抗疟新药咯萘啶及其类似物的合成

作者等根据一些抗疟药的构效关系,合成了一种新化合物2-甲氧基-7-氯-10-[3′,5′-双(四氢吡咯次甲基)一4′-羟基苯胺基]苯骈[b]1,5-萘啶(Ⅰ),代号7351,定名咯萘啶。它对红内期裂殖体的作用显著,毒性低。之后,又合成了它的类似物Ⅱ,这些类似物大多数对鼠疟Plasmodiumberghei的红内期均具有不同程度的作用,其中Ⅱ_1～6,9.10等的作用与Ⅰ相当。对子孢子诱发感染的鼠疟P.yoelii的作用以化合物Ⅰ、Ⅱ_{1,3,5,6,9,10,12,15}等为最强,优于伯喹对照组。值得注意的是,这类化合物既对血液转种的鼠疟P.berghei具有显著的作用,同时对子孢子感染的鼠疟P.yoelii也具有显著的作用。

SYNTHESIS OF NEW ANTIMALARIAL DRUG PYRONARIDINE AND ITS ANALOGUES

On the basis of structure-activity relationship of some antimalarial drugs, the authors synthesized a new compound 2-methoxy-7-chloro-10-[3′, 5′-bis (pyrrolidinomethyl)-4′-hydroxyanilino] benzo[b] 1,5-naphthyridine(Ⅰ), coded 7351 and named poyronaridine. The compound exhibited high schizonticidal activity and low toxicity. Since then, a seriesof analogues Ⅱ, 2-substituent-7-chloro-10-[3′,5′-bis-or 3′-mono-(substituted aminomethyl)-4′-or 2′-hydroxyanilino] benzo[b]-1,5-naphthyridines (Table 4), were synthesized.Compound Ⅰ and its analogues Ⅱ were prepared with 2-substituent-5-aminopyridines as intermediates. These intermediates were. condensed with 2,4-dichlorobenzoic acid to give 2-substituent-5-(2-carboxy-5-chloroanilino) pyridines (Table 1) which were cyclized in the presence of phosphorus oxychloride. The cyclized products 2-substituent-7,10-dichlorobenzo[b] 1,5-naphthyridihes (Table 2) were subsequently condensed with 4-or 2-hydroxyaniline to form 2-substituent-7-chloro-10(4′- or 2′-hydroxyanilino)benzo[b]1,5-naphthyridines (Table 3), the latter being finally, reacted with Mannich reagents to yield the desired compound Ⅰ and its analogues Ⅱ.Among the analogues Ⅱ, most compounds were effective in varying degress against the murine blood schizonticidal test, and the analogues Ⅱ_{1～6, 9, 10} were as effective as compound Ⅰ. In addtion, compounds Ⅰ and Ⅱ_{1, 3, 5, 6, 9, 10, 12, 15} were also highly effective against Plasmodium yoelii-Anopheles stephensi-mouse system, their potency being superior to that of primaquine. It was noteworthy that the substituted benzo-[b]1,5-naphthyridines were effective, not only against P. berghei of blood transmission, but also against P. yoelii through the sporozoite inoculation.