新颖3,4-二氢-苯并[b]氧杂棘-5(2H)-酮类化合物的合成以及蛋白酪氨酸激酶抑制活性研究  

Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors

作　　者：侯桂革[1,2] 江成世[1,3] 刘红椿[1] 童林江[1] 彭霞[1] 季寅淳 耿美玉[1] 肖伟 龚景旭[1] 郭跃伟[1] 

机构地区：[1]中国科学院上海药物研究所新药研究国家重点实验室,上海201203 [2]滨州医学院"方剂效应与临床评价"国家中医药管理局重点实验室,烟台264003 [3]济南大学生物科学与技术学院,济南250022 [4]江苏康源药业股份有限公司,连云港222001

出　　处：《有机化学》2017年第6期1463-1472,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(Nos.81520108028;81273430;21402010;21672230;41506187;81302692;41476063;4167060562;8160131016);国家自然科学基金委员会-山东省人民政府联合资助海洋科学研究中心项目(No.U1406402);上海市科委基金(Nos.14431901100;15431901000);新药研究国家重点实验室项目(No.SIMM1501ZZ-03);中国科学院药物创新研究院自主部署科研(No.CASIMM0120152039)资助项目~~

摘　　要：通过合成得到了一系列新颖的苯并[b]氧杂棘-5(2H)-酮类化合物单晶,结构经~1HNMR,^(13)CNMR和HREIMS确证,E-7-[(2,5-二羟基苯基)甲亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5(2H)-酮(8k)和E-7-[(2,3,4-三羟基苯基)亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5-(2H)-酮(8n)的结构经单晶X衍射方法进一步确证.系统测试了化合物对蛋白酪氨酸激酶(PTKs),如ErbB1,ErbB2,c-Met,ALK,FGFR1,RET和KDR等的抑制活性,结果表明含有邻苯二酚片段的化合物对蛋白酪氨酸激酶具有显著的抑制活性,其中E-7-[(3,4-二羟基苯基)甲亚基]氨基-3,4-二氢-苯并[b]氧杂棘-5(2H)-酮(8i)对ErbB1和ErbB2的IC50分别为1.0和0.33μmol/L,8n对RET的IC_(50)为0.7μmol/L,7-[(3,4-二羟基苯基)甲基]氨基-2,3,4,5-四氢-苯并[b]氧杂棘-5-醇(10b)对ErbB2的IC_(50)为1.02μmol/L.A series of novel 3,4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives were designed and synthesized as potent protein-tyrosine kinases(PTKs, e.g. Erb B1, Erb B2, c-Met, ALK, FGFR1, RET, KDR) inhibitors. All compounds were characterized by NMR and MS. E-7-[(2,5-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one(8k) and E-7-[(2,3,4-trihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one(8n) were further characterized by X-ray single-crystal analysis. The synthesized compounds were further tested for their inhibitory activity on PTKs. The results display compounds with catechol-substitution display the most potent inhibitory activities toward PTKs. The IC50 values for E-7-[(3,4-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one(8i) against ErbB1, ErbB2 are 1.0 and 0.33 μmol/L, respectively. The IC_(50) value for 8n against RET is 0.7 μmol/L, while the IC_(50) value for7-[(3,4-dihydroxyphenyl)methyl]amino-2,3,4,5-tetrahydro-benzo[b]oxazepin-5-ol(10b) against ErbB2 is 1.02 μmol/L.

关 键 词：3 4-二氢-苯并[b]氧杂棘-5(2H)-酮 合成 蛋白酪氨酸激酶抑制剂 ErbB1 ERBB2 

分 类 号：TQ460.1[化学工程—制药化工]