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目的 寻找高效低毒的非甾体抗炎药。方法 以 COX- 2选择性抑制剂罗非昔布为先导化合物 ,合成其开环衍生物 ,应用二甲苯致小鼠耳肿胀模型和角叉菜胶致大鼠足跖肿胀模型评价其抗炎活性 ,并考察连续经口给药对大鼠胃肠道的影响。结果 合成了 17个目标化合物 ( I1 - 1 7) ,I1 - 1 5未见文献报道 ,其结构经 IR、1 HNMR、MS和元素分析确证。 I1 ,3,7,9,1 0 ,1 3,1 5,1 6 对小鼠耳肿胀模型表现显著的抗炎活性 ,I1 ,1 3,1 5对大鼠角叉菜胶致足跖肿胀模型显示较强的抗炎活性 ,在致炎后 3 h I1 5的抗炎活性与双氯芬酸相当 ( P>0 .0 5 ) ,I1 3,1 5与罗非昔布相当 ( P>0 .0 5 )。上述活性化合物的胃肠道副作用小于双氯芬酸 ,但略大于罗非昔布。结论 I1 3,1 5值得深入研究
Objective To search for high efficiency and low toxicity nonsteroidal anti-inflammatory drugs. Methods The COX-2 selective inhibitor rofecoxib was used as the lead compound to synthesize its ring-opening derivatives. The anti-inflammatory activity of xanthine-induced mouse ear swelling model and carrageenan-induced rat paw swelling model were evaluated , And investigated the effect of continuous oral administration on the gastrointestinal tract of rats. Results Seventeen target compounds (I1 - 17) were synthesized. I1 - 15 was not reported in the literature. Its structure was confirmed by IR, 1 HNMR, MS and elemental analysis. I1, 3,7,9,1 0,1 3,1 5,1 6 showed significant anti-inflammatory activity on mice ear swelling model, I1, 1 3,1 5 induced paw edema on rat carrageenan The model showed strong anti-inflammatory activity. The anti-inflammatory activity of I1 5 was comparable to that of diclofenac 3 h after inflammation (P> 0.05), and I1 3,1 5 was comparable to rofecoxib (P> 5). The gastrointestinal side effects of the above active compounds are less than diclofenac, but slightly greater than rofecoxib. Conclusion I1 3,1 5 worth in-depth study