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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。
Starting from Canagliflozin (1), its 6-OH deoxygenation product 4- (6-deoxy-β-D-glucopyranosyl) -2- [5- ) Thiophene-2-methyl] -1-methylbenzene (8), 8 is a novel SGLT2 inhibitor similar to parent 1 with a total yield of 21%. Its structure was characterized by 1H NMR, 13C NMR and MS. In vitro bioassay results showed that IC50 of 1 and 8 for hSGLT2 were 3.9 nM and 4.8 nM, respectively, and the selectivity for SGLT1 (SGLT2 / SGLT1) was 178 and 194, respectively. Urinary glucose excretion in rats (UGE) 8 has a strong urinary excretion, and no significant difference with the mother 1.