benzyl 4-(7-chloro-2-phenyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate | 1025807-12-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: benzyl 4-(7-chloro-2-phenyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
• CAS: 1025807-12-8
• 化学式: C₂₇H₂₃ClN₂O₂
• 分子量: 442.945
• InChiKey: ASYOEBFRWNZHFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  45.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  benzyl 4-(7-chloro-2-phenyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 在 palladium on activated charcoal 甲酸 、 二乙胺基三氟化硫 、 diisopinocampheylborane 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 生成 7-chloro-3-[(3R,4R)-4-fluoropiperidin-3-yl]-2-phenyl-1H-indole
  参考文献：
  名称：

  3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists

  摘要：

  The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the S-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the B-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

  DOI：

  10.1021/jm0004998
• 作为产物：
  描述：

  7-chloro-2-phenyl-1H-indole 在 磷酸 、 溶剂黄146 作用下， 生成 benzyl 4-(7-chloro-2-phenyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
  参考文献：
  名称：

  3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists

  摘要：

  The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the S-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the B-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.

  DOI：

  10.1021/jm0004998