N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide | 1328623-96-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide
• 英文别名: N-[[2-[4-amino-6-[3-methyl-4-(6-methylpyridin-3-yl)oxyanilino]pyrimidin-5-yl]-1,3-oxazol-4-yl]methyl]prop-2-enamide
• CAS: 1328623-96-6
• 化学式: C₂₄H₂₃N₇O₃
• 分子量: 457.492
• InChiKey: JSZFKFRRJJLRNE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  141
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4,6-二氯-5-嘧啶甲醛 在 盐酸 、 lithium aluminium tetrahydride 、 sodium azide 、 磺酰氯 、 偶氮二异丁腈 、 三氯溴甲烷 、 二乙胺基三氟化硫 、 氨 、 水 、 碳酸氢钠 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 四氯化碳 、 乙醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 叔丁醇 为溶剂， 反应 7.5h， 生成 N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases

  摘要：

  A novel series of N-4-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine lcinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.

  DOI：

  10.1021/jm201758g

文献信息

• [EN] NOVEL PYRIMIDINE DERIVATIVE FOR INHIBITING THE GROWTH OF CANCER CELLS<br/>[FR] NOUVEAU DÉRIVÉ DE LA PYRIMIDINE POUR L'INHIBITION DE LA CROISSANCE DES CELLULES CANCÉREUSES
  申请人：HANMI HOLDINGS CO LTD

  公开号：WO2011099764A2

  公开（公告）日：2011-08-18

  The present invention provides a novel pyrimidine derivative or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same, which can effectively inhibit the growth of cancer cells induced by the overexpression of EGFR including subtypes and also prevents the development of drug resistance caused by the mutation of EGFR tyrosine kinase including subtypes.
• Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases
  作者：Mi Young Cha、Kwang-Ok Lee、Seok-Jong Kang、Young Hee Jung、Ji Yeon Song、Kyung Jin Choi、Joo Yun Byun、Han-Jae Lee、Gwan Sun Lee、Seung Bum Park、Maeng Sup Kim

  DOI：10.1021/jm201758g

  日期：2012.3.22

  A novel series of N-4-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine lcinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.