单螺环哌嗪季铵盐类化合物的合成及镇痛活性研究  

Synthesis and Analgesic Activity of Mono-spirocyclopiperazinium Analogues

作　　者：刘文俊[1] 王欣[1] 李刚[1] 叶加[1] 程铁明[1] 李润涛[1] 

机构地区：[1]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

出　　处：《有机化学》2011年第12期2135-2139,共5页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.20772009)资助项目

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,^(13)C 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.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 previous works. The structures of target compounds were characterized by 1H NMR, 13C NMR spectra and elemental 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 pharmacophore and spirocycloammonium salt framework is favorable for the activity. Enlarging the spiro-ring or introducing substituted group is at a disadvantage.

关 键 词：单螺环哌嗪季铵盐 镇痛活性 合成 MANNICH反应 构效关系 

分 类 号：TQ460.1[化学工程—制药化工]