6-羟基脱氧Canagliflozin的合成及其生物活性  

Synthesis and Biological Activities of 6-Deoxylated Canagliflozin

作　　者：韩书文[1,2] 徐华强[2,3] 王玉丽[2] 张玲钰[2,3] 史永恒[2] 刘冰妮[2] 魏群超[2] 徐为人[1,2] 赵桂龙[2] 

机构地区：[1]天津中医药大学研究生院,天津300193 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300193 [3]山东大学化学与化工学院,山东济南250100

出　　处：《合成化学》2014年第1期1-5,共5页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(21302141);天津市科技支撑计划重点项目(10ZCKFSH01300)

摘　　要：以Canagliflozin(1)为起始原料,经7步反应合成了其6-OH脱氧产物4-(6-脱氧-β-D-吡喃葡萄糖基)-2-[5-(4-氟苯基)噻吩-2-甲基]-1-甲基苯(8),8是与母体1相似的新型SGLT2抑制剂,总收率21%,其结构经1H NMR,13C NMR和MS表征。体外生物活性测试结果显示,1和8对hSGLT2的IC50分别为3.9 nM和4.8nM,对SGLT1的选择性(SGLT2/SGLT1)分别为178和194。在大鼠尿糖排泄实验(UGE)中8具有很强的尿糖排泄作用,与母体1并无显著性差异。6-Deoxylated Canagliflozin,4-（ 6-deoxy-β-D-glucopyranosyl）-2-[5-（ 4-fluorophenyl） thiophen-2-yl]-1-toluene（ 8）,a novel SGLT2 inhibitor,was synthesized by a seven-step reaction from Canagliflozin（ 1） in overall yield of 21%. The structure was characterized by1H NMR,13C NMR and MS. In vitro assays showed that the properties of 1 and 8 were as follows： IC 50（ hSGLT2） were 3. 9 nM and 4. 8 nM,selectivity（ SGLT2 / SGLT1） were 178 and 194,respectively. In vivo primary biological assays exhibited that 8 could induce a considerable amount of urinary glucose in rat urinary glucose excretion test,however it was not statistically different from 1.

关 键 词：SGLT2抑制剂 Canagliflozin 脱氧 合成 抑制活性 尿糖排泄实验(UGE) 

分 类 号：O629.11[理学—有机化学] O626.1[理学—化学]