3-甲基-4-甲氧羰基芬太尼类似物的合成与镇痛活性

Synthesis and Analgesic Activity of Analogs of 3-Methyl-4-Methoxycarbonyl Fentanyl

报道某些3-甲基-4-甲氧羰基芬太尼类似物的合成,顺反异构体的分离及其镇痛活性。实验结果表明,该类化合物具有与3-甲基芬太尼类和4-甲氧羰基芬太尼类相当的强效镇痛活性(活性最强的化合物18a镇痛强度为吗啡的2939倍),构效关系更类似于前者。顺式异构体的活性通常强于反式,且二者强度比较小,提示4-甲基羰基引入到3-甲基芬太尼类化合物分子中降低了3位甲基对阿片受体作用的选择性。

The synthesis, separation of diastereo-isomers and analgesic activities of some analogs of N-[1-(2-phenylethyl)-3-methyl-4-methoxycarbonyl-4-piperidinyl]-N-propionylaniline (3-methyl-4-methoxycarbonyl fentanyl) were reported. Preliminary pharmacological results showed that analgesic activities of compounds in this series were strong and corresponding to those of 3-methyl fentanyl derivatives and 4-methoxycarbonyl fentanyl derivatives. Compound N-[-1-(2-hydroxy-2-phenylethyl)-3-methl-4-methoxycarbonyl-4-piperidinyl]-N-propionylaniline (18a) was found to be the most potent. Its analgesic activity was 2939 times more potent than that of morphine. The structure-activity relationship in this series is similar to that of 3-methyl fentanyl series. Usually, the cis-isomer has higher activity than trans-isomer but in individual cases, activity of the trans-isomer is higher than the cis-isomer. However, the analgesic potency ratio between diastereoisomer in this series is smaller than in 3-methyl fentanyl series. It seems that the introduction of 4-methoxycarbonyl group into molecules of 3-methyl fentanyl derivatives may reduce selectivity of action of 3-methyl fentanyl.