(1S,2R)-2-(hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-ethyl]cyclopropanecarboxamide | 96847-49-3

• 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: (1S,2R)-2-(hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-ethyl]cyclopropanecarboxamide
• CAS: 96847-49-3
• 化学式: C₁₉H₂₁NO₂
• 分子量: 295.381
• InChiKey: YEDRZVLQHZSGMM-DKSSEZFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.81
• 重原子数：
  22.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  49.33
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  (1S,2R)-2-(hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-ethyl]cyclopropanecarboxamide 在 硫酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 16.0h， 以100%的产率得到(1S5R)-1-苯基-3-氧杂双环[3.1.0]己烷-2-酮（左米那普仑中间体A）
  参考文献：
  名称：

  Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites

  摘要：

  A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for or, oz, opioid and dopamine (D-2) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for sigma binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in sigma(2) affinity as compared to the parent(+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects sigma(1) selectivity but does not affect ol affinity. The (+/-)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the ol and sigma(2) receptor subtypes compared to the (+/-)-trans 19. interestingly, the enantiomer (-)-cis 18 displayed a preference for ol receptor subtype whereas the (+)-cis 18 did for sigma(2). These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for sigma sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K-i of 0.6 and 4.05 nM for sigma(1) and sigma(2) binding sites, respectively. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00072-9
• 作为产物：
  描述：

  (1S5R)-1-苯基-3-氧杂双环[3.1.0]己烷-2-酮（左米那普仑中间体A） 、 R(+)-alpha-甲基苄胺 在 2-羟基吡啶 作用下， 以 甲苯 为溶剂， 反应 15.0h， 以76.5%的产率得到(1S,2R)-2-(hydroxymethyl)-1-phenyl-N-[(1R)-1-phenyl-ethyl]cyclopropanecarboxamide
  参考文献：
  名称：

  New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands

  摘要：

  人们对开发 KOP 阿片受体配体作为临床有用的镇痛药非常感兴趣。此外，具有混合KOP受体和μ阿片肽（MOP）受体激动剂/拮抗剂特性的化合物可能具有更好的治疗潜力。基于苯并吗喃的合成配体 MPCB 和 CCB 已被证明能够以高亲和力和选择性结合 KOP 受体。我们在这里报告了一系列合成的化合物，用于对 MPCB 进行结构亲和关系 (SAR) 研究。本研究的目的是优化 KOP 受体-配体相互作用并调节 MOP 受体选择性。在 MPCB 的苯甲酰胺类似物（化合物 9）中，第三个芳香核的存在，与芳香药效残基的距离和构象适当，与 MPCB 相比，KOP 受体亲和力增加了约 6 倍（Ki = 35 nM 和 Ki = 240 nM，分别）。相反，氮取代基中具有叔氨基的化合物 28 显示出相当的 KOP 受体亲和力 (Ki = 179 nM)，但也显示出较高的 MOP 受体亲和力 (Ki = 45 nM)。因此，本研究表明，在基于苯并吗喃的配体中，氮取代基中不同官能团的存在（从带正电的胺到额外的芳香环）能够促进芳香族药效基团残基与MOP和KOP的正确对齐受体类型。对化合物 9 和 28 与 KOP 和 MOP 受体的对接模拟评估显示，分别与重要氨基酸残基 Tyr320 (TMVII) 和 Trp318 (TMVII) 发生选择性配体相互作用。

  DOI：

  10.1691/ph.2007.11.7523

文献信息

• Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands
  作者：Agostino Marrazzo、Orazio Prezzavento、Lorella Pasquinucci、Franco Vittorio、Giuseppe Ronsisvalle

  DOI：10.1016/s0014-827x(01)01039-4

  日期：2001.4

  In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (+/-)-10 with high affinity and selectivity for sigma receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (+/-)-10, and binding affinities, with respect to sigma(1), sigma(2), opioid and dopaminergic D-2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for sigma receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different sigma(1), and sigma(2) binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (+/-)-10 and (+/-)-18 in order to evaluate the enantioselectivity for sigma(1) and sigma(2) receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantionter showed a preference for sigma(1) whereas (+)-10 showed a preference for sigma(2), (C) 2001 Elsevier Science S.A. All rights reserved.