JPH0559005A - Gardiotonic agent - Google Patents

Abstract

PURPOSE:To obtain a cardiotonic, a hypotensive and an antiphlogistic agents containing a carbostyril derivative or its salt as an active ingredient and useful for treating various cardiopathies. CONSTITUTION:A cardiotonic agent is obtained by including a compound expressed by formula I [R<1> is H or CN; R is NR<2>R<3>(R<2> and R<3> are H, alkyl, cycloalkyl, alkenyl, phenyl, phenylalkyl, phenylsulfonylalkyl, phenoxyalkyl, pyridylalkyl, anilinothiocarbonyl, benzoyl, pyridyl, etc.)] or its salt, e.g. 6-[3-(N- methyl-N-benzylamino)-2-hydroxypropoxy] carbostyril as an active ingredient. The compound expressed by formula I has action on enhancement of myocardial contraction (positive inotropic action), coronary blood flow increasing, hypotensive actions, vasoconstricting action by norepinephrine and antiphlogistic action with hardly any increasing action on heart rate. The compound is obtained by reacting a compound expressed by formula II (X is halogen, alkanesulfonyloxy, etc.) with a compound expressed by the formula RH.

Description

Detailed Description of the Invention

[0001]

This invention relates to cardiotonic agents.

[0002]

DISCLOSURE OF THE INVENTION The cardiotonic agent of the present invention contains a carbostyril derivative represented by the following general formula (1) or a salt thereof as an active ingredient.

[0003]

[Chemical 4]

[In the formula, R ¹ represents a hydrogen atom or a cyano group. R is a group -NR ² R ³ (R ² and R ³ are the same or different and each is a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a lower alkenyl group, a phenyl group, a phenyl ring. 1 to 3 substituents selected from the group consisting of lower alkoxy lower alkoxy groups, halogen atoms, lower alkoxy groups, nitro groups, lower alkyl groups, cyano groups, lower alkylthio groups and lower alkylsulfinyl groups And a phenyl lower alkyl group that may have a hydroxyl group as a substituent in the alkyl moiety, a phenylsulfonyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring, a phenylthio lower alkyl group, and a phenyl ring 1 is a group selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent. To a phenylsulfinyl lower alkyl group which may have 3 to 3, a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring, and a pyridine ring May have 1 to 3 groups selected from the group consisting of halogen atom and lower alkoxy group as a substituent, pyridyl lower alkyl group, cenyl lower alkyl group, benzoyl lower alkyl group, anilinothiocarbonyl group, benzoyl group, pyridyl Group, a phenyl lower alkenyl group or a group R ⁴ R ⁵ N-A- (wherein R ⁴ and R ⁵ are the same or different and are a lower alkyl group or a group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring). A phenyl group which may have 1 to 3 groups selected from Is a lower alkylene group which may be bonded via a group). The carbostyril derivative represented by the general formula (1) and a salt thereof have an effect of enhancing contraction of myocardium (positive inotropic effect), an effect of increasing coronary blood flow, an antihypertensive effect, and an effect of suppressing vasoconstriction by norepinephrine. And an anti-inflammatory agent, for example, a cardiotonic agent for the treatment of various heart diseases such as congestive heart failure, mitral valve disease, atrial fibrillation, flutter, paroxysmal atrial tachycardia,
It is useful as an antihypertensive agent and an anti-inflammatory agent. In particular, the compound of the present invention has excellent positive inotropic effect, coronary blood flow increasing effect and blood pressure lowering effect, but has a characteristic of having almost no heart rate increasing effect. Further, the above compound has low toxicity,
Central side effects such as vomiting, decreased motor function, convulsions,
It also has the characteristic that there is little vibration. Further, the compound of the present invention is characterized by excellent absorbability and long duration.

In the present specification, R, R ¹ , R ² ,
More specifically, each group represented by R ³ , R ⁴ , R ⁵ and A is as follows.

As the lower alkyl group which may have a hydroxyl group as a substituent, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,
Hexyl, hydroxymethyl, 2-hydroxyethyl,
1-hydroxyethyl, 3-hydroxypropyl, 4-
Hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl group and the like, which has a hydroxyl group as a substituent and has 1 to 6 carbon atoms Mention may be made of straight-chain or branched-chain alkyl groups.

Examples of the lower alkenyl group include straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups. A group can be mentioned.

The halogen atom is, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

As the lower alkoxy group, for example, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. Can be mentioned.

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

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

Examples of the lower alkylsulfinyl group include straight-chain or branched-chain alkylsulfinyl groups having 1 to 6 carbon atoms such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl and hexylsulfinyl groups. Can be mentioned.

Examples of the lower alkylenedioxy group include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy and tetramethylenedioxy groups. it can.

A group selected from the group consisting of a lower alkoxy lower alkoxy group, a halogen atom, a lower alkoxy group, a nitro group, a lower alkyl group, a cyano group, a lower alkylthio group and a lower alkylsulfinyl group as a substituent on the phenyl ring. As the phenyl lower alkyl group which may have 3 to 3 and which may have a hydroxyl group as a substituent in the alkyl moiety, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl,
4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl, 2- (3- Methoxyphenyl) ethyl, 1- (4-methoxyphenyl) ethyl, 2-methoxybenzyl, 3- (2-ethoxyphenyl) propyl, 4- (3-ethoxyphenyl) butyl,
1,1-dimethyl-2- (4-ethoxyphenyl) ethyl, 5- (4-isopropoxyphenyl) pentyl, 6
-(4-hexyloxyphenyl) hexyl, 3,4-
Dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,5-dimethoxybenzyl, 2- (3-methylphenyl) ethyl, 1- (4-methylphenyl) ethyl,
2-methylbenzyl, 3- (2-ethylphenyl) propyl, 4- (3-ethylphenyl) butyl, 1,1-dimethyl-2- (4-ethylphenyl) ethyl, 5- (4
-Isopropylphenyl) pentyl, 6- (4-hexylphenyl) hexyl, 3,4-dimethylbenzyl,
3,4,5-Trimethylbenzyl, 2,5-dimethylbenzyl, 2- (3-methylthiophenyl) ethyl, 1-
(4-methylthiophenyl) ethyl, 2-methylthiobenzyl, 3- (2-ethylthiophenyl) propyl, 4
-(3-Ethylthiophenyl) butyl, 1,1-dimethyl-2- (4-ethylthiophenyl) ethyl, 5- (4
-Isopropylthiophenyl) pentyl, 6- (4-hexylthiophenyl) hexyl, 3,4-dimethylthiobenzyl, 3,4,5-trimethylthiobenzyl, 2,
5-dimethylthiobenzyl, 2- (3-methylsulfinylphenyl) ethyl, 1- (4-methylsulfinylphenyl) ethyl, 2-methylsulfinylbenzyl,
3- (2-ethylsulfinylphenyl) propyl, 4
-(3-Ethylsulfinylphenyl) butyl, 1,1
-Dimethyl-2- (4-ethylsulfinylphenyl)
Ethyl, 5- (4-isopropylsulfinylphenyl) pentyl, 6- (4-hexylsulfinylphenyl) hexyl, 3,4-dimethylsulfinylbenzyl, 3,4,5-trimethylsulfinylbenzyl,
2,5-dimethylsulfinylbenzyl, 4-cyanobenzyl, 2- (3-cyanophenyl) ethyl, 1- (2
-Cyanophenyl) ethyl, 3- (2-cyanophenyl) propyl, 4- (3-cyanophenyl) butyl,
1,1-dimethyl-2- (4-cyanophenyl) ethyl, 5- (4-cyanophenyl) pentyl, 6- (4-
(Cyanophenyl) hexyl, 3,4-dicyanobenzyl, 3,4,5-tricyanobenzyl, 2,5-dicyanobenzyl, 2-chlorobenzyl, 2- (3-bromophenyl) ethyl, 1- (4-chlorophenyl )ethyl,
3- (4-fluorophenyl) propyl, 4- (2,3
-Dichlorophenyl) butyl, 1,1-dimethyl-2-
(2,4-dibromophenyl) ethyl, 5- (3,4-
Difluorophenyl) pentyl, 6- (2,4,6-trichlorophenyl) hexyl, 2-methyl-3- (2-
Fluorophenyl) propyl, 2- (3-methoxymethoxyphenyl) ethyl, 1- (4-methoxymethoxyphenyl) ethyl, 2-methoxymethoxybenzyl, 3-
[2- (2-methoxyethoxy) phenyl] propyl,
4- [3- (3-propoxypropoxy) phenyl] butyl, 1,1-dimethyl-2- [4- (4-butoxybutoxy) phenyl] ethyl, 5- [4- (5-pentyloxypentyloxy) phenyl ] Pentyl, 6- [4
-(6-hexyloxyhexyloxy) phenyl] hexyl, 3,4-dimethoxymethoxybenzyl, 3,
4,5-trimethoxymethoxybenzyl, 2,5-dimethoxymethoxybenzyl, 2-nitrobenzyl, 2-
(3-nitrophenyl) ethyl, 1- (4-nitrophenyl) ethyl, 3- (2-nitrophenyl) propyl,
4- (3-nitrophenyl) butyl, 1,1-dimethyl-2- (4-nitrophenyl) ethyl, 5- (5-nitrophenyl) pentyl, 6- (6-nitrophenyl) hexyl, 3,4- Dinitrobenzyl, 2,5-dinitrobenzyl, 2,4,6-trinitrobenzyl, 2-fluoro-3-methylbenzyl, 2-chloro-4-methoxybenzyl, 1-phenyl-1-hydroxymethyl, 2-
Hydroxy-2-phenylethyl, 3-hydroxy-3
-Phenylpropyl, 4-hydroxy-4-phenylbutyl, 1,1-dimethyl-2-hydroxy-2-phenylethyl, 5-hydroxy-5-phenylpentyl, 6
-Phenyl-6-hydroxyhexyl, 2-methyl-3
-Phenyl-3-hydroxypropyl, 2- (4-methoxyphenyl) -2-hydroxyethyl, 2- (3-ethoxyphenyl) -2-hydroxyethyl, 3-hydroxy-3- (4-fluorophenyl) propyl, 4-hydroxy-4- (3,4-dimethoxyphenyl) butyl, 5-hydroxy-5- (4-methylsulfinylphenyl) pentyl, 6-hydroxy-6- (2-methylphenyl) hexyl, 3-methoxybenzyl, An alkyl moiety such as 4-methoxybenzyl, 3-chlorobenzyl, 4-chlorobenzyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl moiety has a hydroxyl group as a substituent. And an alkoxy group having a carbon number of 1 to 6 on the phenyl ring is a linear or branched alkoxy group. Alkoxy group, halogen atom, straight or branched chain alkoxy group having 1 to 6 carbon atoms, nitro group, straight chain or branched chain alkyl group having 1 to 6 carbon atoms, cyano group, 1 to 6 carbon atoms There may be mentioned a phenylalkyl group which may have 1 to 3 groups selected from the group consisting of a linear or branched alkylthio group and a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms. .

As the phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring as a substituent,
Phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 1,1-dimethyl-2-phenoxyethyl, 5
-Phenoxypentyl, 6-phenoxyhexyl, 2-
Methyl-3-phenoxypropyl, 2- (3-methoxyphenoxy) ethyl, 1- (4-methoxyphenoxy)
Ethyl, (2-methoxyphenoxy) methyl, 3- (2
-Ethoxyphenoxy) propyl, 4- (3-ethoxyphenoxy) butyl, 1,1-dimethyl-2- (4-ethoxyphenoxy) ethyl, 5- (4-isopropoxyphenoxy) pentyl, 6- (4-hexyloxy) Phenoxy) hexyl, (3,4-dimethoxyphenoxy)
Methyl, (3,4,5-trimethoxyphenoxy) methyl, (2,5-dimethoxyphenoxy) methyl, (2-
Chlorophenoxy) methyl, 2- (3-bromophenoxy) ethyl, 1- (4-chlorophenoxy) ethyl, 3
-(4-fluorophenoxy) propyl, 4- (2,3
-Dichlorophenoxy) butyl, 1,1-dimethyl-2
-(2,4-dibromophenoxy) ethyl, 5- (3,
4-difluorophenoxy) pentyl, 6- (2,4,
6-trichlorophenoxy) propyl, (2-chloro-
An alkyl moiety such as 6-methoxyphenoxy) methyl group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and a halogen atom and a straight-chain or branched chain having 1 to 6 carbon atoms on the phenyl ring. A group selected from the group consisting of
Mention may be made of phenoxyalkyl groups which may have three.

The cycloalkyl group has, for example, 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The cycloalkyl group of 8 can be mentioned.

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

The phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring includes a phenyl group and a 2-
Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl,
2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,
4-ethoxyphenyl, 3-isopropoxyphenyl,
Phenyl such as 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chloro-6-methoxyphenyl, 2-methoxy-3-chlorophenyl group 1 is a group selected from the group consisting of a halogen atom and a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms as a substituent on the ring.
There may be mentioned phenyl groups which may have 3 to 3.

As the phenylthio lower alkyl group, phenylthiomethyl, 2-phenylthioethyl, 1-phenylthioethyl, 3-phenylthiopropyl, 4-phenylthiobutyl, 1,1-dimethyl-2-phenylthioethyl, A phenylthioalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety of 5-phenylthiopentyl, 6-phenylthiohexyl, 2-methyl-3-phenylthiopropyl group, etc. Can be mentioned.

Examples of the phenylsulfinyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring include phenylsulfinylmethyl and 2-phenylsulfinylethyl. , 1-phenylsulfinylethyl, 3-phenylsulfinylpropyl, 4-phenylsulfinylbutyl, 1,1-dimethyl-2-phenylsulfinylethyl, 5-phenylsulfinylpentyl, 6-phenylsulfinylhexyl, 2- (3
-Methoxyphenylsulfinyl) ethyl, 1- (4-
Methoxyphenylsulfinyl) ethyl, (2-methoxyphenylsulfinyl) methyl, 3- (2-ethoxyphenylsulfinyl) propyl, 4- (3-ethoxyphenylsulfinyl) butyl, 1,1-dimethyl-2
-(4-Ethoxyphenylsulfinyl) ethyl, 5-
(4-isopropoxyphenylsulfinyl) pentyl, 6- (4-hexyloxyphenylsulfinyl)
Hexyl, (3,4-dimethoxyphenylsulfinyl) methyl, (3,4,5-trimethoxyphenylsulfinyl) methyl, (2,5-dimethoxyphenylsulfinyl) methyl, (2-chlorophenylsulfinyl) methyl, 2- (3 -Bromophenylsulfinyl)
Ethyl, 1- (4-chlorophenylsulfinyl) ethyl, 3- (4-fluorophenylsulfinyl) propyl, 4- (2,3-dichlorophenylsulfinyl) butyl, 1,1-dimethyl-2- (2,4-dibromophenyl) Sulfinyl) ethyl, 5- (3,4-difluorophenylsulfinyl) pentyl, 6- (2,4,6-
Trichlorophenylsulfinyl) propyl, (2-chloro-6-methoxyphenylsulfinyl) methyl group, etc., which is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and has a halogen atom on the phenyl ring. And a phenylsulfinylalkyl group which may have 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms.

Examples of the pyridyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the pyridine ring include (2-pyridyl) methyl and 2- ( 3-pyridyl) ethyl, 1- (4-pyridyl) ethyl, 3- (2-pyridyl) propyl, 4- (3-pyridyl) butyl, 1,1-
Dimethyl-2- (4-pyridyl) ethyl, 5- (2-pyridyl) pentyl, 6- (3-pyridyl) hexyl, 2
-(3-Methoxy-4-pyridyl) ethyl, 1- (4-
Methoxy-2-pyridyl) ethyl, (2-methoxy-3
-Pyridyl) methyl, 3- (2-ethoxy-4-pyridyl) propyl, 4- (3-ethoxy-2-pyridyl) butyl, 1,1-dimethyl-2- (4-ethoxy-3-pyridyl) ethyl, 5- (4-isopropoxy-3-pyridyl) pentyl, 6- (4-hexyloxy-2-pyridyl) hexyl, (3,4-dimethoxy-2-pyridyl) methyl, (3,4,5-dimethoxy- 4-pyridyl) methyl, (2,5-dimethoxy-3-pyridyl) methyl, (2-chloro-4-pyridyl) methyl, 2- (3
-Bromo-2-pyridyl) ethyl, 1- (4-chloro-
2-pyridyl) ethyl, 3- (4-fluoro-2-pyridyl) propyl, 4- (2,3-dichloro-4-pyridyl) butyl, 1,1-dimethyl-2- (2,4-dibromo-3) -Pyridyl) ethyl, 5- (3,4-difluoro-2-pyridyl) pentyl, 6- (2,4,6-trichloro-3-pyridyl) propyl, (2-chloro-6-methoxy-3-pyridyl) A straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as a methyl group, and a halogen atom and a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms on the pyridyl ring. 1 to a group selected from the group
Mention may be made of pyridylalkyl groups which may have three.

As the phenylsulfonyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring, for example, phenylsulfonylmethyl, 2-
Phenylsulfonylethyl, 1-phenylsulfonylethyl, 3-phenylsulfonylpropyl, 4-phenylsulfonylbutyl, 1,1-dimethyl-2-phenylsulfonylethyl, 5-phenylsulfonylpentyl, 6
-Phenylsulfonylhexyl, 2- (3-methoxyphenylsulfonyl) ethyl, 1- (4-methoxyphenylsulfonyl) ethyl, (2-methoxyphenylsulfonyl) methyl, 3- (2-ethoxyphenylsulfonyl) propyl, 4- ( 3-ethoxyphenylsulfonyl) butyl, 1,1-dimethyl-2- (4-ethoxyphenylsulfonyl) ethyl, 5- (4-isopropoxyphenylsulfonyl) pentyl, 6- (4-hexyloxyphenylsulfonyl) hexyl, ( A straight chain having 1 to 6 carbon atoms in the alkyl moiety such as 3,4-dimethoxyphenylsulfonyl) methyl, (3,4,5-trimethoxyphenylsulfonyl) methyl, (2,5-dimethoxyphenylsulfonyl) methyl group or the like. A branched chain alkyl group and on the phenyl ring A straight-chain or branched alkoxy group having prime 1-6 can be mentioned phenylsulfonyl group which may have 1 to 3.

Examples of the pyridyl lower alkyl group include (3-pyridyl) methyl, (2-pyridyl) methyl and 2
-(4-pyridyl) ethyl, 1- (2-pyridyl) ethyl, 3- (2-pyridyl) propyl, 4- (2-pyridyl) ethyl, 1,1-dimethyl-2- (3-pyridyl)
The alkyl moiety such as ethyl, 5- (2-pyridyl) pentyl, 6- (4-pyridyl) hexyl group has 1 to 6 carbon atoms.
The pyridylalkyl group which is a straight chain or branched chain alkyl group can be mentioned.

Examples of the benzoyl lower alkyl group include benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3-benzoylpropyl, 4-benzoylbutyl, 1,1-dimethyl-2-benzoylethyl,
Examples thereof include a benzoylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as 5-benzoylpentyl and 6-benzoylhexyl groups.

Examples of the phenyl lower alkenyl group include styryl, 3-phenyl-1-propenyl, 3-phenyl-2-propenyl, 4-phenyl-3-butenyl,
4-phenyl-2-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl, 6-phenyl-5-hexenyl, 6
-Phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl-2-hexenyl, 2-methyl-
4-phenyl-3-butenyl, 2-methyl-styryl,
Examples thereof include a phenylalkenyl group which is a linear or branched alkenyl group having 2 to 6 carbon atoms in the alkenyl moiety such as a 1-methyl-styryl group.

Examples of the lower alkoxy lower alkoxy group include methoxymethoxy, 2-methoxyethoxy,
1-ethoxyethoxy, 3-propoxypropoxy, 4
-Butoxybutoxy, 5-pentyloxypentyloxy, 6-hexyloxyhexyloxy, 1,1-dimethyl-2-methoxyethoxy, 2-methyl-3-methoxypropoxy and the like have an alkoxy moiety having 1 to 6 carbon atoms. An alkoxyalkoxy group which is a linear or branched alkoxy group can be mentioned.

Examples of the lower alkylene group which may have an oxo group in the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, and 2,2.
-Dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, 2-oxoethylene, 3
An alkylene group such as -oxopropylene, 1-oxoethylene, 4-oxotetramethylene, 5-oxopentamethylene, and 6-oxohexamethylene that may have an oxo group and have a straight or branched chain having 1 to 6 carbon atoms. A branched alkylene group can be mentioned.

As the cenyl lower alkyl group, for example, (2-cenyl) methyl, 2- (3-cenyl) ethyl, 1- (2-cenyl) ethyl, 3- (3-cenyl) propyl, 4- (2- Cenyl) butyl, 5- (3
Examples thereof include a cenylalkyl group which is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as -Cenyl) pentyl and 6- (2-Cenyl) hexyl group.

The carbostyril derivative represented by the above general formula (1) can be produced by various methods. If one example is shown, it can be easily produced according to the method shown by the following reaction formula.

[Reaction Formula-1]

[0031]

[Chemical 5]

[Wherein R and R ¹ are the same as defined above]. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. The reaction between the compound of general formula (2) and the compound of general formula (3) is carried out without solvent or in a suitable solvent in the presence or absence of a basic compound. The reaction is usually at room temperature to 200
℃, preferably at room temperature to 150 ℃, generally 1
It ends in about 30 hours. Examples of the solvent used here include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol and isopropanol, and dimethyl. Formamide (D
Examples thereof include polar solvents such as MF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, pyridine and acetone. Examples of the basic compound used include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium amide, sodium hydride, potassium hydride, triethylamine, and the like. Examples thereof include organic bases such as tripropylamine, pyridine and quinoline. If an alkali metal iodide such as potassium iodide or sodium iodide is added to the reaction system of the reaction, the above reaction can proceed advantageously. The compound of general formula (3) is usually at least equimolar to the compound of general formula (2),
It is preferable to use an equimolar to 5-fold molar amount.

In the above reaction formula-1, the lower alkanesulfonyloxy group represented by X is specifically methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butane. Examples thereof include sulfonyloxy, pentanesulfonyloxy, and hexanesulfonyloxy groups. Specific examples of the arylsulfonyloxy group include phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-
Examples of the substituted or unsubstituted arylsulfonyloxy group such as chlorophenylsulfonyloxy, α-naphthylphenylsulfonyloxy group and the like, and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-
Substitution of phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group, etc. Alternatively, an unsubstituted aralkylsulfonyloxy group can be exemplified.

[Reaction formula-2]

[0035]

[Chemical 6]

[Wherein R ¹ , X and R are the same as defined above]. Y is the base

[0037]

[Chemical 7]

Is shown. The reaction of the compound of general formula (4) with the epihalogenohydrin of general formula (5) is carried out in the presence of a basic compound, in a suitable solvent or without solvent. As the basic compound used here, sodium hydroxide, potassium hydroxide,
Examples thereof include inorganic bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium, metallic potassium and sodium amide, and organic bases such as piperidine, pyridine and triethylamine. As the solvent to be used, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane and diethylene glycol dimethyl ether, aromatic carbonization such as benzene, toluene and xylene. Examples thereof include hydrogens and water. The compound of the general formula (5) is usually at least an equimolar amount, preferably 5 to 10 with respect to the compound of the general formula (4).
It is recommended to use a double molar amount. The reaction is usually 0 to 150.
The reaction proceeds at 0 ° C, preferably around 50 to 100 ° C, and the reaction is generally completed in about 1 to 10 hours.

By the above reaction, the hydroxyl group of the compound of the general formula (4) reacts with the epihalogenohydrin of the general formula (5) to give a (2,3-epoxy) propoxy group and 3-halogeno-2-hydroxypropoxy group. The compound converted into the group is obtained as a mixture, and this mixture is subjected to a reaction with a compound of the following general formula (3) without being purified and separated. Alternatively, by a conventional means such as recrystallization or column chromatography, the (2,3-epoxy) propoxy group or 3
The compound having a -halogeno-2-hydroxypropoxy group may be separated and purified, and then reacted with the compound of the general formula (3).

The reaction of the compound of general formula (6) with the compound of general formula (3) is carried out in the presence of a basic compound, in the presence or absence of a solvent. The reaction is usually at room temperature to 200
C., preferably about 60 to 120.degree. C., and generally the reaction is completed in about 1 to 24 hours. As the solvent and the basic compound used, any of the solvent and the basic compound used in the reaction of the compound of the general formula (2) and the compound of the general formula (3) in the reaction formula-1 can be used. The compound of the general formula (3) is usually at least equimolar amount, preferably equimolar to the compound of the general formula (6).
It is preferable to use a 5-fold molar amount.

[Reaction Formula-3]

[0042]

[Chemical 8]

[In the formula, R ¹ , R and X are the same as defined above. The reaction of the compound of the general formula (4) with the compound of the general formula (7) is carried out in a suitable solvent, preferably using a basic compound as a dehydrohalogenating agent, usually at room temperature to 200 ° C., preferably at 50 ° C.
It is carried out under a temperature condition of ~ 150 ° C for about 1 to 15 hours. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane and diethylene glycol dimethyl ether, and aromatic hydrocarbons such as toluene and xylene. , DMF, DMSO, hexamethylphosphoric triamide, and the like. Examples of the basic compound that can be used as a dehydrohalogenating agent include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, potassium metal, and sodium. Examples thereof include inorganic bases such as amides, organic bases such as pyridine, quinoline, triethylamine and tripropylamine. In the reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can be added to the reaction system as a reaction accelerator.
The amount of the compound of the general formula (7) used is not particularly limited,
It is usually an equimolar to 5-fold molar amount, preferably an equimolar to 2-fold molar amount with respect to the compound of the general formula (4).

The reaction between the compound of the general formula (4) and the compound of the general formula (8) is carried out by the reaction of the general formula (4) in the reaction formula-2.
The reaction is carried out under the same reaction conditions as the reaction of the compound of formula (5) with the compound of general formula (5).

[Reaction Formula-4]

[0046]

[Chemical 9]

[In the formula, R ¹ and X are the same as defined above. R ^{2 ′} and R ^{3 ′} represent the above R ² and R ³ other than a benzoyl group or an anilinothiocarbonyl group. The reaction of the compound of the general formula (1a) and the compound of the general formula (9) is similar to the reaction condition of the reaction of the compound of the general formula (2) and the compound of the general formula (3) in the reaction formula-1. You can go down.

[Reaction Formula-5]

[0049]

[Chemical 10]

[In the formula, R ^{2 '} is the same as above. R ^{3 ″} represents a benzoyl group and X ₁ represents a hydroxyl group. The reaction between the compound of general formula (1a) and the compound of general formula (10) is carried out according to a usual amide bond forming reaction.
As the amide bond formation reaction, known amide bond formation reaction conditions can be easily applied. For example (a)
A mixed acid anhydride method, that is, a method of reacting a carboxylic acid (10) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with an amine (1a), (b) an active ester method, that is, a carboxylic acid (10 ) Is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester and the like, and the amine (1a) is reacted therewith, (C)
The carbodiimide method, that is, the method in which the amine (1a) is condensed with the carboxylic acid (10) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole. (D) Other methods include converting the carboxylic acid (10) into acetic anhydride, etc. A carboxylic acid anhydride with the dehydrating agent described above, and reacting this with an amine (1a), carboxylic acid (10)
Examples thereof include a method of reacting an amine (1a) with an ester of a lower alcohol and a lower alcohol under high pressure and high temperature, a method of reacting an acid halide of carboxylic acid (10), that is, a carboxylic acid halide with amine (1a).

The mixed acid anhydride used in the mixed acid anhydride method is obtained by a conventional Schotten-Baumann reaction, and is usually reacted with the amine (1a) without isolation to give a compound of the general formula (1c). The compound is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used, and examples thereof include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine and 1,5-diazabicyclo [4,3,0] nonene-5. (DBN), 1,
8-diazabicyclo [5,4,0] undecene-7 (D
BU), 1,4-diazabicyclo [2,2,2] octane (DABCO), and other organic bases; potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, and other inorganic bases. The reaction is usually -20 to 10
The reaction is carried out at 0 ° C, preferably about 0 to 50 ° C, and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (1a) is usually about −20 to 150 ° C., preferably 10 to
It is carried out at about 50 ° C. and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is generally performed in a solvent. The solvent used can be any of the conventional solvents for the mixed acid anhydride method,
Specifically, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, methyl acetate, ethyl acetate and the like. Esters, DMF, DMS
Examples thereof include aprotic polar solvents such as O and hexamethylphosphoric triamide. Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like.
In the method, the carboxylic acid (10), the alkylhalocarboxylic acid and the amine (1a) are usually used in an equimolar ratio, but the alkylhalocarboxylic acid and the carboxylic acid (10) are added to the amine (1a). It is preferable to use 1 to 1.5 times the molar amount of each.

Further, the carboxylic acid halide is converted to the amine (1a).
When the method of reacting with is employed, the reaction is carried out in the presence of a basic compound in a suitable solvent. As the basic compound to be used, known compounds can be widely used. For example, in addition to the basic compound used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate. , Sodium methylate, sodium ethylate, and other alcoholates. Examples of the solvent include methanol, ethanol, propanol, butanol, and 3-methoxy-, in addition to the solvent used in the mixed acid anhydride method.
Examples thereof include alcohols such as 1-butanol, ethyl cellosolve and methyl cellosolve, pyridine, acetone, acetonitrile and the like, and mixed solvents thereof. The use ratio of the amine (1a) and the carboxylic acid halide is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least about equimolar amount, preferably equimolar to 5 with respect to the former. It is preferable to use a double molar amount. The reaction is usually about −30 to 180 ° C., preferably 0 to 15
The reaction is carried out at about 0 ° C., and generally the reaction is completed in about 5 minutes to 30 hours.

[Reaction Formula-6]

[0054]

[Chemical 11]

[In the formula, R ^{2 '} is the same as above. ] The compound of general formula (1a) and phenyl isocyanate (1
The reaction with 1) is carried out by the general formula (2) in the reaction formula-1.
In a solvent similar to the solvent used in the reaction of the compound of formula (3) with the compound of general formula (3), usually at room temperature to 100 ° C., preferably at room temperature to around 70 ° C., generally for about 0.5 to 5 hours. The reaction is complete. Phenyl isocyanate (1
The amount of 1) used is usually an equimolar to 2-fold molar amount, and preferably an equimolar to 1.5-fold molar amount, relative to the compound of the general formula (1a).

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid and benzoic acid can be mentioned.

Further, among the carbostyril derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. .. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like. The target compound thus obtained in each step can be easily isolated and purified by a conventional separation means. Examples of the separation means include solvent extraction method, dilution method, recrystallization method, column chromatography,
Examples include preparative thin layer chromatography.

The present invention naturally includes optical isomers.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using diluents or excipients which are usually used such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.) and the like can be mentioned. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipient, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac,
Methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate,
Disintegrants such as calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium ularyl sulfate, stearic acid monoglyceride, starch, lactose, etc., sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium salt base, lauryl Absorption promoters such as sodium sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder,
Lubricants such as polyethylene glycol can be exemplified. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthanthene and the like. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solutions, pills and suspensions, they are used as diluents. Any of those commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the cardiotonic agent may contain a sufficient amount of salt, fudose sugar or glycerin to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the therapeutic agent.

The amount of the compound of the general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and may be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 70% by weight in the whole composition.
It is 30% by weight.

The administration method of the cardiotonic agent of the present invention is not particularly limited, and various dosage forms, patient's age, sex and other conditions,
It is administered by a method depending on the degree of disease and the like. For example tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, it is orally administered. Further, in the case of an injection, it is administered alone or mixed intravenously with a normal replacement fluid such as glucose or amino acid, and further intramuscularly, intracutaneously, if necessary, alone.
It is administered subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the cardiotonic agent of the present invention is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease and the like, but the amount of the compound of the general formula (1) which is an active ingredient is usually 1 It is recommended that the daily dose is about 0.1-10 mg / kg body weight, and the active ingredient is 1-200 mg in dosage unit form.
Good to contain.

[0063]

[Examples] Reference examples, examples, pharmacological test results and formulation examples are listed below.

Reference Example 1 4.2 g of N-methyl-N- (4-methylthiobenzyl) amine and 5.2 g of potassium carbonate were dissolved in a mixed solution of 20 ml of acetone and 20 ml of water, and 3.7 ml of benzoyl chloride was stirred under ice cooling. Is gradually added dropwise. After stirring for 30 minutes at the same temperature, the reaction mixture is poured into water and extracted with dichloromethane. After washing with brine, it is dried over magnesium sulfate. Dichloromethane is distilled off to obtain 6.8 g of N-benzoyl-N-methyl-N- (4-methylthiobenzyl) amine.

Reference Example 2 A solution of 6.8 g of N-benzoyl-N-methyl-N- (4-methylthiobenzyl) amine in 120 ml of dichloromethane was stirred at 5 ° C. or lower, and 5.5 g of m-chloroperbenzoic acid was gradually added. Add. Then, the mixture is stirred at the same temperature for 15 minutes. After completion of the reaction, the reaction mixture is washed with a 5% aqueous solution of potassium carbonate and brine in that order, and then dried over magnesium sulfate. After distilling off dichloromethane, the residue was subjected to silica gel column chromatography (eluent; dichloromethane: methanol =
Purification at 100: 0 to 100: 5) to obtain 4.1 g of N-benzoyl-N-methyl-N- (4-methylsulfinylbenzyl) amine.

Reference Example 3 4.1 g of N-benzoyl-N-methyl-N- (4-methylsulfinylbenzyl) amine was added to 40 ml of ethanol,
Add to a mixture of 20 ml of water and 60 ml of concentrated hydrochloric acid and heat to reflux for 12 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 20% aqueous sodium hydroxide solution is added to the obtained residue, and the mixture is extracted with diethyl ether. After washing with water and saline, it is dried over magnesium sulfate. Distill off the diethyl ether,
2.2 g of N-methyl-N- (4-methylsulfinylbenzyl) amine are obtained.

Reference Example 4 6-Hydroxycarbostyril 3.5 g and S-(+)
5 g of epichlorohydrin are added to 100 ml of methanol, 0.5 ml of triethylamine is added, and the mixture is heated under reflux for 8 hours. After cooling, chloroform was added, and the mixture was sprinkled on silica gel and purified by column chromatography (silica gel chloroform: methanol = 100: 0 to 100: 3).
1.13 g of S-6- (3-chloro-2-hydroxypropoxy) carbostyril are obtained.

Reference Example 5 R-6- (3-chloro-2-hydroxypropoxy) carbostyril was obtained in the same manner as in Reference Example 4 using R-(-)-epichlorohydrin.

Reference Example 6 0.65 g of 85% potassium hydroxide was dissolved in 30 ml of methanol, and 1.03 g of R-6- (3-chloro-2-hydroxypropoxy) carbostyril was added at room temperature to the same temperature. And stir for 5 hours. After the reaction, the mixture is ice-cooled, neutralized with 1N hydrochloric acid, and concentrated under reduced pressure at room temperature. Water is added to the residue and the crystals are filtered. After heating in 15 ml of methanol for 2-3 minutes,
Allow to cool to give 0.5 g of S-6- (2,3-epoxypropoxy) carbostyril.

Reference Example 7 R-6- was prepared in the same manner as in Reference Example 6 using S-6- (3-chloro-2-hydroxypropoxy) carbostyril.
(2,3-Epoxypropoxy) carbostyril is obtained.

Example 1 6- (2,3-epoxypropoxy) carbostyril 1
A suspension of 5 g and 11 g of N-methylbenzylamine in 150 ml of methanol is heated under reflux for 2.5 hours. Methanol was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/2
After purification in 5), it was recrystallized in ethanol and 7.6 g of 6- [3- (N-methyl-N-benzylamino) -2-
Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 2 A solution of 5.05 g of 5- (3-chloro-2-hydroxypropoxy) carbostyril and 6.0 g of N-methylbenzylamine in 50 ml of dimethylformamide was added.
Heat and stir at 0-60 ° C. for 5 hours. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/25).
After purification in, recrystallized from ethanol and 2.5 g of 6-
[3- (N-Methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 3 1.6 g of 6-hydroxycarbostyril and 1 g of sodium hydride (50% oily) dimethylformamide 30
1-chloro-2-hydroxy-3 in ml solution at room temperature
-(N-methyl-N-benzylamino) propane 2.2
g, and after heating, the mixture is heated and stirred at 70 to 80 ° C. for 3 hours. The reaction mixture is poured into water, extracted with chloroform and dried over magnesium sulfate. After the chloroform was distilled off, the resulting residue was subjected to silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/2).
After purification in 5), recrystallize from ethanol to give 0.76 g.
6- [3- (N-methyl-N-benzylamino) -2
-Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 4 To a solution of 21 g of N-methylbenzylamine in 50 ml of methanol was added a solution of 4.4 g of 6- (2,3-epoxypropoxy) carbostyril in 70 ml of methanol under heating to reflux.
Drop in minutes. After completion of the dropping, the mixture is heated and refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/25) and recrystallized from ethanol to give 5 g of 6- [3- (N-Methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 5 S- (2,3-epoxypropoxy) carbostyril 1
A suspension of 5 g and 11 g of N-methyl-N-benzylamine in 150 ml of methanol is heated under reflux for 2 hours. Methanol was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/1 /
25) and then recrystallized twice from ethanol to give 9.3.
g4S-(-)-6- [3- (N-Methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

Colorless prism, mp. 142-144 ° C. [α] _D = −32.20 (C = 1.0, chloroform).

Example 6 R-6 was used in the same manner as in Example 5 except that R-6- (2,3-epoxypropoxy) carbostyril was used as the starting material.
(+)-6- [3- (N-Methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

Colorless prism, mp. 142-144 ° C. [α] _D = + 31.44 (C = 1.1, chloroform).

Using the appropriate starting materials, the compounds shown in Tables 1 to 42 below are obtained in the same manner as in Examples 1 to 4.

[0084]

[Table 1]

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

[Table 7]

[0091]

[Table 8]

[0092]

[Table 9]

[0093]

[Table 10]

[0094]

[Table 11]

[0095]

[Table 12]

[0096]

[Table 13]

[0097]

[Table 14]

[0098]

[Table 15]

[0099]

[Table 16]

[0100]

[Table 17]

[0101]

[Table 18]

[0102]

[Table 19]

[0103]

[Table 20]

[0104]

[Table 21]

[0105]

[Table 22]

[0106]

[Table 23]

[0107]

[Table 24]

[0108]

[Table 25]

[0109]

[Table 26]

[0110]

[Table 27]

[0111]

[Table 28]

[0112]

[Table 29]

[0113]

[Table 30]

[0114]

[Table 31]

[0115]

[Table 32]

[0116]

[Table 33]

[0117]

[Table 34]

[0118]

[Table 35]

[0119]

[Table 36]

[0120]

[Table 37]

[0121]

[Table 38]

[0122]

[Table 39]

[0123]

[Table 40]

[0124]

[Table 41]

[0125]

[Table 42]

NMR ¹⁾ : 200 MHz (CDCl ₃ ) δ
ppm: 1.09 (3H, t, J = 7.2Hz), 1.3
6-1.46 (3H, m), 2.42-2.85 (4
H, m), 3.70 (1H, broads), 3.90-4.
05 (4H, m), 6.71 (1H, d, J = 9.4H
z), 6.95 (1H, d, J = 2.4 Hz), 7.1
4 (1H, dd, J = 9.0 Hz, 2.4 Hz), 7.
25-7.37 (6H, m), 7.72 (1H, d, J
= 9.4 Hz), 11.83 (1H, broads).

Example 132 6- (3-Methylamino-2-hydroxypropoxy)
Carbostyril 3.0 g, sodium iodide 11.8 g,
50 ml of a dimethylformamide suspension containing 2.2 ml of triethylamine and 3.9 g of 2- (4-fluorophenylsulfinyl) ethyl bromide was heated and stirred at 80 to 90 ° C. for 5 hours. The residue obtained after concentration under reduced pressure was subjected to silica gel column chromatography (eluent, dichloromethane: methanol: ammonium hydroxide = 200: 10: 1 to 1).
Purify at 50: 10: 1). Recrystallize from dichloromethane-diethyl ether to give 0.7 g of 6- [3-
Obtain {N- [2- (4-fluorophenylsulfinyl) ethyl] -N-methylamino} -2-hydroxypropoxy] carbostyril.

Mp126-129 ° C., white powder.

Examples 7-80, 82-123 and 125 as described in Example 132, using appropriate starting materials.
~ 131 compounds are obtained.

Example 133 6- (3-Methylamino-2-hydroxypropoxy)
To a suspension of 0.7 g of carbostyril in 10 ml of ethanol, 0.35 ml of phenylisothiocyanate was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The insoluble matter was collected by filtration and recrystallized from chloroform-methanol to give 0.83 g of 6
-[3- (1-Methyl-3-phenylthioureido)-
2-Hydroxypropoxy] carbostyril is obtained.

Mp185.0-186.5 ° C. (decomposition),
White powder.

Examples 134 to 165 The compounds shown in Tables 43 to 53 below are obtained in the same manner as in Examples 1 to 4 and 132 using appropriate starting materials.

[0133]

[Table 43]

[0134]

[Table 44]

[0135]

[Table 45]

[0136]

[Table 46]

[0137]

[Table 47]

[0138]

[Table 48]

[0139]

[Table 49]

[0140]

[Table 50]

[0141]

[Table 51]

[0142]

[Table 52]

[0143]

[Table 53]

NMR ²⁾ : 200 MHz (DMSO-d ₆ ) δpp
m; 2.50 (1H, brs), 2.65 (2H, m),
3.91 (2H, s), 3.80-4.10 (3H,
m), 5.02 (1H, s), 6.48 (1H, d, J
= 9.5 Hz), 6.90-7.10 (2H, m),
7.10-7.30 (4H, m), 7.30-7.50
(1H, m), 7.83 (1H, d, J = 9.5H
z).

Examples 166 to 171 Table 5 below is prepared in the same manner as in Example 5 using appropriate starting materials.
4 to obtain the compounds shown in Table 56.

[0146]

[Table 54]

[0147]

[Table 55]

[0148]

[Table 56]

Examples 172 to 173 The compounds shown in Table 57 below are obtained in the same manner as in Examples 1 to 4 and 132 using appropriate starting materials.

[0150]

[Table 57]

Examples 174 to 186 Table 5 below is prepared in the same manner as in Example 5 using appropriate starting materials.
8 to obtain the compounds shown in Table 62.

[0152]

[Table 58]

[0153]

[Table 59]

[0154]

[Table 60]

[0155]

[Table 61]

[0156]

[Table 62]

Pharmacological test (blood perfusion extraction papillary muscle preparation) Pentoparbital was administered to adult male and female dogs weighing 8 to 13 kg.
Anesthesia was performed by intravenously administering sodium salt at a rate of 30 mg / kg. The sodium salt of heparin was intravenously administered at a rate of 1000 U / kg, and then killed by bleeding and the heart was excised. The specimen mainly consisted of papillary muscles and ventricular septum, and the blood introduced from the donor dog from the cannula inserted into the anterior septal artery was used.
It was perfused with a constant pressure of 0 mmHg. Donors weigh 18-27
30 kg / kg of pentoparbital sodium salt in advance
Is anesthetized by intravenous administration of heparin sodium salt 10
00 U / kg had been administered intravenously. With bipolar electrodes,
The papillary muscle was stimulated with a rectangular wave having a voltage 1.5 times the threshold value (0.5 to 3 V), a stimulation width of 5 msec, and a stimulation frequency of 120 times per minute. The resting tension of the papillary muscle was 1.5 g, and the generated tension of the papillary muscle was measured via a force displacement exchanger. The recording of the generated tension was recorded on an ink recording recorder. The details of this method have already been reported by Endo and Hashimoto (Am. J. Physiol., 2
18 , 1459-1463, 1970).

The test compound was intraarterally administered in a volume of 10/30 μl for 4 seconds. Regression analysis was performed at 10, 100, and 1000 nmoles, and the ED ₃₀ value was obtained from the regression equation. ED
_{The 30} value is the dose of the test compound when the contractile force was increased by 30% with respect to the control value. Using amrinone as a control,

[0159]

[Equation 1]

The results are shown in Tables 63 to 64 below.

Test compound No. 1.6- [3- (N-methyl-N-benzylamino)-
2-Hydroxypropoxy] carbostyril 2.6- [3- (N-ethyl-N-benzylamino)-
2-Hydroxypropoxy] carbostyril 3.6- [3- (N-ethyl-N-β-phenethylamino) -2-hydroxypropoxy] carbostyryl 4.6- [3- (N-propyl-N-benzylano) −
2-Hydroxypropoxy] carbostyril 5.6- {3- [N-methyl-N- (4-chlorobenzyl) amino] -2-hydroxy-propoxy} carbostyril 6.6- [3- (N-methylanilino) 2-Hydroxypropoxy] carbostyril 7.6- [3- (N-ethylanilino) -2-hydroxypropoxy] carbostyryl 8.6- {3- [N-methyl-N- (2-fluorobenzyl) amino] 2-Hydroxypropoxy} carbostyril 9.6- [3- (N-n-butyl-N-benzylamino) -2-hydroxypropoxy] carbostyril 10.6- {3- [N-methyl-N- ( 2-Chlorobenzyl) amino] -2-hydroxypropoxy} carbostyril 11.6- {3- [N-ethyl-N- (2-phenoxyethyl) Mino] -2-hydroxypropoxy} carbostyril 12.6- {3- [N-methyl-N- (4-methylthiobenzyl) amino] -2-hydroxypropoxy} carbostyril 13.6- [3- (N- Allyl-N-benzylamino)-
2-Hydroxypropoxy] carbostyril 14.6- [3- {N-ethyl-N- [2- (4-methoxyphenyl) ethyl] amino} -2-hydroxypropoxy] carbostyril 1/4 hydrate 15 .6- {3- [N-methyl-N- {2- [N-methyl- (4-fluoroanilino)] ethyl} amino] -2-
Hydroxypropoxy} carbostyril 16.6- {3- [N-ethyl-N- (3-methoxybenzyl) amino] -2-hydroxypropoxy] carbostyril 17.6- {3- [Nn-propyl-N] -(3,4-Dimethoxybenzyl) amino] -2-hydroxypropoxy} carbostyryl 18.6- [3- (3-phenylpropyl) amino-2-
Hydroxypropoxy] carbostyril 19.6- [3- (3-methoxybenzyl) amino-2-
Hydroxypropoxy] carbostyril 20.6- [3- {N-benzyl-N- [2- (3,4-
Dimethoxyphenyl) ethyl] amino} -2-hydroxypropoxy] carbostyril 21.6- [3- (N-ethyl-N-benzoylamino)
-2-Hydroxypropoxy] carbostyril 22.6- {3- [N-ethyl-N- (3-phenyl-2
-Propenyl) amino] -2-hydroxypropoxy}
Carbostyril 23.6- {3- [N-ethyl-N- (1-phenylethyl) amino] -2-hydroxypropoxy} carbostyril 24.6- [3- {N-ethyl-N- [2- ( 3-Methoxyphenyl) ethyl] amino} -2-hydroxypropoxy] carbostyryl 1/2 fumarate 25.6- [3- (2,2-diphenylethylamino)-
2-Hydroxypropoxy] carbostyril 26.6- [3- (4-chlorobenzylamino) -2-hydroxypropoxy] carbostyril 27.6- [3- (2-chlorobenzylamino) -2-hydroxypropoxy] carbo Styryl 28.6- {3- [N-methyl-N- (2-pyridylmethyl) amino] -2-hydroxypropoxy} carbostyril 29.6- [3- {N-methyl-N- [2- (N -Methylanilino) ethyl] amino} -2-hydroxypropoxy] carbostyryl-oxalate 30.6- [3- (2-methoxybenzylamino) -2-
Hydroxypropoxy] carbostyril 31.6- [3- (4-methoxybenzylamino) -2-
Hydroxypropoxy] carbostyril 32.6- [3- (3-fluorobenzylamino) -2-
Hydroxypropoxy] carbostyril 33.6- [3- (2-phenylthioethyl) amino-2
-Hydroxypropoxy] carbostyril 34.6- [3- (4-fluorobenzyl) amino-2-
Hydroxypropoxy] carbostyril 35.6- [3- (1-methyl-3-phenylthioureido) -2-hydroxypropoxy] carbostyril 36.6- {3- [N-methyl-N- (3-benzoylpropyl) ) Amino] -2-hydroxypropoxy} carbostyril 37.6- {3- [2- (3-methoxyphenoxy) ethylamino] -2-hydroxypropoxy} carbostyryl hydrochloride 38.6- [3- (3 , 4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 39.6- [3- (3-chlorobenzyl) amino-2-hydroxypropoxy] carbostyril 40.6- [3- (2-fluorobenzyl) Amino-2-
Hydroxypropoxy] carbostyril 41.6- {3- [N-methyl-N- (2-phenylsulfinylethyl) amino] -2-hydroxypropoxy} carbostyril 42.6- {3- [N- (2-hydroxy Ethyl) -N-
(4-Fluorobenzyl)]-2-hydroxypropoxy} carbostyril 43.6- [3- (N-cyclopropyl-N-benzylamino) -2-hydroxypropoxy] carbostyril 44.6- [3- (3 -Ethoxybenzyl) amino-2-
Hydroxypropoxy] carbostyryl hydrochloride 45.6- [3- (3-phenylthiopropyl) amino-
2-Hydroxypropoxy] carbostyril 46.6- {3- [N- (2-hydroxyethyl) -N-
(3-Methoxybenzyl) amino] -2-hydroxypropoxy} carbostyril 47.6- [3- (4-methylbenzyl) amino-2-hydroxypropoxy] carbostyril 48.6- [3- (4-nitrobenzyl) ) Amino-2-hydroxypropoxy] carbostyril 49.6- [3- (4-cyanobenzyl) amino-2-hydroxypropoxy] carbostyril 50.6- [3- {N-ethyl-N- [2- ( 3-Methoxyphenyl) ethyl] amino} -2-hydroxypropoxy] carbostyryl fumarate 51.6- [3- (3-Methoxymethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 52.6- {3 -[N-methyl-N- (2-phenyl-2
-Hydroxyethyl) amino] -2-hydroxypropoxy} carbostyril 53.6- [3- (2-phenoxyethyl) amino-2-
Hydroxypropoxy] carbostyryl hydrochloride 54.6- [3- (2,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyryl hydrochloride 55.6- [3- (2,3-dimethoxybenzyl) Amino-2-hydroxypropoxy] carbostyril 56.6- [3- (N-methyl-N-benzylamino)-
2-Hydroxypropoxy] -3-cyano-carbostyril 57.6- {3- [N-methyl-N- (2-phenylsulfonylethyl) amino] -2-hydroxypropoxy}
Carbostyril 58.6- [3- (3,4,5-trimethoxybenzyl)
Amino) -2-hydroxypropoxy] carbostyryl hydrochloride 59.6- [3- {N-methyl-N- [2- (4-fluorophenyl) sulfinylethyl] amino} -2-hydroxypropoxy] carbostyril 60 6- [3- {N-methyl-N- [2- (N-methylanilinocarbonyl) ethyl] amino} -2-hydroxypropoxy] carbostyril 61.6- [3- {N- (2-hydroxy Ethyl) -N-
[2- (3-Methoxyphenyl) ethyl] amino} -2
-Hydroxypropoxy] carbostyril 62.6- {3- [2- (3-methoxyphenyl) ethyl] amino-2-hydroxypropoxy} carbostyryl hydrochloride 63.6- {3- [N- (2-hydroxy Ethyl) -N-
(4-Ethoxybenzyl) amino] -2-hydroxypropoxy} carbostyril 64.6- {3- [N- (4-ethoxybenzyl) amino] -2-hydroxypropoxy} carbostyryl.1
Hydrochloride 65.6- {3- [N-methyl-N- (3-phenylthiopropyl) amino] -2-hydroxypropoxy} carbostyril 66.6- {3- [N-methyl-N- (3- Phenylsulfinylpropyl) amino] -2-hydroxypropoxy} carbostyryl 1/2 fumarate 67.6- {3- [N-methyl-N- (2-phenylsulfinylethyl) amino] -2-hydroxypropoxy} Carbostyril 1/2 fumarate 68.6- [3- (2-Methoxy-4-methylsulfinylbenzyl) amino-2-hydroxypropoxy] carbostyryl monohydrochloride 1/2 hydrate 69.6 -{3- [N-methyl-N- (4-methoxy-2
-Pyridylmethyl) amino] -2-hydroxypropoxy} carbostyryl dihydrate 70.6- {3- [N-methyl-N- (4-chloro-2-
Pyridylmethyl) amino] -2-hydroxypropoxy} carbostyril 71.6- {3- [N- (4-chloro-2-pyridylmethyl) amino] -2-hydroxypropoxy} carbostyril monohydrate 72. 6- {3- [N- (2-thienylmethyl) amino]
2-Hydroxypropoxy} carbostyril monohydrate 73.6- {3- [N- (4-methoxy-2-pyridylmethyl) amino] -2-hydroxypropoxy} carbostyril 74. R-(+)-6- [3- (3,4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 75.6- {3- [N- (2-phenylsulfinylethyl) amino] -2- Hydroxypropoxy} carbostyril 76.6- {3- [N-methyl-N- (2-pyridyl) amino] -2-hydroxypropoxy} carbostyril 77.6- [3- {N-methyl-N- [2 -(N-Methylanilino) acetyl] amino} -2-hydroxypropoxy] carbostyril 78.6- [3- {N-methyl-N- [3- (N-methylanilino) propionyl] amino} -2-hydroxypropoxy] Carbostyril 79.6- [3- (3-methoxy-4-methylsulfinylbenzyl) amino-2-hydroxypropoxy] carbostyril monohydrochloride 2.5 hydrate 80.6- [3- {N-methyl-N- [2- (4-methoxyphenyl) sulfonylethyl] amino} -2-hydroxypropoxy] carbostyril 81.6- [3- { N-methyl-N- [2- (4-methoxyphenyl) sulfinylethyl] amino} -2-hydroxypropoxy] carbostyryl monooxalate dihydrate 82. S-(-)-6- [3- (3-methoxybenzyl)
Amino-2-hydroxypropoxy] carbostyril 83. R-(+)-6- [3- (3-methoxybenzyl)
Amino-2-hydroxypropoxy] carbostyril 84.6- {3- [N- (3,5-dimethoxybenzyl)
Amino] -2-hydroxypropoxy} carbostyryl monohydrochloride 85.6- [3- {N-methyl-N- [2- (4-fluorophenyl) sulfinylethyl] amino} -2-hydroxypropoxy] carbostyril 86.6- [3- {N-Methyl-N- [3- (N-methylanilino) propyl] amino} -2-hydroxypropoxy] carbostyril 87.6- [3- {N-methyl-N- [2 -(N-methylanilinocarbonyl) ethyl] amino} -2-hydroxypropoxy] carbostyril 88.6- {3- [N- (3,4,5-trimethoxybenzyl) amino] -2-hydroxypropoxy} Carbostyril monohydrochloride 89.6- [3- (4-methylsulfinylbenzyl) amino-2-hydroxypropoxy] carbostyril 90.6- {3- N- methyl-N-(2-phenylsulfonylethyl) amino] -2-hydroxypropoxy}
Carbostyril 91. S-(-)-6- [3- (N-methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril 92. R-(+)-6- [3- (N-Methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril 93.6- {3- [N- (2-hydroxyethyl) -N-
(3-Ethoxybenzyl) amino] -2-hydroxypropoxy} carbostyril 94. R-(+)-6- [3- (4-Fluorobenzylamino) -2-hydroxypropoxy] carbostyril 95. S-(-)-6- [3- (4-Fluorobenzylamino) -2-hydroxypropoxy] carbostyril 96. R-(+)-6- [3- (4-methoxybenzylamino) -2-hydroxypropoxy] carbostyryl.
Hydrochloride 97. R-(+)-6- [3- (3-ethoxybenzylamino) -2-hydroxypropoxy] carbostyryl.
Hydrochloride 98. S-(−)-6- [3- (3-ethoxybenzylamino) -2-hydroxypropoxy] carbostyryl.
Hydrochloride 99. R-(+)-6- [3- (4-chlorobenzylamino) -2-hydroxypropoxy] carbostyryl hydrochloride 100.S-(-)-6- [3- (4-chlorobenzylamino)- 2-Hydroxypropoxy] carbostyryl hydrochloride 101.R-(+)-6- {3- [N- (2-hydroxyethyl) -N- (4-fluorobenzyl) amino] -2-
Hydroxypropoxy} carbostyril 102.S-(−)-6- {3- [N- (2-hydroxyethyl) -N- (4-fluorobenzyl) amino] -2-
Hydroxypropoxy} carbostyril 103.R-(+)-6- [3- (3,4-diethoxybenzylamino) -2-hydroxypropoxy] carbostyryl hydrochloride 104.S-(-)-6- [ 3- (3,4-diethoxybenzylamino) -2-hydroxypropoxy] carbostyryl hydrochloride 105.R-(+)-6- [3- (3,5-dimethoxybenzylamino) -2-hydroxypropoxy ] Carbostyril 106.6- [3- (3,4-diethoxybenzylamino)
-2-Hydroxypropoxy] carbostyril hydrochloride

[0162]

[Table 63]

[0163]

[Table 64]

Formulation Example 1 6- [3- (2,4-dimethoxybenzylamino) -2-hydroxypropoxy] carbostyril hydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg A tablet containing the above composition was produced.

Formulation Example 2 6- {3- [N-methyl-N- {2- [N-methyl- (4-fluoroanilino)] ethyl} amino] -2-hydroxypropoxy} carbostyril 500 mg Polyethylene glycol ( Molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 100 ml Parabens and meta Sodium bisulfite and sodium chloride were dissolved in the above distilled water at 80 ° C with stirring. The obtained solution is cooled to 40 ° C., and the compound of the present invention,
Polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, and then distilled water for injection is added to the solution to adjust the final volume, sterile filtration is performed using an appropriate filter paper, and 1 ml aliquots are dispensed into ampoules. Then, an injection was prepared.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/47 ABU C07D 215/48 7019-4C 215/54 7019-4C 401/12 8829-4C 409/12 8829 -4C

Claims (8)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom or a cyano group. R is a group -N
R ² R ³ (R ² and R ³ are the same or different and each is a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a lower alkenyl group, a phenyl group or a substituent on the phenyl ring. May have 1 to 3 groups selected from the group consisting of a lower alkoxy lower alkoxy group, a halogen atom, a lower alkoxy group, a nitro group, a lower alkyl group, a cyano group, a lower alkylthio group and a lower alkylsulfinyl group, and A phenyl lower alkyl group that may have a hydroxyl group as a substituent on the alkyl part, a phenylsulfonyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring, a phenylthio lower alkyl group, and a substituent on the phenyl ring Have 1 to 3 groups selected from the group consisting of halogen atoms and lower alkoxy groups A phenylsulfinyl lower alkyl group, a halogen atom or a lower alkoxy group as a substituent on the phenyl ring.
A phenoxy lower alkyl group which may have 3 groups, a pyridyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the pyridine ring, a cenyl lower alkyl group, Benzoyl lower alkyl group, anilinothiocarbonyl group,
Benzoyl group, pyridyl group, phenyl lower alkenyl group or group R ⁴ R ⁵ N-A- (wherein R ⁴ and R ⁵ are the same or different and are a lower alkyl group or a halogen atom and a lower group as a substituent on the phenyl ring. A phenyl group which may have 1 to 3 groups selected from the group consisting of alkoxy groups, A
Represents a lower alkylene group which may have an oxo group in the lower alkylene group). ) Is shown. ] A cardiotonic agent characterized by containing a carbostyril derivative represented by: or a salt thereof. 2. A general formula: [In the formula, R ¹ represents a cyano group. R is a group —NR ² R ³ (R
² and R ³ are the same or different and each is a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a lower alkenyl group, a phenyl group, a lower alkoxy lower alkoxy group as a substituent on the phenyl ring. ,
It may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group, a nitro group, a lower alkyl group, a cyano group, a lower alkylthio group and a lower alkylsulfinyl group, and a hydroxyl group as a substituent in the alkyl part. A phenyl lower alkyl group which may have a phenyl lower alkyl group, a phenylsulfonyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring, a phenylthio lower alkyl group, a halogen atom and a lower alkoxy group which may have a substituent on the phenyl ring. 1 to 3 groups selected from the group
Phenylsulfinyl lower alkyl group, which may have 1 to 3, a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring, substituted on the pyridine ring As a group, a pyridyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group, a cenyl lower alkyl group, a benzoyl lower alkyl group, an anilinothiocarbonyl group, a benzoyl group, a pyridyl group, Phenyl lower alkenyl group or group R ⁴
R ⁵ N-A- (wherein R ⁴ and R ⁵ are the same or different and each is 1 to 3 groups selected from the group consisting of a lower alkyl group or a halogen atom and a lower alkoxy group as a substituent on the phenyl ring. A phenyl group which may have, A is a lower alkylene group which may have an oxo group in the lower alkylene group)
Indicates. ) Is shown. ] The carbostyril derivative or its salt represented by these. 3. A general formula: [Wherein R ² is a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a lower alkenyl group, a phenyl group, a lower alkoxy lower alkoxy group as a substituent on the phenyl ring, a halogen atom, Lower alkoxy group, nitro group, lower alkyl group, cyano group,
A phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkylthio group and a lower alkylsulfinyl group, and which may have a hydroxyl group as a substituent on the alkyl part, and a substituent on the phenyl ring. Phenylsulfinyl that may have 1 to 3 groups selected from the group consisting of a phenylsulfonyl lower alkyl group that may have a lower alkoxy group, a phenylthio lower alkyl group, a halogen atom and a lower alkoxy group as a substituent on the phenyl ring. A lower alkyl group, a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring, a halogen atom and a lower alkoxy group as a substituent on the pyridine ring 1 to 1 selected from the group consisting of
A pyridyl lower alkyl group, a cenyl lower alkyl group, a benzoyl lower alkyl group, an anilinothiocarbonyl group, a benzoyl group, a pyridyl group, a phenyl lower alkenyl group or a group R ⁴ R ⁵ NA- (where R ⁴ and R ⁵ are the same or different and each is a lower alkyl group or a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring as a substituent, and A is a lower group. A lower alkylene group which may have an oxo group in the alkylene group) is shown. ) Is shown. R
³ is a phenyl lower alkyl group having a hydroxyl group as a substituent in the alkyl moiety, a phenylsulfonyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring, a phenylthio lower alkyl group, and a halogen atom as a substituent on the phenyl ring. A phenylsulfinyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of atoms and lower alkoxy groups, a phenoxy lower alkyl group having 1 to 3 halogen atoms on the phenyl ring as a substituent, and a pyridine ring May have 1 to 3 groups selected from the group consisting of halogen atom and lower alkoxy group as a substituent, pyridyl lower alkyl group, cenyl lower alkyl group, benzoyl lower alkyl group, anilinothiocarbonyl group, benzoyl group, pyridyl Group, a phenyl lower alkenyl group or Group R ⁴ R ⁵ N—A— (wherein R ⁴ and R ⁵ are the same or different and each is a lower alkyl group or a group selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring; A phenyl group which may have 3 to 3, A is a lower alkylene group which may have oxo in the lower alkylene group). ) Is shown. ] The carbostyril derivative and its salt represented by these. 4. A carbostyril derivative or a salt thereof is 6-
[3- (3-methoxybenzyl) amino-2-hydroxypropoxycarbostyril or a salt thereof or 6- [3
The cardiotonic agent according to claim 1, which is-(3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril or a salt thereof. 5. A coronary blood flow increasing agent comprising the carbostyril derivative according to claim 1 or a salt thereof. 6. An antihypertensive agent comprising the carbostyril derivative according to claim 1 or a salt thereof. 7. A vasoconstriction inhibitor comprising the carbostyril derivative or the salt thereof according to claim 1. 8. An anti-inflammatory agent comprising the carbostyril derivative according to claim 1 or a salt thereof.