3-(benzyloxy)-4,5α-epoxy-6β,14-dihydroxy-17-(cyclopropylmethyl)morphinan | 141555-34-2

• 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: 3-(benzyloxy)-4,5α-epoxy-6β,14-dihydroxy-17-(cyclopropylmethyl)morphinan
• 英文别名: 3-O-benzyl-6β-naltrexol；3-(benzyloxy)-17-(cyclopropylmethyl)-6β-14-hydroxy-4,5α-epoxymorphinan；3-O-Bn-6β-naltrexol；17-cyclopropylmethyl-4,5α-epoxy-3-benzyloxy-6β,14-dihydroxymorphinan；17-Cyclopropylmethyl-4,5alpha-epoxy-3-benzyloxy-6beta,14-dihydroxymorphinan；(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-9-phenylmethoxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol
• CAS: 141555-34-2
• 化学式: C₂₇H₃₁NO₄
• 分子量: 433.547
• InChiKey: AAKAKADMVSRQEP-GIBBRDMCSA-N

物化性质

• 沸点：
  624.9±55.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  62.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(benzyloxy)-4,5α-epoxy-6β,14-dihydroxy-17-(cyclopropylmethyl)morphinan 在 lithium aluminium tetrahydride 、 盐酸羟胺 、 草酸 、 potassium hydride 、 碳酸氢钠 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 25.5h， 生成 3-(benzyloxy)-4,5α-epoxy-14-hydroxy-6β-(2-aminoethoxy)-17-(cyclopropylmethyl)morphinan
  参考文献：
  名称：

  Electrophilic opioid ligands. Oxygen-tethered .alpha.-methylene-.gamma.-lactone, acrylate, isothiocyanate, and epoxide derivatives of 6.beta.-naltrexol

  摘要：

  O6-Ether derivatives of 6-beta-naltrexol in which the ether substituent includes various electrophilic groups have been synthesized in an effort to examine structure-activity requirements at the 6-beta-substituent for receptor affinity and irreversibility of binding in opioid receptor preparations. A series of tethered 6-beta-ethers having terminal epoxides, alpha-methylene-gamma-lactones, and an isothiocyanate group were prepared. The stereochemistry of the alpha-methylene-gamma-lactones was established by convergent synthesis of their reduction products from epoxides of known absolute stereochemistry. In general, the tested compounds showed comparable affinity and selectivity for the receptor subtypes. All were found with high affinity for mu-sites. The terminal epoxide ether diastereomers 8 and 9 were not bound irreversibly in the assay for total opioid receptors. The alpha-methylene-gamma-lactone diastereomers 10 and 11, and their O-14-acetyl precursors 20 and 21, respectively, varied in their irreversible effects, but where noted these effects were mu-site selective. Methacrylate ether 7 and isothiocyanate ether 12 were bound irreversibly at both mu- and delta-sites.

  DOI：

  10.1021/jm00091a005
• 作为产物：
  描述：

  纳曲酮 在 甲醇 、 sodium tetrahydroborate 、 potassium carbonate 作用下， 以 乙醇 、 丙酮 为溶剂， 反应 24.0h， 生成 3-(benzyloxy)-4,5α-epoxy-6β,14-dihydroxy-17-(cyclopropylmethyl)morphinan
  参考文献：
  名称：

  从纳曲酮有效合成3-OBn-6β，14-环氧桥联阿片剂并鉴定相关的双重MOR逆向激动剂/ KOR激动剂

  摘要：

  为了更好地理解告知纳曲酮和相关纳曲醇衍生物的生物学活性的构象偏好，描述了限制性类似物3-OBn-6β，14-环氧吗啡喃4的新合成。从纳曲酮开始以总产率的50％合成4，然后通过OBn-6α-三氟甲磺酸酯中间体8进行合成。合成的关键步骤包括苄基化（96％的收率），还原（90％的收率，α：β：3：2），然后是一锅法的三氟甲磺酸酯/置换顺序（96％的收率），以产生所需的桥连环氧衍生物4。中间体3-OBn-6α-纳曲醇7a的X射线晶体学分析支持环氧环封闭所需的关键舟形构造的填充。我们还报告说，使用Herkinorin预处理的细胞和激动剂在6β-甲磺酸酯10-高亲和力的阿片受体配体，11的差向异构体衍生物和12的类似物在mu阿片受体上起反向激动剂的作用。当在独立的体外[ 35 S]-GTP-γ-S分析中评估时，κ阿片受体。

  DOI：

  10.1016/j.bmcl.2012.06.056

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。
• Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent
  作者：Sidnee L. Hedrick、Dan Luo、Sophia Kaska、Kumar Kulldeep Niloy、Karen Jackson、Rupam Sarma、Jamie Horn、Caroline Baynard、Markos Leggas、Eduardo R. Butelman、Mary Jeanne Kreek、Thomas E. Prisinzano

  DOI：10.1186/s12929-021-00758-y

  日期：2021.12

  is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced

  美国最突出的阿片类镇痛药之一是高效激动剂芬太尼。它用于治疗急性和慢性疼痛并作为麻醉辅助剂。然而，如果使用不当，仅摄入几毫克芬太尼或其他合成阿片类药物就会导致阿片类药物引起的呼吸抑制 (OIRD)，通常会导致死亡。目前，OIRD 的首选治疗方法是阿片受体拮抗剂纳洛酮。然而，最近的报告表明，可能需要更高剂量或重复给药的纳洛酮（由于呼吸抑制复发）才能完全逆转芬太尼诱导的呼吸抑制，从而导致这种治疗不足。为了应对这种合成阿片类药物过量危机，该研究旨在确定一种新型阿片类药物逆转剂，其对芬太尼和其他合成阿片类药物具有增强的功效。一系列纳曲酮类似物的特征在于它们能够利用改良的毛喉素诱导的 cAMP 积累测定在体外拮抗芬太尼的作用。选择铅类似物 29 进行进一步的 PK 研究，然后进行体内药理学分析，以确定其在热板试验中拮抗阿片类药物诱导的镇痛作用的能力。确定了一系列有效的 MOR 拮抗剂，包括高效的类似物
• Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin
  作者：Priyanka Ghosh、DoMin Lee、Kyung Bo Kim、Audra L. Stinchcomb

  DOI：10.1007/s11095-013-1147-8

  日期：2014.1

  The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

  这项研究的目的是优化共价药物的结构，以延长微针治疗皮肤的给药时间。模型化合物纳曲酮与非特异性环氧化酶抑制剂双氯芬酸连接，以提高微针处理后的毛孔寿命，并开发出纳曲酮的 7 天透皮系统。对纳曲酮和双氯芬酸的四种不同复方药物的稳定性和溶解性进行了比较。对母药和同系物的透皮通量、渗透性和皮肤浓度进行了量化，以形成结构渗透关系。结果表明，所有同系物都能在皮肤中发生生物转化。转化程度取决于结构，与仲醇连接的结构相比，苯酚连接的同系物稳定性较差。苯酚连接的联名药物在经微针处理的皮肤中的纳曲酮通量和双氯芬酸的皮肤浓度更高。聚乙二醇连接增强了联名药物的溶解度，从而提高了通量。目前的研究表明，可以通过结构设计优化来提高联名药物的制剂稳定性和纳曲酮的通量。聚乙二醇连接的纳曲酮双氯芬酸同系物在稳定性和给药方面都更适合用于 7 天给药系统。
• Compounds including Cox inhibitor moiety and enhanced delivery of active drugs using same
  申请人：Stinchcomb Audra

  公开号：US09566341B1

  公开（公告）日：2017-02-14

  The presently-disclosed subject matter includes compounds including a cyclooxygenase enzyme inhibitor moiety and a moiety derived from a drug of interest. In some embodiments, the drug of interest is an opioid. In some embodiments, the compound includes a diclofenac moiety and a naltrexone or naltrexol moiety. The compounds allow for enhanced delivery rates across skin.

  目前公开的主题包括化合物，其中包括一个环氧合酶抑制剂基团和一个来自感兴趣药物的基团。在某些实施例中，感兴趣的药物是阿片类药物。在某些实施例中，化合物包括一个双氯芬酸基团和一个纳曲酮或纳曲醇基团。这些化合物允许皮肤跨膜增强输送速率。
• 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。