JPS6338005B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cardiotonic agents. More specifically, the present invention
is the general formula [R in the formula ¹ is a hydrogen atom, a lower alkyl group or a
Enyl indicates a lower alkyl group. R ² and R ³ are each
Hydrogen atom, may have a hydroxyl group as a substituent
lower alkyl group, as a substituent on the phenyl ring
Lower alkoxy groups, halogen atoms and nitro groups
may have 1 to 3 groups selected from the group
Substituted on phenyl lower alkyl group or phenyl ring
Fluids that may have a lower alkoxy group as a group
Indicates an enoxy lower alkyl group. Also this R ² Reach
BiR ³ are the substituents along with the nitrogen atoms to which they are bonded.
1-Pi, which may have a lower alkyl group as
loridyl group, morpholino group, phenylene as a substituent
1-Piperi, which may have a lower alkyl group
Phenyl group, phenyl group as zyl group or substituent
alkyl group or hydroxy lower alkyl group
forming a 1-piperazinyl group that may have
It's okay. A represents a lower alkylene group. Calbo
The carbon-carbon bond at the 3rd and 4th positions of the styryl skeleton is a single bond.
indicates a bond or a double bond. ] The carbostyril derivative or its salt represented by
A cardiotonic agent characterized by containing it as an active ingredient
Pertains to. Carbostyryl induction represented by the above general formula (1)
A part of the body is a known compound, and the compound
has antibacterial effect, anti-inflammatory effect, platelet aggregation inhibiting effect, and lipid
Quality content lowering effect, central nervous system depressant effect or antihyster
It is already a known fact that it has a min effect.
(Japanese Patent Application Laid-open No. 50-142576, JP-A No. 50-151881
Publication, JP-A-54-30184 and JP-A-54-
(See Publication No. 130587). As a result of further research, the inventors found that the above general
The carbostyril derivative of formula (1) has antibacterial and anti-inflammatory effects.
for use, platelet aggregation inhibitory effect, lipid content lowering effect, medium
Absolutely free from central nervous system depressant and antihistamine effects
Unpredictable effect: enhances myocardial contraction
(positive inotropic effect) and coronary blood flow increasing effect.
Therefore, for example, congestive heart failure, mitral valve disease,
Heart diseases such as atrial fibrillation, flutter, and paroxysmal atrial tachycardia
It has been shown to be effective as a cardiotonic agent for the treatment of patients with
I found it. The present invention has been completed based on this knowledge.
It is something that was given. Characteristics of the carbostyryl derivative of general formula (1) above
has excellent positive inotropic effect and coronary blood flow increasing effect.
However, the effect of increasing heart rate is said to be extremely weak.
It's on point. In this specification R ¹ ,R ² ,R ³ and indicated by A
More specifically, each group is as follows. Lower alkyl group...methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, pliers
yl, hexyl group, etc. Phenyl lower alkyl group...benzyl, 2-phene
Nylethyl, 1-phenylethyl, 3-phenyl
Propyl, 4-phenylbutyl, 1,1-dimethy
Ru-2-phenylethyl, 5-phenyl pliers
6-phenylhexyl, 2-methyl-3-phenyl
enylpropyl group, etc. Lower amines that may have a hydroxyl group as a substituent
Rukyl group...methyl, hydroxymethyl, ethyl,
2-hydroxyethyl, propyl, isopropy
2-hydroxypropyl, 3-hydroxypropyl
Lopyl, 1-methyl-2-hydroxyethyl, butyl
chill, tert-butyl, 2-hydroxybutyl, 3
-Hydroxybutyl, 4-hydroxybutyl,
1,1-dimethyl-2-hydroxyethyl, pen
tyl, 2-hydroxypentyl, 3-hydroxy
Pentyl, 4-hydroxypentyl, 5-hydro
xypentyl, hexyl, 2-hydroxyhexy
3-hydroxyhexyl, 4-hydroxyhexyl
xyl group etc. Lower alkoxy group...methoxy, ethoxy, pro
Poxy, isopropoxy, butoxy, tert-butoxy
xy, pentyloxy, hexyloxy groups, etc. Halogen atoms...fluorine, chlorine, bromine and iodine atoms
Child. Lower alkoxy as a substituent on the phenyl ring
selected from the group consisting of groups, halogen atoms and nitro groups.
phenyl lower atom which may have 1 to 3 groups
Rukyl group...benzyl, 2-methoxybenzyl, 3
-methoxybenzyl, 2-phenylethyl, 2-
(4-methoxyphenyl)ethyl, 2-ethoxy
Benzyl, 1-(3-ethoxyphenyl)ethyl
3-phenylpropyl, 3-(4-ethoxy
phenyl)propyl, 6-phenylhexyl, 6
-(4-isopropoxyphenyl)hexyl, 4
-Phenylbutyl, 4-(4-hexyloxif)
enyl)butyl, 1,1-dimethyl-2-(3,
4-dimethoxyphenyl)ethyl, 5-phenyl
Pentyl, 5-(3,4-diethoxyphenyl)
Pentyl, 6-(3,4,5-trimethoxyphene)
hexyl, 2-methyl-3-(2,5-di
methoxyphenyl)propyl, 2-nitrobendi
1-(3-nitrobenzyl), 3-nitrobenzyl, 1-(3-nitrobenzyl)
(nitrophenyl)ethyl, 6-(4-nitrophenyl)hexyl
sil, 2-chlorobenzyl, 3-bromobenzi
fluorophore, 4-iodobenzyl, 2-(4-fluorophore)
enyl)ethyl, 1-(3-chlorophenyl,)
Ethyl, 6-(4-bromophenyl)hexyl,
5-(3,4-dichlorophenyl)pentyl,
1,1-dimethyl-2-(2,5-dibromphene)
nil) propyl group, etc. Lower alkoxy group as a substituent on the phenyl ring
Phenoxy lower alkyl group that may have...
Phenoxymethyl, 2-methoxyphenoxymethy
2-phenoxyethyl, 2-(3-methoxy
phenoxy)ethyl, 1-phenoxyethyl, 1
-(4-methoxyphenoxy)ethyl, 1-(2
-ethoxyphenoxy)ethyl, 2-(3-ethyl)
(xyphenoxy)ethyl, 4-ethoxyphenoxy
dimethyl, 3-phenoxypropyl, 3-(4-
Isopropoxyphenoxy)propyl, 4-phene
Noxybutyl, 4-(4-hexyloxypheno
xy)butyl, 5-phenoxypentyl, 5-
(3,4-dimethoxyphenoxy)pentyl, 6
-Phenoxyhexyl, 6-(3,4-diethyl)
siphenoxy)hexyl, (3,4,5-trimethane)
Toxyphenoxy)methyl, 2-(2,5-dimethyl)
Toxyphenoxy)ethyl, 6-(4-pentyl)
oxyphenoxy)hexyl group, etc. May have a lower alkyl group as a substituent
1-pyrrolidyl group...1-pyrrolidyl, 2-methane
Thyl-1-pyrrolidyl, 3-ethyl-1-pyrroli
Zyl, 2-propyl-1-pyrrolidyl, 3-butyl
Leu-1-pyrrolidyl, 2-t-butyl-1-pyro
Lysyl, 2-pentyl-1-pyrrolidyl, 3-h
xyl-1-pyrrolidyl, 1-methyl-1-pyro
Lysinium group etc. Has a phenyl lower alkyl group as a substituent
Occasional 1-piperidyl group...1-piperidyl group
L, 4-benzyl-1-piperidyl, 2-(2-
phenylethyl)-1-piperidyl, 3-(3-
phenylpropyl)-1-piperidyl, 4-(3
-phenylbutyl)-1-piperidyl, 4-(5
-phenylpentyl)-1-piperidyl, 4-
(6-phenylhexyl)-1-piperidyl group, etc. Phenyl group, phenyl lower alkyl as a substituent
or hydroxy lower alkyl group
Occasional 1-piperidyl group...1-piperazine
2-phenyl-1-piperazinyl, 3-phenyl
Nyl-1-piperazinyl, 4-phenyl-1-pi
perazinyl, 4-benzyl-1-piperazinyl,
2-(2-phenylethyl)-1-piperazini
3-(3-phenylpropyl)-1-pipera
Dinyl, 4-(4-phenylbutyl)-1-pipe
Radinyl, 4-(3-phenylpentyl)-1-
Piperazinyl, 4-(6-phenylhexyl)-
1-piperazinyl group, etc. Lower alkylene group...methylene, ethylene, tri
Methylene, 2-methyltrimethylene, 2,2-di
Methyltrimethylene, 1-methyltrimethylene,
Methylmethylene, ethylmethylene, tetramethylene
pentamethylene, hexamethylene groups, etc. Carbostyryl induction represented by the above general formula (1)
Typical compounds included in the body are illustrated below.
In addition, the 3,4-position dehydrated hydrogen product of each compound is carbos
The carbon-carbon bonds at the 3rd and 4th positions of the chiryl skeleton are double bonds.
Let it represent a compound that is . Γ 6-(3-benzylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-(3-β-phenethylaminopropoxy)
c)-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 6-[3-(1,1-dimethyl-2-phenylene
ruethylamino)propoxy]-3,4-dihi
Dolocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenated product Γ 6-(3-morpholinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 6-[3-(N-methyl-N-benzylamine
Nopropoxy]-3,4-dihydrocarbosti
Lyle and its 3,4-position dehydrogenate Γ 1-methyl-6-{3-[2-(3,4-di
methoxyphenyl)ethyl]aminopropoxy
C}-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 1-benzyl-6-{3-[2-(3,4-
dimethoxyphenyl)ethyl]aminopropoxy
C}-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 6-[3-(1,1-dimethyl-2-phenylene
ruethylamino)propoxy]-3,4-dihi
Dolocarbostyril and its 3,4-dehydrogenated product Γ 1-benzyl-6-[3-(1-methyl-2
―Phenoxyethylamino)propoxy〕―
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-[3-(2-phenoxyethylamino)
Propoxy]-3,4-dihydrocarbostili
6-{3-[2-(4-methoxyphenoxylene)
c) Ethylamino]propoxy}-3,4-di
Hydrocarbostyryl and its 3,4-position dehydrogenation
Body Γ 6-{3-[2-(3,5-dimethoxyphene)
noxy)ethylamino]propoxy}-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 1-methyl-6-{3-[2-(4-methoxy)
Siphenoxy)ethylamino]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-[3-{N-methyl-N-[2-(3,
4-dimethoxyphenyl)ethyl]amino]
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-dehydrogenated product Γ 6-[3-(1-phenylethylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(2-phenylethylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-{3-[N-methyl-(2-phenylethyl)
Chyl)amino]propoxy}-3,4-dihyde
Locarbostyril and its 3,4-dehydrogenated product Γ 6-[3-(N,N-dibenzylamino)propylene
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 7-[3-(N-methyl-N-benzylamine
(g) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-position dehydrogenate Γ 8-[3-(N-methyl-N-benzylamine
(g) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-dehydrogenated product Γ 1-methyl-6-[3-(N-methyl-N-
benzylamino)propoxy]-3,4-dihi
Dolocarbostyril and its 3,4-position dehydrogenate Γ 6-[3-(2-hydroxyethylamino)
Propoxy]-3,4-dihydrocarbostili
6-(3-pyrrolidinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen Γ 6-[3-(1-piperazinyl)propoxy
[S]-3,4-dihydrocarbostyryl and its
3,4-dehydrogenated product Γ 5-(3-benzylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 1-benzyl-6-[3-(N-methyl-N
-benzylamino)propoxy]-3,4-di
Hydrocarbostyryl and its 3,4-position dehydrogenation
Body Γ 6-(3-benzylamino-2-methylpro
poxy)-3,4-dihydrocarbostyryl and
3,4-position dehydrogenated product Γ 5-(3-benzylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-(3-benzylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-(3-benzylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-[3-(1-methyl-1-pyrrolidium
) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3- and 4-position dehydrogenates/iodine
DoΓ 6-(3-n-butylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-(3-propylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-(3-pentylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-(3-hexylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-(3-propylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-(3-pentylaminopropoxy)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-(3-N-methyl-N-benzylamino
Propoxy)-3,4-dihydrocarbostili
and its 3,4-position dehydrogenate Γ 6-{3-[2-(3,4-dimethoxy)
enylethyl]aminopropoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Element Γ 5-(3-morpholinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 7-(3-morpholinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 8-(3-morpholinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 6-(3-isopropylaminopropoxy)
-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenate Γ 6-[3-(N,N-dibenzylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(1-methylbenzylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-(2-benzylaminoethoxy)-3,
4-dihydrocarbostyryl and its 3 and 4 positions
Dehydrogen Γ 6-(4-benzylaminobutoxy)-3,
4-dihydrocarbostyryl and its 3 and 4 positions
Dehydrogenate Γ 1-methyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl and
1-benzyl-6-(3-benzylaminopropylene)
Ropoxy)-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 7-(3-pyrrolidinopropoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 6-[3-(3-phenylpropylamino)
Propoxy]-3,4-dihydrocarbostili
6-[3-(2-phenoxy-1-methyl ester)
thylamino)propoxy]-3,4-dihydro
Carbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(4-benzyl-1-piperid
) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-position dehydrogenate Γ 6-[3-(6-phenylhexyl)amino
Propoxy]-3,4-dihydrocarbostili
6-[3-(N-propyl-N-benzyl)
Aminopropoxy]-3,4-dihydrocarbo
Styryl and its 3,4-position dehydrogenate Γ 6-[3-(N-hexyl-N-benzyl)
Aminopropoxy]-3,4-dihydrocarbo
Styryl and its 3,4-position dehydrogenated product Γ 6-{3-[3-(4-methoxyphenoxylene)
C) Propylamino]propoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Element Γ 6-(3-phenoxymethylaminopropoxy)
c)-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 6-[3-(di-2-hydroxyethylamine
(g) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-position dehydrogenate Γ 6-{3-[N-methyl-N-(2-hydro
xyethyl)]aminopropoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Prime body Γ 6-{3-[N-benzyl-N-(2-hydro
(loxyethyl)]aminopropoxy}-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 1-methyl-6-[3-(2-hydroxye
thylamino)propoxy]-3,4-dihydro
Carbostyril and its 3,4-dehydrogenated product Γ 1-benzyl-6-[3-(2-hydroxy
ethylamino)propoxy]-3,4-dihyde
Locarbostyril and its 3,4-dehydrogenated product Γ 6-[3-(4-chlorobenzylamino)bu
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(2-chlorobenzylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(3-brombenzylamino)propylene
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(4-iodobenzylamino)propylene
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(2-fluorobenzylamino)
Propoxy]-3,4-dihydrocarbostili
6-[3-(3,4-dichlorobenzylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-position dehydrogenate Γ 6-[3-(3,4,5-trichlorobendi
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril and its 3,4-position dehydrogenate Γ 6-{3-[N-(4-chlorobenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl and its 3,4-position dehydrogenation
Body Γ 6-{3-[N-(3-iodobenzyl)-
N-benzylamino}propoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Elementary body Γ 6-{3-[N-(3,4,5-trichloro
benzyl)-N-methylamino]propoxy}
-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenated product Γ 6-[3-(4-methoxybenzylamino)
Propoxy]-3,4-dihydrocarbostili
6-[3-(3-ethoxybenzylamino)
Propoxy]-3,4-dihydrocarbostili
6-[3-(4-hexyloxybenzyl)
Mino)propoxy]-3,4-dihydrocarbo
Styryl and its 3,4-dehydrogenated product Γ 6-[3-(2-t-butyloxybenzyl
amino)propoxy]-3,4-dihydrocal
Bostyril and its 3,4-dehydrogenated product Γ 6-{3-[N-methyl-N-(4-methoxy)
cybenzyl)amino]propoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Prime body Γ 6-{3-[N-benzyl-N-(4-meth
xybenzyl)amino]propoxy)-3,4
-Dihydrocarbostyryl and its 3 and 4 decomposition
Hydrogen body Γ 6-[3-(4-nitrobenzylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenated product Γ 6-[3-(3-nitrobenzylamino)
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-[3-(2-nitrobenzylamino)propylene
Ropoxy]-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenated product Γ 6-[3-(3,4-dinitrobenzylamine
(g) Propoxy]-3,4-dihydrocarbos
Tyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-(2-hydroxyethyl)
-1-piperazinyl]propoxy}-3,4-
Dihydrocarbostyryl and its 3 and 4 position dehydration
Element Γ 1-methyl-6-[3-(4-chlorobenzi
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril and its 3,4-dehydrogenated product Γ 1-benzyl-6-[3-(4-methoxybenzene)
propoxy]-3,4-dihyde
Locarbostyril and its 3,4-dehydrogenated product Γ 1-Methyl-6-[3-(4-nitrobendi
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril and its 3,4-position dehydrogenate Γ 1-methyl-6-{3-[N-(4-methoxy)
(cybenzyl)-N-methylamino]propoxy
-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 1-benzyl-6-{3-[4-(2-hydro
(oxyethyl)-1-piperazinyl]propoxy
C}-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 6-{3-[N-bis-(4-methoxyben
zyl)amino]propoxy}-3,4-dihyde
Locarbostyril and its 3,4-dehydrogenated product Γ 6-{3-[N-bis-(3-chlorobenzi
amino]propoxy}-3,4-dihydro
Carbostyryl and its 3,4-dehydrogenated product Γ 6-{3-[N-bis-(4-nitrobenzene)
amino]propoxy}-3,4-dihydro
Carbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[N-(4-brombenzyl)-
N-(3-methoxybenzyl)amino]propo
xy}-3,4-dihydrocarbostyryl and
Its 3,4-position dehydrogenated product Γ 6-{3-[N-(3-nitrobenzyl)-
N-(4-chlorobenzyl)amino]propoxy
C}-3,4-dihydrocarbostyryl and its
3,4-position dehydrogenation product Γ 6-{3-[N-bis-(4-methoxyphenylene)
amino)propoxy}-3,4-dihi
Dolocarbostyril and its 3,4-dehydrogenated product Γ 6-{3-[N-(3-methoxyphenoxylene)
C)-N-(2-chlorobenzyl)amino]
Ropoxy}-3,4-dihydrocarbostyryl
and its 3,4-position dehydrogenate Γ 6-{3-[N-(3,4-dimethoxyphene)
Noxy)-N-(3-methoxybenzyl)ami
[Propoxy}-3,4-dihydrocarbos
Chiril Γ 6-{3-[N-(2-methoxyfuenoki)
C)-N-(4-nitrobenzyl)amino]
Ropoxy}-3,4-dihydrocarbostyryl The compound represented by the above general formula (1) is, for example,
Manufactured by the method shown in Equation-1. [In the formula, X represents a halogen atom. R ¹ ,R ² ,R ³ ,
A and between the carbons at the 3rd and 4th positions of the carbostyril skeleton
The connections are the same as above. ] Reaction between the compound of general formula (2) and the compound of general formula (3)
is carried out in a suitable solvent using a deoxidizing agent. melt
An inert medium that does not adversely affect the reaction
are used, for example methanol, ethanol
Lower alcohols such as alcohol, propanol, and isopropanol
Alcohols, dimethyl ether, dioxane, etc.
Ethers, acetone, methyl ethyl ketone, etc.
Aromatics such as ketones, benzene, toluene, xylene, etc.
Aromatic hydrocarbons, acetonitrile, N,N-dimethyl
Chylformamide, dimethyl sulfoxide,
Polar solvents such as hexamethylphosphoric acid triamide, water, etc.
can be mentioned. Also used as a deoxidizing agent
For example, sodium hydroxide, potassium hydroxide
potassium carbonate, sodium carbonate, metal sodium
um, metallic potassium, potassium bicarbonate, carbonated water
Sodium, lithium hydride, sodium amine
pyridine, quinoline, triethylamine,
Lipropylamine, piperidine, etc. may be mentioned.
can. The compound of general formula (2) and the compound of general formula (3)
There is no particular limit to the usage rate, and a wide range of
The former is selected as appropriate, but the former is usually selected from the latter.
in an equimolar to excess amount, preferably an equimolar to 3 times molar amount.
It is preferable to use the same amount. Also, the reaction temperature
The temperature is not particularly limited, but usually room temperature to 150℃,
It is preferably carried out at room temperature to 100°C. reaction time
is usually 0.5 to 10 hours. The compound of general formula (3) used in the above reaction is, for example,
General formula [R in the formula ² and R ³ is the same as above. ]
Amines and dihalogenoethane or dihalogenope
Lopan and ether, benzene, toluene, xylene
organic compounds such as urethane, ethyl acetate, and tetrahydrofuran.
Reaction in a solvent at room temperature, reflux or cooling
can be easily obtained. The compound represented by the above general formula (1) is
It can also be produced by the method shown in Formula-2. [X in the formula ¹ indicates a halogen atom. R ¹ ,R ² ，
R ³ , A, X and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] Reaction between the compound of general formula (2) and the compound of general formula (5)
and the reaction between the compound of general formula (6) and the compound of general formula (4)
The reaction is the compound of the general formula (2) and the compound of the general formula (3).
It can be carried out in the same way as the reaction with. Furthermore, the compound of the present invention represented by general formula (1)
ChiR ¹ is lower alkyl group or phenyl lower alkyl group
Compounds (compounds of general formula (1b)) exhibiting a group are:
As shown in the reaction scheme-3 below, R ¹ is a hydrogen atom
(Compound of general formula (1a))
Also by reacting the compound of general formula (7) of
Manufactured. [R in the formula ¹ ' is lower alkyl group or phenyl lower
Indicates an alkyl group. R ² ,R ^Four , A, X and carbo
The carbon-carbon bonds at the 3rd and 4th positions of the styryl skeleton are as described above.
same. ] A compound of general formula (1a) and a compound of general formula (7)
The reaction can be carried out, for example, in the presence of a basic compound in a suitable solvent.
It is best to do it inside. Here, as a basic compound
For example, sodium hydride, potassium, sodium
um, sodium amide, potassium amide, etc.
can be given. In addition, as a solvent, for example,
Xane, diethylene glycol methyl ether, etc.
ethers, aromatic charcoal such as toluene, xylene, etc.
Hydrogenides, dimethylformamide, dimethylsulfate
Phoxide, hexamethylphosphate triamide, etc.
can be given. A compound of general formula (1a) and
There is no particular limitation on the proportion of the compound of general formula (7) used.
You can choose as appropriate within a wide range, but usually the former
The latter is preferably at least equimolar to
It is preferable to use about equimolar to twice the molar amount. Applicable
The reaction is usually carried out at a temperature of about 0 to 70°C, preferably from 0°C to room temperature.
It is carried out in the vicinity, and generally takes about 0.5 to 15 hours.
The response ends. In addition, the compound of general formula (1) is shown in reaction scheme-4.
Between the 3rd and 4th carbons of the carbostyryl skeleton,
Compound (1c) in which the bond is a single bond and a double bond
Compound (1d) showing reduction reaction and dehydrogenation reaction
They can be mutually converted by [R in the formula ¹ ,R ² ,R ³ and A are the same as above. ] The dehydrogenation reaction of the compound of general formula (1c) can be carried out using an appropriate solvent.
It is carried out using a dehydrogenating agent in a medium. used
Examples of dehydrogenating agents include 2,3-dichloro-
5,6-dicyanobenzoquinone, chloranil
(2,3,5,6-tetrachlorobenzoquinone)
benzoquinones such as N-bromosuccinimide
Halogens such as do, N-chlorosuccinimide, bromine, etc.
oxidizing agent, selenium dioxide, palladium on carbon, para
Dium black, palladium oxide, Raney nickel, etc.
Mention may be made of hydrogenation catalysts. dehydrogenating agent and
When using benzoquinones or halogenating agents
If so, the amount used is not particularly limited and can be used over a wide range.
The general formula (1c) can be selected as appropriate.
Usually 1 to 5 times the molar amount of the compound, preferably
It is preferable to use 1 to 2 times the molar amount. Also dehydrogenation
If a hydrogenation catalyst is used as an agent, the amount used
As for the normal amount of catalyst, for example, general formula (1c)
It is preferable that the amount is approximately equal to the weight of the compound. Ma
Dioxane and tetrahydrofurane are used as solvents.
methoxyethanol, dimethoxyethane, etc.
Ethers, benzene, toluene, xylene, ethers
Aromatic hydrocarbons such as toralin and cumene, dichloro
lomethane, dichloroethane, chloroform, tetrasalt
Halogenated hydrocarbons such as carbon dioxide, butanol,
Alcohols such as amyl alcohol and hexanol
, polar proton solvents such as acetic acid, dimethylform
Muamide, dimethyl sulfoxide, hexamethyl
Polar aprotic solvents such as phosphoric acid triamide, etc.
I can give an example. The reaction is usually carried out at room temperature to 300°C, preferably
The process is usually carried out at room temperature to 200℃, and generally from 1 to 40 p.m.
The reaction completes in about a few minutes. For the reduction reaction of the compound of general formula (1d), the usual
A wide range of catalytic reduction conditions can be applied. reduction used
As a catalyst, for example, palladium, palladium-charcoal
List metals such as copper, platinum, and Raney nickel.
You can use these with normal catalyst amounts.
Good. In addition, examples of the solvent used include methane.
alcohol, ethanol, isopropanol, dioxin
San, tetrahydrofuran, hexane, cyclohexane
Examples include xane and ethyl acetate. Applicable
The reaction is carried out under normal pressure or elevated pressure;
Pressure~10Kg/cm ² , preferably normal pressure to 3Kg/cm ² to be
It is better. The reaction temperature is usually 0 to 100°C, preferably
Preferably, the temperature is between room temperature and 70°C. 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 at position 4 is a double bond are as follows:
As shown in reaction scheme-5, lactam-lacti
It can have tautomerism. [R in the formula ² ,R ³ and A are the same as above. ] The carboxylic acid represented by the general formula (1) obtained in this way
Styryl derivatives act with pharmaceutically acceptable acids.
It can be easily made into an acid addition salt by
Wear. Examples of the acid include hydrochloric acid, sulfuric acid, and phosphoric acid.
acids, inorganic acids such as hydrobromic acid, acetic acid, oxalic acid,
Huccinic acid, maleic acid, fumaric acid, malic acid, alcoholic acid
Tartaric acid, citric acid, malonic acid, methanesulfonic acid,
Organic acids such as benzoic acid can be used. Also, among the compounds represented by general formula (1), carbo
The carbon-carbon bonds at the 3rd and 4th positions of the styryl skeleton form a double bond.
Compounds that exhibit this combination include, for example, sodium hydroxide and water.
Potassium oxide, calcium hydroxide, sodium carbonate
Reacts with basic compounds such as aluminum and potassium hydrogen carbonate.
can easily form salts. Furthermore, the compound represented by general formula (1) can react
As shown in formula-6, the nitrogen of the amino group of the compound is
Lower atom halide represented by general formula (8)
A quaternary salt is generated by reacting with
can be done. [R in the formula ^Four represents a lower alkyl group. R ¹ ,R ² ，
R ³ , A, X and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] Reaction between the compound of general formula (1) and the compound of general formula (8)
is advantageously carried out in a suitable inert solvent. The melt
Examples of media include methanol, ethanol, and
Lower alcohols such as panol, benzene, tol
Aromatic hydrocarbons such as ene and xylene,
Ethers such as dorofuran and dioxane, chloro
Form, trichlorethylene, dimethylformua
Mido (DMF), dimethyl sulfoxide
(DMSO), hexametaphosphoric acid triamide, etc.
can be shown. Amount of compound represented by general formula (8) used
is usually less than the compound represented by general formula (1).
About the same molar amount, preferably equimolar to 5 times the molar amount.
It is better to use quantity. Reaction temperature is usually about 0 to 200℃
temperature, preferably room temperature to 80°C, and the reaction is carried out at 1 to 8°C.
It will be completed in about an hour. General formula (9) produced by the above reaction scheme-6
An element in which X is larger than a chlorine atom in the compound represented by
When a halogen atom with a valence number of
By reacting this with silver chloride, X becomes a chlorine source.
It can be converted into its child compound. Similarly, X is a bromine source
A halogen atom with a valence number greater than its child.
The compound can be converted to X by reacting it with silver bromide.
can be converted to a compound where is a bromine atom. This etc.
The conversion reaction of halogen atoms is, for example, the lower atom mentioned above.
Contains alcohols, DMF, DMSO and water as solvents.
You can do it to your advantage. The amount of silver halide used is based on raw materials.
at least equimolar, preferably equimolar to the compound.
It is said to be about mol to 6 times the mol, and the reaction is about 0 to 80℃
temperature, preferably room temperature to 50℃ for about 5 to 24 hours.
It is done. 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.
absorption enhancer, glycerin, starch humectant,
Starch, lactose, kaolin, bentonite, colo
Adsorbent such as id-like silicic acid, purified talc, stair
Phosphates, boric acid powder, polyethylene glycol, etc.
Examples include any lubricant. Need more pills
Tablets with customary coatings, such as sugar-coated tablets,
Gelatin-coated tablets, enteric-coated tablets, film coated tablets
Can be made into double-layered tablets, double-layered tablets, or multi-layered tablets.
Ru. When forming into pill form, it is necessary to use it as a carrier.
Conventionally known levers can be widely used in the field of levers, e.g.
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. liquid when prepared as an injection;
and the suspension is sterile and isotonic with blood.
These solutions, emulsions and suspensions are preferably
When molding into a shape, use this as a diluent.
You can use whatever is customary in your field.
For example, water, ethyl alcohol, propylene
Recall, 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 may add any. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavors, sweeteners, etc. and other pharmaceutical products
may be included in the therapeutic agent. 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 rectally. 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 of the substance should be approximately 0.1 to 10 mg per 1 kg of body weight per day.
It is better to It also contains the active ingredient in dosage unit form.
It is preferable to contain 1 to 200 mg. Reference example 6-hydroxy-3,4-dihydrocarbosuti
16.4g of rill, 9g of potassium hydroxide and isopropano
Mix it with 150ml of water and stir at 70-80℃ for 30 minutes, then
Add 25g of 1,3-dibromopropane for 6 hours.
Heat to reflux. After the reaction is complete, add 2N hydroxide to the reaction solution.
in 200 ml of aqueous sodium solution to remove insoluble matter.
Remove, wash, and dry. Crude crystals from methanol
When recrystallized, it produces 6-(3-bromine) with a melting point of 121-124℃.
propoxy)-3,4-dihydrocarbostyryl
17g is obtained. Example 1 2-benzylaminoethyl chloride hydrochloride 4.6
Dissolve g in 8 ml of water and add 30 ml of benzene to this.
Under ice-cooling, alkali was added with dilute aqueous sodium hydroxide solution.
It is assumed that the Separate the benzene layer and dry it with potassium carbonate.
dry Meanwhile, add 0.46g of metallic sodium to methanol.
6-Hydroxy-3,4-dihydre dissolved in 30ml
Obtained by adding 3.2 g of locarbostyril and refluxing for 30 minutes.
A base of 2-benzylaminoethyl chloride is added to the solution.
Add Angel's solution and heat under reflux for 4 hours. cold
Separate the sodium chloride that precipitates later, and drain the liquid.
Concentrate to dryness under reduced pressure. Dissolve the residue in chloroform
After washing with dilute aqueous sodium hydroxide solution,
Dry with Glauber's salt and distill off the chloroform. concentrated hydrochloric acid
-Methanol is used to make hydrochloride, and methanol or
Recrystallize from 6-(2-benzylaminoethyl)
c)-3,4-dihydrocarbostyril hydrochloride
Obtain 2.1g. mp.258-259℃. Compounds of Examples 2 to 33 were prepared in the same manner as in Example 1.
obtain. Example 2 6-(3-benzylamino-2-methylpropo
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.187-188℃ (isopropanol) Example 3 5-(3-benzylaminopropoxy)-3,
4-dihydrocarbostyryl monohydrochloride mp.218.5-221.5℃ (water) Example 4 7-(3-benzylaminopropoxy)-3,
4-dihydrocarbostyryl monohydrochloride mp.221.0-223.0℃ (methanol) Example 5 8-(3-benzylaminopropoxy)-3,
4-dihydrocarbostyryl monohydrochloride mp.223.5-225.5℃ (water) Example 6 6-(3-benzylaminopropoxy)-cal
Bostyril monohydrobromide mp.244.5-246.5℃ (water-acetone) Example 7 6-(3-n-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.239-241℃ (ethanol) Example 8 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.266.5-268℃ (decomposition) (ethanol) Example 9 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.263.5-265.0 (decomposition) (ethanol) Example 10 7-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.269-270℃ (decomposition) (methanol) Example 11 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.259.5-260.5℃ (ethanol) Example 12 6-(3-N-methyl-N-benzylaminoplast)
Ropoxy)-3,4-dihydrocarbostili
197-199.5℃ (ethanol) Example 13 6-[3-(2-phenylethylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.233-234.5℃ (methanol) Example 14 6-{3-[2-(3,4-dimethoxy)phene
Nylethyl]aminopropoxy}-3,4-di
Hydrocarbostyryl monohydrochloride mp.178.5-179.5℃ (methanol) Example 15 6-(3-isopropylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.192.5-194.5℃ (ethanol) Example 16 6-[3-(N,N-dibenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.225-226.5℃ (methanol) Example 17 6-[3-(1-methylbenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.163-165℃ (decomposition) (ethanol) Example 18 6-(4-benzylaminobutoxy)-3,4
-Dihydrocarbostyryl monohydrochloride mp.202.5-204.5℃ (methanol) Example 19 1-Methyl-6-(3-benzylaminoprop.
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.184.5-185.5℃ (ethanol) Example 20 1-benzyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.222-223.5℃ (methanol) Example 21 6-[3-(3-phenylpropylamino)propylamino]
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.222.0-225.0℃ (methanol) Example 22 6-[3-(2-phenoxy-1-methylethyl
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril monohydrochloride mp.199.5-201.0℃ (ethanol) Example 23 6-{3-[2-(4-methoxyphenoxy)
ethylaminopropoxy}-3,4-dihyde
Locarbostyryl monohydrobromide mp.211.0-212.0℃ (methanol) Example 24 6-[3-(di-2-hydroxyethylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide mp.150.0-152.0℃ (ethanol) Example 25 6-[3-(2-hydroxyethylamino)propylene
Ropoxy]-3,4-dihydrocarbostili
179.5-180.5℃ (water-acetone) Example 26 6-[3-(4-chlorobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.238-240℃ (decomposition) Example 27 6-[3-(4-methoxybenzylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.230-231.5℃ Example 28 6-[3-(4-nitrobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.214-216℃ (decomposition) Example 29 6-{3-[N-(4-methoxybenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.197-198.5℃ Example 30 6-{3-[4-(2-hydroxyethyl)-
1-piperazinyl]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.251-252℃ (decomposition) Example 31 Dissolve 0.46g of metallic sodium in 30ml of methanol
6-hydroxy-3,4-dihydrocarbos
Add 3.2 g of Tyril and reflux for 30 minutes.
-Morpholinopropyl chloride 3.7g benzene
Add 30 ml of the solution and heat under reflux for 4 hours. cold
Separate the sodium chloride that precipitates later, and drain the liquid.
Concentrate to dryness under reduced pressure. Dissolve the residue in chloroform
After washing with dilute aqueous sodium hydroxide solution,
Dry with Glauber's salt and distill off the chloroform. This residue
After recrystallizing the distillate from isopropanol,
The pH was adjusted to 1 by adding concentrated acid. Analysis
Remove the crystals and recrystallize from ethanol to obtain 6-
(3-morpholinopropoxy)-3,4-dihyde
2.3 g of locarbostyril hydrochloride was obtained. mp.207-209.5℃ Compounds of Examples 35 to 45 were prepared in the same manner as in Example 31.
obtain. Example 32 6-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.148.0-151.0℃ (isopropanol) Example 33 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Example 34 5-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.269.5-272℃ (methanol) Example 35 7-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.159-162℃ (ethanol) Example 36 8-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.210-211.5℃ (ethanol) Example 37 6-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostili
1 hydrochloride mp.206-208.5℃ (isopropanol) Example 38 7-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.166.5-168.0℃ (isopropanol) Example 39 6-(3-morpholinopropoxy)carbosti
Rilu monohydrochloride mp.225.5-226.5℃ (ethanol) Example 40 6-(3-pyrrolidinopropoxy)carbosuti
Rilu monohydrochloride mp.178-181℃ (ethanol) Example 41 6-[3-(1-methyl-1-pyrrolidium)
Propoxy] carbostyryl iodide mp.232-233℃ (ethanol) Example 42 6-[3-(1-piperazinyl)propoxy]
-3,4-dihydrocarbostyryl mp.241.5 - 243℃ (methanol-ether) Example 43 6-(3-bromopropoxy)-3,4-dihydryl
Dorocarbostyril 4.26g and 6.34g p-chloro
Benzylamine and 20ml of acetonitrile
and stir at room temperature for 1-2 hours. Further 40~60℃
Stir for 2-3 hours. After cooling, remove the precipitated crystals and
Suspend it in acetone, add 48% hydrobromic acid and adjust the pH.
≒1. Take the precipitated crystals, mp.238~240℃
(Decomposition) of 6-[3-(p-chlorobenzylamine)
(g) Propoxy]-3,4-dihydrocarbosti
2.3 g of lylu hydrobromide was obtained. Compounds of Examples 47 to 79 were prepared in the same manner as in Example 43.
obtain. Example 44 6-(3-benzylamino-2-methylpropo
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.187-188℃ (isopropanol) Example 45 5-benzylaminopropoxy-3,4-dihyde
Dolocarbostyril monohydrochloride mp.218.5-221.5℃ (Water) Example 46 7-benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.221.0-223.0℃ (methanol) Example 47 8-benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.223.5-225.5℃ (Water) Example 48 6-benzylaminopropoxycarbostyril
1-hydrobromide mp.244.5-246.5℃ (water-acetone) Example 49 6-(3-n-butylaminopropyloxy)
-3,4-dihydrocarbostyryl monohydrochloride mp.239-241℃ (ethanol) Example 50 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.266.5-268℃ (decomposition) (ethanol) Example 51 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.263.5-265.0℃ (decomposition) (ethanol) Example 52 7-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.269-270℃ (decomposition) (methanol) Example 53 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.259.5-260.5℃ (ethanol) Example 54 6-(3-N-methyl-N-benzylaminopropylene)
Ropoxy)-3,4-dihydrocarbostili
197-199.5℃ (ethanol) Example 55 6-[3-(2-phenylethylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.233-234.5℃ (methanol) Example 56 6-{3-[2-(3,4-dimethoxy)phene
Nylethylpropoxy}-3,4-dihydro
Carbostyril monohydrochloride mp.178.5-179.5℃ (methanol) Example 57 6-(3-isopropylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.192.5-194.5℃ (ethanol) Example 58 6-[3-(N,N-dibenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.225-226.5℃ (methanol) Example 59 6-[3-(1-methylbenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.163-165℃ (decomposition) (ethanol) Example 60 6-(2-benzylaminoethoxy)-3,4
-Dihydrocarbostyryl hydrochloride mp.258-259.5℃ (methanol) Example 61 6-(4-benzylaminobutoxy)-3,4
-Dihydrocarbostyryl monohydrochloride mp.202.5-204.5℃ (methanol) Example 62 1-Methyl-6-(3-benzylaminoprop.
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.184.5-185.5℃ (ethanol) Example 63 1-benzyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.222-223.5℃ (methanol) Example 64 6-[3-(3-phenylpropylamino)propylamino]
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.222.0-225.0℃ (methanol) Example 65 6-[3-(2-phenoxy-1-methylethyl
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril monohydrochloride mp.199.5-201.0℃ (ethanol) Example 66 6-{3-[2-(4-methoxyphenoxy)
ethylaminopropoxy}-3,4-dihyde
Locarbostyryl monohydrobromide mp.211.0-212.0℃ (methanol) Example 67 6-[3-(di-2-hydroxyethylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide mp.150-152.0℃ (ethanol) Example 68 6-[3-(2-hydroxyethylamino)propylene
Ropoxy]-3,4-dihydrocarbostili
179.5-180.5℃ (water-acetone) Example 69 6-[3-(4-chlorobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.238-240℃ (decomposition) Example 70 6-[3-(4-methoxybenzylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.230-231.5℃ Example 71 6-[3-(4-nitrobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.214-216℃ (decomposition) Example 72 6-{3-[N-(4-methoxybenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.197-198.5℃ Example 73 6-{3-[4-(2-hydroxyethyl)-
1-piperazinyl]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.251-252℃ (decomposition) Example 74 6-(3-bromopropoxy)carbostyryl
2g, acetonitrile 20ml, morpholine 1.84g
After refluxing for 7 hours, the reaction solution was concentrated to dryness. on the residue.
Add 0.5NNaOH to loloform, extract, and chloroform.
The lume layer is washed with water, dried, and the solvent is distilled off. obtained
Dissolve the solid matter in ethanol and add concentrated hydrochloric acid.
Let PH≒1. The solution was concentrated to dryness and diluted with acetone.
Add sopropanol to crystallize and remove the precipitated crystals.
The crystals were then recrystallized from ethanol to give 6-
(3-morpholinopropoxy) carbostyryl
1.15 g of hydrochloride was obtained. mp.225.5-226.5℃ Compounds of Examples 75 to 85 were prepared in the same manner as in Example 74.
obtain. Example 75 6-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.148.0-151.0℃ (isopropanol) Example 76 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Example 77 6-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.207-209.5℃ (ethanol) Example 78 5-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.269.5-272℃ (methanol) Example 79 7-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.159-162℃ (ethanol) Example 80 8-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.210-211.5℃ (ethanol) Example 81 6-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostili
1 hydrochloride mp.206-208.5℃ (isopropanol) Example 82 6-(3-pyrrolidinopropoxy)carbosuti
Rilu monohydrochloride mp.178-181℃ (ethanol) Example 83 6-[3-(1-methyl-1-pyrrolidium)
Propoxy] carbostyryl iodide mp.232-233℃ (ethanol) Example 84 7-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.166.5-168.0℃ (isopropanol) Example 85 6-[3-(1-piperazinyl)propoxy]
-3,4-dihydrocarbostyryl mp.241.5-243℃ (methanol-ether) Example 86 6-(3-chloro-2-methylpropoxy)-
3,4-dihydrocarbostyryl 3g, sodium iodide
70% of a mixture of 2g of thorium and 30ml of acetonitrile
Stir at ~80°C for 2 hours. Furthermore, triethyl a
Add 2ml of amine and 3ml of benzylamine and bring to the same temperature.
Stir for 8 hours. Distill acetonitrile under reduced pressure
Add dilute sodium hydroxide solution to the residue and chlorinate it.
Extract with holm. After washing with water, dissolve the residue in concentrated hydrochloric acid-meth
Make the hydrochloride with alcohol. Reconstituted from isopropanol
6-(3-benzyl acetate) crystallized, mp.187-188℃
mino-2-methylpropoxy)-3,4-dihyde
Obtain 80 mg of locarbostyril monohydrochloride. Compounds of Examples 87 to 127 in the same manner as Example 86
get. Example 87 5-benzylaminopropoxy-3,4-dihydrogen
Dolocarbostyril monohydrochloride mp.218.5-221.5℃ (Water) Example 88 7-benzylaminopropoxy-3,4-dihyde
Dolocarbostyril monohydrochloride mp.221.0-223.0℃ (methanol) Example 89 8-benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.223.5-225.5℃ (Water) Example 90 6-benzylaminopropoxycarbostyril
1-hydrobromide mp.244.5-246.5℃ (water-acetone) Example 91 6-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.148.0-151.0℃ (isopropanol) Example 92 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Example 93 6-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.207-209.5℃ (ethanol) Example 94 6-(3-n-butylaminopropyloxy)
-3,4-dihydrocarbostyryl monohydrochloride mp.239-241℃ (ethanol) Example 95 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.266.5-268℃ (decomposition) (ethanol) Example 96 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.263.5-265.0℃ (decomposition) (ethanol) Example 97 7-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.269-270℃ (decomposition) (methanol) Example 98 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.259.5-260.5℃ (ethanol) Example 99 6-(3-N-methyl-N-benzylaminoplast)
Ropoxy)-3,4-dihydrocarbostili
1-hydrochloride mp.197-199.5℃ (ethanol) Example 100 6-[3-(2-phenylethylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.233-234.5℃ (methanol) Example 101 6-{3-[2-(3,4-dimethoxy)phene
Nylethylpropoxy}-3,4-dihydro
Carbostyril monohydrochloride mp.178.5-179.5℃ (methanol) Example 102 5-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.269.5-272℃ (methanol) Example 103 7-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.159-162℃ (ethanol) Example 104 8-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.210-211.5℃ (ethanol) Example 105 6-(3-isopropylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.192.5-194.5℃ (ethanol) Example 106 6-[3-(N,N-dibenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.225-226.5℃ (methanol) Example 107 6-[3-(1-methylbenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.163-165℃ (decomposition) (ethanol) Example 108 6-(3-pyrrolidinopropoxy)carbosti
Rilu monohydrochloride mp.178-181℃ (ethanol) Example 109 6-[3-(1-methyl-1-pyrrolidium)
Propoxy] carbostyryl iodide mp.232-233℃ (ethanol) Example 110 6-(2-benzylaminoethoxy)-3,4
-Dihydrocarbostyryl hydrochloride mp.258-259.5℃ (methanol) Example 111 6-(4-benzylaminobutoxy)-3,4
-Dihydrocarbostyryl monohydrochloride mp.202.5-204.5℃ (methanol) Example 112 1-Methyl-6-(3-benzylaminoprop.
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.184.5-185.5℃ (ethanol) Example 113 1-benzyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.222-223.5℃ (methanol) Example 114 7-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyril monohydrochloride mp.166.5-168.0℃ (isopropanol) Example 115 6-(3-morpholinopropoxy)carbosti
Rilu monohydrochloride mp.225.5-226.5℃ (ethanol) Example 116 6-[3-(3-phenylpropylamino)propylamino]
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.222.0-225.0℃ (methanol) Example 117 6-[3-(2-phenoxy-1-methylethyl
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril monohydrochloride mp.199.5-201.0 (ethanol) Example 118 6-[3-(4-benzylpiperidine-1-i)
) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrochloride mp.206-208.5℃ (isopropanol) Example 119 6-{3-[2-(4-methoxyphenoxy)
ethylaminopropoxy}-3,4-dihyde
Locarbostyryl monohydrobromide mp.211.0-212.0℃ (methanol) Example 120 6-[3-(di-2-hydroxyethylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide mp.150.0-152.0℃ (ethanol) Example 121 6-[3-(2-hydroxyethylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
179.5-180.5℃ (water-acetone) Example 122 6-[3-(1-piperazinylamino)propo
[oxy]-3,4-dihydrocarbostyryl mp.241.5-243℃ (methanol ether) Example 123 6-[3-(4-chlorobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.238-240℃ (decomposition) Example 124 6-[3-(4-methoxybenzylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.230-231.5℃ Example 125 6-[3-(4-nitrobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.214-216℃ (decomposition) Example 126 6-{3-[N-(4-methoxybenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.197-198.5℃ Example 127 6-{3-[4-(2-hydroxyethyl)-
1-piperazinyl]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.251-252℃ (decomposition) Example 128 6-(3-chloropropoxy)-3,4-dihyrochloride
Dolocarbostyril 3g, Sodium Iodide 2.82
g, reflux 20 ml of acetone for 3 hours. Concentrate the reaction solution.
Condensed to dryness to give 6-(3-iodopropoxy)-
3,4-dihydrocarbostyryl was obtained. With this
DMF15ml, benzylpiperidine 2.82g 70-80
Stir at ℃ for 8 hours. The reaction solution was concentrated to dryness, and the residue
Extract with chloroform. chloroform layer
After washing with 0.5N-sodium hydroxide aqueous solution,
Wash with water, dry and remove the solvent. Obtained crude crystals
was recrystallized from ethanol, concentrated hydrochloric acid-methanol
to make the hydrochloride. Recrystallized from isopropanol
6-[3-(4-benzylpiperidine-1-i)
) Propoxy]-3,4-dihydrocarbosti
3.8 g of ril monohydrochloride was obtained. mp.206-208.5℃ Compounds of Examples 129 to 169 in the same manner as Example 128
get something Example 129 6-(3-benzylamino-2-methyllupro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.187-188℃ (isopropanol) Example 130 5-benzylaminopropoxy-3,4-dihyde
Dolocarbostyril monohydrochloride mp.218.5-221.5℃ (Water) Example 131 7-benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.221.0-223.0℃ (methanol) Example 132 8-Benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.223.5-225.5℃ (Water) Example 133 6-benzylaminopropoxycarbostyril
1-hydrobromide mp.244.5-246.5℃ (water-acetone) Example 134 6-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.148.0-151.0℃ (isopropanol) Example 135 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Example 136 6-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.207-209.5℃ (ethanol) Example 137 6-(3-n-butylaminopropyloxy)
-3,4-dihydrocarbostyryl monohydrochloride mp.239-241℃ (ethanol) Example 138 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.266.5-268℃ (decomposition) (ethanol) Example 139 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.263.5-265.0℃ (decomposition) (ethanol) Example 140 7-(3-t-butylaminopropoxy)-3,
4-dihydrocarbostyryl monohydrochloride mp.269-270℃ (decomposition) (methanol) Example 141 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.259.5-260.5℃ (ethanol) Example 142 6-(3-N-methyl-N-benzylaminopropylene)
Ropoxy)-3,4-dihydrocarbostili
1 hydrochloride mp.197-199.5℃ (ethanol) Example 143 6-[3-(2-phenylethylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.233-234.5℃ (methanol) Example 144 6-{3-[2-(3,4-dimethoxy)phene
Nylethylpropoxy}-3,4-dihydro
Carbostyril monohydrochloride mp.178.5-179.5℃ (methanol) Example 145 5-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.269.5-272℃ (methanol) Example 146 7-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.159-162℃ (ethanol) Example 147 8-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.210-211.5℃ (ethanol) Example 148 6-(3-isopropylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.192.5-194.5℃ (ethanol) Example 149 6-[3-[N,N-dibenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.225-226.5℃ (methanol) Example 150 6-[3-(1-methylbenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.163-165℃ (decomposition) (ethanol) Example 151 6-(3-pyrrolidinopropoxy)carbosti
Rilu monohydrochloride mp.178-181℃ (ethanol) Example 152 6-[3-(1-methyl-1-pyrrolidium)
Propoxy] carbostyril iodide mp.232-233℃ (ethanol) Example 153 6-(2-benzylaminoethoxy)-3,4
-Dihydrocarbostyryl hydrochloride mp.258-259.5℃ (methanol) Example 154 6-(4-benzylaminobutoxy)-3,4
-Dihydrocarbostyryl monohydrochloride mp.202.5-204.5℃ (methanol) Example 155 1-Methyl-6-(3-benzylaminoprop.
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.184.5-185.5℃ (ethanol) Example 156 1-benzyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.222-223.5℃ (methanol) Example 157 7-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.166.5-168.0℃ (isopropanol) Example 158 6-(3-morpholinopropoxy)carbostyril
Rilu monohydrochloride mp.225.5-226.5℃ (ethanol) Example 159 6-[3-(3-phenylpropylamino)propylamino]
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.222.0-225.0℃ (methanol) Example 160 6-[3-(2-phenoxy-1-methylamino)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrochloride mp.199.5-201.0℃ (ethanol) Example 161 6-{3-[2-(4-methoxyphenoxy)
ethylaminopropoxy}-3,4-dihyde
Locarbostyryl monohydrobromide mp.211.0-212.0℃ (methanol) Example 162 6-[3-(di-2-hydroxyethylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide mp.150.0-152.0℃ (ethanol) Example 163 6-[3-(2-hydroxyethylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.179.5-180.5℃ (water-acetone) Example 164 6-[3-(1-piperazinyl)propoxy]
-3,4-dihydrocarbostyryl mp.241.5-243℃ (methanol-ether) Example 165 6-[3-(4-chlorobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.238-240℃ (decomposition) Example 166 6-[3-(4-methoxybenzylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.230-231.5℃ Example 167 6-[3-(4-nitrobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.214-216℃ (decomposition) Example 168 6-{3-[N-(4-methoxybenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.197-198.5℃ Example 169 6-{3-[4-(2-hydroxyethyl)-
1-piperazinyl]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.251-252℃ (decomposition) Example 170 6-(3-bromopropoxy)-3,4-dihyrochloride
Dorocarbostyril 2g, methanolamine 3
g, reflux 20 ml of methanol for 10 hours, and add 2N-hydroxy acid.
Add 3.5 ml of sodium chloride-methanol and concentrate.
Dry. Add acetone to the residue to crystallize it,
take. The crude crystals are refined using thin layer chromatography.
6-(3-ethanolaminopropoxy)
c)-3,4-dihydrocarbostyril was obtained.
Add 48% hydrobromic acid in methanol to the pH ≒
1 and concentrate to dryness. Add acetone to the residue and
Crystallize and take. Reconstitute the crude crystals from water-acetone.
It crystallizes into 6-[3-(2-hydroxyethyl acetate)
Mino)propoxy]-3,4-dihydrocarbos
1 g of tyryl monobromate was obtained. mp.179.5-180.5℃ Compounds of Examples 171 to 211 in the same manner as Example 170
get something Example 171 6-(3-benzylamino-2-methylpropo
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.187-188℃ (isopropanol) Example 172 5-benzylaminopropoxy-3,4-dihyde
Dolocarbostyril monohydrochloride mp.218.5-221.5℃ (Water) Example 173 7-benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.221.0-223.0℃ (methanol) Example 174 8-Benzylaminopropoxy-3,4-dihydrochloride
Dolocarbostyril monohydrochloride mp.223.5-225.5℃ (Water) Example 175 6-benzylaminopropoxycarbostyril
1-hydrobromide mp.244.5-246.5℃ (water-acetone) Example 176 6-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.148.0-151.0℃ (isopropanol) Example 177 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Example 178 6-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.207-209.5℃ (ethanol) Example 179 6-(3-n-butylaminopropyloxy)
-3,4-dihydrocarbostyryl monohydrochloride mp.239-241℃ (ethanol) Example 180 5-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.266.5-268℃ (decomposition) (ethanol) Example 181 6-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.263.5-265.0℃ (decomposition) (ethanol) Example 182 7-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.269-270℃ (decomposition) (methanol) Example 183 8-(3-t-butylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.259.5-260.5℃ (ethanol) Example 184 6-(3-N-methyl-N-benzylaminopropylene)
Ropoxy)-3,4-dihydrocarbostili
197-199.5℃ (ethanol) Example 185 6-[3-(2-phenylethylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.233-234.5℃ (methanol) Example 186 6-{3-[2-(3,4-dimethoxy)phene
Nylethylpropoxy}-3,4-dihydro
Carbostyril monohydrochloride mp.178.5-179.5℃ (methanol) Example 187 5-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.269.5-272℃ (methanol) Example 188 7-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.159-162℃ (ethanol) Example 189 8-(3-morpholinopropoxy)-3,4-
Dihydrocarbostyryl monohydrochloride mp.210-211.5℃ (ethanol) Example 190 6-(3-isopropylaminopropoxy)-
3,4-dihydrocarbostyryl monohydrochloride mp.192.5-194.5℃ (ethanol) Example 191 6-[3-N,N-dibenzylamino)propo
[oxy]-3,4-dihydrocarbostyryl 1
Hydrochloride mp.225-226.5℃ (methanol) Example 192 6-[3-(1-methylbenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrochloride mp.163-165℃ (decomposition) (ethanol) Example 193 6-(3-pyrrolidinopropoxy)carbosti
Rilu monohydrochloride mp.178-181℃ (ethanol) Example 194 6-[3-(1-methyl-1-pyrrolidium)
Propoxy] carbostyryl iodide mp.232-233℃ (ethanol) Example 195 6-(2-benzylaminoethoxy)-3,4
-Dihydrocarbostyryl hydrochloride mp.258-259.5℃ (methanol) Example 196 6-(4-benzylaminobutoxy)-3,4
-Dihydrocarbostyryl monohydrochloride mp.202.5-204.5℃ (methanol) Example 197 1-Methyl-6-(3-benzylaminoprop.
xy)-3,4-dihydrocarbostyryl 1
Hydrochloride mp.184.5-185.5℃ (ethanol) Example 198 1-benzyl-6-(3-benzylaminopro
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride mp.222-223.5℃ (methanol) Example 199 7-(3-pyrrolidinopropoxy)-3,4-
Dihydrocarbostyril monohydrochloride mp.166.5-168.0℃ (isopropanol) Example 200 6-(3-morpholinopropoxy)carbosti
Rilu monohydrochloride mp.225.5-226.5℃ (ethanol) Example 201 6-[3-(3-phenylpropylamino)propylamino]
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.222.0-225.0℃ (methanol) Example 202 6-[3-(2-phenoxy-1-methylethyl
(Ruamino)propoxy]-3,4-dihydroca
Luvostyril monohydrochloride mp.199.5-201.0℃ (ethanol) Example 203 6-[3-(4-benzylpiperidine-1-i)
) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrochloride mp.206-208.5℃ (isopropanol) Example 204 6-{3-[2-(4-methoxyphenoxy)
ethylaminopropoxy}-3,4-dihyde
Locarbostyril monohydrobromide mp.211.0-212.0℃ (methanol) Example 205 6-[3-(di-2-hydroxyethylamine)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide mp.150.0-152.0℃ (ethanol) Example 206 6-[3-(1-piperazinylamino)prop.
[oxy]-3,4-dihydrocarbostyryl mp.241.5-243℃ (methanol-ether) Example 207 6-[3-(4-chlorobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.238-240℃ (decomposition) Example 208 6-[3-(4-methoxybenzylamino)prop.
Ropoxy]-3,4-dihydrocarbostili
1-hydrobromide mp.230-231.5℃ Example 209 6-[3-(4-nitrobenzylamino)pro
poxy]-3,4-dihydrocarbostyryl
Monohydrobromide mp.214-216℃ (decomposition) Example 210 6-{3-[N-(4-methoxybenzyl)-
N-methylamino]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.197-198.5℃ Example 211 6-{3-[4-(2-hydroxyethyl)-
1-piperazinyl]propoxy}-3,4-di
Hydrocarbostyryl monohydrobromide mp.251-252℃ (decomposition) Example 212 6-(3-piperidinopropoxy)carbosti
1.6 g of rill, 2 ml of methyl iodide, 30 ml of methanol
After refluxing for 2.5 hours, the solvent was distilled off and the residue was evaporated.
Add tanol-acetone to crystallize and remove.
Crude crystals were obtained. Recrystallize this from ethanol
1-methyl iodide-1-6-[3-(1-methyl
-1-pyrrolidium) propoxy] carbostiri
1.4 g of iodide was obtained. mp.232-233℃ The compound of Example 213 was prepared in the same manner as in Example 212.
Obtained. Example 213 6-[3-(1-methyl-1-pyrrolidium)
Propoxy]-3,4-dihydrocarbostili
Iodide mp.189.5-190.5℃ (ethanol-acetone) Pharmacological test
Intravenous administration of the sodium salt of 30 mg/Kg
The patient is given anesthesia. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
The heart is removed in locks fluid. sinus from the right coronary artery
Insert the cannula toward the nodal artery and insert the cannula into the right atrium.
Extract it along with the cannula. Then, set Pentoba in advance.
Rubital sodium salt (30 mg/Kg, intravenous administration)
anesthesia with heparin treatment (1000U/Kg,
(intravenous administration) of male and female mixed-breed adult dogs weighing 18 to 27 kg.
Blood is drawn from the carotid artery via a peristaltic pump.
into the cannula inserted into the right coronary artery, and insert the cannula into the right heart.
Irrigate the chamber. The perfusion pressure should be a low pressure of 100 mmHg.
The movement of the right atrium was measured under a resting tension of 2 g using a force-displacement transducer.
Measure the contractile force of the atrial muscle through the . coronary blood flow
The amount is measured using an electromagnetic flowmeter. All records are
Record it on the ink recorder. Furthermore, this method
Details are reported by Chiba et al. [Japan, J.
Pharmacol, twenty five , 433-439 (1975), Naunyn.
Schmiedbergs Arck.Pharmacol, 289 , 315～
325 (1975)]. The test compound was administered via a cannula inserted into the right coronary artery.
artery via a rubber tube connected in close proximity to the
Inject in a volume of 10-30 μl. Positive of test compound
Inotropy is % of the developed tension before compound administration.
Changes in coronary blood flow are expressed as changes in coronary blood flow before administration.
Expressed as absolute value (ml/min) from Result 1st
Shown in the table. 1 6-(2-benzylaminoethoxy)-3,
4-dihydrocarbostyryl monohydrochloride 2 7-(3benzylaminopropoxy)-3,
4-dihydrocarbostyryl monohydrochloride 3 6-(3-benzylaminopropoxy)cal
Bostyril monohydrobromide 4 6-(3-pyrrolidinopropoxy)-3,4
-Dihydrocarbostyryl monohydrochloride 5 6-[3-(1-methyl-1-pyrrolidinium)
) Propoxy]-3,4-dihydrocarbos
Tyryl iodide 6 6-(3-morpholinopropoxy)-3,4
-dihydrocarbostyryl monohydrochloride 7 6-[3-(N-methyl-N-benzylamide
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrochloride 8 6-[3-(2-phenylethylamino)p
Ropoxy]-3,4-dihydrocarbostili
1 hydrochloride 9 7-(3-morpholinopropoxy)-3,4
-Dihydrocarbostyryl monohydrochloride 10 1-benzyl-6-(3-benzylaminoprol)
Ropoxy)-3,4-dihydrocarbostili
1-methyl-6-(3-benzylaminopro-
poxy)-3,4-dihydrocarbostyryl
Monohydrochloride 12 6-(3-pyrrolidinopropoxy)carbos
Tyryl monohydrochloride 13 6-[3-(1-methyl-1-pyrrolidinium)
Propoxy] carbostyryl iodide
Do14 7-[3-(1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl15 6-(3-morpholinopropoxy)carbos
Tyryl monohydrochloride 16 6-[3-(3-phenylpropylamino)
Propoxy]-3,4-dihydrocarbostili
1-hydrobromide 17 6-[3-(1-methyl-2-phenoxyene)
thylamino)propoxy]-3,4-dihydro
Carbostyril monohydrochloride 18 6-[3-(4-benzyl-1-piperidi
) Propoxy]-3,4-dihydrocarbos
Tyril 1-hydrochloride 19 6-{3-[2-(4-methoxyphenolica)
c) Ethyl]aminopropoxy}-3,4-di
Hydrocarbostyryl monohydrobromide20 6-[3-(di-2-hydroxyethylamide)
(g) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrobromide21 6-[3-(4-phenyl-1-piperazine)
) Propoxy]-3,4-dihydrocarbos
Tyryl monohydrochloride monohydrate salt 22 6-[3-(4-benzyl-1-piperazini)
) Propoxy]-3,4-dihydrocarbos
Tyryl dihydrochloride 23 6-[3-(1-piperazinyl)propox
[C]-3,4-dihydrocarbostyryl 2 salt
Acid acid 24 6-[3-(4-phenyl-1-piperazine)
Propoxy]-carbostyryl monohydrochloric acid
Salt/monohydrate salt 25 6-[3-(4-chlorobenzyl)aminop
Ropoxy]-3,4-dihydrocarbostyryl26 6-[3-(4-methoxybenzyl)amino
Propoxy]-3,4-dihydrocarbostili
27 6-[3-(4-nitrobenzyl)aminop
Ropoxy]-3,4-dihydrocarbostyryl28 6-{3-[N-methyl-N-(4-methoxy)
cybenzyl)]aminopropoxy}-3,4-
Dihydrocarbostyryl29 6-{3-[4-(2-hydroxyethyl)
-1-piperazinyl]propoxy}-3,4-
Dihydrocarbostyryl 30 Papaverine (control compound)

【table】

[Acute toxicity test]

The test compound was orally administered to male mice, and its acute toxicity (LD50mg/Kg) was determined. The results are shown in Table 2.

【table】

[Table] Formulation example 1 6-[3-(4-nitrobenzyl)aminopropoxy]-3,4-dihydrocarbostyryl
5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 2 6-[3-(4-benzyl-1-piperidyl)
Aminopropoxy]-3,4-dihydrocarbostyryl monohydrochloride 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 3 6-{3-[2-(4-methoxyphenoxy)
Ethyl]aminopropoxy}-3,4-dihydrocarbostyryl monohydrobromide 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 1000ml 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 40°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.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. R ² and R ³ each contain 1 to 3 groups selected from the group consisting of a hydrogen atom, a lower alkyl group that may have a hydroxyl group as a substituent, a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring. This refers to a phenyl lower alkyl group that may be present individually or a phenoxy lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring. Also this
R ² and R ³ may have a lower alkyl group as a substituent together with the nitrogen atom to which they are bonded.
- Forms a pyrrolidyl group, a morpholino group, a 1-piperidyl group that may have a phenyl lower alkyl group as a substituent, or a 1-piperazinyl group that may have a phenyl group, a phenyl lower alkyl group, or a hydroxy lower alkyl group as a substituent. You may. A represents a lower alkylene group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton represent a single bond or a double bond. ] A cardiotonic agent characterized by containing a carbostyril derivative or a salt thereof as an active ingredient.