Procedure for the production of new Sulfonylaminopyrimidinen as well as their salts

From the German patent specification Nr.1801817 are 2 (Furoyl and/or. ThenoyIaminoalkylbenzolsulfonamido) - - pyrimidine with good to blood-sugar-lower effect bekarmtgeworden. It was now surprisingly found, since 2 - (A cyIaminoalkylben zolsulfonamido) - pyrimidine, which i n D it A cylgruppe e Inc. n bieyclische n sour - stoffoder sulfur Heteroeyelus carry, by a still more stronger antidiabetischeWirksamkeit are characterised. The subject of the invention is a procedure for the production of new Sulfonylaminopyr [dine of the general formula R < 5 A-CO-Nh-¥-- --SOz--NH -- R2 R-S (I) in A one if necessary by halogeneous, Alkyloder alkoxy groups with 1 to 3 carbon atoms sub! 0 set, more sauerstoffoder schwefelhaltigen bicyelisehen remainder, Y a low group of alkyls with 1 to 3 C-atoms, R hydrogen or with Y, branched out if necessary, together a bridge of 3 or 4 C-flavours, 1 a geradkettigen or branched alkyl, Cycloalky! -, C] eloalkylalkyl, Alkoxy, Cycloalkoxy, AlkoxyalkyI, AIkoxyalkox3r, Alkylmereaptobzw. Alkylmereaptoalkyl remainder or a PhenyIbzw. Benzyle remainder, R-S hydrogen or a low Alkylgtuppe means, whereby t and R3 can form also together a bridge from 3 to 5 groups of groupgroups, as well as from of them physiologically harmless salts. If connections are preferential, in which A a Benzofuranyl, a 2,8-Dihydrobenzofuranyl, a Chromanyloder Homochromanyl remainder and/or an appropriate Thio analogue, e.g. the 2,3-Dihydrobenzothienyl-Rest, means. The effindungsgemäße procedure for the production of connections of the general formula (I) and of of them physiologically compatible salts is characterized by it that one has substances of the general formula \ R s, (IL) in Y, g 1, and RA the meaning indicated above, by reactive derivatives of acids of the general formula A--COOH, (nI) in The meaning indicated above has, converts and gewünschtenfalls into physiologiseh harmless salts passage. The Aeylierung of the connections (II) becomes in usual way by conversion with reakfionsfähigen Deriraten of the acids fflI) (e.g. with Säurehalogeräden) accomplished, preferably in presence of a Säureaceeptors. As physiologically harmless salts in particular alkali, Erdalkaliund of ammonium salts, as well as salts with blutzuekersenkend effective basic connections are applicable, primarily Biguaniden. The production of these salts takes place in actually well-known way, for example via conversion with AlkaIibzw. Alkaline-earth caustic solutions, w ässerigem Ammeniak and/or entslxechenden carbonates. The substances I and of them physiologically harmless salts can be appliziert in liquid or firm form duck ral and parenterally. As injection medium water is preferably used, which contains the additives usual with injection solutions such as Stabilisierungsmittel, solution mediators and/or buffers. Such additives are e.g. Tartratoder borate buffer, ethanol, complexing agent (like ethylen diamine - tetraessigsäure and their niehttoxisehe salts), hoehmolekulare polymers (like fltäs*iges PL oxide) to the Viskositätsreguliernng. Firm one of carrier materials are e.g. strength, lactose, Mannit, methyl cellulose, talcum powder, hochdisperse silicic acid, high-molecular fatty acids (like stearic acid), gel, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, firm high-molecular polymers (like PL glycols). For the oral application suitable Zubereitnngen can contain gewünschtenfalls Geschmacksund of Süßstoffe. 48 the new substances and the procedure according to invention is described on the basis the following examples. B ice piel I: 4 [2 (5 Meth XY 2 methy 2 - dihydr benz fur y - (7) arn n) äthy] n [5 (cyc hexylmethyl) - pyrimidinyl (2)] - benzene sulfone amide 2.1 g 5-Methoxy-2-methyl-2, 3-dihydro-benzo furan-7-carbonsäure (Fp. 122 to 123°C) and 4 ml Thionylehlorid 3 h under return flow are heated up. Afterwards the libersehüssige Thionylchlorid in the vacuum is completely abdestilliert and the 5-Methoxy-2-methyl-2,8-dihydro-benzo staying is taken up furan7-carbonsäurechlorid to I0 ml exp. dichloromethane. This solution becomes under Eisktlhlung the solution of flat steel bar, 3 g 4 (2-Amino-äthyl-N - (eyclohexylmethyl) - - pyrimidinyl (2)] - benzolsulfonamid hydroehlorid (Fp. 260 to 262°G) in 8 ml 2n-Natronlauge and 30 ml water course-drips. The pH value is held by gradual addition of further caustic soda solution about 12. Still 1 h is agitated, acidified then along acetic acid and evaporated the dichloromethane by warming up. The failed raw product solved in very diluted caustic soda solution, which treats solution with activated charcoal, the substance solved by introducing carbon dioxide pleases, again in caustic soda solution and precipitated with hydrochloric acid. To the further the substance is recrystallized twice from ethanol. Yield: 3, 2 g (= 70, 7°/o D. Th. ); Fp. 183 to 185°C. In anäloger way one receives the following connections: 4 [2 - (2,4-Dimethyl-2, 8dihydro-benzo furoyl (7) - amino) - ethyl] - n [5-propyi-pyrimidinyl (2)] - benzolsttlfonamid, Fp. 169 to 172°C (from Nitromethan) 4 - [2 - (2, 5-Dimethyl-2, 3dihydro-benzo furoyI (?)- amino) - ethyl] - n [5-benzyl-pyrimidinyl (2)] - benzelsulfonamid, Fp. 182 to! 84°C (from Nitropropan) 4 [2 - (2, 5Dimethyl2, 8dihydrobenzo furoyl (Y) - amino) - äthy 1] - n [5 (2-methoxyäthoxy) - pyrimidinyl (2)] - benzene sulfone amide, Fp. 157 to 159°C (from ethanol) 4 [2 (2, 5-Dimethyl-2, 8-dihydro-henzo furoyl (7) - amino) - äthyI] - n [5phenyl-pyrimidinyl (2)] - benzene sulfone amide, Fp. 188 to 185°C (from Nitropropan) 4 - [2 (5Chlor-2-methyl-benzo furoyl (7) - amino) - ethyl] - n [5-isobuty1-pyrlmidinyl (2)] - benzene sulfone amide, Fp. 181 to 182°C (the product first from a methanol Methylenchlerid mixture and then from acetone is recrystallized, it contains 1/2 mol crystal acetone. ) 4 - [2 - (5-Chlor-2-methyl-2, 3 - dihydrobenzo fuxoyl (2) - amino) - ethyl] - n [5 - (äthylmereaptomethyl) - - pydmidinyl (2)] - benzene sulfone amide, Fp. 168 to 170°C (from ethanol) 2 [5Chlor2 methyl2, 3dihydro-benzo furoyl (7) - amino] - n [5-isobutyl-pyrimidinyl (2)] - indan -5-sulfonamid, Fp. 241 to 244°C (from Nitromethan) 2 - [Cbxomanyl (8) - C arbony lamino] - n [5-isopr opylmereaptoir/rimidinyl (2)] - l, 2, 3,4-tetrahydronaphthalin-7-sulfonamid, Fp. 118 to 120°C (the product first from einemMethanol Methylenehlorid mixture and then from Aeeton umkristal38 is associated, it contains! /2 mol crystal acetone.) 4 [2 (Homoehromanyl (9) - earbo lamino) - ethyl] - n, 6, 7, 8-tetxahydrochinazoltnyl (2)] - benzene sulfone amide, Fp. 221 to 223°C (from a isopropanol benzene Gernisch) 4 - [2 (2-Methyl-2, A-dihydro-benzo thenoyl (7) - amino) - ethyl] - n [5-isobutyl-pffimidinyl (2)] - benzene sulfone amide, Fp. ! 68 to! 70°C B egg s pi e 1 2: 4 [2 (5-Ch1 r-2-methy1-benz fur y - () - amine) - äthy] - n [5-is but XY-py m diny - - (2)] - benzene sulfone amide 2.6 g 5-Chlor-2-methyl-benzo furan-7-carbonsäure (Fp. 230°C) in 30 ml Aeeten are suspended and under agitating and ice cooling with 1,26 g tri ethyl amine and afterwards with 1, 2 g chlorine formic acid ethyl esters shifted. One agitates to 10 min after and gives under cooling the reaction mixture portiousweise to a solution of 4,35 g 4 (/3-Amino-äthyl) - n [5-isobutoxy-pyrimidinyI (2)] - benzene sulfone amide (Fp. 239°C) undNatr [water and 20 umaeetat ml acetone in a mixture from 20 ml. The beginning is acidified still 1 h at ambient temperature naehgeriährt, with water shifted, with hydrochloric acid, which istallisiert product sucked off and from ethanol dimethylformamide over. Received 4 [2 (5-Chlor-2-methyl-benzo furoyl (7) - amino) - ethyl] - n [5-isobutoxy - pyrimidiayl (2)] - benzoßulfonamid melts with 198 to 199°C. In similar way one receives the following connections: 4 [2 - (5Chlor-2-methyl-benzo ftttoyI (7) - amino) - äthyI] - n [5eyelohexyl-pyrimidinyl (2)] - benzene sulfone amide, Fp. 218 to 220°C (from ethanol dimethylformamide) 4 - [2 - (5-Chlor-2methyl-benzo furoyl (7) - amino) - äthyI] - n [4-methyl5-isopropyl-pyrimidinyl (2)] - - benzene sulfone amide, Fp. 190 to 192°C (at ethanol dimethylformamide) 4 [2 - (5-Chlor-2-methyl2, 3dihydro-benzo furoyl (7) - amino) - ethyl] - n [5-isopropoxy-pyrimidinyl - - (2)] - benzene sulfone amide, Fp. 196°C 4 - [2 (5-Clal (r-2-methyl-2,3-dihyro-benzo furoyl (7) - amino) - ethyl] - n [5-isobutyl-pyrimidinyl (2)] - - benzene sulfone amide, Fp. 169°C (from ethanol) 4 - [2 - (5-Chlor-2methyl-2, 3dihydrobenzo furoyl (7) - amino) - ethyl] - n [5 - (äthylmercaptomethyl) - - pyrimidinyl (2)] - henzolsulfonamid, Fp. 168 to 170°C (from ethanol) _ o 4 - [2 (8-Chlor-2-methyl-2, 8-dihydro-benzo furoyl (7) - amino) - ethyl] - n [4-methyl-5äthylmercapto - pyrimidinyl (2)] - benzene sulfone amide, Fp. ] 60 to 162°C (from methanol) 4 [2 - (6-Chlor-chromanyl (8) - C arbonylamino) - ethyl] - n [5 - (methoxymethyl) - pyrimidinyl (2)] - beuzolsttlfonamid, Fp. 116 to 218°C (from benzene and afterwards from methanol umlffistallisiert). Example 3:2 - (2-Phenyl-äthyl) - biguanid salt the 4 [2 (2,5-Dimethyl-2,3-dihydro-benzo furoyl - (7) - amino) - ethyl] - n [5 (2-me thoxy äthoxy) - pyrimidinyl (2)] - benzene sulfone amide 75 g 4 [2 - (2, 5-Dimethyl-2, 3dihydrobenzo furoyl (7) - amino) - ethyl] - n [6 (2-methoxyäthoxy) - - py imidinyl (2)] - benzene sulfone amide and 0, 63 ml 30% ige Natriumme¢hylaflö ung are warmed up to 0, S g in 50 ml exp. ethanol,] - (2-Phenyl-äthyl) - biguaräd hydrochloride admitted and the mixture 4 h under Rtickfluß heats up. After cooling off failed sodium chloride is sucked off and the filtrate in the vacuum on approximately! and the Produlet shifts 0 ml restricted, with approximately 30 ml exp. ethers sucked off. It scbmilztbeil08bis 110°C.