JPS6354364A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A carbostyril derivative expressed by formula I (R<1> is H, lower alkyl, lower alkenyl, lower alkynyl or phenyl lower alkyl; R<2> is H or activated substituent group of carboxyl group; the carbon bond at the 3- and 4-positions of the carbostyril skeleton is single or double bond). EXAMPLE:6-Dibromoacetyl-3,4-dihydrocarbostyril. USE:Capable of exhibiting improved positive inotropic, coronary blood stream increasing and hypotensive action and useful as a synthetic intermediate for carbostyril derivatives useful as a cardiotonic agent for treating various cardiopathies without side effect on increasing action of heart rate. PREPARATION:For example, as shown in the reaction formula, a compound expressed by formula II is reacted with an aromatic amine expressed by formula III in preferably a large excess amount based on the compound expressed by formula II at a temperature within the range of 70-150 deg.C to afford the aimed compound expressed by formula Ia in the compound expressed by formula I.

Description

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

DISCLOSURE OF THE INVENTION The carbostyril derivative of the present invention is a novel compound at the end of the literature, and is represented by the following general formula (1).
COOR2 (In the formula, R1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R2 represents a hydrogen atom or an activated substituent of a carboxyl group. 3 of the carbostyryl skeleton and the carbon-carbon bond at the 4-position represent a single bond or a double bond.] The carbostyryl derivative represented by the general formula (1) above is a carbostyryl derivative represented by the general formula (A>) as shown below. It is a compound useful as an intermediate for synthesis.The carbostyril derivative of the general formula (A) has the effect of enhancing myocardial contraction (positive inotropic effect), the effect of increasing coronary surface flow, and the effect of lowering blood pressure. For example, it is useful as a cardiotonic agent for the treatment of various heart diseases such as congestive heart failure, mitral valvular disease, atrial fibrillation, flutter, and paroxysmal atrial tachycardia.In particular, carbostyril derivatives of the general formula (A> Although it has excellent positive inotropic effect, coronal flow increasing effect, and antihypertensive effect,
It is placed at a point where it has almost no effect on increasing heart rate.

In this book, each group shown is specifically as follows.

Lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, pendel,
Examples include straight or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

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

Examples of lower alkynyl groups include edynyl, 2-propynyl, 2-butenyl, 3-butenyl, 1-methyl-2-propynyl, 2-pentynyl, ? A linear chain having 2 to 6 carbon atoms, such as -hexynyl, can be exemplified as a branched alkynyl group.

Examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1.1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl. , 2-=methyl-3-phenylpropyl group and the like are phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 atoms.

The carbostyril derivatives of the present invention are subjected to I4a according to the methods shown in the following reaction schemes-1 to 7, for example.

R'
R-blindness (2>
(4) OOH (1a) [In the formula, R1 and the carbon-carbon bonds at the 3- and 4-positions of the carposudidil skeleton are the same as above. R3 represents an aromatic amine residue. Xl represents a halogen atom. ) The reaction to obtain the compound of general formula (4) from the compound of general formula (2) is to react the aromatic amine of general formula (3) with the compound of general formula (2) in a suitable solvent or without a solvent. The result is 1q. Any solvent can be used as long as it does not affect the reaction, such as halogenated hydrocarbons such as methylene chloride, chloroform, and dichloromethane, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and acetic acid. Examples include esters such as methyl and ethyl acetate, aprotic polar solvents such as N,N-dimethylbormamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Examples of the aromatic amine of general formula (3) include pyridine and quinoline. The amount of the aromatic amine of general formula (3) to be used is at least equimolar to the compound of general formula (2), preferably in large excess. The reaction temperature is 50 to 200°C, preferably 70 to 150°C, and the reaction is completed in 3 to 10 hours.

The hydrolysis reaction of the compound of general formula (4) obtained above is carried out in water or an alcohol such as methanol or ethanol, an inorganic base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or hydrobromic acid. room temperature to 150
It takes about 1 to 10 hours under ``C'' conditions.

Reaction scheme-2 COCH3COC] (X2) 2RI
R+ <5) (6) (1a) [In the formula, R1 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. X2 represents a halogen atom.

] The reaction between the compound of general formula (5) and a halogen is usually carried out in a solvent. Examples of the solvent used include ethers such as tetrahydrofuran and dioxane, carboxylic acids such as acetic acid and propionic acid, aromatic hydrocarbons such as benzene, dimedylformamide, and dimethyl sulfoxide. In this reaction, calcium carbonate or the like may be added as a deoxidizing agent to remove by-produced hydrogen halide. The compounding ratio of the compound of general formula (5) and the halogen is not particularly limited and is appropriately selected within a wide range, but the latter is usually 2 to 5 times the former by mole, preferably 2 to 3 times by mole. It is better to hang it. The reaction is usually O
The reaction is preferably carried out at ~50°C, and the reaction is usually completed within several hours to 24 hours.

From the compound of general formula (6) to the compound of general formula (1a) (
The protecting reaction is preferably carried out in an aqueous solvent in the presence of a basic compound. As the basic compound, a wide variety of known compounds can be used, such as alkali metal hydroxides or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide.

Examples include oxides. The amount of the basic compound to be used is not particularly limited and can be selected within a wide range,
Generally, it is preferable to use the compound in an amount ranging from 2 times the mole to a large excess amount relative to the compound of general formula (6). The reaction is usually carried out at a temperature of 50 to 150°C,
Preferably, the temperature is 70 to 120°C, and usually 1 to 120°C.
The reaction is completed in about 12 hours.

In the above reaction schemes -1 and -2, the compounds of general formulas (2) and (5) used as raw materials include new compounds, and can be produced, for example, according to the methods shown in the following reaction schemes -3 and -4. be done.

Reaction Scheme-3 ↓ COCH2X' [In the formula, R1 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ×3 indicates a halogen atom.

×4 represents a hydrogen atom or a halogen atom. ] The reaction between the compound of general formula (7) and the compound of general formula (8) or (9) is generally called Friedel-Krach reaction, and this reaction is carried out in the presence of a Lewis acid in a solvent. . As the solvent used in this case, those commonly used in this type of reaction are advantageously used, and examples thereof include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane. . Furthermore, conventionally used Lewis acids are preferably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like.

The amount of Lewis acid to be used may be determined as appropriate, but it is usually about 2 to 6 times the mole, preferably about 3 to 4 times the mole of the compound of general formula (7).

The amount of the compound of general formula (8) or (9) to be used is - general formula (
The amount is usually at least equimolar, preferably equimolar to 3 times the molar amount of the compound 7). The reaction temperature is appropriately selected, but is usually about 20 to 120°C, preferably about 40 to 70°C. Although the reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., it cannot be stated unconditionally, but the reaction usually ends in about 0.5 to 24 hours.

Reaction formula-4 [In the formula, X2, X3 and X4 are the same as above.

R1+ represents an R1 group other than a hydrogen atom. R' represents a hydrogen atom or a lower alkyl group. ) The reaction between the compound of general formula (12) and the compound of general formula (8) or (9) is the same as the reaction between the compound of general formula (7) and the compound of general formula (8) or (9). It can be done by However, the reaction temperature is usually about -50 to 120°C, preferably about 0 to 70'C. Also, the reaction time is
The reaction usually completes in about 0.5 to 24 hours, although it depends on the raw materials, catalyst, reaction temperature, etc. and cannot be generalized.

The nitration reaction of the compound of general formula (13) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, without a solvent or using a nitration agent in a suitable inert solvent. Examples of inert solvents include acetic acid, acetic anhydride, a-sulfuric acid, etc., and examples of 21-bro-forming agents include fuming nitric acid, concentrated nitric acid,
Examples include mixed acids (sulfuric acid, fuming acid, phosphoric acid or acetic anhydride and nitric acid), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid. The amount of the above-mentioned nitrating agent to be used may be at least equimolar to the raw material compound, usually in excess.The reaction is usually carried out at -30°C to around room temperature, preferably around -30'C for 5 minutes to 4 hours. Implemented.

The reaction of reducing and ring-closing the benzene derivative of general formula (14) to obtain the compound of general formula (15) can be carried out by: (1) reduction using a catalytic reduction catalyst in an appropriate solvent, or (2) reduction in an appropriate inert solvent. The reduction is carried out by 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 employing the catalytic reduction method (2), the solvents used include, for example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, di-engineered ethylene glycol dimethyl ether, and dioxane. , ethers such as tetrahydrofuran and diethyl ether, Nisdels such as ethyl acetate and methyl acetate, and aprotic polar solvents such as dimethylformamide. Examples of the catalytic reduction catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. When using the catalyst 1, it is preferable to use the catalyst at a weight of 0.02 to 1.00 times the weight of the compound of general formula (14). The reaction is carried out at -20 to 100°C, preferably 0 to 50°C, and the hydrogen pressure is generally 0.5 to 10 atm.
It will take about 10 hours. In this reaction, the reaction proceeds advantageously by the presence of a basic compound such as helium hydroxide or potassium hydroxide in the reaction system.

In addition, when using method ■, iron, zinc, tin or stannous chloride and hydrochloric acid, lii! ! Mineral acids such as acids, or mixtures of iron, sulfurized ferrous, zinc or tin with alkali metal hydroxides such as sodium hydroxide, sulfides such as ammonium sulfide, ammonium salts such as ammonia water, ammonium chloride, etc. Used as a reducing agent. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, dioxane, and the like. The conditions for the above reduction reaction are:
It may be selected appropriately depending on the reducing agent used, and usually -
The reaction proceeds at 50-100'C, and at 0.5-10'C.
It will take about a while to finish. For example, when using stannous chloride and hydrochloric acid as reducing agents, advantageously 120-50'C
It is better to carry out the reaction nearby. The amount of the reducing agent to be used is preferably at least equimolar to the raw material compound, usually equimolar to 3 times the molar range. In the above reaction, the nitro group of the compound of general formula (14) is first converted into an amine group using a reducing agent to produce a benzene derivative represented by the general formula (in the formula, R4 and x4 are the same as above). It is believed that this compound is then ring-closed to produce the compound of general formula (15). Further, when reducing the compound of general formula (14), the carbonyl group is not changed in the case (1) above, but the carbonyl group may be converted into a methylene group in the case (2).

However, it is of course possible to maintain the carbonyl group as it is by appropriately selecting reaction conditions.

The reaction between the compound of general formula (15) and the compound of general formula (16) is preferably carried out, for example, in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. Examples of the solvent include ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The combination of the compound of general formula (15) and the compound of general formula (16) is not particularly limited and can be appropriately selected within a wide range, and usually the latter is at least equimolar to the former, preferably equimolar. It is preferable to set it to about 2 times the mole. The reaction is usually carried out at a temperature of about 0 to 70°C.
It is preferably carried out at a temperature between O'C and room temperature, and generally at a temperature of 0.
The reaction is completed in about 5 to 12 hours.

Reaction formula ~5 H00CQCI・(2CF(2C0OR'
-1→C In the formula, R4 and X4 are the same as above. ] The nitration of the compound of the general formula (13) can be carried out in the same manner as the nitration of the compound of the general formula (13) according to the reaction scheme-4. However, the reaction temperature The temperature is preferably -10°C to around room temperature.

By reducing and ring-closing the compound of general formula (19), the compound of general formula (19) is
The reaction for obtaining the compound of b) can be carried out under the same conditions as the reaction for obtaining the compound of the general formula (15) from the compound of the general formula (14) in the reaction scheme-4. In this reaction (d'3), the compound of general formula (19) is used as a reducing agent, and the lintro group is converted to an amino group to form a benzene derivative represented by the general formula (wherein R4 is the same as above). is formed, and this compound is then ring-closed to form the general formula (l
It is thought that the compound b) is produced.

Reaction Scheme-6 [In the formula, R4 and x3 are the same as above. R5 represents a lower alkyl group. ] The reaction between the compound of general formula (21) and the compound of general formula (22) is carried out in a suitable solvent in the presence or absence of a basic compound. As the basic compound, a wide variety of known compounds can be used, such as triethylamine, 1-limethylamine, pyridine, dimedylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo(4,3,O)nonene- 5(DBN>, 1.5
-diazabicyclo(5,4,0)undecene-5(DB
U>, 1,4-diazabicyclo(2,2゜2)octane (DABCO>, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, Examples include silver carbonate, sodium methylate, sodium edilate, etc. Incidentally, the compound of general formula (21) can be used in an excess amount to also serve as a basic compound.

Examples of solvents include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, methyl acetate, and ethyl acetate. esters such as
methanol, ethanol, propatool, butanol,
Alcohols such as 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; non-butylene polar solvents such as pyridine, acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric acid 1-helamide; and mixed solvents thereof. The ratio of the compound of general formula (21) and the compound of general formula (22) to be used is such that the former is at least equimolar to the latter, preferably equimolar to 5 times the molar amount. The reaction is usually carried out at about -30 to 180°C, preferably about 0 to 150°C, and generally takes 5 to 30 minutes.
The reaction is completed in time.

The cyclization reaction of the compound of 'Aa formula (23) is carried out in the presence of an acid in the absence of a solvent or in an appropriate solvent.

As the acid, there are no particular limitations, and a wide range of ordinary inorganic acids and organic acids can be used.Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, and @acid, aluminum chloride, boron trifluoride, titanium tetrachloride, etc. Examples include organic acids such as Lewis acid, formic acid, acetic acid, ethanesulfonic acid, and p-toluenesulfonic acid. Among these acids, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are preferred. The amount of such acid to be used is not particularly limited and may be appropriately selected within a wide range, but it is usually at least equal in weight to the compound of general formula (23), preferably 10 to 50 (8 weight of acid). Also, a wide range of common inert solvents can be used as the vehicle, such as water, lower alcohols such as methanol, ethanol, and propatool, ethers such as dioxane and tetrahydrofuran, benzene,
Aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ace1
~n, dimethyl sulfoxide, dimethyl bormamide,
Examples include hexamethylphosphoric triamide. Among these, water-soluble solvents such as the lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide are preferred.

The reaction is usually carried out at a temperature of 0 to 100°C, preferably room temperature to 60°C.
The reaction is usually completed in about 5 minutes to 6 hours.

Reaction scheme-7 (ld) (le) [in the formula R1
is the same as above. ] The dehydrogenation reaction of the compound of general formula (1d) is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include henzoquinones such as 2,3-dichloro-5゜6-dicyazbenzoquinone and chloranil (2,3゜5.6-titrachlorobenzoquinone), bromo-bromosuccinimide, and N-chlorosuccinimide. Acid imide, halogenating agent such as bromine, selenium dioxide, palladium carbon, palladium black,
Dehydrogenation catalysts such as palladium oxide and Raney nickel can be mentioned. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but in the case of a halogenating agent, it is usually an equimolar to 5 times the molar amount of the compound of general formula (1d), preferably It is preferable to use equimolar to twice the molar amount, and in the case of a dehydrogenation catalyst, it is usually preferable to use an excess amount.

In addition, as a solvent, dioxane, tetrahydrofuran,
Ethers such as methoxymethanol and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, and cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, butanol, amyl alcohol, hexanol, etc. Alcohols, polar proton solvents such as acetic acid, dimethylformamide,
Examples include polar aprotic solvents such as dimethyl sulfoxide and hexamethyl phosphoric triamide.

The reaction is usually carried out at room temperature to 300' C1, preferably at room temperature to
The reaction is carried out at 200° C. and is generally completed in about 1 to 40 hours.

Conventional catalytic reduction conditions are applied to the reduction of the compound of general formula (1e). The catalyst used is palladium,
Examples include metals such as palladium-carbon, platinum, and Raney nickel, and it is preferable to use such metals in conventional catalytic amounts. Examples of solvents that can be used include water, methanol, ethanol, inpropatol, dioxane, tetrahydrofuran, hexane, cyclohexane, ethyl acetate, and mixed solvents thereof. The reaction can be carried out under either normal pressure or increased pressure, but usually normal pressure to 20 kg/cm2, preferably normal pressure to 10 kg.
/cm2 is recommended. The reaction temperature is usually about 0 to 150'C, preferably room temperature to 100'C.
It is better to

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

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

Incidentally, the present invention naturally includes optical isomers.

The compound of the present invention is induced into a carbostyril derivative represented by the general formula (A), for example, by the method shown in the following reaction scheme-8.

Reaction Scheme-8 (1a>(A) (In the formula, R1 and the carbon-carbon bonds at the 3rd and 4th positions of the carposudidil skeleton are as described above. R8 and R7 are the same or different, and each has a hydroxy group as a substituent. or a lower alkyl group that may have a halogen atom, or a phenyl ring that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent on the phenyl ring, or a lower algylenedioxy group. Indicates a lower alkyl group. R2 and R3 may form a 5- or 6-membered saturated heterocycle together with the nitrogen atom to which they are bonded, with or without an oxygen atom or nitrogen atom.] The method shown in the above reaction scheme-8 is based on the general formula (1a)
By reacting the carbostyril derivative represented by or its carboxy group-activated derivative with the amine represented by general formula (24) or its amino group-activated compound in a normal amide bond-forming reaction. Implemented. Conditions for known amide bond-forming reactions can be easily applied to this reaction. For example, (a) mixed acid anhydride method, that is, a method of reacting carbostyril 11 (1a) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with amine (24), (b) active ester method , that is, a method in which a carbostyril derivative (1a > is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc.) and reacting this with an amine (24), (c) carbodiimide (d) A method in which carbostyryl derivative (1a) is condensed with amine (24) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; is converted into carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with amine (24), and amine (24) is reacted with Nisdel of carbostyril derivative (1a) and lower alcohol under high pressure and high temperature. Examples include a method of reacting an acid halide of carbostyryl derivative (1a), that is, a carboxylic acid halide, with an amine (24). It is also possible to use a method in which the amine (24) is reacted with the amine (24).

The mixed acid anhydride used in the mixed acid anhydride method is obtained by the usual Schotten-Baumann reaction, and the compound of general formula (A) is produced by reacting it with an amine (24) without isolation. be done. short story
The Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as 1-heliethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU, DABCO, etc. Examples include organic bases, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is usually carried out at -20 to 100°C, preferably 0 to 50'C, and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours.

The reaction between the obtained mixed acid anhydride and amine (24) is usually carried out at -20 to 150'C, preferably at 10 to 50'C.
The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is carried out in the absence of a suitable solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, ethers such as diethyl ether, tetrahydrofuran, and 1-xyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, etc. can be mentioned. The alkylhalocarboxylic acids used in the production of mixed acid anhydrides include, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc., and these are usually carbostyryl derivatives. It is used in at least an equimolar amount, preferably about 1 to 2 times the molar amount of (1a). Further, the amine (24) is usually used in an amount of at least equimolar, preferably about 1 to 2 times the molar amount of the carbostyryl derivative (1a).

Further, the active ester method, for example when N-hydroxysuccinimide ester is used, is carried out in a suitable solvent that does not affect the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane,
Examples include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is carried out at 0-150°C, preferably at 10-10°C.
Finish in 5-30 hours at 0'C. The ratio of the amine (24) and N-hydroxysuccinimide ester to be used is usually at least equimolar, preferably equimolar to twice the molar amount of the former to the latter.

Further, when a method of reacting a carboxylic acid halide with an amine (24) is adopted, the reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent.

As the dehydrohalogenating agent, a common basic compound is used. As the basic compound, a wide variety of known compounds can be used. For example, in addition to the basic compounds used in the Schotten-Baumann reaction described in Section 2, sulfur hydroxide - thulium potassium hydroxide, hydride 1 - lithium, hydrogen potassium chloride,
Examples include alcoholades such as silver carbonate, sodium methylate, sodium helium ethylate, and the like. still,
The amine (24) can be used in excess to double as a dehydrohalogenating agent. Examples of solvents include methanol, ethanol, propatool, butanol, 3-methyl(
Examples include alcohols such as -xy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, and mixed solvents thereof. Amine (24
) and carboxylic acid halide, there is no particular limitation and the ratio may be selected appropriately within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar to twice the molar amount. It is preferable to use hard culm.
The reaction is generally completed within 5 minutes or about 30 hours.

In the above, the carboxylic acid halide is produced, for example, by reacting the carbostyril derivative (1a) with a halogenating agent in the absence of a solvent or in the presence of a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, 1-toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and dioxane. , tetrahydrofuran, ethers such as diethyl needle, dimethylformamide, dimethyl sulfoxide, and the like. As the halogenating agent, a normal halogenating agent that converts 1 g of water in a carboxyl group into a halogen atom can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. be done. The ratio of the carbostyryl derivative (1a) and the halogenating agent to be used is not particularly limited and is selected as appropriate. However, when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or when the solvent is used. When the reaction is carried out in a reactor, the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former.

The reaction temperature (and reaction time) is also not limited, but is usually room temperature to about 100°C, preferably 50 to 80°C.
It is carried out for about 30 minutes to 6 hours.

Further, the method of activating the carbostyril derivative (1a) with a phosphorus compound such as triphenylbosphine or diethylchlorophosphate and reacting it with the amine (24) for 1J can be carried out in an appropriate solvent. Here), any solvent can be used as long as it does not affect the reaction, but specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate, N, N
Examples include nonprone polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In the above reaction, since the amine (24) itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other basic compounds such as triethylamine, etc. 1
Helimethylamine, pyridine, dimethylaniline, N-
Organic bases such as methylmorpholine, DBN, DBU, and DABCO and inorganic bases such as potassium carbonate, sodium helium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate can also be used. The reaction is carried out at about 0 to 7150°C, preferably about 0 to 100'C, and the reaction time is about 1
~30 hours.

The ratio of the phosphorus compound and the amine (24) to the carbostyril derivative (1a) is usually at least equimolar, preferably 1 to 3 times the molar amount.

In this way, a carbostyryl derivative of the general formula (△) is produced.

Implementation - One Example Below, Examples, Reference Examples, and pharmacological test results are presented to further clarify the present invention.

Reference Example 1 6-acediyl-3.4-dihydrocarbostyryl 15.1Q was added to 100ml of acetic acid and dissolved, and the internal temperature was 35-4.
Acetic acid 1 containing Br211.2m12 kept at 0'C
The QmQ solution is added dropwise with stirring over a period of 3.5 hours. After allowing the reaction solution to stand overnight, the precipitated product is collected and washed with a small amount of acetic acid. 1? The resulting crystals were treated with activated carbon in an ethanol solvent and recrystallized from ethanol to give pale yellow needle-like crystals of 6-dibromoacetyl-3°4-dihydrocarbostyryl 19.5
Stop 0 by 1.

Melting point: 168-169.5°C Reference Example 2 60C1 of 6-(α-chloroacetyl)carbostyryl @ 0.5 kg of pyridine was suspended in pyridine, stirred at 80°C to 90°C for 2 hours, and then stirred under water cooling for 2 hours. Stir for an hour. The precipitated crystals were counted and recrystallized from methanol to obtain 70q of 6-(α-pyridinium acetyl) carbostyryl chloride 1/2 permanent product.

Melting point: 300° C. or higher Colorless needle crystals Reference Example 3 100 C1 of m-aminobenzoic acid is suspended in ether 1Q, and 44.6 Cl of β-acrylic acid chloride is added dropwise at room temperature with stirring. After dropping and reacting at 40'C for 5 hours, the precipitate was collected as a liquid. Wash the crystals three times with water, dry them,
Recrystallized from methanol to give m-carboxy-N-(β-
60 g of ethoxyacryloyl)aniline are obtained.

Melting point 200.5-202.0'C Colorless flocculent reference example 4 Methyl 3-phenylpropionate 50CI! , 51.6 g of chloroacetyl chloride and 250 g of dichloromethane
Cool the mixture of m(2 to O'C. From O to 10'C,
While stirring, 122q of aluminum chloride is gradually added. Then stir at room temperature for 2 hours. After standing at room temperature for a while, the reaction mixture was poured into ice-concentrated hydrochloric acid and extracted with chloroform.

The chloroform layer is washed with water, dried, and the chloroform is distilled off. Add isopropyl needle to the residue and crystallize it.
The crystals were collected and recrystallized from ethanol to give 3-(4-
Methyl chloroacetylphenyl)propionate 53.4
get g.

Melting point 90.0-92.0'C Colorless needle crystals Reference example 5 Methyl 3-(4-chloroacetylphenyl)propionate 36.26C] was dissolved in 300 m2 of concentrated sulfuric acid, and fuming nitric acid (d=1.52) was dissolved in 300 m2 of concentrated sulfuric acid. 20.9C] was added dropwise while stirring under ice-water cooling. After stirring for 3 hours at room temperature, the reaction mixture is poured into ice water and extracted with chloroform. After washing the chloroform layer with water and drying, the chloroform is distilled off. The residue is purified by silica gel column chromatography and crystallized by adding needles. Collect the crystals and recrystallize them from methanol to obtain 3-(4-carboxy-2-nitrophenyl).
26.7 Cl of methyl propionate is obtained.

Melting point 120-122°C Pale yellow prismatic product Reference example 6 Dichloromethane 4 of chloroacetyl chloride 467q
Add 735 g of aluminum chloride in 17/3 portions to the 00mQ solution under stirring at below 30°C. Next, add 200 g of Lupostiril under stirring at the same temperature.

Thereafter, the mixture is heated under reflux for 604 minutes. After the reaction, the reaction mixture is poured into ice-hinohydrochloric acid, and the precipitated crystals are collected.

This is washed with methanol and hot methanol to obtain 6-chloroacetylcarbostyryl 153q.

The mother liquor was concentrated to dryness, the residue was purified by silica gel column chromatography, and recrystallized from methanol to give 8-
35.41 g of chloroacetylcarbostyryl are obtained.

Melting point: 177.5-179.0'C Pale yellow needle-shaped crystals Reference Example 7 30 CI of 8-chloroacetylcarbostyryl and 300 ml of pyridine are mixed and heated and stirred at 80-90°C for 2.5 hours. The reaction solution was cooled with ice water and the amount of precipitate was collected. Wash with ether and recrystallize from methanol to obtain 1/2 of 8-(α-pyridinium acedel)carbostyryl chloride.
40.850 of the hydrate is obtained.

? (j points 261.5 to 264, O'C (decomposition) colorless needle crystals Example 1 6- (α-pyridinium acedel)-3,4-dihydrolyl posdilyl chloride 50q and hydroxide 1- Suspend Rium 5(E) in 1Q of water and stir at 90-100'C for 3 hours. After the reaction is complete, add concentrated hydrochloric acid to give pt-+ approx.
The precipitated amount was collected and recrystallized from dimethylformamide to obtain 19.1 g of 6-carboxy-3,4-dihydrocarbostyryl.

Pale yellow powder with melting point of 300'C or higher Example 2 6-carboxy-3,4-dihydrocarbostyryl IO
g and N-hydroxysuccinimide 6, Og are suspended in 200 mQ+ of dioxane. Next, under water-cooling and stirring, 50 m12 of dicyclohexylcarbodiimide 12.4Q was added.
Add dioxane solution dropwise.

Thereafter, the mixture was further heated and stirred at 90'C for 4 hours. After the reaction is completed, the mixture is allowed to cool to room temperature, the precipitated amount is collected as a liquid, and the mother liquor is distilled off.

Recrystallized from dimemethylformamide ethanol,
Succinimide 10.8 g of 3,4-dihydrocarbomethylate 1 true 6-carboxylate (q.

Melting point: 234.5-236°C Colorless flaky crystal Example 3 Dissolve 26q of NaOH in 250mQ of water,
While stirring at 0'C, 6-dipromoacetyl-3-4-dihydrocarbostyryl 35Q was added and reacted for 3 hours.

After cooling, insoluble materials are removed, the mother liquor is made acidic with concentrated hydrochloric acid, and the precipitated amount is collected and washed with water.

The obtained crystals are recrystallized twice from ethanol to obtain 6-carboxy-3,4-dihydrocarbostyryl 10.5c;+ as a pale yellow amorphous product.

Melting point: 324.5 to 327°C (decomposed) Example 4 69.7Q of 6-(α-pyridinium acedel)carbostyryl chloride and 1 to 5 g of thulium hydroxide were added to 0 g of water.
．． Dissolve in 6Q and stir at 60-70'C for 3 hours. While cooling with water, add concentrated hydrochloric acid to the reaction mixture to adjust the pH to 2.The precipitated amount was collected and recrystallized from dimethylformamide.
1.4 g of 6-carboxycarbostyryl light brown powder with melting point of 300°C or higher Example 5 m-carboxy-N-(β-1-xacryloyl)
Add aniline 8q to concentrated hydrochloric acid 80111Q and stir at room temperature for 2 hours, followed by 1 hour at 50°C. The reaction solution is poured into water and adjusted to pH 3-4 with 1ON aqueous sodium hydroxide solution. The precipitated crystals were collected, washed with water, and recrystallized from dimethylformamide to give 5-carboxycarbostyryl with a melting point of 320'C or higher.Example 6 Methyl 3-(4-carboxy-2-nitrophenyl)propionate 5g, 2.226N water Sodium oxide methanol solution 8.87+nQ, methanol 100m2 and 5
% Pd-C (50% water content) is mixed and catalytically reduced at room temperature and pressure. The catalyst was removed, 11 portions of concentrated hydrochloric acid was added to the mother liquor to adjust the pH to 1, and the precipitated crystals were collected and recrystallized from methanol to give 7-carboxy-3,4-dihydrocarbostyryl. Get 62q.

Melting point 320'C or higher Colorless needle crystal NMR (DMSO) δppm: 2, 33-2. 60 (m, 2
1), 2, 77-3. 05 (m,
2H), 7, 21 (d, J=8.5Hz.1
H), 7,38-7.53 (m.2H), 10,15 (s, IH) Example 7 32 g of 8-(α-pyridinium acetyl)carbostyryl chloride, 300 m12 of water and 32 Cl of sodium hydroxide Mix and heat and stir at 80-90'C for 5 hours. The reaction mixture was washed with activated carbon, and the pH was adjusted to 3-4 by adding concentrated hydrochloric acid to the mother liquor. The precipitated crystals were collected and recrystallized from methanol-chloroform to give 8-carboxycarbostyryl 20,17Cl.

Melting point 320°C or higher Colorless needle crystal NMR (DMSO) δppm: 6, 57 (d, J = 9.5Hz.1H>, 7, 25
(t, J=8.0Hz, IH), 7, 94 (d,
d. J=8.0Hz.

1, 5Hz, 1H), 7, 98 (d.J=9.5Hz, IH), 8, 14
(d, d, J=8.0Hz.

1,5Hz, 1H) Reference Example 8 6-carboxy-3,4-dihydrocarbostyryl 3.
Dissolve 5 g in 30 mf2 of dimethylformamide. Add 2.4 g of triethylamine to this. 2.75 g of isobutyl chloroformate was added dropwise to the mixture under ice-water cooling and stirring for 30 minutes. This was added to N-methyl-N-(4
-methoxy>benzylamine 3.19C] was added dropwise, and 5
Stir for an hour. The reaction solution was concentrated to dryness, chloroform, 1
Add 7 JO of aqueous solution of sodium to lithium N hydroxide and extract. After washing the chloroborum layer with water and drying, add needles to the residue to crystallize and collect the liquid. This was recrystallized from methanol to give colorless needle-like crystals of 6-(N-methyl-N-(4-methoxybenzyl)carbamoyl)-3.

4-dihydrocarbostyryl 1.84! : Stop I one stop.

Melting point: 144.5-146.5°C Reference Example 9 The following compound was obtained in the same manner as in Reference Example 8 using appropriate starting materials.

06-(N-methyl-N-(3.4-methylenedioxybenzyl)carbamoyl: Hydrocarbostyryl melting point 170-171°C Colorless prismatic crystals o6-(N-methyl-N-(4-chlorobenzyl)carbamoyl Melting point: 171.5-172.5°C Colorless prismatic crystal Reference example 10 ] Succinimide 3,4-dihydrolyl-
Dissolve 127 mg of 6-carboxylate and benzylpiperazine 931+1 in dimethylformamide and stir overnight.Water is added to the reaction mixture, extracted with chloroform, and washed with water and saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and acetone was added to the residue to crystallize it. Recrystallization from ethanol gave 6-(4-benzyl-1-piperazinylcarbonyl). Add 130 mq of -3,4-dihydrocarbostyryl.

Melting point: 198-200'C Colorless needle-like crystals Reference Example 11 A manure compound is obtained in the same manner as in Reference Example 10 using appropriate starting materials.

06-C4-(2-phenoxyethyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
1 Hydrochloride Melting point 271 to 274°C (decomposition) Colorless needle crystals 06- (4-(2-cyanoT-thyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.1
Hydrochloride Melting point: 240-243°C (decomposition) Colorless phosphorus columnar crystals 06-(4-(3)-3,4-dihydrocarbostyryl Melting point: 211.5-213°C ,4-lame1-xybenzyl)-1-
Piperazinylcarbonyl)-3,4-dihydrocarbostyryl Melting point 240-242°C (decomposition) Colorless granular crystals 06- (4- (4-Methylbenzyl)-1-piperazinylcarbonyl)-3,4-dihydro Carbostyryl 1-hydrochloride Melting point: 280-283°C (decomposition) Colorless phosphorus columnar crystals 06- (1- (4-methoxybenzyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl 1-hydrochloride Melting point 262-264°C (decomposition) Colorless granular crystals 06-(4-(4-chlorobenzyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl.
1-hydrochloride Melting point 300'C or higher Colorless needle crystals 06-(4-(4-nitrobenzyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl.
Monohydrochloride/1/2 hydrate Melting point: 268-271°C (decomposition) Pale yellow granular crystals 06- (4-(3.4-dimethoxybenzoyl)-1
-piperazinylcarbonyl)-3.4-dihydrocarbostyryl Melting point 238-239.5°C Colorless granular crystals 06- (1- (4-cyanobenzoyl)-1-piperazinylcarbonyl)-3.4-dihydro Carbostyril melting point 294-297°C Colorless needle crystals 06- (1- (4-methoxybenzoyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyril Melting point 247-249°C Colorless powder 06- ( 4- (3-chlorobenzoyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl Melting point 258.5-260°C Colorless powder 06- (4-(3,4-dichlorobenzoyl)- 1-
piperazinylcarbonyl)-3,4-dihydrocarbostyril melting point 265-267°C (decomposition) Colorless granules 06- (4-(4-nitrobenzoyl)-1-piperazinylcarbonylrubostyril melting point 287-289 °C (decomposition) Pale yellow granular crystals 06-(4-(4-methylbenzoyl)-1-piperazinylcarbonylrubostyryl Melting point 262-264.5°C Colorless phosphorus columnar product 06-(4-methyl-1-piperazinyl carbonyl) Nil 13
．． 4-Dihydrophosphodilyl 1-hydriodide Melting point: 258-259.5°C (decomposition) Colorless powder 06-(4--methanesulfonyl-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl Melting point 115-116.5°C Colorless needle crystals 06-(4-ethoxycafflebonyl-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl Melting point 180-182°C Colorless powder 06- ( 4-n-hexyl-1-piperazinyl carbonyl 1 salt Melting point 276-280'C (decomposition) Colorless flaky crystals 06-(4-cyclohexylmethyl-1-piperazinyl carbonyl)-3. 4-dihydrocarbostyryl monohydrochloride Melting point: 300'C or higher Colorless phosphorus-like product 06-<4-isobutyl-1-piperazinylcarbonyl 1-hydrochloride Melting point: 292-293.5°C (decomposition) Colorless phosphorus-like product 06-(4-allyl-1-piperazinylcarbonyl)-
3.4-Dihydrocarbostyryl 1-hydrochloride Melting point 235-238°C (decomposed) Colorless phosphorus columnar product 06- (4-Propargyl-rubonyl 1-hydrochloride Melting point 249-251°C (decomposed) Colorless granular product 06- (4-(4-Methylthiobenzyl)-1-piperazinylcarbonyl: l-3.4-dihydrocarbostyryl monohydrochloride Melting point: 264-268°C (decomposition) Colorless granular product o5- (4-(4-amino) benzyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl Melting point 213.5-214.5°C Colorless granular product 06- (4- (4-acedelaminobenzyl)-1
-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 3/2 hydrate Melting point 229-231
．． 5°C Colorless powder crystals 01-Methyl-6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl Melting point 145-146°C Colorless phosphorus columnar crystals 01-allyl-6-(4 -(2-phenoxyethyl)-
1-Piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydrochloride Melting point: 239-241°C Colorless powder crystals 01-Benzyl-6-(4-<2-phenoxyethyl)
-1-piperazinylcarbonyl]-3゜4-dihydrocarbostyryl 1-hydrochloride Melting point 261-264°C Silent powder 06- (4-(2-furoyl)-1-piperazinylcarbonyl)-3 , 4-dihydrocarbostyryl melting point 181-183.5°C Colorless powder 06- (4-formyl melting point 198-201°C decomposed) Colorless powder crystal 06- (1- (3,4.5- 1-Tume1-xybenzyl)-1-piperazinylcarbonyl)-3. 4-dihydrocarbostyryl monohydrochloride Melting point 160-164°C Colorless needles o5- c4- (2-human[]]xyexy)-1-
piperazinylcarbonyl)-3.4-dihydrocarbostyryl dihydrate melting point 277-279°C (decomposition) colorless twill crystals 06-(4-cyclohexyl-1-piperazinylcarbonyl)-3. 4-Dihydrocarbostyril Melting point 170-172.5°C Colorless needle crystals 06-(1-piperidylcarbonyl)-3.4-dihydrocarbostyril Melting point 173-174°C Colorless powder crystals 06-(4-Methyl-1 -piperidylcarbonyl-3,
4-dihydrocarbostyryl melting point 212-213.5°C Colorless crystalline crystals 06-(4-benzyl-1-piperidylcarbonyl dihydrate Melting point 235-236.5°C Colorless powdery crystal 06-(1-pyrroli (dylcarbonyl)-3.4-dihydrocarbostyryl Melting point 200-202°C Colorless needles 06-(4-C3-(2-chlorophenoxy)propyl]-1-piperazinylcarbonyl)-3.

4-dihydrocarbostyryl monohydrochloride melting point 256-2
58℃ Colorless powder o5- (4- (2- (3.4-methylenedioxyphenoxy)ethyl)-1-piperazinylcarbonyl 1 hydrochloride Melting point 164-166℃ (decomposition) Colorless needle crystals 06 - (1- ((4-Methoxybenzoyl)methyl]-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride Melting point 266, 5-269°C (decomposition) Colorless powder part 06- (1-C(3-chloro[]benzoyl)methyl)-
1-Piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate Melting point 143.5-146°C (decomposition) Colorless powder 06-(4-((4- methyl benzoyl) methyl two 1
-piperazinylcarbonyl)-3,4-dihydrocarbostyryl Melting point 270-272°C (decomposition) Colorless powder 06-(4-((4-hydroxybenzoyl)methyl-1-piperazinylcarbonyl)-3.

4-dihydrocarbostyryl monohydrochloride 1/2 hydrate Melting point 162-164°C Colorless powder 06- (4- (2-benzoylethyl)-1-piperazinylcarbonylrubostyryl monohydrochloride Melting point 205-207°C Colorless flaky crystals 06- (4- (3-benzoylpropyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl monohydrochloride 1/2 hydrate Melting point 241 ~241.5
°C Colorless needle crystals 06- (4- (5-benzoylpentyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl monohydrochloride monohydrate Melting point 239-242 °C Colorless powder Part 06- (4- (,3- (3.4--dimethoxybenzoyl)propyl)-1-piperazinylcarbonyl)
-3.4-dihydrocarbostyryl monohydrochloride 1/2
Hydrate Melting point 225-228°C Colorless powder 06- (4- (2- <4-acetylaminobenzoyl)ethyl]-1-piperazinylcarbonyl)-3,
4-Dihydrocarbostyryl monohydrochloride monohydrate Melting point 207-209°C (decomposition) Colorless powder 06-(4-(3-chlorocinnamoyl)-1-piperazinylcarbonyl)-3.4 -Dihydrocarbostyryl quarter hydrate Melting point 239.5-241.5°C Colorless granular crystals 06- (4- (3.4.5-trimethoxycinnamoyl)-1-piperazinylcarbonyl)- 3.

4-Dihydrocarbostyryl Melting point 281-284℃ Colorless granular crystals 06-(1-Piperazinylcarbonyl)carbostyryl 1 hydrochloride Melting point 300'C or higher Colorless granular crystals o5- (4- (2-Phenoxyethyl)-1 -Piperazinylcarbonyl)carbostyryl 1-hydrochloride Melting point: 286-289°C (decomposition) Colorless powder 06-(4-(3-phenylpropyl)-1-piperazinylcarbonyl)carbostyryl 1-hydrochloride Melting point 290-293°C (decomposed) Colorless powder 06-(4-isobutyl-1-piperazinylcarbonyl)carbostyryl monohydrochloride 1/2 hydrate Melting point 300°C or higher Colorless powder nuclear crystal o6- (4-(4-chlorobenzyl)-1-piperazinylcarbonyl)carbostyryl 1-hydrochloric acid tower Melting point 300'C or higher Colorless ε (Form crystal o5-(4-isobutyl-1-piperazinylcarbonyl)carpostyryl 1-hydrochloric acid Salt, hemihydrate Melting point 251-254°C (decomposition) Colorless powder 07-(4-hensyl-1-piperazinylcarnyl L-
3.4-Dihydrocarbostyryl 1-hydrochloride Melting point: 260-262°C (decomposition) Colorless twill crystals 06-(4-(2-chloropropyl)-1-piperazinylcarbonylbostyryl 1-hydrochloride Melting point: 238 ~239°C (decomposed) Colorless powder 06- (1-1-ethyl-1-ethyl-1-piperazinyl)-3,4-dihydrocarbostyryl 1-hydrochloride Melting point 232-244°C (decomposed) Colorless Powdered nucleus crystal 06- (4- (2-ethoxycarbonylethyl-1
-piperazinylcarbonyl)-3.4-dihydrocarbostyryl 1 hydrochloride Melting point 227-229.5°C (decomposition) Colorless powder 06-(4-propyl-1-piperazinylcarbonyl hydrochloride 1 /dihydrate Melting point: 259-262°C Colorless phosphorus columnar crystals 06-(4-isopentyl-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl monohydrochloride Melting point: 300°C or higher Colorless phosphorus columnar crystals 06 -(4- <4-methoxyphenyl)acetyl-1
-piperazinylcarbonyl)-3,4-dihydrocarbostyryl Melting point 158-160'C Colorless powder reference example 12 6-carpoxy 3,4-dihydrocarbostyryl 1.
○Q and triethylamine 0.8mi2 in tetrahydrogen■
Fran 10m! :! Suspend 1.0 g of diethyl chlorophosphate in 10 g of tetrahydrofuran and stir at room temperature.
Add mQ solution dropwise and stir at room temperature for 3 hours. To this, add 1.1q of benzylpiperazine and 10% of tetrahydrofuran.
Add the mG solution dropwise and stir for an additional 10 hours at room temperature. After the reaction is complete, the precipitated crystals are removed, the mother liquor is concentrated, and the residue is poured with saturated soda water and extracted with chloroform. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and then the solvent is distilled off. Recrystallization from ethanol yields 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.

Melting point: 198-200°C Colorless needle crystals Reference example 13 34.5 g of 6-carpoxycarbostyryl and 31 mQ of triethylamine were dissolved in 350 mQ of dimethylformamide, and 28 m of isobutyl chloroformate was dissolved under stirring at room temperature.
A solution of Q in 14 mg of dimethylborumamide is added dropwise. After stirring at room temperature for 1 hour, a solution of 37 g of benzylpiperazine in cymedylformamide 21 times was added dropwise, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform was washed with water and saturated brine, and then dried over sulfuric acid. The solvent was removed under reduced pressure, and ether was added to the residue. Crystallize and collect the liquid.

Dissolve the crystals in methanol and add concentrated hydrochloric acid to pH = 1.
shall be. 30. The obtained crude crystals were recrystallized from ethanol-water. "IQ 6-(4-benzyl-1-piperazinylcarbonyl monohydrochloride monohydrate) is obtained.

Melting point: 300'C or higher Colorless granular crystal Reference example 14 6-carboxy-3,4-dihydrocarbostyryl 5.
0q and triethylamine 4+nQ in dimethylbormamide 50mQ solution (this, isobutyl chloroformate 3
．． Add a solution of 87Q in dimethylformamide dropwise.

After stirring for 30 minutes at room temperature, a solution of 5.5 g of benzylpiperazine in 3 ml of dimethylbormamide is added dropwise and stirred for 30 minutes at room temperature and then for 1 hour at 50-60°C. The reaction mixture is poured into a large amount of saturated brine, extracted with chloroform, washed with water, and then dried. The solvent was distilled off, diethyl ether was added to the residue for crystallization, and the resulting crude crystals were recrystallized from ethanol to give 6-4-benzyl-1-piperazinylcarbonyl 13.4-dihydrocarbostyryl. Melting point: 198-200°C Colorless needle crystals Reference example 15 0.5 C of 6-nitoxycarbonyl tritrium ethylate in 100 mQ of ethanol and benzylpiperazine 1.
Add 6g to eid crepe, 110 atm, 140~
React at 150°C for 6 hours.

After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform 2
After dissolving in 0Off'j2 and sequentially washing with 1% potassium carbonate aqueous solution, dilute hydrochloric acid and water, drying with sulfuric acid (helium), distilling off the solvent, and subjecting the residue to silica gel column chromatography (silica gel: Wako C). -200, extract: chloroform: methanol (v/'V) -20:
1), and recrystallize the crude crystals from ethanol to obtain 6
-(4-benzyl-1-piperazinylcarbonyl)-3
, 300 mf2 of 4-dihydrocarbostyryl are obtained.

Melting point: 198-200'C Colorless needle crystals Reference example 16 Local boxy 3,4-dihydrocarbostyryl 1.
90 was suspended in 200 ITI2 of methylene chloride, 2 mQ of pyridine was added, and 1.40 thionyl chloride was added dropwise with stirring while maintaining the internal temperature at 0 to 20°C. After the dropwise addition was completed, stirred at the same temperature for 1 hour, and added 1.74Cl of benzylpiperazine.
A solution of 10 ml of methylene chloride is added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours.

The reaction solution is thoroughly washed with an aqueous potassium carbonate solution, washed with water and diluted hydrochloric acid, dried over sodium sulfate, and then the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography (silica gel: Wako C-200, extract: chloroborum: methanol (V/V) = 20: 1).
After isolation and purification, recrystallization from ethanol yields 6-
(4-benzyl-1-piperazinylcarbonyl)-3.
325 mg of 4-dihydrocarbostyryl are obtained.

Melting point 198-200'C Colorless needle crystals Reference example 17 6-(4-(2-hydroxypropyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl 0.5 g and triethylamine 0, 31 TIQ was dissolved in 10 mg of dichloromethane, and while stirring at room temperature, 0.15 g of acetyl chloride was gradually added to the solution at room temperature, and then stirred for an additional 1 hour at the lowest temperature.

The reaction mixture is poured into saturated hydrogenated water and extracted with chloroform. The organic layer was washed with water, washed with saturated brine, then dried (Na2 Sot), and then the solvent was distilled off under reduced pressure. The remaining 1q was purified by silica gel column chromatography, dissolved in methanol, and diluted with a-hydrochloric acid. Salt. Recrystallized from water-acetic acid and 0.22 g of 6-(4
-(2-acetyloxypropyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl monohydrochloride is obtained.

Melting point: 239-241°C (decomposed) <Pharmacological test A> A dtIt male juvenile adult dog weighing 8-13 kq is anesthetized by intravenously administering the sodium salt of bendoparvicur at a rate of 30 mM kg. 1 tzutrium salt of heparin
After intravenous administration at a rate of 1,000 U/kg, the animals were sacrificed by exsanguination and the hearts were placed in lock fluid. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Next, add pen 1 to barbital slurry in advance.
Blood was pumped from the carotid artery into the right coronary artery via a peristaltic pump from an adult male and female dog weighing 18 to 27 kg that was anesthetized with sodium salts (30 mM kq, intravenous administration) and treated with heparin (1000 U/kq, intravenous administration). The cannula is inserted into the artery and the right atrium is perfused.

The perfusion pressure is a constant pressure of 100 mmHa. The movement of the right atrium is measured by measuring the contractile force of the atrial muscle under a resting tension of 2q via a force displacement transducer. Coronary blood flow is measured using an electromagnetic flowmeter. All records shall be recorded in ink on the record. The details of this h method have been reported by Chiba et al. (J
apan, J. Pharmacol, 25.433
~439 (1975), Naunyn-3chmie
dberg's Arch, Pharmacol
, 289°315-325 (1975)).

The test compound was injected into the artery for 10 to 30 minutes via a rubber tube connected closely to a cannula inserted into the right coronary artery.
Inject in a volume of μQ. The positive inotropic effect of the test compound is
Expressed as % change relative to developed tension before compound administration,
In addition, the change in coronary blood flow is expressed as an absolute value (mQ/min) from before administration.

The results are shown in Tables 1 and 2 below.

<Test compound> Compound no.

1 6-(1--piperazinylcarbonyl)-3゜4-
Dihydrocarbostyryl 2 6-[:4-(2-phenoxyedyl)-1=piperazinylcarbonyl)-3,4-dihydrocarbostyryl 3 6-(4-(2-cyanoethyl>-1-piperazinylcarbonyl) -3,4-dihydrocarpostyl
1-hydrochloride 4 6-(4-methyl-1-piperazinylcarbonyl)
-3,4-dihydrocarbostyryl 5 6-(4-(3,4-dimethoxybenzoyl)-
1-Piperazinylcarbonyl]-3゜4-dihydrocarbostyryl 6 6-(4-(4-cyanobenzoyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 7 1-piperazinylcarbonyl )-3.4-dihydrocarbostyryl 8 6-(4-(3-chlorobenzoyl)-1-hyde
Perazinylcarboxyl L-3.4-dihydrocarbostyryl 9 6-(4-(3.4-dichlorobenzoyl)-1
-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 10 6-(4-(4-nitrobenzoyl)-1-piperazinylcarbonyl)-3,4-dihydrocarpostyryl 11 6-(4-(4 -Methylbenzoyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl126-(4-1hexycarbonyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl136-(4 -furoyl-1-piperazinylcarbonyluryl 146-(4-benzyl-1-piperazinylcarbonyluryl monohydrochloride 15 6-(1-(4-methylbenzyl)-1-goberazinyl carbonyl)-3 .4-dihydrocarbostyryl 16 6-(4-(4-methoxybenzyl)-1=piperazinylcarbonyl)-3.4-dihydrocarbostyryl 1 salt 17 6-(4-(4-chlorobenzyl) )-1-Piperazinylcarbonyl)-3.4-dihydrocarbostyryl 18 6- (4-(3.4-dimethoxybenzyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl monohydrochloric acid Salt 19 6-(4-(4-nitrobenzyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1 hydrochloride 206-(N-methyl-N-(4-methoxybenzyl)
carbamoyl)-3,4-dihydrocarbostyryl 216-[N-methyl-N-(3,4-methylenedioxybenzyl)carbamoyl 4-dihydrocarbostyryl 226-(N-methyl-N-(4-chlorobenzyl) Carbamoyl carbostyril 23 Amrinone (control compound) 24 6-(4-(2-phenoxyethyl)-1-piperazinylcarbonyl monohydrochloride 25 6-C4- (3-phenylpropyl)-1-
Piperazinylcarbonyl 1-hydrochloride 26 6-(4-(2-benzoylethyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 27 Dobutamine (comparative compound) 28 6-(4-( 4-chlorobenzyl)-1-piperazinylcarbonyl monohydrochloride 29 6-(413-benzoylpropyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 1/2 water 30 6-(4-(4-hydroxybenzoyl)methyl-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 316-(4-propyl-1 -piperazinylcarbonyl)-3,4-dihydrocarbostyryl 32 6-(4-(3-chlorobenzoyl>methyl-
1-piperazinylcarbonyl]-3.

4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 336-(4-isopentyl-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl 34 6-(4-(4-methylthiobenzyl) -1-
piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1 hydrochloride 35 6- (4- (3,4,5-trimethoxybearyl)-1.~piperazinylcarbonyl 3,4-
Dihydrocarbostyryl monohydrochloride 36 6-(4-(4-aminepencyl)-1=piperazinylcarbinyl)-3,4-dihydrocarbostyryl 37 6-(4-(4-acedelaminobenzyl)=
1-piperazinylcarbonyl)-3,4-dihyde 1”
Carbostyril monohydrochloride 3/2 hydrate 386-(4-isobutyl-1-piperazinylcarbonyl) Carbostyril monohydrochloride 1,/2 hydrate 39 6-(4-(4- Methylbenzoylmethyl) = 1
-Piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydrochloride 406-(4-cyclohexylmethyl-1-piperazinylcarbonyl)-3,4-dihydro-1carbostyryl 1-hydrochloride 41 614-- isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydrochloride 426-(4-probargyl-1-piperazinylcarbonylstyryl 1-hydrochloride 43 6-(4- (1-methoxybenzoyl) Methyl-1-piperazinylcarbonyl)-3.

4-dihydrocarbostyryl monohydrochloride 446-(4-
n--hexyl-1-piperazinylcarbonylsdiryl monohydrochloride 45 1-methyl-6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 466-(4- Allyl-1-piperazinylcarbonyl 1
3,4-dihydrocarbostyryl 1-hydrochloride 47 1-propargyl-6-(4-(2-phenoxyethyl)-1-piperazinylcarbonyl)-3.4-
Dihydrocarbostyryl monohydrochloride 48 1-benzyl-6- (4- (2-phenoxyethyl)-1-hyperazinylcarponyl]-3,4-
Dihydrocarbostyryl 1 salt 49 1-allyl-6-
(1-(2-]Etsukidiethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyrylate 50 6-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-3 .4-dihydrocarbostyryl dihydrate 516-(1-piperidylcarbonyl)-3.

4-dihydrocarbostyryl 52614-Methyl-1-piperidylcarbonyl 536-(4-benzyl-1-piperidylcarbonyl hemihydrate 546-(1-pyrrolidylcarbonyl 4-dihydrocarbostyryl 55 6- (4-(3-(2-chlorophenoxy)propyl]~1-piperazinylcarbonyl)-3,
4-dihydrocarbostyryl 1 hydrochloride 58 6- (4- (2-(4-methoxyphenoxy)ethyl]-1-piperazinylcarbonyl)-3.4
-dihydrocarbostyryl 1 hydrochloride 57 6- (4- (2- (3.4-methylenedioxyphenoxy)ethyl)-1-piperazinylcarbonyl)-3.4-dihydrocarbostyryl 1 Hydrochloride 58 6-(4-(5-benzoylpentyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate 59 6-(4-(3-(3 ,4-dimethoxybenzoyl)propyl)-1-piperazinylcarbonyl13.
4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 60 6-(4-(3-chlorocinnamoyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1/4 water 61 6- (4-(3,4,5-
trimethoxycinnamoyl)-1-piperazinylcarbonyl'l-3,4-dihydrocarbostyryl 62 6-
(4-(2-acetyloxypropyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
Monohydrochloride, 1/2 hydrate 635-(4-isobutyl-1-piperazinylcarbonyl)carbostyryl, monohydrochloride, 1/2 hydrate 647-(4-benzyl-1-piperazinylcarbonyl i3 ,4-dihydrocarbostyryl monohydrochloride 65 8-(4-(3-phenylpropyl)-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 666-(4-ethoxycarbonylmethyl -1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 67 6-(4i2-ethoxycarbonylethyl 4-dihydrocarbostyryl 68 6-(4-(2-chloropropyl)-1-biperazinyl) carbonyl: l-3.4-dihydrocarbostyryl 1-hydrochloride 696-(4-methanesulfonyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 707-(4-formyl-1-piperazinyl) carbonyluryl 71 6- (4- (2- (4-acetylaminobenzoyl)ethyl]-1-piperazinylcarbonyl)
-3.4-dihydrocarbostyryl 72 6- (4-(4-methoxyphenyl)acetyl-1-piperazinylcarbonyl)-3.

4-Dihydrocarbostyril Table 1 <Pharmacological Test B> Male and female hybrid adults weighing 9 to 15 kg were used. The dog was anesthetized by intravenous administration of bendoparbital sodium 30 mCl/kQ, followed by continuous intravenous infusion of bendoparbital sodium 4 mM kMhr to maintain a constant depth of anesthesia. Using an artificial respirator, artificial respiration was performed at a rate of 18 breaths per minute and an inhalation rate of 2QmQ/kfj, and the chest was opened. Left ventricular contractile force was measured using an arch-type strain gauge attached to the outer wall of the left ventricle. A pressure transducer was inserted by inserting a polyethylene tube into the left femoral artery.
Systemic blood pressure was measured via an ink recorder 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 expressed as a percent change in the tension generated before compound administration. Changes in blood pressure (mmtlq) were expressed as absolute values from before administration. The results are shown in Table 3.

Table 3 (Pharmacological test C) Pre-papillary specimen isolated from blood perfusion Adult male and female hybrids weighing 8-13 kg are anesthetized by intravenously administering bendoparbital salt at a dose of 30 m (1/2!). .100% sodium salt of heparin
After intravenous administration at a dose of 0 U/Ivg, the animal was bled to death and the heart was removed. The specimen mainly consists of papillary muscles and obligate septum;
The cannula inserted into the anterior septal artery is perfused with blood drawn from a donor volume at a constant pressure of 100 mm1lc+.

To donate blood, a person weighing 18 to 27 kg should be anesthetized in advance by intravenously administering bendoparbital sodium salt 30mMk (), and heparin sodium salt 1000 U/kg intravenously.Using bipolar electrodes, the threshold value of 1 .5 times the voltage (
Papillary muscles are stimulated with a square wave of 0.5 to 3 V), a stimulation width of 5 m5ec, and 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. The generated tension and blood flow rate were recorded using an ink recorder. Details of this method have been previously reported by Endo and Hashimoto (Am, J. Physiol, 218
．． 1459-1463゜1970>.

The test compound was intra-arterially administered in a volume of 10-30 μQ for 4 seconds. The inotropic effect of the test compound was expressed as a % change in the tension developed before drug administration. The effect on coronary blood flow was expressed as the change in absolute value (n+Q/min) from before administration. The results are shown in Table 4 below.

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R^2 represents a hydrogen atom or an activated substituent of a carboxyl group. 3rd and 4th positions of carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond. ] A carbostyryl derivative represented by