FI59253B - PROCEDURE FOR THERAPEUTIC PREPARATION OF THERAPEUTIC 4-HYDROXY-2H-THIENO (2,3-E) OCH (3,4-E) -1,2-THIAZINE-3-CARBOXAMIDE-1,1-DIOXIDE DERIVATIVES - Google Patents

Description

RSfir ^ l M (11) ULUTUSJULJAI * U c O O C 7 JBa LJ 1 'UTLÄGG N I NGSSKRIFT 3 ~ ^ ^ • »Sv C ¢, 45 ^ Patent granted 10 07 1901

Patent title (S1) Kv.lfcVci.3 C 07 D 513/04 FINLAND —FINLAND (21) Pitssttlhilnmu · —P »Mi * tin« eki »ng 752393 (22) HtkamitpHvt - Aiwekningsdag 26.08 · 75 (23) AlkuplWt— GlMgkuudag 26.08-75 (41) Tulkit fulkbutal - Wtvlt offuncllg 27.02.76

National Board of Patents and Registration .... ........... ., „, _ '(44) Date of initial publication. -

Patent- och registerstyrelsen '7 Amekm wdagd och «Ukrtfun puMtc * r» d 31.03.8l (32) (33) (31) «Ή * · **« Uoikaui —Bpglrd priority 26.08.71 *

09.09.7 ^ Swiss-Swiss (CH) II582 / 7U 12157 / 7U

(71) F. Hofftnann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Otto Hromatka, Vienna, Dieter Binder, Vienna, Austria-Austria (AT),

Rudolf Pfister, Basel, Paul Zeller, Allschvil, Switzerland-Schweiz (CH) (lb) Oy Kolster Ab (5 ^) Method for the treatment of therapeutically useful U-hydroxy-2H-thieno / 2,3- ^ 7 and / 3, l * - for the preparation of ε-1,2-thiazine-3-carboxamide-1,1-dioxide derivatives - For the preparation of a therapeutically active compound U-hydroxy-2H-thieno Z2,3-eJ och / 3, U- -tiazin-3-carboxamide-l, l-dioxide derivative of

The present invention relates to a process for the preparation of therapeutically useful N-hydroxy-H-thieno [1,3-e] and Z3,1-e7-1,2-thiazine-3-carboxamide-1,1-dioxide derivatives of the general formula SO

QG

C-C0-WH-R 2

OH

where A together with both carbon atoms denotes the group 1- / / == rf "

J J or S

And the dashed line in the first case means a double bond, R 1 is C alkyl, R 8 is 2-thiazolyl, 1-methyl-2-thiazolyl, N, 5-dimethyl-2-thiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 2- pyridyl, 3-pyridyl, U-pyridyl, 3-methyl-2-pyridyl, k-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 1,6-dimethyl-2- pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3, t-dimethyl-5-isoxazolyl, 2,6-dimethyl-k-pyrimidinyl, 1,2,3-U-tetrazol-4-yl or phenyl optionally substituted by halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy.

As used herein, the term "lower alkyl" means straight-chain or branched saturated hydrocarbon groups having 1 to U carbon atoms, such as methyl, ethyl, propyl, isopropyl or tert-butyl. The term "lower alkoxy" means hydrocarbon hydroxy groups having up to U C atoms. The term "halogen" means chlorine, bromine, fluorine or iodine. R 1 is preferably a methyl group. R 2 is preferably 2Hiazolyl, 5-isoxazolyl or 2-pyridyl.

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

DE-A-193, 3 265 and 2,208,351, U.S. Patent No. 3,591,500 and Journal of Medicinal Chemistry 1A (1971) disclose benzothiazine dioxide derivatives which have been reported to have anti-inflammatory and analgesic activity. Structurally, these known compounds differ from those prepared according to the invention in that they have a benzene ring fused to a thiazine ring instead of a thiophene ring. Surprisingly, the therapeutic effect of the new compounds is therefore considerably better than that of the known ones, as shown by comparative pharmacological experiments which have shown the effect of the compound on artificially induced swelling in the rat foot.

Thienothiazine derivatives of the formula I can be prepared according to the invention in such a way that a) a compound of the general formula .SO 4 (X!

I ^ C00R

OH

wherein R is lower alkyl, and A and R 1 are as defined above, are reacted with an amine of general formula

h2n-r2 III

wherein R 2 is as defined above, or 3 59253 b) formula n

„SO2N

Π Γ 'v - CH -CO-NH-Bp

COOH

a reactive derivative of an acid according to the formula wherein A, R 1 and R 2 have the same meaning as above, is cyclized, or c) a compound of the general formula v 1 s → 2x 1 I f v N · Λ \ C 1 -C 2 -CO-NH-R 2

OH

wherein A and R 1 are as defined above, are lower alkylated, or d) a compound of general formula ch 2 xix

II

o wherein A and R 1 are as defined above, is reacted with an isocyanate of formula in the presence of a strong base

o = c = n-r2 XX

wherein R 1 is as defined above, or e) hydrolyzing an enamine of general formula

SO. R

ΓΥ γ t

OF

R 5 R 6 wherein A, R 1 and R 2 are as defined above, and R 1 and R 8 are each alkyl or together with the nitrogen atom form pyrroline, pyrrolidine, piperidine, morpholine or N- (lower alkyl) -. a piperazine ring.

11 59253

The reaction according to process variant a) can be carried out 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, etc., carbon tetrachloride, carbon tetrachloride, etc. dimethylformamide or dioxane. The reaction is preferably carried out by heating, with the melting point or reflux temperature of the reaction mixture being considered highly preferable.

According to process variant b) of the present invention, a reactive functional derivative of a compound of formula IV is cyclized. This cyclization takes place in the presence of a vessel 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. Suitable hydrates, amides or alcoholates of alkali metals are particularly suitable. Suitable solvents are aprotic and protic solvents, such as alcohols, e.g. methanol, ethanol, ethers, e.g. dioxane and acid amides, e.g. dimethylformamide. Suitably the cyclization is carried out by dissolving the starting compound of formula IV in a solvent, adding a base and allowing the reaction mixture to stand for 1 to ¾ hours at either room temperature or at a temperature not exceeding 60 ° C.

Particularly suitable as reactive functional derivatives of the compounds of the formula IV are their lower alkyl esters, e.g. their methyl esters.

According to process variant c), a compound of formula V is alkylated. This alkylation is conveniently carried out by dissolving the starting compound of formula V in an aprotic solvent such as acetonitrile, dioxane or dimethylformamide, converting it to an alkali metal salt with an alkali metal amide or hydride and then treating with an alkylating agent, especially an alkyl halide or other sulfate, compound. Temperature and pressure are not critical in this process, so that for simplicity the reaction is preferably carried out at room temperature and atmospheric pressure.

According to process option d), a compound of general formula XIX is reacted with an isocyanate of general formula XX in the presence of a strong base. Suitable strong bases are alkali amides, alkali or alkaline earth metal hydrides and alkali or alkaline earth metals. The reaction is preferably carried out in an inert gas atmosphere, for example a nitrogen atmosphere, at a temperature of 0 ° C to 50 ° C, preferably at room temperature, and in the presence of an inert polar solvent such as toluene, dioxane, dimethylformamide, dimethylsulfoxide, or hexamethylphosphoric acid triamide (HMTPTPriamide). The isocyanates of the formula XX required as starting materials are either known or can be synthesized analogously to the preparation of known compounds.

According to process alternative condition e), the enamine of general formula XXI is hydrolyzed. The hydrolysis is preferably carried out with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, or trifluoroacetic acid, working at a temperature between 50 ° C and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture. In this hydrolysis, the acid is used simultaneously as a solvent.

The starting materials of formula II required in process variant a) can be prepared according to the following reaction scheme I.

The starting materials of formulas XIX and XXI required in process conditions d) and e) can be prepared in the following steps according to Reaction Scheme II.

6 59253

Reaction Scheme I

OC "^ 0 *"

COOH. COOH

V1 ^ Vll aSO3H ^ v ^ SO3H ^ VS ° 2Hal - <χ— QC or COOH ^^ COOR ^ <; OOR COHal vm ix X I I xi ^ _ ^^ SO2-NH-CH2-C00R / __ ^ SO2-NH-R1

OC I <X

1 Xu \ L x, v

SO 2 SO 2 -N-CH 2 -COOR

nr r xm <X

^ * FSoo

OH J

_ / SO 2 ^ ^ S ~ X n-r, ❖ i. I 1 11

COOR

OH

In this scheme, Hal is halogen and A, R and R 1 are as defined above.

'Λ "· * 59253

Reaction Scheme II

aSO -NH-R

XIV

COOR

in K0H

Vv ^ SOj-NH-R, \ JL XXII ',

COOH

I PCI5

2, CH 2 N 2 Ψ 3) HCl

ASC ^ NH-R

XXIII

CO-CH2-Hal

....... lNaH

aSO2s x-Rl ¥ xix

= CH

2

II

I HNR5R6 <Ts ° 2> "R1 1} phosgene, ocs ° 2 ',?" "R | C ^ CH 2) H NR (ΠΙ) C' ^ 'C'S" CO-NH-R- I 2 I 2 R5 R6 R5 R6

XXI

‘*% 8 59253

Of the compounds of formula VI, 3-chloro-thiophene-2-carboxylic acid and 4-bromo-thiophene-3-carboxylic acid are known, the preparation of the former being relatively difficult. In a simpler process for the preparation of 3-chloro-thienylene-2-carboxylic acid, the known 3-hydroxythiophene-2-carboxylic acid methyl ester is converted in an inert solvent boiling above 80 ° C, such as chloroform or dioxane, with a chlorinating agent such as phosphorus pentachloride-phosphorus pentachloride. thiophene-2-carboxylic acid chloride and this is hydrolyzed to the corresponding acid.

Although in principle a chromium compound, e.g. a known 1 + -bromo-thiophene-3-carboxylic acid, can also be used as a starting material for the preparation of a compound of the formula VII, it is recommended to use a corresponding chlorine compound. U-chloro-thiophene-3-carboxylic acid, not described in the literature, can be prepared from the known 3-ketothiophene-β-carboxylic acid methyl ester by converting it with phosphorus pentachloride by aromatization to U-chloro-thiophene-3-carboxylic acid chloride and hydrolyzing it acid.

The conversion of a halothiophenecarboxylic acid of formula VI to a potassium salt of a sulfothiophene carboxylic acid of formula VII is carried out according to methods known per se by reacting a compound of formula VI with sodium hydrogen sulphite in the presence of a copper (I) salt catalyst, especially copper (I) chloride * In reaction with sodium bisulfite, the temperature should be maintained at about 1 to 3 ° C to achieve optimal yields.

The conversion of a compound of formula VII to the corresponding acid of formula VIII takes place in a manner known per se, for example by means of a strong ion exchanger.

The esterification of the acid of formula VIII to the ester of formula IX takes place autocatalytically (in the presence of a sulpho group) in an alcohol / chloroform mixture. To form methyl esters, 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 conversion of a compound of the formula IX into an acid halide of the formula X takes place 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 take place without solvent at reflux temperature. When phosphorus pentachloride is used, it is possible to work in the presence of an inert solvent, such as chloroform, carbon tetrachloride, dioxane, and at a temperature of 50 ° C and the reaction mixture to reflux temperature.

A compound of formula X may also be prepared starting from a potassium salt of a sulfothiophene carboxylic acid of formula VII via a compound of formula XI. In this case, said potassium salt is reacted, for example, with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as a solvent at a temperature of 95,525 to 30 ° C and the boiling point of phosphorus oxychloride. But 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 a 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. As the solvent, an alcohol or an inert solvent such as chloroform, carbon tetrachloride, dioxane or benzene can be used.

The starting material of formula X can be obtained from the starting material of formula II in two different ways. One route leads to compounds of formulas XII and XIII and the other, optionally via compound XIV to compound XV.

According to the former method, a compound of the formula X is reacted with glycine alkyl ester hydrochloride, preferably glycine ethyl ester hydrochloride, in a manner known per se. 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 formula XII thus obtained is cyclized at a temperature between 1 * 0-65 ° C in ethanol with an alkali or alkaline earth ethylate, in particular sodium ethylate, to give a compound of 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, conveniently in a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or hexamethapol, with an alkylating agent such as an alkyl halide or dialkyl sulphate at a temperature between 0 ° C and room temperature.

Alternatively, a compound of formula X is either aminoalkylated first to a compound of formula XIV, which is then converted to a compound of formula XV, or the compound of formula X is converted directly to compound XV. In both cases, the resulting compound of formula XV is cyclized to a compound of formula II.

Aminoalkylation of a compound of formula X takes place in a manner known per se by reacting it with an alkylamine in the presence of an inert organic solvent such as chloroform, methylene chloride, carbon tetrachloride, benzene or dioxane and at room temperature.

To prepare a compound of formula XV, the compound of formula XIV thus obtained is reacted in a manner known per se in the presence of a polar aprotic solvent, such as dimethylformamide, dimethyl sulphoxide or hexamethapol, with a compound of formula

x-ch2-coor-r XVI

wherein R is as defined above and X is halogen.

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

10 59253

On the other hand, a compound of formula XV is obtained in a manner known per se by reacting a compound of formula X in a bar of a compound of formula R 11.

H-N-CH2-C00R XVII

wherein R and R 2 are as defined above, or its acid addd spore with salt n.

The reaction is conveniently carried out at room temperature. When an acid addition salt of a compound of formula XVII is used, pyridine is conveniently employed. But instead of the acid addition salt, 2 moles of free amine can also be used, in which case it is preferred to work in dioxane, methylene chloride, benzene or carbon tetrachloride.

The cyclization of the compound of formula XV to the starting material of formula II is expediently carried out at a temperature between room temperature and 65 ° C by means of alkali or alkali metal methylate or ethylate, 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 the acids of formula IV used as starting materials in condition b) can be obtained by reacting the amine of formula III with chloroacetyl chloride and the product of formula 0 obtained.

»I

R2-NH-C-CH2-C1 XVIII

wherein Rg is as defined above, is reacted with a compound of formula XIV. Other reactive functional derivatives of the acid of formula IX can be prepared from inhibitors obtained in a manner known per se.

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

The compounds of formulas II, IV and VII-XV are novel.

The compounds of the general formula I have an anti-inflammatory (analgesic), analgesic (analgesic) and antirheumatic effect. These valuable pharmacological properties can be determined using standard methods, for example, the known kaolin paw test (rat). In this test, 0.1 ml of a 10% kaolin suspension (Bolus Alba) is injected intradermally into the right hind paw of the rat to induce acute local inflammation. The test substance is administered orally and the following parameters are measured: 1. Paw diameter in mm (as an indication of the intensity of inflammation) ^ 2. Paw on the paw (in g) (to transmit a wave of pain).

1/2 hour before and 3 1/2 hours after the kaolin injection, the test substance is administered, and the above parameters are measured h hours after the kaolin injection. The anti-edematous (swelling) effect is expressed as a percentage, based on the difference in edema intensity between untreated and test-treated animals, antinociceptive activity as a percentage increase in pain wave.

In this test, 1 + -hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [1,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide with 1D <_q about 900 mg / kg, orally (mouse) j7 at a dose of 3 mg / kg orally given 27% inhibition of edema and an increase in U # pain wave and at a dose of 10 mg / kg orally given 1 * 3 # of edema inhibition and 23 % increase in pain wave.

The compounds of the formula I have a qualitatively similar effect to phenylbutazone, which is a known therapeutic drug.

The compounds of the formula I can be used as medicaments, e.g. as pharmaceutical preparations, containing them in admixture with pharmaceutical, organic or inorganic inert carriers suitable for enteral or parenteral administration, such as, for example, water, gelatin, acacia, lactose, starch. , magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations can be in solid form, e.g. tablets, granules, suppositories, capsules, in semi-solid form, e.g. ointments, or in liquid form, e.g. solutions, suspensions or emulsions. Optionally, they are sterilized and / or contain excipients such as reservoirs, stabilizers or emulsifiers, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The following examples, in which all temperature values are expressed in degrees Celsius, illustrate the invention.

Example 1: β-Hydroxy-2-methyl-K-2-thiolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1- dioxide 52.1 g of phosphorus pentachloride are dissolved in 600 ml of abs. carbon tetrachloride, and the solution is heated to boiling, after which a solution of 15.8 g of 3-hydroxy-2-methoxycarbonylthiophene in 200 ml of carbon etrachloride is added dropwise over 3 hours. Boil under reflux for 13 hours, then distill off the carbon tetrachloride and evaporate the reaction mixture to near dryness in vacuo. While cooling, add 1 + 50 ml of water, then bring to the boil and then allow 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, after which the activated carbon is filtered off with suction and the cooled solution is acidified with hydrochloric acid to give 3-chlorothiophene-2-carboxylic acid, m.p. is 1885-186 ° C.

In a glass autoclave, 8.6 g of 3-chlorothiophene-2-carboxylic acid are dissolved in 23 ml of an aqueous solution of NaOH (2.1 g), followed by the addition of a solution of 5.6 g of 12,59,253 sodium hydrogen sulphite in 16 ml of water, and the solution is made 30%. : 11a with sodium hydroxide just alkaline. Then 0.3 g of copper (I) chloride is added and the mixture is heated for 16 hours at 11 + 3 ° C. After cooling, the red copper oxide is filtered off with suction. It is then acidified with 7 ml of conc. hydrochloric acid, whereupon the unreacted starting material precipitates and is removed by shaking with methylene chloride. To the acidic solution is added, with heating, 12 g of potassium chloride, whereby, after cooling to 0 [deg.] C., the potassium salt of 3-sulfothiophene-2-carboxylic acid separates as colorless crystals.

8.2 g of the above potassium salt of 3-sulfothiophene-2-carboxylic acid are dissolved in 50 ml of water. This solution is allowed to drain through a column containing an ion exchanger (H + form), rinsing with water until the pH of the flowing solution is 5. The solution is evaporated to dryness in vacuo and the crystalline residue consisting of 3-sulfothiophene-2-carboxylic acid, recrystallized from a small amount of water.

7.6 g of 3-sulfothiophene-2-carboxylic acid are dissolved in 10 ml of abs. methanol and 65 ml of abs. chloroform and reflux, the reaction water being distilled as a ternary azeotrope (chloroform, methanol, water) via a packed column (1 m). It is then evaporated in vacuo. To completely remove the methanol, 100 ml of chloroform are added to the residue, followed by evaporation under normal pressure. The residual brown oil, consisting of 3-sulfothiophene-2-carboxylic acid methyl ester, crystallizes immediately after cooling. However, the crystals are hygroscopic and disintegrate in air.

7.1+ g of crude. 3-Sulphothiophene-2-carboxylic acid methyl esters are dissolved in 50 ml of thionyl chloride and refluxed for 16 hours. It is then evaporated to dryness in vacuo, after which the pale yellow oil remaining from petroleum ether, consisting of 3-chlorosulphonyl-thiophene-2-carboxylic acid methyl ester, is crystallized.

20 g of 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester are dissolved in absolute chloroform, followed by dropwise addition of 21 g of sarcosine ethyl ester over 10 minutes. indoors. The reaction mixture is then heated to 50 °. 20 min. after cooling, shake each time with water, 0.5 N hydrochloric acid and bicarbonate solution, dry and evaporate. The residual oil consisting of 3- (N-carboethoyl-N-methylsulfamoyl) -thiophene-2-carboxylic acid methyl ester is crystallized from ethanol; mp. is 8ä-Ö5 °.

13.2 g of 3- (N-carboethylmethyl-N-methylsulfamoyl) -thiophene-2-carboxylic acid methyl ester are suspended in cold h2 ml of 1N methanolic sodium methylate solution in a stream of nitrogen. After stirring for 15 minutes, a clear solution is obtained. Heat for 20 min. under reflux, then cooled, neutralized and evaporated in vacuo. The residue is dissolved in methylene chloride, shaken once with water and bicarbonate solution, dried and evaporated. The residue consisting of 3-carbomethoxy-1-hydroxy-2-methyl-2H-thienene 59253 / 2,3-e7-1,2-thiazine-1,1-dioxide is crystallized from methanol, m.p. is 193-195.

1.9 g of 3-carbomethoxy-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide are suspended together with 0.9 g of 2-amino-thiazole in 250 ml of abs. xylene and heated at reflux for 7 hours, slowly distilling off 150 ml of xylene. The remaining xylene is then evaporated in vacuo. The crystalline residue consisting of H-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide is recrystallized from ethanol. , sp. 217 ° (decomp.).

Example 2: 4-Hydroxy-2-methyl-N-2-thiolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide 50 g ( 0.203 moles) of the monopotassium salt of 3-sulfothiophene-2-carboxylic acid is suspended in 250 ml of phosphorus oxychloride and 85 g (0.01 + 06 moles) of phosphorus pentachloride are added with stirring (vigorous evolution of HCl begins). Then heat for another 90 min. while stirring in a water bath, cooled to room temperature, suction (filter off the inorganic salts, distill off the phosphorus oxychloride in vacuo as much as possible. The oily residue is dissolved to remove the remaining inorganic salts * + 00 ml of dry chloroform, the solution is filtered and evaporated. -chlorosulfonyl-thiophene-2-carboxylic acid chloride crystallizes on cooling and is used without further purification in the next step.

* + 8 g (0.196 mol) of 3-chlorosulfonyl-d] iophene-2-carboxylic acid chloride thus obtained are dissolved in 500 ml of abs. chloroform, 9.6 g (0.3 mol) of abs. methanol and reflux for 3 hours. (Until the end of HCL development). It is then evaporated to dryness in vacuo to give a residue of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester. The crude product can be used in the next step.

* + 3.5 g (0.18 mol) of the 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester thus obtained are dissolved in 1 * 50 ml of abs. chloroform and methylamine, dried at 10 °, is introduced into the solution until the wetted pH paper shows an alkaline reaction in the solution. The reaction is then allowed to proceed for a further 2 hours at room temperature, at which point the solution must still remain alkaline. The mixture is then shaken with 500 ml of water and 500 ml of 5N sodium hydrogen carbonate solution (the aqueous phases are shaken once with chloroform each time), the combined organic phases are dried over sodium sulfate and evaporated. The crystalline residue is purified by digestion with ether. 3-Methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained, m.p. is 115-122 °.

* + 3.5 g (0.18 * + moles) of the 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester thus obtained are dissolved in * + 00 ml of abs. dimethylformamide, and the solution is added dropwise at 0 ° over 1 hour to a stirred suspension of * +.5 g (0.187 mol) of sodium hydride in 50 ml of abs. dimethylformamide. 1 + 0 g (0.187 mol) of iodoacetic acid ethyl ester are then dissolved in the mixture at 59-5 ° with cooling, and the mixture is added dropwise to 50 ml of abs. dimethylformamide for 2 hours and react for 1 hour (until the moistened pH paper shows 7-8) · Then evaporate in vacuo, dissolve the residue in 300 ml of 0.5 N hydrochloric acid and 300 ml of methylene chloride, separate the organic phase, shake the aqueous phase twice. shake twice with a small amount of methylene chloride and shake the combined organic phases twice with 100 ml of 5% sodium hydrogen carbonate solution (the aqueous phases are shaken once more with a small amount of methylene chloride each time. The combined organic phases are dried over sodium sulfate and dried over sodium sulfate. by digestion with a small amount of cold ethanol to give 3- (N-ethoxycarbonylmethyl) -N-methyl / sulfamoylthiophene-2-carboxylic acid methyl ester, m.p. is 83-85 °.

13.2 g (0.01 + 1 mol) of the 3- (TN-ethoxycarbonylmethyl) -N-methyl / sulfamoyl-thiophene-2-carboxylic acid methyl ester thus obtained are suspended in cold 1 + 2 ml of 1N methanolic sodium methylate solution under a nitrogen atmosphere, whereby 15 min. during sustained mixing, everything dissolves. Then boil for 25 min. under reflux, cooled, neutralized conc. hydrochloric acid and evaporated in vacuo. The residue is dissolved in methylene chloride, shaken once with water and 5% sodium hydrogen carbonate solution, dried and evaporated. The crystalline residue is purified by digestion with a small amount of methanol. 1 + -Hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained, m.p. is 193-195 °, which can be modified as described in the last part of Example 1 by reacting with 2-aminothiazole 1+ -hydroxy-2-methyl-N-2-tholyl-2H-thienol - / 2,3-and -1,2-thiazine-3-arboxy-amide-1,1-dioxide, m.p. is 217 ° (decomp.).

Example 3: 1 + -hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide.

50 g (0.203 mol) of the monopotassium salt of 3-sulfothiophene-2-carboxylic acid are suspended in 250 ml of phosphorus oxychloride and 85 g (0.1 * 06 mol) of phosphorus pentachloride are added with stirring (vigorous evolution of HCl begins). Then heat for another 90 min. with stirring in a water bath, cooled to room temperature, the inorganic salts are filtered off with suction and the phosphorus oxychloride is distilled off in vacuo as far as possible. The oily residue is dissolved in 1 + 00 ml of dry chloroform to remove any remaining inorganic salts, filtered and evaporated. The oily residue, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride, crystallizes on cooling and is used without further purification for the next step.

1 + 8 g (0.196 mol) of the 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride thus obtained are dissolved in 500 ml of abs. chloroform, 9.6 g (0.3 mol) of abs. methanol, and the mixture is heated at reflux for 3 hours i5 59253 (until the end of HCl evolution). It is then evaporated to dryness in vacuo to give a residue of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester. The crude product can be used for the next step.

2.1 g (10 mol) of the 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester thus obtained and 1.53 g of sarcosine ethyl ester hydrochloride are stirred at room temperature in 10 ml of abs. pyridine. After 2 hours, the mixture is poured into 50 ml of ice-cold 2N hydrochloric acid and extracted five times with 20 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The crystalline residue is digested with a small amount of ice-cold ethanol.

13.2 g (0.1 mol) of the 3 - [(N-ethoxycarbonylmethyl) -N-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester thus obtained are suspended in cold k2 ml; a 1 N methanolic sodium methylate solution under a nitrogen atmosphere, giving 15 min. during mixing, everything dissolves. It is then heated for 25 min. under reflux, cooled, neutralized conc. hydrochloric acid and evaporated in vacuo. The residue is dissolved in methylene chloride, shaken once with water and 5% sodium bicarbonate solution, dried and evaporated. To purify the crystalline residue, a small amount of methano-1 is digested. 1+ -Hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained, m.p. is 193-195 °, which can be modified as described in the last part of Example 1 by reacting with 2-aminothiazole it-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1 , 2-thiazine-3-carnoxamide-1,1-dioxide, m.p. is 217 ° (decomp.).

Example N-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-11-dioxide 12.03 g (0.05 mol) of 3-chlorosulfonyl -thiophene-2-carboxylic acid methyl ester and 7 g of glycine ethyl ester hydrochloride (0.05 mol) are suspended in 50 ml of abs. pyridine, giving 30 min. inside everything dissolves. Stir for a further 5 hours at room temperature and finally distill the pyridine. The residue is dissolved in 50 ml of 2N hydrochloric acid and 50 ml of methylene chloride, the organic phase is separated, the aqueous layer is shaken b x a small amount of methylene chloride, the combined organic phases are washed with water and dried over sodium sulfate. After filtration, evaporate; The oily residue containing 3- (N-ethoxycarbonylmethyl) -sulfamoyl-thiophene-2-carboxylic acid methyl ester can be used without further purification for the next step.

To a solution of 1.38 g of sodium (θ, θβ moles) in 20 ml of absolute ethanol is added at i + 0 ° a solution of 9.22 g (0.03 moles) of the 3- (N- ethoxycarbonylmethyl) sulfamoyl-thiophene-2-carboxylic acid ethyl ester in 10 ml of ethanol, and the mixture is heated at 60-65 °. After stirring for a further 2 hours at this temperature, the mixture is poured into 100 ml of ice-cold 2N hydrochloric acid and shaken several times with a small amount of methylene chloride. The combined 16 5 9253 organic extracts are shaken twice with 20 ml each of 5 # of sodium acetate solution and then x x 25 ml each with 10 ml of 10 # sodium carbonate solution. By drying and evaporating the organic phase, 2.5 g of starting material are recovered. The combined carbonate extracts are acidified with hydrochloric acid and shaken with methylene chloride. After drying over sodium sulfate, the solvent is distilled off and the crystalline residue is digested with a small amount of ether. 3-Ethoxycarbonylmethyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained, m.p. is lit8-150O.

1.93 g (7 mmol) of 3-ethoxycarbonylmethyl-1-hydroxy-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide are dissolved in 1 ml of abs. dimethylformamide, and the solution is added at 0 ° for 30 min. to a dropwise stirred suspension of 0.185 g of sodium hydride (7.7 mmol) in 2 ml of abs. dimethylformamide; then stirred for another 1 hour at room temperature. To the sodium salt solution is first added 0.53 mL (1.2 g; 8.5 mmol) over 30 min. after a further 0.25 ml (0.565 g; mmol) of methyl iodide and continue to react for 1 hour. After distilling off the solvent, the residue 30 is dissolved in 0.5 N hydrochloric acid and 30 methylene chloride, the organic phase is separated off and the aqueous layer is shaken twice with a small amount of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol. 3-Ethoxycarbonylmethyl-U-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained, m.p. is 161-163 ° (change in crystal form at 151-1520).

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

Example 5: H-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3,3-b] 1,2-thiazine-3-carboxamide-1,1-dioxide

To a boiling solution of 100 g of phosphorus pentachloride in 250 ml of abs. Carbon tetrachloride is added dropwise 25 g of 3-keto-thiophene-t-carboxylic acid methyl ester dissolved in a small amount of abs. carbon tetrachloride within 2 hours.

It is then refluxed for a further 15 hours until the evolution of hydrogen chloride has ceased and then evaporated in vacuo to remove most of the phosphorus chloride. The residue is stirred with ice water for 1 hour, after which the organic phase is separated, the aqueous phase is shaken once more with methylene chloride and the combined organic phases are dried over sodium sulfate and then evaporated. The remaining brown oil, consisting of h -chloro-thiophene-3-carboxylic acid chloride, is heated with 2N aqueous sodium hydroxide solution at 50 ° until a homogeneous brown solution is formed. This is shaken once with methylene chloride, acidified with conc. with hydrochloric acid, IT 59253 after which the precipitated crystals consisting of crude 4-chlorothiophene-3-carboxylic acid are filtered off with suction. For purification, the suction-filtered crystals are dissolved in sodium bicarbonate solution and precipitated with conc. hydrochloric acid again; the melting point after recrystallization from water is 16k °.

In a glass autoclave, 8.6 g of 4-chlorothiophene-3-carboxylic acid are dissolved in 23 ml of water containing 2.1 g of sodium hydroxide, followed by the addition of a solution of 5.6 g of sodium hydrogen sulphite in 16 ml of water, and the solution is made just alkaline with 30% sodium hydroxide solution. Then Q, k3 g of copper (I) chloride are added and heated for 16 hours at 1 + 3 °. After cooling, the red copper oxide is filtered off with suction. The filtrate is acidified with 7 ml of conc. hydrochloric acid, whereupon the unreacted starting material precipitates, and is removed by shaking with ether. To the acidic solution is added 12 g of potassium chloride with heating, whereupon, after cooling to 0 °, the potassium salt of U-sulfothiophene-3-carboxylic acid separates as colorless crystals. This is dissolved in 50 ml of water and the solution is applied to a column containing an ion exchanger (H + form), which is rinsed with water until the pH of the effluent solution is 5. The eluate is evaporated to dryness in vacuo to give lt-sulfothiophene-3-carboxylic acid as a crystalline residue. . Sp. (from water) 15-7.6 g of 4-sulfothiophenyl-3-carboxylic acid are dissolved in 1 * ι0 ml of abs. methanol and 65 ml of abs. chloroform, and the solution is refluxed, whereby the reaction water is distilled off as a tannic azeotrope (chloroform, methanol, water) via a packed column (ml). It is then evaporated in vacuo. To completely remove the methanol, 100 ml of chloroform are added to the residue, after which the solution is evaporated under normal pressure. The residual brown oil, consisting of h-sulfothiophene-3-carboxylic acid methyl ester, crystallizes immediately after cooling (air-decomposing hygroscopic crystals).

7.1 g of crude h-sulfothiophene-3-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride, and the solution is refluxed for 16 hours. It is then evaporated to dryness in vacuo and the residual pale yellow oil consisting of U-chlorosulfonylthiophene-3-carboxylic acid methyl ester is crystallized from petroleum ether; mp. (petroleum ether) 71 ° · 50 g of U-chlorosulfonyl-thiophene-3-carboxylic acid methyl ester are dissolved in 500 ml of abs. of chloroform. Dried methylamine is introduced into the cooled solution until the moistened indicator paper shows a permanent basic reaction. The methylammonium chloride formed is removed by shaking with water. The organic phase is dried and evaporated. The residual pale yellow oil, consisting of N- (N-methylsulfamoyl) -thiophene-3-carboxylic acid methyl ester, crystallizes immediately; Sp. II + 2 °.

h6 g of 1- (N-methylsulfamoyl) -thiophene-3-carboxylic acid methyl ester are dissolved in U50 ml of dimethylformamide. The solution is cooled to 0 ° and 7 g (excess $ 20) of sodium hydride are added, whereupon strong hydrogen evolution occurs.

18 5925 3

The solution is slowly warmed to room temperature and 32.6 g of dried potassium iodide and 21.3 g of chloroacetic acid methyl ester are added successively. The temperature rises to 1 + 5 ° and a white precipitate forms. The dimethylformamide is finally evaporated, after which the residual yellow oil is partitioned between 0.5N hydrochloric acid and methylene chloride. The organic phase is shaken with bicarbonate and water, dried and evaporated. The residual yellow oil, consisting of 1- + (n-methoxycarbonylmethyl-N-methylsulfamoyl) -thiophene-3-carboxylic acid methyl ester, crystallizes immediately. Sp. from ethanol: 12 * + °.

Ul, 6 g of 1- (N-methoxycarbonylmethyl-N-ethylsulfamoyl) -thiophene-3-carboxylic acid methyl ester are dissolved in 11 ml of 1N sodium methylate solution, and the solution is refluxed. The solution turns yellow first and then rapidly deep red; 20 min. after which the solution becomes cloudy and a precipitate forms.

The mixture is cooled, acidified and evaporated in vacuo. The residue is dissolved in methylene chloride and water; the organic phase is shaken with bicarbonate solution and water and finally extracted with 0.5 N chilled sodium hydroxide solution. Acidification of the aqueous sodium hydroxide solution gives 1 + -hydroxy-3-methoxy-β-carbonyl-2-methyl-2H-thiol./3, 1 + -e / -1,2-thiazine-1,1 -dioxide as colorless crystals; mp. 190 ° from methanol. 0.9 g of hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno-N, N'-thiazine-1-dioxide is suspended together with 0.1 + g of 2-aminothiazole in 100 ml. abs-xylene and the suspension are heated under reflux for 1+ hours, whereupon 70 ml of xylene are slowly distilled off A crystalline precipitate of a cooling solution consisting of 1 + -hydroxy-2-methylethyl-N-2-thiazolyl-2H-thieno / 3,1 + -e / -1, 2-thiazine-3-carboxamide-1,1-dioxide, suction filtered from ethanol 2l + 3-2l + 5 ° (decomp.).

-

Example 6: 1+ -hydroxy-2-methyl-M-2-thiolyl-2H-thieno [3,1+-e] -1,2-thiazine-3-carboxamide-1.1- dioxide 91 +, 6 g (0.381+ moles) of the monopotassium salt of 1 + -sulfothiophene-3-carboxylic acid are suspended in 390 ml of phosphorus oxychloride and 160.8 g (0.768 moles) of phosphorus pentachloride are added to the solution with stirring (vigorous evolution of HCl begins). It is then heated for a further 3 hours with stirring in a water bath, cooled to room temperature, the inorganic salts are filtered off and the phosphorus oxychloride is distilled off in vacuo as well as possible. The residue is dissolved in 1 + 00 of any dry chloroform to remove any remaining inorganic salts, filtered and evaporated. The residue, consisting of 1 + -chlorosulfonyl-thiophene-3-carboxylic acid chloride, crystallizes on cooling and is used without further purification for the next step.

1 + 1 +, 1 g (0.18 mol) of the 1 + chlorosulfonyl-thiophene-3-carboxylic acid chloride thus obtained are dissolved in 1 + 50 ml of abs. chloroform, 9.6 g (0.3 mol) of abs. methanol and reflux for 9 hours (until HCl evolution ceases). It is then evaporated to dryness in vacuo, whereupon the residue 19 5 9253 crystallizes. U-Chlorosulfonyl-thiophene-3-carboxylic acid methyl ester is obtained, which can be converted as described in the last paragraph of Example 5, 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [3, U-e7 -1,2-thiazine-3-carboxamide to -1,1-dioxide.

Example 7: U-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -H-thieno [2% 3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

By the same procedure as in Example 1, 3-carbomethoxy-14-hydroxy-2-methyl-thieno [2,3- b] -1,2-thiazine-1,1-dioxide is reacted for 3 hours with 3-amino-5- with methyl isoxazole 14-hydroxy-2-methyl-N- (5-methyl-3-isoxazolyl) -2H-thieno '[2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide , with a decomposition point of 239-21 * 3 °.

Example 8: 4-Hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxyanilide-1,1-dioxide

By the same procedure as in Example 1, 3-carbomethoxy-1-hydroxy-2-methyl-thieno [2,3-d] -1,2-thiazine-1,1-dioxide is reacted with aniline for 7 hours. the title compound having a decomposition point of 2U8-2510 (xylene).

Example 9 'H-Hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-d] -1,2-thiazine-3-carboxamide-1,1-dioxide

By proceeding in the same manner as in Example 1, 3-carbomethoxy-14-hydroxy-2-methyl-thieno [2,3 "g7" -12-thiazine-1,1-dioxide is obtained by reacting it with 2-pyridylamine for 7 hours. , with a decomposition point of 209-213 ° (xylene).

Example 10: 1 * -Hydroxy-2-methyl-N-3-pyridyl-2H-thieno [1,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

By proceeding in the same manner as in Example 1, 3-carbomethoxy-1 + -hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is reacted with 3-pyridylamine for 7 hours to give the title compound. , with a decomposition point of 2 ^ 1-21 + 4 ° (from pyridine).

Example 11: 14-Hydroxy-2-methyl-M-4-pyridyl-2H-thieno [1,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

By proceeding as in Example 1, 3-carbomethoxy-1-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is reacted by reacting it. With 7-pyridylamine for 7 hours with the title compound having a decomposition point of 263-267 ° (from dimethylformamide).

Example 12: 1'-Dihydroxy-4-methyl-1H-thieno [R,] [3- [1,2-thiazine-3-carboxyanilide-1,1-dioxide "

By the same procedure as in Example 1, 3-carbomethoxy-U-hydroxy-2-methylthieno [2,3-e] -1,2-thiazine -1,1-dioxide is obtained by reacting it with 7 for 1 hour with k-hydroxyaniline, the title compound having a decomposition point of 287-290 ° (from dioxane).

20 5925 3

Example 13: U-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic toluide-1,1-dioxide

By proceeding in the same manner as in Example 1, 3-carbomethoxy-U-hydroxy-2-methylthieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it for 3 hours with 3-methyl with aniline, the title compound having a decomposition point of 191-199 ° (from benzene; crystalline change in 185-1880).

Example li: 3, -chloro-14-hydroxy-2-methyl-2H-thieno / 2,3-e-1,2-thiazine-3-carboxanilide-1,1-dioxide

By proceeding as in Example 1, 3-carbomethoxy-1H-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it for 3 hours with 3-chloro. with aniline, the title compound having a decomposition point of 2k-2k3 ° (xylene).

Example 15: k-hydroxy-2-methyl-N-pyrazinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide

By proceeding as in Example 1, 3-carbomethoxy-1-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it for 7 hours with aminopyrazine under the title compound. a compound having a decomposition point of 2 ^ 5-2 ^ 8 ° (of xylene).

K S 1 ΤΠ py-N- (3,4-dimethyl-β-isoxazolyl) -k-hydroxy-2-methyl-2H-thieno [2,3-e] -1-1. 2-tazine-3-carboxamide-1,1-dioxide

By proceeding as in Example 1, S-carbomethoxy-1'-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it every hour for 5- with amino-3,1 + -dimethylisoxazole, the title compound having a decomposition point of 206-208 ° (from benzene).

Example 17: N- (2,6-Dimethyl-N-pyrimidinyl) -N-hydroxy-2-methyl-2H-thieno [2,3-d] -1,2-thiazine-3-carboxamide-1,1-oxide

By proceeding in the same manner as in Example 1, 3-carbomethoxy-U-hydroxy-2-methyl-thieno72,3-e7,2,2-thiazine-1,1-dioxide is obtained by reacting it for 7 hours with ii-amino-2,6- with dimethylpyrimidine, the title compound having a decomposition point of 270-271 ° (from xylene).

Example 18: k-Hydroxy-2-methyl-N- (6-methyl-2-pyridyl) -2K-thieno [2,3-b] -1,2-thiazine-3-carboxamide-1,1-dioxide.

By proceeding in the same manner as in Example 1, 3-carbomethoxy-H-hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it for 2 hours with 2-amino-6- with methylpyridine, the title compound having a decomposition point of 216-218 ° (from benzene).

21 59253

Example 19! N-hydroxy-2-methyl-N- (5-1,2,3k-tetrazolyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-11-dioxide correspondingly as in Example 1, 3-carbomethoxy-1 + -hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide is obtained by reacting it for 11 + hours with 5-α-amino-1 , 2,3,1 + -tetrazole, the title compound with a decomposition point of 22 l + ° (from ethanol).

Example 20: 1 + -Hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide The same procedure as in Example 1 gives 3 -carbomethoxy-1 + -hydroxy-2-methyl-thieno [2,3-e] -1,2-thiazine-1,1-dioxide by reacting it with 2-aminopyrimidine for 18 hours, the title compound having a decomposition point of 221 -223 ° (from ethanol).

Example 21: 1 + -hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide 0.82 g (0.003 mol) of 3'-ethoxycarbonyl- hydroxy-2H-thieno [1,3-e] -7,2-thiazine-1,1-dioxide is suspended together with 0.1 + g (0.00U mol) of 2-aminothiazole in 100 ml of xylene, and the mixture is heated to boiling. During 7 hours, 50 ml of the solvent are azeotroped slowly with the ethanol formed, so that after 2 hours 1 + -hydroxy-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-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 (m.p. 209-290 °; decomp.) But is sufficiently pure for further reactions.

0.329 g (1 mmol) of this product is dissolved in 2 ml of abs. dimethylformamide and the solution is added at 0 ° to a stirred suspension of 0.026 g (1.1 mmol) of sodium hydride in 1 ml of abs. dimethylformamide; then stirred for another 1 hour at room temperature. To the sodium salt solution is added 0.1 mL (0.226 g; 1.6 mmol) of methyl iodide and allowed to react for 1 hour. After distilling off the solvent, the residue is dissolved in 200 ml of methylene chloride and 10 ml of 0.5 N hydrochloric acid, the organic phase is separated and shaken with a total of 50 ml of 0.5% sodium hydrogen carbonate solution. The aqueous layer containing the desired product is shaken several more times with methylene chloride and acidified with hydrochloric acid. The acidic aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol to give the title compound with a melting point of 217 ° (decomposed).

Example 22: 1 + -hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide 1 + 0 g (0.1 mol) of 2-amines ages sol are dissolved in 1 + 00 ml of abs. dioxane, and 100 g of freshly annealed potassium carbonate are added to the solution. Then added. . . . .. o.

in portions 95 ml of chloroacetyl clone, bringing the temperature to 7® 1. · Then 22 59253 is stirred for 90 minutes; finally poured into an ice-cold solution of 150 g of potassium carbonate in 1000 ml of water, whereupon 2-chloroacetylaminothiazole precipitates. After stirring for a further 1 hour, the product is filtered off with suction, washed well with water and recrystallized from ethanol. Sp. 176-177 °.

0.5 (2.12 mmol) of methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is dissolved in 8 ml of abs. dimethylformamide, and the solution is added at 0 ° to a stirred suspension of 0.06 g of sodium hydride in 2 ml of abs. dimethylformamide. It is then stirred for a further 1 hour at room temperature. To the sodium salt solution are added 0.38 g (2.15 mmol) of the 2-chloroacetylaminothiazole obtained above and 0.36 g (2.17 mmol) of potassium iodide and stirred for a further 2 hours. After distilling off the solvent, the residue is dissolved in 20 ml of 0.5 ml of hydrochloric acid and 50 ml of methylene chloride, and the aqueous phase is shaken several times and is not usually treated with chloride. The combined organic phases are washed with water, dried over sodium sulfate, filtered and evaporated. 3 - [[N- (2-thiazolyl-carbamoylmethyl) -N-methylsulfamoyl] thiophene-2-carboxylic acid methyl ester is obtained.

0.1 g (0.27 mmol) of the 3- [N- (2-thiazolylcarbamoylmethyl) -N-methyl] sulfamoylthiophene-2-carboxylic acid methyl ester thus obtained is dissolved in 5 ml of abs. Dimethylformamide and in solution 0.01 g of sodium hydride is added.

After stirring for 2 hours, the desired compound can be detected by thin layer chromatography.

Example 23: N-hydroxy-N-methyl-3- (phenylcarbamoyl) -2H-thieno [2,3 / b] 1,2-thiazine-11-dioxide 23.5 g (0.1 mol) of 3-methylsulfamoyl-thiophene-2- the carboxylic acid methyl ester is dissolved in 50 ml of ethanol, 50 ml of 3N potassium hydroxide solution are added to the solution, and the mixture is heated under reflux for 3 hours. After cooling, dilute with water and shake with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted several times with 50 ml of ether each time. After drying over sodium sulfate and evaporation of the solvent, colorless crystals are obtained which are still sufficiently pure for further reactions. The resulting 3-methylsulfamoyl-thiophene-2-carboxylic acid can be recrystallized from water, m.p. is 1882-18i + 0C.

11.06 g (0.05 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid and 11.5 g (0.055 mol) of phosphoric acid pentachloride are slurried in 150 ml of dry chloroform, and the suspension is stirred for 30 min. at ^ 0 ° C. From the clear solution formed, half of the solvent is evaporated in vacuo without heating. This acid chloride solution is added dropwise over 1 hour to a freshly prepared solution of 3 g of nitrosomethyl urea in ether-cooled in -20 ° C in ether. The mixture is then allowed to warm to room temperature. After 1 hour, carefully add dropwise 80 ml of conc. hydrochloric acid and heated to reflux for 1 hour. Finally, shake with 200 ml of water and shake once more with ether. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The crystal porridge thus obtained is digested with> a small amount of ether. The resulting 3-methylsulfamoyl-2-chloroacetyl-thiophene is sufficiently pure for further reactions, but can be recrystallized from benzene. Sp. 182-1814 ° C.

2.53 g (0.01 mol) of 3-methylsulfamoyl-2-chloroacetylthiophene in 20 ml of anhydrous dimethylformamide are added dropwise over 20 minutes under a nitrogen atmosphere to a suspension of 0.27 g of sodium hydride in 5 ml of absolute dimethylformamide. Initially, the pale solution turns dark over time, the pH drops to about 7.5. Another 10 min. after which it is neutralized with hydrochloric acid and the solvent is distilled off. The oily residue is partitioned between 2N hydrochloric acid and methylene chloride. After phase separation, the aqueous layer is shaken several times with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol.

3,4-Dihydro-2-methyl-b-oxo-2H-eno [2,3-a] -1,2-thisine-1,1-dioxide is obtained.

Sp. 130-131 ° C.

0.9 g (0.1 mmol) of 3,3-dihydro-2-methyl-4-oxo-2H-thieno [2,3-e] 7,2,2-thiazine-1,1-dioxide and 1 + 9 g (2.1 mmol) of phenyl isocyanate are dissolved in 9 ml of absolute dimethylformamide and the solution is added dropwise under a nitrogen atmosphere for 10 min. to a suspension of 0.11 g of sodium hydride. Another 15 min. after which time the dark solution is poured into 50 ml of ice-cold 3 .mu.l of hydrochloric acid to give a yellow solid. The aqueous layer is shaken several times with methylene chloride and the combined organic phases are extracted with sodium carbonate solution. After the carbonate solution has been acidified with hydrochloric acid, shake again with methylene chloride. The organic phase thus obtained is dried over sodium sulfate, mixed with activated carbon, filtered and evaporated. The oily residue is crystallized from benzene. The title compound obtained can be recrystallized from benzene. Sp. 2i + 8-251 ° C (dec.).

Example 2h: U-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno [2,3-b] -1,2-thiazine-3-carboxamide-1,1-dioxide 1.1 g (5 mmol) 3 Dissolve 1,1'-dihydro-2-methyl-1+ -oxo-2H-thieno [2,3-7-1,2-thiazine-1,1-dioxide and 0.75 g of freshly distilled pyrrolidine in 1.5 ml absolute benzene, and the solution is heated to reflux for 72 hours using a water generator. The solvent is then distilled off and the crystalline residue is dried in vacuo. The resulting 2-methyl-h- (1-pyrrolidino) -2H-thieno-β, 1,3-e-1,2-thiazine-1,1-dioxide is sufficiently pure for further reactions, but can be recrystallized from benzene / ether = 1 : 9. mp 183-18 ° C +.

Slurry with 1.2 g (U, U mmol) of 2-methyl-U- (1-pyrrolidino) -2H-thieno [2,3-b] -1,2-thiazine-1,1-dioxide 20 ml in absolute tetrahydrofuran and 5 ml of absolute benzene and 0.8 ml of triethylamine, a solution of 0.5 g (5 mmol) of phosgene in 5.5 ml of absolute benzene is added dropwise at -10 ° C over 2 k 59253. and 3 ml of absolute tetrahydrofuran. The brown suspension is warmed to room temperature and stirred for 3 hours. It is then added dropwise over 30 minutes. a solution of 0.68 g of 2-aminothiazole and 0.8 ml of triethylamine in 5 ml of absolute tetrahydrofuran is heated and the mixture is refluxed for 16 hours. Finally, the mixture is poured into ice water and extracted with methylene chloride. The combined extracts are dried over sodium sulfate, filtered and concentrated to 30 ml. A yellow precipitate then forms, in which case it is a by-product whose m.p. is 319-321 ° C. The solution is now completely evaporated and the oily residue is separated by column chromatography (60 g of silica gel, grain size 0.063-0.2 mm, eluent: benzene / ethanol = 9: 1). The purest fractions are combined and evaporated. The residue crystallizes immediately to give 2-methyl-N- (1-pyrrolidino) -3- (2-thiolylcarbamoyl) -2H-thieno [2,3-e] -2,2-thiazine-1, 1-dioxide, which can be used directly for the next reaction. Sp. 1T7 ~ 1T9 ° C.

0.6 g (1.5 mmol) of 2-methyl-N- (1-pyrrolidino) -3- (2-thiazolylcarbamoyl) -2H-thieno [2,3-e] -1,2-thiazine-1,1 The dioxide is heated in 20 ml of 2N hydrochloric acid for 1 hour under reflux. After cooling, shake several times with methylene chloride. The combined organic phases are extracted with sodium carbonate solution. Acidification of the aqueous layer releases the title compound. It can be dissolved in methylene chloride, dried over sodium sulfate and evaporated to give a pure product which can be recrystallized from ethanol. Sp. 225 ° C (dec.).

Claims (2)

25 5 925 3 Patents: 1. A process for the preparation of therapeutically useful U-hydroxy-2H-thieno [2,3-e] and [3,3-e] -1,2-thiazine-3-carboxamide-1,1 for the preparation of -dioxide derivatives of the general formula CC2> 'C-CO-NH-R2 OH in which A together with the molar carbon atoms represents the group τ-γ! or s 1 and the dashed line in the first case represent a double bond, R 1 is C 1 alkyl, R 1 is 2-thiazolyl, 1 + -methyl-2-thiazolyl, 1 +, 5-dimethyl-2-thiazolyl, 2-pyrazinyl, 2-pyrimidinyl , 2-pyridyl, 3-pyridyl, U-pyridyl, 3-methyl-2-pyridyl, 1-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6- dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3, .alpha.-dimethyl-5-isoxazolyl, 2,6-dimethyl-.alpha.-pyrimidipyl, 1,2,3) -yl or phenyl optionally substituted by halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy, characterized in that a) a compound of general formula v! f | COOR OH 26 5 92 5 3 wherein R is lower alkyl and A and R 1 are as defined above is reacted with an amine of general formula h 2 n -r 2 'm wherein R 1 is as defined above, or b) the formula ✓ a reactive derivative of an acid according to the formula wherein A, R 1 and R 2 have the same meaning as above, is cyclized, or c) a compound having is the general formula A! I v 1. C-CO-NH-Ro V OH - wherein A and R g are as defined above, lower alkylated, or d) a compound of general formula, a; 1 XK it 0 wherein A and R 1 are as defined above is reacted in the presence of a strong base with an isocyanate of formula o = c = n-r 2 XX '* wherein R 2 is as defined above, or 27 5 925 3 e) hydrolysed enamine of general formula SO Λ T λ 'i XXI V__ | CO-NH-Kg R5 where A, R1 and R2 are as defined above, and R1. and R 9 are each alkyl or together with the nitrogen atom form a pyrroline, pyrrolidine piperidine, morpholine or N- (lower alkyl) piperazine ring. Process for the preparation of k-hydroxy-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide derivatives of the formula I according to Claim 1, in which formula A together with both carbon atoms R 2 is 2-thiazolyl, k-methyl-2-thiolyl, t, 5-dimethyl-2-thiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridyl, 3 -methyl-2-pyridyl, -methyl-2-pyridyl, 5'-ethyl-2-pyridyl, 6-methyl-2-pyridyl, 1 ', 6-dimethyl-2-pyridyl, 5-isoxazolyl or phenyl optionally substituted by halogen, hydroxy, former alkyl, trifluoromethyl or alanipalkoxy, and R 1 is as defined in claim 1, characterized in that a compound of formula II in which A, R and R 1 are as defined above is reacted with a compound of formula With the amine of formula III, wherein R 2 is as defined above. A process for the preparation of U-hydroxy-2H-thieno [3,3e] -1,2-thiazine-3-carboxamido-1,1-dioxide derivatives of the formula I according to claim 1, wherein in formula A together with the molar carbon atoms SR 2 and R 2 are as defined in claim 2, characterized in that the amine of formula II in which A, R and R 1 are as defined above is reacted with an amine of formula III in which R 2 is as defined above. . A process for the preparation of H-hydroxy-2-methyl-N-2-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamide-1,1-dioxide according to claim 1. characterized in that a compound of formula II in which A is as defined in claim 2 and R 1 is methyl is reacted with an amine of formula III in which R 2 is 2-pyridyl or a reactive derivative of an acid of formula IV in which in formula R 1 is methyl and R 8 is 2-pyridyl, cyclized, or a compound of formula V wherein R 8 is 2-pyridyl and A is as defined in claim 2, methylated, or a compound of formula IX wherein R 1 is methyl, and A is as defined in claim 2, is reacted with a compound of formula XX wherein R 1 is 2-pyridyl, or a compound of formula XXI wherein R 1 is methyl, R 2 is 2-pyridyl, and A is as defined in claim 2. , hydrolyzed. 29 5925 3 Pat entkrav: 1. A compound for the therapeutic use of U-hydroxy-2H-thieno [2 ”, 3-e / och / 3 *, k-ej-1,2-thiazine-3-carboxamide-1,1-dioxide derivatives denmänna formuleln so5 GC -, C-C0-NH-Ro 2 OH color A tillsammans med de bäda kolatomerna betecknar Gruppen I | eli er? and in the case of a straight-chain bed and a double bond, C 1-4 alkyl, R 2 and 2-thiazolyl, U-methyl-2-thiazolyl, U, 5-dimethyl-2-thiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 2-pyridyl, 3-pyridyl, t-pyridyl, 3-methyl-2-pyridyl, U-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3,1-dimethyl-5-isoxazolyl, 2,6-dimethyl-pyrimidinyl, 1,2,3,11- tetrazol-5-yl or, optionally, halogen, hydroxy, englycyl, trifluoromethyl or haloalkoxy substituted with phenyl, känneteck-n at därav, att mana) asätter en förening med den allmänna formuleln S02 »/ · NV .1 I ii c ^ \, ncoor OH color R är lägrealkyl, och A och R ^ har ovan nämnda betydelse, med en Amin med Dai allmänna formeln H2N-R2 III color R2 har ovan nämnda betydelse, eller i p1 30 5 9 2 5 3 b) cyclical and reactive derivatives of the formula A 'ΐ Rl IV c Hg -c 0-KH -R2 COOH color A, R ^ and R ^ har ovan nämnda betydelse, elle r c) a first alkylate having a formulation of AA »'NH A I I ^ P-C0-NH-R2 v! OH color A and R2 are present in these forms, or (d) in the case of the same form A '] * IX fl 0 color A and R1 are present in the form of a form 0 = C = N-R2 XX color R2 har ovan nämnda betydelse, eller e) hydrolyserar en enamin med den allmänna formuleln aS0? RY c ^ 'cv, NCO-NH-R A R5 R6 color A, R ^ och and R2 haranan nämnda betydelse, och R, - och R ^ bdada betecknar alkyl-grupper eller bildar tillsammans med kväveatomen en pyrrolin-, en pyrrolidin- , en piperidine, and morpholine or N- (lower real) piperazine.