1-[(1S,2S,5R)-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]non-8-yl]-2-(3,4-dichlorophenyl)ethanone | 1228313-62-9

• 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: 1-[(1S,2S,5R)-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]non-8-yl]-2-(3,4-dichlorophenyl)ethanone
• CAS: 1228313-62-9
• 化学式: C₁₉H₂₅Cl₂N₃O
• 分子量: 382.333
• InChiKey: UVHAUXFBRJCDAW-JLSDUUJJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.96
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  35.58
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  1-[(1S,2S,5R)-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]non-8-yl]-2-(3,4-dichlorophenyl)ethanone 、 氯甲酸甲酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以70 mg的产率得到(+)-methyl (1S,2S,5R)-8-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylate
  参考文献：
  名称：

  Conformationally Constrained κ Receptor Agonists: Stereoselective Synthesis and Pharmacological Evaluation of 6,8-Diazabicyclo[3.2.2]nonane Derivatives^†

  摘要：

  Three sets of stereoisomeric bicyclic kappa agonists with defined orientation of the pharmacophoric elements pyrrolidine and dichlorophenylacetamide were stereoselectively prepared and pharmacologically evaluated. Stereoselective reduction, reductive amination, and Mitsunobu inversions were the key steps for the establishment of the desired stereochemistry. The kappa affinity decreased in the following order depending on the N-substituent: CO2CH3 > benzyl > COCH2CH3. Bicyclic derivatives with (IS,2R, 5R)-configuration showed the highest kappa receptor affinity, which led to dihedral angles of 97 degrees and 45 degrees for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent K agonist of this series was (+)-methyl (1S,2R,5R)-8-[2-(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylate (ent-23, WMS-0121) with an kappa(i) value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [S-35]GTP gamma-S-binding assay at human kappa-opioid receptors, ent-23 was proved to be a full agonist with the same EC50 value (87 nM) as the prototypical full agonist U-69,593 (EC50 = 80 nM).

  DOI：

  10.1021/jm100182p
• 作为产物：
  描述：

  (+)-1-[(1S,2S,5R)-6-benzyl-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]non-8-yl]-2-(3,4-dichlorophenyl)ethanone 在 盐酸 、 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.5h， 以65%的产率得到1-[(1S,2S,5R)-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]non-8-yl]-2-(3,4-dichlorophenyl)ethanone
  参考文献：
  名称：

  Conformationally Constrained κ Receptor Agonists: Stereoselective Synthesis and Pharmacological Evaluation of 6,8-Diazabicyclo[3.2.2]nonane Derivatives^†

  摘要：

  Three sets of stereoisomeric bicyclic kappa agonists with defined orientation of the pharmacophoric elements pyrrolidine and dichlorophenylacetamide were stereoselectively prepared and pharmacologically evaluated. Stereoselective reduction, reductive amination, and Mitsunobu inversions were the key steps for the establishment of the desired stereochemistry. The kappa affinity decreased in the following order depending on the N-substituent: CO2CH3 > benzyl > COCH2CH3. Bicyclic derivatives with (IS,2R, 5R)-configuration showed the highest kappa receptor affinity, which led to dihedral angles of 97 degrees and 45 degrees for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent K agonist of this series was (+)-methyl (1S,2R,5R)-8-[2-(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylate (ent-23, WMS-0121) with an kappa(i) value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [S-35]GTP gamma-S-binding assay at human kappa-opioid receptors, ent-23 was proved to be a full agonist with the same EC50 value (87 nM) as the prototypical full agonist U-69,593 (EC50 = 80 nM).

  DOI：

  10.1021/jm100182p