17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan | 1192546-36-3

• 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: 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan
• 英文别名: 6-β-(4'-trifluoromethyl)benzamido-14-hydroxy-17-(cyclopropylmethyl)nordesmorphine；17-Cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[(4''-trimethylfluoro)benzamido]morphinan-oxalate；N-[(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-4-(trifluoromethyl)benzamide
• CAS: 1192546-36-3
• 化学式: C₂₈H₂₉F₃N₂O₄
• 分子量: 514.544
• InChiKey: VRIWDQKPTOTRNK-XGTKUTNFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  82
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan 、 草酸 以 甲醇 为溶剂， 生成 6-β-(4'-trifluoromethyl)benzamido-14-hydroxy-17-(cyclopropylmethyl)nordesmorphine oxalate
  参考文献：
  名称：

  [EN] SYNTHESIS OF METABOLICALLY STABLE AGENTS FOR ALCOHOL AND DRUG ABUSE
  [FR] SYNTHÈSE D'AGENTS MÉTABOLIQUEMENT STABLES POUR L'ALCOOLISME ET LA TOXICOMANIE

  摘要：

  本文披露了式（I）的化合物；如本文所定义，或其药用可接受的盐，包括相同的药物组合物，以及使用这些化合物治疗物质成瘾的方法。

  公开号：

  WO2010006119A1
• 作为产物：
  描述：

  4-三氟甲基苯甲酰氯 、 (5alpha,6beta)-6-氨基-17-(环丙基甲基)-4,5-环氧-吗喃-3,14-二醇 在 三乙胺 、 potassium carbonate 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 反应 14.0h， 以78%的产率得到17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation

  摘要：

  A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K-i values for mu and kappa opioid receptors. Functional assays for stimulation of [S-35] GTP gamma S binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED50 values 19-50 mu g/kg). (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.07.069

文献信息

• Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation
  作者：Senait Ghirmai、Marc R. Azar、John R. Cashman

  DOI：10.1016/j.bmc.2009.07.069

  日期：2009.9

  A series of substituted aryl amide derivatives of 6-naltrexamine, 3 designed to be metabolically stable were synthesized and used to characterize the structural requirements for their potency to binding and functional activity of human mu (mu), delta (delta) and kappa (kappa) opioid and nociceptin (NOP) receptors. Binding assays showed that 4-10 had subnanomolar K-i values for mu and kappa opioid receptors. Functional assays for stimulation of [S-35] GTP gamma S binding showed that several compounds acted as partial or inverse agonists and antagonists of the mu and delta, kappa opioid or NOP receptors. The compounds showed considerable stability in the presence of rat, mouse or human liver preparations and NADPH. The inhibitory activity on the functional activity of human cytochrome P450s was examined to determine any potential inhibition by 4-9. Only modest inhibition of CYP3A4, CYP2C9 and CYP2C19 was observed for a few of the analogs. As a representative example, radiolabeled 6 was examined in vivo and showed reasonable brain penetration. The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED50 values 19-50 mu g/kg). (C) 2009 Elsevier Ltd. All rights reserved.
• [EN] SYNTHESIS OF METABOLICALLY STABLE AGENTS FOR ALCOHOL AND DRUG ABUSE<br/>[FR] SYNTHÈSE D'AGENTS MÉTABOLIQUEMENT STABLES POUR L'ALCOOLISME ET LA TOXICOMANIE
  申请人：HUMAN BIOMOLECULAR RES INST

  公开号：WO2010006119A1

  公开（公告）日：2010-01-14

  Disclosed herein are compounds of formula (I); as defined herein, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, and methods of using these compounds for the treatment of substance addiction.

  本文披露了式（I）的化合物；如本文所定义，或其药用可接受的盐，包括相同的药物组合物，以及使用这些化合物治疗物质成瘾的方法。