Patent GB-808071-A (GB)
Title: Manufacture of new sulphonyl-ureas
IPC: C07C311/54
Filed: 1956-05-08
Abstract: The invention comprises sulphonyl ureas of the general formula <FORM:0808071/IV (b)/1> n which R2 and R3 represent hydrogen atoms or alkyl or alkoxy groups containing not more than 6 carbon atoms and R1 represents an aliphatic or cycloaliphatic hydrocarbon radical containing from 2 to 8, more preferably 3 to 5, carbon atoms, and non-toxic salts of these compounds.  The products can be prepared by known methods for the production of sulphonyl ureas, for example, (1) a benzene-sulphonyl isocyanate is reacted with a primary alkylamine, cycloalkylamine, alkenylamine or cycloalkyl-alkylamine, or conversely a benzene sulphonamide is reacted with the appropriate isocyanate, or in place of the isocyanate, a compound which is convertible to an isocyanate, such as an azide, or a urethane or carbamic acid halide may be used; (2) a benzene sulphonyl urea which is unsubstituted in the -NH2 group is converted into a benzene sulphonyl alkyl urea by alkylation, for example by butylation with butylamine, or conversely an alkyl urea is reacted with a benzene sulphonamide; (3) a benzene sulphonic acid chloride is reacted with an iso-urea alkyl ether and the product obtained is converted by acid hydrolysis into the desired sulphonyl urea; (4) the corresponding benzene sulphonyl thiourea compound is prepared and the sulphur is eliminated therefrom in a conventional manner, e.g. by treatment with a heavy metal oxide or salt; (5) an N-benzene-sulphonyl-N1-alkylguanidine is made (for example by treating a benzenesulphonyl-cyanamide with butylamine or another primary amine), and the resulting guanidine is hydrolysed. In the above processes, the benzene sulphonyl compound may be alkyl- or alkoxy-substituted and the alkylamine may be an alkenylamine cycloalkylamine or cycloalkyl-alkylamine. The preferred processes are the reaction of a sulphonamide of the formula <FORM:0808071/IV (b)/2> with an isocyanate R1-NCO and the reaction of a benzene sulphonyl carbamic acid ester <FORM:0808071/IV (b)/3> in which R4 is a hydrocarbon residue, with an amine R1NH2.  Examples describe the preparation of N-benzenesulphonyl-N1-n-butyl urea and the corresponding p-methyl-, p-ethyl-, p-n-propyl- and p-methoxy-derivatives; p-methyl-, p-methoxy-, m-methyl- and 3:4-dimethoxy-, N - benzenesulphonyl - N1 - isobutyl - urea; N-p - methylphenylsulphonyl - N1 - tert. - butyl-, sec. - butyl -, cyclohexyl -, allyl -, iso - amyl-, n - amyl -, cyclopentyl -, heptyl - (4), cyclo - hexylmethyl-, and n-hexyl-urea; and urea derivatives in which the N- and N1-substituents are respectively p-ethylphenylsulphonyl, cyclohexyl, 2 : 4 - dimethylphenylsulphonyl, cyclohexyl; m-methoxyphenylsulphonyl, n-hexyl; m-methoxyphenylsulphony, cyclohexyl.  Many other products are specified.  N - 4 - Methyl - benzenesulphonyl - carbamic acid ethyl ester and the corresponding methyl ester are made by treating 4-methylbenzenesulphonamide with ethyl or methyl chloroformate in the presence of potassium carbonate.  N - 4 - Methylbenzenesulphonyl - and carbamoyl chloride is made by passing hydrogen chloride into 4-methylbenzenesulphonyl isocyanate.ALSO:Preparations suitable for the oral treatment of diabetes comprise compounds of the formula <FORM:0808071/VI/1> wherein R1 is an aliphatic or cycloaliphatic hydrocarbon radical of 2-8 carbon atoms and R2 and R3 are each hydrogen or an alkyl of alkoxy group of 1-6 carbon atoms, or salts of these compounds with bases which give physiologically tolerable salts in admixture with a pharmaceutically suitable carrier.  The preparations suitably take the form of tablets, pills, capsules, cachets, mixtures, solutions or powders containing for example 0.5 grams of sulphonyl urea compound per dosage unit.  In the above general formula R1 may suitably be an alkyl group such as propyl, butyl, pentyl, hexyl, heptyl or octyl, an alkenyl group such as allyl or crotyl, a cycloalkyl group such as cyclopentyl or cyclohexyl, or a cycloalkyl-alkyl group such as cyclohexyl-methyl or cyclohexylethyl. The benzene residue containing R2 and R3 is preferably a p-methyl-phenyl group.  Many suitable products are specified (see Group IV (b)).  In an example N-(4-methyl-benzene-sulphonyl) - N1 - n - butyl - urea is made up into tablets with wheat or maize starch, talc and magnesium stearate.