5-[4-(4-benzylpiperidin-1-yl)but-1-ynyl]-2-nitrophenyl ethyl carbonate | 302800-05-1

• 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-benzylpiperidin-1-yl)but-1-ynyl]-2-nitrophenyl ethyl carbonate
• 英文别名: [5-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]-2-nitrophenyl] ethyl carbonate
• CAS: 302800-05-1
• 化学式: C₂₅H₂₈N₂O₅
• 分子量: 436.508
• InChiKey: XRWFYNKAYVEDKG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  84.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-[4-(4-benzylpiperidin-1-yl)but-1-ynyl]-2-nitrophenyl ethyl carbonate 在 盐酸 、 铁粉 作用下， 以 乙醇 为溶剂， 反应 0.5h， 以53%的产率得到5-[4-(4-benzylpiperidin-1-yl)but-1-ynyl]-2-aminophenyl ethyl carbonate
  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-benzyl-1-(3-Butynyl)piperidine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 potassium carbonate 、 三乙胺 作用下， 以 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 17.5h， 生成 5-[4-(4-benzylpiperidin-1-yl)but-1-ynyl]-2-nitrophenyl ethyl carbonate
  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

• Subtype-Selective <i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor Antagonists:  Synthesis and Biological Evaluation of 1-(Heteroarylalkynyl)-4-benzylpiperidines
  作者：Jon L. Wright、Tracy F. Gregory、Suzanne R. Kesten、Peter A. Boxer、Kevin A. Serpa、Leonard T. Meltzer、Lawrence D. Wise、Stephen A. Espitia、Christopher S. Konkoy、Edward R. Whittemore、Richard M. Woodward

  DOI：10.1021/jm000023o

  日期：2000.9.1

  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.