14β-amino-7,8-dihydro-17-cyclopropylmethylnormorphinone | 151334-35-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 14β-amino-7,8-dihydro-17-cyclopropylmethylnormorphinone
• 英文别名: (4R,4aS,7aR,12bR)-4a-amino-3-(cyclopropylmethyl)-9-hydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• CAS: 151334-35-9
• 化学式: C₂₀H₂₄N₂O₃
• 分子量: 340.422
• InChiKey: UGMHMJLRYWSMNU-XFWGSAIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  75.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  14β-amino-7,8-dihydro-17-cyclopropylmethylnormorphinone 在 对甲基苯磺酰甲基异腈 、 potassium carbonate 、 盐酸 作用下， 以 甲醇 为溶剂， 以23%的产率得到(1S,2R,6R,14R,15R)-5-(cyclopropylmethyl)-13-oxa-5,17-diazahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11,16-tetraene-11,15-diol
  参考文献：
  名称：

  具有氮杂双环[2.2.2]辛烷骨架的新型阿片样物质配体的设计与合成及其药理作用

  摘要：

  合成了一种具有稳定的环状亚胺16的新型阿片样物质配体及其具有氮杂双环[2.2.2]辛烷骨架的衍生物。与具有氧杂双环[2.2.2]辛烷骨架的化合物21相比，亚胺16对μ受体的亲和力更高。在合成的衍生物中，在8-氮上带有环丙基甲基的氮杂双[2.2.2]辛烷衍生物18d对μ受体的亲和力最高。

  DOI：

  10.1016/j.bmcl.2012.03.001
• 作为产物：
  描述：

  蒂巴因 在 sodium periodate 、 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 吡啶盐酸盐 、 三溴化硼 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 苯 为溶剂， 20.0 ℃ 、413.7 kPa 条件下， 反应 16.0h， 生成 14β-amino-7,8-dihydro-17-cyclopropylmethylnormorphinone
  参考文献：
  名称：

  Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives

  摘要：

  Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the S-35-GTP[gamma S] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.05.027

文献信息

• [EN] N-OXIDES OF 4,5-EPOXY-MORPHINANIUM ANALOGS<br/>[FR] N-OXYDES D'ANALOGUES 4,5-ÉPOXY-MORPHINANIUM
  申请人：PROGENICS PHARM INC

  公开号：WO2009067275A1

  公开（公告）日：2009-05-28

  Novel N-oxides of 4,5-epoxy-morphinanIum analogs are disclosed. Pharmaceutical compositions containing the N-oxides of 4,5-epoxy-morphinanium analogs and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as modulators of opioid receptors.

  揭示了4,5-环氧吗啡啉盐类的新型N-氧化物。还揭示了含有4,5-环氧吗啡啉盐类的N-氧化物的药物组合物，以及它们的药用方法。所揭示的化合物可用作阿片受体调节剂等用途。
• Substituted morphinans and methods of their use
  申请人：Dolle E. Roland

  公开号：US20060063792A1

  公开（公告）日：2006-03-23

  Novel 4,5-α epoxy-morphinan compounds are disclosed. Pharmaceutical compositions containing the 4,5-α epoxy-morphinan compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as modulators of opioid receptors.

  揭示了新型的4,5-α环氧吗啡酮类化合物。还揭示了含有这些4,5-α环氧吗啡酮类化合物的药物组合物以及它们在药物用途中的方法。所揭示的化合物可作为阿片受体的调节剂等用途。
• Structural Determinants of Opioid Activity in Derivatives of 14-Aminomorphinones:  Effects of Changes to the Chain Linking of the C₁₄-Amino Group to the Aryl Ring
  作者：David Rennison、Humphrey Moynihan、John R. Traynor、John W. Lewis、Stephen M. Husbands

  DOI：10.1021/jm060595u

  日期：2006.10.1

  The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. To investigate the importance of the 14-substituent, a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu-opioid receptor (MOR), was largely determined by

  14-氨基二氢吗啡酮和可待因酮系列阿片样物质配体已经产生了许多令人感兴趣的配体。为了研究14位取代基的重要性，已经制备了一系列类似物，其中侧链长度变化并且酰胺和烯烃的功能降低。结合亲和力，特别是对μ-阿片受体（MOR）的结合亲和力很大程度上取决于侧链的芳族基团。在[35S] GTPgammaS功能测定中，具有三碳侧链的配体比其长链对应物更有效，而较短的二碳链类似物具有更高的MOR功效，这一作用已在体内得到证实。在该系列中观察到耐洗涤结合，并且似乎与侧链长度无关。
• Design and synthesis of unique morphinan-type molecules: Their application to the search for the unexplored binding domain between opioid receptors and morphinan ligands
  作者：Kenta Maeda、Tomoya Sugai、Akihisa Tokuda、Keita Kajino、Tsuyoshi Saitoh、Hiroshi Nagase、Noriki Kutsumura

  DOI：10.1016/j.bmcl.2024.129611

  日期：2024.2

  The morphinan skeleton is valued in drug discovery for its beneficial physicochemical properties and is recognized as a crucial template for opioid receptor ligands. In morphinan derivatives, it is well-established that the nitrogen atom within the piperidine ring (D-ring) interacts with the amino acid residues of the opioid receptors. This interaction is recognized as one of the crucial pharmacophores

  吗啡喃骨架因其有益的理化特性而在药物发现中受到重视，并被认为是阿片受体配体的重要模板。在吗啡喃衍生物中，哌啶环（D 环）内的氮原子与阿片受体的氨基酸残基相互作用，这一点已得到证实。这种相互作用被认为是吗啡喃分子和阿片受体之间的重要药效团之一。因此，由于担心 17 位氮周围的结构转变可能会破坏这种相互作用，D 环周围的构效关系 (SAR) 尚未得到充分研究。在这项研究中，我们发现我们的新型吗啡喃型配体具有位于环上方含有杂原子的侧链，对阿片受体具有结合亲和力。这些新颖的骨架可以提供独特的模板，在吗啡喃骨架的 D 环上方具有所需的侧链，从而有可能推进吗啡喃配体与阿片受体的 SAR 研究。
• 14β-Arylpropiolylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones and Related Opioids. Further Examples of Pseudoirreversible μ Opioid Receptor Antagonists
  作者：Nick P.R. Nieland、David Rennison、Jillian H. Broadbear、Lauren Purington、James H. Woods、John R. Traynor、John W. Lewis、Stephen M. Husbands

  DOI：10.1021/jm901074a

  日期：2009.11.12

  14 beta-4'-Chlorocinnamoylaminodihydronormorphinone (2a), and analogues, are selective pseudoirreversible antagonists of the mu opioid receptor (MOR). The preparation of analogues with ethynic bonds, replacing the ethenic bond of 2a, is described. The new ligands, in mouse antinociceptive assays, had pseudoirreversible MOR antagonist activity, which, in the case of 8b was of longer duration than that of 2a. The related codeinone (9b) had only antagonist activity in vivo, in contrast to 2a's codeinone equivalent 3a, which had potent antinociceptive activity.