抗疟药的研究 Ⅺ.4-甲基-5取代苯氧基伯喹的合成及其抗疟作用

本文报道了6个4-甲基-5取代苯氧基-6-甲氧基-8-(1-甲基-4-氨基丁氨基)喹啉(Ⅲ)的合成。除Ⅲ₃外,所有化合物对鼠疟P.berghei的抑制性治疗作用和对鼠疟P.yoelii的病因性预防作用均优干伯喹,其中以Ⅲ₁最强。Ⅲ₁口服治疗作用的SD₅₀和SD₉₀分别为0.65 mg/kg和1.60 mg/kg,口服预防作用的最小有效剂量(MED)和最小完全有效剂量(MFAD)分别为2.5mg/kg和5.0 mg/kg。对这类化合物的根治作用和毒性试验正在进行中。

STUDIES ON ANTIMALARIALS.Ⅺ.SYNTHESIS AND ANTIMALARIAL EFFECTS OF 4-METHYL-5-SUBSTITUTED PHENOXY PRIMAQUINE ANALOGUES

In searching for a safe and radically curative agent for malaria and a causal prophylactic, six 4-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino) quinolines (Ⅲ_1～6) were prepared.Compounds Ⅲ_1～6 were synthesized from 2-nitro-4-methoxy-5-bromo-acetanilide by condensation with potassium salts of substituted phenols, hydrolysis with dilute alcoholic hydrochloric acid to give the corresponding 2-nitro-4-methoxy-5-substituted phenoxy anilines (Ⅵ) which underwent Skraup reaction to provide the key intermediates 4-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (Ⅶ). In the usual manner Ⅶ were reduced with iron powder, condensed with N-(4-bromopentyI) phthalimide and hydrolyzed with hydrazine hydrate to yield the final products.All compounds, with the exception of Ⅲ₃, exhibited both stronger suppressive antimalarial activity against P berghei in mice and greater prophylactic activity against P yoelii in mice than primaquine. Among them, Ⅲ₁ was found to be the most potent in both tests. Results were expressed both in terms of SD₅₀ (0.65 mg/kg) and SD₉₀ (1.60 mg/kg) in blood schizonticidal test, and in terms of minimal effective dose (2.5 mg/kg)and minimal fully active dose (5 mg/kg) in causal prophylactic screening.