BRIEF chemical study was designed to pro-A vide analogs of the antimalarial agent amodiaquine ( I ) hydrochloride U.S.P. (1) in which the diethylamino group was replaced by pyrrolidino, hexamethylenimino, and 4-methylpiperazino (structures 11, IV, and V, respectively). The piperidino CHz-NRz --SIX. c1 /CHzCH3 I (amodiaquine) -N 'CH~CH~ I1 (amopyroquine) -N 3 I11 IV v -N , analog 111 has been previously described (1). The ethyl groups of I are free to move, while the movements of the corresponding groups of 11, 111, I V , and V are restricted owing to the cyclic structures.
Models readily show the three-dimensional nature of the cyclic amines piperidine, hexamethylenimino, and N-methylpiperazine, while all the carbon atoms of pyrrolidine occupy the same plane. Also, V contains an additional ionic center as seen in the second basic nitrogen. I n view of these considerations, the compounds were desired for a study of relative antimalarial activity and usefulness.
In order to obtain amopyroquinone (II),I pacetamidophenol, pyrrolidine. and aqueous formaldehyde were subjected to Mannich conditions (1). When the intermediate p-acetamido-a-pyrrolidino- o-cresol was not obtained in crystalline form, the oily substance was hydrolyzed by acid and the unisolated diamine condensed with 4,7-dichloroquinoline to give 4-(7-chloro-4-quinolylamino)-apyrrolidino-o-cresol (amopyroquine 11) in 787, yield. Compounds I V and V were similarly prepared by substitution of hexamethylenimine and N-methylpiperazine for pyrrolidine. I n the case