摘要
目的设计合成芳甲酰烷基哌嗪类化合物。研究它们的抗脑缺氧缺血活性并评价此类化合物作为脑中风治疗剂的潜力。方法哌嗪经甲酰基或苄基保护后,与相应的卤代芳烃进行烷基化反应,制备47个芳甲酰烷基哌嗪类化合物;以化学品致小鼠缺氧模型、大鼠四动脉结扎全脑缺血再灌注模型及大鼠大脑中动脉结扎脑缺血模型,测试了目标化合物的抗脑缺氧、脑缺血活性;采用NMDA所致大鼠原代培养大脑皮层神经细胞损伤模型,研究化合物Ⅲ2对神经细胞损伤的保护作用。结果与结论共合成47个未见文献报道的新化合物,其结构经质谱、核磁共振谱确证。药理试验显示:47个化合物中,15个化合物具有显著的抗缺氧活性;8个化合物具有显著的抗全脑缺血活性;3个化合物显示较强的抗大鼠局灶性脑缺血作用;化合物Ⅲ2同时具有较强的抗脑缺氧缺血活性及神经细胞保护作用,具有作为新型抗脑卒中脑神经保护剂深入开发的价值。
Aim To study the anti-cerebral anoxia and anti-cerebral ischemia biological activities of aroylpiperazine derivatives and to evaluate their potential to he neuroprotective candidates. Methods The one nitrogen atom of the piperazine ring is protected by forrnyl group or benzyl group firstly, then the unprotected nitrogen atom is alkylated to prepare 47 compounds of aroylpiperazlne derivatives. Their antl-cerebral anoxia and antl-cerebral ischemla biological activities were well studied by the mice model of anoxia induced by sodium nitrite, the rat model of global cerebral ischemia and the focal ischemia rat model by occlusion of cerebral artery（MCA）. Results and conclusions The tests indicate that 15 compounds have potent anti-cerebral anoxia activities, 8 compounds have strong anti-global cerebral ischemia effects, 3 compounds have strong antl-focal cerebral ischemia effects and compound Ⅲ2 has outstanding activities on these three aspects. Compound Ⅲ2 is more worthy of further research as a neuroprotectlve agent, especially in the treatment of ischemic cerebral apoplexy.
出处
《中国药物化学杂志》
CAS
CSCD
2006年第1期6-14,共9页
Chinese Journal of Medicinal Chemistry
基金
国家高技术研究发展计划(863计划)重大专项(2002AA2Z3124)
上海市科学技术委员会重点科技攻关项目(044319215)
关键词
药物化学
化合物制备
化学合成
芳甲酰烷基哌嗪类化合物
抗脑缺氧
抗脑缺血
medicinal chemistry
compound preparation
derivatives
anti-cerebral anoxia
anti-cerebral ischemia chemical synthesis
aralkyl formyl alkylpiperazine
