Procedure for the production of new 1-Phenyl-3-hydroxy-3-methyl-triazene

The invention concerns a procedure for the production of new 1-Phenyl-8-hydroxy-3-methyl-triazene of the general formula H'C \ NN N__/----\ “R H°/% Z” I R2 (D where g 1 fiir the Carbamoyl, one N-Niederalkyl-carbamoyl, a Alkoxycarbonyl, which stands for Phenyloder the Cyanogruppe and R2 for hydrogen or group of methyls. The new connections can be manufactured according to invention by Diazotieren of a connection of the general formula RST %N I= \ R --%-- i I R2 (II) where g 1 and RZ the meaning stated above come, to and conversion of in such a way received Diazoverbindung with N-Methylhydroxylamin and/or one of its salts. The Diazotierung of a connection of the formula (II) takes place in usual way via loosening and/or Außehlämmen of the connection in water, treatment with a surplus of a concentrated mineral acid, e.g. hydrochloric acid and the causing of Natrtumnitrit under Ktlhlung. After completion of the Diazotiemng the Diazoniumsalz.lösung is cast in by portion slowly into a cooled and aqueous N-Methylhydroxylamin-hydrechlorid-solution buffered to a pH value of approximately six at a temperature between 0 and + 10oc under strong agitating, some time is nachgertlhrt and the formed final product is regenerated in usual way. The Aniline of the general formula (II) used as basic materials by chemical or catalytic reduction of the appropriate p-Nitro-Verbindtmgen, e.g. by means of iron splinters and more aqueous sour one can be for example received or by means of PtOz in ethanol. The new Triazene possesses a strong immunosuppressive effect, which makes its use possible both with organ transplant ions and with such diseases, a whose cause lies in the increased formation of antibody. For example S. Cell Bound Anübodies in the so-called PFC test (Plaques Forming Cell test) after Jerne, Nordin and Henry {(B. Amos and H. Koprowski, Wistar of institutes press, Philadelphia, becomes, P. 109)} by daily gift of 150 mg/kg i.p and/or 200 mg/kg p.o. 1 [p (Isopropylcarbamoyl) - phenyl] -3 - - hydroxy-3-methyl-lxiazen the immunity caused by Schaferythrocyten praküsch completely suppresses (96, 6 and/or 96, 0%). A Immunosuppression of this extent could be caused so far only by Antilymphocytenserum or with large doses Procarbazin [N-Isopropyl “- (2-methylhydrazino) - p-toluamid], whereby however strong side effects arise, which were not observed in the available case. Similar to the data of B.B. the Newbould, Brit. J. Pharmacol. Bd.24, P. 632 Polyarthritistest accomplished at rats resulted in 1 [p (Isopropylcarbamoyl) - phenyl] -8-hydroxy-3-methyl-trtazen a reduction of swelling the treated and the unhehandelten paw in the case of an oral dose of 200 (3 days) and/or 100 (11 days) mg/kg around 58.7 and/or 83,8%. In the Hautlxamplantationstest (Dosterung of the connection specified above: 100 mg/kg i.p from the day -4 up to the day + 3 and 50 mg g i.p from the day + 4 up to the day +18) amounted to the Üherlebenszeit of the transplant moults on 21.1 days (untreated Kontrolltiete: 12, 6 days). The middle lethal dose (LDsa) of the 1 [p (Isopropylcarhamoyl) - phenyl] - 3-hydroxy-8-methyl-triazens at mice amount to over 1000 mg/kg with oral gift. For application in the therapy the new connections with tlblichen pharmaceutical Fülloder carrier materials, stretching, blowing up, connection, sliding, Dickungsoder diluents are mixed. As pharmaceutical preparation forms tablets, dragees it, pills, caps or dispersible powders are e.g. applicable. - S - Nr.818559 appropriate tablets can be received for example by mixing or the active substances with well-known auxiliary materials, for example inert dilution center] to n such as calcium carbonate, calcium phosphate or lactose, Sprengmittelu such as corn strength or Alginsäure, bonding agents such as strength or gel, Schrniermitteln such as magnesium stearate or talc, if necessary also Mitteha for the achievement of a Depoteffekter such as Carboxypolymethylen, Carboxymethylcellulose, Celluloseacetatphthalat or Polyvinylacetat. Accordingly dragees cannot do it by covering of similar to the tablets manufactured with usually in dragee etlberztlgen used means, for example Ko] lidon or Schellaek, Gummiarabicum, talc, titanium dioxide or sugar to be manufactured. For the achievement of a depot effect or for the avoidance of inkompatibilitäten the core can consist of several layers. In the same way also the dragees ehülle can consist for the achievement of a depot effect of several layers, whereby the I tilfsstoffe mentioned above with the tablets can be used. That or the active substances containing caps belspielsweiGe can be manufactured, by one the active substances with inert carriers, as lactose or Sorbit mixes and in gelatin capsules in-encased. The daily dose for the application available of the according to invention connections of the general formula (I) amounts to 50 to 300 mg and can in i to 4 single doses be given. The following examples are to describe the invention more near: B e i s p i e I I: 1 [p (Isopropylcarbamoyl) - phenyl] -3-hydroxy-3-methyl-triazen " to on I0°C cooled a Aufschlammung of i0 g p-lsopropylcarbamoylanilin in 100 ml 12 is admitted to water ml concentrated hydrochloric acid. This solution is cooled on 0 to 5°C and prays this Ternperatur 4, 8 g Natriumnitrit slowly registered. Auschlieöend wlrd the Diazoniumsalzlösung at a temperature between 0 and I0°C by portion into a solution of 6,7 g N-Methylhydroxylamin-hydrochloride in 100 ml water, with a RST? oigen sodium acetate solution to a pH value of six abgepuffert was stirred. The pH value is kept constant by further addition of well iumacetatlösung and the solution is agitated a further hour with for instance 5°C. The screen end precipitation sucks themselves off, one washes, one dries and one cleans by recrystallizing from Acetoni IL. Yield: 6.2 g (= 39% d.Th.) of the Fp. 212 to 213°C. B e is p i e 1 2: 1 [p (n-Propylcarbamoyl) - phenyl] -3-hydroxy-3-methyl-triazen: One consisting on 10°C cooled mixture, of 15 g p-u-Propylcarbamoylanilin in 130 ml water, is eingertlhrt into 16 ml concentrated salt-sour, which shifts solution to 0oc cooled down and by portion with 6 g Natriumnitrit. Into in such a way received D azoninmsalzlösung a solution is eingerflhrt by portion by 8,4g N-Methylhydroxylaminhydrochlorid in 125 ml water (abgepuffert with a 10%igen well iumacetatlösung to a pH value of approximately six). If necessary, to the maintenance of the pH value further sodium acetate solution is added. The reaction mixture is agitated 1 h with for instance 5°C, which recrystallizes precipitation sucked off, washed, dried and from acetonitrile, yield: 11.2 g (= 56.0% d.Th.) of the Fp. 209 to 2! 0°C. B e is p i e I 3 • 1 - (p-Cyanophenyl) - 3-hydroxy-3-methyliazen: 59 g (0.5 mol) 4-Aminobenzonitril are inserted at room temperature into 1 1 water. To hydrochloric acid concentrated on a temperature of 0 Smpension cooled to 5oc drop by drop I00 are admitted ml and afterwards 34, 5 g Natriumnitrit in 100 ml to water. The screen end Diazoniurmalz pours oneself into a cold solution of 55 g (0, 66 mol) N-Methylhydroxylamin-hydrochloride in i 1 water and a pH value from 6 to 7 Natriumcafbonatlö¢ung satisfied by causing is maintained. Crystals ahscheidenden themselves filtered, in chloroform are solved, which solution over water-free sodium sulfate evaporates dried and the chloroform. The UmI f¢tallisation comes from chloroform/ether. One receives 40, 5 g (46% D. Th.) the title connection of the fusion point 190 to 192°C. B e i s p i e 1 4: 1 - Kp-Biphenylyl) - 3-hydroxy-3-methyl-triazem 50.0 g (0.296 mol) 4-Aminobiphenyl pray room temperature introduced to 600 ml water. The Suspenston is cooled for concentrated hydrochloric acid (38%) on 5°C and acidified with 60 ml. To in such a way received clear solution a solution of 20 g (0.29 mol) Natriumnitrit in 50 ml water admitted, which the Diazo5ü niumsalz abstention solution poured into a cold solution of 33 g (0t40 mol) N-Methylhydroxylamin-hydrochloride in 60O ml water and by causing a satisfied sodium carbonate solution a pH value from 6 to 7 maintain, that received product is filtered, tn chloroform gelest the solution over Natr/urmulfat getrockuet and in the vacuum to the Tmckne evaporated, the raw product becomes three times from chloroform/ether umI istallisier t, Ausbeute' 38.3 g (= 07% d.Th.) of the Fp. 162 to 163oc. - - Nr.318559 keep similar: furthermore in the examples the 1 to 3 described reaction the following connections HsC N - N - became N__/= \ _ % HO/ --i¢ (1) example No.: 6 7 8 g 1 - CONHC CH (CH - COOC CH - CONH2 - CONH2 R2 H H CH H Fp. °C is9 - zgo 144 - 146,213,205 - 206