6β-N-methylnaltrexamine | 102869-99-8

• 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: 6β-N-methylnaltrexamine
• 英文别名: 17-Cyclopropylmethyl-4,5alpha-epoxy-3,14beta-dihydroxy-6beta-methylaminomorphinan；(4R,4aS,7R,7aR,12bS)-3-(cyclopropylmethyl)-7-(methylamino)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol
• CAS: 102869-99-8
• 化学式: C₂₁H₂₈N₂O₃
• 分子量: 356.465
• InChiKey: MDPFGNLTFZJSEZ-GQHLEUQBSA-N

物化性质

• 沸点：
  541.6±50.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)
• 溶解度：
  溶于DMSO、乙酸乙酯、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  65
• 氢给体数：
  3
• 氢受体数：
  5

制备方法与用途

用途
Opioid receptor antagonist. 用于制备镇痛药激动剂TRK-820及其他相关化合物。

反应信息

• 作为反应物：
  描述：

  6β-N-methylnaltrexamine 在 盐酸 、 platinum(IV) oxide 作用下， 以 水 为溶剂， 以100%的产率得到(4R,4aS,7R,7aR,12bS)-7-(methylamino)-3-(2-methylpropyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol
  参考文献：
  名称：

  The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives

  摘要：

  We have previously reported the essential structure of the opioid kappa receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the kappa receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the j receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the mu and delta opioid receptors, but the binding affinity for the j receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the j receptor than did nalfurafine itself. With regard to the j agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the j receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the j receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the j receptor. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.100
• 作为产物：
  描述：

  纳曲酮 在 5%-palladium/activated carbon 、 氢气 、 sodium cyanoborohydride 、 对甲苯磺酸 、 溶剂黄146 、 苯甲酸 作用下， 以 甲醇 、 甲苯 为溶剂， 20.0 ℃ 、300.01 kPa 条件下， 反应 18.0h， 生成 6β-N-methylnaltrexamine
  参考文献：
  名称：

  Crystals of morphinan derivative, manufacturing method thereof, and pharmaceutical composition using the same

  摘要：

  本发明涉及一种17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反-3-(3-呋喃基)丙烯酰胺基]吗啡烷盐酸盐的X形晶体及其制备方法，其中该化合物的X形晶体在其粉末X射线衍射图谱中具有特征性的衍射峰，位置分别为2θ为13.6°(±0.2°)、17.2°(±0.2°)、19.1°(±0.2°)、23.2°(±0.2°)和23.8°(±0.2°)。本发明还涉及一种包括上述吗啡烷衍生物盐酸盐的X形晶体的药物组合物。

  公开号：

  US08816084B1

文献信息

• [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。
• [EN] NOVEL MORPHINANS USEFUL FOR TREATING MEDICAL DISORDERS<br/>[FR] NOUVEAUX MORPHINANES UTILES POUR LE TRAITEMENT DE TROUBLES MÉDICAUX
  申请人：HUMANWELL PHARMACEUTICAL US

  公开号：WO2020205735A1

  公开（公告）日：2020-10-08

  The present invention related to novel morphinans, compositions comprising the novel morphinans, and their uses as agonists of the kappa opioid receptor.

  本发明涉及新型吗啡酮类化合物，包括这些新型吗啡酮类化合物的组合物，以及它们作为κ阿片受体激动剂的用途。
• Discovery of a Structurally Novel Opioid .KAPPA.-Agonist Derived from 4,5-Epoxymorphinan.
  作者：Hiroshi NAGASE、Jun HAYAKAWA、Kuniaki KAWAMURA、Kouji KAWAI、Yuko TAKEZAWA、Hirotoshi MATSUURA、Chiko TAJIMA、Takashi ENDO

  DOI：10.1248/cpb.46.366

  日期：——

  hypothesis. The "message-address concept" for opioid antagonists and the "accessory site" for general antagonists were applied to design TRK-820. A unique structural feature of TRK-820, which is different from other prototypical kappa-opioid receptor agonists, is the existence of the 4,5-epoxymorphinan structure with a tyrosine-glysine moiety for endogenous opioid peptides such as dynorphins. TRK-820 exhibited

  一种新型的kappa激动剂17-环丙基甲基-3，14β-二羟基-4,5α-环氧-6β-[N-甲基-反式-3-（3-呋喃基）丙烯酰胺基]吗啡喃盐酸盐（1， TRK-820），是通过一个新的工作假设发现的。阿片类药物拮抗剂的“消息地址概念”和一般拮抗剂的“附件位点”被用于设计TRK-820。TRK-820的独特结构特征与其他典型的κ阿片受体激动剂不同，它是内源性阿片肽（例如强啡肽）具有酪氨酸-赖氨酸部分的4,5-环氧吗啡喃结构。TRK-820在豚鼠回肠（GPI）和小鼠输精管（MVD）制剂中表现出高效力和高kappa选择性。在小鼠乙酸诱发的扭体模型和小鼠尾部甩动模型的抗伤害作用中，TRK-820的效力是吗啡的85-140倍，效力是U-50488H的85-350倍。尽管kappa激动剂（U-50488H衍生物）的原型表现出厌恶感，但这种结构新颖的kappa激动剂在条件位置偏好测试中既没有表现出厌恶感，也没有表现出偏好。
• Morphinan derivative and its pharmaceutical applications
  申请人：Toray Industries, Inc.

  公开号：US06323212B1

  公开（公告）日：2001-11-27

  A morphinan derivative or its pharmacologically allowed acid addition salt represented with compound I, an analgesic and diuretic having its derivative or its salt as the active ingredient, and its production process are described. The compound of the present invention possesses strong analgesic activity and diuretic action as a highly selective &kgr;-opioid agonist, allowing it to be used as a useful analgesic and diuretic.

  本发明涉及一种吗啡型衍生物或其药理学上允许的酸盐加成物，用化合物I表示，其中该衍生物或其盐为活性成分的镇痛和利尿剂，以及其制备方法。本发明化合物具有强烈的镇痛作用和利尿作用，作为高度选择性的&kgr;-阿片受体激动剂，使其能够用作有用的镇痛剂和利尿剂。
• MORPHINAN DERIVATIVE AND MEDICINAL USE
  申请人：TORAY INDUSTRIES, INC.

  公开号：EP0577847A1

  公开（公告）日：1994-01-12

  A morphinan derivative represented by general formula (1) or a pharmacologically acceptable acid addition salt thereof, an analgesic and diuretic containing the same as the active ingredient, and a process for producing the same The invention compound has potent analgesic and diuretic activities as a highly selective κ-opioid agonist, thus being useful as an analgesic and diuretic.

  一种由通式（1）代表的吗啡南衍生物或其药理上可接受的酸加成盐，一种含有吗啡南衍生物作为活性成分的镇痛剂和利尿剂，以及生产吗啡南衍生物的工艺。 本发明化合物作为一种高选择性κ-阿片激动剂，具有强效的镇痛和利尿活性，因此可用作镇痛剂和利尿剂。