NO146096B

NO146096B - ANALOGY PROCEDURE FOR THE PREPARATION OF THIENOTHIAZINE DERIVATIVES

Info

Publication number: NO146096B
Application number: NO752932A
Authority: NO
Inventors: Otto Hromatka; Dieter Binder; Rudolf Pfister; Paul Zeller
Original assignee: Hoffmann La Roche
Priority date: 1974-08-26
Filing date: 1975-08-26
Publication date: 1982-04-19
Also published as: LU73257A1; SE412066B; SU603338A3; ATA655975A; FR2309558A1; GB1519811A; LU88312I2; YU216675A; FI59253C; NL7510057A; NL930080I2; FR2309558B1; FR2303803B1; FI59253B; NO752932L; YU40266B; DK137835B; DK137835C; NL930080I1; NO146096C

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk virksomme, nye thienothiazinderivater av den generelle formel The present invention relates to an analogue method for the production of therapeutically effective, new thienothiazine derivatives of the general formula

hvori A danner med gruppen in which A forms with the group

den stiplede linjen viser doppeltbindingen i the dashed line shows the double bond i

gruppe (A) , group (A),

betyr lavere alkyl, means lower alkyl,

1*2 resten av en eventuelt med 1 eller 2 lavere alkyl- ;grupper substituert aromatisk heterosyklus med 1-4 ;heteroatomer eller en eventuelt ved halogen, hydrqksy, ;lavere alkyl, trifluormetyl eller lavere alkoksy substituert fenylrest og ;R og R^ hver betyr hydrogen eller lavere alkyl. ;Uttrykket "lavere alkyl" som anvendes i denne beskrivelsen betegner rettkjedede eller forgrenede mettede hydrokarbon-grupper med 1-4 karbonatomer, som f.eks. metyl, etyl, propyl, isopropyl, t-butyl og lignende. Uttrykket "lavere alkoksy" refererer seg til hydrokarbonoksygruppen med opptil 4 karbonatomer.- Betegnelsen "halogen", referer seg til de 4 halogenene klor, brom, fluor, jod. Begrepet "resten av en eventuelt ved en eller to lavere alkylgrupper substituert aromatisk heterosyklus med 1-4 heteroatomer" omfatter eventuelt ved en eller to lavere alkylgrupper substituerte rester av 5- eller 6-leddete aromatiske heterocykler med 1-4 nitrogenatomer og/eller oksygen-og eller svovelatomer, som 2-thiazolyl, 4-metyl-2-thiazolyl, 4, 5-dimetyl-2-thiazolyl, 5-metyl-l, 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-isooksazolyl, 5-metyl-3-isoksazyl, 3,4-dimetyl-5-isoksazyl, 2,6-dimetyl-4-pyrimidinyl, 6-metyl-2-pyridyl, 1,2,3,4-tetrezol-5-yl og lignende. ;I en foretrukket klasse av forbindelser av formel I betyr R 3 og R^ hydrogen, R^ er fortrinnsvis metylgruppen. R£ forestiller fortrinnsvis 2-thiazolyl, 5-isoksazolyl eller 2-pyridyl. ;En spesielt foretrukket forbindelse er 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno^2,3-e_7-l,2-thiazin-3-karboksamid-1,1-dioksyd. ;Thenothiazinderivatene av formel I kan ifolge oppfinnelsen fremstilles ved at man • ;a) omsetter en forbindelse av den generelle formel ;;hvori R betyr lavere alkyl og ;A, R , R, og R. har den oven angitte betydning, A, 6 4 med et amin av den generelle formel ;hvori R2 har den oven angitte betydning, ;eller ;b) cykliserer et reaksjonsdyktig funksjonelt derivat av en syre av formelen ;hvori A, R , R^, R^ og R^ har den oven angitte betydning, eller at man c) lavere alkylerer en forbindelse av den generelle formel ;hvori A, R2, R^ og R^ har de oven angitte betydninger, ;eller omsetter ;d) omsetter en forbindelse av den generelle formel ;;hvori A og R-^ har oven angitte betydning, ;i nærvær av en sterk base med et isocyanat av den generelle formel ;;hvori R2 har oven angitte betydning, ;eller ;e) hydrolyserer et enamin av den generelle formel ;;hvori A, R-^ og R2 har den oven angitte betydning, og ;R5 og R6 hver betyr lavere alkyl eller sammen med nitrogenatomet,danner pyrrolin, pyrrollidin, piperidin, morfolin eller N-(Lavere alkyl)-piperazin. ;Omsetningen etter fremgangsmåteaspekt a) kan foregå i nær- ;eller fravær av et inert opplosningsmiddel. Som opplosningsmiddel egner seg alkoholer, som etanol etc. Hydrokarboner som benzen, toluen, xylen, etc, halogenerte hydrokarboner, som kloroform, klorbenzen, metylenklorid, tetraklorkarboner, etc, eller dimetylformamid eller dioksan. Omsetninger foregår fortrinnsvis ;ved oppvarming, hvorved smelte- hhv. tilbakelopstemperaturen til reaksjonsblandingen er spesielt foretrukket. ;Etter fremgangsmåteaspekt b) ifolge foreliggende oppfinnelse ;blir et reaksjonsdyktig funksjonelt derivat av en forbindelse av formel IV cyklisert. Denne cyklisasjon foregår i nærvær av en base og fortrinnsvis i nærvær av et opplosningsmiddel ved en temperatur mellom 0°C og tilbakelopstemperaturen til reaksjonsblandingen, fortrinnsvis mellom romtemperatur og 60 oC. Som base kommer spesielt hydrider, amider og alkoholater av alkalimetaller på tale. Som opplosningsmiddel egner seg aprotiske og protiske, som alkoholer, f.eks. metanol, etanol, ;eter, f.eks. dioksan og syreamider, f.eks. dimetylformamid. Hensiktsmessig blir cyklisasjonen således utfort at man opploser utgangsforbindelsen av formel IV i opplosningsmiddel, tilsetter basen og lar reaksjonsblandingen stå i 1 - 4 timer enten ved romtemperatur eller oppvarmer til en temperatur opptil 6o°C. ;Som reaksjonsdyktig funksjonelt derivat av forbindelsene av ;formel IV egner seg spesielt disses lavere alkylestere, f.eks. deres metylestere. ;Etter fremgangsmåteaspekt-c) blir en forbindelse av formel V alky-lert. Denne alkyleringen blir hensiktsmessig således utfort at man opploser utgangsforbindelsen av formel V i et aprotisk opplosningsmiddel, som acetonitril, dioksan eller dimetylforma- ;mid, overforer med et alkalimetallamid eller - hydrid i alkalimetallsalfeet og så overforer til den tilsvarende forbindelsen av formel I ved behandling med et alkyleringsmiddel, spesielt et alkylhalogenid eller -sulfat. Temperatur og trykk er for disse fremgangsmåter ikke kritisk, slik at reaksjonen for enkelt-hets skyld blir utfort fortrinnsvis ved romtemperatur og atmosfære-trykk. ;De for fremgangsmåteaspekt a) nodvendige utgangsstoffer av ;formel II kan fremstilles ifolge de etterfolgende reaksjonsskjemaer. ;I dette skjemaet betyr Hal halogen og A, R og R^ har oven angitte betydning. Av forbindelsene av formel VI er 3-klor-thiofen-2-karboksylsyre, samt' 4-brom-thiofen-3-karboksylsyre bekj ent, hvorved den første ble fremstilt på relativt komplisert måte. En enklere metode for fremstilling av 3-klor-thiofen-2-karboksylsyre består deri at man intermediært overfører den kjente 3-hydroksythiofen-2-karboksylsyre-metylesteren i et inert, over 80°C kokende oppløs-ningsmiddel, som kloroform eller dioksan med et kloreringsmiddel som fosforpentaklorid i 3-klor-thiofen-2-karboksylsyrekloridet og hydrolyserer dette til tilsvarende syre. På analog måte kan også substituert 3-klor-thiofen-2-karboksylsyre (forbindelser av formel VI, hvori Hal betyr klor, A danner med begge karbonatomene gruppen hvori og eller R^ er forskjellige fra hydrogen). Selv om prinsipielt også en bromforbindelse f.eks. den kjente 4-brom-thiofen-3-karboksylsyren kan innsettes san utgangsmateriale ved fremstillingen av en forbindelse av formel VII, er anvendelsen av den tilsvarende klorforbindelsen tilrådelig. 4-klor-thiofen-3-karboksylsyre, som ikke er beskrevet i litteraturen, kan fremstilles ved å gå ut fra den bekjente 3-ketothifen-4-karboksylsyremetylesteren, idet man overfører denne ved hjelp av fosforpentaklorid under aromatisering i 4-klor-thiofen-3-karboksylsyreklorid og hydrolyserer dette til den tilsvarende syren. På analog måte kan også substituerte 4-klor-thiof en-3-karboksylsyrer (forbindelser av formel VI, hvori Hal betyr klor, A danner med begge karbonatomene gruppen ;hvori R^ og/eller R^ er forskjellige fra hydrogen, fremstilles. ;Overføringen av en halothiofenkarboksylsyre tilsvarende formel VI i et kaliumsalt av en sulfo-thiofenkarboksylsyre av formel VII foregår etter i og for seg kjente metoder ved omsetning av forbindelsen av formel VI med natriumhydrogensulfitt i nærvær av en kopper(I)saltkatalysator, spesielt kopper(I)klorid, og omsetning av det erholdte reaksjonsproduktet med kaliumklorid. Ved omsetning med natriumhydrogensulfid skulle for å få opti-malt utbytte holdes en temperatur på 143°C. ;Overføringen av forbindelsen av formel VII i den frie syren av formel VIII foregår på i og for seg kjent måte, med f.eks. en sterk ionebytter. ;Forestringen av syren av formel VIII til en ester av formel IX foregår autokatalytisk (nærvær av sulfogruppen) i en alkohol/ kloroform-blanding. For dannelse av metylesteren blir syren oppløst i metanol/kloroform og reaksjonsblandingen oppvarmet til kokepunktet til den ternære azeotropen (metanol/kloroform/ reaksjonsvann). ;Overføringen av en forbindelse av formel IX i syrehalogenidet av formel X foregår på i og for seg kjentimåte med et halogen-erings-, fortrinnsvis kloreringsmiddel, som thionylklorid eller - fosforpentaklorid. Kloreringen med thionylklorid kan også foregå uten oppløsningsmiddel ved tilbakeløpsoppvarmning. Ved anvendelse av fosforpentaklorid kan arbeides i nærvær av et inert oppløsningsmiddel, som kloroform, tetraklorkarbon, dioksan og ved en temperatur mellom 50°C og tilbakeløpstemperaturen til reaksjonsblandingen. ;Forbindelsen av formel X kan også fremstilles ved å gå ut fra et kaliumsalt av en sulfo-thiofen-karboksylsyre tilsvarende formelen VII over en forbindelse av formel XI. Til dette blir det nevnte kaliumsaltet overført f.eks. med 2 mol fosforpentaklorid og i nærvær av fosforoksyklorid som oppløsningsmiddel ved en temperatur mellom 30°C og fosforoksykloridets kokepunkt. I stedet for fosforoksyklorid kan imidlertid også et inert organisk oppløsningsmiddel, som dioksan, kloroform, tetraklorkarbon, benzen, toluen eller lignende anvendes. ;Forestringen av forbindelsen av formel XI til tilsvarende ester av formel X foregår med det tilsvarende alkohol, spesielt metanol, ved en temperatur mellom romtemperatur og tilbakeløpstempera-tur. Som oppløsningsmiddel kan alkoholen eller et- inert oppløs-ningsmiddel, som kloroform, tetraklorkarbon, dioksan eller benzen tjene. ;Fra mellomproduktet av formel X kan man komme frem til utgangsmaterialet av forne 1 II på to forskjellige måter. Den ene måten forer over en forbindelsene av for.m^L XII og XIII og den andre, eventuelt via forbindelsen XIV over forbindelsen XV. ;Etter den forstnevnte måte blir en forbindelse av formel X ;omsatt på i og for seg kjent måte med et glycinalkylester-hydroklorid, fortrinnsvis glycinetylesterhydroklorid. Omsetningen foregår fortrinnsvis i nærvær av et inert opplosningsmiddel, som pytidin, kloroform, dioksan, metylenklorid, benzen eller tetraklorkarbon, og ved romtemperatur. Den på denne måten erholdte forbindelsen av formel XII blir cyklisert ved en temperatur mellom 4o og 65°C i etanol med et alkali- eller jordalkalietylat, spesielt natriumetylt til forbindelsen av formel XIII, hvori R betyr etyl. Alkyleringen til utgangsmaterialet av forme II foregår på i . og for seg kjent måte, hensiktsmessig i et polart aprotisk opplosningsmiddel, som dimetylformamid, dimetylsulfoksyd eller heksametapol, med et alkyleringsmiddel, som et alkylhalogenid eller et dialkylsulfat ved en temperatur mellom 0°C og romtemperatur. ;Etter den andre måten blir en forbindelse av formel X enten forst aminoalkylert til en forbindelse av formel XIV og så overfort til forbindelsen XV eller forbindelsen X blir direkte overfort i forbindelsen XV. I begge tilfeller blir den erholdte forbindelsen av formel XV cyklisert til forbindelsen av formel ;II. ;Aminoalkyleringen av en forbindelse iav formel X foregår på i og for seg kjent måte ved omsetning med et alkylamin i nærvær av et inert organisk opplosningsmiddel, som kloroform, metylenklorid, tetraklorkarbon, benzen eller dioksan og ved romtemperatur. ;For fremstilling av forbindelsen av formel XV blir en således erholdt forbindelse av formel XIV omsatt påii og for seg kjent måte i nærvær av et polart aprotisk .opplosningsmiddel, som dimetylformamid, dimetylsulfoksyd eller heksametapol, med en forbindelse av formelen ;hvori R har den oven angitte betydning og ;X betyr halogen. ;Omsetningen foregår hensiktsmessig ved en temperatur mellom 0°C og romtemperatur. ;På den annen side erholder man på i og for seg kjent måte en forbindelse av formel XV, når man omsetter en forbindelse av formel X med en forbindelse av formel ;;hvori R og R^ har den oven angitte betydning, ;eller et syreaddisjonssalt derav. ;Omsetningen foregår hensiktsmessig ved romtemperatur. Ved innsetningen av et syreaddisjonssalt av en forbindelse av formel XVII blir det hensiktsmessig arbeidet i pyridin. I stedet for ;et syreaddisjonssalt kan imidlertid også 2 mol fritt amin anvendes, i hvilke tilfelle man foretrukket arbeider i dioksan, metylenklorid, benzen eller tetraklorkarbon. ;Cykliseringen av en forbindelse av formel XV til utgangsmateriale av formel II foregår hensiktsmessig ved en temperatur fra romtempetur til 65°C ved hj.elp av et alkali- eller jordalkali-metylat eller -etylat, fortrinnsvis natriummetylat eller natriumetylat i nærvær av metanol eller etanol. ;Forbindelsene av formel XVI og XVII er kjente eller kan fremstilles på i og for seg kjente måter. ;De for fremgangsmåteaspekt b) som utgangsforbindelser anvend-bare lavere alkylestere av syrer av formel IV kan erholdes idet man omsetter et amin av formel III med kloracetylklorid og omsetter det erholdte produktet av formel ;;hvori R2 har den oven angitte betydning, ;med en forbindelse av formel XIV. Andere reaksjonsdyktige funksjonelle derivater av syre av formel IX kan fremstilles ;på i og for seg kjente måter fra de erholdte estere. ;De for fremgangsmåte c) nodvendige utgangsstoffer av formel ;V kan erholdes ved omsetning av 'en forbindelse av formel XIII met et amin av formelen III. i ;Forbindelsene av formlene II, IV og VII til XV er nye og horer til foreliggende oppfinnelses gjenstand, likeledes som fremgangsmåten for fremstilling av disse forbindelsene. ;Forbindelsene av den generelle formel I har en- antiflammatorisk, analgetisk.. og antirheumatisk.. virkning. Disse verdifulle farmakologiske egenskapene kan bestemmes ved anvendelse av standardmetoder, eksempelvis i kjente^kaolin-poteodemtest ( på rotten). I denne testen blir den/hoyre bakpoten til- ;rotten fremkalt en akutt lokal betennelse ved intradermal injek-sjon av o,l ml av en lo%'ig kaolinsuspensjon (bolus alba). Substansen som skal undersokes blir administrert på oral måte ;og de folgende parametere blir målt: ;1. Gjennomsnitt av poten i mm ( som uttrykk for heftigheten av betennelsen) , ;2) Trykk (i g) på poten ( for å bestemme smertenivå). ;1/2 time for og 3 1/2 time etter kaolininjeksjonen blir den substansen som skal undersokes administrert, og 4 timer etter kaolin-injeksjonen blir blir de ovennevnte parametre målt. ;Den odemhemmende effekten blir angitt i prosent, basert på differansen av odemintensiteten mellom ubehandlede og med dyr behandlet med substansen som skal undersokes, den antino-siceptive aktivitet ved den prosentuelle forhoyning av smertenivået. ;I denne testen viser 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno / 2, 3-e7-l,2-thiazin-3-karboksyamid-l,1-dioksyd /LD^q ca 9oomg/kg, p.o. (mus)/ ved en dosering på 3 mg/kg p.o. en 27%'ig odemhemming og en 4%'ig forhoyning av smertenivået og ved en dosering på ;lo mg/kg p.o. en 43%'ig odemhemming og en 23%'ig forhoyning av smertenivået. ;Forbindelsene av formel I besitter kvalitativt en lignende virkning som fenylbutazon, som er kjent på grunn av sin terapeutiske anvendelse og egenskaper. ;Forbindelsene av formel I kan finne anvendelse som medisin, ;f.eks. i form av farmasoytiske .preparater, som inneholder dem i blandinger med en for den eHterale eller parenterale applikasjon egnet, farmasoytisk, organisk eller uorganisk inert bærermateriale• ;De etterfølgende eksemplene, i hvilke alle temperaturer er ;angitt i °C, illustrerer oppfinnelsen. ;EKSEMPEL 1 ;52,1 g fosforpentaklorid blir opplost i 600 ml abs. tetraklorkarbon og oppvarmet til koking, hvoretter i lopet av 3 timer ble tildryppet en opplosning på 15,8 g 3-hydroksy-2-metoksykar-bonylthiofen i 2oo ml tetraklorkarbon. Det blir kokt i 13 ;timer ved tilbakelop, så blir tetrjaklorkarbonet avdestillert og reaksjonsblandingen blir inndampet :i vakuum til nesten torrhet. ;i ;Under kjoling blir 45o ml van tildryppet, hvoretter man oppvarmer til koking og så lar avkjoles. Det utfelte produktet blir oppsugd og en opplosning av 25 g natriumhydrogenkarbonat blir kokt opp med lo g aktivkarbon, hvoretter aktivkarbonet blir oppsugd og den avkjolte opplosningen blir surgjort med saltsyre, hvorved man erholder 3-klor-thiofen-2-karboksylsyre med smp. 185-186°C. ;I en glassautoklav blir 8,6 g 3-klorthiofen-2-karboksylsyre ;i 23 ml 2,1 g natriumhydroksyd innholdende vann opplost, hvoretter en opplosning på 5,6 g natriumhydrogensulfitt i 16 ml vann blir tilsatt og opplosningen blir gjort alkalisk ;I ;med 3o%'ig natronlut. Deretter blir; tilsatt o,43 g kopper(I) klorid og oppvarmet i 16 timer til 143°C. Etter avkjoling blir det rode kopperoksydet avsuget. Heretter blir surgjort med 7 ml kons. saltsyre, hvorved ikke-omsatt utgangsmateriale blir utfelt, som blir fjernet mved utrystning med metylenklorid. ;Den sure opplosningen blir tilsatt under oppvarming med ;12 g kaliumklorid, hvorved etter kjoling til 0°Ckaliumsaltet til 3-sulfo-thiofen-2-karboksylsyre fraskilles i fargelose krystaller. ;8,2 g av ovennevnte kaliumsalt til 3-sulfo-thiofen-2-karboksylsyre blir opplost i 5o ral vann. Denne opplosningen blir latt flyte igjennom en ioneutbyttersoyle7 som er beladet med protoner, hvorved så lenge blir etterspylt med vann til pH-verdien til den utflytende opplosningen er 5. Opplosningen blir inndampet til torrhet i vakuum og den krystallinske resten som består av 3-sulfo-thiofen-2-karboksylsyre blir omkrystallisert fra litt vann. ;7,6 g 3-sulfo-thiofen-2-karboksylsyre blir opplost i 14o ml abs. metanol og 65 ml abs. kloroform og kokt ved tilbakelop, ;hvorved reaksjonsvannet blir avdestillert som ternaer azeotrop ;( kloroform, metanol, vann) over en fyllstoffkolonne. Så blir det avdampet i vakuum. For fjerning av spor metanol blir resten tilsatt med loo ml kloroform, hvoretter det blir inndampet ved normaltrykk. Den gjenblivende brune oljen, bestående av 3-sulfo-thiofen-2-karboksylsyremetylester, utkrystalliseres straks etter avkjolingen. Krystallene er dog hygroskopiske og blir flytende i luften. ;7.4 g rå 3-sulfo-thiofen-2-karboksylsyremetylester blir opplost i 5o ml thionylklorid og kokt 16 timer ved tilbakelop. ;Så blir det inndampet i vakumm til torrhet, hvoretter den gjenblivende lysgule oljen, bestående av 3-klorsulfonyl-thiofen-2-karboksylsyreetylester, blir brakt til krystallisa- ;sjon med petroleter. ;2o g 3-klorsulfonyl-thiofen-2-karboksylsyremetylester blir opplost i abs~ kloroform, hvoretter 21 g sarcosinetylester blir tildryppet i lopet av lo min. Deretter oppvarmer reaksjonsblandingen seg til 5o°c,Etter 2o min. blir det avkjolt, rystet med vann, o,5 n saltsyre og bikarbonatopplbsning, hver en gang, torket og inndampet. Den tilbakeblivende oljen, bestående av 3-(N-karboetoylmetyl-N-metyl-sulfamoyl)-thiofen-2-karboksyl-syremetylester, blir brakt til krysaatlisasjon med etanol, ;smp. 84-85°C, ;13,2 g 3-(N-karboetoylmetyl-N-metyl-sulfamoyl)-thiofen-2-karboksylsyremetylester blir suspendert i kulden i 42 ml ln metanolisk natriummetylatopplosning under nitrogenstrom. ;Etter 15 minutters roring foreligger en klar opplosning. Det ;blir oppvarmet i 2o min. ved tilbakelop, så avkjolt, noytralisert og inndampet i vakuum. Resten blir opptatt i metylenklorid, ;rystet hver en gang med vann og bikarbonatopplosning, torket og inndampet. Resten, bestående av 3-karbometoksy-4-hydroksy-2-metyl-2H-thieno,/2,3-e7~l,2-thiazin-l,1-dioksyd,blir brakt til krystallisasjon med metanol, smp. 193-195°C„ ;1,9 g 3-karbometoksy-4-hydroksy-2-metyl-2H-thieno/2 ,3-e7~ 1,2-thiazin-l,1-dioksyd blir sammen med o,9 g 2-amino-thiazol suspendert i 2 5o ml abs. xylen og oppvarmet 7 timer ved tilbakelop. ;hvorved 15o ml xylen blir langsomt avdestillert. Så blir den restlige xylen avdampet i vakuum. Den krystallinske resten, bestående av 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thienol £2, 3-e7-l,2-thiazin-3-karboksamid-l,1-dioksyd, blir omkrystallisert fra etanol, smp. 217°c(spaltning). ;EKSEMPEL 2 ;5o g ( o,2o3 mol) mono-kaliumsalt av 3-sulfothiofen-2-karboksylsyre blir suspendert i 25o ml fosforoksyklorid og tilsatt 85 g ( o,4o6 mol) fosforpentakloridI under roring ( heftig HCl-utvikling begynner). Så blir dét enda 9o min. på ;vannbadet oppvarmet under roring, avkjolt til romtemperatur, avsuget av uorganiske salter og fosforoksykloridet blir i vakuum avdestillert så godt som mulig. Den oljeaktige resten blir opplost for fjerning av enda forekommende uorganiske salter opplost i 4oo ml torr kloroform, filtrert og inndampet. Den oljeaktige resten, bestående av 3-klorsulfonyl-thiofen-2-karboksylsyreklorid krystalliseres ved avkjoling fra og blir innsatt i det neste trinnet uten ytterligere rensing. 48 g (o,196 mol) av det således erholdte 3-klorsulfonyl-thiof en-2-karboksylsyrekloridet blir opplost i 5oo ml abs. kloroform, tilsatt 9,6 g (o,3 mol) abs. metanol og oppvarmet i 3 timer ved tilbakelop ( til slutten av HCl-utviklingen). Deretter det inndampet i vakuum til ;torrhet, hvoretter resten bestående av ren 3-klorsulfonyl-thiofen-2-karboksylsyremetylester ble utkrystallisert. Råproduktet kan innsettes i det neste trinnet. ;43,5 g ( o,18 mol) av den således erholdte 3-klorsulfonyl-thiof en- 2- karboksylsyremety lesteren blir opplost i 45o ml abs. kloroform og innledet ved lo°cmed tort metylamin til et pH-papir fuktet med opplosningen viser alkalisk reaksjon. ;Så blir det latt etterreagere enda 2 timer ved romtemperauur, hvorved opplosningen alltid må være alkalisk. Heretter blir utrystet med 5oo ml vann og 5oo ml 5%'ig natriumhydrogenkarbonatopplosning ( den vandige fasene blir hver en gang med kloroform gjenrystet), de forente organiske fasene blir torket med natriumsulfat og inndampet. Den krystallinske resten blir digerert med ;i ;I ;eter. Man erholder 3-metylsulfamoyl-thiofen-2-karboksylsyre-metylester med smp. 115-122°c, ;43,5 g ( o,184 mol) av den således erholdte 3-metylsulfamoyl-thiofen-2-karboksylsyre-metylesteren blir opplost i 4oo ml abs. dimetylformamid og tildryppet til en rort suspensjon av 4,5 g ( o,187 mol) natriumhydrid i 5o ml abs. dimetylformamid i lopet av 1 time. Så blir det opplost ved o - 5°C( under kjoling) 4o g ( o,187 mol) jodeddiksyreetylester, tildryppet til 5o ml abs. dimetylformamid i lopet av 32 timer og latt etterreagere i 1 time ( til et fuktet pH-papir viser 7 - 8). Så blir det inndampet i vakuum, resten blir opptatt med 3oo ml o,5 n saltsyre og 3oo ml metylenklorid, den organiske fasen fraskilt, den vandige fasen etterrystet to ganger med litt metylenklorid og de forente organiske fasene utrystet med hver loo ml 5%'ig natriumhydrogenkarbonatopplosning ( de vandige fasene blir hver gjenrystet en gang med litt metylenklorid). De forente organiske fasene blir torket med natriumsulfat og inndampet. ;Den krystallinske resten blir for rensing digerert med litt kald etanol. Man erholder 3-,/TN-etoksykarbonylmetyl) -N-metyl7-sulf a-moyl-thiofen-2-karboksylsyremetylester med smp. 83-85°C, ;13,2 g ( o,o41 mol) av den således erholdte 3-</7N-etoksykarbonyl-metyl)-N-metyl7-sulfamoyl-thiofen-2-karboksylsyremetylesteren blir suspendert i kulden i 42 ml metanolisk natriummetylatopplosning i nitrogenatmosfære, hvorved alt opploser seg i lopet av 15 min. roring. Heretter blir det tilbakelopsoppvarmet i 25 min., avkjolt, noytralisert med kons. saltsyre og inndampet i vakuum. Resten blir tatt opp i metylenklorid, utrystet med hver eng gang med vann og 5%'ig natriumhydrogenkarbonatopplosning, torket og inndampet. Den krystallinske resten blir digerert med litt metanol for rensing. Man erholder 4-hydroksy-3-metoksykarbonyl-2-metyl-2H-thieno/2,3-e7-l,2-thiazin-l,1-dioksyd med smp. 193-195°csom kan .overfores ved omsetning med 2-amino-thiazol i 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno/2,3-e/- 1,2-thiazin-3-karboksamid-l,1-dioksyd med smp. 217°C(spaltning). ;EKSEMPEL 3 ;5o g ( o,2o3 mol) mono-kaliumsalt av 3-sulfothiofen-2-karboksylsyre blir suspendert i 25o ml fosforoksyklorid og under roring blir 85 g ( o,4o6 mol) fosforpentaklorid tilsatt ;(heftig HCl-utvikling begynner)j Deretter blir enda 9o min. oppvarmet på vannbadet under roring, avkjolt til rompemperatur, fra uorganiske salter avsuget og fosforoksykloridit så godt som mulig avdestillert. Den oljeartige resten blir opplost i 4oo ml i torr kloroform for å fjerne enda forekommende uorganiske salter, filtrert og inndampet. Den oljeaktige resten, bestående av 3-klorsulfonyl-thiofen-2-karboksylsyreklorid, krystalliseres ved avkjolingen fra og blir uten videre rensing innsatt i det neste trinnet. ;i ;48 g ( o,196 mol) av det således erholdte 3-klorsulfonyl-thiofen-2-karboksylsyrekloridet blir opplost i 5oo ml abs. kloroform, 9,6 g (o,3 mol) abs. metanol tilsatt og 3 timer tilbakelopsoppvarmet ( inntil slutten av HCl-utviklingen). ;Så blir inndampet i vakuum, hvorved den av ren 3-klorsulfonyl-thiof en-2-karboksylsyremetylester bestående resten utkrystalliseres. Råproduktet kan innsettes i det neste trinnet. ;2.41 g ( lo mraol) av den således erholdte 3-klorsulfonyl-thiof en-2-karboksylsyremetylesteren blir fordelt i lo ml abs. pyridin sammen med 1,53 g sarcosinetylesterhydroklorid og rort ved romtemperatur. Etter 2 timer blir det helt på 5o ml iskald 2n saltsyre og ekstrahert fem ganger med hver 2o ml metylenklorid. De forente organiske fasene ble torket med natriumsulfat, filtrert og inndampet. Den krystallinske resten ble digerert med litt iskald etanol. ;13,2 g ( o,o4 mol) av den således erholdte 3-,/TN-etoksy-karbonyl-metyl)-N-metyl7-sulfamoyl-thiofen-2-karboksylsyremetylesteren blir suspendert i kulde i 42 ml metanolisk natriummetylatopplosning i nitrogenatomsfære, hvorved alt opploser seg i lopet av 15 min. Heretter blir tilbakelopsoppvarmet i 25 min., avkjolt, noytralisert med kons. saltsyre og inndampet i vakuum. Resten ble tatt opp i metylenklorid, utrystet hver en gang ;med vann og 5%'ig natriumhydrogenkarbonatopplosning, torket og inndampet. Den krystallinske resten blir digerert med litt metanol for rensing. Man erholder -4-hydroksy-3-metoksykarbonyl- ;2-metyl-2H-thieno,/2", 3-e7-l, 2-thiazin-l, 1-dioksyd med smp. 193-195°c som kan overfores ved omseijaing med 2-aminothiazol til 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno/2, 3- e/- l,2-thiazin-3-karboksamid-l, 1-dioksyd med smp. 217°Q (spaltn.) som beskrevet i eksempel 1. ;. EKSEMPEL 4 ;12,o3 g ( o,o5 mol) 3-klorsulfonyl-thiofen-2-karboksylsyre-metylester og 7 g glycinetylesterhydroklorid ( o,o5 mol) blir suspendert i 5o ml abs. pyridin, hvorved alt sammen loser seg i lopet av 3o min. Det blir rort ytterligere 5 timer ved romtemperatur og deretter blir pyridinet avdestillert. Resten blir opptatt i 5o ml 2n saltsyre og 5o ml metylenklorid, den organiske fasen avseparert, det vandige sjiktet etterrystet fire ganger med litt metylenklorid, de forente organiske fasene vasket med vann og torket med natriumsulfat under tilsetning av aktivkarbon. Etter filtreringen blir inndampet, den oljeaktige resten inneholdende 3-(N-etoksykarbonylmetyl)-sulfmoyl-thiofen-2-karboksylsyremetylester kan uten ytterligere rensing innsettes i det neste trinnet. ;Til en opplosning av 1,38 g natrium ( o,o6 mol) i 2o ml abs. etanol blir tilsatt ved 4o°cen opplosning av 9,22 g ( o,o3 mol) ;av den ifolge ovenstående erholdte 3-(N-etoksykarbonylmetyl)-sulfamoyl-thiofen-2-karboksylsyreesteren i lo ml etanol og oppvarmet til 6o-65°c.Det blir enda rort i 2 timer ved denne temperaturen, deretter helt på loo ml iskald 2n saltsyre og utrystet med litt metylenklorid mange ganger. De forente organiske ekstraktene blir utrystet to ganger med hver 2o ml 5%'ig natriumacetatopplosning og så fire ganger med hver 25 ml lo%'ig natriumkarbonatopplosning. Ved torking og inndamping av den organiske fasen kan 2,5 g av utgangsmaterialet gjenvinnes. ;De forente karbonatekstraktene blir surgjort med saltsyre og utrystet med metylenklorid. Etter torkningen med natriumsulfat blir opplbsningsmiddelet avdestillert og den krystallinske resten digerert med litt eter. Man erholder 3-etoksykarbonyl-4-hydroksy-2H-thieno/2,3-§7-l,2-thiazin-l,1-dioksyd med smp. 148-15o°C. ;1,93 g ( 7 mmol) 3-etoksykarbonyl- 4-hydroksy-2H-thieno/2,3-§7-1, 2-thiazin-l, 1-dioksyd bli-r opplost i 4 ml abs. dimetylformamid og tildryppet til en rort suspensjon av o,185 g natriumhydrid ( 7,7 mmol) i 2 ml abs. dimetylformamid i lopet av 3o min. ved 0°c deretter blir det rort i 1 time til ved romtemperatur. Til opplosningen av natriumsaltet blir deretter o,53 ml ( 1,2 g, 8,45 mmol) og etter 3o min. ytterligere o,25 ml ( o,565 g, 4 mmol) metyljodid tilsatt og latt 1 time etterreagere. Etter avdestillering av opplosningsmidlet blir resten opptatt med 3o ml o,5 n saltsyre og 3o ml metylenklorid, den organiske fasen fraskilt, det vandige sjiktet to -ganger etterrystet med litt metylenklorid, det forente organiske ekstraktene torket over natriumsulfat og inndampet. Den krystallinske resten blir digerert med litt kald etanol. Man erholder 3-etoksykarbonyl- 4-hydroksy-2-metyl-2H-thieno^2,3-§7-l,2-thiazin-l,1-dioksyd med smp. 161-163°C( krystallomvandling ved 151-152° c), ;På analog måte som i siste avsnitt i eksempel 1 kan dette produktet omsettes med 2-aminothiazol til 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno,/2, 3-e7-l, 2-thiazin-3-karboksyamid-l, 1-dioksyd med spaltningspunkt 217°ci>;EKSEMPEL 5 ;Til en kokende opplosning av lod g fosforpentaklorid i 25o ml abs. tetraklorkarbon blir 25 g 3-keto-thiofan-4-karboksylsyre-metylester, opplost i litt abs. tetraklorkarbon, tildryppet i lopet av 2 timer. Så blir det kokt ved tilbakelop i 15 timer til avslutning av hydrogenkloridutviklingen og så inndampet, hvorved hovedmengden av fosforkloridet blir fordrevet. ;Resten blir rort med isvann i 1<;>time, hvoretter den organiske fasen fraskilles, den vandige fasen blir utrystet en gang til med metylenklorid og den forente organiske fasene'blir torket med natriumsulfat og deretter inndampet. Den gjenblivende brune oljen, bestående av 4-klor-thiofen-3-karboksylsyreklorid blir oppvarmet med 2n vandig natronlut ved 5o°Cså lenge som til det oppstår en homogen brun opplosning. Denne blir utrystet en gang med metylenklorid og surgjort med kons. saltsyre, hvoretter de utfelte krystallene, bestående av rå 4-klorthiofen-3-karboksylsyre,blir oppsugd. For rensning av de oppsugede krystallene blir de opplost i natriumbikarbonat og igjen utfelt med kons. saltsyre, smp. etter omkrystallisasjon fra vann 164°c. ;I en glassautoklav blir 8,6 g 4-klorthiofen-3-karboksylsyre opplost i 23 ml 2,1 g natriumhydroksyd-inneholdende vann, hvoretter en opplosning av 5,6 g natriumhydrogensulfit blir tilsatt til 16 ml vann og opplosning blir gjort akkurat alkalisk med 3o%'ig natronlut. Så blir det tilsatt med o,43 g kopper(I)klorid og oppvarmet til 143°Ci 16 timer. Etter avkjoling blir det rode kopperoksydet oppsuget. Filtratet blir surgjort med 7 ml kons. saltsyre, hvorved ikke-omsatt utgangsmateriale blir utfelt, dette blir fjernet ved utrystning med eter. Den sure opplosningen blir tilsatt under oppvarming med 12 g kaliumklorid, hvorved kaliumsaltet til 4-sulfothiofen-3-karboksylsyren fraskiller seg som fargelbse krystaller etter avkjoling til 0°C,Dette blir opplost i 5o ml vann og opplosningen får flyte gjennom en ioneutbyttersoyle, som er ladet med protoner, hvorved det blir etterspylt med vann så lenge inntil pH til den utflytende opplosningen er 5. Eluatet blir inndampet til torrhet i vakuum og så erholdes 4-sulfothiofen-3-karboksylsyre som krystallinsk rest. Smp. (fra vann) 154°C. ;7,6 g 4-sulfothiofen-3-karboksylsyre blir oppløst i 140 ml abs. metanol og 65 ml abs. kloroform kokt under tilbakelop, hvorved reaksjonsvannet blir avdestiller som terniær azeotrop (kloroform, metanol, vann) over en fyllmassekolonne (lm). ;Så blir det inndampet i vakuum. For fjerning av spor metanol blir resten tilsatt loo ml kloroform, hvoretter opplosningen blir inndampet ved normaltrykk. Den gjenblivende brune oljen, bestående av 4-sulfothiofen-3-karboksylsyremetylester, krystalliseres ut straks etter avkjolingen ( i luften utflytende hygroskopiske krystaller). ;7,4 g rå 4-sulfothiofen-3-karboksylsyremetylester blir opplost i 5o ml thionylklorid og kokt 16 timer under tilbakelop. Så blir det inndampet til torrhet i vakuum og den gjenblivende lysgule oljen, bestående av 4-klor-sulfonylthiofen-3-karboksylsyremetyl-ester, blir brakt til krystallisasjon med petroleter, smp. ;(fra petroleter) 71°C. ;5o g 4-klorsulfonyl-thiofen-3-karboksylsyremetylester blir opplost i 5oo ml abs. kloroform. Under kjoling blir torr metylamin innledet, til et fuktet indikatorpapir viser konstant basisk reaksjon. Det utfelte metylammoniumkloridet blir fjernet ved utrystning med vann. Den gjenblivende lysgule* oljen, bestående av 4-(N-metyl-sulfamoyl)-thiofen-3-karboksylsyremetyl-ester, krystalliseres straks ut,, smp. 142°C. 46 g 4-(N-metyl-sulfamoyl)-thiofien-3-karboks<y>ls<y>remet<y>lester blir opplost i 45o ml dirre tylformamid. Opplosningen blir avkjolt til 0°Cog tilsatt 7 g (2o%'ig overskudd) natriumhydrid, hvorved folger heftig hydrogenutvikling. Opplosningen blir langsomt oppvarmet til romtemperatur og tilsatt etter hverandre med 32,6 g torr kaliumjodid og 21,3 g kloreddiksyremetylester. Temperaturen stiger til 45°Cog et hvitt bunnfall blir utfelt. Dimetylformamidet blir deretter avdampet, hvoretter den gjenblivende gule oljen blir fordelt mellom o,5 n saltsyre og metylenklorid. Den organiske fasen blir utrystet med bikarbonat og vann, torket og inndampet. Den gjenblivende gule oljen, bestående av 4-(N-metoksy-karbonylmetyl-N-metyl-sulfamoyl)-thiofen-3-karboksylsyremetylesteren, krystalliseres straks ut, smp. fra etanol: 124°c . 1*2 the residue of an aromatic heterocycle optionally substituted with 1 or 2 lower alkyl groups with 1-4 heteroatoms or a phenyl residue optionally substituted by halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy and R and R each means hydrogen or lower alkyl. ;The term "lower alkyl" used in this description denotes straight-chain or branched saturated hydrocarbon groups with 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, t-butyl and the like. The term "lower alkoxy" refers to the hydrocarbonoxy group with up to 4 carbon atoms.- The term "halogen" refers to the 4 halogens chlorine, bromine, fluorine, iodine. The term "residue of an optionally substituted by one or two lower alkyl groups aromatic heterocycle with 1-4 heteroatoms" includes optionally substituted by one or two lower alkyl groups residues of 5- or 6-membered aromatic heterocycles with 1-4 nitrogen atoms and/or oxygen and or sulfur atoms, such as 2-thiazolyl, 4-methyl-2-thiazolyl, 4, 5-dimethyl-2-thiazolyl, 5-methyl-1, 3, 4-thiadiazolyl, 2-pyrazinyl-, 2-pyrimidinyl, 1, 2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl- 2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazyl, 3,4-dimethyl-5-isoxazyl, 2,6-dimethyl-4-pyrimidinyl, 6-methyl- 2-pyridyl, 1,2,3,4-tetrezol-5-yl and the like. In a preferred class of compounds of formula I, R 3 and R 3 mean hydrogen, R 3 is preferably the methyl group. R£ preferably represents 2-thiazolyl, 5-isoxazolyl or 2-pyridyl. A particularly preferred compound is 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno^2,3-e_7-1,2-thiazine-3-carboxamide-1,1-dioxide. According to the invention, the thenothiazine derivatives of formula I can be prepared by: a) reacting a compound of the general formula, in which R means lower alkyl and A, R, R, and R have the above meaning, A, 6 4 with an amine of the general formula ; in which R2 has the meaning indicated above, ; or ; b) cyclizes a reactive functional derivative of an acid of the formula ; in which A, R , R^, R^ and R^ have the meaning indicated above , or that one c) lower alkylates a compound of the general formula ;in which A, R 2 , R^ and R^ have the meanings given above, ;or converts ;d) converts a compound of the general formula ;;in which A and R -^ has the above meaning, ;in the presence of a strong base with an isocyanate of the general formula ;;in which R 2 has the above meaning, ;or ;e) hydrolyzes an enamine of the general formula ;;in which A, R-^ and R2 has the above meaning, and R5 and R6 each mean lower alkyl or, together with the nitrogen atom, form pyrroline, pyrrolidine , piperidine, morpholine or N-(Lower alkyl)-piperazine. The reaction according to process aspect 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, tetrachlorocarbons, etc., or dimethylformamide or dioxane. Conversions preferably take place by heating, whereby melting or the reflux temperature of the reaction mixture is particularly preferred. According to method aspect b) according to the present invention, a reactive functional derivative of a compound of formula IV is cyclized. This cyclization takes place in the presence of a base and preferably in the presence of a solvent at a temperature between 0°C and the reflux temperature of the reaction mixture, preferably between room temperature and 60°C. As a base, hydrides, amides and alcoholates of alkali metals are particularly suitable. Suitable solvents are aprotic and protic, such as alcohols, e.g. methanol, ethanol, ether, e.g. dioxane and acid amides, e.g. dimethylformamide. Conveniently, the cyclization is carried out by dissolving the starting compound of formula IV in a solvent, adding the base and allowing the reaction mixture to stand for 1 - 4 hours either at room temperature or heating to a temperature of up to 6o°C. As a reactive functional derivative of the compounds of formula IV, their lower alkyl esters are particularly suitable, e.g. their methyl esters. According to method aspect c) a compound of formula V is alkylated. This alkylation is suitably carried out by dissolving the starting compound of formula V in an aprotic solvent, such as acetonitrile, dioxane or dimethylformamide, transferring with an alkali metal amide or hydride in the alkali metal sulphide and then transferring to the corresponding compound of formula I by treatment with an alkylating agent, especially an alkyl halide or sulfate. Temperature and pressure are not critical for these methods, so that for the sake of simplicity the reaction is preferably carried out at room temperature and atmospheric pressure. The starting materials of formula II required for method aspect a) can be prepared according to the following reaction schemes. In this scheme, Hal means halogen and A, R and R^ have the meaning given above. Of the compounds of formula VI, 3-chloro-thiophene-2-carboxylic acid and 4-bromo-thiophene-3-carboxylic acid are known, whereby the first was prepared in a relatively complicated manner. A simpler method for the production of 3-chloro-thiophene-2-carboxylic acid consists in intermediately transferring the known 3-hydroxythiophene-2-carboxylic acid methyl ester into an inert solvent boiling above 80°C, such as chloroform or dioxane with a chlorinating agent such as phosphorus pentachloride in the 3-chloro-thiophene-2-carboxylic acid chloride and hydrolyzes this to the corresponding acid. In an analogous way, substituted 3-chloro-thiophene-2-carboxylic acid (compounds of formula VI, in which Hal means chlorine, A forms with both carbon atoms the group in which and or R^ are different from hydrogen) can also be substituted. Although in principle also a bromine compound e.g. the known 4-bromo-thiophene-3-carboxylic acid can be used as starting material in the preparation of a compound of formula VII, the use of the corresponding chlorine compound is advisable. 4-chloro-thiophene-3-carboxylic acid, which is not described in the literature, can be prepared starting from the known 3-ketothiphene-4-carboxylic acid methyl ester, transferring this with the aid of phosphorus pentachloride during aromatization in 4-chloro-thiophene -3-carboxylic acid chloride and hydrolyzes this to the corresponding acid. In an analogous manner, substituted 4-chloro-thiophene-3-carboxylic acids (compounds of formula VI, in which Hal means chlorine, A forms with both carbon atoms the group ; in which R^ and/or R^ are different from hydrogen, can be prepared. ; The transfer of a halothiophene carboxylic acid corresponding to formula VI in a potassium salt of a sulfothiophene carboxylic acid of formula VII takes place according to methods known per se by reacting the compound of formula VI with sodium hydrogen sulphite in the presence of a copper (I) salt catalyst, especially copper (I) chloride, and reaction of the obtained reaction product with potassium chloride. When reacting with sodium hydrogen sulphide, in order to obtain an optimal yield, a temperature of 143° C. should be maintained. The transfer of the compound of formula VII into the free acid of formula VIII takes place in and for in a known manner, with e.g. a strong ion exchanger. The esterification of the acid of formula VIII to an ester of formula IX takes place autocatalytically (presence of the sulfo group) in an alcohol/chloroform mixture. 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/water of reaction). The transfer of a compound of formula IX into the acid halide of formula X takes place in a manner known per se with a halogenating, preferably chlorinating agent, such as thionyl chloride or phosphorus pentachloride. The chlorination with thionyl chloride can also take place without a solvent by reflux heating. When using phosphorus pentachloride, work can be done in the presence of an inert solvent, such as chloroform, carbon tetrachloride, dioxane and at a temperature between 50°C and the reflux temperature of the reaction mixture. The compound of formula X can also be prepared by starting from a potassium salt of a sulfothiophene carboxylic acid corresponding to formula VII over a compound of formula XI. To this, the mentioned potassium salt is transferred, e.g. with 2 moles of phosphorus pentachloride and in the presence of phosphorus oxychloride as solvent at a temperature between 30°C and the boiling point of phosphorus oxychloride. Instead of phosphorus oxychloride, however, an inert organic solvent such as dioxane, chloroform, carbon tetrachloride, benzene, toluene or the like can also be used. The esterification of the compound of formula XI to the corresponding ester of formula X takes place with the corresponding alcohol, especially methanol, at a temperature between room temperature and reflux temperature. The alcohol or an inert solvent such as chloroform, carbon tetrachloride, dioxane or benzene can serve as solvent. From the intermediate product of formula X, one can arrive at the starting material of former 1 II in two different ways. One way leads over one the compounds of for.m^L XII and XIII and the other, possibly via compound XIV over compound XV. According to the first-mentioned method, a compound of formula X is reacted in a manner known per se with a glycine alkyl ester hydrochloride, preferably glycine ethyl ester hydrochloride. The reaction preferably takes place in the presence of an inert solvent, such as pytidine, chloroform, dioxane, methylene chloride, benzene or carbon tetrachloride, and at room temperature. The thus obtained compound of formula XII is cyclized at a temperature between 40 and 65°C in ethanol with an alkali or alkaline earth ethylate, especially sodium ethyl to the compound of formula XIII, in which R means ethyl. The alkylation of the starting material of form II takes place at i . and in a manner known per se, suitably in a polar aprotic solvent, such as dimethylformamide, dimethylsulfoxide or hexametapol, with an alkylating agent, such as an alkyl halide or a dialkyl sulfate at a temperature between 0°C and room temperature. According to the second method, a compound of formula X is either first aminoalkylated to a compound of formula XIV and then transferred to the compound XV or the compound X is directly transferred to the compound XV. In both cases, the compound of formula XV obtained is cyclized to the compound of formula II. The aminoalkylation of a compound of formula X takes place in a manner known per se by reaction 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. For the preparation of the compound of formula XV, a thus obtained compound of formula XIV is reacted in a manner known per se in the presence of a polar aprotic solvent, such as dimethylformamide, dimethylsulfoxide or hexametapol, with a compound of the formula, wherein R has the above indicated meaning and ;X means halogen. The reaction conveniently takes place at a temperature between 0°C and room temperature. On the other hand, a compound of formula XV is obtained in a manner known per se, when one reacts a compound of formula X with a compound of formula ;;in which R and R^ have the meaning indicated above, ;or an acid addition salt hence. ;The turnover takes place appropriately at room temperature. In the insertion of an acid addition salt of a compound of formula XVII, the work is expediently carried out in pyridine. Instead of an acid addition salt, however, 2 mol of free amine can also be used, in which case one preferably works in dioxane, methylene chloride, benzene or carbon tetrachloride. The cyclization of a compound of formula XV to starting material of formula II conveniently takes place at a temperature from room temperature to 65°C with the aid of an alkali or alkaline earth methylate or ethylate, preferably sodium methylate or sodium ethylate in the presence of methanol or ethanol . The compounds of formulas XVI and XVII are known or can be prepared in ways known per se. The lower alkyl esters of acids of formula IV that can be used as starting compounds for method aspect b) can be obtained by reacting an amine of formula III with chloroacetyl chloride and reacting the obtained product of formula ;;in which R2 has the above meaning, ;with a compound of formula XIV. Other reactive functional derivatives of acid of formula IX can be prepared in ways known per se from the obtained esters. The starting materials of formula V required for method c) can be obtained by reacting a compound of formula XIII with an amine of formula III. The compounds of the formulas II, IV and VII to XV are new and belong to the subject of the present invention, as does the method for producing these compounds. The compounds of the general formula I have an anti-inflammatory, analgesic... and antirheumatic... action. These valuable pharmacological properties can be determined using standard methods, for example in the known ^kaolin poteodem test (on the rat). In this test, an acute local inflammation is induced in the right hind paw of the rat by intradermal injection of 0.1 ml of a 1% kaolin suspension (bolus alba). The substance to be examined is administered orally and the following parameters are measured: 1. Average of the paw in mm (as an expression of the intensity of the inflammation), ;2) Pressure (in g) on the paw (to determine pain level). 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 parameters are measured. ;The oedema-inhibiting effect is indicated as a percentage, based on the difference in the oedema-intensity between untreated and animals treated with the substance to be examined, the antinociceptive activity by the percentage increase in the pain level. ;In this test, 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno / 2, 3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide /LD^q shows about 9oomg /kg, p.o. (mouse)/ at a dosage of 3 mg/kg p.o. a 27% inhibition of edema and a 4% increase in the pain level and at a dosage of ;lo mg/kg p.o. a 43% reduction in edema and a 23% increase in the pain level. The compounds of formula I possess a qualitatively similar action to phenylbutazone, which is known for its therapeutic use and properties. The compounds of formula I may find use as medicine, e.g. in the form of pharmaceutical preparations, which contain them in mixtures with a pharmaceutical, organic or inorganic inert carrier material suitable for the oral or parenteral application; The following examples, in which all temperatures are indicated in °C, illustrate the invention. EXAMPLE 1 52.1 g of phosphorus pentachloride is dissolved 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 200 ml of carbon tetrachloride was 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 to almost dryness. ;i ;During cooling, 45o ml of water is added, after which it is heated to boiling and then allowed to cool. The precipitated product is sucked up and a solution of 25 g of sodium hydrogen carbonate is boiled with activated carbon, after which the activated carbon is sucked up and the cooled solution is acidified with hydrochloric acid, whereby 3-chloro-thiophene-2-carboxylic acid with m.p. 185-186°C. In a glass autoclave, 8.6 g of 3-chlorothiophene-2-carboxylic acid is dissolved 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 alkaline; In ;with 30% caustic soda. Then becomes; added o.43 g of cupric (I) chloride and heated for 16 hours to 143°C. After cooling, the red copper oxide is sucked off. It is then acidified with 7 ml conc. hydrochloric acid, whereby unreacted starting material is precipitated, which is removed by shaking with methylene chloride. ;The acidic solution is added while heating with ;12 g of potassium chloride, whereupon, after cooling to 0°C, the potassium salt of 3-sulpho-thiophene-2-carboxylic acid separates in colorless crystals. ; 8.2 g of the above-mentioned potassium salt of 3-sulfo-thiophene-2-carboxylic acid are dissolved in 50 ral water. This solution is allowed to flow through an ion exchange column7 which is charged with protons, whereby it is backwashed with water until the pH value of the flowing solution is 5. The solution is evaporated to dryness in vacuo and the crystalline residue consisting of 3-sulfo- thiophene-2-carboxylic acid is recrystallized from a little water. 7.6 g of 3-sulfo-thiophene-2-carboxylic acid are dissolved in 140 ml of abs. methanol and 65 ml abs. chloroform and boiled at reflux, whereby the reaction water is distilled off as a ternary azeotrope (chloroform, methanol, water) over a filler column. It is then evaporated in a vacuum. To remove traces of methanol, the residue is added with 100 ml of chloroform, after which it is evaporated at normal pressure. The remaining brown oil, consisting of 3-sulfo-thiophene-2-carboxylic acid methyl ester, crystallizes immediately after cooling. However, the crystals are hygroscopic and become liquid in the air. ; 7.4 g of crude 3-sulfo-thiophene-2-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride and boiled for 16 hours at reflux. It is then evaporated in vacuo to dryness, after which the remaining pale yellow oil, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid ethyl ester, is brought to crystallization with petroleum ether. 20 g of 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester is dissolved in abs~ chloroform, after which 21 g of sarcosine ethyl ester is added dropwise in the course of lO min. Then the reaction mixture warms up to 5o°c, After 2o min. it is cooled, shaken with water, o.5 n hydrochloric acid and bicarbonate solution, one at a time, dried and evaporated. The remaining oil, consisting of 3-(N-carboetoylmethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester, is subjected to crystallization with ethanol, m.p. 84-85°C, 13.2 g of 3-(N-carboetoylmethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester is suspended in the cold in 42 ml of methanolic sodium methylate solution under a stream of nitrogen. After 15 minutes of stirring, a clear solution is obtained. It is heated for 2o min. by reflux, then cooled, neutralized and evaporated in vacuum. The residue is taken up in methylene chloride, shaken each time with water and bicarbonate solution, dried and evaporated. The residue, consisting of 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno,/2,3-e7~1,2-thiazine-1,1-dioxide, is brought to crystallization with methanol, m.p. 193-195°C„ ;1.9 g of 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno/2 ,3-e7~ 1,2-thiazine-1,1-dioxide becomes together with o.9 g of 2-amino-thiazole suspended in 2 5o ml of abs. xylene and heated 7 hours at reflux. whereby 15o ml of xylene is slowly distilled off. The remaining xylene is then evaporated in a vacuum. The crystalline residue, consisting of 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thianol £2,3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide, is recrystallized from ethanol , m.p. 217°c (decomposition). ;EXAMPLE 2 ;5o g ( o.2o3 mol) mono-potassium salt of 3-sulfothiophene-2-carboxylic acid is suspended in 25o ml of phosphorus oxychloride and 85 g ( o.4o6 mol) of phosphorus pentachloride are added with stirring (vigorous HCl evolution begins). Then it will be another 90 minutes. on the water bath heated with stirring, cooled to room temperature, inorganic salts are sucked off and the phosphorus oxychloride is distilled off in a vacuum as well as possible. The oily residue is dissolved in 400 ml of dry chloroform, filtered and evaporated to remove any inorganic salts still present. The oily residue, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride, crystallizes on cooling from and is inserted into the next step without further purification. 48 g (0.196 mol) of the 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride thus obtained is dissolved in 500 ml abs. chloroform, added 9.6 g (o.3 mol) abs. methanol and heated for 3 hours at reflux (until the end of HCl evolution). It was then evaporated in vacuo to dryness, after which the residue consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester was crystallized out. The raw product can be used in the next step. ; 43.5 g (o.18 mol) of the thus obtained 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester is dissolved in 45o ml abs. chloroform and preceded by lo°cmed tort methylamine until a pH paper moistened with the solution shows alkaline reaction. Then it is left to react for a further 2 hours at room temperature, whereby the solution must always be alkaline. The mixture is then shaken with 500 ml of water and 500 ml of 5% sodium hydrogen carbonate solution (the aqueous phases are re-shaken each time with chloroform), the combined organic phases are dried with sodium sulfate and evaporated. The crystalline residue is digested with ether. 3-Methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained with m.p. 115-122°c, 43.5 g (0.184 mol) of the thus obtained 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester is dissolved in 400 ml abs. dimethylformamide and added dropwise to a stirred suspension of 4.5 g (o.187 mol) sodium hydride in 50 ml abs. dimethylformamide over the course of 1 hour. Then 40 g (0.187 mol) iodoacetic acid ethyl ester is dissolved at o - 5°C (under cooling), added dropwise to 50 ml abs. dimethylformamide over the course of 32 hours and left to react for 1 hour (until a moistened pH paper shows 7 - 8). It is then evaporated in vacuo, the residue is taken up with 300 ml of 0.5 N hydrochloric acid and 300 ml of methylene chloride, the organic phase is separated, the aqueous phase is shaken twice with a little methylene chloride and the combined organic phases are shaken with each loo ml of 5%' ig sodium bicarbonate solution (the aqueous phases are each re-shaken once with a little methylene chloride). The combined organic phases are dried with sodium sulfate and evaporated. ;The crystalline residue is digested with a little cold ethanol for purification. One obtains 3-,(TN-ethoxycarbonylmethyl)-N-methyl7-sulfa-moyl-thiophene-2-carboxylic acid methyl ester with m.p. 83-85°C, 13.2 g (0.041 mol) of the thus obtained 3-[7N-ethoxycarbonyl-methyl)-N-methyl7-sulfamoyl-thiophene-2-carboxylic acid methyl ester is suspended in the cold in 42 ml methanolic sodium methylate solution in a nitrogen atmosphere, whereby everything dissolves in the course of 15 min. rowing. It is then refluxed for 25 min., cooled, neutralized with conc. hydrochloric acid and evaporated in vacuo. The residue is taken up in methylene chloride, shaken every time with water and 5% sodium bicarbonate solution, dried and evaporated. The crystalline residue is digested with a little methanol for purification. 4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno/2,3-ε7-1,2-thiazine-1,1-dioxide is obtained with m.p. 193-195°c which can be transferred by reaction with 2-amino-thiazole to 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno/2,3-e/- 1,2-thiazine-3- carboxamide-1,1-dioxide with m.p. 217°C (decomposition). EXAMPLE 3 5o g (o.2o3 mol) mono-potassium salt of 3-sulphothiophene-2-carboxylic acid is suspended in 25o ml phosphorus oxychloride and, with stirring, 85 g (o.4o6 mol) phosphorus pentachloride is added (violent HCl evolution begins )j Then another 9o min. heated on the water bath with stirring, cooled to room temperature, inorganic salts suctioned off and phosphorus oxychloridite distilled off as best as possible. The oily residue is dissolved in 4oo ml of dry chloroform to remove any inorganic salts still present, filtered and evaporated. The oily residue, consisting of 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride, crystallizes on cooling from and is used without further purification in the next step. 48 g (0.196 mol) of the 3-chlorosulfonyl-thiophene-2-carboxylic acid chloride thus obtained is dissolved in 500 ml abs. chloroform, 9.6 g (o.3 mole) abs. methanol added and refluxed for 3 hours (until the end of HCl evolution). It is then evaporated in a vacuum, whereby the residue consisting of pure 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester crystallizes out. The raw product can be used in the next step. 2.41 g (100 ml) of the 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester thus obtained is distributed in 100 ml abs. pyridine together with 1.53 g of sarcosine ethyl ester hydrochloride and stirred at room temperature. After 2 hours, it is poured into 50 ml of ice-cold 2N hydrochloric acid and extracted five times with 20 ml of methylene chloride each. The combined organic phases were dried with sodium sulfate, filtered and evaporated. The crystalline residue was digested with some ice-cold ethanol. ;13.2 g (o.o4 mol) of the 3-,/TN-ethoxy-carbonyl-methyl)-N-methyl-7-sulfamoyl-thiophene-2-carboxylic acid methyl ester thus obtained is suspended in the cold in 42 ml of methanolic sodium methylate solution in a nitrogen atmosphere , whereby everything dissolves in the course of 15 min. It is then refluxed for 25 min., cooled, neutralized with conc. hydrochloric acid and evaporated in vacuo. The residue was taken up in methylene chloride, shaken each time with water and 5% sodium bicarbonate solution, dried and evaporated. The crystalline residue is digested with a little methanol for purification. One obtains -4-hydroxy-3-methoxycarbonyl-;2-methyl-2H-thieno,/2",3-e7-1,2-thiazine-1,1-dioxide with m.p. 193-195°C which can be transferred by reaction with 2-aminothiazole to 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno/2, 3-e/- 1,2-thiazine-3-carboxamide-1, 1-dioxide with m.p. 217°C (decomposition) as described in example 1. EXAMPLE 4 12.03 g (0.05 mol) 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester and 7 g glycine ethyl ester hydrochloride (0.05 mol) are suspended in 5o ml of abs. pyridine, whereby everything dissolves over the course of 3o min. It is stirred for a further 5 hours at room temperature and then the pyridine is distilled off. The residue is taken up in 5o ml of 2N hydrochloric acid and 5o ml of methylene chloride, the organic phase separated , the aqueous layer was shaken four times with a little methylene chloride, the combined organic phases were washed with water and dried with sodium sulfate while adding activated carbon. After filtration, it was evaporated, the oily residue containing 3-(N-ethoxycarbonylmethyl)sulfmo yl-thiophene-2-carboxylic acid methyl ester can be used in the next step without further purification. ;To a solution of 1.38 g sodium (o.o6 mol) in 2o ml abs. ethanol is added at 40°C, dissolving 9.22 g (0.03 mol) of the 3-(N-ethoxycarbonylmethyl)-sulfamoyl-thiophene-2-carboxylic acid ester obtained as above in 10 ml of ethanol and heated to 60-65 °c. It is still stirred for 2 hours at this temperature, then poured into loo ml of ice-cold 2N hydrochloric acid and shaken with a little methylene chloride many times. The combined organic extracts are shaken twice with each 20 ml of 5% sodium acetate solution and then four times with each 25 ml of 10% sodium carbonate solution. By drying and evaporating the organic phase, 2.5 g of the starting material can be recovered. The combined carbonate extracts are acidified with hydrochloric acid and stripped with methylene chloride. After drying with sodium sulphate, the solvent is distilled off and the crystalline residue is digested with a little ether. One obtains 3-ethoxycarbonyl-4-hydroxy-2H-thieno[2,3-β7-1,2-thiazine-1,1-dioxide with m.p. 148-15o°C. 1.93 g (7 mmol) of 3-ethoxycarbonyl-4-hydroxy-2H-thieno/2,3-§7-1,2-thiazine-1,1-dioxide is dissolved in 4 ml abs. dimethylformamide and added dropwise to a stirred suspension of o.185 g sodium hydride (7.7 mmol) in 2 ml abs. dimethylformamide in the course of 3o min. at 0°C then it is stirred for 1 more hour at room temperature. To the solution of the sodium salt is then added o.53 ml (1.2 g, 8.45 mmol) and after 3o min. a further o.25 ml (o.565 g, 4 mmol) of methyl iodide added and left to react for 1 hour. After distilling off the solvent, the residue is taken up with 30 ml of 0.5 N hydrochloric acid and 30 ml of methylene chloride, the organic phase is separated, the aqueous layer is shaken twice with a little methylene chloride, the combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a little cold ethanol. One obtains 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno^2,3-§7-1,2-thiazine-1,1-dioxide with m.p. 161-163°C (crystal conversion at 151-152°c), ;In an analogous way as in the last paragraph in example 1, this product can be reacted with 2-aminothiazole to 4-hydroxy-2-methyl-N-2-thiazolyl-2H -thieno,/2,3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide with cleavage point 217°ci>; EXAMPLE 5; To a boiling solution of lod g phosphorus pentachloride in 25o ml abs. tetrachlorocarbon becomes 25 g of 3-keto-thiophane-4-carboxylic acid methyl ester, dissolved in a little abs. carbon tetrachloride, added dropwise over the course of 2 hours. It is then boiled at reflux for 15 hours until hydrogen chloride evolution is complete and then evaporated, whereby the main amount of phosphorus chloride is expelled. 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 with sodium sulfate and then evaporated. The remaining brown oil, consisting of 4-chloro-thiophene-3-carboxylic acid chloride, is heated with 2n aqueous caustic soda at 5o°C until a homogeneous brown solution occurs. This is shaken once with methylene chloride and acidified with conc. hydrochloric acid, after which the precipitated crystals, consisting of crude 4-chlorothiophene-3-carboxylic acid, are absorbed. For purification of the absorbed crystals, they are dissolved in sodium bicarbonate and again precipitated with conc. hydrochloric acid, m.p. after recrystallization from water 164°c. ;In a glass autoclave, 8.6 g of 4-chlorothiophene-3-carboxylic acid is dissolved in 23 ml of 2.1 g of sodium hydroxide-containing water, after which a solution of 5.6 g of sodium hydrogen sulphite is added to 16 ml of water and the solution is made just alkaline with 30% caustic soda. It is then added with 0.43 g of cupric (I) chloride and heated to 143°Ci for 16 hours. After cooling, the red copper oxide is absorbed. The filtrate is acidified with 7 ml conc. hydrochloric acid, whereby unreacted starting material is precipitated, this is removed by shaking with ether. The acidic solution is added while heating with 12 g of potassium chloride, whereby the potassium salt of the 4-sulfothiophene-3-carboxylic acid separates as colorless crystals after cooling to 0°C. This is dissolved in 50 ml of water and the solution is allowed to flow through an ion exchange column, which is charged with protons, whereby it is rinsed with water until the pH of the flowing solution is 5. The eluate is evaporated to dryness in vacuum and 4-sulfothiophene-3-carboxylic acid is then obtained as a crystalline residue. Temp. (from water) 154°C. ; 7.6 g of 4-sulfothiophene-3-carboxylic acid are dissolved in 140 ml of abs. methanol and 65 ml abs. chloroform boiled under reflux, whereby the reaction water is distilled off as a ternary azeotrope (chloroform, methanol, water) over a packed mass column (lm). ;It is then evaporated in a vacuum. To remove traces of methanol, 100 ml of chloroform is added to the residue, after which the solution is evaporated at normal pressure. The remaining brown oil, consisting of 4-sulfothiophene-3-carboxylic acid methyl ester, crystallizes out immediately after cooling (hygroscopic crystals floating in the air). 7.4 g of crude 4-sulfothiophene-3-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride and boiled for 16 hours under reflux. It is then evaporated to dryness in vacuo and the remaining pale yellow oil, consisting of 4-chloro-sulfonylthiophene-3-carboxylic acid methyl ester, is brought to crystallization with petroleum ether, m.p. ;(from petroleum ether) 71°C. 50 g of 4-chlorosulfonyl-thiophene-3-carboxylic acid methyl ester is dissolved in 500 ml of abs. chloroform. During cooling, dry methylamine is introduced, until a moistened indicator paper shows a constant basic reaction. The precipitated methylammonium chloride is removed by shaking with water. The remaining pale yellow* oil, consisting of 4-(N-methyl-sulfamoyl)-thiophene-3-carboxylic acid methyl ester, is immediately crystallized out,, m.p. 142°C. 46 g of 4-(N-methyl-sulfamoyl)-thiophene-3-carboxyl ester are dissolved in 450 ml of diethylformamide. The solution is cooled to 0°C and 7 g (20% excess) of sodium hydride are added, whereby vigorous hydrogen evolution follows. The solution is slowly warmed to room temperature and 32.6 g of dry potassium iodide and 21.3 g of chloroacetic acid methyl ester are added one after the other. The temperature rises to 45°C and a white precipitate is precipitated. The dimethylformamide is then evaporated, after which the remaining yellow oil is partitioned between 0.5 N hydrochloric acid and methylene chloride. The organic phase is shaken off with bicarbonate and water, dried and evaporated. The remaining yellow oil, consisting of 4-(N-methoxy-carbonylmethyl-N-methyl-sulfamoyl)-thiophene-3-carboxylic acid methyl ester, crystallizes out immediately, m.p. from ethanol: 124°c .

j j

41,6 g 4- (N-metoksykarbonylmetyl^-N-metyl-sulf amoyl)-thiof en-3-karboksylsyremetylester blir opptatt i 14o ml ln natriummetylatopplosning og opplost under koking ved tilbakelop. Opplosningen farger seg over gult raskt dyprod, etfcer 2o min. folger grumsing av opplosningen ved bunfellingsdannelse. Det blir kjolt, surgjort og inndampet i vakuum. Resten blir opptatt i metylenklorid og vanri, 1 den organiske fasen blir rystet med bikarbonatopplosning og vann og deretter ekstrahert med o,5 n kjolt natronlut. Ved surgjoring av den vandige natronlutopplosningen blir 4-hydroksy-3-metoksykarbonyl-2-metyl-2H-thieno/3,4-e7-l,2-thiazin-l,1-dioksyd i form av fargelose krystaller erholdt, smp. fra metanol 19o°C . 41.6 g of 4-(N-methoxycarbonylmethyl-N-methyl-sulfamoyl)-thiophene-3-carboxylic acid methyl ester are taken up in 140 ml of 1N sodium methylate solution and dissolved under reflux. The solution turns yellow quickly deep red, etfcer 2o min. turbidity of the solution follows when precipitation forms. It is cooled, acidified and evaporated in a vacuum. The residue is taken up in methylene chloride and anhydrous, 1 the organic phase is shaken with bicarbonate solution and water and then extracted with 0.5 n chilled caustic soda. By acidifying the aqueous caustic soda solution, 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno/3,4-ε7-1,2-thiazine-1,1-dioxide is obtained in the form of colorless crystals, m.p. from methanol 19o°C .

0, 9 g 4-hydroksy-3-metoksykarbonyl-2-metyl-2H-thieno-/3,4-e7-1, 2-thiazin-l,1-dioksyd blir sammen med o,4 g 2-aminothiazol suspendert i loo ml abs. xylen og oppvarmet 4 timer ved tilbakelop, hvorved 7o ml xylen langsomt blir avdestillert. Det fra den 0.9 g of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno-[3,4-e7-1,2-thiazine-1,1-dioxide are suspended together with 0.4 g of 2-aminothiazole in loo ml abs. xylene and heated for 4 hours at reflux, whereby 70 ml of xylene is slowly distilled off. That from it

avkjolte opplosningen utfelte krystallinske bunnfallet, cooled the solution precipitated the crystalline precipitate,

bestående av 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno,/3, 4-e7-1,2-thiazin-3-karboksamid-l,1-dioksyd blir oppsuget, smp. consisting of 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno,/3,4-e7-1,2-thiazine-3-carboxamide-1,1-dioxide is absorbed, m.p.

fra etanol 243-245°C(spaltning). from ethanol 243-245°C (decomposition).

EKS EMPEL 6 EKS EMPEL 6

94,6 g (o,384 mol) monokaliumsalt av 4-sulfo-thiofen-3-karboksylsyre blir suspendert i 39o ml fosforoksyklorid og under roring blir 16o,8 g (o,768 mol) fosforpentaklorid tilsatt (heftig HCl-utvikling begynner). Så blir det oppvarmet i enda 3 timer 94.6 g (o.384 mol) monopotassium salt of 4-sulfo-thiophene-3-carboxylic acid is suspended in 39o ml phosphorus oxychloride and with stirring 16o.8 g (o.768 mol) phosphorus pentachloride is added (vigorous HCl evolution begins) . Then it is heated for another 3 hours

på vannbadet under roring, avkjolt til romtemperatur, frafiltrert for uorganiske salter og fosforksykloridet blir avdestillert on the water bath while stirring, cooled to room temperature, filtered off for inorganic salts and the phosphorus oxychloride is distilled off

så godt som mulig i vakuum. Resten blir opplost i 4oo ml torr kloroform for å fjerne uorganiske salter som enda er til-stedet, filtrert og inndampet. Resten, bestående av 4-klorsulfonyl-thiof en-3-karboksylsyreklorid, krystalliserer ved avkjoling ut og blir innsatt i det neste trinnet uten videre rensing. as well as possible in a vacuum. The residue is dissolved in 400 ml of dry chloroform to remove inorganic salts still present, filtered and evaporated. The residue, consisting of 4-chlorosulfonyl-thiophene-3-carboxylic acid chloride, crystallizes on cooling and is used in the next step without further purification.

44,1 g ( o,18 mol) av det således erholdte 4-klorsulfonyl-thiof en- 3-karboksylsyreklor idet blir opplost i 45o ml abs. kloroform, tilsatt 9,6 g (o,3 mol) abs. metanol og tilbakelopsoppvarmet i 9 timer ( inntil slutten av HCl-utviklingen). 44.1 g (o.18 mol) of the 4-chlorosulfonyl-thiophene-3-carboxylic acid chlorine thus obtained is dissolved in 45o ml abs. chloroform, added 9.6 g (o.3 mol) abs. methanol and refluxed for 9 hours (until the end of HCl evolution).

Så blir det inndampet i vakuum til torrhet, hvorved resten utkrystalliseres. Man erholder 4-klorsulfonyl-thiofen-3-karboksylsyremetylester, som kan overfores som beskrevet i 4 siste avsnittene i eksempel 5 til 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno^3,4-§7-l,2-thiazin-3-karboksamid-l,1-dioksyd. It is then evaporated in vacuo to dryness, whereby the residue crystallizes out. 4-chlorosulfonyl-thiophene-3-carboxylic acid methyl ester is obtained, which can be transferred as described in the last 4 paragraphs of example 5 to 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno^3,4-§7- 1,2-thiazine-3-carboxamide-1,1-dioxide.

E KSEMPEL 7 EXAMPLE 7

Ved en analog fremgagnsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2,3-e7-l,2-thiazin-1.1- dioksyd ved 7 timers omsetning med 3-amino-5-metyl-isoksazol 4- hydroksy-2-metyl-N- (5-metyl-3-isoksazolyl) -2H-thieno,/2, 3-e7-1.2- thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 239-243°C. In an analogous procedure as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-e7-1,2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with 3-amino-5 -methyl-isoxazole 4- hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-thieno,/2, 3-e7-1.2- thiazine-3-carboxamide-1,1-dioxide with cleavage point 239-243°C.

EKSEMPEL_8 EXAMPLE_8

Véd en analog fremgangsmåte som ieeksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno/2, 3-e"7-l, 2-thiazin-1,1-dioksyd ved 7 timers omsetning med analin 4-hydroksy-2-metyl-2H-thieno/2,3-<§7-l,2-thiazin-3-karboksanilid-l,1-dioksyd med Using a method analogous to example 1, one obtains from 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-e"7-1,2-thiazine-1,1-dioxide by reaction for 7 hours with analin 4 -hydroxy-2-methyl-2H-thieno/2,3-<§7-1,2-thiazine-3-carboxanilide-1,1-dioxide with

spaltningspunkt 248-251°C(fra xylen). decomposition point 248-251°C (from xylene).

E KSEMPEL 9 EXAMPLE 9

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-.thieno/2, 3-§7-l, 2-thiazin-l, 1 - dioksyd ved 7 timers omsetning med 2-pyridylamin 4-hydroksy-2-metyl-N-2-pyridyl-2H-thieno,/2, 3-67-1, 2-thiazin-3-karboksamid-1, 1-dioksyd med spaltningspunkt 2o9-213°C( fra zxylen). By an analogous method as in example 1, one obtains from 3-carbomethoxy-4-hydroxy-2-methyl-.thieno/2, 3-§7-1, 2-thiazin-1, 1 - dioxide by reacting for 7 hours with 2- pyridylamine 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno,/2, 3-67-1, 2-thiazine-3-carboxamide-1, 1-dioxide with decomposition point 2o9-213°C ( from zxylene).

EKSEMPEL lo EXAMPLE lo

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2, 3--§7-1, 2-thiazin-1,1-dioksyd ved 7 timers omsetning med 3-pyridylamin 4- hydroksy-2-metyl-N-3-pyridyl-2H-thieno/2, 3-§7-l,2-thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 241-244°C(fra pyridin). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2, 3--§7-1, 2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with 3- pyridylamine 4-hydroxy-2-methyl-N-3-pyridyl-2H-thieno/2,3-§7-1,2-thiazine-3-carboxamide-1,1-dioxide with decomposition point 241-244°C (from pyridine).

EKSEMPEL 11 EXAMPLE 11

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2, 3-e7-l, 2-thiazin-, 1,1-dioksyd ved 7 timers omsetning med 4-pyridyl-amin 4- hydroksy-2-metyl-N-4-pyridyl-2H-thienoZ2,3-e/-l,2-thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 263-267°C (fra dimetylformamid). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-e7-1,2-thiazine-,1,1-dioxide is obtained from 7 hours of reaction with 4-pyridyl -amine 4-hydroxy-2-methyl-N-4-pyridyl-2H-thienoZ2,3-e/-1,2-thiazine-3-carboxamide-1,1-dioxide with decomposition point 263-267°C (from dimethylformamide ).

EKSEMPEL 12 EXAMPLE 12

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thienoZ2,3-e7-l,2-thiazin-1, 1-dioksyd ved 7 timers omsetning med 4-hydroksy-anilin 4, 4' -dihydroksy-2-metyl-2H-thienOj/2, 3-e/-l, 2-thiazin-3-karboks-anilid-1,1-dioksyd med spaltningspunkt 287-29o°C (fra dioksan). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thienoZ2,3-e7-1,2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with 4-hydroxy-aniline 4 .

EKSEMPEL 13 EXAMPLE 13

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2,3-§7-l,2-thiazin-1,1-dioksyd ved 7 timers omsetning med 3-metyl-anilin 4- jydroksy-2-metyl-2H-thieno//2, 3-§7~l, 2-thiazin-3-karboksy-m-toluidid-1,1-dioksyd med spaltningspunkt 197-199°C (fra benzen, krystallisasjonsomdannelse ved 185-188WC) . By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-§7-1,2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with 3-methyl -aniline 4- hydroxy-2-methyl-2H-thieno//2, 3-§7~1, 2-thiazine-3-carboxy-m-toluidide-1,1-dioxide with decomposition point 197-199°C (from benzene, crystallization conversion at 185-188WC) .

EKSEMPEL 14 EXAMPLE 14

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno/2~, 3-.e/-l, 2-thiazin-1,1-dioksyd ved 7 timers omsetning med 3-klor-anilin 31-klor-4-hydroksy-2-metyl-2H-thieno/2,3-e7-l,2-thiazin-3-karboksanilid-1,1-dioksyd med spaltningspunkt 241-243°C (fra xylen). By an analogous method as in example 1, one obtains from 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2~, 3-.e/-1, 2-thiazine-1,1-dioxide by reaction for 7 hours with 3 -chloro-aniline 31-chloro-4-hydroxy-2-methyl-2H-thieno/2,3-e7-1,2-thiazine-3-carboxanilide-1,1-dioxide with decomposition point 241-243°C (from xylene).

EKSEMPE L 15 EXAMPLE L 15

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno</2/ 3-e/-l, 2-thiazin-1,1-dioksyd ved 7 timers reaksjon med aminopyrazin 4-hydroksy-2- metyl-N-pyrazinyl-2H-thieno^2,3-e7-l,2-thiazin-3-karboksamid-1,1-dioksyd med spaltningspunkt 245-248°c (fra xylen). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno</2/ 3-e/-1, 2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with aminopyrazine 4 -hydroxy-2-methyl-N-pyrazinyl-2H-thieno^2,3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide with decomposition point 245-248°c (from xylene).

EKSEMPEL 16 EXAMPLE 16

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2,3-e7-l,2-thiazin-1,1-dioksyd ved 14 timers omsetning med 5-amino-3,4-dimetyl-isoksazol N-(3,4-dimetyl-5-isoksazolyl)-4-hydroksy-2-metyl-2H-thieno/.2, 3-e/-l, 2-thiazin-3-karboksamid-l, 1-dioksyd med spaltningspunkt 2o6-2o8°C (fra benzen). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-e7-1,2-thiazine-1,1-dioxide is obtained from 14 hours of reaction with 5-amino- 3,4-dimethyl-isoxazole N-(3,4-dimethyl-5-isoxazolyl)-4-hydroxy-2-methyl-2H-thieno/.2, 3-e/-l, 2-thiazine-3-carboxamide -1,1-dioxide with decomposition point 2o6-2o8°C (from benzene).

EKSEMPEL 17 EXAMPLE 17

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno/2,3-.e7-l,2-thiazin-1,1-dioksyd ved 7 timers omsetning med 4-amino-2,6-dimetyl-pyrimidin N-(2,6-dimetyl-4-pyrimidinyl)-4-hydroksy-2-metyl-2H-thieno/2,3-e7-l,2-thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 27o-271°C (fra xylen). By an analogous method as in example 1, one obtains from 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-.e7-1,2-thiazine-1,1-dioxide by reaction for 7 hours with 4-amino -2,6-dimethyl-pyrimidine N-(2,6-dimethyl-4-pyrimidinyl)-4-hydroxy-2-methyl-2H-thieno/2,3-e7-1,2-thiazine-3-carboxamide- 1,1-dioxide with decomposition point 27o-271°C (from xylene).

EKSEMPEL 18 EXAMPLE 18

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3- karbometoksy-4-hydroksy-2-metyl-thieno/2,3-e7-l,2-thiazin-1,1-dioksyd ved 7 timers omsetning med 2-amino-6-metyl-pyridin 4- hydroksy-2-metyl-N-)(6-metyl-2-pyridyl)-2H-thieno/2,3-§7-1, 2-thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 216-218°C (fra benzen). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno/2,3-e7-1,2-thiazine-1,1-dioxide is obtained from 7 hours of reaction with 2-amino- 6-methyl-pyridine 4-hydroxy-2-methyl-N-(6-methyl-2-pyridyl)-2H-thieno/2,3-§7-1, 2-thiazine-3-carboxamide-1,1 -dioxide with a decomposition point of 216-218°C (from benzene).

EKSEMPEL 19 EXAMPLE 19

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno,/2, 3~e7-l, 2-thiazin-1,1-dioksyd ved 14 timers omsetning med 5-amino-l,2,3,4-tetrazol 4-hydroksy-2-metyl-N-(5-1,2,3,4-tetrazolyl)-2H-thieno 12, 3-e7-l,2-thiazin-3-karboksamid-l,1-dioksyd med spaltningspunkt 224°C (fra etanol). By an analogous procedure as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno,/2,3~e7-1,2-thiazine-1,1-dioxide is obtained from 14 hours of reaction with 5-amino -1,2,3,4-tetrazole 4-hydroxy-2-methyl-N-(5-1,2,3,4-tetrazolyl)-2H-thieno 12, 3-e7-1,2-thiazine-3 -carboxamide-1,1-dioxide with a decomposition point of 224°C (from ethanol).

EKSEMPEL 2o EXAMPLE 2o

Ved analog fremgangsmåte som i eksempel 1 erholder man fra 3-karbometoksy-4-hydroksy-2-metyl-thieno(/2, 3-e7-l, 2-thiazin-1, 1-dioksyd ved 18 timers omsetning med 2-amino-pyrimidin 4-hydroksy- 2-metyl-N-2-pyrimidinyl-2H-thieno/j>, 3-e7-l, 2-thiazin-3-karboksamid-1,1-dioksyd med spaltningspunkt 221—223°C (fra etanol). By an analogous method as in example 1, 3-carbomethoxy-4-hydroxy-2-methyl-thieno(/2,3-ε7-1,2-thiazine-1,1-dioxide is obtained from 18 hours of reaction with 2-amino -pyrimidine 4-hydroxy-2-methyl-N-2-pyrimidinyl-2H-thieno/j>, 3-e7-1, 2-thiazine-3-carboxamide-1,1-dioxide with decomposition point 221-223°C ( from ethanol).

E KSEMPEL 21 EXAMPLE 21

o,82 g ( o,oo3 mol) 3-etoksykarbonyl-4-hydroksy-2H-thieno 3-§7-l, 2-thiazin-l, 1-dioksyd blir suspendert sammen med o,4 g ( o,oo4 mol) 2-aminothiazol i loo ml abs. xylen og oppvarmet til koking. I lopet av 7 timer blir 5o ml opplosningsmiddel langsomt avdestillert azeotropt med den oppståtte etanolen, hvorved o.82 g ( o.oo3 mol) of 3-ethoxycarbonyl-4-hydroxy-2H-thieno 3-§7-1,2-thiazine-1,1-dioxide is suspended together with o.4 g ( o.oo4 mol ) 2-aminothiazole in loo ml abs. xylene and heated to boiling. Over the course of 7 hours, 50 ml of solvent is slowly distilled off azeotropically with the resulting ethanol, whereby

4-hydroksy-N-2-thiazolyl-2H-thieno/2,3-e7-l,2-thiazin-3-karboks-amid-1, 1-dioksyd begynner å utkrystallisere etter 2 timer. 4-Hydroxy-N-2-thiazolyl-2H-thieno[2,3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide starts to crystallize after 2 hours.

Etter avkjoling blir det filtrert og vasket med petroleter. Produktet kan omkrystalliseres fra xylen eller dioksan ( smp. 289-29o°c, spaltning) men er for den videre omsetning rent nok. After cooling, it is filtered and washed with petroleum ether. The product can be recrystallized from xylene or dioxane (m.p. 289-29o°c, decomposition) but is pure enough for further processing.

o,329 g ( 1 mmol) av dette produktet blir opplost i 2 ml abs. dimetylformamid og tilsatt ved 0°C til en rort suspensjon av o,o26 g ( l,lmmol) natriumhydrid i 1 ml abs. dimetylformamid, deretter blir det rort i nok en time ved romtemperatur. o.329 g (1 mmol) of this product is dissolved in 2 ml abs. dimethylformamide and added at 0°C to a stirred suspension of 0.026 g (1.lmmol) sodium hydride in 1 ml abs. dimethylformamide, then it is stirred for another hour at room temperature.

Til opplosningen av natriumsaltet blir o,l ml ( o,226 g, 1,6 For the solution of the sodium salt, 0.1 ml (0.226 g, 1.6

mmol) metyljodid tilsatt og latt etterreagere i 1 time. mmol) methyl iodide added and left to react for 1 hour.

Etter avdestillering av losningsmidlet blir resten tatt oppå After distilling off the solvent, the residue is taken up

i 2oo ml metylenklorid og lo ml o,5 n saltsyre, den organiske fasen fraseparert og utrystet med tilsammen 5o ml av en o,5%'ig hydrogenkarbonatopplosning. Det vandige sjikt, som nå inneholder det onskede produkt, blir etterrystet flere ganger med metylenklorid og surgjort med saltsyre. Den sure, vandige fasen blir in 200 ml of methylene chloride and 100 ml of 0.5 N hydrochloric acid, the organic phase separated and shaken with a total of 50 ml of a 0.5% hydrogen carbonate solution. The aqueous layer, which now contains the desired product, is shaken several times with methylene chloride and acidified with hydrochloric acid. The acidic, aqueous phase becomes

ekstrahert med metylenklorid, de forente organiske ekstraktene blir torket med natriumsulfat og inndampet. Den krystallinske resten blir digerert med litt kald etanol, man erholder 4-hydroksy-2-metyl-N-2-thiazolyl-2H—thieno/2, 3-e7-l, 2-thiazin-3-karboksamid-1,1-dioksyd med smp. 217°C(spaltning). extracted with methylene chloride, the combined organic extracts are dried with sodium sulfate and evaporated. The crystalline residue is digested with a little cold ethanol, 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno/2,3-e7-1,2-thiazine-3-carboxamide-1,1- dioxide with m.p. 217°C (decomposition).

EKSEMPEL 22 EXAMPLE 22

4o g (o,4 mol) 2-aminothiazol blir opplost i 4oo ml abs. 40 g (0.4 mol) of 2-aminothiazole is dissolved in 400 ml of abs.

dioksan og tilsatt med loo g frisk glodet kaliumkarbonat. dioxane and added with loo g fresh annealed potassium carbonate.

Så blir 95 ml kloracetylklorid porsjonsvis tilsatt, hvorved temperaturen stiger til'70°C. Det blir så rort i 9o min., deretter blir det helt på.en iskald opplosning av 15o g kaliumkarbonat i 4o.oo ml vann, hvorved 2-kloracetylaminothiazol utfelles. Det blir rort i nok en time, så blir produktet oppsuget, vasket med vann og omkrystallisert fra etanol, smp. 176-177°C. Then 95 ml of chloroacetyl chloride is added in portions, whereby the temperature rises to 70°C. It is then stirred for 9o min., then an ice-cold solution of 15o g of potassium carbonate in 4o.oo ml of water is poured in, whereby 2-chloroacetylaminothiazole is precipitated. It is stirred for another hour, then the product is sucked up, washed with water and recrystallized from ethanol, m.p. 176-177°C.

o,5 g (2,12 mmol) metylsulfamoyl-thiofen-2-karboksylsyremetyl- o.5 g (2.12 mmol) methylsulfamoyl-thiophene-2-carboxylic acid methyl-

ester blir opplost i 8 ml abs. dimetylformaid og tilsatt ved 0°c til en rort suspensjon av 0,06 g natriumhydrid i 2 ml abs. dimetylformamid. Så blir det rort i nok 1 time vdd romtemperatur. Til en opplosning av natriumsaltet blir o,38 ( 2,15 mmol) av ester is dissolved in 8 ml abs. dimethylformamide and added at 0°c to a stirred suspension of 0.06 g sodium hydride in 2 ml abs. dimethylformamide. Then it is stirred for another 1 hour at room temperature. For a solution of the sodium salt, o.38 (2.15 mmol) of

det ovenfor erholdte 2-kloracetylaminothiazol og o,36 g ( 2,17 the above obtained 2-chloroacetylaminothiazole and 0.36 g (2.17

mmol) kaliumjodid tilsatt og rort i enda 2 timer. Etter avdestillering av opplosningsmidlet blir resten opptatt i 2o ml o,5n saltsyre og 5o ml metylenklorid og den vandige fasen blir flere ganger utrystet med metylenklorid. De forente organiske fasene blir vasket med vann, torket med natriumsulfat, filtrert og inndampet. Man erholder 3-/N-(2-thiazolyl-karbamoyl-metyl)-N-metyl?sulfamoyl-thiofen-2-karboksylsyremetylester. mmol) potassium iodide added and stirred for a further 2 hours. After distilling off the solvent, the residue is taken up in 2o ml of o.5n hydrochloric acid and 5o ml of methylene chloride and the aqueous phase is shaken several times with methylene chloride. The combined organic phases are washed with water, dried with sodium sulfate, filtered and evaporated. 3-[N-(2-thiazolyl-carbamoyl-methyl)-N-methyl?sulfamoyl-thiophene-2-carboxylic acid methyl ester is obtained.

o,l g ( o,27 mmol) av den således erholdte 3-/N-(2-thiazolyl-karbamoyl-metyl)-N-metyl7-sulfamoyl-thiofen-2-karboksylsyre-metylesteren blir opplost i 5 ml abs. dimetylformamid og tilsatt o,ol g natriumhydrid. Etter 2 timers roring kan det onskede 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno/.2~, 3-e_7-l, 2-thiazin-3-karboksamid-1,1-dioksyd påvises ved tynnsjiktsktskromatografi. 0.1 g (0.27 mmol) of the thus obtained 3-[N-(2-thiazolyl-carbamoyl-methyl)-N-methyl-7-sulfamoyl-thiophene-2-carboxylic acid methyl ester is dissolved in 5 ml of abs. dimethylformamide and added o.ol g of sodium hydride. After 2 hours of stirring, the desired 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno/.2~,3-e_7-1,2-thiazine-3-carboxamide-1,1-dioxide can be detected by thin layer chromatography.

EKSEMPEL 23 EXAMPLE 23

23,5 g ( o,l mol) 3-metylsulfanoyl-thiofen-2-karboksylsyre-metylester blir opplost under oppvarming i 5o ml etanol, tilsatt 23.5 g (0.1 mol) of 3-methylsulfanoyl-thiophene-2-carboxylic acid methyl ester is dissolved under heating in 50 ml of ethanol, added

5o ml 3n kaliumhydroksy-oppldsning og oppvarmet 3 timer under tilbakelop. Etter avkjolingen blir fortynnet med vann og utrystet med metylenklorid. Den vandige fasen blir surgjort med saltsyre og ekstrahert flere ganger med hver 5o ml eter. Etter torkingen med natriumsulfat og avdamping av opplosningsmidlet erholder man fargeldse krystaller, som er rene nok for den videre omsetning. Den erholdte 3-metyl-su]famoyl-thiofen-2-karboksylsyren kan omkrystalliseres fra vann. Smp. 182-184°C. 5o ml of 3n potassium hydroxy solution and heated for 3 hours under reflux. After cooling, it is diluted with water and shaken with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted several times with 50 ml each of ether. 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. Temp. 182-184°C.

ll,o6 g ( o,o5 mol) 3-metylsulfamoyl-thiofen-2-karboksylsyre og 11,5 g ( o,o55 mol) fosforpentaklorid blir oppslemmet i 15o ml torr kloroform og rort i 3o min. ved 4o°C. Av den dannede klare opplosningen blir uten oppvarming halvparten av opplosningsmidlet avdampet i vakuum. Denne surekloridopplos-ningen blir kjolt til -2o°C, tildryppet fra 34 g nitrosometyl-urea frisk laget diazometanopplosning i eter i lopet av 60 min. Så blir det oppvarmet til romtemperatur. Etter 1 time blir 80 ml kons. saltsyre forsiktig tildryppet og 1 time oppvarmet under tilbakelop. Deretter blir utrystet med 2oo ml vann og etterrystet med eter. De forente organiske fasene blir torket med natriumsulfat og inndampet etter filtreringen. Den således erholdte krystallgroten blir digerert med litt eter. Den erholdte 3-metylsulfamoyl-2-kloracetylthiofen er ren nok for den videre omsetningen, kan imidlertid omkrystalliseres fra benzen. Smp. 182-184°C. 11.06 g (0.05 mol) of 3-methylsulfamoyl-thiophene-2-carboxylic acid and 11.5 g (0.055 mol) phosphorus pentachloride are slurried in 150 ml of dry chloroform and stirred for 30 min. at 4o°C. Of the clear solution formed, half of the solvent is evaporated in vacuum without heating. This acid chloride solution is cooled to -20°C, added dropwise from 34 g of nitrosomethyl urea freshly prepared diazomethane solution in ether over the course of 60 minutes. It is then heated to room temperature. After 1 hour, 80 ml conc. hydrochloric acid carefully dripped in and heated under reflux for 1 hour. It is then shaken with 200 ml of water and re-shaken with ether. The combined organic phases are dried with sodium sulfate and evaporated after filtration. The crystal grain thus obtained is digested with a little ether. The 3-methylsulfamoyl-2-chloroacetylthiophene obtained is pure enough for the further reaction, but can, however, be recrystallized from benzene. Temp. 182-184°C.

2, 53 g ( o,ol mol) 3-metylsulfamoyl-2-kloracetyl-thiofen blir tildryppet i 2o ml vannfritt dimetylformamid og under nitrogen-atmsofære til en suspensjon av o,27 g natriumhydrid i 5 ml 2.53 g (0.01 mol) of 3-methylsulfamoyl-2-chloroacetyl-thiophene is added dropwise to 20 ml of anhydrous dimethylformamide and under a nitrogen atmosphere to a suspension of 0.27 g of sodium hydride in 5 ml

abs. dimetylformamid ved 0°C innen 2o minutter. Den i begynnelsen lyse opplosningen farger seg med tiden mork, pH-verdien synker til ca. 7,5. Etter ytterligere lo min. blir det noytralisert med saltsyre og opplosningsmidlet avdestillert. Den oljeaktige resten blir fordelt melbm 2n saltsyre og metylenklorid. Etter fasedelingen blir det vandige sjiktet utrystet flere ganger med metylenklorid. De forente organiske fasene blir torket med natriumsulfat og inndampet, den krystallinske resten blir digerert med litt kald etanol. Man erholder 3,4-dihydro-2-metyl-4-okso-2H-thieno/_2, 3-e/l, 2-thiazin-l, 1-dioksyd. Smp. 13o-131°C. abs. dimethylformamide at 0°C within 2o minutes. The initially light solution darkens over time, the pH value drops to approx. 7.5. After further lo min. it is neutralized with hydrochloric acid and the solvent distilled off. The oily residue is partitioned between 2N hydrochloric acid and methylene chloride. After the phase separation, the aqueous layer is shaken several times with methylene chloride. The combined organic phases are dried with sodium sulfate and evaporated, the crystalline residue is digested with a little cold ethanol. 3,4-dihydro-2-methyl-4-oxo-2H-thieno[2,3-e/1,2-thiazine-1,1-dioxide is obtained. Temp. 13o-131°C.

o,9 g (4,1 mmol) 3,4-dihydro-2-metyl-4-okso-2H-thieno /2 ,3-e_7-l,2-thiazin-1,1-dioksyd og o,49 g (4,1 mmol) fenylisocyanat blir opplost i 9 ml abs. dimetylformamid og tildryppet til en suspensjon av o,ll g natriumhydrid under nitrogenatmosfære i lopet av lo min. Etter ytterligere 15 min. blir den morke opplosningen helt på o.9 g (4.1 mmol) 3,4-dihydro-2-methyl-4-oxo-2H-thieno /2,3-e_7-1,2-thiazine-1,1-dioxide and o.49 g (4.1 mmol) of phenyl isocyanate is dissolved in 9 ml of abs. dimethylformamide and added dropwise to a suspension of o.ll g of sodium hydride under a nitrogen atmosphere in the course of lo min. After another 15 min. the dark solution becomes completely on

5o ml iskald 3n saltsyre, hvorved utfelles et gult faststoff. Det vandige sjiktet blir utrystet flere ganger med metylenklorid og de forente organiske fasene blir ekstrahert med natriumkarbonat-opplosnings. Etter surgjbring av karbonatopplosningen med saltsyre blir det igjen utrystet med metylenklorid. Den således erholdte organiske fasen blir torket med natriumsulfat, rort med aktivkaraon, filtrert og inndampet. Den forst oljeaktige resten blir brakt til krystallisasjon med benzen og gir 4-hydroksy-2-metyl-3- (f enyl-karbamoyl) -2H-thieno,/2, 3- e/ l, 2-thiazin-l, 1-dioksyd som kan omkrystalliseres fra benzen. Smp. 248-251°C (spaltning). 5o ml of ice-cold 3N hydrochloric acid, whereby a yellow solid is precipitated. The aqueous layer is extracted several times with methylene chloride and the combined organic phases are extracted with sodium carbonate solution. After acidifying the carbonate solution with hydrochloric acid, it is again equipped with methylene chloride. The organic phase thus obtained is dried with sodium sulphate, stirred with activated charcoal, filtered and evaporated. The initially oily residue is crystallized with benzene to give 4-hydroxy-2-methyl-3-(phenyl-carbamoyl)-2H-thieno,/2,3-e/l,2-thiazin-1,1- dioxide which can be recrystallized from benzene. Temp. 248-251°C (decomposition).

E KSEMPEL 24 EXAMPLE 24

1,1 g ( 5 mmol) 3, 4-dihydro-2-metyl-4-okso-2H-thieno/j2, 3-e7-1,2-thiazin-l,1-dioksyd og o,75 g friskt destillert pyrrolidin blir opplost i 45 ml abs. benzen og tilbakelopsoppvarmet i 72 timer på vannfraskiHer. Så blir opplosningsmidlet avdestillert og den krystallinske resten torket i vakuum. Det erholdte 2-metyl-4-(1-pyrrolidino)-2H-thieno-/2,3-§7l,2-thiazin-l,1-dioksyd er rent nok for den videre omsetning, kan imidlertid omkrystalliseres fra benzen/eter = 1:9. Smp. 183-184°C. 1.1 g (5 mmol) 3, 4-dihydro-2-methyl-4-oxo-2H-thieno/j2, 3-e7-1,2-thiazine-1,1-dioxide and 0.75 g freshly distilled pyrrolidine is dissolved in 45 ml abs. benzene and refluxed for 72 hours in a water bath. The solvent is then distilled off and the crystalline residue is dried in a vacuum. The 2-methyl-4-(1-pyrrolidino)-2H-thieno-[2,3-§71,2-thiazine-1,1-dioxide obtained is pure enough for the further reaction, but can be recrystallized from benzene/ether = 1:9. Temp. 183-184°C.

En oppslemming av 1,2 g (4,4 mmol) 2-metyl-4-(1-pyrrolidino)-2H-thieno/J2, 3-&/ 1, 2-thiazin-l, 1-dioksyd i 2o ml abs. tetrahydrofuran, 5 ml benzen og o,8 ml trietylamin blir ved -lo°C langsomt tildryppet til en opplosning av o,5 g ( 5 mmol) fosgen i 5,5 ml abs. benzen og 3 ml abs. tetrahydrofuran. Den brune suspensjonen blir oppvarmet til romtemperatur og latt rores i 3 timer. Så blir en opplosning på o,68 g 2-aminothiazol og o,8 A slurry of 1.2 g (4.4 mmol) of 2-methyl-4-(1-pyrrolidino)-2H-thieno/J2,3-&/1,2-thiazine-1,1-dioxide in 20 ml abs . tetrahydrofuran, 5 ml benzene and o.8 ml triethylamine are slowly added dropwise at -lo°C to a solution of o.5 g (5 mmol) phosgene in 5.5 ml abs. benzene and 3 ml abs. tetrahydrofuran. The brown suspension is warmed to room temperature and allowed to stir for 3 hours. Then a solution of o.68 g of 2-aminothiazole and o.8

ml trietylamin i 5 ml abs. tetrahydrofuran tildryppet i lopet av 3o min. og 16 timer oppvarmet, under tilbakelcp. Deretter blir helt på isvann og ekstrahert med metylenklorid. De forente ekstraktene blir torket med natriumsulfat, filtrert og inndampet til 3o ml. Derved utfelles et gult bunnfall, ved hvilket det dog handler seg om et biprodukt med smp. 319-321°C. Moderluten ml triethylamine in 5 ml abs. tetrahydrofuran added dropwise over the course of 3o min. and 16 hours heated, during return lcp. It is then poured into ice water and extracted with methylene chloride. The combined extracts are dried with sodium sulfate, filtered and evaporated to 30 ml. Thereby a yellow precipitate is precipitated, which is, however, a by-product with m.p. 319-321°C. The mother liquor

blir nå inndampet helt og den oljeaktige resten blir oppdelt ved hjelp av soylekromatografi ( 60 g kiselgel 60, partikkel-storrelse o,o63 - o,2 mm, eluent: benzen/etanol = 9:1). Den reneste fraksjonen blir renset og inndampet. Resten krystalliseres straks ut og gir 2-metyl-4-(1-pyrrolidino)-3-(2-thiazolyl-karbamoyl) -2H-thieno-i/2, 3-e/l, 2-thiazin-l, 1-dioksyd og innsettes- direkte i den neste reaksjonen. Smp. 177-179°C. is now completely evaporated and the oily residue is separated using soil chromatography (60 g silica gel 60, particle size o.o63 - o.2 mm, eluent: benzene/ethanol = 9:1). The purest fraction is purified and evaporated. The residue is immediately crystallized out and gives 2-methyl-4-(1-pyrrolidino)-3-(2-thiazolyl-carbamoyl)-2H-thieno-1/2, 3-e/1, 2-thiazine-1, 1- dioxide and insert directly into the next reaction. Temp. 177-179°C.

0,6 g (1,5 mmol) 2-metyl-4-(1-pyrrolidino)-3-(2-thiazolyl-karbamoyl)-2H-thieno,/2, 3-e7l, 2-thiazin-l, 1-dioksyd blir oppvarmet i 2o ml 3n saltsyre i 1 time ved tilbakelop. Etter avkjoling blir det utrystet flere ganger med metylenklorid. De forente organiske faser blir ekstrahert med natriumkarbonatopplosning. Ved surgjo_ ring av det vandige sjikt blir 4-hydroksy-2-metyl-N-2-thiazolyl-2H-thieno/_2, 3-e7-l, 2-thiazin-3-karboksamid-l, 1-dioksyd satt fritt og kan opptas i metylenklorid. Etter torkning med natriumsulfat og avdestillering av opplosningsmidlet erholder man rent produkt, som kan omkrystalliseres fra etanol. Smp. 225°C (spaltning). 0.6 g (1.5 mmol) 2-methyl-4-(1-pyrrolidino)-3-(2-thiazolyl-carbamoyl)-2H-thieno,/2,3-e7l,2-thiazine-1,1 -dioxide is heated in 20 ml of 3N hydrochloric acid for 1 hour at reflux. After cooling, it is shaken several times with methylene chloride. The combined organic phases are extracted with sodium carbonate solution. On acidification of the aqueous layer, 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno[2,3-e7-1,2-thiazine-3-carboxamide-1,1-dioxide is set free and can be taken up in methylene chloride. After drying with sodium sulfate and distilling off the solvent, pure product is obtained, which can be recrystallized from ethanol. Temp. 225°C (decomposition).

Claims

1. Analogous process for the preparation of therapeutically effective new thienothiazine derivatives of the general formula in which A together with both carbon atoms form the group and the dashed line shows the double bond in group (A.i R means lower alkyl, R2 the residue of an optionally substituted by one or two lower alkyl groups aromatic heterocycle with 1-4 heteroatoms or a optionally substituted by halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy phenyl residue and R^ and R^ each means hydrogen or lower alkyl, characterized by a) reacting a compound of the general formula in which R means lower alkyl and A, R^, R^ and R^ have the meaning indicated above, with an amine of the general formula wherein R 2 has the above meaning, or b) cyclizes a reactive functional derivative of an acid of formula in which A, R 1 , R 2 , and R 4 have the above meaning, or that one c) lower alkylates a compound of the general formula in which A, R^, R^ and R^ have the above meaning, or d) reacts with a compound of the general formula wherein A 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, or e) hydrolyzes an enamine of the general formula wherein A, R^ and R^ have the meaning given above, and Rr and R each mean lower alkyl or together with 5 6 the nitrogen atom forms pyrroline, pyrrolidine, piperidine, morpholine or N-(lower alkyl)-piperazine.

2. Process according to claim 1, characterized by reacting a compound of formula II, in which A together with both carbon atoms form the group and the dashed line shows the double bonds present and R, R^, R^ and R^ have the meanings given in claim 1, with an amine of formula III, in which R2 means the residue of a heterocycle optionally substituted by one or two lower alkyl groups with 1 to 3 heteroatoms or a phenyl radical optionally substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy.

3. Method according to claim 1, characterized in that a compound of formula II is reacted, wherein A together with both carbon atoms form the group and R, R^, R^ and R^ have the meanings given in claim 1, with an amine of formula III, in which R2 means a residue of a heterocycle optionally substituted by one or two lower alkyl groups with

1-3 heteroatoms or a phenyl radical optionally substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy.

4. Method according to claim 1 for the production of 4-hydroxy-2-methyl-N-2-thiazolyl-2H-thieno/2,3-e7l,2-thiazine-3-carboxamide-1,1-dioxide, characterized in that one uses correspondingly substituted starting materials.

5. Process according to claim 4, characterized by reacting 3-ocarbomethoxy-4-hydroxy-2-methylthieno-2,3-e_7~1,2-thiazine-1,1-dioxide with 2-aminothiazole.

6. Process according to claim 1, characterized in that 4-hydroxy-2-methyl-2H-thieno[2,3-e7~1,2-thiazine-3-carboxanilide-1,1-dioxide is produced.

7. Method according to claim 1 for the production of 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno/2~,,2-thiazine-3-carboxamide-1,1-dioxide, characterized in that one uses correspondingly substituted starting materials.