DE2537070A1 - THIAZINE DERIVATIVES - Google Patents

Description

The present invention relates to thiazine derivatives, specifically thienothiazine derivatives of the general formula

^Ri ι

OH

where A with the two carbon atoms

Group 4 ^ "S S or ⁴ \ / forms and

the dashed line indicates the double bond present in the first case, R, lower alkyl R2 denotes the radical of one which is optionally substituted by one or two lower alkyl groups aromatic heterocycle with 1 to 4 heteroatoms or an optionally by halogen, hydroxy,

Kit / 3.7.1975 609 812/0962,

■ · 2 -

is lower alkyl, tri fluorine thy 1 or lower alkoxy substituted phenyl radical and R ₃ and R _{4 are} each hydrogen or lower alkyl.

The term "lower alkyl" as used in this specification denotes straight or branched chain saturated ones Hydrocarbon groups with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, t-butyl and the like. The The term "lower alkoxy" refers to hydrocarbonoxy groups with up to 4 carbon atoms. The term "halogen" refers to on the 4 halogens chlorine, bromine, fluorine, iodine. The term "remainder of one optionally followed by one or two lower alkyl substituted aromatic heterocycle having 1-4 heteroatoms "optionally encompassed by one or two lower alkyl groups substituted radicals of 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, 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-isoxazyl, 3,4-dimethyl-5-isoxazyl, 2,6-dimethyl-4-pyrimidinyl, 6-methyl-2-pyridyl, 1,2,3,4-tetrazol-5-yl and the like.

In a preferred class of compounds of the formula I, R ₃ and R are hydrogen. R, is preferably the methyl group. R ₂ preferably represents 2-thiazolyl, 5-isoxazolyl or 2-pyridyl.

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

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

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a) a compound of the general formula

<X

• ν »

I COOR

OH

where R is lower alkyl and A,

R ,, R ₃ and R _{4 have} the meaning given, with an amine of the general formula

H ₂ N-R2

Ul

wherein R _{2 has} the meaning mentioned, converts, or

b) a reactive functional derivative of an acid of the formula

p ^iv

^C00H CH ₂ -CO-NH-R ₂

wherein A, R ,, R ₂ , R ₃ and R. have the meaning given,
cyclized, or that one

c) a compound of the general formula

R ^V

ΧΟΗ

wherein A, R ₂ , R ₃ and R- have the aforesaid

Have meaning
lower alkylated.

The reaction according to process aspect a) can take place in the presence or absence of an inert solvent. as Solvents are alcohols such as ethanol etc.,

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Hydrocarbons such as benzene, toluene, xylene, etc., halogenated Hydrocarbons such as chloroform, chlorobenzene, methylene chloride, carbon tetrachloride, etc., or dimethylformamide or dioxane. The reaction is preferably carried out by heating, the melting or reflux temperature of the reaction mixture being particularly preferred.

According to process aspect b) according to the present invention, a reactive functional derivative of a compound of the formula IV is cyclized. This cyclization takes place in the presence of a base and preferably in the presence of a solvent at a temperature between ⁰ ° C. and the reflux temperature of the reaction mixture, preferably between room temperature and 60 C. Particularly suitable bases are hydrides, amides or alcoholates of alkali metals. Suitable solvents are aprotic and protic, such as alcohols, for example methanol, ethanol, ethers, for example dioxane and acid amides, for example dimethylformamide. The cyclization is expediently carried out in such a way that the starting compound of the formula IV is dissolved in the solvent, the base is added and the reaction mixture is either left to stand at room temperature or heated to a temperature of up to 60 ° C. for 1 to 4 hours. Particularly suitable reactive functional derivatives of the compounds of the formula IV are their lower alkyl esters, for example their methyl esters.

According to process aspect c), a compound of the formula V is alkylated. This alkylation is conveniently carried out in such a way that the starting compound of the formula V is dissolved in an aprotic solvent such as acetonitrile, dioxane or dimethylformamide, converted into the alkali metal salt with an alkali metal amide or hydride and then treated with an alkylating agent, in particular an alkyl halide or sulfate, converted into the corresponding compound of formula I. The temperature and pressure are not critical for this process, so that, for the sake of simplicity, the reaction is preferably carried out at room temperature and atmospheric pressure. _A " _{A t} . _Λ _ _Λ

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The starting materials of the formula II required for process aspect a) can be prepared according to the reaction scheme below.

609812/096 2,

QC

COOH

VIl

a i

COOH

SO ₃ H

COOR

SO ₂ shark

COHaI

IX

SO ₂ -NH-CH ₂ -COOR COOR

XH

Xl

COOR

XlV

^ SO ₉ .
ΓΎ NH

^A 8 I XHI

OH

COOR SO ₂ -N-CH ₂ -COOR

XV

COOR

-Ri

COOR

In this scheme, Hal means halogen, and A, R and R, have the meaning mentioned.

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Of the compounds of the formula VI, 3-chloro-thiophene-2-carboxylic acid and 4-bromo-thiophene-3-carboxylic acid are known, the former being produced in a relatively complicated manner. A simpler method for the preparation of 3-chloro-thiophene-2-carboxylic acid is 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 as an intermediate and hydrolyzed this to the corresponding acid. In an analogous manner, substituted 3-chloro-thiophene-2-carboxylic acids (compounds of the formula VI, in which Hal is chlorine, A with the two carbon atoms forms the group 4 ^v v -S , in which

R, and / or R. is different from hydrogen yi ^ ^). Although a bromine compound, for example the known 4-bromo-thiophene-3-carboxylic acid, can in principle also be used as starting material for the preparation of a compound of the formula VII, 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-ketothiophene-4-carboxylic acid methyl ester by converting it into 4-chloro-thiophene-3-carboxylic acid chloride with phosphorus pentachloride with aromatization transferred and this hydrolyzed to the corresponding acid. In an analogous manner, substituted 4-chloro-thiophene-3-carboxylic acids (compounds of the formula VI, in which Hal is chlorine, A with the two carbon atoms forms the group ^R 4 \ •, in which R ₃ and / or R _{4 are} hydrogen / I am different, be made.

The transfer of a halothiophenecarboxylic acid accordingly of the formula VI into a potassium salt of a sulfo-thiophenecarboxylic acid of the formula VII is carried out according to known methods Methods by reacting the compound of the formula VI with sodium hydrogen sulfite in the presence of a copper (I) salt catalyst, in particular copper (I) chloride, and converting the

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253707Q

obtained reaction product with potassium chloride. When converting with sodium hydrogen sulfide should be optimal to achieve Yields a temperature of 143 ° C are maintained.

The conversion of the compound of formula VII into the Free acid of the formula VIII takes place in a manner known per se, e.g. with a strong ion exchanger.

The esterification of the acid of the formula VIII to the ester of the formula IX takes place autocatalytically (presence of the Sulfo group) in an alcohol / chloroform mixture. For education of the methyl ester, the acid is dissolved in methanol / chloroform and the reaction mixture reaches the boiling point of the ternary azeotrope (Methanol / chloroform / water of reaction) heated.

The conversion of a compound of the formula IX into the Acid halide of the formula X is carried out in a manner known per se with a halogenating agent, preferably a chlorinating agent, such as thionyl chloride or phosphorus pentachloride. Chlorination with thionyl chloride can be carried out by refluxing in the absence of a solvent take place. When using phosphorus pentachloride, in the presence of an inert solvent such as chloroform, Carbon tetrachloride, dioxane, and "at one temperature between 50 ° C and the reflux temperature of the reaction mixture are operated.

The compound of the formula X can, however, also proceed accordingly, starting from a potassium salt of a sulfo-thiophene-carboxylic acid of the formula VII can be prepared via a compound of the formula XI. For this purpose, the mentioned potassium salt is mixed 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 implemented. Instead of phosphorus oxychloride, however, an inert organic Solvents such as dioxane, chloroform, carbon tetrachloride, benzene, toluene and the like can be used.

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The esterification of the compound of formula Xl to the corresponding Ester of the formula X is carried out with the corresponding alcohol, in particular methanol, at a temperature between Room temperature and reflux temperature. The solvent can be alcohol or an inert solvent such as chloroform, Carbon tetrachloride, dioxane or benzene are used.

From the intermediate of the formula X one can get to the starting material of the formula II in two different ways. One route leads via the compounds of the formulas XII and XIII and the other, optionally via compound XIV the compound XV.

According to the first-mentioned route, a compound of the formula X is reacted in a manner known per se with a glycine alkyl ester hydrochloride, preferably glycine ethyl ester hydrochloride. The reaction is preferably carried out in the presence of an inert solvent, such as pyridine, chloroform, dioxane, methylene chloride, benzene or carbon tetrachloride, and at room temperature. The compound of the formula XII obtained in this way is cyclized at a temperature between 40 and 65 ° C. in ethanol with an alkali metal or alkaline earth metal ethylate, in particular sodium ethylate, to give the compound of the formula XIII in which R is ethyl. The alkylation to the starting material of the formula II takes place in a manner known per se, expediently in a polar aprotic solvent, such as dimethylformamide, dimethyl sulfoxide or hexametapole, with an alkylating agent, such as an alkyl halide or a dialkyl sulfate, at a temperature between ⁰ ° C. and room temperature.

In the second way, a compound of the formula X is either aminoalkylated first to give a compound of the formula XIV and then converted into the compound XV or the compound X is converted directly into the compound XV. In both cases the compound of the formula XV obtained is cyclized to the compound of the formula II.

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

To prepare the compound of the formula XV, a compound of the formula XIV obtained in this way is known per se Way in the presence of a polar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or hexametapol with a compound of the formula

X-CH ₂ -COO-R XVI

where R has the meaning mentioned and X is halogen,

implemented. The reaction is conveniently carried out at a temperature between ⁰ ° C. and room temperature.

On the other hand, a compound of the formula XV is obtained in a manner known per se in which a compound of the Formula X with a compound of the formula

HN-CH ₂ -COOR XVII

where R and R have the meaning given, or an acid addition salt thereof.

The reaction is conveniently carried out at room temperature. When using an acid addition salt of a compound of the formula XVII is expediently carried out in pyridine. Instead of an acid addition salt, however, 2 mol can be used on free amine, in which case one is preferred in dioxane, methylene chloride, benzene or carbon tetrachloride is working.

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The cyclization of a compound of the formula XV to give the starting material of the formula II is expediently carried out at a temperature from room temperature to 65 ° C. by means of an alkali or Eralkali methylates or ethylates, preferably sodium methylate or sodium ethylate in the presence of methanol or Ethanol.

The compounds of the formulas XVI and XVII are known or can be prepared in a manner known per se.

The lower alkyl esters of acids of the formula IV which can be used as starting compounds for process aspect b) can be obtained by reacting an amine of formula III with chloroacetyl chloride converts and the product of the formula obtained

O
U
R ₂ -NH-C-CH ₂ -Cl XVIII

wherein R _{2 has} the meaning mentioned,

with a compound of the formula XIV. Others responsive functional derivatives of acid of the formula IX can be prepared from the esters obtained in a manner known per se.

The starting materials of the formula V required for process c) can be prepared by reacting a compound of the formula XIII be obtained with an amine of the formula III.

The compounds of the formulas II, IV and VII to XV are new and also form part of the subject matter of the present invention the processes for making these compounds.

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

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1. Diameter of the paw in now (as an expression of the severity of the inflammation);

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

The substance to be examined is administered 1/2 hour before and 3 1/2 hours after the kaolin injection, and 4 hours after the kaolin injection, the parameters mentioned above are measured. The edema-inhibiting effect is given as a percentage, based on the difference in edema intensity between untreated and with the substance to be examined treated animals, 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] -1,2-thiazine-3-carboxamide-1,1-dioxide [LDc ₀ about 900 mg / kg, po (mouse)] at a dose of 3 mg / kg po a 27% edema inhibition and a 4% increase in the pain threshold and at a dose of 10 mg / kg po a 43% edema inhibition and a 23% some increase in the Schraerz threshold.

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

The compounds of the formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations, which they are mixed with a pharmaceutical, organic or inorganic inert carrier material, such as water, gelatin, gum arabic, milk sugar, starch, Magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline etc. contain. Pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules, in semi-solid form, e.g. as ointments, or

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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 to change the osmotic pressure or buffers. You can have others too Contain therapeutically valuable substances.

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

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example 1

52.1 g of phosphorus pentachloride are abs in 600 ml. Carbon tetrachloride dissolved and heated to boiling, whereupon a solution of 15.8 g of 3-hydroxy-2-methoxycarbonylthiophene for 3 hours in 200 ml of carbon tetrachloride is added dropwise. It is refluxed for 13 hours, then the carbon tetrachloride becomes distilled off and the reaction mixture evaporated to almost dryness in vacuo. Be under cooling 450 ml of water were added dropwise, whereupon the mixture is heated to the boil and then allowed to cool. The precipitated product is filtered off with suction and boiled in a solution of 25 g of sodium hydrogen carbonate with 10 g of activated carbon, whereupon the activated carbon is sucked off and the cooled solution is acidified with hydrochloric acid, 3-chloro-thiophene-2-carboxylic acid having a melting point of 185-186 °.

8.6 g of 3-chlorothiophene-2-carboxylic acid are placed in a glass autoclave dissolved in 23 ml of water containing 2.1 g of sodium hydroxide, followed by a solution of 5.6 g of sodium hydrogen sulfite in 16 ml of water and the solution is made just alkaline with 30% sodium hydroxide solution. Then with

ο 0.43 g copper (I) chloride added and 16 hours to 143 heated. After cooling, the red copper oxide is sucked off. This is followed by 7 ml of conc. Hydrochloric acid acidified, not being converted starting material precipitates, which is removed by shaking with methylene chloride. The acidic solution is taking 12 g of potassium chloride are added to the heating, and after cooling to 0 °, the potassium salt of 3-sulfo-thiophene-2-carboxylic acid deposited in colorless crystals.

8.2 g of the above potassium salt of 3-sulfo-thiophene-2-carboxylic acid are dissolved in 50 ml of water. This solution will Hesse is passed through an ion exchange column loaded with protons, while rinsing is carried out with water for as long as until the pH of the solution flowing out is 5. The solution is evaporated to dryness in vacuo, and the

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crystalline residue consisting of 3-sulfo-thiophene-2-carboxylic acid, is recrystallized from a little water.

7.6 g of 3-sulfo-thiophene-2-carboxylic acid are in 140 ml Section. Methanol and 65 ml of abs. Dissolved chloroform and refluxed, the water of reaction as a ternary azeotrope (Chloroform, methanol, water) is distilled off via a packed column (1 m). It is then evaporated in vacuo To remove traces of methanol, 100 ml of chloroform are added to the residue, whereupon the mixture is evaporated at normal pressure will. The remaining brown oil, consisting of 3-sulfo-thiophene-2-carboxylic acid methyl ester, recrystallizes immediately after cooling off. However, the crystals are hygroscopic and dissolve in the air.

7.4 g of crude methyl 3-sulfo-thiophene-2-carboxylate are dissolved in 50 ml of thionyl chloride and reflux for 16 hours cooked. It is then evaporated to dryness in vacuo, whereupon the remaining light yellow oil, consisting of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester, is brought to crystallization with petroleum ether.

20 g of 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester are dissolved in abs. Dissolved chloroform, whereupon 21 g of sarcosine ethyl ester are added dropwise over 10 minutes. The reaction mixture warms up to 50 °. After 20 minutes it is cooled down, shaken once each with water, 0.5N hydrochloric acid and bicarbonate solution, dried and evaporated. The remaining oil, consisting of 3- (N-Carboäthoylmethyl-N-methyl-sulfamoyl) -thiophene-2-carboxylic acid methyl ester, is brought to crystallization with ethanol; M.p. 84-85 °.

13.2 g of S-fN-carboethoylmethyl-N-methyl-sulfamoyD-thiophene-2-carboxylic acid methyl ester are in the cold in 42 ml of methanolic sodium methylate solution under a stream of nitrogen suspended. A clear solution is obtained after stirring for 15 minutes. It is refluxed for 20 minutes, then cooled,

60981 2/0962

neutralized and evaporated in vacuo. The residue is taken up in methylene chloride, once each with water and Bicarbonate solution shaken, dried and evaporated. The residue, consisting of S-carbomethoxy-'i-hydroxy - ^ - methyl- ^ H-thieno [2,3-e] -l, 2-thiazine-l, l-dioxide, is brought to crystallization with methanol, m.p. 193-195 °.

1.9 g of 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -l, 2-thiazine-l, l-dioxide are combined with 0.9 g of 2-aminothiazole in 250 ml of abs . Suspended xylene and refluxed for 7 hours, 150 ml of xylene being slowly distilled off. Then the remaining xylene is evaporated in vacuo. The crystalline residue, consisting of 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1, 2-thiazine-3-carboxamide-1,1-dioxide, is made from ethanol recrystallized, m.p. 217 ° (dec.).

Example 2

50 g (0.203 mol) of monopotassium 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 (vigorous evolution of HCl begins). Then it is heated for a further 90 minutes on the water bath with stirring, cooled to room temperature, the inorganic salts are suctioned off 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 out on cooling and is used in the next stage without further purification.

48 g (0.196 mol) of the 3-chlorosulfonylthiophene-2-carboxylic acid chloride thus obtained are in 500 ml abs. Dissolved chloroform, 9.6 g (0.3 mol) of abs. Methanol added and 3 hours refluxed (until HCl evolution ceases). then

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is evaporated to dryness in vacuo, the methyl ester consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylate The residue crystallized out. The crude product can be used in the next stage.

43.5 g (0.18 mol) of the methyl 3-chlorosulfonylthiophene-2-carboxylate thus obtained are in 450 ml abs. Dissolved chloroform and methylamine dried at 10 ° introduced until a moistened pH paper shows an alkaline reaction with the solution. Then another 2 hours allowed to react at room temperature, the solution should always remain alkaline. This is followed by 500 ml of water and 500 ml of 5% sodium hydrogen carbonate solution (the aqueous phases are each shaken once with Chloroform shaken back), the combined organic phases dried with sodium sulfate and evaporated. Of the crystalline residue is digested with ether for purification. 3-Methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained from melting point 115-122.

43.5 g (0.184 mol) of the methyl 3-methylsulfamoylthiophene-2-carboxylate thus obtained are in 400 ml abs. Dissolved dimethylformamide and at 0 to form a stirred suspension of 4.5 g (0.187 mol) of sodium hydride in 50 ml of abs. Dimethylformamide was added dropwise over 1 hour. Then be at 0-5 ° (with cooling) 40 g (0.187 mol) of ethyl iodoacetate dissolved in 50 ml of abs. Dimethylformamide was added dropwise over 2 hours and left to react for 1 hour (until a moistened pH paper shows 7-8). Then it is evaporated in a vacuum, the residue was taken up with 300 ml of 0.5N hydrochloric acid and 300 ml of methylene chloride, the organic phase was separated off, the aqueous phase is shaken twice with a little methylene chloride and the combined organic phases twice shaken with 100 ml of 5% sodium hydrogen carbonate solution each time (the aqueous phases are each shaken once with a little Methylene chloride shaken back). The combined organic phases are dried with sodium sulfate and evaporated.

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- JLö -

The crystalline residue is digested with a little cold ethanol for purification. Methyl 3 - [(N-ethoxycarbonylmethyl) N-methyl] sulfamoyl-thiophene-2-carboxylate is obtained with a melting point of 83-85 °.

13.2 g (0.041 mol) of the 3 - [(N-ethoxycarbonylmethyl) obtained in this way -N-methyl] -sulfamoyl-thiophene-2-carboxylic acid methyl ester are suspended in the cold in 42 ml of methanolic sodium methylate solution in a nitrogen atmosphere, everything dissolves within 15 minutes of stirring. It is then refluxed for 25 minutes, cooled, treated with conc. hydrochloric acid neutralized and evaporated in vacuo. The residue is taken up in methylene chloride, once each with water and Shaken out 5% sodium hydrogen carbonate solution, dried and evaporated. The crystalline residue is with a little methanol digested for purification. 4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno is obtained [2,3-e] -1,2-thiazine-1,1-dioxide from melting point 193-195, which as described in the last part of Example 1 by reacting with 2-aminothiazole into the 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide from melting point 217 ° (decomp.) can be converted.

Example 3

50 g (0.203 mol) mono-potassium salt of 3-sulfothiophene-2-carboxylic acid are suspended in 250 ml of phosphorus oxychloride and, with stirring, 85 g (0.406 mol) of phosphorus pentachloride added (vigorous evolution of HCl begins). Then it will be Heated for a further 90 minutes on the water bath with stirring, cooled to room temperature, suctioned off inorganic salts and the phosphorus oxychloride is distilled off in vacuo as well as possible. The oily residue is used to remove dissolved inorganic salts still present in 400 ml of dry chloroform, filtered and evaporated. The oily one Residue consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride, crystallizes out on cooling and is used in the next stage without further purification.

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48 g (0.196 mol) of the 3-chlorosulfonylthiophene-2-carboxylic acid chloride thus obtained are in 500 ml abs. Dissolved chloroform, 9.6 g (0.3 mol) of abs. Methanol added and Refluxed for 3 hours (until HCl evolution ceased). It is then evaporated to dryness in vacuo, the methyl ester consisting of pure -3-chlorosulfonyl-thiophene-2-carboxylate Crystallized residue. The crude product can be used in the next stage.

2.41 g (10 mmol) of the 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester thus obtained are together with 1.53 g of sarcosine ethyl ester in 10 ml of abs. Pyridine distributed and stirred at room temperature. After 2 hours, it is poured onto 50 ml of ice-cold 2N hydrochloric acid and five times with each Extracted 20 ml of methylene chloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated. The crystalline residue is digested with a little ice-cold ethanol.

13.2 g (0.041 mol) of the 3 - [(N-ethoxycarbonylmethyl) -N-methyl] -sulfamoyl-thiophene-2-carboxylic acid methyl ester obtained in this way are suspended in the cold in 42 ml of methanolic sodium methylate solution in a nitrogen atmosphere, everything dissolves within 15 minutes of stirring. It is then refluxed for 25 minutes, cooled, treated with conc. Hydrochloric acid neutralized and evaporated in vacuo. The residue is taken up in methylene chloride, once each with Shaken out water and 5% sodium hydrogen carbonate solution, dried and evaporated. The crystalline residue is with a little methanol digested for purification. 4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained of melting point 193-195 °, which as described in the last part of Example 1 by reacting with 2-aminothiazole into the 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide from melting point 217 ° (decomp.) can be converted.

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Example 4

12.03 g (0.05 mol) of S-chlorosulfonyl-thiophene ^ -carboxylic acid methyl ester and 7 g of glycine ethyl ester hydrochloride (0.05 mol) are suspended in 50 ml of absolute pyridine, everything dissolving within 30 minutes. It is stirred for a further 5 hours at room temperature and then the pyridine is distilled off. The residue is taken up in 50 ml of 2N hydrochloric acid and 50 ml of methylene chloride, the organic phase is separated off, the aqueous layer is shaken four times with a little methylene chloride, and the combined organic phases are washed with water and dried with sodium sulfate with the addition of activated charcoal. After filtration, it is evaporated , the oily residue containing methyl 3- (N-ethoxycarbonylmethyl) sulfamoyl-thiophene-2-carboxylate can be used in the next stage without further purification.

A solution of 9.22 g is added at 40 ° to a solution of 1.38 g of sodium (0.06 mol) in 20 ml of absolute ethanol (0.03 mol) of the 3- (N-ethoxycarbonylmethyl) sulfamoyl-thiophene-2-carboxylic acid ethyl ester obtained according to the above added in 10 ml of ethanol and heated to 60-65 °. It is stirred for a further 2 hours at this temperature, then on Pour 100 ml of ice-cold 2N hydrochloric acid and shake out several times with a little methylene chloride. The united organic Extracts are mixed twice with 20 ml of 5% sodium acetate solution each time and then four times with 25 ml of 10% sodium carbonate solution each time shaken out. 2.5 g of starting material can be recovered by drying and evaporating the organic phase will. The combined carbonate extracts are acidified with hydrochloric acid and extracted with methylene chloride. After drying with sodium sulfate, the solvent is distilled off and the crystalline residue with a little ether digested. 3-Aethoxycarbonylmethyl-4-hydroxy-2H-thieno [2,3-e] -l, 2-thiazine-l, l-dioxide is obtained with a melting point of 148-150 °.

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1.93 g (7 mmol) of S-ethoxycarbonylmethyl - ^ - hydroxy- ^ H-thieno [2,3-e] -l, 2-thiazine-l, l-dioxide are dissolved in 4 ml of absolute dimethylformamide and at 0 to form a stirred suspension 0.185 g of sodium hydride (7.7 mmol) in 2 ml of absolute dimethylformamide were added dropwise over 30 minutes; then stirring is continued for 1 hour at room temperature. First 0.53 ml (1.2 g; 8.45 mmol) and after 30 minutes a further 0.25 ml (0.565 gj 4 mmol) of methyl iodide are added and the reaction is continued for 1 hour calmly. After the solvent has been distilled off, the residue is treated with 30 ml of 0.5N hydrochloric acid and 30 ml of methylene chloride taken up, the organic phase separated, the aqueous layer shaken twice with a little methylene chloride, the combined organic extracts dried with sodium sulfate and evaporated. The crystalline residue is with a little cold ethanol digested. 3-Aethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained with a melting point of 161-163 ° (crystal transformation at 151-152 °).

In a manner analogous to that described in the last paragraph of Example 1, this product can be used with 2-aminothiazole 4-Hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide can be converted from the decomposition point 217 °.

Example 5

To a boiling solution of 100 g of phosphorus pentachloride in 250 ml abs. Carbon tetrachloride is 25 g of 3-ketothiophane-4-carboxylic acid methyl ester, solved in little abs. Carbon tetrachloride was added dropwise over 2 hours. It then takes 15 hours for the evolution of hydrogen chloride to cease boiled under reflux and then evaporated in vacuo, driving off most of the phosphorus chlorides will. The residue is stirred with ice water for 1 hour, whereupon the organic phase is separated off, the aqueous phase as well

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extracted once with methylene chloride and dried the combined organic phases with sodium sulfate and then be evaporated. The remaining brown oil, consisting of from 4-chloro-thiophene ~ 3-carboxylic acid chloride is heated with 2N aqueous sodium hydroxide solution at 50 ° until a homogeneous brown solution has arisen. This is extracted once with methylene chloride and treated with conc. Acidified hydrochloric acid, whereupon the precipitating crystals, consisting of crude 4-chlorothiophene-3-carboxylic acid, are suctioned off. To the Purification, the extracted crystals are dissolved in sodium bicarbonate and treated with conc. Hydrochloric acid precipitated again? After recrystallization from water 164.

8.6 g of 4-chlorothiophene-3-carboxylic acid are placed in a glass autoclave dissolved in 23 ml of water containing 2.1 g of sodium hydroxide, followed by a solution of 5.6 g of sodium hydrogen sulfite in 16 ml of water and the solution is made just alkaline with 30% sodium hydroxide solution. Then with 0.43 g of copper (I) chloride were added and the mixture was heated to 143 ° for 16 hours. After cooling, the red copper oxide is sucked off. The filtrate is concentrated with 7 ml. Hydrochloric acid acidified, whereby unreacted starting material precipitates through Shaking with ether is removed. The acidic solution is mixed with 12 g of potassium chloride while warming, whereby after cooling to 0 °, the potassium salt of 4-sulfothiophene-3-carboxylic acid separates out in colorless crystals. This will dissolved in 50 ml of water and the solution passed through an ion exchange column loaded with protons, rinsing with water until the pH of the solution flowing out is 5. The eluate is in a vacuum evaporated to dryness and so the 4-sulfothiophene-3-carboxylic acid obtained as a crystalline residue. M.p. (from water) 154 °.

7.6 g of 4-sulfothiophenyl-3-carboxylic acid are dissolved in 140 ml of abs. Methanol and 65 ml of abs. Chloroform dissolved at reflux boiled, the water of reaction as a ternary azeotrope

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(Chloroform, methanol, water) via a packed column (1 m) is distilled off. Then it is evaporated in vacuo. To remove traces of methanol, the residue is mixed with 100 ml of chloroform are added, whereupon the solution is evaporated at normal pressure. The remaining brown oil, consisting of from 4-sulfothiophene-3-carboxylic acid methyl ester, crystallizes out immediately after cooling (which dissolves in the air hygroscopic crystals).

7.4 g of crude methyl 4-sulfothiophene-3-carboxylate are dissolved in 50 ml of thionyl chloride and refluxed for 16 hours cooked. Then it is evaporated to dryness in vacuo and the remaining light yellow oil, consisting of 4-chlorosulfonylthiophene-3-carboxylic acid methyl ester brought to crystallization with petroleum ether? Mp (from petroleum ether) 71 °.

50 g of 4-chlorosulfonyl-thiophene-3-carboxylic acid methyl ester are in 500 ml abs. Dissolved chloroform. With cooling, dried methylamine is passed in until it is moistened Indicator paper shows sustained basic reaction. The precipitating methylammonium chloride is extracted by shaking with Water removed. The organic phase is dried and evaporated. The remaining light yellow oil, consisting of 4- (N-methyl-sulfamoyl) -thiophene-3-carboxylic acid methyl ester, crystallizes out immediately; 142 °.

46 g of 4- (N-methyl-sulfamoyl) -thiophene-3-carboxylic acid methyl ester are dissolved in 450 ml of dimethylformamide. The solution is cooled to 0 ° and treated with 7 g (20% excess) sodium hydride added, with vigorous evolution of hydrogen. The solution is slowly warmed to room temperature and successively with 32.6 g of dried potassium iodide and 21.3 g Methyl chloroacetate added. The temperature rises to 45 ° and a white precipitate separates out. That Dimethylformamide is then evaporated, whereupon the remaining yellow oil between 0.5N hydrochloric acid and methylene chloride is distributed. The organic phase is with

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Bicarbonate and water extracted, dried and evaporated. The remaining yellow oil, consisting of 4- (N-methoxycarbonylmethyl-N-methy1-sulfamoyl) -thiophene-3-carboxylic acid methyl ester, crystallizes out immediately? Melting point from ethanol: 124 °.

41.6 g of methyl 4- (N-methoxycarbonylmethyl-N-methy1-sulfamoyl) -thiophene-3-carboxylate are taken up in 140 ml of sodium methylate solution and dissolved under reflux while boiling. The solution quickly turns deep red over yellow ; after 20 minutes, the solution becomes cloudy due to the formation of precipitates. It is cooled, acidified and evaporated in vacuo. The residue is taken up in methylene chloride and water; the organic phase is shaken with bicarbonate solution and water and finally extracted with 0.5N cooled sodium hydroxide solution. By acidifying the aqueous sodium hydroxide solution, 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [3,4-e] -l, 2-thiazln-l, l-dioxide is obtained in the form of colorless crystals, mp. From methanol 190 °.

0.9 g of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno- [3,4-e] -1, 2-thiazln-1,1-dloxide are together with 0.4 g of 2-aminothiazole in 100 ml of abs. Suspended xylene and 4 hours heated to reflux, 70 ml of xylene being slowly distilled off. The crystalline precipitating from the cooling solution Precipitate consisting of 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,4-e] -1,2-thiazine-3-carboxamide-1,1-dioxide is sucked off? From ethanol 243-245 ° (decomp.).

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Example 6

94.6 g (0.384 mol) of the monopotassium salt of 4-sulfo-thiophene-3-carboxylic acid are suspended in 390 ml of phosphorus oxychloride and 160 _f 8 g (0.768 mol) of phosphorus pentachloride are added with stirring (vigorous evolution of HCl begins). The mixture is then heated for a further 3 hours on the water bath with stirring, cooled to room temperature, inorganic salts are filtered off and the phosphorus oxychloride is distilled off in vacuo as well as possible. To remove any inorganic salts still present, the residue is dissolved in 400 ml of dry chloroform, filtered and evaporated. The residue consisting of 4-chlorosulfonyl-thiophene-3-carboxylic acid chloride crystallizes out on cooling and is used in the next stage without further purification.

44.1 g (0.18 mol) of the 4-chlorosulfonylthiophene-3-carboxylic acid chloride thus obtained are in 450 ml abs. Dissolved chloroform, 9.6 g (0.3 mol) of abs. Methanol added and Refluxed for 9 hours (until HCl evolution ceased). It is then evaporated to dryness in vacuo, the The residue crystallized out. 4-chlorosulfonylthiophene-3-carboxylic acid methyl ester is obtained, which as described in the last 4 paragraphs of Example 5 into 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,4-e] -1,2-thiazine-3-carboxamid-1, 1-dioxide can be transferred.

Example 7

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reaction with 3-amino-5-methylisoxazole for 7 hours, the 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno [2,3-e] -l, 2-thiazine -3-carboxamide-l, l-dioxide from the decomposition point 239-243 °.

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Example 8

With a procedure analogous to Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -l, 2-thiazine-1,1-dioxide is obtained by reacting with aniline for 7 hours, the 4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxanilide 1,1-dioxide of decomposition point 248-251 (from xylene).

Example 9

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -l, 2-thiazine-l, l-dioxide is obtained by reacting with 2-pyridylamine for 7 hours, the 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide from the decomposition point 209-213 ° (from xylene).

Example 10

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 3-pyridylamine for 7 hours, the 4-hydroxy-2-methyl-N-3-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide from the decomposition point 241-244 ° (from pyridine).

Example 11

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 4-pyridylamine for 7 hours, the 4-hydroxy-2-methyl-N-4-pyridyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from the decomposition point 263-267 ° (from dimethylformamide).

609812/0962

Example 12

Using a procedure similar to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2 _r 3-e] -l ₇ 2-thiazine-1,1-dioxide is obtained by reacting with 4- Hydroxy-aniline 4,4'-dihydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxanilide-l _f 1-dioxide with a decomposition point of 287-290 ° (from dioxane ).

Example 13

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 3-methyl-aniline for 7 hours, the 4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxy-m-toluidide-1,1-dioxide from the decomposition point 197-199 ° (from benzene - crystal transformation at 185-188 °).

Example 14

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 3-chloro-aniline for 7 hours, the 3 '-chloro ^ -hydroxy ^ -methyl ^ H-thieno [2,3-e] -1,2-thiazine-3-carboxanilide-1,1-dioxide from the decomposition point 241-243 ° (from xylene).

Example 15

In similar procedure how [2,3-e] -1, 2-thiazine-1,1-dioxide obtained in Example 1 from 3-carbomethoxy-4-hydroxy-2-methyl-thieno with 7-hour reaction with the aminopyrazine 4-Hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide of decomposition point 245-248 ° (from xylene).

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Example 16

With an analogous procedure as in Example 1, one obtains from 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide by reacting with 5-alino-3,4-dimethyl-isoxazole for 14 hours the N- (3,4-dimethyl-5-isoxazolyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide from the decomposition point 206-208 ° (from benzene),

Example 17

Using a procedure similar to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 4- amino-2,6-dimethyl-pyrimidin the N- (2,6-dimethyl-4-pyrimidinyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -1, 2-thiazine-3 -carboxamide-1,1-dioxide with a decomposition point of 270-271 ° (from xylene).

Example 18

Using a procedure analogous to Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 2- Amino-6-methylpyridine 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1 _/ 1 -dioxide with a decomposition point of 216-218 ° (from benzene).

Example 19

With an analogous procedure as in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting for 14 hours with 5- Amino-l _f 2,3,4-tetrazole 4-hydroxy-2-methyl-N- (5Tl, 2 _/ 3,4-tetrazolyl) -2H-thieno [2,3-e] -l, 2-thiazine -3-carboxamide-l, l-dioxide with a decomposition point of 224 ° (from ethanol).

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Example 20

If the procedure is analogous to that in Example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting with 2-aminopyrimidine for 18 hours 4-Hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide from the decomposition point 221-223 ° (from ethanol).

Example 21

0.82 g (0.003 mol) of 3-ethoxycarbonyl-4-hydroxy-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide are together with 0.4 g (0.004 mol) of 2-aminothiazole in 100 ml of abs. Suspended xylene and heated to the boil. During 7 hours, 50 ml of solvent are azeotroped with the ethanol formed slowly distilled off, after 2 hours 4-hydroxy-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide starts to uninstall. After cooling, it is filtered and washed with petroleum ether. The product can be recrystallized from xylene or dioxane (m.p. 289-290 °; decomp.) but is pure for the further reaction enough.

0.329 g (1 mmol) of this product are dissolved in 2 ml of abs. Dissolved dimethylformamide and at 0 ° to a stirred suspension of 0.026 g (1.1 mmol) of sodium hydride in 1 ml of abs. Dimethylformamide added; then stirring is continued for 1 hour at room temperature. To the solution of the sodium salt 0.1 ml (0.226 g; 1.6 mmol) of methyl iodide are added and Left to react for 1 hour. After the solvent has been distilled off, the residue is dissolved in 200 ml of methylene chloride and 10 ml of 0.5N hydrochloric acid were added, the organic phase was separated off and mixed with a total of 50 ml of a 0.5% strength sodium hydrogen carbonate solution shaken out. The aqueous layer, which now contains the desired product, is repeated several times shaken back with methylene chloride and with hydrochloric acid

809812/0962

acidified. The acidic, aqueous phase is treated with methylene chloride extracted, the combined organic extracts dried with sodium sulfate and evaporated. The crystalline The residue is digested with a little cold ethanol, man receives 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1 ^ -thiazine-S-catboxamide-1,1-dioxide of melting point 217 ° (decomp.).

Example 22

40 g (0/4 mol) of 2-aminothiazole in 400 ml of abs. Dissolved dioxane and admixed with 100 g of freshly calcined potassium carbonate. Then 95 ml of chloroacetyl chloride are added in portions added, the temperature rising to 70 °. It is then stirred for 90 minutes; then it is on an ice cold Poured a solution of 150 g of potassium carbonate into 4000 ml of water, 2-chloroacetylaminothiazole precipitating out. It still will Stirred for 1 hour, then the product is filtered off with suction, washed well with water and recrystallized from ethanol. 176-177 °.

0.5 g (2.12 mmol) methylsulfamoyl-thiophene-2-carboxylic acid methyl ester are in 8 ml abs. Dissolved dimethylformamide and at 0 to a stirred suspension of 0.06 g of sodium hydride in 2 ml abs. Dimethylformamide added. The mixture is then stirred for a further 1 hour at room temperature. To the solution of the sodium salt, 0.38 g (2.15 mmol) of the 2-chloroacetylaminothiazole obtained above and 0.36 g (2.17 mmol) Potassium iodide was added and the mixture was stirred for a further 2 hours. After the solvent has been distilled off, the residue is dissolved in 20 ml of 0.5N hydrochloric acid and 50 ml of methylene chloride were added and the aqueous phase was extracted several times with methylene chloride. The combined organic phases are washed with water, dried with sodium sulfate, filtered and evaporated. Methyl 3- [N- (2-thiazolyl-carbamoyl-methyl) -N-methyl] -sulfamoyl-thiophene-2-carboxylate is obtained.

60981 2/0962

0.1 g (0.27 mmol) of the methyl 3- [N- (2-thiazolylcarbamoyl-methyl) -N-methyl] -sulfamoyl-thiophene-2-carboxylate thus obtained are in 5 ml of abs. Dissolved dimethylformamide and admixed with 0.01 g of sodium hydride. After stirring for 2 hours can the desired 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno 12,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide by thin-layer chromatography be detected.

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Example A.

The following suppositories are used in the usual way
Composition made:

4-hydroxy-2-methyl-N-2-thiazolyl-2H-

thieno [2,3-e] -1,2-thiazine-3-carboxamide-

1,1-dioxide 0.025 g

Hydrogenated Coconut Oil 1.230 g

Carnauba wax 0.045 g

Example B.

The following tablets are used in the usual way
Composition made:

Per tablet

4-hydroxy-2-methyl-N-2-thiazolyl-2H-

thieno [2,3-e] -1,2-thiazine-3-carboxamide-

1,1-dioxide 25.00 mg

Lactose 64.50 mg

Corn starch 10.00 mg

Magnesium stearate 0.50 mg

Example C

The following capsules are conventionally used
Composition made:

4-Hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

Lactose corn starch talc

Total weight 210 mg

Per capsule 50 mg 125 mg 30th mg 5 mg

60981 2/0962

Claims (1)

Claims 4k 1. Process for the preparation of ThienoSiazine derivatives of general formula ^ C-CO-NH-R ₂ OH wherein A with the two carbon atoms forms the group R ^ ^ , or R ₄ ν , and JOL the dashed line indicates the double bond present in the first case, R, is lower alkyl, R _{2 is} the radical 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 is a lower alkoxy-substituted phenyl radical and R ₃ and R are each hydrogen or lower alkyl,
characterized in that one a) a compound of the general formula II "COOR OH where R is lower alkyl and A, R ,, R ₃ and R. have the meanings given, with an amine of the general formula 609812/0962 H ₂ NR ₂ 111 wherein R_ has the meaning mentioned, converts, or b) a reactive functional derivative of an acid of the formula AlF
• I A -I NR ₁ ^ COOH ^> v ι CH ₂ -CO-NH-R ₂ wherein A, R ,, R2, R ₃ and R. have the meaning mentioned,
cyclized, or that one c) a compound of the general formula OH wherein A, R ₂ , R_ and R _{4 have} the aforesaid Have meaning
lower alkylated. 2. The method according to claim 1, characterized in that a compound of the formula II in which A ^{forms the group R} l ^ S with the two carbon atoms and the dashed line indicates the JP 'I ^ double bond and R, R ,, R ₃ and R- ^R 3 have the meaning given in claim 1, with an amine of the formula III, wherein R ~ is the radical of a heterocycle optionally substituted by one or two lower alkyl groups with 1 to 3 heteroatoms or one optionally by halogen, lower alkyl, Trifluoromethyl or lower alkoxy-substituted phenyl radical means, converts. 60981 2/0962 3. The method according to claim 1, characterized in that a compound of the formula II, wherein A with the two Carbon atoms form the group 4 \ / and R, R ,, 'given meaning Formula III, wherein R ₃ and R. have those in claim 1 with an amine of R2 is the radical of a _{heterocycle optionally substituted by R 3} by one or two lower alkyl groups and having 1 to heteroatoms or one optionally substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy Phenyl radical means, converts. 4. Process according to claims 1 to 3, characterized in that R _{2 is} 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, S-methyl-3-isoxazyl, 3,4-dimethyl-5-isoxazyl, 2,6- Denotes dimethyl-4-pyrimidinyl or 6-methyl-2-pyridyl. 5. The method according to claim 1, characterized in that R _{2 is} l, 2,3,4-tetrazol-5-yl. 6. The method according to any one of claims 1 to 5, characterized in that R ₃ and R- are hydrogen. 7. The method according to any one of claims 1 to 6, characterized in that R. is methyl. 8. The method according to any one of claims 1 to 7, characterized characterized in that R «2-thiazolyl, 5-isoxazolyl or Means 2-pyridyl. 9. The method according to claim 8, characterized in that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, l -dioxide manufactures. 609812/0962 10. The method according to claim 9, characterized in that 3-carbomethoxy-4-hydroxy-2-methylthieno [2,3-e] -l, 2-thiazine-l, l-dioxide with 2-aminothiazole. 11. The method according to claim 8, characterized in that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,4-e] -1,2-thiazine-3-carboxamide-1,1 -dioxide manufactures. 12. The method according to claim 11, characterized in that 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [3,4-e] 1,2-thiazine-1,1-dioxide is reacted with 2-aminothiazole. 13. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno [2,3-eJ-1,2-thiazine-3- carboxamide-1,1-dioxide manufactures. 14. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxanilide-1,1-dioxide manufactures. 15. The method according to claim 1, characterized in ^ that 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide manufactures. 16. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-3-pyridyl-2H-thieho [2,3-e] -1,2-thiazine-3-carboxamide-1,1 -dioxide manufactures. 17. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-4-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1 -dioxide manufactures. 18. The method according to claim 1, characterized in that 4,4'-dihydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxanilide-1,1-dioxide manufactures. 609812/0962 19. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxy-m-toluidide-1,1-dioxide manufactures. 20. The method according to claim 1, characterized in that 3'-chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1, 2-thiazine-3-carboxanilide ~ l, 1- dioxide manufactures. 21. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide manufactures. 22. The method according to claim 1, characterized in that N- (3,4-dimethyl-5-isoxazolyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine -3-carboxamide-1,1-dioxide manufactures. 23. The method according to claim 1, characterized in that N- {2,6-dimethyl-4-pyrimidinyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine -3-carboxamide-1,1-dioxide manufactures. 24. 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-1,1-dioxide produces. 25. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (5-l, 2,3,4-tetrazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide produces. 26. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1 -dioxide manufactures. 609812/0962 27. Process for the production of preparations with anti-inflammatory, analgesic and anti-rheumatic properties, characterized in that one is a thienothiazine derivative of the general formula I given in claim 1 as an active ingredient with non-toxic, inert, per se in such, suitable for therapeutic administration
Preparations usual solid and liquid carriers and / or
Mixed excipients. 28. Pharmaceutical preparations with anti-inflammatory, analgesic and anti-rheumatic properties, containing a thienothiazine derivative of the type specified in claim 1
general formula I. 609812/0962 29). ThienQthiazine derivatives of the general formula OH where A with the two carbon atoms Group ^R a * V s or ⁴ \ / forms and ⁴ XX ,H ^R 3 the dashed line indicates the double bond present in the first case, R, denotes lower alkyl, R ₂ denotes the radical of an aromatic rletarocycle with 1 to 4 heteroatoms, optionally substituted by one or two lower alkyl groups, or an optionally substituted by halogen> hydroxy, lower alkyl, Tr i fluorine thy I odör denotes lower alkoxy substituted phenyl radical and R ₃ and R. each denote hydrogen or lower alkyl. 609812/0962 30. Compounds geraäss claim 29, wherein A with the two carbon atoms form the group ^R 4 \ ^ and the dashed line indicates the JP ^ l double bond present, R, R ,, R ₂ , R ₃ and R. ^R 3 have the meaning given in claim 4έ and R is the radical of a heterocycle with 1 which is optionally substituted by one or two lower alkyl groups up to 3 heteroatoms or a phenyl radical which is optionally substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy. 31. Compounds according to claim 29, wherein A forms the group 4 \ / with the two carbon atoms, R, R ,, R ₂ , R ₃ and R _{4 are} those in claim 46 specified of a given R ₂ denotes the radical Λ if substituted by one or two lower R ₃ alkyl groups and has 1 to 3 heteroatoms or a phenyl radical which is optionally substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy. 32. Compounds according to any one of claims 29 to 31 _f in which R _{2 is} 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-isoxazyl, 3,4-dimethyl-5-isoxazyl, 2,6-dimethyl Is 4-pyrimidinyl or 6-methyl-2-pyridyl. 33. Compounds according to claim 29, wherein R _{2 is} 1,2,3,4-tetrazol-5-yl. 34. Compounds according to any one of claims 29 to 33, wherein R ₃ and R _{4 are} hydrogen. 35. Compounds according to any one of claims 29 to 34, wherein R 1 is methyl. 60981 2/0962 36. Compounds according to any one of claims 2 9 to 35 _f in which R _{2 is} 2-thiazolyl, 5-isoxazoyl or 2-pyridyl. 37. 4-Hydroxy-2-methyl-N-2-thiazoiyl-2H-thieno [2 _f 3 _{-e] -1 f} 2-thiazine -3-carboxamide-1,1-dioxide. 38. 4-Hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,4-ej-1,2-thiazine-3-carboxamide-1,1-dioxide. 39. 4-Hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide. 40. 4-Hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-2-carboxanilide-1 _f 1-dioxide. 41. 4-Hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide. 42. 4-Hydroxy-2-methyl-N-3-pyridyl-2H-thieno [2 _f 3-e] -1,2-thiazine -3-carboxamide-1,1-dioxide. 43. 4-Hydroxy-2-methyl-N-4-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide. 44. 4,4'-Dihydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxanilide-1,1-dioxide. 45. 4-Hydroxy-2-methyl-2H-thieno [2,3-e] -1, 2-thiazine-3-carboxy-m-toluidide-1,1-dioxide. 46. 3'-Chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-2-carboxanilide-1,1-dioxide. 47. 4-Hydroxy-2-methyl-N -pyrazinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamld-1,1-dioxide. 609812/0962 4 & N- (3,4-Diraethyl-5-isoxazolyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide. 49. N- (2,6-Dimethyl-4-pyrimidinyl) -4-hydroxy-2-methy 1-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-l, 1- dioxide. 50. 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno [2,3-e] -1,2-thiazin-2-carboxamide-l, 1-dioxide. 51 * 4-Hydroxy-2-methyl-N- (5-l, 2,3,4-tetrazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-l, 1 -dioxide. 52. 4-hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno [2, 3-e] -1,2-thiazine-3-carboxamide-l, 1-dioxide. 609812/0962