2-(2-([D3]methoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | 1454558-24-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-(2-([D3]methoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
• 英文别名: 2-(2-(methoxy-d₃)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane；2-(2-(Methoxy-D3)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane；4,4,5,5-tetramethyl-2-[2-(trideuteriomethoxy)phenyl]-1,3,2-dioxaborolane
• CAS: 1454558-24-7
• 化学式: C₁₃H₁₉BO₃
• 分子量: 237.079
• InChiKey: ASDFSWMHZSWXPO-VPYROQPTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.99
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  27.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(2-([D3]methoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 、 (S)-2-((6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-phenylethan-1-ol 在 potassium carbonate 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 1.0h， 生成 (S)-2-((6-(2-(methoxy-d₃)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-phenylethan-1-ol
  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
• 作为产物：
  描述：

  2-溴苯酚 在 2-双环己基膦-2',6'-二甲氧基联苯 、 双(乙腈)氯化钯(II) 、 三乙胺 、 potassium hydroxide 作用下， 以 乙腈 为溶剂， 反应 8.5h， 生成 2-(2-([D3]methoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  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] PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE<br/>[FR] COMPOSÉS À BASE DE PYRAZOLO[1,5-A] PYRIMIDINE, COMPOSITIONS LES COMPRENANT ET UTILISATIONS DE CEUX-CI
  申请人：LEXICON PHARMACEUTICALS INC

  公开号：WO2013134228A1

  公开（公告）日：2013-09-12

  Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

  基于吡唑并[1,5-a]嘧啶的化合物的公式如下：其中R1、R2和R3在此处被定义。还公开了包含这些化合物的组合物以及它们的使用方法，用于治疗、管理和/或预防由适配器相关激酶1活性介导的疾病和紊乱。
• 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.