(S)-N-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide | 1402086-20-7

• 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: (S)-N-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide
• 英文别名: Afatinib impurity 11；N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]prop-2-enamide
• CAS: 1402086-20-7
• 化学式: C₂₁H₁₈ClFN₄O₃
• 分子量: 428.85
• InChiKey: MLHDLQIHGCIPJQ-ZDUSSCGKSA-N

物化性质

• 沸点：
  642.9±55.0 °C(Predicted)
• 密度：
  1.445±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  85.4
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

Afatinib impurity 11 是一种杂质，而 Afatinib 则是一种不可逆的 EGFR 家族抑制剂，能够有效抑制 EGFRwt、EGFRL858R 及 EGFRL858R/T790M 和 HER2，其 IC50 值分别为 0.5 nM、0.4 nM、10 nM 和 14 nM。

反应信息

• 作为产物：
  描述：

  4-氯-7-氟-6-硝基喹唑啉 在 铁粉 、 sodium hydride 、 氯化铵 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 水 、 乙腈 为溶剂， 反应 6.0h， 生成 (S)-N-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide
  参考文献：
  名称：

  Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors

  摘要：

  We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.08.026

文献信息

• Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors
  作者：Long Zhang、Yingying Yang、Haojie Zhou、Qingmei Zheng、Yuhao Li、Shansong Zheng、Shuyong Zhao、Dong Chen、Chuanwen Fan

  DOI：10.1016/j.ejmech.2015.08.026

  日期：2015.9

  We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies. (C) 2015 Elsevier Masson SAS. All rights reserved.