5-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile | 370882-26-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile
• 英文别名: 5-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile；5-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]pyridine-3-carbonitrile
• CAS: 370882-26-1
• 化学式: C₁₁H₁₂N₄
• 分子量: 200.243
• InChiKey: GPXAWLDGWSBLKM-ONGXEEELSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  52
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile 、 富马酸 以90%的产率得到5-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile fumarate
  参考文献：
  名称：

  Diazabicyclic central nervous system active agents

  摘要：

  式I1的化合物，这些化合物的药物组合物，以及利用这些组合物来控制哺乳动物的突触传递。

  公开号：

  US20020019388A1
• 作为产物：
  描述：

  5-溴烟腈 在 tris(dibenzylideneacetone)dipalladium (0) caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 甲苯 、 三氟乙酸 为溶剂， 反应 41.0h， 生成 5-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile
  参考文献：
  名称：

  A-366833: A novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models

  摘要：

  5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([H-3]-cytisine) with K-i value of 3.1 nM and exhibits agonist selectivity at alpha 4 beta 2 nAChR relative to the alpha 3 beta 4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 mu mol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2-19.0 mu mol/kg, i.p.), formalin (1.9-19 mu mol/kg i.p.) and SNL (1.9-19 mu mol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 mu mol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5 h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha 4 beta 2 vs. alpha 3 beta 4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects. (C) 2007 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2007.08.010

文献信息

• Synthesis and Structure−Activity Relationship Studies of 3,6-Diazabicyclo[3.2.0]heptanes as Novel α4β2 Nicotinic Acetylcholine Receptor Selective Agonists
  作者：Jianguo Ji、Michael R. Schrimpf、Kevin B. Sippy、William H. Bunnelle、Tao Li、David J. Anderson、Connie Faltynek、Carol S. Surowy、Tino Dyhring、Philip K. Ahring、Michael D. Meyer

  DOI：10.1021/jm070755h

  日期：2007.11.1

  influences of the 3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl-substituted 3,6-diazabicyclo[3.2.0]heptanes are selective for the alpha4beta2

  合成了一系列从3,6-二氮杂双环[3.2.0]庚烷衍生的新型有效神经元烟碱乙酰胆碱受体（nAChR）配体，并评估了其对alpha4beta2 nAChR亚型的结合亲和力和激动剂活性。这些新型nAChR配体的结构活性关系研究集中于对吡啶环的取代作用以及3,6-二氮杂双环[3.2.0]庚烷核心的立体和区域化学影响。吡啶环上的5个小取代基对结合亲和力和功能活性影响不大。吡啶环上的6-溴，6-氯和6-甲基取代基导致增加的结合亲和力和改善的功能活性。大多数6-N-吡啶基取代的3,6-二氮杂双环[3.2.0]庚烷对alpha4beta2 nAChR亚型具有选择性。化合物（1R，5S）-25，（1R，5S）-55，和（1R，5S）-56在halpha3beta4 nAChR上几乎没有活性，但在halpha4beta2 nAChR亚型上保留了效力和功效。3-N-吡啶基取代的系列显示出更复杂的SAR。发现（
• DIAZABICYCLIC CENTRAL NERVOUS SYSTEM ACTIVE AGENTS
  申请人：Schrimpf R. Michael

  公开号：US20080097094A1

  公开（公告）日：2008-04-24

  Compounds of formula I pharmaceutical compositions of these compounds, and use of said compositions to control synaptic transmission in mammals.

  化合物I的配方药物组合物，以及使用该组合物来控制哺乳动物的突触传递。
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  公开（公告）日：2020-12-09