目的 自拟合成路线对马尼地平对映异构体进行手性拆分,并对比其盐酸盐的降压效果。方法 采用化学成盐析晶法,利用马尼地平对映异构体与不同的手性拆分剂[D-(+)-二对甲基苯甲酰酒石酸及L-(-)-二对甲基苯甲酰酒石酸]所生成的盐在特定的溶剂中溶解性的差异实现手性拆分,分别得到S型和R型马尼地平;通过植入式生理信号遥感测压监测系统(DSI)监测已给药盐酸马尼地平、S-盐酸马尼地平、R-盐酸马尼地平前后的自发性高血压大鼠(SHR)的收缩压、舒张压、平均动脉压等数值变化情况。结果 自拟合成路线的拆分工艺简单、可操作性强,得到的S型和R型对映异构体的ee值和纯度都较高;在SHR模型中,S-盐酸马尼地平组与盐酸马尼地平组降压效果相当;R-盐酸马尼地平无降压作用。结论 马尼地平对映异构体的手性拆分研究具有一定的科学价值,对提高药效和用药安全、开发马尼地平单一对映体新药都具有重要意义。
Abstract
OBJECTIVE To investigate the chiral separation of the manidipine enantiomers by the proposed synthetic route, and the blood pressure effect of the hydrochlorides. METHODS Based on the solubility differences of the salts which are the reaction products of the manidipine enantiomers and the different chiral resolution agents[(+)-Di-p-toluoyl-D-tartaric acid/(-)-Di-p-toluoyl-L-tartaric acid] in the specific solvents, the S and R manidipine enantiomers were obtained respectively, which is called the chemical salting out crystal method. The changes of systolic pressure, diastolic pressure, and mean arterial pressure of spontaneously hypertensive rats(SHR) before and after manidipine hydrochloride medications administration were monitored through implantable physiological signal remote sensing pressure monitoring system (data science international, DSI). RESULTS The chiral separation process is simple, maneuverability is strong and the ee values and purity of the S and R enantiomorphism isomers are both higher in the synthetic route; in the SHR model, the antihypertensive effect was equivalent between manidipine hydrochloride group and S-manidipine hydrochloride group; R-manidipine hydrochloride did not have the antihypertensive effect. CONCLUSION The chiral resolution of manidipine enantiomers has certain scientific value, which can improve the efficacy and safety of drug, and which is of great significance to develop manidipine single enantiomeric new drugs.
关键词
马尼地平 /
手性拆分 /
自发性高血压大鼠 /
S-盐酸马尼地平 /
R-盐酸马尼地平 /
降压作用
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Key words
manidipine /
chiral separation /
spontaneously hypertensive rats
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中图分类号：
R965.1
R972.4
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参考文献
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脚注
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基金
北京市科技计划项目资助(Z151100003915066)
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