(R)-3-methoxy-4-(4-((1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde | 1637437-71-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (R)-3-methoxy-4-(4-((1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde
• 英文别名: 3-methoxy-4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzaldehyde
• CAS: 1637437-71-8
• 化学式: C₂₂H₂₀N₄O₂
• 分子量: 372.426
• InChiKey: NBGVBQWEHSXTMH-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  79.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-3-methoxy-4-(4-((1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde 在 sodium tetrahydroborate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.17h， 以80%的产率得到(R)-(3-methoxy-4-(4-((1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methanol
  参考文献：
  名称：

  [EN] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES FOR THE INHIBITION OF EGFR TYROSINE KINASE
  [FR] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES POUR L'INHIBITION DE LA TYROSINE KINASE AU NIVEAU DE L'EGFR

  摘要：

  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。

  公开号：

  WO2015000959A1
• 作为产物：
  描述：

  4-羟基吡咯并[2,3-d]嘧啶 在 甲醇 、 XPhos Pd G2 、 potassium carbonate 、 sodium hydroxide 、 sodium t-butanolate 、 lithium diisopropyl amide 、 2-二环己基磷-2,4,6-三异丙基联苯 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正庚烷 、 乙基苯 、 水 、 正丁醇 为溶剂， 反应 37.0h， 生成 (R)-3-methoxy-4-(4-((1-phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzaldehyde
  参考文献：
  名称：

  [EN] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES FOR THE INHIBITION OF EGFR TYROSINE KINASE
  [FR] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES POUR L'INHIBITION DE LA TYROSINE KINASE AU NIVEAU DE L'EGFR

  摘要：

  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。

  公开号：

  WO2015000959A1

文献信息

• Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors
  作者：Jin Han、Silje Henriksen、Kristin G. Nørsett、Eirik Sundby、Bård Helge Hoff

  DOI：10.1016/j.ejmech.2016.08.068

  日期：2016.11

  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.
• Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity
  作者：Svein Jacob Kaspersen、Jin Han、Kristin G. Nørsett、Line Rydså、Eli Kjøbli、Steffen Bugge、Geir Bjørkøy、Eirik Sundby、Bård Helge Hoff

  DOI：10.1016/j.ejps.2014.04.011

  日期：2014.8

  The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFRL858R cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures. (C) 2014 Elsevier B.V. All rights reserved.