronkite method (B
30,000 for diluting PRP with PPP and subjecting it to an adenosine diphosphate (ADP)-induced agglutination test.
450,000 to prepare PRP samples containing platelets of 0/TlUft and to subject them to collagen-induced aggregation tests.
/TnlL platelet-containing PRP samples are prepared. 0.01 solution containing the compound to be tested at a predetermined concentration
Add 0.6ml of the PRP sample prepared above to m1,
The mixture is placed in a constant temperature bath at a temperature of 37° C. for 1 minute. Next, add 0.07 g of ADP or collagen solution to the mixture.
Add m1. The permeability of this mixture is measured and the change in permeability is measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. To prepare the solution of ADP or collagen in this test, Oren-Veronal buffer (
pH7.35) is used. The above ADP solution has a concentration of 7.
The collagen solution is prepared to 5×10 −5 M by adding 5 ml of the above buffer to 100 m 9 of collagen and grinding it, and the supernatant is used as a collagen inducer.
Adenosine is used as a control substance in the ADP-induced agglutination test, and acetylsalicylic acid is used as a control substance in the collagen-induced agglutination test. Platelet aggregation inhibitory effect has inhibition rate (%) with respect to control aggregation rate.
Measure as. The aggregation rate is calculated according to the formula below. Table 21 shows the inhibitory effect on rabbit platelet aggregation induced by collagen. The inhibitory effect on rabbit platelet aggregation is shown in the second method. The test compounds are as follows. Test compound A6-(3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy)carbostyryl B6-(3-[N-methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl C6-(3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy)carbostyryl D6-(3-[N-methyl-N-(
2-3″●4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl E6-[3-(
N-cyclohexyl-N-benzylaminocarbonyl)
propoxy) carbostyril F5-chlororu6-[3-
(N-methyl-N-cyclohexylaminocarbonyl)
propoxy]carbostyryl G6-(3-[N-benzyl-N-(2-chlorocyclohexyl)aminocarbonyl]propoxy)-3,4-dihydrocarbostyryl H
6-[2-hydroxy-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl 16-[3-(N-methyl-N-cyclohexylaminocarbonyl)-2-methylpropoxy]carbostyryl 8-hydroxy-5- [3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-
Dihydrocarbostyryl K6-(3-[N-benzyl-N-(2-3″·4″-dimethoxyphenylethyl)aminocarbonyl]propoxy)-3,4-dihydrocarbostyryl L6·8-dichloro-5-[3-( N-ethylanilinocarbonyl)propoxy]-3●4-dihydrocarbostyryl M6-[3-(N-oc, thiruN-
cyclohexylaminocarbonyl)propoxy]carbostyryl N6-[3-(N-ethyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl 01-aryl6-[6-(N-cyclohexylaminocarbonyl)hexyloxy]-3●4 -dihydrocarbostyryl P6-(3-[N-cyclohexyl N-
(2-phenylethyl)aminocarbonyl]propoxy)carbostyryl Q11-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl R6-(3-[
N-cyclohexyl-N-(2-3''-4''-dimethoxyphenylethyl)aminocarbonyl]propoxy)carbostyryl S6-(3-[N-(2-chlorocyclohexyl)-N-cyclohexylmethylaminocarbonyl]propoxy) -3,4-dihydrocarbostyryl T8
-benzyloxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)puropoxy]-3●4
-dihydrocarbostyryl U6-[3-(N-butyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl V6-(3-[N-cyclohexyl-N-(2-3"●4"-dimethoxyphenylethyl)
aminocarbonyl]propoxy)-3●4-dihydrocarbostyrylW6-(3-[N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy)carbostyryl(6-(3-[N-ethyl-N-(1-methyl- 2-cyclopentylethyl)aminocarbonyl]propoxy)carbostyryl 6-[1-(N-methyl-N-cyclohexylaminocarbonyl)ethoxy]carbostyrinole 1.7-gulol 6-[3-(N-methyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl 1-methyl-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl 16-(3-[N-methyl-N-(2-3″・4
"-dimethoxyphenylethyl)aminocarbonyl]propoxy)-3,4-dihydrocarbostyryl ■5-carbamoylmethoxy3●4-dihydrocarbostyryl (compound of Example 1 of JP-A-51-23271)
5-(N-isopropylcarbamoyl)methoxy3.
4-dihydrocarbostyryl (JP-A-51-23271
5-(1-morpholinocarbonyl)methoxy-3,4-dihydrocarbostyryl (compound of Example 4 of JP-A-51-23271)
7-Carbamoylmethoxy3●4-dihydrocarbostyryl (compound of Example 7 of JP-A-51-23271) N-ethyl-5-(3-benzylcarbamoyl)
Propoxy 3,4-dihydrocarbostyryl (compound of Example 1 of JP-A-51-136676), 8-
(4-Carbamoyl)butoxycarbostyryl (compound of Example 2 of JP-A-51-136676) From Table 21 and Table n above, all of the compounds of the present invention are
It is clear that it exhibits an excellent platelet aggregation inhibiting effect (inhibition rate) in the Gen-induced aggregation test and the ADP-induced aggregation test. In general, the compounds of the present invention have the superior feature of the above-mentioned platelet aggregation inhibiting action in that the action time is longer and the action strength is stronger than that of conventionally known substances that act to inhibit platelet aggregation. <Pharmacological test 2> Test compound A suspended in water (30M9lk9) was orally administered to male Wistar rats and male vehicle dogs that had been fasted overnight, and blood was collected after a certain period of time to obtain plasma. 2 to 3 ml of 0.1N NaOH to 1 ml of obtained plasma
and CHCl32WLt, shaken and extracted using a shaker for 2 hours, and after centrifugation, the organic layer was diluted with 0.1N HCl2W.
Lt was washed. After freezing and thawing the organic layer and removing chloroform under a stream of nitrogen, the residue was redissolved in 100 μe of chloroform and dissolved in Silica Gel 60F'25 manufactured by Merck & Co.
4” was spotted on the thin layer plate. This was expanded with a 5:1 mixed solvent of chloroform, nibbutanol, and the same Rf as the test compound.
Quantitative measurement was performed by measuring spots with a certain value using a Shimadzu CS-9W thin-layer chromatography scanner using the absorbance method, and the blood concentrations of test compound A1, compound J, and compound K (μYlm
l) was calculated. The results are shown in Section 2 below. Compound B
A similar test was conducted for the above, and almost the same results as in the second case were obtained. <Pharmacological test 3> The inhibitory effect of the compound of the present invention on cyclic adenosine monophosphate phosphodiesterase (C-AMP-PDE) was evaluated using BiOchimicaetBiOphisic.
a-, Acta Vol. 429, pp. 485-497 (197
6) and BiOchemical Medicine, Vol. 10, pp. 301-311 (1974jV.). That is, first, to the precipitated platelets obtained by centrifuging rabbit PRP at 3000 rpm, 10 mt of a solution prepared by adding 1 mmol of MgCl2 to 50 mmol Tris-HCl buffer (pH 7.4) was added. The platelets were suspended and ground using a Teflon potter type homogenizer, then freeze-dried twice, and after being disrupted using 200 watts of ultrasound for 30 minutes, the platelets were ultracentrifuged at 100,000 G for 6 minutes. , and use the supernatant as the crude enzyme solution. 50 mmol in advance
1.5 buffered with Tris acetate buffer (PH6.O)
Pass 10 ml of the crude enzyme solution prepared above through a cellulose column for 2 hours, elute with 30 ml of 50 mmol-Tris acetate buffer, and add 0 to 1 mol of sodium acetate-Tris acetate buffer to this buffer. Elute using a linear gradient of 300 mL of eluate (total volume of eluate: approximately 300 ml). The flow rate was 0.5) ml/min, and each fraction was 5 ml/min.
Take it out one by one. By the above operation, 100 pmol of high C
- has weak activity of less than 0.4 mol/ml/min at M2 substrate concentration and as low as 0.4 μmol C-, 10 at AMP substrate concentration.
Collect fractions with strong activity of 0 Pmol/ml/min or more. This is referred to as C-AMP-PDE. 0.1ml of aqueous solution of test compound at each concentration and 0.4μ
PH containing moles of C-AMP (tritium C-AMP)
40 mmol Tris-HCl buffer (contains 50 μy bovine serum albumin and 47 TL, mil MgCl2)
A total of 0.2 ml of the mixed solution with 0.2 ml of the substrate solution was added with 0.2 ml of the C-AMP-PDE solution with a constant concentration prepared above.
was added and the two powders were reacted at 30℃ to form tritium C-AM.
Tritium 5-AMP is produced from P. Next, to stop the reaction, the reaction solution was immersed in boiling water for 2 minutes, cooled in ice water, and added as 5''-nucleotidase with no snake venom.
Add 0.05 ml of 91 ml) and conduct a one-powder reaction at 30°C to convert tritium 5''-AMP to tritium adenosine.The entire amount of the resulting reaction solution was added to the cation exchange resin [
A.G. 5OW×4, 200-400 mesh (BiO-
Rml Co., Ltd. product), column size 0.5 x 1.5 cm] to bind only the tritiated adenosine produced,
After washing with 6ml of distilled water, add 1.5mt of ammonia water.
Elute with PDE activity is measured by adding 10 ml of a triton-toluene type scintillator to the entire volume of the eluate and measuring the tritium adenosine produced using a liquid scintillation counter. PDE activity value (■s) and control value (Vc) of each test compound measured according to the above method (water containing no test compound)
From this, the PDE inhibition rate (%) is calculated using the following formula. PDE inhibition rate (%) = ■ mowing 00 The obtained inhibition rates are shown in Table 24. Table 24 also lists the results of similar tests using 1-methyl-3-isobutylxanthine (Control 1), papaverine (Control 2), theophylline (Control 3), and dipyridamole (Control 4) as control compounds. do. <Acute toxicity test> Test compounds A and B were administered subcutaneously or intraperitoneally to mice,
LD,O (M9Ikg) was measured.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
an alkenyl group or a phenylalkyl group having 2 to 4 carbon atoms; R^2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a phenylalkoxy group; R^3 is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 4 carbon atoms; R^4 represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a cycloalkylalkyl group, or a 2-(3,4-dimethoxyphenyl)ethyl group. The cycloalkyl group and phenyl group include a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkanoylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkylcarbamoyl group, a lower alkylamino group, One or two of the same or different substituents selected from the group consisting of a nitro group, a carboxy group, a hydroxyl group, an aminosulfonyl group, a carbamoyl group, and an amino group may be substituted. R^5 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl group, or a cycloalkylalkyl group. m represents an integer of 1 to 3. l and n are the same or different and represent 0 or an integer from 1 to 7, but l and n
The total shall not exceed 7. However, R^4 is a cycloalkyl group having 3 to 8 carbon atoms without a substituent, a phenyl group having no substituent, or an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms as a substituent. , represents a phenyl group having one or two halogen atoms, hydrogen groups, or alkanoylamino groups having 2 to 4 carbon atoms, and R^5 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a phenyl group having 3 to 8 carbon atoms.
represents a cycloalkyl group and 0≦l+n≦5, at least one of R^1, R^2 and R^3 shall not represent a hydrogen atom, and R^4 is a cycloalkyl group. Indicates an alkyl group, and when 0≦l+n≦3 and the aminocarbonyl alkoxy group is bonded to the 6-position of the carbostyril skeleton, R^1, R^2, R^3 and R
At least one of ^5 shall not represent a hydrogen atom. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] or a salt thereof. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
R^2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a phenylalkoxy group, and m represents an integer of 1 to 3. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. ] Hydroxycarbostyryl derivatives represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^3 represents a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 4 carbon atoms. R^4 represents a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group, a cycloalkylalkyl group, or a 2-(3,4-dimethoxyphenyl)ethyl group. The cycloalkyl group and phenyl group include a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkanoylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkylcarbamoyl group, a lower alkylamino group, One or two of the same or different substituents selected from the group consisting of a nitro group, a carboxy group, a hydroxyl group, an aminosulfonyl group, a carbamoyl group, and an amino group may be substituted. R^5 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl group, or a cycloalkylalkyl group. 1 and n are the same or different and represent 0 or an integer from 1 to 7,
The sum of 1 and n cannot exceed 7. X represents a halogen atom. ] is reacted with a haloamide derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5, m,
The carbon-carbon bonds between l, n and the 3rd and 4th positions of the carbostyril skeleton are the same as above. However, R^4 is a cycloalkyl group having 3 to 8 carbon atoms without a substituent, a phenyl group having no substituent, or an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms as a substituent. , represents a phenyl group having one or two halogen atoms, hydroxyl groups, or alkanoylamino groups having 2 to 4 carbon atoms, and R^5 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclo group having 3 to 8 carbon atoms. Indicates an alkyl group and 0≦
When l+n≦5, at least one of R^1, R^2 and R^3 does not represent a hydrogen atom, and R^4 represents a cycloalkylalkyl group, and 0≦l+n
≦3 and when the aminocarbonyl alkoxy group is bonded to the 6-position of the carbostyril skeleton, R^1, R
At least one of ^2, R^3 and R^5 shall not represent a hydrogen atom. A method for producing a carbostyril derivative, which comprises obtaining a carbostyril derivative represented by the formula: 3 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
An alkenyl group or a phenylalkyl group having 2 to 4 carbon atoms, R^2 is a hydrogen atom, a halogen atom, a hydroxyl group, or a phenylalkoxy group, and R^3 is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 4 carbon atoms, respectively. show. m represents an integer of 1 to 3. l and n are the same or different and represent 0 or an integer from 1 to 7, but the sum of l and n does not exceed 7. Also, the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond. ] Carboxyalkoxycarbostyryl derivatives represented by or compounds with activated carboxyl groups and general formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^4 is carbon number 3
-8 cycloalkyl group, phenyl group, cycloalkylalkyl group or 2-(3,4-dimethoxyphenyl)ethyl group. The cycloalkyl group and phenyl group include a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkanoylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkylcarbamoyl group, a lower alkylamino group, One or two of the same or different substituents selected from the group consisting of a nitro group, a carboxy group, a hydroxyl group, an aminosulfonyl group, a carbamoyl group, and an amino group may be substituted. R^5 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a phenylalkyl group, or a cycloalkylalkyl group. ] is reacted with an amine represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5, m,
The carbon-carbon bonds between l, n and the 3rd and 4th positions of the carbostyril skeleton are the same as above. However, R^4 is a cycloalkyl group having 3 to 8 carbon atoms without a substituent, a phenyl group having no substituent, or an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms as a substituent. , represents a phenyl group having one or two halogen atoms, hydroxyl groups, or alkanoylamino groups having 2 to 4 carbon atoms, and R^5 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclo group having 3 to 8 carbon atoms. Indicates an alkyl group and 0≦
When l+n≦5, at least one of R^1, R^2 and R^3 does not represent a hydrogen atom, and R^4 represents a cycloalkylalkyl group, and 0≦l+n
≦3 and when the aminocarbonyl alkoxy group is bonded to the 6-position of the carbostyril skeleton, R^1, R
At least one of ^2, R^3 and R^5 shall not represent a hydrogen atom. ] A method for producing a carbostyril derivative, which comprises obtaining a carbostyril derivative represented by the formula: