methyl 3-(3-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl)propanoate | 755029-50-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: methyl 3-(3-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl)propanoate
• 英文别名: Methyl 3-(9-chloro-6-oxo-5,11-dihydrobenzo[b][1,4]benzodiazepin-3-yl)propanoate
• CAS: 755029-50-6
• 化学式: C₁₇H₁₅ClN₂O₃
• 分子量: 330.771
• InChiKey: CWVHRWIKSOEYRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-(3-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl)propanoate 在 palladium diacetate lithium hydroxide 、 cesium fluoride 作用下， 以 甲醇 、 乙二醇二甲醚 为溶剂， 反应 12.0h， 生成 3-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]propanoic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[b,e][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors

  摘要：

  A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.

  DOI：

  10.1021/jm070105d
• 作为产物：
  描述：

  4-氯-2-碘苯甲酸甲酯 在 palladium diacetate 、 platinum on activated charcoal 1,1'-双(二苯基膦)二茂铁 、 氢气 、 caesium carbonate 、 对甲苯磺酸 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 64.0h， 生成 methyl 3-(3-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl)propanoate
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[b,e][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors

  摘要：

  A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.

  DOI：

  10.1021/jm070105d

文献信息

• Heterocyclic kinase inhibitors
  申请人：——

  公开号：US20040254159A1

  公开（公告）日：2004-12-16

  Compounds having the formula 1 are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

  具有1式的化合物对于抑制蛋白激酶非常有用。还揭示了制备该化合物的方法，含有该化合物的组合物，以及使用该化合物进行治疗的方法。
• Heterocyclic Kinase Inhibitors
  申请人：Hasvold A. Lisa

  公开号：US20070254867A1

  公开（公告）日：2007-11-01

  Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

  具有公式的化合物对于抑制蛋白激酶很有用。还公开了制备这些化合物的方法、含有这些化合物的组合物和使用这些化合物的治疗方法。
• 5,10-DIHYDRO-11H-DIBENZO[B,E][1,4]DIAZEPIN-11-ONE AS KINASE INHIBITORS
  申请人：AbbVie Inc.

  公开号：EP1606268B1

  公开（公告）日：2015-05-20
• US7456169B2
  申请人：——

  公开号：US7456169B2

  公开（公告）日：2008-11-25
• Design, Synthesis, and Biological Activity of 5,10-Dihydro-dibenzo[<i>b</i>,<i>e</i>][1,4]diazepin-11-one-Based Potent and Selective Chk-1 Inhibitors
  作者：Le Wang、Gerard M. Sullivan、Laura A. Hexamer、Lisa A. Hasvold、Reema Thalji、Magdalena Przytulinska、Zhi-Fu Tao、Gaoquan Li、Zehan Chen、Zhan Xiao、Wen-Zhen Gu、John Xue、Mai-Ha Bui、Philip Merta、Peter Kovar、Jennifer J. Bouska、Haiying Zhang、Chang Park、Kent D. Stewart、Hing L. Sham、Thomas J. Sowin、Saul H. Rosenberg、Nan-Horng Lin

  DOI：10.1021/jm070105d

  日期：2007.8.1

  A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.