GB1106616A - Benzenesulphonyl-ureas and process for preparing them - Google Patents

Abstract

Novel benzenesulphonyl ureas of the formula <FORM:1106616/C2/1> and their physiologically tolerable salts, in which the "phenylene" group is unsubstituted or is substituted by one or more C1- 4 alkyl, C1- 4 alkoxy or halogen substituents, X is an aromatic bicyclic group which may be partially hydrogenated in one ring and which may be linked to the adjacent carbonyl group by a C1- 4 alkylene, C1- 4 oxa-alkylene, C1- 4 thia-alkylene or -CH = CH- group, Z is hydrogen, halogen, hydroxyl, C1- 4 alkyl or C1- 4 alkoxy, Z1 is hydrogen, halogen, C1- 4 alkyl or C1- 4 alkoxy, Y is a straight or branched chain hydrocarbon group of 1-4 carbon atoms, R is hydrogen, C1- 4 alkyl or phenyl-C1- 4 alkyl and R1 represents (a) a C2- 8 alkyl, alkenyl or mercaptoalkyl group, (b) an alkoxyalkyl, alkylmercaptoalkyl or alkylsulphinylalkyl group of 4-8 carbon atoms of which at least 2 belong to the alkylene residue, (c) a phenyl-C1- 4 alkyl or phenylcyclopropyl group, (d) a cyclohexyl-C1- 4 alkyl, cycloheptylmethyl, cycloheptylethyl or cyclooctylmethyl group, (e) an endoalkylene-cyclohexyl, endoalkylenecyclohexenyl, endoalkylene - cyclohexylmethyl or endoalkylene - cyclohexenylmethyl group having 1 or 2 carbon atoms in the endoalkylene part, (f) a C1- 4 alkylcycloalkyl group containing 5-8 ring carbon atoms or a C1- 4 alkoxy-cyclohexyl group, (g) a C5- 8 cycloalkyl group, (h) a cyclohexenyl or cyclohexenylmethyl group or (i) a heterocyclic ring containing 4 or 5 carbon atoms, 1 oxygen or sulphur atom and up to 2 ethylenic double bonds optionally linked to the adjacent nitrogen atom through a methylene group, are made by (a) reacting a benzenesulphonyl-isocyanate benzenesulphonyl - carbamic acid ester or halide, benzenesulphonylthiocarbamic ester or benzenesulphonyl urea carrying the substituent ZZ1-X-CO-NR-Y- with an R1 substituted amine or salt thereof while protecting any hydroxyl group represented by Z by benzylation or esterification; (b) reacting a benzenesulphonamide bearing a substituent ZZ1-X-CO-NR-Y- or a salt thereof with an R1-substituted isocyanate, carbamic acid ester or halide, thiocarbamic acid ester or urea; (c) reacting a correspondingly substituted benzenesulphonyl halide with an R1-substituted urea; (d) hydrolysing a correspondingly substituted benzenesulphonyl iso-urea ether, benzenesulphonyl isothiourea ether or benzenesulphonyl-parabanic acid, which may have been obtained by reacting a benzenesulphonyl halide with the appropriate isothiourea ether, isourea ether or parabanic acid; (e) replacing the sulphur atom in a correspondingly substituted benzenesulphonyl-thiourea by an oxygen atom by known methods; (f) oxidizing a corresponding benzenesulphinyl or benzenesulphenyl urea; (g) introducing the radical ZZ1-X-CO- by acylation into a benzenesulphonyl urea of the formula RNH-Y-phenylene -SO2-NH-CO-NHR1 and/or (h) splitting off the hydroxyl group protected by esterification or etherification from a benzenesulphonyl urea of the above formula in which Z is a protected hydroxyl group, by hydrogenation or saponification. Suitably the group represented by X is a naphthyl, tetrahydronaphthyl or indanyl radical. N - [4 - (b - Tetrahydronaphthylcarb-(21)-amidoethyl) - benzenesulphonyl] - N1 - cyclohexyl - isourea methyl ether is prepared by reacting the corresponding thiourea with mercury oxide in methanol. N - [4 - (b - Tetrahydronaphthylcarb - (21)-amidoethyl) - benzenesulphonyl] - N1 - cyclohexyl-thiourea is made by reacting tetrahydronaphthylcarbamidoethylbenzene sulphonamide with cyclohexyl mustard oil. Pharmaceutical preparations for the treatment of diabetes mellitus comprise the above compounds of the invention in admixture or conjunction with a carrier, preferably in a form adapted to oral administration such as tablets.