格列本脲衍生物的设计、合成与降血糖活性
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摘要
目的设计合成格列本脲衍生物并进行降血糖活性研究。方法以5-氯-2-甲氧基苯甲酸为原料,经甲基化、胺解、氯磺化、氮化、缩合反应得到格列本脲二氟衍生物。通过链脲佐菌素(streptozotocin,STZ)配合高脂饲料诱发大鼠Ⅱ型糖尿病模型,评价其降血糖作用。结果经过5步反应合成目标化合物格列本脲二氟衍生物,总收率为28.1%,目标化合物和中间体的结构经1H-NMR和MS确证。活性实验显示格列本脲二氟衍生物具有明显降糖作用。结论在格列本脲的环己烷对位上用2个氟原子取代有利于增加其降血糖活性。
Objective To research on design,synthesis and hypoglycemia activity of glibenclamide derivative. Methods The synthesis of 4',4'-difluoroglibenclamide derivative had been accomplished from 5-chloro-2-methoxybenzoic acid,through five steps in 28. 1% overall yield( based on 5-chloro-2-methoxybenzoic acid),including methylation,aminolysis,chlorosulfonation,nitrification and condensation reactions. Its hypolycemic effect w as observed in type 2 diabetic rat model induced by high lipid food plus STZ. Results The target structure w as identified by ESI-M S and1H-NM R,and the result of hypoglycemic effect show ed that the difluoroglibenclamide had pow erful hypoglycemic activity. Conclusions It's a good strategy to increase hypoglycemic activity by introducing tw o fluorine atoms into glibenclamide.
Objective To research on design,synthesis and hypoglycemia activity of glibenclamide derivative. Methods The synthesis of 4',4'-difluoroglibenclamide derivative had been accomplished from 5-chloro-2-methoxybenzoic acid,through five steps in 28. 1% overall yield( based on 5-chloro-2-methoxybenzoic acid),including methylation,aminolysis,chlorosulfonation,nitrification and condensation reactions. Its hypolycemic effect w as observed in type 2 diabetic rat model induced by high lipid food plus STZ. Results The target structure w as identified by ESI-M S and1H-NM R,and the result of hypoglycemic effect show ed that the difluoroglibenclamide had pow erful hypoglycemic activity. Conclusions It's a good strategy to increase hypoglycemic activity by introducing tw o fluorine atoms into glibenclamide.
引文
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[5]HEPTNER W,KELLNER,H M,CHRIST O,et al.Metabolism of HB 419[N-4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenylsulfonyl-N'-cyclohexylurea]in the animal[J].Arzneimittel-Forschung,1969,19(8):1400-1404.
[6]RUPP W,CHRIST O,HEPTNER W.Reabsorption,excretion,and metabolism of carbon-14-labeled HB 419[N-4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenylsulfonyl-N'-cyclohexylurea]after intravenous and oral application to humans[J].Arzneimittel-Forschung,1969,19(8):1428-1434.
[2]占建,邓小鹏,夏文.2型糖尿病药物治疗进展[J].中国民康医学,2014,26(15):72-74.
[3]蒋居辰.格列本脲致低血糖昏迷27例临床分析[J].临床合理用药,2015,8(2):109-110.
[4]XU Y,WANG L,HE J,et al.Prevalence and control of diabetes in Chinese adults[J].JAMA,2013,310(9):948-958.
[5]HEPTNER W,KELLNER,H M,CHRIST O,et al.Metabolism of HB 419[N-4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenylsulfonyl-N'-cyclohexylurea]in the animal[J].Arzneimittel-Forschung,1969,19(8):1400-1404.
[6]RUPP W,CHRIST O,HEPTNER W.Reabsorption,excretion,and metabolism of carbon-14-labeled HB 419[N-4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenylsulfonyl-N'-cyclohexylurea]after intravenous and oral application to humans[J].Arzneimittel-Forschung,1969,19(8):1428-1434.