(1-苯乙基-哌啶-4-基)-氨基甲酸叔丁酯 | 1159824-87-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (1-苯乙基-哌啶-4-基)-氨基甲酸叔丁酯
• 英文名称: tert-butyl (1-phenethylpiperidin-4-yl)carbamate
• 英文别名: (1-Phenethyl-piperidin-4-yl)-carbamic acid tert-Butyl ester；tert-butyl N-[1-(2-phenylethyl)piperidin-4-yl]carbamate
• CAS: 1159824-87-9
• 化学式: C₁₈H₂₈N₂O₂
• mdl: MFCD11707175
• 分子量: 304.433
• InChiKey: IVRZAYIFKATGFM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.611
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1-苯乙基-哌啶-4-基)-氨基甲酸叔丁酯 在 三氟乙酸 作用下， 反应 1.0h， 以100%的产率得到N-苯乙基-4-氨基哌啶
  参考文献：
  名称：

  多巴胺转运蛋白中一系列（双（4-氟苯基）甲基）亚磺酰基乙基-氨基哌啶和-哌啶胺的构效关系：哌嗪的生物等排置换提高了代谢稳定性。

  摘要：

  尽管在开发治疗精神兴奋剂使用障碍的药物方面付出了相当大的努力，但没有一种药物被证明是有效的，这使得患者群体服务不足，并且关于开发药物疗法应该针对什么作用机制的问题也没有得到解答。基于 (±) 莫达非尼的非典型多巴胺转运蛋白 (DAT) 抑制剂已在精神兴奋剂滥用的临床前模型中显示出治疗潜力。然而，代谢不稳定以及哌嗪类似物的其他局限性1-3阻碍了进一步的发展。在本文中，用一系列氨基哌啶 (A) 和哌啶胺 (B) 探索了哌嗪环的生物等排取代，其中合成了具有末端叔胺或酰胺的化合物。几种先导化合物在大鼠肝微粒体中显示出高至中等的 DAT 亲和力和代谢稳定性。 与可卡因相比，氨基哌啶7 (DAT K i  = 50.6 nM)、21b (DAT K i  = 77.2 nM) 和33 (DAT K i = 30.0 nM) 仅对小鼠的行走活动产生最小的刺激，表明非典型的 DAT 抑制剂谱.

  DOI：

  10.1016/j.ejmech.2020.112674
• 作为产物：
  描述：

  4-氨基-1-苄基哌啶 在 palladium on activated charcoal 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、344.74 kPa 条件下， 反应 78.0h， 生成 (1-苯乙基-哌啶-4-基)-氨基甲酸叔丁酯
  参考文献：
  名称：

  1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one:  A Selective High-Affinity Antagonist for the Human Dopamine D₄ Receptor with Excellent Selectivity over Ion Channels

  摘要：

  After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1,3-dihydroimidazol-2-yl)piperidine . Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot'' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or B-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater Selectivity( > 1000-foId) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over-all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D-4 receptor.

  DOI：

  10.1021/jm991029k

文献信息

• Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
  作者：Thuy Nguyen、Yuji Sakasegawa、Katsumi Doh-ura、Mei-Lin Go

  DOI：10.1016/j.ejmech.2011.04.016

  日期：2011.7

  In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different

  在本文中，我们报道了用4-（4-甲基哌嗪-1-基）苯基，（1-苄基哌啶-4- yl）及其结构变体。发现在不同different病毒感染的鼠细胞模型的效价和活性方面，一些有前途的类似物在抗病毒方面比奎纳克林更有利。它们还表现出对人类病毒蛋白片段的更高结合亲和力（hPrP 121–231）比奎纳克林高，并且在PAMPA-BBB分析中的渗透率在CNS渗透候选物范围内。当在过表达Pgp的细胞系上进行双向分析评估时，与奎纳克林相比，一种类似物对Pgp外排活性的敏感性较低。两者合计，结果表明连接到a啶，四氢ac啶和喹啉骨架上的取代9-氨基侧链的重要作用。该侧链的性质影响基于细胞的效能，PAMPA渗透性和对hPrP 121-231的结合亲和力。
• [EN] ATYPICAL INHIBITORS OF MONOAMINE TRANSPORTERS; METHOD OF MAKING; AND USE THEREOF<br/>[FR] INHIBITEURS ATYPIQUES DE TRANSPORTEURS DE MONOAMINE ; LEUR PROCÉDÉ DE PRODUCTION ET D'UTILISATION
  申请人：US HEALTH

  公开号：WO2019094856A1

  公开（公告）日：2019-05-16

  Disclosed herein are a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine (DA) transporter (DAT) and several analogues also having affinity for the serotonin (5-HT) transporter (SERT) and/or sigma-1 receptor. Employing aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, desired dopamine transporter affinity has been retained along with improved metabolic stability over unsubstituted piperazine ring analogues. Importantly, these compounds have no predicted addictive liability. Also disclosed are methods for treating substance use disorders as well as other neuropsychiatric disorders such as ADHD, depression, narcolepsy, and cognitive impairment.

  本发明公开了一系列莫达非尼类似物化合物，这些化合物以中等至高亲和力结合多巴胺（DA）转运体（DAT），并且其中几种类似物还对血清素（5-HT）转运体（SERT）和/或σ-1受体具有亲和力。通过使用氨基哌啶、哌啶氨基、螺二氮杂环或取代的哌嗪功能团，不仅保留了对多巴胺转运体的亲和力，而且相对于未取代的哌嗪环类似物，其代谢稳定性得到了改善。重要的是，这些化合物没有预测到的成瘾性。此外，还公开了治疗物质使用障碍以及其他神经精神障碍如注意力缺陷多动障碍（ADHD）、抑郁症、嗜睡症和认知损害的方法。
• Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability
  作者：JoLynn B. Giancola、Alessandro Bonifazi、Jianjing Cao、Therese Ku、Alexandra J. Haraczy、Jenny Lam、Rana Rais、Mark A. Coggiano、Gianluigi Tanda、Amy Hauck Newman

  DOI：10.1016/j.ejmech.2020.112674

  日期：2020.12

  psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1–3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT

  尽管在开发治疗精神兴奋剂使用障碍的药物方面付出了相当大的努力，但没有一种药物被证明是有效的，这使得患者群体服务不足，并且关于开发药物疗法应该针对什么作用机制的问题也没有得到解答。基于 (±) 莫达非尼的非典型多巴胺转运蛋白 (DAT) 抑制剂已在精神兴奋剂滥用的临床前模型中显示出治疗潜力。然而，代谢不稳定以及哌嗪类似物的其他局限性1-3阻碍了进一步的发展。在本文中，用一系列氨基哌啶 (A) 和哌啶胺 (B) 探索了哌嗪环的生物等排取代，其中合成了具有末端叔胺或酰胺的化合物。几种先导化合物在大鼠肝微粒体中显示出高至中等的 DAT 亲和力和代谢稳定性。 与可卡因相比，氨基哌啶7 (DAT K i  = 50.6 nM)、21b (DAT K i  = 77.2 nM) 和33 (DAT K i = 30.0 nM) 仅对小鼠的行走活动产生最小的刺激，表明非典型的 DAT 抑制剂谱.
• Atypical inhibitors of monoamine transporters; method of making; and use thereof
  申请人：THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：US11365195B2

  公开（公告）日：2022-06-21

  Disclosed herein are a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine (DA) transporter (DAT) and several analogues also having affinity for the serotonin (5-HT) transporter (SERT) and/or sigma-1 receptor. Employing aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, desired dopamine transporter affinity has been retained along with improved metabolic stability over unsubstituted piperazine ring analogues. Importantly, these compounds have no predicted addictive liability. Also disclosed are methods for treating substance use disorders as well as other neuropsychiatric disorders such as ADHD, depression, narcolepsy, and cognitive impairment.

  本文公开了一系列莫达非尼类似物，它们能与多巴胺（DA）转运体（DAT）产生中度到高度的亲和力，还有几种类似物也能与5-羟色胺（5-HT）转运体（SERT）和/或sigma-1受体产生亲和力。与未取代的哌嗪环类似物相比，采用氨基哌啶、哌啶氨基、螺双环偶氮或取代的哌嗪官能团的多巴胺转运体亲和性得到了保留，代谢稳定性也得到了改善。重要的是，这些化合物没有预测的成瘾性。还公开了治疗药物使用障碍以及其他神经精神疾病（如多动症、抑郁症、嗜睡症和认知障碍）的方法。
• ATYPICAL INHIBITORS OF MONOAMINE TRANSPORTERS; METHOD OF MAKING; AND USE THEREOF
  申请人：THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPT. OF HEALTH AND HUMAN SERVICES

  公开号：US20210024523A1

  公开（公告）日：2021-01-28

  Disclosed herein are a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine (DA) transporter (DAT) and several analogues also having affinity for the serotonin (5-HT) transporter (SERT) and/or sigma-1 receptor. Employing aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, desired dopamine transporter affinity has been retained along with improved metabolic stability over unsubstituted piperazine ring analogues. Importantly, these compounds have no predicted addictive liability. Also disclosed are methods for treating substance use disorders as well as other neuropsychiatric disorders such as ADHD, depression, narcolepsy, and cognitive impairment.