tert-butyl 4-[4-(methylcarbamoyl)benzyl]piperidine-1-carboxylate | 333987-75-0

• 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: tert-butyl 4-[4-(methylcarbamoyl)benzyl]piperidine-1-carboxylate
• 英文别名: tert-Butyl 4-{4-[(Methylamino)carbonyl]benzyl}-1-piperidinecarboxylate；Tert-butyl 4-(4-(methylcarbamoyl)benzyl)piperidine-1-carboxylate；tert-butyl 4-[[4-(methylcarbamoyl)phenyl]methyl]piperidine-1-carboxylate
• CAS: 333987-75-0
• 化学式: C₁₉H₂₈N₂O₃
• 分子量: 332.443
• InChiKey: UGEMRWBYQHNVJR-UHFFFAOYSA-N

物化性质

• 熔点：
  148-150 °C
• 沸点：
  484.1±28.0 °C(Predicted)
• 密度：
  1.095±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-[4-(methylcarbamoyl)benzyl]piperidine-1-carboxylate 在 盐酸 、 乙酸乙酯 作用下， 以 甲醇 为溶剂， 以100%的产率得到N-methyl-4-(piperidin-4-ylmethyl)benzamide hydrochloride
  参考文献：
  名称：

  Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

  摘要：

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

  DOI：

  10.1021/jm051034q
• 作为产物：
  描述：

  4-(diethyoxyphosphorylmethyl)benzoic acid methyl ester 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 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 4-[4-(methylcarbamoyl)benzyl]piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

  摘要：

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

  DOI：

  10.1021/jm051034q

文献信息

• Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity
  作者：Shinichi Imamura、Takashi Ichikawa、Youichi Nishikawa、Naoyuki Kanzaki、Katsunori Takashima、Shinichi Niwa、Yuji Iizawa、Masanori Baba、Yoshihiro Sugihara

  DOI：10.1021/jm051034q

  日期：2006.5.1

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.