NO144344B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N-ARYLSULPHONYL N`- (3-AZABICYCLOALKYL) - Google Patents

Description

The present invention provides a process for the preparation of N-arylsulfonyl N'-(3-azabicycloalkyl)ureas of the general formula I

where X denotes a halogen atom or an alkyl radical with

from 1 to 5 carbon atoms, and

n is an index from 1 to 3,

and acid addition salts of these, and then more especially physiological

mechanically acceptable salts thereof with suitable acids or bases.

French patent no. 1,510,714 relates to the N-substituted azabicycloalkanes which are produced according to the present invention. The compounds of formula I are thus known from the aforementioned French patent, but the present method must be considered to represent a technical advance in relation to the previously known method.

According to the aforementioned patent, a method is described for the production of N-arylsulfonyl N<1->(3-azabicycloalkyl)-urea with formula I:

in which an N-amino-3-azabicycloalkane of formula (II): is reacted with an arylsulfonyl urethane of formula (III): In the present process, the compounds of formula I are prepared by reducing, either by catalytic hydrogenation or with diborane, a compound of the general formula

where n has the aforementioned meaning, and

Z denotes -CH0- or -C-,

2 II

O

nitrosate the 3-azabicycloalkane thus formed according to the following reaction

whereupon the N-nitroso-3-azabicycloalkane thus obtained is reduced, either by catalytic hydrogenation or with a mixture of sodium, ethanol; ammonia, to obtain N-amino-3-azabicycloalkane of the general formula which is then condensed, either in the form of base or hydrochloride, with a urea of the general formula

The present method, which differs from that described in the aforementioned French patent, is also most interesting in light of the obtained yield and purity of the final product. E.g. when the compound N-(4-methylbenzenesulfonyl)-N'-[3-azabicyclo (3,3,0)oct-3-yl]urea is prepared according to example 1

in the aforementioned French patent, a yield of 59% was obtained. When the compound was prepared according to what is indicated in the present application's example lcA, the yields were always better than 60%, regardless of the conditions used.

Furthermore, when the compound is prepared according to the present method as indicated in example 1cA, the compound is purer than when it is prepared in the method described in example 1 of the aforementioned French patent, as the compound in this case will contain approx. 5% paratoluenesulfonamide as an impurity.

The starting material of the general formula II, where Z denotes

-C- , was prepared starting from the corresponding 1,2-cyclo-6

alkanedicarboxvlsp of the fnrmple.

where n has the above meaning.

The starting material of the general formula II, where Z denotes

-CH2-, was produced itself:

either by electrolytic reduction of the compound II, where Z denotes -C-,

in

■ or by hydrogenation of ethyl 2-cyanocycloalkarycarboxylate or ethyl 2-cyano-1-cycloalkenecarboxylate of the respective general formulas:

where n has the above meaning.

This hydrogenation is carried out in a solvent, e.g. such as isopropanol in the presence of ammonia, with Raney nickel, under a pressure of hydrogen of from 17 to 20 kg/cm 2 and at a temperature within the range 60 - 100°C.

One of the most satisfactory ways of carrying out such a process consists in carrying out the catalytic hydrogenation of the compound II in a solvent such as e.g. dioxane, with copper and barium chromite, at a temperature in the range of 250 to 300°C, under a hydrogen pressure in the range of 100 to 180 kg/cm 2 , or by a o carrying out the reduction of compound II by means of diborane and reflux treatment in a solvent, such as e.g. tetrahydrofuran. The nitrosation and the compounds III are carried out with the aid of sodium nitrite. in aqueous

phase.

The catalytic hydrogenation of N-nitroso 3-azabicycloalkanes is carried out in the aqueous phase, using palladium charcoal with 5% palladium in the presence of ferrous sulphate and urea, at a temperature of approx. 30°C under a hydrogen pressure in the range 7 to 10 kg/cm 2.

It must be stated that the processes consisting of a catalytic hydrogenation show valuable industrial interest, in that these must make it possible to obtain a pure product and carry out the following synthesis step directly on the filtered hydrogenation liquid without it being necessary to isolate the product.

The condensation of the compounds IV and V is advantageously carried out in a solvent such as glacial acetic acid. One of the compounds IV and V is conveniently crystallized from acetic acid, or when the compound IV is used in the form of hydrochloride its condensation with the compound V can advantageously be carried out, not only in glacial acetic acid, but also in dimethylformamide or in a mixture of acetonitrile dimethylformamide.

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

The compounds of the general formula I and physiologically acceptable salts thereof have valuable pharmacological and therapeutic properties, and in particular a very interesting hypoglycemic effect. Moreover, they reduce platelet stickiness and capillary permeability, increase fibrinolytic potential and capillary resistance and exhibit low toxicity. Consequently, the compounds of general formula I and physiologically acceptable salts can be used as pharmaceuticals, particularly in the treatment of diabetes and diabetic angiopathy.

The following examples illustrate the invention, and the melting points are determined according to the Kofler method.

EXAMPLE la

N- nitroso-3- azabicyclo (3, 3, 0) octane

A) 83.4 g of 1,2-cyclopentanedicarboximide, in solution in 278 ml of anhydrous dioxane, was hydrogenated with 24 g of copper and barium chromite (prepared according to the method described by A. DUNET et al. Bull. Soc. Chim. France (1956 ) 906-10) at 276°C under a hydrogen pressure in the range of 110 kg/cm 2 , until the absorption of hydrogen ceases, which requires 5 to 6 hours. The catalyst was filtered off, and the filtrate was collected in 57.6 g of acetic acid. The solvent was then evaporated under vacuum, and the residue was taken up with 390 ml of water.

The solution thus obtained was extracted with chloroform for

to eliminate the non-basic products, then it was nitrosated at 70°C by rapidly adding 41.4 g of sodium nitrite in 131 ml of water, and then heating the mixture at 70°C for 1 hour. After cooling, the reaction mixture was extracted with ether, the extracts were washed with a sodium bicarbonate solution; then with water. These extracts were dried, the solvent was eliminated by distillation and the product was distilled. About. 56.7 to 59.7 g of N-nitroso-3-azabicyclo(3,3,0) octane, yellow oil (b.p. / 0.1 mm Hg: 90-95°C, n^° 1.5153) were obtained.

The starting material 1,2-cyclopentanedicarboximide was prepared itself starting 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 solution in 250 ml of anhydrous dioxane, was hydrogenated with 7.2 g of copper and barium chromite at 300°C under a hydrogen pressure within " ' <<>-.'..-■■■■.. for the range 140 to 130 kg/cm , until the absorption of hydrogen ceased. The reaction mixture, treated as described front, made it possible to obtain 19.2 g of N-nitroso-3-azabicyclo (3,3,0) octane, b.p. / 0.1 mm Hg: 90-95°C, n^<4> •= 1.513. The starting material 3-azabicyclo (3,3,0)octan-2-one can be prepared either by electrolytic reduction of 1,2-cyclopentanedicarboximide according to the method of K.N. Menon and J.L. Simonsen, J. Chem. Soc. (1929), pp. 302-305, or by hydrogenation of ethyl 2-cyanocyclopentanecarboxylate or ethyl 2-cyanocyclopentane-1-enecarboxylate according to the following methods: a) 33.4 g of ethyl 2-cyanocyclopentanecarboxylate, in solution in 334 ml of isopropanol and 4 g NH 2 , was hydrogenated in the presence of Raney nickel under a hydrogen pressure in the range of 17 to 20 kg/cm 2 until the absorption of hydrogen ceased. The catalyst was filtered off and the solvent eliminated by distillation. The residue, recrystallized from 130 ml of isopropyl ether, gave 18.2 g of 3-azabicyclo(3,3,0)octan-2-one, m.p.: 88-90°C.

b) 49.5 g of ethyl 2-cyanocyclopent-1-ene-carboxylate, in solution in 459 ml of isopropanol and 5.1 g of NH 3 were hydrogenated in the presence of

Raney nickel at 60°C under a hydrogen pressure in the range of 17 to 20 kg/cm 2 , until the absorption of hydrogen ceased. The catalyst was filtered off, the solvent was distilled off and the residue was recrystallized in 300 ml of cyclohexane. It was achieved approx. 20.5 to 21 g of 3-azabicyclo(3,3,0)octan-2-one, m.p. 89-90°C. C) Another particularly interesting process for the production of N-nitroso-3-azabicyclo (3,3,0) octane was carried out as follows: Diborane, prepared by adding 40.8 g of BH^Na in 1000 ml of diglyme to 228 g (<C>2H5)2 0BF3 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 hydrolyzed by adding 150 ml of a 6N HCl solution, and then refluxed again for 5 hours.

After cooling, insoluble material was filtered off, and the solution thus obtained made alkaline with 200 ml of a 10 N NaOH solution, then steam distilled and the distillate collected in a 12 N HCl solution. The acidic medium was brought to dryness using 100 ml of ethanol, then 100 ml of acetone to eliminate the last traces of 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 was obtained, m.p.: 136-137°C, which was nitrosated with sodium nitrite, as mentioned above, for to give N-nitroso-3-azabicyclo(3,3,0) octane, b.p. / 0.1 mm Hg = 90-95°C.

EXAMPLE lb

N-amino-3-azabicyclo(3,3,0) octane

A) 1050 g of N-nitroso-3-azabicyclo(3,3,0)octane in suspension in 3500 ml of water was hydrogenated in the presence of 6 g of FeSO^, 7H2O and 17.5 g of urea with 21 g of palladated charcoal with 5% Pd under a hydrogen pressure in the range of 10 to 7 kg/cm at a temperature of 30°C until the absorption of hydrogen ceased. The catalyst was filtered off, 1000 ml of benzene was added and 2400 g of potassium carbonate was dissolved. The reaction mixture was decanted from, extracted with benzene and dried over potassium carbonate. The solution thus obtained made it possible to obtain 690 g of N-amino-3-azabicyclo(3,3,0)octane, b.p. / 18 mmHg: 86°C. 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 of absolute ethanol in 500 ml of liquid NH2 was added to 18.4 g of sodium over 90 minutes while maintaining a constant level. The reaction mixture was then stirred for 1 hour, after which NH 3 was slowly expelled by the simultaneous addition of 300 ml of water and 200

ml of ether. The aqueous phase was saturated with 100 g of pelletized sodium hydroxide. After decantation, extraction with ether and drying, the solvent was eliminated. 13 g of N-amino-3-aza-bicyclo(3,3,0)octane were obtained, b.p. / 18 mm Hg = 86°C.

EXAMPLE 1c N-(4-methylbenzenesulfonyl) - N' - | 3-azabicyclo (3,3,0)oct-3-yl |-urea A) 8.1 g of N-amino-3-azabicyclo(3,3,0)octane hydrochloride was added to a lukewarm solution (40-50° C) of 10.7 g of para-toluenesulfonylurea and 100 ml of a mixture (4/1) of acetonitrile and dimethylformamide, and then everything was refluxed. A slight turbidity was observed, which is enhanced by the formation of a precipitate of NH^Cl. After refluxing for 45 minutes, the reaction mixture was diluted with 90 ml of water. The precipitate thus formed was filtered off by 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. Dividend 7 4%.

Such a synthesis was also carried out with advantage by working in dimethylformamide at 80°C for 45 minutes. 10 g of N-(4-methylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)-oct-3-yl]urea were then obtained, m.p.: 178°C, yield 62%, or by work in crystallizable acetic acid according to the following method: 10.7 g of para-toluenesulfonyl urea, 8.1 g of N-amino-3-azabicyclo(3,3,0)octane hydrochloride and 50 g of crystallizable acetic acid were heated at 80°C in 30 minutes. The mixture became homogeneous after 10 minutes, when a slight precipitation was observed. The mixture was diluted with 50 ml of water and the precipitate thus formed was filtered off by suction and recrystallized from 90 ml of reflux treated ethanol. 11.5 g of N-(4-methylbenzene-sulfonyl)-N'-|_3-azabicyclo(3,3,0)oct-3-yl]urea were obtained, m.p. 178°C.

In this last example, 8.1 g of N-amino-3-azabicyclo(3,3,0)-octane hydrochloride can be replaced with 6.3 g of the corresponding base, and 11.7 g of N-(4- methylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p. 178°C, yield 72%.

EXAMPLE 2 to 8

The following compounds were prepared according to the procedures described in examples 1a to 1c using the corresponding starting materials: 2. N-(4-ethylbenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-ylurea, m.p.: 149°C (ethanol). 3. N-(4-chlorobenzenesulfonyl)-N'-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p.: 207-208°C (ethanol).. 4. N-( 4-bromobenzenesulfonyl)-N1-[3-azabicyclo(3,3,0)oct-3-yl]-urea, m.p. 213°C (toluene). 5. N-(4-methylbenzenesulfonyl)-N 1 -[3-azabicyclo(3,2,0)nept-3-yl]-urea, m.p. 228-230°C (dimethylformamide/water). 6. N-(4-ethylbenzenesulfonyl)-N'-[3-azabicyclo(3,2,0)hept-3-yl]-urea, m.p. 200-201°C (ethanol). 7. N-(4-Chlorobenzenesulfonyl)-N'-[3-azabicyclo(3,2,O)hept-3-yl]urea, m.p. 234-236°C (dimethylformamide/water). 8. N-(4-methylbenzenesulfonyl)-N'-[3'-azabicyclo(3,1,0)hex-3-ylurea, m.p.: 206-207°C (dimethylformamide/water).

Claims (1)

1. Process for the preparation of therapeutically active N-arylsulfonyl-N1-(3-azabicycloalkyl)ureas with the general formula where X denotes halogen and alkyl with from 1 to 5 carbon atoms, and n is an index from 1 to 3, and physiologically acceptable salts thereof with suitable acids or bases, characterized in that a compound of formula where n has the above meaning, and Z denotes a group -CH» or -C- Z 2 0 is reduced by catalytic hydrogenation or with diborane, the thus formed 3-azabicycloalkane of the general formula nitrosated, whereupon the obtained N-nitroso-3-azabicycloalkane is reduced, either by catalytic hydrogenation or with a mixture of sodium, ethanol and ammonia to produce N-amino-3-azabicycloalkane of the general formula whereupon this last compound is condensed, either in the form of base or hydrochloride with a urea derivative of the general formula the condensation being carried out in glacial acetic acid when the compound of formula IV is in the form of a base, or in glacial acetic acid, dimethylformamide or a mixture of acetonitrile/dimethylformamide when the compound IV is in the form of a hydrochloride and, if desired, the thus obtained N- arylsulfonyl-N'-(3-azabicycloalkyl)-ureas with suitable acids or bases to the corresponding acid addition salts.