JPS6122014A - Cardiotonic agent - Google Patents

Abstract

PURPOSE:A cardiotonic agent, containing a specific oxindole derivative or a salt thereof as an active constituent, having increasing action on myocardial contraction and coronary blood stream, and useful for treating cardiopathy, e.g. congestive heart failure with little influence on heart rate. CONSTITUTION:A cardiotonic agent obtained by incorporating an oxindole derivative expressed by formula 1 [A is lower alkylene; n is 0 or 1; B is OH or a group expressed by formula 3 (R is H, lower alkyl group, etc.)] and a salt thereof as an active constituent. The compound expressed by formula 1 has increasing action on myocardial contraction (positive inotropic action) and increasing action on coronary blood stream. In particular, the compound is characterized in that the heart rate is not increased or is slightly increased. The compound expressed by formula 1 can be obtained by reacting an oxyindole derivative expressed by formula 1a with a compound expressed by formula 2 using the ordinary amide bond forming reaction.

Description

[Detailed description of the invention] Industrial applications FIELD OF THE INVENTION The present invention relates to cardiotonic agents.

Disclosure of the Invention The cardiotonic agent of the present invention contains an oxindole derivative represented by the following general formula (1) and a salt thereof as an active ingredient.

[In the formula, A represents a lower alkylene group, n is O or R is a hydrogen atom, a lower alkyl group, a phenoxy lower alkyl group,
Phenyl lower alkyl group, lower alkanoyl group, benzoyl lower alkyl group, benzoyl group which may have 1 to 3 groups selected from the group consisting of lower alkyl group, lower alkoxy group and halogen atom as substituents on the phenyl ring. Alternatively, it represents a benzoyl group having a lower alkylenedioxy group as a substituent on the phenyl ring. ] The compound of the present invention represented by the above general formula (1) has an effect of increasing myocardial contraction (positive inotropic effect) and an effect of increasing coronary flow, and is effective for heart diseases such as congestive heart failure. Useful as a cardiotonic agent for treatment. In particular, the compounds of the present invention are characterized in that they do not increase heart rate, or the degree of increase is only slight.

More specifically, each group shown in the above general formula (1) is as follows.

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

Examples of the phenoxy lower alkyl group include phenoxymethyl, 2-phenoxyethyl, 2-phenoxypropyl, 3
-phenoxypropyl, 1-methyl-2-phenoxyethyl, 2-phenoxybutyl, 3-phenoxybutyl,
Substitution of 2-phenoxy groups such as 4-phenoxybutyl, 1.1-di, methyl-2-phenoxybutyl, 2-phenoxypentyl, 3-phenoxypentyl, 4-phenoxyhexyl, 6-phenoxyhexyl, 5-phenoxypentyl groups, etc. Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms.

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, Examples include phenylalkyl groups having a straight chain or branched alkyl group having 1 to 6 carbon atoms such as 2-methyl-3-phenylpropyl group.

Lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl 1
．． 1 carbon number such as tert-butylcarbonylnoyl group
-6 straight-chain or branched alkanoyl groups can be exemplified.

Benzoyl lower alkyl groups include benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3
-benzoylpropyl, 4-benzoylethyl, 1,1
-Dimethyl-2-benzoylethyl, 5-benzoylpentyl, 6-benzoylhexyl, 2-methyl-3-benzoylpropyl and other benzoylalkyl groups having a straight chain or branched alkyl group having 1 to 6 carbon atoms can be exemplified. .

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

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

Examples of the lower alkylenedioxy group include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, and trimethylenedioxy.

Examples of lower alkylene groups include methylene, ethylene, trimethylene, 2-methyltrimethylene, and 2.

2-dimethyltrimethylene, 1-methyltrimethylene,
Examples include linear or branched alkylene groups having 1 to 6 carbon atoms such as methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups.

Examples of the benzoyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a halogen atom or a lower alkylene dioxy group as a substituent on the phenyl ring include benzoyl, 2- ,3
- or 4-chlorobenzoyl, 2-, 3- or 4-fluorobenzoyl, 2-, 3- or 4-brombenzoyl, 2- or 4-iodobenzoyl,
3.

5-dichlorobenzoyl, 2.6-dichlorobenzoyl, 3,4-dichlorobenzoyl, 3.4-difluorobenzoyl, 3.5-dibrombenzoyl, 3,4.5-
Trichlorobenzoyl, 2-.

3- or 4-methylbenzoyl, 2-. 3- or 4-ethylbenzoyl, 3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 3. ．． 4.5-trimethylbenzoyl, 2-93- or 4-methoxybenzoyl, 2-13- or 4-ethoxybenzoyl, 4-iso10boxybenzoyl, 4-hexyloxybenzoyl, 3.4-dimethoxybenzoyl, 3 .4-
Jetoxybenzoyl, 3.4.5-trimethoxybenzoyl, 2,5-dimethoxybenzoyl, 3.4-methylenedioxybenzoyl, 3.4-ethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl, 3-
Alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms on the phenyl ring, such as methyl-4-chlorobenzoyl, 2-chloro-6-methylbenzoyl, 2-methoxy-3-chlorobenzoyl groups, etc. and a benzoyl group which may have as a substituent one to three groups selected from the group consisting of halogen atoms or an alkylenedioxy group having 1 to 4 carbon atoms.

The compound of the present invention can be produced by various methods, but one preferred example thereof is the method shown in Reaction Scheme-1 below. - Reaction Scheme-1 (1a) (In the formula, R is the same as above) The method shown in the above Reaction Scheme-1 is based on general formula (1a)
By reacting the oxindole derivative represented by or its carboxy group-activated derivative with the amine represented by general formula (2) or its amino group-activated compound in a normal amide bond-forming reaction. Implemented. The amide bond formation reaction can be carried out using various known methods such as (a) mixed acid anhydride method, such as oxindole derivative (1).
a) A method of reacting ゛ with an alkyl halocarboxylic acid to form a mixed acid anhydride, which is then reacted with an amine (2); (b) an active ester method, such as an oxindole derivative (1);
a) is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and amine (2
) = (c) Carbodiimide method, that is, a method of condensing amine (2) with oxindole derivative (1a) in the presence of an activator such as dicyclohexylcarbodiimidoimidazole:
(2) Other methods, such as oxindole derivatives (
A method in which 1a) is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then reacted with an amine (2).A method in which amine (2) is reacted with an ester of an oxindole derivative (1a) and a lower alcohol under high pressure and high temperature. This can be carried out by a method of reacting, a method of reacting an acid halide of the oxindole derivative (1a), that is, a carboxylic acid halide, with the amine (2), and the like. Also, oxindole derivatives (
1a) is activated with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate, and then an amine (2
) may also be used.

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by the usual Schotten-Baumann reaction, and by reacting it with the amine (2) without isolation, the general formula Compound (1b) is produced. The Schotten-Baumann reaction is usually carried out using basic compounds commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline,
N-methylmorpholine, 4-dimethylaminopyridine,
1,5-Diazabishif0 (4.3.0)Nonene-5
(DBN), 1,8-diazabicyclo(5,4.0)undecene-7 (DBU), 1.

4-Diazabicyclo(2.2.2)octane (DABG
organic bases such as O) and potassium carbonate, sodium carbonate,
In the presence of an inorganic base such as potassium hydrogen carbonate or sodium hydrogen carbonate, about -20 to 100'C, preferably 0 to 50'C
It takes about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The obtained mixed acid anhydride and amine (2
) at about -20 to 150°C, preferably 10 to 150°C.
About 5 minutes to 10 hours at 50°C, preferably about 5 minutes to
It takes about one hour to complete. The above mixed acid anhydride is generally a solvent commonly used in this type of mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric acid triamide. carried out in the presence or absence of The alkylhalocarboxylic acids used in the production of the above mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate,
Examples include ethyl bromoformate and isobutyl chloroformate, which are usually used in at least an equimolar amount, preferably about 1 to 2 times the molar amount of the oxindole derivative (1a).

The ratio of amine (2) used is usually oxind, -
It is preferable to use the compound in an amount of at least an equimolar amount, preferably about 1 to 2 times the molar amount of the compound (1a).

The active ester method shown in (b) above, 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, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and methyl acetate. , esters such as ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction is completed at 0 to 150°C, preferably 10 to 100°C, in 5 to 30 hours. The ratio of the amine (2) and N-hydroxysuccinimide ester used is usually at least equimolar, preferably equimolar to twice the molar amount of the former to the latter.

When employing the method of reacting the carboxylic acid halide with the amine (2) shown in (d) above, the reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. A normal basic compound is used as this dehydrohalogenation agent,
A wide range of known basic compounds can be used, and for example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, Examples include alcoholades such as sodium ethylate. Note that the amine (2) can also be used as a dehydrohalogenation agent by using an excess amount. In addition to the solvent used in the Schotten-Baumann reaction, examples of the solvent include methanol, ethanol, propanol, butanol,
Examples include alcohols such as 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and a mixed solvent of two or more of the above solvents. The ratio of the amine (2) and the carboxylic acid halide to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in at least an equimolar amount, preferably an equimolar to twice the molar amount of the former. Good. The reaction is usually carried out at about -30 to 180°C, preferably about 0°C.
The reaction is carried out at ˜150° C. and is generally complete in 5 minutes to 30 hours.

In the above, the carboxylic acid halide is produced, for example, by reacting the oxindole 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, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, and tetrahydrofuran. , ethers such as diethyl ether, dimethylformamide, dimethyl sulfoxide, and the like. As the halogenating agent, a usual halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. . The ratio of the oxindole derivative (1a) and the halogenating agent is not particularly limited and is selected as appropriate, but when the reaction is carried out without a solvent,
The latter is usually used in a large excess of the former, and when the reaction is carried out in a solvent, 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 particularly limited, but usually at room temperature to about 100°C, preferably 50 to 80°C.
It takes about 30 minutes to 6 hours.

Further, a method of activating the oxindole derivative (1a) with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate and reacting it with the amine (2) is as follows:
It can be carried out in a suitable solvent. 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, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether,
Examples include ethers such as tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In the above reaction, since the amine (2) 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 may be used. Organic bases such as , trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBLI, DABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate can also be used. The reaction is carried out at a temperature of about 0-150°C, preferably about 0-100°C.
The reaction time is about 1 to 30 hours. The ratio of the phosphorus compound-depleted amine (2) to the oxindole derivative (1a) is usually at least equimolar, preferably 1 to 3 times the molar amount.

[Reaction scheme-2] (3) ' C1e) [In the formula, R
is the same as above. ×1 indicates a halogen atom. ] The reaction between the compound of general formula (3) and the piperazine derivative (2) is carried out without a solvent or in an inert solvent at a temperature of room temperature to about 200°C, preferably room temperature to 120°C, for about 1 to 24 hours. Be ahead of time. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and dimethyl ether. Polar solvents such as formamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, acetonitrile, etc. can be used.

The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. The basic compound includes the piperazine derivative itself used as a raw material, and when using an excess amount of this, there is no need to use other basic compounds, such as potassium carbonate, sodium carbonate, sodium hydroxide, etc. Sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine,
Tertiary amines such as quinoline can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound of general formula (3) and the piperazine derivative (2) in the above reaction is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in equimolar proportions to the former.
It is preferable to use an excess amount, preferably equimolar to 5 times the molar amount.

Reaction scheme-3 (ld) (Ie) [wherein A and n are the same as above. R' is a lower alkanoyl group, a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a halogen atom as a substituent on the phenyl ring;
A benzoyl group that may have ~3 benzoyl groups or a benzoyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring. ×2 indicates a hydroxyl group. ] That is, the compound represented by the above general formula (1e) is obtained by reacting the compound of general formula (1d) or its amino group-activated compound with the general formula (4) or its carboxy group-activated compound. Manufactured by The above reaction involves the activation of the oxindole derivative represented by the general formula (1a) shown in the reaction scheme-1 or its carboxy group activated compound and the amine represented by the general formula (2) or its amino group. The reaction can be carried out under the same operation and conditions as for the reaction with the compound.

Reaction Scheme-4 (1#) (G) In the formula C, R" represents a lower alkyl group, a phenoxy lower alkyl group, a phenyl lower alkyl group, or a benzoyl lower alkyl group. x
3 is a halogen atom, a lower alkanesulfonyloxy group,
Indicates an arylsulfonyloxy group or an aralkylsulfonyloxy group. ] That is, the compound represented by the general formula (1f) is the compound represented by the general formula (1f).
It is produced by reacting the compound represented by d) with the compound represented by general formula (5). This reaction can be carried out under the same operation and conditions as in the method of reacting carbonyl halide with amine (2) described above.

In addition, in the compound represented by the above general formula (5), X
Specifically, the halogen atoms defined in 3 include chlorine, fluorine,
These are bromine and iodine atoms, and examples of lower alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy,
propanesulfonyloxy, butanesulfonyloxy,
Examples include tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, etc.
Further, specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-
Examples include substituted or unsubstituted arylsulfonyloxy groups such as nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include is benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy.

In the reaction scheme-1 detailed above, general formula (1b)
The compound of general formula (1a) used in the production of the compound can be produced, for example, by the method shown in the following reaction scheme -5 or -6.

Reaction Scheme-5 COOH [In the formula, X1 is the same as above. R3 represents an aromatic amine residue. ] In the above, the reaction to obtain the compound of general formula (8) can be carried out by reacting the compound of general formula (6) with aromatic amine (7) in a suitable solvent or in the absence of a solvent. 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, Examples include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Examples of aromatic amines include pyridine and quinoline. The amount of the aromatic amine to be used is at least equimolar, preferably in large excess, relative to the five compounds of general formula (6). The reaction temperature is 50-200°C, preferably 70-15°C.
The temperature is 0°C, and the reaction is completed in 1 to 10 hours.

In addition, the hydrolysis reaction of the compound of general formula (8) obtained as above can be carried out using an inorganic base such as sodium hydroxide or potassium hydroxide, or hydrochloric acid, hydrobromic acid, etc. in water or an alcohol such as methanol or ethanol. This is carried out using an acid at room temperature to 150° C. for about 10 minutes to 10 hours.

Reaction scheme-6 (9) (to) (XI
is the same as above. ) The reaction between the compound of general formula (9) and a halogen is usually carried out in a solvent. Examples of solvents that can be used include ethers such as tetrahydrofuran and dioxane, carboxylic acids such as acetic acid and propionic acid, aromatic hydrocarbons such as benzene, dimethylformamide, and dimethyl sulfoxide. In this reaction, calcium carbonate or the like may be added as a deoxidizing agent in order to remove by-produced hydrogen halide.

The compounding ratio of the compound of general formula (9) and the halogen is not particularly limited and can be appropriately selected within a wide range, but the latter is usually used in an amount of 2 to 5 times the former, preferably 2 to 3 times the molar amount. It's better. The reaction is usually carried out at a temperature of 0 to 50°C, and the reaction is usually completed in about several hours to 24 hours.

The reaction for obtaining the compound of general formula (1a) from the compound of general formula (10) 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 metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The amount of the basic compound to be used is not particularly limited and can be selected within a wide range, but it is generally preferable to use it in an amount of 2 times to a large excess of the compound of general formula (10). The reaction is usually 50~
The reaction is preferably carried out at 150°C, preferably 70 to 126°C, and the reaction is usually completed in about 1 to 12 hours.

In the reaction scheme-2 detailed above, general formula (1C)
The compound of general formula (3) used for the production of the compound of
Some new compounds are included, and these compounds are produced, for example, according to the method shown in Reaction Scheme-7 below.

Reaction formula-7 (++) (3) [A in the formula
and x3 are the same as above. xl represents a halogen atom.

] The reaction between the oxindole of the general formula (11) and the compound of the general formula (12) is generally called the Friedel-Crach reaction, and is usually carried out in the presence of a Lewis acid in a solvent. As the solvent, those commonly used in this type of reaction, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane, can be used. Any conventionally used Lewis acid can be suitably used.
For example, aluminum chloride, zinc chloride, iron chloride, tin chloride,
Boron tribromide, boron trifluoride, concentrated sulfuric acid, etc. are used. The amount of Lewis acid to be used may be determined as appropriate, but is usually about 2 to 6 times the mole, preferably about 2 to 4 times the mole of oxindole (11). The amount of the compound of general formula (12) to be used relative to oxindole (11) is usually at least about an equimolar amount, preferably an equimolar m-2 times molar amount. The reaction temperature is selected appropriately, but usually O
The temperature is preferably about 0 to 70'C, preferably about 0 to 70'C. Although the reaction time varies depending on the raw materials, catalyst, reaction temperature, etc., it cannot be stated unconditionally, but the reaction is usually completed in about 0.5 to 6 hours.

Among the compounds of the present invention, those in which R represents a hydrogen atom are R
It can be obtained by dephenyl lower alkylation and de-lower alkanoylation of a compound in which is a phenyl lower alkyl group or a lower alkanoyl group, respectively.

The dephenyl lower alkylation reaction is a normal! It can be carried out under the conditions of a 12N-phenyl lower alkylation reaction. Specifically, the reaction is carried out in a suitable solvent in the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, etc. at 0° C. to around room temperature for about 0.5 to 3 hours. Examples of solvents that can be used include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and acetic acid.

The de-lower alkanoylation reaction is carried out in the same manner as a normal hydrolysis reaction. For example, it is carried out using an inorganic base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or hydrobromic acid in water or an alcohol such as methanol or ethanol.

The above dephenyl lower alkylation reaction can also be carried out under the same conditions as the above de-lower alkanoylation reaction.

The oxindole derivative represented by the general formula (1) of the present invention can easily form 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. .

Further, among the oxindole derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The target 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, suspensions, emulsions, granules, capsules, skewers, injections (liquids, suspending agents, 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, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran Sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Disintegrants such as sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate, glycerin, starch Examples include humectants such as starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, and tragacanth. Examples include binders such as gelatin and ethanol, and disintegrants such as laminar agar. When forming into a skewer, a wide variety 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 injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, such as water, ethyl alcohol,
Examples include propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the cardiotonic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isopotent solution, and a common solubilizing agent, 1
! I! An IR agent, a soothing agent, etc. may be added. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary.

The amount of the compound of general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and can be appropriately selected within a wide range,
It is usually 1 to 70% by weight, preferably 1 to 30% by weight of the total composition.

There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and administration may be carried out in a manner depending on the various formulation forms, age, sex, and other conditions of the patient, and the severity of the patient. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they are administered intravenously either alone or mixed with normal replacement fluids such as glucose and amino acids.
Additionally - administered alone intramuscularly, subcutaneously, subcutaneously or intraperitoneally as required. In case of skewering, it is administered rectally.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually 1 ka body weight per day. The amount is preferably about 0.1 to 1011 g per serving.

Further, it is preferable that the dosage unit form contains 1 to 200 mo of the active ingredient.

Tomo-凰-1 Reference examples and examples are listed below.

Reference Example 1 45 g of 5-chloroacetyloxindole was added to 180 g of pyridine, and the mixture was heated and stirred at 80° C. for 1 hour. After the reaction is completed, the mixture is allowed to cool, and the precipitated crystals are collected, washed with acetone, and recrystallized with methanol to obtain 5-α-pyridinium acetyloxindole chloride in the form of colorless needle-like crystals with a mp of 300° C. or higher. The obtained compound was placed in a solution of 17.2% sodium hydroxide and 60% water, and the mixture was heated for 30 minutes at 70°C.
Heat and stir at 80°C. After the reaction is completed, the mixture is allowed to cool and the reaction solution is made acidic with concentrated hydrochloric acid. Collect the precipitated crystals and wash with water. Recrystallize from dimethylformamide (DMF)-water 2
8 g of 5-carboxyoxindole are obtained.

mE), colorless powder crystal at 300°C or higher Elemental analysis value C* Hy Oa C as N, HN Calculated value 61.01 3.98 7.90% Actual value 6
1,12 3,81 8.10% Reference Example 2 α-chloroacetyl chloride 47. lJ, finely ground anhydrous chloride a) plium 80. Oa under ice cooling with carbon disulfide 100
- Suspend the oxindole 26 with vigorous stirring.
．． 60 and reflux for about 3 hours. After the reaction is complete, the solvent is removed under reduced pressure, the residue is added to 1Q of ice-water for decomposition, and the mixture is allowed to cool for a while.

The precipitated crystals are collected, washed with water, methanol, and then ether, and then dried. 15CJ of 5-(α-chloroacetyl)oxindole is obtained.

mE), 246.5-247.0°C Example 1 DMFl of 5-carboxyoxindole 0.880
Add 0.82 m of triethylamine to the o-solution under water cooling and stirring.
was added, and further 0.7719 g of isobutyl chloroformate was added, and the mixture was stirred at the same temperature for 1 hour.

Then, 1.1 g of 1-benzylpiperazine was added, and the mixture was stirred overnight in the eastern part. After the reaction is completed, DMF is distilled off under reduced pressure,
Add aqueous sodium hydrogen carbonate solution to the residue and extract with chloroform. Wash with water, dry the bales with magnesium sulfate, and remove chloroform under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol - 50 = 1), and then recrystallized from isopropanol to obtain 0.7G of 5-(4-benzyl-1-piperazine). carbonyl)oxindole is obtained.

mp, 151-153°C Colorless prism-shaped product The following 1st product was prepared in the same manner as in Example 1 using appropriate starting materials.
Obtain the compounds in the table.

Example 9 5-(1-piperazinylcarbonyl)oxindole hydrochloride 1Q was suspended in 20d of dichloromethane, 1.32m of triethylamine was added, and after stirring for 10 minutes under water cooling,
Add 0.3 - of acetyl chloride, and stir further at the same temperature for 30 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is made alkaline with sodium carbonate. Extract with dichloromethane, wash with water and saturated saline, and dry over magnesium sulfate. Dichloromethane was distilled off under reduced pressure,
The resulting residue was subjected to silica gel column chromatography (
Eluent: Purify with methylene chloride:methanol-50:1). Recrystallized from isopropanol, 0.3
5-(4-acetyl-1-piperazinylcarbonyl)oxindole of 9 is obtained.

mp, 181-182°C Colorless powder crystal Example 10 The compound of Example 4 is obtained in the same manner as in Example 9 using appropriate starting materials.

Example 11 A mixture of 0.8 G of β-chloropropiophenone, 1.0 Q of sodium iodide, and 20 Q of acetone is heated under reflux for 1 hour. After distilling off acetone, DMF10111 is added to the residue.
9.5-(1-piperazinylcarbonyl)oxindole hydrochloride 1. Add OQ and 1.5 m2 of triethylamine and react at room temperature for 3 hours. After the reaction is completed, DMF is distilled off under reduced pressure and the residue is washed with water. The obtained residue is purified by silica gel column chromatography (eluent: dichloromethane:methanol=100:5). Recrystallized from methanol-dichloromethane to give 5-(
4-(2-Benzylethyl)-1-piperazinylcarbonyl)oxindole is obtained.

ff1.208-210°C Colorless prismatic crystals Example 12 5-(1-piperazinylcarbonyl)oxindole hydrochloride 1. OQ, DBUL, 2CJ and 0.73Q of isobutyl bromide are suspended in 1511 fl of acetonitrile and heated to reflux for 6 hours. Then, further triethylamine 0.619 and isobutyl bromide 0.73
0 was added and the mixture was further heated under reflux for 8 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer is washed with saturated saline and dried over sodium sulfate.

The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol-20:1). The hydrochloride was prepared with acetone-concentrated hydrochloric acid and recrystallized from ethanol-methanol to give 5-
0.399 of (4-isobutyl-1-piperazinylcarbonyl)oxindole hydrochloride is obtained. - mp, 285-289°C (decomposition) Colorless needle crystals Example 13 Using appropriate starting materials, the compounds of Example 6.8 above and Example 17 below are obtained in the same manner as in Example 11 or 12.

Example 14 5-(α-chloroacetyl)oxindole 1, OQ
, 3.4-dimethoxybenzoyl-1-piperazine 1-
．． 2Q and 0.8% of triethylamine are suspended in 10III2 of acetonitrile and stirred at room temperature for 17 hours. After removing insoluble materials and concentrating the mother liquor, it was poured into saturated sodium bicarbonate solution.
Extract with chloroform. The chloroform layer was washed with water and saturated brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform:methanol = 20 = 1
). Make the hydrochloride with methanol-concentrated hydrochloric acid. Recrystallized from ethanol-methanol to give 5- (2-
(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)acetyl)oxindole hydrochloride 0.34 to 1 is obtained.

mp, 218 DEG -221 DEG C. (decomposition) Pale yellow needle crystals Using appropriate starting materials, the compounds shown in Table 2 below are obtained in the same manner as in Example 14.

Example 23 5-(2-(1-piperazinyl)acetyl)oxindole dihydrochloride 1.OQ, potassium carbonate 0.630
A solution of m-chlorobenzoyl chloride 0.63a in acetone 211110 is added dropwise to a suspension solution of , water 5- and acetone 101G while stirring under water cooling, and the mixture is stirred at the same temperature for 1.5 hours. After the reaction is complete, the reaction mixture is poured into ice water and extracted with chloroform. The chloroform layer was washed with water and saturated brine in that order, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (I eluent: chloroform:methanol = 20:1
) and recrystallized from ethanol-chloroform to give 5-(2-(4-(3-chlorobenzoyl)-1
-piperazinylcoacetyl)oxindole 0.34
Get 9.

ml), 215-218°C (decomposition) Pale yellow prismatic crystals Example 24 The compounds of Examples 14-16, 18, 19 and 22 are obtained in the same manner as in Example 23 using appropriate starting materials.

Example 25 5-(2-(4-benzyl-1-piperazinyl)acetyl)oxindole 11Q1 and 10% Pd-C1
G is suspended in a mixed solvent of ethanol 10011i11 and water 5-' and hydrogenolyzed at room temperature and pressure. After the reaction is completed, the catalyst is removed and the reactor liquid is concentrated. The obtained residue was recrystallized from methanol-water to give 5-(2-(1-piperazinyl)acetyl)oxindole dihydrochloride 4.
．． Obtain 0g.

ff1.232-235°C (decomposition) Colorless prismatic crystals Example 26 The compound of Example 2 is obtained in the same manner as in Example 25 using appropriate starting materials.

Example 27 5-carboxyoxindole 0.931; l.

DCCl, 3Q, and 1.10 g of benzylpiperazine are suspended in 10 g of dioxane and stirred at 60-70<0>C for 5 hours. After the reaction is completed, the solvent is distilled off, and ether is added to remove the precipitated crystals. After concentrating the mother liquor, the residue is dissolved in chloroform and washed with water and saturated brine. After drying with sodium sulfate, the solvent is distilled off. Recrystallized from isopropanol, 5-(4-benzyl-1-piperazinylcarbonyl)oxindole 30011! Get J.

mp, 151-153°C Colorless prismatic crystals Example 28 The compounds of Examples 2-8 are obtained in the same manner as in Example 27 using appropriate starting materials.

Example 29 5-carboxyoxindole 0.930 and triethylamine 0.811111! Tetrahydrofuran (
THF) 10- and diethyl chlorophosphate 1. OQ T) (F10 Peng solution is added dropwise and stirred at room temperature for 3 hours. A solution of 1.1Q of benzylpiperazine in 10IIg of THF is added dropwise to this solution and further stirred at room temperature for 10 hours. After the reaction is completed, the solvent crystals are removed. Then, concentrate the mother liquor, pour saturated aqueous sodium bicarbonate into the residue, and extract with chloroform. - Wash the organic layer with water and saturated brine, dry over sodium sulfate, and then distill off the solvent. Crystallization yields 1.01 G of 5-(4-benzyl-1-piperazinylcarbonyl), oxindole.

mp, 151-153°C Colorless prismatic crystals Example 30 The compounds of Examples 2-8 are obtained in the same manner as in Example 29 using appropriate starting materials.

Example 31 1.760 of 6-carpoxyoxindole is suspended in 200+11Q of methylene chloride, 2 parts of pyridine is added, and 1.40 of thionyl chloride is added dropwise with stirring while maintaining the internal temperature at 0 to 20°C. . After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and a solution of 1.740% benzylpiperazine in 10% methylene chloride was 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 isolated and purified by silica gel column chromatography (silica gel Niwako C-200, eluent: chloroform:methanol (V/V) = 20:1), and then recrystallized from isopropanol. -(4-benzyl-1
-piperazinylcarbonyl)oxindole 298r
get ag.

rrl, 151-153°C Colorless prismatic crystals - Compounds of Examples 2-8 are obtained in the same manner as in Example 31 using appropriate starting materials.

Example 32 A solution of 3.87 g of isobutyl uroformate in dimethylformamide 2 is added dropwise to a solution of 3.2 g of benzoic acid and triethylamine 4III2 in dimethylformamide 50112. After stirring at room temperature for 30 minutes, a 3-solution of 8.89 of 5-(1-piperazinylcarbonyldol) in dimethylformamide is added dropwise, and the mixture is stirred at room temperature for 30 minutes and then at 50-60°C for 1 hour. Pour into saturated brine, extract with chloroform, wash with water and dry.The solvent is distilled off and the residue is recrystallized from methanol to give 5-(4-benzoyl-1
-piperazinylcarbonyl)oxindole 1.9g
get.

mp, 268-270°C Colorless prismatic crystals Compounds of Examples 3.14-16.18.19.21 and 22 are obtained in the same manner as in Example 32 using appropriate starting materials.

Example 33 Ethyl benzoate 1.1 to 100 I112 ethanol.
36G, sodium ethylate 0.50 and 5-(1-
Piperazinylcarbonyl)oxindole hydrochloride 2.
Add 6g, autoclave at 110 atm, 140~
React at 150°C for 6 hours. After 6, reduce the pressure of the reaction solution a
- and dissolve the residue in 200ml of chloroform,
% potassium carbonate aqueous solution, diluted hydrochloric acid and water, dried over sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform: methanol (V 5-(4-benzoyl-1-
Piperazinyl carbonyl) oxindole 215 servings 0
get.

ff1.268-270°C Colorless prismatic crystals Compounds of Examples 3.14-16.18.19.21 and 22 are obtained in the same manner as in Example 33 using appropriate starting materials.

Example 34 Benzoic acid 1.2Q and 5-(1-piperazinylcarbonyl)oxindole hydrochloride 3. OQ and dioxane 20
In addition to a mixed solvent of 1 fl and 20 WIJ of methylene chloride, a solution prepared by dissolving 2.1 g of N,N-dicyclohexylcarbodiimide in 5-methylene chloride was added dropwise under external water cooling and stirring while maintaining the temperature at 10 to 20°C. 3. At temperature after dropping.
Stir for 5 hours.

The precipitated crystals are removed, and the furnace solution is concentrated to dryness under reduced pressure. The resulting residue was dissolved in 100% methylene chloride, and the organic layer was washed successively with a 5% aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain colorless prismatic crystals of 6-(4-benzoyl-1-piperazinylcarbonyl)oxiin rule 0.79a.

mp, 268-270°C Compounds of Examples 3.14-16.18.19.21 and 22 are obtained in the same manner as in Example 34 using appropriate starting materials.

<Pharmacological test> Bendoparbital sodium salt is intravenously administered to adult male and female hybrids weighing 8 to 13 kG at a rate of 30 to/ka to anesthetize them. 1000LI of heparin sodium salt
After intravenous administration at a rate of /ka, the animals were sacrificed by exsanguination and the hearts were removed. The specimen mainly consists of papillary muscles and ventricular septum, and is perfused at a constant pressure of 100118 O with blood led from the blood donor hole through a cannula inserted into the anterior septal artery. The donor hole was anesthetized in advance by intravenous administration of bendoparbital sodium salt 30,107 kQ, and heparin.
Sodium salt 1000 U/kO was administered intravenously (.

Using bipolar electrodes, a voltage of 1.5 times the threshold value (0.5 to 3
VJ, stimulate the papillary muscles with a square wave with a stimulation width of 5 g*sec 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 m 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 Toro and Specimen (AtJ, Physiol
, '218, pp. 1459-1463, 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 coronary blood flow is expressed as the change in absolute value from before administration (-/■ in >). The results are shown in Table 3 below.

Test compound no.

1. 5-(4-isobutyl-1-piperazinylcarbonyl)oxindole hydrochloride 2, 5-(4-(2-phenoxyethyl)-1-piperazinylcarbonyl)oxindole 3, 5-(2
-(4-(3,4-dimethoxybenzo-,yl)-1-
Piperazinyl)acetyl)oxindole hydrochloride 4,5-(2-(4-benzyl-1-piperazinyl)
Acetyl]oxindole dihydrochloride monohydrate 5, 5-(2-(4-(3,4-methylenedioxybenzoyl)-1-piperazinylcoacetyl)oxindole hydrochloride 6, 5-(2 -(4-(4-methylbenzoyl)-1
-piperazinylcoacetyl)oxindole quarter hydrate 7, 5-(2-(4-(3-chlorobenzoyl)-1
-Piperazinyl)acetyl)oxindole Table 3 Formulation Example 1 5- (2-(4-(3,4-5dimethoxybenzoyl)-1-piperazinyl]acetyl) Oxindole Starch 132■0 Magnesium Stearate 18- g lactose
45Iig total 200+a Tablets of the above composition were prepared in one tablet by a conventional method.

Formulation example 2 5-(4-benzoyl-1-10-〇piperazinylcarbonyl) oxindole starch 127-a, -
Magnesium stearate 18m.

lactose
45sQ meter
200 mg tablets of the above composition were prepared in one tablet using a conventional method.

Formulation example 3 5- (2-(4-(4-5001!I+methylbenzoyl)-1-piperazinyl]acetyl) oxindole polyethylene glycol 0.30 (molecule 11
:4000) Sodium chloride 0.9a Polyoxyethylene sorbitan 0.4 to 1 monooleate Sodium metabisulfite 0.1(1) Methyl-paraben o, isa Propyl-paraben 0.020 Distilled water for injection
100 mIQ The above parabens, sodium metabisulfite and sodium chloride are dissolved in the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C and the compound of the invention, followed by polyethylene glycol and oxyethylene sorbitan monooleate were dissolved into the solution. Next, distilled water for injection is added to the solution to make up the final volume, sterilized by sterile filtration using a suitable filter paper, and dispensed into ampoules in 1-hour portions to prepare injections.

Formulation example 4 5-(4-(2-phenoxy 5II1g ethyl)-1-piperazinylcarbonyl]oxindole starch 132111g magnesium stearate 18ml 1g Lactose
45Il1g meter
2001 () Tablets of the above composition were manufactured in a conventional manner.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. are available ▼ [In the formula, A represents a lower alkylene group, and n represents 0 or 1. B is a hydroxyl group or ▲There are mathematical formulas, chemical formulas, tables, etc.▼
Indicates the group. R is selected from the group consisting of a hydrogen atom, a lower alkyl group, a phenoxy lower alkyl group, a phenyl lower alkyl group, a lower alkanoyl group, a benzoyl lower alkyl group, a lower alkyl group, a lower alkoxy group, and a halogen atom as a substituent on the phenyl ring. This refers to a benzoyl group that may have 1 to 3 groups, or a benzoyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring. ] A cardiotonic agent characterized by containing an oxindole derivative represented by the following and its salt as an active ingredient.