JPH04995B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel pyrido [1,2,3-de]
[1,4]-Benzothiazine derivatives and salts thereof. The derivative of the present invention has the general formula [In the formula, R ¹ is a lower alkyl group, R ² is a halogen atom or group

[Formula] are shown respectively. In the above group, R ⁴ and R ⁵ represent a group that is bonded to each other with or without an oxygen atom or a nitrogen atom to form a 5- or 6-membered saturated heterocyclic group with these bonded nitrogen atoms, The heterocyclic group is
As a substituent, it may have a lower alkyl group, a lower alkanoyl group, a hydroxyl group, or a lower alkyl group-substituted amino group. ] These are the compounds represented by these and their salts. In this specification, examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl,
Examples include alkyl groups having 1 to 6 carbon atoms such as butyl, tert-butyl, pentyl, and hexyl groups, and examples of halogen atoms include chlorine atoms, fluorine atoms, and bromine atoms. Also base

Examples of the 5- or 6-membered saturated heterocyclic group that may have a substituent represented by the formula include the above-mentioned lower alkyl group, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl group, etc. having 1 carbon number. -6 alkanoyl groups, hydroxyl groups and dimethylamino, diethylamino, dipropylamino, methylethylamino, dibutylamino, dipentylamino, dihexylamino, methylisopropylamino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert -butylamino,
1 carbon number such as pentylamino, hexylamino group, etc.
A 5-membered or 6-membered group having or not having as a substituent a group selected from the group consisting of an amino group having one or two of ~6 alkyl groups as a substituent.
An example is a saturated heterocyclic group having a member. Representative examples include morpholino, 1-piperazinyl, 1-
unsubstituted saturated heterocyclic groups such as piperidinyl, 1-pyrrolidinyl, and e.g. 4-ethyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, 4
-butyl-1-piperazinyl, 4-hexyl-1
-piperazinyl, 4-formyl-1-piperazinyl, 4-acetyl-1-piperazinyl, 4-propionyl-1-piperazinyl, 4-isobutyryl-1-piperazinyl, 4-hexanoyl-1-piperazinyl, 4-hydroxy-1-piperazinyl , 4-methyl-1-piperidinyl, 4-hydroxy-1-pyrrolidinyl, 4-methyl-1-pyrrolidinyl, 4-dimethylamino-1-piperidinyl, 4-dimethylamino-1-piperazinyl, 4
Examples include saturated heterocyclic groups having substituents such as -diethylamino-1-piperidinyl and 8-hydroxy-1-piperidinyl groups. The compound of the present invention represented by the above general formula (1) is:
It exhibits excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, has low toxicity, and has few side effects, and is a therapeutic drug for diseases caused by various pathogenic bacteria in humans, animals, fish, etc. It is also very useful as an external disinfectant and disinfectant for medical instruments, etc. In particular, the compounds of the invention are
It has remarkable antibacterial activity against Pseudomonas aeruginosa, glucose non-fermenting bacteria, anaerobic bacteria, Mycobacterium tuberculosis, etc. Furthermore, the compound of the present invention has excellent absorption properties, is not easily metabolized, and has a high urinary excretion rate, so that it is particularly useful as a therapeutic agent for urinary tract infections. The compound represented by the above general formula (1) can be produced by various methods, and a preferred example thereof is, for example, by the following method. [In each formula, R ¹ and R ² are the same as above. X represents a halogen atom. R ³ represents a lower alkyl group. ] The nitration reaction of the compound represented by the general formula (2) above is carried out without a solvent or in a suitable solvent using a conventional nitration agent such as fuming nitric acid or concentrated nitric acid. As the solvent, for example, nitric acid, concentrated sulfuric acid, etc. can be advantageously used. The nitrating agent is generally used in at least an equimolar amount, preferably 2 to 10 times the molar amount of the starting compound. The reaction temperature is usually room temperature to about 100°C, preferably around 50 to 60°C, and the reaction is completed in about 1 to 6 hours. The dimerization reaction of the compound represented by general formula (3) is
For example, using an alkali metal sulfide such as sodium sulfide or sodium hydrosulfide in at least an equimolar amount, preferably about 2 to 10 times the molar amount of the raw material compound,
Performed in an inert solvent. Examples of the inert solvent include water, dimethyl sulfoxide (DMSO),
Aromatic hydrocarbons such as dimethylformamide (DMF), hexamethylphosphoric triamide, benzene, toluene, etc. can be preferably used. The reaction is usually carried out at a temperature of room temperature to 150°C, preferably room temperature to about 100°C, and takes about 30 minutes to 3 hours. The production of the compound represented by general formula (5) by reduction of the compound represented by general formula (4) is carried out using an appropriate solvent and reducing agent. As the solvent, for example, water, acetic acid, dilute hydrochloric acid, aqueous ammonia, etc. can be used. As reducing agents, common ones that can reduce disulfide bonds to mercapto groups, such as iron,
Combinations of metals or metal compounds such as tin, zinc, tin chloride and mineral acids such as hydrochloric acid can be advantageously used. The amount of reducing agent used is not particularly limited, but usually the general formula (4)
The amount is at least equimolar, preferably about 2 to 10 times the molar amount of the compound. The reduction reaction is generally completed at a temperature of about 50 to 120°C, preferably about 70 to 90°C, in about 30 minutes to 3 hours. The thus obtained compound of general formula (5) and general formula (6)
The reaction with the compound is usually carried out in a suitable inert solvent,
It is carried out in the presence of a dehydrohalogenating agent. Examples of inert solvents include alcohols such as methanol, ethanol, and propanol, ethers such as dioxane and tetrahydrofuran (THF), nitriles such as acetonitrile, DMSO,
Examples include DMF, hexamethylphosphoric acid triamide (HMPA), and acetone.
Examples of the dehydrohalogenation agent include inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and tertiary amines such as pyridine, quinoline, and triethylamine. The amount of the compound of general formula (6) and the dehydrohalogenating agent to be used relative to the compound of general formula (5) is determined appropriately, but usually the compound of general formula (6) is used in at least an equimolar amount, preferably about The amount of the dehydrohalogenating agent is usually at least equimolar, preferably 1.5 to 5 times the molar amount. The above reaction is generally carried out at a temperature of about 0 to 100°C, preferably about room temperature to 50°C, and is completed in about 30 minutes to 5 hours. The compound obtained after the completion of the reaction is subsequently subjected to a reduction reaction without being particularly isolated within the reaction system, and thus a compound represented by general formula (7) is derived. The reduction reaction is carried out according to various conventional methods.
Preferred reduction reaction methods include, for example, a method using a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, etc.
A catalytic reduction method using a reducing catalyst such as Raney nickel can be employed. For example, the reaction using a reducing agent can be carried out in an appropriate solvent similar to that used in the reaction of the compound of general formula (5) and the compound of general formula (6). The reaction is carried out in the presence of the above-mentioned reducing agent at about 0° C. to about 50° C., preferably at about room temperature, for about 1 to 6 hours. The proportion of the reducing agent used is usually about 2 to 10 times the molar amount, preferably about 2 to 5 times the molar amount of the raw material compound. The cyclization reaction of the compound (7) thus obtained can be carried out according to various conventionally known cyclization reactions. Examples include a heating method, and a cyclization method using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid (PPA), and polyphosphoric acid ethyl ester (PPE). When employing the cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. is used, and usually 100 to 250
Heating conditions of 180-250°C can be employed. In addition, when adopting an oxidation method using an acidic substance, it is added in an equimolar amount to a large excess amount relative to compound (7).
Preferably 10 to 20 times the mole amount, usually 100 to 180℃
It is sufficient to allow the reaction to take place for about 0.5 to 6 hours. The hydrolysis reaction of compound (8) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide, or barium hydroxide, a mineral acid such as sulfuric acid, hydrochloric acid, or nitric acid, or acetic acid. , in the presence of conventional catalysts such as organic acids such as aromatic sulfonic acids. The reaction is generally carried out using water, methanol, ethanol, isopropanol, acetone,
It is carried out in common solvents such as methyl ethyl ketone, dioxane, ethylene glycol, acetic acid, etc. The reaction temperature is usually room temperature to 200℃, preferably 50 to 150℃
It is. In this way, the compound of general formula (9) is easily obtained. The thus obtained compound of general formula (9) and general formula (10)
In the reaction with the compound, the ratio of the two to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is used in an equimolar amount or more, preferably equimolar to 5 times the molar amount of the former. It is better to use the amount. The reaction is carried out in an inert solvent. Specific examples of such solvents include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, and isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as tetrahydrofuran, dioxane, and diglyme. Examples include dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and N-methylpyrrolidone (NMP). The reaction may be carried out in the presence of a deoxidizing agent. Specifically, such deoxidizing agents include sodium carbonate, potassium carbonate, potassium hydrogen carbonate,
Examples include inorganic carbonates such as sodium hydrogen carbonate, tertiary amines such as pyridine, quinoline, and triethylamine. The reaction is usually carried out at 100 to 250°C under a pressure of 1 to 20 atm (preferably 1 to 10 atm).
(preferably 140 to 200°C), and the reaction is generally completed in about 5 to 20 hours. In this way, the compound of the present invention represented by general formula (1) is obtained. The compound represented by the general formula (1) of the present invention can be easily formed into a salt by reacting with a pharmaceutically acceptable acid or basic compound.
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. , and the basic compounds include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,
Examples include potassium hydrogen carbonate. The compounds of the present invention and salts thereof thus obtained 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. When the compound represented by general formula (1) and its salt are used as an antibacterial agent, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. Various dosage unit forms of antibacterial agents can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, and suppositories. , injections (solutions, suspensions, etc.), ointments, etc. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaria powder , disintegrants such as sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc,
Examples include lubricants such as stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar. Furthermore, tablets may be coated with conventional coatings as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-coated tablets.
It can be a multi-layered tablet. When forming into a suppository, a wide variety of conventionally known carriers can be used, including polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions and suspensions, they are used as diluents in the art. All those commonly used in the art can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. In this case, the antibacterial agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffering agents, soothing agents,
In addition, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the therapeutic agent, if necessary. When forming into a paste, cream or gel form, a wide range of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the compound of the present invention to be included in the antibacterial agent is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight based on the total composition. Furthermore, there are no particular restrictions on the use of the antibacterial agents, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it is administered rectally; and in the case of an ointment, it is applied. The dosage of the compound of the present invention as an antibacterial agent is appropriately selected depending on the purpose of use, symptoms, etc. The dose of the compound of the present invention is usually about 2 to 20 mg/Kg per day, and the above pharmaceutical composition is divided into 3 to 4 doses. Just administer it. Antibacterial test In order to investigate the antibacterial effects of the test compounds shown below against various bacteria, the minimum growth-inhibiting concentration was determined by the agar dilution plate method [CHEMOTHERAPY, 22 , 1126-1128 (1974)]
reference〕. The results obtained are shown in Table 1. Each type of bacteria was prepared at a concentration of 1×10 ⁸ bacteria/ml (OD660mμ, 0.07 to 0.16) and 1×10 ⁶ bacteria/ml (100-fold dilution). (Test bacteria) A...S.aureus FDA 209P B...S.pyorgenes IID S-23 C...E.coli NIHJ JC-2 D...K.pneumoniae NCTC 9632 E...P.rettgeri NIH 96 F...S.sonnei EW −33 G…S.typhi NCTC 8393 H…S.marcescens IFO 12648 I…P.aeruginosa ATCC 10145 J… 〃 NCTC
10490 K... 〃 E-2 (Test compound) 1... Compound obtained in Example 2 2... Example 3 〃 3... Example 4 〃 4... Example 6 〃

[Table] Hereinafter, production examples of the raw material compounds used to produce the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples, but the present invention is not limited thereto. Reference Example 1 Synthesis of 1,2,3-trichloro-4-nitrobenzene 1000 ml of fuming nitric acid (d=1.52) was heated to 50°C on a water bath, and 500 g of 1,2,3-trichlorobenzene was added.
Drop in small portions between 50 and 55℃ (dropping time
2.5 hours). After the dropwise addition, reaction was carried out at 50°C for 1 hour, and then the reaction solution was poured into ice water 2. Pale yellow crystals precipitate. The crystals were collected, dissolved in chloroform 2, washed with water, the chloroform layer was dried over anhydrous magnesium sulfate, filtered, and the liquid was concentrated and dried to obtain 1,2,3-trichloro-4-nitrobenzene.
Obtain 574g. mp 55-56℃ Reference example 2 Synthesis of 2,2',3,3'-tetrachloro-6,6'-dinitrodiphenyl disulfide 1,2,3-trichloro-4-nitrobenzene
Dissolve 175g in DMSO300ml and add sodium sulfide.
Add 210g and heat to react at 90°C for 1 hour. After the reaction, the reaction solution was poured into water 3, and the pH was adjusted to 2 with concentrated hydrochloric acid.
shall be. After adding 2 portions of chloroform and stirring, filter out the insoluble matter. Transfer the liquid to a separating funnel and separate the chloroform layer. Dry over anhydrous magnesium sulfate, filter and concentrate to obtain 114 g of the above compound as a crude product. mp 112-114℃ Reference Example 3 Synthesis of 1,2-dichloro-5-amino-benzenethiol Dissolve 60g of the compound obtained in Reference Example 2 above in 800ml of acetic acid, add 60g of reduced iron, and heat to 80℃. . Next, add 50 ml of concentrated hydrochloric acid and react for 1 hour. After the reaction,
The solvent is distilled off under reduced pressure, 200 ml of water is added, and 10% sodium hydroxide is added to adjust the pH to 7.0. Chloroform 1.5
Add and stir, and pass through Celite to remove insoluble matter. Separate the chloroform layer and dry with anhydrous sodium sulfate. Subsequently, the mixture is filtered and concentrated to obtain 35 g of 1,2-dichloro-5-aminobenzenethiol. mp 52-55℃ Reference Example 4 Synthesis of 7,8-dichloro-2,3-dihydro-3-methyl-4H-benzothiazine 6g of potassium hydroxide and 140ml of 99.5% ethanol
Then, 14 g of 1,2-dichloro-5-amino-benzenethiol was added and cooled on ice. Add 12 ml of monochloroacetone dropwise at the same temperature. After dropping, react at 40°C for 30 minutes, then cool on ice again. Add 6 g of sodium borohydride to this reaction solution and react at 45°C for 2 hours. After the reaction, return to room temperature and add acetone.
Add 10 ml to destroy excess sodium borohydride. Filter the reaction solution and concentrate the solution. Next, add 100 ml of water and 200 ml of chloroform and stir. The chloroform layer was separated, dried over anhydrous potassium carbonate, and the chloroform was distilled off under reduced pressure, and purified by silica gel column chromatography to obtain 6.5 g of the above compound. NMR ( _CDCl3 ): δppm=1.16 (d, 3H, J=6Hz, _-CH3 ) 2.5-2.9 (m, 2H,

【formula】) 3.3~3.6 (m, 1H,

[Formula]) 3.82 (bs, 1H, -NH) 6.12 (d, 1H, J = 9Hz) 6.75 (d, 1H, J = 9Hz) Example 1 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]benzothiazine-6-carboxylic acid synthesis Add 2.8 g of EMME to 3 g of 7,8-dichloro-2,3-dihydro-3-methyl-4H-benzothiazine and heat at 140 to 150°C for 40 minutes. do. After the reaction, add 20g of polyphosphoric acid and react at 140-150°C for 20 minutes.
After the reaction, the reaction product was poured into 400 ml of ice water and extracted with 200 ml of chloroform. Separate the chloroform layer, dry with magnesium sulfate, filter, and concentrate. Add 16 ml of acetic acid and 4 ml of concentrated hydrochloric acid to the residue, and heat under reflux for 4 hours. After the reaction, add 100ml of water to precipitate brown crystals. The crystals were filtered and ethanol-
Washing with ether (1:4) gives white crystals. Recrystallization from DMF gives 2 g of the title compound. mp 300℃ or higher Elemental analysis value (as C ₁₃ H ₉ O ₈ NSCl ₂ ) C (%) H (%) N (%) Calculated value 47.29 2.75 4.24 Actual value 47.15 2.92 4.36 Example 2 9-chloro-10-( 4-Methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,
4] Production of benzothiazine-6-carboxylic acid 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
de] [1,4] Add 20 ml of N-methylpyrrolidone to 2 g of benzothiazine-6-carboxylic acid, and
- Add 3.5 ml of methylpiperazine and place on oil bath at 180°C.
React for 6 hours. After the reaction, the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue to crystallize it. Take the crystals, suspend them in 100 ml of water, and adjust the pH to 3 with dilute hydrochloric acid. Filter out the insoluble matter, and adjust the pH of the solution to 7.8 with 10% sodium hydroxide. Extract with chloroform, dry the extract over anhydrous sodium sulfate, filter,
The liquid was concentrated, and the crude crystals were recrystallized with DMF to obtain 9-chloro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1 ,2,3-de][1,
4] Obtain 670 mg of benzothiazine-6-carboxylic acid. White edge-like crystals Melting point 283-286℃ (decomposition) Elemental analysis value (as C ₁₈ H ₂₀ Cl ₃ O ₃ S) C (%) H (%) N (%) Calculated value 54.89 5.12 10.67 Analytical value 54.78 5.31 10.48 Implemented Example 3 9-chloro-10-(1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-
Production of pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid monohydrochloride monohydrate 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
4 g of de][1,4]benzothiazine-6-carboxylic acid and 5.3 g of anhydrous piperazine are dissolved in 40 ml of N-methylpyrrolidone and reacted at 150-160°C for 6 hours. After the reaction, the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue to crystallize it. Take the crystals and 400ml
of water, adjust the pH to 2 with dilute hydrochloric acid, and heat to 50°C. Filter out the insoluble matter, and concentrate the liquid under reduced pressure. The residue was recrystallized from ethanol-water to give pale yellow edge-like crystals of 9-chloro-10-(1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1, 1.3 g of 2,3-de][1,4]benzothiazine-6-carboxylic acid monohydrochloride monohydrate is obtained. Melting point 300℃ or higher Elemental analysis value (as C ₁₇ H ₁₈ ClN ₃ O ₃ S・HCl・H ₂ O) C (%) H (%) N (%) Calculated value 47.01 4.87 9.67 Analysis value 46.86 4.98 9.52 Example 4 9-chloro-10-(4-formyl-1-piperazinyl)-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [1,2,3-de]
[1,4] Production of benzothiazine-6-carboxylic acid Add 1.5 ml of 90% formic acid to 2 ml of acetic anhydride and heat at 50°C.
Stir for 15 minutes and then cool on ice. Among these, 9-chloro-10-(1-piperazinyl)-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [1,
Add 750 mg of 2,3-de][1,4]benzothiazine-6-carboxylic acid and react on a water bath at 80°C for 2.5 hours. After the reaction, return to room temperature and add 20ml of diethyl ether.
When added, a precipitate separates out. The precipitate was collected and recrystallized with dimethylformamide to obtain 9-chloro-10-(4-formyl-1-
piperazinyl)-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [1,2,3-de]
[1,4]Benzothiazine-6-carboxylic acid 385mg
get. Melting point 300℃ or higher Elemental analysis value (as C ₁₈ H ₁₈ ClN ₃ O ₄ S) C (%) H (%) N (%) Calculated value 53.01 4.45 10.30 Analysis value 52.87 4.52 10.41 Example 5 9-chloro-10- (4-morpholinyl)-3-methyl-7-oxo-2,3-dihydro-7H-
Production of pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
30 ml of N-methylpyrrolidone and 4 ml of morpholine are added to 3 g of de][1,4]benzothiazine-6-carboxylic acid, and the mixture is reacted for 7 hours at 170°C in a stainless steel autoclave in a 100 ml container. After the reaction, the mixture is cooled and the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue to crystallize it, and then filtered. The crude crystals were recrystallized three times from dimethylformamide to obtain white ridge-like crystals of 9-chloro-10-(4-morpholinyl)-3-methyl-7-oxo-2,3.
-dihydro-7H-pyrido [1,2,3-de]
[1,4]Benzothiazine-6-carboxylic acid 870mg
get. Melting point 300℃ or higher Elemental analysis value (as C ₁₇ H ₁₇ ClN ₂ O ₄ S) C (%) H (%) N (%) Calculated value 53.61 4.50 7.36 Analysis value 53.58 4.57 7.48 Example 6 9-chloro-10- (4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3
-dihydro-7H-pyrido [1,2,3-de]
[1,4] Production of benzothiazine-6-carboxylic acid 9,10-dichloro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
de〕[1,4]benzothiazine-6-carboxylic acid
Add 20 ml of N-methylpyrrolidone and 3.8 g of 4-hydroxypiperidine to 2.5 g, and heat on an oil bath at 170°C.
React for 10 hours. After the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for crystallization. The crystals were collected and recrystallized three times with dimethylformamide to obtain 9-chloro-10-(4-
Hydroxy-1-piperidinyl)-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzothiazine-
347 mg of 6-carboxylic acid are obtained. Melting point 281~
285℃ (decomposition) Elemental analysis value (as C ₁₈ H ₁₉ ClN ₂ O ₄ S) C (%) H (%) N (%) Calculated value 54.75 4.85 7.09 Analytical value 54.58 4.97 7.21 The following formulations using the compound of the present invention Give an example. Formulation example 1 9-chloro-10-(1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-
Pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid monohydrochloride monohydrate
200mg Glucose 250mg Distilled Water for Injection Appropriate Total Volume 5ml Dissolve the compound of the present invention and glucose in distilled water for injection, then inject into a 5ml ampoule, replace with nitrogen, and sterilize under pressure at 121°C for 15 minutes. An injection having the above composition is obtained. Formulation Example 2 9-chloro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,
4] Benzothiazine-6-carboxylic acid 100g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Cornstarch 30g Magnesium stearate 2g TC-5 (trade name manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) 10g Macrogol-6000 3g castor oil 40g methanol 40g Take the compound of the present invention, Avicel, cornstarch and magnesium stearate, mix and polish and coat with ^sugar.
Compress into tablets with a 10mm kine. The obtained tablets were designated as TC-5,
A film coated tablet having the above composition is produced by coating with a film coating agent consisting of polyethylene glycol-6000, castor oil and methanol. Formulation Example 3 9-chloro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,
4] Benzothiazine-6-carboxylic acid 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax is heated to make it liquid, then the compound of the present invention, purified lanolin and white petrolatum are added and heated until it becomes liquid. and stir until it begins to solidify to obtain an ointment having the above composition.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a lower alkyl group, and R ² represents a halogen atom or group [Formula], respectively. In the above group, R ⁴ and R ⁵ represent a group that is bonded to each other with or without an oxygen atom or a nitrogen atom to form a 5- or 6-membered saturated heterocyclic group with these bonded nitrogen atoms, The heterocyclic group may have a lower alkyl group, a lower alkanoyl group, a hydroxyl group, or a lower alkyl group-substituted amino group as a substituent. ] Pyrido [1,2,3-de] [1,
4]-benzothiazine derivatives and salts thereof.