3-methoxy-6-keto-N-cyclopropylmethyl-normorphinan | 71968-38-2

• 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: 3-methoxy-6-keto-N-cyclopropylmethyl-normorphinan
• 英文别名: N-cyclopropylmethyl-O-methyl dihydrothebainone；17-cyclopropylmethyl-3-methoxymorphinan-6-one；(1S,9R,10R)-17-(cyclopropylmethyl)-4-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-13-one
• CAS: 71968-38-2
• 化学式: C₂₁H₂₇NO₂
• 分子量: 325.451
• InChiKey: TVSUSZBGGNVGHO-TYPHKJRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-methoxy-6-keto-N-cyclopropylmethyl-normorphinan 在 氢溴酸 、 溴 、 sodium acetate 、 三溴化硼 、 溶剂黄146 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 18.0h， 生成 6,7-(2-N-methyl)aminothiazolo-N-cyclopropylmethyl-morphin-3-ol
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Aminothiazolomorphinans at the Mu and Kappa Opioid Receptors

  摘要：

  Previous studies with aminothiazolomorphinans suggested that this class of opioid ligands may be useful as a potential pharmacotherapeutic to decrease drug abuse. Novel aminothiazole derivatives of cyclorphan were prepared to evaluate a series of aminothiazolomorphinans with, varying pharmacological properties at the kappa opioid receptor (KOR) and mu opioid receptor (MOR). This study was focused on exploring the regioisomeric analogs with the aminothiazole on the C-ring of the morphinan skeleton. Receptor binding and [S-35]GTP gamma S binding assays were used to characterize the affinity and pharmacological properties of the aminothiazolomorphinans. Intracranial self-stimulation (ICSS) was used to compare the effects of a representative aminothiazolomorphinan with the morphinan mixed-KOR/MOR agonist butorphan (MCL-101) on brain-stimulation reward.

  DOI：

  10.1021/jm401290y
• 作为产物：
  描述：

  二氢可待因酮 在 吡啶 、 盐酸 、 氨 、 sodium 、 氯甲酸乙酯 、 铜 、 碳酸氢钠 、 potassium carbonate 、 caesium carbonate 、 对甲苯磺酸 、 溶剂黄146 、 锌 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 、 甲苯 、 苯 为溶剂， 反应 111.0h， 生成 3-methoxy-6-keto-N-cyclopropylmethyl-normorphinan
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of 6,7-Indolo/Thiazolo-MorphinansFurther SAR of Levorphanol

  摘要：

  To further extend the structure-activity relationships of levorphanol, two series of novel morphinans were prepared by incorporation of an indole or aminothiazole fragment to the hexyl ring (ring C) in levorphanol. Such morphinans differed from previously reported ligands in that such indole- or aminothiazole-containing morphinans displayed enhanced binding affinity to the delta opioid receptor, while the affinity to kappa and mu receptors was slightly reduced.

  DOI：

  10.1021/jm0701674

文献信息

• Analgesic narcotic antagonists. 2. 8-Alkylmorphinan-6-ones
  作者：Joseph O. Polazzi、Robert N. Schut、Michael P. Kotick、John F. Howes、Patricia F. Osgood、Raj K. Razdan、Julian E. Villarreal

  DOI：10.1021/jm00176a013

  日期：1980.2

  -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds

  通过将二烷基铜酸锂共轭添加到相应的7,8-二氢-6-烷基中来制备一系列的8-烷基-3-甲氧基-17-甲基吗啡喃-6-（3C）和-异吗啡喃-6-酮（3T）。 2C和2T。这些17-甲基化合物是有效的镇痛药，并通过用环烷基甲基部分取代17-甲基而转化为混合的麻醉激动剂-拮抗剂7-10。8个取代基改变了观察到的活性类型。这些化合物之一，即17-（环丁基甲基）-3-羟基-8β-甲基吗啡喃-6-（10Ca）的激动剂与拮抗剂之比为0.1。化合物10Ca在大鼠中不支持或不引起依赖性。然而，该化合物似乎是吗啡依赖性猴子中的典型麻醉剂。
• Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists
  作者：Yoshihiro Ida、Toru Nemoto、Shigeto Hirayama、Hideaki Fujii、Yumiko Osa、Masayuki Imai、Takashi Nakamura、Toshiyuki Kanemasa、Akira Kato、Hiroshi Nagase

  DOI：10.1016/j.bmc.2011.11.047

  日期：2012.1

  The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the delta opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4-hydroxy group (SN-24, 26, 27) showed higher selectivities for the 8 receptor over the mu receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Derivatives with the 4-hydroxy group showed potent agonist activities for the 5 receptor in the [S-35]GTPyS binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed the lowest selectivity for the delta receptor among the morphinan derivatives, the agonist activity toward the delta receptor was the most potent for candidates with the 3-hydroxy group. (C) 2011 Elsevier Ltd. All rights reserved.
• Design and synthesis of novel delta opioid receptor agonists and their pharmacologies
  作者：Hiroshi Nagase、Yumiko Osa、Toru Nemoto、Hideaki Fujii、Masayuki Imai、Takashi Nakamura、Toshiyuki Kanemasa、Akira Kato、Hiroaki Gouda、Shuichi Hirono

  DOI：10.1016/j.bmcl.2009.03.099

  日期：2009.5

  We re-examined the accessory site of the 4,5-epoxymorphinan skeleton by CAMDAS conformational analysis in an effort to deign novel delta opioid receptor antagonists. We synthesized three novel compounds (SN-11, 23 and 28) with a 10-methylene bridge and without a 4,5-epoxy ring. Among them, compounds SN-23 (17-isobutyl derivative) and SN-28 (17-methyl derivative) showed very strong agonist activity (over 10 times more than TAN-67). SN-28 also showed high delta selectivity. The delta agonist activity of SN-23 was weaker than that of SN-28, but in terms of the delta selectivity, SN-23 was higher than that of SN-28. These unexpected results indicated that the 4,5-epoxy ring, but not the 10-methylene bridge, was an accessory site in delta opioid receptor agonists. (C) 2009 Elsevier Ltd. All rights reserved.
• Novel opiates and antagonists. 5. 7-Carbethoxy-N-(cycloalkylmethyl)-3-hydroxymorphinan-6-ones and -isomorphinan-6-ones
  作者：Patricia Herlihy、Haldean C. Dalzell、John F. Howes、Raj K. Razdan

  DOI：10.1021/jm00350a020

  日期：1982.8

  A direct conversion of deoxydihydrothebaine-phi (1) to 3-methoxymorphinan-6-one (3Ca) and its trans isomer 3Ta was achieved in excellent yield by the catalytic reduction of 1 in AcOH containing CF3COOH. Treatment of 3Ca or 3Ta with NaH and diethyl carbonate formed the corresponding 7-carbethoxy derivatives 4a which, on O-demethylation, furnished the 3-hydroxy compounds 4b. The analgesic N-methyl compounds 3 were converted to the 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 6--8. Two of these compounds, one in the cis (7Ca) and the other in the trans (7Ta) series, showed mixed agonist/antagonist activity in the pentazocine range.
• SPIROCYCLIC MORPHINANS AND THEIR USE
  申请人：Purdue Pharma LP

  公开号：EP2931726B1

  公开（公告）日：2017-01-25