4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline | 848942-78-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline
• 英文别名: 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-N,N-dimethylacetamide
• CAS: 848942-78-9
• 化学式: C₂₄H₂₇ClFN₅O₃
• 分子量: 487.961
• InChiKey: HJDSISDQNHYQBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  79.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  tert-butyl 4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate 在 potassium carbonate 、 三氟乙酸 、 potassium iodide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 3.0h， 生成 4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline
  参考文献：
  名称：

  Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

  摘要：

  Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

  DOI：

  10.1021/ml400146c

文献信息

• [EN] QUINAZOLINE DERIVATIVES<br/>[FR] DERIVES DE QUINAZOLINE
  申请人：ASTRAZENECA AB

  公开号：WO2005028469A1

  公开（公告）日：2005-03-31

  The invention concerns quinazoline derivatives of Formula (I): wherein each of R1, X1, R2, R3, R5, n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

  这项发明涉及式(I)的喹唑啉衍生物：其中R1、X1、R2、R3、R5、n和m中的每一个具有描述中定义的任意含义；它们的制备方法，含有它们的药物组合物以及它们在制造用作抗增殖剂的药物时的用途，用于预防或治疗对EGF和erbB受体酪氨酸激酶抑制敏感的肿瘤。
• Quinazoline Derivatives
  申请人：Hennequin Laurent Francois Andre

  公开号：US20080096881A1

  公开（公告）日：2008-04-24

  The invention concerns quinazoline derivatives of Formula (I): wherein each of R 1 , X 1 , R 2 , R 3 , R 5 , n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

  本发明涉及式（I）的喹唑啉衍生物：其中R1，X1，R2，R3，R5，n和m中的每一个具有在说明书中定义的任何含义；制备它们的过程，包含它们的制药组合物以及它们在制造用作抗增殖剂的药物中的使用，以预防或治疗对EGF和erbB受体酪氨酸激酶抑制敏感的肿瘤。
• QUINAZOLINE DERIVATIVES
  申请人：Hennequin Laurent Francois Andre

  公开号：US20120329795A1

  公开（公告）日：2012-12-27

  The invention concerns quinazoline derivatives of Formula I: wherein each of R 1 , X 1 , R 2 , R 3 , R 5 , n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

  本发明涉及公式I的喹唑啉衍生物：其中R1、X1、R2、R3、R5、n和m中的每一个都具有在说明书中定义的任何含义；它们的制备过程、含有它们的制药组合物以及它们用于制造抗增殖剂的药物，用于预防或治疗对EGF和erbB受体酪氨酸激酶抑制敏感的肿瘤。
• US8318752B2
  申请人：——

  公开号：US8318752B2

  公开（公告）日：2012-11-27
• Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
  作者：Bernard Barlaam、Judith Anderton、Peter Ballard、Robert H. Bradbury、Laurent F. A. Hennequin、D. Mark Hickinson、Jason G. Kettle、George Kirk、Teresa Klinowska、Christine Lambert-van der Brempt、Cath Trigwell、John Vincent、Donald Ogilvie

  DOI：10.1021/ml400146c

  日期：2013.8.8

  Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.