benzo[b]thiophene-2-carboxylic acid [4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]amide

• 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: benzo[b]thiophene-2-carboxylic acid [4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]amide
• 英文别名: N-[(4aR,6R,8aS)-4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)-3,4,5,6,7,8-hexahydro-1H-isoquinolin-6-yl]-1-benzothiophene-2-carboxamide
• 化学式: C₃₅H₄₀N₂O₂S
• 分子量: 552.781
• InChiKey: PRZZCTHNMSYVML-DISZHMCESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.3
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  69.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  benzo[b]thiophene-2-carboxylic acid [4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]amide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以88%的产率得到benzo[b]thiophene-2-carboxylic acid [4a-(3-hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]amide
  参考文献：
  名称：

  N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

  摘要：

  N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctabydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [S-35]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K-e of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the mu and 6 receptors, respectively, possessed the best combination Of K potency and selectivity.

  DOI：

  10.1021/jm058261c
• 作为产物：
  描述：

  Acetic acid 3-bromo-1-[4-(3-methoxy-phenyl)-1,5-dimethyl-1,2,3,4-tetrahydro-pyridin-4-ylmethyl]-propyl ester 在 草酰氯 、 1-氯乙基氯甲酸酯 、 盐酸羟胺 、 sodium 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 一水合肼 、 二甲基亚砜 、 三乙胺 、 异丙醇 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 77.5h， 生成 benzo[b]thiophene-2-carboxylic acid [4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]amide
  参考文献：
  名称：

  N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

  摘要：

  N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctabydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [S-35]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K-e of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the mu and 6 receptors, respectively, possessed the best combination Of K potency and selectivity.

  DOI：

  10.1021/jm058261c