NO148374B - PROCEDURE FOR THE PREPARATION OF 9- (2,6-DIHALOGENBENZYL) -ADENINES - Google Patents

Description

Process for the production of hydroxybenzenesulfonylureas.

It is known that sulfonylureas such as

N-(4-amino-benzenesulfonyl)-N'-butyl-urea f

and N-(4-methyl-benzenesulfonyl)-N'-butylurea has a beneficial effect in certain

liver damage. However, as already known, these compounds lead to a strong lowering

of the blood sugar mirror, moreover, has N-(4-amino-benzenesulfonyl)-N'-butyl-urea as well

moreover, an undesirable bacteriostatic effect in this connection. Consequently, these compounds have considerable disadvantages for general liver therapy.

It has been found that hydroxybenzenesulfonyl ureas of the general formula

wherein R means a 5 to 8 carbon-containing

cycloalkyl or cycloalkenyl radical and theirs

salts have a strong liver protective effect

without lowering the blood sugar level or having one

chemotherapeutic effect. The object of the invention is the production of such hydroxybenzenesulfonylureas.

The method according to the invention is

characterized by the fact that one

I. reacts the hydroxybenzenesulfonamide

with formula

possibly in the form of suitable salts,

a) with isocyanates of the formula R-NCO or b) with carbamic acid esters of the formula R-NH-COOR', in which R' means a low molecular weight alkyl group or a phenyl radical or, with corresponding monothiocarbamic acid esters or c) with carbamic acid halides of the formula R-NH -CO-hal., or d) with ureas of the formula R-NH-CO-NH2 which, on the side of the molecule facing away from the residue R, can likewise be substituted with the residue R or with one or two phenyl residues, which can also be connected to each other either directly or via a bridge, or which may be substituted with a preferably low molecular weight aliphatic or aromatic acyl residue or with the nitro group, possibly the OH group during the reaction is protected with an acyl or benzyl residue and this residue is cleaved off after the reaction has been carried out or that one II. reacts the amine of formula R-NH2, optionally in the form of their salts, with a) hydroxybenzenesulfonyl-carbamic acid esters of formula in which R' means a low molecular weight alkyl group or a phenyl residue, or corresponding hydroxybenzenesulfonyl monothiocarbamic acid esters or b) with hydroxybenzenesulfonylurea of formula which, on the side facing away from the sulfonyl group of the urea molecule, is unsubstituted or mono- or di-substituted with alkyl groups or aryl residues or mono-substituted with a preferably low molecular weight aliphatic or aromatic acid residue, or reacts with corresponding bis-(hydroxy-benzenesulfonyl) ureas in that the reaction can also be carried out with such hydroxybenzenesulfonic acid derivatives, in which the hydroxy group is protected with an acyl residue or with the benzyl group and the protective groups are removed if these are not already split off during the reaction, or c) react with acyloxy- or benzyloxy-benzenesulfonyl isocyanates or d) react with acyloxy- or benzyloxy-benzene-sulfonyl-carbamic acid halides

and cleaves the protecting group,

and transfers the formed products possibly using bases to the corresponding salts.

In the methods, the m- and p-hydroxybenzenesulfonyl chlorides used as starting materials can resp. the corresponding amides, -carbamic acid esters, -ureas are used both in free form and also in the form of compounds where the hydroxy group is protected with a later cleavable residue. Acyl residues such as acetyl, propionyl, benzoyl, alkoxycarbonyl residues such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl as well as the benzyl groups are preferably used as protecting groups. As long as the protective group is not already split off during the reaction, they can be removed from the formed N-(acyloxy-benzene-sulfonyl)- or N-(benzyloxy-benzenesulfonyl)-N'-cycloalkylureas or their derivatives by hydrolysis with alkali or acids or removed hydrogenolytically.

The use of protecting groups enables the conversion of acylated hydroxybenzenesulfony isocyanates or -carbamic acid halides with amines of the formula FUNrL,^ or also derivatives of such compounds as formylated compounds. From the products formed, the protecting group and any group introduced with the amines are subsequently removed by hydrolysis.

As amines, the turnover can include are used: cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooxylamine, 2-, 3- and 4-methylcyclohexylamine, A 2-cyclopentylamine, A-cyclohexenylamine. Instead of the mentioned amines, the carbamic acid esters, carbamic acid halides or ureas produced from these can also be used for the reaction with suitable hydroxybenzenesulfonamides.

The embodiments of the method according to the invention can be widely varied with regard to reaction conditions and adapted to the possible conditions. For example, the reactions can be carried out using solvents at room temperature or at an elevated temperature.

Other methods for the production of the hydroxybenzenesulfonylureas are the subject of Norwegian patents (pat. no. 110 342).

The benzenesulfonylureas obtained by the method according to the invention are due to their pharmacological properties valuable drugs. The new compounds are particularly distinguished by a necrotrophic liver protective effect. The following table shows, for some of the hydrobenzenesulfonylureas produced according to the invention and which are used here as examples, the reduction of the necrosis-forming effect of allyl alcohol on rats. The values were compared with liver damage of similar control animals not treated with N-(4-hydroxybenzenesulfonyl)-N'-cyclohexylurea. The method of measuring liver damage and the effect of necrotropic substances is described by W. Eger (compare Arznei-mittelforschung 7, 601 (3 957)).

From the table it appears that, for example, N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexyl urea in a dosage of 50 mg/100 g in rats reduces the necrosis-forming effect of allyl alcohol in the preventive test by 65%. In a dosage of 25 mg/100 g, a necrotropic effect of the preparation of approximately 45% is achieved.

The process products are particularly suitable as hepatoprotectors as they either cause no or only practically negligible lowering of blood sugar and also have no chemotherapeutic effect as for a sulfonamide. For example, the peroral administration of 400 mg/kg of N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea to rabbits does not lead to any lowering of blood glucose levels.

The process products are preferably used for the production of orally or parenterally administrable preparations with a liver protective effect and can be applied as such or in the form of salts. For salt formation, for example, alkaline agents, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, and physiologically tolerable organic bases can be used.

Tablets, capsules, dragees, solutions and suspensions containing the process products or their salts in addition to the usual indifferent carrier and auxiliaries such as milk sugar, starch, gelatin, magnesium stearate, vegetable oil, talc, tragacanth can be used as medical preparation forms. , water etc.

Example 1.

N-(^- hydroxy- benzenesulfonyl)-

N'-cyclohexyl urea.

34.6 g of 4-hydroxybenzenesulfonamide are dissolved in 800 ml of acetone and heated after adding 83 g of ground potassium carbonate for one hour until boiling. Now add 25 g of cyclohexyl isocyanate; the reaction mixture is boiled for a further 15 hours. After the acetone has been distilled off in a vacuum, the remaining residue is dissolved in water, the solution is clarified with charcoal and the filtrate is acidified with dilute hydrochloric acid. The precipitate that has formed is sucked off and recrystallized from aqueous methanol. N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea is thus obtained in the form of white crystals with a melting point of 192-194°C (yield 37-40 g).

In an analogous way, from 4-hydroxy-benzenesulfonamide and A<3->cyclohexenyl isocyanate, N-(4-hydroxy-benzenesulfonyl-N'-( A 3-cyclohexenyl)-urea is obtained, which after recrystallization from ethanol and good drying at 120°C melts at 166-168°C.

Example 2.

N-(4-hydroxy-benzenesulfonyl)-

N'-cyclohexyl urea.

14.4 g of N-(4-carbomethoxy-oxy-benzenesulfonyl)-carbamic acid methyl ester with a melting point of 126-130°C (produced by reacting 4-hydroxy-benzenesulfonamide with the 2.5 times the molar amount of chloroformic acid methyl

ester in the presence of ground potassium carbonate and acetone) is mixed with 10 g of cyclohexylamine and heated for 35 minutes at 130 °C. The reaction product is dissolved in acetic acid and the solution is shaken several times with diluted ammonia (1:25). The combined alkaline solutions are clarified with charcoal and the filtrate acidified with dilute hydrochloric acid. The precipitate that has formed is sucked off and recrystallized from diluted methanol while charcoal is added. N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexyl urea with a melting point of 192-194°C is obtained. The product is identical to that formed by the isocyanate method (compare example 1).

Example 3.

N-( lf- hydroxy- benzenesulfonyl)-

N'-cyclohexyl urea.

11.6 g of N-(4-hydroxy-benzenesulfonyl)-carbamic acid methyl ester with melting point 160-162°C (produced by reacting 4-hydroxy-benzenesulfonamide with chloroformic acid methyl ester in the presence of ground potassium carbonate and acetone and treating the first resulting sulphonylurethane with diluted caustic soda in the heat) is mixed with 5 g of cyclohexylamine and heated for 45 minutes at 140-145°C. The resulting melt is treated with dilute ammonia, filtered from insoluble parts and acidified with dilute hydrochloric acid. The N'-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea thus formed melts after recrystallization from methanol at 192-194°C and is identical to the products produced by other methods.

Example 4.

N-(4-hydroxy-benzenesulfonyl)-N'-(4'-methyl-cyclohexyl)-urea: 21.6 g N-(4-hydroxy-benzenesulfonyl)-urea with melting point 186-187°C (prepared by boiling of 4-hydroxy-benzenesulfonamide with potassium cyanate in aqueous ethanol) is boiled in 400 ml of toluene and 80 ml of glycol mono-methyl ether while adding 6 g of glacial acetic acid with 12.4 g of 4-methyl-cyclohexylamine for 21/2 hours under reflux. The reaction product is shaken with 1% caustic soda; the combined aqueous phases are clarified with charcoal and acidified with dilute hydrochloric acid. The precipitated product is dissolved in 1% ammonia, the solution is clarified again with charcoal and the filtrate is acidified. The precipitate that has formed is sucked off and recrystallized from diluted methanol. This gives N-(4-hydroxybenzenesulfonyl)-N'-(4'-methyl- cyclohexylurea as hemihydrate with melting point 102-104 °C in a yield of 12 g.

In an analogous manner, from N-(4-hydroxy-benzenesulfonyl)-urea and cyclopentylamine N-(4-hydroxy-benzene-sulfonyl)-N'-cyclopentyl urea with a melting point of 185-187°C (after recrystallization from vinegars).

In the same way, using cycloheptylamine gives N-(4-hydroxy-benzenesulfonyl)-N'-cycloheptylurea, which melts after recrystallization from acetic ester at 176-178°C.

By using cyclooctylamine, a N-(4-hydroxy-benzenesulfonyl)-N'-cyclooctylurea is obtained by the same method, which

after recrystallization from dilute ethanol

appears as monohydrate and has a melting point of 122-124° C.

Example 5.

N-(4-hydroxy-benzenesulfonyl)-

N'-cyclohexyl urea.

10.8 g of 4-acetoxy-benzenesulfonamide and a solution of 2 g of sodium hydroxide in 4 ml of water are dissolved in 30 ml of acetone. Add 6.5 g of cyclohexyl isocyanate to the solution under ice-cooling and stirring, stir until the isocyanate smell has disappeared, evaporate most of the acetone and mix the residue with water and acid. The product (after recrystallization (melting point 172-174°C) is heated with 100 ml of 2n sodium hydroxide solution for 1/2 hour on a steam bath, the solution is clarified with charcoal, acidified, the product is suctioned off and recrystallized from ethanol/water. N- (4- hydroxy-benzenesulfonyl) - N'-cyclohexyl-urea melts after drying at 100°C at 192-194°C.

Example 6.

N-(3-hydroxy-benzenesulfonyl)-

N'-cycloheptyl urea.

23 g of 3-hydroxy-benzenesulfonyl-carbamic acid methyl ester are mixed with 14 g of cycloheptylamine and heated in an oil bath for one hour at 130 °C. A clear melt occurs, from which methanol escapes. It is allowed to cool, the product is treated with approximately 1% ammonia, filtered and acidified. The precipitated substance is separated and recrystallized from water while adding a little ethanol. The formed N-(3-hydroxybenzenesulfonyl)-N'-cycloheptylurea melts at 108-110° C,

Example 7.

N- f Jf- hydroxy- benzenesulfonyl) -

N'-cyclohexyl urea.

27.3 g of 4-acetoxy-benzenesulfonyl-methyl-urethane (prepared from 4-hydroxy-benzenesulfonyl-methyl-urethane and acetic anhydride in pyridine) is mixed well with 9.9 g of cyclohexylamine and heated in a bath for 1 hour at 130 °C. A clear melt occurs from which the methanol escapes. It is allowed to cool, the reaction product is taken up in 100 ml of 2 N caustic soda and heated for 1/2 hour on a steam bath.

The solution is clarified with charcoal and acidified after cooling. The precipitated product is suctioned off and recrystallized from ethanol/water. The N-(4-hydroxy-benzene-sulfonyl)-N'-cyclohexylurea has a melting point of 192-194°C.

Example 8.

N-(4-hydroxy-benzenesulfonyl)-

N'-cyclohexyl urea.

17.3 g of 4-hydroxybenzenesulfonamide are heated with 27.6 g of powdered potassium carbonate and 250 ml of dimethylformamide for 4 hours with stirring at 100°C. 55.8 g of N,N-diphenyl-N'-cyclohexyl urea are then added and heated with stirring for a further 4 hours at 100 °C. After cooling, the reaction mixture is poured into water, the solution is mixed with some diluted caustic soda and cooled with ice. Filter, acidify the filtrate with dilute hydrochloric acid and reprecipitate the aspirated precipitate from dilute ammonia. N-(4-hydroxy-benzene-sulfonyl)-N'-cyclohexyl-urea is recrystallized from methanol and melts after drying at 192-194°C.

Example 9.

N-(4-hydroxy-benzenesulfonyl)-

N'-cyclohexyl urea.

17.3 g of 4-hydroxybenzenesulfonamide are heated with 27.6 g of powdered potassium carbonate and 250 ml of dimethylformamide for 4 hours with stirring at 110 °C. 58.8 g of NPN-diphenyl-N'-cyclohexyl urea are then added. stir again for 4 hours at 110 °C, pour into water and cool after adding a few drops of concentrated caustic soda. The secreted diphenylamine and unreacted diphenylcyclohexylurea are sucked off and the filtrate is acidified with dilute hydrochloric acid. The crystalline precipitate is suctioned off, reprecipitated with 1% ammonia and recrystallized from methanol-water. The formed N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea melts at 192 to 193°C.

Example 10.

N-(4-hydroxy-benzenesulfonyl)-

N'-cyclohexyl urea.

8.7 g of 4-hydroxybenzenesulfonamide is mixed well with 12 g of ground potassium carbonate and 15.7 g of cyclohexyl urea methyl ester and heated in an oil bath for 3 hours at 130 °C. After cooling, the reaction mixture is mixed with water, excess urea ester is removed by extraction with ether and the aqueous solution is acidified. The precipitated product is suctioned off, reprecipitated from 1% ammonia and recrystallized from methanol. The formed N-(4-hydroxybenzenesulfonyl)-N'-cyclohexylurea melts at 192 to 193°C.

Example 11.

N - ( 4- hydroxy- benzenesulf onyl) -

N'-cyclohexyl urea.

27.3 g of 4-acetoxybenzenesulfonyl-methyl-urethane (prepared from 4-hydroxy-benzenesulfonyl-methyl-urethane and acetic anhydride in pyridine) is mixed well with 9.9 g of cyclohexylamine and heated in a bath for 1 hour at 130°C. A clear melt occurs from which methanol escapes. It is allowed to cool and the reaction product is taken up in 100 ml of 2-n sodium hydroxide solution and heated for 1/2 hour on a steam bath. The solution is clarified with charcoal and acidified after cooling. The precipitated product is suctioned off and recrystallized from ethanol-water. The melting point of N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea is 192 to 194°C.

Claims (1)

Process for the preparation of new therapeutically effective benzenesulfonylureas with the general formula in which R means cycloalkyl, or cycloalkenyi with 5 to 8 carbon atoms, or their salts, characterized in that one reacts I. hydroxybenzenesulfonamide of formula optionally in the form of suitable salts, a) with isocyanates of formula R-NCO or b) with carbamic acid esters of formula R-NH-COOR', in which R' means a low molecular weight alkyl group or a phenyl residue, or with corresponding monothiocarbamic acid esters or c) with carbamic acid halides of the formula R-NH-CO-hal., or d) with ureas of the formula R-NH -CO-NH2 which, on the side of the molecule facing away from the residue R, may optionally be substituted with the residue R or with one or two phenyl residues, which may also be connected to each other either directly or via a bridge, or which may be substituted with a preferably low molecular weight aliphatic or aromatic acyl residue or with the nitro group, possibly the OH group during the reaction is protected with an acyl or benzyl residue and this residue is split off after the reaction has been carried out or that one II. reacts the amine of formula R-NH2, optionally in the form of their salts, with a) hydroxybenzenesulfonyl-carbamic acid esters of formula wherein R' means a low molecular weight alkyl group or a phenyl residue, or equivalent hydroxybenzenesulfonyl monothiocarbamic acid esters or b) with hydroxybenzenesulfonylurea of formula which, on the side facing away from the sulfonyl group of the urea molecule, is unsubstituted or mono- or di-substituted with alkyl or aryl groups or mono-substituted with a preferably low-molecular-weight aliphatic or aromatic acid residue, or reacts with corresponding bis(hydroxy-benzenesulfonyl)ureas while the reaction can also be carried out with such hydroxybenzenesulfonic acid derivatives, in which the hydroxy group is protected with an acyl residue or with the benzyl group and the protective groups are removed if these are not already split off during the reaction, or c) react with acyloxy- or benzyloxy-benzenesulfonyl isocyanates or d) react with acyloxy- or benzyloxy-benzene-sulfonyl-carbamic acid halides and cleaves the protecting group, and transfers the formed products possibly using bases to the corresponding salts.