CH620446A5 - Process for the preparation of thienothiazine derivatives - Google Patents

Abstract

Thienothiazine derivatives of the formula <IMAGE> in which A forms the group <IMAGE> or <IMAGE> with the two carbon atoms, where the dashed line indicates the double bond present in the first case and R1, R2, R3 and R4 have the meaning given in Claim 1, have anti-inflammatory, analgesic and antirheumatic properties. They can be prepared by hydrolysing corresponding enamines of the formula <IMAGE> in which R5 and R6 have the meaning given in Claim 1.

Description

The present invention relates to the preparation of 35 thienothiazine derivatives of the general formula

CO-NH-R.

XXI

Ç-CO-NH-R,

"OH

wherein A with the two carbon atoms has the group in which A, Ri and R2 have the above meaning, and Rs and Rf> each represent lower alkyl or together with the nitrogen atom pyrroline, pyrrolidine, piperidine, morpholine or N- (lower alkyl) -piperazine .

2. The method according to claim 1, characterized in that R2 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-l, 3,4-thiadiazolyl, 2-pyrazinyl, 2-pyrimidynyl, l, 2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl- 2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl 4-pyrimidinyl, 6-methyl-2-pyridyl or l, 2,3,4-tetrazol-5-yl.

3. The method according to claim 1 or 2, characterized in that R3 and R4 are hydrogen.

4. The method according to any one of claims 1 to 3, characterized in that Ri is methyl.

5. The method according to any one of claims 1 to 4, characterized in that R2 is 2-thiazolyl, 5-isoxazolyl or 2-pyridyl.

6. The method according to claim 5, characterized in

or

"0 forms and the dashed line indicates the double bond present in the first case, R 1 denotes lower alkyl, R 2 the residue of an aromatic heterocycle optionally substituted by one or two lower alkyl groups with 1 to 4 heteroatoms or one optionally substituted by halogen, 65 hydroxy, is lower alkyl, trifluoromethyl or lower alkoxy substituted phenyl and R3 and R4 each represent hydrogen or lower alkyl.

The expression "lower" used in this description

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Alkyl »denotes straight-chain or branched saturated hydrocarbon groups with 1-4 carbon atoms, e.g. Methyl, ethyl, propyl, isoproyl, t-butyl and the like. The term “lower alkoxy” refers to hydrocarbon oxy groups having up to 4 carbon atoms. The term «halogen» refers to the 4 halogens chlorine, bromine, fluorine, iodine. The term “radical of an aromatic heterocycle with 1-4 heteroatoms optionally substituted by one or two lower alkyl groups” includes radicals of optionally substituted by one or two lower alkyl groups

5- or 6-membered aromatic heterocycles with 1-4 nitrogen "and / or oxygen and / or sulfur atoms, such as 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl -l, 3-4-thiadiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4 -Methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-isoxazolyl, 3,4-dimethyl -5-isoxazolyl, 2,6-dimethyl-4-pyrimidinyl,

6-methyl-2-pyridyl, l, 2,3,4-tetrazol-5-yl and the like.

In a preferred class of compounds of the formula I, R3 and R4 are hydrogen. Ri is preferably the methyl group. R2 preferably represents 2-thiazolyl, 5-isoxazolyl or 2-pyridyl.

A particularly preferred compound is 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamid-1,1-dioxide.

Thiazine derivatives which have a certain structural similarity to the compounds of the formula I are known, for example, from US Pat. 3,591,584. In contrast to the compounds of the formula I, however, these known compounds are benzothiazine derivatives and not thienothiazine derivatives.

The thienothiazine derivatives of the formula I can

according to be prepared by using an enamine of the general formula

CO-NH-R,

XXI

IS

wherein A, Ri and R2 are as defined above, and Rs and Rf> each hydrolyze lower alkyl or together with the nitrogen atom pyrroline, piperidine, morpholine or N- (lower alkyl) piperazine.

The hydrolysis according to the invention is preferably carried out with an aqueous mineral acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, or with trifluoroacetic acid, the temperature being between 50 ° C. and the boiling point of the reaction mixture, preferably the boiling point of the reaction mixture for 2 seconds. In this hydrolysis, the acid also serves as a solvent.

The compounds of the formula XXI required as starting materials can be prepared according to the reaction scheme 30 I below; the preparation of the compounds of the formula XIV used as starting products in reaction scheme I is shown in the following reaction scheme II and is subsequently explained in more detail.

Reaction scheme I

C00R

XIV

l

KOH

oc

C00H

XXII

1) PCls

2) CH2N2

3) HCl so2-nh-r1

C0-CH2-Hal

X

XXIII

Close

620 446

I.

qT!>

OK. / C!

.R,

, CH Z '2

II

0

I.

HNRsRe

/ ^ V ^ S ° 2 ^ k, ^ "R1

UL

N

I.

CH

N

/ \

R-RC D 6

IXX

1) Phosgene

->

2) H2N-R2 (III)

oor ■

C ^ CO-NH-R.

I.

N

/ N

XXI

R,

R

In the above Reaction Scheme I, shark means halogen and R is lower alkyl, and A, Ri, R2, Rs and R «have the above meaning.

Reaction scheme II

"^ -SO.K

OC

eoo H

VII

Vili

C00R

IX

XI

A \

S02-NH-RJ

CO OR

XIV

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In this scheme, shark means halogen and R means lower alkyl, and A and Ri have the above meaning.

3-chloro-thiophene-2-carboxylic acid and 4-bromo-thiophene-3-carboxylic acid are known from the compounds of the formula VI, the former being prepared in a relatively complicated manner. A simpler method for the preparation of 3-chloro-thiophene-2-carboxylic acid consists in that the known 3-hydroxythiophene-2-carboxylic acid methyl ester in an inert solvent boiling above 80 ° C, such as chloroform or dioxane, with a chlorinating agent , such as phosphorus pentachloride, converted into the 3-chloro-thiophene-2-carboxylic acid chloride and hydrolyzed this to the corresponding acid. Substituted 3-chloro-thiophene-2-carboxylic acids (compounds of the formula VI in which Hai is chlorine, A with the two carbon atoms forms the group in which R3 and / or R4 is different from hydrogen) can also be prepared in an analogous manner. Although in principle a bromine compound e.g. the known 4-bromo-thiophene-3-carboxylic acid can be used as the starting material, the use of the corresponding chlorine compound is recommended. The 4-chloro-thiophene-3-carboxylic acid, which is not described in the literature, can be prepared starting from the known 3-ketothio-phen-4-carboxylic acid methyl ester by using phosphorus pentachloride to aromatize it in 4-chloro-thiophene-3 -converts carboxylic acid chloride and this hydrolyzed to the corresponding acid. Substituted 4-chloro-thiophene-3-carboxylic acids (compounds of the formula VI in which shark means chlorine, A with the two carbon atoms forms the group in which R3 and / or R4 is different from hydrogen can also be prepared in an analogous manner .

The conversion of a halothiophene carboxylic acid corresponding to formula VI into a potassium salt of a sulfothiophenic carboxylic acid of formula VII is carried out according to methods known per se by reacting the compound of formula VI with sodium bisulfite in the presence of a copper (I) salt catalyst, in particular copper (I )chloride. In the reaction product obtained with potassium chloride. When converting with sodium hydrogen sulfide, a temperature of 143 ° C. should be maintained in order to achieve optimum yields.

The compound of formula VII is converted into the free acid of formula VIII in a manner known per se, e.g. with a strong ion exchanger.

The esterification of the acid of formula VIII to the ester of formula IX is carried out autocatalytically (presence of the sulfo group) in an alcohol / chloroform mixture. To form the methyl ester, the acid is dissolved in methanol / chloroform and the reaction mixture is heated to the boiling point of the ternary azeotrope (methanol / chloroform / water of reaction).

A compound of the formula IX is converted into the acid halide of the formula X in a manner known per se using a halogenating agent, preferably a chlorinating agent, such as thionyl chloride or phosphorus pentachloride. Chlorination with thionyl chloride can be carried out without solvent by refluxing. When using phosphorus pentachloride, it is possible to work in the presence of an inert solvent, such as chloroform, carbon tetrachloride, dioxane, and at a temperature between 50 ° C. and the reflux temperature of the reaction mixture.

However, the compound of the formula X can also be prepared starting from a potassium salt of a sulfothiophene-carboxylic acid corresponding to the formula VII via a compound of the formula XI. For this purpose the potassium salt mentioned is e.g. with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as a solvent at a temperature between 30 ° C and the boiling point of phosphorus oxychloride. Instead of phosphorus oxychloride, an inert organic solvent such as dioxane, chloroform, carbon tetrachloride, benzene, toluene and the like can also be used.

The esterification of the compound of formula XI to the corresponding ester of formula X takes place with the corresponding alcohol, in particular methanol, at a temperature between room temperature and reflux temperature. The alcohol or an inert solvent such as chloroform, carbon tetrachloride, dioxane or benzene can serve as the solvent.

The compound of formula X is then aminoalkylated to a compound of formula XIV.

The aminoalkylation of a compound of the formula X is carried out in a manner known per se by reaction with an alkylamine in the presence of an inert organic solvent such as chloroform, methylene chloride, carbon tetrachloride, benzene or dioxane and at room temperature.

The compounds of general formula I have an anti-inflammatory, analgesic and anti-rheumatic effect. These valuable pharmacological properties can be determined using standard methods, for example in the known kaolin paw edema test (on the rat). In this test, an acute local inflammation is generated in the right hind paw of the rat by intradermal injection of 0.1 ml of a 10% kaolin suspension (bolus alba). The substance to be examined is administered orally and the following parameters are measured:

1. diameter of the paw in mm (as an expression of the severity of the inflammation);

2. Pressure (in g) on the paw (to determine the pain threshold).

V2 hour before and 3 1/2 hours after the kaolin injection, the substance to be examined is administered, and 4 hours after the kaolin injection, the parameters mentioned above are measured. The edema-inhibiting effect is given in percent, based on the difference in edema intensity between untreated animals and those treated with the substance to be examined, the antinociceptive activity by the percentage increase in the pain threshold.

In this test, the 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide [LDso shows about 900 mg / kg, po (Mouse)] at a dosage of 3 mg / kg p.o. a 27% inhibition of edema and a 4% increase in the pain threshold and at a dosage of 10 mg / kg p.o. a 43% inhibition of edema and a 23% increase in the pain threshold.

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The compounds of formula I have a qualitatively similar effect to phenylbutazone, which is known for its therapeutic use and properties.

The compounds of formula I can be used as medicines, e.g. in the form of pharmaceutical preparations which they mix with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules, in semi-solid form, e.g. as ointments or in liquid form, e.g. as solutions, suspensions or emulsions. If appropriate, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

The following examples, in which all temperatures are given in degrees Celsius, illustrate the invention.

example 1

52.1 g of phosphorus pentachloride in 600 ml of abs. Carbon tetrachloride dissolved and heated to boiling, whereupon a solution of 15.8 g of 3-hydroxy-2-meth-oxycarbonylthiophene in 200 ml of carbon tetrachloride is added dropwise over 3 hours. The mixture is boiled under reflux for 13 hours, then the carbon tetrachloride is distilled off and the reaction mixture is evaporated to dryness in vacuo. 450 ml of water are added dropwise while cooling, and the mixture is heated to boiling and then allowed to cool. The precipitated product is filtered off and boiled in a solution of 25 g of sodium bicarbonate with 10 g of activated carbon, whereupon the activated carbon is suctioned off and the cooled solution is acidified with hydrochloric acid, 3-chloro-thiophene-2-carbonic acid of mp. 185-186 ° C.

In a glass autoclave, 8.6 g of 3-chlorothiophene-2-carboxylic acid are dissolved in 23 ml of water containing 2.1 g of sodium hydroxide, whereupon a solution of 5.6 g of sodium bisulfite in 16 ml of water is added and the solution is diluted with 30% sodium hydroxide solution is made alkaline. Then 0.43 g of copper (I) chloride is added and the mixture is heated to 143 ° C. for 16 hours. After cooling, the red copper oxide is suctioned off. It is then concentrated with 7 ml. Acidified hydrochloric acid, whereby unreacted starting material precipitates, which is removed by shaking with methylene chloride. 12 g of potassium chloride are added to the acidic solution while heating, the mono-potassium salt of 3-sulfo-thiophene-2-carboxylic acid separating out in colorless crystals after cooling to 0 ° C.

50 g (0.203 mol) of mono-potassium salt of 3-sulfothiophene-2-carboxylic acid are suspended in 250 ml of phosphorus oxychloride, and 85 g (0.406 mol) of phosphorus pentachloride are added with stirring (violent HCl evolution sets in). The mixture is then heated for 90 minutes on a water bath with stirring, cooled to room temperature, suctioned off from inorganic salts and the phosphorus oxychloride is distilled off in vacuo as well as possible. To remove any inorganic salts still present, the oily residue is dissolved in 400 ml of dry chloroform, filtered and evaporated. The oily residue, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride, crystallizes on cooling and is used in the next step without further purification.

48 g (0.196 mol) of the 3-chlorosulfonyl-thio-phen-2-carboxylic acid methyl ester thus obtained are dissolved in 450 ml of abs. Chlo-dissolved, 9.6 g (0.3 mol) abs. Methanol was added and the mixture was heated under reflux for 3 hours (until the end of the HCl development). Then it is evaporated to dryness in vacuo, the residue consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester crystallizing out. The raw product can be used in the next stage.

43.5 g (0.18 mol) of the 3-chlorosulfonyl-thio-phen-2-carboxylic acid methyl ester thus obtained are dissolved in 450 ml of abs. Dissolved chloroform and introduced dried methylamine at 10 ° C until a moistened pH paper with the solution shows an alkaline reaction. Then the mixture is left to react for a further 2 hours at room temperature, the solution always being to remain alkaline. It is then shaken out with 500 ml of water and 500 ml of 5% sodium hydrogen carbonate solution (the aqueous phases are each shaken back once with chloroform), the combined organic phases are dried with sodium sulfate and evaporated. The crystalline residue is digested with ether for purification. 3-Methylsulfamoyl-thiophene-2-carboxylic acid, methyl ester of melting point 115-122 ° C.

23.5 g (0.1 mol) of 3-MethylsuIfamoyI-thiophene-2-carboxylic acid remethyl ester are dissolved in 50 ml of ethanol with heating, mixed with 50 ml of 3N potassium hydroxide solution and

Heated under reflux for 3 hours. After cooling, it is diluted with water and shaken out with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted several times with 50 ml ether. After drying with sodium sulfate and evaporation of the solvent, colorless crystals are obtained which are pure enough for the further reaction. The 3-methylsulfamoyl-thiophene-2-carboxylic acid obtained can be recrystallized from water. Mp 182-184 ° C.

11.06 g (0.05 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid and 11.5 g (0.055 mol) of phosphorus pentachloride are slurried in 150 ml of dry chloroform and stirred at 40 ° C. for 30 minutes. Half of the solvent is evaporated off in vacuo from the resulting clear solution without heating. This acid chloride solution is added dropwise to a diazomethane solution cooled to -20 ° C. and freshly prepared from 34 g nitrosomethyl urea in ether within 60 minutes. Then it is allowed to warm to room temperature. After 1 hour, 80 ml of conc. Hydrochloric acid was carefully added dropwise and heated under reflux for 1 hour. It is then shaken out with 200 ml of water and shaken back with ether. The combined organic phases are dried with sodium sulfate and evaporated after filtering. The crystal slurry obtained in this way is digested with a little ether. The 3-methylsulfamoyl-2-chloroacetyl-thiophene obtained is pure enough for the further reaction, but can be recrystallized from benzene. Mp 182-184 ° C.

2.53 g (0.01 mol) of 3-methylsulfamoyl-2-chloroacetyl-thio-phen in 20 ml of anhydrous dimethylformamide and under a nitrogen atmosphere to a suspension of 0.27 g of sodium hydride in 5 ml of absolute dimethylformamide at 0 ° C within Added dropwise for 20 minutes. The initially bright solution turns dark with time, the pH value drops to about 7.5. After a further 10 minutes, the mixture is neutralized with hydrochloric acid and the solvent is distilled off. The oily residue is partitioned between 2N hydrochloric acid and methylene chloride. After phase separation, the aqueous layer is shaken out several times with methylene chloride. The combined organic phases are dried with sodium sulfate and evaporated; the crystalline residue is digested with a little cold ethanol. 3,4-Dihydro-2-methyl-4-oxo-2H-thieno [2,3-e] 1,2-thiazine-1,1-dioxide is obtained. M.p. 130-131 ° C.

1.1 g (5 mmol) of 3,4-dihydro-2-methyl-4-oxo-2H-thieno [2,3-e] -l, 2-thiazine-l, 1-dioxide and 0.75 g fresh Distilled pyrrolidine are dissolved in 45 ml of absolute benzene and refluxed for 72 hours on a water separator. Then the solvent is distilled off and the crystalline residue in vacuo

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dried. The 2-methyl-4- (l-pyrrolidino) -2H-thieno [2,3] 1,2-thiazine-1,1-dioxide obtained is pure enough for the further reaction, but can be derived from benzene / ether = 1 : 9 be recrystallized. Mp 183-184 ° C.

A slurry of 1.2 g (4.4 mmol) of 2-methyl-4- (l-pyrrolidino) -2H-thieno [2,3-e] 1,2-thiazine-1,1-dioxide in 20 ml of absolute Tetrahydrofuran 5 ml of absolute benzene and 0.8 ml of triethylamine is slowly added dropwise at -10 ° C. to a solution of 0.5 g (5 mmol) of phosgene in 5.5 ml of absolute benzene and 3 ml of absolute tetrahydrofuran. The brown suspension is at room temp. warmed and allowed to stir for 3 hours. A solution of 0.68 g of 2-aminothiazole and 0.8 ml of triethylamine in 5 ml of absolute tetrahydrofuran is then added dropwise over the course of 30 minutes and the mixture is heated under reflux for 16 hours. It is then poured onto ice water and extracted with methylene chloride. The combined extracts are dried with sodium sulfate, filtered and concentrated to 30 ml. A yellow precipitate is formed, which is a by-product of mp. 319-321 ° C. The mother liquor is now completely evaporated and the oily residue is separated by means of column chromatography (60 g of silica gel 60, particle size 0.063-0.2 mm, eluent: benzene / ethanol = 9: 1). The purest fractions are combined and evaporated. The residue crystallizes immediately and provides 2-methyl-4- (l-pyrrolidino) -3- (2-thiazolylcarbamoyl) -2H-thieno- [2,3-e] 1,2-thiazine-1,1- dioxide and can be used directly in the next reaction. Mp 177-179 ° C.

0.6 g (1.5 mmol) of 2-methyl-4- (l-pyrrolidino) -3- (2-thiazolyl-carbamoyl) -2H-thieno [2,3-e] l, 2-thiazine-l, 1-dioxide is refluxed in 20 ml of 3N hydrochloric acid for 1 hour. After cooling, it is shaken out several times with methylene chloride. The combined organic phases are extracted with sodium carbonate solution. Acidification of the aqueous layer releases 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide and can be taken up in methylene chloride. After drying with sodium sulfate and distilling off the solvent, pure product is obtained, which can be recrystallized from ethanol. Mp 225 ° C (dec.).

Example 2

Following an analogous procedure as in Example 1, the following compounds can be obtained:

4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno-3,4-e] -l, 2-thia-zin-3-carboxamide-1,1-dioxide,

Mp from ethanol 243-245 ° C (dec.). 4-Hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno-5 [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from the decomposition point 239-243 ° C;

4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxanilide-1,1-dioxide with decomposition point 248-251 ° C (from xylene); 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -l, 2-thia-io zin-3-carboxamide-1,1-dioxide from decomposition point 209-213 ° ( from xylene);

4-Hydroxy-2-methyl-N-3-pyridyl-2H-thieno [2,3-e] -l, 2-thia-tin-3-carboxamide-l, 1-dioxide from the decomposition point 241-244 ° (from Pyridine); 15 4-Hydroxy-2-methyl-N-4-pyridyl-2H-thieno [2,3-e] -l, 2-thia-tin-3-carboxamide-l, 1-dioxide from the decomposition point 263-267 ° ( from dimethylformamide);

4,4-dihydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-car-boxanilide-1,1-dioxide from the decomposition point 287-290 ° (from 20 dioxane);

4-Hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxy ~ m-toluidide-1,1-dioxide from decomposition point 197-199 ° (from benzene; crystal transformation at 185-188 °); 3'-Chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazin-3-c-2s arboxanilide-1,1-dioxide from decomposition point 241-243 ° (from Xylene);

4-Hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carbocamide-1,1-dioxide with decomposition point 245-248 ° (from xylene) ; 30 N- (3,4-dimethyl-5-isoxazolyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-i, 1-dioxide from Decomposition point 206-208 ° (from benzene);

N- (2,6-Dimethyl-4-pyrimidinyl) -4-hydroxy-2-methyl-2H-thie-no [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from decomposition point of ignition 270-271 ° (from xylene);

4-Hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno- [2,3-e] - 1,2-thiazine-3-carboxamide-1,1-dioxide from the decomposition point 216-218 ° (from benzene);

4-Hydroxy-2-methyl-N- (5-l, 2,3,4-tetrazolyl) -2H-thieno- [2,3-40 e] -l, 2-thiazine-3-carboxmid-l, 1 -dioxide from decomposition point 224 ° (from ethanol); and

4-Hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from decomposition point 221-223 ° (from ethanol).

B

Claims (9)

620446 2nd PATENT CLAIMS 1. Process for the preparation of thienothiazine derivatives of the general formula I 1 / C-CO-NH-R2 where A with the two carbon atoms is the group or / forms and the dashed line indicates the double bond present in the first case, R 1 denotes lower alkyl, R.2 the residue of an aromatic heterocycle optionally substituted by one or two lower alkyl groups with 1 to 4 heteroatoms or one optionally substituted by halogen, hydroxy, lower Alkyl, trifluoromethyl or lower alkoxy is substituted phenyl and R3 and R4 are each hydrogen or lower alkyl, characterized in that an enamine of the general formula that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno- [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide. 7. The method according to claim 5, characterized in that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno- [3,4- s e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide. 8. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno [2,3-e] -1, 2-thiazine-3 -carboxamide-l, 1-dioxide. 9. The method according to claim 1, characterized in 10 that 4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine 3-Carboxanilide-1,1-dioxide produces. 10. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno- [2,3-3] -l, 2-thiazine-3-carboxamide-l, Manufactures 1-dioxide. 11. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-3-pyridyl-2H-thieno- [2,3-e] -l, 2-thiazine-3-carboxamide-l , Produces 1-dioxide. 12. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine 20 3-carboxy-m-toluidide-l, 1-dioxide. 13. The method according to claim 1, characterized in that 3'-chloro-4-hydroxy-2-methyl-2H-thieno- [2,3-e] -l, 2-thiazine-3-carboxanilide-1,1 - produces dioxide. 14. The method according to claim 1, characterized in that 25 that 4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -1, 2-thiazine-3-carboxamide-1,1-dioxide is produced. 15. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno [2,3-e] -1, 2-thiazine-3 -carboxamide-l, 1-dioxide. 30th