5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indazole

• 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: 5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indazole
• 英文别名: 5-[4-(4-benzylpiperidin-1-yl)but-1-ynyl]-1H-indazole
• 化学式: C₂₃H₂₅N₃
• 分子量: 343.472
• InChiKey: JTHIYPHEWHYVLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  31.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  5-碘-1H-吲唑 、 4-benzyl-1-(3-Butynyl)piperidine 在 四氢吡咯 、 四(三苯基膦)钯 作用下， 以65%的产率得到5-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indazole
  参考文献：
  名称：

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

  摘要：

  4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl phenol (9) are potent NR1A/2B receptor antagonists (IC50 values 0.17 and 0.10 mu M, respectively). Administered intraperitoneally, they both potentiated the activity of L-DOPA in the unilaterally 6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, compound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The preference for a para arrangement between the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the piperidine had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demonstrated slightly improved selectivity for NR1A/2B receptors versus alpha-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzo-imidazol-2-one (46b) was identified as a very potent, selective NR1A/2B receptor antagonist (IC50 value 0.0053 mu M). After oral administration at 10 and 30 mg/kg, 46b potentiated the effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability but lower brain penetration compared to phenol 9.

  DOI：

  10.1021/jm000023o

文献信息

• 4-Substituted piperidine analogs and their use as subtype selective NMDA receptor, antagonists
  申请人：——

  公开号：US20030105133A1

  公开（公告）日：2003-06-05

  Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 4-substituted piperidine analogs as selectively active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, glaucoma, CMV retinitis, chronic pain, opioid tolerance or withdrawals, or neurodegenerative disorders, such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease are described. Also described are novel methods for preparing 4-substituted piperidine analogs and novel intermediates of the 4-substituted piperidine analogs.

  本文介绍了新型4-取代哌啶类似物、含有相同成分的制药组合物以及使用4-取代哌啶类似物作为选择性活性N-甲基-D-天门冬氨酸（NMDA）受体亚型拮抗剂治疗中风、脑缺血、中枢神经系统创伤、低血糖、焦虑、惊厥、氨基糖苷类抗生素引起的听力损失、偏头痛、青光眼、巨细胞病毒性视网膜炎、慢性疼痛、阿片类耐受或戒断综合征或神经退行性疾病，如拉蒂病、阿尔茨海默病、帕金森病和亨廷顿病的条件。还介绍了制备4-取代哌啶类似物的新方法和4-取代哌啶类似物的新中间体。
• 4-SUBSTITUTED PIPERIDINE ANALOGS AND THEIR USE AS SUBTYPE SELECTIVE NMDA RECEPTOR ANTAGONISTS
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0869791A1

  公开（公告）日：1998-10-14
• EP0869791A4
  申请人：——

  公开号：EP0869791A4

  公开（公告）日：1999-04-28
• US6130234A
  申请人：——

  公开号：US6130234A

  公开（公告）日：2000-10-10
• US6448270B1
  申请人：——

  公开号：US6448270B1

  公开（公告）日：2002-09-10