(S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxooxazolidine-4-carboxamide

• 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-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxooxazolidine-4-carboxamide
• 英文别名: (S)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)oxazolidin-2-one-4-carboxamide；(4S)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-2-oxo-1,3-oxazolidine-4-carboxamide
• 化学式: C₁₉H₁₅ClFN₅O₄
• 分子量: 431.811
• InChiKey: DJAUDRYHVNOPNC-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-氯-7-氟-6-硝基喹唑啉 在 sodium tetrahydroborate 、 草酰氯 、 nickel(II) chloride hexahydrate 、 potassium tert-butylate 作用下， 以 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.67h， 生成 (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxooxazolidine-4-carboxamide
  参考文献：
  名称：

  6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR

  摘要：

  Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFR(T790M) and EGFR(L858R) kinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2016.04.046

文献信息

• 含噁唑烷酮环侧链的喹唑啉衍生物及制备和应 用
  申请人：浙江大学

  公开号：CN103570704B

  公开（公告）日：2016-05-18

  本发明提供一种如式I所示的含噁唑烷酮环侧链的喹唑啉衍生物或其对映异构体，主要是以4-芳胺基喹唑啉为母核，通过与噁唑烷酮甲酸一步缩合得到目标化合物。实验证明，在细胞水平对与EGFR酪氨酸激酶活性相关的肿瘤细胞（过表达EGFR的人表皮癌细胞株A431、对Gefitinib耐药的人肺腺癌细胞株H1975）具有显著的增殖抑制作用，特别是对耐药细胞株H1975有较好的抑制效果，可制备相应抗肿瘤细胞药物。结构通式：。
• 6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR
  作者：Jiaan Shao、En Chen、Ke Shu、Wenteng Chen、Guolin Zhang、Yongping Yu

  DOI：10.1016/j.bmc.2016.04.046

  日期：2016.8

  Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFR(T790M) and EGFR(L858R) kinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants. (C) 2016 Published by Elsevier Ltd.