1-[2-amino-3-(propane-2-sulfonyl)-3H-benzoimidazol-5-yl]-2-(2,4-difluoro-phenyl)-ethane-1,2-dione | 849064-39-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 1-[2-amino-3-(propane-2-sulfonyl)-3H-benzoimidazol-5-yl]-2-(2,4-difluoro-phenyl)-ethane-1,2-dione
• 英文别名: 1-[2-amino-3-(propane-2-sulfonyl)-3H-benzimidazol-5-yl]-2-(2,4-difluorophenyl)ethane-1,2-dione；1-(2-Amino-1-(isopropylsulfonyl)-1H-benzo[d]imidazol-6-yl)-2-(2,4-difluorophenyl)ethane-1,2-dione；1-(2-amino-3-propan-2-ylsulfonylbenzimidazol-5-yl)-2-(2,4-difluorophenyl)ethane-1,2-dione
• CAS: 849064-39-7
• 化学式: C₁₈H₁₅F₂N₃O₄S
• 分子量: 407.398
• InChiKey: VDJFSBCLGDWBFU-UHFFFAOYSA-N

物化性质

• 沸点：
  623.9±65.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-[2-amino-3-(propane-2-sulfonyl)-3H-benzoimidazol-5-yl]-2-(2,4-difluoro-phenyl)-ethane-1,2-dione 在 ammonium acetate 作用下， 以 甲醇 、 正丁醇 为溶剂， 反应 24.17h， 生成 6-[2-tert-butyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]-1-(propane-2-sulfonyl)-1H-benzoimidazol-2-ylamine monomesylate
  参考文献：
  名称：

  Synthesis of Imidazole Based p38 MAP (Mitogen-Activated Protein) Kinase Inhibitors under Buffered Conditions

  摘要：

  This article describes chemistry that was developed to give access to multigram quantities of imidazole 479754 and several related analogues for Eli Lilly's p38 MAPK program targeting therapies to address inflammation. The molecules of interest have an isopropyl sulfonyl group present on the 2-aminobenzimidazole heterocycyle that was found to be labile when heated in polar solvents and/or exposed to high or low pH. Due to this instability issue, the syntheses of the target molecules required optimizing Sonogashira reaction conditions, employing a buffered oxidative method to produce alpha-diones, developing buffered reaction conditions to generate imidazoles, and developing final recrystallization conditions.

  DOI：

  10.1021/op060042t
• 作为产物：
  描述：

  1-乙炔基-2,4-二氟苯 在 potassium permanganate 、 copper(l) iodide 、 bis(triphenylphosphine) palladium (Il) acetate 、 碳酸氢钠 、 magnesium sulfate 、 三乙胺 作用下， 以 二甲基亚砜 、 丙酮 为溶剂， 反应 16.0h， 生成 1-[2-amino-3-(propane-2-sulfonyl)-3H-benzoimidazol-5-yl]-2-(2,4-difluoro-phenyl)-ethane-1,2-dione
  参考文献：
  名称：

  具有有效的体内功效的有效和选择性的基于2-氨基苯并咪唑的p38alpha MAP激酶抑制剂的设计。

  摘要：

  我们报告了基于2-氨基苯并咪唑的有效和高度选择性的p38alphainhibitors系列的设计和发现。铅化合物1在ATP竞争性酶结合和巨噬细胞中的TNFα释放抑制方面均具有低纳摩尔活性。与其他p38参考化合物相比，化合物18在大鼠胶原蛋白诱发的关节炎模型中显示出出色的药代动力学特性和口服活性。还介绍了解决CyP3A4责任的SAR策略。

  DOI：

  10.1021/jm048978k

文献信息

• Design of Potent and Selective 2-Aminobenzimidazole-Based p38α MAP Kinase Inhibitors with Excellent in Vivo Efficacy
  作者：Alfonso de Dios、Chuan Shih、Beatriz López de Uralde、Concepción Sánchez、Miriam del Prado、Luisa M. Martín Cabrejas、Sehila Pleite、Jaime Blanco-Urgoiti、María José Lorite、C. Richard Nevill、Rosanne Bonjouklian、Jeremy York、Michal Vieth、Yong Wang、Nicholas Magnus、Robert M. Campbell、Bryan D. Anderson、Denis J. McCann、Deborah D. Giera、Paul A. Lee、Richard M. Schultz、Li、Lea M. Johnson、Jeffrey A. Wolos

  DOI：10.1021/jm048978k

  日期：2005.4.1

  We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other

  我们报告了基于2-氨基苯并咪唑的有效和高度选择性的p38alphainhibitors系列的设计和发现。铅化合物1在ATP竞争性酶结合和巨噬细胞中的TNFα释放抑制方面均具有低纳摩尔活性。与其他p38参考化合物相比，化合物18在大鼠胶原蛋白诱发的关节炎模型中显示出出色的药代动力学特性和口服活性。还介绍了解决CyP3A4责任的SAR策略。
• Synthesis of Imidazole Based p38 MAP (Mitogen-Activated Protein) Kinase Inhibitors under Buffered Conditions
  作者：Nicholas A. Magnus、William D. Diseroad、C. Richard Nevill、James P. Wepsiec

  DOI：10.1021/op060042t

  日期：2006.5.1

  This article describes chemistry that was developed to give access to multigram quantities of imidazole 479754 and several related analogues for Eli Lilly's p38 MAPK program targeting therapies to address inflammation. The molecules of interest have an isopropyl sulfonyl group present on the 2-aminobenzimidazole heterocycyle that was found to be labile when heated in polar solvents and/or exposed to high or low pH. Due to this instability issue, the syntheses of the target molecules required optimizing Sonogashira reaction conditions, employing a buffered oxidative method to produce alpha-diones, developing buffered reaction conditions to generate imidazoles, and developing final recrystallization conditions.