8-chloro-4-[(dimethylamino)methylene]-1-(2,6-difluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one | 869366-10-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 8-chloro-4-[(dimethylamino)methylene]-1-(2,6-difluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one
• 英文别名: 8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one；8-chloro-1-(2,6-difluorophenyl)-4-(dimethylaminomethylidene)-3H-2-benzazepin-5-one
• CAS: 869366-10-9
• 化学式: C₁₉H₁₅ClF₂N₂O
• 分子量: 360.791
• InChiKey: ADRUNBZCGFRJEL-UHFFFAOYSA-N

物化性质

• 沸点：
  467.9±45.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  32.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-chloro-4-[(dimethylamino)methylene]-1-(2,6-difluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one 在 potassium carbonate sesquihydrate 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 17.0h， 生成 sodium 4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoate
  参考文献：
  名称：

  MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

  摘要：

  The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.

  DOI：

  10.1021/ml500409n
• 作为产物：
  描述：

  (5-氯-2-碘苯基) 2,6-二氟苯甲烷 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 水 、 碳酸氢钠 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 26.0h， 生成 8-chloro-4-[(dimethylamino)methylene]-1-(2,6-difluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one
  参考文献：
  名称：

  MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

  摘要：

  The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.

  DOI：

  10.1021/ml500409n

文献信息

• Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor
  作者：Yuexian Li、Shimoga R. Prakash

  DOI：10.1002/jlcr.1607

  日期：2009.7

  Sodium ring-[14C]-4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [14C]-cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [14C]-4-guanidinobenzoic acid, was prepared by coupling [14C]-cyanamide with 4-aminobenzoic acid. Sodium carboxyl-[14C]-4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoate (1B) was synthesized from carboxyl-[14C]-4-guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D4,15N]-4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (1C) was synthesized from [15N2]-cyanamide and [D4]-4-aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β-acyl glucuronide of 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (14), was synthesized from D-glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.

  环-[14C]-4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂卓-2-基]氨基]-苯甲酸钠（1A，MLN8054）是一种极光 A 激酶抑制剂，由[14C]-氰酰胺分两步合成，总放射化学收率为 7%。中间体[14C]-4-胍基苯甲酸是通过将[14C]-氰酰胺与 4-氨基苯甲酸偶联制备的。羧基-[14C]-4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂卓-2-基]氨基]-苯甲酸钠（1B）由羧基-[14C]-4-胍基苯甲酸一步合成，放射化学收率为 35%。[D4,15N]-4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂卓-2-基]氨基]-苯甲酸（1C）由[15N2]-氰酰胺和[D4]-4-氨基苯甲酸分两步合成，总产率为 37%。主要代谢物 4-[[9-氯-7-（2,6-二氟苯基）-5H-嘧啶并[5,4-d][2]苯并氮杂卓-2-基]氨基]-苯甲酸的 β-酰基葡萄糖醛酸（14）由 D-葡萄糖醛酸经三个步骤合成，总产率为 1%。合成葡萄糖醛酸的关键中间体是由 4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂卓-2-基]氨基]-苯甲酸与葡萄糖醛酸烯丙基酯在 HATU 催化下偶联制备的。Copyright © 2009 John Wiley & Sons, Ltd. 版权所有。
• Compounds and methods for inhibiting mitotic progression
  申请人：Claiborne F. Christopher

  公开号：US20050256102A1

  公开（公告）日：2005-11-17

  This invention relates to compounds and methods for the treatment of cancer. In particular, the invention provides compounds that inhibit Aurora kinase, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer.

  本发明涉及化合物和治疗癌症的方法。具体而言，本发明提供了抑制极化丝激酶的化合物、包含该化合物的制药组合物以及使用该化合物治疗癌症的方法。
• COMPOUNDS AND METHODS FOR INHIBITING MITOTIC PROGRESSION
  申请人：Claiborne Christopher F.

  公开号：US20090299060A1

  公开（公告）日：2009-12-03

  This invention relates to compounds and methods for the treatment of cancer. In particular, the invention provides compounds that inhibit Aurora kinase, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer.

  本发明涉及化合物和治疗癌症的方法。具体来说，本发明提供抑制极化激酶的化合物，包含该化合物的制药组合物以及使用该化合物治疗癌症的方法。