(1'R,9'R,10'S)-17'-(cyclopropylmethyl)-4'-methoxyspiro[1,3-dioxolane-2,13'-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene]-10'-ol | 1043876-55-6

• 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: (1'R,9'R,10'S)-17'-(cyclopropylmethyl)-4'-methoxyspiro[1,3-dioxolane-2,13'-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene]-10'-ol
• CAS: 1043876-55-6
• 化学式: C₂₃H₃₁NO₄
• 分子量: 385.503
• InChiKey: BVDCTVCUBCYJSF-MQSCRBSSSA-N

物化性质

• 熔点：
  125-127 °C(Solv: ethyl acetate (141-78-6))
• 沸点：
  545.1±50.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1'R,9'R,10'S)-17'-(cyclopropylmethyl)-4'-methoxyspiro[1,3-dioxolane-2,13'-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene]-10'-ol 在 盐酸 、 lithium aluminium tetrahydride 、 甲烷磺酸 、 氢气 、 三溴化硼 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 、 1,1,2,2-四氯乙烷 为溶剂， 反应 57.5h， 生成 6,7-didehydro-7'-(N,N-dimethylamino)-3-methoxy-17-methylquinolino[2',3':6,7]morphinan-14β-ol
  参考文献：
  名称：

  Synthesis of quinolinomorphinan derivatives as highly selective δ opioid receptor ligands

  摘要：

  We have reported previously the novel delta opioid agonist KNT-127 which showed high affinity and selectivity for the delta receptor. Moreover, the analgesic effect of subcutaneously administered KNT-127 was more potent than that of a prototypical delta agonist (-)-TAN-67 in the acetic acid writhing test. This study of the structure-activity relationship of KNT-127 derivatives focused on the introduction of substituents onto the 5'-, 6'-, 7'- or 8'-position of the quinoline ring and revealed that many derivatives with 5'- or 8'-substituents showed high affinities and selectivities for the delta receptor. Especially, SYK-153 with an 8'-OH group showed the highest affinity and the most balanced and highest selectivity for the delta receptor among the synthesized compounds. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.08.004
• 作为产物：
  描述：

  盐酸纳洛酮 在 四(三苯基膦)钯 、 1,3-二甲基巴比妥酸 、 1,3-双(二苯基膦)丙烷 、 palladium diacetate 、 potassium carbonate 、 氯化铵 、 caesium carbonate 、 对甲苯磺酸 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 乙腈 为溶剂， 反应 94.49h， 生成 (1'R,9'R,10'S)-17'-(cyclopropylmethyl)-4'-methoxyspiro[1,3-dioxolane-2,13'-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene]-10'-ol
  参考文献：
  名称：

  7,8-Cyclicmorphinan Analogs

  摘要：

  本申请涉及式I-A的化合物以及药用可接受的盐和溶剂化物，其中Cy、R1a-R3a、R4a和R4b的定义如说明书所述。本发明还涉及将式I-A的化合物用于治疗对一或多个阿片受体调节有反应的疾病，或作为合成中间体。本发明中的某些化合物特别适用于治疗疼痛。

  公开号：

  US20140187571A1

文献信息

• BENZOMORPHAN ANALOGS AND THE USE THEREOF
  申请人：Purdue Pharma L.P.

  公开号：US20140221419A1

  公开（公告）日：2014-08-07

  The present invention is directed to Benzomorphan Analog compounds of the Formula I-ID as shown below, wherein R 1 , R 2a , R 2b , R 3 and R 4 are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

  本发明涉及如下所示的Formula I-ID的苯吗啉类似化合物，其中R1、R2a、R2b、R3和R4的定义如本文所述。本发明的化合物可用于治疗疼痛、便秘以及其他受阿片类和ORL-1受体活性调节的疾病。
• Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 3: Synthesis of decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position and their pharmacologies
  作者：Hideaki Fujii、Satomi Imaide、Shigeto Hirayama、Toru Nemoto、Hiroaki Gouda、Shuichi Hirono、Hiroshi Nagase

  DOI：10.1016/j.bmcl.2012.09.101

  日期：2012.12

  an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized the decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position. The introduction of a hydroxy group to the derivatives increased the affinity and selectivity to the κ receptor regardless of the configuration at the 3-position. However, their affinities were

  为了阐明阿片样物质κ受体选择性激动剂那氟拉芬与κ受体结合的基本结构，我们设计并合成了在3位具有氧官能团的十氢（亚氨基乙基）菲衍生物。羟基的引入增加了对κ受体的亲和力和选择性，而与3位上的构型无关。然而，它们的亲和力低于具有酚羟基的那氟萘芬的亲和力。结果表明羟基的酸度将在与阿片样物质受体的相互作用中起重要作用。3-酮衍生物的低亲和力表明3-羟基基团可以不作为氢受体而是作为氢供体参与与受体位点的氢键结合。这是吗啡烷中3-羟基作为氢供体的第一个实验证据。此外，这些具有6α-酰胺侧链的衍生物的κ选择性受3-羟基的影响。预期获得的结构-活性关系信息将有助于设计针对κ受体的更具选择性的配体。
• Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 2: Synthesis of decahydro(iminoethano)phenanthrene derivatives and their pharmacologies
  作者：Hiroshi Nagase、Satomi Imaide、Shigeto Hirayama、Toru Nemoto、Hideaki Fujii

  DOI：10.1016/j.bmcl.2012.05.122

  日期：2012.8

  To clarify the essential structures of an opioid kappa receptor selective agonist, nalfurafine, for binding to the kappa receptor, we designed and synthesized some nalfurafine derivatives and the decahydro(iminoethano)phenanthrene derivatives with a cyclohexene moiety as a surrogate for the phenol ring. In addition to the 6-amide side chain and the 17-nitrogen substituted by a cyclopropylmethyl group, the 4,5-epoxy ring, phenolic hydroxy group, and angular hydroxy group played important roles in eliciting the binding properties of nalfurafine but these three moieties were not indispensable for binding to the kappa receptor. Moreover, the phenol ring was also not essential for the binding to the kappa receptor, and the cyclohexene moiety would play an important role in fixing the conformation of decahydro(iminoethano) phenanthrene derivatives to effectively raise the amide side chain, rendering a conformation that resembled the active one of nalfurafine. (C) 2012 Elsevier Ltd. All rights reserved.
• Design and synthesis of KNT-127, a δ-opioid receptor agonist effective by systemic administration
  作者：Hiroshi Nagase、Toru Nemoto、Ayaka Matsubara、Manabu Saito、Naoshi Yamamoto、Yumiko Osa、Shigeto Hirayama、Mayumi Nakajima、Kaoru Nakao、Hidenori Mochizuki、Hideaki Fujii

  DOI：10.1016/j.bmcl.2010.08.083

  日期：2010.11

  We have reported previously the novel delta-opioid agonist, SN-28, which was more potent in in vitro assays than the prototype delta-agonists, TAN-67 and SNC-80. However, when administered by subcutaneous injection, this compound showed no analgesic effect at dosages greater than 30 mg/kg in the acetic acid writhing test. We speculated that SN-28 was not effective in the test because the presence of the charged ammonium groups prevented its penetration through the blood-brain barrier. On the basis of our proposal, we designed the novel delta-agonist, KNT-127, which was effective with systemic administration. (C) 2010 Elsevier Ltd. All rights reserved.
• 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.