(2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide | 639489-80-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: (2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide
• 英文别名: N-[(2R,3R)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzofuran-2-carboxamide
• CAS: 639489-80-8
• 化学式: C₂₂H₂₃N₃O₂
• 分子量: 361.444
• InChiKey: OXKRFEWMSWPKKV-WIYYLYMNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  58.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  meso-galactaric acid 、 (2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide 以 乙醇 为溶剂， 反应 0.08h， 生成 (2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide galactarate
  参考文献：
  名称：

  2S,3R)-N-(2-((3-PYRIDINYL)METHYL)-1-AZABICYCLO[2.2.2]OCT-3-YL-BENZYOFURAN-2-CARBOXAMIDE, NOVEL SALT FORMS, AND METHODS OF USE THEREOF

  摘要：

  本发明涉及（2S,3R）-N-(2-((3-吡啶基)甲基)-1-氮杂双环[2.2.2]辛-3-基)苯并呋喃-2-甲酰胺，其新型盐形式，其制备方法，新型中间体以及治疗多种疾病和紊乱的方法，包括与中枢神经系统和自主神经系统功能障碍有关的疾病。

  公开号：

  US20090048290A1
• 作为产物：
  描述：

  3-奎宁环酮 在 palladium on activated charcoal 氢氧化钾 、 氢气 、 甲酸铵 、 sodium cyanoborohydride 、 三乙胺 、 氯磷酸二苯酯 、 zinc(II) chloride 作用下， 生成 (2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide
  参考文献：
  名称：

  2-(Arylmethyl)-3-substituted quinuclidines as selective α7 nicotinic receptor ligands

  摘要：

  A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha 7 over other nAChRs (e.g., the alpha A beta 2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha 7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-81), has potent agonistic activity for the alpha 7 nAChR (EC50 = 33 nM, I-max = 1.0), at concentrations below those that result in desensitization. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.02.045

文献信息

• Discovery of (2<i>S</i>,3<i>R</i>)-<i>N</i>-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[<i>b</i>]furan-2-carboxamide (TC-5619), a Selective α7 Nicotinic Acetylcholine Receptor Agonist, for the Treatment of Cognitive Disorders
  作者：Anatoly A. Mazurov、David C. Kombo、Terry A. Hauser、Lan Miao、Gary Dull、John F. Genus、Nikolai B. Fedorov、Lisa Benson、Serguei Sidach、Yunde Xiao、Philip S. Hammond、John W. James、Craig H. Miller、Daniel Yohannes

  DOI：10.1021/jm301048a

  日期：2012.11.26

  (2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]-furan-2-carboxamide (7a, TC-561), a novel selective agonist Of the alpha 7 neuronal nicotinic acetylcholine receptor, has been as a promising drug candidate for the treatment of.cognitiVe. impairment 'associated with neurological.. disorders demonstrated more than a thousand fold separation between the affinities for the alpha 7 and alpha 4 beta 2 receptor subtypes and had no detectable effects On muscle or ganglionic nicotinic receptor subtypes, indicating a marked selectivity for the central nervous system over the peripheral nervous system. Results obtained from homology Modeling and docking explain the observed selectivity. 7a had positive effects cognitive, positive, negative symptoms of schizophrenia in animal models and was additive or synergistic with the antipsychotic. Clozapine. Compound 7a, as an augmentation: therapy to the standard treatment with antipsychotics, demonstrated encouraging results on measures. : of negative symptoms and cognitive dysfunction in schizophrenia and was well tolerated.: in a phase II clinical proof Of concept trial in patients With Schizophrenia.

  (2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]-furan-2-carboxamide（7a，TC-561）是一种新型选择性α7神经性烟碱型乙酰胆碱受体激动剂。它作为一种有前景的药物候选物，用于治疗与神经系统疾病相关的认知功能障碍。其对α7和α4β2受体亚型的亲和力分离系数超过千倍，并对肌肉或节交感神经烟碱型受体亚型无可检测到的影响，表明其对中枢神经系统相对于外周神经系统的显著选择性。 通过同源建模和对接研究获得的结果解释了观察到的选择性。在动物模型中，7a对认知功能、精神分裂症的阳性症状和阴性症状均表现出积极效果，并与抗精神病药物Clozapine表现出叠加或协同作用。在II期临床概念验证试验中，化合物7a作为标准抗精神病药物治疗的辅助疗法，在改善精神分裂症患者的阴性症状和认知功能障碍方面表现出令人鼓舞的结果，并且耐受性良好。
• (2S,3R)-N-(2-((3-PYRIDINYL)METHYL)-1-AZABICYCLO[2.2.2]OCT-3-YL)BENZYOFURN-2-CARBOXAMIDE, NOVEL SALT FORMS, AND METHODS OF USE THEREOF
  申请人：Targacept,Inc.

  公开号：US20140024673A1

  公开（公告）日：2014-01-23

  The present invention relates to (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms thereof, methods for its preparation, novel intermediates, and methods for treating a wide variety of conditions and disorders, including those associated with dysfunction of the central and autonomic nervous systems.

  本发明涉及(2S,3R)—N-(2-((3-吡啶基)甲基)-1-氮杂双环[2.2.2]辛-3-基)苯并呋喃-2-羧酰胺、其新的盐形式、其制备方法、新的中间体，以及治疗各种与中枢神经系统和自主神经系统功能失调相关的疾病和症状的方法。
• (2S,3R)-N-2-3-PYRIDINYLMETHYL-1-AZABICYCLO 2.2.2 OCT-3-YL BENZOFURAN-2-CARBOXAMIDE, NOVEL SALT FORMS, AND METHODS OF USE THEREOF
  申请人：Targacept, Inc.

  公开号：US20150045386A1

  公开（公告）日：2015-02-12

  The present invention relates to (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms thereof, methods for its preparation, novel intermediates, and methods for treating a wide variety of conditions and disorders, including those associated with dysfunction of the central and autonomic nervous systems.

  本发明涉及(2S,3R)-N-(2-((3-吡啶基)甲基)-1-氮杂双环[2.2.2]辛-3-基)苯并呋喃-2-羧酰胺及其新的盐形式、制备方法、新的中间体以及治疗各种与中枢和自主神经系统功能障碍相关的疾病和症状的方法。
• (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms, and methods of preparation
  申请人：Targacept Inc.

  公开号：EP2465501A1

  公开（公告）日：2012-06-20

  The present invention provides methods for the manufacture of (2S,3R)-N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof and the novel intermediates (2S,3R)-2-((3-pyridinyl)methyl)-3-amino-1-azabicyclo[2.2.2]octane and (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one di-p-toluoyl-D-tartrate.

  本发明提供了(2S,3R)-N-(2-((3-吡啶基)甲基-1-氮杂双环[2.2.2]辛-3-基)苯并呋喃-2-甲酰胺或其药学上可接受的盐以及新型中间体(2S,3R)-2-((3-吡啶基)甲基)-3-氨基-1-氮杂双环[2.2.2]辛烷和(2S)-2-((3-吡啶基)甲基)-1-氮杂双环[2.2.2]辛烷-3-酮二对甲苯酰-D-酒石酸盐的制造方法。
• (2S,3R)-N-(2-((3-PYRIDINYL)METHYL)-1-AZABICYCLO[2.2.2]OCT-3-YL)BENZOFURAN-2-CARBOXAMIDE, NOVEL SALT FORMS, AND METHODS OF USE THEREOF
  申请人：Targacept Inc.

  公开号：EP2182949B1

  公开（公告）日：2013-01-02