JPS5976091A - Pyrido (1,2,3-de)(1,4)benzothiazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound(salt) shown by the formula I [R<1> is lower alkyl; R<2> is halogen, or group shown by the formula II (R<4> and R<5> are linked through O or N or directly to form 5- or 6-membered saturated heterocyclic group, etc.); X is halogen]. EXAMPLE:9-Chloro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydr o-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid. USE:An antibacterial agent against Gram-positive and Cram-negative bacteria. PROCESS:For example, a trihalobenzene shown by the formula III is nitrated, reacted with NaS, dimerized, the nitro group is reduced, the resultant compound is reacted with a compound shown by the formula CH2COR<1>, subjected to ring formation, reduced, further subjected to ring formation by a conventional procedure, hydrolyzed, and reacted with a compound shown by the formula R<2>H to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel pyrido[1,2,8-ae) (1,4
)-benzothiazine derivatives and salts thereof.

The derivative of the present invention has the general formula [wherein R1 represents a lower alkyl group and R2 represents a halogen atom]. In the above group, R4 and R6 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 together with the bonded nitrogen atom; The cyclic 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. ] These are the compounds represented by these and their salts.

In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, ter
Examples include alkyl groups having 1 to 6 carbon atoms such as t-butyl, pentyl, and hexyl groups, and examples of halogen atoms include 5- or 6-membered groups that may have a substituent such as a chlorine atom or a fluorine atom. Examples of the saturated heterocyclic group include the lower alkyl group, formyl, acetyl, propionyl,
butyryl, isobutyryl, pentanoyl, hexanoyl groups and other fluorocarbon groups having 1 to 6 carbon atoms, hydroxyl groups, and dimethylamino, diethylamino, dibutylamino, methylethylamino, dibutylamino, diethylamino, diethylamino, methylisopropylamino, methylamino, ethylamino, A group consisting of an amino group having one or two alkyl groups having 1 to 6 carbon atoms as a substituent, such as propylamino, isopropylamino, butylamino, tart-butylamino, pentylamino, and hexylamino group. A 5- or 6-membered saturated heterocyclic group may be exemplified, which may or may not have a group as a substituent. Representative examples include morpholino, 1-piperazinyl,
Unsubstituted saturated heterocyclic groups such as 1-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-biperazinyl, 4-propionyl-1-piperazinyl, 4-
Isobutyryl-1-piperazinyl, 4-hexanoyl-
1-piperazinyl, 4-hydroxy-1-piperidinyl, 4-methyl-1-piperidinyl, 4-hydroxy-1
-pyrrolidinyl, 4-methyl-1-pyrrolidinyl, 4-
Examples include saturated heterocyclic groups having substituents such as dimethylamino-1-piperidinyl, 4-dimethylamino-1-piperazinyl, 4-diethylamino-1-piperidinyl, and 8-hydroxy-1-piperidinyl groups.

The compound of the present invention represented by the above general formula (1) exhibits excellent antibacterial activity against a wide range of Durum-positive bacteria and Durum-negative bacteria, and is characterized by low toxicity and weak side effects. It is useful as a therapeutic agent for diseases caused by various pathogenic bacteria in animals, fish, etc., and is also useful as an external disinfectant and disinfectant for medical instruments, etc. In particular, the compounds of the present invention have remarkable antibacterial activity against Pseudomonas aeruginosa, glucose non-fermenting bacteria, anaerobic bacteria, Mycobacterium tuberculosis, and the like. In addition, the compounds of the present invention have excellent absorption properties and are easily metabolized.
Because of its high urinary excretion rate, it is particularly useful as a therapeutic agent for urinary tract infections.

The compound represented by the above general formula (1) can be manufactured by various methods, and one preferred example thereof is the following method.

Reaction scheme-1 (2) (a) (9)
(1) [R1 in each formula
, B2 and X are the same as above. R8 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 raw material compound. The reaction temperature is usually room temperature to about 100°C, preferably 50 to 60°C.
A temperature around 0°C is used, and the reaction is completed in about 1 to 6 hours.

The dimerization reaction of the compound represented by the general formula (8) is carried out using, for example, an alkali metal sulfide such as sodium sulfide or sodium hydrosulfide in at least an inert solvent for the starting compound. Examples of the inert solvent include water, dimethyl sulfoxide (DMSO), dimethyl formamide (DM
F), aromatic hydrocarbons such as hexamethylphosphoric triamide, benzene, toluene, etc. can be preferably used.

The reaction is usually carried out at room temperature to 150°C, preferably at room temperature to about 10°C.
It takes about 80 minutes to 8 hours at a temperature of 0°C.

The general formula (
The compound represented by 5) is produced using a suitable solvent and reducing agent. Examples of solvents include water, acetic acid,
Dilute hydrochloric acid, aqueous ammonia, etc. can be used. Further, as the reducing agent, it is possible to advantageously use a conventional reducing agent capable of reducing a disulfide bond to a mercapto group, such as a combination of a metal or a metal compound such as iron, tin, zinc, or tin chloride, and a mineral acid such as hydrochloric acid. The amount of reducing agent used is not particularly limited, but it is usually expressed by the general formula (
The amount is at least equimolar, preferably about 2 to 10 times the molar amount of the compound 4). The reduction reaction generally takes about 5
The process is completed in about 80 minutes to 8 hours at a temperature of 0 to 120°C, preferably about 70 to 90°C.

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 in the presence of a dehydrohalogenating agent. Examples of inert solvents include alcohols such as methanol, ethanol, propatool, dioxane, and tetrahydrofuran (TH).
? ), nitrites such as acetonitrile,
DMSO, DMF, hexamethylphosphoric triamide (H
MPA), acetone, and the like. Examples of the dehydrohalogenation agent include inorganic carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, and sodium frozen carbonate, and 8th class amines such as pyridine, quinoline, and triethylamine.

The amount of the compound of general formula (6) and the dehydrohalogenating agent to be used with respect to the compound of general formula (5) is appropriately determined by law, but usually the compound of general formula (6) is used in at least an equimolar amount, preferably about The dehydrohalogenating agent is usually at least an equimolar amount, preferably 1.5 to 5 times the molar amount.
It is said to be 5 times the mole size. The above reaction is generally about 0-100°
C1 is preferably carried out at a temperature of about room temperature to 50°C, and the reaction is completed in about 80 minutes to 6 hours. The compound obtained as a reaction termination agent is not isolated from the reaction system,
Subsequently, it is subjected to a reduction reaction, 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, methods using reducing agents such as sodium borohydride, lithium borohydride, and lithium aluminum hydride, and catalytic reduction methods using reduction catalysts such as Raney nickel. The reaction is carried out in an appropriate solvent similar to that used in the reaction between the compound of general formula (5) and the compound of general formula (6), in the presence of the reducing agent, at a temperature of about 0.
°C to around 50 °C, preferably around room temperature, about 1 to 6
It takes time. The proportion of the reducing agent used is usually about 2 to 10 times the molar amount of the raw material compound, preferably 2 to 10 times the molar amount of the raw material compound.
It is said to be about 5 times the molar amount.

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 a cyclization method by heating is employed, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, and diethylene glycol dimethyl ether is used, and the temperature is usually 100 to 250°C.
, preferably 180 to 250°C, can be employed. In addition, when employing an oxidation method using an acidic substance, it is used in an equimolar amount to a large excess amount, preferably 10 to 20 times the mole amount, relative to compound (7), and is usually heated to 100 to 180°C.
．． The reaction may be carried out for about 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 in conventional solvents such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, acetic acid and the like. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C. In this way, the compound of general formula (9) is easily obtained.

In the reaction between the compound of general formula (9) obtained in this way and the compound of general formula α1, the proportion of the two used is not particularly limited and may be appropriately selected within a wide range, but usually the former is The latter is preferably used in an equimolar amount or more, preferably in an equimolar to 5-fold molar amount. The reaction is carried out in an inert solvent. Specifically, such solvents include water, alcohols such as methanol, ethanol, impropatol, butanol, amyl alcohol, isoamyl alcohol,
Aromatic hydrocarbons such as benzene, toluene, xylene,
Examples include ethers such as tetrahydrofuran, dioxane and diglyme, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and N-methylpyrrolidone (NMP). The reaction may be carried out in the presence of a deoxidizing agent.

Specific examples of such deoxidizing agents include inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and 8th class amines such as pyridine, quinoline, and triethylamine. The reaction is usually 1 to
100 atm under a pressure of 20 atm (preferably 1 to 10 atm)
The reaction is carried out at ~260°C (preferably 140-200°C) and is generally completed in about 5-20 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 nucleic acids 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. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

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, and preparative thin-chest chromatography.

When the compound represented by the 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, gunpowders, powders, solutions, suspensions, emulsions, granules, capsules, and suppositories. , injections (liquids, suspensions, etc.), soft stimulants, and the like. 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, propatool, simple syrup, glucose, starch solution, gelatin solution.

Binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride.

Disintegrants such as starch and lactose, white sugar, and stearin.

Disintegration inhibitors such as cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose,
Examples include adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, and solid polyethylene glycol. In forming the gunpowder, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose, starch, cocoa butter, and hydrogenated vegetable oil.

Excipients such as kaolin and talc, and gum arabic powder.

Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.

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, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, and gelatin.

Semi-synthetic glycerides and the like can be mentioned. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, they are used as diluents in the art. You can use all the things commonly used in
For example, water, ethyl alcohol, propylene glycol,
Examples include 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, buffers, soothing agents, preservatives, etc. Furthermore, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent, if necessary.

When forming pastes, creams, and gels, a wide variety of diluents conventionally known in the art can be used as diluents, such as White Curly. Examples include phosphorus, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, and bentonite.

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 usually 1 to 1% of the total composition.
The content is preferably 70% by weight.

Furthermore, there are no particular restrictions on the use of the above-mentioned antibacterial agents, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, gunpowder, 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 replacement fluids such as glucose and amino acids. administered,
Furthermore, 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.
~20 myh11, and the above pharmaceutical composition may be administered in 8 to 4 doses.

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 (OHEMOTHERAPY).

1126-1128 (1974)]. The results obtained are shown in Table 1. In addition, each type of bacteria is 1 x 10 bacteria/m1 (
0-D-660mμs0.07-0.16) and lXl
The number of bacteria was adjusted to 0' bacteria/ml (100 times diluted).

19- (Test bacteria) A-S, aureus FDA 209 PB ・
” S, pyogenes IID S -280-
Fi, coli NIHJ JO-2D ・K, p
pneumoniae N0T096 B 2E ・P,
rettgeri NIB 96F・S, 5on
nei EW-88G...S, typhi NO'
l'0889 BH=-8, maroescens I
FO12648I = P, aeruginosa
ATOO10145J... // N0T
O10490K...〃E-2 (Test compound) l...Compound obtained in Example 2 2...Example 3 〃 8...Example 4 〃 4...Example 6 〃-20 = 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 to these.

Reference Example 1 Synthesis of 1,2.8-trichloro-4-nitrobenzene 1000 m41 of fuming nitric acid (d=1.52) was heated on a water bath,
Warm to 0°C, 1.2.8-)lichlorobenzene 50o
t was added dropwise little by little at a temperature of 50 to 66°C (dropping time 2.5 hours). After the dropwise addition, the reaction mixture was reacted at 50° C. for 1 hour, and then the reaction solution was poured into ice water 21. Pale yellow crystals precipitate. The crystals were taken to the bottom of the furnace, dissolved in 211 tons of chloroform and washed with water, and the chloroform layer was dried over anhydrous magnesium sulfate and filtered.
By concentrating and drying the filtrate, 1) 1,2.8-)dichloro-4-nitrobenzene 674f is obtained. mp55~
56℃ Reference Example 2 2, 2: Synthesis of a, a'-tetrachloro-6,6'-dinitrodiphenyl disulfide 1.2.8-) Lichloro-4-nitrobenzene 175
Dissolve in tftDM80B00mJ, add 210v of sodium sulfide, and react by heating at 90°C for 1 hour.

After the reaction, the reaction solution was poured into water 81, and the pH was adjusted to 2 with concentrated hydrochloric acid.
shall be. After adding 21 ml of chloroform and stirring, insoluble matter is filtered. Transfer the P solution to a separating funnel and separate the chloroform layer. Dry with anhydrous magnesium sulfate, filter,
Concentration gives the above compound 114f as a crude product. m
p 112-114°C Reference Example 8 Synthesis of 1.2-dichloro-5-amino-benzenethiol Compound 60F obtained in Reference Example 2 above was dissolved in 800 mII of acetic acid, reduced iron 60f was added, and the mixture was heated to 80°C. Warm up. Next, 50 mJ of concentrated hydrochloric acid was added and reacted for 1 hour.

After the reaction, the solvent was distilled off under reduced pressure, 200 ml of water was added, and 1
Add 0% sodium hydroxide to adjust the pH to 7.0.

Add 1.51 g of chloroform, stir, and filter the insoluble matter through Celite. Separate the chloroform layer and dry with anhydrous sodium sulfate. By subsequent filtration and concentration, 1,2-dichloro-5-amino-benzenethiol 8
Get 5f. mp52-55°C Reference Example 4 7.8-dichloro-2,8-dihydro-8-methyl-4
■-Synthesis of benzothiazine 6f potassium hydroxide 140ml 99.5% ethanol
Then, 14 g of 1,2-dichloro-5-amino-benzenethiol was added and cooled on ice. At the same temperature, 12 ml of monochloroacetone was added dropwise. After dropping, react at 40°C for 80 minutes, and then cool on ice again. Add 6 parts of sodium borohydride to this reaction solution! Add I and react at 45°C for 2 hours. After the reaction, return to room temperature, add 10 ml of acetone,
Decompose excess sodium borohydride. Filter the reaction solution and concentrate the P solution. Subsequently, 100 ml of water and 200 ml of chloroform were added and stirred. The chloroform layer was separated, dried over anhydrous potassium carbonate, filtered, chloroform was distilled off under reduced pressure, and purified by silica gel column chromatography to obtain 6.5 g of the above compound.

NMR (ODOJ8): δppm=1.16 ((1,8E, J=6H2, O
H2>2.5~2.9 (m, 2H, -8-on,
-on<0H8) 8.8~8.6 (m, IH, 0
0H 8.82 (1) S, IH, -Nu”
) 6.12 (d, IH, J = 9Hz) 6.75 (d, IR, J = 9Hz) Example 1 9.10-dichloro-8-methyl-7-oxo-2°8
-dihydro 0-7B-pyrido (1,2,8-+18)
(1゜4) Synthesis of benzothiazine-6-carboxylic acid 7.
8-dichloro-2,8-dihydro-8-methyl-4H-
F to 8g of benzothiazine! Add MM12.89, 14
Heat at 0-150°C for 40 minutes. After the reaction, add 20f of polyphosphoric acid and react at 140-160°C for 20 minutes.

After the reaction, the reaction product was poured into 400 ml of ice water and extracted with 200 mA' of chloroform. The chloroform layer is separated, dried over magnesium sulfate, filtered, and concentrated. 16 mJ of acetic acid and 4 ml of concentrated hydrochloric acid are added to the residue, and the mixture is heated under reflux for 4 hours. When 100 ml of reaction water is added, brown crystals are precipitated. The crystals were filtered and ethanol-ether (1:
When washed with step 4), it becomes white crystals. Recrystallize with DMP,
2 g of the title compound are obtained.

mp 800°C or higher Elemental analysis value (assuming 01sHeOsN80) 0 (%)
H (%) N (%) Calculated value 47.29 2.75 4.24 Actual value 47
,15 2.92 4.86 Example 2 9-chloro-10-(4-methyl-1-biperazinyl)
-8-methyl-7-oxo-2,8-dihydro-7H-
Pyrido(1,2,8-tie) (1,4) Preparation of benzothiazine-6-carboxylic acid 9.10-Dichloro-8-methyl-7-oxo-2,8
-dihydro111-7H-pyrido (1,2,8-de))
(1゜4)N to 2g of benzothiazine-6-carboxylic acid
-Add 20 ml of methylpyrrolidone, further add 8.5 ml of N-methylbiperazine, and incubate on an oil bath at 180°C for 6 hours.
Time reacts. After the reaction, the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue to crystallize it. 100 m
1 of water, and adjust the pH to 8 with dilute hydrochloric acid.

Filter the insoluble matter, and pH the P solution with 10% sodium hydroxide.
7, 8. Extract with chloroform, dry the extract over anhydrous sodium sulfate, filter, concentrate P solution, and recrystallize the crude crystals with DMF to obtain 9-chloro-10-(
4-Methyl-1-piperazinyl)-8-methyl-7-oxo-2,8-dihydro0-7H-pyrido(1,2,8-
da) 670 mF of (1,4)benzothiazine-6-carboxylic acid are obtained. White edge-like crystals, melting point 288-28
6°C (decomposition) elemental analysis value (C18■2oC4N808
As S)C (%) HC%)N (%) Calculated value 54.89 5.12 10.67 Analysis value 54.78 5.31 10.48 Example 8 9-chloro-10-(1-piperazinyl) -8-Methyl-7-oxo-2,8-dihydro-7H-pyrido (1,
2,8-de) (1,4) Production of benzothiazine-6-carboxylic acid monohydrochloride monohydrate 9.10-dichloro-3-methyl-7-oxo-2,8-dihydre l:l -7
H-pyrido(1,2,8-de)(1°4)benzothiazine-6-carboxylic acid 4f and anhydrous piperazine 5.8
1 in 40 ml of N-methylpyrrolidone,
React for 6 hours at ~160°C. After the reaction, the solvent is distilled off under reduced pressure. Ethyl acetate is added to the residue to crystallize it. The crystals were taken to the bottom of the furnace, suspended in 400 ml of water, and adjusted to pH 2 with dilute hydrochloric acid.
Warm to 50°C. Insoluble materials are filtered and the P solution is concentrated under reduced pressure.

)-3-methyl-7-oxo-2,8-dihydro-7
H-pyrido(1,2,8-cle) (1,4)]benzothiazine-6-carboxylic acid monohydrochloride monohydrate 1.8
get g. Melting point: 800℃ or higher Analysis value (0□7.H1gC!lNgO,5-HOI
・As H2O) 0 (%) H (%) N (
%) Calculated value 47.01 4.87 9.6
7 Analysis value 46.86 4.98 9.52 Example 4 9-chloro-10-(4-formyl-1-piperazinyl)-3-methyl-7-oxo-2,8-dihydro-7■
-Pyrido(1,2,8-4e) (1,4) Production of benzothiazine-6-carboxylic acid Add 1.5 mJ of 90% formic acid to 2 ml of acetic anhydride, and
Stir for 15 minutes at C and cool on ice. Among these, 9-chloro-10-(1-piperazinyl)-8-methyl-7-oxo-2,8-dihydro-7-pyrido(1,2,8-
ae) C1,4) Benzothiazine-6-carboxylic acid'
Add 150 mf and react for 2.5 hours at 80°C on a water bath. After the reaction, the temperature is returned to room temperature and 20 ml of diethyl ether is added to form a precipitate. 9-chloro-10-(4-formyl-1-piperazinyl)-8 was obtained by boiling the precipitate to the bottom of the furnace and recrystallizing it from dimethylformamide.
-Methyl-7-oxo-2,8-dihydro-7H-pyrido(1,2,8-de:)(1,4)benzothiazine-
6-carboxylic acid 885mII is obtained. Melting point 800°
Elemental analysis value of C or higher (as 018HIBOIN804B) C (%) H (%) N (%) Calculated value 5B, 01 4.45 10.80 Analysis value 52.87 4.52 10.41 Example 5 9-chloro- 10-(4-morpholinyl)-8-methyl-7-oxo-2,8-dihydro-7I(-pyrido(1
, 2,8-46) (1,4) Production of benzothiazine-6-carboxylic acid 9.10-dichloro-8-dimethyl-7-oxo-2,8
-dihydro a-7H-pyrido (1,2,8-do:) (1
゜4] Add 80 ml of N-methylpyrrolidone and 4 mJ of morpholine to 8 f of benzothiazine-6-carboxylic acid, and place in a stainless steel autoclave in a 100 m# container.
React at 0°C for 7 hours. 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. By recrystallizing the crude crystals eight times in dimethylformamide, 9-chloro-1, which is a white ridge-shaped crystal, is obtained.
0-(4-morpholinyl)-8-methyl-7-oxo-
2,8-dihydro-7H-pyrido (1,2,8-de)
(1,4)Benzothiazine-6-carboxylic acid 870
Get mf.

Melting point: 800℃ or higher Elemental analysis value (as C17H1701N204S) C (
%) ■ (%) N (%) Calculated value 58.61 4.50 7.86 Analytical value 5B, 58 4.57 7.48 Example 6 9-chloro-10-(4-hydroxy-1-piperidinyl) -3-methyl-7-oxo-2,8-dihyde 1:l
-7H-pyrido(1,2,8-de) (1,4,1 Preparation of benzothiazine-6-carboxylic acid 9.10-dichloro-8-methyl-7-oxo-2,8
-dihydro0-72(-pyrido(1,2,8-de)(1
゜4] N- to benzothiazine-6-carboxylic acid 2,5f
Add 20 ml of methylpyrrolidone and 8.8 g of 4-hydroxypiperidine, and react on an oil bath at 170°C for 10 hours. After the reaction, the solvent is distilled off under reduced pressure, and ethyl acetate is added to the remaining liquid to crystallize it. 9-chloro-10-(4-hydroxy-1-piperidinyl)-8-, which is a white ridge-shaped crystal, was obtained by boiling the crystals to the bottom and recrystallizing them eight times with dimethylformamide.
One Jl/847 mg of methyl-7-oxo-2,8-dihydro-7-pyrido(1,2,8-de][1,4)benzothiazine-6/bonic acid is obtained. Melting point 281
~285°C (decomposition) elemental analysis value (C! 18H190
1N2 as C48) C (%) H (%)
N (%) Calculated value 54.75 4.85 7.
09 Analysis value 54.58 4.97 7.21 Examples of formulations using the compound of the present invention are listed below.

Formulation Example 1 9-chloro-10-(1-piperazinyl)-8-carboxylic acid monohydrochloride hydrate glucose 250 mf
Appropriate amount of distilled water for injection
Amount: Dissolve the compound of the present invention and glucose in 6 ml of distilled water for injection, inject into a 5 ml ampoule, purify with nitrogen, and autoclave at 121° C. for 15 minutes to obtain an injection with the above composition.

Formulation Example 2 9-chloro-10-(4-methyl-1-piperadiazine-6-carboxylic acid Avicel (trade name, manufactured by Asahi Kasei ■) 40
f cornstarch 80F magnesium stearate 2gTo-5 (trade name: Shin-Etsu Chemical Co., Ltd., 10g hydroxypropyl methylcellulose) macrogol-6000
89 Castor oil 40f Methanol 409 The compound of the present invention, Avicel, cornstarch and magnesium stearate are mixed and tableted using a grinder with sugar coating radius 10 mm. T. the obtained tablets.

-5. Film coated tablets having the above composition are produced by coating with a film coating agent consisting of polyethylene glycol-6000, castor oil and methanol.

Formulation Example 8 9-chloro-10-(4-methyl-1-piperazithiazine-6-carboxylic acid purified lanolin 5f white beeswax 5g total f
i 10 (if white beeswax is heated to make it liquid, then the compound of the present invention, purified lanolin and white wax (-11) are added and heated until it becomes liquid, then stirred until it starts to solidify to make an ointment with the above composition. get the agent.

(that's all) Agent: Patent Attorney San Eiji 85- 956-

Claims (1)

[Claims] ■ General formula [In the formula, R1 represents a lower alkyl group, 12 represents a halogen atom or a group -N<R6, and X represents a halogen atom, respectively. In the above group, R4 and R6 represent a group that is bonded to each other with or without an oxygen atom or a nitrogen atom to form a 6-membered or 6@ saturated heterocyclic group together with the bonded nitrogen atom; The cyclic 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 C1,2,8-4e) (1,4)
-Benzothiazine derivatives and salts thereof.