GB918396A - Benzenesulphonyl ureas and process for their manufacture - Google Patents

Abstract

The invention comprises sulphonyl ureas of the formula <FORM:0918396/IV (b)/1> and physiologically tolerable salts thereof, wherein R is a C1-6 alkyl, phenyl or tolyl radical and R1 is a saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radical which may be interrupted by oxygen and/or sulphur having from 2-8, or in the case of a cyclic radical 3-8, carbon atoms, or is a benzyl or phenylethyl radical. The compounds are made by reacting an acyl-benzenesulphonyl isocyanate RCO.C5H4.SO2.NCO with an amine R1NH2 or conversely reacting the sulphonamide RCO.C6H4.SO2NH2 with an isocyanate R1NCO; in place of the isocyanates, compounds which act like isocyanates in the reaction may be used such as carbamic esters, thiocarbamic esters, carbamoyl halides, ureas of the formula RCO.C6H4.SO2.NH2.CO.NH2 or R1.NH.CO.NH2 or their N1-acyl, -alkyl or -aryl substituted derivatives wherein the acyl group may include the nitro group as well as aliphatic and aromatic acyl radicals. Other processes comprise the reaction of a benzenesulphonyl halide with an isourea ether, guanidine or a tertiary amine salt of an R1-substituted parabanic acid followed by hydrolysis of the sulphonyl isourea, guanidine or parabanic acid; forming a benzenesulphonyl thiourea and exchanging the sulphur for oxygen e.g. by reaction with heavy metal oxides or oxidation with sodium peroxide or hydrogen peroxide; or oxidising a benzenesulphenyl- or benzenesulphinyl-urea. Examples describe the preparation of compounds of the above general formula wherein R is methyl, ethyl, phenyl or p-tolyl and R1 is cyclohexyl, cyclopentyl, 41-methylcyclohexyl, cyclohexylmethyl, n-butyl, phenylethyl or isobutyl. p-Acylbenzenesulphonamides of the general formula R.CO.C6H4.SO2NH2 used as starting materials are made by reacting the corresponding sulphonyl chlorides R.CO.C6H4.SO2.Cl (obtainable by diazotising a p-acylaniline and treating the diazonium salt with sulphur dioxide in the presence of hydrochloric acid and copper salts) with ammonia. Urethanes such as methyl N-p-acetylbenzensulphonyl- and N-benzophenone-4-sulphonylurethane are made by treating the benzenesulphonamide with a chloroformic ester. Benzophenone-4-sulphonyl-urea is prepared by the action of potassium cyanate on benzophenone-4-sulphonamide. b -Phenylethyl-isourea methyl ether is made by the action of dimethyl sulphate on b -phenylethyl urea. Isobutyl-parabanic acid is made by reaction of isobutyl urea with oxalyl-chloride and is treated with 4-acetylbenzenesulphonyl chloride to give 1-(41-acetylbenzenesulphonyl)-3-isobutyl-parabanic acid. N-(4-acetylbenzenesulphonyl)-N1-cyclohexylmethyl- and N1-isobutyl-thioureas are prepared by treating 4-acetylbenzenesulphonamide with cyclohexylmethyl or isobutyl isothiocyanate, respectively. Pharmaceutical preparations for the treatment of diabetes comprise the above compounds of the invention and a carrier, preferably in a form suitable for oral administration, for example, tablets containing in addition to the active compound or its alkali or alkaline earth metal salt, talc, starch, lactose, tragacanth and magnesium stearate.