Chin. J. Org. Chem. ›› 2017, Vol. 37 ›› Issue (6): 1463-1472.DOI: 10.6023/cjoc201611005 Previous Articles     Next Articles

Articles

新颖3,4-二氢-苯并[b]氧杂(艹卓)-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

侯桂革a,b, 江成世a,c, 刘红椿a, 童林江a, 彭霞a, 季寅淳a, 耿美玉a, 肖伟d, 龚景旭a, 郭跃伟a   

  1. a. 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;
    b. 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;
    c. 济南大学生物科学与技术学院 济南 250022;
    d. 江苏康源药业股份有限公司 连云港 222001
  • 收稿日期:2016-11-02 修回日期:2017-01-09 出版日期:2017-06-25 发布日期:2017-02-15
  • 通讯作者: 龚景旭,肖伟 E-mail:jxgong@mail.shcnc.ac.cn;wzhzh-nj@163.net
  • 基金资助:

    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.

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

Hou Guigea,b, Jiang Chengshia,c, Liu Hongchuna, Tong Linjianga, Peng Xiaa, Ji Yinchuna, Geng Meiyua, Xiao Weid, Gong Jingxua, Guo Yueweia   

  1. a. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203;
    b. Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai 264003;
    c. School of Biological Science and Technology, Jinan University, Jinan 250022;
    d. Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang 222001
  • Received:2016-11-02 Revised:2017-01-09 Online:2017-06-25 Published:2017-02-15
  • Contact: 10.6023/cjoc201611005 E-mail:jxgong@mail.shcnc.ac.cn;wzhzh-nj@163.net
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 81520108028, 81273430, 21402010, 21672230, 41506187, 81302692, 41476063, 4167060562, 8160131016), and the National Natural Science Foundation of China-Shandong Joint Fund for Marine Science Research Centers (No. U1406402), the Shanghai Science and Technology Committee Project (Nos. 14431901100, 15431901000), the State Key Laboratory of Drug Research/Shanghai Institute of Materia Medica Projects (No. SIMM1501ZZ-03), the Institutes for Drug Discovery and Development, Chinese Academy of Sciences (No. CASIMM0120152039).

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. ErbB1, ErbB2, 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 IC50 value for 8n against RET is 0.7 μmol/L, while the IC50 value for 7-[(3,4-dihydroxyphenyl)methyl]amino-2,3,4,5-tetrahydro-benzo[b]oxazepin-5-ol (10b) against ErbB2 is 1.02 μmol/L.

Key words: 3,4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives, synthesis, protein-tyrosine kinases inhibitors, ErbB1, ErbB2