N-[2-amino-1-(3-amino-3-oxopropyl)-1H-benzimidazol-5-yl]-N-methylcyclohexanecarboxamide | 658700-07-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N-[2-amino-1-(3-amino-3-oxopropyl)-1H-benzimidazol-5-yl]-N-methylcyclohexanecarboxamide
• 英文别名: cyclohexanecarboxylic acid [2-amino-1-(2-carbamoylethyl)-1H-benzimidazol-5-yl](methyl)amide；N-(2-amino-1-(3-amino-3-oxopropyl)-1H-benzo[d]imidazol-5-yl)-N-methylcyclohexanecarboxamide；N-[2-amino-1-(3-amino-3-oxopropyl)benzimidazol-5-yl]-N-methylcyclohexanecarboxamide
• CAS: 658700-07-3
• 化学式: C₁₈H₂₅N₅O₂
• 分子量: 343.429
• InChiKey: VIZZIFTYDVKPCM-UHFFFAOYSA-N

物化性质

• 沸点：
  640.8±61.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-[2-amino-1-(3-amino-3-oxopropyl)-1H-benzimidazol-5-yl]-N-methylcyclohexanecarboxamide 、 4-乙酰基苯甲酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4-acetyl-N-(1-(3-amino-3-oxopropyl)-5-(N-methylcyclohexanecarboxamido)-1H-benzo[d]imidazol-2-yl)benzamide
  参考文献：
  名称：

  Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)

  摘要：

  A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.09.015
• 作为产物：
  描述：

  4-氟-3-硝基苯胺 在 palladium on activated charcoal 甲酸铵 、 sodium hexamethyldisilazane 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二甲基亚砜 为溶剂， 反应 4.0h， 生成 N-[2-amino-1-(3-amino-3-oxopropyl)-1H-benzimidazol-5-yl]-N-methylcyclohexanecarboxamide
  参考文献：
  名称：

  Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors

  摘要：

  Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.04.045

文献信息

• [EN] SUBSTITUTED BENZIMIDAZOLE COMPOUNDS<br/>[FR] COMPOSES BENZIMIDAZOLE SUBSTITUES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2004014905A1

  公开（公告）日：2004-02-19

  Disclosed are substituted benzimidazole compounds of formula (I) wherein R1, R2, R3, R4 and Xa are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for treating diseases and pathological conditions involving inflammation, immunological disorders and allergic disorders. Also disclosed are processes for preparing these compounds and the pharmaceutical compositions comprising these compounds.

  揭示了一种化学式（I）中的取代苯并咪唑化合物，其中R1、R2、R3、R4和Xa在此处定义。该发明的化合物抑制Itk激酶，因此可用于治疗涉及炎症、免疫紊乱和过敏性疾病的疾病和病理状况。还揭示了制备这些化合物的方法以及包含这些化合物的药物组合物。
• Crystal structure of the ITK kinase domain
  申请人：Bentzien Martin Joerg

  公开号：US20070032403A1

  公开（公告）日：2007-02-08

  Disclosed are polypeptides encoding the ITK kinase domain and nucleic acids encoding such polypeptides, crystal structures of various polypeptide-ligand complexes comprising the ITK kinase domain bound to a ligand, methods of producing the aforementioned polypeptides and nucleic acids which encode them and methods of producing crystal structures of the aforementioned polypeptides comprising the ITK kinase domain bound to a ligand.
• [EN] CRYSTAL STRUCTURE OF THE INTERLEUKIN-2-INDUCIBLE CELL KINASE (ITK) KINASE DOMAIN<br/>[FR] STRUCTURE DE CRISTAUX DU DOMAINE KINASE DE LA KINASE CELLULAIRE INDUCTIBLE PAR L'INTERLEUKINE-2
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2005066335A1

  公开（公告）日：2005-07-21

  Disclosed are polypeptides encoding the ITK kinase domain and nucleic acids encoding such polypeptides, crystal structures of various polypeptide-ligand complexes comprising the ITK kinase domain bound to a ligand, methods of producing the aforementioned polypeptides and nucleic acids which encode them and methods of producing crystal structures of the aforementioned polypeptides comprising the ITK kinase domain bound to a ligand.
• Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)
  作者：Kevin J. Moriarty、Hidenori Takahashi、Steven S. Pullen、Hnin Hnin Khine、Rosemarie H. Sallati、Ernest L. Raymond、Joseph R. Woska、Deborah D. Jeanfavre、Gregory P. Roth、Michael P. Winters、Lei Qiao、Declan Ryan、Renee DesJarlais、Darius Robinson、Matthew Wilson、Mark Bobko、Brian N. Cook、Ho Yin Lo、Peter A. Nemoto、Mohammed A. Kashem、John P. Wolak、André White、Ronald L. Magolda、Bruce Tomczuk

  DOI：10.1016/j.bmcl.2008.09.015

  日期：2008.10

  A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK. (c) 2008 Elsevier Ltd. All rights reserved.
• Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors
  作者：Roger J. Snow、Asitha Abeywardane、Scot Campbell、John Lord、Mohammed A. Kashem、Hnin Hnin Khine、Josephine King、Jennifer A. Kowalski、Steven S. Pullen、Teresa Roma、Gregory P. Roth、Christopher R. Sarko、Noel S. Wilson、Michael P. Winters、John P. Wolak、Charles L. Cywin

  DOI：10.1016/j.bmcl.2007.04.045

  日期：2007.7

  Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed. (c) 2007 Elsevier Ltd. All rights reserved.