抗疟新药的研究5-取代苯氧基-6-甲氧基-8-取代氨基喹啉的合成

根据5-(对-氟苯氧基)-6-甲氧基-8-(4-氨基-1-甲基-丁氨基)喹啉(Ⅰ₁)(表1)对猴疟原虫(Plasmodium cynomolgi)的作用略优于伯喹而毒性较低的报道,合成了化合物Ⅰ₁(代号M7844),同时还合成了衍生物5-取代苯氧基-6-甲氧基-8-(4-取代氨基-1-甲基丁氨基)喹啉(Ⅰ_3～17)(表1)以及其同分异构体5-取代苯氧基6-甲氧基-8-(5-取代氨基戊氨基)喹啉(Ⅱ_13～28)(表2)。药理研究证明化合物Ⅰ_1～7、Ⅰ₁₆及Ⅱ₁₈等对鼠疟P.yoelii均有不同程度的作用。化合物Ⅰ₁(M7844)的毒性甚低,对小鼠的毒性比磷酸伯喹低20余倍,对家兔的溶血反应也明显低干伯喹。但在相同剂量下,对猴疟P.cynomolgi的作用不及伯喹。对鼠疟红前期的作用比伯喹低4～5倍。

STUDIES ON NEW ANTIMALARIALS SYNTHESIS OF DERIVATIVES OF SUBSTITUTED 5-PHENOXY-6-METHOXY-8-AMINOQUINOLINE

5-(p-Fluorophenoxy)-6-methoxy-8-(4-amino-1-methylbutylamino)-quinolinc (Ⅰ₁) has been reported to be more potent and less toxic than primaquine for radical cure against Plasmodium cynomolgi in monkeys. This compound coded M7844 as well as a series of derivatives 5-phenoxy-6-methoxy-8-(4-substituent-amino-1-methyl-butylamino) quinolincs (Ⅰ_2～17) and their isomers 5-phcnoxy-6-mcthoxy-8-(5-substituent-amino-amylamino) quinolines (Ⅱ_18～28) were synthesized.Compounds Ⅰ and Ⅱ were synthesized from 6-methoxy-8-nitroquinoline by bromination, condensation and reduction to give 5-phenoxy-6-methoxy-8-aminoquinolines which were subsequently reacted with 4-bromo-1-phthalimidopentane or 5-bromo-1-phthalimidopentane to yield the corresponding compounds 5-phenoxy-6-methoxy-8-(4-phthalimido-1-methylbutylamino)quinolincs Ⅰ_10～17 (Table 1) or their isomers 5-phenoxy-6-mcthoxy-8-(5-phthalimidoamylamino) quinolines Ⅱ_24～28 (Table 2). They were subsequently hydrolyzcd, and then prepared as their salts Ⅰ_1～9 (Table 1) or their isomers Ⅱ_18～23 (Table 2).Compounds Ⅰ_1～7, Ⅰ₁₆ and Ⅱ₁₈ exhibited some activities against P. yoelii in mice. Preliminary experiments showed that M7844 (Ⅰ₁) possessed activity against P. cynomolgi in monkeys, but less effective than primaquine at the same dosage. M7844 is 20 times less toxic and 4～5 times less effective than primaquine in mice.