JP2531962B2 - 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. Also Represents a group —CH ₂ CH ₂ — or a group —CH═CH—. 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.

Examples of the lower alkoxy group include a linear or branched C1-C6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

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 compound of the present invention has excellent positive inotropic effect, coronary blood flow increasing effect and antihypertensive effect, but has a characteristic that it has almost no heart rate increasing effect. In addition, the above-mentioned compounds have low toxicity and are characterized by having few 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 the method shown in the following reaction scheme.

[Reaction formula-1] [Wherein R is as defined above. The cyclization reaction of compound (2) can be carried out in a suitable solvent in the presence of a suitable basic compound. Examples of the basic compound include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium acetate, potassium acetate, sodium hydroxide, sodium hydrogen carbonate, sodium metal, potassium metal, sodium amide, sodium hydride, sodium ethylate, and the like. Sodium methylate, potassium tert
-Alcoholates such as butoxide, triethylamine,
Organic basic compounds such as tripropylamine, pyrrolidine, piperidine and pyridine can be used. The amount of the monobasic compound used is usually at least an equimolar amount, preferably an equimolar to 2 times the molar amount of the compound (2). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, isopropanol and tert-butanol, diethyl ether, dioxane, tetrahydrofuran (THF) and ethers such as ethylene glycol dimethyl ether. , N-methylpyrrolidone, dimethylformamide (DMF), dimethylsulfoxide (DMS
O), hexamethylphosphoric triamide (HMPA), a polar solvent such as acetic anhydride, or a mixed solvent thereof.

The above reaction normally proceeds well at room temperature to about 150 ° C, preferably at room temperature to 100 ° C, and is generally completed in about 1 to 10 hours.

[Reaction formula-2] [Wherein R is as defined above. X ¹ represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. In the above, the lower alkanesulfonyloxy group defined by X ¹ is, for example, methanesulfonyloxy,
Examples thereof include ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy and hexanesulfonyloxy groups. Examples of the aryl group sulfonyloxy include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α-naphthyl. A substituted or unsubstituted arylsulfonyloxy group such as a sulfonyloxy group can be exemplified. Examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4
Examples thereof include a substituted or unsubstituted aralkylsulfonyloxy group such as -methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy groups.

The cyclization reaction of the compound (3) can be carried out in the same manner as the cyclization reaction of the compound (2) shown in the reaction formula-1.

[Reaction Formula-3] [In the formula, R and Z are the same as defined above. X ² represents a halogen atom. The reaction of the compound (4) with the compound (5) is 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, methanol,
Alcohols such as ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, DMF, DMS
O, 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 and the like can be used. Compound (4) and compound (5)
The use ratio of and is not particularly limited and can be appropriately selected within a wide range, but the latter is usually used at least about equimolar amount, preferably equimolar to 5 times molar amount with respect to the former.
The reaction is usually room temperature to about 180 ° C, preferably 100 to 150 ° C.
It will be 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.

[Reaction Formula-4] [In formula, R and Z are the same as the above. The reaction between the compound (6) and the compound (7) 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 (7) is reacted with an alkylhalocarboxylic acid to give a mixed acid anhydride, and compound (6) is reacted therewith. Method (b) active ester method, for example, compound (7) is used as an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, and compound (6) is reacted therewith. (C) Carbodiimide method, that is, compound (7) is condensed with compound (6) in the presence of an activator such as dicyclohexylcarbodiimide or carbonylimidazole, (d) Other method, for example compound (7) To a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and reacting the compound (6) with the compound (7). A process of reacting an ester compound of grade alcohol (6) under high pressure and temperature, acid halide of the compound (7), i.e. can be carried out by methods such as reacting the carboxylic acid halide compound (6). Alternatively, the compound (7) may be activated with a phosphorus compound such as triphenylphosphine, diethyl cyanophosphate, and diethylchlorophosphate, and the compound (6) 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, and this is usually reacted with the compound (6) 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 resulting mixed acid anhydride and the compound (6) 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.
The mixed acid anhydride is generally a solvent commonly used in this kind of mixed acid anhydride method, specifically 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
Etc. in a solvent such as an aprotic polar solvent or without solvent. Examples of the alkylhalocarboxylic acid used in the production of the above mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. ), At least an equimolar amount, preferably 1 to 2 times the molar amount. The compound (6) is usually used in an amount of at least an equimolar amount, preferably about 1 to 2 times the molar amount of the compound (7).

In the active ester method shown in (b) above, for example, when an N-hydroxysuccinimide ester is used, a suitable solvent that does not adversely affect the reaction, for example, halogenated carbonization of methylene chloride, chloroform, dichloroethane or the like is used. Hydrogen, aromatic hydrocarbons such as benzene, toluene and xylene, 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. Etc., about 0 to 150 ° C., preferably about 10 to 100 ° C.
It takes 30 hours. The ratio of the compound (6) to the N-hydroxysuccinimide ester used is usually at least equimolar to the latter, preferably equimolar to the latter.
It is preferable that the amount is about twice the molar amount.

The compound (6) is added to 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, for example, a basic compound used in the Schotten-Baumann reaction, specifically, triethylamine, trimethylamine, pyridine,
Dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU ), 1,4-diazabicyclo [2,2,2] octane (DABCO) and other organic bases and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate, as well as sodium hydroxide and potassium hydroxide. , Potassium hydride, sodium hydride, silver carbonate, sodium methylate, sodium ethylate, and other alcoholates can be used. 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, THF and dimethoxyethane, methyl acetate, ethyl acetate and the like. Ester of 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 (6) and the compound (7) is not particularly limited and is appropriately selected within a wide range, but usually the latter is at least about equimolar amount to the former, preferably equimolar to 2-fold 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.

The method of activating the compound (7) with a phosphorus compound such as triphenylphosphine, diethyl cyanophosphate, diethylchlorophosphate, and reacting the compound (6) 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 (6) used with respect to the compound (7) are usually at least equimolar amounts, preferably equimolar to 3-fold molar amounts.

The compound (1) can be converted to the compound (6) 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 and the like, mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, and organic acids such as acetic acid and aromatic sulfone. An acid or the like can be exemplified. The reaction is carried out, for example, with water, methanol, ethanol,
Alcohols such as isopropanol, acetone, ketones such as methyl ethyl ketone, dioxane, ethers such as ethylene glycol, solvents such as acetic acid or a mixed solvent thereof, usually room temperature to 200 ° C, preferably room temperature to 1
It progresses at around 50 ° C and generally finishes in about 0.5 to 18 hours.

[Reaction Formula-5] [Wherein, R is as defined above. The dehydrogenation reaction of compound (1c) is performed using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent include 2,3-
Benzoquinones such as dichloro-5,6-dicyanobenzoquinone and chloranil (2,3,5,6-tetrachlorobenzoquinone), halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide and bromine, selenium dioxide, A dehydrogenation catalyst such as palladium carbon, palladium black, palladium oxide or Raney-Nitzkel can be used, and the amount thereof is not particularly limited and can be appropriately selected from a wide range, but in the case of a halogenating agent, it can be used with respect to the compound (1c). It is usually an equimolar to 5-fold molar amount, preferably an equimolar to 2-fold molar amount, and in the case of a dehydrogenation catalyst, it is usually an excessive amount. Examples of the solvent include ethers such as dioxane, THF, methoxyethanol and dimethoxyethane,
Benzene, toluene, xylene, cumene and other aromatic hydrocarbons, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons, butanol, amyl alcohol, hexanol and other alcohols, acetic acid and other polar protic solvents, Polar aprotic solvents such as DMF, DMSO and HMPA can be used. The reaction is usually carried out at room temperature to 300 ° C, preferably room temperature to 200 ° C, and is generally completed in about 1 to 40 hours.

The reduction reaction of compound (1d) is carried out under usual catalytic reduction conditions. Examples of the catalyst used here include metals such as palladium, palladium-carbon, platinum, and Raney-Nitzkel. Such metals are usually used in catalytic amounts. As the solvent, for example, water, methanol, ethanol, isopropanol, dioxisan, THF, hexane, cyclohexane, acetic acid, ethyl acetate, a mixed solvent thereof or the like can be used. The reaction may be carried out under normal pressure or under pressure, but it is usually carried out under normal pressure to 20 kg / cm ² , preferably under normal pressure to 10 kg / cm ² . The reaction temperature is
It is usually about 0 to 150 ° C, preferably room temperature to 100 ° C.

[Reaction Formula-6] [In the formula, R and Z are the same as defined above. X ³ represents a hydroxyl group or the above X ¹ group. The reaction between the compound (8) and the compound (9) is carried out when X ^{2 of} the compound (9) used as a starting material is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. Is
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 (8) and compound (9) 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 an equimolar amount, preferably an equimolar to 5-fold molar amount for the former. The reaction is usually performed at about 40 to 120 ° C., preferably 50 to 100 ° C., and generally completed in about 5 to 30 hours.

When X ^{2 of} the compound (9) used as a starting material is a hydroxyl group, the reaction between the compound and the compound (8) is carried out in the presence of a dehydration condensing agent without solvent or in a suitable solvent. Examples of the dehydration-condensation agent used include condensed phosphoric acids such as polyphosphoric acid, orthophosphoric acid, pyrophosphoric acid, phosphoric acids such as metaphosphoric acid, phosphorous acids such as orthophosphorous acid, and anhydrous such as phosphorus pentoxide. Acids such as phosphoric acid, hydrochloric acid, sulfuric acid, boric acid, sodium phosphate, boron phosphate, ferric phosphate, metal phosphates such as aluminum phosphate, activated alumina,
Examples include sodium hydrogensulfate and Raney nickel.
Examples of the solvent include high boiling point solvents such as DMF and tetralin. The ratio of the compound (8) to the compound (9) used is not particularly limited and can be appropriately selected within a wide range.
The latter is usually used in an equimolar amount or more, preferably in an equimolar to 2-fold molar amount with respect to the former. The amount of the dehydration condensing agent used is not particularly limited and may be appropriately selected from a wide range, but is usually a catalytic amount or more, preferably the compound (8).
It is preferable to use about 0.5 to 5 times the molar amount. The above reaction is preferably carried out in a stream of an inert gas such as carbon dioxide or nitrogen 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 reaction normally proceeds suitably at about 100 to 350 ° C, preferably 125 to 255 ° C, and generally 3
It ends in about 10 hours. In the above reaction, compound (9) 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. Formulations include commonly used fillers, fillers, binders,
It is prepared using a diluent or excipient such as a moisturizer, a disintegrant, a surface active agent, a lubricant and the like. 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, Examples include injections (solutions, suspensions, etc.). 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,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl Binders such as pyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, white sugar , Stearin,
Cocoa butter, disintegration inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, moisturizers such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid Examples thereof include adsorbents, purified talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. 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, it is preferable that the solution and suspension are sterilized and isotonic with blood. Any of those commonly used in the 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 Examples and formulation examples are given below.

Example 1 A mixture of 3- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -6-methylsulfonylaminobenzaldehyde 2.0 g, potassium tert-butoxide 2.0 g, tert-butanol 10 ml and DMF 20 ml for 3 hours. Heated to reflux. The residue obtained by concentrating the solvent was poured into water, the precipitated crystals were collected, purified by silica gel column chromatography (eluent; dichloromethane: methanol = 100: 1), and recrystallized from ethanol-chloroform. 6
-[4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -2,1-benzothiazine-2,2-dioxide 0.78
got g.

Properties: Yellow needle crystals Melting point: 226 to 228 ° C Example 2 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -2,1-benzothiazine-2,2-dioxide
A mixture of 0.35 g, 5% palladium-carbon 0.25 g and acetic acid 100 ml was hydrogenated at 55 ° C. and 3 atm. After the catalyst was filtered through Celite, the liquid was concentrated and subjected to silica gel column chromatography (eluent; dichloromethane: methanol =
100: 1) and recrystallized from ethanol-chloroform to give 6- [4- (3,4-dimethoxybenzoyl)
0.28 g of -1-piperazinyl] -3,4-dihydro-2,1-benzothiazine-2,2-dioxide 1/4 hydrate was obtained.

Properties: Light yellow needle crystals Melting point: 216 to 220 ° C Formulation Example 1 Compound obtained in Example 1 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg According to a conventional method, the above composition is contained in one tablet. Tablets were produced.

Formulation Example 2 Compound obtained in Example 2 500 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Injection 100 ml of distilled water for use 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.

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. Also Represents a group —CH ₂ CH ₂ — or a group —CH═CH—. ] The benzoheterocyclic derivative represented by these, and its salt.