JPS5976076A - Benzothiazine derivative - Google Patents

Abstract

NEW MATERIAL:A benzothiazine derivative shown by the formula I (R<1> is lower alkyl; X<1> and X<2> are halogen) and its salt. EXAMPLE:7,8-Dichloro-2,3-dihydro-3-methyl-4H-benzothiazine. USE:An intermediate for synthesizing a pyrido[1,2,3-de][1,4]benzothiazine derivative useful as a remedy for diseases caused by various kinds of pathogenic microorganisms of men, animals, fishes, etc., surgical germicide for medical tools, and disinfectant. Showing improved antibacterial activity against Gram- positive and Gram-negative bacteria, having low toxicity and weak side effect. PROCESS:A compound shown by the formula II (X<3> is halogen) is nitrated to give a compound shown by the formula III, which is reacted with an alkali metal sulfide so that it is dimerized to give a compound shown by the formula IV. This compound is then reduced with iron, etc. to give a compound shown by the formula V, which is reacted with a compound shown by the formula VI (X=X<3>) in the presence of a dehydrohalogenating agent, further reduced with NaBH4, etc. to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzothiazine derivatives and salts thereof.

The benzothiazine derivative of the present invention has the general formula [wherein R represents a lower alkyl group, and xl and x2 represent a halogen atom, respectively. ] It is expressed as .

In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, ter
Examples of the halogen atom include alkyl groups having 1 to 6 carbon atoms such as t-butyl, pentyl, and hexyl groups, and examples of the halogen atom include a chlorine atom, a fluorine atom, and a bromine atom.

The compound of the present invention represented by the above general formula (1) exhibits excellent antibacterial activity against a wide range of Gram-negative bacteria and Gram-negative bacteria, and has low toxicity and weak side effects against various pathogenic bacteria of humans, animals, fish, etc. Pyrid (1) is useful as an easy treatment for diseases caused by
,2,8-de) (l.

4] Useful as a synthetic intermediate for benzothiazine derivatives. Details of the final compound and the method for deriving the compound from the compound of the present invention are as described below.

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 of the above formulas, xl, 7 and R1 are the same as above. X
and X8 represents a halogen atom. The nitration reaction of the compound represented by the general formula (2) above is carried out in a solvent-free or appropriate solvent using a conventional nitration agent such as fuming nitric acid or concentrated nitric acid. As the solvent, for example, nitric acid, concentrated nitric acid, etc. can be advantageously used. The nitrating agent is generally used in at least an equimolar amount relative to the starting compound, preferably from 2 to
It is used in 10 molar quantities. The reaction temperature is usually room temperature ~
The temperature is about 100°C, preferably about 50 to 60'C, and the reaction is completed in about 1 to 6 hours.

In the dimerization reaction of the compound represented by the general formula (3), an alkali metal sulfide such as Uram or sodium hydroxide (for example, sulfurization) is added in at least an equimolar amount, preferably about 2 to 10 times the amount of the raw material compound. Molar amounts are used and carried out in an inert solvent. Examples of the inert solvent include water, dimethyl sulfoxide (DMSO), and dimethyl lumamide (DMF).
, hexamethylphosphoric acid triamide, benzene, toluene, and other aromatic hydrocarbons can be preferably used. The reaction is usually carried out at room temperature to 150°C, preferably at room temperature to about 150°C.
It takes about 30 minutes to 3 hours at a temperature of '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).
Ethers such as F), nitriles such as a7tonitrile, DMSO, DMF, hexamethylphosphoric triamide (
HMPA), acetone, etc.

Examples of dehydrohalogenation agents include sodium carbonate,
Examples include inorganic carbonates such as potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and 8th class amines such as pyridine, quinoline, and triethylamine. The amount of the compound of general formula (6) and the dehydrohalogenation agent to be used with respect 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 about 0 to too'c,
The reaction is preferably carried out at a temperature of about room temperature to 50°C, and the reaction 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 from the reaction system, and thus the compound of the present invention represented by the general formula (1) 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, and lithium aluminum hydride, and a catalytic reduction method using a reduction catalyst such as Raney nickel. For example, a method using a reducing agent is carried out in the presence of the reducing agent in a suitable solvent similar to that used in the reaction between the compound of the general formula (5) and the compound of the general formula (6) at a temperature of about 0°C to This is carried out at around 50°C, preferably around room temperature, and takes about 1 to 6 hours. The proportion of reducing agent used is
Usually, the amount is about 2 to 10 times the molar amount, preferably about 2 to 5 times the molar amount of the raw material compound.

The thus obtained 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 desired compounds of the present invention and salts thereof can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction method, dilution method, recrystallization method, column chromatography, and V puff tape thin layer chromatography.

Biryl' (t, 2.a -de) (1,4) / which is the final compound useful as an antibacterial agent etc. from the compound of the present invention
<The production of the ndzothiazine visiting conductor is carried out, for example, by the method shown in the following reaction scheme-2.1. Ru.

Reaction formula-2 (LQ [In each of the above formulas, Xl, x2 and R1 are the same as above.

-Rogen atom or group -<'5 (R and R5 are bonded to each other with or without an oxygen atom or a nitrogen atom, and together with the nitrogen atom to which they bond, a 5- or 6-membered saturated heterocyclic group 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), and - represents a lower alkyl group. show. ] The cyclization reaction of the compound (1) of the present invention shown in the above reaction scheme-2 can be carried out according to various conventionally known cyclization reactions. For example, heating methods, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid (
Can you give an example of a cyclization method using an acidic substance such as PPE) or polyphosphoric acid ethyl ester (PPE)? When a cyclization method by heating is employed, a solvent such as high-boiling hydrogen ash and high-boiling ethers such as evatetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. is used, and usually t
oo~250''C1 Preferably, a heating condition of tgo~250°C can be adopted.Also, when an oxidation method using an acidic substance is adopted, it is used in an equimolar amount to a large excess amount of compound (1), preferably 10~ Use 20 times the amount, usually 100-18
The reaction may be carried out at 0°C for about 0.5 to 6 hours.

The hydrolysis reaction of compound (7) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide, or barium hydroxide, or a mineral acid such as sulfuric acid, hydrochloric acid, or nitric acid, according to a conventional method. , acetic acid, aromatic sulfonic acids and other organic 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.
It is. In this way, the compound of general formula (8) is easily obtained.

The thus obtained compound of general formula (8) and general formula (9)
In the reaction with the compound, the ratio of both 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 relative to the former, preferably equimolar -5.
It is better to use a double mortar. The reaction should be carried out in an aqueous medium. Specific examples of such solvents include water, alcohols such as methanol, ethanol, isopropanol, buknol, amyl alcohol, and isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, and xylene, tetrahydrofuran, dioxane, diglyme, and the like. ethers, dimethyl sulfoxide, dimethylform 7
Examples include amide, hexamethylphosphoric acid triamide, N-methylpyrrolidone (NMP), and the like. 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 #acid, potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and tertiary 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 ~250°C (preferably 140-200°C) and is generally completed in about 5-20 hours. Thus, pyrido (L, 2.8-d
e) A (L,4) benzothiazine derivative can be obtained.

The derivative can be easily converted into a salt by the action of the above-mentioned pharmaceutically acceptable acid or basic compound, and the above-mentioned derivative α and its salt can be easily isolated and purified by conventional separation means. be able to. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Examples of the production of raw material compounds used for producing the compounds of the present invention and production examples of the compounds of the present invention are listed below, but the present invention is not limited thereto.

Production Example 1 1.2.8-) Synthesis of dichloro-4-nitrobenzene 1000 m/f of fuming nitric acid (d=1.52) was heated on a water bath for 50 m/s.
Warm to °CK, 1,2,8-trichlorobenzene 500
f was added dropwise little by little between 50°C and 55°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. Separate the crystals, dissolve in chloroform 21, wash with water,
The chloroform layer was dried with anhydrous magnesium sulfate, filtered, and the furnace solution was concentrated and dried to obtain 1,2.8-)
Dichloro-4-nitrohenzene 5'14f is obtained. mp
55-56°C Production Example 2 2.2,8.8-Tetrachloro-6,6-cinitrodiphenyl disulfitono synthesis 1.2.8-) Sacrolo-4-nitrobenzene 175
V was dissolved in 00 ml of DM80 B, 210 g of sodium sulfide was added, and the mixture was heated and reacted 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. After adding 2 (l) of chloroform and stirring, filter out the insoluble matter. Transfer the p solution to a separating port and separate the chloroform layer. Dry over anhydrous magnesium sulfate, filter, and concentrate to obtain a crude product. Obtain 114 g of the above compound.mp
t t 2-114°C Production Example 3 Synthesis of 1.2-dichloro-5-amino-benzenethiol Compound 601 obtained in Production Example 2 above was dissolved in 800ml of acetic acid, 60f of reduced iron was added, and the mixture was heated to 80°C. Warm up. Next, 50 ml of concentrated hydrochloric acid was added and reacted 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 7.9. Chloroform 1.54
Add and stir, and filter the insoluble matter through Celite. Separate the chloroform layer and dry with anhydrous sodium sulfate. Subsequently, by filtration and concentration, 1,2-dichloro-
5 g of 5-amino-benzenethio-IvB are obtained.

mI) 52-55°C Production Example 4 7.8-dichloro-2,8-dihydro-3-methyl-4
Synthesis of u-benzothiazine Add 6f of potassium hydroxide to 140ml of 99.5% ethanol
Then add 1,2-dichloro-5-amino-benzenethiol 14f and cool on ice.

At the same temperature, 12 ml of monochloroacetone was added dropwise.

After dropping, react at 40°C for 80 minutes, then cool on ice again.

Add 6f of sodium borohydride to this reaction solution,
React for 2 hours at °C. After the reaction, the temperature is returned to room temperature, and 10m/l of acetone is added to decompose excess sodium borohydride. Filter the reaction solution and concentrate the P solution. followed by water
Add oom6 and 200 m7 of chloroform and stir. The chloroform layer was separated, dried over anhydrous potassium acetate, filtered, chloroform was distilled off under reduced pressure, and purified by silica gel column chromatography to obtain the above compound 6.5f.

NMR ((3DC$8): δppm” 1.16 (d, 8H, J=6Hz,
-CR2) 2.5 to 2.9 (m, 2E[, -8-
(3H, -OH'?"') 8.82 (bs, IH, -
N■) 6.12 (d, IH, J=9]E[Z')6.
75 (d, l, J=gHz) An example of producing a pyrido(1,2,8-de)(1,4)benzothiazine derivative from the compound of the present invention will be given below as a reference example.

Reference Example 1 (1) 9.10-dichloro-8-methyl-7-oxo-2,8-dihydro-TK-HiJ 1'(1,2,
8-d”) (1,4) Synthesis of benzothiazine-6-carboxylic acid 7.8-dichloro-2,8-dihydro-8-methyl 4H
-Add 2.8f of EMME to 8f of benzothiazine, 14
Heat at 0-150°C for 40 minutes. After the reaction, polyphosphoric acid 2Of is added and reacted at 140 to 150°C for 20 minutes. After the reaction, the reaction product was poured into 400 ml of ice water and extracted with 2001 nl of chloroform.

After separating the chloroform layer and drying it with magnesium sulfate,
Filter and concentrate. Add 16 nil of acetic acid and 4 ml of concentrated hydrochloric acid to the residue.
ml and heated under reflux for 4 hours. Reaction water removal to
When 0 ml is added, brown crystals are precipitated. The (7) crystals were all filtered and washed with ethanol-ether (1:4) to form white crystals. Recrystallize from DMF to obtain the title compound 2v
get.

Elemental analysis value (c13Hgo, Nsc$, as) C (%
') ■C%) N (%) Calculated value 47.29 2.75 4.24 Actual value 47.15 2,92 4.86 (2) 9-chloro-10-(4-methyl-1-bibefujinik )-8-
Mayp-rv-r-oxo-2,B-dihydro a-7H
-Pyrido (L, 2.8-de) (1,4) Preparation of benzothiazine-local ponic acid9. lO-dichloro-3-
Methyl-7-oxo-2,8-dihydro-7H-pyrido(1,2,8-de)(1°4]benzothiazine-6-
Add 20 mf of N-methylpyrrolidone to 2f of carboxylic acid, and further add 8.5 m# of N-methylbiperazine, and react on an oil bath at 180°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 crystal p and t
Suspend in o ml of water and adjust to pH 8 with dilute hydrochloric acid. Insoluble matter was filtered, and the p solution was diluted with 10% sodium hydroxide.
Let E['y, s. Extract with chloroform, dry the extract over anhydrous sodium sulfate, filter, concentrate the p liquid,
By recrystallizing the crude crystals with DMF, 9-chloro-1
0-(4-methyl-1-piperazinyl)-3-methyv
-7-oxo-2゜8-dihydro a-7u-pyrido (1,
2,8-de) (1°4) 670 mf of benzothiazine-local phosphoric acid is obtained. White edge-shaped crystals melting point 283-286°C (decomposition) Elemental analysis value (as C+aH2oO#N5O38) C(
%) H (%) N (%) Calculated value 54.89 5.12 10.67 Analyzed value 54.78 5.81 10.48 (3) 9-chloro-10-(1-piperazinyl)-8-methyl -7-
Oxo-2,8-dihydro-7H-pyrido (1121B
-de) (114) Production of benzothiazine-6-carboxylic acid l-hydrochloride l-hydrate 9, lO-dichloro-8-methyl-7-oxo-2,3
-dihydro-7u-pyrido (1,2,8-de XL.

4] 4 g of benzothiazine-6 monocarboxylic acid and 5.37 g of anhydrous piperazine were added to 40 ml of N-methylpyrrolidone.
and react at 1506-160°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. The crystals were separated, suspended in 400 ml of water, adjusted to pH 2 with dilute hydrochloric acid, and heated to 50°C. Insoluble materials were filtered, and the p solution was concentrated under reduced pressure.
7-oxo-2,3-dihydro a-7u-pyrido [: 1
, 2.8-de) (1,4) 1.3 g of benzothiazine-local ponic acid monohydrochloride hydrate is obtained. melting point g
o o 'c or higher elemental analysis value (C77Tl, ClN
303B・■C1・1'I20）C(%) E
[(%) N (%) Calculated value 47. Ql 4.
87 9.67 Analysis value 46.86 4.98
9.52(4)9-chloro-10-(4-formyl-
1-piperazinyl)-8-methyl-7-oxo-2,3
Monodihydro w-7H-pyrido (: 1,2.8-de)
(1゜4) Production of benzothiazine-6-carboxylic acid Add 1.57211 l of 90% formic acid to 2 Wll of acetic anhydride,
Stir at 0°C for 15 minutes and cool on ice. Among these, 9-chloro-10-(1-piperazinyl')-8'-methy/l/-7-oxo-2,3-dihydro-7-pyri)
(+, 2..3 de) (1%4) 750 ηIg of Henzo f-7 gin-6-carboxylic acid was added and reacted on a water bath at 80°C for 2.5 hours. 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)-3-methyl-7-oxo-
2,8-dihydro-7II-pyrido (1,2,8-da
) (1,4) Benzothiazine-local ponic acid a s
Get 5 my.

Elemental analysis value (as 0+a■+5OINs048)C(
%) H (%) N (%) Calculated value 5B, 0
1 4.45 Lo, 80 analysis value 52.87
4.52 10.41(5)9-chloro-10-
(4-morpholinyl)-8-methyl-7-oxo-2,
8-dihydro-7H-pyrido C1,2,3-de) C
1,4) Production of benzothiazine-local ponic acid 9, 1O-dichloro-3-methyl-7-oxo-2,3
-dihydro-7EI-pi! I)' (1,2,8-d
e) (1°4)benzothiazine-6-carboxylic acid 8f/
CN-methylpyrrolidone 80 ml and morpholine 4
ml and reacted for 7 hours at 170°C in a 100 m/volume stainless steel O-F crepe. After the reaction, cool
The solvent is removed 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-10-(4-morpholinyl)-3-methy)v-
7-oxo-2,8-dihydro a-7 to monopyrido (1,2
, 8-de) (1,4)benzothiazine-local ponic acid 870 tnf is obtained. Melting point 800°C or higher Elemental analysis value (01tH]tCIJN, as Oa8)C
(%) H (%) N (%) Calculated value 53.
61 4.50 7.86 Analysis value 58,58
4.57 7.48(6)9-chloro-1n-(4
-hydroxy-1-piperidinyl)-3-methy/l/-
7-oxo-2゜3-dihumanry-7H-pyrido (11
21B -deX1t4] Preparation of benzothiazine-local phosphoric acid 9. 10-dichloro-8-methyl-7-oxo-2,8-dihydro-7u-pyrido (t I 2 @
a' e) (t+4) 25 g of benzothiazine-6-carboxylic acid and 2 n mI of N-methylpyrrolidone!
and 4-hydroxypiperidine B, 8f, and reacted on an oil bath at 170°C for 10 hours. After the reaction, the solvent is distilled off under one pressure, and ethyl acetate is added to the residue for crystallization. By separating the crystals and recrystallizing them 8 times with dimethylformamide, υ
9-chloro-1(1-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2), which is a white edge-shaped crystal.
,3-dihydro-7■-pyrido (1,2°8-de)
(1,4)benzothiazine-6-carboxylic acid 847mf
get. Melting point 281-285°C (decomposition) Elemental analysis (0,sE[,,0pN2048)C(
%) ■ (%) N (%) Calculated value 54.75 4.85 7.09 Analytical value 54.58 4.97 7.21 Hereinafter, antibacterial test examples of the derivatives obtained in the above reference examples will be given.

Antibacterial test In order to investigate the antibacterial effects of the test compounds shown below against various bacteria, the minimum growth inhibition degree was determined by the agar dilution plate method [OE [EMOTHERAPY].

22.1126-1128 (1974)]. The results obtained are shown in Table 1. In addition, each type of bacteria has a number of 1x108 bacteria/
mll (0,D, 660m/j, 0.07-0.L6
) and I X I O' bacterial count/ml (100-fold dilution).

(Test bacteria) A...-S, aureus FDA 2Q9PB-
...8. pyogenes ITD 8-28 (3・
E, coli NIHJ JC-2D ■Self K,
pneumoniae N0T0 9682B
,,・P, rettgeri NIH96F ---
8,5onei EW-39G...8. Typh
i N0T0889BH-・80maresaen
s IFO12648I...P, aeruginos
a A'l'OC10145J ,,, tt
N0T010490K...〃E-2 (Test compound)

Claims (1)

[Claims] ■ General formula [The hollow hole in the formula represents a lower alkyl group, and xl and f each represent a halogen atom. ] A benzothiazine derivative and its salt represented by: