JP2719740B2 - Cardiotonic - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present 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 (1A) or a salt thereof as an active ingredient.

[0003]

Embedded image [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 are a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a phenyl group, a halogen atom as a substituent on a phenyl ring, A phenyl lower alkyl group, a phenylsulfonyl lower alkyl group, a phenylthio lower alkyl group, a phenylthio lower alkyl group, which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a nitro group, a lower alkyl group, a cyano group and a lower alkylthio group; A phenylsulfinyl 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 ring, and one halogen atom as a substituent on the pyridine ring. A pyridyl lower alkyl group, an anilinothiocarbonyl group which may have up to 3 Lysyl 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, 1 to 3 halogen atoms as a substituent on the lower alkyl group or a phenyl ring A phenyl group which may have, A represents a lower alkylene group which may be oxo-mediated in the lower alkylene group.). However, when R ¹ represents a hydrogen atom, R ² must not be a hydrogen atom and R ³ must not be a 3,4-dimethoxybenzyl group. R ¹ is water
R ² is a cycloalkyl group,
Lower alkyl group, phenyl group, phenyl lower alkyl group or
Represents a phenoxy lower alkyl group, and R ³ represents a hydrogen atom
, A lower alkyl group, a cycloalkyl group, a phenyl group or
Must not be a phenyl lower alkyl group. ] Or
In addition, the cardiotonic agent of the present invention is 6- "3- (3-methoxybenz)
Jill) amino-2-hydroxypropoxycarbostil
Or a salt thereof as an active ingredient. Book
Among the carbostyril derivatives of the invention, represented by the following general formula:
Are new compounds. General formula

Embedded image [Wherein R ¹ represents a cyano group. R represents a group —NR ² R ³ (R
² and R ³ are the same or different and each is a lower alkyl group or
Indicates a phenyl lower alkyl group. Carbo represented by ]
Styryl derivatives and salts thereof. General formula

Embedded image [Where R ² Represents a hydrogen atom or a lower alkyl group. R
³ Is a phenylsulfonyl lower alkyl group, phenylthio
Lower alkyl group, halogen as a substituent on the phenyl ring
A group selected from atoms and lower alkoxy groups
Phenylsulfinyl lower alkyl optionally having three
A halogen atom as a substituent on the
Pyridyl lower alkyl group which may have 3
Nothiocarbonyl group, pyridyl group, phenyl lower alk
Nyl group or group R ⁴ R ⁵ NA- (where R ⁴ And R
⁵ Is the same or different and is a lower alkyl group or phenyl
Having 1 to 3 halogen atoms as substituents on the ring
Phenyl group, A is lower alkenyl Oxo in the kylene group
Lower alkylene group which may be interposed). ). ]
And a salt thereof.above
Each carbostyril derivative and its salt increase myocardial contraction.
Intensifying effect (positive inotropic effect), increasing coronary blood flow, hypotensive
Action, vasoconstriction inhibitory action by norepinephrine and
Has an anti-inflammatory effect, such as congestive heart failure, mitral valvular disease,
Various heart diseases such as atrial fibrillation, flutter, paroxysmal atrial tachycardia
Useful as a cardiotonic, antihypertensive and anti-inflammatory agent for the treatment of
is there. In particular, the compound of the present invention has an excellent positive inotropic effect,
It has a coronary blood flow increasing action and a hypotensive action,
It has a characteristic that it has almost no increasing effect. Also the above
The compound is low toxic and has central side effects such as vomiting,
Fewer motor functions, less convulsions and tremors
Also have. Further, the compound of the present invention has excellent absorbability.
And have a long duration.

[Wherein 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 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, a phenyl group, a phenyl ring which may have a hydroxyl group as a substituent; Having 1 to 3 groups 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 as substituents And a phenyl lower alkyl group which may have 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, a phenyl ring. A group selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent A phenylsulfinyl lower alkyl group which may have 1 to 3 phenoxy lower alkyl groups which may have 1 to 3 groups selected from a halogen atom and a lower alkoxy group as a substituent on the phenyl ring, and a pyridine ring A pyridyl lower alkyl group, a chenyl lower alkyl group, a benzoyl lower alkyl group, an anilinothiocarbonyl group, a benzoyl group, a pyridyl 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. 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 halogen atom and a lower alkoxy group as substituents on a lower alkyl group or a phenyl ring) A phenyl group which may have from 1 to 3 groups selected from the group consisting of A lower alkylene group which may be bonded through an azo group). The carbostyril derivative represented by the general formula (1) and a salt thereof enhance cardiac muscle contraction (positive inotropic effect), increase coronary blood flow, reduce blood pressure, and inhibit vasoconstriction by norepinephrine. And has an anti-inflammatory effect, for example, congestive heart failure, mitral valvular disease, atrial fibrillation, flutter, inotropic agents for the treatment of various heart diseases such as paroxysmal atrial tachycardia,
Useful as antihypertensive and anti-inflammatory. In particular, the compound of the present invention has an excellent positive inotropic effect, an effect of increasing coronary blood flow and an antihypertensive effect, but has a characteristic of hardly having an effect of increasing heart rate. The above compounds have low toxicity,
Central side effects such as vomiting, decreased motor function, convulsions,
It also has the feature of little tremor. Further, the compound of the present invention is excellent in absorbability and long in duration.

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

The lower alkyl group which may have a hydroxyl group as a substituent includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,
Hexyl, hydroxymethyl, 2-hydroxyethyl,
1-hydroxyethyl, 3-hydroxypropyl, 4-
C1-C6 which may have a hydroxyl group as a substituent such as hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl and 2-methyl-3-hydroxypropyl group. A straight-chain or branched-chain alkyl group can be mentioned.

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

As the halogen atom, for example, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

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

The lower alkyl group includes, 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 straight-chain or branched-chain 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 linear or branched alkylsulfinyl groups having 1 to 6 carbon atoms such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl and hexylsulfinyl. 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 is substituted on the phenyl ring by 1 Examples of the phenyl lower alkyl group which may have from 3 to 3 and which may have a hydroxyl group as a substituent in the alkyl portion include, 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,
-(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, Alkyl moieties such as 4-methoxybenzyl, 3-chlorobenzyl, and 4-chlorobenzyl are straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms, and the alkyl moiety has a hydroxyl group as a substituent. Which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety on the phenyl ring An alkoxy group, a halogen atom, a linear or branched C1-C6 alkoxy group, a nitro group, a linear or branched C1-C6 alkyl group, a cyano group, a C1-C6 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 can be given. .

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 as a substituent on the phenyl ring includes:
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,
-(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 a 6-methoxyphenoxy) methyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and a halogen atom and a linear or branched chain having 1 to 6 carbon atoms on a phenyl ring. A group selected from the group consisting of
Examples include a phenoxyalkyl group which may have three.

Examples of the cycloalkyl group include those having 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
To 8 cycloalkyl groups.

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, and 2-methyl-3-phenylpropyl is a straight or branched alkyl group having 1 to 6 carbon atoms; Can be exemplified.

A phenyl group which may have 1 to 3 groups selected from a halogen atom and a lower alkoxy group as a substituent on the phenyl ring includes a phenyl group and a 2-phenyl group.
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 A group selected from the group consisting of a halogen atom and a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent on the ring;
And phenyl groups which may have up to 3 phenyl groups.

Examples of the phenylthio lower alkyl group include 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 such as 5-phenylthiopentyl, 6-phenylthiohexyl and 2-methyl-3-phenylthiopropyl group 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 as a substituent on the phenyl ring include, for example, phenylsulfinylmethyl, 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-
An alkyl moiety such as trichlorophenylsulfinyl) propyl or (2-chloro-6-methoxyphenylsulfinyl) methyl group, which is a linear or branched alkyl group having 1 to 6 carbon atoms, and a halogen atom on the phenyl ring And a phenylsulfinylalkyl group which may have 1 to 3 groups selected from the group consisting of linear or branched alkoxy groups 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 as a substituent 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,
-(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) The alkyl moiety such as a methyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and a halogen atom and a straight-chain or branched alkoxy group having 1 to 6 carbon atoms on the pyridyl ring. Groups selected from the group
And pyridylalkyl groups which may have three.

Examples of the phenylsulfonyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring include phenylsulfonylmethyl, 2-phenyl
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 a 3,4-dimethoxyphenylsulfonyl) methyl, (3,4,5-trimethoxyphenylsulfonyl) methyl, (2,5-dimethoxyphenylsulfonyl) methyl group or A branched 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,
-(4-pyridyl) ethyl, 1- (2-pyridyl) ethyl, 3- (2-pyridyl) propyl, 4- (2-pyridyl) ethyl, 1,1-dimethyl-2- (3-pyridyl)
The alkyl portion such as ethyl, 5- (2-pyridyl) pentyl, 6- (4-pyridyl) hexyl group has 1 to 6 carbon atoms.
And a pyridylalkyl group which is a linear or branched alkyl group.

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 portion such as a 5-benzoylpentyl and 6-benzoylhexyl group.

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 an alkenyl moiety such as a 1-methyl-styryl group.

The lower alkoxy group includes, for example, methoxymethoxy, 2-methoxyethoxy,
1-ethoxyethoxy, 3-propoxypropoxy, 4
Having 1 to 6 carbon atoms in an alkoxy moiety such as butoxybutoxy, 5-pentyloxypentyloxy, 6-hexyloxyhexyloxy, 1,1-dimethyl-2-methoxyethoxy, and 2-methyl-3-methoxypropoxy; An alkoxyalkoxy group which is a linear or branched alkoxy group can be exemplified.

The lower alkylene group which may have an oxo group in the lower alkylene group includes, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2
-Dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, 2-oxoethylene,
A straight-chain or branched group having 1 to 6 carbon atoms which may have an oxo group in an alkylene group such as -oxopropylene, 1-oxoethylene, 4-oxotetramethylene, 5-oxopentamethylene or 6-oxohexamethylene; Examples include a branched alkylene group.

Examples of the phenyl lower alkyl group include (2-phenyl) methyl, 2- (3-phenyl) ethyl, 1- (2-phenyl) ethyl, 3- (3-phenyl) propyl and 4- (2-phenyl) ethyl. Chenyl) butyl, 5- (3
Examples thereof include a chenylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl portion, such as-(thenyl) pentyl and 6- (2-thenyl) hexyl group.

The carbostyril derivative represented by the above general formula (1) can be produced by various methods. For example, the carbostyril derivative is easily produced according to, for example, a method represented by the following reaction formula.

[Reaction formula-1]

[0031]

Embedded image

Wherein R and R ¹ are 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 the general formula (2) and the compound of the general formula (3) is carried out without a solvent or in a suitable solvent in the presence or absence of a basic compound. The reaction is usually carried out at room temperature to 200
C., preferably at room temperature to 150.degree.
It ends in about 30 hours. Examples of the solvent used here include dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethers such as diethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, lower alcohols such as isopropanol, and dimethyl. Formamide (D
Polar solvents such as MF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, pyridine, and acetone can be exemplified. Examples of the basic compound used include, for example, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium amide, sodium hydride, and potassium hydride; triethylamine; Examples include organic bases such as tripropylamine, pyridine, and quinoline. The reaction proceeds advantageously by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system of the reaction. The compound of the general formula (3) is usually at least equimolar to the compound of the general formula (2),
Preferably, it is used in 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 Sulfonyloxy, pentane sulfonyloxy, hexanesulfonyloxy group and the like can be exemplified, and as the arylsulfonyloxy group, specifically, phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-
Chlorophenylsulfonyloxy, a substituted or unsubstituted arylsulfonyloxy group such as α-naphthylphenylsulfonyloxy group can be exemplified, 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]

Embedded image

Wherein R ¹ , X and R are as defined above. Y is a group

[0037]

Embedded image

Is shown. The reaction of the compound of the general formula (4) with the epihalogenohydrin of the 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, metal sodium, metal potassium, and sodium amide; and organic bases such as piperidine, pyridine, and triethylamine. Examples of the solvent used include 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 benzene, toluene and xylene. Examples include hydrogens and water. The compound of the general formula (5) is usually at least equimolar to the compound of the general formula (4), preferably 5 to 10
It is preferable to use a double molar amount. The reaction is usually performed at 0 to 150
C., preferably at around 50-100.degree. C., and the reaction is generally completed in about 1-10 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 a 3-halogeno-2-hydroxypropoxy group. The compound converted to 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 purification and separation. Or (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 between the compound of the general formula (6) and the compound of the 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 carried out at room temperature to 200
C., preferably at about 60 to 120.degree. C., and the reaction is generally completed in about 1 to 24 hours. As the solvent and the basic compound to be used, any of the solvent and the basic compound used in the reaction of the compound of the general formula (2) and the compound with the general formula (3) in the above Reaction Scheme-1 can be used. The compound of the general formula (3) is usually at least equimolar, preferably equimolar to the compound of the general formula (6).
It is preferable to use a 5-fold molar amount.

[Reaction formula-3]

[0042]

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Wherein R ¹ , R and X are as defined above. The reaction between the compound of the general formula (4) and 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 50 ° C.
The reaction is performed at a temperature of about 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, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metal potassium, sodium Examples include inorganic bases such as amides, and organic bases such as pyridine, quinoline, triethylamine, and tripropylamine. In the reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide may be added to the reaction system as a reaction accelerator.
The amount of the compound of the general formula (7) is not particularly limited,
The molar amount is usually 1 to 5 times, preferably 1 to 2 times the molar amount of the compound of the formula (4).

The reaction between the compound of the general formula (4) and the compound of the general formula (8) is performed by the reaction of the general formula (4) in the above-mentioned reaction formula-2.
And the compound of the general formula (5).

[Reaction formula-4]

[0046]

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Wherein R ¹ and X are as defined above. R 2 ^'and R ^3' represents the R ^2, R ³ other than a benzoyl group or anilinocarbonyl thiocarbonyl group. The reaction between the compound of the general formula (1a) and the compound of the general formula (9) is carried out under the same reaction conditions as the reaction of the compound of the general formula (2) with the compound of the general formula (3) in the aforementioned reaction formula-1. You can go down.

[Reaction formula-5]

[0049]

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[Wherein R ^{2 ′} is as defined above. R ^{3 ″} represents a benzoyl group and X ₁ represents a hydroxyl group. The reaction between the compound of the general formula (1a) and the compound of the general formula (10) is performed according to a usual amide bond formation 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 it with an amine (1a); ) Is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester and the like, which is reacted with an amine (1a).
A carbodiimide method, that is, a method in which an amine (1a) is condensed with a carboxylic acid (10) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; A carboxylic acid anhydride with a dehydrating agent, and reacting the carboxylic acid anhydride with an amine (1a);
A method in which an amine (1a) is reacted with an ester of a compound and a lower alcohol under high pressure and high temperature; and a method in which an amine (1a) is reacted with an acid halide of a carboxylic acid (10), that is, a carboxylic acid halide.

The mixed acid anhydride used in the mixed acid anhydride method is obtained by a usual Schotten-Baumann reaction, which is usually reacted without isolation to react with the amine (1a) to obtain the compound of the general formula (1c). A compound is produced. The Schotten-Baumann reaction is performed in the presence of a basic compound. As the basic compound to be used, a compound commonly used in the Schotten-Baumann reaction is used, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5. (DBN), 1,
8-diazabicyclo [5,4,0] undecene-7 (D
Organic bases such as BU) and 1,4-diazabicyclo [2,2,2] octane (DABCO); and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is usually performed at -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 carried out at about -20 to 150 ° C., preferably at about 10 to 150 ° C.
The reaction is performed at about 50 ° C., and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed anhydride method is generally performed in a solvent. As the solvent used, any of the solvents commonly used in the mixed acid anhydride method can be used,
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
O, aprotic polar solvents such as hexamethylphosphoric triamide and the like. Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.
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 used with respect to the amine (1a). It is preferable to use 1 to 1.5 times by mole each.

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

[Reaction formula-6]

[0054]

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[Wherein R ^{2 ′} is as defined above. The compound of the general formula (1a) and phenyl isocyanate (1
The reaction with 1) is carried out according to the general formula (2)
In a solvent similar to the solvent used in the reaction of the compound of the formula (3) with the compound of the general formula (3), usually at room temperature to 100 ° C, preferably at room temperature to about 70 ° C, and generally in about 0.5 to 5 hours. The reaction is completed. Phenyl isocyanate (1
The amount of 1) to be used is usually 1 to 2 times, preferably 1 to 1.5 times the molar amount of the compound of the formula (1a).

The carbostyril derivative of the present invention represented by the general formula (1) can be easily converted into an acid addition salt by acting 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, the compounds having an acidic group among the carbostyril derivatives represented by the general formula (1) of the present invention can easily form salts by the action of 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 ordinary separation means. Examples of the separation means include a solvent extraction method, a dilution method, a recrystallization method, column chromatography,
Examples include preparative thin-layer chromatography.

The present invention naturally includes optical isomers.

The compound of the formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned. For molding into tablets, those conventionally known in the art 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,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate,
Disintegrators such as calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium uraryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, lauryl Absorption promoters such as sodium sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearates, boric acid powder,
Lubricants such as polyethylene glycol can be exemplified. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In molding into the form of pills, carriers 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, and a disintegrant such as laminaran agar. For shaping 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 semi-synthetic glycerides. When prepared as an injection, the liquid preparations and suspensions are preferably sterilized and isotonic with blood. In forming these liquid preparations, pills and suspensions, they may be 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, a sufficient amount of salt, fructose or glycerin for preparing an isotonic solution may be contained in the inotropic agent, and a usual solubilizing agent, buffer, soothing agent and the like may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like or 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 from a wide range, but is usually from 1 to 70% by weight, preferably from 1 to 70% by weight of the whole composition.
30% by weight.

The method of administering the cardiotonic agent of the present invention is not particularly limited, and may include various preparation forms, patient age, sex, other conditions,
The drug is administered according to the degree of the disease. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered alone or mixed with a normal replenisher such as glucose and amino acids for intravenous administration.
It is administered subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, etc. The amount of the compound of the general formula (1), which is usually the active ingredient, is 1%. The dose is preferably about 0.1 to 10 mg per kg of body weight per day, and the active ingredient in a dosage unit form is 1 to 200 mg.
It is good to contain.

[0063]

EXAMPLES Reference Examples, Examples, Pharmacological Test Results and Formulation Examples are given 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 mixture of 20 ml of acetone and 20 ml of water, and 3.7 ml of benzoyl chloride was stirred under ice cooling. Is slowly dropped. After stirring at the same temperature for 30 minutes, the reaction mixture is poured into water and extracted with dichloromethane. After washing with saline, it is dried over magnesium sulfate. The dichloromethane is distilled off to give 6.8 g of N-benzoyl-N-methyl-N- (4-methylthiobenzyl) amine.

Reference Example 2 5.5 g of m-chloroperbenzoic acid was gradually added to a solution of 6.8 g of N-benzoyl-N-methyl-N- (4-methylthiobenzyl) amine in 120 ml of dichloromethane while stirring at 5 ° C. or less. Add. Thereafter, 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 from 100: 0 to 100: 5) gives 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,
The mixture is added to a mixture of 20 ml of water and 60 ml of concentrated hydrochloric acid, and heated under reflux for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and a 20% aqueous sodium hydroxide solution was added to the obtained residue, followed by extraction 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 3.5 g of 6-hydroxycarbostyril and S-(+)
5 g of epichlorohydrin are added to 100 ml of methanol, 0.5 ml of triethylamine are added and the mixture is refluxed for 8 hours. After allowing to cool, chloroform was added, 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 Using R-(-)-epichlorohydrin, R-6- (3-chloro-2-hydroxypropoxy) carbostyril was obtained in the same manner as in Reference Example 4.

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. And stir for 5 hours. After the reaction, the mixture is cooled on ice, neutralized with 1N hydrochloric acid, and then 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 obtain 0.5 g of S-6- (2,3-epoxypropoxy) carbostyril.

Reference Example 7 Using S-6- (3-chloro-2-hydroxypropoxy) carbostyril, the procedure of R-6 was carried out in the same manner as in Reference Example 6.
(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 is distilled off under reduced pressure, diethyl ether is added to the residue obtained, and the precipitated crystals are collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/2)
After purification in 5), recrystallization from ethanol gave 7.6 g of 6- [3- (N-methyl-N-benzylamino) -2-.
[Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 26 A solution of 5.05 g of 2- (3-chloro-2-hydroxypropoxy) carbostyryl and 6.0 g of N-methylbenzylamine in 50 ml of dimethylformamide was added to 5
Heat and stir at 0-60 ° C for 5 hours. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/25).
After recrystallization from ethanol, 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) in dimethylformamide 30
ml solution at room temperature in 1-chloro-2-hydroxy-3
-(N-methyl-N-benzylamino) propane 2.2
g, and 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 obtained residue was subjected to silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/2).
After purification in 5), recrystallization from ethanol yielded 0.76 g
6- [3- (N-methyl-N-benzylamino) -2
-Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Example 4 A solution of 4.4 g of 6- (2,3-epoxypropoxy) carbostyryl in 70 ml of methanol was added to 21 g of N-methylbenzylamine in 50 ml of methanol.
Drop in minutes. After the completion of the dropwise addition, the mixture is further heated under reflux 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 is distilled off under reduced pressure, diethyl ether is added to the residue obtained, and the precipitated crystals are collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1 /
After purification in 25), recrystallization was performed twice with ethanol to obtain 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 Using R-6- (2,3-epoxypropoxy) carbostyryl as a 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, compounds shown in Tables 1 to 42 below were 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 = 7.2 Hz), 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);
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,
A suspension of 2.2 ml of triethylamine and 3.9 g of 2- (4-fluorophenylsulfinyl) ethyl bromide in 50 ml of a dimethylformamide suspension is 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).
50: 10: 1). Recrystallization from dichloromethane-diethyl ether gave 0.7 g of 6- [3-
{N- [2- (4-Fluorophenylsulfinyl) ethyl] -N-methylamino} -2-hydroxypropoxy] carbostyril is obtained.

Mp 126-129 ° C., white powder.

Using the appropriate starting materials, in the same manner as in Example 132, the above Examples 7 to 80, 82 to 123 and 125
~ 131 are obtained.

Example 133 6- (3-Methylamino-2-hydroxypropoxy)
To a suspension of 0.7 g of carbostyril in 10 ml of ethanol was added 0.35 ml of phenylisothiocyanate at room temperature, and the mixture was stirred at the same temperature for 1 hour. The insolubles were 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.

Mp 185.0-186.5 ° C. (decomposition)
White powder.

Examples 134 to 165 The compounds shown in the following Tables 43 to 53 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 Using the appropriate starting materials, in the same manner as in Example 5, the following Table 5 was used.
4 to give the compounds shown in Table 56.

[0146]

[Table 54]

[0147]

[Table 55]

[0148]

[Table 56]

Examples 172 to 173 Using the appropriate starting materials, the compounds shown in the following Table 57 were obtained in the same manner as in Examples 1 to 4 and 132.

[0150]

[Table 57]

Examples 174 to 186 The following Table 5 was prepared in the same manner as in Example 5 using appropriate starting materials.
8 to give the compounds shown in Table 62.

[0152]

[Table 58]

[0153]

[Table 59]

[0154]

[Table 60]

[0155]

[Table 61]

[0156]

[Table 62]

Pharmacological test (blood-perfused papillary muscle specimen) Adult male and female hybrid dogs weighing 8 to 13 kg were treated with pentoparbital
Anesthesia was performed by intravenously administering the sodium salt at a rate of 30 mg / kg. Heparin sodium salt was intravenously administered at a rate of 1000 U / kg, and the blood was killed and the heart was removed. The specimen consists mainly of papillary muscle and ventricular septum, and is derived from a cannula inserted into the anterior septum artery by 10% of blood derived from a donor dog.
Perfused at a constant pressure of 0 mmHg. Donor dogs weigh 18-27
30mg / kg pentopalbital sodium salt in kg
Was intravenously administered and anesthetized with 10% sodium salt of heparin.
00U / kg was administered intravenously. Using bipolar electrodes,
The papillary muscle was stimulated with a square wave having a voltage 1.5 times the threshold (0.5-3 V), a stimulation width of 5 msec, and a stimulation frequency of 120 times per minute. The static 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 writing recorder. Details of this method have already been reported by Endo and Hashimoto (Am. J. Physiol., 2
18 , 1459-1463, 1970).

The test compounds were administered intraarterially 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 determined 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 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] carbostyryl 2.6- [3- (N-ethyl-N-benzylamino)-
2-hydroxypropoxy] carbostyril 3.6- [3- (N-ethyl-N-β-phenethylamino) -2-hydroxypropoxy] carbostyril 4.6- [3- (N-propyl-N-benzylano) −
2-Hydroxypropoxy] carbostyryl 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] carbostyril 8.6- {3- [N-methyl-N- (2-fluorobenzyl) amino] -2-Hydroxypropoxy} carbostyril 9.6- [3- (Nn-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] carbostyryl 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-hydroxypropoxydicarbostyryl 18.6- [3- (3-phenylpropyl) amino-2-
Hydroxypropoxy] carbostyryl 19.6- [3- (3-methoxybenzyl) amino-2-
Hydroxypropoxy] carbostyryl 20.6- [3- {N-benzyl-N- [2- (3,4-
Dimethoxyphenyl) ethyl] amino {-2-hydroxypropoxy] carbostyril 21.6- [3- (N-ethyl-N-benzoylamino)
-2-Hydroxypropoxy] carbostyryl 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] carbostyryl 31.6- [3- (4-methoxybenzylamino) -2-
Hydroxypropoxy] carbostyryl 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] carbostyryl 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-hydroxypropoxydicarbostyril 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] carbostyryl 46.6- {3- [N- (2-hydroxyethyl) -N-
(3-methoxybenzyl) amino] -2-hydroxypropoxydicarbostyril 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] carbostyryl 52.6- {3 -[N-methyl-N- (2-phenyl-2
-Hydroxyethyl) amino] -2-hydroxypropoxydicarbostyril 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] carbostyryl 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] carbostyryl 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] carbostyryl 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} carbostyril / 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] carbostyril monohydrochloride 1/2 hydrate 69.6 -{3- [N-methyl-N- (4-methoxy-2
-Pyridylmethyl) amino] -2-hydroxypropoxy {carbostyril dihydrate 700.6- {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]
72.6- {3- [N- (4-Methoxy-2-pyridylmethyl) amino] -2-hydroxypropoxy} carbostyril 74.-2-Hydroxypropoxy} carbostyril monohydrate 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] carbostyryl 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-} 81. N-methyl-N- [2- (4-methoxyphenyl) sulfinylethyl] amino} -2-hydroxypropoxy] carbostyril monooxalate dihydrate S-(-)-6- [3- (3-methoxybenzyl)
Amino-2-hydroxypropoxy] carbostyril 83. R-(+)-6- [3- (3-methoxybenzyl)
Amino-2-hydroxypropoxy] carbostyryl 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] carbostyryl 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] carbostyryl 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 R-(+)-6- [3- (N-methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril 93.6- {3- [N- (2-hydroxyethyl) -N-
(3-ethoxybenzyl) amino] -2-hydroxypropoxydicarbostyril 94. R-(+)-6- [3- (4-Fluorobenzylamino) -2-hydroxypropoxy] carbostyril 95. S-(-)-6- [3- (4-Fluorobenzylamino) -2-hydroxypropoxy] carbostyril R-(+)-6- [3- (4-methoxybenzylamino) -2-hydroxypropoxy] carbostyril
Hydrochloride 97. R-(+)-6- [3- (3-ethoxybenzylamino) -2-hydroxypropoxy] carbostyril.
Hydrochloride 98. S-(-)-6- [3- (3-ethoxybenzylamino) -2-hydroxypropoxy] carbostyril.
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 {carbostyryl 102.S-(-)-6- {3- [N- (2-hydroxyethyl) -N- (4-fluorobenzyl) amino] -2-
Hydroxypropoxydicarbostyryl 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] carbostyryl hydrochloride

[0162]

[Table 63]

[0163]

[Table 64]

Formulation Example 1 6- [3- (2,4-Dimethoxybenzylamino) -2-hydroxypropoxy] carbostyryl hydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg One tablet in a conventional manner. Tablets containing the above composition were 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 Sodium bisulfite and sodium chloride were dissolved in the above distilled water at 80 ° C. while 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 the resulting solution is adjusted to the final volume by adding distilled water for injection, sterile filtered using an appropriate filter paper, and dispensed into ampoules in 1 ml portions. Then, an injection was prepared.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-56-8319 (JP, A) JP-A-56-95115 (JP, A) JP-A-57-80322 (JP, A) JP-A Sho 52- 122382 (JP, A) JP-A-52-108980 (JP, A)

Claims (4)

(57) [Claims] 1. A compound of the 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 are a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a cycloalkyl group, a phenyl group, a halogen atom as a substituent on a phenyl ring, A phenyl lower alkyl group, a phenylsulfonyl lower alkyl group, a phenylthio lower alkyl group, a phenylthio lower alkyl group, which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a nitro group, a lower alkyl group, a cyano group and a lower alkylthio group; A phenylsulfinyl 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 ring, and one halogen atom as a substituent on the pyridine ring. A pyridyl lower alkyl group, an anilinothiocarbonyl group which may have up to 3 Lysyl 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, 1 to 3 halogen atoms as a substituent on the lower alkyl group or a phenyl ring A phenyl group which may have, A represents a lower alkylene group which may be oxo-mediated in the lower alkylene group.). However, when R ¹ represents a hydrogen atom, R ² must not be a hydrogen atom and R ³ must not be a 3,4-dimethoxybenzyl group. R ¹ is water
R ² is a cycloalkyl group,
Lower alkyl group, phenyl group, phenyl lower alkyl group or
Represents a phenoxy lower alkyl group, and R ³ represents a hydrogen atom
, A lower alkyl group, a cycloalkyl group, a phenyl group or
Must not be a phenyl lower alkyl group. A cardiotonic agent comprising the carbostyril derivative represented by the formula: or a salt thereof. 2. A compound of the general formula [Wherein R ¹ represents a cyano group. R represents a group —NR ² R ³ (R
² and R ³ are the same or different and each represents a lower alkyl group or a phenyl lower alkyl group. And a salt thereof. 3. A compound of the general formula [In the formula, R ² represents a hydrogen atom or a lower alkyl group. R
³ is a phenylsulfonyl lower alkyl group, a phenylthio lower alkyl group, a group selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring, and
A phenylsulfinyl lower alkyl group which may have three, and a halogen atom as a substituent on the pyridine ring of 1 to 1
A pyridyl lower alkyl group, an anilinothiocarbonyl group, a pyridyl group, a phenyl lower alkenyl group or a group R ⁴ R ⁵ NA- (where R ⁴ and R
⁵ is the same or different, a lower alkyl group or a phenyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring, and A is a lower alkylene group which may be oxo-mediated in the lower alkylene group) Is shown. ). ]
And a salt thereof. 4. The method of claim 1, wherein the carbostyril derivative or a salt thereof is 6-
[3- (3-methoxybenzyl) amino-2-hydroxypropoxycarbostyril or a salt thereof.
The described inotropic agent.