N-(5-((4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(5-((4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
• 英文别名: N-[5-[[4-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide
• 化学式: C₃₀H₃₃N₇O₂
• 分子量: 523.638
• InChiKey: KCJAGFYOSRXDBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  87.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5,6-二氢-4H-吡咯并[3,2,1-ij]喹啉 在 aluminum (III) chloride 、 palladium 10% on activated carbon 、 氢气 、 对甲苯磺酸 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 16.83h， 生成 N-(5-((4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
  参考文献：
  名称：

  Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants

  摘要：

  Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4-Hpyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.04.036

文献信息

• 3-(4,5-取代氨基嘧啶)苯基衍生物及其应用
  申请人：江苏正大丰海制药有限公司

  公开号：CN106810553B

  公开（公告）日：2020-03-17

  本发明公开了一类3‑(4,5‑取代氨基嘧啶)苯基衍生物及其应用，其为具有式(I)结构的化合物或其药学上可接受的盐，这些化合物或其盐可通过某些突变形式的表皮生长因子受体而用于疾病或病况的治疗或预防，可以有效抑制多种肿瘤细胞的生长，并对EGFR、Her家族其他蛋白酶产生抑制作用，可用于制备抗肿瘤药物。
• Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants
  作者：Haoyang Zhang、Wenkui Wu、Chao Feng、Zhaogang Liu、Enhe Bai、Xueyuan Wang、Meng Lei、Hao Cheng、Huayun Feng、Jingmiao Shi、Jia Wang、Zhao Zhang、Tao Jin、Shanshan Chen、Shihe Hu、Yongqiang Zhu

  DOI：10.1016/j.ejmech.2017.04.036

  日期：2017.7

  Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4-Hpyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model. (C) 2017 Elsevier Masson SAS. All rights reserved.