(+)-(1S,2R,5S)-6-benzyl-2-hydroxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione | 960599-48-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (+)-(1S,2R,5S)-6-benzyl-2-hydroxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione
• 英文别名: (1S,2R,5S)-6-benzyl-2-hydroxy-8-[(4-methoxyphenyl)methyl]-6,8-diazabicyclo[3.2.2]nonane-7,9-dione
• CAS: 960599-48-8
• 化学式: C₂₂H₂₄N₂O₄
• 分子量: 380.444
• InChiKey: RJJYPJMSHGTTEL-ZCNNSNEGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+)-(1S,2R,5S)-6-benzyl-2-hydroxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 以86%的产率得到(+)-(1R,2R,5S)-6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol
  参考文献：
  名称：

  具有细胞毒活性的双环西格玛受体配体的合成。

  摘要：

  所有可能的立体异构醇（6-苄基-8-（4-甲氧基苄基）-6,8-二氮杂双环[3.2.2]壬南-2-醇）和甲基醚（6-苄基-2-甲氧基-8-（4-由（R）-和（S）-谷氨酸制备甲氧基苄基）-6，8-二氮杂双环[3.2.2]壬烷。Dieckmann类似物环化利用了Me3SiCl捕获主要的环化产物，从而生成了双环骨架。立体选择性LiBH4还原和Mitsunobu转化建立了位置2的构型。对映体醇15（1S，2S，5R）和ent-15（1R，2R，5S）以及对映体甲基醚ent-17（1R，2R，5S）和ent-22（1R，2S，5S）显示高sigma1受体亲和力。研究了立体异构醇和甲基醚对五种人类肿瘤细胞系的细胞生长抑制作用。特别是，当浓度为20μM时，四种甲基醚完全停止了小细胞肺癌细胞系A-427的细胞生长，表明该细胞系中有特定的靶标。甲基醚ent-17和ent-22的IC50值在抗肿瘤药顺铂和奥

  DOI：

  10.1021/jm070620b
• 作为产物：
  描述：

  (+)-(1S,5S)-6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-2,7,9-trione 在 锂硼氢 作用下， 以 四氢呋喃 为溶剂， 以84%的产率得到(+)-(1S,2R,5S)-6-benzyl-2-hydroxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione
  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

文献信息

• Synthesis of Bicyclic σ Receptor Ligands with Cytotoxic Activity
  作者：Christian Geiger、Christel Zelenka、Manuela Weigl、Roland Fröhlich、Birgit Wibbeling、Kirstin Lehmkuhl、Dirk Schepmann、Renate Grünert、Patrick J. Bednarski、Bernhard Wünsch

  DOI：10.1021/jm070620b

  日期：2007.11.1

  Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high sigma1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 muM the four methyl ethers stop completely the cell growth of

  所有可能的立体异构醇（6-苄基-8-（4-甲氧基苄基）-6,8-二氮杂双环[3.2.2]壬南-2-醇）和甲基醚（6-苄基-2-甲氧基-8-（4-由（R）-和（S）-谷氨酸制备甲氧基苄基）-6，8-二氮杂双环[3.2.2]壬烷。Dieckmann类似物环化利用了Me3SiCl捕获主要的环化产物，从而生成了双环骨架。立体选择性LiBH4还原和Mitsunobu转化建立了位置2的构型。对映体醇15（1S，2S，5R）和ent-15（1R，2R，5S）以及对映体甲基醚ent-17（1R，2R，5S）和ent-22（1R，2S，5S）显示高sigma1受体亲和力。研究了立体异构醇和甲基醚对五种人类肿瘤细胞系的细胞生长抑制作用。特别是，当浓度为20μM时，四种甲基醚完全停止了小细胞肺癌细胞系A-427的细胞生长，表明该细胞系中有特定的靶标。甲基醚ent-17和ent-22的IC50值在抗肿瘤药顺铂和奥
• Conformationally Constrained κ Receptor Agonists: Stereoselective Synthesis and Pharmacological Evaluation of 6,8-Diazabicyclo[3.2.2]nonane Derivatives^†
  作者：Christian Geiger、Christel Zelenka、Kirstin Lehmkuhl、Dirk Schepmann、Werner Englberger、Bernhard Wünsch

  DOI：10.1021/jm100182p

  日期：2010.5.27

  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).