1-苄基-4-羟基-4-(4-甲基苄基)哌啶 | 193357-89-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 1-苄基-4-羟基-4-(4-甲基苄基)哌啶
• 英文名称: 1-benzyl-4-hydroxy-4-(4-methylbenzyl)piperidine
• 英文别名: 1-Benzyl-4-hydroxy4-(4-methylbenzyl)piperidine；1-Benzyl-4-(4-methylbenzyl)piperidin-4-ol；1-benzyl-4-[(4-methylphenyl)methyl]piperidin-4-ol
• CAS: 193357-89-0
• 化学式: C₂₀H₂₅NO
• 分子量: 295.425
• InChiKey: BHQHJYOITIKYQO-UHFFFAOYSA-N

物化性质

• 沸点：
  442.8±30.0 °C(Predicted)
• 密度：
  1.111±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-苄基-4-羟基-4-(4-甲基苄基)哌啶 在 palladium on activated charcoal 氢气 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 生成 4-羟基-4-(4-甲基-苄基)-哌啶
  参考文献：
  名称：

  Subtype-Selective N-Methyl-d-aspartate Receptor Antagonists:  Synthesis and Biological Evaluation of 1-(Arylalkynyl)-4-benzylpiperidines

  摘要：

  A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)-piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl approximate to propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.

  DOI：

  10.1021/jm990148x
• 作为产物：
  描述：

  N-苄基哌啶酮 、 4-甲基氯苄 在 magnesium 、 1,2-二溴乙烷 作用下， 生成 1-苄基-4-羟基-4-(4-甲基苄基)哌啶
  参考文献：
  名称：

  4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine:  A Novel, Potent, and Selective NR1/2B NMDA Receptor Antagonist

  摘要：

  A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 mu M). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a similar to 25-fold increase in NR1A/2B potency (IC50 = 0.025 mu M). p-Methyl substitution on the benzyl ring (10b) produced a similar to 3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of Kf channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.

  DOI：

  10.1021/jm990246i

文献信息

• Method for treating diseased-related or drug-induced dyskinesias
  申请人：——

  公开号：US06284776B1

  公开（公告）日：2001-09-04

  Dyskinesias in humans are treated by administering a therapeutically effective dose of an NR1A/2B site-selective NMDA receptor antagonist compound to a human suffering therefrom.

  人类的运动障碍症状可以通过给患者口服一种NR1A/2B位点选择性NMDA受体拮抗剂的治疗剂量来治疗。
• Subtype-Selective <i>N</i>-Methyl-<scp>d</scp>-aspartate Receptor Antagonists:  Synthesis and Biological Evaluation of 1-(Arylalkynyl)-4-benzylpiperidines
  作者：Jon L. Wright、Tracy F. Gregory、Christopher F. Bigge、Peter A. Boxer、Kevin Serpa、Leonard T. Meltzer、Lawrence D. Wise、Sui Xiong Cai、Jon E. Hawkinson、Christopher S. Konkoy、Edward R. Whittemore、Richard M. Woodward、Zhang-Lin Zhou

  DOI：10.1021/jm990148x

  日期：1999.7.1

  A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)-piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl approximate to propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.
• US6124323
  申请人：——

  公开号：——

  公开（公告）日：——
• US06124323
  申请人：——

  公开号：——

  公开（公告）日：——
• EP0869792A4
  申请人：——

  公开号：EP0869792A4

  公开（公告）日：1999-09-22