Epibatidine开链类似物的合成和镇痛活性研究

以ABT-594为先导化合物,根据生物电子等排和相似基团替代原理,设计并通过M itsunobu缩合反应合成了10个开链Ep ibatid ine类似物,用¹H NMR,¹³CNMR,MS orHRMS和元素分析对其结构进行了表征.采用小鼠醋酸扭体模型,分别对所合成的10个化合物进行了体内镇痛活性实验.结果表明,除化合物6外,其余化合物均显示出一定的镇痛活性.其中含有呋喃环的化合物的镇痛活性最高;用2-甲基-5-硝基咪唑或5-甲基四氮唑代替吡啶和2-氯吡啶,用亚甲基代替氧桥键作为连接臂所合成的化合物,其镇痛活性并无明显下降;这些化合物的毒性都明显比Ep ibatid ine的低.

Synthesis and Analgesic Activity of Novel Open-chained Epibatidine Analogues

Based on the structure of the leading compound ABT-594 and the bioisosteric replancement rule,ten new open-chain EP analogues were designed and synthesized by the PTC and Mitsunobo reactions.Their structures were confirmed by ¹H and ¹³C NMR,elemental analysis,MS or HRMS.All the target compounds were evaluated for their analgesic activity in vivo.The result revealed that most of them showed some activity.Though their analgesic activity was not so satisfactory,some interesting SAR was found.The compounds containing furan ring exhibited a higher activity than others.Replaced 2-chloropyridine in ABT-594 with 2-methyl-5-nitroimidazole or 5-methyl tetrazole,and(or) instead of the CH₂O with CH₂ as linking arm,the analgesic activity didn't obviously decrease.Additionally,the toxicity of all tested compounds was lower than epibatidine itself significantly.