疟原虫组织期裂殖体杀灭剂的研究:2-取代苄氧基(或甲氧基)-5-取代苯氧基-伯氨喹类似物的合成

本文报道了间日疟根治药伯氮喹2位引入取代苄氧基或甲氧基,5位引入取代苯氧基的类似物的合成。其中以化合物39及45对疟原虫组织期裂殖体的作用最强,约氏疟原虫子孢子感染的小鼠喂服100mg/kg单剂,分别有80%及90%的受试小鼠未查见原虫血症。化合物45降至20mg/kg单剂时,80%的受试小鼠也未出现原虫;对小鼠的急性毒性低于伯氨喹。

STUDIES ON TISSUE SCHIZONTICIDE OF MALARIA PARASITE:SYNTHESIS OF 2-SUBSTITUTED BENZYLOXY(OR METHOXY)-5- SUBSTITUTED PHENOXY ANALOGUES OF PRIMAQUINE

2-Chloro-6-methoxy-8-nitroquinoline was reacted with substituted benzyl alcohols (or sodium methanol) and then brominated to give 2-substituted benzyloxy-6-methoxy- and 2,6-dimethoxy-5-bromo-8-nitroquinolines (compounds 5-8 in Table 1). These products were condensed with substituted phenols to form corresponding 5-substituted phenoxy compounds (9-19 in Tables 1 and 2) which were subsequently reduced to afford 2-substituted benzyloxy-6-methoxy- and 2,6-dimethoxy-5-substituted phenoxy-8-aminoquinolines (20-28, 47 and 48 in Tables 3 and 6). Condensation with 4-bromophthalimidopentane yielded corresponding 8-(4-phthalimido-1-methylbutyl)aminoquinolines (29-37, 49 and 50 in Tables 4 and 6) which were subsequently treated with hydrazine hydrate to give 2-substituted benzyloxy-6-methoxy- and 2,6-dimethoxy-5-substituted phenoxy-8-(4-amino-1-methylbutyl)amino-quinolines, compounds III and IV (38-46, 51 and 52 in Tables 5 and 6), the analogues of primaquine. Compounds III and IV were tested against Plasmodium yoenii in mice infected with sporozoites. The parasitaemia of 80% and 90% of tested mice was negative at an oral single dose of 100 mg/kg of compounds 39 and 45, respectively. The results of further studies on compound 45 showed that the parasitaemia of 80% of mice was negative at a single dose of 20 mg/kg, and the acute toxicity in mice was less than that of primaquine.