(±)-2β-carboethoxy-3α-bis[(4-fluorophenyl)methoxy]tropane

• 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: (±)-2β-carboethoxy-3α-bis[(4-fluorophenyl)methoxy]tropane
• 英文别名: ethyl (1S,2S,3S,5R)-3-[bis(4-fluorophenyl)methoxy]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• 化学式: C₂₄H₂₇F₂NO₃
• 分子量: 415.48
• InChiKey: FRGNNZYHLRTEQP-MLNNCEHLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (±)-2β-carboethoxy-3α-bis[(4-fluorophenyl)methoxy]tropane 在 1-氯乙基氯甲酸酯 、 sodium carbonate 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 3.0h， 以97%的产率得到S-(+)-N-nor-2β-carboethoxy-3α-[bis(4-fluorophenyl)methoxy]tropane
  参考文献：
  名称：

  结构-活性关系研究的一系列新的（S）-2β取代的3alpha- [双（4-氟-或4-氯苯基）甲氧基]托烷类似物用于体内研究。

  摘要：

  通常，基于3α-​​（二苯甲氧基）托烷（苯并卓平）的多巴胺摄取抑制剂在精神兴奋剂滥用模型中未显示出可卡因样的药理活性，因此已被提议作为治疗可卡因成瘾的潜在药物。然而，发现一些（S）-2-碳烷氧基取代的3α-[双（4-氟苯基）甲氧基]托烷类似物可刺激运动能力并替代受过训练的可卡因识别对象，这表明了2-位取代基的作用。调解这些可卡因样的行为。在这里，我们描述了一系列新型的N和2-取代的3α-[双（4-氟-或4-氯苯基）甲氧基]托烷类似物的合成。这些类似物大多数都表现出与多巴胺转运蛋白的高亲和力结合（DAT； K（i）= 1.8-40 nM），和其他单胺转运蛋白和毒蕈碱M（1）受体的选择性。当（S）-2-羰基烷氧基取代基被（S）-2-乙烯基取代时，所得类似物11在该系列（K（i）= 1.81 nM）中显示出最高的DAT结合亲和力，其DAT选择性优于血清素转运蛋白（ SERT； 989倍），去甲肾上腺素转运蛋白（NET；

  DOI：

  10.1021/jm060762q
• 作为产物：
  描述：

  托品酮 在 platinum(IV) oxide 盐酸 、 正丁基锂 、 水 、 氢气 、 对甲苯磺酸 、 (R)-(-)-N-新戊基-1-苯基-2-(1-吡啶烷)乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 苯 为溶剂， -78.0~20.0 ℃ 、344.74 kPa 条件下， 反应 141.0h， 生成 (±)-2β-carboethoxy-3α-bis[(4-fluorophenyl)methoxy]tropane
  参考文献：
  名称：

  Structure−Activity Relationship Comparison of (S)-2β-Substituted 3α-(Bis[4-fluorophenyl]methoxy)tropanes and (R)-2β-Substituted 3β-(3,4-Dichlorophenyl)tropanes at the Dopamine Transporter

  摘要：

  Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [H-3]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K-i = 5.5 - 100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis [4-fluorophenyl] methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC50 = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.

  DOI：

  10.1021/jm0300375

文献信息

• Structure–Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders
  作者：Mu-Fa Zou、Jianjing Cao、Ara M. Abramyan、Theresa Kopajtic、Claudio Zanettini、Daryl A. Guthrie、Rana Rais、Barbara S. Slusher、Lei Shi、Claus J. Loland、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.7b01454

  日期：2017.12.28

  synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from

  迄今为止，治疗可卡因使用障碍的药物开发尚未取得成功，使该患者群体没有药物治疗选择。由于多巴胺转运蛋白 (DAT) 在可导致成瘾的可卡因增强作用中发挥着重要作用，因此开发了非典型 DAT 抑制剂来阻止可卡因与 DAT 结合，但它们本身并不像可卡因。在此，合成了一系列新型 DAT 抑制剂，并根据其药理学特征，在小鼠肝微粒体的 I 期代谢稳定性研究中评估了先导化合物 10a，并在小鼠的运动活性和药物辨别范例中与可卡因进行了比较。一项分子动力学模拟研究支持了以下假设：非典型 DAT 抑制剂在 DAT 上具有相似的结合姿势，其构象与可卡因不同。这些差异可能最终有助于它们独特的行为特征和作为可卡因使用障碍疗法的开发潜力。
• Enantioselective synthesis of S-(+)-2β-carboalkoxy-3α-[bis(4-fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter
  作者：Mu-Fa Zou、Gregory E Agoston、Yuri Belov、Theresa Kopajtic、Jonathan L Katz、Amy Hauck Newman

  DOI：10.1016/s0960-894x(02)00155-5

  日期：2002.5

  Synthesis of a series of pure S-(+)-2beta-carboalkoxy-3alpha-[bis(4-fluotophenyl)metlioxy]tropanes (>99% ee) was achieved by employing a chiral amine-induced asymmetric reaction of tropinone with methyl cyanoformate as the key step. In this series, all of the S-(+)-enantiomers were 2-fold more potent than their racemic mixtures and all displayed high-affinity binding for DAT (K-i - 13-40 nM). These data support previous findings of significant divergence in structural requirements for high-affinity DAT binding among tropane-based inhibitors. Furthermore, the 2-substituent in the 3alpha-[bis(4-fluorophenyl)methoxy]tropane series is well tolerated at the DAT but not at SERT (K-i = 690-2040 nM), or muscarinic M-1 receptors (K-i - 133-4380 nM) resulting in highly selective DAT ligands that may provide new leads toward a cocaine-abuse therapeutic. (C) 2002 Elsevier Science Ltd. All rights reserved.
• WO2007/25055
  申请人：——

  公开号：——

  公开（公告）日：——
• Structure−Activity Relationship Comparison of (<i>S</i>)-2β-Substituted 3α-(Bis[4-fluorophenyl]methoxy)tropanes and (<i>R</i>)-2β-Substituted 3β-(3,4-Dichlorophenyl)tropanes at the Dopamine Transporter
  作者：Mu-Fa Zou、Theresa Kopajtic、Jonathan L. Katz、Amy Hauck Newman

  DOI：10.1021/jm0300375

  日期：2003.7.1

  Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [H-3]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K-i = 5.5 - 100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis [4-fluorophenyl] methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC50 = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.
• Structure−Activity Relationship Studies on a Novel Series of (<i>S</i>)-2β-Substituted 3α-[Bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane Analogues for in Vivo Investigation
  作者：Mu-Fa Zou、Jianjing Cao、Theresa Kopajtic、Rajeev I. Desai、Jonathan L. Katz、Amy Hauck Newman

  DOI：10.1021/jm060762q

  日期：2006.10.1

  yet inhibition of dopamine uptake potency remained comparably high (IC(50) range = 1.5-2.5 nM). Interestingly, the 4'-Cl analogue (+/-)-6 substituted less in rats trained to discriminate cocaine than the 4'-F analogue (+/-)-5. These studies demonstrate that manipulation of the 2-, N-, and 3-position substituents in the 3alpha-(diphenylmethoxy)tropane class of dopamine uptake inhibitors can result in ligands

  通常，基于3α-​​（二苯甲氧基）托烷（苯并卓平）的多巴胺摄取抑制剂在精神兴奋剂滥用模型中未显示出可卡因样的药理活性，因此已被提议作为治疗可卡因成瘾的潜在药物。然而，发现一些（S）-2-碳烷氧基取代的3α-[双（4-氟苯基）甲氧基]托烷类似物可刺激运动能力并替代受过训练的可卡因识别对象，这表明了2-位取代基的作用。调解这些可卡因样的行为。在这里，我们描述了一系列新型的N和2-取代的3α-[双（4-氟-或4-氯苯基）甲氧基]托烷类似物的合成。这些类似物大多数都表现出与多巴胺转运蛋白的高亲和力结合（DAT； K（i）= 1.8-40 nM），和其他单胺转运蛋白和毒蕈碱M（1）受体的选择性。当（S）-2-羰基烷氧基取代基被（S）-2-乙烯基取代时，所得类似物11在该系列（K（i）= 1.81 nM）中显示出最高的DAT结合亲和力，其DAT选择性优于血清素转运蛋白（ SERT； 989倍），去甲肾上腺素转运蛋白（NET；