Patent GB-1080705-A (GB)
Title: Benzenesulphonyl-ureas and process for their manufacture
IPC: C07D307/22
Filed: 1964-10-19
Abstract: The invention comprises sulphonyl ureas of the formula <FORM:1080705/C2/1> and their salts, wherein R is hydrogen or a C1- 4 alkyl or phenyl-(C1- 4 alkyl) group; R1 represents (a) C2- 8 alkoxyalkyl, alkylmercaptoalkyl or alkylsulphinylalkyl, (c) phenylalkyl or phenylcyclopropyl, (d) cyclohexyl-(C1- 4 alkyl), cycloheptylmethyl, cycloheptylethyl or cyclooctylmethyl, (e) an endo-alkylene-cyclohexyl, -cyclohexenyl, -cyclohexylmethyl or -cyclohexenylmethyl group wherein the endoalkylene portion contains 1 or 2 carbon atoms, (f) C1- 4 alkylcyclohexyl or C1- 4 alkoxy-cyclohexyl, (g) C5- 8 cycloalkyl, (h) cyclohexenyl or cyclohexenylmethyl or (i) a heterocyclic ring of 4-5 carbon atoms and one oxygen or sulphur optionally containing up to two ethylenic double bonds, linked directly or through a methylene group to the nitrogen atom; X is a single bond or an aliphatic or cycloaliphatic bridge member containing 1-6 carbon atoms, optionally containing an -O-, -S-, -SO- or -SO2- link; Y is a C1- 4 hydrocarbon group; Z is hydrogen or halogen or a C1- 4 alkyl or alkoxy, C5- 6 cycloalkoxy, cyclohexyl, C1- 4 alkylmercapto, C1- 4 alkylsulphinyl, C1- 4 alkylsulphonyl phenylsulphonyl, phenyl, phenyl-(C1- 4 alkyl), C1- 4 acyl, benzoyl, trifluoromethyl, hydroxy, C1- 4 acyloxy, benzyloxy, carboxy, carbo-(C1- 4 alkoxy), nitrile, carbamoyl, C1- 4 alkyl-carbamoyl, di-(C1- 4 alkyl)-carbamoyl or nitro group, and Z1 and Z11 are hydrogen or if Z is hydrogen, hydroxy, carboxy, alkyl, alkoxy or halogen, may each be a C1- 4 alkyl or alkoxy group or halogen or if Z is hydrogen, may together form a methylenedioxy group, and wherein the "phenylene" group may optionally bear alkyl, alkoxy or halogen substituents.  The compounds are prepared by (a) reacting an amine R1NH2 or a salt thereof with a benzene-sulphonyl-isocyanate, -carbamic ester, -thiocarbamic ester, -carbamic halide or -urea carrying the substituent <FORM:1080705/C2/2> (b) reacting a benzenesulphonamide carrying the substituent II and R1-substituted isocyanate, carbamic ester, thiocarbamic ester, carbamic halide or urea; (c) reacting a benzene-sulphonyl chloride carrying the substituent II with an R1-substituted urea, isourea ether, isothiourea ether or parabanic acid, and hydrolysing the resulting benzenesulphonyl isourea ether, isothiourea ether or parabanic acid; (d) treating a corresponding substituted benzene-sulphonyl thiourea by known methods to replace the sulphur by oxygen; (e) oxidizing corresponding substituted benzenesulphenyl or benzenesulphinyl ureas; (f) acylating a benzene-sulphonyl urea of the formula RNH-Y-phenylene-SO2-NH-CO-NH-R1 to introduce the substituted or unsubstituted C6H5.X.CO- radical; (g) subjecting a compound corresponding to the Formula (I) in which Z is an etherified or esterified hydroxy or carboxylic group or in which X is a direct bond and R is hydrogen and Z is an o-carboxylic group protected by phthalimide formation, to hydrolysis or hydrogenation to liberate the carboxy or hydroxy group; or (h) hydrogenating a corresponding compound in which X contains one or more ethylenic double bonds. N - Substituted - carbamic acid esters in which the N-substituent is a cyclo-octyl, 4-(a -benzamidoethyl) - benzenesulphonyl, 4 - (b  - benzamidopropyl) - benzenesulphonyl, 4 - (g  - benzamidopropyl) - benzenesulphonyl, 4 - phenoxyacetamidomethyl - benzenesulphonyl and 3-(b -benzamidoethyl)-benzenesulphonyl group are made by reacting the appropriate amine or benzenesulphonamide with a chloroformic ester. Sulphonamides.-4 - (a  - Benzamidoethyl)-benzenesulphomide, 4 - (b  - acetamidopropyl)-benzenesulphonamide, 4 - chloro - 3 - (b  - benzamidoethyl) - benzenesulphonamide and 2-(b -benzamidoethyl) - 4 - methoxy - benzenesulphonamide are made via the corresponding sulphonyl chlorides by treatment with ammonia. 4-(b -Phenoxacetamidoethyl) - benzenesulphonamide, 4 - (b  - phenoxyacetamidomethyl) - benzenesulphonamide, 4 - [b  - (4 - methoxyphenylacetamido) - ethyl] - benzenesulphonamide, 4 - (b -2,4,6 - trimethyl - benzamidoethyl) - benzenesulphonamide and 4-(b  - 3,5 - dimethoxybenzamido - ethyl) - benzenesulphonamide are made by acylating the appropriate aminobenzenesulphonamide with the corresponding acyl chloride.  Sulphonyl ureas.-N - [4 - (b  - Phenylacetamido - ethyl) - benzenesulphonyl] urea and 4-phenoxyacetamidomethyl) - benzenesulphonyl urea are made by treating the corresponding sulphonamides with potassium cyanate. Sulphonyl thioureas.-N - [4 - (b  - Benzamidoethyl) - benzenesulphonyl] - N1 - cyclohexyl - thiourea, N - [4 - (b  - cinnamoylaminoethyl) - benzenesulphonyl] - N1 - cyclohexyl-thiourea, N - [4 - (b  - 2,6 - dimethylbenzamido-ethyl) - benzenesulphonyl] - N1 - cyclohexylthiourea and N - [4 - (b  - 4 - n - butoxybenzamido - ethyl) - benzenesulphonyl] - N1 - isobutyl - thiourea are made by reaction of the appropriate benzenesulphonamide with cyclohexyl or isobutyl mustard oil.  Sulphonyl isourea ethers.-N - [4 - (b  - Benzamidoethyl) - benzenesulphonyl] - N1 - cyclohexyl-N - [4 - (b  - cinnamoylaminoethyl) - benzenesulphonyl - N1 - cyclohexyl -, N - [4 - (b  - 2,6-dimethylbenzamidoethyl) - benzenesulphonyl] - N1-cyclohexyl - and N - [4 - (b  - 4 - n - butoxy-benzamidoethyl) - benzenesulphonyl] - N1 - isobutyl-, isourea methyl ethers are made by treating the corresponding thioureas with mercuric oxide in methanol. Sulphonylparabanic acids.-The 1 - [4 - (b -benzamidoethyl) - benzenesulphonyl] - , 1 - [4-(b  - 4 - chlorobenzamidoethyl) - benzenesulphonyl]-and 1 - [4 - (b  - 2 - methyl - 6 - chloro - benzamidoethyl) - benzenesulphonyl] -, 3 - cyclohexylparabanic acids are made by treating cyclohexylparabanic acid with the appropriate benzenesulphonyl chloride.  Cyclo-octyl urea is prepared from cyclo-octyl urea and potassium cyanate.  Pharmaceutical preparations having hypoglycaemic activity 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.