3-(1-Methyl-piperidin-3-yl)-2-phenyl-1H-indole

• 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: 3-(1-Methyl-piperidin-3-yl)-2-phenyl-1H-indole
• 英文别名: 3-(1-methylpiperidin-3-yl)-2-phenyl-1H-indole
• 化学式: C₂₀H₂₂N₂
• 分子量: 290.408
• InChiKey: JRFXDRYERZNJFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  19
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  1-苄基-3-哌啶酮盐酸盐 在 10percent Pd/C 磷酸 、 ammonium formate 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 、 水 为溶剂， 反应 31.0h， 生成 3-(1-Methyl-piperidin-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

文献信息

• [EN] INDOLE DERIVATIVES AS 5-HT2A RECEPTOR ANTAGONISTS<br/>[FR] DERIVES DE L'INDOLE ANTAGONISTES DU RECEPTEUR 5-HT2A
  申请人：MERCK SHARP & DOHME LIMITED

  公开号：WO1999047511A1

  公开（公告）日：1999-09-23

  (EN) A class of 3-(piperidin-3-yl)-1$i(H)-indole derivatives and tetrahydropyridine analogues thereof bearing a range of substituents (including optionally substituted phenyl) at the 2-position of the indole ring system are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.(FR) L'invention porte sur une classe de dérivés de la 3-(pipéridine -3-yl)-1$i(H)-indole et ses analogues de tétrahydropyridine présentant une série de substituants (dont un phényle facultativement substitué) en position 2 du cycle de l'indole et s'avérant être des antagonistes sélectifs du récepteur humain 5-HT2A, et de ce fait utiles comme agents pharmaceutiques notamment pour le traitement d'états adverses du SNC dont certains troubles psychotiques tels que la schizophrénie.

  一种3-（吡啶-3-基）-1-i(H)-龙胆碱衍生物及其带有各种取代基的四氢吡啶类似物（包括可能带有取代基的苯环在龙胆碱环系统2号位置）是作为人类5-HT2A受体的选择性拮抗剂，并因此作为药物剂，尤其在治疗或预防中枢神经系统不良状态，如精神疾病，如精神分裂症中应用。
• 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT_2A Receptor Antagonists
  作者：Michael Rowley、David J. Hallett、Simon Goodacre、Christopher Moyes、James Crawforth、Timothy J. Sparey、Smita Patel、Rose Marwood、Shil Patel、Steven Thomas、Laure Hitzel、Desmond O'Connor、Nicola Szeto、Jose L. Castro、Peter H. Hutson、Angus M. MacLeod

  DOI：10.1021/jm0004998

  日期：2001.5.1

  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.