trans-4-(dimethylamino)-4-phenyl-4',9'-dihydro-3’H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: trans-4-(dimethylamino)-4-phenyl-4',9'-dihydro-3’H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]
• 英文别名: trans-4',9'-dihydro-N,N-dimethyl-4-phenyl-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine；4',9'-dihydro-N,N-dimethyl-4-phenyl-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine
• 化学式: C₂₄H₂₈N₂O
• 分子量: 360.499
• InChiKey: PICPCIFZWHBKPD-RQNOJGIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.97
• 重原子数：
  27.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  28.26
• 氢给体数：
  1.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  trans-4-(dimethylamino)-4-phenyl-4',9'-dihydro-3’H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole] 在 三甲基氯硅烷 作用下， 以 丁酮 为溶剂， 反应 3.0h， 以420 mg的产率得到trans-4',9'-dihydro-N,N-dimethyl-4-phenyl-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine hydrochloride
  参考文献：
  名称：

  Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

  摘要：

  We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.

  DOI：

  10.1021/ml500116x
• 作为产物：
  描述：

  4-dimethylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride 在 盐酸 、 三氟甲磺酸三甲基硅酯 、 水 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 15.0h， 生成 trans-4-(dimethylamino)-4-phenyl-4',9'-dihydro-3’H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]
  参考文献：
  名称：

  Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

  摘要：

  In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

  DOI：

  10.1021/ml500117c

文献信息

• Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol
  作者：Daniel Wachtendorf、Marc Schmidtmann、Jens Christoffers

  DOI：10.1021/acs.orglett.0c02234

  日期：2020.8.21

  decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet–Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual

  通过将二甲基氨基变为硝基，开发了一种新的合成方法来合成螺环阿片类止痛药西布兰多醇，与已建立的途径相比，该方法更为有效。基于α-硝基甲苯的α-酸度，丙烯酸酯的两次迈克尔加成反应得到无环前体化合物，其易于通过狄克曼缩合和脱羧反应转化为环己酮环化所需的环己酮衍生物。 oxa-Pictet-Spengler反应。另外一个好处是，硝基的还原提供了一种胺，可以在后期分散为羧酰胺，磺酰胺，尿素和氮-烷基同类物。用锌/甲酸/甲醛一步完成了螺环骨架上的硝基到实际标题化合物的二甲基氨基官能团的转化，收率为83％。
• GEMISCHTE ORL1/µ -AGONISTEN ZUR BEHANDLUNG VON SCHMERZ
  申请人：Grünenthal GmbH

  公开号：EP2081571B1

  公开（公告）日：2010-08-25
• Mixed ORL1/mu-agonists for the treatment of pain
  申请人：LINZ KLAUS

  公开号：US20080125475A1

  公开（公告）日：2008-05-29

  The invention relates to the use of compounds which exhibit an affinity for the μ-opioid receptor of at least 100 nM (K i value, human) and an affinity for the ORL-1 receptor, wherein the ratio between the affinities ORL1/μ defined as 1/[K i(ORL1) /K i(μ) ] is from 0.1 to 30, for the treatment of pain.
• MIXED ORL1/MU-AGONISTS FOR THE TREATMENT OF PAIN
  申请人：LINZ KLAUS

  公开号：US20110015220A1

  公开（公告）日：2011-01-20

  The invention relates to the use of compounds which exhibit an affinity for the μ-opioid receptor of at least 100 nM (K i value, human) and an affinity for the ORL-1 receptor, wherein the ratio between the affinities ORL1/μdefined as 1/[K i(ORL1) /K i(μ) ] is from 0.1 to 30, for the treatment of pain.
• Mixed ORL1/mu-agonists for the Treatment of Pain
  申请人：Gruenenthal GmbH

  公开号：US20150342929A1

  公开（公告）日：2015-12-03

  The invention relates to the use of compounds which exhibit an affinity for the μ-opioid receptor of at least 100 nM (K i value, human) and an affinity for the ORL-1 receptor, wherein the ratio between the affinities ORL1/μ defined as 1/[K i(ORL1) /K i(μ) ] is from 0.1 to 30, for the treatment of pain.