JPS61267556A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is alkanoyl, alkoxy carbonyl, phenylalkyl, benzoyl, naphthylcarbonyl, etc.; R2 is benzoyl which may have an alkoxy group) and a salt thereof. EXAMPLE:1-Acetyl-6-[4-(3, 4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydro carbostyril. USE:A cardiotonic agent. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by the formula R<1>X (S is halogen) in a suitable solvent in the presence of a basic compound, e.g. NaH, metallic K or sodium amide, at -20 deg.C-room temperature for several minutes-12hr to afford the aimed compound expressed by formula I.

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel carbostyril derivatives.

Disclosure of the Invention The carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

"In the R1C formula, R1 is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group,
A phenyl lower alkyl group having a lower alkanoyloxy group or a hydroxyl group as a W1 substituent on the phenyl ring, an amino group that may have a nitro group or a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkoxy group, a hydroxyl group, a carboxy group, phenyl lower alkoxycarbonyl lower alkoxy group, lower alkanoyloxy group,
It represents a benzoyl group or a naphthylcarbonyl group which may have a substituent selected from the group consisting of a carboxy lower alkoxy group and an amino lower alkyl group having a lower alkyl group. R2 represents a benzoyl group that may have a lower alkoxy group on the phenyl ring. ) The carbostyril derivative represented by the general formula (1) of the present invention has an effect of increasing myocardial contraction (positive inotropic effect), and is useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. It is.

Furthermore, in addition to the above-mentioned effects, secondary compounds have the effect of increasing coronary blood flow, and also have the characteristics of not increasing heart rate or increasing the degree of increase only to a small extent, and having a long duration. ing.

In this specification, examples of lower alkanoyl groups include straight or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl groups.

Examples of the lower alkoxycarbonyl group include straight or branched alkoxy having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl group. An example is a carbonyl group.

Lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1.1-dimethyl-2-butoxycarbonylethyl, The alkoxy moiety of the 2-methyl-3-tert-butoxycarbonylprobyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylethyl group, etc. is a straight or branched chain alkoxy having 1 to 6 carbon atoms, and the alkyl moiety is Examples include alkoxycarbonylalkyl groups which are straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms.

The phenyl lower alkyl group having a lower alkanoyloxy group or a hydroxyl group as a substituent on the phenyl ring includes 2-. 3- or 4-hydroxybenzyl, 2°-(
3,4-dihydroxyphenyl)ethyl, 1-(3,4
-dihydroxyphenyl)ethyl, 2-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)
Propyl, 6-(3,4-dihydroxyphenyl)
hexyl, 3.4-dihydroxybenzyl, 3.4.5
-Trihydroxypencyl, 2-formyloxybenzyl, 3-7 cetyloxybenzyl, 3- (2-7 cedyloxyphenyl) propyl, 4- (4-7 cetyloxyphenyl) butyl, 2-propionyloxybenzyl , 3-(3-butyryloxyphenyl)propyl,
4-(4-isobutyryloxyphenyl)butyl, 5-
A straight chain with 1 to 6 carbon atoms as a substituent on the phenyl ring such as (2-tert-butylcarbonyloxyphenyl)pentyl, 6-(3-pentanoyloxyphenyl)hexyl, (2゜4-diacetyloxy)benzyl, etc. or a branched alkanoyloxy group or water i! Examples include phenylalkyl groups having 1 to 3 groups and in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms.

An amino group that may have a nitro group or a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkoxy group, a hydroxyl group, a carboxy group, a lower alkanoyloxy group, a carboxy lower alkoxy group, and an amino lower alkyl group that has a lower alkyl group. Examples of the benzoyl group which may have a substituent selected from the group consisting of: benzoyl, 2-13- or 4-nitrobenzoyl, 2,4-dinitrobenzoyl, 2-93- or 4-aminobenzoyl , 2.4-diaminobenzoyl, 2-. 3- or 4-hydroxybenzoyl, 3,4-dihydroxybenzoyl, 2,3-dihydroxybenzoyl, 2,4-dihydroxybenzoyl, 2,6-dihydroxybenzoyl, 3
．． 5-dihydroxybenzoyl, 2.5-dihydroxybenzoyl, 3.4.5-trihydroxybenzoyl,
2,4°6-trihydroxybenzoyl, 2-. 3- or 4-carboxybenzoyl, 2,4-dicarboxybenzoyl, 3,5-dicarboxybenzoyl, 2-23
- or 4-benzyloxybenzoyl, 2-(2-phenylethoxy)benzoyl, 3-(1-phenylethoxy)benzoyl, 4-(3-phenylpropoxy)benzoyl, 3-<1゜1-dimethyl-2-phenyl ethoxy)benzoyl, 4-(5-phenylpentyloxy)benzoyl, 3-(6-phenylhexyloxy)
Benzoyl, 3,4-dibenzyloxybenzoyl, 2
．． 5-dibenzyloxybenzoyl, 3.4° 5-tribenzyloxybenzoyl, 2-. 3- or 4-dimethylaminobenzoyl, 2-methylaminobenzoyl, 3
-ethylaminobenzoyl, 4-propylaminobenzoyl, 2-isopropylaminobenzoyl, 3-n-butylaminobenzoyl, 4-tert-butylaminobenzoyl, 2-pentylaminobenzoyl, 3-hexylaminobenzoyl, 4-dipentylaminobenzoyl Benzoyl, 2-methyl, n-butylaminobenzoyl, 3゜5
-di(dimethylamino)benzoyl, 2-93-1 or 4-acetyloxybenzoyl, 2-propionyloxybenzoyl, 3-butyryloxybenzoyl, 4-pentanoyloxybenzoyl, 2-hexanoyloxybenzoyl, 2,4 -Diacetyloxybenzoyl, 3
, 5-diacetyloxybenzoyl, 4-carboxymethoxybenzoyl, 2-(2-carboxyethoxy)benzoyl, 3-(1-carboxyethoxy)benzoyl, 2-(3-carboxypropoxy)benzoyl, 3
- (4-carboxybutoxy)benzoyl, 4-(5
-carboxypentyloxy)benzoyl, 2-(6-
carboxyhexyloxy)benzoyl, 2,4-dicarboxymethoxybenzoyl, 2,6-dicarboxymethoxybenzoyl, 3,5-dicarboxymethoxybenzoyl, 2,5-dicarboxymethoxybenzoyl, 2
゜4.6-1-dicarboxymethoxybenzoyl, 4-
Hydroxy-3-dimethylaminomethylbenzoyl, 3
-carboxymethoxy-5-hydroxybenzoyl, 3
-Hydroxy-5-dimethylaminomethylbenzoylboxymethoxybenzoyl, 4-carboxymethoxy-
2-Hydroxybenzoyl, 4-phenylmethoxycarbonylmethoxybenzoyl, 3-(2-(2-phenylethoxycarbonyl)nidoxinbenzoyl, 2-(
1-(1-phenylethoxycarbonyl)ethoxy)benzoyl, 4-(3-(3-phenylpropoxycarbonyl)propoxy]benzoyl, 3-(4- (4-
phenylptoxycarbonyl)butoxy]benzoyl,
2-(6-(6-phenylhexyloxycarbonyl)hexyloxybenzoyl, 2,4-di(phenylmethoxycarbonylmethoxy)benzoyl, 3,5-di(
Phenylmethoxycarbonylmethoxy)benzoyl, 3
．． 4-di(phenylmethoxycarbonylmethoxy)benzoyl, 2,4゜6-tri(phenylmethoxycarbonylmethoxy)benzoyl, 4-methylaminomethylbenzoyl, 3-(2-ethylaminoethyl)benzoyl,
2-(1-pro-ruaminoethyl)benzoyl, 3-(
3-isopropylaminopropyl)benzoyl, 4-
(4-n-butylaminobutyl)benzoyl, 2-(6
-pentylaminohexyl)benzoyl, 2-(dimethylaminomethyl)benzoyl, 3-(3-diethylaminopropyl)benzoyl, 4-(5-(methyl, ethylamino)pentyl)benzoyl, 2-(6-(methyl, propyl) [amino)hexyl] An amino group that may have a nitro group or 1 or 2 straight or branched alkyl groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as benzoyl group, or an alkoxy moiety having 1 carbon number. A phenylalkoxy group which is a straight chain or branched chain alkoxy group of 6, a hydroxyl group, a carboxy group, a phenylalkoxycarbonyl alkoxy group where the two alkoxy moieties are a straight chain or branched alkoxy group having 1 to 6 carbon atoms Straight chain or branched chain alkanoyloxy group of number 1 to 6, carbon number of alkoxy moiety is 1 to 6
Carbonyl alkoxy group which is a straight chain or branched chain alkoxy of 6, and aminoalkyl having 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms (straight chain or branched chain having 1 to 6 carbon atoms) 1 substituent selected from the group consisting of (chain alkyl) groups
Examples include benzoyl groups which may have up to 3 benzoyl groups.

Examples of the benzoyl group that may have one or two lower alkoxy groups on the phenyl ring include benzoyl, 2-. 3-
or 4-methoxybenzoyl, 2-93- or 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-
1 carbon number on the phenyl ring such as pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-jethoxybenzoyl, 2,5-dimethoxybenzoyl, 2゜6-simethoxybenzoyl group, etc. Examples include benzoyl groups which may have 1 to 2 linear or branched alkoxy groups of 6 to 6.

Examples of lower alkanoyloxy groups include formyloxy,
Examples include straight or branched alkanoyloxy groups having 1 to 6 carbon atoms such as acetyloxy, propionyloxy, butyryloxy, pentanoyloxy, and hexanoyloxy groups.

Examples of phenyl lower alkoxy groups include benzyloxy,
2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,
1-dimethyl-2-phenylethoxy, 2-methyl-3
-The alkoxy moiety such as phenylpropoxy has 1 or more carbon atoms
An example is a phenylalkoxy group which is a straight chain or branched chain alkoxy group of 6.

Examples of lower alkoxy groups include straight or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.

Amino groups that may have a lower alkyl group include amino, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, tert
-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, di-n-butylamino, diethylamino, dihexylamino, methyl, ethylamino, methyl.

propylamino, methyl, n-butylamino, ethyl,
Examples include amino groups that may have 1 to 2 alkyl groups, which are linear or branched alkyl groups having 1 to 6 carbon atoms in the alkyl moiety, such as pentylamino, propyl, and hexylamino groups.

Carboxy lower alkoxy groups include carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy 1-dimethyl-2-carboxyethoxy, 2-methyl-
Examples include carboxyalkoxy groups which are linear or branched alkoxy groups having 1 to 6 carbon atoms in the alkoxy moiety such as 3-carboxypropoxy group.

Examples of the amino lower alkyl group having a lower alkyl group include methylaminomethyl, 2-ethylaminoethyl, 1-
Propylaminoethyl, 3-isopropylaminopropyl, 4-n-butylaminobutyl, 5-tert-
Butylaminopentyl, 6-pentylaminohexyl,
1,1-dimethyl-2-hexylaminoethyl, dimethylaminomethyl, 2-methyl-3-diethylaminopropyl, dipropylaminomethyl, 2-diisopropylaminoethyl, 1-di-n-butylaminoethyl, 3- diethylaminopropyl, 4-dimethylaminomethyl, 5
-(methyl, ethylamino)pentyl, 6-(methyl,
propylamino)hexyl, 1,1-dimethyl-2-(
Methyl, n-butylamino)ethyl, 2-methyl-3-
(Ethyl, pentylamino)propyl, (propyl, hexylamino)methyl group, etc. have 1 or more carbon atoms
Examples include aminoalkyl (straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms) having 1 to 2 straight-chain or branched-chain alkyl groups.

Examples of the phenyl lower alkoxycarbonyl lower alkoxy group include phenylmethoxycarbonylmethoxy, 2-
(2-phenylethoxycarbonyl)ethoxy, 1-(
1-phenylethoxycarbonyl)ethoxy, 3-(
3-phenylpropoxycarbonyl)propoxy, 4-
(4-phenylbutoxycarbonyl 2-(2-phenylethoxycarbonyl)ethoxy, 5
-(5-phenylpentyloxycarbonyl)pentyloxy, 6-(6-phenylhexyloxycarbonyl)hexyloxy, 2-medyl-3-(3-phenylpropoxycarbonyl)propoxy, etc. where the number of carbon atoms in the two alkoxy moieties is Examples include phenylalkoxycarbonylalkoxy groups which are 1 to 6 straight or branched chain alkoxy groups.

The compound of the present invention can be synthesized by various methods, for example, by the method shown in the reaction scheme below.

[Reaction Scheme-1] [In the formula, R1 and R2 are the same as above. X represents a halogen atom. ] The reaction between the compound of general formula (2) and the compound of general formula (3) is carried out in an appropriate solvent in the presence of a basic compound. Examples of the basic compound used here include alkali metal compounds such as sodium hydride, metallic potassium, metallic sodium, sodium amide, and potassium amide, and lithium compounds such as lithium and n-butyllithium.

Examples of solvents used include ethers such as dioxane, diethylene glycol dimethyl ether, diethyl ether, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, and polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. can be exemplified. The amount of the compound of general formula (3) to be used is usually at least equimolar, preferably about equimolar to twice the molar amount of the compound of general formula (2). The reaction normally proceeds suitably at -20 to 70°C, preferably 0°C to around room temperature, and generally takes several minutes to around room temperature.
It will be completed in about 12 hours.

[Reaction Scheme-2] (2) (1a) (In the formula, R2 is the same as above. R1' is a lower alkanoyl group, a lower alkoxycarbonyl group, or) a nitro group, a lower alkyl group as a substituent on the engineered nitrogen ring. selected from the group consisting of an amino group, a phenyl lower alkoxy group, a hydroxyl group, a carboxy group, a lower alkanoyloxy group, a phenyl lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group, and an amino lower alkyl group having a lower alkyl group. represents a benzoyl group which may have a substituent. ] The reaction between the compound of general formula (2) and the compound of general formula (4) is the reaction between the compound of general formula (2) and the compound of general formula (3).
can be carried out under @-like reaction conditions.

In the compound of general formula (1), when R1 is a phenyl lower alkyl group having a lower alkanoyloxy group as a substituent on the phenyl ring, or a benzoyl group having a phenyl lower alkoxy group on the phenyl ring, the compound is hydrated. By decomposition or catalytic reduction, a compound of formula (1) in which R1 is a phenyl lower alkyl group having a hydroxyl group as a substituent on the phenyl ring or a benzoyl group having a hydroxyl group as a substituent on the phenyl ring is produced. be done.

The above hydrolysis reaction (de-lower alkanoylation reaction) is carried out in a suitable solvent in the presence of an acid or a basic compound. Examples of solvents used here include water, alcohols such as methanol, ethanol, and isopropanol,
Examples include ethers such as dioxane and tetrahydrofuran, and mixed solvents thereof. 1 as the acid used
1 Mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and basic compounds such as metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium carbonate, sodium carbonate, and sodium bicarbonate. Examples include metal carbonates and hydrogen carbonates.

The reaction is usually carried out at a temperature of 0 to 150°C, preferably room temperature to 100°C.
It progresses suitably at around 0.degree. C. and generally finishes in about 10 minutes to 15 hours.

The above catalytic reduction (defhenylated lower alkylation reaction) can be carried out under a wide variety of conditions for ordinary defhenylated lower alkylation reactions, such as the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, platinum black, etc. in an appropriate solvent. It is carried out for about 0.5 to 5 hours at around 0 to 100°C. Examples of the solvent here include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, polar solvents such as acetic acid and dimethylformamide, or mixed solvents thereof. . The catalytic reduction catalyst is usually 10 to 10% of the raw material compound.
It is used in an amount of about 50% by weight. The reaction can also be accelerated by adding an acid such as concentrated hydrochloric acid into the reaction system.

In the compound of general formula (1), in a compound in which R1 is a penzoyl group having an amino group as a substituent on the phenyl ring, the corresponding R2 is a benzoyl group having a nitro group as a substituent on the phenyl ring. It is also produced by reducing the compound.

For the above-mentioned reduction reaction, a wide range of conventional conditions for reducing an aromatic nitro group to an aromatic amino group can be adopted. For example, ■ reduction using a catalytic reduction catalyst in an appropriate solvent, or ■ reduction using a suitable inert The reduction is carried out in a solvent using a mixture of a metal or a metal salt and an acid or a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc. as a reducing agent.

When using the catalytic reduction described in (■), the solvent used is:
For example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol; hydrocarbons such as hexane and cyclohexane; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether; esters such as ethyl acetate and methyl acetate; Examples include aprotic polar solvents such as dimethylformamide, and mixed solvents thereof. Examples of the catalytic reduction catalyst used include palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount of catalyst to be used is preferably 0.02 to i,0 times the weight of the raw material compound. The reaction is carried out at -20 DEG to 100 DEG C., preferably 0 DEG to 70 DEG C., and at a hydrogen pressure of 1 to 10 atm, generally for about 0.5 to 10 hours.

When using method (2), iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide such as sodium hydroxide or sulfide. Sulfides such as ammonium, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride are used as reducing agents.

Examples of the inert solvent used include water, acetic acid, methanol, ethanol, and dioxane.

The conditions for the above-mentioned reduction reaction may be appropriately selected depending on the reducing agent used, and the reaction usually proceeds at -50 to 100°C, and the reaction is completed over a period of about 0.5 to 10 hours. For example, when stannous chloride and hydrochloric acid are used as reducing agents, it is advantageous to carry out the reaction at around -20 to 70°C. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound.

The compound of general formula (1) in which R1 is a benzoyl group having at least one carboxy lower alkoxy group or phenyl lower alkoxycarbonyl lower alkoxy group as a substituent is a benzoyl group in which R1 has at least one hydroxy group as a substituent. Monohalogeno lower alkanoic acids (e.g. α-chloroacetic acid, α-
bromoacetic acid, β-O-loprobionic acid, etc.) or monohalogeno-lower alkanoic acid phenyl lower alkyl ester (
For example, it can be produced by reacting α-chloroacetic acid, benzyl ester, β-buOmobuO benzyl Nisder pionate, etc.), and then, in the case of monohalogeno lower alkanoic acid phenyl lower alkyl ester, by hydrolysis or catalytic reduction. .

The reaction between the compound of general formula (1) in which R1 is a benzoyl group having at least one hydroxyl group as a substituent and a monohalogeno lower alkanoic acid or a monohalogeno lower alkanoic acid phenyl lower alkyl ester can be carried out in the presence of a basic compound in an appropriate solvent. It is done below. As the solvent used here, any conventionally known solvent can be used as long as it does not adversely affect the reaction, such as benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane, diethylene glycol dimethyl ether, diethyl ether, and tetrahydrofuran, halogenated hydrocarbons such as chloroform, methane, and carbon tetrachloride, dimethylformamide, dimethyl sulfoxide, and hexamethyl Examples include polar solvents such as phosphoric acid triamide. Examples of basic compounds include triethylamine, pyridine, N,N-dimethylaniline, 1,5-diazabicyclo(4,3,0)nonene-5 (DBN), 1
．． 8-Diazabicyclo(5,4,0)undecene-7(
DBU), IN bases such as 1,4-diazabicyclo(2,2,2)octane (DABGO), inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. etc. can be mentioned. The amount of monohalogeno lower alkanoic acid or phenyl lower alkyl ester of monohalogeno lower alkanoic acid used is usually at least equimolar, preferably equimolar to about 5 times the molar amount, relative to the raw material compound. The above reaction normally proceeds suitably at about 0 to 150°C, preferably at room temperature to about 100°C, and is generally completed in about 1 to 20 hours.

The subsequent hydrolysis or catalytic reduction is performed using R as described above.
Hydrolysis or catalytic reduction of a compound of general formula (1) where 1 is a phenyl lower alkyl group having a lower alkanoyloxy group as a substituent on the phenyl ring or a benzoyl group having a phenyl lower alkoxy group as a substituent on the phenyl ring It can be carried out under similar reaction conditions.

The compound of general formula (1) in which R1 is a benzoyl group having at least one amino lower alkyl group as a substituent having a lower alkyl group on the phenyl ring, R1 has a water wave group or a lower alkyl group on the phenyl ring. The compound of the general formula (1), which is a benzoyl group that may have an amino group as a substituent, contains ■R3R4NH and formaldehyde, and also GEE, ■CH-N@R3RA-X'' [In the above, R3 is a hydrogen atom or lower alkyl group, R4
represents a lower alkyl group. X is the same as above. ] It can be produced by reacting.

The reaction (2) is called the Mannich reaction, and is usually carried out in an appropriate solvent in the presence of an acid. As the solvent, any solvent commonly used in Mannich reactions can be used, such as water, alcohols such as methanol, ethanol, and isopropanol, alkanoic acids such as acetic acid and propionic acid, and acid anhydrides such as acetic anhydride. , acetone, dimethylformamide, or a mixed solvent thereof. Examples of acids include mineral acids such as hydrochloric acid and hydrobromic acid, and organic acids such as acetic acid. Further, as formaldehyde, 20 to 40% by weight formalde, a solution containing humans, a trimer, a polypolymer (bara formaldehyde), etc. are usually used. The amount of formaldehyde to be used is preferably at least equimolar, usually in large excess, relative to the raw material compound. Also R3 R
' The amount of NH to be used is usually at least about the same mole, preferably about the same mole to about 2 times the mole of the raw material compound. The above reaction normally proceeds suitably at about 0'-200°C, preferably from room temperature to about 150°C, and is generally completed in about 0.5 to 10 hours.

The reaction (2) is carried out in an appropriate solvent in the presence or absence of a basic compound. As the solvent used here, any conventionally known solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, dioxane, diethylene glycol dimethyl ether, etc. , diethyl ether, ethers such as tetrahydrofuran, chloroform,
Examples include halogenated hydrocarbons such as dichloromethane and carbon tetrachloride, polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of basic compounds include triethylamine, pyridine, N,N-dimethylaniline, DBNlDBU,
17) Organic bases such as 0ABGO, and inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. CH-N@R3R'・>(The amount of e to be used is usually at least equimolar, preferably equimolar - 3 times the molar amount of the raw material compound. The reaction proceeds suitably at about 0.degree. C., preferably from room temperature to about 100.degree. C., and is generally completed in about 1 to 20 hours.

General formula (where R1 is a phenyl lower alkyl group having a lower alkanoyloxy group as a substituent on the phenyl ring (both having one) or a benzoyl group having a lower alkanoyloxy group as a substituent (both having one) on the phenyl ring In the compound of 1), R1 is a phenyl lower alkyl group having at least one hydroxyl group as a substituent on the phenyl ring, or a phenyl lower alkyl group having at least one hydroxyl group as a substituent on the phenyl ring.
It can also be produced by acylating a compound of general formula (1) which has a benzoyl group.

This acylation reaction is carried out using an acylating agent having a carbon number of 1, for example.
This is carried out according to a conventional method using an acid anhydride such as an alkanoic acid halide having 1 to 6 carbon atoms or an alkanoic acid anhydride having 1 to 6 carbon atoms.

The reaction using an acid halide is carried out in an inert solvent using a dehydrohalogenating agent if necessary, such as amines such as triethylamine, diisopropylethylamine, pyridine, N,N-diethylaniline, etc., at -50 to 150°C. It takes about 1 to 24 hours at a temperature range of .

Further, the reaction using an acid anhydride is carried out in an inert solvent, using the above dehydrohalogenating agent if necessary, in a temperature range of V temperature to 200° C. for about 1 to 10 hours. Examples of inert solvents in each of the above reactions include aromatic hydrocarbons such as nitrobenzene and benzene chloride, pyridine, N,
Amines such as N-dimethylaniline, ethers such as ethyl ether, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc. can be used. The amount of the acylating agent to be used relative to the raw material compound is usually small (equimolar or so, preferably equimolar to a large excess).

Among the carbostyryl derivatives represented by the general formula (1) of the present invention, a basic compound can be easily converted into an acid addition salt by reacting with a common pharmaceutically acceptable acid. Examples of nucleic acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, menleic acid,
Organic acids such as fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid may be mentioned.

Among the carbostyril derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can form a salt with a pharmacologically acceptable basic compound.

Examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; alkali metal carbonates or bicarbonates such as sodium carbonate and sodium bicarbonate; sodium methylate; Examples include alkali metal alcolades such as Lato.

The compounds of the invention in salt form exhibit very good water solubility and are very suitable, for example, as injection drugs.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparatape thin layer chromatography, and the like.

Incidentally, the present invention naturally also includes optical isomers.

The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders,
It is prepared using diluents or excipients such as binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, and I! clouding agent,
Examples include emulsions, granules, capsules, whole drugs, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, single syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder , laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and other disintegrants; white sugar, stearin, cocoa butter, hydrogenated oil, and other disintegrants. , quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate,
Humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid;
Examples include lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets can be made into conventional shelled tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include tragacanth powder, gelatin, binders such as ethanol, and disintegrants such as laminar agar. When molding into a whole form, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as an injection, solutions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of solutions, emulsions, and suspensions, a diluent is used. All those customary in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the above preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceuticals may be included in the preparation, if necessary.

The amount of the compound of general formula (1) to be contained in the preparation of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 301i, based on the total composition. %.

There are no particular restrictions on the method of administering the preparation of the present invention (it can be administered in a manner depending on the various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, liquids, suspensions, etc.) In the case of tablets, emulsions, granules, and capsules, it is administered orally.In the case of injections, it is administered intravenously either alone or mixed with normal replacement fluids such as glucose and amino acids.
Furthermore, it can be administered alone intramuscularly, subcutaneously, subcutaneously or intraperitoneally as necessary. In full stage cases, it is administered rectally.

The dosage of the preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually determined per body weight per day. The amount is preferably about 0.1 to 101 g per gram. Also,
The dosage unit form preferably contains 2 to 200 ma of active ingredient.

Ura-Emperor-1 Reference examples and examples are listed below.

Example 1 263 vaa of 60% sodium hydride was dispersed in 301 tI of dimethylformamide (DMF), and 6-
Add (4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 2Q and stir at 70-80°C for 30 minutes. After cooling, 0.4311 G of acetyl chloride was gradually added while stirring under water cooling, and the mixture was stirred at the same temperature for 5 minutes. After the reaction is completed, the reaction solution is poured into ice water and extracted with chloroform. The chloroform layer is washed with water and saturated saline, and then dried over magnesium sulfate. Chloroform was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent dichloromethane:methanol-100:1), and further recrystallized from dichloromethane-diethyl ether to obtain 1- Acetyl-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

ml), 192-194°C (decomposition) Colorless prismatic crystals Examples 2-15 The compounds shown in Table 1 are obtained in the same manner as in Example 1 using appropriate starting materials.

1) NMR (CDC123) δ: 2.60~
2.90 (m, 2H) 2.90-3.20 (m, 2H) 3.0-3.31 (m, 4) () 3.60-3-98 (m, 4H) 3.90 (
s, 6f-1) 6.60-7.14 (m, 4H) 7.86 (d, 2)-1, J-9Hz) 8.2
8 (d, 2H, J=9Hz)2) NMR (
CDCQ3) δ: 2.52 to 3.30 (
m, 8H) 3.65-3.92 (m, 4H) 3.90 (s, 6H) 5.10 (s, 2H) 6.65-7.60 (m, 15H) 3) N
MR(CDCQ3) δ:2, 52-2.
85 (m, 2 t1) 2.85~
3. 15 (m, 2H) 2.90-3.30 (m
, 4H) 3160-4.10 (m, 4H) 3.82 (s, 3H) 3.88 (s, 3H) 6.65-7.40 (m, 10t()IRνKBr
.

■ax' 3430.1725.1630,1610°1585.
1505.1435.1290゜1270.1230,
1020cm-'4) NMR (DMSO-dB
') δ; 2.60-2.75 (m, 2H) 2 , 90-3. 20 (m, 6N) 3.50
~3.75 (m, 4H) 3.79 (s, 3H) 3.81 (S, 3H) 6.48 (d, IH, J-9,0Hz) 6.75
(dd, IH, J-9,0Hz, J-2,5H
z) 6.88 (d, 2H, J-8, 5Hz > 6.99
(d, 1H, J-2, 5Hz) 7.01 (s, 3
H) 7.77 (6,2H, J-8,5Hz) B to IRν
r・11aX' 3430.1725.1630,1610°1585.
1505.1435.1290°1270.1230.
102102O'5) NMR (DMSO-ds
)5: 2.50-2.70 (m, 2H) 2.90-3.05 (m, 2H) 3.05-3.25 (m, 4H) 3.5-3.75 (m, 4H ) 3.82 (s, 3H) 3.84 (s, 3H) 6.05 (d, 2H, J-9,0Hz) 6.551
-d, 1H, J-9,0Hz, J-2,5H2) 6.95 (d, IH, J, -2,58Z') 7.0
4 (s, 3H) 7.36 (d, 2H, J-9,0Hz)IRνKB
r・11aXゝ3450.1580.1505.1440゜1340.
1285.1235.1160.1020.875cm
+-' 6) NMR (DMSO-da) δ; 2.7~
2.85 (m, 2H) 2.95-3.3 (m, 6H) 3.7-3.9 (m, /IH) 3.90 (s, 3H) 3.91 (S, 3H) 6 .6~7.1 (m, 6H) 7.57 (t, IH, J-8,0Hz) 8.06
(d-m, IH, J=8Hz)8.27 (d-
m, IH, J-8Hz) 8.48 (m, IH) IRνKB ``・ wax ' ・ 3450.2940.2840.1720.1605.
1580, 1505.1470°1435.1270.
1235.1020C■-1 7) NMRCCDC123) δ:2,. 52
~2.90 (m, 2H)2.90~3.40 (
m, 6H) 3.60-4.0 (m, 4H) 3.90 (s, 6H) 6.60-7.20 (m, 6H) 7.86 (d, 2H, J-8Hz)8. 15
(d, 2H, J-8Hz) Br in IRν.

laX” 3450.2940.2840.1720.16051
．． 1580.1505.1470.1435.1270
, 1235.1020cm"' 8) NMR (CDCI2s) δ: 2.65
~2.85 (m, 2H) 2.85~3.30 (m, 6H) 3.66~4.00 (m, 6H) 3.90 (s, 6H) 6, 60~7. 30 (m, 10
1) Br・IaX' 3450.3375.1720, 1670°1630. to IRν.
1610.1515.1435.1270.1235.
1140.1025CI-' 9) NMR (CDC(!a) δ: 2.65
~2.90 (m, 2H) 2.90 ~ 3.33 (m, 6H) 3.60 ~ 4.00 (m, 4H) 3.90 (s, 6H) 6.60 ~ 7.10 (m , 6H) ° 7.65 (m, IH) 8.10 (m, IH) 8.45 (m, IH) 8.57 (m, IH) IRνKBr.

IaX' 1680.1635.1535.1435.1355.
1270.1240, 1230.1025.660C1
-' 1G) NMR (CDCQ3) δ: 2.72-2
．． 79 (m, 2H) 3.06 (s, 6H) 2.88-3.19 (m, 6H) 3.70-3.92 (m, 4H) 3.90 (s, 3H) 3.97 ( s, 3H) 6.59-7.02 (m, 8H) 7.79 (6,2H, J-8Hz) 11) NM
R(DMSO-ds) δ: 2.32 to 2.92
(m, 4H) 2.90-3.40 (m, 4H) 3.40-3.80 (m, 4H) 3.82 (S, 6H) 6.32-7. ' 20 (m, 9H) 12) NMR (
CDC93) δ: 2.28 (s, 6H) 2.50-2.90 (m, 2H) 2.82-3.30 (m, 6H) 3.60-4.00 (m, 4H) 3. 90 (S, 6H) 6.65-7.50 (m, 9H) 13) NMR (CDCQa) δ: 2.62-2
．． 93 (m, 2H) 2.93-3.50 (m, 6H) 3.70-4.00 (m, 4H) 3.90 (s, 6H) 6.70-7.90 (m, 11H) 14) NMR (CDCQ 3 ) δ:2, 60
~2. 90 (m, 2H) 2.90~3
．． 30 (m, 6 days) 3.60-4.00 (m, 4H) 3.90 (s, 6H) 4.70 (s, 2H) 5, 21 (s, 2H) 6.70-7.10 (m, 8H) 7.34 (s, 5H) 7.82 (d, 2H, J-9Hz) 15) NM
R(CDCQ3) δ: 2°68 to 2.81
(m, 2H) 2.90-3.30 (m, 6H) 3.60-3.90 (m, 4H) 3.88 (s, 3H) 3, 91 (s, 3H) 4.63 (
brs, 2H) 6.60-7.05 (m,
8H) 7.82 (d, 2H, J=9Hz >16)NM
R(CDCQ3) δ: 2.76 to 2.83
(m, 2H) 3, 30 ~3. 1 5 (m, 6
H) 3.69~3°91 (brs, 4H)
3.89 (s, 3H) 3.91 (s, 3H) 6.24 (s, IH) 6, 26 (dd, IH, J=2.4Hz
, 10Hz) 6.66-7.03 (m, 6H) 7.23 (d, 1H, J-10Hz) 8.41
(brs, 1H) 11.15 (s, IH) 17) NMR (CDC(i3) δ: 2.34
(s, 6H) 2.60-2.90 (m, 2H) 2.90-, -3.30 (m, 6H) 3.70
(s, 2) () 3.65-3.90 (m, 4H) 3.90 (s, 6H) 6.65-7.1 1 (m, 7H) 7.65 (
dd, 1 H, J=2Hz, 8Hz >7,
78 (s, 1) ()18) NMR (CDC
Q3) δ: 2.52 to 2.82 (m, 2
H) 2.82-3.30 (m, 6H) 3.60-4.10 (m, 4H) 3.88 (s, 6H) 6.65 (m, 12H) 8.50-8.70 ( m, IH) 19) NMR (DMSO-ds) δ: 2.5
0-3.00 (m, 2H) 2.70-3.30 (m, 6H) 3.80 (s, 6H) 4.68 (s, 2H) 6.50-7.10 (m', 9H ) Example 26 6-(4-(3,4-dimethoxybenzoyl)-1
-piperazinyl)-3,4-dihydrocarbostyryl 1
Disperse 0a in 250 tablespoons of anhydrous tetrahydrofuran, and add n-butyllithium (1,5N hexane solution) under water cooling and stirring.
Gradually add 20-.

After the addition is complete, stir at air temperature for 2 hours. Next, under ice-cooling stirring,
A solution of 6.1 g of p-nitrobenzoyl chloride in anhydrous tetrahydrofuran (25 mm) is gradually added dropwise. After dropping, stir at the same temperature for 30 minutes.

After the reaction is completed, the reaction solution is poured into water and extracted with chloroform.

The chloroform layer is washed with water and saturated brine in that order, and then dried over magnesium sulfate. 00 form was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (I
1-(4-nitropenzoyl) of 2.60 was prepared by M using dichloromethane: methanol = 100:1).
-6-(4-(3,4-dimethoxybenzoyl)-1
-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

NMR (COCO2) δ: 2.60-2.90 (m, 2H) 2.90-3.20 (m, 2H) 3.0-3.31 (m, 4H) 3.60-3.98 ( m, 4H) 3.90 (s, 6H) 6.60-7.14 (m, 4H) 7.86 (d, 2H, J-9) 1z ) 8.28 (
d, 2H, -J-9Hz) Example 27 1-(4-acetyloxybenzyl)-6-(4-(3
,4-dimethoxybenzoyl)-1-piperazinyl)-
3,4-dihydrocarbostyryl 2Q in methanol 20
111 I2 dissolved in water 2 of potassium carbonate 1.530
- Add solution and stir at room temperature for 30 minutes. After the reaction is completed, the reaction solution is poured into water and extracted with chloroform. After washing with saturated brine and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. Recrystallized from ethanol,
950+aa 1-(4-hydroxybenzyl)-6-
(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

mg), 203-204°C Colorless prismatic product Example 28 1-(4-nitrobenzoyl) -6-(4-(3,4
-dimethoxybenzoyl)-1-piperazinyl)-3,
4-dihydrocarbostyryl 1.5g to ethanol 30g
- plus 5 ml of DMF) and 10% Pd-C3
00110 is added and catalytic reduction is carried out at 50-60°C. After the reaction is completed, the catalyst is removed and the furnace liquid is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent;
Purified with dichloromethane:methanol=100:2),
Then, it was recrystallized from ethanol to obtain 0.45 g of 1-(
4-aminobenzoyl)-6-(4-(3<4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

mp, 197-198°C Colorless prismatic product The compound of Example 14 is obtained in the same manner as in Example 28 using appropriate starting materials.

Example 29 1-(3-benzyloxybenzoyl)-6-(4-(
3,4-dimethoxybenzoyl)-1-piperazinyl)
-6 g of 3,4-dihydrocarbostyryl in 1 ethanol
0〇- and DMF50- dissolved in 10% Pd-Cl
Add Q and perform catalytic reduction at 50°C. After the reaction is completed, the catalyst is removed and the tP liquid is distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:methanol-100:2) to obtain 4.0 g of 1-(3-hydroxybenzoyl)-6-(4-(3)
,4-dimethoxybenzoyl)-1-piperazinyl)-
3,4-dihydrocarbostyryl is obtained.

mp. 114-134°C (decomposition) Yellow powder NMR (COCO2) δ: 2,52-2.85 (m.21-1)2,85-
3.15 (m, 2H) 2, 90 ~ 3.30 (m, 4H) 3, 60 ~ 4.10 (m, 4H) 3, 82 (s. 3H) 3, 88 (s. 3H) 6, 65 ~7.40 (m, IOH) IR ν to B
r.

a+ax' 3430, 1725, 1630, 1610, 1585.
1505.1435.1290.1270.1230.
102 Qcm-'Example 30 1-(4-hydroxybenzoyl") -6-(4-(
3,4-dimethoxybenzoyl-1-piperazinyl)-
3,4-dihydrocarbostyryl 9Q was dispersed in dimethylformamide 90% and potassium carbonate 2. Add B10 and 3.81 G+ of benzyl monochloroacetate, and stir at room temperature overnight. After the reaction is complete, the reaction mixture is poured into water and extracted with dichloromethane. After washing with water and saturated saline,
Dry with magnesium hydrochloride. It was purified by silica gel column chromatography (1 eluent, dichloromethane → dichloromethane:methanol - 100:5), and 4 g of 1-(4-benzyloxycarbonylmethoxybenzoyl)-6-(4-(3,4 -dimethoxybenzoyl)-
1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

NMR (CDCQ3) δ: 2.60-2.90 (m, 2H) 2.90-3.30 (m, 6H) 3.60-4.00 (m, 4H) 3.90 (s, 6H) 4.70 (s, 2H) 5.21 (S, 2H) 6.70-7.10 (m, 8H) 7.34 (s, 5H) 7.82 (6,2H, J-9Hz) Example 31 4Q 1-(4-benzyloxycarbonylmethoxybenzoyl)-6-(4-(3,4-dimethoxybenzoyl-1-piperazinyl)-3,4-dihydrocarbostyryl) in dimethylformamide-ethanol (1:1) 6
0-, add 10% PD-050010, and perform catalytic reduction at room temperature and pressure. After the reaction is complete, remove the catalyst,
After drying, the furnace liquid is distilled off under reduced pressure. The residue was dissolved in dichloromethane and washed with water. Dichloromethane was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (dichloromethane: methanol - 100:2 to 1:1) to obtain 3.19 1-(4-carboxymethoxybenzoyl)- 6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

Yellow crystal NMR (CDCQ3) δ: 2.68-2.81 (m, 2H) 2.90-3.30 (m, 6H) 3.60-3.90 (m, 4H) 3.88 (s, 3H) 3, 91 (s, 3H) 4, 63 (b
rs, 2H) 6.60-7.05 (m, 8H) 7.82 (d, 2H, J-9Hz) Example 31
Example 2 was prepared in the same manner as in Example 2 using appropriate starting materials.
Compound 5 is obtained.

Example 32 1-(4-hydroxybenzoyl)-6-(4-(3,
4-dimethoxybenzoyl)-1-piperazinyl)-3
,4-dihydrocarbostyryl 900m! J, N, N-
360 o of dimethylmethylene ammonium iodite and 36011 g of potassium carbonate were added to 30 m12 of dichloromethane.
and stirred at room temperature for 4 hours. After that, further N
, N-dimethylmethylene ammonium iodite 180
Add mQ and 180 ma of potassium carbonate and stir overnight at room temperature. After the reaction is completed, the precipitated crystals are removed and dichloromethane is distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent dichloromethane:methanol - 100:1 to 100:2) to give a concentration of 0.8
0 of 1-(4-hydroxy-3-dimethylaminomethylbenzoyl')-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

Yellow crystal NMR (CDCQ3) δ: 2.34 (s, 6H) 2.60-2.90 (m, 2H) 2.90-3.30 (m, 6H) 3.70 (s, 2H) 3. 65-3.90 (m, 4H) 3.90 (s, 6H) 6.65-7.11 (m, 7H) 7,65 (dd, I H8J-2Hz, 8)-
1z )7.78 (s, IH) Example 33 1-(3,5-dihydroxybenzoyl)-6-(4-
Dissolve (3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 301B in dichloromethane, add 24 μQ of triethylamine and 16 μQ of acetic anhydride, and stir at room temperature for 1.5 hours. After the reaction is completed, it is purified by thin layer chromatography,
261 g of 1-(3,5-diacetyloxybenzoyl)-6-(4-(3,4-dimethoxybenzoyl)-1
-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

Yellow crystal NMR (CDCQs) δ: 2.28 (s, 6H) 2.50-2.90 (m, 2H) 2.82-3.30 (m, 6H) 3.60-4.00 (m, 4H) 3.90 (s, 6H) 6.65-7.50 (m, 9H) In the same manner as in Example 33, using appropriate starting materials, the compound of Example 4 is obtained.

Example 34 6-(4-(3,4-dimethoxybenzoyl)-1-
piperazinyl)-3,4-dihydrocarbostyryl7.
59 was dispersed in dimethylformamide 75 precepts, 60%
Add 0.830 of sodium hydride and heat at 80-90°C.
Stir for an hour. After cooling, it was further cooled to about -10°C, and while stirring, 5.06% of benzoic anhydride (J of 2% tetrahydrofuran) was added.
Add the solution dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then the reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and saturated brine, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane→dichloromethane:methanol-100:1.5) to obtain 4Q 1-benzoyl-6-(4-(3°4-dimethoxybenzoyl)).
-1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

Yellow crystal NMR (COO(i3)δ: 2.62-2.93 (m, 2H) 2.93-3.50 (m, 6H) 3.70-4.00 (m, 4H) 3.90 ( 8,6H) 6.70-7.90 (m, 11H) In the same manner as in Example 34, using appropriate starting materials, the compounds of Examples 1.2.6 to 25 are obtained.

Formulation Example 1 l-(4-hydroxybenzoyl)-6-(4-(3,4-dimethoxybenzoyl)-piperazinyl)-3,4-dihydrocarbostyryl 510 Starch 132I1g Magnesium Stearate 18m!11 Milk
Sugar 45+
11 (1 total 2
Tablets of the above composition were prepared in one tablet using a conventional method using 00 mCl.

Formulation Example 2 l-(3-hydroxybenzoyl)-6-(4-(3,4-dimethoxybenzoyl)-piperazinyl)-3,4-dihydrocarbostyryl 10111g Starch 127II1g Magnesium Stearate 18II1g Milk
sugar 4
5mQ meter 20
0++.

Tablets of the above composition were manufactured in a conventional manner.

Formulation example 3 Sodium (6-(4-(3,4-dimethoxybenzoyl)-,1-piperazinyl)-1,2,3,4-1-tetrahydro-2-oxoquinoline-1-carbonyl)-4-ferulate 5001 mg chloride Sodium 0.9g Distilled water for injection 100 - Dissolve 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 was dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using an appropriate filter paper, and the solution is dispensed into ampoules to prepare an injection.

Formulation Example 4 l-(3-carboxybenzoyl)-6-(4-(3,4-dimethoxybenzoyl)-piperazinyl)-3,4-dihydrocarbostyryl 511(It
Starch 1321H Magnesium Stearate 18mg Milk
sugar 45
11111 total
200 fitO Tablets of the above composition were manufactured in a conventional manner.

Pharmacology Test A> Bendoparbital sodium salt is intravenously administered at a rate of 30111 MJl to an adult male and female mixed breed dog weighing 8 to 13 ka to anesthetize it. 100OL of heparin sodium salt
After intravenous administration at a ratio of J/kO, the animals were bled to death and the heart was removed. The specimen mainly consists of papillary muscles and ventricular septum, and is perfused with blood drawn from a donor dog at a constant pressure of 100 ml H1) through a cannula inserted into the anterior septal artery. Donor dogs weigh between 18 and 27 kilograms.

Bendoparbital sodium salt 30mg/k in advance
Anesthetize by intravenously administering heparin sodium salt 1
000 U/Jl was administered intravenously. Using bipolar electrodes, voltage 1.5 times the threshold (0.5-3V), 5m5ec
Stimulus width 1. Papillary muscles are stimulated with a square wave with a stimulation frequency of 120 times per minute. The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of generated tension and blood flow are recorded on an ink recorder. The details of this method have already been reported by Endo and Hashimoto (
Am, J. Physiol, 218, No. 1
459-1463, 1970).

The test compound is administered intraarterially in a volume of 10-30 μQ over 4 seconds. The inotropic effect of the test compound is expressed as a % change in the tension generated before drug administration. The effect on the coronary blood flow group is expressed as the change in absolute value (mQ/min) from before administration. The results are shown in Table 2 below.

Test compound no.

1, 1-acetyl-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 2. 1-(3-carboxybenzoyl)-6-(4-
(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 3, Sodium (6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-1,2,3, 4-tetrahydro-2-oxoquinoline-1-carbonyl)-
4-ferulate 4, 1-(3-hydroxybenzoyl)-6-(4
-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 5, 1-(4-carboxybenzoyl)-6-(4
-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 6, 1-ethoxycarbonyl-6-(4-(3゜4-
dimethoxybenzoyl)-1-piperazinyl)-3,4
-dihydrocarbostyryl 7, amrinone (control compound) 8, 1-benzoyl-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 9, 1-(2, 4-dihydroxybenzoyl)-6
-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl 10, 1-(4-7minobenzoyl)-6-(4-
(3,4-dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydrocarbostyryl Table 2 <Pharmacological test B> Male and female hybrid adults weighing 9 to 15 ko were used. The dog was anesthetized by intravenous administration of bendoparbital sodium 3011MkO, followed by continuous intravenous infusion of bendoparbital sodium 4 mQ/kQ/11'.
A constant depth of anesthesia was maintained. Using an artificial respirator, artificial respiration was performed at a respiratory rate of 18 breaths per minute and an inspiratory volume of 201,117 kQ, and the chest was opened. Left ventricular contractile force was measured via an arch-shaped strain gauge attached to the outer wall of the left ventricle. A polyethylene tube was inserted into the left femoral artery and systemic blood pressure was measured via a pressure transducer, and all parameters were recorded on an ink recorder. Drugs were administered via a catheter inserted into the femoral vein. The inotropic effect of the test compound was determined at 1 minute, 5 minutes, 10 minutes, and 30 minutes after compound administration.
% of developed tension before compound administration after min and 60 min
Expressed as a change. The results are shown in Table 3.

Table 3 Procedural Negotiations (spontaneous) January 22, 1985 1 Indication of the case 1985 Patent Application No. 272086 2 Name of the invention Otsuka Pharmaceutical Co., Ltd. 4 Agent 2-10 Hirano-cho, Higashi-ku, Osaka City Tsuru Building Spontaneous 6 Section 7 "Detailed Description of the Invention" in the Specification Subject to Amendment Contents of Amendment 1 As attached in the appendix Contents of Amendment 1 Page 12 of the specification, line 11, "carbonyl" has been replaced with "carbonyl"
"Carboxy," he corrected.

2 Delete "1 to 2 pieces" in the second line from the bottom of page 12 of the specification.

3. Page 13, line 13 of the specification “pentanoyloxy”,
Correct the statement to "Penta 4/Iloxy".

4 Specification page 28, line 16 and page 31, line 6 rCH
-N” R3R4・XeJ respectively rCH2-N
Correct it as 'R3R' ・XeJ.

5. In the 12th line of page 40 of the specification, "Examples 2 to 15" is corrected to "Examples 2 to 25."

6 In the table described on page 44 of the specification, "Example No.

20” column, “R1” column I am corrected.

7 Page 55 of the specification cylinder, line 4 r3.30J is replaced by r3.
Corrected to 03J.

8. The words "piperazinyl" on page 69, line 14 and page 70, line 7 of the specification are respectively corrected to "1-piperazinyl."

(that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkanoyloxy group or Phenyl lower alkyl group having a hydroxyl group, amino group which may have a nitro group or lower alkyl group as a substituent on the phenyl ring, phenyl lower alkoxy group, hydroxyl group, carboxy group, phenyl lower alkoxycarbonyl lower alkoxy group, lower alkanoyloxy basis,
It represents a benzoyl group or a naphthylcarbonyl group which may have a substituent selected from the group consisting of a carboxy lower alkoxy group and an amino lower alkyl group having a lower alkyl group. R^2 represents a benzoyl group that may have a lower alkoxy group on the phenyl ring. ] A carbostyryl derivative represented by these and its salt.