芬太尼类化合物4-N-环己基类似物的合成与镇痛活性及构效关系研究

Synthesis, Analgesic Activity and Structure-Activity Relationship of 4-N-Cyclohexyl Analogs of Some Fentanyl Derivatives

以环己基取代芬太尼、顺-3-甲基芬太尼和4-乙酰基芬太尼中的4-N-苯基合成了三个化合物(化合物1～3)。镇痛试验结果表明,环己基取代苯基导致镇痛活性显著降低。对于4位带有活性取代基(COMe,COOMe)的化合物,其活性降低的程度显著小于4位不带有活性取代基的化合物。应用半经验的INDO法对化合物1～4及其相应的4-N-苯基类似物进行了量子化学计算,讨论了电子结构与镇痛活性的关系。证实在芬太尼类化合物中某些4位活性取代基的存在对产生镇痛活性有重要作用。

The synthesis of 4-N-cyclohexyl analogs of fentanyl, cis-3-methylfentanyl and 4-acetyl fentanyl was reported. Results in mouse hot plate test showed that the substitution of 4-N-phenyl by cyclohexyl caused decrease of analgesic activity, and the degree of decrease of analgesic activity in 4-substituted compounds was remarkably lower than that in non-4-substituted compounds. Semiempirical INDO calculations have been undertaken for 8 compounds. The relationship between analgesic activity and the electronic structure of these compounds was discussed. Results showed that the active substitute group in 4-site of piperidyl is very important to analgesic activity.