O-1228 | 204068-79-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: O-1228
• 英文别名: (1R)-2β-carboxymethoxy-3α-(2-naphthyl)-8-methyl-8-azabicyclo[3.2.1]octane；3α-(2-naphthyl)tropane-2β-carboxylic acid methyl ester；(1R)-N-methyl-2β-methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]octane；methyl (1R,2S,3R,5S)-8-methyl-3-naphthalen-2-yl-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 204068-79-1
• 化学式: C₂₀H₂₃NO₂
• 分子量: 309.408
• InChiKey: ITFWLAOOLMWNLG-OKYOBFRVSA-N

物化性质

• 熔点：
  117-118 °C
• 沸点：
  438.0±45.0 °C(Predicted)
• 密度：
  1.146±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  O-1228 在 1-氯乙基氯甲酸酯 、 甲醇 作用下， 反应 5.75h， 以78%的产率得到(1R)-2β-methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]-octane
  参考文献：
  名称：

  Intermediates for the synthesis of radiolabelled tropanes

  摘要：

  本发明的化合物包括一种特定结合到特罗班识别位点的特罗班化合物或配体，例如神经元转运体如DAT。特罗班配体通过连接剂连接到特罗班配体的螯合配体上，用放射性锝或铼进行放射标记。本发明实施中有用的特罗班化合物或配体通常可用以下公式表示，其中R1和R2如上定义，且R1也可取代于特罗班环的C4位置：只要结合到DAT，任何符合上述一般公式II的特罗班化合物在本发明中均有用。有用的特罗班类似物具有3α-基团，即处于船状构型。本发明要求合成放射标记特罗班的中间体。

  公开号：

  EP1238978A3
• 作为产物：
  描述：

  盐酸古柯碱 在 硫酸 、 magnesium 、 三氯氧磷 作用下， 以 甲醇 为溶剂， 反应 27.0h， 生成 O-1228
  参考文献：
  名称：

  (−)-3β-Substituted Ecgonine Methyl Esters as Inhibitors for Cocaine Binding and Dopamine Uptake

  摘要：

  Ten 3 beta-ecgonine analogues were synthesized and characterized by H-1 and C-13 NMR, MS, and elemental analysis. The compounds were synthesized as (-)-stereoisomers from (-)-cocaine. These compounds were assessed for their ability to inhibit [H-3]cocaine binding to rat striatal tissue and to inhibit [H-3]DA uptake into rat striatal synaptosomes. In this series of compounds, the length of the spacer between the aryl group and the tropane skeleton ranged from 1 to 4 bond distances, and conformational flexibility of the linkage and orientation of the aryl ring system were controlled by various types of linkages. The most potent of the analogues was methyl-(1R-2-exo-3-exo)-8-methyl-3-(beta-styrenyl)-8-azabicyclo-[3.2.1]octane-2-carboxylate. One of the less potent compounds was found to inhibit [H-3]cocaine binding and [H-3]DA uptake with significantly different IC50 values, in contrast to 14 other 3 beta-substituted analogues. Molecular modeling and CoMFA analysis were used to obtain a rigorous structure-function relationship for the studied compounds. The results showed that the potencies of these 3 beta-substituted ecgonine methyl esters were dominated by steric effects and were acutely sensitive to the distance between the aryl ring and the tropane skeleton and to the orientation of the aryl ring system relative to the tropane skeleton. The current study provides a clearer picture of the shape and size of the putative hydrophobic binding pocket for the 3 beta substituent at the cocaine receptor as well as emphasizing the importance of a drug's free energy of solvation in obtaining structure-activity relationships.

  DOI：

  10.1021/jm970025h

文献信息

• Synthesis and Transporter Binding Properties of 3β-[4‘-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters:  Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporter
  作者：Bruce E. Blough、Kathryn I. Keverline、Zhe Nie、Hernán Navarro、Michael J. Kuhar、F. Ivy Carroll

  DOI：10.1021/jm020098n

  日期：2002.8.1

  series of 4'-substituted 3beta-phenyltropane-2beta-carboxylic acid methyl esters were synthesized and evaluated for binding at the dopamine transporter (DAT) in order to better define the pharmacophore for the cocaine binding site on the DAT. Results from the study of 3beta-[(4'-phenylalkyl)phenyl]tropane-2beta-carboxylic acid methyl esters (5a-c and 6a,b) revealed strong evidence of a previously unknown

  合成了一系列4'-取代的3β-苯基托烷-2β-羧酸甲酯，并评估了在多巴胺转运蛋白（DAT）上的结合，以便更好地定义DAT上可卡因结合位点的药效基团。3β-[（（4'-苯基烷基）苯基]托烷-2β-羧酸甲酯（5a-c和6a，b）的研究结果显示了以前未知的远程结合域的有力证据。3beta-[（（4'-苯乙基）苯基] tropane-2beta-羧酸甲酯（5a）在3beta-苯基和远端苯基之间有两个亚甲基接头，其IC（50）值为DAT为5.14 nM。在DAT，3beta- [4'-（苄基）苯基]和3beta- [4'-（苯丙基）苯基]类似物6b和5b的效力分别比5a低102倍和68倍。化合物5a对5-羟色胺和去甲肾上腺素转运蛋白也具有良好的亲和力（分别为K（i）= 21和6.5 nM），因此是非选择性单胺摄取抑制剂。静电效应对3beta-[（4'-苯基烯基）苯基] tropane-2beta-羧
• A Second-Generation ^99mTechnetium Single Photon Emission Computed Tomography Agent That Provides in Vivo Images of the Dopamine Transporter in Primate Brain
  作者：Peter C. Meltzer、Paul Blundell、Thomas Zona、Lihua Yang、Hong Huang、Ali A. Bonab、Eli Livni、Alan Fischman、Bertha K. Madras

  DOI：10.1021/jm0301484

  日期：2003.7.1

  The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for Parkinson's disease (Pd) and attention deficit hyperactivity disorder (ADHD). In ADHD, DAT density levels are elevated, while in Pd these levels are depleted. The depletion of DAT levels also corresponds with the loss of dopamine. We now describe the design, synthesis, biology, and SPECT imaging in nonhuman primates of second-generation (99m)technetium-based tropane ligands that bind potently and selectively to the DAT. We demonstrate that improved selectivity and biological stability allows sufficient agent to enter the brain and label the DAT in vivo to provide a quantitative measure of DAT density in nonhuman primates. We introduce FLUORATEC (N-[(2-((3'-N-propyl-(1"R)-3"alpha-(4-fluorophenyl)tropane-2"beta-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide), a DAT imaging agent that has emerged from these studies and is now in phase 1 clinical trials in the U.S.
• Intermediates for the synthesis of radiolabelled tropanes
  申请人：PRESIDENT AND FELLOWS OF HARVARD COLLEGE

  公开号：EP1238978A3

  公开（公告）日：2005-03-02

  The compounds of the present invention comprise a tropane compound or ligand that selectively binds to tropane recognition sites, e.g., neuron transporters such as the DAT. The tropane ligand is radiolabeled with a radioactive technetium or rhenium by a chelating ligand which is attached to the tropane ligand by a linker.Tropane compounds or ligands useful in the pratice of the present invention can generally be represented by formula II where R1 and R2 are defined as above and where R1 can also be substituted at the C4 position of the tropane ring:Any tropane compound of the general formula II is useful in the present invention so long as it binds to DAT.Useful tropane analogs have a 3α-group, i.e., are of the boat configuration.Intermediates for the synthesis of the radiolabeled tropanes are claimed.

  本发明的化合物包括一种特定结合到特罗班识别位点的特罗班化合物或配体，例如神经元转运体如DAT。特罗班配体通过连接剂连接到特罗班配体的螯合配体上，用放射性锝或铼进行放射标记。本发明实施中有用的特罗班化合物或配体通常可用以下公式表示，其中R1和R2如上定义，且R1也可取代于特罗班环的C4位置：只要结合到DAT，任何符合上述一般公式II的特罗班化合物在本发明中均有用。有用的特罗班类似物具有3α-基团，即处于船状构型。本发明要求合成放射标记特罗班的中间体。
• (−)-3β-Substituted Ecgonine Methyl Esters as Inhibitors for Cocaine Binding and Dopamine Uptake
  作者：Spencer F. Lieske、Biao Yang、Mohyee E. Eldefrawi、Alexander D. MacKerell,、Jeremy Wright

  DOI：10.1021/jm970025h

  日期：1998.3.1

  Ten 3 beta-ecgonine analogues were synthesized and characterized by H-1 and C-13 NMR, MS, and elemental analysis. The compounds were synthesized as (-)-stereoisomers from (-)-cocaine. These compounds were assessed for their ability to inhibit [H-3]cocaine binding to rat striatal tissue and to inhibit [H-3]DA uptake into rat striatal synaptosomes. In this series of compounds, the length of the spacer between the aryl group and the tropane skeleton ranged from 1 to 4 bond distances, and conformational flexibility of the linkage and orientation of the aryl ring system were controlled by various types of linkages. The most potent of the analogues was methyl-(1R-2-exo-3-exo)-8-methyl-3-(beta-styrenyl)-8-azabicyclo-[3.2.1]octane-2-carboxylate. One of the less potent compounds was found to inhibit [H-3]cocaine binding and [H-3]DA uptake with significantly different IC50 values, in contrast to 14 other 3 beta-substituted analogues. Molecular modeling and CoMFA analysis were used to obtain a rigorous structure-function relationship for the studied compounds. The results showed that the potencies of these 3 beta-substituted ecgonine methyl esters were dominated by steric effects and were acutely sensitive to the distance between the aryl ring and the tropane skeleton and to the orientation of the aryl ring system relative to the tropane skeleton. The current study provides a clearer picture of the shape and size of the putative hydrophobic binding pocket for the 3 beta substituent at the cocaine receptor as well as emphasizing the importance of a drug's free energy of solvation in obtaining structure-activity relationships.