单螺环哌嗪季铵盐类化合物的合成及镇痛活性研究有机化学.pdfVIP

2011 年第 31 卷 有 机 化 学 Vol. 31, 2011 第 12 期, 2135～2139 Chinese Journal of Organic Chemistry No. 12, 2135～2139 ·研究简报· 单螺环哌嗪季铵盐类化合物的合成及镇痛活性研究 刘文俊 王 欣* 李 刚 叶 加 程铁明 李润涛* (北京大学药学院天然药物及仿生药物国家重点实验室 北京 100191) 摘要 为寻找镇痛活性更好的化合物, 以前期发现的螺环哌嗪季铵盐类化合物 1 为先导物, 设计合成了 8 个未见文献 报道的衍生物. 通过 1H NMR, 13C NMR 和元素分析或高分辨质谱确定了化合物的结构. 利用小鼠醋酸扭体模型初步评 价了它们的镇痛活性, 构效关系研究表明, 苯环上的羟基是关键的药效团, 与开链季铵盐相比, 螺环季铵盐结构对活 性更有利; 扩大螺环和引入取代基对活性不利. 关键词 单螺环哌嗪季铵盐; 镇痛活性; 合成; Mannich 反应; 构效关系 Synthesis and Analgesic Activity of Mono-spirocyclopiperazinium Analogues Liu, Wenjun Wang, Xin* Li, Gang Ye, Jia Cheng, Tieming Li, Runtao * (State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191) Abstract In order to find more potent analgesics, eight new mono-spirocyclopiperazinium analogues were designed and synthesized by selecting compound 1 as lead compound, which was obtained from our previ- 1 13 ous works. The structures of target compounds were characterized by H NMR, C NMR spectra and ele- mental analysis or HRMS. The synthesized compounds were evaluated for their in vivo analgesic activity by acetic acid induced writhing test. The results indicate that hydroxyl group on the aryl ring is the key phar- macophore and spirocycloammonium salt framework is favorable for the activity. Enlarging the spiro-ring or introducing substituted group is