JPH0251913B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzothiazine derivatives. The benzothiazine derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R represents a phenyl group which may have a substituent selected from a lower alkoxy group and a halogen atom, A represents a group [formula] or a group [formula], and B represents a lower alkylene group. ] The compound of the present invention represented by the above general formula (1) is
It has central nervous system depressant effect, antihistamine effect, antihypertensive effect, etc., such as analgesic, sedative, tranquilizer,
It is useful as an antipyretic, antispasmodic, antihistamine, antihypertensive, etc. More specifically, the group defined by R in the above general formula (1) has 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group, etc. an alkoxy group and one substituent selected from the group consisting of fluorine, chlorine, bromine and iodine atoms
Indicates a phenyl group which may have ~3. Representative examples of the group include the following groups. Phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromphenyl, 3-bromphenyl, 4-bromphenyl, 2-iodophenyl,
4-iodophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl,
2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2-ethoxyphenyl,
3-ethoxyphenyl, 4-ethoxyphenyl,
4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,
4-diethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methoxy-3-chlorophenyl groups, etc. Examples of the lower alkylene group defined by B in general formula (1) include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, and ethylmethylene. , tetramethylene, pentamethylene, hexamethylene, and other alkylene groups having 1 to 6 carbon atoms. The compound of the present invention can be produced by various methods, for example, by the method shown in the following reaction scheme. [In the formula, R, A and B are the same as above. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. ] That is, the compound of the present invention is produced by reacting a compound represented by general formula (2) with a known phenylpiperazine derivative represented by general formula (3). The above reaction is completed in a few hours to about 24 hours at a temperature of room temperature to 200°C, preferably 60 to 120°C, without a solvent or in a common inert solvent. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran (THP), ethylene glycol, and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol,
Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, acetonitrile,
Polar solvents such as N-methylpyrrolidone (NMP) and hexamethylphosphoric triamide (HMPA) can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), and triethylamine. Examples include tertiary amines such as tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary.
The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is usually an equimolar to excess amount of the latter, preferably an equimolar to 5 times the molar amount of the former. Preferably it is 1 to 1.2 times the mole. In the compound represented by the general formula (2) used as a starting material, the lower alkanesulfonyloxy group represented by X is specifically methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butane Sulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy,
Examples include hexanesulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-
Examples include substituted or unsubstituted arylsulfonyloxy groups such as methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and examples of aralkylsulfonyloxy groups include benzylsulfonyloxy , 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,
Substituted or terminally substituted arachis such as 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group, etc. An example is a sulfonyloxy group. The compound of general formula (2) having such a group X can be produced, for example, by the method shown in Reaction Scheme-2 below. [In the formula, B and X are the same as above. X ¹ represents a halogen atom, and R ¹ represents a lower alkyl group, an aryl group, or an aralkyl group. ] In other words, among the compounds of general formula (2), the compound in which A represents a group [formula] [compound of general formula (2a)] is a compound of general formula (5) known to the compound of general formula (4) Alternatively, a known compound of general formula (6) is reacted,
Alternatively, it is produced by reacting the compound of general formula (4) with a known compound of general formula 7, and then reacting the resulting compound of general formula (8). Further, among the compounds of general formula (2), a compound in which A represents a group [formula] [compound of general formula (2b)] is produced by reducing the compound of general formula (2a). In the above, the reaction between the compound of general formula (4) and the compound of general formula (5) or the compound of general formula (6) is generally called Friedel-Crafts reaction, and this reaction is carried out in the presence of an acid in a solvent. It will be held in
The solvents used in this case include various solvents commonly used in this type of reaction, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane,
Dichloroethane, trichloroethane, tetrachloroethane, etc. can all be used advantageously. Furthermore, various conventionally used acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, polyphosphoric acid, concentrated sulfuric acid, etc. can be suitably used. The amount of the acid to be used may be determined as appropriate, but it is usually about 2 to 6 times the mole, preferably about 3 to 4 times the mole of the compound of general formula (4). Also, compounds of general formula (5) or general formula (6)
The amount of the compound used is usually at least an equimolar amount, preferably an equimolar amount to twice the molar amount of the compound of general formula (4). The reaction temperature is selected as appropriate, but is usually about 20 to 120°C, preferably 40°C.
It is best to keep the temperature at ~70°C. The reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., and cannot be generalized, but it is usually 0.5 to 24 hours, preferably 0.5 to 6 hours.
The reaction is completed in about an hour. The reaction between the compound of general formula (4) and the compound of general formula (7) can be carried out in the same manner as the reaction between the compound of general formula (4) and the compound of general formula (5) or general formula (6). Bye. The reaction between the compound of general formula (8) and the compound of general formula (9) is carried out in the presence of the above-mentioned deoxidizer, in a suitable inert solvent,
It is usually carried out at about -30°C to 50°C, preferably from 0°C to room temperature, for about 1 to 12 hours. The ratio of the compound of general formula (8) and the compound of general formula (9) to be used may be appropriately selected within a wide range, and usually the latter is about equal mole or more to the former, preferably equimolar to 2 times the mole. It is better to use the amount. . Examples of inert solvents include halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene,
dimethyl sulfoxide, dimethyl formamide,
Examples include pyridine. The aryl group represented by R ¹ in the above general formula (9) is specifically substituted with phenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-chlorophenyl, naphthyl group, etc. or unsubstituted aryl groups, and specific examples of aralkyl groups include benzyl, 2-phenylethyl, 4-phenylbutyl, 4-methylbenzyl, 2-methylbenzyl, 4-nitrobenzyl, 4-methoxybenzyl, Examples include substituted or unsubstituted aralkyl groups such as 3-chlorobenzyl and α-naphthylmethyl groups. Further, the reaction between the compound of general formula (8) and the halogenating agent is carried out in a suitable inert solvent. Here, as the halogenating agent, for example, N,N-diethyl-
Examples include 1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, and thionyl chloride. Examples of inert solvents include ethers such as dioxane and THF, and halogenated hydrocarbons such as chloroform and methylene chloride. The ratio of the halogenating agent to the compound of general formula (8) is at least 2
It is preferable to use twice the molar amount, usually a supercharged amount. The reaction is usually carried out at room temperature to about 100°C, preferably room temperature to 70°C.
The reaction is generally completed in about 1 to 24 hours. The reduction of the compound of general formula (2a) is carried out by a reduction method using a hydrogenation reducing agent, a catalytic reduction method, or the like. When adopting a reduction method using a hydrogenated reducing agent,
As the hydrogenation reducing agent, for example, sodium borohydride, lithium aluminum hydride, etc., preferably sodium borohydride is used. The hydrogenation reducing agent is usually used in an amount of at least equimolar, preferably equimolar to 3 times the molar amount of the compound of general formula (2a). The reduction reaction is usually carried out in an appropriate solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran and ethyl ether.
It is carried out at a temperature of about -50°C, preferably -30°C to room temperature, and is generally completed in about 10 minutes to 3 hours. Note that when lithium aluminum hydride is used as a reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether or tetrahydrofuran. Further, when employing the catalytic reduction method, a commonly used catalyst for catalytic reduction such as a palladium-based catalyst such as barium sulfate-palladium is used as the reduction catalyst. The amount of catalyst used is given by the general formula (2a)
The amount is usually about 0.2 to 0.5 times the weight of the compound. This catalytic reduction is carried out in a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl ether, etc. by stirring thoroughly in a hydrogen atmosphere, usually at 1 to 10 atm, preferably at 1 to 3 atm. The reduction is generally carried out in the range of -30°C to the boiling point of the solvent, preferably from 0°C to around room temperature. In addition, the compound of the present invention in which A in general formula (1) is a [formula] group can be prepared by reducing the compound of the present invention in which A is a [formula] group, as shown in the following reaction scheme-3. can also be manufactured. [In the formula, R and B are the same as above. ] The reduction of the compound of the present invention represented by the general formula (1a) shown in Reaction Scheme-3 above is carried out by a method using a hydrogenation reducing agent, a catalytic reduction method, or the like. This reduction method is carried out under substantially the same operation and conditions as the above-mentioned reduction reaction of the compound of general formula (2a), and thus the compound of the present invention represented by general formula (1b) can be obtained. The benzothiazine derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. . The target 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, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. When the compound of general formula (1) and its salts are used as antihistamines, antihypertensives, and central nervous system depressants, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. Can be used. Various dosage unit forms for antihistamines, antihypertensives, and central nervous system depressants can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, suspensions, emulsions, and granules. Examples include drugs, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, carriers include excipients such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water, ethanol, propanol, and simple syrup. , glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, twin, laminaria sulfate. Disintegrants such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate, glycerin, starch, etc. Humectants, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, and solid polyethylene glycol can be used. When forming into a pill form, carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and laminaria. , agar, etc. can be used. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into a suppository, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Solutions, emulsions, suspensions, etc. prepared as injections are usually sterilized and preferably isotonic with blood. When molding these liquid preparations, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, etc. can be used as a diluent. can. In this case, a sufficient amount of salt, glucose or glycerin may be included in the preparation to prepare an isotonic solution. In addition, the preparations in the various forms mentioned above contain usual solubilizing agents, buffering agents, soothing agents, preservatives, etc., as well as coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc. and other pharmaceuticals as necessary. can be added and blended. When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents. The amount of the compound of general formula (1) or its salt to be contained in antihistamines, antihypertensives, and central nervous system depressants is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight of the total composition. It is better to Further, the above-mentioned antihistamines, antihypertensive agents, and central nervous system depressants are administered by methods depending on various forms.
For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules may be administered orally, and injections may be administered intravenously, either alone or mixed with normal replacement fluids such as glucose or amino acids. Alternatively, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally, suppositories can be administered rectally, and ointments can be applied. The dosage of the compound of the present invention and its salt as an antihistamine, antihypertensive, and central nervous system depressant is appropriately selected depending on the purpose of use, symptoms, and the like. Usually general formula
40 μg to 10 mg of the compound (1) or its salt per day
A pharmaceutical composition containing about 1 kg may be administered in 3 to 4 divided doses. Hereinafter, preparation agents for raw material compounds used to produce compounds of the present invention will be listed as reference examples, and then preparation agents for compounds of the present invention will be listed as examples, but the present invention is not limited thereto. Reference Example 1 125 g of ground anhydrous aluminum chloride is suspended in 350 ml of carbon disulfide, and 51 ml of 4-chlorobutyric acid chloride is added under water cooling, followed by 50 g of 2H-1,4-benzothiazin 3-(4H)-one. After stirring at room temperature for 3 hours and then under reflux for 2 hours, the reaction mixture was cooled to 30°C, the carbon disulfide was removed by decantation, and the residual oil was dissolved in ice-diluted hydrochloric acid. inject. After crystallization by adding ether, the crystals were collected, washed with water, washed with ether, and dried under reduced pressure heating to give 6-(4-chloro-1
71 g of -oxobutyl)-2H-1,4-benzothiazin-3(4H)-one are obtained. This can be used in the next step without purification. Colorless phosphorus crystal (ethanol) Melting point 151-152℃ Reference example 2 6-(4-chloro-1-oxobutyl)-2H-
5 g of 1,4-benzothiazin-3(4H)-one was suspended in 300 ml of methanol, 2.5 g of sodium borohydride was added under water cooling, and after stirring at room temperature for 1 hour,
Add acetone and dry under reduced pressure. Water is added to the residue, extracted with chloroform, and purified by column chromatography to obtain 3.0 g of 6-(4-chloro-1-hydroxy-2H-1,4-benzothiazin-3(4H)-one. NMR ( d ₆ −DMSO) δ ^ppm _TSP = 1.4-1.8 (ClCH ₂ C H ₂ C H ₂ , 4H, m) 3.42 (SCH ₂ , 2H, s) 3.62 (ClCH ₂ , 2H, t, 6Hz) 4.43 (C H OH, 1H, t, 4.5Hz) 5.37 (OH, 1H, Braads) 6.6-7.3 (Aromatic, 3H, m) 10.41 (NH, 1H, s) Example 1 6-(4-chloro-1-oxobutyl)- 2H−
5 g of 1,4-benzothiazin-3(4H)-one and 3.1 g of sodium iodide were dissolved in 10 ml of hexamethylphosphoric acid triamide, and after stirring at 40°C for 3 hours, 2.1 g of triethylamine and 1-(2-ethoxyphenate) were dissolved. Add 3.8 g of enyl) piperazine and add 40 g
Stir at ℃ for 2 hours. A 5% aqueous sodium bicarbonate solution is added, extracted with chloroform, washed with hot water, and the chloroform layer is dried over anhydrous sodium sulfate. The sodium sulfate was removed, the liquid was dried under reduced pressure, ethanol-hydrochloric acid was added to the residue, and the mixture was concentrated under reduced pressure. Recrystallize from ethanol-water to give 6-[4-
{4-(2-ethoxyphenyl)piperazine-1-
5.2 g of yl}-1-oxobutyl]-2H-1,4-benzothiazin-3(4H)-one hydrochloride hydrate are obtained. Colorless needle crystals (ethanol-water) Melting point 189-190℃ (decomposition) Example 2 6-(3-chloro-1-oxopropyl)-2H
-1,4-benzothiazin-3(4H)-one 1.0g
and 0.7 g of sodium iodide were suspended in 10 ml of dimethylformamide, and after stirring at 60°C for 1 hour, 1-
Add 0.8 g of (2-ethoxyphenyl)piperazine and 0.5 g of triethylamine, and then heat at 60°C for 1 hour.
Stir for an hour. After drying under reduced pressure, diluted aqueous sodium oxide solution was added to the residue, followed by extraction with chloroform. After drying the chloroform under reduced pressure, ethanol-hydrochloric acid was added to the residue, and the mixture was dried again under reduced pressure. Recrystallized from ethanol-water to give 6-[3-{4-(2-ethoxyphenyl)piperazin-1-yl}-1-oxopropyl]-2H-1,4-benzothiazine-3(4H)-
Obtain 0.5 g of On dihydrochloride. Colorless needle crystals (ethanol-water) Melting point 138-139°C Examples 3-7 The following Examples 3-7 were prepared in the same manner as Examples 1 and 2.
7 are obtained. Example 3 -6{3-4(-phenylpiperazin-1-yl)-1-oxopropyl}-2H-1,4-benzothiazin-3(4H)-one 1.2 hydrochloride pale yellow needles ( ethanol-water) Melting point 221-222°C (decomposition) Example 4-6 [3-{4-(3-chlorophenyl)piperazin-1-yl}-1-oxopropyl]-2H
-1,4-benzothiazin-3(4H)-one
1.5 Hydrochloride Pale yellow needles (ethanol-water) Melting point 148-149°C Example 5 6-{4-(4-phenylpiperazin-1-yl)-1-oxobutyl}-2H-1,4-benzothiazine -3(4H)-one Pale yellow plate crystals (ethanol-water) Melting point 203-204°C Example 6 6-[4-{4-(3-chlorophenyl)piperazin-1-yl}-1-oxobutyl]- 2H−
1,4-Benzothiazin-3(4H)-one 2
Hydrochloride Colorless needles (ethanol-water) Melting point 186-187°C (decomposition) Example 7 6-[1-hydroxy-4-{4-(3-chlorophenyl)piperazin-1-yl}butyl]-
2H-1,4-Benzothiazin-3(4H)-one Colorless needle crystals (ethanol) Melting point 166-167°C Example 8 6-[4-{4-(3-chlorophenyl)piperazin-1-yl}-1 -oxobutyl]-2H-1,
1 g of 4-benzothiazin-3(4H)-one was suspended in 20 ml of methanol, 0.5 g of sodium borohydride was added under water cooling, and after stirring for 1 hour, acetone was added and the mixture was dried under reduced pressure. Water was added to the residue, extracted with chloroform, chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 6-[4-{4-(3-chlorophenyl)piperazin-1-yl}-1-hydroxybutyl]. -2H-1,4-benzothiazine-
0.5 g of 3(4H)-one is obtained. Colorless needle crystals Melting point: 166-167°C The results of pharmacological tests on the compound of the present invention are listed below. Pharmacological test example 1 Inhibitory effect on jumping behavior in mice induced by methamphetamine and L-dopa The test compound was orally administered to DDY male mice (6 mice per group) weighing 17 to 25 g that had been fasted overnight. After 40 minutes, 4 mg/Kg of methamphetamine was administered intraperitoneally.
Further, 15 minutes after administration of methamphestamine, 40 mg/Kg of L-dopa is intraperitoneally administered. After L-dopa administration
Measure the number of jumps of the mouse during 60 minutes.
Mice were placed one by one in two glass beakers for measurement, and those that jumped 10 times or less within 1 hour after L-dopa administration were considered positive for inhibition, and those that jumped more than 10 times were considered negative. 3 out of 6 animals in a group
Calculate the effective dose (ED ₅₀ value) of the test compound that can cause the animal to become positive. The number of jumping times per hour for the saline administration group was 150 to 200 times. [H.Lal, F.C.
colparet and P.Laduron European J.Pharm.,
30, 113-116 (1975)] Results using the following test compounds are shown below. Test compound example 1...6-[4-{4-(2-ethoxyphenyl)piperazin-1-yl}-1-oxobutyl]-2H-1,4-benzothiazine-3
(4H)-one monohydrochloride monohydrate Example 8...6-[4-{4-(3-chlorophenyl)piperazin-1-yl}-1-hydroxybutyl]-2H-1,4 -Benzothiazine-3
(4H)-ON [Table] Pharmacological test example 2 Mouse epinephrine antagonism The test compound was orally administered to DDY male mice (10 mice per group) weighing 17 to 20 g that had been fasted overnight.
One hour later, 40 mg/Kg of epinephrine is administered intraperitoneally. The number of surviving and dead mice is measured until 24 hours have elapsed since administration of epinephrine, and the ED ₅₀ value is calculated from the number of survivors. In the saline-administered control group, all 10 animals died within a few minutes of epinephrine administration. [Loew.ER
and Micetich A., J.Pharmacol.Exp.Ther.
93, 434-443 (1948) and L.E. Allen, H.C.
Ferguson, and RHCox, Jr., Arzneim−
Forsch (Drug Res.), 24 , 917-922 (1974)] As a result of the above test using the compound of the present invention obtained in Example 1 above as a test compound, the ED ₅₀ value of the compound was 2.17. It was mg/Kg. Examples of formulations using the compounds of the present invention are listed below. Formulation example 1 6-[4-{4-(2-ethoxyphenyl)piperazin-1-yl}-1-oxobutyl-2H-1,
4-benzothiazin-3(4H)-one monohydrochloride monohydrate 5 mg Cornstarch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition in each tablet are manufactured by a conventional method.

Claims (1)

[Claims] 1. General formula [In the formula, R represents a phenyl group which may have a substituent selected from a lower alkoxy group and a halogen atom, A represents a group [formula] or a group [formula], and B represents a lower alkylene group. ] A benzothiazine derivative and its salt represented by these.