O-603

• 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: O-603
• 英文别名: methyl (1R,2R,3R,5S)-3-[bis(4-fluorophenyl)methoxy]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• 化学式: C₂₃H₂₅F₂NO₃
• 分子量: 401.453
• InChiKey: XSYGBVSQKPLETJ-DOIPELPJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 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 盐酸 、 甲醇 、 sodium tetrahydroborate 、 水 、 sodium hydride 、 对甲苯磺酸 作用下， 以 甲醇 、 环己烷 、 苯 为溶剂， 反应 41.0h， 生成 O-603
  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

• Tropane analogs and methods for inhibition of monoamine transport
  申请人：——

  公开号：US20030105125A1

  公开（公告）日：2003-06-05

  New tropane analogs that bind to monoamine transporters are described, particularly, 8-aza, 8carbo and 8-oxo tropanes having 6- or 7-hydroxyl or ketone substituents. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Certain preferred compounds of the present invention have a high selectivity for the DAT versus the SERT. Also described are pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier and a method for inhibiting 5-hydroxy-tryptamine reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxytryptamine reuptake inhibiting amount of a compound of the present invention. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.

  描述了结合到单胺转运体的新的曲梯酮类似物，特别是8-氮杂、8-羰基和8-酮基曲梯酮，具有6-或7-羟基或酮基取代基。本发明的化合物可以是外消旋体、纯R-对映体或纯S-对映体。本发明的某些优选化合物对DAT与SERT具有很高的选择性。还描述了包含所述化合物的药用治疗组合物，其配制在药用可接受载体中，并通过将所述单胺转运体与本发明的化合物的5-羟色胺再摄取抑制量接触的方法来抑制单胺转运体的5-羟色胺再摄取。本发明实施的首选单胺转运体包括多巴胺转运体、5-羟色胺转运体和去甲肾上腺素转运体。
• Tropane analogs and methods for inhibition of monoamine
  申请人：——

  公开号：US20030069269A1

  公开（公告）日：2003-04-10

  New tropane analogs that bind to monoamine transporters are described, particularly, 8-aza, 8carbo and 8-oxo tropanes having 6- or 7- substituents. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers Certain preferred compounds of the present invention have a high selectivity for the DAT versus the SERT. Also described are pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier and a method for inhibiting 5-hydroxy-tryptamine reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxytryptamine reuptake inhibiting amount of a compound of the present invention. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.

  本文描述了能够结合单胺转运体的新的范围内的替罗巴因类似物，特别是具有6-或7-取代基的8-氮杂、8-碳基和8-氧杂替罗巴因。本发明的化合物可以是外消旋体、纯R对映体或纯S对映体。本发明的某些优选化合物具有高选择性，能够选择性地结合到多巴胺转运体而不是选择性地结合到血清素转运体。此外，本文还描述了制备药物治疗组合物的方法，该组合物包括以药学可接受的载体为基础的化合物，并通过将本发明的化合物与单胺转运体接触来抑制5-羟色胺的再摄取。本发明实施的优选单胺转运体包括多巴胺转运体、血清素转运体和去甲肾上腺素转运体。
• Boat tropanes
  申请人：——

  公开号：US20020131931A1

  公开（公告）日：2002-09-19

  Radiopharmaceutical compounds are disclosed. A tropane compound is linked through the N atom at the 8-position to a chelating ligand capable of complexing technetium or rhenium to produce a neutral labeled complex that selectively binds to the dopamine transporter over the serotonin transporter with a ratio of 10 or more. These compounds can be prepared as separate diastereoisomers as well as a mixture of diastereoisomers. Also disclosed are radiopharmaceutical kits for preparing the labeled radiopharmaceutical compounds.

  本发明公开了放射性药物复合物。一种托烷化合物通过 8 位上的 N 原子与一种能与锝或铼络合的螯合配体相连，从而产生一种中性标记的复合物，该复合物能选择性地与多巴胺转运体结合，而与血清素转运体的结合比例为 10 或更高。这些化合物既可以制备成单独的非对映异构体，也可以制备成非对映异构体的混合物。还公开了用于制备标记放射性药物化合物的放射性药物试剂盒。
• 2-Carbomethoxy-3-(diarylmethoxy)-1α<i>H</i>,5α<i>H</i>-tropane Analogs:  Synthesis and Inhibition of Binding at the Dopamine Transporter and Comparison with Piperazines of the GBR Series
  作者：Peter C. Meltzer、Anna Y. Liang、Bertha K. Madras

  DOI：10.1021/jm950463t

  日期：1996.1.1

  We recently reported a new class of tropanes, based on benztropine, that bind uniquely, in the S-configuration, to the dopamine transporter. We have now extended this series to evaluate the effects of substituents on the nitrogen and the diarylmethoxy group. Herein we have described the synthesis and biological evaluation of a series of 2-carbomethoxy-3-( diarylmethoxy)-1 alpha H,5 alpha H-tropane (2-carbomethoxybenztropine) analogs. Examination of the binding data obtained for these compounds shows that while the 4,4'-difluoro compound is potent and selective for the dopamine transporter, introduction of larger groups such as 4,4'-dichloro, 4,4'dibromo, 4,4'-diiodo, or 4,4'-dimethyl on the 3-diphenylmethoxy moiety reduces this potency. However, although introduction of only one group (e.g., 4-chloro, 4-bromo, 4-iodo, or 4-methyl) leads to a similar reduction of binding affinity, these monosubstituted 2-carbomethoxybenztropines are significantly more potent than the related disubstituted compounds. Finally, from the data for the N-substituted 2-carbomethoxybenztropine analogs, it is evident that steric bulk can be tolerated at the nitrogen site. A comparison of structure-activity relationship data for the tropanes, GBR analogs, and these benztropines indicates that the 8-carbomethoxybenztropine analogs may be more like the GBR analogs in their mode of binding to the dopamine transporter than like the tropanes. This conclusion supports the notion that the binding site for (-)-cocaine [and the (1R)-tropanes] may differ from that of the 2-carbomethoxybenztropine analogs.
• Dopamine transporter imaging agents
  申请人：President and Fellows of Harvard College

  公开号：EP1051980B1

  公开（公告）日：2010-12-15