SGLT2抑制剂偕二甲基化Canagliflozin的设计、合成与活性研究  

Design,Synthesis and Biological Activity of gem-Dimethylated Canagliflozin as Sodium-glucose Co-transporter 2(SGLT2) Inhibitor

作　　者：尹玲[1] 王玉丽[2] 魏群超[2] 王影影[1] 赵桂龙[2] 

机构地区：[1]济宁学院化学与化工系,曲阜273155 [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

出　　处：《化学通报》2013年第8期730-734,共5页Chemistry

基　　金：天津市科技支撑计划重点项目(10ZCKFSH01300);济宁学院“国家级基金计划预研项目”(2012YYJJ07)资助

摘　　要：由1-(5-溴-2-甲基苯基)-1-甲基乙醇(1)通过6步反应,制得了钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂偕二甲基化canagliflozin,总产率38.1%,其中关键的一步是叔醇和噻吩发生的傅-克烷基化反应。利用1H NMR、13C NMR和HR-MS表征了最终产物的结构。最终产物利用大鼠尿糖排泄试验(UGE)进行了活性评价,结果显示合成的化合物具有一定的尿糖诱导能力,但不如母体化合物canagliflozin活性高。Abstract The titled compound, gem-dimethylated canagliflozin, was designed as sodium-glucose co-transporter 2 （SGLT2） inhibitor. It was synthesized by 1-（ 2-methyl-5-bromophenyl）-l-methylethanol as starting material through 6 steps, in which anhydrous aluminum chloride-catalyzed Friedel-Crafts alkylation of the tertiary alcohol and thiophene to construct the gem-dimethyl-bearing aglycone as key step, in 38. 1% overall yield. The as-synthesized titled compound was fully characterized by 1H NMR, 13C NMR and HR-MS, and evaluated in vivo with urinary glucose excretion （UGE） test in rats. It was found that the synthesized compound can induce an appreciable amount of urinary glucose compared with the vehicle group, which is however much lower than that for positive control canagliflozin.

关 键 词：SGLT2抑制剂 偕二甲基 合成 傅-克烷基化反应 尿糖排泄试验 

分 类 号：TQ460.1[化学工程—制药化工]