FI61880C - EXAMINATION OF N-ARYL SULPHONYL-N '- (3-AZABICYCLOALKYL) -URINAEMNEN - Google Patents

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Patent * och registeretyrelaen Antttku utiagd och uti. «Krut * n pubiieund 30.06.82 (32) (33) (31) Pyy * · ** * Tuo» k * ui —Begird priority Oh. 07.73

Canada (CA) 175626 (71) Science Union et Cie Societe Frangaise de Recherche Medicale, ll +, Rue du Val-d'Or, 92150 Suresnes, France-Frankrike (FR) , France-Frankrike (FR) (7 ^) Oy Jalo Ant-Wuorinen Ab (5 ^) Method for the preparation of N-arylsulfonyl-N '- (3-azabicycloalkyl) ureas - Preparation of N-arylsulfone 1-N This invention relates to a process for the preparation of arylsulfonyl-N '- (3-azabicycloalkyl) ureas having the general formula SO 2 - NH - CO - NH - t / n 1 2 61 880 wherein X represents halogen or alkyl having 1 to 5 carbon atoms and N is an integer from 1 to 3, and their addition salts, in particular physiologically tolerable addition salts with suitable acids or bases. For the preparation of N '- (3-azabicycloalkyl) ureas, which go to According to the process, an N-amino-3-azabicycloalkane of the formula H2N - N2 - (^ ^ ^ ^ JCH2) n is reacted with an arylsulfonylurethane of the formula 'O SO2 - NH - C00 - C2H5

The compounds of the general formula I are prepared according to the invention by reducing, either catalytically by hydrogenation or with diborane, a compound of the general formula: wherein n is the same as above and Z is -C 1-10 or -C the N-nitroso-3-azabicycloalkane thus obtained is reduced, either by catalytic hydrogenation or with a mixture of sodium, ethanol and ammonia, to give the 3-azabicycloalkane thus formed, of the general formula: ch2 »j> __ ^ _ ^ * R 111 3 61880 To prepare a 3-azabicycloalkane of the general formula _ * - NH2 iv and compound IV in the form of a base or hydrochloride with a urea of the general formula

X

SOj - NH - C - NH2 V

wherein the condensation is carried out in glacial acetic acid when the compound IV is in the form of a base, or in glacial acetic acid, dimethylformamide or a mixture of acetonitrile and dimethylformamide when the compound IV is in the hydrochloride form, and if desired treating the N-arylsulfonyl-N '- (3-azabicycloalkyl) ureas thus obtained with suitable acids or with bases to prepare the corresponding addition salts.

The process according to the invention represents a clear advance over the process described in GB 1 153 982, both in terms of yields and purity of the product obtained.

For example, when N- (4-methylbenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea was prepared according to the method of Example 1 of GB 1,153,982, the yield was 59%. When again prepared according to Example 3 of this application, the yields were always above 60% regardless of the reaction conditions. In addition to the better yield, the product was also purer than the product prepared according to Example 1 of the GB patent, which contained about 5% p-toluenesulfonamide as an impurity.

The starting material of general formula II wherein Z represents a group g was prepared from the corresponding 1,2-cycloalkanedicarboxylic acid C-formula of formula

______COOH

<CH2> n_. _

COOH

where n means the same as above.

The starting material of general formula II in which Z represents a group of 61880 4 -Cl 2 - in turn was prepared either by electrolytically reducing a compound of formula II in which Z represents a group -C-; lf o or by hydrogenation of ethyl 2-cyanocycloalkanecarboxylate or ethyl 2-cyano-1-cycloalkene carboxylate of the general formulas --- COOC-Ης-COOC-H,

<™ 2> Γ <= h2tT

"" --- CN "" "---- CN

wherein n is as defined above; wherein this hydrogenation is carried out in a solvent such as isopropanol in the presence of ammonia, Raney nickel, at a hydrogen pressure of 17-20 kg / cm, at a temperature of 60-100 ° C.

A very preferred way of carrying out this process involves carrying out the catalytic hydrogenation of compound II in a solvent such as dioxane, copper and barium chromium, at a temperature of 250-300 ° C, at a hydrogen pressure of 100-180 kg / cm 2, or The reduction II is carried out with diborane by refluxing in a solvent such as tetrahydrofuran. The nitration of compounds III is carried out with sodium nitrite in the aqueous phase.

The catalytic hydrogenation of the N-nitroso-3-azabicycloalkanes is carried out in the aqueous phase on 5% palladium on carbon in the presence of ferrous sulphate and urea, at a temperature of about 30 ° C and a hydrogen pressure of 7-10 kg / cm 3.

In particular, the catalytic hydrogenation processes are of great industrial interest because they make it possible to obtain a pure product and carry out the next synthesis step directly using the filtered liquid obtained in the hydrogenation without isolating the product.

The condensation of the compounds IV and V is suitably carried out in glacial acetic acid, or when the compound IV is used in the form of the hydrochloride, its condensation with the compound V can preferably be carried out not only in glacial acetic acid but also in dimethylformamide or a mixture of acetonitrile and dimethylformamide.

The compounds of general formula I can be converted into addition salts with acids such as, for example, hydrochloric, hydrobromic, sulfonic, acetic, malonic, maleic, fumaric, tartaric and malic acids, or alkali or alkaline acids. with alkali metal hydroxides and carbonates or alkali metal bicarbonates.

The compounds of the general formula I and their physiologically tolerable salts have valuable pharmacological and therapeutic properties and, in particular, very interesting hypo-glycemic activity. In addition, they reduce the accumulation of blood particles and capillary permeability, increase fibrinolytic potential and capillary resistance, and have very low toxicity. Thus, the compounds of the general formula I and their physiologically tolerable salts can be used as medicaments, in particular in the treatment of diabetes and diabetic angiopathy.

The following examples illustrate the invention; melting points were determined by the Kofler method.

Example 1: N-nitroso-3-azabicyclo (3,3,0) octane / Τλ

(N - NO

vly A) 83.4 g of 1,2-cyclopentane-dicarboximide in a solution of 278 ml of anhydrous dioxane were hydrogenated with 24 g of copper and barium chromite (prepared by A.Dunet et al., Bull.Soc. Chim. France (1956) 906-10) at 276 ° C and 110-100 kg / cm hydrogen pressure until hydrogen absorption ceased, which took 5-6 hours. The catalyst was filtered off and the filtrate was collected in 57.6 g of acetic acid. The solvent was then evaporated in vacuo and the residue was dissolved in 390 ml of water.

The solution thus obtained was extracted with chloroform to remove non-basic products, then nitrosated at 70 ° C by rapidly adding 41.4 g of sodium nitrite in 131 ml of water, and then the mixture was heated at 70 ° C for one hour. After cooling, the reaction mixture was extracted with ether, the extracts were washed with sodium bicarbonate solution and then with water. These extracts were dried, the solvent was removed by distillation and the product was distilled. Approximately 56.7-59.7 g of N-nitroso-3-azabicyclo (3.3.0) octane were obtained, a yellow oil (b.p. ).

The 1,2-cyclopentanedicarboximide used as starting material was in turn prepared from 1/2-cyclopentanedicarboxylic acid.

B) N-nitroso-3-azabicyclo (3,3,0) octane was also prepared as follows: 25 g of 3-azabicyclo- (3,3,0) -octan-2-one in a solution of 250 ml of anhydrous dioxane, hydrogenated with 7.2 g of copper and barium chromite at 300 ° C under a hydrogen pressure of 140-130 kg / cm 2 until hydrogen absorption ceased. The reaction mixture, which was treated as described above, gave 19.2 g of N-nitroso-3-azabicyclo (3.3.0) octane, b.p. / 0.1 mm Hg; 90-95 ° C, n24 = 1.513.

The 3-azabicyclo- (3,3,0) -octan-2-one used as starting material can be prepared either by electrolytic reduction of 1,2-cyclopentanedicarboximide in K.N. Menon and J.L. Simonsen, J.Chem. Soc. (1929), pp. 302-305, or by hydrogenation of ethyl 2-cyanocyclopentane carboxylate or ethyl 2-cyanocyclopent-1-enecarboxylate according to the following methods: a) 33.4 g of ethyl The 2-cyanocyclopentane carboxylate in a solution of 334 ml of isopropanol and 4 g of NHL · was hydrogenated using Raney nickel at a hydrogen pressure of 17-20 kg / cm until hydrogen absorption ceased. The catalyst was then filtered off and the solvent was removed by distillation. The residue, which was recrystallized from 130 ml of isopropyl ether, gave 18.2 g of 3-azabicyclo- (3, 3,0) -octan-2-one, b.p. 88-90 °.

b) 49.5 g of ethyl 2-cyanocyclopent-1-ene carboxylate in a solution of 495 ml of isopropanol and 5.1 g of NH 4 were hydrogenated in the presence of Raney nickel at 60 ° C at 17-20 kg / cm 2: n hydrogen pressure until hydrogen absorption ceased. The catalyst was filtered off, the solvent was distilled off and the residue was recrystallized from 300 ml of cyclohexane. About 20.5-21 g of 3-azabicyclo- (3,3,0) -octan-2-one were obtained, m.p. 89-90 ° C.

C) Another process of particular interest for the preparation of N-nitroso-3-azabicyclo- (3,3,0) -octane was performed as follows:

Diborane prepared by adding 40.8 g of BH 2 Na in 1000 ml of diglyme to 228 g of 2 (2) 2 OBF in 400 ml of diglyme was added at 0 ° C over 5 hours to a solution of 27 , 8 g of 1,2-cyclopentanedicarboximide in 500 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0 ° C for 2 hours, allowed to stand for 24 hours, refluxed for 8 hours, carefully hydrolysed by the addition of 150 ml of 6N HCl solution, then refluxed again for 5 hours. After cooling, the insoluble constituents were filtered off and the solution thus obtained was made alkaline with 200 ml of 10N NaOH solution, followed by steam distillation, and the distillate was collected in 12N HCl solution. The acidic medium was dried over 100 mL of ethanol followed by 100 mL of acetone to remove all water. The residue was suspended in 100 ml of anhydrous acetone, and after filtration, 12.8 g of 3-azabicyclo- (3,3,0) -octane hydrochloride, m.p. 136-137 ° C, which was nitrosated with sodium nitrite as mentioned above to prepare N-nitroso-3-azabicyclo- (3,3,0) -octane, b.p. / 0.1 mm Hg = 90-95 ° C.

Example 2: N-Amino-3-azabicyclo- (3,3,0) -octane <N - NH0 / L / 2A) 1050 g of N-nitroso-3-azabicyclo- (3,3,0) -octane were hydrogenated in a suspension of 3500 ml of water using 6 g of FeSO 4, 7H-O and 17.5 g of urea, 21 g of palladium on carbon, 5% Pd, 10-7 kg / cm of hydrogen at 30 ° C until hydrogen absorption ceased. The catalyst was filtered off, 1000 ml of benzene and 2400 g of potassium carbonate were added. The reaction mixture was decanted, extracted with benzene and dried over potassium carbonate. From the solution thus obtained, 690 g of N-amino-3-azabicyclo- (3,3,0) -octane, b.p. / 10 mm Hg = 86 ° C, were obtained.

B) N-amino-3-azabicyclo- (3,3,0) -octane was also prepared as follows: to 28 g of N-nitroso-3-azabicyclo- (3,3,0) -octane and 36.8 g To 500 ml of absolute ethanol in 500 ml of liquid ammonia was added 18.4 g of sodium over 90 minutes while maintaining a constant level. The reaction mixture was then stirred for 1 hour, then the NH 4 was slowly removed by the simultaneous addition of 300 ml of water and 200 ml of ether. The aqueous phase was saturated with 100 g of granular sodium hydroxide. After decantation, extraction with ether and drying, the solvent was removed. 13 g of N-aminoazabicyclo- (3,3,0) -octane, b.p. / 18 mm Hg = 86 [deg.] C. were obtained.

Example 3: N- (4-methylbenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl] urea ___ H3Cl2) -SO2 - NH - CO - NH - / 8 61 880 8.1 g of N-amino-3-azabicyclo- (3,3,0) -octane hydrochloride were added to a lukewarm solution (40-50 ° C) of 10.7 g of paratoluenesulphonylurea and 100 g of ml of a 4/1 mixture of acetonitrile and dimethylformamide, then the mixture was refluxed. Slight turbidity was observed, which intensified with the formation of NH 4 Cl precipitate. After refluxing for 45 minutes, the reaction mixture was diluted with 90 ml of water. The precipitate thus formed was filtered off with suction and recrystallized from 100 ml of ethanol. 12 g of N- (4-methylbenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea were obtained, m.p. 178 ° C, yield 74%.

Such synthesis was also preferably performed by working in dimethylformamide at 80 ° C for 45 minutes; 10 g of N- (4-methylbenzenesulphonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea were obtained, m.p. 178 ° C, yield 62%, or by working in glacial acetic acid according to the following method: 10.7 g of para-toluenesulphonylurea, 8.1 g of N-amino-3-azabicyclo- (3,3,0) -octane hydrochloride and 50 g of g of glacial acetic acid was heated at 80 ° C for 30 hours. The mixture became homogeneous after 10 minutes where a small precipitate was observed. The mixture was diluted with 50 ml of water and the precipitate thus formed was filtered off with suction and recrystallized from 90 ml of refluxing ethanol. 11.5 g of N- (4-methylbenzenesulphonyl) -N '- (3-aza-bicyclo- (3,3,0) -oct-3-yl) -urea were obtained, m.p. 178 ° C.

In this latter example, 8,1 N-amino-3-aza-bicyclo- (3,3,0) -octane hydrochloride can be replaced by 6.3 g of the corresponding base to give 11.7 g of N- (4-methylbenzenesulfonyl ) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea, m.p. 178 ° C. Examples 4-10:

The following compounds were prepared according to the procedures described in Examples 1-3 using the corresponding starting materials: 4. N- (4-ethylbenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea , sul.p. 149 ° C (ethanol); 5. N- (4-chlorobenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea, m.p. 207-208 ° C (ethanol); 6. N- (4-bromobenzenesulfonyl) -N '- (3-azabicyclo- (3,3,0) -oct-3-yl) urea, m.p. 213 ° C (toluene); 7. N- (4-methylbenzenesulfonyl) -N '- (3-azabicyclo- (3,2,0) -hept-3-yl) urea, m.p. 228-230 ° C (dimethylformamide / water);

Claims (4)

9 61880 8. N- (4-ethylbenzenesulfonyl) -N '- (3-azabicyclo- (3,2,0) -hept-3-yl) urea, m.p. 200-201 ° C (ethanol); 9. N- (4-chlorobenzenesulfonyl) -N '- (3-azabicyclo- (3,2,0) -hept-3-yl) urea, m.p. 234-236 ° C (dimethylformamide / water); 10. N- (4-methylbenzenesulfonyl) -N '- (3-azabicyclo- (3,1,0) -hex-3-yl) urea, m.p. 206-207 ° C (dimethylformamide / water). The claims; Process for the preparation of N-arylsulfonyl-N1- (3-azabicycloalkyl) ureas of the general formula My 2 2n wherein X represents halogen or alkyl having 1 to 5 carbon atoms and n is an integer from 1 to 3, and their physiologically tolerable acid addition salts with suitable acids or bases, which process comprises reducing, either catalytically by hydrogenation or diborane, a compound of the general formula (CH- \ ϊΗ II λ ^ n ______ j wherein n is as defined above and Z is -CH-- or -C-, nitro The 3-azabicycloalkane of the general formula thus formed is reduced by reducing the N-nitroso-3-azabicycloalkane thus obtained, either by catalytic hydrogenation or by a mixture of sodium, ethanol and ammonia, and condensing the resulting N-amino -3-azabicycloalkane of the general formula 10 61 880 (CH, fI - NH, IV with a benzenesulfonyl urea derivative, characterized in that the compound of curvature IV is condensed with a base t in the form of a hydrochloride with a urea derivative of the general formula XNC ~ \ yy SO 2 - NH - C - NH 2 V wherein the condensation is carried out ✓ in glacial acetic acid when the compound IV is in the form of a base, or in glacial acetic acid, dimethylformamide or a mixture of acetonitrile and dimethylformamide when the compound IV is in the form of the hydrochloride, and, if desired, treating the N-arylsulfonyl-N '- (3-azabicycloalkyl) ureas thus obtained with suitable acids or bases to prepare the corresponding addition salts. For example, N-arylsulfonyl-N '- (3-azabicycloalkyl) -urea with the formula x ^ C ~ \ / V SO- - NH - CO - NH - N (CH-) I w vU-' 2 of which X is a halogen or alkyl group having 1 to 5 chapters and 1-3 or more physiologically acceptable additions to a solid with a sulfur or baser, a color reducing agent, a catalyst with a catalytic hydrogenation or a diborane, in the case of all forms (CH-, ίΓ ^ Nnh II i vilken n betecknar decamma som ovan oc Z Zeckecknar -CH2 ~ eller