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

doi:10.6023/cjoc201611005

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

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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

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 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 Guige^a,b, Jiang Chengshi^a,c, Liu Hongchun^a, Tong Linjiang^a, Peng Xia^a, Ji Yinchun^a, Geng Meiyu^a, Xiao Wei^d, Gong Jingxu^a, Guo Yuewei^a

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 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).

1. Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors.PDF(3687KB)

Abstract

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

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Hou Guige, Jiang Chengshi, Liu Hongchun, Tong Linjiang, Peng Xia, Ji Yinchun, Geng Meiyu, Xiao Wei, Gong Jingxu, Guo Yuewei. Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors[J]. Chin. J. Org. Chem., 2017, 37(6): 1463-1472.

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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

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

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