S-(-)-carbomethoxytropinone | 112652-64-9

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: S-(-)-carbomethoxytropinone
• 英文别名: (-)-2α-carbomethoxytropinone；(S)-(-)-2-(carbomethoxy)-3-tropinone；(R)-2-carbomethoxy-3-tropinone；methyl (1S,2R,5R)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 112652-64-9
• 化学式: C₁₀H₁₅NO₃
• 分子量: 197.234
• InChiKey: WXEMSGQRTGSYOG-BKPPORCPSA-N

物化性质

• 沸点：
  294.1±35.0 °C(Predicted)
• 密度：
  1.173±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  S-(-)-carbomethoxytropinone 在 platinum(IV) oxide 氢气 作用下， 以 乙醇 为溶剂， 反应 96.0h， 以86%的产率得到(S)-allopseudoecgonine methyl ester
  参考文献：
  名称：

  Enantioselective synthesis of S-(+)-2β-carboalkoxy-3α-[bis(4-fluorophenyl)methoxy]tropanes as novel probes for the dopamine transporter

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(02)00155-5
• 作为产物：
  描述：

  托品酮 在 甲醇 、 sodium hydride 作用下， 以 环己烷 为溶剂， 生成 S-(-)-carbomethoxytropinone
  参考文献：
  名称：

  The Discovery of an Unusually Selective and Novel Cocaine Analog: Difluoropine. Synthesis and Inhibition of Binding at Cocaine Recognition Sites

  摘要：

  Cocaine is a stimulant drug with a high abuse liability. Although it inhibits several monamine transporters in the mammalian brain, its primary mechanism of action has been ascribed to its inhibition of the dopamine transporter. The synthesis, characterization, and receptor binding properties of all eight isomers of a unique tropane analog, 2-carbomethoxy-3-[bis(4-fluorophenyl)methoxy]tropane is described. In addition, we report that the S-enantiomer, (S)-(+)-2 beta-carbomethoxy-3 alpha-[bis(4-fluorophenyl)methoxy]tropane, Difluoropine, is a potent (IC50 10.9 nM) and selective (324 [DA/5HT]) ligand for the dopamine transporter.

  DOI：

  10.1021/jm00039a014

文献信息

• Synthesis and ligand binding of cocaine isomers at the cocaine receptor
  作者：F. Ivy Carroll、Anita H. Lewin、Philip Abraham、Karol Parham、John W. Boja、Michael J. Kuhar

  DOI：10.1021/jm00107a003

  日期：1991.3

  transporter has been found to be stereoselective. Thus, the seven possible stereoisomers of (-)-cocaine have been synthesized and found to inhibit [3H]-2 beta-carbomethoxy-3 beta-(4-fluoro-phenyl)tropane [( 3H]WIN 35,428) with potencies ranging from 1/60 to 1/600 of that of (-)-cocaine. The synthesis and characterization of all new compounds is presented.

  已经发现多巴胺转运蛋白上的可卡因结合位点是立体选择性的。因此，已经合成了（-）-可卡因的七个可能的立体异构体，并发现其抑制[3H] -2β-羰甲氧基-3β-（4-氟-苯基）托烷[（3H] WIN 35,428）的能力范围为（-）-可卡因的1/60至1/600。介绍了所有新化合物的合成和表征。
• Synthesis and Ligand Binding of Tropane Ring Analogues of Paroxetine
  作者：Kathryn I. Keverline-Frantz、John W. Boja、Michael J. Kuhar、Philip Abraham、Jason P. Burgess、Anita H. Lewin、F. Ivy Carroll

  DOI：10.1021/jm970669p

  日期：1998.1.1

  binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by

  （3S，4R）-4-（4-氟苯基）-3-[[3,4-（亚甲基二氧基）苯氧基]甲基]哌啶[（3S，9R）-3，帕罗西汀]是选择性5-羟色胺再摄取抑制剂（SSRI）在人类中用作抗抑郁药。在以前的研究中，我们报道了某些（1R）-3β-（取代的苯基）降冰片烷2β-羧酸甲酯（2a）对5-羟色胺转运蛋白（5-HTT）表现出高亲和力和合理的选择性。2a和（3S，4R）-3之间的主要结构差异是2a具有不同的绝对立体化学，并具有3中不存在的亚乙基桥。此外，2a具有与芳基环相邻的碳甲氧基取代基，而（3S， 4R）-3含有[3，4-（亚甲基二氧基）苯氧基]甲基。在这项研究中，我们介绍了3-（4-氟苯基）-2-[[3，4-（亚甲基二氧基）苯氧基]甲基]降冰片烷++（4）。抑制[3H]帕罗西汀结合的数据表明，具有与帕罗西汀相同的立体化学的（1R）-2 beta，3 alpha-4c对5-HTT具有最高的亲和力。令人惊讶的是，抑制[3H]
• Stereoselective inhibition of human butyrylcholinesterase by pbosphonotbiolate analogs of (+)- and (−)-cocaine
  作者：Clifford E. Berkman、Gail E. Underiner、John R. Cashman

  DOI：10.1016/s0006-2952(97)00403-6

  日期：1997.12

  analogs for both (-)- and (+)-cocaine hydrolysis were synthesized and tested as inhibitors of human BuChE-catalyzed hydrolysis of butyrylthiocholine. The phosphonothiolate corresponding to the transition state for (-)-cocaine hydrolysis was a competitive inhibitor with a Ki value of 55.8 microM. The phosphonothiolate corresponding to the transition state for (+)-cocaine hydrolysis gave a Ki value of

  先前已经显示，人丁酰胆碱酯酶（BuChE； EC 3.1.1.8）将可卡因（苯甲酰芽子碱甲酯）水解为芽子甲酯，是将这种物质解毒成无药理活性代谢物的重要手段。天然存在的（-）-可卡因水解成芽子碱甲酯的速度比非天然（+）-可卡因异构体慢约2000倍。与先前的研究很好地吻合，（-）可卡因以相对良好的亲和力与人BuChE结合，并竞争性地抑制了Ki值为8.0 microM的分光光度法底物丁酰硫代胆碱的水解。同样，（+）可卡因也显示出对人BuChE的相对高亲和力，竞争性抑制了丁酰硫代胆碱的水解，Ki值为5.4 microM。合成了对应于（-）-和（+）-可卡因水解的过渡态类似物的硫代膦酸酯，并作为人BuChE催化的丁硫代胆碱水解的抑制剂进行了测试。对应于（-）-可卡因水解的过渡态的硫代磷酸硫醚是竞争性抑制剂，Ki值为55.8 microM。对应于（+）-可卡因水解的过渡态的硫代膦酸酯给出的Ki值为25
• A practical synthesis of (+)-cocaine
  作者：Anita H. Lewin、T. Naseree、F. Ivy Carroll

  DOI：10.1002/jhet.5570240104

  日期：1987.1

  (+)-Cocaine has been prepared from commercially available 3-tropinone in four steps. Synthetic procedures and experimental details are provided.

  （+）-可卡因已经由市售的3-tropinone分四个步骤制备。提供了合成程序和实验细节。
• 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.