Novel 1-Amidino-3-Phenyl-Urea Derivatives, the preparation thereof and Compositions containing the same

摘要

1,194,835. 1 - Amidino - 3 - phenylurea derivatives. WELLCOME FOUNDATION Ltd. 21 June, 1967 [7 July, 1966; 16 Dec., 1966; 3 Feb., 1967; 25 April, 1967], Nos. 30479/66, 56546/66, 5391/67 and 19028/67. Heading C2C. Novel 1-amidino-3-phenylurea derivatives of the general formula wherein Y4 is a halogen when Y is a trihalomethyl, nitrile or nitro substituent at the 3- position or a halogen substituent at the 3- position or at both the 3- and 6-positions; or Y4 is trihalomethyl or nitrile when Y is hydrogen or a halogen or C 1 -C 4 alkyl substituent at the 2- or 3-position; or Y4 is nitro when Y is a trihalomethyl or halogen substituent at the 3-position; and acid addition salts thereof are prepared (a) by treatment of a biguanide of the general formula with excess of nitrous acid or by hydrolysis of the said biguanide with a strong aqueous acid; (b) by oxidation of an S-alkyl-1-amidino-3- phenyl-isothiourea of the general formula wherein the alkyl group has 1 to 4 carbon atoms; (c) by reaction of guanidine with a reactive derivative of a phenylcarbamic acid of the general formula e.g. an isocyanate, a urea or a urethane; (d) by reaction of an aniline derivative of the general formula with dicyandiamide in the presence of a strong aqueous acid; (e) by ammonolysis of an S- alkylthiobiuret derivative of the general formula wherein R is an amino group and R1 is an S- alkyl group; or (f), when the phenyl ring is substituted by a nitrile group, by diazotization of the corresponding amino compound and subsequent reaction with the cyanide of an alkali metal in the presence of a copper salt, followed optionally by conversion of the product to an acid addition salt thereof. Pharmaceutical compositions having antimalarial activity comprise as active ingredient a 1-amidino-3-phenylurea derivative of the first general formula above or an acid addition salt thereof in association with a pharmaceutical carrier. p-Gyanophenylurethane is prepared by reaction of 4-cyanoaniline and ethyl chloroformate. Methyl 3-chloro-4-cyanophenyl carbamate is prepared by reaction of 3-chloro-4- cyanoaniline and methyl chloroformate. 1- (3 - Chloro - 4 - cyanophenyl) - 3,3 - diethylurea is prepared by reaction of 3-chloro-4-cyanophenyl isocyanate with diethylamine. 3-Chloro- 4-cyanophenyl isothiocyanate is prepared by treatment of 3-chloro-4-cyanoaniline with thiophosgene. S - Alkyl - 1 - amidino - 3 - phenylisothioureas of the second general formula above wherein X is an S-alkyl group are prepared by alkylation of the corresponding 1-amidino-3- phenylthiourea, which can in turn be prepared from the appropriate isothiocyanate and guanidine. 1 - Amidino - 3 - (4 - amino - 3 - chlorophenyl) urea dihydrochloride is prepared by reduction of 1-amidino-3-(3-chloro-4-nitrophenyl) urea methanesulphonate with stannous chloride and hydrochloric acid. 1-(3,4-Dichlorophenyl)- 4-thiobiuret is prepared by reaction of 3,4- dichlorophenyl isocyanate and thiourea.