(2R)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-3-phenylpropan-2-ol | 406945-32-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-3-phenylpropan-2-ol
• 英文别名: (2R)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazin-1-yl]-3-phenylpropan-2-ol
• CAS: 406945-32-2
• 化学式: C₂₈H₃₂F₂N₂O₂
• 分子量: 466.571
• InChiKey: GJDQYWYMCFMZIM-HHHXNRCGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  35.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-3-phenylpropan-2-ol 在 二乙胺基三氟化硫 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以305 mg的产率得到1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-[(2S)-2-fluoro-3-phenylpropyl]piperazine
  参考文献：
  名称：

  Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

  摘要：

  Novel derivatives of 1- [2- [bis(4-fluorophenyl)methoxy] ethyl] -4-(3 -phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethy1]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp(2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.

  DOI：

  10.1021/jm701270n
• 作为产物：
  描述：

  (R)-1-chloro-3-phenyl-2-propanol 、 1-[2-[双(4-氟苯基)甲氧基]乙基]哌嗪 在 N,N-二异丙基乙胺 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以83%的产率得到(2R)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-3-phenylpropan-2-ol
  参考文献：
  名称：

  长效多巴胺转运蛋白配体作为潜在可卡因滥用治疗剂的开发：1- [2- [双（4-（氟苯基）甲氧基]乙基] -4-（3-苯基丙基）哌嗪和1- [2-（二苯基甲氧基）乙基] -4-（3-苯基丙基）哌嗪。

  摘要：

  在寻找用于治疗可卡因滥用的长效剂时，一系列1- [2- [双[4-（4-氟苯基）甲氧基]乙基] -4-（3-苯基丙基）哌嗪的光学纯羟基化衍生物（1 ）和1- [2-（二苯基甲氧基）乙基] -4-（3-苯基丙基）哌嗪（2）（分别为GBR 12909和GBR 12935），并在体外和体内进行了评估。2-羟基化类似物的对映异构体显示出相当大的对映选择性。S对映异构体显示出更高的多巴胺转运蛋白（DAT）亲和力，并且发现R对映异构体在血清素转运蛋白（SERT）上具有更高的亲和力。羟基和哌嗪环之间的两个碳间隔基对于对映选择性至关重要，苯基和哌嗪环之间的烷基链长度会影响DAT和SERT的结合亲和力和选择性。与相应的苯丙基类似物相比，苯乙基类似物对SERT的结合亲和力更高，对DAT的亲和力和选择性更弱。因此，（S）-（+）-1- [4- [2- [双（4-（4-氟苯基）甲氧基]乙基]哌嗪基] -3-苯基丙烷-2-醇（6）对DAT的亲和力最高，

  DOI：

  10.1021/jm010430f

文献信息

• Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters
  作者：Ling-Wei Hsin、Li-Te Chang、Richard B. Rothman、Christina M. Dersch、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1021/jm701270n

  日期：2008.5.1

  Novel derivatives of 1- [2- [bis(4-fluorophenyl)methoxy] ethyl] -4-(3 -phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethy1]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp(2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.
• Development of Long-Acting Dopamine Transporter Ligands as Potential Cocaine-Abuse Therapeutic Agents:  Chiral Hydroxyl-Containing Derivatives of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine
  作者：Ling-Wei Hsin、Christina M. Dersch、Michael H. Baumann、David Stafford、John R. Glowa、Richard B. Rothman、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1021/jm010430f

  日期：2002.3.1

  In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909 and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The enantiomers of the 2-hydroxylated analogues

  在寻找用于治疗可卡因滥用的长效剂时，一系列1- [2- [双[4-（4-氟苯基）甲氧基]乙基] -4-（3-苯基丙基）哌嗪的光学纯羟基化衍生物（1 ）和1- [2-（二苯基甲氧基）乙基] -4-（3-苯基丙基）哌嗪（2）（分别为GBR 12909和GBR 12935），并在体外和体内进行了评估。2-羟基化类似物的对映异构体显示出相当大的对映选择性。S对映异构体显示出更高的多巴胺转运蛋白（DAT）亲和力，并且发现R对映异构体在血清素转运蛋白（SERT）上具有更高的亲和力。羟基和哌嗪环之间的两个碳间隔基对于对映选择性至关重要，苯基和哌嗪环之间的烷基链长度会影响DAT和SERT的结合亲和力和选择性。与相应的苯丙基类似物相比，苯乙基类似物对SERT的结合亲和力更高，对DAT的亲和力和选择性更弱。因此，（S）-（+）-1- [4- [2- [双（4-（4-氟苯基）甲氧基]乙基]哌嗪基] -3-苯基丙烷-2-醇（6）对DAT的亲和力最高，