N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide | 492456-86-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide
• 英文别名: (E)-But-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-amide；(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]but-2-enamide
• CAS: 492456-86-7
• 化学式: C₂₂H₁₈ClFN₄O₂
• 分子量: 424.862
• InChiKey: WPNUYJGYQVXMPI-HWKANZROSA-N

物化性质

• 沸点：
  628.1±55.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  间氨基苯乙醚 在 N-甲基吗啉 、 diphenyl ether-biphenyl eutectic 、 亚硝酸铵 、 铁粉 、 氯化铵 、 三氟乙酸酐 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 异丙醇 、 甲苯 为溶剂， 反应 28.25h， 生成 N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

  摘要：

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm020241c

文献信息

• 3-cyanoquinolines as inhibitors of EGF-R and HER2 kinases
  申请人：American Cyanamid Company

  公开号：US20030149056A1

  公开（公告）日：2003-08-07

  This invention provides compounds of Formula (I), represented by the structure 1 wherein G 1 , G 2 , G 3 , G 4 , Z, X and n are defined herein, or a pharmaceutically acceptable salt thereof which are useful as antineoplastic agents and in the treatment of polycystic kidney disease.

  本发明提供了公式（I）的化合物，其结构如下： 其中G1，G2，G3，G4，Z，X和n的定义如下，或其药学上可接受的盐，可用作抗肿瘤剂和多囊肾病的治疗剂。
• 3-CYANOQUINOLINES AS INHIBITORS OF EGF-R AND HER2 KINASES
  申请人：Wyeth Holdings Corporation

  公开号：EP1448531A1

  公开（公告）日：2004-08-25
• US6821988B2
  申请人：——

  公开号：US6821988B2

  公开（公告）日：2004-11-23
• [EN] 3-CYANOQUINOLINES AS INHIBITORS OF EGF-R AND HER2 KINASES<br/>[FR] 3-CYANOQUINOLINES EN TANT QU'INHIBITEURS DE KINASES EGF-R ET HER2
  申请人：WYETH CORP

  公开号：WO2003050090A1

  公开（公告）日：2003-06-19

  This invention provides compounds of Formula (I), represented by the structure wherein G1, G2, G3, G4, Z, X and n are defined herein, or a pharmaceutically acceptable salt thereof which are useful as antineoplastic agents and in the treatment of polycystic kidney disease.
• Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)
  作者：Allan Wissner、Elsebe Overbeek、Marvin F. Reich、M. Brawner Floyd、Bernard D. Johnson、Nellie Mamuya、Edward C. Rosfjord、Carolyn Discafani、Rachel Davis、Xiaoqing Shi、Sridhar K. Rabindran、Brian C. Gruber、Fei Ye、William A. Hallett、Ramaswamy Nilakantan、Ru Shen、Yu-Fen Wang、Lee M. Greenberger、Hwei-Ru Tsou

  DOI：10.1021/jm020241c

  日期：2003.1.1

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.