Procedure for the production of new benzene sulphonyl urea and their salts

The subject of the invention is a procedure for the production of new benzene sulphonyl urea of the general formula X-CONù-¥ “¢--%-- Sun COR in which mean X a) z o - alkyl whereby Z hydrogen, halogen, tri fluorine methyl, alkyl or Alkoxy in 4oder 5-Stellung means, b) o - alkyl whereby Z” hydrogen, halogen or alkyl means, Y - CHz - CH z - '- CH - (CHs) - CHzoder - CHz - CH (CHs) -, R a) Pentamethylenimin, which by I up to 8 groups of methyls or a Endoalkylenrest with I to 3 C - atoms, b) Hexamethylerämin can be replaced, if necessary substituted with a Endoäthylengruppe in t5 - ₜ - position, c) Heptamethylenimin, d) Hexahydroisoindolin, Tetrahydroisoindolin, 4, 7-Endoalkylen-hexahydrooder - tetrahydro isoindolin, whereby those Endoalkylengruppe I to 2 C-atoms contains and the double bond of the Tetrahydroverbindung in 5, 6-Stellung stands. e) N-3-Azaspim [5,5] - and CAN, --N f) the remainders of n ---7 and their salts, by the fact characterized that one converts X-CO-NH-Ysubstituterte Benzolsulfonylcarbamtnsäureester with Arntnen of the formula with the group RH or their salts and with alkali-seen means treats the received products if necessary. In the managing and the following definitions “alkyl” always stands for such with 1 to 4 C-flavours in straight lines or branched chain. According to invention the connections available in the procedure possess blutzuekersenkende characteristics as substance or in form of their salts and to draw look by a strong and long lasting lowering of the Blutzuekerspiegels. As X in the above formula in question coming Ringsysterne is for example following: a) C1 Br c1 \ \ \ _ // % _ // % // % _ ci_ 2%-- \. =. /\ __/-- \ __. /\ --/\ ocH --\ ocHù \ degrees, H ocHs 5i CH ù ù \ Hs _ \ 1 _ // % // % //-- % // % \ =1 \ =1 \ = \ =! \ ocH \ ocu ù \ degrees, ocu II c1 CI 2--% _ //--- % _ 2% _ // % _ F-X_/\. =. /\--/\ _/I “OCsH? OC4 H9 t b) OCH3 JJ II JJ Jl J] JJ ùs \” s s1 0 (; 2 H s degrees H 3 I Jl IL IJ/s \ of /-s c1 Br as examples of R are mentioned: a) /-- \/\ /H, - N \/-/\ “% H /--? CH3 - R/ --N > __/CHa I 11, CH3 OCH I II/s H3C CH3 --N I0 b) --N I --N H C H2Ckj c) d) - N (CH#7 ./-1-7 -- I II \ l \ 5; This procedure is characterized by that one converts X-CO-NH-Ysubstituierte Benzolsulfonylcarbaminsäureester with amines of the formula with the group RH or their salts. The mentioned Benzolsulfonylcarbaminsäureester can exhibit a niedrigmolekulaten alkyl residue or a Phenylrest in the alcohol component. The Ausftlhrungsformen of the procedure in accordance with the invention can be adapted generally regarding the Reakt2onsbedingungenweitgchendvariiert and to respective conditions. Example - point can the conversions using inert Lösungsmittein, like Dioxan or toluol, at temperatures from 80 bis1I, '0°C and at different pH values (by use of salts of the amines pH) be accomplished. It proved as favourable to use the amine and/or its salts in the surplus. To blood-sugar-lower the effect of the descriptive Benzolsulfonylharmtoffderivate could be stated thereby that one Hagedern lensen it e.g. in form of sodium salt in doses from 10 mg/kg on normally nourished rabbits fed and the Blutzuekerwert according to the well-known method of or determined with a Autoanalyser over a longer length of time. Thus it was for example determined that 10 mg/kg N - {4 [8 - (: 2-Methoxy-5 -10 mbenzamid0) - ethyl] - - benzene sulphonyl} - N', N' (3,3-dfmethylpentamethylen) - urea after 3 h a blood sugar lowering of 23%bewirkt, serve oh 24 h still 24% amounts to and only after 48 h to the zero value again drops, during which well-known n [4-Methyl-henzolsulfonyl] - Nl-butylharnstoff with a dosage of less than 25 mg/kg at the rabbit no more lowering of the Blutzuekerspiegels causes. The strong effectiveness of the descriptive Benzolsulfonylhamstoffe becomes particularly clear, if those dose further reduce will. Given N4 [8 manden -. (2-Methoxy-5-brombenzamido). - äthyI] - - bermolsulfonyl} - N! N! _ (8.3 - dimethylpentamethyIen) - urea in a dosage of 0,2 mg/kg to rabbits and the n {4 [8 - < 2 - Methoxy-5-chlorbenzamido) - ethyl] - benzolsulf0nyl} - N! No. (3.3 - di - methylpentamethylen) - urea in a dosage of 0,2 mg/kg at rabbits, then is to be still determined a clear blood sugar lowering. Regarding the Toxlzität of the connections values, those result in the order of magnitude of Ben - zelsulfenylharnstoffenwie of the n [4-Methyl-beazolsulfenyl] - N' n-butyl urea and the n [4-Methy! - benzene sulphonyl] - for N of t-cyclohexyl-urea are appropriate, whose LDs0 amounts to p.o with 2,5 and/or 4, 8 g/kg. The procedure products possess thus a very strong to blood-sugar-lower effectiveness with an extraordinarily good compatibility. The besehriebenenBeazolsulfonylharnstoffesollen for the production of orally giving cash preparations with to preferably blood-sugar-lower effectiveness for the treatment the diabetes mellitus serves and can be appliziert as such or in form of its salts and/or in presence of rigid ones, which lead to a Salzbildung. For the Salzbildung for example alkalisehe means can be consulted such as Alkalioder Erdalkalihyclroxyde, - catbonate or - bicarbonate. When mediziräschePräparate are possible verzugsweise tablets, which contain usual Hilfsund of carrier materials beside the Verfahrenserzeugrässendie such as talcum powder, strength, lactose, Tragant or Magaesiumstearat. A preparation, which contains the descriptive benzene sulphonyl urea as active substance, e.g. a tablet or a powder with or without the additives mentioned, is appropriately into one suitably proportioned form brought. As dose thereby such is to be selected, which is adapted to the effectiveness of the venvendeten benzene sulphonyl urea and the desired effect. Amounts to appropriate the dosage for each unit about 0.5 to! 00 mg, verzugsweise 2 to 10 mg, however also substantially over it or among them lying dosage units can be used, - the 5 Nr.29! 274 gegebenenfaIls before application to divide and/or multiply is. B e i s p i e 1! : N {4 - [T3 - (2 - Methoxy - 5 - methyIbenz amido) - ethyl] - benzene sulphonyl} - N “, N” - (3 - - methylpent amethylen) - urea 4 g n {4 - [- (2-Methoxy -5 - Methylbenzamido) - ethyl] - benzolsulfonyI} - methyIurethan (S ehmelz - punkt175 to 177°C) are suspended in 75 ml Dioxan and after addition of 1,1 g 4-Methylpiperidin! 5minauf I! 0°C heats up. One admits then again 1.1 g 4-Methylpiperidin, heated up! h under return flow and shifts after cooling with water. The failed n {4 [13 (2-Methoxy-5-methylbenzamido) - ethyl] - benzene sulphonyl} - N', N' - (3 - methylpentamethylen) - harmtoff by Umfällen with Ammoniakes alzsäure and through over istallisieren from methanol one cleans (fusion point 167 to 169°C). ! 0 in similar way one receives “from the N - {4 - [8 - (2 - Methoxy - 5 - chlorbenzamido) - ethyl] - benzene sulphonyl} - methyl urethane (Sehmelzpunkt! 89 to 191°C) the n {4 - [8 - (2-Methoxy-5-ehlotbenzamido) - ethyl] - benzene sulphonyl} - - N', N' - pentamethyIen - urea in front fusion point 184 to 1860C (from methanol) and the n {4 [13 - - (2 - Methoxy - 5 - ehlorbenzamido) - ethyl] - benzene sulphonyl} - N “, N” - (2 - methylpentamethylen) - harmtoff of the Sehmelzpunkt 150 to 159.°C (from methanol from the n {4 - [6 - (2-Methoxybenzamido) - ethyl] - benzolsulfonyI} - methyl urethane (fusion point 174 to 176°C) the n {4 - [8 “(2-Meth°xybenzamid°) -ethyl] - benzene sulphonyl} - N “, N! - (3 - methylpenta - methylen) - urea of the fusion point 149 bis151°C (from methanol) $ from the N - {4 - [B - (2 - Methoxy -4chlorbertzamido) - ethyl] - benzene sulphonyl} - methyl urethane (fusion point 178 to 180°C) the n {4 - [6 - (2 - Methoxy-4-chlorbenzamido) - ethyl] - bermolsulfonyl} - - N”, N' (3 - methylpentamethylen) - urea of the fusion point 194 to 196°C (from methanol from the N - {4 - [- (2 - Methoxy - 5 - brombenzamido - äthyI] - benzene sulphonyl} - methyl urethane (fusion point 197 to 199°C) the n{4 [8 (2-Methoxy-5-brombenzamido) - ethyl] - ber olsulfonyl} - - N 1, N “- (3,3-dtmethylpentamethylen) - urea (of the fusion point 143°C from ethyl acetate from the N - 4 [6 - (2 - Methoxy - 5 - more chlorber amido) - ethyl] - bermolsulfonyl} - methyl urethane (fusion point 189 to 191°C) the n {4 - - (2-Methoxy-5 - chlorbermamido) - ethyl] - bertzolsulfonyl} - - NI, N” - hexamethylen - urea of the fusion point! 00. bis102°C (from methanol), the n {4 - [1 - (2 - - Methoxy-5-chlorbenzamido) - ät.h I] - benzene sulphonyl} -4, %methano hexahydro isoindolinyl carboxamid of the fusion point 193 to 195 C (on methanol) and the n {4 [JB - (2-Methoxy-5-chlorbenzamido) - - ethyl] - benzene sulphonyl -4, 7-methanoI-AS, 6-tetrakydro - isoindolinyl-2-carboxamid of the fusion point 191 to! 93 °C (from methanol/Dioxan) from the n {4 [6 (2-Methoxybenzamido) - ethyl] - benzoIsulfonyI} - methyl urethane (fusion point lq4 to 176°C) the n {4 - [- (2-Methoxybenzamido) - ethyl] - benzoIsulfonyl} - N! , N, _hexamethylen - urea of the fusion point 168 to 170°C (from methanol); from the N - {4 - [t - (2 - Methoxy - 5 - chlorbenzamido) - ethyl] - benzene sulphonyl} - methyl urethane (Sehmelzpunkt 189 to 191°C) the n {t [13 - (2-Methoxy-5-ehlorbenzamido) - ethyl] - benzene sulphonyl} - - N', N' (3 - methylpentamethylen) - urea of the Sehmelzpunkt 172 to 174°C (umgefällt from soda/hydrochloric acid), the n [4 - - (9, - methoxy -5 - ehlorbermamido) - ethyl] - benzoIsulfonyl} - As - tetrahydro - tsOin - dolino -2 - carboxamid of the Sehmelzpunkt! 61 to 163°C, the N - {4 - - (2 - methoxy -5 - ehlorbep.z arrädo) - - ethyl] - benzoIsulfonyl} - hexahydro isoindolino -2-earboxamid of the Sehmelzpunkt 189 to! 90,5°C, the N - {4 - - (2-Methoxy-5-ehlorbenzamido) - ethyl] - benzene sulphonyl} - NI, N, - (3,3-dimethylpentamethylen) - urea of the Sehmelzpunkt 145°C (umgefällt to the soda/hydrochloric acid), the n {4 [1 - (2-Methoxy - 5 - ehlorbenzamido) - ethyl] - benzene sulphonyl} - N t; N. (1,5-endoäthylenpentamethylen) - urine material of the Sehmelzpunkt! 95 bis196°C (from dimethylformamide/methanol/water), the n {4 - [1 - (2-Methoxy -5 - - ehlorbenzamido) - ethyl] - benzene sulphonyl} - N', N' - (1.4 - endoäthylenpentamethylen) - urea of the SehmeIzpunkt 178 bis180°C (cleaned over ammonia) and the n {4 [13 - (2-Methoxy-5-ehlorbenzamido) - ethyl] - benzene sulphonyl} - N', N “- (1.5 - endopropylenpentamethylen) - urea of S ehmelzpnnkt 152 to I530C (from dimethylformamide/methanol/water) from the n {4 - - (2-Methoxy-5methylbenzamido) - äthyI] - benzene sulphonyl} - methyl urethane (Sehmelspunkt 175 to! 77°C) the n {4 - - (2-Methoxy-5 - methylbenzamido) - ethyl] - benzene sulphonyl} - - N 1, N” - (3.3 - dimethylpentamethylen) - urea by the Schmelzpunkt132°C (laber sodium s alz cleaned). In similar way Main from the n receives {4 - [8 (3-Meth0 xythi0 phen-2-carb0 namid0) - to ethyl] - benzene sulphonyl} - methyl urethane (fusion point 226 to 228°C) the n {4 - [8 “(3-Methoxythiophen-2-carb°namid°) - ethyl] - benzene sulphonyl} - hexahydm-indolinyl-2-carboxamid of the fusion point 190 to I92°C; from the N - {4 - [T3 - (3 - Methoxythiophen - 2 - carbamido) - äthyi] - benzene sulphonyl} - methyl urethane (Fp. 226 to 228°C) the n {4 [B - (3 - Methoxythiophen-2-carbonamido) - gthyl] - benzene sulphonyl} - N', N “- - (3-methylpentamethylen) - urea of the fusion point 215 to 217oc (from methanol/dimethylformamide); from the n {4 - [B (2 - Äthöxybenzamido) - ethyl] - benzene sulphonyl} - methyl urethane (Fp. 172 to 174°C) the n {4 - [B - (2-Äthoxybenzamido) - ethyl] - benzene sulphonyl} - N”, N' (3 - methylpentamethylen) - - harustoff of the fusion point 156 to 158°C (from methanol); from the n {4 [IS - (2-Methoxyäthoxybenzamido) - ethyl] - benzene sulphonyl} - methylutethan (Fp. 123 to 125°C) the N - {4 - [B - (2-Methoxyäthoxybenzamido) - ethyl] benzene sulphonyl} - N', N' (3 - methylpentamethylen) - hamstoff of the fusion point 112 to I13°C (decomposition) (from methanol); I0 from the n {4 [8 - (2-Äthoxy-5-fluorbenzamido) - ethyl] - benzolsulfenyl} - methyl urethane (Fp. 193 to 195°C) the n {4 [IS (2-Äthoxy-5-fluorbenzamido) - thyl] - benzene sulphonyl} - N', N' (3-methylpentamethylen) - urea in front fusion point 178 to 179°C (from methanol); from the n {4 - [6 (3 - Chlorbenzamido) - ethyl] - benzene sulphonyl} - methyl urethane (Fp. 173 to l? 5°C) the n {4 [- (3-Chlorbenzarnido) - ethyl] - benzene sulphonyl} - N', N' (2-methylpentamethylen) - harustoff of the fusion point 159 to 161°C (from methanol); from the n {4 - [IS - (2 - Methoxy - 5 - methylbenzamido) - thyl] - benzene sulphonyl} - methyluzethan (Fp. 175 to 177°C) the n {4 - [- (2-Methoxy-5 - methylbenzamido) - ethyl] - benzene sulphonyl} - N “, N” - - (2-methylpemtamethylen) - urea of the Sehmelzpunkt 156 bis158°C (from methanol); from the n {4 - [IS - (2 - Methoxy-5 - tri fluorine methylbenz amido) - ethyl] - benzene sulphonyl} - methyluzethan (Fp. 179 to 181°C) the n {4 - [B - (2-Methoxy-5-trifluormethylbenzamido) - ethyl] - benzene sulphonyl} - - N “, N” - (3-methylpentam thylen) - urea of the fusion point 158 to 160°C (carrion methanol); from the n {4 - [B - (2 - Methoxy-5 - chlorbenzamido) - ethyl] - benzene sulphonyl} - methyl urethane (Fp. 178 to 179°C) the n {4 - [IS - (2-Methoxy-5 - chlorbenzamido) - ethyl] - benzene sulphonyl - arnino earbonyl} -3 - - azaspiro [5,5] - undeean, Fp. 125°C; from the n {4 [IS - (2 - Methoxy-5 - methylbenzamido) - ethyl] - benzene sulphonyl} - ethyl urethane (Fp. 166 to 170°C) the n {4 - {IS - (2-Methoxy -5 - methylbenzarnido) - ethyl] - benzolsulfonyl A mfn'o carbonyl} - -3-azaspiro [5, 5] - and CAN, Fp. 110°C (Zexsetzung); from the n [4 (B-Benzamidoäthyl) '- benzolsulfor*yl] - methyl urethane (Fp. 186°C) the n [4 (- Benz - amidoäthyl) - benzolsulfonyl amino earbonyl] -3 - azaspiro [5, 5] - undeean, Fp. 171 to 173°C; from the n {4 [IS - (2 - Methoxy-5-flucrbenzamido) - ethyl] - benzene sulphonyl} - ethyl urethane (Fp. 123°C) the n {4 - [8 - (2 - Methoxy - 5 - fluorbenzamido) - ethyl] - benzolsulfonyl amino - carbonyl} -3 - azaspiro - - [5, 5] - and CAN, Fp. 151 to 153°C from the n [4 [IS - (3 - Chlorbenzamido) - ethyl] - benzene sulphonyl} - methyluzethan (Fp. 174 to 176°C) the n {4 - [6 (3-Chlerbenzamido) - ethyl] - benzolsulfonyl amino earbonyl} -3 - azaspko [5,5] - and CAN, Fp. 218°C; from the n {4 - [IS (2-Methoxybenzamido) - ethyl] - benzene sulphonyl} - ethyl, rethan (Fp.144°C) the n {4 - [6 (2 - Methoxybenza mido) - thyl] - benzolsulfonyl amino carbony]} -3 - az aspiro - [5,5] - and CAN, Fp. 166 bis168°C. B e i s p i e 1 2: N {4 - [B - (5-ChIor -2-methoxybenz amido) - ethyl] - benzolsulfonyl amino - carbonyl} - -4, 7 - endocyclopropylenA5 - hexadecimal hydraulic - isoindol! 0, 7 g N - [4 (-5-Chlor-2-methoxybenzamido-äthyI) - benzene sulphonyl] - methyl urethane in 100 ml Dioxan and after addition from 4.08 g 4, 7-Endocyclopropylen-A5 are solved - hexahydro isoindoI 1 1/2 h under ückfluß to-simmer heated up. One distills the Dioxan in the vacuum off. The received n - {4 - [- (5 - chlorine - 2 - methoxybenza mido) - ethyl] - benzolsulfonyl-amino-carbony.1} - 4, q-endocyclopropylen-A - hexahydro isoindol melts after the Uml istallisiexen from Essigestar/Dioxan with 179 to 181°C. Into similar-wise one receives: from the sulphonyl urethane and 4 mentioned, 7-Endocyclopropylen-octahydro-isoindol the n {4 [6 - - (5 - chlorine - 2 - methoxybenzamido) - ethyl] - benzolsulfonyl amino carbonyl} -4, 7 - endocyclopropylen - octahydro isoindol from the fusion point 186 to 188°C; from the sulphonyl mentioned, rethan and 4, 7-Endocyclobutylen-octahydro-isoindol the n {4 - [t - - (5 - chlorine -2 - methoxybenzamido) - ethyl] - benzolsulfonyl amino car bonyl} -4.7 - endocyclobutylen octa - hydraulic isoindol of the Schmelzpunld 161°C from Dioxan. PATENT CLAIM " procedure for the production of new Benzolsulfonylhamstoffen of the general forms! m X-CO-Nh-y--/ -- SO - NH - CO - R, \ = 2 in which mean X a) z \ ___/0 Alky! how Z hydrogen, halogen, tri fluorine methyl, Alky! or Alkoxy in 4oder S-position meant, b) o - alkyl z, + IL S \ \ whereby Z' hydrogen, halogen or alkyl means, Y - CHz - CHz -, - CH (CH - CHz= or - CHz CH (CH) -, R I0 a) Pentamethylenimin, which by I to 3 Methylgmppen or a Endoalkylenrest with I to 8 C - atoms to be substituted can, b) Hexamethylen2min, if necessary replaces with a Endoäthylengruppe in /3- - position, e) Heptamethylenimin, d) Hexahydroisoindolin, Tetrahydroisoindolin, 4, 7-Endoalkylen-hexahydrooder - tetrahydro isoindolin, whereby the Endoalkylengruppe 1 to 2 C-atoms contains and stands the double bond of the Tetrahydroverbindung in fi, of 6-Stellung, e) N-3 - Azaspiro [5, 5] - and CAN, - N \/\/f) the remainders --N C> II --N \ \/\ _ _ \. /• _ _ l, bù and their salts, thereby characterized that one substituted NH - Y - with the group of X - CO - Benzolsulfonylcarbaminsäureester with amines of the formula RH