(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carbonyl chloride | 717110-11-7

• 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: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carbonyl chloride
• CAS: 717110-11-7
• 化学式: C₁₃H₁₅Cl₂NO
• 分子量: 272.174
• InChiKey: DYKXDPJNHALZKV-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carbonyl chloride 在 盐酸 、 草酰氯 、 silver benzoate 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 19.5h， 生成 2-[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]acetyl chloride
  参考文献：
  名称：

  Synthesis, Molecular Modeling, and Biological Studies of Novel Piperidine-Based Analogues of Cocaine:  Evidence of Unfavorable Interactions Proximal to the 3α-Position of the Piperidine Ring

  摘要：

  A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.

  DOI：

  10.1021/jm0303296
• 作为产物：
  描述：

  (+)-4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylic Acid 在 草酰氯 作用下， 以 二氯甲烷 为溶剂， 生成 (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carbonyl chloride
  参考文献：
  名称：

  1-氮杂双环-[3.2.1]辛烷的合成和生物学评估：新型多巴胺转运蛋白抑制剂。

  摘要：

  描述了一系列6-取代的1-氮杂双环[3.2.1]辛烷的合成和生物活性。1-氮杂双环[3.2.1]辛烷代表一类新的化合物，这些化合物表现出高度依赖于分子的整体拓扑结构和绝对立体化学的单胺转运蛋白抑制活性。

  DOI：

  10.1016/s0960-894x(00)00308-5

文献信息

• Synthesis and biological evaluation of 1-azabicyclo-[3.2.1]octanes: new dopamine transporter inhibitors
  作者：Amir P Tamiz、Miles P Smith、Istvan Enyedy、Judith Flippen-Anderson、Mei Zhang、Kenneth M Johnson、Alan P Kozikowski

  DOI：10.1016/s0960-894x(00)00308-5

  日期：2000.8

  The synthesis and biological activity of a series of 6-substituted 1-azabicyclo[3.2.1]octanes are described. 1-Azabicyclo[3.2.1]octanes represent a new class of compounds that exhibit monoamine transporter inhibitory activity highly dependent on the overall topology and the absolute stereochemistry of the molecule.

  描述了一系列6-取代的1-氮杂双环[3.2.1]辛烷的合成和生物活性。1-氮杂双环[3.2.1]辛烷代表一类新的化合物，这些化合物表现出高度依赖于分子的整体拓扑结构和绝对立体化学的单胺转运蛋白抑制活性。
• Pharmacological and Behavioral Analysis of the Effects of Some Bivalent Ligand-Based Monoamine Reuptake Inhibitors
  作者：Amir P. Tamiz、Bidhan C. Bandyopadhyay、Jianrong Zhang、Judith L. Flippen-Anderson、Mei Zhang、Chen Z. Wang、Kenneth M. Johnson、Srihari Tella、Alan P. Kozikowski

  DOI：10.1021/jm000552s

  日期：2001.5.1

  the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as

  以对映体纯形式制备新型的基于哌啶的二价配体，并评估其抑制多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）向大鼠脑神经末梢（突触小体）再摄取的能力。在这项研究中，我们成功地使用了（1）连接两个基于哌啶的单体单元的连接链的长度，以及（2）哌啶单体的绝对构型作为调整在三个单胺转运蛋白上的活性和选择性的手段经过测试。在这个系列中，由两个由五亚甲基间隔基连接的（+）-反-哌啶单元组成的二价配体16具有高DA转运蛋白（DAT）和5-HT转运蛋白（SERT）活性的组合（K（i）分别为39 nM和7 nM）。哌啶16能够还原可卡因 单独对小鼠的运动产生影响，而对运动没有任何影响。此外，在大鼠的药物鉴别研究中，化合物16（1-10 mg / kg）不能替代可卡因。但是，由两个（-）-反式-哌啶单元组成的类似的二价配体15具有SERT选择性，在拮抗可卡因的运动刺激活性方面效果较差。本文所述的基于哌
• Application of the Bivalent Ligand Approach to the Design of Novel Dimeric Serotonin Reuptake Inhibitors
  作者：Amir P. Tamiz、Jianrong Zhang、Mei Zhang、Cheng Z. Wang、Kenneth M. Johnson、Alan P. Kozikowski

  DOI：10.1021/ja000199f

  日期：2000.6.1
• SAR Studies of Piperidine-Based Analogues of Cocaine. Part 3: Oxadiazoles
  作者：Pavel A Petukhov、Mei Zhang、Kenneth J Johnson、Srihari R Tella、Alan P Kozikowski

  DOI：10.1016/s0960-894x(01)00379-1

  日期：2001.8

  The synthesis of novel 4 beta -aryl-1-methyl-3 alpha-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT. NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4 beta-(4-Chlorophenyl)-1-methyl-3 alpha-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Synthesis, Molecular Modeling, and Biological Studies of Novel Piperidine-Based Analogues of Cocaine:  Evidence of Unfavorable Interactions Proximal to the 3α-Position of the Piperidine Ring
  作者：Pavel A. Petukhov、Jianrong Zhang、Cheng Z. Wang、Yan Ping Ye、Kenneth M. Johnson、Alan P. Kozikowski

  DOI：10.1021/jm0303296

  日期：2004.6.1

  A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.