(R)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | 1478018-32-4

• 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: (R)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
• 英文别名: (R)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1Η)-one；3-benzyl-7-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]-4H-pyrimido[4,5-d]pyrimidin-2-one
• CAS: 1478018-32-4
• 化学式: C₃₃H₄₀N₈O₃
• 分子量: 596.732
• InChiKey: NSAJROLZGLVIST-HHHXNRCGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  97.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-(-)-1-Boc-3-氨基哌啶 在 manganese(IV) oxide 、 lithium aluminium tetrahydride 、 potassium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 仲丁醇 为溶剂， 反应 30.0h， 生成 (R)-1-(1-acryloylpiperidin-3-yl)-3-benzyl-7-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of 2-Oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties

  摘要：

  Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.

  DOI：

  10.1021/jm4012388

文献信息

• Design, Synthesis, and Biological Evaluation of 2-Oxo-3,4-dihydropyrimido[4,5-<i>d</i>]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties
  作者：Shilin Xu、Tianfeng Xu、Lianwen Zhang、Zhang Zhang、Jinfeng Luo、Yingxue Liu、Xiaoyun Lu、Zhengchao Tu、Xiaomei Ren、Ke Ding

  DOI：10.1021/jm4012388

  日期：2013.11.14

  Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.