2-isopropyl-N-(piperidin-4-ylmethyl)-1H-benzo[d]imidazole-4-carboxamide

• 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: 2-isopropyl-N-(piperidin-4-ylmethyl)-1H-benzo[d]imidazole-4-carboxamide
• 英文别名: 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (piperidin-4-ylmethyl)amide；N-(piperidin-4-ylmethyl)-2-propan-2-yl-1H-benzimidazole-4-carboxamide
• 化学式: C₁₇H₂₄N₄O
• 分子量: 300.404
• InChiKey: BDAGPLIEWRSZCY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  69.8
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-isopropyl-N-(piperidin-4-ylmethyl)-1H-benzo[d]imidazole-4-carboxamide 在 三乙酰氧基硼氢化钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide
  参考文献：
  名称：

  Discovery of TD-8954, a clinical stage 5-HT4 receptor agonist with gastrointestinal prokinetic properties

  摘要：

  The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.018
• 作为产物：
  描述：

  tert-butyl 4-((2-isopropyl-1H-benzo[d]imidazole-4-carboxamido)methyl)piperidine-1-carboxylate 在 盐酸 作用下， 以 水 、 乙腈 为溶剂， 反应 1.0h， 以88%的产率得到2-isopropyl-N-(piperidin-4-ylmethyl)-1H-benzo[d]imidazole-4-carboxamide
  参考文献：
  名称：

  超越有机溶剂：在水中合成5-HT4受体激动剂

  摘要：

  减少或消除药物生产中使用有机溶剂可能是减少药物生产对环境，健康和安全影响的最有效方法。考虑到这一点，我们已经开发出一种制造可研究的5-HT 4受体激动剂的方法，该方法几乎完全在水中进行，包括多重控制分离。在水性介质中进行的关键转化包括苯并咪唑环化，酰胺键形成，还原胺化和脂族醇的选择性氧化。与使用有机溶剂的第一代制造工艺相比，此处描述的水性工艺使用的材料输入量减少了77％，有机溶剂减少了94％，令人惊讶的是，水使用量减少了48％，同时将总产率从35％提高到56％。

  DOI：

  10.1039/d0gc03316b

文献信息

• Benzimidazole-carboxamide compounds as 5-HT4, receptor agonists
  申请人：McKinnell Murray Robert

  公开号：US20060270652A1

  公开（公告）日：2006-11-30

  The invention relates to benzimidazole-carboxamide 5-HT 4 receptor agonist compounds of formula (I) wherein R 1 and X are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention also relates to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

  这项发明涉及式(I)的苯并咪唑-羧酰胺5-HT4受体激动剂化合物，其中R1和X如规范中定义，或其药学上可接受的盐、溶剂合物或立体异构体。该发明还涉及包含这种化合物的药物组合物，使用这种化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这种化合物的过程和中间体。
• Crystalline form of a benzimidazole-carboxamide medicinal compound
  申请人：Dalziel M. Sean

  公开号：US20060270854A1

  公开（公告）日：2006-11-30

  The invention provides crystalline forms of the novel benzimidazole-carboxamide 5-HT 4 receptor agonist compound, 4-(4-[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylic acid methyl ester. The invention also provides pharmaceutical compositions comprising the crystalline compound, methods of using the compound to treat diseases associated with 5-HT 4 receptor activity, and processes useful for preparing crystalline forms of the compound.

  本发明提供了一种新型苯并咪唑-羧酰胺5-HT4受体激动剂化合物的晶体形式，即4-(4-[(2-异丙基-1H-苯并咪唑-4-羧酰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-羧酸甲酯。本发明还提供了包括该晶体化合物的制药组合物，使用该化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备该化合物晶体形式的有用工艺。
• CRYSTALLINE FORM OF A BENZIMIDAZOLE-CARBOXAMIDE MEDICINAL COMPOUND
  申请人：Dalziel Sean M.

  公开号：US20100029946A1

  公开（公告）日：2010-02-04

  The invention provides crystalline forms of the novel benzimidazole-carboxamide 5-HT 4 receptor agonist compound, 4-(4-[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylic acid methyl ester. The invention also provides pharmaceutical compositions comprising the crystalline compound, methods of using the compound to treat diseases associated with 5-HT 4 receptor activity, and processes useful for preparing crystalline forms of the compound.

  本发明提供了一种新型苯并咪唑-羧酰胺5-HT4受体激动剂化合物的晶体形式，化合物为4-(4-[(2-异丙基-1H-苯并咪唑-4-羧酰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-羧酸甲酯。本发明还提供包含该晶体化合物的制药组合物，使用该化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备该化合物晶体形式的有用过程。
• BENZIMIDAZOLE-CARBOXAMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
  申请人：McKinnell Robert Murray

  公开号：US20100249186A1

  公开（公告）日：2010-09-30

  The invention relates to benzimidazole-carboxamide 5-HT 4 receptor agonist compounds of formula (I) wherein R 1 and X are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention also relates to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

  本发明涉及一种苯并咪唑-羧酰胺5-HT4受体激动剂化合物，其化学式为(I)，其中R1和X如规范中所定义，或其药学上可接受的盐、溶剂或立体异构体。本发明还涉及包含这种化合物的制药组合物，使用这种化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这种化合物的过程和中间体。
• Benzimidazole-carboxamide compounds as 5-HT4 receptor agonists
  申请人：Theravance, Inc.

  公开号：US08143279B2

  公开（公告）日：2012-03-27

  The invention relates to benzimidazole-carboxamide 5-HT4 receptor agonist compounds of formula (I) wherein R1 and X are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention also relates to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds. The invention further relates to crystalline forms of a compound of formula (I).

  本发明涉及式(I)的苯并咪唑-羧酰胺5-HT4受体激动剂化合物，其中R1和X如规范所定义，或其药学上可接受的盐或溶剂或立体异构体。本发明还涉及包含这些化合物的制药组合物，使用这些化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这些化合物的过程和中间体。本发明还涉及式(I)化合物的晶体形式。