2-(piperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one | 1224698-10-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 2-(piperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one
• 英文别名: 2-(Piperidin-4-YL)-1H-pyrrolo[1,2-C]imidazol-3(2H)-one；2-piperidin-4-yl-1H-pyrrolo[1,2-c]imidazol-3-one
• CAS: 1224698-10-5
• 化学式: C₁₁H₁₅N₃O
• 分子量: 205.26
• InChiKey: SBBUMLUAJWFQAX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoic acid 、 2-(piperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以48%的产率得到2-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one
  参考文献：
  名称：

  Discovery of a Tetrahydropyrimidin-2(1H)-one Derivative (TAK-442) as a Potent, Selective, and Orally Active Factor Xa Inhibitor

  摘要：

  Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

  DOI：

  10.1021/jm901699j
• 作为产物：
  描述：

  2-(1-benzylpiperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one 在 氢气 、 palladium(II) hydroxide 作用下， 以 甲醇 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 15.0h， 以67%的产率得到2-(piperidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one
  参考文献：
  名称：

  Discovery of a Tetrahydropyrimidin-2(1H)-one Derivative (TAK-442) as a Potent, Selective, and Orally Active Factor Xa Inhibitor

  摘要：

  Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

  DOI：

  10.1021/jm901699j

文献信息

• Discovery of a Tetrahydropyrimidin-2(1<i>H</i>)-one Derivative (TAK-442) as a Potent, Selective, and Orally Active Factor Xa Inhibitor
  作者：Takuya Fujimoto、Yasuhiro Imaeda、Noriko Konishi、Katsuhiko Hiroe、Masaki Kawamura、Garret P. Textor、Kathleen Aertgeerts、Keiji Kubo

  DOI：10.1021/jm901699j

  日期：2010.5.13

  Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.