Patent GB-815885-A (GB)
Title: Sulphonyl-ureas and a process for their manufacture
Filed: 1957-08-12
Abstract: The invention comprises sulphonyl urea compounds of the formula R-SO2-NH-CO-NHR wherein R is a phenyl radical optionally containing one or two substituents selected from alkyl or alkoxy groups, preferably containing up to 8 carbon atoms, and halogen atoms, or is an aliphatic or cycloaliphatic hydrocarbon radical of 3 to 8 carbon atoms, or a naphthalene-(2), a 5 : 6 : 7 : 8 - tetrahydro - naphthalene - (2) or a 4-phenoxyphenyl radical and R1 is the radical C6H5-(CH2)n-, wherein n is a whole numbe from 2 to 4 and salts of these compounds with bases which give physiologically tolerable salts.  The compounds are prepared by known methods for the production of sulphonyl ureas, for example: (1) a sulphonyl isocyanate of the formula R-SO2-NCO is reacted with an amine R1NH2 or conversely an isocyanate R1NCO is reacted with a sulphonamide R-SO2NH2; (2) a sulphonyl urethane of the formula R.SO2.NH.COO.R2 is reacted with an amine R1NH2, or, conversely, a sulphonamide R.SO2NH2 is reacted with a urethane of the formula R1.NH.COO.R2, R2 being a hydrocarbon radical; (3) a sulphonyl-carbamoyl halide of the formula R.SO2NH.CO.Hal is reacted with an amine R1NH2, or a sulphonamide R.SO2.NH2 is reacted with a carbamoyl halide R1NH.CO.Hal; (4) a urea containing an aliphatic or cycloaliphatic substituent is reacted with a sulphonamide, or, conversely, a sulphonyl urea R.SO2.NH.CO.NH2 is reacted with an amine R1NH2; (5) a sulphonyl halide R-SO2-Hal is reacted with an iso-urea ether and the resulting sulphonyl iso-urea ether is converted to the desired sulphonyl urea; (6) the corresponding sulphonyl thio-urea is decomposed by means of heavy metal oxides or by oxidation, for example by sodium peroxide or nitrous oxide to give the urea derivative; and (7) the corresponding sulphonyl guanidine obtainable by reaction of a sulphonyl-cyanamide with an amine is hydrolysed.  Many variations on these methods, wherein the starting materials may be replaced by salts and addition products or by compounds which decompose to form the required starting materials are suggested.  The products are used therapeutically for the oral treatment of diabetes. Examples describe the preparation of N-cyclohexane-sulphonyl-, N-(4 - methoxy - 3 - methyl - benzenesulphonyl) -, N - 4 - methylbenzenesulphonyl -, N - 3 : 4 - dimethylbenzenesulphonyl -, N - naphthalene - (2) - sulphonyl -, N - isopropylbenzenesulphonyl -, N - (3 - chloro - 4 - methyl - benzenesulphonyl) -, N - pentane - 3 - sulphonyl - and N - 4 - phenoxyphenylsulphonyl -, N1 - (b  - phenylethyl)-urea and N-cyclohexanesulphonyl-N1 - phenylpropyl - urea; N - 4 - methylbenzenesulphonyl - N1 - phenylpropyl - urea and N - 4 - methylbenzenesulphonyl - N1 - 4 - phenylbutyl-urea. Sulphonyl-urethanes.-The ethyl esters of cyclohexane - sulphonyl -, 3 - methyl - 4 - methoxy - benzenesulphonyl -, p - toluenesulphony -, 3 - chloro - 4 - methyl - benzenesulphonyl - and pentane-3-sulphonyl-, carbamic acid and the methyl esters of p-toluenesulphonyl-, 3 : 4-dimethyl - benzenesulphonyl - naphthalene - 2 - sulphonyl -, 4 - isopropylbenzenesulphonyl - and 4 - phenoxybenzenesulphonyl -, carbamic acid are made by treating the appropriate sulphonamide with ethyl or methyl chloroformate.  Cyclohexane - sulphonyl - isocyanate is made from cyclohexane-sulphonamide and phosgene.  Specifications 595,472, [Group IV], and 604,259 are referred to.ALSO:Preparations for the treatment of diabetes comprise compounds of the formula R-SO2-NH-CO-NHR1 wherein R is a phenyl radical optionally containing one or two substituents selected from alkyl or alkoxy groups, preferably containing 1-8 carbon atoms and halogen atoms, or is an aliphatic or cycloaliphatic hydrocarbon radical of 3-8 carbon atoms, or a naphthalene-(2), a 5 : 6 : 7 : 8 - tetrahydronaphthalene - (2) or a 4-phenoxyphenyl radical and R1 is the radical C6H5-(CH2)nwherein n is a whole number from 2 to 4, and salts of these compounds with bases which give rise to physiologically tolerable salts, e.g. ammonium, alkali metal and alkaline earth metal and organic base salts, in conjunction with a pharmaceutical carrier.  The preparations are preferably administered orally.  Many suitable active sulphonamides of the above general formula are specified (see Group IV (b)).  Specifications 595,472, [Group IV], and 604,259, [Group IV (b)], are referred to.