(1S,5S)-5-(3-methoxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-one | 949139-45-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: (1S,5S)-5-(3-methoxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-one
• 英文别名: (1S,5S)-5-(3-methoxyphenyl)-2-(2-phenylethyl)-2-azabicyclo[3.3.1]nonan-9-one
• CAS: 949139-45-1
• 化学式: C₂₃H₂₇NO₂
• 分子量: 349.473
• InChiKey: JABNHELHFBUFHY-GMAHTHKFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 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：

  (1S,5S)-5-(3-methoxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-one 在 盐酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 水 为溶剂， 生成
  参考文献：
  名称：

  一种在非对映体 C9-烷基取代的 N-苯乙基-5-(3-羟基)苯基吗啡类中具有高效力和拮抗功效的 MOR 拮抗剂

  摘要：

  5-(3-羟基)苯基吗啡烷结构类化合物与经典吗啡喃、4,5-环氧吗啡喃和6,7-苯并吗啡喃不同，因为它们具有赤道取向的芳环，而不是发现的该环的轴向取向在经典阿片类药物中。这种经过修饰和简化的阿片样结构已被证明保留了抗伤害活性，具体取决于其立体化学和取代基，并且其中一些已被发现比吗啡更有效。研究发现，一种简单的 C9-羟基-5-(3-羟基)苯基吗啡烷对映体在体内的效力比吗啡强约 500 倍。我们之前已经研究过 N-苯乙基-5-(3-羟基)苯基吗啡烷类化合物中的 C9-烯基和羟烷基取代基。尚未探索类似的 C9-烷基（甲基至丁基）取代基及其非对映体组。所有这些化合物现已合成，以确定分子中 C9 位点的链长和立体化学可能对其与阿片受体相互作用的影响。我们现在使用毛喉素诱导的 cAMP 积累抑制测定报告了 16 种化合物（C9-甲基、乙基、丙基和丁基非对映体）的合成和体外活性。几种有效的（亚纳摩尔和纳摩尔）MOR

  DOI：

  10.3390/molecules28145411
• 作为产物：
  描述：

  (1S,5S)-9-ketophenylmorpohan tartrate 在 溴化氰 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 32.0h， 生成 (1S,5S)-5-(3-methoxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-one
  参考文献：
  名称：

  一种在非对映体 C9-烷基取代的 N-苯乙基-5-(3-羟基)苯基吗啡类中具有高效力和拮抗功效的 MOR 拮抗剂

  摘要：

  5-(3-羟基)苯基吗啡烷结构类化合物与经典吗啡喃、4,5-环氧吗啡喃和6,7-苯并吗啡喃不同，因为它们具有赤道取向的芳环，而不是发现的该环的轴向取向在经典阿片类药物中。这种经过修饰和简化的阿片样结构已被证明保留了抗伤害活性，具体取决于其立体化学和取代基，并且其中一些已被发现比吗啡更有效。研究发现，一种简单的 C9-羟基-5-(3-羟基)苯基吗啡烷对映体在体内的效力比吗啡强约 500 倍。我们之前已经研究过 N-苯乙基-5-(3-羟基)苯基吗啡烷类化合物中的 C9-烯基和羟烷基取代基。尚未探索类似的 C9-烷基（甲基至丁基）取代基及其非对映体组。所有这些化合物现已合成，以确定分子中 C9 位点的链长和立体化学可能对其与阿片受体相互作用的影响。我们现在使用毛喉素诱导的 cAMP 积累抑制测定报告了 16 种化合物（C9-甲基、乙基、丙基和丁基非对映体）的合成和体外活性。几种有效的（亚纳摩尔和纳摩尔）MOR

  DOI：

  10.3390/molecules28145411

文献信息

• [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。
• G-Protein biased opioid agonists: 3-hydroxy-<i>N</i>-phenethyl-5-phenylmorphans with three-carbon chain substituents at C9
  作者：Eugene S. Gutman、Eric Bow、Fuying Li、Agnieszka Sulima、Sophia Kaska、Rachel Crowley、Thomas E. Prisinzano、Yong-Sok Lee、Sergio A. Hassan、Gregory H. Imler、Jeffrey R. Deschamps、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1039/d0md00104j

  日期：——

  A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy-N-phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter

  已经合成了一系列基于3-羟基-N-苯乙基-5-苯基吗啉（3-（2-（2-苯乙基-2-氮杂双环[3.3。 1] nonan-5-yl）phenol）。在抑制福斯高林诱导的cAMP积累试验中，发现其中三个是μ阿片受体激动剂，在PathHunter试验和Tango试验中根本不募集β-arrestin。化合物12（3-（（（1 S，5 R，9 R）-2-苯乙基-9-丙基-2-氮杂双环[3.3.1] nonan-5-yl）苯酚），13（3-（（1 S，5 R，9 R）-9-（（E）-3-羟基丙-1-烯-1-基）-2-苯乙基-2-氮杂双环[3.3.1]壬基-5-基）苯酚）和15a（3-（（1 S，5 R，9 R）-9-（2-羟丙基）-2-苯乙基-2-氮杂双环[3.3.1]壬基-5-基）苯酚）是部分μ激动剂。他们中的两个有中等效率（E MAX大约为65％），一个有较低的效力，他们是大约。5，3和4倍更有
• Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans
  作者：Joshua A. Lutz、Agnieszka Sulima、Eugene S. Gutman、Eric W. Bow、Dan Luo、Sophia Kaska、Thomas E. Prisinzano、Carol A. Paronis、Jack Bergman、Gregory H. Imler、Andrew T. Kerr、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.3390/molecules28124795

  日期：——

  All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.

  我们合成了所有可能的非对映异构体 C9-羟甲基、羟乙基和羟丙基取代的 5-苯基吗啡，以探索 C9 取代基周围的三维空间，从而寻找强效的 MOR 部分激动剂。设计这些化合物的目的是为了降低其 C9-烯基取代亲缘化合物的亲脂性。在 12 种非对映异构体中，许多化合物在福斯可林诱导的 cAMP 积累试验中都具有纳摩尔或亚纳摩尔的效力。几乎所有这些强效化合物都完全有效，其中三种被选作体内评估的化合物（15、21 和 36）都极度偏向于 G 蛋白；这三种化合物都没有招募 beta-arrestin2。12 种非对映异构体中只有 21（3-((1S,5R,9R)-9-(2-羟乙基)-2-苯乙基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚）是一种 MOR 部分激动剂，在 cAMP 试验中具有良好但非完全的功效（Emax = 85%）和亚纳摩尔效力（EC50 = 0.91 nM）。它没有任何 KOR 激动剂活性。这种化合物与吗啡不同，它在体内的通气作用有限。21 号化合物的活性可能与三个著名理论中的一个或多个理论有关，这三个理论试图预测所需的镇痛与与临床使用的阿片类药物相关的不良阿片样副作用的分离。根据这些理论，21 是一种强效的 MOR 部分激动剂，它具有高度的 G 蛋白偏向性，不会吸引 beta-arrestin2，而且发现它同时具有 MOR 和 DOR 激动剂活性。合成的所有其他非对映异构体要么药效远低于 21，要么药效过低或过高，无法达到我们的目的。我们还注意到，具有 1R,5S,9R 立体化学结构的 C9-甲氧基甲基化合物（41）比同类的 C9-羟甲基化合物 11 更有效（41 的 EC50 = 0.65 nM 对 11 的 EC50 = 2.05 nM）。41 和 11 均完全有效。
• 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] SELECTIVE OPIOID RECEPTOR AGONISTS AND ANTAGONISTS<br/>[FR] AGONISTES ET ANTAGONISTES SÉLECTIFS DU RÉCEPTEUR OPIOÏDE
  申请人：[en]THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：WO2024026350A1

  公开（公告）日：2024-02-01

  Compounds having opioid characteristics are provided that can be used for various therapeutic methods including the treatment of pain and opioid use disorders, and compounds having opioid antagonist properties that can be used to treat opioid overdoses. These compounds include agonists and antagonists having selective activity toward more one or more opioid receptors. Such compounds can be full or partial agonists, or can be antagonists lacking agonist properties toward delta and kappa opioid receptors. The partial agonists can diminish side effects associated with traditional opioid medications, and the antagonists can overcome respiratory depression caused by potent narcotics. Structurally these compounds include constrained piperidines with alkenyl or cyanoalkyl groups, as well as other substituents providing desired properties.