2-(Morpholin-4-ylmethyl)prop-2-enoyl chloride | 492456-78-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 2-(Morpholin-4-ylmethyl)prop-2-enoyl chloride
• CAS: 492456-78-7
• 化学式: C₈H₁₂ClNO₂
• 分子量: 189.642
• InChiKey: HDDPCGPZDUQICV-UHFFFAOYSA-N

物化性质

• 沸点：
  281.1±30.0 °C(Predicted)
• 密度：
  1.166±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(Morpholin-4-ylmethyl)prop-2-enoyl chloride 、 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-quinoline-3-carbonitrile 在 N-甲基吡咯烷酮 作用下， 反应 1.0h， 生成 N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolinyl}-2-morpholin-4-ylmethyl-2-propenamide
  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
• 作为产物：
  描述：

  2-(morpholin-4-yl)methylacrylic acid hydrochloride 在 草酰氯 作用下， 以 乙腈 为溶剂， 反应 0.25h， 生成 2-(Morpholin-4-ylmethyl)prop-2-enoyl chloride
  参考文献：
  名称：

  优化6,7-二取代的-4-（芳基氨基）喹啉-3-甲腈作为人类表皮生长因子受体2激酶活性的口服活性，不可逆抑制剂的作用。

  摘要：

  一系列新的6,7-二取代的4-（芳基氨基）喹啉-3-甲腈衍生物可作为人类表皮生长因子受体2（HER-2）和表皮生长因子受体（EGFR）激酶的不可逆抑制剂发挥作用。准备好了。与我们的EGFR激酶抑制剂86（EKB-569）相比，这些化合物表现出增强的抑制HER-2激酶和HER-2阳性细胞生长的活性。使用三种合成途径来制备这些化合物。它们的制备主要是通过6-氨基-4-（芳基氨基）喹啉-3-腈与不饱和酰氯的酰化作用或通过4-氯-6-（巴豆酰胺基）喹啉-3-腈与单环或双环苯胺的胺化而制备的。开发了第三条路线来制备关键中间体，即6-乙酰氨基-4-氯喹啉-3-腈，该中间体涉及更安全的环化步骤。我们显示，在4-（芳基氨基）环的对位上附加一个大的亲脂基团会导致抑制HER-2激酶的效力提高。我们还显示了在迈克尔受体末端的碱性二烷基氨基对于活性的重要性，这归因于迈克尔加成的分子内催化作用。这与改善的水溶性一起

  DOI：

  10.1021/jm040159c

文献信息

• [EN] PROTEIN TYROSINE KINASE MODULATORS AND METHODS OF USE<br/>[FR] MODULATEURS DE LA PROTÉINE TYROSINE KINASE ET MÉTHODES D'UTILISATION
  申请人：BETTA PHARMACEUTICALS CO LTD

  公开号：WO2015003658A1

  公开（公告）日：2015-01-15

  Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and/or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative,and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.

  揭示了调节突变选择性表皮生长因子受体（EGFR）和ALK激酶活性的杂环嘧啶化合物。更具体地，该发明提供了抑制、调节和/或调节激酶受体的嘧啶类化合物，特别是在选择性调节各种EGFR突变活性和ALK激酶活性方面已经被揭示。揭示了包括嘧啶衍生物的药物组合物，以及用于治疗与蛋白激酶酶活性相关的疾病的方法，特别是包括非小细胞肺癌的EGFR或ALK激酶活性，其中包括给予嘧啶衍生物的治疗。
• PROTEIN TYROSINE KINASE MODULATORS AND METHODS OF USE
  申请人：BETTA PHARMACEUTICALS CO., LTD

  公开号：US20160145237A1

  公开（公告）日：2016-05-26

  Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and/or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative, and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.
• US9783524B2
  申请人：——

  公开号：US9783524B2

  公开（公告）日：2017-10-10