NO760614L - THIAZINE DERIVATIVES. - Google Patents

Description

Thiazine derivatives.

The present invention relates to thiazine derivatives and then to thieno-thiazine derivatives with a general formula

wherein R-^ means lower alkyl,

R-2 the residue of an aromatic heterocycle with 1 to 4 heteroatoms optionally substituted with one or two lower alkyl groups or a phenyl residue optionally substituted with halogen, hydroxy, lower alkyl, nitro, trifluoromethyl or lower alkoxy and R^ and R^ each mean hydrogen or lower alkyl.

The term "lower alkyl" used in the description denotes straight-chain or branched saturated hydrocarbon groups with 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, t-butyl etc. The term "lower alkoxy" refers to hydrocarbonoxy groups with up to 4 C atoms. The term "halogen" refers to the 4 halogens chlorine, bromine, fluorine, iodine. The term "residue of an optionally substituted with one or two lower alkyl groups aromatic heterocycle with 1-4 heteroatoms" includes optionally substituted with one or two lower alkyl groups residues of 5- or 6-membered aromatic heterocycles with 1-4 nitrogen and/or or oxygen and/or sulfur atoms, such as 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-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-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl-4- pyrimidinyl, 1,2,3,4-tetrazol-5-yl, etc.

In a preferred class of compounds of formula I means

and R₂ hydrogen. R 1 is preferably the methyl group. is preferably 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl; further preferred compounds for the substituent R 1 are 4-fluorophenyl, 3-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-tolyl, 2,5-dichlorophenyl, 4-nitro-2- tolyl, 4-iodophenyl and 4-n-butylphenyl.

Representative representatives of the thienodiazine derivatives with

the general formula I is 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-εJ1,2-thiazine-1,1-dioxide.

The thienothiazine derivatives of formula I can be prepared according to the invention by

a) reacts a compound with the general formula

wherein R means lower alkyl and

R-j^, R^ and R^ have the above meaning,

with an amine of the general formula

wherein R^ has the above meaning, b) cyclizes a reactive acid derivative of the general formula

wherein R, R.sub.2, R.sub.2, R.sub.4 and R.sub.4 have the above meaning,

or that one

c) reacts a compound with the general formula

wherein R-j^, R^ and R^ have the above meanings, in the presence of a strong base with an isocyanate of the general formula

wherein R^ has the above meaning.

The reaction according to method variant a) can take place in the presence or absence of an inert solvent. Suitable solvents are alcohols such as ethanol etc, hydrocarbons such as benzene, toluene, xylene etc, halogenated hydrocarbons such as chloroform, chlorobenzene, methylene chloride, carbon tetrachloride etc or dimethylformamide or dioxane. The reaction preferably takes place by heating whereby the melting or reflux temperature of the reaction mixture is particularly preferred.

According to method aspect b) according to the present invention, a reactive acid derivative with the formula iy is cyclized. This cyclization takes place in the presence of a base and preferably in the presence of a solvent at a temperature between o°C and the reflux temperature of the reaction mixture, preferably between room temperature and 6o°C. As bases, in particular hydrides, amides or alcoholates of alkali metals come into consideration-As solvents suitable are aprotic and protic, such as alcohols (e.g. methanol, ethanol), ether (e.g. dioxane), acid amides (e.g. dimethylformamide ), dimethyl sulfoxide, etc. The cyclization is expediently carried out so that the starting compound is dissolved in the solvent, mixed with the base and either left to stand for 1 to 4 hours at room temperature or heated to a temperature of up to 6o°C. The dimethyl esters are particularly suitable as reactive acid derivatives of formula IV.

According to method aspect c) a compound is reacted with

of the general formula V in the presence of a strong base with an isocyanate of the general formula VI. Tertiary amines, particularly trialkylamines, are suitable as strong bases.

such as triethylamine. The reaction preferably takes place under an inert gas, e.g. nitrogen, at a temperature between o°C and 5o°C, preferably at room temperature and in the presence of an aprotic solvent, such as toluene, dioxane, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide (HMTP).

They used isocyanates of formula VI as starting materials

are either known or can be synthesized analogously to the production of the known representatives.

The starting materials of the formulas II, IV and V can be prepared

according to the subsequent reaction nucleus in which hal means halogen and R, R^, R2 > R^ and R4 have the above-mentioned meanings.

Of the compounds with formula VII, 3-chloro-thiophene-2-carboxylic acid is known, whereby this was, however, produced in a relatively complicated manner. A simpler way of producing 3-chloro-thiophene-2-carboxylic acid consists in transferring the known 3-hydroxythiophene-2-carboxylic acid methyl ester into an inert solvent boiling above 8o°C, such as chloroform or dioxane with a chlorinating agent as phosphorus pentachloride, intermediate to the 3-chloro-thiophene-2-carbonic acid chloride and hydrolyzes this to the corresponding acid. In an analogous way, substi-

tuated 3-chloro-thiophene-2-carboxylic acids (compounds of formula VII in which Hal is chlorine and R₂ and/or R₂ is different from hydrogen). Although a bromine compound can in principle also be used as starting material for the preparation of a compound of formula VIII described below, it is worthwhile to

use the corresponding chlorine compound.

The transfer of a halothiophenecarboxylic acid corresponding to the formula

VII in a potassium salt of a sulfo-thiophene-carboxylic acid of formula

VIII takes place according to per se known methods during turnover

of the compound of formula VII with sodium hydrogen sulphite in the presence of a copper (I) salt catalyst, in particular copper (I) chloride,

and reaction of the obtained reaction product with potassium

chloride. When reacting with sodium hydrogen sulphite, a temperature of 143°C should be maintained to achieve optimum yields.

The conversion of the compound of formula VIII into the corresponding

the free acid with formula IX takes place in a manner known per se,

e.g. with a strong ion exchanger.

The esterification of the acid of formula IX to the ester of formula X

occurs autocatalytically (presence of the sulfo group) in an alcohol/chloroform mixture. For the formation of 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/reaction water).

The transfer of a compound of formula X into the acid halide

with formula XI takes place in a manner known per se with a halogenating agent, preferably with a chlorinating agent such as thionyl chloride

or phosphorus pentachloride. The chlorination with thionyl chloride can take place without a solvent by reflux heating. When applying

of phosphorus pentachloride can in the presence of an inert solvent such as chloroform, carbon tetrachloride, dioxane be worked on and at a . temperature between 5o°c and the reflux temperature of the reaction mixture.

However, the compound with formula XI can also be prepared from the above-mentioned potassium salt of a sulfothiophene carboxylic acid corresponding to formula VIII over a compound with formula XII. For this, the aforementioned potassium salt is converted, e.g. with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as solvent at a temperature between 3o°C and the boiling point of phosphorus oxychloride. Instead of phosphorus oxychloride, however, an inert organic solvent such as dioxane, chloroform, carbon tetrachloride, benzene, toluene etc. can also be used.

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

The compound of formula XI is then aminoalkylated to a compound of formula XIII.

The aminoalkylation of a compound of the formula XI takes place on

in a manner known per se by reaction with an alkylamine of the general formula

in which has the above-mentioned meaning,

in the presence of an inert organic solvent such as chloroform, methylene chloride, carbon tetrachloride, benzene or dioxane at room temperature.

The compound of formula XIII is then saponified to the corresponding free carbonic acid, for example by heating with alkali such as potassium hydroxide, preferably in an aqueous/alcoholic medium. The free carbonic acid obtained is then transferred into the corresponding acid chloride, this is converted with diazomethane into the corresponding diazomethyl ketone, and the latter gives, on treatment with solvnitrate and a lower alkanol, the corresponding compound with the formula XIV (whereby the product can appear in two conformationally isomeric forms, one of which corresponds to the formula XIV and the other which, as a result of a chelate-like hydrogen bridge, exhibits a cyclic structure and whereby, as by-products, similar compounds to the formula XVI and/or V can sometimes also occur). By reacting the compound XIV or its conformational isomers with a chloroformate ester of the general formula

wherein R has the above meaning,

in the presence of a strong base such as sodium methylate, a compound of formula XV is obtained, which by cyclization in analogy to the cyclization of a compound of formula IV described further above (e.g. by heating with sodium hydride in dioxane) can be transferred in the corresponding compound of formula II.

For the preparation of compounds of the formula IV, a compound of the formula XIV, respectively its conformational isomers (or also a compound of the formula XV) is reacted with an amine of the formula III, whereby it appears analogously to the further above described reaction of the compounds of the formula II and III and whereby one then, when a compound of formula XIV has been selected as a reaction partner for the amine of formula III, the product obtained must then also be reacted in the presence of a strong base with a chloroformate ester of formula XVIII.

Compounds of formula V can be reached by saponification

a compound of formula XIV (respectively their conformational isomers) (e.g. under alkaline conditions) and then cyclizes the resulting compound of formula XVI, for example by treatment with thionyl chloride.

The compounds of formulas II, IV, V and XIV to Xyi are new

and belongs to the object of the present invention, as does the method for the production of these compounds.

Compounds of the 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-Pfotenoe-dem test (on rats). In this test, acute local inflammation is induced in the rat's right hind paw by intradermal injection of 0.1 ml of a 10% kaolin suspension (bolus alba). The substance to be examined is administered per oral route,

and the following parameters are measured:

1. The cross-section of the paw in mm (as an expression of the severity of the inflammation); 2. Press (in g) on the paw (to determine the pain threshold).

1/2 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 above-mentioned parameters are measured. The edema-inhibiting effect is stated in percentage based on the difference in the edema intensity between untreated and with the animals treated with the substance to be investigated, the antinociceptive activity by the percentage increase in the pain threshold.

In this test, the compounds of formula I show an inhibition of edema and an increase in the pain threshold. In addition, they - as can also be shown in a corresponding standard test - inhibit platelet aggregation and thus also have antithrombotic properties.

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

The compounds of formula I can find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations containing them in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral application, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules, in semi-solid form, e.g. as ointments, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers. They may also still contain other therapeutically valuable substances.

The following examples, in which all temperatures are indicated

in degrees Celsius, explains the invention.

EXE MPEL 1

Dissolve 52.1 g of phosphorus pentachloride in 600 ml abs. carbon tetrachloride and heated to boiling, after which, over the course of 3 hours, a solution of 15.8 g of 3-hydroxy-2-methoxycarbonylthiophene in 2oo ml of carbon tetrachloride is added dropwise. It is boiled for 13 hours at reflux, then the carbon tetrachloride is distilled off and the reaction mixture is evaporated in vacuo almost to dryness. During dressing, 450 ml of water is added, after which it is heated to boiling and then left to cool. The precipitated product is filtered off and boiled in a solution of 25 g of sodium bicarbonate with 100 g of activated carbon, after which the activated carbon is filtered off and the cooled solution is acidified with hydrochloric acid, whereby 3-chloro-thiophene-2-carbonic acid with a melting point of 185 - 186° is obtained.

Dissolve 8.6 g of 3-chlorothiophene-2-carbonic acid in a glass autoclave

in 23 ml of water containing 2.1 g of sodium hydroxide, after which a solution of 5.6 g of sodium hydrogen sulphite in 16 ml of water is added and the solution is made just alkaline with 30% caustic soda. It is then mixed with 0.43 g of cupric (I) chloride and heated for 16 hours at 143°. After cooling, the red copper oxide is filtered off. The mixture is then acidified with 7 ml of concentrated hydrochloric acid, whereby unreacted starting material falls out, which is removed by shaking with methylene chloride. The acidic solution is mixed while heating with 12 g of potassium chloride, whereby after . cooling to o° the mono-potassium salt of 3-sulpho-thiophene-2-carboxylic acid separates in colorless crystals.

8.2 g of the above-mentioned mono-potassium salt of 3-sulfo-thiophene-2-carboxylic acid are dissolved in 50 ml of water. This solution is allowed to flow through an ion exchange column that is charged with protons, whereby it is washed with water until the pH value of the flowing solution is 5. The solution is evaporated in vacuo to dryness, and the crystalline residue, which consists of 3-sulfo -thiophene-2-carboxylic acid is recrystallized with a little water.

7.6 g of 3-sulfo-thiophene-2-carboxylic acid is dissolved in 140 ml abs. methanol and 65 ml abs. chloroform and boiled at reflux, whereby the reaction water is distilled off as a ternary azeotrope (chloro-

form, methanol, water) over a column of fillers (lm). It is then evaporated in a vacuum. To remove traces of methanol, the residue is mixed with 100 ml of chloroform, after which it is evaporated under normal pressure. The remaining brown oil, consisting of 3-sulfothiophene-2-carboxylic acid methyl ester, crystallizes immediately after cooling. However, the crystals are hygroscopic and melt in the air.

7.4 g of crude 3-sulfo-thiophene-2-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride and boiled for 16 hours at reflux. It is then evaporated in vacuo to dryness, after which the remaining pale yellow oil, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester, is crystallized with petroleum ether.

The conversion of the monopotassium salt of 3-sulfothiophene-2-carboxylic acid into the 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester can also be carried out as follows: 5o g (0.2o3 mol) monopotassium salt of 3-sulfothiophene-2-carboxylic acid is suspended in 250 ml of phosphorus oxychloride and, with stirring, add 85 g (0.406 mol) of phosphorus pentachloride (violent HCl evolution takes place). It is then heated for another 9o minutes in the water bath while stirring, cooled to room temperature, inorganic salts are filtered off and the phosphorus oxychloride is distilled off in vacuum as best as possible. The oily residue is dissolved in 400 ml of dry chloroform to remove any inorganic salts still present, filtered and evaporated. The oily residue, consisting of 3-chlorosulphonyl-thiophene-2-carbonic acid chloride, crystallizes on cooling and is used without further purification in the next step. 48 g (0.196 mol) of the thus obtained 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride is dissolved in 500 ml abs. chloroform, add 9.6 g (0.3 mol) abs. methanol and heated for 3 hours at reflux (until the end of HCl evolution). It is then evaporated in vacuo to dryness, whereby the residue consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester crystallizes out. The raw product can be fed into the next step.

43.5 g (0.18 mol) of the 3-chlorosulfonyl-thiophene thus obtained

The 2-carboxylic acid methyl ester is dissolved in 45o ml abs. chloroform and at lo o introduce dried methylamine until a pH paper moistened

with the solution showing alkaline reaction. It is then left to react for 2 hours at room temperature, whereby the solution must always remain alkaline. Hereafter shake with 500 ml of water and 500 ml

5% sodium bicarbonate solution (the aqueous phases are shaken back each time with chloroform), the combined organic phases are dried with sodium sulphate and evaporated. The crystalline residue is triturated with ether for purification. 3-Methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained with a melting point of 115 - 122°.

23.5 g (0.1 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester are dissolved under heating in 50 ml of ethanol, mixed with 50 ml of 3N potassium hydroxide solution and heated for 3 hours under reflux. After cooling, dilute with water and shake out with methylene chloride. The aqueous phase is acidified with hydrochloric acid

and extracted several times with 5o ml of ether each time. After drying with sodium sulphate and evaporation of the solvent, colorless crystals are obtained which are pure enough for further processing. The 3-methyl-sulfamoyl-thiophene-2-carboxylic acid obtained can be recrystallized from water. Melting point 182 - 184°.

11.06 g (o.o5 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid and 15.8 g (o.o75 mol) of phosphorus pentachloride are suspended in 15o ml of abs. chloroform and stirred for 3o minutes at 4o°. Then gently evaporate in a vacuum to half the volume. Dilute with 400 ml abs. ether and drop the concentrated solution over the course of 1 hour into a -2o° cooled ethereal diazomethane solution prepared from 5o g of nitrosomethylurea. After removal of the dressing bath, the reaction is left for another 1 1/2 hours and then cooled to -4o°, after which the precipitated diazomethyl-(3-methyl-sulfamoyl-thiophen-2-yl)-ketone is filtered off; melting point llo - 111° (from ethanol).

3 g (0.0122 mol) of diazomethyl-(3-methylsulfamoyl-thiophen-2-yl)-ketone are dissolved in 30 ml of abs. methanol and heated after adding 50 g of solvate nitrate for 45 minutes at reflux. It is then evaporated in a vacuum, after which the residue is boiled off with ether several times, the combined ether phases are stirred with activated charcoal and filtered. The filtrate mainly contains 3-methyl-sulphamoyl-2-thiophene-acetic acid methyl ester, in addition to a small amount of 3-methyl-sul£amoyl-2-thiopheneacetic acid and 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2, 3-εJ1,2-thiazine-1,1-dioxide. To remove the 3-methylsulfamoyl-2-thiophene-acetic acid, the ether solution is shaken several times with sodium bicarbonate solution, dried and evaporated. For ring opening of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide, the evaporation residue just mentioned is taken up with 12 ml of methanolic sodium methylate solution, after which the solution is allowed to stand for 2o minutes at room temperature, then just acidified with conc. hydrochloric acid and evaporated in vacuo to dryness. The evaporation residue is taken up with methylene chloride and water; the organic phase is dried and evaporated. The oily residue consists of approximately equal parts of two conformationally isomeric forms of 3-methylsulfa-moyl-2-thiophene-acetic acid niethyl ester and can be used in the next step without further purification.

The two forms can be separated by soil chromatography (silica gel, grain size o.o63 - o.2 mm; eluent: benzene/glacial vinegar = 4:1): Faster eluting form:

<X>H-NMR (CDC13): é = 7.2 - 7.4 (qAB, 2H, H-4thiophene and

H-<5>thiQphene), <f = 4.8-5.3 (m, 1H, N-H,

D20 exchangeable) , </ = 4.15 (s, 2H, -CH2-COOCH3), cf = 3.7 (s, 3H, 0-CH3), cf = 2.65

(d, 3H, NH-CH3, J = 6 Hz).

Slower eluting form:

<1>H-NMR (CDC1J : / =7.65 (s, 2H, H-4,,. _ and

3 thiophene ^

H-<5>^.£), ( f = 5, 8o - 6, 2o (m, 1H, -N-H,

thiophene

D„0 exchangeable), /= 4, 4o (s, 2H,

-CH2-COOCH3) , <f = 3.4o (s, 3H, 0-CH3) ,

</ = 2.6 ppm (d, 3H, NH-CH3, J = 6 Hz).

Both forms are split by distillation in high vacuum.

1.15 g (0.oo461 mol) of crude 3-methylsulfamoyl-2-thiophene-acetic acid methyl ester are dissolved in 4.7 ml of methanolic sodium methylate solution, after which the solution is evaporated in vacuo to dryness, the residue taken up with 10 ml of abs. dimethylformamide, cool to o° and add dropwise o.5o g (o.oo525 mol) chloroformic acid methyl ester. After stirring for 1/2 hour at room temperature, evaporate in a vacuum, after which the remainder

is taken up with methylene chloride and water and the organic phase is separated, dried and evaporated. The oily residue consisting of pure 3-(N-methoxycarbonyl-N-methyl-sulfamoyl)-2-thiophene-acetic acid methyl ester can be used in the next step without further purification.

■ 1H-NMR spectrum (CDCl3): <f = 7.2 - 7.4 (qAB, 2H,

H-4^. _ and H-5^ . • )

thiophene thiophene

/= 4.2 (s, 2H, CH2-COOCH3),

6' = 3.65 (s, 3H, -N-CO-OCH3),

é= 3.62 (s, 3H, CH2-COOCH3),

c/ = 3.3 ppm (s, 3H, -N-CH3).

1.42 g (0.oo461 mol) crude 3-(N-methoxycarbonyl-N-methylsulfamoyl)-2-thiophene-acetic acid methyl ester is dissolved in 10 ml abs. dioxane and mixed with o.21 g (o.oo485 mol) 55% sodium hydride suspension (in mineral oil), after which 50 mg of methanol is added and stirred for 1 hour at 5o - 6o°. It is then cooled, acidified with glacial acetic acid and evaporated in a vacuum. The residue is taken up with methylene chloride and a saturated sodium bicarbonate solution; the organic phase is shaken several more times with sodium bicarbonate solution, after which the aqueous phases are combined and acidified with conc. hydrochloric acid. The precipitate is shaken with methylene chloride, after which the organic phase is dried and evaporated. The immediately crystallizing residue consists of pure 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide; melting point 124 - 126° (from ether).

o.3 g (1.1 mmol) 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide and o.13 g (1.38 mmol) of 2-aminopyridine is dissolved in 3o ml of abs. xylene and heated for 1 hour at reflux. After cooling, the crystals are filtered off and recrystallized from glacial acetic acid; 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno [2,3-e]1,2-thiazine-1,1-dioxide is obtained with a melting point of 255 - 256° (cleavage).

EXAMPLE 2

o.15 g (o.55 mmol) 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno [2,3-e]1,2-thiazine-1,1-dioxide and o.o71 g (o.71 mmol) of 2-aminothiazole is dissolved in 3o ml of abs. xylene and heated for 1/2 hour

in case of backflow. After cooling, the crystals are filtered off and recrystallized from glacial acetic acid; 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide is obtained with melting point 236 - 238° (cleavage).

EXE MPEL A

In the usual way, suppositories are produced with the following composition:

EXAMPLE B

In the usual way, tablets are prepared with the following composition:

EXAMPLE C

In the usual way, capsules are produced with the following composition:

Claims (29)

1. Process for the preparation of thienothiazine derivatives of the general formula wherein means lower alkyl, R^ means the residue of an aromatic heterocycle with 1 to 4 heteroatoms optionally substituted with one or two lower alkyl groups and a phenyl residue optionally substituted with halogen, hydroxy, lower alkyl, nitro, trifluoromethyl or lower alkoxy and R^ and R^ each mean hydrogen or lower alkyl, characterized in that mana) reacts with a compound of the general formula wherein R means lower alkyl and A, R^ , R^ and R^ have the above meaning, with an amine of general formula wherein R 2 has the above meaning, orb) cyclizes a reactive acid derivative of the general formula wherein R, R^ , R 2 , R^ and R^ have the above meaning, or that manc) reacts with a compound of the general formula wherein R^ , R^ and R^ have the above meaning, in the presence of a strong base with an isocyanate of the general formula wherein R 2 has the above meaning. 2. Process according to claim 1, characterized by atR2 t'etYr 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-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-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl- 4 - pyrimidinyl or 1,2,3,4-tetrazol-5-yl. 3. Process according to claim 1 or 2, characterized in that R^ and R^ mean hydrogen. 4. Process according to one of claims 1-3, characterized in that R means methyl. 5. Process according to one of claims 1-4, characterized by R2 being 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl. 6. Method according to one of claims 1, 3 and 4, characterized in that R2 ketY is 4-fluorophenyl, 3-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-tolyl, 2,5-dichlorophenyl, 4-nitro-2-tolyl, 4-iodophenyl or 4-n-butyl-phenyl. 7. Method according to claim 5, characterized in that 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno [2,3-e]1,2- thiazine-1,1-dioxide. 8. Process according to claim 5, characterized in that 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno [2,3-e]l,2- thiazine-1,1-dioxide. 9. Procedure for the production of preparations with anti-inflammatory, analgesic, anti-rheumatic and anti-throm. botical properties, characterized by mixing a thienothiazine derivative with the general formula I specified in claim 1 as an active ingredient with suitable for therapeutic use, non-toxic, inert, as far as solid and liquid carriers common in such preparations and/or excipients pienter. 10 . Pharmaceutical preparation with anti-inflammatory, analgesic, antirheumatic and antithrombotic properties, containing a thienothiazine derivative with the general formula I specified in claim 1 and a carrier. 11. Compounds with the general formula. wherein R, R^, R^ and R^ have the meaning stated in claim 1. 12. 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide. 13. Compounds with the general formula wherein R, R^, R^, R^ and R^ have the meaning stated in claim 1. 14. Compounds with the general formula in which R^ , R^ and R 4 have the meaning stated in claim 1. 15. 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2,3^e]1,2-thiazine-1,1-dioxide. 16. Compounds with the general formula. wherein R, R^, R^ and R^ have the meaning stated in claim 1. \ 17. 3-Methylsulfamoyl-2-thiopheneacetic acid methyl ester. 18. Compounds with the general formula wherein R, R^, R^ and R^ have the meaning stated in claim 1. 19. 3-(N-Methoxycarbonyl-N-methyl-sulfamoyl)-2-thiophene-acetic acid methyl ester. 20 . Compounds with the general formula in which R , R^ and R^ have the meaning stated in claim 1. 21. 3-Methylsulfamoyl-2-thiopheneacetic acid. 22. Compounds with the general formula. wherein R^ means lower alkyl, . R^ means the residue of an aromatic heterocycle with 1 to 4 heteroatoms optionally substituted with one or two lower alkyl groups or a phenyl residue optionally substituted with halogen, hydroxy, lower alkyl, nitro, trifluoromethyl or lower alkoxy and R 1 and R 2 each mean hydrogen or lower alkyl. 23. Compounds according to claim 22, characterized in that Rp means 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 1,2,4-triazin-2-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 or 1,2,3,4-tetrazol-5-yl. 24. Compounds according to one of claims 22 and 23, characterized in that R^ and R^ mean hydrogen. 25. Compounds according to one of claims 22 - 24, characterized in that means methyl. 26. Compounds according to one of claims 22 - 25, characterized in that R 2 means 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl. 27. Compounds according to one of claims 22, 24 and 25, characterized in that R2 means 4-fluorophenyl, 3-trifluoromethyl-phenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-tolyl, 2, 5-dichlorophenyl, 4-nitro-2-tolyl, 4-iodophenyl or 4-n-butyl-phenyl. 28. 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-. 2H-thieno [2, 3-e] 1, 2-thiazine-1, 1-dioxide. 29. 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide.