(R)-6-(2,6-dimethoxyphenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: (R)-6-(2,6-dimethoxyphenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• 英文别名: 6-(2,6-dimethoxyphenyl)-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• 化学式: C₂₂H₂₂N₄O₂
• 分子量: 374.442
• InChiKey: MWYDZOGYPFSWHW-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  72.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (R)-6-iodo-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 、 2,6-二甲氧基苯硼酸 在 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 8.0h， 以76%的产率得到(R)-6-(2,6-dimethoxyphenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

  摘要：

  The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC50 values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFR(L858R) reporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.08.068

文献信息

• [EN] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES FOR THE INHIBITION OF EGFR TYROSINE KINASE<br/>[FR] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES POUR L'INHIBITION DE LA TYROSINE KINASE AU NIVEAU DE L'EGFR
  申请人：NORWEGIAN UNIV SCI & TECH NTNU

  公开号：WO2015000959A1

  公开（公告）日：2015-01-08

  This invention relates to certain new pyrrolo-, thieno-, and furo-[2,3- d]pyrimidine compounds, such as of general formula (I) These compounds are epidermal growth factor receptor tyrosine kinase inhibitors and therefore offer potential in the treatment of cancer.

  这项发明涉及某些新的吡咯基、噻吩基和呋喃基[2,3-d]嘧啶化合物，如一般式(I)所示。这些化合物是表皮生长因子受体酪氨酸激酶抑制剂，因此在癌症治疗中具有潜力。