Patent GB-1366855-A (GB)
Title: Biologically active substituted amidines
IPC: C07C279/24
Filed: 1970-12-23
Abstract: 1366855 1 - Amidino - 3 - phenylurea derivatives WELLCOME FOUNDATION Ltd 28 Sept 1971 [30 June 1970 23 Dec 1970 30 April 1971 25 June 1971] 31772/70 61029/70 12366/71 and 29959/71 Heading C2C Novel 1 - amidino - 3 - phenylurea derivatives of the formula wherein Y<SP>3</SP> is halogen or trihalomethyl, Y<SP>4</SP> is cyano or halogen and Y<SP>5</SP> is halogen and acid addition salts thereof are prepared (a) by reacting the corresponding 1-(Y<SP>3</SP>,Y<SP>4</SP>,Y<SP>5</SP>-phenyl)- biguanides, obtained by treating the appropriate anilines with dicyandiamide, with an excess of nitrous acid or with a strong aqueous acid; (b) by oxidizing compounds of the formula wherein X is alkyl or aralkyl; (c) by reacting guanidine with reactive derivatives of the appropriately substituted phenylcarbamic acids, e.g. alkyl esters, or N,N-dialkylamides; (d) by reacting the corresponding anilines with dicyandiamide in the presence of strong aqueous acids; (e) ammonolysis of compounds of the formula wherein R is NH 2  and R<SP>1</SP> is C 1-4  alkylthio; or (f) by hydrolysing ureas of the formula R is H, alkyl or aryl, and A is H or the group CO.B, wherein B is aryl, obtained by reacting the corresponding phenyl isocyanates with N,N<SP>1</SP>- dibenzoylguanidine or benzoylguanidine. (R= H.) 3,5 - Dibromo - 4 - chloroaniline is obtained by reducing 3,5-dibromo-4-chloronitrobenzan3. 3,5 - Dibromo - 4 - cyanoaniline, 3 - bromo - 4,5- dichloroaniline, 3 - bromo - 4 - chloro - 5 - fluoroaniline 3,4 - dichloro - 5 - fluoroaniline and 3- bromo - 4 - chloro - 5 - trifluoromethylaniline are also obtained by reducing the appropriate nitrobenzenes. 3,5 - Dichloro - 4 - cyanophenyl isocyanate, 3,5 - dibromo - 4 - chlorophenyl isocyanate, and 3,5 - dibromo - 4 - cyanophenyl isocyanate are prepared by reacting phosgene with the appropriate anilines. 3,5 - Dibromo - 4 - cyanonitrobenzene is made by diazotizing 2,6-dibromo-4-nitroaniline and reacting the resulting diazonium salt with potassium cyanide. 1 - (3,4,5 - Trichlorophenyl) - 3,3 - diethylurea is obtained by treating 3,4,5-trichlorophenyl isocyanate with diethylamine. 3 - Bromo - 4 - chloro - 5 - fluoronitrobenzene, 3,4 - dichloro - 5 - fluoronitrobenzene and 3- bromo - 4 - chloro - 5 - trifluoromethylnitrobenzene are obtained by diazotizing 2-bromo-6-fluoro-4- nitroaniline, 2 - chloro - 6 - fluoro - 4 - nitroaniline and 3 - bromo - 4 - chloro - 5 - trifluoromethylnitrobenzene respectively and treating the resulting diazonium salt with cuprous chloride. 3 - Amidino - 1 - (3,4,5 - trichlorophenyl) - 2- methylisothiourea is prepared by reacting methyl iodide with 1-amidino-3-(3,4,5-trichlorophenyl)- thiourea, resulting from the reaction between sodium, guanidine thiocyanate and 3,4,5-trichlorophenyl isothiocyanate, which is made by reacting thiophosgene with 3,4,5-trichloroaniline. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above novel compounds or acid addition salts thereof in association with acceptable carriers therefor. The compounds possess antimalarial activity.