NO760614L

NO760614L - THIAZINE DERIVATIVES.

Info

Publication number: NO760614L
Application number: NO760614A
Authority: NO
Inventors: Dieter Binder; Otto Hromatka; Rudolf Pfister; Paul Zeller
Original assignee: Hoffmann La Roche
Priority date: 1976-02-24
Filing date: 1976-02-24
Publication date: 1977-08-25

Description

Tiazinderivater.Thiazine derivatives.

Foreliggende oppfinnelse vedrorer tiazinderivater og da tieno-tiazinderivater med generell formel The present invention relates to thiazine derivatives and then to thieno-thiazine derivatives with a general formula

hvori R-^betyr lavere alkyl, wherein R-^ means lower alkyl,

R-2 resten av en eventuelt med en eller to lavere alkylgrupper substituert aromatisk heterocyklus med 1 til 4 heteroatomer eller en eventuelt med halogen, hydroksy, lavere alkyl, nitro, trifluormetyl eller lavere alkoksy substituert fenylrest og R^og R^betyr hver hydrogen eller lavere alkyl. R-2 the residue of an aromatic heterocycle with 1 to 4 heteroatoms optionally substituted with one or two lower alkyl groups or a phenyl residue optionally substituted with halogen, hydroxy, lower alkyl, nitro, trifluoromethyl or lower alkoxy and R^ and R^ each mean hydrogen or lower alkyl.

Det i beskrivelsen anvendte uttrykk "lavere alkyl" betegner rettkjedede eller forgrenede mettede hydrokarbongrupper med 1-4 karbonatomer, som f.eks. metyl, etyl, propyl, isopropyl, •t-butyl o.l.. Uttrykket "lavere alkoksy" refererer seg til hydrokarbonoksygrupper med opp til 4 C-atomer. Betegnelsen "halogen", refererer seg til de 4 halogene klor, brom, fluor, jod. Begrepet "rest av en eventuelt med en eller to lavere alkylgrupper substituert aromatisk heterocyklus med 1-4 heteroatomer" omfatter eventuelt med en eller to lavere alkylgrupper substituerte rester av 5- eller 6-leddede aro-matiske heterocykler med 1-4 nitrogen- og/eller surstoff-og/eller svovelatomer, som 2-tiazolyl, 4-metyl-2-tiazolyl, 4,5-dimetyl-2-tiazolyl, 5-metyl-l,3,4-tiadiazolyl, 2-pyrazinyl, The term "lower alkyl" used in the description denotes straight-chain or branched saturated hydrocarbon groups with 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, t-butyl etc. The term "lower alkoxy" refers to hydrocarbonoxy groups with up to 4 C atoms. The term "halogen" refers to the 4 halogens chlorine, bromine, fluorine, iodine. The term "residue of an optionally substituted with one or two lower alkyl groups aromatic heterocycle with 1-4 heteroatoms" includes optionally substituted with one or two lower alkyl groups residues of 5- or 6-membered aromatic heterocycles with 1-4 nitrogen and/or or oxygen and/or sulfur atoms, such as 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl,

2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 3-metyl-2-pyridyl, 4-metyl-2-pyridyl, 5-metyl-2-pyridyl, 6-metyl-2-pyridyl, 4,6-dimetyl-2-pyridyl, 5-isoksazolyl, 5- metyl-3-isoksazolyl, 3,4-dimetyl-5-isoksazolyl, 2,6-dimetyl-4-pyrimidinyl, 1,2,3,4-tetrazol-5-yl o.l. 2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2- pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5- methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl-4- pyrimidinyl, 1,2,3,4-tetrazol-5-yl, etc.

I en foretrukket klasse av forbindelser med formel I betyrIn a preferred class of compounds of formula I means

og R^hydrogen. R^er fortrinnsvis metylgruppen. utgjor fortrinnsvis 2-tiazolyl, 5-metyl-3-isoksazolyl eller 2-pyridyl; videre foretrukne forbindelser for substituenten R^ er 4-fluorfenyl, 3-trifluormetylfenyl, 2,4-diklorfenyl, 4-bromfenyl, 4-nitrofenyl, 3-klorfenyl, 2-tolyl, 2, 5-diklorfenyl, 4-nitro-2-tolyl, 4-jodfenyl og 4-n-butylfenyl. and R₂ hydrogen. R 1 is preferably the methyl group. is preferably 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl; further preferred compounds for the substituent R 1 are 4-fluorophenyl, 3-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-tolyl, 2,5-dichlorophenyl, 4-nitro-2- tolyl, 4-iodophenyl and 4-n-butylphenyl.

Representative representanter for tienodiazinderivatene medRepresentative representatives of the thienodiazine derivatives with

den generelle formel I er 3,4-dihydro-2-metyl-3-okso-4-(2-pyridyl-karbamoyl)-2H-tieno [2, 3-e] 1, 2-tiazin-l, 1-dioksyd og 3,4-dihydro-2-metyl-3-okso-4-(2-tiazolyl-karbamoyl)-2H-tieno [2,3-eJ1,2-tiazin-1,1-dioksyd. the general formula I is 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide and 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-εJ1,2-thiazine-1,1-dioxide.

Tienotiazinderivatene med formel I kan fremstilles ifolge oppfinnelsen ved at man The thienothiazine derivatives of formula I can be prepared according to the invention by

a) omsetter en forbindelse med den generelle formela) reacts a compound with the general formula

hvori R betyr lavere alkyl og wherein R means lower alkyl and

R-j^, R^ogR^har ovennevnte betydning, R-j^, R^ and R^ have the above meaning,

med et amin med den generelle formel with an amine of the general formula

hvori R^har ovennevnte betydning, b) cykliserer et reaktivt syrederivat med den generelle formel wherein R^ has the above meaning, b) cyclizes a reactive acid derivative of the general formula

hvori R, R.^, R2, R^ og R4 har ovennevnte betydning, wherein R, R.sub.2, R.sub.2, R.sub.4 and R.sub.4 have the above meaning,

eller at manor that one

c) omsetter en forbindelse med den generelle formel c) reacts a compound with the general formula

hvori R-j^, R^ og R^har ovennevnte betydning, i nærvær av en sterk base med et isocyanat med den generelle formel wherein R-j^, R^ and R^ have the above meanings, in the presence of a strong base with an isocyanate of the general formula

hvori R^ har ovennevnte betydning. wherein R^ has the above meaning.

Omsetningen ifolge fremgangsmåtevariant a) kan skje i nærvær eller fravær av et inert losningsmiddel. Som losningsmidler egner seg alkoholer som etanol etc, hydrokarboner som benzen, toluen, xylen etc, halogenerte hydrokarboner som kloroform, klorbenzen, metylenklorid, tetraklorkullstoff etc eller dimetylformamid eller dioksan. Omsetningen skjer fortrinnsvis ved oppvarming hvorved smelte- eventuelt tilbakelopstemperaturen av reaksjonsblandingen er særlig foretrukket. The reaction according to method variant a) can take place in the presence or absence of an inert solvent. Suitable solvents are alcohols such as ethanol etc, hydrocarbons such as benzene, toluene, xylene etc, halogenated hydrocarbons such as chloroform, chlorobenzene, methylene chloride, carbon tetrachloride etc or dimethylformamide or dioxane. The reaction preferably takes place by heating whereby the melting or reflux temperature of the reaction mixture is particularly preferred.

Ifolge fremgangsmåteaspektet b) ifolge foreliggende oppfinnelse cykliseres et reaktivt syrederivat med formelen iy. Denne cykliseringen skjer i nærvær av en base og fortrinnsvis i nærvær av et losningsmiddel ved en temperatur mellom o°C og til-bakelopstemperatur for reaksjonsblandingen, fortrinnsvis mellom romtemperatur og 6o°C. Som baser kommer særlig hydrider, amider eller alkoholater av alkalimetaller i betraktning-Som losningsmidler egner seg aprotiske og protiske, som alkoholer (f.eks. metanol, etanol), eter (f.eks. dioksan), syreamider (f.eks. dimetylformamid), dimetylsulfoksyd osv. Hensiktsmessig gjennom-føres cykliseringen slik at man loser utgangsforbindelsen i løsningsmiddelet, blander med basen og enten lar reaksjonsblandingen stå i 1 til 4 timer ved romtemperatur eller oppvarmer til en temperatur opp til 6o°C. Som reaktive syre-derivater med formel IV egner særlig dimetylestrene seg. According to method aspect b) according to the present invention, a reactive acid derivative with the formula iy is cyclized. This cyclization takes place in the presence of a base and preferably in the presence of a solvent at a temperature between o°C and the reflux temperature of the reaction mixture, preferably between room temperature and 6o°C. As bases, in particular hydrides, amides or alcoholates of alkali metals come into consideration-As solvents suitable are aprotic and protic, such as alcohols (e.g. methanol, ethanol), ether (e.g. dioxane), acid amides (e.g. dimethylformamide ), dimethyl sulfoxide, etc. The cyclization is expediently carried out so that the starting compound is dissolved in the solvent, mixed with the base and either left to stand for 1 to 4 hours at room temperature or heated to a temperature of up to 6o°C. The dimethyl esters are particularly suitable as reactive acid derivatives of formula IV.

Ifolge fremgangsmåteaspekt c) omsettes en forbindelse medAccording to method aspect c) a compound is reacted with

den generelle formel V i nærvær av.en sterk base med et isocyanat med den generelle formel VI. Som sterke baser egner i forste rekke seg tertiære aminer, særlig trialkylaminer, of the general formula V in the presence of a strong base with an isocyanate of the general formula VI. Tertiary amines, particularly trialkylamines, are suitable as strong bases.

som trietylamin. Omsetningen skjer fortrinnsvis under en inertgass, f.eks. nitrogen, ved en temperatur mellom o°C og 5o°C, fortrinnsvis ved romtemperatur og i nærvær av et apro-tisk losningsmiddel, som toluen, dioksan, dimetylformamid, dimetylsulfoksyd eller heksametylfosforsyretriamid (HMTP). such as triethylamine. The reaction preferably takes place under an inert gas, e.g. nitrogen, at a temperature between o°C and 5o°C, preferably at room temperature and in the presence of an aprotic solvent, such as toluene, dioxane, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide (HMTP).

De som utgangsstoffer benyttede isocyanater med formel VIThey used isocyanates of formula VI as starting materials

er enten kjente eller kan syntetiseres analogt til fremstillingen av de kjente representanter. are either known or can be synthesized analogously to the production of the known representatives.

Utgangsstoffene med formlene II, IV og V kan fremstillesThe starting materials of the formulas II, IV and V can be prepared

ifolge etterfølgende reaksjonsskjerna hvori hal betyr halogen og R, R^, R2> R^ og R4har ovenfor nevnte betydning. according to the subsequent reaction nucleus in which hal means halogen and R, R^, R2 > R^ and R4 have the above-mentioned meanings.

Av forbindelsene med formel VII er 3-klor-tiofen-2-karbonsyren kjent, hvorved denne imidlertid ble fremstilt på relativt komplisert måte. En enklere måte for fremstilling av 3-klor-tiof en- 2-karbonsyre består deri at man overforer den kjente 3-hydroksytiofen-2-karbonsyre-metylesteren i et inert, over 8o°C kokende losningsmiddel, som kloroform eller dioksan med et kloreringsmiddel som fosforpentaklorid, intermediært til 3-klor-tiofen-2-karbonsyrekloridet og hydrolyserer dette til den tilsvarende syren. På analog måte kan også substi- Of the compounds with formula VII, 3-chloro-thiophene-2-carboxylic acid is known, whereby this was, however, produced in a relatively complicated manner. A simpler way of producing 3-chloro-thiophene-2-carboxylic acid consists in transferring the known 3-hydroxythiophene-2-carboxylic acid methyl ester into an inert solvent boiling above 8o°C, such as chloroform or dioxane with a chlorinating agent as phosphorus pentachloride, intermediate to the 3-chloro-thiophene-2-carbonic acid chloride and hydrolyzes this to the corresponding acid. In an analogous way, substi-

tuerte 3-klor-tiofen-2-karbonsyrer (forbindelser med formel VII hvori hal betyr klor og R^. og/eller R^ er forskjellig fra hydrogen). Skjont det for etterfølgende beskrevne fremstilling av en forbindelse med formel VIII prinsipielt også kan anvendes en bromforbindelse som utgangsmateriale, lonner det seg å tuated 3-chloro-thiophene-2-carboxylic acids (compounds of formula VII in which Hal is chlorine and R₂ and/or R₂ is different from hydrogen). Although a bromine compound can in principle also be used as starting material for the preparation of a compound of formula VIII described below, it is worthwhile to

anvende den tilsvarende klorforbindelsen.use the corresponding chlorine compound.

Overforingen av en halogentiofenkarbonsyre tilsvarende formelenThe transfer of a halothiophenecarboxylic acid corresponding to the formula

VII i et kaliumsalt av en sulfo-tiofen-karbonsyre med formelVII in a potassium salt of a sulfo-thiophene-carboxylic acid of formula

VIII skjer ifolge i og for seg kjente metoder ved omsetningVIII takes place according to per se known methods during turnover

av forbindelsen med formel VII med natriumhydrogensulfitt i nærvær av en kopper(I)salt-katalysator, særlig kopper(I)klorid, of the compound of formula VII with sodium hydrogen sulphite in the presence of a copper (I) salt catalyst, in particular copper (I) chloride,

og omsetning av det erholdte reaksjonsproduktet med kalium-and reaction of the obtained reaction product with potassium

klorid. Ved omsetning med natriumhydrogensulfitt burde for oppnåelse av optimale utbytter en temperatur på 143°C holdes. chloride. When reacting with sodium hydrogen sulphite, a temperature of 143°C should be maintained to achieve optimum yields.

Overforingen av forbindelsen med formel VIII i den tilsvarendeThe conversion of the compound of formula VIII into the corresponding

frie syren med formel IX skjer på i og for seg kjent måte,the free acid with formula IX takes place in a manner known per se,

f.eks. med en sterk ionebytter.e.g. with a strong ion exchanger.

Forestringen av syren med formel IX til esteren med formel XThe esterification of the acid of formula IX to the ester of formula X

skjer autokatalytisk (nærvær av sulfogruppen) i en alkohol/ kloroform-blanding. For dannelsen av metylesteren loses syren i metanol/kloroform og reaksjonsblandingen oppvarmes til kokepunktet for den ternære azeotropen (metanol/kloroform/ reaksjonsvann). occurs autocatalytically (presence of the sulfo group) in an alcohol/chloroform mixture. For the formation of the methyl ester, the acid is dissolved in methanol/chloroform and the reaction mixture is heated to the boiling point of the ternary azeotrope (methanol/chloroform/reaction water).

Overforingen av en forbindelse med formel X i syrehalogenidetThe transfer of a compound of formula X into the acid halide

med formel XI skjer på i og for seg kjent måte med et halogenerings-middel, fortrinnsvis med et kloreringsmiddel som tionylklorid with formula XI takes place in a manner known per se with a halogenating agent, preferably with a chlorinating agent such as thionyl chloride

eller fosforpentaklorid. Kloreringen med tionylklorid kan skje uten losningsmiddel ved tilbakelopsoppvarming. Ved anvendelse or phosphorus pentachloride. The chlorination with thionyl chloride can take place without a solvent by reflux heating. When applying

av fosforpentaklorid kan i nærvær av et inert losningsmiddel som kloroform, tetraklorkullstoff, dioksan arbeides og ved en . temperatur mellom 5o°c og tilbakelopstemperaturen for reaksjonsblandingen. of phosphorus pentachloride can in the presence of an inert solvent such as chloroform, carbon tetrachloride, dioxane be worked on and at a . temperature between 5o°c and the reflux temperature of the reaction mixture.

Forbindelsen med formel XI kan imidlertid også fremstilles ut fra det videre ovenfor nevnte kaliumsaltet av en sulfo-tiofen-karbonsyre tilsvarende formelen VIII over en forbindelse med formelen XII. Hertil omsettes det nevnte kaliumsalt f.eks. med 2 mol fosforpentaklorid og i nærvær av fosforoksyklorid som losningsmiddel ved en temperatur mellom 3o°C og kokepunktet for fosforoksyklorid. I stedet for fosforoksyklorid kan imidlertid også anvendes et inert organisk losningsmiddel som dioksan, kloroform, karbontetraklorid, benzen, toluen o.l. However, the compound with formula XI can also be prepared from the above-mentioned potassium salt of a sulfothiophene carboxylic acid corresponding to formula VIII over a compound with formula XII. For this, the aforementioned potassium salt is converted, e.g. with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as solvent at a temperature between 3o°C and the boiling point of phosphorus oxychloride. Instead of phosphorus oxychloride, however, an inert organic solvent such as dioxane, chloroform, carbon tetrachloride, benzene, toluene etc. can also be used.

Forestringen av forbindelsen med formel XII til tilsvarende ester med formel XI skjer med den tilsvarende alkoholen, særlig metanol ved en temperatur mellom romtemperatur og til-bakelopstemperatur. Som losningsmiddel kan alkoholen tjene eller et inert losningsmiddel som kloroform, karbontetraklorid, dioksan eller benzen. The esterification of the compound of formula XII to the corresponding ester of formula XI takes place with the corresponding alcohol, in particular methanol at a temperature between room temperature and reflux temperature. Alcohol or an inert solvent such as chloroform, carbon tetrachloride, dioxane or benzene can serve as solvent.

Forbindelsen med formelen XI aminoalkyleres så til en forbindelse med formelen XIII. The compound of formula XI is then aminoalkylated to a compound of formula XIII.

Aminoalkyleringen av en forbindelse med formelen XI skjer påThe aminoalkylation of a compound of the formula XI takes place on

i og for seg kjent måte ved omsetning med et alkylamin med den generelle formel in a manner known per se by reaction with an alkylamine of the general formula

hvori har ovenfor nevnte betydning, in which has the above-mentioned meaning,

i nærvær av et inert organisk losningsmiddel som kloroform, metylenklorid, karbontetraklorid, benzen eller dioksan ved romtemperatur. in the presence of an inert organic solvent such as chloroform, methylene chloride, carbon tetrachloride, benzene or dioxane at room temperature.

Forbindelsen med formel XIII forsåpes så til tilsvarende fri karbonsyre, eksempelvis ved oppvarming med alkali .som kalium-hydroksyd, fortrinnsvis i vandig/alkoholisk medium.' Den erholdte frie karbonsyren overfores heretter i det tilsvarende syrekloridet, dette omvandles med diazometan i det tilsvarende diazometylketonet, og siste gir ved behandling med solvnitrat og en lavere alkanol den tilsvarende forbindelsen med formelen XIV (hvorved produktet kan opptre i to konformasjonsisomere former, hvorav den ene til-svarer formelen XIV og den andre som folge av en kelataktig hydrogenbro oppviser en cyklisk struktur og hvorved som bipro-dukter somme tider også kan oppstå tilsvarende forbindelser til formelen XVI og/eller V). Ved omsetning av forbindelsen XIV henholdsvis dens konformasjonsisomere med en klormaursyreester med den generelle formel The compound of formula XIII is then saponified to the corresponding free carbonic acid, for example by heating with alkali such as potassium hydroxide, preferably in an aqueous/alcoholic medium. The free carbonic acid obtained is then transferred into the corresponding acid chloride, this is converted with diazomethane into the corresponding diazomethyl ketone, and the latter gives, on treatment with solvnitrate and a lower alkanol, the corresponding compound with the formula XIV (whereby the product can appear in two conformationally isomeric forms, one of which corresponds to the formula XIV and the other which, as a result of a chelate-like hydrogen bridge, exhibits a cyclic structure and whereby, as by-products, similar compounds to the formula XVI and/or V can sometimes also occur). By reacting the compound XIV or its conformational isomers with a chloroformate ester of the general formula

hvori R har ovennevnte betydning, wherein R has the above meaning,

i nærvær av en sterk base som natriummetyla.t, erholder man en forbindelse med formel XV, som ved cyklisering i analogi med den lenger ovenfor beskrevne cykliseringen av en forbindelse med formel IV (f.eks. ved oppvarming med natriumhydrid i dioksan) kan overfores i den tilsvarende forbindelsen med formelen II. in the presence of a strong base such as sodium methylate, a compound of formula XV is obtained, which by cyclization in analogy to the cyclization of a compound of formula IV described further above (e.g. by heating with sodium hydride in dioxane) can be transferred in the corresponding compound of formula II.

For fremstilling av forbindelser med formelen IV omsetter man en forbindelse med formel XIV, henholdsvis dens konformasjonsisomere (eller også en forbindelse med formel XV) med et amin med formel III, hvorved man fremgår analogt til den lenger ovenfor beskrevne omsetningen av forbindelsene med formel II og III og hvorved man så, når man som reaksjonspartner for aminet med formelen III har valgt en forbindelse med formelen XIV, må omsette det erholdte produktet deretter også i nærvær av en sterk base med en klormaursyreester med formelen XVIII. For the preparation of compounds of the formula IV, a compound of the formula XIV, respectively its conformational isomers (or also a compound of the formula XV) is reacted with an amine of the formula III, whereby it appears analogously to the further above described reaction of the compounds of the formula II and III and whereby one then, when a compound of formula XIV has been selected as a reaction partner for the amine of formula III, the product obtained must then also be reacted in the presence of a strong base with a chloroformate ester of formula XVIII.

Til forbindelser med formel V kan man nå ved at man forsåperCompounds of formula V can be reached by saponification

en forbindelse med formel XIV (henholdsvis deres konformasjonsisomere) (f.eks. under alkaliske betingelser) og deretter cykliserer den erholdte forbindelsen med formelen XVI, eksempelvis ved behandling med tionylklorid. a compound of formula XIV (respectively their conformational isomers) (e.g. under alkaline conditions) and then cyclizes the resulting compound of formula XVI, for example by treatment with thionyl chloride.

Forbindelsene med formlene II, IV, V og XIV til Xyi er nyeThe compounds of formulas II, IV, V and XIV to Xyi are new

og tilhorer gjenstanden for foreliggende oppfinnelse, likeså fremgangsmåten for fremstillingen av disse forbindelsene. and belongs to the object of the present invention, as does the method for the production of these compounds.

Forbindelser med den generelle formel I har en antiinflamma-torisk, analgetisk og antireumatisk virkning. Disse verdifulle farmakologiske egenskapene kan bestemmes under anvendelse av standardmetoder, eksempelvis i den kjente Kaolin-Pfotenoe-demtesten (på rotte). I denne testen fremkalles i rottens hoyre bakpote ved intradermal injeksjon av o,1 ml av en lo%'ig kaolinsuspensjon (bolus alba) en akutt lokalbetennelse. Substansen som skal undersokes administreres pr. oral vei, Compounds of the general formula I have an anti-inflammatory, analgesic and anti-rheumatic effect. These valuable pharmacological properties can be determined using standard methods, for example in the known Kaolin-Pfotenoe-dem test (on rats). In this test, acute local inflammation is induced in the rat's right hind paw by intradermal injection of 0.1 ml of a 10% kaolin suspension (bolus alba). The substance to be examined is administered per oral route,

og de folgende parametrene måles:and the following parameters are measured:

1. Tverrsnittet av poten i mm (som uttrykk for betennelsens heftighet); 2. Trykk (i g) på poten (for bestemmelse av smertegrensen). 1. The cross-section of the paw in mm (as an expression of the severity of the inflammation); 2. Press (in g) on the paw (to determine the pain threshold).

1/2 time for og 3 1/2 time etter kaolininjeksjonen administreres substansen som skal undersokes, og 4 timer etter kaolininjeksjonen måles de ovenfor nevnte parametre. Den odemhemmende effekten angis i prosent basert på differansen av odemintensi-teten mellom ubehandlede og med de dyr som er behandlet med substansen som skal undersokes, den antinoziseptive aktiviteten ved den prosentuale forhoyelsen av smertegrensen. 1/2 hour before and 3 1/2 hours after the kaolin injection, the substance to be examined is administered, and 4 hours after the kaolin injection, the above-mentioned parameters are measured. The edema-inhibiting effect is stated in percentage based on the difference in the edema intensity between untreated and with the animals treated with the substance to be investigated, the antinociceptive activity by the percentage increase in the pain threshold.

I denne testen viser forbindelsene med formel I en odemhemming og en forhoyelse av smertegrensen. Dessuten hemmer de - som det også kan vises i en tilsvarende standardtest - blodplate-aggregeringen og har dermed også antitrombotiske egenskaper. In this test, the compounds of formula I show an inhibition of edema and an increase in the pain threshold. In addition, they - as can also be shown in a corresponding standard test - inhibit platelet aggregation and thus also have antithrombotic properties.

Forbindelsene med formel I besitter kvalitativt en lignende virkning som fenylbutazon, som er kjent for sin terapeutiske anvendelse og egenskaper. The compounds of formula I possess a qualitatively similar action to phenylbutazone, which is known for its therapeutic use and properties.

Forbindelsene med formel I kan finne anvendelse som legemidler, f.eks. i form av farmasoytiske preparater som inneholder dem i blanding med et for enteral eller parenteral applikasjon egnet, farmasoytisk, organisk eller uorganisk inert bæremateriale, som f.eks. vann, gelatin, gummi arabicum, melkesukker, stivelse, magnesiumstearat, talkum, planteoljer, polyalkylenglykoler, vaselin osv. De farmasoytiske preparatene kan foreligge i fast form, f.eks. som tabletter, drasjéer, suppositorier, kapsler, i halvfast form, f.eks. som salver, eller i flytende form, f.eks. som losninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og/eller inneholder hjelpestoffer, som konserverings-, stabiliserings- eller emulgeringsmidler, salter for endring av det osmotiske trykk eller puffer. De kan også enda inneholde andre terapeutisk verdifulle stoffer. The compounds of formula I can find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations containing them in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral application, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules, in semi-solid form, e.g. as ointments, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers. They may also still contain other therapeutically valuable substances.

De etterfolgende eksempler, hvori alle temperaturer er angittThe following examples, in which all temperatures are indicated

i Celsiusgrader, belyser oppfinnelsen.in degrees Celsius, explains the invention.

EKSE MPEL 1EXE MPEL 1

52,1 g fosforpentaklorid opploses i 600ml abs. karbontetraklorid og oppvarmes til koking, hvoretter i lopet av 3 timer en losning av 15,8 g 3-hydroksy-2-metoksykarbonyl-tiofen i 2oo ml karbontetraklorid tildryppes. Det kokes 13 timer ved tilbakelop, så blir karbontetrakloridet avdestillert og reaksjonsblandingen inndampet i vakuum nesten til torrhet. Under kjoling tildryppes 45o ml vann hvoretter man oppvarmer til koking og så lar avkjole. Det utfelte produktet frafiltreres og kokes opp i en losning av 25 g natriumhydrogenkarbonat med lo g aktivkull, hvoretter aktivkullet frafiltreres og den avkjolte losningen surgjores med saltsyre, hvorved man erholder 3-klor-tiofen-2-karbonsyre med smeltepunkt 185 - 186°. Dissolve 52.1 g of phosphorus pentachloride in 600 ml abs. carbon tetrachloride and heated to boiling, after which, over the course of 3 hours, a solution of 15.8 g of 3-hydroxy-2-methoxycarbonylthiophene in 2oo ml of carbon tetrachloride is added dropwise. It is boiled for 13 hours at reflux, then the carbon tetrachloride is distilled off and the reaction mixture is evaporated in vacuo almost to dryness. During dressing, 450 ml of water is added, after which it is heated to boiling and then left to cool. The precipitated product is filtered off and boiled in a solution of 25 g of sodium bicarbonate with 100 g of activated carbon, after which the activated carbon is filtered off and the cooled solution is acidified with hydrochloric acid, whereby 3-chloro-thiophene-2-carbonic acid with a melting point of 185 - 186° is obtained.

I en glassautoklav opploses 8,6 g 3-klortiofen-2-karbonsyreDissolve 8.6 g of 3-chlorothiophene-2-carbonic acid in a glass autoclave

i 23 ml vann inneholdende 2,1 g natriumhydroksyd, hvoretter en losning av 5,6 g natriumhydrogensulfitt i 16 ml vann tilsettes og losningen blir gjort akkurat alkalisk med 3o%'ig natronlut. Så blandes med o,43 g kopper(I)klorid og oppvarmes 16 timer på 143°. Etter avkjølingen frafiltreres det rode kopperoksydet. Heretter surgjores med 7 ml konsentrert saltsyre hvorved ikke-omsatt utgangsmateriale faller ut, som fjernes ved utrysting med metylenklorid. Den sure losningen blandes under oppvarming méd 12 g kaliumklorid, hvorved etter . avkjoling til o° mono-kaliumsaltet av 3-sulfo-tiofen-2-karbonsyre skiller seg ut i fargelose krystaller. in 23 ml of water containing 2.1 g of sodium hydroxide, after which a solution of 5.6 g of sodium hydrogen sulphite in 16 ml of water is added and the solution is made just alkaline with 30% caustic soda. It is then mixed with 0.43 g of cupric (I) chloride and heated for 16 hours at 143°. After cooling, the red copper oxide is filtered off. The mixture is then acidified with 7 ml of concentrated hydrochloric acid, whereby unreacted starting material falls out, which is removed by shaking with methylene chloride. The acidic solution is mixed while heating with 12 g of potassium chloride, whereby after . cooling to o° the mono-potassium salt of 3-sulpho-thiophene-2-carboxylic acid separates in colorless crystals.

8,2 g av det ovenfor nevnte mono-kaliumsaltet av 3-sulfo-tiofen-2-karbonsyren opploses i 5o ml vann. Denne losningen blir latt strommme gjennom en ionebyttersoyle som er ladet med protoner, hvorved det ettervaskes så lenge med vann til pH-verdien av den utstrommende losningen utgjor 5. Losningen inndampes i vakuum til torrhet, og den krystalline resten, som består av 3-sulfo-tiofen-2-karbonsyre omkrystalliseres med lite vann. 8.2 g of the above-mentioned mono-potassium salt of 3-sulfo-thiophene-2-carboxylic acid are dissolved in 50 ml of water. This solution is allowed to flow through an ion exchange column that is charged with protons, whereby it is washed with water until the pH value of the flowing solution is 5. The solution is evaporated in vacuo to dryness, and the crystalline residue, which consists of 3-sulfo -thiophene-2-carboxylic acid is recrystallized with a little water.

7,6 g 3-sulfo-tiofen-2-karbonsyre opploses i 14o ml abs. metanol og 65 ml abs. kloroform og kokes ved tilbakelop, hvorved reaksjonsvannet avdestilleres som ternær azeotrop (kloro- 7.6 g of 3-sulfo-thiophene-2-carboxylic acid is dissolved in 140 ml abs. methanol and 65 ml abs. chloroform and boiled at reflux, whereby the reaction water is distilled off as a ternary azeotrope (chloro-

form, metanol, vann) over en kolonne med fyllegemer (lm). Så avdampes i vakuum. For å fjerne sporene metanol blandes resten med loo ml kloroform, hvoretter det inndampes under normaltrykk. Den forblevne brune oljen, bestående av 3-sulfo-tiofen-2-karbonsyremetylester, utkrystalliserer straks etter avkjolingen. Krystallene er dog hygroskopiske og smelter ved luften. form, methanol, water) over a column of fillers (lm). It is then evaporated in a vacuum. To remove traces of methanol, the residue is mixed with 100 ml of chloroform, after which it is evaporated under normal pressure. The remaining brown oil, consisting of 3-sulfothiophene-2-carboxylic acid methyl ester, crystallizes immediately after cooling. However, the crystals are hygroscopic and melt in the air.

7,4 g rå 3-sulfo-tiofen-2-karbonsyremetylester opploses i 5o ml tionylklorid og kokes 16 timer ved tilbakelop. Så inndampes i vakuum til torrhet, hvorpå den tilbakeblevne lysegule oljen, bestående av 3-klorsulfonyl-tiofen-2-karbonsyremetylester, bringes til krystallisasjon med petroleter. 7.4 g of crude 3-sulfo-thiophene-2-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride and boiled for 16 hours at reflux. It is then evaporated in vacuo to dryness, after which the remaining pale yellow oil, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester, is crystallized with petroleum ether.

Overforingen av mono-kaliumsaltet av 3-sulfo-tiofen-2-karbonsyre i 3-klorsulfonyltiofen-2-karbonsyremetylesteren kan også gjennomføres som folger: 5o g (o,2o3 mol) mono-kaliumsalt av 3-sulfotiofen-2-karbonsyre suspenderes i 25o ml fosforoksyklorid og under roring tilsettes 85 g (o,4o6 mol) fosforpentaklorid (heftig HCl-utvikling finner sted). Så oppvarmes enda 9o minutter på vannbadet under roring, avkjoles til romtemperatur, uorganiske salter frafiltreres og fosforoksykloridet avdestilleres i vakuum så godt som mulig. Den oljeaktige resten opploses for fjerning av enda tilstede-værende uorganiske salter i 4oo ml torr kloroform, filtreres og inndampes. Den oljeaktige resten, bestående av 3-klorsul-fonyl-tiofen-2-karbonsyreklorid, utkrystalliserer ved avkjoling og innsettes uten videre rensing i det neste trinnet. 48 g (o, 196 mol) av det således erholdte 3-klorsulfonyl-tiofen-2-karbonsyreklorid opploses i 5oo ml abs. kloroform, tilsettes 9,6 g (o,3 mol) abs. metanol og oppvarmes 3 timer ved tilbakelop (til slutten av HCl-utviklingen). Så inndampes i vakuum til torrhet hvorved den av ren 3-klorsulfonyl-tiofen-2-karbon-syremetylester bestående resten utkrystalliserer. Råproduktet kan settes inn i det neste trinn. The conversion of the monopotassium salt of 3-sulfothiophene-2-carboxylic acid into the 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester can also be carried out as follows: 5o g (0.2o3 mol) monopotassium salt of 3-sulfothiophene-2-carboxylic acid is suspended in 250 ml of phosphorus oxychloride and, with stirring, add 85 g (0.406 mol) of phosphorus pentachloride (violent HCl evolution takes place). It is then heated for another 9o minutes in the water bath while stirring, cooled to room temperature, inorganic salts are filtered off and the phosphorus oxychloride is distilled off in vacuum as best as possible. The oily residue is dissolved in 400 ml of dry chloroform to remove any inorganic salts still present, filtered and evaporated. The oily residue, consisting of 3-chlorosulphonyl-thiophene-2-carbonic acid chloride, crystallizes on cooling and is used without further purification in the next step. 48 g (0.196 mol) of the thus obtained 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride is dissolved in 500 ml abs. chloroform, add 9.6 g (0.3 mol) abs. methanol and heated for 3 hours at reflux (until the end of HCl evolution). It is then evaporated in vacuo to dryness, whereby the residue consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester crystallizes out. The raw product can be fed into the next step.

43,5 g (o,18 mol) av den således erholdte 3-klorsulfonyl-tiofen- 43.5 g (0.18 mol) of the 3-chlorosulfonyl-thiophene thus obtained

2-karbonsyremetylesteren opploses i 45o ml abs. kloroform og ved lo o innfores torket metylamin inntil et pH-papir fuktet The 2-carboxylic acid methyl ester is dissolved in 45o ml abs. chloroform and at lo o introduce dried methylamine until a pH paper moistened

med losningen viser alkalisk reaksjon. Så blir det latt etter-reagere 2 timer ved romtemperatur hvorved losningen alltid skal forbli alkalisk. Heretter utrystes med 5oo ml vann og 5oo ml with the solution showing alkaline reaction. It is then left to react for 2 hours at room temperature, whereby the solution must always remain alkaline. Hereafter shake with 500 ml of water and 500 ml

5%'ig natriumhydrogenkarbonatlosning (de vandige fasene tilbake-rystes hver én gang med kloroform), de forenede organiske fasene torkes med natriumsulfat og inndampes. Den krystalline resten rives med eter for rensing. Man erholder 3-metylsulfamoyl-tiofen-2-karbonsyremetylester med smeltepunkt 115 - 122°. 5% sodium bicarbonate solution (the aqueous phases are shaken back each time with chloroform), the combined organic phases are dried with sodium sulphate and evaporated. The crystalline residue is triturated with ether for purification. 3-Methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained with a melting point of 115 - 122°.

23.5 g (o,l mol) 3-metylsulfamoyl-tiofen-2-karbonsyremetyl-ester opploses under oppvarming i 5o ml etanol, blandes med 5o ml 3n kaliumhydroksydlosning og oppvarmes 3 timer under tilbakelop. Etter avkjoling fortynnes med vann og utrystes med metylenklorid. Den vandige fasen surgjores med saltsyre 23.5 g (0.1 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester are dissolved under heating in 50 ml of ethanol, mixed with 50 ml of 3N potassium hydroxide solution and heated for 3 hours under reflux. After cooling, dilute with water and shake out with methylene chloride. The aqueous phase is acidified with hydrochloric acid

og ekstraheres flere ganger med hver gang 5o ml eter. Etter torking med natriumsulfat og avdamping av løsningsmiddelet erholder man fargelose krystaller som er rene nok for videre omsetning. Den erholdte 3-metyl-sulfamoyl-tiofen-2-karbonsyren kan omkrystalliseres fra vann. Smeltepunkt 182 - 184°. and extracted several times with 5o ml of ether each time. After drying with sodium sulphate and evaporation of the solvent, colorless crystals are obtained which are pure enough for further processing. The 3-methyl-sulfamoyl-thiophene-2-carboxylic acid obtained can be recrystallized from water. Melting point 182 - 184°.

11.06 g (o,o5 mol) 3-metylsulfamoyl-tiofen-2-karbonsyre og 15,8 g (o,o75 mol) fosforpentaklorid oppslemmes i 15o ml abs. kloroform og rores 3o minutter ved 4o°. Så inndampes skånsomt i vakuum til det.halve volum. Man fortynner med 4oo ml abs. eter og drypper den kjoiede losningen i lopet av 1 time til en på -2o° avkjolt eterisk diazometanlosning fremstilt av 5o g nitrosometylurea. Etter fjerning av kjolebadet las utreagere enda 1 1/2 time og avkjoles så til -4o°, hvorpå det utfelte diazometyl-(3-metyl-sulfamoyl-tiofen-2-yl)-ketonet frafiltreres; smeltepunkt llo - 111° (fra etanol). 11.06 g (o.o5 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid and 15.8 g (o.o75 mol) of phosphorus pentachloride are suspended in 15o ml of abs. chloroform and stirred for 3o minutes at 4o°. Then gently evaporate in a vacuum to half the volume. Dilute with 400 ml abs. ether and drop the concentrated solution over the course of 1 hour into a -2o° cooled ethereal diazomethane solution prepared from 5o g of nitrosomethylurea. After removal of the dressing bath, the reaction is left for another 1 1/2 hours and then cooled to -4o°, after which the precipitated diazomethyl-(3-methyl-sulfamoyl-thiophen-2-yl)-ketone is filtered off; melting point llo - 111° (from ethanol).

3 g (o,ol22 mol) diazometyl-(3-metylsulfamoyl-tiofen-2-yl)-keton opploses i 3o ml abs. metanol og oppvarmes etter tilsetning av 5o g solvnitrat 45 minutter ved tilbakelop. Så inndampes i vakuum hvorpå man koker ut resten med eter flere ganger, rorer de forenede eterfåsene med aktivkull og filtrerer. Filtratet inneholder hovedsakelig 3-metyl-sulfamoyl-2-tiofen- eddiksyremetylester ved siden av lite 3-metyl-sul£amoyl-2-tiofeneddiksyre og 3,4-dihydro-2-metyl-3-okso-2H-tieno[2,3-eJ1,2-tiazin-1,1-dioksyd. For fjerning av 3-metylsulfamoyl-2-tiofen-eddiksyren blir eterlosningen flere ganger utrystet med natrium-hydrogenkarbonatlésning, torket og inndampet. For ringåpning av 3,4-dihydro-2-metyl-3-okso-2H-tieno[ 2, 3-e]1,2-tiazin-l,1-dioksyd opptas den nettopp nevnte inndampingsresten med 12 ml ln metanolisk natriummetylatlosning, hvoretter losningen får stå 2o minutter ved romtemperatur, så surgjores akkurat med kons. saltsyre og inndampes i vakuum til torrhet. Inndampingsresten opptas med metylenklorid og vann; den organiske fasen torkes og inndampes. Den oljeaktige resten består til omtrent like deler av to konformasjonsisomere former av 3-metylsulfa-moyl-2-tiofen-eddiksyrenietylester og kan uten videre rensing anvendes i det neste trinn. 3 g (0.0122 mol) of diazomethyl-(3-methylsulfamoyl-thiophen-2-yl)-ketone are dissolved in 30 ml of abs. methanol and heated after adding 50 g of solvate nitrate for 45 minutes at reflux. It is then evaporated in a vacuum, after which the residue is boiled off with ether several times, the combined ether phases are stirred with activated charcoal and filtered. The filtrate mainly contains 3-methyl-sulphamoyl-2-thiophene-acetic acid methyl ester, in addition to a small amount of 3-methyl-sul£amoyl-2-thiopheneacetic acid and 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2, 3-εJ1,2-thiazine-1,1-dioxide. To remove the 3-methylsulfamoyl-2-thiophene-acetic acid, the ether solution is shaken several times with sodium bicarbonate solution, dried and evaporated. For ring opening of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide, the evaporation residue just mentioned is taken up with 12 ml of methanolic sodium methylate solution, after which the solution is allowed to stand for 2o minutes at room temperature, then just acidified with conc. hydrochloric acid and evaporated in vacuo to dryness. The evaporation residue is taken up with methylene chloride and water; the organic phase is dried and evaporated. The oily residue consists of approximately equal parts of two conformationally isomeric forms of 3-methylsulfa-moyl-2-thiophene-acetic acid niethyl ester and can be used in the next step without further purification.

De to formene kan man atskille soylekromatografisk (kiselgel, kornstorrelse o,o63 - o,2 mm; eluent: benzen/iseddik = 4:1): Raskere eluerbar form: The two forms can be separated by soil chromatography (silica gel, grain size o.o63 - o.2 mm; eluent: benzene/glacial vinegar = 4:1): Faster eluting form:

<X>H-NMR (CDC13): é = 7,2 - 7,4 (qAB, 2H, H-4tiofen og<X>H-NMR (CDC13): é = 7.2 - 7.4 (qAB, 2H, H-4thiophene and

H-<5>tiQfen), <f = 4,8-5,3 (m, 1H, N-H,H-<5>thiQphene), <f = 4.8-5.3 (m, 1H, N-H,

D20 utvekselbar) , </ = 4,15 (s, 2H, -CH2-COOCH3), cf = 3,7 (s, 3H, 0-CH3), cf = 2,65 D20 exchangeable) , </ = 4.15 (s, 2H, -CH2-COOCH3), cf = 3.7 (s, 3H, 0-CH3), cf = 2.65

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

Langsommere eluerbar form:Slower eluting form:

<1>H-NMR (CDC1J : / =7,65 (s, 2H, H-4,,. _ og<1>H-NMR (CDC1J : / =7.65 (s, 2H, H-4,,. _ and

3 tiofen ^3 thiophene ^

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

tiofenthiophene

D„0 utvekselbar), /= 4, 4o (s, 2H,D„0 exchangeable), /= 4, 4o (s, 2H,

-CH2-COOCH3) ,<f = 3,4o (s, 3H, 0-CH3) ,-CH2-COOCH3) , <f = 3.4o (s, 3H, 0-CH3) ,

</ = 2,6 ppm (d, 3H, NH-CH3, J = 6 Hz).</ = 2.6 ppm (d, 3H, NH-CH3, J = 6 Hz).

Begge formene spaltes ved destillasjon i hoyvakuum.Both forms are split by distillation in high vacuum.

1,15 g (o,oo461 mol) rå 3-metylsulfamoyl-2-tiofen-eddiksyre-metylester opploses i 4,7 ml ln metanolisk natriummetylatlosning hvorpå man inndamper losningen i vakuum til torrhet, opptar resten med lo ml abs. dimetylformamid, avkjoler til o° og tildrypper o,5o g (o,oo525 mol) klormaursyremetylester. Etter 1/2 times roring ved romtemperatur inndampes i vakuum, hvoretter resten 1.15 g (0.oo461 mol) of crude 3-methylsulfamoyl-2-thiophene-acetic acid methyl ester are dissolved in 4.7 ml of methanolic sodium methylate solution, after which the solution is evaporated in vacuo to dryness, the residue taken up with 10 ml of abs. dimethylformamide, cool to o° and add dropwise o.5o g (o.oo525 mol) chloroformic acid methyl ester. After stirring for 1/2 hour at room temperature, evaporate in a vacuum, after which the remainder

opptas med metylenklorid og vann og den organiske .fasen atskilles, torkes og inndampes. Den av rent 3-(N-metoksykarbonyl-N-metyl-sulf amoyl) -2-tiof en-eddiksyremetylester bestående oljeaktige resten kan uten videre.rensing anvendes i det neste trinn. is taken up with methylene chloride and water and the organic phase is separated, dried and evaporated. The oily residue consisting of pure 3-(N-methoxycarbonyl-N-methyl-sulfamoyl)-2-thiophene-acetic acid methyl ester can be used in the next step without further purification.

■ 1H-NMR-spektrum (CDCl3) : <f = 7,2 - 7,4 (qAB, 2H,■ 1H-NMR spectrum (CDCl3): <f = 7.2 - 7.4 (qAB, 2H,

H-4^ . _ og H-5^ . • )H-4^. _ and H-5^ . • )

tiofen tiofenthiophene thiophene

/= 4,2 (s, 2H, CH2-COOCH3),/= 4.2 (s, 2H, CH2-COOCH3),

6 ' = 3,65 (s, 3H, -N-CO-OCH3),6' = 3.65 (s, 3H, -N-CO-OCH3),

é= 3,62 (s, 3H, CH2-COOCH3),é= 3.62 (s, 3H, CH2-COOCH3),

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

1,42 g (o,oo461 mol) rå 3-(N-metoksykarbonyl-N-metylsulfamoyl)-2-tiofen-eddiksyremetylester opploses i lo ml abs. dioksan og blandes med o,21 g (o,oo485 mol) 55%'ig natriumhydrid-suspen-sjon (i mineralolje), hvoretter man tilsetter 5o mg metanol og rorer 1 time ved 5o - 6o°. Så avkjoles, surgjores med iseddik og inndampes i vakuum. Resten opptas med metylenklorid og en mettet natriumhydrogenkarbonatlosning; den organiske fasen utrystes enda flere ganger med natriumhydrogenkarbonatlosning, hvorpå de vandige fasene forenes og surgjores med kons. saltsyre. Det utfelte bunnfallet utrystes med metylenklorid, hvorpå den organiske fasen torkes og inndampes. Den straks krystalliserende resten består av rent 3,4-dihydro-4-metoksykarbonyl-2-metyl-3-okso-2H-tieno[2,3-e]1,2-tiazin-l,1-dioksyd; smeltepunkt 124 - 126° (fra eter). 1.42 g (0.oo461 mol) crude 3-(N-methoxycarbonyl-N-methylsulfamoyl)-2-thiophene-acetic acid methyl ester is dissolved in 10 ml abs. dioxane and mixed with o.21 g (o.oo485 mol) 55% sodium hydride suspension (in mineral oil), after which 50 mg of methanol is added and stirred for 1 hour at 5o - 6o°. It is then cooled, acidified with glacial acetic acid and evaporated in a vacuum. The residue is taken up with methylene chloride and a saturated sodium bicarbonate solution; the organic phase is shaken several more times with sodium bicarbonate solution, after which the aqueous phases are combined and acidified with conc. hydrochloric acid. The precipitate is shaken with methylene chloride, after which the organic phase is dried and evaporated. The immediately crystallizing residue consists of pure 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide; melting point 124 - 126° (from ether).

o,3 g (1,1 mmol) 3,4-dihydro-4-metoksykarbonyl-2-mety1-3-okso-2H-tieno[2,3-e]1,2-tiazin-l,1-dioksyd og o,13 g (1,38 mmol) 2- aminopyridin opploses i 3o ml abs. xylen og oppvarmes 1 time ved tilbakelop. Etter avkjolingen frafiltreres krystallene og omkrystalliseres fra iseddik; man erholder 3,4-dihydro-2-metyl-3- okso-4-(2-pyridyl-karbamoyl)-2H-tieno [2,3-e]1,2-tiazin-l,1-dioksyd med smeltepunkt 255 - 256° (spalting). o.3 g (1.1 mmol) 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide and o.13 g (1.38 mmol) of 2-aminopyridine is dissolved in 3o ml of abs. xylene and heated for 1 hour at reflux. After cooling, the crystals are filtered off and recrystallized from glacial acetic acid; 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno [2,3-e]1,2-thiazine-1,1-dioxide is obtained with a melting point of 255 - 256° (cleavage).

EKSEMPEL 2EXAMPLE 2

o,15 g (o,55 mmol) 3,4-dihydro-4-metoksykarbonyl-2-metyl-3-okso-2H-tieno [2,3-e]1,2-tiazin-l,1-dioksyd og o,o71 g (o,71 mmol) 2-aminotiazol loses i 3o ml abs. xylen og oppvarmes 1/2 time o.15 g (o.55 mmol) 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno [2,3-e]1,2-thiazine-1,1-dioxide and o.o71 g (o.71 mmol) of 2-aminothiazole is dissolved in 3o ml of abs. xylene and heated for 1/2 hour

ved tilbakelop. Etter avkjoling frafiltreres krystallene og omkrystalliseres fra iseddik; man erholder 3,4-dihydro-2-metyl-3-okso-4-(2-tiazolyl-karbamoyl)-2H-tieno[2,3-e]1,2-tiazin-l,1-dioksyd med smeltepunkt 236 - 238° (spalting). in case of backflow. After cooling, the crystals are filtered off and recrystallized from glacial acetic acid; 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide is obtained with melting point 236 - 238° (cleavage).

EKSE MPEL AEXE MPEL A

På vanlig måte fremstilles suppositorier med folgende sammensetning: In the usual way, suppositories are produced with the following composition:

EKSEMPEL B EXAMPLE B

På vanlig måte fremstilles tabletter med folgende sammensetning : In the usual way, tablets are prepared with the following composition:

EKSEMPEL C EXAMPLE C

På vanlig måte fremstilles kapsler med folgende sammensetning: In the usual way, capsules are produced with the following composition:

Claims

1. Process for the preparation of thienothiazine derivatives of the general formula

wherein means lower alkyl, R^ means the residue of an aromatic heterocycle with 1 to 4 heteroatoms optionally substituted with one or two lower alkyl groups and a phenyl residue optionally substituted with halogen, hydroxy, lower alkyl, nitro, trifluoromethyl or lower alkoxy and R^ and R^ each mean hydrogen or lower alkyl, characterized in that mana) reacts with a compound of the general formula

wherein R means lower alkyl and A, R^ , R^ and R^ have the above meaning, with an amine of general formula

wherein R 2 has the above meaning, orb) cyclizes a reactive acid derivative of the general formula

wherein R, R^ , R 2 , R^ and R^ have the above meaning, or that manc) reacts with a compound of the general formula

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

wherein R 2 has the above meaning.

2. Process according to claim 1, characterized by atR2 t'etYr 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl , 2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2 -pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl- 4 - pyrimidinyl or 1,2,3,4-tetrazol-5-yl.

3. Process according to claim 1 or 2, characterized in that R^ and R^ mean hydrogen.

4. Process according to one of claims 1-3, characterized in that R means methyl.

5. Process according to one of claims 1-4, characterized by R2 being 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl.

6. Method according to one of claims 1, 3 and 4, characterized in that R2 ketY is 4-fluorophenyl, 3-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl,

3-chlorophenyl, 2-tolyl, 2,5-dichlorophenyl, 4-nitro-2-tolyl, 4-iodophenyl or 4-n-butyl-phenyl.

7. Method according to claim 5, characterized in that 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno [2,3-e]1,2- thiazine-1,1-dioxide.

8. Process according to claim 5, characterized in that 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno [2,3-e]l,2- thiazine-1,1-dioxide.

9. Procedure for the production of preparations with anti-inflammatory, analgesic, anti-rheumatic and anti-throm. botical properties, characterized by mixing a thienothiazine derivative with the general formula I specified in claim 1 as an active ingredient with suitable for therapeutic use, non-toxic, inert, as far as solid and liquid carriers common in such preparations and/or excipients pienter.

10 . Pharmaceutical preparation with anti-inflammatory, analgesic, antirheumatic and antithrombotic properties, containing a thienothiazine derivative with the general formula I specified in claim 1 and a carrier.

11. Compounds with the general formula.

wherein R, R^, R^ and R^ have the meaning stated in claim 1.

12. 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide.

13. Compounds with the general formula

wherein R, R^, R^, R^ and R^ have the meaning stated in claim 1.

14. Compounds with the general formula

in which R^ , R^ and R 4 have the meaning stated in claim 1.

15. 3,4-dihydro-2-methyl-3-oxo-2H-thieno[2,3^e]1,2-thiazine-1,1-dioxide.

16. Compounds with the general formula.

wherein R, R^, R^ and R^ have the meaning stated in claim 1. \

17. 3-Methylsulfamoyl-2-thiopheneacetic acid methyl ester.

18. Compounds with the general formula

wherein R, R^, R^ and R^ have the meaning stated in claim 1.

19. 3-(N-Methoxycarbonyl-N-methyl-sulfamoyl)-2-thiophene-acetic acid methyl ester.

20 . Compounds with the general formula

in which R , R^ and R^ have the meaning stated in claim 1.

21. 3-Methylsulfamoyl-2-thiopheneacetic acid.

22. Compounds with the general formula.

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

23. Compounds according to claim 22, characterized in that Rp means 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 1,2,4-triazin-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2- pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl-4- pyrimidinyl or 1,2,3,4-tetrazol-5-yl.

24. Compounds according to one of claims 22 and 23, characterized in that R^ and R^ mean hydrogen.

25. Compounds according to one of claims 22 - 24, characterized in that means methyl.

26. Compounds according to one of claims 22 - 25, characterized in that R 2 means 2-thiazolyl, 5-methyl-3-isoxazolyl or 2-pyridyl.

27. Compounds according to one of claims 22, 24 and 25, characterized in that R2 means 4-fluorophenyl, 3-trifluoromethyl-phenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 3-chlorophenyl, 2-tolyl, 2, 5-dichlorophenyl, 4-nitro-2-tolyl, 4-iodophenyl or 4-n-butyl-phenyl.

28. 3,4-dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-. 2H-thieno [2, 3-e] 1, 2-thiazine-1, 1-dioxide.

29. 3,4-dihydro-2-methyl-3-oxo-4-(2-thiazolyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine-1,1-dioxide.