(E)-4-(dimethylamino)-N-(4-(3-ethynylphenylamino)-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-6-yl)but-2-enamide

• 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: (E)-4-(dimethylamino)-N-(4-(3-ethynylphenylamino)-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-6-yl)but-2-enamide
• 英文别名: (E)-6-(4-(dimethylamino)crotonylamino)-7-(tetrahydropyran-4-yloxy)-N-(3-ethynylphenyl)quinazolinamine；(E)-4-(dimethylamino)-N-[4-(3-ethynylanilino)-7-(oxan-4-yloxy)quinazolin-6-yl]but-2-enamide
• 化学式: C₂₇H₂₉N₅O₃
• 分子量: 471.559
• InChiKey: WRUAWDJRNXGHMT-RMKNXTFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  88.6
• 氢给体数：
  2
• 氢受体数：
  7

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 、 potassium carbonate 、 氯化铵 、 三乙胺 、 potassium iodide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 7.0h， 生成 (E)-4-(dimethylamino)-N-(4-(3-ethynylphenylamino)-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-6-yl)but-2-enamide
  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

• 4-(取代苯氨基)喹唑啉衍生物及其制备方法、 药物组合物和用途
  申请人：齐鲁制药有限公司

  公开号：CN103073539B

  公开（公告）日：2016-05-11

  本发明涉及4-(取代苯氨基)喹唑啉衍生物及其制备方法、药物组合物和用途。具体地说，本发明涉及式I化合物或其药学上可接受的盐或溶剂合物，其中，R1、R2和R3的定义如说明书中所述。本发明还涉及式I化合物的制备方法，包括它的药物组合物以及它们用于制备治疗和/或预防哺乳动物(包括人)的与受体酪氨酸激酶相关的疾病或病症药物的用途。本发明的式I化合物是有效的酪氨酸激酶不可逆抑制剂。
• 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.