顺-3-甲基芬太尼的4-N-丙酰基结构类似物的合成与镇痛活性及构效关系的研究

以不同电性的基团取代顺-3-甲基芬太尼中4-N-丙酰基上的乙基,合成某些顺-3-甲基芬太尼的结构类似物。药理试验结果表明,所合成的化合物均有典型的吗啡样作用。化合物3的镇痛活性略强于顺-3-甲基芬太尼。应用半经验的INDO方法对4个代表化合物进行了量子化学计算,讨论了电子结构与镇痛活性间的关系,化合物3由于氯乙烯基的引入具有与顺-3-甲基芬太尼不同的电子结构特征,氯乙烯基可能作为电子接受体参与了与受体的作用。

SYNTHESIS,ANALGESIC ACTIVITY AND STUCTUREACTIVITY RELATIONSHIP OF 4-N-PROPIONYL ANALOGS OF CIS-3-METHYL FENTANYL

The synthesis of some 4-N-propionyl analogs of cis-3-methyl fentanyl by acyl chloride method. anhydride method, mixed anhydride method and DCC method is reported. The ethyl group in 4-N-propionyl portion of cis-3-methyl fentanyl was substituted by some groups with different electronic property. In mouse hot plate test, all compounds showed typical morphine-like action with analgesic potency corresponding to 49-1963 times that of morphine. Compound 3 was found to exhibit higher analgesic activity than cis-3-methyl fentanyl. Semiempirical INDO calculations have been undertaken for 4 typical compounds and it was found that as a result of introduction of chlorovinyl, compound 3 exhibited characteristics of electronic structure different from that of cis-3-methyl fentanyl. The relationships between analgesic activity and the electronic structure of these compounds were discussed.