4-benzyl-1-(3-Butynyl)piperidine | 192989-99-4

• 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: 4-benzyl-1-(3-Butynyl)piperidine
• 英文别名: 1-(3-Butynyl)-4-benzylpiperidine；4-benzyl-1-but-3-ynylpiperidine
• CAS: 192989-99-4
• 化学式: C₁₆H₂₁N
• 分子量: 227.349
• InChiKey: IPHNHHOINYUNHW-UHFFFAOYSA-N

物化性质

• 沸点：
  333.4±25.0 °C(Predicted)
• 密度：
  0.987±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  4-benzyl-1-(3-Butynyl)piperidine 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 铁粉 、 potassium carbonate 、 三乙胺 作用下， 以 乙醇 、 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 21.0h， 生成 6-[4-(4-Benzyl-piperidin-1-yl)-but-1-ynyl]-3H-benzooxazol-2-one
  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
• 作为产物：
  描述：

  4-苄基哌啶 、 对甲苯磺酸 3-丁炔酯 在 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以90%的产率得到4-benzyl-1-(3-Butynyl)piperidine
  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

文献信息

• 4-substituted piperidine analogs and their use as subtype selective NMDA
  申请人：Warner-Lambert Company

  公开号：US06130234A1

  公开（公告）日：2000-10-10

  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.

  新型4-取代哌啶类似物，含有这些类似物的药物组合物以及将4-取代哌啶类似物作为选择性活性N-甲基-D-天冬氨酸（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、抽搐、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、阿片类耐受性或戒断症状，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治疗方法被描述。还描述了制备4-取代哌啶类似物的新方法以及4-取代哌啶类似物的新中间体。
• Subtype-selective NMDA receptor ligands and the use thereof
  申请人：——

  公开号：US20010051633A1

  公开（公告）日：2001-12-13

  The invention relates to subtype-selective NMDA receptor ligands and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, Parkinson's disease, glaucoma, CMV retinitis, urinary incontinence, opioid tolerance or withdrawal, and inducing anesthesia, as well as for enhancing cognition.

  本发明涉及亚型选择性NMDA受体配体及其用于治疗或预防与中风、缺血、中枢神经系统创伤、低血糖和手术相关的神经元丧失，以及治疗包括阿尔茨海默病、肌萎缩性侧索硬化症、亨廷顿病和唐氏综合症在内的神经退行性疾病，治疗或预防兴奋性氨基酸过度刺激的不良后果，治疗焦虑，精神病，惊厥，氨基糖苷类抗生素引起的听力损失，偏头痛，慢性疼痛，帕金森病，青光眼，巨细胞病毒性视网膜炎，尿失禁，阿片类耐受或戒断，并诱导麻醉，以及增强认知能力。
• 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：US06448270B1

  公开（公告）日：2002-09-10

  Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using the 4-substituted piperidine analogs as selectively active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as cerebral ischemia, central nervous system trauma, hypoglycemia, neurodegenerative disorders, anxiety, migraine headaches, convulsions, aminoglycoside antibiotics-induced hearing loss, chronic pain, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, urinary incontinence and neurodegenerative disorders such as lathyrism, Alzheimers' 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.

  本发明涉及一种新型的4-取代哌啶类似物、含有它们的制药组合物以及使用这些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）受体亚型拮抗剂来治疗脑缺血、中枢神经系统创伤、低血糖、神经退行性疾病、焦虑、偏头痛、惊厥、氨基糖苷类抗生素引起的听力损失、慢性疼痛、精神病、青光眼、巨细胞病毒性视网膜炎、阿片类耐受或戒断、尿失禁以及神经退行性疾病，例如荚藤病、阿尔茨海默病、帕金森病和亨廷顿病的方法。本发明还涉及制备4-取代哌啶类似物的新方法以及4-取代哌啶类似物的新中间体。
• Discovery of subtype-selective NMDA receptor ligands: 4-Benzyl-1-piperidinylalkynylpyrroles, pyrazoles and imidazoles as NR1a/2B antagonists
  作者：Jon L. Wright、Tracy F. Gregory、Peter A. Boxer、Leonard T. Meltzer、Kevin A. Serpa、Lawrence D. Wise、Soo Hong-Bae、Jin Cheng Huang、Christopher S. Konkoy、Ravindra B. Upasani、Edward R. Whittemore、Richard M. Woodward、Kevin C. Yang、Zhang-Lin Zhou

  DOI：10.1016/s0960-894x(99)00482-5

  日期：1999.10

  4-Benzyl-1-[4-(1 (H) under bar-imidazol-4-yl)but-3-ynyl]piperidine (8) has been identified as a potent antagonist of the NR1A/2B subtype of the NMDA receptor. When dosed orally, this compound potentiates the effects of L-DOPA, in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease. (C) 1999 Elsevier Science Ltd. All rights reserved.