2-甲基-5-取代苯氧基伯氨喹的合成及其抗疟活性

SYNTHESIS OF 2-METHYL-5-SUBSTITUTED PHENOXY-PRIMAQUINE AND ANTIMALARIALS ACTIVITY

为寻找高效低毒的间日疟根治药,合成了7个2-甲基-5-取代苯氧基伯氨喹Ⅱ_(1～7),以与强效的4-甲基取代类似物比较,探索构效关系。初步生物评价结果表明,化合物Ⅱ_(1～7)对鼠疟Plasmodium berghei的抑制性治疗作用及对鼠疟P.yoelii的病因性预防作用均明显弱于其4-甲基对应物,略低于伯氨喹。

In searching for efficient, safe and radically curative agen^+ and causal prophylactics for malaria, seven 2-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino)-quinolines (Ⅱ_(1～7)) were synthesized and their antimalarial activities were compared with the corresponding 4-methyl substituted derivatives of primaquine. The starting material, 2-nitro-4-methoxy-5-bromo-acetanilide (Ⅲ),was prepared from p-methoxy aniline through acetylation, bromination and nitration. Ⅲ was then condensed with substituted phenols in the presence of potassium carbonate. The condensed products were subsequently hydrolyzed with dilute alcoholic hydrochloric acid to yield 2-nitro-4-methoxy-5-substituted phenoxy-aniline (Ⅴ) which underwent Skraup's reaction with 2-butenal to provide the key intermediates 2-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (Ⅵ). These 8-nitroquinoline derivatives were reduced to 8-aminoquinoline derivatives (Ⅶ). The latter were condensed with 4-bromo-1-phthalimido-pentane and then hydrolyzed with hydrazine hydrate, the final products were obtained as oxalate or succinate. The structure of the target compounds and unknown intermediates were confirmed by elementary and spectral analysis. Primary biolological evaluation showed that all compounds Ⅱ_(1～7) were much less active than the 4-methyl substituted derivatives and slightly less active than primaquine in both causal prophylactic test against plasmodium yoelii and suppressive antimalarial test against P. berhei.