2-phenyl-3-piperidin-3-yl-1H-indole | 244086-74-6

• 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: 2-phenyl-3-piperidin-3-yl-1H-indole
• CAS: 244086-74-6
• 化学式: C₁₉H₂₀N₂
• 分子量: 276.381
• InChiKey: FYHCOUIJWCQUMZ-UHFFFAOYSA-N

物化性质

• 熔点：
  258-262 °C(Solv: ethanol (64-17-5))
• 沸点：
  487.1±45.0 °C(Predicted)
• 密度：
  1.130±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  27.8
• 氢给体数：
  2
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  乙基溴苯 、 2-phenyl-3-piperidin-3-yl-1H-indole 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以87%的产率得到3-(1-Phenethyl-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
• 作为产物：
  描述：

  1-苄基-3-哌啶酮盐酸盐 在 10percent Pd/C 磷酸 、 ammonium formate 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 28.0h， 生成 2-phenyl-3-piperidin-3-yl-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。
• Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)
  作者：Young Shin Cho、Lewis Whitehead、Jianke Li、Christine H.-T. Chen、Lei Jiang、Markus Vögtle、Eric Francotte、Paul Richert、Trixie Wagner、Martin Traebert、Qiang Lu、Xueying Cao、Berengere Dumotier、Jasna Fejzo、Srinivasan Rajan、Ping Wang、Yan Yan-Neale、Wenlin Shao、Peter Atadja、Michael Shultz

  DOI：10.1021/jm100007m

  日期：2010.4.8

  Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating h ERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.
• SYSTEMS AND METHODS FOR PREDICTING CARDIOTOXICITY OF MOLECULAR PARAMETERS OF A COMPOUND BASED ON MACHINE LEARNING ALGORITHMS
  申请人：UTI Limited Partnership

  公开号：US20180172667A1

  公开（公告）日：2018-06-21

  Systems and methods are provided for predicting cardiotoxicity of molecular parameters of a compound. A computer can provide as input to a machine learning algorithm the molecular parameters of the compound. The molecular parameters can include at least structural information about the compound. The machine learning algorithm can have been trained using respective molecular parameters of compounds known to have cardiotoxicity and of compounds known not to have cardiotoxicity. The computer can receive as output from the machine learning algorithm a representation of the predicted cardiotoxicity of each molecular parameter of at least a subset of the molecular parameters of the compound.
• 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.