The reaction between fi-chlorophenyldiguanide and acetone under acid conditions yields a compound identical with the highly active metabolite (Crowther and Levi, Brit. J . Pharnzacol., 1953, 8, 93) of the antimalarial drug " Paludrine " (proguanil, W-p-chlorophenyl-N%sopropyldiguanide). The compound is readily converted under alkaline conditions into an inactive isomer, 4-amino-6-~-chloroanilino-l : 2-dihydro -2 : 2dimethyl -1 : 3 : 5-triazine (I1 ; R = R' = Me) (cf. Birtwell, Curd, Hendry, and Rose, J., 1948, 1645), the structure of which has been confirmed by the optical resolution of its 2-ethyl-2-methyl homologue (11; R = Me, R' = Et).From a study of the reactions of the active metabolite of proguanil, and of the condensation under both acid and basic conditions of a number of N1-aryldiguanides bearing other substituents on one or more of the nitrogen atoms, it is concluded that the active metabolite is 4 : 6-diamino-l-~-chlorophenyl-THE isolation of a metabolite of " Paludrine " (proguanil, N1-f-chlorophenyl-N5-isopropyldiguanide) (I) with high antimalarial activity, from the urine of rabbits and of human volunteers receiving the drug, was described by Carrington, Crowther, Davey, Levi, and Rose (Nature, 1951, 168, lOSO), and a detailed account of this work has since been given by Crowther and Levi (Brit. J . Pharmacol., 1953,8,93). The present communication describes studies on the structure of this and related substances.The active metabolite, strongly basic in nature, was characterised first as the picrate, and then as the free base, and was found to have the empirical formula Cl1H1,N,Cl, the molecule having two atoms of hydrogen less than that of proguanil itself. On treatment with warm dilute aqueous sodium hydroxide, it was readily converted into an isomeric compound which had no antimalarial activity and was identical with 4-amino-6-f-chloroanilino-1 : Z-dihydro-2 : 2-dimethyl-1 : 3 : 5-triazine (IT; R = R' = Me) which Birtwell, Curd, Hendry, and Rose (J., 1948Rose (J., , 1645 had already prepared both by heating fi-chlorophenyldiguanide with * Patent protection pending.
