(+)-(5Α,7Α,8Β)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺 | 96744-75-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (+)-(5Α,7Α,8Β)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺
• 中文别名: (+)-(5α,7α,8β)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺；(+)-(5Alpha,7Alpha,8Beta)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺
• 英文名称: N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide
• 英文别名: U 69593；(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide；[3H]-U 69593；(+)-(5a,7a,8b)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide；N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl]acetamide；5,7,8-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide；N-methyl-2-phenyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide
• CAS: 96744-75-1
• 化学式: C₂₂H₃₂N₂O₂
• 分子量: 356.508
• InChiKey: PGZRDDYTKFZSFR-ONTIZHBOSA-N

物化性质

• 熔点：
  120-123℃
• 沸点：
  518.7±50.0 °C(Predicted)
• 密度：
  1.13
• 溶解度：
  H2O: 14 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  、 、 、 (+)-(5Α,7Α,8Β)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺 、 纳洛酮 、 去甲-BINALTORPHIMINE二盐酸盐 、 吗啡 、 纳美芬 、 (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[[(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-1-hydroxy-3-(4-hydroxyphenyl)propylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-phenylpropylidene]amino]-1-hydroxy-4-methylpentylidene]amino]-5-carbamimidamido-1-hydroxypentylidene]amino]-5-carbamimidamido-1-hydroxypentylidene]amino]-1-hydroxy-3-methylpentylidene]amino]-5-carbamimidamidopentanoyl]pyrrolidin-2-yl]-hydroxymethylidene]amino]-1-hydroxyhexylidene]amino]-1-hydroxy-4-methylpentylidene]amino]-1-hydroxyhexylidene]amino]-1-hydroxy-3-(1H-indol-3-yl)propylidene]amino]-3-carboxy-1-hydroxypropylidene]amino]-1,4-dihydroxy-4-iminobutylidene]amino]-5-hydroxy-5-iminopentanoic acid 、 L-酪氨酰-D-丙氨酰甘氨酰-N-(2-羟基乙基)-NALPHA-甲基-L-苯丙氨酰胺 、 生成 (±)-ibogaine
  参考文献：
  名称：

  METHODS AND COMPOSTIONS FOR POTENTIATING THE ACTION OF OPIOID ANALGESICS USING IBOGA ALKALOIDS

  摘要：

  使用伊波卡生物碱或其药用可接受盐和/或溶剂的增强量，且不会使患者QT间期延长超过约50毫秒的方法和组合物，以增强正在接受或计划接受阿片类镇痛治疗的患者的阿片类镇痛剂效果。

  公开号：

  US20160220579A1
• 作为产物：
  描述：

  (-)-(5α,7α,8β)-N-methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro<4,5>decan-8-amine 、 苯乙酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以91%的产率得到(+)-(5Α,7Α,8Β)-N-甲基-N-[7-(1-吡咯烷基)-1-氧螺[4.5]十二-8-基]-苯乙酰胺
  参考文献：
  名称：

  A Practical Synthesis of the Kappa Opioid Receptor Selective Agonist (+)-5R,7S,8S-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxospiro[4,5]dec-8-yl]ben­zeneacetamide (U69,593)

  摘要：

  一种新颖的合成κ阿片受体激动剂U69,593的方法已被开发出来。该方法通过用稳定且可分离的环状硫酸盐替代不稳定的环氧化物，改善了目前文献中的合成方法。这种新方法能够获取克级的目标化合物，并在相对立体化学方面表现出优异的控制能力。使用X射线晶体结构分析和κ阿片受体结合实验验证了这种新方法合成的U69,593的绝对立体化学及其生物活性。

  DOI：

  10.1055/s-2008-1032185

文献信息

• [EN] ANTAGONISTS OF THE KAPPA OPIOID RECEPTOR<br/>[FR] ANTAGONISTES DU RÉCEPTEUR OPIOÏDE KAPPA
  申请人：UNIV KANSAS

  公开号：WO2016086149A1

  公开（公告）日：2016-06-02

  The present technology is directed to compounds, compositions, and methods related to non-morphinan-like kappa opioid receptor (KOR) antagonists. The technology is suited to treat addiction, diuresis, depression, post traumatic stress disorder, an eating disorder, panic disorder, social anxiety disorder, general anxiety disorder, obsessive compulsive disorders, excessive or unreasonable specific phobias, and/or other conditions related to anxiety or aversion-reward responses.

  本技术涉及非吗啡样的kappa阿片受体（KOR）拮抗剂相关的化合物、组合物和方法。该技术适用于治疗成瘾、利尿、抑郁症、创伤后应激障碍、进食障碍、惊恐障碍、社交焦虑障碍、广泛性焦虑障碍、强迫症、过度或不合理的特定恐惧症，以及/或其他与焦虑或厌恶-奖赏反应有关的疾病。
• [EN] NOVEL MORPHINANS USEFUL AS ANALGESICS<br/>[FR] NOUVEAUX MORPHINANES UTILES EN TANT QU'ANALGÉSIQUES
  申请人：PHEONIX PHARMALABS INC

  公开号：WO2012088494A1

  公开（公告）日：2012-06-28

  Compounds of Formula (I) are disclosed. The variables R1 R11 are described herein. Certain compounds of Formula (I) are partial agonists of the mu, delta, and kappa opioid receptors, and are useful for treating pain and opioid addiction, with fewer side effects than conventional opioids. Methods for preparing the disclosed compounds, pharmaceutical compositions containing compounds of Formula (I), and methods of treating pain and opioid addiction in patients are also disclosed.

  公开了化学式(I)的化合物。变量R1和R11在此描述。化学式(I)的某些化合物是mu、delta和kappa阿片受体的部分激动剂，可用于治疗疼痛和阿片类药物成瘾，副作用比传统阿片类药物少。还公开了制备上述化合物的方法，含有化学式(I)化合物的制药组合物，以及治疗患者的疼痛和阿片类药物成瘾的方法。
• METHODS AND COMPOSITIONS FOR REDUCING TOLERANCE TO OPIOID ANALGESICS
  申请人：DemeRx, Inc.

  公开号：US20150258108A1

  公开（公告）日：2015-09-17

  A method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides a therapeutic serum concentration of noribogaine. In some embodiments, the therapeutic average serum concentration is 50 ng/mL to 180 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.

  一种用于调节接受阿片类镇痛治疗的患者对阿片类镇痛剂的耐受性的方法，该方法包括在阿片类镇痛治疗期间中断或同时给予一定量的诺利波甲胺、诺利波甲胺衍生物或其药学上可接受的盐和/或溶剂，以提供治疗性血清浓度的诺利波甲胺。在某些实施例中，治疗性平均血清浓度为50ng/mL至180ng/mL，该浓度足以使患者对阿片类镇痛剂重新敏感作为镇痛剂，同时在治疗期间维持QT间期小于约500ms。
• NOVEL MIXED μ AGONIST/ δ ANTAGONIST OPIOID ANALGESICS WITH REDUCED TOLERANCE LIABILITIES AND USES THEREOF
  申请人：COOP Andrew

  公开号：US20160016965A1

  公开（公告）日：2016-01-21

  An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through μ receptors. Although, traditional μ agonists can cause undesired side effects, including tolerance, addition of δ antagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacks δ-specific motifs, conformationally sampled pharmacophore models for μ and δ receptors predict it to have efficacy similar to morphine at μ receptors and similar to naltrexone at δ receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed μ agonist/δ antagonist profile as determined in receptor binding. UMB 425 has mixed μ agonist/δ antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

  一种阿片类麻醉药物，用于治疗中度到重度疼痛，主要通过μ受体发挥其镇痛作用。尽管传统的μ激动剂可能会引起不良反应，包括耐受性，但加入δ拮抗剂可以减轻这些不良反应。本发明包括4a，9-二羟基-7a-（羟甲基）-3-甲基-2，3，4，4a，5，6-六氢-1H-4，12-甲烷基苯并呋喃[3，2-e]异喹啉-7（7aH）-酮（UMB 425），一种基于5,14-桥接吗啡的奥维诺前体，以及吗啡，二氢吗啡，羟吗啡，可待因，二氢可待因，氢可酮和乙基吗啡的类似物。虽然UMB 425缺乏δ特异性基序，但μ和δ受体的构象采样药效模型预测其在μ受体上具有类似吗啡的功效，在δ受体上具有类似于纳曲酮的功效，因为化合物采样与奥维诺尔类似的构象，其中羟基部分与受体相互作用。UMB 425在受体结合中表现出混合的μ激动剂/δ拮抗剂特性。UMB 425在体外表现出混合的μ激动剂/δ拮抗剂特性，这种特性在体内可转化为降低耐受性的效果。
• mu-OPIOID RECEPTOR AGONIST AND PREPARATION METHOD THEREFOR AND USE THEREOF IN FIELD OF MEDICINE
  申请人：Shanghai Synergy Pharmaceutical Sciences Co., Ltd

  公开号：EP3686198A1

  公开（公告）日：2020-07-29

  Disclosed are a class of µ-opioid receptor agonists and a preparation method therefor and the use thereof in the field of medicine, belonging to the field of medicinal chemistry. The µ-opioid receptor agonists significantly increase the selectivity for a G protein signaling pathway, and not only can exhibit excellent pharmacodynamic effects, but also significantly improve safety.

  本发明公开了一类μ-阿片受体激动剂及其制备方法，以及其在医药领域的用途，属于药物化学领域。该μ-阿片受体激动剂显著提高了对G蛋白信号通路的选择性，不仅能表现出优异的药效学效应，还能显著提高安全性。