14-methoxycodeinone | 38252-24-3

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: 14-methoxycodeinone
• 英文别名: 14-O-methylcodeinone；(4R,4aS,7aR,12bS)-4a,9-dimethoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• CAS: 38252-24-3
• 化学式: C₁₉H₂₁NO₄
• 分子量: 327.38
• InChiKey: YUGMSZACTDKLDJ-GRGSLBFTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  14-methoxycodeinone 在 氢溴酸 、 sodium carbonate 作用下， 生成 9(S)-9-Hydroxy-indolinocodeinon
  参考文献：
  名称：

  Fleischhacker,W. et al., Monatshefte fur Chemie, 1972, vol. 103, p. 1069 - 1077

  摘要：

  DOI：
• 作为产物：
  描述：

  4,5α-epoxy-3,6,6,14-tetramethoxy-17-methyl-morphin-7-ene 在 盐酸 作用下， 生成 14-methoxycodeinone
  参考文献：
  名称：

  Fleischhacker,W. et al., Monatshefte fur Chemie, 1972, vol. 103, p. 1069 - 1077

  摘要：

  DOI：

文献信息

• Mechanistic Diversity of the van Leusen Reaction Applied to 6-Ketomorphinans and Synthetic Potential of the Resulting Acrylonitrile Substructures
  作者：Johannes Schütz、Petra Windisch、Elka Kristeva、Klaus Wurst、Karl-Hans Ongania、Ulrike E. I. Horvath、Herwig Schottenberger、Gerhard Laus、Helmut Schmidhammer

  DOI：10.1021/jo050362v

  日期：2005.6.1

  8-tetradehydromorphinan-6-carbonitriles. Addition of nucleophiles such as Li diisopropylamide or Grignard reagents to the acrylonitrile substructure yielded ring-opened 5,6-didehydro products. Seven products were characterized by X-ray crystal structure analysis and revealed insight into the mechanistic diversity of the van Leusen reaction.

  甲苯磺酰基甲基异氰化物用于将7,8-二氢-6-吗啡酮转化为6,7-二氢吗啡-6-腈，并保留了4,5-环氧环。然而，在NaH存在下开环发生，得到5,6,7,8-四氢吗啡喃-6-腈。将亲核试剂如锂二异丙基酰胺或格利雅试剂添加到丙烯腈亚结构中，得到开环的5，6-二氢加氢产物。通过X射线晶体结构分析对7种产物进行了表征，并揭示了对Van Leusen反应机理多样性的见解。
• Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate
  作者：Ferenc Zádor、Amir Mohammadzadeh、Mihály Balogh、Zoltán S. Zádori、Kornél Király、Szilvia Barsi、Anna Rita Galambos、Szilvia B. László、Barbara Hutka、András Váradi、Sándor Hosztafi、Pál Riba、Sándor Benyhe、Susanna Fürst、Mahmoud Al-Khrasani

  DOI：10.3390/molecules25061370

  日期：——

  The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

  这项研究代表了新型化合物14-甲氧基可待因-6-O-硫酸酯（14-OMeC6SU）的体外（效力、亲和力、功效）和体内（镇痛、便秘）阿片类药理学，与参考化合物可待因-6-O-硫酸酯（C6SU）、可待因和吗啡进行比较。根据体外实验（小鼠和大鼠输精管、受体结合和[35S]GTPγS激活实验），14-OMeC6SU具有µ-阿片受体介导的活性，显示出比母体化合物更高的亲和力、效力和功效。在大鼠中，14-OMeC6SU在尾巴反射实验中显示出比可待因更强的镇痛效果，并且与吗啡具有相同的效力，而C6SU在皮下给药后的效力较低。经脑室内注射后，14-OMeC6SU比吗啡更有效。在完全弗氏佐剂诱导的炎症性高敏感性实验中，14-OMeC6SU和C6SU在皮下剂量分别为6.1和13.2 µmol/kg时显示出外周抗高敏感性效果，因为共同给予的外周作用阿片受体拮抗剂纳洛酮甲碘化物拮抗了测得的抗高敏感性。此外，皮下给药的C6SU对胃肠道传递的抑制作用较14-OMeC6SU、可待因和吗啡为轻。这项研究首次证明了14-OMeC6SU在体内和体外比可待因或C6SU更有效。此外，尽管C6SU具有外周抗高敏感性作用且胃肠道副作用较轻，但在整个研究中14-OMeC6SU的优越性是显而易见的。
• 14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity
  作者：Ferenc Zádor、Mihály Balogh、András Váradi、Zoltán S. Zádori、Kornél Király、Edina Szűcs、Bence Varga、Bernadette Lázár、Sándor Hosztafi、Pál Riba、Sándor Benyhe、Susanna Fürst、Mahmoud Al-Khrasani

  DOI：10.1016/j.ejphar.2017.08.034

  日期：2017.11

  oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O-MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal

  据报道，吗啡-6-O-硫酸盐（M6SU）或羟吗啡酮中的14-O-甲基（14-O-Me）基团对于增强这些类阿片的亲和力，效力和抗伤害感受至关重要。在此，我们报道了新化合物14-O-甲基吗啡（14-O-MeM）在体外的药理特性（效力，亲和力和功效）。此外，我们还研究了该新型化合物的抗伤害感受作用及其在体内对胃肠道转运的抑制作用。通过[35S]GTPγS结合，分离的小鼠输精管（MVD）和大鼠输精管（RVD）测定来测量测试化合物的效力和功效。通过放射性配体结合和MVD分析评估14-O-MeM对阿片样物质受体的亲和力。分别在大鼠甩尾试验和木炭粉试验中评估了新化合物的抗伤害感受和胃肠道作用。吗啡，DAMGO，Ile5,6 deltorphin II，deltorphin II和U-69593被用作参考化合物。14-O-MeM在MVD，RVD或[35S]GTPγS结合中显示出比吗啡更高的功效（Emax）
• Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds
  作者：Helmut Schmidhammer、Colin F. C. Smith、Daniela Erlach、Martin Koch、Roland Krassnig、Wolfgang Schwetz、Christine Wechner

  DOI：10.1021/jm00166a018

  日期：1990.4

  A series of cyprodime-related compounds (2, 4-12, and 26) has been synthesized and evaluated for opioid agonist and antagonist activity with the mouse vas deferens and guinea pig ileum preparations. None of the changes to cyprodime, including the introduction of a 3-OMe group, increasing and decreasing the size of or completely removing the substituent in position 4, replacing the N-cyclopropylmethyl

  已经合成了一系列与环丙二胺相关的化合物（2、4-12和26），并与小鼠输精管和豚鼠回肠制剂一起评估了阿片类激动剂和拮抗剂的活性。环丙啶没有任何变化，包括引入3-OMe基团，增加和减小第4位的取代基的大小或完全去除该取代基的大小，或用N-烯丙基取代N-环丙基甲基，或取代14-具有14-OEt取代基的OMe可以改善mu拮抗剂的分布，并且大多数对mu的选择性和效力或增加的激动剂活性都是有害的。增加位置4上的取代基的长度，得到的化合物（6a）的轮廓与嘧啶非常相似。
• Synthesis and biological evaluation of 14-alkoxymorphinans. Part 7. 14,14?-dimethoxy analogues of norbinaltorphimine: Synthesis and determination of their ? opioid antagonist selectivity
  作者：Helmut Schmidhammer、Ernst Ganglbauer、J�rg Mitterdorfer、Judith M. Rollinger、Colin F. C. Smith

  DOI：10.1002/hlca.19900730622

  日期：1990.9.19

  The bimorphinans 6 and 7 have been prepared from 14-O-methylnaloxone (2) and 14-O-methylnaltrexone (3), respectively. The known compounds 2 and 3 were synthesized by a different route than the route described. Bimorphinan 7 possessed a similar χ receptor affinity to norbinaltorphimine (1) but had a reduced selectivity due to marked increases in μ and δ receptor affinity. Bimorphinan 6 was both a less

  双吗啡喃6和7分别由14 - O-甲基纳洛酮（2）和14- O-甲基纳曲酮（3）制备。已知化合物2和3是通过与所述途径不同的途径合成的。双吗啡喃7具有与norbinaltorphimine（1）相似的χ受体亲和力，但由于μ和δ受体亲和力显着增加，选择性降低。双吗啡喃6的选择性和活性均低于1。