Patent GB-1422455-A (GB)
Title: Hydroxy-guanidine-o-carbamates
IPC: C07D317/58
Filed: 1973-08-22
Abstract: 1422455 Carbonates of N-hydroxy guanidines E I DU PONT DE NEMOURS & CO 22 Aug 1973 [25 Aug 1972 25 June 1973] 39851/73 Heading C2C Novel compounds in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are selected from (A) hydrogen, (B) a C 1-8  aliphatic hydrocarbon which may contain up to two substituents selected from fluoro, chloro, bromo and C 1-4  alkoxy and (C) a group of Formula III in which X is fluoro, chloro, C 1-3  alkyl, C 1-3  alkoxy nitro, trifluoromethyl, R<SP>5</SP>R<SP>6</SP>N-CO-, R<SP>5</SP>R<SP>6</SP>N-SO 2 - (in which R<SP>5</SP> and R<SP>6</SP> are hydrogen or C 1-4  alkyl) or R<SP>7</SP>-SO 2 - (in which R<SP>7</SP> is trifluoromethyl or C 1-4  alkyl), or when n is 2, both X's may together represent methylenedioxy, m is 0 to 2 and n is 0 to 3 and in addition R<SP>1</SP> and R<SP>2</SP> together may be -(CH 2 ) 4-9 - and R<SP>3</SP> is selected from (A), (B) or (C) and R<SP>4</SP> is hydrogen or C 1-3  alkyl with the provisos that (i) up to one of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is selected from (A); up to two of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are selected from (B) and up to one of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is selected from (C), (ii) when R<SP>1</SP> is methyl and R<SP>2</SP> is hydrogen, R<SP>3</SP> is not an unsubstituted benzyl or phenyl group, (iii) when R<SP>1</SP> is methyl and R<SP>3</SP> is hydrogen, R<SP>2</SP> is not unsubstituted phenyl and (iv) when one of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is hydrogen and the other two groups are selected from (B) the total carbon atoms in these groups is 3 to 9 are prepared by reacting a hydroxy guanidine R<SP>1</SP>R<SP>2</SP>N-C(= NOH)-NHR<SP>3</SP> with an isocyanate R<SP>4</SP>NCO at a temperature - 20 to 50 C. in an aqueous solution when R<SP>4</SP> is hydrogen and in a non-hydroxylic organic solvent when R<SP>4</SP> is C 1-3  alkyl. When R<SP>4</SP> is hydrogen the reaction may be carried out with the HX salt of the hydroxy guanidine and an alkali metal cyanate MOCN (where X is chloro, bromo, or fluoro and M is sodium, lithium or potassium). Compounds prepared are those in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are selected from C 1-6  alkyl (optionally substituted by methoxy, ethoxy, chloro or bromo) cyclopentyl, cyclohexyl, C 3-5  alkenyl, phenyl (optionally substituted by nitro, fluoro, chloro, trifluoromethyl, dimethylcarbamyl, methylsulphonyl or dimethylsulphamyl), benzyl (optionally substituted by nitro, chloro, fluoro, methyl, methoxy, ethoxy or trifluoromethyl), phenethyl, 3,4-methylenedioxyphenyl or 3,4- methylenedioxyphenethyl or R<SP>1</SP>R<SP>2</SP>N represents piperidino or hexamethyleneimino. Hydroxy guanidines are prepared by (1) reacting a cyanamide R<SP>1</SP>R<SP>2</SP>N-CN or carbodiimide R<SP>1</SP>N=C=NR<SP>3</SP> with hydroxylamine to form an R 1  and R 2  or R 1  and R 3  disubstituted hydroxyguanidine or (2) reacting an isothiourea R<SP>1</SP>R<SP>2</SP>N-C(SCH 3 )= NR<SP>3</SP> with hydroxylamine to form R<SP>1</SP>R<SP>2</SP>R<SP>3</SP>-trisubstituted hydroxyguanidines. Compounds I have anti-hypertensive activity and form with a carrier a pharmaceutical composition which may be administered orally or parenterally.