4-fluoro-N-(4-fluorophenyl)-N-[3-(piperazin-1-yl)propyl]aniline | 212832-16-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-fluoro-N-(4-fluorophenyl)-N-[3-(piperazin-1-yl)propyl]aniline
• 英文别名: 1-[3-[N,N-bis(4-fluorophenyl)amino]propyl]piperazine；Bis-(4-fluoro-phenyl)-(3-piperazin-1-yl-propyl)-amine；4-fluoro-N-(4-fluorophenyl)-N-(3-piperazin-1-ylpropyl)aniline
• CAS: 212832-16-1
• 化学式: C₁₉H₂₃F₂N₃
• 分子量: 331.409
• InChiKey: LRJWNYKCDTWXAG-UHFFFAOYSA-N

物化性质

• 沸点：
  459.8±45.0 °C(Predicted)
• 密度：
  1.162±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  18.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-fluoro-N-(4-fluorophenyl)-N-[3-(piperazin-1-yl)propyl]aniline 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 2.0h， 生成 JJC 2-010
  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
• 作为产物：
  描述：

  4,4'-二氟二苯胺 在 lithium aluminium tetrahydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 5.0h， 生成 4-fluoro-N-(4-fluorophenyl)-N-[3-(piperazin-1-yl)propyl]aniline
  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

• Syntheses of Novel Diphenyl Piperazine Derivatives and Their Activities as Inhibitors of Dopamine Uptake in the Central Nervous System
  作者：Makoto Kimura、Tomoko Masuda、Koji Yamada、Masaki Mitani、Nobuo Kubota、Nobuyuki Kawakatsu、Kenichi Kishii、Masato Inazu、Yuji Kiuchi、Katsuji Oguchi、Takayuki Namiki

  DOI：10.1016/s0968-0896(03)00061-0

  日期：2003.4

  A new series of diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, which were modified at sites between the diphenyl and piperazine moieties, was prepared and evaluated for dopamine transporter binding affinity with [(3)H]GBR12935 in rat striatal membranes. These synthesized compounds showed apparent dopamine transporter binding affinities (IC(50)<30 nM) and some

  制备了一系列新的含有苯基取代的氨基丙醇部分的二苯基哌嗪衍生物，该衍生物在二苯基和哌嗪部分之间的位点进行了修饰，并评估了大鼠纹状体膜中多巴胺转运蛋白与[（3）H] GBR12935的结合亲和力。这些合成的化合物表现出明显的多巴胺转运蛋白结合亲和力（IC（50）<30 nM），其中一些活性与被称为强力多巴胺摄取抑制剂的GBR12909活性相当，显示出具有纳摩尔范围IC（50）值的活性。其中，使用体内脑微透析评估了大鼠纹状体中1- [4,4-双（4-氟苯基）丁基] -4- [2-羟基-3-（苯基氨基）丙基]哌嗪2的细胞外多巴胺水平。腹膜内给药2（0.01、0.03或0。1 mmol / kg）引起大鼠纹状体透析液中多巴胺水平的剂量依赖性增加。2引起的多巴胺水平的最大增加大于GBR12909。这些新颖的二苯基哌嗪衍生物的药理数据表明，该化合物在中枢神经系统中具有有效的多巴胺摄取抑制活性。
• Novel Azido and Isothiocyanato Analogues of [3-(4-Phenylalkylpiperazin-1-yl)propyl]bis(4-fluorophenyl)amines as Potential Irreversible Ligands for the Dopamine Transporter
  作者：Jianjing Cao、John R. Lever、Theresa Kopajtic、Jonathan L. Katz、Anh T. Pham、Muhsinah L. Holmes、Joseph B. Justice、Amy Hauck Newman

  DOI：10.1021/jm049670w

  日期：2004.12.1

  Potential irreversible ligands were prepared, based on a series of 3-(1-piperazinyl)propyl-N,N-bis(4-fluorophenyl)amines, as molecular probes for the dopamine transporter (DAT). Both azido and isothiocyanato-substituted phenylalkyl analogues were synthesized and evaluated for displacement of [H-3]WIN 35 428 in rat caudate putamen tissue. All of the analogues showed moderate binding potencies at the DAT. The azido analogue, 16b, was radiolodinated and used to photolabel human DAT-transfected HEK 293 cell membranes. [I-125] 16b irreversibly labeled an similar to80 kDa band corresponding to the DAT detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This radioligand provides a novel addition to the growing arsenal of structurally diverse irreversible ligands that are being used to identify binding domains on the DAT Characterizing points of attachment of these irreversible probes to the DAT protein will ultimately help elucidate the three-dimensional arrangement of the transmembrane domains, identify individual binding sites of the DAT inhibitors, and direct future drug design.
• Dual DAT/σ1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol
  作者：Jianjing Cao、Theresa Kopajtic、Jonathan L. Katz、Amy Hauck Newman

  DOI：10.1016/j.bmcl.2008.08.065

  日期：2008.10

  Ester analogs of (+/-) 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma 1 receptors, and compared to GBR 12909 and several known sigma 1 receptor ligands. Most of these compounds demonstrated high affinity (K(i) = 4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma 1 receptors was observed and most of the ester analogs of the more active S- enantiomer showed comparable binding affinities at both DAT and sigma 1 receptors with a maximal 16-fold DAT/sigma 1 selectivity. Published by Elsevier Ltd.
• [EN] SIGMA LIGANDS AND IKK / NF - KB INHIBITORS FOR MEDICAL TREATMENT<br/>[FR] LIGANDS DES RÉCEPTEURS SIGMA ET INHIBITEURS D'IKK / NF-KB POUR TRAITEMENT MÉDICAL
  申请人：UNIV DUNDEE

  公开号：WO2009074809A1

  公开（公告）日：2009-06-18

  The present invention relates to agents that act in concert with sigma receptor ligands to enhance their effectiveness in the treatment of cancer and inflammatory disease. It also relates to methods whereby agents can be identified that will be of use in combination with sigma ligands in the treatment of the aforesaid diseases.
• 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.