14-amino dihydrocodeinone | 180415-87-6

• 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: 14-amino dihydrocodeinone
• 英文别名: N-cylopropylmethyl-14β-amino-7,8-dihydronorcodeinone；N-cyclopropylmethyl-14β-amino-7,8-dihydronorcodeinone；14β-amino-7,8-dihydro-17-cyclopropylmethylnorcodeinone；17-cyclopropylmethyl-4,5α-epoxy-3-methoxy-14-amino morphinan-6-one；(4R,4aS,7aR,12bR)-4a-amino-3-(cyclopropylmethyl)-9-methoxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• CAS: 180415-87-6
• 化学式: C₂₁H₂₆N₂O₃
• 分子量: 354.449
• InChiKey: XKAZFSCJCHAEET-MBPVOVBZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  64.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  14-amino dihydrocodeinone 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 5.0h， 生成 14β-amino-7,8-dihydro-17-cyclopropylmethylnormorphinone
  参考文献：
  名称：

  14-氨基吗啡酮衍生物中阿片类药物活性的结构决定因素：C14-氨基与芳基环链连接变化的影响。

  摘要：

  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。

  DOI：

  10.1021/jm060595u
• 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 、 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 9.5h， 生成 14-amino dihydrocodeinone
  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

• Design and synthesis of novel opioid ligands with an azabicyclo[2.2.2]octane skeleton and their pharmacologies
  作者：Yoshikazu Watanabe、Shota Kitazawa、Hideaki Fujii、Toru Nemoto、Shigeto Hirayama、Hiroshi Nagase

  DOI：10.1016/j.bmcl.2012.03.001

  日期：2012.4

  A novel opioid ligand possessing a stable and cyclic imine 16 and its derivatives with an azabicyclo[2.2.2]octane skeleton were synthesized. The imine 16 showed higher affinity for the μ receptor than compound 21 with an oxabicyclo[2.2.2]octane skeleton. Azabicyclo[2.2.2]octane derivative 18d with a cyclopropylmethyl group on the 8-nitrogen showed the highest affinity for the μ receptor among the synthesized

  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。
• N-Oxides of 4,5-Epoxy-Morphinanium Analogs
  申请人：Perez Julio

  公开号：US20080234306A1

  公开（公告）日：2008-09-25

  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.

  本发明公开了4,5-环氧-吗啡铵类似物的新型N-氧化物。本发明还公开了含有4,5-环氧-吗啡铵类似物的N-氧化物的制药组合物及其制药用途的方法。公开的化合物可用作阿片受体调节剂等用途。
• WO2008/70462
  申请人：——

  公开号：——

  公开（公告）日：——
• Structural Determinants of Opioid Activity in Derivatives of 14-Aminomorphinones:  Effect of Substitution in the Aromatic Ring of Cinnamoylaminomorphinones and Codeinones
  作者：Nick P. R. Nieland、Humphrey A. Moynihan、Simon Carrington、Jillian Broadbear、James H. Woods、John R. Traynor、Stephen M. Husbands、John W. Lewis

  DOI：10.1021/jm0604777

  日期：2006.8.1

  In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the A opioid receptor than their 17-cyclopropylmethyl counterparts.
• 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.