(+/-)-5-(3-methoxyphenyl)-2-methyl-9-oxo-2-azabicyclo[3.3.1]nonane | 88550-34-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (+/-)-5-(3-methoxyphenyl)-2-methyl-9-oxo-2-azabicyclo[3.3.1]nonane
• 英文别名: 5-(3-methoxy-phenyl)-2-methyl-2-aza-bicyclo[3.3.1]nonan-9-one；5-(3-Methoxy-phenyl)-2-methyl-2-aza-bicyclo[3.3.1]nonan-9-on；5-(3-Methoxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9-one
• CAS: 88550-34-9
• 化学式: C₁₆H₂₁NO₂
• 分子量: 259.348
• InChiKey: IHMDTGDWBXXODI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (+/-)-5-(3-methoxyphenyl)-2-methyl-9-oxo-2-azabicyclo[3.3.1]nonane 在 溴化氰 、 potassium carbonate 、 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 20.0h， 以78%的产率得到rac-5-(3-Methoxyphenyl)-2-azabicyclo[3.3.1]nonan-9-one
  参考文献：
  名称：

  [EN] BIASED POTENT OPIOID-LIKE AGONISTS AS IMPROVED MEDICATIONS TO TREAT CHRONIC AND ACUTE PAIN AND METHODS OF USING THE SAME
  [FR] AGONISTES DE TYPE OPIOÏDE PUISSANTS BIAISÉS AGISSANT EN TANT QUE MÉDICAMENTS AMÉLIORÉS POUR LE TRAITEMENT D'UNE DOULEUR CHRONIQUE ET AIGUË ET PROCÉDÉS D'UTILISATION ASSOCIÉES

  摘要：

  本发明涉及具有化学式（I）及其对映体的化合物：其中n、R、X、Y、Y3和Z的定义在公开说明书中提供。该发明还涉及所述化合物的药物组合物，以及它们作为阿片样激动剂在疼痛治疗中的用途。

  公开号：

  WO2019182950A1
• 作为产物：
  描述：

  5-(3-methoxy-phenyl)-2,2-dimethyl-9-oxo-2-azonia-bicyclo[3.3.1]nonane, bromide 210.0~225.0 ℃ 、66.66 Pa 条件下， 生成 (+/-)-5-(3-methoxyphenyl)-2-methyl-9-oxo-2-azabicyclo[3.3.1]nonane
  参考文献：
  名称：

  STRUCTURES RELATED TO MORPHINE. IV.¹ m-SUBSTITUTED PHENYLCYCLOHEXANE DERIVATIVES

  摘要：

  DOI：

  10.1021/jo01126a008

文献信息

• 9α- and 9β-Hydroxyphenylmorphans
  作者：Hiroyoshi Awaya、Everette L. May、Arthur E. Jacobson、Mario D. Aceto

  DOI：10.1002/jps.2600731261

  日期：1984.12

  Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9α-hydroxy racemate (II) whose phenolic analogue (III) is a strong antinociceptive agent, fully supportive of morphine dependence in rhesus monkeys. The di-O-acetyl derivative (VI) of III was similar to III in its profile of activity. The diastereoisomer of III (VII), obtained by hydrogenation of the methobromide of

  5-间甲氧基苯基-2-甲基-9-氧代吗啡烷的氧化铂加氢（I）得到9α-羟基外消旋体（II），其酚类似物（III）是强抗伤害剂，完全支持猕猴对吗啡的依赖性。III的二-O-乙酰基衍生物（VI）在活性方面类似于III。III（VII）的非对映异构体是通过I（IV）的甲基溴化物的氢化，甲基溴的挤出以及所得游离碱（VIII）的O-去甲基化而得到的，几乎无杀痛作用，并且不能抑制吗啡的戒断症状依赖的猴子。由光谱数据并通过类推推导C-9羟基的取向。
• Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure−Activity Relationships of a Potent μ-Agonist δ-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-<i>N</i>-phenylethylmorphan Series
  作者：Anne-Cécile Hiebel、Yong Sok Lee、Edward Bilsky、Denise Giuvelis、Jeffrey R. Deschamps、Damon A. Parrish、Mario D. Aceto、Everette L. May、Louis S. Harris、Andrew Coop、Christina M. Dersch、John S. Partilla、Richard B. Rothman、Kejun Cheng、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1021/jm061325e

  日期：2007.8.1

  Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9 alpha-methyl, C9-methylene, C9-keto, and C9 alpha- and C9 beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3. I]nonane ((IR,5S)-(+)-14), and (IR,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo-[3.3. I]nonane ((lR,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (K-i = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (I R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9 beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (IR,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9 beta-OH substituent in (lR,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the,mu-opioid receptor.
• [EN] BIASED POTENT OPIOID-LIKE AGONISTS AS IMPROVED MEDICATIONS TO TREAT CHRONIC AND ACUTE PAIN AND METHODS OF USING THE SAME<br/>[FR] AGONISTES DE TYPE OPIOÏDE PUISSANTS BIAISÉS AGISSANT EN TANT QUE MÉDICAMENTS AMÉLIORÉS POUR LE TRAITEMENT D'UNE DOULEUR CHRONIQUE ET AIGUË ET PROCÉDÉS D'UTILISATION ASSOCIÉES
  申请人：US HEALTH

  公开号：WO2019182950A1

  公开（公告）日：2019-09-26

  The present invention is directed to a compound having Formula (I) and its enantiomer: wherein the definitions of n, R, X, Y and Y3, and Z are provided in the disclosure. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use as opioid-like agonists in the treatment of pain.

  本发明涉及具有化学式（I）及其对映体的化合物：其中n、R、X、Y、Y3和Z的定义在公开说明书中提供。该发明还涉及所述化合物的药物组合物，以及它们作为阿片样激动剂在疼痛治疗中的用途。
• STRUCTURES RELATED TO MORPHINE. IV.¹ m-SUBSTITUTED PHENYLCYCLOHEXANE DERIVATIVES
  作者：EVERETTE L. MAY、JAMES G. MURPHY

  DOI：10.1021/jo01126a008

  日期：1955.9