3-(4-甲磺酰氨基/乙酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物的设计、合成及α-糖苷酶抑制活性  

Design,synthesis and α-glucosidase inhibitory activity of 3-(4-methylsulfonylamido/acetylamido)benzoyl-2H-1-benzopyran-2-one derivatives

作　　者：王绍杰[1] 晏菊芳 杨卓[1] 王晓艳[1] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]成都地奥制药集团有限公司药物筛选中心,四川成都610041

出　　处：《中国药物化学杂志》2010年第6期490-495,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的在研究非糖类α-糖苷酶抑制剂的过程中,发现3-(4-苯磺酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物具有显著的α-糖苷酶抑制活性。为进一步探讨该类化合物的构效关系,将4-位的苯磺酰氨基替换为甲磺酰氨基和乙酰氨基,合成3-(4-甲磺酰胺基/乙酰基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物,并评价其α-糖苷酶抑制活性。方法以4-硝基苯甲酸为原料,经氯代、酰化、水解、还原反应制得4-氨基-β-氧代苯丙酸乙酯,与甲磺酰氯/乙酰氯经酰化反应得4-甲磺酰氨基/乙酰氨基-β-氧代苯丙酸乙酯,再与取代水杨醛经Knoev-ernagel缩合,同时环合得到目标化合物。采用酵母α-葡萄糖苷酶对所合成的目标化合物进行α-糖苷酶抑制活性评价。结果合成了22个目标化合物,结构经1H-NMR和IR确证。大部分3-(4-甲磺酰氨基/乙酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物未表现出α-糖苷酶抑制活性,只有化合物3-(4-甲磺酰氨基)苯甲酰基-6,8-二叔丁基-2H-1-苯并吡喃-2-酮(10f)表现出良好的α-糖苷酶抑制活性,IC50值为10.16μmol.L-1。结论对于3-苯甲酰基-2H-1-苯并吡喃-2-酮类化合物,其苯甲酰基以4-位甲磺酰氨基/乙酰氨基取代对该类化合物的α-糖苷酶抑制活性不利,该类化合物的构效关系值得进一步研究。Aim In the course of study on the non-sugar α-glucosidase inhibitors,3-（4-phenylsulfonylamido）benzoyl-2H-1-benzopyran-2-one derivatives were found to be good α-glucosidase inhibitors.In order to investigate the structure-activity relationship of this type of compounds,4-phenylsulfonylamido group was replaced with 4-methylsulfonylamido and 4-acetylamido,respectively.3-（4-Methylsulfonylamido/acetylamido） benzoyl-2H-1-benzopyran-2-one derivatives were designed and synthesized,and their α-glucosidase inhibitory activity was assayed.Methods Treatment of 4-nitrobenzoic acid with thionyl chloride gave 4-nitrobenzoyl chloride,which was reacted with ethyl acetoacetate and followed by hydrolysis to afford ethyl 3-（4-nitrophenyl）-3-oxopropanoate.Then it was hydrogenated over Pd/C catalyst and acylated with methylsulfonyl chloride and acetyl chloride to give two key intermediates ethyl 3-（4-（methylsulfonylamido）phenyl）-3-oxopropanoate and ethyl 3-（4-acetylamido）phenyl）-3-oxopropanoate,respectively.Lastly the target compounds were obtained by the reaction of either key intermediate with the corresponding substituted salicylic aldehyde via Knoevernagel condensation and cyclization.The α-glucosidase inhibitory activity of the target compounds was evaluated on yeast α-glucosidase.Results 22 Target compounds were obtained and their structures were confirmed by 1H-NMR and IR.Most 3-（4-methylsulfonylamido/ acetylamido）benzoyl-2H-1-benzopyran-2-one derivatives did not show α-glucosidase inhibitory activity,only compound 3-（4-methylsulfonylamido）benzoyl-6,8-di-tert-butyl-2H-1-benzopyran-2-one（10f） showed good α-glucosidase inhibitory activity with an IC50 value of 10.16 μmol·L-1.Conclusion In 3-benzoyl-2H-1-benzopyran-2-one derivatives,methylsulfonylamido/acetylamido group at the position 4 of benzoyl moiety was unfavorable for α-glucosidase inhibitory,and the structure-activity relationship of 3-（4-amino）benzoyl-2H-1-benzopyran-2-one derivatives should be investigated further.

关 键 词：化学合成 Α-糖苷酶抑制剂 3-苯甲酰基-2H-1-苯并吡喃-2-酮类化合物 

分 类 号：R914[医药卫生—药物化学]