CH621791A5 - Process for the preparation of thienothiazine derivatives - Google Patents

Abstract

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

Description

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

.so2

nh

35

OC <

^ c-co-nh-fu

40

i

0h in which A, R2, R3 and R4 have the meaning given, «

lower alkylated.

2. The method according to claim 1, characterized in that

that R2 is 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- so 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. ss

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 means 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

that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide is produced.

7. The method according to claim 5, characterized in that

that 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,4-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide is produced.

c-co-nh-r2

where A with the two carbon atoms is the group or

'H

y forms and

60

65

\

the dashed line indicates the double bond present, R 1 denotes lower alkyl, R 2 denotes the remainder of an aromatic heterocycle optionally substituted by one or two lower alkyl groups with 1 to 4 heteroatoms or one optionally substituted by halogen, hydroxyl, lower alkyl, Trifluoromethyl or lower alkoxy is substituted phenyl and R3 and R4 are each hydrogen or lower alkyl.

The term "lower alkyl" used in this specification denotes straight-chain or branched saturated hydrocarbon groups with 1-4 carbon atoms, such as e.g. B. methyl, ethyl, propyl, isopropyl, t-butyl and the like. The term "lower alkoxy" refers to hydrocarbon-oxy groups with up to 4 carbon atoms. The term «halogen» refers to the 4 halogens chlorine, bromine, fluorine, iodine. The term “residue of an aromatic heterocycle with 1-4 heteroatoms optionally substituted by one or two lower alkyl groups” optionally includes by

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one or two lower alkyl groups substituted residues 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, 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-pyrimid-ynyl, 6-methyl-2-pyridyl, l, 2,3,4-tetrazol-5-yl and the like.

10th

In a preferred class of compounds of the formula I, R.3 and R.4 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.

According to the invention, the thienothiazine derivatives of the formula I can be prepared by adding a compound of the general formula

OC

so2

i

-NViH

^ c-c0-nh-r2

OH

wherein A, R2, R3 and R4 have the meaning given, lower alkylated.

This alkylation is conveniently carried out in such a way that the starting compound of the formula V in

Alkyl halide or sulfate, converted into the corresponding compound of formula I. Temperature and pressure are not critical to this process, so for convenience, the reaction is preferably at room temperature and atmospheric

an aprotic solvent, such as acetonitrile, dioxane or pressure is carried out.

Dimethylformamide, dissolves with an alkali metal amide or The starting materials of formula V can according to

-hydride converted into the alkali metal salt and then prepared by the following reaction scheme. Treat with an alkylating agent, especially a vili so3h cooh iL

.so3H

'coor

IX

A S

vil

SO ^ K

cooh s02Hal <3

coor

.S02Hal cohal

XI

oc

S02-nh-ch2-coor coor xll

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4th

HS

OH

R2-NH2 III

Y

V

In this scheme, sharks are halogen and R is lower alkyl, and A, Ri and R2 are as defined above.

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. In an analogous manner, substituted 3-chloro-thiophene-2-carboxylic acids (compound of the formula VI in which Hai is chlorine, A with the two carbons)

forms in which R3 and / or R4 is different from hydrogen) are prepared. Although in principle a bromine compound z. B. 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 .

A halothiophene carboxylic acid corresponding to the formula VI is converted into a potassium salt of a sulfothiophene carboxylic acid of the formula VII by methods known per se by reacting the compound of the formula VI with sodium bisulfite in the presence of a copper (I) salt catalyst, in particular copper ( I) chloride, and thus reacting 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 yield.

The conversion of the compound of formula VU into the 55 free acid of formula VHI is carried out in a manner known per se, e.g. B. 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 phos-

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phorpentachloride can be carried out 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 start from a potassium salt of a sulfothiophene-carboxylic acid corresponding to the formula VII via a compound of the formula

XI can be produced. For this purpose, the potassium salt mentioned. B. with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as 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 obtained 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 thus obtained

XII is cyclized at a temperature between 40 and 65 ° C in ethanol with an alkali or alkaline earth ethylate, in particular sodium ethylate, to the compound of the formula XIII, in which R is ethyl.

The compounds of formula V can be obtained by reacting a compound of formula XIII with an amine of formula III.

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).

The substance to be examined is administered V2 hours before and 3 V2 hours after the kaolin injection, and the above-mentioned parameters are measured 4 hours after the kaolin injection. 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.

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. B. in the form of pharmaceutical preparations are used, which they mix with a suitable for enteral or parenteral application, pharmaceutical, organic or inorganic inert carrier material, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules, in semi-solid form, e.g. B. as ointments, or in liquid form, e.g. B. as solutions, suspensions or emulsions. If necessary, 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

0.82 g (0.003 mol) of 3-ethoxycarbonyl-4-hydroxy-2H-thieno [2,3-e] -1, 2-thiazine-1,1-dioxide are added together with 0.4 g (0.004 mol) 2 -Aminothiazole in 100 ml abs. Suspended xylene and heated to boiling. 50 ml of solvent are slowly distilled off azeotropically with the ethanol formed in the course of 7 hours, after 4 hours 4-hydroxy-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide- 1,1-dioxide begins to crystallize. After cooling, it is filtered and washed with petroleum ether. The product can be recrystallized from xylene or dioxane (mp 289-290 °; dec.) But is pure enough for the further reaction.

0.329 g (1 mmol) of this product in 2 ml abs. Dimethylformamide dissolved and at 0 ° to a stirred suspension of 0.026 g (1.1 mmol) sodium hydride in 1 ml abs. Added dimethylformamide; then stirring is continued for 1 hour at room temperature. 0.1 ml (0.226 g; 1.6 mmol) of methyl iodide are added to the solution of the sodium salt and the mixture is left to react for 1 hour. After the solvent has been distilled off, the residue is taken up in 200 ml of methylene chloride and 10 ml of 0.5N hydrochloric acid, the organic phase is separated off and extracted with a total of 50 ml of a 0.5% sodium hydrogen carbonate solution. The aqueous layer, which now contains the desired product, is shaken back several times with methylene chloride and acidified with hydrochloric acid. The acidic, aqueous phase is extracted with methylene chloride, the combined organic extracts are dried with sodium sulfate and evaporated. The crystalline residue is digested with a little cold ethanol, and 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxa-mid-1 is obtained , 1-dioxide with a melting point of 217 ° (dec.).

The 3-ethoxycarbonyl-4-hydroxy-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide can be prepared as follows:

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, whereby 3-chloro-thiophene-2-carbonic acid from the mp. 185-186 °.

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 s

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0.43 g of copper (I) chloride are added and the mixture is heated to 143 ° 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 with heating, the mono-potassium salt of 3-sulfo-thiophene-2-carboxylic acid separating out in colorless crystals after cooling to 0 °.

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 chloride thus obtained are dissolved in 500 ml of abs. Chloroform dissolved, 9.6 g (0.3 mol) abs. Methanol was added and the mixture was heated under reflux for 3 hours (until the evolution of HCl had ended). 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.

12.03 g (0.05 mol) of 3-chlorosulfonyl-thiophene-2-carboxylic acid remethyl 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. The mixture 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, the combined organic phases are washed with water and dried with sodium sulfate with the addition of activated carbon. After filtering, evaporate; the oily residue containing 3- (N-ethoxycarbonylmethyl) sulfamoyl-thiophene-2-carboxylic acid methyl ester can be used in the next step without further purification.

At 40 °, a solution of 9.22 g (0.03 mol) of the 3- (N-ethoxycarbonyl-methyl) obtained according to the above is added to a solution of 1.38 g of sodium (0.06 mol) in 20 ml of absolute ethanol. -sulfamoyl-thiophene-2-carboxylic acid methyl ester in 10 ml of ethanol and heated to 60-65 °. It is stirred for a further 2 hours at this temperature, then poured onto 100 ml of ice-cold 2N hydrochloric acid and shaken out several times with a little methylene chloride. The combined organic extracts are extracted twice with 20 ml of 5% sodium acetate solution and then four times with 25 ml of 10% sodium carbonate solution. By drying and evaporating the organic phase, 2.5 g of starting material can be recovered. 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 is digested with a little ether. 3-Ethoxycarbo-nyl-4-hydroxy-2H-thieno [2,3-e] -1, 2-thiazine-1,1-dioxide with a melting point of 148-150 ° is obtained.

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-thiazine-3-carboxamide-l, 1-dioxide,

Mp from ethanol 243-245 ° (dec.);

4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-

thieno- [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from

Decomposition point 239-243 °;

4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine

3-carboxanilide-l, 1-dioxide from decomposition point 248-251 ° (from xylene);

4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from decomposition point 209-213 ° (from xylene) ;

4-hydroxy-2-methyl-N-3-pyridyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from decomposition point 241-244 ° (from pyridine) ;

4-hydroxy-2-methyl-N-4-pyridyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide with decomposition point 263-267 ° (from dimethylformamide) ;

4,4 / -dihydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxanilide-1,1-dioxide with decomposition point 287-290 ° (from 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-thiazine

3-carboxanilide-l, 1-dioxide from decomposition point 241-243 ° (from xylene);

4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from decomposition point 245-248 ° (from xylene);

N- (3,4-Dimethyl-5-isoxazolyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from the decomposition point 206-208 ° (from benzene); N- (2,6-Dimethyl-4-pyrimidinyl) -4-hydroxy-2-methyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from the decomposition point 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 decomposition point 216 -218 ° (from B enzol); 4-Hydroxy-2-methyl-N- (5-l, 2,3,4-tetrazolyl-2H-thieno [2,3-e] -l, 2-thiazine-3-carboxamide-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 the decomposition point 221-223 ° (from ethanol).

6

s

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Claims (10)

621791 PATENT CLAIMS 1. Process for the preparation of thienothiazine derivatives of the general formula I 1 c-co-nh-r. where A with the two carbon atoms is group 4 or 10th 15 forms and 20th R. the dashed line indicates the double bond present, R 1 denotes lower alkyl, R 2 denotes the remainder of an aromatic heterocycle optionally substituted by one or two lower alkyl groups with 1 to 4 heteroatoms or one optionally substituted by halogen, hydroxyl, lower alkyl, Trifluoromethyl or lower alkoxy is substituted phenyl and R3 and R4 are each hydrogen or lower alkyl, characterized in that a compound of the general formula 8. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno- [2,3-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide is produced . 9. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-2H-thieno [2,3-e] -1, 2-thiazine-3-carboxanilide-1,1-dioxide is produced. 10. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno- [2,3-e] -l, 2-thiazine-3-carboxamide-l, produces l-dioxide. 11. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-3-pyridyl-2H-thieno- [2,3-e] -1,2-thiazine-3-carboxamide-1, Manufactures 1-dioxide. 12. 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-l, 1- produces 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-l, 1st - produces dioxide. 14. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-l, 1- produces dioxide. 15. The method according to claim 1, characterized in that 4-hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2H-thieno- [2,3, -e] -l, 2-thiazine -3-carboxamide-l, 1-dioxide. 25th 30th