2-(3,4-dichlorophenyl)-1-((4aS,8S,8aS)-8-(pyrrolidin-1-yl)-octahydroquinoxalin-1(2H)-yl)ethanone

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(3,4-dichlorophenyl)-1-((4aS,8S,8aS)-8-(pyrrolidin-1-yl)-octahydroquinoxalin-1(2H)-yl)ethanone
• 英文别名: 1-[(4aS,8S,8aS)-8-pyrrolidin-1-yl-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoxalin-1-yl]-2-(3,4-dichlorophenyl)ethanone
• 化学式: C₂₀H₂₇Cl₂N₃O
• 分子量: 396.36
• InChiKey: LWDJYEJRZVMWMH-BJLQDIEVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(3,4-dichlorophenyl)-1-((4aS,8S,8aS)-8-(pyrrolidin-1-yl)-octahydroquinoxalin-1(2H)-yl)ethanone 在 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 mineral oil 为溶剂， 反应 6.0h， 生成 2-(3,4-dichlorophenyl)-1-{(4aRS,8RS,8aSR)-4-[2-(2-fluoroethoxy)acetyl]-8-(pyrrolidin-1-yl)-3,4,4a,5,6,7,8,8a-octahydroquinoxalin-1(2H)-yl}ethan-1-one
  参考文献：
  名称：

  Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation

  摘要：

  Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (T(H)1) and T(H)17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective K-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.

  DOI：

  10.1021/acs.jmedchem.8b01609
• 作为产物：
  描述：

  2',3',4'-三氯苯乙酮 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 2-(3,4-dichlorophenyl)-1-((4aS,8S,8aS)-8-(pyrrolidin-1-yl)-octahydroquinoxalin-1(2H)-yl)ethanone
  参考文献：
  名称：

  [EN] PERHYDROQUINOXALINE DERIVATIVES USEFUL AS ANALGESICS
  [FR] DÉRIVÉS DE PÉRHYDROQUINOXALINE UTILES EN TANT QU'ANALGÉSIQUES

  摘要：

  本发明涉及按照通式（1）的过氧化喹啉化合物，其作为药物的用途，特别是作为止痛、抗瘙痒和抗炎药剂，以及它们的制备。

  公开号：

  WO2014184356A1

文献信息

• Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity<i>in Vivo</i>
  作者：Michael Soeberdt、Peter Molenveld、Roy P. M. Storcken、Renaud Bouzanne des Mazery、Geert Jan Sterk、Reshma Autar、Marjon G. Bolster、Clemens Wagner、Sebastianus N. H. Aerts、Frank R. van Holst、Anita Wegert、Giovanni Tangherlini、Bastian Frehland、Dirk Schepmann、Dieter Metze、Tobias Lotts、Ulrich Knie、Kun-Yuan Lin、Tai-Yu Huang、Chih-Ching Lai、Sonja Ständer、Bernhard Wünsch、Christoph Abels

  DOI：10.1021/acs.jmedchem.6b01868

  日期：2017.3.23

  enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5–8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5–8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full

  为了发展限制到周边新颖κ激动剂，（4a的diastereo-和对映选择性合成- [R，5小号，8α小号）构型decahydroquinoxalines 5 - 8被开发。通过对药效基团的芳基乙酰胺和胺部分以及药效基团外的胺部分进行结构修饰，可以对生理化学和药理特性进行微调。所述decahydroquinoxalines 5 - 8示出的个位数纳摩尔至亚纳摩尔κ阿片受体的亲和力，完全κ激动活性在[ 35 S]GTPγS测定法，并用μ高选择性，δ，σ 1，σ 2受体以及NMDA受体的PCP结合位点。几种类似物对外周具有选择性。在两种皮炎小鼠模型中研究了局部应用后5 – 8的抗炎活性。含有（S）构型的羟基吡咯烷环的甲磺酰胺8a被确定为对外周有选择性的强效（K i = 0.63 nM）和高度选择性的κ激动剂（EC 50 = 1.8 nM），具有急性剂量依赖性的抗炎活性和慢性皮肤发炎。
• PERHYDROQUINOXALINE DERIVATIVES
  申请人：DR. AUGUST WOLFF GMBH & CO. KG ARZNEIMITTEL

  公开号：US20160122307A1

  公开（公告）日：2016-05-05

  The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic and anti-inflammatory agents, and their preparation.

  本发明涉及通式（1）的过氢化喹喔啉化合物，它们作为药物的用途，特别是作为镇痛剂、止痒剂和抗炎剂，以及它们的制备方法。
• PERHYDROQUINOXALINE DERIVATIVES USEFUL AS ANALGESICS
  申请人：Dr. August Wolff GmbH & Co. KG Arzneimittel

  公开号：EP2997025A1

  公开（公告）日：2016-03-23
• [EN] PERHYDROQUINOXALINE DERIVATIVES USEFUL AS ANALGESICS<br/>[FR] DÉRIVÉS DE PÉRHYDROQUINOXALINE UTILES EN TANT QU'ANALGÉSIQUES
  申请人：WOLFF AUGUST GMBH & CO KG ARZNEIMITTEL DR

  公开号：WO2014184355A1

  公开（公告）日：2014-11-20

  The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic and antiinflammatory agents, and their preparation.

  本发明涉及按照通式（1）的过氧化喹啉化合物，其作为药物的用途，特别是作为镇痛、止痒和抗炎药剂，以及它们的制备。
• Development of Novel Quinoxaline-Based κ-Opioid Receptor Agonists for the Treatment of Neuroinflammation
  作者：Giovanni Tangherlini、Dmitrii V. Kalinin、Dirk Schepmann、Tao Che、Nadine Mykicki、Sonja Ständer、Karin Loser、Bernhard Wünsch

  DOI：10.1021/acs.jmedchem.8b01609

  日期：2019.1.24

  Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (T(H)1) and T(H)17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective K-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.