3β-(4'-isopropylphenyl)nortropane-2β-carboxylic acid methyl ester | 181796-46-3

• 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: 3β-(4'-isopropylphenyl)nortropane-2β-carboxylic acid methyl ester
• 英文别名: methyl (1R,2S,3S,5S)-3-(4-propan-2-ylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate
• CAS: 181796-46-3
• 化学式: C₁₈H₂₅NO₂
• 分子量: 287.402
• InChiKey: URPCLNZVIYJBCJ-HZMVEIRTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3β-(4'-isopropylphenyl)nortropane-2β-carboxylic acid methyl ester 、 (E)-3-n-tributylstannylprop-2-enyl chloride 在 碘 、 三乙胺 、 potassium iodide 作用下， 生成 (1R,2S,3S,5S)-8-((E)-3-Iodo-propenyl)-3-(4-isopropyl-phenyl)-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester
  参考文献：
  名称：

  Synthesis and Ligand Binding of Nortropane Derivatives:  N-Substituted 2β-Carbomethoxy-3β-(4‘-iodophenyl)nortropane and N-(3-Iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstituted phenyl)nortropane. New High-Affinity and Selective Compounds for the Dopamine Transporter

  摘要：

  Two novel series of iodinated N-substituted analogs of 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-disubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HTT), and norepinephrine (NET) transporters in rat brain homogenates using [H-3]GBR-12935, [H-3]paroxetine, and [H-3]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DA(T) selectivity over both 5-HTT and NET than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DAT agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT), The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K-i values of N-(3-iodoprop-(2E)-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-disubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

  DOI：

  10.1021/jm960795d
• 作为产物：
  描述：

  (1R,2S,3S,5S)-3-(4-碘苯基)-8-甲基-8-氮杂双环[3.2.1]辛烷-2-羧酸甲酯 在 palladium on activated charcoal 甲醇 、 bis-triphenylphosphine-palladium(II) chloride 、 正丁基锂 、 1-氯乙基氯甲酸酯 、 氢气 、 zinc(II) chloride 作用下， 以 乙醇 为溶剂， 反应 30.0h， 生成 3β-(4'-isopropylphenyl)nortropane-2β-carboxylic acid methyl ester
  参考文献：
  名称：

  Synthesis and Transporter Binding Properties of 3β-(4‘-Alkyl-, 4‘-alkenyl-, and 4‘-alkynylphenyl)nortropane-2β-carboxylic Acid Methyl Esters:  Serotonin Transporter Selective Analogs

  摘要：

  New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkyne analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.

  DOI：

  10.1021/jm960409s

文献信息

• Synthesis and Ligand Binding of Nortropane Derivatives:  N-Substituted 2β-Carbomethoxy-3β-(4‘-iodophenyl)nortropane and <i>N</i>-(3-Iodoprop-(2<i>E</i>)-enyl)-2β-carbomethoxy-3β-(3‘,4‘-disubstituted phenyl)nortropane. New High-Affinity and Selective Compounds for the Dopamine Transporter
  作者：Patrick Emond、Lucette Garreau、Sylvie Chalon、Miriam Boazi、Mireille Caillet、Jacques Bricard、Yves Frangin、Laurent Mauclaire、Jean-Claude Besnard、Denis Guilloteau

  DOI：10.1021/jm960795d

  日期：1997.4.1

  Two novel series of iodinated N-substituted analogs of 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-disubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HTT), and norepinephrine (NET) transporters in rat brain homogenates using [H-3]GBR-12935, [H-3]paroxetine, and [H-3]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DA(T) selectivity over both 5-HTT and NET than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DAT agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT), The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K-i values of N-(3-iodoprop-(2E)-enyl)-2 beta-carbomethoxy-3 beta-(3',4'-disubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.
• Synthesis and Transporter Binding Properties of 3β-(4‘-Alkyl-, 4‘-alkenyl-, and 4‘-alkynylphenyl)nortropane-2β-carboxylic Acid Methyl Esters:  Serotonin Transporter Selective Analogs
  作者：Bruce E. Blough、Philip Abraham、Anita H. Lewin、Michael J. Kuhar、John W. Boja、F. Ivy Carroll

  DOI：10.1021/jm960409s

  日期：1996.1.1

  New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkyne analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.