JP2517309B2 - Benzoheterocycle derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a benzoheterocyclic derivative and a salt thereof.

2. Description of the Related Art The benzoheterocycle derivative of the present invention is a novel compound that has not been described in the literature.

Problems to be Solved by the Invention An object of the present invention is to provide a compound useful as a medicine as described below.

Means for Solving the Problems The above object is achieved by a benzoheterocyclic derivative represented by the following general formula (1) and a salt thereof.

[In the formula, R represents a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring, A represents an oxygen atom or a sulfur atom, and B represents an oxygen atom or a sulfur atom. In the general formula (1), the benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring is more specifically, for example, benzoyl, 4-methoxybenzoyl, 3-ethoxybenzoyl, 2-propoxy. On phenyl ring such as benzoyl, 4-n-butoxybenzoyl, 3-pentyloxybenzoyl, 2-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl group Can be exemplified by a benzoyl group which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent.

The benzoheterocyclic derivative represented by the general formula (1) and a salt thereof have an action of enhancing contraction of myocardium (positive inotropic action), an action of increasing coronary blood flow, an antihypertensive action, an action of suppressing vasoconstriction by norepinephrine, and A cardiotonic agent having an anti-inflammatory effect, for example, for the treatment of various heart diseases such as congestive heart failure, mitral valve disease, atrial fibrillation, flutter, paroxysmal atrial tachycardia,
It is useful as an antihypertensive agent and an anti-inflammatory agent. In particular, the above-mentioned compound of the present invention has excellent positive inotropic effect, coronary blood flow increasing effect and antihypertensive effect, but is characterized by having almost no heart rate increasing effect. Further, the above compound has low toxicity,
It is also characterized by a small number of central side effects such as vomiting, deterioration of motor function, and tremor.

The compound of the present invention represented by the above general formula (1) can be produced, for example, by various methods shown in the following reaction formulas.

[In the Formula, R, A, and B are the same as the above. R ¹ is a halogen atom,
A lower alkoxy group or an imidazolyl group which may have a halogen atom as a substituent is shown. R ² represents a halogen atom, an imidazolyl group or a group —SM (M is an alkali metal). When B is a sulfur atom, R ¹ and R ² may together form a thio group (= S). In the above, examples of the alkali metal represented by M include sodium and potassium. Examples of the halogen atom include chlorine, fluorine, bromine and iodine atoms. Further, as the lower alkoxy group which may have a halogen atom as a substituent, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,
Unsubstituted straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as pentyloxy and hexyloxy groups and chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, 1-chloroethoxy, 2-bromoethoxy, Three
Examples thereof include the above lower alkoxy groups having the above halogen atom as a substituent, such as -fluoropropoxy, 1-chlorobutoxy and 4-chlorobutoxy groups. These are the same in the following specification, and the description of lower alkoxy group is the same as the above-mentioned unsubstituted lower alkoxy group.

The reaction between the compound (2) and the compound (3) can be carried out in a suitable solvent in the presence or absence of a basic compound. Examples of the solvent include lower alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran (THF), ethers such as diethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene. , Dichloromethane,
Halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, etc., polar solvents such as acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), etc. can be used alone or in combination. .

As the basic compound, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, inorganic basic compounds such as potassium hydrogen carbonate, pyridine, piperidine, triethylamine, 1,5-
Diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-
Organic basic compounds such as diazabicyclo [2,2,2] octane (DABCO) can be used.

The amount of the compound (3) used in the above reaction can be usually equimolar to large excess amount, preferably equimolar to about 5-fold molar amount with respect to the compound (2). When carbon disulfide (CS ₂ ) is used as the compound (3), it is usually preferable to use it in a large excess amount. In addition, the above reaction is usually 0 to 150.
1 to 20 at a temperature of about 0 ° C, preferably 0 to 120 ° C.
It takes about time.

[In the formula, R and A are the same as defined above. R ³ represents a lower alkoxy group or a phenoxy group, and R ⁴ represents a lower alkanoyl group. The reduction reaction of the above compound (4) is carried out, for example, in a suitable solvent using a catalytic reduction catalyst, or in a suitable inert solvent, a metal or metal salt and an acid or a metal or metal salt and an alkali metal water. It is carried out using a mixture with oxides, sulfides, ammonium salts, etc. as a reducing agent.

When employing the above catalytic reduction method, the solvent is
For example, water, alcohols such as acetic acid, methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, THF and diethyl ether, esters such as ethyl acetate and methyl acetate, DMF, etc. The aprotic polar solvent and the like can be used. As the catalytic reduction catalyst, for example, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney-Nitzkel, etc. can be used. The amount of the catalyst used is usually about 0.02 to 1 times the weight of the compound (4), and the reaction is usually at a temperature of about 50 to 150 ° C, preferably about 50 to 100 ° C, and a hydrogen pressure of 1 to 1. It is carried out at about 10 atmospheres and is generally
It will be completed in about 0.5 to 10 hours.

When the above method is adopted, the reducing agent is
For example, iron, zinc, tin or stannous chloride and hydrochloric acid, mineral acids such as sulfuric acid, or iron, ferrous sulfate, alkali metal hydroxides such as zinc or tin and sodium hydroxide, sulfides such as ammonium sulfide, A mixture of aqueous ammonia and an ammonium salt such as ammonium chloride can be used. As the inert solvent, for example, water, acetic acid, methanol, ethanol, dioxane or the like can be used. The conditions of the reduction reaction can be appropriately selected depending on the type of the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as the reducing agents, it is preferably 0 to 150.
It is advisable to carry out the reaction at around ℃ for 0.5 to 10 hours. The reducing agent is used in an amount of at least an equimolar amount, usually an equimolar to 5-fold molar amount with respect to the compound (4).

The reaction for converting the compound (5) thus obtained to the compound (6) is carried out in the presence of a lower alkanoylating agent.
As the lower alkanoylating agent, for example, lower alkanoic acid such as formic acid, acetic acid and propionic acid, lower alkanoic acid anhydride such as acetic anhydride and lower alkanoic acid halide such as acetyl chloride and propionyl bromide can be used. When an acid anhydride or an acid halide is used as the lower alkanoylating agent, a basic compound may be present in the reaction system. Examples of the basic compound include alkali metals such as metallic sodium and potassium, hydroxides, carbonates and bicarbonates of these alkali metals, and organic bases such as triethylamine, pyridine and piperidine.

The above-mentioned reaction proceeds both in the absence of solvent and in the solvent, but it is usually preferable to use a suitable solvent.
Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, Examples thereof include acetic acid, acetic anhydride, water, pyridine and the like. The amount of the lower alkanoylating agent used is at least about equimolar to the compound (5), and is generally equimolar to a large excess. The reaction temperature is usually about 0 to 150 ° C, preferably about 0 to 100 ° C, and the reaction is generally completed in about 5 minutes to 15 hours. When using a lower alkanoic acid as a lower alkanoylating agent,
Further, as a dehydrating agent in the reaction system, mineral acids such as sulfuric acid and hydrochloric acid and p
-Sulfonic acids such as toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid are preferably added in advance. In this case, the reaction temperature is preferably about 50 to 120 ° C.

Furthermore, the cyclization reaction of the compound (5) and the cyclization reaction of the compound (6) can be carried out in the presence or absence of a basic compound or an acid, preferably an acid, in a suitable solvent.
Examples of the solvent include methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol,
Alcohols such as ethyl cellosolve and methyl cellosolve, ethers such as THF, diethyl ether, dimethoxyethane and diphenyl ether, benzene, toluene,
Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform,
Esters such as methyl acetate and ethyl acetate, pyridine, acetone and the like, polar solvents such as DMF, DMSO and HMPA and the like can be used alone or in combination.

Examples of the basic compound include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride,
Inorganic basic compounds such as potassium hydride, triethylamine, trimethylamine, pyridine, dimethylaniline,
Organic basic compounds such as N-methylmorpholine, DBN, DBU and DABCO can be used. Examples of the acid include hydrochloric acid,
Inorganic acids such as sulfuric acid, hydrobromic acid, nitric acid and polyphosphoric acid, and organic acids such as paratoluenesulfonic acid, ethanesulfonic acid and trifluoroacetic acid can be used.

The above reaction is generally about -20 to 200 ° C, preferably 0 to 170.
It is carried out at about ℃, and is generally completed in about 5 minutes to 30 hours.

According to the reduction reaction of the compound (4), the compound (5) obtained under the reduction reaction conditions can be isolated without isolation.
In some cases, it can be directly induced to the compound (1b).

[In the formula, R and A are the same as defined above. R ⁵ represents a lower alkoxy group. The cyclization reaction of the compound (7) can be carried out in the same manner as the cyclization reaction of the compound (2) represented by the reaction formula-1.

[In the Formula, R, A, and B are the same as the above. X ¹ represents a halogen atom. The reaction of the compound (8) with the compound (9) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve, pyridine and acetone. DM
F, DMSO, HMPA, etc. can be used. As the basic condensing agent, for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, triethylamine, etc. can be used. The use ratio of the compound (8) and the compound (9) is not particularly limited and may be appropriately selected within a wide range, but the latter is usually at least about equimolar amount, preferably equimolar to 5 with respect to the former. It is recommended to use a double molar amount. The reaction is usually at room temperature to about 180 ° C, preferably 100
It is carried out at ~ 150 ° C and is generally completed in about 3 to 30 hours. Further, in the reaction, copper powder can be used as a catalyst, which allows the reaction to proceed advantageously.

[In the Formula, R, A, and B are the same as the above. The reaction between the compound (1d) and the compound (10) can be carried out according to a usual amide bond forming reaction. The amide bond-forming reaction is carried out by various known methods, for example, (a) mixed acid anhydride method, for example, compound (10) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is reacted with compound (1d). Method, (b) active ester method, for example compound (1
0) as an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester and 1-hydroxybenzotriazole ester, and compound (1
d) reacting, (c) carbodiimide method, that is, compound (10) is condensed with compound (1d) in the presence of an activator such as dicyclohexylcarbodiimide or carbonylimidazole, (d) other method, for example Method of converting compound (10) into carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and reacting compound (1d) with this, or reacting compound (10) with an ester of lower alcohol to compound (1d) under high pressure and high temperature It can be carried out by a method of reacting, an acid halide of the compound (10), that is, a method of reacting the compound (1d) with a carboxylic acid halide. Alternatively, the compound (10) may be activated with a phosphorus compound such as triphenylphosphine, diethyl cyanophosphate, and diethylchlorophosphate, and the compound (1d) may be reacted therewith.

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is usually obtained by the Schotten-Baumann reaction, which is usually reacted with the compound (1d) without isolation to give the compound (1 ) Is manufactured. The Schotten-Baumann reaction is usually carried out in the presence of the above-mentioned various basic compounds conventionally used for the reaction at about −20 to 100 ° C., preferably at about 0 to 50 ° C. for about 5 minutes to 10 hours, preferably 5 minutes to It takes about 2 hours. The reaction between the obtained mixed acid anhydride and the compound (1d) takes about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours at about -20 to 150 ° C, preferably about 10 to 50 ° C. Done.
Further, the mixed acid anhydride is generally a solvent commonly used in this kind of mixed anhydride method, specifically, methylene chloride, chloroform, dichloroethane and other halogenated hydrocarbons, benzene, toluene, xylene and other aromatic hydrocarbons, It is carried out in a suitable solvent such as ethers such as diethyl ether, THF and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as DMF, DMSO and HMPA, or in the absence of a solvent. Examples of the alkylhalocarboxylic acid used in the production of the mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like.
These are usually at least equimolar amounts to the compound (10),
It is preferably used in an amount of 1 to 2 times the molar amount. The compound (1d) is usually used in an amount of at least an equimolar amount, preferably about 1 to 2 times the molar amount of the compound (10).

The active ester method shown in (b) above is carried out in a suitable solvent that does not affect the reaction, for example, when N-hydroxysuccinimide ester is used.
Examples of the solvent include methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane, benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, THF and dimethoxyethane, esters such as methyl acetate and ethyl acetate, DMF, DMSO, HMPA
Aprotic polar solvents and the like. The reaction is 0
Finish at 150 ° C, preferably 10-100 ° C, in 5-30 hours.
The compound (1d) and the N-hydroxysuccinimide ester are used in a proportion of usually at least equimolar, preferably equimolar to 2 times the molar ratio of the former to the latter.

Compound (1d) in the carboxylic acid halide shown in (d) above
When the method of reacting is employed, the reaction is carried out in the presence of a dehydrohalogenating agent in a suitable solvent. As the dehydrohalogenating agent, an ordinary basic compound is used, and as the basic compound, for example, a basic compound used in the Schotten-Baumann reaction, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine is used. , 4-dimethylaminopyridine, organic bases such as DBN, DBU, DABCO and potassium carbonate,
Inorganic bases such as sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc., as well as alcoholates such as sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, silver carbonate, sodium methylate, sodium ethylate, etc. it can. As the solvent, methylene chloride,
Halogenated hydrocarbons such as chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, THF and dimethoxyethane, esters such as methyl acetate and ethyl acetate, DM
F, DMSO, aprotic polar solvent such as HMPA, water, alcohol such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, acetonitrile or the like Two or more kinds of mixed solvents can be used. An alkali metal iodide such as potassium iodide or sodium iodide may be added to the above reaction system. The use ratio of the compound (1d) and the compound (10) is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least about equimolar amount to the former, preferably equimolar to 2 times molar amount. Good to use. The reaction is usually -30 to 180
℃, preferably about 0 ~ 150 ℃, generally 5
It takes about 30 minutes to 30 minutes.

Further, the method of activating the compound (10) with a phosphorus compound such as triphenylphosphine, diethyl cyanophosphate, diethylchlorophosphate and the like, and reacting the compound (1d) with this can be carried out in a suitable solvent. Various solvents that do not adversely affect the reaction, specifically, methylene chloride, chloroform, dichloroethane and other halogenated hydrocarbons, benzene, toluene, xylene and other aromatic hydrocarbons, diethyl ether, THF, dimethoxy Ethers such as ethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as DMF, DMSO, and HMPA can be used. In the above reaction, if necessary, a basic compound,
For example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, D
It is also possible to use organic bases such as BU and DABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is about 0 to 150 ° C,
It is preferably carried out at about 0 to 100 ° C., and completed in about 1 to 30 hours. The proportions of the phosphorus compound and the compound (1d) used with respect to the compound (10) are usually at least equimolar amounts, preferably equimolar to 3-fold molar amounts.

The compound (1) can be converted to the compound (1d) by hydrolysis. Any ordinary hydrolysis reaction conditions can be applied to the hydrolysis reaction, and it is usually carried out in a suitable solvent in the presence of a basic compound, a mineral acid, an organic acid or the like. Examples of the basic compound include sodium hydroxide,
Potassium hydroxide, barium hydroxide, potassium carbonate, etc.,
Examples of the mineral acid include sulfuric acid, hydrochloric acid and nitric acid, and examples of the organic acid include acetic acid and aromatic sulfonic acid. The reaction is usually carried out at room temperature to a solvent such as water, alcohols such as methanol, ethanol and isopropanol, acetone and ketones such as methyl ethyl ketone, dioxane and ethers such as ethylene glycol, acetic acid and the like or a mixed solvent thereof. The process proceeds at about 200 ° C, preferably at room temperature to about 150 ° C, and is generally completed in about 0.5 to 18 hours.

[In the Formula, R, A, and B are the same as the above. X ² represents a hydrogen group, a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. In the above compound (12), examples of the lower alkanesulfonyloxy group defined by X ² include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy. , Pentanesulfonyloxy, and hexanesulfonyloxy groups can be exemplified. Examples of the aryl group sulfonyloxy include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-
Examples thereof include substituted or unsubstituted arylsulfonyloxy groups such as methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy and α-naphthylsulfonyloxy groups. Examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-
Examples include substituents such as methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy groups, or unsubstituted aralkylsulfonyloxy groups.

The reaction between the compound (11) and the compound (12) is carried out when X ^{2 of} the compound (12) used as a starting material is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. ,
It is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol, isopropanol and butanol, acetic acid, ethyl acetate, DMF and DMS.
O, HMPA, etc. can be used. As the basic condensing agent,
For example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcoholates such as sodium methylate and sodium ethylate,
Tertiary amines such as pyridine and triethylamine can be used. The ratio of compound (11) and compound (12) used is
There is no particular limitation and it can be appropriately selected within a wide range, but the latter is usually used in at least about equimolar amount, preferably about equimolar to 5 times molar amount. The reaction is usually
It is carried out at about 40 to 120 ° C, preferably at 50 to 100 ° C, and is generally completed in about 5 to 30 hours.

When X ^{2 of} the compound (12) used as a starting material is a hydroxyl group, the reaction between the compound (11) and the compound (12) is carried out in the presence of a dehydration condensing agent without solvent or in a suitable solvent. Done. Examples of the dehydration condensing agent used include:
Condensed phosphoric acid such as polyphosphoric acid, orthophosphoric acid, pyrophosphoric acid, phosphoric acid such as metaphosphoric acid, phosphorous acid such as orthophosphorous acid, anhydrous phosphoric acid such as phosphorus pentoxide, hydrochloric acid, sulfuric acid, boric acid, etc. Examples thereof include acids, metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, and aluminum phosphate, activated alumina, sodium hydrogen sulfate, Raney nickel and the like. Examples of the solvent include high boiling point solvents such as DMF and tetralin. Compound (11) and compound (1
The use ratio with 2) is not particularly limited and can be appropriately selected within a wide range, but the latter is usually about equimolar amount or more, preferably about equimolar to 2 times the molar amount. The amount of the dehydration condensing agent used is not particularly limited and may be appropriately selected from a wide range, but it is usually a catalytic amount or more, preferably about 0.5 to 5 times the molar amount with respect to the compound (11).
The above reaction is preferably carried out in an inert gas stream, for example, carbon dioxide or nitrogen stream, in order to prevent the oxidation reaction. The above reaction can be carried out either under normal pressure or under pressure, but it is preferably carried out under normal pressure. The above reaction normally proceeds suitably at about 100 to 350 ° C, preferably 125 to 255 ° C, and is generally completed in about 3 to 10 hours. In the above reaction, compound (12) may be used in the form of salt.

In the benzoheterocyclic derivative of the present invention represented by the general formula (1), the compound having a basic group can be easily converted into an acid addition salt by reacting it with a pharmaceutically acceptable acid according to a conventional method. You can Examples of the acid include
Examples thereof 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 benzoheterocyclic derivatives of the present invention, the compound having an acidic group can be easily converted into a salt by reacting it with a pharmaceutically acceptable basic compound according to a conventional method. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

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

The present invention naturally includes optical isomers.

The benzoheterocyclic derivative of the present invention represented by the general formula (1) and a salt thereof are usually used in the form of general pharmaceutical preparations. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, Injection (liquid,
Suspension agents, etc.) and the like. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate,
Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, disintegration of sucrose, stearin, cocoa butter, hydrogenated oil, etc. Inhibitors, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, moisturizers such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate. Examples thereof include lubricants such as boric acid powder, polyethylene glycol, and the like. Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layered tablet or a multi-layered tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and gum arabic powder. , Tragacanth powder, gelatin, binders such as ethanol, disintegrators such as laminaran and agar. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solution, emulsion and suspension, they are used as a diluent. Any of those commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. Good. If necessary, coloring agents, preservatives, fragrances, flavors,
A sweetener and other pharmaceuticals may be included in the preparation.

The amount of the active ingredient (benzoheterocyclic derivative of the general formula (1) and a salt thereof) to be contained in the thus-prepared pharmaceutical preparation is not particularly limited and may be appropriately selected from a wide range, but usually the entire composition 1 to 70% by weight, preferably 1 to
30% by weight is recommended.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replenisher such as glucose or amino acid, and if necessary, may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally alone. In the case of suppositories, they are administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected depending on the usage, age of the patient, sex and other conditions, degree of disease and the like, but usually the amount of the active ingredient is preferably about 0.01 to 10 mg per 1 kg of body weight per day. In addition, 0.1 to 2 active ingredient in the dosage unit form
It is recommended to include 00mg.

Examples Below, examples, pharmacological test results and formulation examples are given.

Example 1 A solution of 1.7 g of 2-hydroxymethyl-4- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] aniline and 1.6 g of potassium xanthate in 20% of 90% ethanol was heated under reflux for 5 hours. Then, acetic acid was added to make the mixture acidic, the solvent was concentrated, water was added to the residue, and the mixture was extracted with dichloromethane. This is a saturated sodium hydrogen carbonate aqueous solution,
After washing successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, the solvent was evaporated, the resulting residue was purified by silica gel column chromatography (eluent; methanol: dichloromethane = 1: 10), and then ethanol-chloroform. Recrystallization from 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -4H-3,1-benzoxazine-2-thione (I) (1.09 g) and 6- [4- (3 , 4-Dimethoxybenzoyl) -1-piperazinyl] -4H-3,1
-0.4 g of benzothiazine-2-thione (II) were obtained respectively.

Compound (I) Property: Pale yellow needle crystal Melting point: 193 to 195 ° C Compound (II) Property: Yellow needle crystal Melting point: 244 to 247 ° C (recrystallization from water-methanol) Example 2 Example In a similar manner to 1, using the appropriate starting materials, the following compounds were obtained.

6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -4H-3,1-benzoxazin-2-one
Monohydrochloride / monohydrate Property: colorless fine needle crystals Melting point: 173-175 ° C Example 3 2-hydroxymethyl-4- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] aniline A solution of 3.05 g and 2.8 ml of triethylamine in 30 ml of dichloromethane was added to methoxycarbonyl chloride with stirring at 0 to 5 ° C.
1.1 ml was added dropwise, then, after stirring at 0-5 ° C. for 30 minutes and then at room temperature for 5 hours, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane, 0.5N
After washing successively with hydrochloric acid and saturated saline, the organic layer was dried over sodium sulfate and the solvent was distilled off. The residue thus obtained was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 70: 1) and recrystallized from water-methanol to give 6- [4- (3,4-dimethoxybenzoyl)- 1.11 g of 1-piperazinyl] -2H-3,1-benzoxazin-2-one monohydrochloride monohydrate was obtained.

Properties: colorless fine needle crystals Melting point: 173-175 ° C <Pharmacological reagent (blood perfusion extracted papillary muscle sample)> Pentoparbital for adult male and female dogs weighing 8 to 13 kg
Anesthesia was performed by intravenous administration of sodium salt at a rate of 30 mg / kg. Heparin sodium salt was intravenously administered at a rate of 1000 U / kg, and then the blood was killed and the heart was removed. The specimen consisted mainly of papillary muscle and ventricular septum, and was perfused with blood derived from a donor dog at a constant pressure of 100 mmHg from a cannula inserted into the anterior septum artery. The blood donated dogs weighed 18-27 kg and were anesthetized with 30 mg / kg of pentoparbital sodium salt intravenously beforehand, and 1000 U / kg of heparin sodium salt was intravenously administered. A voltage of 1.5 times the threshold value (0.5 ~
3V) The papillary muscle was stimulated with a square wave having a stimulation width of 5 msec and a stimulation frequency of 120 times per minute. The papillary muscle resting tension was 1.5 g, and the generated papillary muscle tension was measured via a force-displacement exchanger. The blood volume in the anterior septal artery was measured using an electromagnetic flow meter. Records of the generated tension and blood volume were recorded on an ink recording recorder. The details of this method have already been reported by Endo and Hashimoto [Am. J. Physiol., 218 , 1459-1463, 1970].

The test compound was intraarterially administered in a volume of 10 to 30 μl for 4 seconds. The inotropic effect of the test compound was expressed as a% change with respect to the tension generated before drug administration. The effect on coronary blood flow was expressed as the change in absolute value (ml / min) from before administration.

Table 1 shows the results obtained by using the compounds obtained in the respective Examples as test compounds.

Formulation Example 1 Compound obtained in Example 3 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition in one tablet were produced by a conventional method.

Formulation Example 2 Compound obtained in Example 1 (I) 500 mg Polyethylene glycol 0.3 g (Molecular weight: 4000) Sodium chloride 0.9 g Polyoxyethylene sorbitan 0.4 g Monooleate sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 100 ml The above parabens, sodium metabisulfite and sodium chloride were dissolved in the above distilled water at 80 ° C with stirring. The obtained solution is cooled to 40 ° C., the compound of the present invention, polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, and then distilled water for injection is added to the solution to adjust the final volume, An injection was prepared by sterilizing with a filter paper and dispensing 1 ml each into an ampoule.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/54 ABU A61K 31/54 ABU

Claims (1)

(57) [Claims] 1. A general formula [In the formula, R represents a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring, A represents an oxygen atom or a sulfur atom, and B represents an oxygen atom or a sulfur atom. ] The benzoheterocyclic derivative represented by these, and its salt.