S-(+)-2β-carbobenzoxy-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: S-(+)-2β-carbobenzoxy-3α-(bis[4-fluorophenyl]methoxy)tropane
• 英文别名: benzyl (1S,2S,3S,5R)-3-[bis(4-fluorophenyl)methoxy]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• 化学式: C₂₉H₂₉F₂NO₃
• 分子量: 477.551
• InChiKey: DCRIIMMZVJPZAH-WKAQUBQDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 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， -78.0~50.0 ℃ 、344.74 kPa 条件下， 反应 141.0h， 生成 S-(+)-2β-carbobenzoxy-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

• 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.
• 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.