3β-(4-aminophenyl)-2β-tropane-2β-carboxylic acid methyl ester | 134052-62-3

• 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: 3β-(4-aminophenyl)-2β-tropane-2β-carboxylic acid methyl ester
• 英文别名: 3β-(4-aminophenyl)tropan-2β-carboxylic acid methyl ester；3β-(4'-aminophenyl)tropane-2β-carboxylic acid methyl ester；methyl (1R-2-exo-3-exo)-3-(4-aminophenyl)-8-methyl-8-azabicyclo<3.2.1>octane-2-carboxylate；RTI 29；methyl (1R,2S,3S,5S)-3-(4-aminophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 134052-62-3
• 化学式: C₁₆H₂₂N₂O₂
• 分子量: 274.363
• InChiKey: NFYQZRCMOMKICY-YJNKXOJESA-N

物化性质

• 沸点：
  404.9±45.0 °C(Predicted)
• 密度：
  1.152±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3β-(4-aminophenyl)-2β-tropane-2β-carboxylic acid methyl ester 在 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.0h， 生成
  参考文献：
  名称：

  Synthesis and Monoamine Transporter Binding Properties of 2,3-Cyclo Analogues of 3β-(4‘-Aminophenyl)-2β-tropanemethanol

  摘要：

  A series of cyclo-3 beta-(4-aminophenyl)-2 beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3 beta-(4-aminophenyl)-2 beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3 beta-(4-aminophenyl)2 beta-tropanemethanol sebacic acid ester/amide (5e) had a K-i of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.

  DOI：

  10.1021/jm060287w
• 作为产物：
  描述：

  methyl (1R,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate 在 platinum(IV) oxide 硫酸 、 氢气 、 硝酸 作用下， 以 甲醇 为溶剂， 4.0 ℃ 、344.73 kPa 条件下， 反应 3.5h， 生成 3β-(4-aminophenyl)-2β-tropane-2β-carboxylic acid methyl ester
  参考文献：
  名称：

  Synthesis of 3-arylecgonine analogs as inhibitors of cocaine binding and dopamine uptake

  摘要：

  3-Arylecgonine analogues were synthesized and characterized by 1H and 13C NMR, IR, and MS. The compounds were synthesized as racemates from cycloheptatriene-7-carboxylic acid or enantiomerically from (-)-cocaine. These analogues were tested for their ability to inhibit [3H]cocaine binding to bovine striatal tissue and to inhibit [3H]dopamine uptake into striatal synaptosomes. Methyl (1RS-2-exo-3-exo)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-ca rboxylate was the most potent analogue. IC50 values for inhibition of cocaine binding and dopamine uptake were 20 and 100 nM, respectively. The racemates and the 1R isomers were equally potent inhibitors of binding and uptake. Methyl (1RS-2-endo-3-exo)-3-(2,4-dinitrophenyl)-8-methyl-8-azabicyclo[3.2 .1]octane- 2-carboxylate was the least potent. IC50 for inhibition of both binding and uptake was 40 microM.

  DOI：

  10.1021/jm00169a036

文献信息

• Synthesis and Monoamine Transporter Binding Properties of 3β-(3‘,4‘-Disubstituted phenyl)tropane-2β-carboxylic Acid Methyl Esters
  作者：F. Ivy Carroll、Bruce E. Blough、Zhe Nie、Michael J. Kuhar、Leonard L. Howell、Hernan A. Navarro

  DOI：10.1021/jm040185a

  日期：2005.4.1

  3-(4-chlorophenyl)tropane-2-carboxylic acid phenyl ester (RTI-113), 3b shows no detectible DAT occupancy when dosed at its ED(50) for reduction of cocaine self-administration. In contrast, it highly occupies the 5-HTT at this dose. In this study, we report the synthesis and monoamine transporter binding potency of several new 3-(3',4'-disubstituted phenyl)tropane-2-carboxylic acid methyl esters (3c-k), which have binding

  3β-（3'-甲基-4'-氯苯基）肌烷-2-羧酸甲酯（3b，RTI-112）是对多巴胺和5-羟色胺转运蛋白（DAT和5-羟色胺都具有高亲和力的3-苯基环烷类似物分别为HTT）。化合物3b在恒河猴中显示出可卡因自我给药的显着减少，但仍不能维持强大的药物自我给药。PET研究表明，与更多DAT选择性类似物（例如GBR 12909和3-（4-氯苯基）托烷-2-羧酸苯基酯（RTI-113））不同，当3b以其ED剂量给药时，DAT占有率未检测到（50）用于减少可卡因的自我管理。相反，在该剂量下它高度占据5-HTT。在这项研究中，我们报告了几种新的3-（3'，4' -二取代的苯基）托烷-2-羧酸甲酯（3c-k），其结合性质与3b非常相似。除3'，4'-二甲基类似物3k外，所有化合物在DAT和5-HTT处分别具有亚纳摩尔的IC（50）和K（i）值。3'-氯-4'-溴类似物3e（IC（50）= 0.12 n
• Synthesis, Ligand Binding, and QSAR (CoMFA and Classical) Study of 3.beta.-(3'-Substituted phenyl)-, 3.beta.-(4'-Substituted phenyl)-, and 3.beta.-(3',4'-Disubstituted phenyl)tropane-2.beta.-carboxylic Acid Methyl Esters
  作者：F. Ivy Carroll、S. Wayne Mascarella、Michael A. Kuzemko、Yigong Gao、Philip Abraham、Anita H. Lewin、John W. Boja、Michael J. Kuhar

  DOI：10.1021/jm00044a007

  日期：1994.9

  Several new 3 beta-(4'-substituted phenyl)-, 3-beta-(3'-substituted phenyl)-, and 3 beta-(3',4'-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters were prepared and assayed for inhibition of [3H]WIN 35,428 binding to the dopamine transporter. The 3 beta-(3',4'-dichloro) and 3 beta-(4'-chloro-3'-methyl) analogues (2w and 2y; RTI-111 and RTI-112, respectively) with IC50 values of 0.79

  几种新的3β-（4'-取代的苯基）-，3-β-（3'-取代的苯基）-和3β-（3'，4'-二取代的苯基）tropane-2β-羧酸甲酯制备并测定对[3H] WIN 35,428与多巴胺转运蛋白结合的抑制作用。3个beta-（3'，4'-dichloro）和3个beta-（4'-chloro-3'-methyl）类似物（分别为2w和2y; RTI-111和RTI-112），IC50值为0.79和0.81 nM显示最高亲和力。研究了从经典和比较分子场分析（CoMFA）方法获得的定量构效关系（QSAR）模型对合理药物设计的贡献。CoMFA模型是使用具有SYBYL默认值的空间和静电势导出的，而经典模型是根据pi和MR参数导出的。使用12个化合物的训练集，两个模型都用于预测训练集内外的化合物的结合亲和力。CoMFA研究为影响与DA转运蛋白结合的空间和静电因素提供了新的见解，并为我们最初的发现提供了额
• Cocaine receptor binding ligands
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：EP0897922A2

  公开（公告）日：1999-02-24

  Novel compounds show high affinity for specific cocaine receptors in the brain, particularly dopamine transporter sites, and have the formula Wherein Y =CO2R2, R1 =hydrogen, C1-5 alkyl, R2 =hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-6 alkynyl, halogen or amine, R3 =OH, hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, Cl, Br, I, CN, NH2, NHC1-6 alkyl, NC1-6 alkyl, OCOC1-6 alkyl, OCOC1-3 alkylaryl, A =S, O or NH X =C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-6 alkynyl, halogen, amino, acylamido, and Z =I, Br, Cl, F, CN, CF3 NO2, N3, OR1, CO2NH2, CO2R1, C1-6 alkyl, NR4R5, NHCOR5, NHCO2R6, wherein R4-R6 are each C1-6 alkyl and wherein said compound bears at least one iodine or carbon atom which is radioactive.

  新型化合物对大脑中特定的可卡因受体，特别是多巴胺转运体位点具有高亲和力，其分子式为 其中 Y =CO2R2 R1 = 氢、C1-5 烷基、 R2 =氢、C1-6 烷基、C3-8 环烷基、C1-4 烷氧基、C1-6 烷炔基、卤素或胺、 R3 =OH、氢、C1-6 烷基、C3-8 环烷基、C1-4 烷氧基、Cl、Br、I、CN、NH2、NHC1-6 烷基、NC1-6 烷基、OCOC1-6 烷基、OCOC1-3 烷芳基、 A =S、O 或 NH X =C1-6烷基、C3-8环烷基、C1-4烷氧基、C1-6炔基、卤素、氨基、酰氨基、 和 Z=I、Br、Cl、F、CN、CF3 NO2、N3、OR1、CO2NH2、CO2R1、C1-6 烷基、NR4R5、NHCOR5、NHCO2R6、 其中 R4-R6 各为 C1-6 烷基，且所述化合物含有至少一个具有放射性的碘原子或碳原子。
• Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter
  作者：F. Ivy Carroll、Yigong Gao、Philip Abraham、Anita H. Lewin、Robert Lew、Amrat Patel、John W. Boja、Michael J. Kuhar

  DOI：10.1021/jm00088a017

  日期：1992.5

  Several potentially irreversible ligands (i.e., wash-resistant binding inhibitors) for the cocaine receptor site on the dopamine transporter, derived from (-)-cocaine or 3-beta-phenyltropan-2-beta-carboxylic acid methyl ester (WIN 35,065-2), were prepared and shown to produce wash-resistant inhibition of [H-3]-3-beta-(p-fluorophenyl)tropan-2-beta-carboxylic acid methyl ester ([H-3]WIN 35,428) binding. All the compounds prepared had the same absolute configuration as cocaine; they include analogues possessing chemically reactive groups such as the isothiocyanato and bromoacetamido as well as photoactive azido groups. The potentially irreversible ligands, as well as all the intermediates prepared in this study, were evaluated for their ability to inhibit the binding of [H-3]WIN 35,428 in coincubation experiments. Of the potentially irreversible ligands, 3-beta-(p-chlorophenyl)tropan-2-beta-carboxylic acid 2-[p-(bromoacetamido)phenyl]ethyl ester (6c) had the highest apparent potency. The potentially irreversible ligands were also preincubated, and inhibition of [H-3]WIN 35,428 binding was determined both before and after washing the ligand-exposed tissues. The most effective ligands in this regard were 3-beta-(3-iodo-4-azidophenyl)tropan-2-beta-carboxylic acid methyl ester (5) and 3-beta-(p-chlorophenyl)tropan-2-beta-carboxylic acid 2-(3-iodo-4-azidophenyl)ethyl ester (6d). The structure-activity relationships of these data are discussed.
• US5380848A
  申请人：——

  公开号：US5380848A

  公开（公告）日：1995-01-10