(+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine | 263769-24-0

• 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: (+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine
• 英文别名: (3R,4S)-4-(4-chlorophenyl)-3-(hydroxymethyl)-1-methylpiperidine；[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanol
• CAS: 263769-24-0
• 化学式: C₁₃H₁₈ClNO
• 分子量: 239.745
• InChiKey: MVNHJEXPDKVMJY-DGCLKSJQSA-N

物化性质

• 沸点：
  329.2±42.0 °C(Predicted)
• 密度：
  1.129±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine 在 咪唑 、 碘 、 caesium carbonate 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 26.5h， 生成 (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-N-methylacetamide
  参考文献：
  名称：

  Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors:  Efficient Drug Discovery by Rational Lead Hybridization

  摘要：

  Some piperidine-based nocaine/modafinil hybrid ligands have been designed, synthesized, and found to display an improved potency at all three monoamine transporters and particularly for DAT and/or NET. Some highly active and selective monoamine transporter inhibitors with low nanomolar to subnanomolar potency were identified. Ligands of this type may find important applications as positron emission tomography imaging tools and in the treatment of central nervous system disorders such as depression and sleep apnea.

  DOI：

  10.1021/jm040117o
• 作为产物：
  描述：

  槟榔碱 在 lithium aluminium tetrahydride 、 sodium methylate 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， 反应 25.5h， 生成 (+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine
  参考文献：
  名称：

  基于可卡因的哌啶类似物的化学和药理作用。鉴定缺乏托烷骨架的有效DAT抑制剂。

  摘要：

  为了发现可用于治疗可卡因滥用的药物，我们选择重新探索Clarke等人首先报道的一类分子。于1973年被证实具有小鼠运动刺激活性。这些化合物是在4位带有4-氯苯基的哌啶-3-羧酸酯，因此，这些结构可被视为WIN系列化合物的截短形式，即，它们缺少托烷的二碳桥。该类别的所有成员均从氢溴槟榔碱开始合成，并通过拆分方法使用（+）-或（-）-二苯甲酰基酒石酸以光学纯净形式获得。有趣的是，我们发现这些哌啶确实在WIN 35，428在多巴胺转运蛋白上的结合和在[3 H]多巴胺摄取的抑制中的结合。在所有合成的化合物中，发现3-n-丙基衍生物（-）-9最有效，结合亲和力为3 nM。因此，这种简单的哌啶在结合亲和力方面的效果比可卡因高33倍，在抑制多巴胺摄取方面的效果比可卡因高29倍。尽管目前还没有努力“优化” DAT处的结合亲和力，但是发现正丙基衍生物（-）-9的实质活性是显着的。该化合物的活性仅比WIN系列

  DOI：

  10.1021/jm980028+

文献信息

• Monomeric and dimeric heterocycles, and therapeutic uses thereof
  申请人：Georgetown University

  公开号：US06440996B1

  公开（公告）日：2002-08-27

  The invention provides compounds of formula (I): X—L—X1  (I) wherein X and X1 are substituted piperidine, cyclohexane, or tetrahydropyran rings, and L is a linking group between X and X1; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson's disease, depression, or a disease wherein the administration of cocaine is indicated, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

  该发明提供了以下式（I）的化合物：X—L—X1（I），其中X和X1为取代的哌啶、环己烷或四氢吡喃环，L为连接X和X1之间的连接基团；以及包括式I化合物的药物组合物；用于制备式I化合物的中间体和方法；以及治疗药物成瘾、帕金森病、抑郁症或需要使用可卡因的疾病的治疗方法，包括向需要此类治疗的哺乳动物施用式I化合物或其药用盐。
• Development of new brain imaging agents based upon nocaine–modafinil hybrid monoamine transporter inhibitors
  作者：John L. Musachio、Jinsoo Hong、Masanori Ichise、Nicholas Seneca、Amira K. Brown、Jeih-San Liow、Christer Halldin、Robert B. Innis、Victor W. Pike、Rong He、Jia Zhou、Alan P. Kozikowski

  DOI：10.1016/j.bmcl.2006.03.066

  日期：2006.6

  C-11-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([C-11]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([C-11]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [C-11]5 and [C-11]6 display high affinity for the NET in vitro (K-i = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT. (c) 2006 Elsevier Ltd. All rights reserved.
• [EN] DOPAMINE-, NOREPINEPHRINE- AND SEROTONIN- TRANSPORTER- SELECTIVE HETEROCYCLIC COMPOUNDS AND THEIR THERAPEUTIC APPLICATIONS<br/>[FR] COMPOSES HETEROCYCLIQUES SELECTIFS VIS-A-VIS DES TRANSPORTEURS DE LA DOPAMINE, DE LA NOREPINEPHRINE ET DE LA SEROTONINE ET LEURS APPLICATIONS THERAPEUTIQUES
  申请人：UNIV GEORGETOWN

  公开号：WO2005041875A3

  公开（公告）日：2005-11-24
• 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.
• ANALOGS OF COCAINE
  申请人：GEORGETOWN UNIVERSITY

  公开号：EP0975595B1

  公开（公告）日：2009-06-17