2-(3,4-dichlorophenyl)-1-[(2S,6R)-2,6-dimethyl-4-[3-(N-phenylanilino)propyl]piperazin-1-yl]ethanone | 409313-71-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-(3,4-dichlorophenyl)-1-[(2S,6R)-2,6-dimethyl-4-[3-(N-phenylanilino)propyl]piperazin-1-yl]ethanone
• CAS: 409313-71-9
• 化学式: C₂₉H₃₃Cl₂N₃O
• 分子量: 510.507
• InChiKey: DZBWZIUWBWWPQJ-ZRZAMGCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  26.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(3,4-dichlorophenyl)-1-[(2S,6R)-2,6-dimethyl-4-[3-(N-phenylanilino)propyl]piperazin-1-yl]ethanone 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 [3-(cis-3,5-dimethyl-4-[2-(3,4-dichlorophenyl)ethyl]-1-piperazinyl)propyl]diphenylamine
  参考文献：
  名称：

  [3-顺式3,5-二甲基-（1-哌嗪基）烷基]-双-（4'-氟苯基）胺类似物作为多巴胺转运蛋白的新探针。

  摘要：

  在不断努力确定用于研究多巴胺转运蛋白（DAT）的新型探针中，我们发现sigma受体拮抗剂rimcazole以中等亲和力（K（i）= 224nM）与DAT结合。先前SAR研究的结果表明，用双-（4'-氟苯基）胺取代rimcazole的咔唑环系统可能会改善DAT的结合亲和力和选择性。因此，合成了一系列新的[3-顺式-3，5-二甲基-（1-哌嗪基）烷基]双-（4′-氟苯基）胺。该系列中最有效的化合物（9b）取代了大鼠尾状-丘脑（K（i）= 17.6nM）中的[3H] WIN 35,428结合，具有与GBR 12909相当的亲和力。尽管在DAT上具有高亲和力结合，并且与GBR 12909，

  DOI：

  10.1016/s0960-894x(01)00662-x
• 作为产物：
  描述：

  3,4-二氯苯乙酸 以 氯化亚砜 、 甲苯 为溶剂， 生成 2-(3,4-dichlorophenyl)-1-[(2S,6R)-2,6-dimethyl-4-[3-(N-phenylanilino)propyl]piperazin-1-yl]ethanone
  参考文献：
  名称：

  Dual Probes for the Dopamine Transporter and σ₁ Receptors:  Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

  摘要：

  Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K-i = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues. (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K-i = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K-i = 77 and 124 nM, respectively, 17; K-i = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.

  DOI：

  10.1021/jm030008u

文献信息

• [3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4′-fluorophenyl)amine analogues as novel probes for the dopamine transporter
  作者：Jianjing Cao、Stephen M Husbands、Theresa Kopajtic、Jonathan L Katz、Amy Hauck Newman

  DOI：10.1016/s0960-894x(01)00662-x

  日期：2001.12

  rimcazole, binds with moderate affinity (K(i)=224nM) to the DAT. The results from previous SAR studies suggested that substitution of the carbazole ring system of rimcazole with bis-(4'-fluorophenyl)amine might improve binding affinity and selectivity for the DAT. Thus, a novel series of [3-cis-3,5-dimethyl-(1-piperazinyl)alkyl]bis-(4'-fluorophenyl)amines were synthesized. The most potent compound in this

  在不断努力确定用于研究多巴胺转运蛋白（DAT）的新型探针中，我们发现sigma受体拮抗剂rimcazole以中等亲和力（K（i）= 224nM）与DAT结合。先前SAR研究的结果表明，用双-（4'-氟苯基）胺取代rimcazole的咔唑环系统可能会改善DAT的结合亲和力和选择性。因此，合成了一系列新的[3-顺式-3，5-二甲基-（1-哌嗪基）烷基]双-（4′-氟苯基）胺。该系列中最有效的化合物（9b）取代了大鼠尾状-丘脑（K（i）= 17.6nM）中的[3H] WIN 35,428结合，具有与GBR 12909相当的亲和力。尽管在DAT上具有高亲和力结合，并且与GBR 12909，
• Dual Probes for the Dopamine Transporter and σ₁ Receptors:  Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents
  作者：Jianjing Cao、Santosh S. Kulkarni、Stephen M. Husbands、Wayne D. Bowen、Wanda Williams、Theresa Kopajtic、Jonathan L. Katz、Clifford George、Amy Hauck Newman

  DOI：10.1021/jm030008u

  日期：2003.6.1

  Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K-i = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues. (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K-i = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K-i = 77 and 124 nM, respectively, 17; K-i = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.