JPH0141128B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cardiotonic agents. The present invention provides a cardiotonic agent represented by the following general formula (1).
Carbostyril derivative or its salt as an active ingredient
It contains [R in the formula ¹ is a hydrogen atom, a lower alkyl group, a lower
Alkenyl group, lower alkynyl group or phenyl group
represents a class alkyl group. R ² is a hydrogen atom or a lower atom
Indicates a lucoxy group. R ³ is a hydrogen atom, lower alkali
noyl group, furoyl group, pyridylcarbonyl group,
Lower alkanesulfonyl group, lower alkoxylic
Bonyl group, lower alkoxycarbonyl lower alkyl group
lower alkyl group as a substituent on the phenyl ring
phenylsulfonyl group, which may have a
alkyl group, lower alkenyl group, lower alkynyl group
phenyl carbonyl group, phenyl lower alkyl group, phenylcarbonyl group, phenyl lower alkyl group
Indicates a kyl group or a phenyl lower alkanoyl group.
The above phenylcarbonyl group, phenyl lower alkyl group
phenyl group and phenyl lower alkanoyl group
Lower alkoxy groups, halogen atoms, lower
Alkyl group, cyano group, nitro group, amino group, water
Acid group, lower alkanoylamino group, lower alkyl
From the group consisting of thio group and lower alkanoyloxy group
1 to 3 selected groups or lower alkylene dioxyl
It may have a cy group as a substituent. Calbos
The carbon-carbon bond between the 3rd and 4th positions of the chiryl skeleton is a single bond.
indicates a bond or a double bond. ] A compound represented by the above general formula (1) or a salt thereof
has the effect of increasing myocardial contraction (positive inotropy)
) and has the effect of increasing coronary blood flow, for example, for depression.
As a cardiotonic agent for the treatment of heart diseases such as heart failure.
It is useful. In particular, the compound of general formula (1) or a salt thereof
does not increase heart rate or the degree of increase is
It has the characteristic of being very small. Each group represented in the above general formula (1) is more specifically
Physically, they are as follows. Lower alkyl groups include methyl, ethyl, and
lopyl, isopropyl, butyl, tert-butyl,
Straight chain or carbon number 1 to 6 such as pentyl, hexyl group, etc.
can be exemplified by a branched alkyl group. Lower alkenyl groups include vinyl, allyl,
2-butenyl, 3-butenyl, 1-methylaryl
carbon, such as 2-pentenyl, 2-hexenyl, etc.
Examples of linear or branched alkenyl groups of 2 to 6
can. Examples of lower alkynyl groups include ethyl and 2-propylene.
pinyl, 2-butynyl, 3-butynyl, 1-methy
Ru-2-propynyl, 2-pentynyl, 2-hexyl
Straight chain or branched atom having 2 to 6 carbon atoms such as cinyl group
An example is a rukynyl group. Examples of phenyl lower alkyl groups include benzyl,
2-phenylethyl, 1-phenylethyl, 3-
Phenylpropyl, 4-phenylbutyl, 1,1
-dimethyl-2-phenylethyl, 5-phenyl
Pentyl, 6-phenylhexyl, 2-methyl-
Carbon of alkyl moiety such as 3-phenylpropyl group
A straight chain or branched alkyl group having a number of 1 to 6
An example is a phenyl alkyl group. Lower alkoxy groups include methoxy, ethoxy
cy, propoxy, isopropoxy, butoxy,
tert-butoxy, pentyloxy, hexyloxy
Straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as
An example is xyl group. Examples of lower alkanoyl groups include formyl and acetate.
chill, propionyl, butyryl, isobutyryl,
Pentanoyl, tert-butylcarbonyl, hexa
Straight chain or branched atom having 1 to 6 carbon atoms such as noyl group
An example is a lucanoyl group. Halogen atoms include fluorine, chlorine, bromine and
Indicates an iodine atom. As a lower alkylene dioxy group, methylene
Dioxy, ethylenedioxy, trimethylenedioxy
Straight-chain or branched alkali having 1 to 4 carbon atoms such as xy group
An example is a kylenedioxy group. Lower alkoxy as a substituent on the phenyl ring
group, halogen atom, lower alkyl group, cyano group,
Nitro group, amino group, hydroxyl group, lower alkanoyl
Amino group, lower alkylthio group and lower alkano group
1 to 3 groups selected from the group consisting of yloxy groups or
is a phenyl carbon having a lower alkylenedioxy group.
Rubonyl groups include 2-chlorobenzoyl, 3
-Chlorbenzoyl, 4-chlorobenzoyl, 2
-Fluorobenzoyl, 3-fluorobenzoy
L, 4-fluorobenzoyl, 2-bromobenzo
yl, 3-brombenzoyl, 4-brombenzoyl
yl, 2-iodobenzoyl, 4-iodobenzoyl
yl, 3,5-dichlorobenzoyl, 2,6-di
Chlorbenzoyl, 3,4-dichlorobenzoy
3,4-difluorobenzoyl, 3,5-di
Brombenzoyl, 3,4,5-trichlorobene
Zoyl, 2-methylbenzoyl, 3-methylbenzoyl
Zoyl, 4-methylbenzoyl, 2-ethylbenzoyl
Zoyl, 3-ethylbenzoyl, 4-ethylbenzoyl
Zoyl, 3-isopropylbenzoyl, 4-hexyl
Silbenzoyl, 3,4-dimethylbenzoyl,
2,5-dimethylbenzoyl, 3,4,5-tri
Methylbenzoyl, 2-methoxybenzoyl, 3
-Methoxybenzoyl, 4-methoxybenzoy
2-ethoxybenzoyl, 3-ethoxyben
Zoyl, 4-ethoxybenzoyl, 4-isopro
Poxybenzoyl, 4-hexyloxybenzoy
3,4-dimethoxybenzoyl, 3,4-di
Ethoxybenzoyl, 3,4,5-trimethoxy
Benzoyl, 2,5-dimethoxybenzoyl, 2
-Nitrobenzoyl, 3-nitrobenzoyl, 4
-Nitrobenzoyl, 2,4-dinitrobenzoy
2-aminobenzoyl, 3-aminobenzoyl
4-aminobenzoyl, 2,4-diaminobenzoyl
cyanobenzoyl, 2-cyanobenzoyl, 3-cyanobe
Nzoyl, 4-cyanobenzoyl, 2,4-disy
Anobenzoyl, 3,4-methylenedioxyben
zoyl, 3,4-ethylenedioxybenzoyl,
2,3-methylenedioxybenzoyl, 3-methy
Ru-4-chlorobenzoyl, 2-chloro-6-methane
Tilbenzoyl, 2-methoxy-3-chloroben
Zoyl, 2-hydroxybenzoyl, 3-hydro
xybenzoyl, 4-hydroxybenzoyl,
3,4-dihydroxybenzoyl, 3,4,5-
Trihydroxybenzoyl, 2-formylamino
Benzoyl, 3-acetylaminobenzoyl, 4
-acetylaminobenzoyl, 2-acetylamide
Nobenzoyl, 3-propionylaminobenzoy
L, 4-butyrylaminobenzoyl, 2-isobu
tyrylaminobenzoyl, 3-pentanoylamide
Nobenzoyl, 3-tert-butylcarbonylamide
Nobenzoyl, 4-hexanoylaminobenzoy
2,6-diacetylaminobenzoyl, 2-
Methylthiobenzoyl, 3-methylthiobenzoy
, 4-methylthiobenzoyl, 2-ethylthio
Benzoyl, 3-ethylthiobenzoyl, 4-ethyl
Tylthiobenzoyl, 3-isopropylthioben
Zoyl, 4-hexylthiobenzoyl, 3,4-
Dimethylthiobenzoyl, 2,5-dimethylthio
Benzoyl, 3,4,5-trimethylthiobenzo
yl, 2-formyloxybenzoyl, 3-acetyl
Tyloxybenzoyl, 4-acetyloxyben
Zoyl, 2-acetyloxybenzoyl, 3-propylene
Ropionyloxybenzoyl, 4-butyryloxybenzoyl
Sibenzoyl, 2-isobutyryloxybenzoy
3-pentanoyloxybenzoyl, 3-
tert-butyryloxybenzoyl, 4-hexano
yloxybenzoyl, 3,4-diacetyloxy
Cybenzoyl, 3,4,5-triacetyloxy
Carbon as a substituent on the phenyl ring such as benzoyl group
Straight chain or branched alkoxy group with prime number 1 to 6, ha
halogen atom, straight chain or branched atom with 1 to 6 carbon atoms
Alkyl group, cyano group, amino group, hydroxyl group, number of carbon atoms
1 to 6 linear or branched alkanoylamino
group, straight chain or branched alkyl group having 1 to 6 carbon atoms
o group, carbon number and 1 to 6 straight chain or branched alkali
1 to 3 groups selected from the group consisting of canoyloxy groups
or an alkylenedioxy group having 1 to 4 carbon atoms.
Examples include phenylcarbonyl groups. As a lower alkanesulfonyl group, methane
sulfonyl, ethanesulfonyl, propanesulfonyl
, isopropanesulfonyl, butanesulfonyl
tert-butanesulfonyl, pentanesulfonyl
A straight chain with 1 to 6 carbon atoms, such as hexane sulfonyl group,
Sulfonyl group with chain or branched alkyl group
can be exemplified. As the lower alkoxycarbonyl group, methoxy
cycarbonyl, ethoxycarbonyl, propoxy
Carbonyl, isopropoxycarbonyl, butoki
Cycarbonyl, tert-butoxycarbonyl, pen
Tyloxycarbonyl, hexyloxycarbonyl
A linear or branched alkoxy group having 1 to 6 carbon atoms such as
An example is a carbonyl group having an xy group. lower alkoxycarbonyl lower alkyl group
methoxycarbonylmethyl, 3-methoxy
Carbonylpropyl, 4-ethoxycarbonylbu
chill, 6-propoxycarbonylhexyl, 5-
Isopropoxycarbonylpentyl, 1,1-di
Methyl-2-butoxycarbonylethyl, 2-methyl
thyl-3-tert-butoxycarbonylpropyl,
2-pentyloxycarbonylethyl, hexyl
of alkoxy moieties such as oxycarbonylmethyl groups
The number of carbon atoms is 1 to 6, and the number of carbon atoms in the alkyl moiety is 1 to 6.
Examples of alkoxycarbonylalkyl groups that are 6
can. Lower alkyl group as a substituent on the phenyl ring
As a phenylsulfonyl group that may have
is phenylsulfonyl, p-toluenesulfonyl
2-methylphenylsulfonyl, 3-ethyl
Phenylsulfonyl, 4-propylphenylsulfonyl
Honyl, 2-butylphenylsulfonyl, 3-
tert-butylphenylsulfonyl, 4-pentyl
Phenylsulfonyl, 2-hexylphenylsulfonyl
Straight chain or branched atom having 1 to 6 carbon atoms such as honyl group
Phenyl which may have alkyl group as a substituent
An example is a rusulfonyl group. Lower alkoxy as a substituent on the phenyl ring
group, lower alkyl group, halogen atom, nitro group,
Cyano group, amino group, hydroxyl group, lower alkanoyl
Amino group, lower alkylthio group and lower alkano group
1 to 3 groups selected from the group consisting of yloxy groups or
is a phenyl compound with a lower alkylenedioxy group.
Examples of class alkyl groups include 2-chlorobenzyl, 2
-(3-chlorophenyl)ethyl, 1-(4-k)
rolfenyl)ethyl, 3-(2-fluorophene)
4-(3-fluorophenyl)propyl, 4-(3-fluorophenyl)
Butyl, 1,1-dimethyl-2-(4-fluoro
phenyl)ethyl, 5-(2-bromphenyl)
Pentyl, 6-(3-bromphenyl)hexy
2-methyl-3-(4-bromphenyl)
Lopil, 3-iodobenzyl, 2-(4-iodo
phenyl)ethyl, 1-(3,5-dichlorophene)
ethyl), 2-(3,4-dichlorophenylene)
) ethyl, 3-(2,6-dichlorophenyl)
Propyl, 4-(3,4-dichlorophenyl)bu
Chil, 1,1-dimethyl-2-(3,4-diflu
olophenyl)ethyl, 5-(3,5-dibrome)
phenyl)pentyl, 6-(3,4,5-tric
rolfenyl)hexyl, 4-methylbenzyl,
2-(2-methylphenyl)ethyl, 1-(3-
methylphenyl)ethyl, 3-(3-ethylphenyl)
4-(2-ethyl phenyl) propyl, 4-(2-ethyl phenyl) propyl
tyl, 5-(4-ethylphenyl)pentyl, 6
-(3-isopropylphenyl)hexyl, 2-
Methyl-3-(4-hexylphenyl)propyl
2-(3,4-dimethylphenyl)ethyl,
2-(2,5-dimethylphenyl)ethyl, 2-
(3,4,5-trimethylphenyl)ethyl, 4
-Methoxybenzyl, 3,4-dimethoxybenzyl
3,4,5-trimethoxybenzyl, 1-
(3-methoxyphenyl)ethyl, 2-(2-methoxyphenyl)
toxyphenyl)ethyl, 3-(2-ethoxyphenyl)
enyl)propyl, 4-(4-ethoxyphenylene)
) butyl, 5-(3-ethoxyphenyl) pen
Chil, 6-(4-isopropoxyphenyl)hex
sil, 1,1-dimethyl-2-(4-hexyl)
xyphenyl)ethyl, 2-methyl-3-(3,
4-dimethoxyphenyl)propyl, 2-(3,
4-dimethoxyphenyl)ethyl, 2-(3,4
-diethoxyphenyl)ethyl, 2-(3,4,
5-trimethoxyphenyl)ethyl, 1-(2,
5-dimethoxyphenyl)ethyl, 3-nitrobe
1-(2-nitrophenyl)ethyl, 2
-(4-nitrophenyl)ethyl, 3-(2,4
-dinitrophenyl)propyl, 4-(2-ami
nophenyl)butyl, 5-(3-aminophenyl)
) pentyl, 6-(4-aminophenyl)hexyl
sil, (2,4-diamino)benzyl, 2-sia
Nobenzyl, 1,1-dimethyl-2-(3-sia
nophenyl)ethyl, 2-methyl-3-(4-cy)
anophenyl)propyl, 2,4-dicyanoben
Zyl, 3,4-methylenedioxybenzyl, 3,
4-ethylenedioxybenzyl, 2,3-methylene
dioxybenzyl, 2-(3,4-methylenedi
oxyphenyl)ethyl, 1-(3,4-ethyl)
dioxyphenyl)ethyl, 3-methyl-4-
Chlorbenzyl, 2-chloro-6-methylbenzi
2-Methoxy-3-chlorobenzyl, 2-H
Droxybenzyl, 2-(3,4-dihydroxy
phenyl)ethyl, 1-(3,4-dihydroxy
phenyl)ethyl, 2-(3-hydroxyphenyl)
) ethyl, 3-(4-hydroxyphenyl)
Lopyru, 6-(3,4-dihydroxyphenyl)
hexyl, 3,4-dihydroxybenzyl, 3,
4,5-trihydroxybenzyl, 2-formyl
aminobenzyl, 3-acetylaminobenzyl,
3-(2-acetylaminophenyl)propyl,
4-(4-acetylaminophenyl)butyl, 2
-Propionylaminobenzyl, 3-(3-buty)
lylaminophenyl)propyl, 4-(4-iso
Butyrylaminophenyl)butyl, 5-(2-
tert-butylcarbonylaminophenyl) pliers
6-(3-pentanoylaminophenyl)
xyl, (2,4-diacetylamino)benzyl,
4-methylthiobenzyl, 2-(2-methylthio
phenyl)ethyl, 1-(3-methylthiophenyl)
) ethyl, 3-(3-ethylthiophenyl)
Lopyru, 4-(2-ethylthiophenyl)buty
5-(4-ethylthiophenyl)pentyl,
6-(3-isopropylthiophenyl)hexy
2-methyl-3-(4-hexylthiophene
) propyl, 2-(3,4-dimethylthiophene)
ethyl), 2-(2,5-dimethylthiophe)
ethyl), 2-(3,4,5-trimethoxy)
phenyl)ethyl, 4-acetyloxybendi
3,4-acetyloxybenzyl, 3,4,
5-triacetyloxybenzyl, 1-(3-a
Cetyloxyphenyl)ethyl, 2-(2-acetyl)
methyloxyphenyl)ethyl, 3-(2-propyl)
onyloxyphenyl)propyl, 4-(4-pe
ntanoyloxyphenyl)butyl, 5-(3-
propionyloxyphenyl)pentyl, 6-
(4-isobutyryloxyphenyl)hexyl,
1,1-dimethyl-2-(4-hexylnoyl)
xyphenyl)ethyl, 3-butyryloxyben
1 carbon number as a substituent on the phenyl ring such as a zyl group
~6 linear or branched alkoxy groups, 1 carbon number
~6 linear or branched alkyl group, halogen source
child, nitro group, cyano group, amino group, hydroxyl group, carbon
Straight chain or branched alkanoylamine with prime numbers 1 to 6
straight chain or branched alkyl having 1 to 6 carbon atoms
Thio group and straight chain or branched alkali having 1 to 6 carbon atoms
1 to 3 groups selected from the group consisting of canoyloxy groups
linear or branched alkylene having 1 to 4 carbon atoms
Contains a phenyl group that may have a dioxy group
A straight or branched alkyl group having 1 to 6 carbon atoms
can be exemplified. As a lower alkanoylamino group, formyl
amino, acetylamino, propionylamino,
Butyrylamino, Isobutyrylamino, Pentano
ylamino, tert-butylcarbonylamino,
Straight chain with 1 to 6 carbon atoms such as xanoylamino group or
An example is a branched alkanoylamino group. Examples of lower alkylthio groups include methylthio and ethylthio.
Chilthio, propylthio, isopropylthio, butylthio
Chilthio, tert-butylthio, pentylthio,
A straight chain having 1 to 6 carbon atoms such as xylthio group or
An example is a branched alkylthio group. As a lower alkanoyloxy group, formyl
Oxy, acetyloxy, propionyloxy,
Butyryloxy, Isobutyryloxy, Pentano
yloxy, tert-butylcarbonyloxy,
Straight chain with 1 to 6 carbon atoms such as xanoyloxy group or
An example is a branched alkanoyloxy group. As the phenyl lower alkanoyl group, 2-phenyl
enylacetyl, 3-phenylpropionyl, 4
-Phenylbutyryl, 2-phenylbutyryl, 6
-Phenylhexanoyl, 2-phenylpropio
nyl, 3-phenylbutyryl, 4-phenyl-3
-Methylbutyryl, 5-phenylpentanoyl,
2-methyl-3-phenylpropionyl group etc.
Straight or branched chain with 1 to 6 carbon atoms in the lucanoyl moiety
Examples include alkanoyl groups such as Lower alkoxy as a substituent on the phenyl ring
group, lower alkyl group, halogen atom, nitro group,
Cyano group, amino group, hydroxyl group, lower alkanoyl
Amino group, lower alkylthio group and lower alkano group
1 to 3 groups selected from the group consisting of yloxy groups or
is a phenyl compound with a lower alkylenedioxy group.
As the class alkanoyl group, 2-(2-chloroph)
enyl)acetyl, 2-(3-chlorophenyl)
Acetyl, 2-(4-chlorophenyl)acetyl
3-(2-fluorophenyl)propioni
4-(3-fluorophenyl)butyryl, 2
-(4-fluorophenyl)acetyl, 5-(2
-bromphenyl)pentanoyl, 6-(3-butyl)
romphenyl)hexanoyl, 2-methyl-3-
(4-bromphenyl)propanoyl, 2-(3
-iodophenyl)acetyl, 2-(4-iodo
phenyl)acetyl, 2-(3,5-dichloroph)
enyl)acetyl, 2-(3,4-dichlorophene)
acetyl, 3-(2,6-dichlorophenylene)
) propionyl, 4-(3,4-dichlorophene)
butyryl, 2-(3,4-difluorophe)
acetyl, 5-(3,5-dibromphene)
) pentanoyl, 6-(3,,4,5-tric)
rolfenyl)hexanoyl, 2-(4-methyl
phenyl)acetyl, 2-(2-methylphenyl)
) Acetyl, 2-(3-methylphenyl)acetyl
Chill, 3-(3-ethylphenyl)propioni
4-(2-ethylphenyl)butyryl, 5-
(4-ethylphenyl)pentanoyl, 6-(3
-isopropylphenyl)hexanoyl, 2-methane
Chil-3-(4-hexylphenyl)propioni
2-(3,4-dimethylphenyl)acetylene
2-(2,5-dimethylphenyl)acetylene
2-(3,4,5-trimethylphenyl)a
Cetyl, 2-(4-methoxyphenyl)acetyl
2-(3,4-dimethoxyphenyl)acetylene
2-(3,4,5-trimethoxyphenyl)
Acetyl, 2-(3-methoxyphenyl)acetyl
2-(2-methoxyphenyl)acetyl, 3
-(2-ethoxyphenyl)propionyl, 4-
(4-ethoxyphenyl)butyryl, 5-(3-
ethoxyphenyl)pentanoyl, 6-(4-i)
Sopropoxyphenyl)hexanoyl, 2-(4
-hexyloxyphenyl)acetyl, 2-methy
Ru-3-(3,4-dimethoxyphenyl)propyl
onyl, 2-(3,4-dimethoxyphenyl)a
Cetyl, 2-(3,4-diethoxyphenyl)a
Cetyl, 2-(3,4,5-trimethoxyphenylene)
) acetyl, 2-(2,5-dimethoxyphenyl)
) Acetyl, 2-(3-nitrophenyl)acetyl
Chil, 2-(2-nitrophenyl)acetyl, 2
-(4-nitrophenyl)acetyl, 3-(2,
4-dinitrophenyl)propionyl, 4-(2
-aminophenyl)butyryl, 5-(3-amino
phenyl)pentanoyl, 6-(4-aminophenylene)
nyl)hexanoyl, (2,4-diamino)phene
Nylacetyl, 2-cyanophenylacetyl, 2
-(3-cyanophenyl)acetyl, 2-methyl
-3-(4-cyanophenyl)propionyl, 2
-(2,4-dicyanophenyl)acetyl, 2-
(3,4-methylenedioxyphenyl)acetyl,
2-(3,4-ethylenedioxyphenyl)acetate
Chil, 2,3-methylenedioxyphenylacetyl
2-(3,4-methylenedioxyphenyl)
Acetyl, 2-(3,4-ethylenedioxyphene)
acetyl, 2-(3-methyl-4-chloro)
phenyl)acetyl, 2-(2-chloro-6-meth)
tylphenyl)acetyl, 2-(2-methoxy-
3-chlorophenyl)acetyl, 2-(2-hydro
roxyphenyl)acetyl, 2-(3,4-dihyphenyl)
droxyphenyl)acetyl, 2-(3-hydro
xyphenylacetyl, 3-(4-hydroxyphenyl)
enyl)propionyl, 6-(3,4-dihydro
xyphenyl)hexanoyl, 2-(3,4,5
-trihydroxyphenyl)acetyl, 2-(2
-formylaminophenyl)acetyl, 2-(3
-acetylaminophenyl)acetyl, 3-(2
-acetylaminophenyl)propionyl, 4-
(4-acetylaminophenyl)butyryl, 2-
(2-propionylaminophenyl)acetyl,
3-(3-butyrylaminophenyl)propioni
4-(4-isobutyrylaminophenyl)butylene
Tyryl, 5-(2-tert-butylcarbonylamine)
nophenyl) pentanoyl, 6-(3-pentano
ylaminophenyl)hexanoyl, 2-(2,
4-diacetylaminophenyl)acetyl, 2-
(4-methylthiophenyl)acetyl, 2-(2
-Methylthiophenyl)acetyl, 2-(3-methyl)
methylthiophenyl)acetyl, 3-(3-ethyl)
thiophenyl)propionyl, 4-(2-ethyl)
thiophenyl)butyryl, 5-(4-ethylthio)
phenyl)pentanoyl, 6-(3-isopropylene)
ruthiophenyl)hexanoyl, 2-methyl-3
-(4-hexylthiophenyl)propioni
2-(3,4-dimethylthiophenyl)acetate
Chil, 2-(2,5-dimethylthiophenyl)a
Cetyl, 2-(3,4,5-trimethoxyphenylene)
) Acetyl, 2-(4-acetyloxyphenylene)
) acetyl, 2-(3,4-acetyloxyph)
enyl)acetyl, 2-(3,4,5-triacetyl)
tyloxyphenyl)acetyl, 2-(3-acetyl)
tyloxyphenyl)acetyl, 2-(2-acetyl)
tyloxyphenyl)acetyl, 3-(2-pro
pionyloxyphenyl)propionyl, 4-
(4-pentanoyloxyphenyl)butyryl,
5-(3-propionyloxyphenyl)penta
Noyl, 6-(4-isobutyryloxyphenylene)
) hexanoyl, 2-(4-hexanoyloxy)
cyphenyl) acetyl, 2-(4-butyryl oxychloride)
Cyphenyl) Substituted on the phenyl ring such as acetyl group
Straight chain or branched alkoxycarbonate having 1 to 6 carbon atoms as a group
xy group, straight chain or branched alkyl group having 1 to 6 carbon atoms
group, halogen atom, nitro group, cyano group, amino group
group, hydroxyl group, straight chain or branched chain having 1 to 6 carbon atoms
Alkanoylamino group, straight chain having 1 to 6 carbon atoms or
Branched alkylthio group and straight chain with 1 to 6 carbon atoms
or a branched alkanoyloxy group.
Straight chain with 1 to 3 exposed groups or 1 to 4 carbon atoms or
May have a branched alkylene dioxy group
A straight chain or branched chain having 1 to 6 carbon atoms having a phenyl group
An example is a branched alkanoyl group. Compounds of the invention can be produced by a variety of methods.
However, a preferable example is the following reaction scheme:
- Manufactured by the method shown in 1. [In the formula, X is a halogen atom, lower alkane sulfo
Nyloxy group, arylsulfonyloxy group, a
Indicates a ralkylsulfonyloxy group or a hydroxyl group.
R ¹ ,R ² ,R ³ and positions 3 and 4 of the carbostyril skeleton.
The carbon-carbon bond with the position is the same as above. ] In general formula (3), a halogen atom represented by X
Specifically, chlorine, fluorine, bromine and iodine
as a lower alkanesulfonyloxy group.
Specifically, methanesulfonyloxy, ethane
Sulfonyloxy, isopropanesulfonyloxy
cy, propanesulfonyloxy, butanesulfony
fluoroxy, tert-butanesulfonyloxy, pen
Thanesulfonyloxy, hexanesulfonyloxy
Examples include cy groups, and arylsulfonyl groups.
Specifically, phenylsulfonyloxy group is
cy, 4-methylphenylsulfonyloxy, 2-
Methylphenylsulfonyloxy, 4-nitroph
enylsulfonyloxy, 4-methoxyphenyl
Sulfonyloxy, 3-chlorophenylsulfony
group, α-naphthylsulfonyloxy group, etc.
Substituted or unsubstituted arylsulfonyloxy group
For example, aralkylsulfonyloxy group and
Specifically, benzylsulfonyloxy, 2
-Phenylethylsulfonyloxy, 4-phenyl
Rubbutylsulfonyloxy, 4-methylbenzyl
Sulfonyloxy, 2-methylbenzylsulfony
4-nitrobenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy
cy, 4-methoxybenzylsulfonyloxy, 3
-Chlorbenzylsulfonyloxy, α-naphthi
Substituted or unsubstituted methylsulfonyloxy group, etc.
Examples include aralkylsulfonyloxy groups. Among the compounds of general formula (3) as starting materials, X is
rogen atom, lower alkanesulfonyloxy group,
Arylsulfonyloxy group or aralkylsulfur
When using a compound exhibiting a fonyloxy group,
Reaction between the compound of general formula (2) and the compound of general formula (3)
generally involves the presence of a basic condensing agent in a suitable inert solvent.
It is carried out in the presence or absence of the person. The metal used
Examples of active solvents include benzene, toluene, and
Aromatic hydrocarbons such as silene, methanol, ethanol
Lower grades such as alcohol, isopropanol, butanol, etc.
Alcohols, acetic acid, ethyl acetate, dimethylsulfate
Phoxide, dimethylformamide, hexamethyl
Examples include phosphoric acid triamide. Also
Examples of basic condensing agents include sodium carbonate and charcoal.
acid potassium, sodium bicarbonate, potassium bicarbonate
Carbonates such as aluminum, sodium hydroxide, potassium hydroxide
Metal hydroxides such as um, sodium methylate,
Metal alcoholates such as sodium ethylate,
Tertiary amines such as lysine, triethylamine, etc.
can be mentioned. Compound of general formula (2) and general formula
There is no particular limitation on the ratio of use with compound (3).
You can choose as appropriate within a wide range, but for the former
The latter is usually in at least an equimolar amount, preferably in an equimolar amount.
is preferably used in an equimolar to 5-fold molar amount. The reaction is
Usually carried out at about 40 to 120℃, preferably 50 to 100℃.
Generally, the reaction is completed in about 5 to 30 hours.
Ru. In the compound of general formula (3) as a starting material, X is water.
When using a compound showing an acid group, general formula (2)
The reaction between the compound and the compound of general formula (3) is dehydration condensation.
in the presence of a solvent without a solvent or in an appropriate solvent.
It will be done. The dehydration condensation agent used is, for example, polyester.
Condensed phosphoric acids such as phosphoric acid, orthophosphoric acid, pyrophosphoric acid,
Phosphates such as metaphosphoric acid, phosphorous such as orthophosphorous acid
Acids, phosphoric anhydrides such as phosphorus pentoxide, hydrochloric acid, sulfur
Acids, acids such as boric acid, sodium phosphate, boron
Phosphate, ferric phosphate, aluminum phosphate
Metal phosphates such as aluminum, activated alumina, sodium bisulfate
Thorium, Raney nickel, etc. can be mentioned.
Ru. In addition, the solvent used is, for example, dimethyl
High boiling point solvents such as formamide and tetralin are listed.
can be done. The compound of general formula (2) and the compound of general formula (3)
There are no particular restrictions on the ratio of use with compounds, and there is a wide range of usage ratios.
You can choose as appropriate within the range, but usually the former
of the latter in an equimolar amount or more, preferably an equimolar amount
It is preferable to use a molar to twice the molar amount. dehydration condensation agent
The amount used is not particularly limited and can be selected from a wide range.
However, the compound of general formula (2) is usually used as a catalyst.
amount or more, preferably about 0.5 to 5 times the molar amount
It is better. In the above reaction, the advantageous oxidation reaction is prevented.
For example, carbon dioxide or
It is preferable to carry out the reaction in a nitrogen stream. the above
The reaction can be carried out both under normal pressure and under pressure.
However, it is preferable to carry out the reaction under normal pressure. Up
The reaction temperature is usually about 100 to 350℃, preferably 125 to 350℃.
Proceeds optimally at 255℃, generally for about 3 to 10 hours
The reaction ends. In addition, in the above reaction, the general formula
The compound (3) may be used in the form of a salt. [R in the formula ³ ' is lower alkanoyl group, phenyl ring
A lower alkoxy group or a halogen group as a substituent on the
child, lower alkyl group, cyano group, nitro group, amino group
- group, hydroxyl group, lower alkanoylamino group, lower
Alkylthio group and lower alkanoyloxy group
1 to 3 groups selected from the group of
Phenylcarboxylic acid that may have dioxy group
Nyl group, phenylalkanoyl group, furoyl group,
Pyridylcarbonyl group or lower alkoxycarbo
Indicates a nyl group. X ¹ indicates a hydroxyl group. R ¹ ,R ² as well as
Carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton
is the same as above. ] The method shown in Reaction Scheme-2 is expressed by general formula (4).
The carbostyryl derivative represented by general formula (5)
A normal amide bond formation reaction with the carboxylic acid
This is a method of reacting at Amide bond formation reaction
This simplifies the conditions for the known amide bond formation reaction.
It can be applied to For example (a) mixed acid anhydride
In other words, alkylhalocarboxylic acid is added to carboxylic acid (5).
React to form a mixed acid anhydride, to which amine (4) is added.
Reaction method (b) Active ester method, i.e. carvone
acid (5) as p-nitrophenyl ester, N-hydro
Xysuccinimide ester, 1-hydroxybenzene
active esters such as zotriazole esters and
and (3) a method of reacting amine (4) with this.
Diimide method, in which amine (4) is added to carboxylic acid (5)
lohexylcarbodiimide, carbonyldiimide
A method of condensation in the presence of an activator such as sol,
(d) Another method is to convert carboxylic acid (5) into acetic anhydride, etc.
A dehydrating agent converts it into a carboxylic acid anhydride, which is then converted into an amine.
Method of reacting carbon (4) with carboxylic acid (5) and lower alkali
Adding amine (4) to ester with cocol under high pressure and high temperature
Method of reaction, acid halide of carboxylic acid (5)
That is, reacting carboxylic acid halide with amine (4)
Examples include methods. Mixed acid anhydride used in mixed acid anhydride method
can be obtained by the usual Schotten-Baumann reaction.
This is usually reacted with amine (4) without isolation.
The compound of the present invention of general formula (1a) can be prepared by
is manufactured. Schotten-Baumann reaction is a base
carried out in the presence of a chemical compound. Basicity used
As a compound, it is commonly used in the Schotten-Baumann reaction.
For example, triethylamine,
Trimethylamine, pyridine, dimethylanili
N, N-methylmorpholine, 1,5-diazabisi
Kuro [4,3,0] Nonene-5 (DBN), 1,5
-Diazabicyclo[5,4,0]undecene-5
(DBU), 1,4-diazabicyclo[2,2,2]
Organic bases such as octane (DABCO), potassium carbonate
aluminum, sodium carbonate, potassium hydrogen carbonate, carbonated water
Examples include inorganic bases such as basic sodium. the reaction
is carried out at -20 to 100°C, preferably 0 to 50°C.
The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours.
done in time. The resulting mixed acid anhydride and amine
The reaction (4) is carried out at -20 to 150℃, preferably 10 to 50℃.
The reaction time is preferably 5 minutes to 10 hours.
It is carried out under conditions of 5 minutes to 5 hours. mixed acid anhydride
The method is generally carried out in a solvent. The solvent used is
Any solvent commonly used in the mixed acid anhydride method can be used.
Specifically, methylene chloride, chloroform
halogenated hydrocarbons such as dichloroethane,
Aromatic hydrocarbons such as benzene, toluene, xylene, etc.
elements, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, ethyl acetate,
Esters such as methyl acetate, N,N-dimethylphos
lumamide, dimethyl sulfoxide, hexamethylene
Aprotic polar solvents such as luric acid triamide
Which can be mentioned. Used in mixed acid anhydride method
The alkylhalocarboxylic acid used is chloroformic acid.
Methyl, methyl bromoformate, ethyl chloroformate,
Ethyl bromoformate, isobutyl chloroformate, etc.
can be lost. Carboxylic acid (5) and alkyl in this method
The ratio of halocarboxylic acid and amine (4) used is usually
The alkyl is used in combination with the amine (4).
1 to 1.5 times the group halocarboxylic acid and carboxylic acid (5)
Molar amounts may be used. In addition, by reacting amine (4) with carboxylic acid halide,
When a method is adopted, the reaction is performed using a basic compound.
The reaction is carried out in the presence of a suitable solvent. used
A wide range of known basic compounds can be used.
For example, it can be used in the above-mentioned Schotten-Baumann reaction.
In addition to basic compounds, sodium hydroxide,
Potassium hydroxide, sodium hydride, potassium hydride
Um etc. can be mentioned. the solvent used and
For example, for the Schotten-Baumann reaction mentioned above,
In addition to the solvents used, methanol and ethanol
alcohol, propanol, butanol, 3-methoxy-
1-butanol, ethyl cellosolve, methyl cello
Alcohols such as Solv, pyridine, acetone, etc.
can be mentioned. Amine (4) and carboxylic acid ha
There is no particular restriction on the ratio of use with rides, and there is a wide range.
You can choose as appropriate within the range, but usually for the former
and the latter in at least equimolar amounts, preferably equimolar amounts.
It is preferable to use a molar to 5 times molar amount. The reaction is usually
-20~180℃, preferably 0~150℃
Generally, the reaction is completed in 5 minutes to 30 hours. [R in the formula ³ ″ is lower alkanesulfonyl group, lower
Alkoxycarbonyl lower alkyl group, phenyl
Having a lower alkyl group as a substituent on the ring
phenylsulfonyl group, lower alkyl group,
lower alkenyl group, lower alkynyl group or phenylene
Lower alkoxy group, lower alkyl group as a substituent on the ring
alkyl group, halogen atom, nitro group, cyano group,
Amino group, hydroxyl group, lower alkanoylamino group,
Lower alkylthio group and lower alkanoyloxy
1 to 3 groups selected from the group consisting of
Phenyl compounds that may have a kylenedioxy group
represents a class alkyl group. X ² indicates a halogen atom.
R ¹ ,R ² and the 3rd and 4th positions of the carbostyril skeleton.
The carbon-carbon bonds in are the same as above. ] A compound represented by general formula (4) and a compound represented by general formula (6)
The reaction with the compound represented by the general formula (4)
under conditions similar to the reaction between and carboxylic acid halide.
It is done. Furthermore, in the compound represented by general formula (1), R ¹ but
Indicates a hydrogen atom and the 3rd position of the carbostyril skeleton
Compounds in which the carbon-carbon bond with the 4th position is a double bond are:
As shown in the reaction scheme-4 below, lactam-lactam
Possible chim-type tautomerism. [R in the formula ² and R ³ is the same as above. ] Also, among the compounds represented by general formula (1c),
Compounds in which the substituent on the enyl ring represents an amino group are:
Compounds where the substituent on the phenyl ring is a nitro group
It is easily produced by reduction. This reduction
For example, reducing an aromatic nitro group to an aromatic amino group
It is possible to adopt the usual conditions for
Those who use reducing agents such as sodium sulfate and sulfur dioxide gas
method, contact using a reduction catalyst such as palladium-carbon
A reduction method etc. can be used. Of the compounds represented by the above general formula (1), R ² but
Compounds exhibiting a hydrogen atom have the corresponding R ² is a lower grade
Etherization of compounds exhibiting a lukoxy group
Also manufactured by. This ether decomposition is an example
Boron tribromide, boron trifluoride, aluminum chloride, etc.
is carried out in the presence of a Lewis acid. Lewis
It is usually best to use an excess amount of acid relative to the raw material compound.
stomach. The reaction temperature is usually around -30°C to room temperature.
Ru. Of the compounds of general formula (2) above, R ¹ and R ² is hydrogen
A compound in which an amino group is substituted at the 8-position (1)
Compounds of general formula (14) or (15)) follow the reaction process below.
It is also produced by the method shown in Formula-5. [R in the formula ^Four is a lower alkanoyl group, R ^Five is a lower class
Indicates a rukyl group. X ² is the same as above. ] Acylation of the compound of general formula (7) is carried out using a suitable acyl compound.
This is done by using a curing agent. reeds here
For example, lower alkanoic acids such as acetic acid,
Lower alkanoic anhydrides such as acetic anhydride, acetyl
Examples include lower alkanoic acid halides such as loride.
can be given. Lower alkali as acylating agent
using alkanoic acid anhydride or lower alkanoic acid halide.
When used, the acylation reaction is performed in the presence of a basic compound.
It takes place below. As the basic compound used
For example, metal sodium, metal potassium, etc.
alkali metals and hydroxides of these alkali metals,
Carbonate, bicarbonate, pyridine, piperidine, etc.
aromatic amine compounds, and the like. The reaction is
It proceeds either without solvent or in a solvent, but
This is usually carried out using a suitable solvent. as a solvent
For example, acetone, methyl ethyl ketone, etc.
ethers, ethers, dioxane, etc.
Aromatic hydrocarbons such as benzene, toluene, xylene, etc.
Examples include elementary substances, water, and the like. Acylating agent is a raw material compound
It is used in the range of equimolar to large excess of the substance.
However, it is generally better to use 5 to 10 times the mole. Ma
The reaction proceeds at 0 to 150°C, but generally at 0 to 150°C.
It is best to do this at ~80°C. Furthermore, acylating agent
When using lower alkanoic acids as
Mineral acids such as sulfuric acid and hydrochloric acid and paratoluene are used as dehydrating agents.
Benzenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid
Add sulfonic acids such as fonic acid, preferably 50
acyl by maintaining the reaction temperature at ~120 °C
The reaction proceeds favorably. The reduction of the nitro group of the compound of general formula (8) can be carried out, for example, by
Is it reduced using a catalytic reduction catalyst in an appropriate solvent?
or with a metal or metal salt in a suitable inert solvent.
Acids or metals or metal salts and alkali metal hydroxides
mixtures with substances, sulfides, ammonium salts, etc.
This is done by using it as a base agent and reducing it.
Ru. When using catalytic reduction of
For example, water, acetic acid, methanol, ethanol
Alcohols such as alcohol, isopropanol,
Hydrocarbons such as san, cyclohexane, diethyl
glycol dimethyl ether, dioxane, te
Ethers such as trahydrofuran and diethyl ether
esters such as ethyl acetate, methyl acetate,
Aprotic such as N,N-dimethylformamide
Examples include polar solvents. Catalytic reduction catalyst used
As a medium, for example, palladium, palladium-
Black, palladium-carbon, platinum, platinum oxide, subchrome
Muic acid copper, Raney nickel, etc. are used. catalyst
The amount used is 0.02 for the compound of general formula (8).
It is best to use ~1.00 times the weight. The reaction is usually -20
~ around room temperature, preferably around 0~room temperature, hydrogen pressure is
The reaction takes place at 1 to 10 atmospheres and takes about 0.5 to 10 hours.
It ends with. In addition, when using the method described above, iron,
Lead, tin or stannous chloride and mineral acids such as hydrochloric acid and sulfuric acid
or iron, ferrous sulfate, zinc or tin and sodium hydroxide.
Alkali metal hydroxides such as thorium, ammonium sulfide
Sulfides such as Ni, aqueous ammonia, ammonium chloride
A mixture with ammonium salts such as
It is used as The inert solvent used is
For example, water, acetic acid, methanol, ethanol,
Examples include xane. The conditions for the above reduction reaction are
The reducing agent should be selected appropriately depending on the reducing agent used.
For example, stannous chloride and hydrochloric acid are used as reducing agents.
If there is, it is advantageous to keep it at 0 to room temperature for about 0.5 to 10 hours.
It is better to carry out the reaction once. As the amount of reducing agent used
is generally at least equimolar to the starting compound.
It is usually used in an equimolar to 5-fold molar amount. Reaction between the compound of general formula (9) and the compound of general formula (10)
is usually at least equimolar of the former to the latter,
Except for preferably using 1 to 5 times the molar amount, the above formula
In the reaction between compound (4) and compound (5), compound (5) is
under the same conditions as the reaction using carboxylic acid halide.
However, in the absence of basic compounds,
The reaction continues. Reduction of the compound of general formula (11) is carried out without solvent in the presence of an acid.
or in a suitable solvent. as an acid
There are no particular limitations on this, and ordinary inorganic acids and organic acids can be widely used
Specifically, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
Inorganic acids, aluminum chloride, boron trifluoride, tetrachloride
Lewis acids such as titanium, formic acid, acetic acid, ethanesulfonate
Examples include organic acids such as phosphoric acid and p-toluenesulfonic acid.
can be shown. Among these acids, hydrochloric acid, hydrogen bromide
Acids, sulfuric acid, etc. are preferred. As the amount of such acid used
is usually at least equal weight to the compound of general formula (11).
It is best to use 10 to 50 times the weight of the acid.
stomach. Also, common inert solvents are widely used as solvents.
For example, water, methanol, ethanol,
Lower alcohols such as lopanol, dioxane,
Ethers such as tetrahydrofuran, benzene,
Aromatic hydrocarbons such as toluene, methylene chloride,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride
elements, acetone, dimethyl sulfoxide, dimethy
Formamide, hexamethyl phosphate triamide
etc. can be exemplified. Among these, the lower alcohol
alcohols, ethers, acetone, dimethyl sulfonate
oxide, dimethylformamide, hexamethylformamide
Water-soluble solvents such as acid triamide are preferred. Applicable
The temperature is usually 0 to 100℃, preferably room temperature to 60℃.
The reaction usually takes about 5 minutes to 6 hours to complete.
Ru. Conventional catalytic reduction conditions are used for reduction of the compound of general formula (12).
applicable. The catalyst used is paradi
um, palladium-carbon, platinum, ranenitz
An example of this is metals such as kerosene.
It is best to use medium amounts. Also used as a solvent
For example, methanol, ethanol, isopropyl
Nor, dioxane, THF, hexane, cyclo
Examples include hexane and ethyl acetate.
The reduction reaction is carried out both under normal pressure and under increased pressure.
However, normal pressure ~ 20Kg/cm ² , preferably
is normal pressure ~ 10Kg/cm ² It is better to do it at Reaction again
The temperature is usually about 0 to 150℃, preferably room temperature.
It is best to keep the temperature between 100℃ and 100℃. Hydrolysis of the compound of general formula (12) or (13) can be carried out as appropriate.
carried out in the presence of an acid or basic compound in a suitable solvent.
It will be done. Examples of solvents include water, methanol, and ethanol.
Lower alcohols such as alcohol and isopropanol
ethers such as dioxane, tetrahydrofuran, etc.
and mixtures of these solvents.
Ru. Examples of acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
mineral acids, etc., and basic compounds such as water.
Sodium oxide, potassium hydroxide, calci hydroxide
metal hydroxides such as
can. The reaction is usually carried out at room temperature to 150°C, preferably
Proceeds best at 80-120°C, generally for 1-15 hours
The reaction ends at a certain point. Carbostyryl represented by general formula (1) of the present invention
Derivatives can be prepared by the action of pharmaceutically acceptable acids.
It can be easily converted into an acid addition salt by Applicable
Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, and aqueous bromide.
Inorganic acids such as elementary acid, oxalic acid, maleic acid, fumer
Ruic acid, malic acid, tartaric acid, citric acid, benzoic acid, etc.
organic acids. Further, the carbostyl alcohol represented by the general formula (1) of the present invention
Among the ryl derivatives, compounds with acidic groups are used as pharmaceuticals.
By applying a basic compound that is permissible to
Salts can be formed more easily. the base
Examples of chemical compounds include sodium hydroxide and hydroxyl.
potassium chloride, calcium hydroxide, sodium carbonate
and potassium hydrogen carbonate. The target compound obtained in each step in this way
can be easily isolated and purified by conventional separation means.
I can do it. The separation means includes, for example, solvent extraction.
Extraction method, dilution method, recrystallization method, column chromatography
E, preparative thin layer chromatography, etc.
can be exemplified. Note that the present invention naturally includes optical isomers.
be. Compounds of general formula (1) are usually used in common pharmaceutical formulations.
used in form. The formulation is usually used for filling
agent, filler, binder, wetting agent, disintegrant, surface active
using diluents or excipients such as agents, lubricants, etc.
prepared. This pharmaceutical preparation comes in various forms.
It can be selected depending on the treatment purpose, and the typical
Tablets, pills, powders, solutions, suspensions, emulsions, granules
Granules, capsules, suppositories, injections (solutions, suspensions)
etc.). To form into tablet form
In this case, carriers that are conventionally known in this field may be used.
can be widely used, e.g. lactose, sucrose, sodium chloride
um, glucose, urea, starch, calcium carbonate
minerals, kaolin, crystalline cellulose, silicic acid, etc.
Excipients, water, ethanol, propanol, single syrup
liquid, glucose solution, starch solution, gelatin solution,
Ruboxymethyl cellulose, shellac, methylcellulose
Lulose, potassium phosphate, polyvinylpyrrolid
Binders such as starch, dried starch, sodium alginate
aluminum, agar powder, laminaran powder, sodium bicarbonate
Thorium, calcium carbonate, polyoxyethylene
Sorbitan fatty acid esters, sodium lauryl sulfate
Lium, stearic acid monoglyceride, starch
disintegrants such as lactose, sucrose, stearin, and cocoa.
Disintegration inhibitors such as butter, hydrogenated oil, etc., quaternary
Ammonium base, sodium lauryl sulfate, etc.
Moisturizing agents such as absorption enhancers, glycerin, and starch
agent, starch, lactose, kaolin, bentonite,
Adsorbents such as colloidal silicic acid, purified talc,
Tearate, boric acid powder, polyethylene glycol
Examples include lubricants such as . Furthermore, the tablets
Tablets with a conventional coating if necessary, e.g. sugar-coated
Tablets, gelatin-covered tablets, dissolvable tablets, film-coated tablets
It can be made into single-layered tablets, double-layered tablets, or multi-layered tablets.
Wear. When molding into pill form, carrier and
Therefore, it is possible to use a wide range of conventionally known products in this field.
For example, glucose, lactose, starch, cocoa butter, hard
Excipients such as chemically modified vegetable oils, kaolin, and talc,
Beer gum powder, tragacanth powder, gelatin, ethanol
Disintegration of binders such as silica, laminalan agar, etc.
Examples include agents. When forming into suppository form
Therefore, conventionally known carriers can be widely used.
For example, polyethylene glycol, cocoa butter,
Higher alcohols, esters of higher alcohols,
List gelatin, semi-synthetic glycerides, etc.
Can be done. When prepared as an injection, the liquid
Agents and suspensions are sterile and isotonic with blood.
These solutions, emulsions and suspensions are preferably
When molding into the form of
Use everything that is customary in the field of
For example, water, ethyl alcohol, propylene
Glycol, ethoxylated isostearyl alcohol
polyoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Lioxyethylene sorbitan fatty acid esters
What can you name? In this case, isotonic
Add enough salt, glucose, and
Alternatively, glycerin may be included in cardiotonic drugs.
It also contains conventional solubilizing agents, buffering agents, soothing agents, etc.
You can add anything. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavors, sweeteners, etc. and other pharmaceutical products
may be included during the treatment. of the general formula (1) to be contained in the cardiotonic agent of the present invention.
The amount of the compound is not particularly limited and can be selected from a wide range.
usually 1 to 70% by weight of the total composition, preferably
It is 1 to 30% by weight. There are no particular restrictions on the method of administering the cardiotonic agent of the present invention.
various drug formulations, patient age, gender, and other conditions.
The method of administration depends on the condition and severity of the disease.
For example, tablets, pills, solutions, suspensions, emulsions, granules
and oral administration in the case of capsules. Ma
In the case of injections, it may be used alone or with glucose, alcohol, etc.
Administered intravenously by mixing with regular fluids such as amino acids.
In addition, if necessary, intramuscular, intradermal,
Administered subcutaneously or intraperitoneally. In the case of suppositories
Administered directly into the abdomen. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
Appropriate selection based on gender, other conditions, severity of disease, etc.
The compound of general formula (1), which is usually an active ingredient,
The amount should be approximately 0.1 to 10 mg per kg of body weight per day.
It is better. It is also possible to contain two or more active ingredients in a dosage unit form.
It is best to contain ~200mg. Reference examples and examples are listed below. Reference example 1 Add 29.3 ml of concentrated nitric acid to 50 ml of concentrated sulfuric acid under external ice cooling and stirring.
Add 50g of m-chlorobenzaldehyde
is added dropwise at a temperature below 5°C. Stir for 1 hour at room temperature
After that, pour the reaction mixture into ice and remove the precipitated solid.
do. After washing the precipitated solid with water, dissolve it in methylene chloride.
Then, wash the methylene chloride layer with dilute caustic soda aqueous solution.
After further washing with water, dry with sodium sulfate and remove the solvent.
to remove. 62.3g of 2-nitro-5-chlorobe
Obtain nzaldehyde. mp65～69℃ Reference example 2 2-nitro-5-chlorobenzaldehyde 100
Dissolve g in 1000ml of toluene. Next, p-Tolue
10g of sulfonic acid and 87.8g of ethyl orthoformate.
Add and stir at room temperature for 1 hour. dilute caustic soda water
Neutralize with a solution, wash the toluene layer with water, and then add anhydrous sulfuric acid.
Dry with thorium and concentrate to produce 138g of oil.
2-nitro-5-chlorobenzaldehyde
Obtain tylacetal. Reference example 3 2-nitro-5-chlorobenzaldehyde diethyl
Dissolve 138g of tylacetal in 750ml of DMF,
Add 250g of water piperazine and stir at 80℃ for 4 hours.
Ru. Excess piperazine and DMF were distilled off under reduced pressure,
Add dilute caustic soda aqueous solution to the residue, and after dissolving it, add chloride solution to the residue.
Extract with tyrene. After washing the methylene chloride layer with water,
After drying with sodium sulfate, the solvent is distilled off. residue
Add 850ml of isopropyl alcohol to dissolve
Ru. Add 65 ml of concentrated HCl and heat to reflux for 1 hour. cold
After cooling, remove the precipitated crystals. 93g of 2-nitro-
Obtain 5-piverazinylbenzaldehyde hydrochloride
Ru. mp 195-201℃ Reference example 4 2-nitro-5-piverazinylbenzaldehy
Dissolve 47g of hydrochloride in 500ml of pyridine and add piperidine.
Add 5g of malonic acid and 100g of malonic acid and heat under reflux for 5 hours.
Ru. After cooling, collect the precipitated crystals. to the crystals taken
Add 100 ml of methanol and heat under reflux for 1 hour. cold
I will take over the refusal. 42g of 2-nitro-5-piveraj
Obtain nylcinnamic acid. mp 229-237℃ Reference example 5 10g of 2-nitro-5-piverazinylcinnamic acid
Suspend in 100ml of ethyl alcohol and stir with external ice cooling.
Drop 3 ml of thionyl chloride at the bottom. 3 hours
Heat to reflux. Ethyl alcohol, thionylchloride
Distill the ride and add isopropanol to the residue.
Heat, melt, and cool. yellow crystals that precipitate
take. 4.3g of 2-nitro-5-piveragini
cinnamic acid ethyl ester hydrochloride is obtained. mp 210-220℃ Reference example 6 2-nitro-5-piverazinylbenzaldehy
Suspend 5g of DMF in 50ml of DMF, add triethylamine
Add 6 ml of 3,4-dimethoxychloride under external ice-cooling and stirring.
Dissolve 4.4g of cybenzoyl chloride in 20ml of DMF
Add the solution dropwise. Stir at room temperature for 2 hours until saturated.
Pour into Japanese salt water. Extracted with methylene chloride
After washing the methylene chloride layer with water, remove the anhydrous sodium sulfate layer.
Dry in a vacuum. Distill the solvent and remove methyl alcohol.
Add, heat, cool, and remove. Re-use in DMF
It crystallized and gave 4.5 g of 2-nitro-5-[4-(3,
4-dimethoxybenzoyl)-1-piperazini
] Obtain yellow crystals of benzaldehyde. mp 196-198℃ Reference example 7 2-nitro-5-[4-(3,4-dimethoxy
benzoyl)-1-piperazinyl]benzalde
Add 4g of Hyde to 20ml of pyridine, dissolve it, and
Add 2.1g of acid and 0.4ml of piperidine and heat at 80℃ for 4 hours.
Stir for a while. Concentrate pyridine and piperidine,
Pour into dilute hydrochloric acid aqueous solution and extract with methylene chloride.
Ru. Wash the methylene chloride layer with water and concentrate the solvent.
Add methanol to the residue, cool it, and remove the precipitated crystals.
take. 3.7g of 2-nitro-5-[4-(3,
4-dimethoxybenzoyl)-1-piperazini
] Obtain cinnamic acid. mp 197～202℃ Reference example 8 2-nitro-5-[4-(3,4-dimethoxy
12g of benzoyl)piperazino]cinnamic acid in concentrated hydrochloric acid
Dissolve in 60ml. Concentrate 20g of stannous chloride in this.
A solution dissolved in 40 ml of hydrochloric acid is added dropwise at room temperature. 2
After stirring for an hour, collect the precipitated crystals. meta this crystal
Dissolved in 240ml of alcohol and 10% caustic soda aqueous solution.
Neutralize and remove the precipitated crystals. methanol solution
Concentrate and recrystallize from ethanol. 2 of 6.3g
-Amino-5-[4-(3,4-dimethoxyben)
zoyl)piperazino]cinnamic acid is obtained. mp 168-170.5℃ Pale yellow powder crystal reference example 9 2-amino-5-[4-(3,4-dimethoxy
5 g of cinnamic acid (benzoyl) piperazino
5% palladium on carbon dissolved in a mixed solvent of alcohol and water
Add 0.5g and reduce at normal pressure. Theoretical amount of hydrogen
After absorbing the ethanol and water, pass through the catalyst.
Concentrate to dryness. Silica dissolved in chloroform
Decomposed by gel chromatography, 1.5g of 3-[2-
Amino-5-{4-(3,4-dimethoxybenzo
yl)piperazino}phenyl]propionic acid was obtained.
Ru. mp 98～101℃ Reference example 10 3-[2-amino-5-{4-(3,4-dime
Toxybenzoyl) piperazino} phenyl} pro
Dissolve 4.4 g of pionic acid in 40 ml of acetic acid, and dissolve 1.1 g of acetic anhydride.
g and stirred at room temperature for 1 hour. After concentrating acetic acid
Add water. Take the precipitated crystals. Acetate after washing with water
Recrystallize in a mixed solvent of water and water. 1.5g of 3-
[2-acetylamino-5-{4-(3,4-di
methoxybenzoyl)piperazino}phenyl
Obtain lopionic acid. mp 78.5～80.5℃ Reference example 11 Dissolve 300g of o-nitroaniline in 620ml of acetic anhydride.
Dissolve and stir at 40-50°C for 3 hours. reaction mixture
Pour into ice water, remove precipitated crystals, and dry.
The obtained o-acetylaminonitrobenzene is
Suspend in 2.4 ml of tanol, add 20 g of 10% Pd/C,
Catalytic reduction is carried out at room temperature and pressure. Catalyst after reaction
Separate and remove the solvent under reduced pressure to obtain crystals.
Ru. Wash this with ethanol and collect the resulting crystals.
Dry under reduced pressure over phosphorus pentoxide to obtain o-aminoacetate.
Obtain 248g of Nilide. Reference example 12 248g of o-acetylaminoaniline was dissolved in dimethyl
Dissolved in formamide 1 and stirred at room temperature.
Toxyacrylic acid chloride 114g dimethylform
Add 400 ml of Muamide solution dropwise over 3.5 hours. So
After that, stir for an additional 30 minutes at the same temperature. reaction mixture
Pour into ice water and remove the precipitated crystals to obtain 1-acetylene.
Ruamino-2-(β-ethoxyacryloylamide)
D) Obtain 84.9 g of benzene. Reference example 13 1-acetylamino-2-(β-ethoxyac
84.9g of benzene (liloylamide) was placed in concentrated sulfuric acid.
Gradually add while stirring warmly. After addition, leave at room temperature.
Stir for 2 hours. Place the reaction mixture in plenty of ice water.
Pour, remove the precipitated crystals, and add 8-acetylamino
Obtain 49.5 g of carbostyril. Reference example 14 15.0g of 8-acetylaminocarbostyryl was diluted with
Suspend in 300ml of oxane and add 2.0g of 10% Pd/C.
Then, catalytic reduction is carried out at 70-80°C and normal pressure. reaction
After completion, the catalyst was separated, the solvent was distilled off under reduced pressure, and 8-
Acetylamino-3,4-dihydrocarbostili
Obtain 14.3g. Reference example 15 8-acetylamino-3,4-dihydrocarbo
Suspend 11.8g of styryl in 90ml of 20% hydrochloric acid and heat to reflux.
Stir under flow for 1 hour. Pour the reaction mixture into ice water.
Mix well, neutralize with 5N sodium hydroxide, and
Add saturated sodium bicarbonate solution to adjust the pH to 8. Precipitated crystals
8-Amino-3,4-dihydrocarbosti
Obtain 7.87 g of Lil. Reference example 16 21.5g of 8-acetylaminocarbostyryl
Suspended in 190ml of % hydrochloric acid and stirred for 1 hour under heating and reflux.
do. Pour the reaction mixture into ice water and dilute with 5N-water.
Neutralize with sodium oxide. Take the precipitated crystals,
15.47 g of 8-aminocarbostyril is obtained. Example 1 6-amino-3,4-dihydrocarbostyryl
9.36g, bis-(β-bromoethyl)amine 1
A mixture of 18 g of hydrobromide and 70 ml of methanol
Stir and reflux for 15 hours. Sodium carbonate after cooling 3.06g
and stir and reflux for 8 hours. Crystals that precipitate after cooling
take. Wash with methanol and remove 9.1 g of 6-
(1-piperazinyl)-3,4-dihydrocarbo
Obtain styryl hydrobromide. mp 289-293℃ (decomposition) (methanol-water) Colorless needle crystals Elemental analysis C H N Calculated value (%) 50.00 5.77 13.46 Actual value (%) 49.95 5.82 13.50 Compound of Example 2 in the same manner as Example 1 get
Ru. Example 2 5-(1-piperazinyl)-3,4-dihydro
Carbostyril monohydrochloride monohydrate mp 300℃ or higher (methanol) Colorless needle crystals Example 3 6-Amino-3,4-dihydrocarbostyril
9.36g, N,N-(di-β-bromoethyl)-
18.3g of 3,4-dimethoxybenzamide and meth
A mixed portion of 70 ml of alcohol was stirred and refluxed for 15 hours. After cooling
Add 3.06 g of potassium carbonate and stir and reflux for 8 hours.
Ru. After cooling, collect the crystals that precipitate. with methanol
Wash and recrystallize with ethanol-chloroform.
8.5g of 6-[4-(3,4-dimethoxybenzo)
yl)-1-piperazinyl]-3,4-dihydro
I got carbostyril. mp 238-239.5℃ Colorless granular crystals Elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.71 6.51 10.52 Compounds of Examples 4-95 were prepared in the same manner as in Example 3.
Obtained. Example 4 6-[4-(4-methoxybenzyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 196-198℃ (ethanol) Colorless needle crystal Example 5 5-[4-(p-toluenesulfonyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril mp 302-304℃ (dimethylformamide) Colorless powder crystal Example 6 6-(4-butyl-1-piperazinyl)-3,
4-dihydrocarbostyryl monohydrochloride/1/2 water
Japanese salt mp 279-281℃ (decomposition) (methanol) Example 7 5-(4-benzoyl-1-piperazinyl)-
3,4-dihydrocarbostyryl mp 248-251℃ (ethanol) Colorless needle crystals Example 8 6-(4-benzoyl-1-piperazinyl)-
3,4-dihydrocarbostyryl mp 221-222.4℃ (ethanol) Pale yellow granular crystals Example 9 5-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril mp 207-208℃ (ethanol) Colorless powder crystal Example 10 5-[4-(3,4,5-trimethoxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 250-251.5℃ (isopropanol) Colorless granular crystal Example 11 6-[4-(3,4,5-trimethoxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 180-182℃ (isopropanol) Colorless granular crystal Example 12 6-[4-(4-methoxybenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Lyru hemihydrate mp 212-213℃ (methanol) Colorless needle crystal Example 13 6-(4-acetyl-1-piperazinyl)-
3,4-dihydrocarbostyryl mp 203-205℃ (isopropanol) Pale yellowish brown needle crystals Example 14 6-(4-furoyl-1-piperazinyl)-
3,4-dihydrocarbostyryl mp 206.5-207.5℃ (ethanol) Pale yellow granular crystals Example 15 6-[4-(2-propynyl)-1-piperazi
[Nil]-3,4-dihydrocarbostyryl mp 174-176℃ (isopropanol) Example 16 6-[4-(4-chlorobenzoyl)-1-dihydryl]
perazinil]-3,4-dihydrocarbostili
Le mp 233-235℃ Pale yellow needle crystals (methanol) Example 17 5-[4-(3,4-dichlorobenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbo
Styryl mp 250-252℃ (methanol) Colorless powder crystal Example 18 5-[4-(3,5-dichlorobenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbo
Styryl mp 255-257℃ (methanol-chloroform) Colorless needle crystals Example 19 6-[4-(4-bromobenzoyl)-1-pyri
perazinil]-3,4-dihydrocarbostili
Le mp 233-234.5°C Colorless granular crystals (methanol-chloroform) Example 20 5-(4-(4-cyanobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 266-269℃ Colorless granular crystals (methanol-chloroform) Example 21 6-[4-(4-nitrobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 235.5-236.5℃ (Methanol-Chloroform) Yellow phosphorous flakes Example 22 6-[4-(3,5-dinitrobenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbo
Styryl mp 262-264℃ (methanol-chloroform) Red-black needle crystals Example 23 6-[4-(4-aminobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 244-246℃ Pale yellow needle crystals (ethanol) Example 24 5-[4-(4-hydroxybenzoyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyril 300℃ or higher (methanol-chloroform) Colorless granular crystal Example 25 6-[4-(3,4-methylenedioxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 191-192.5℃ (methanol) Colorless needle crystals Example 26 5-[4-(4-methylbenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 239.5-240℃ (chloroform-ether) Colorless powder crystal Example 27 6-[4-(methanesulfonyl)-1-pipera
[dinyl]-3,4-dihydrocarbostyryl mp 241.5-243℃ Colorless granular crystals (methanol) Example 28 5-(4-ethyl-1-piperazinyl)-3,
4-dihydrocarbostyryl monohydrochloride mp 293-296℃ (decomposition) (methanol) Colorless granular crystal Example 29 6-(4-allyl-1-piperazinyl)-3,
4-dihydrocarbostyryl mp 175-176℃ (Chloroform-ether) Colorless phosphorus flakes Example 30 5-[4-(2-propynyl)-1-piperazi
Nyl]-3,4-dihydrocarbostyryl mp 225-226°C (chloroform) Pale yellow powder crystal Example 31 6-[4-(2-butenyl)-1-piperazine
]-3,4-dihydrocarbostyryl mp 242-245℃ (decomposition) Example 32 1-benzyl-6-[4-(3,4-dimethoxy)
cybenzoyl)-1-piperazinyl]-3,4
-Dihydrocarbostyryl hemihydrate mp 131.5-132.5℃ (ethanol) Yellow powder crystal Example 33 1-Allyl-5-[4-(3,4-dimethoxy)
benzoyl)-1-piperazinyl]-3,4-
Dihydrocarbostyryl hemihydrate mp 120-122℃ Methanol-ether) Colorless granular crystals Example 34 1-(2-propynyl)-6-[4-(3,4
-dimethoxybenzoyl)-1-piperazini
1-Methyl-6-[4-(3,4-dimethoxy)
benzoyl)-1-piperazinyl]-3,4-
Dihydrocarbostyril mp 146.5-147.5℃ (isopropanol) Pale yellow granular crystals Example 36 8-Methoxy-6-[4-(3,4-dimethoxy)
cybenzoyl)-4-piperazinyl]-3,4
-Dihydrocarbostyryl mp 162.5-163.5℃ (Isopropanol) Colorless needle crystals Example 37 6-[4-(3-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 195-197.5℃ Colorless phosphorus flakes (methanol) Example 38 5-[4-(4-methoxybenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril mp 219-220℃ (Methanol-Chloroform) Colorless needle crystals Example 39 5-(4-ethoxycarbonylmethyl-1-pi)
perazinil)-3,4-dihydrocarbostili
Le mp 206-208℃ (methanol) Colorless needle crystal Example 40 5-[4-(4-formyl)-1-piperazine
]-3,4-dihydrocarbostyryl mp 263-265℃ Colorless granular crystals (methanol) Example 41 6-(4-ethoxycarbonyl-1-piperazi
Nyl)-3,4-dihydrocarbostyryl mp 182.5-184℃ Colorless needle crystals (isopropanol) Example 42 5-[4-(4-methoxybenzyl)-1-dihydryl
perazinil]-3,4-dihydrocarbostili
Le mp 194-196℃ (methanol) Colorless needle crystal Example 43 6-[4-(2-phenethyl)-1-piperazi
]-3,4-dihydrocarbostyryl 1
Hydrochloride mp 274-276℃ (decomposition) (methanol) Colorless powder crystal Example 44 6-[4-(4-chlorobenzyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl mp 190-191.5℃ (chloroform-methanol) Colorless needle crystal Example 45 5-[4-(3,4-dichlorobenzyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyryl monohydrochloride monohydrate mp 298.5-300℃ (decomposition) (methanol) Colorless granular crystal Example 46 5-[4-(4-nitrobenzyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl mp 268-271℃ (decomposition) (methanol) Pale yellow powder crystal Example 47 5-[4-(4-aminobenzyl)-1-pipe
Radinyl]-3,4-dihydrocarbostiri
6-[4-(4-methylbenzyl)-1-pipe
Radinyl]-3,4-dihydrocarbostiri
Dihydrochloride mp 272-273℃ (decomposition) (methanol-water) Colorless powder crystal Example 49 5-[4-(3,4-dimethoxybenzyl)-
1-Piperazinyl]-3,4-dihydrocarbo
Styryl dihydrochloride mp 270-272.5℃ (decomposition) Example 50 6-(4-ethoxycarbonyl-1-piperazi
Nyl)-carbostyryl mp 223-224℃ (methanol) Yellow needle-like crystals Example 51 6-[4-(3-chlorobenzoyl)-1-pi
perazinil]-carbostyril mp 250.5-252℃ (methanol-chloroform) Colorless powder crystal Example 52 6-[4-(4-chlorobenzoyl)-1-pyridyl
perazinil]-carbostyril mp 265-266℃ (methanol-chloroform) Yellow powder crystal Example 53 6-[4-(4-methoxybenzoyl)-1-
Piperazinyl]-carbostyryl mp 230-233℃ (methanol-chloroform) Yellow needles Example 54 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-carbostyryl mp 265-266.5℃ (decomposition) (methanol-chloroform) Yellow granular crystals Example 55 6-[4-(3,4,5-trimethoxybenzo
yl)-1-piperazinyl]-carbostyryl mp 249.5-250℃ (methanol-chloroform) Yellow needle crystals Example 56 6-[4-(4-cyanobenzoyl)-1-pi
perazinil]-carbostyril mp 300-301℃ (decomposition) (methanol-chloroform) Yellow powdery crystals Example 57 6-[4-(3,4-methylenedioxybenzo
yl)-1-piperazinyl]-carbostyryl mp 266-267℃ (decomposition) (methanol-chloroform) Yellow powder crystal Example 58 6-[4-(4-nitrobenzoyl)-1-piperazinyl]-carbostyryl
Perazinyl]-carbostyril mp 265-266℃ (decomposition) (methanol-chloroform) Yellow needle-like crystals Example 59 6-[4-(4-aminobenzoyl)-1-pi
Perazinyl]-Carbostyril mp 287-290℃ (Methanol-Chloroform) Yellow powder crystal Example 60 6-(4-benzoyl-1-piperazinyl)-
Carbostyril mp 264-265℃ (ethanol-chloroform) Yellow needle crystals Example 61 5-[4-(4-acetylaminobenzoyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril mp 300℃ or higher (Chloroform-methanol) Colorless powder crystal Example 62 6-[4-(4-formyl)-1-piperazini]
[L] Carbostyryl mp 286.5-288℃ (methanol) Yellow scaly crystal Example 63 6-[4-(4-methylthiobenzoyl)-1
-Piperazinyl]carbostyryl mp 247.5-249.5℃ (chloroform-methanol) Yellow needle crystal Example 64 6-[4-(3-pyridylcarbonyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Lil mp 250-252℃ (ethanol) Yellow needle crystal Example 65 6-[4-(4-methoxyphenylacetyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril mp 266-268.5℃ (methanol) Yellow powder crystal Example 66 6-(4-phenylpropionyl-1-pipera)
(dinyl)-3,4-dihydrocarbostyryl mp 189.5-191℃ (chloroform-methanol) Yellow granular crystals Example 67 8-(4-benzoyl-1-piperazinyl)ka
Luvostyril mp 244-245℃ (ethanol) Colorless powder crystal Example 68 8-[4-(4-chlorobenzoyl)-1-pi
Perazinil] carbostyril mp 255.5-257℃ (ethanol-chloroform) Colorless powder crystal Example 69 8-[4-(3-chlorobenzoyl)-1-pyri
Perazinil] carbostyril mp 208-209℃ (ethanol) Colorless granular crystals Example 70 8-[4-(2-chlorobenzoyl)-1-pi
Perazinil] carbostyril mp 239-240.5℃ (ethanol) Colorless needle crystals Example 71 8-[4-(4-methoxybenzoyl)-1-
Piperazinyl] carbostyril mp 208-210℃ (ethanol) Colorless scaly crystals Example 72 8-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]carbostyryl mp 197-198℃ (ethanol/ether) Colorless flaky crystals Example 73 8-[4-(3,4-methylenedioxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 195-197℃ (ethanol) Colorless granular crystal Example 74 8-[4-(3-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 152-154℃ (ethanol) Colorless scaly crystal Example 75 8-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril mp 145-148℃ (ethanol) Colorless scaly crystals Example 76 8-[4-(4-methylthiobenzoyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyril mp 178-179.5℃ (ethanol) Colorless granular crystal Example 77 7-[4-(2-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 194-195.5℃ (methanol) Colorless needle crystal Example 78 7-[4-(3-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 136.5-138.5℃ (ethanol) Colorless powder crystal Example 79 7-[4-(4-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 289-291℃ (Chloroform-methanol) Colorless powder crystal Example 80 7-[4-(4-methoxybenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril mp 231-233℃ (ethanol) Colorless needle crystal Example 81 7-[4-(3,4-methylenedioxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 207-208℃ (ethanol) Colorless powder crystal Example 82 7-[4-(4-nitrobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostili
Le mp 240-242℃ (chloroform-methanol) Yellow granular crystal Example 83 7-[4-(3,4,5-trimethoxybenzo
yl)-1-piperazinyl]-3,4-dihyde
Locarbostyril mp 195-196.5℃ (methanol) Colorless edge-shaped crystal Example 84 7-(4-benzoyl-1-piperazinyl)
3,4-dihydrocarbostyryl mp 264.5-265.5℃ (chloroform-methanol) Colorless needle crystal Example 85 7-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril mp 118-120℃ (ethanol) Colorless granular crystal Example 86 7-[4-(4-methylthiobenzoyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyril mp 258-260℃ (chloroform-methanol) Colorless edge-shaped crystal Example 87 7-(4-phenylpropionyl-1-pipera)
(dinyl)-3,4-dihydrocarbostyryl mp 183-184℃ (ethanol) Colorless needle crystals Example 88 6-[4-(4-methoxyphenylacetyl)
-1-piperazinyl]carbostyryl mp 224-225℃ (ethanol) Yellow needle-like crystals Example 89 6-[4-(4-hydroxyphenylacetyl)
5-[4-(4-nitrobenzoyl)-1-piperazinyl]carbostyryl mp 300℃ or higher (dimethylformamide) Yellow powder crystal Example 90 5-[4-(4-nitrobenzoyl)-1-piperazinyl]
perazinil]-3,4-dihydrocarbostili
Le mp 292-294℃ (decomposition) (methanol-chloroform) Yellow granular crystals Example 91 5-[4-(4-aminobenzoyl)-1-pyri
perazinil]-3,4-dihydrocarbostili
Le mp 285-287℃ (decomposition) (methanol-chloroform) Yellow granular crystals Example 92 6-(1-piperazinyl) carbostyryl odor
Hydrohydride salt mp 300℃ or higher (water-ethanol) Pale yellow edge-shaped crystal Example 93 7-(1-piperazinyl)-3,4-dihydro
Carbostyryl hydrobromide mp 174-177℃ (ethanol) Colorless granular crystal Example 94 8-(1-piperazinyl)-3,4-dihydro
Carbostyryl hydrobromide mp 300℃ or higher (methanol-ether) Colorless needle crystal Example 95 8-(1-piperazinyl) carbostyryl odor
Hydrohydride salt mp 300℃ or higher (methanol-ether) Colorless scaly crystal Example 96 6-(1-piperazinyl)-3,4-dihydro
3.5g of carbostyril monohydrobromide in dimethylene
40 ml of formamide (hereinafter abbreviated as "DMF")
Suspend, add 960 mg of sodium hydrogen carbonate and bring to room temperature.
and stirred for 30 minutes to give 6-(1-piperazinyl)-3,
After making 4-dihydrocarbostyryl, triethyl
Add 2.34ml of Ruamine and stir at room temperature for 3.4ml.
-Contains 2.9g of dimethoxybenzoyl chloride
Gradually add 10 ml of DMF solution dropwise. Stir for 0 minutes after dropping
Stir. Pour into a large amount of saturated saline solution and convert into chloroform.
Extract. Saturated sodium bicarbonate solution, rinse with water, sulfuric anhydride
Dry with sodium. Distill the chloroform,
Recrystallize the residual crystals from chloroform-ethanol
mp238~239.5℃ 6-[4-(3,4-di)
methoxybenzoyl)-1-piperazinyl]-34
- Obtain 3.8 g of dihydrocarbostyril. Colorless granular crystal elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.69 6.49 10.51 Example 97 6-piperazinyl-3,4-dihydrocarbos
Suspend 10 g of tyryl monohydrobromide in DMF,
Add 296 mg of sodium hydrogen carbonate and stir at room temperature.
(30 minutes) and 6-piperazinyl-3,4-dihyde
locarbostyril and then triethylamine
After adding 0.62ml, m-chlorobenzoylchlora
Slowly drop the solution into 5 ml of DMF containing 532 mg of hydride.
After dropping, stir at room temperature for 1 hour. Pour into plenty of water.
Then extract with chloroform. saturated sodium bicarbonate
After washing with water and then drying with anhydrous sodium sulfate.
dry Chloroform is distilled off, and the residual crystals are metabolized.
Recrystallized with alcohol and obtained 6-[4
-(3-chlorobenzoyl)-1-piperazini
]-3,4-dihydrocarbostyril 0.4g
Obtained. Colorless scaly crystal Elemental analysis C H N Calculated value (%) 65.04 5.42 11.38 Actual value (%) 64.99 5.35 11.45 Example 98 6-(1-piperazinyl)-3,4-dihydro
Carbostyryl monohydrobromide 35g in DMF40
ml, add 960 ml of sodium bicarbonate and bring to room temperature.
Stir at room temperature for 30 minutes to obtain 6-(1-piperazinyl)-
After making 3,4-dihydrocarbostyryl,
Add 2.34 ml of ethylamine and stir at room temperature.
DMF10 containing 2.5g Chlorbenzoyl Chloride
ml solution gradually dropwise. Stir for 30 minutes after addition.
Pour into a large amount of water and extract with chloroform. saturation
Wash with heavy sodium chloride water, then water and dry with anhydrous sodium sulfate.
do. Distill the chloroform and remove the remaining crystals.
Recrystallize with alcohol and obtain 6-[4-
(4-chlorobenzoyl)-1-piperazinyl]
0.7 g of -3,4-dihydrocarbostyryl is obtained. Pale yellow needle crystals Elemental analysis C H N Calculated value (%) 65.04 5.42 11.38 Actual value (%) 64.89 5.30 11.51 Example 99 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and triethylamine 2.34
ml in DMF40ml and stirred at room temperature for 4-
Contains 2.5g of methoxybenzoyl chloride
Gradually add 10 ml of DMF solution dropwise. Stir for 30 minutes after dropping
Stir. Pour into a large amount of water and extract with chloroform.
Ru. Saturated sodium hydrogen sulfate solution, then washed with water and anhydrous sodium sulfate solution.
Dry in a vacuum. Distill the chloroform and remove the residue.
Recrystallize the crystals from methanol-chloroform,
5-[4-(4-methoxyben) at mp219-220℃
zoyl)-1-piperazinyl]-3,4-dihyde
Obtain 1.1 g of locarbostyril. Colorless needle crystals Elemental analysis C H N Calculated value (%) 69.04 6.30 13.15 Actual value (%) 68.95 6.21 13.24 Example 100 5-(1-piperazinyl)-3,4-dihydro
Carbostyryl monohydrobromide 3.5g in DMF40
ml and add 960 mg of sodium bicarbonate.
Stir at room temperature for 30 minutes to obtain 5-(1-piperazinyl).
-3,4-dihydrocarbostyryl, and then
Add 2.34ml of ethylamine and stir at room temperature.
3.0g of 3,5-dichlorobenzoyl chloride
Gradually add 10 ml of DMF solution dropwise. 40 after dripping
Stir for 1 minute. Pour into a large amount of water and extract with chloroform.
put out Saturated sodium bisulfur solution, then washed with water and anhydrous sodium sulfate.
Dry in a lium. Distill the chloroform and remove the residue.
Recrystallize the crystals from methanol-chloroform,
5-[4-(3,5-dichlor) at mp255-257℃
benzoyl)-1-piperazinyl]-3,4-di
Obtain 1.8 g of hydrocarbostyril. Colorless needle crystals Elemental analysis C H N Calculated value (%) 59.55 4.71 10.42 Actual value (%) 59.43 4.83 10.31 Example 101 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and sodium bicarbonate 1
Add g to 50ml of dimethyl sulfoxide and cool on ice.
4-bromobenzoyl chloride 3.2 with stirring
Gradually add 20 ml of dimethyl sulfoxide solution containing g
Drip. After dropping, stir at room temperature for 60 minutes. Large amounts of
Pour into water and extract with chloroform. Saturated heavy soybean
Wash with water and then dry with anhydrous sodium sulfate.
Chloroform was distilled off, and the remaining crystals were dissolved in methanol.
- Recrystallized with chloroform, mp233~234.5℃
6-[4-(4-bromobenzoyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl
Obtain 0.8g. Colorless granular crystals Elemental analysis C H N Calculated value (%) 57.97 4.83 10.14 Actual value (%) 57.79 4.71 10.23 Example 102 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and trimethylamine 2ml
was added to 40 ml of DMF, and 4-sia was added to 40 ml of DMF at room temperature with stirring.
10ml of DMF containing 2.4g of nobenzoyl chloride
Gradually drip the liquid. After dropping, stir at 40-50℃ for 30 minutes.
Stir. Pour into a large amount of water and extract with chloroform.
Ru. Saturated sodium sulfur solution, then washed with water and anhydrous sodium sulfate
Dry in a vacuum. Distill the chloroform and remove the residue.
Recrystallize the crystals from methanol-chloroform,
mp266-269℃ 5-[4-(4-cyanobenzo
yl)-1-piperazinyl]-3,4-dihydro
Obtain 1.9g of carbostyril. Colorless granular crystals Elemental analysis C H N Calculated value (%) 70.00 5.56 15.56 Actual value (%) 70.14 5.71 15.43 Example 103 6-(1-piperazinyl)-3,4-dihydro
2.6 g of carbostyril and 2 ml of pyridine in DMF40
ml of 4-nitrobenzoi under stirring at room temperature.
Gradually add 10 ml of DMF solution containing 2.7 g of luchloride.
Drip. After dropping, stir at the same temperature for 30 minutes. Large amounts of
Pour into water and extract with chloroform. Saturated heavy soybean
Wash with water and then dry with anhydrous sodium sulfate.
Chloroform was distilled off, and the remaining crystals were dissolved in methanol.
- Recrystallized with chloroform, mp235.5~236.5℃
6-[4-(4-nitrobenzoyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl
Obtain 2.4g. Elemental analysis C H N Calculated value (%) 63.15 5.30 14.73 Actual value (%) 63.09 5.35 14.77 Example 104 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and triethylamine 2.34
ml to 40ml of dimethyl sulfoxide and stir at room temperature.
3,5-dinitrobenzoyl chloride under stirring.
10ml solution of dimethyl sulfoxide containing 3.3g
Drip gradually. Stir for 30 minutes after addition. lots of water
and extract with chloroform. Saturated heavy soybean
Wash with water and then dry with anhydrous sodium sulfate.
Chloroform was distilled off, and the remaining crystals were dissolved in methanol.
-Recrystallized with chloroform, mp262-264℃6
-[4-(3,5-dinitrobenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostiri
Obtain 0.3g. Red-black needle crystals Elemental analysis C H N Calculated value (%) 56.47 4.47 16.47 Actual value (%) 56.34 4.61 16.35 Example 105 6-[4-(4-nitrobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostyryl
Add 400 mg to 20 ml of methanol and add 10% palladium
- Reduction using 50mg of carbon as a catalyst at room temperature and normal pressure.
Ru. After hydrogen absorption is completed, the catalyst is removed. mother liquor
After evaporation under reduced pressure, the residue was purified by silica gel chromatography.
Recrystallized with tanol, 6-[4
-(4-aminobenzoyl)-1-piperazini
]-3,4-dihydrocarbostyril 210mg
obtain. Pale yellow needle-like crystals Elemental analysis C H N Calculated value (%) 68.57 6.29 16.00 Actual value (%) 68.70 6.18 16.14 5-[4-(4-amidium)
Novenzyl)-1-piperazinyl]-3,4-di
Hydrocarbostyril dihydrochloride monohydrate obtained
Ru. mp 224-227℃ (decomposition) (methanol-ether) Yellow granular crystal Example 106 5-[4-(4-methoxybenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostiri
A mixture of 300 mg of chloride and 7 ml of methylene chloride was
2 ml of boron tribromide in methylene chloride under stirring at 5°C.
Add the solution gradually. After dropping, stir at the same temperature for 30 minutes.
Stir and warm to room temperature over about 1 hour. Large amounts of
Pour into water and remove the crystals that precipitate. methanol
-Recrystallized with chloroform and mp300℃ or higher 5-
[4-(4-hydroxybenzoyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl
Get 150mg. Colorless granular crystals Elemental analysis C H N Calculated value (%) 68.38 5.98 11.97 Actual value (%) 68.21 6.11 11.83 Example 107 5-(1-piperazinyl)-3,4-dihydro
2.6g of carbostyril and 4ml of DBU to 40ml of DMF
Add 3,4-dichlorobenzo while stirring at room temperature.
Gradually add 10 ml of DMF solution containing 3.0 g of yl chloride.
Drip into. Stir for 30 minutes after addition. Pour into plenty of water.
Then extract with chloroform. Saturated sodium chloride water, next
Wash with water and dry with anhydrous sodium sulfate. Chrollo
Distill the form and re-crystallize the residual crystals with methanol.
crystallized, mp250~252℃ 5-[4-(3,4-di
Chlorbenzoyl)-1-piperazinyl]-3,
1.2 g of 4-dihydrocarbostyryl is obtained. Colorless powder crystal Elemental analysis C H N Calculated value (%) 59.55 4.71 10.42 Actual value (%) 59.38 4.82 10.34 Example 108 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and triethylamine 2.34
ml to 40 ml of DMF and stirred at room temperature for 3,4 minutes.
-Methylenedioxybenzoyl chloride 2.7g
Gradually add 10 ml of DMF solution containing the solution dropwise. After dripping
Stir for 30 minutes. Pour into a large amount of water and add chloroform.
Extract. Wash with saturated sodium bicarbonate water, then with water and anhydrous sodium sulfate.
Dry with thorium. Distill the chloroform and remove the remaining
The residue crystals were recrystallized with methanol, and mp191~
6-[4-(3,4-methylene dioxide) at 192.5℃
cybenzoyl)-1-piperazinyl]-3,4-
Obtain 1.6 g of dihydrocarbostyril. Colorless needle crystals Elemental analysis C H N Calculated value (%) 66.49 5.54 11.08 Actual value (%) 66.35 5.67 10.94 Example 109 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 2.6g and triethylamine 2.34
ml to 50 ml of chloroform and stirred at room temperature.
4-Methylbenzoyl chloride containing 2.3g
Gradually add 10 ml of loloform solution dropwise. 30 minutes after dripping
Stir for 1 minute. After the reaction is complete, add 100% more chloroform.
ml and poured into a large amount of water to separate the chloroform,
The chloroform layer was washed with saturated sodium bicarbonate water, then water, and anhydrous.
Dry with sodium sulfate. Distill chloroform
and re-crystallize the residual crystals with chloroform-ether.
crystallized, 5-[4-(4-methyl
Rubenzoyl)-1-piperazinyl]-3,4-
Obtain 1.8 g of dihydrocarbostyril. Colorless powder crystal Elemental analysis C H N Calculated value (%) 72.21 6.59 12.03 Actual value (%) 72.34 6.44 11.94 Example 110 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium carbonate 1.17g and
Add 4-methoxybenzylchloride to a mixture of 20 ml of DMF.
Add 720 mg of Ride and stir at 80°C for 2.5 hours.
Pour into a large amount of saturated saline and extract with chloroform.
do. After washing with water, drying with anhydrous sodium sulfate, chloro
After distilling off the form, the residue was purified by silica gel chromatography.
After recrystallization with ethanol, mp196-198℃ 6-
[4-(4-methoxybenzyl)-1-piperazi
[Nil]-3,4-dihydrocarbostyril 950mg
get. Colorless needle crystals Elemental analysis C H N Calculated value (%) 70.00 7.22 11.67 Actual value (%) 69.91 7.15 11.71 Example 111 5-Piperazinyl-3,4-dihydrocarbos
Chiril 1.0g, potassium carbonate 1.11g, p-methoxy
Mixture of 760mg of cybenzyl chloride and 20ml of DMF
Stir the mixture at 70-80°C for 4 hours. Pour into plenty of water.
Then extract with chloroform. After washing with water, sulfuric anhydride
Dry with sodium and distill off the chloroform. Residue
Purify the residue by silica gel column chromatography
After that, recrystallize with methanol, mp194-196℃ 5
-[4-(4-methoxybenzyl)-1-pipera
[Dinyl]-3,4-dihydrocarbostyryl 60mg
I got it. Colorless needle crystals Elemental analysis C H N Calculated value (%) 71.79 7.12 11.97 Actual value (%) 71.84 7.05 11.89 Example 112 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, sodium carbonate 1.17g and
2-phenethyl chloride in a mixture of
Add 646 mg of chloride and stir at 80 to 100°C for 2.5 hours.
Pour into a large amount of water and extract with chloroform. washing with water
After that, dry with anhydrous sodium sulfate and remove chloroform.
After distillation, the residue was chromatographed on silica gel.
After purification, convert to hydrochloride using methanol-hydrochloric acid,
Recrystallized with methanol, mp274-276℃ (decomposition)
6-[4-(2-phenethyl)-1-piperazi
]-3,4-dihydrocarbostyryl hydrochloric acid
Obtain 0.6 g of salt. Colorless powder crystal Elemental analysis C H N Calculated value (%) 67.82 7.05 11.30 Actual value (%) 67.85 6.93 11.39 Example 113 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, Sodium Bicarbonate 1.17
3,4-methoxybenzene in a mixture of g and 20 ml of DMF.
Add 858 mg of dil chloride and heat at 70 to 80℃ for 2 hours.
Stir for an hour. Pour into a large amount of water and add chloroform.
Extract. After washing with water, dry with anhydrous sodium sulfate,
After chloroform is distilled off, the residue is chromatographed on silica gel.
After purification with tography, convert to hydrochloride, mp270～
5-[4-(3,4-dimeth) at 272.5℃ (decomposition)
xybenzyl)-1-piperazinyl]-3,4-
610 mg of dihydrocarbostyril dihydrochloride is obtained. Elemental analysis C H N Calculated value (%) 58.15 6.43 9.25 Actual value (%) 58.08 6.51 9.14 Example 114 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.0g, potassium carbonate 1.11g and
4-chlorobenzylchloride in a mixture of 20 ml of DMF
Add 780 mg of hydroxide and stir at 70 to 80°C for 4 hours.
Pour into a large amount of water and extract with chloroform. Chloroho
After distilling off the lume, the residue was chromatographed on silica gel.
After purification with fluorophore, re-purify with chloroform-methanol.
Crystallized, mp190~191.5℃ 6-[4-(4-k)
lorobenzyl)-1-piperazinyl]-3,4-
Obtain 500mg of dihydrocarbostyril. Colorless needle crystals Elemental analysis C H N Calculated value (%) 67.51 6.23 11.81 Actual value (%) 67.31 6.17 11.85 Example 115 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium carbonate 1.17g and
3,4-dichlorobenzyl in a mixture of 20 ml of DMF
Add 895 mg of chloride and stir at 60-70℃ for 3 hours.
Stir. Pour into a large amount of water and extract with chloroform.
Ru. After washing with water, drying with anhydrous sodium sulfate, chloro
After distilling off the form, the residue was chromatographed on silica gel.
After purification with fluoride, convert it into hydrochloride with methanol-hydrochloric acid.
and recrystallized with methanol, mp298.5~300℃
(Decomposition) of 5-[4-(3,4-dichlorobendi
)-1-piperazinyl]-3,4-dihydroca
Obtained 0.17g of Luvostyril monohydrochloride monohydrate
Ru. Colorless granular crystals C H N Calculated value (%) 54.00 5.44 9.45 Actual value (%) 53.73 5.57 9.29 Example 116 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium carbonate 1.17g,
4-Nitrobenzylchlora in a mixture of 50ml of
Add 789 mg of hydride and stir under reflux for 4 hours. reaction
After distilling off the benzene, convert the residue into chloroform.
After combing and washing the chloroform layer with water, add anhydrous sodium sulfate.
After drying with aluminum and distilling off the chloroform, sift the residue.
After purification by silica gel chromatography, chlorophore
Recrystallize with lume ether, mp268-271℃ (min.
Solution) of 5-[4-(4-nitrobenzyl)-1-
Piperazinyl]-3,4-dihydrocarbostiri
Obtain 0.26 g. Pale yellow powder crystal Elemental analysis C H N Calculated value (%) 65.57 6.01 15.30 Actual value (%) 65.43 5.89 15.42 Example 117 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, Potassium carbonate 1.17g, Di
Add 4-aminobenzene to a mixture of 20 ml of methyl sulfoxide.
Add 650mg of dil chloride and heat at 80℃ for 2.5 hours.
Stir. Pour into a large amount of water and extract with chloroform.
do. After washing with water, dry with anhydrous sodium sulfate and chlorine.
After distilling off the loform, the residue was chromatographed on silica gel.
After purification with roughy, convert to hydrochloride with MeOH/HCl.
Recrystallized with methanol-ether, mp224~
5-[4-(4-aminobenzi) at 227℃ (decomposition)
)-1-piperazinyl]-3,4-dihydroca
0.4 g of rubostyril dihydrochloride monohydrate was obtained. Yellow granular crystals Elemental analysis C H N Calculated value (%) 56.20 6.60 13.11 Actual value (%) 56.19 6.57 13.31 Example 118 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium carbonate 1.17g,
Add 4-
Add 651mg of hydroxybenzyl chloride to 90
Stir for 2.5 hours at °C. Pour chlorine into a large amount of water.
Extract with holm. After washing with water, anhydrous sodium sulfate
After drying with a vacuum cleaner and distilling off the chloroform, the residue was filtered with silica.
After purification by gel chromatography, 6-[4-
(4-hydroxybenzyl)-1-piperazinyl]
0.3 g of -3,4-dihydrocarbostyryl is obtained. Elemental analysis C H N Calculated value (%) 14.24 6.82 12.46 Actual value (%) 14.33 6.74 12.37 Example 119 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium bicarbonate 1.17g,
4-Methylbenzylchlora in a mixture of 20ml DMF
Add 646 mg of hydride and stir at 80°C for 2.5 hours. Many
Pour into a large amount of water and extract with chloroform. washing with water
After that, dry with anhydrous sodium sulfate and remove chloroform.
After distillation, the residue was chromatographed on silica gel.
After purification, extract methanol as hydrochloride with MeOH/HCl.
Leu--recrystallized with water, mp272-273℃ (decomposition) 6
-[4-(4-methylbenzyl)-1-piperazi
]-3,4-dihydrocarbostyryl 2 salt
0.17 g of the acid salt is obtained. Colorless powder crystal Elemental analysis C H N Calculated value (%) 61.91 6.63 10.32 Actual value (%) 61.86 6.59 10.39 Example 120 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium carbonate 1.17g,
4-cyanobenzylchlora in a mixture of 50 ml of
Add 688 mg of Idol and stir under reflux for 3 hours. Large amounts of
Pour into saturated saline and extract with chloroform. water
After washing, dry with anhydrous sodium sulfate, and chloroform.
After distilling off, the residue was subjected to silica gel chromatography.
After purification with 5-[4-(4-cyanobenzyl)-
1-piperazinyl]-3,4-dihydrocarbos
Get Tyril 105mg. Elemental analysis C H N Calculated value (%) 72.83 6.36 16.18 Actual value (%) 72.92 6.51 16.07 Example 121 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1.2g, potassium bicarbonate 1.17g,
3,4-methylenedioxy in a mixture of 20 ml of DMF.
Add 785mg of benzyl chloride and heat at 80-90℃
Stir for 3.5 hours. Pour into a large amount of saturated salt solution
Extract with loform. After washing with water, anhydrous sodium sulfate
After distilling off the chloroform, the residue was
After purification by Kagel chromatography, 6-[4-
(3,4-methylenedioxybenzyl)-1-pi
perazinil]-3,4-dihydrocarbostyryl
Obtain 0.2g. Elemental analysis C H N Calculated value (%) 69.04 6.30 11.51 Actual value (%) 68.89 6.43 11.42 Example 122 5-(1-piperazinyl)-3,4-dihydro
1.0g of carbostyril with 10ml of DMF and triethyl
Add to a mixed solution of 0.85 ml of amine and stir at room temperature.
-Toluenesulfonyl chloride 1.07g DMF5
ml solution gradually dropwise. Another 30 minutes at the same temperature
Stir. Pour chloroform into a large amount of saturated saline.
Extract with After washing with water, dry with anhydrous sodium sulfate.
and chloroform is distilled off. DMF the residual crystals
Recrystallize at 5-[4-(p-
toluenesulfonyl)-1-piperazinyl]-
800 mg of 3,4-dihydrocarbostyril is obtained. Colorless powder crystal Elemental analysis C H N Calculated value (%) 62.34 5.97 10.91 Actual value (%) 62.43 5.89 10.79 Example 123 6-(1-piperazinyl)-3,4-dihydro
1.0g of carbostyril with 10ml of DMF and triethylua
Add methane to a mixed solution of 0.85 ml of mint and stir at room temperature.
A solution of 440 mg of sulfonyl chloride in 5 ml of DMF
Drip gradually. Stir for another 30 minutes at the same temperature.
Ru. Pour into a large amount of water and extract with chloroform.
After washing with water, dry with anhydrous sodium sulfate, and
remove the rum. Recrystallize the residual crystals with methanol
mp241.5~243℃ 6-[4-(methane sulfur)
Honyl)-1-piperazinyl]-3,4-dihyde
Obtain 0.17 g of locarbostyril. Colorless granular crystals Elemental analysis C H N Calculated value (%) 54.37 6.15 13.59 Actual value (%) 54.23 6.24 13.43 Example 124 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1g, DMF 30ml, potassium carbonate
Add 2 ml of butyl bromide to 900 mg of the mixture.
Stir at 80°C for 2.5 hours. in a large amount of saturated saline
Pour and extract with chloroform. Sulfuric anhydride after washing with water
Dry with sodium and distill off the chloroform.
After purifying the residue with silica gel chromatography, HCl/MeOH
It was converted into hydrochloride and recrystallized with methanol, mp279
6-(4-Butyl-1-pipe) at ~281℃ (decomposition)
Radinyl)-3,4-dihydrocarbostyryl
Obtain 700 mg of hydrochloride hemihydrate. Elemental analysis C H N Calculated value (%) 61.46 7.53 12.65 Actual value (%) 61.34 7.45 12.51 Example 125 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1g, DMSO 20ml, potassium carbonate
Add 450 mg of ethyl bromide to the mixture of 1.7 g of
Stir at 70-100°C for 4.5 hours. Pour into plenty of water.
Then extract with chloroform. Anhydrous sodium sulfate after washing with water
Dry with thorium and distill off the chloroform. Residue
After purifying the residue by silica gel chromatography,
Converted to hydrochloride with HCl/MeOH and reconstituted with methanol.
5-(4-E) crystallized and mp293-296℃ (decomposition)
(Tyl-1-piperazinyl)-3,4-dihydroca
Obtain 0.14 g of Luvostyril monohydrochloride. Colorless granular crystals Elemental analysis C H N Calculated value (%) 61.01 7.46 14.24 Actual value (%) 61.08 7.41 14.19 Example 126 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1g, DMF 15ml, potassium carbonate
Add 500 mg of allyl bromide to 1.82 g of the mixture.
Stir at room temperature for 2 hours. Pour in plenty of water and
Extract with loform. After washing with water, anhydrous sodium sulfate
The mixture is dried with a vacuum and the chloroform is distilled off. residue
After purification by silica gel chromatography, chlorophore
Recrystallized with lum-ether, mp 175-176℃ 6
-(4-allyl-1-piperazinyl)-3,4-
0.43 g of dihydrocarbostyril is obtained. Colorless scaly crystal Elemental analysis C H N Calculated value (%) 70.84 7.75 15.50 Actual value (%) 70.73 7.81 15.38 Example 127 5-(1-piperazinyl)-3,4-dihydro
Carbostyril 1g, DMF 30ml, sodium carbonate
Propargyl bromide 491mg in a mixture of 900mg
Add and stir at 80°C for 3 hours. large amounts of saturated food
Pour into salt water and extract with chloroform. After washing with water,
Dry with anhydrous sodium sulfate and remove chloroform.
leave The residue was purified by silica gel chromatography.
After production, recrystallize with chloroform, mp225-226℃
5-[4-(2-propynyl)-1-piperazi
]-3,4-dihydrocarbostyryl 0.1g
get. Pale yellow powder crystal Elemental analysis C H N Calculated value (%) 71.38 7.06 15.61 Actual value (%) 71.23 7.14 15.48 Example 128 6-(1-piperazinyl)-3,4-dihydro
Carbostyril 1g, DMF 30ml, sodium bicarbonate
3-methylallylbroma in a mixture of 900 mg of
Add hydroxide and stir at 100°C for 2.5 hours. Large amounts of
Pour into saturated saline and extract with chloroform. water
After washing, dry with anhydrous sodium sulfate and remove with chloroform.
remove the mu. Chromatograph the residue on silica gel
After purification, convert to hydrochloride with HCl/MeOH and
Recrystallized with tanol, mp242-245℃ (decomposition)
6-[4-(2-butenyl)-1-piperazini
]-3,4-dihydrocarbostyryl dihydrochloric acid
Obtain 0.4 g of salt. Colorless flaky crystals Elemental analysis C H N Calculated value (%) 56.98 7.03 11.73 Actual value (%) 56.92 6.72 11.77 Example 129 3,4-dimethod in 100 ml of dimethylformamide
2.6g of xybenzoic acid and 1,8-diazabicyclo
[5,4,0]Undecene-7 1.65g in dimethic acid
Add to 100 ml of formamide under external ice-cooling stirring.
Add 1.5 ml of isobutyl chloroformate dropwise to the solution. dripping
After stirring for 30 minutes, add 6-(1-piperazinyl)
-3,4-dihydrocarbostyril 2.3g
Add the solution dissolved in 40ml of chillformamide,
Stir for 5 hours at room temperature. After the reaction, the solvent was distilled off.
Extract the residue with approximately 300 ml of chloroform and dilute
NaHCO ₃ Wash with water, water, dilute hydrochloric acid, and water. Black
After distilling off the chloroform, the residue is mixed with ethanol-chloroform.
6-
[4-(3,4-dimethoxybenzoyl-1-pi)
perazinil]-3,4-dihydrocarbostyryl
Obtain 1.7g. Colorless granular crystals Elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.72 6.45 10.52 Example 130 A mixture of 1.22 ml of acetic anhydride and 0.5 ml of formic acid was mixed with 50 to 60
Stir at ℃ for 2 hours. Cool to room temperature and 5-pi
perazinyl-3,4-dihydrocarbostyryl
Gradually add 1.0g. The reactants solidify. Jiku
Add 5 ml of lolomethane and stir at room temperature for 2 hours.
Ru. Add a large amount of water and extract with chloroform.
After washing with water, dry with anhydrous sodium sulfate and chloroform.
remove the mu. The residue was recrystallized with methanol,
5-(4-formyl-1-pipe at mp263~265℃)
Radinyl)-3,4-dihydrocarbostyryl
Obtained 420 mg. Colorless granular crystals Elemental analysis C H N Calculated value (%) 64.84 6.61 16.21 Actual value (%) 64.64 6.57 16.22 Compound of Example 63 in the same manner as Example 130
get. Example 131 6-piperazinyl-3,4-dihydrocarbos
Suspend 1.0 g of tyryl monohydrobromide in DMF,
Add 296 mg of sodium hydrogen carbonate and stir at room temperature.
(30 minutes) and 6-piperazinyl-3,4-dihyde
locarbostyril and then triethylamine
After adding 0.62ml, 4-acetyloxybenzoi
Gradually drop the solution of 605 mg of luchloride into 5 ml of DMF.
down. After dropping, stir at room temperature for 1 hour. Large amounts of
Pour into water and extract with chloroform. saturated bicarbonate
After washing with sodium and water in that order, anhydrous sodium sulfate
Dry in a vacuum. Distill off chloroform and remove 6-[4
-(4-acetyloxybenzoyl)-1-pipe
Radinyl]-3,4-dihydrocarbostyryl
obtain. Elemental analysis (C _{twenty two} H _{twenty three} N ₃ O _Four ) C H N Calculated value (%) 67.16 5.89 10.68 Actual value (%) 67.04 5.98 10.49 Example 132 25 g of 6-aminocarbostyryl, bis(β-butyl)
Romuethyl) amine hydrobromide 50g and
Stir the DMF mixture at 80-90°C for 3 hours.
After cooling to room temperature, add 8.2g of sodium carbonate and add 80~
Stir at 90°C for 4 hours. Cool to room temperature and precipitate
Take the crystals, wash them with ethanol, dry them, and wash them with water and ethanol.
6-(1-piperazine) was recrystallized from tanol.
l) Obtain 22 g of carbostyryl hydrobromic acid. mp 300℃ or higher Pale yellow edge-shaped crystal Example 133 6-(1-piperazinyl)carbostyryl/Odor
Suspend 2 g of hydrochloride in 20 ml of DMF,
Add 2.34 ml of 3,4-meramine and stir at room temperature.
1.43g of ethylene dioxybenzoyl chloride
Gradually add 2 ml of DMF solution dropwise. After dropping, bring to room temperature
After stirring for 30 minutes, pour into a large amount of water to remove the precipitated crystals.
take. After drying, purify with a silica gel column,
Recrystallized with chloroform-methanol, mp266~
6-[4-(3,4-methylene) at 267℃ (decomposition)
dioxybenzoyl)-1-piperazinyl]cal
Obtain 1.9g of Bostyril. Yellow powder crystal Example 134 7-Amino-3,4-dihydrocarbostyryl
23g, bis(β-bromoethyl)amine/water bromide
At 8 o'clock, a mixture of 48 g of acid salt and 200 ml of methanol was added.
Stir and reflux for a while. Sodium carbonate after cooling to room temperature
Add 7.52 g of aluminum and stir and reflux for an additional 8 hours.
Methanol is distilled off under reduced pressure, and the residue contains isopropanol.
Cool, remove the precipitated crystals, and ethanol
Recrystallized three times at
Radinyl)-3,4-dihydrocarbostyryl
15 g of hydrobromide are obtained. mp 174-177℃ Example 135 7-(1-piperazinyl)-3,4-dihydro
800mg of carbostyril hydrobromide in 10ml of DMF
Add 1.2 ml of triethylamine and bring to room temperature.
4-Chlorobenzoyl chloride 730 under stirring at
Gradually add 2 ml of DMF solution dropwise. Room temperature after dropping
After stirring for 30 minutes, pour into a large amount of water to remove the precipitated amount.
After washing with water, dry and perform silica gel chromatography.
Purify and recrystallize from chloroform-methanol.
7-[4-(4-chlorobenzoyl)-1-pi
perazinil]-3,4-dihydrocarbostyryl
Get 700mg. mp 289-291℃ Colorless powder crystal Example 136 8-Amino-3,4-dihydrocarbostyryl
7.5g and bis(β-dibromoethyl)amine.
Suspend 15.9g of hydrobromide in methanol and heat
Stir under reflux for 9 hours. In this, sodium carbonate
Add 2.5 g and stir for a further 8 hours while heating under reflux.
After stirring in an ice water bath for 1 hour, remove the precipitated crystals and obtain the crude crystals.
This was recrystallized from methanol-ether.
8-(1-piperazinyl)-3,4-dihydro
2.4 g of carbostyril hydrobromide is obtained. mp 300℃ or higher Colorless needle crystal Example 137 8-aminocarbostyryl 15.47g and bis
(β-dibromoethyl)amine hydrobromide 33
Suspend g in DMF and stir at 70-80℃ for 10 hours.
Ru. Add 5.1g of sodium carbonate to this and keep at the same temperature.
Stir for 7 hours. After distilling off the solvent under reduced pressure, the residue is
When nol is added and crystallized, crude crystals are obtained. child
This was recrystallized from methanol-ether to give 8-
(1-piperazinyl)carbostyryl/hydrogen bromide
5.1 g of acid salt are obtained. mp 300℃ or higher Colorless scaly crystal Example 138 8-(1-piperazinyl)carbostyryl 0.7
Suspend g and 0.2 g of potassium hydrogen carbonate in 5 ml of DMF.
and stir at room temperature for 30 minutes. Add triethyl chloride to this solution.
Add 0.4ml of 2-chlorobenzoylchlora
Drop a solution of 0.47 g of hydride in 5 ml of DMF and let it cool at room temperature.
Stir for 30 minutes. Pour the reaction mixture into saturated sodium bicarbonate solution
and extract with chloroform. Wash the organic layer with water,
Then washed with saturated saline and dried with sodium sulfate.
After drying, remove the solvent under reduced pressure and add ether to crystallize.
do. Recrystallize from ethanol to obtain 8-[4-(2
-chlorobenzoyl)-1-piperazinyl]cal
Obtain 0.24g of Bostyril. mp 239-240.5℃ Colorless needle crystal pharmacological test a
Sodium salt of tar intravenously at a rate of 30 mg/Kg
Administer intravenously and apply anesthesia. heparin natrium
Blood loss occurred after intravenous administration of mu salt at a rate of 1000U/Kg.
The animal is sacrificed and the heart is removed into Lok's fluid. right coronal
Insert the cannula from the artery toward the sinus node artery.
Then remove the right atrium along with the cannula. next
Sodium salt of pentobarbital (30%
mg/Kg, intravenous administration) and heparinized
Treated (1000U/Kg, intravenous administration) body weight 18~
Blood was taken from the carotid artery of a 27 kg male-male mixed-breed adult dog.
Insert into the right coronary artery via a Starik pump.
Introduce the cannula into the right atrium and perfuse the right atrium. perfusion
The pressure shall be a constant pressure of 100 mmHg. The movement of the right atrium is static.
Under a stop tension of 2 g, the atrial muscle is
Measure the contraction force of. Coronary blood flow is electromagnetic flow
Measure using a meter. All records are written in ink
Record it in the record book. The details of this method are
Reported by Ye et al. [Japan, J.
Pharmacol, twenty five , 433-439 (1975), Naunyn
Schmiedberg, s Arch. Pharmacol, 289,
315-325 (1975)]. The test compound was applied to a cannula inserted into the right coronary artery.
via a rubber tube connected close to the
Inject into the artery in a volume of 10-30μ. Trial version
The positive inotropic effect of a compound is due to the tension generated before compound administration.
It is expressed as a % change in coronary blood flow and
Changes are expressed as absolute values (ml/min) from before administration.
Was. The results are shown in Table 1 below. b. Pentobarbi in male and female mixed breed adult dogs weighing 8-13 kg.
Sodium salt of tar intravenously at a rate of 30 mg/Kg
Administer intravenously and apply anesthesia. heparin natrium
Blood loss occurred after intravenous administration of mu salt at a rate of 1000U/Kg.
Let them die and remove their hearts. The specimens mainly consist of papillary muscles and
It consists of the ventricular septum and the catheter inserted into the anterior septal artery.
100 yen from blood donated from donor dogs from New York
Perfused at a constant pressure of mmHg. Donor dogs weigh 18~
27Kg, pentobarbital sodium in advance
Anesthetize by intravenously administering 30 mg/Kg of salt, and
Administer 1000U/Kg of sodium salt intravenously.
put. Using bipolar electrodes, voltage 1.5 times the threshold
(0.5-3V), stimulation width 5msec and stimulation frequency per minute
Stimulates the papillary muscles with 120 square waves. papillary muscle
The resting tension is 1.5 g, and the generated tension in the papillary muscles changes with force.
Measured via a position transducer. Blood flow in the anterior septal artery
The amount is measured using an electromagnetic flow meter. Generated tension and
Records of blood flow and blood flow are recorded on an ink recorder.
Ru. The details of this method have already been described by Endo and Hashimoto.
(Am.J.Physiol., 218 ,1459
~1463, 1970). The test compound is stabilized in a volume of 10 to 30 μ for 4 seconds.
Administer intravenously. The inotropic effect of the test compound was determined by drug administration.
It is expressed as a % change with respect to the generated tension before application.
The effect on coronary blood flow is based on the absolute value from before administration.
Expressed as change (ml/min). Results below 2nd
Shown in the table. c Each test compound (No. 1 to 57) was given to male rats.
Oral administration and its acute toxicity (LD ₅₀ )
As a result, LD in all compounds ₅₀ ＞7000mg/
It was Kg. Test compound No. 1 6-[4-(3,4-dimethoxybenzoy
)-1-piperazinyl]-3,4-dihydro
Carbostyryl 2 6-[4-(4-methoxybenzoyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyryl 3 6-(4-acetyl-1-piperazinyl)-
3,4-dihydrocarbostyryl 4 6-[4-(4-methoxybenzyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ryl 5 6-[4-(3,4,5-trimethoxyben
zoyl)-1-piperazinyl]-3,4-dihi
Drocarbostyril 6 5-[4-(3,4,5-trimethoxyben
zoyl)-1-piperazinyl]-3,4-dihi
Dolocarbostyril 7 6-[4-(4-chlorobenzyl)-1-pi
perazinil]-3,4-dihydrocarbostili
8 6-(1-piperazinyl)-3,4-dihyde
Locarbostyril 9 6-[4-(4-nitrobenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril 10 6-[4-(4-aminobenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ryl 11 6-[4-(3,4-methylenedioxyben
zoyl)-1-piperazinyl]-3,4-dihi
Dolocarbostyril 12 6-[4-(4-brombenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril 13 6-[4-(4-cyanobenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ryl 14 5-[4-(3,4-dimethoxybenzoy
)-1-piperazinyl]-3,4-dihydro
Carbostyril 15 8-Methoxy-6-[4-(3,4-dimeth)
xybenzoyl)-1-piperazinyl]-3,
4-dihydrocarbostyryl 16 1-methyl-6-[4-(3,4-dimethoxy)
cybenzoyl)-1-piperazinyl]-3,4
-Dihydrocarbostyryl 17 6-(4-furoyl-1-piperazinyl)-
3,4-dihydrocarbostyryl 18 6-(4-benzoyl-1-piperazinyl)
-3,4-dihydrocarbostyryl19 1-benzyl-6-[4-(3,4-dimethod)
xybenzoyl)-1-piperazinyl]-3,
4-dihydrocarbostyryl 1/2 hydrate 20 6-[4-(2-phenethyl)-1-pipera
[dinyl]-3,4-dihydrocarbostyryl
Monohydrochloride 21 6-(4-formyl-1-piperazinyl)-
3,4-dihydrocarbostyryl22 6-(4-ethoxycarbonylmethyl-1-
piperazinyl)-3,4-dihydrocarbosti
Ril23 6-(4-ethoxycarbonyl-1-pipera)
(dinyl)-3,4-dihydrocarbostyryl24 6-[4-(3-chlorobenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril25 6-(4-methanesulfonyl-1-piperazi)
26 6-[4-(4-methylbenzyl)-1-pyl)-3,4-dihydrocarbostyryl
perazinil]-3,4-dihydrocarbostili
27 5-[4-(3,4-dichlorobenzoyl)
-1-piperazinyl]-3,4-dihydrocal
Bostyril monohydrochloride monohydrate 28 6-[4-(35-dinitrobenzoyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyryl29 6-(4-allyl-1-piperazinyl)-
3,4-dihydrocarbostyryl 30 5-[4-(2-propynyl)-1-pipera
[dinyl]-3,4-dihydrocarbostyryl31 5-(4-ethyl-1-piperazinyl)-
3,4-dihydrocarbostyryl monohydrochloride 32 1-allyl-5-[4-(3,4-dimethoxy)
cybenzoyl)-1-piperazinyl]-3,4
-dihydrocarbostyryl 1/2 hydrate 33 1-(2-propynyl)-6-[4-(3,
4-dimethoxybenzoyl)-1-piperazini
]-3,4-dihydrocarbostyryl 34 5-[4-(p-toluenesulfonyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyryl 35 6-[4-(4-methylthiobenzoyl)-
1-piperazinyl]-carbostyryl36 6-[4-(3-peridylcarbonyl)-1
-Piperazinyl]-3,4-dihydrocarbos
Tyryl 37 6-[4-(4-methoxyphenylacetyl)
)-1-piperazinyl]-3,4-dihydro
Carbostyryl 1/2 hydrate 38 6-(4-phenylpropionyl-1-pipe
Radinyl)-3,4-dihydrocarbostyryl39 8-[4-(3,4-dimethoxybenzoy
)-1-piperazinyl]carbostyryl40 5-[4-(4-hydroxybenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbo
Styryl 41 6-[4-(3,4-dimethoxybenzoy
)-1-piperazinyl]carbostyryl42 6-[4-(3-chlorobenzoyl)-1-
Piperazinyl] carbostyril 43 6-[4-(3,4-methylenedioxyben
zoyl)-1-piperazinyl]carbostyryl44 6-[4-(4-nitrobenzoyl)-1-
Piperazinyl] carbostyril 45 6-[4-(4-cyanobenzoyl)-1-
Piperazinyl] Carbostyryl 46 6-(4-benzoyl-1-piperazinyl)
Carbostyril 47 6-[4-(4-chlorobenzoyl-1-pi)
perazinil] carbostyril 48 6-[4-(3,4,5-trimethoxyben
zoyl)-1-piperazinyl]carbostyryl49 6-(4-ethoxycarbonyl-1-pipera
(dinyl) carbostyril 50 6-[4-(4-aminobenzoyl)-1-
Piperazinyl] Carbostyryl 51 6-[4-(4-formyl)-1-piperazi
Carbostyryl 52 5-(4-benzyl-1-piperazinyl)-
3,4-dihydrocarbostyryl monohydrochloride 53 7-[4-(3,4-methylenedioxyben
zoyl)-1-piperazinyl]-3,4-dihi
Drocarbostyril 54 7-[4-(3,4,5-trimethoxyben
zoyl)-1-piperazinyl]-3,4-dihi
Dolocarbostyril 55 7-[4-(2-chlorobenzoyl)-1-
piperazinyl]-3,4-dihydrocarbosti
Ril56 7-(4-phenylpropionyl-1-pipe
Radinyl)-3,4-dihydrocarbostyryl57 7-[4-(3,4-dimethoxybenzoy
)-1-piperazinyl]-3,4-dihydro
Carbostyril 58 Papaverine (control compound) 59 Amrinone (control compound)

【table】

【table】

【table】

[Table] Formulation example 1 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation example 2 6-[4-(4-methoxybenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostyryl 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation example 3 6-[4-(4-nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl 500mg polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml Dissolve the above parabens, sodium metabisulfite and sodium chloride in the above distilled water at 80°C with stirring. The resulting solution was cooled to 400°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, sterilized by sterilization using a suitable filter paper, and the solution is dispensed into ampoules in 1 ml portions to prepare injections. Formulation example 4 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]carbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R ² represents a hydrogen atom or a lower alkoxy group. R ³ is a hydrogen atom, a lower alkanoyl group, a furoyl group, a pyridylcarbonyl group,
Lower alkanesulfonyl group, lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, phenylsulfonyl group that may have a lower alkyl group as a substituent on the phenyl ring, lower alkyl group, lower alkenyl group, lower alkynyl group, It represents an enylcarbonyl group, a phenyl lower alkyl group, or a phenyl lower alkanoyl group.
On the phenyl ring of the above phenylcarbonyl group, phenyl lower alkyl group, and phenyl lower alkanoyl group, there is a lower alkoxy group, a halogen atom, a lower alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group. It may have 1 to 3 groups selected from the group consisting of groups and lower alkanoyloxy groups or lower alkylenedioxy groups as substituents. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] A cardiotonic agent characterized by containing a carbostyril derivative or a salt thereof as an active ingredient. 2 General formula [In the formula, the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] The cardiotonic agent according to claim 1, which contains a carbostyril derivative or a salt thereof as an active ingredient.