(S)-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑啉]-2'-酮 | 178419-47-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 中文名称: (S)-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑啉]-2'-酮
• 英文名称: (-)-AAR 17779
• 英文别名: (S)-(-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidine-2'-one]；(-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one]；(S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-one；spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-one；AR-R17779；(3S)-spiro[1-azabicyclo[2.2.2]octan-3,5'-oxazolidin]-2'-one；(5S)-spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one
• CAS: 178419-47-1
• 化学式: C₉H₁₄N₂O₂
• 分子量: 182.222
• InChiKey: TYAGAVRSOFABFO-VIFPVBQESA-N

物化性质

• 沸点：
  411.7±34.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑啉]-2'-酮 在 copper(l) iodide 、 三氯化铝 、 potassium carbonate 作用下， 以 硝基苯 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 (5R)-3-(5-acetylthiophen-2-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one
  参考文献：
  名称：

  Discovery of the α7 Nicotinic Acetylcholine Receptor Agonists. (R)-3‘-(5-Chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5‘-[1‘,3‘]oxazolidin-2‘-one as a Novel, Potent, Selective, and Orally Bioavailable Ligand

  摘要：

  Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the 0 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha 7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'(5-chlorothiophen-2-yl)spiro-l-azabicyclo[2.2.2]octane-3,5'-[1',3'loxazolidin-2'-one (25). Compound 25 has potent binding affinity (K-i = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha A beta 2 and a1 beta 2 gamma delta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.

  DOI：

  10.1021/jm049188d
• 作为产物：
  描述：

  ((S)-3-Hydroxy-1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid hydrazide 在 盐酸 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 3.0h， 生成 (S)-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑啉]-2'-酮
  参考文献：
  名称：

  A Chiral Synthesis of (−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘- oxazolidin-2‘-one]:  A Conformationally Restricted Analogue of Acetylcholine That Is a Potent and Selective α7 Nicotinic Receptor Agonist

  摘要：

  A direct, short chiral synthesis of the selective 0 nicotinic receptor agonist (-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.

  DOI：

  10.1021/jo049404q

文献信息

• [EN] SPIRO '1-AZABICYCLO '2.2.2!OCTAN-3,5'-OXAZOLIDIN -2'-ONE! DERIVATIVES WITH AFFINITY TO THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR<br/>[FR] DERIVES DE SPIRO '1-AZABICYCLO '2.2.2!OCTAN-3,5'-OXAZOLIDIN -2'-ONE! POSSEDANT UNE AFFINITE AVEC LE RECEPTEUR D'ACETYLCHOLINE NICOTINIQUE ALPHA7
  申请人：ASTRAZENECA AB

  公开号：WO2005005435A1

  公开（公告）日：2005-01-20

  Compounds of formula (I) and pharmaceutically-acceptable salts thereof, wherein Arl, A and Ar2 are as defined in the specification, pharmaceutical compositions and formulations containing them, methods of using them to treat diseases and conditions either alone or in combination with other therapeutically-active compounds or substances, processes and intermediates used to prepare them, uses of them as medicaments for therapy, uses of them in the manufacture of medicaments and uses of them for diagnostic and analytic purposes.

  式(I)的化合物及其药用盐，其中Arl、A和Ar2如规范中所定义，含有它们的药用组合物和配方，使用它们单独或与其他治疗活性化合物或物质结合治疗疾病和状况的方法，用于制备它们的过程和中间体，用作治疗药物的用途，用于制造药物的用途以及用于诊断和分析目的的用途。
• Spiro '1-azabicyclo' 2.2.2! octan-3,5'-oxazolidin - 2'-one! derivatives with affinity to the alpha7 nicotinic acetylcholine receptor
  申请人：Chang Hui-Fang

  公开号：US20060154945A1

  公开（公告）日：2006-07-13

  Compounds of formula I: and pharmaceutically-acceptable salts thereof, wherein Q, Ar 1 , A and Ar 2 are as defined in the specification, pharmaceutical compositions and formulations containing them, methods of using them to treat diseases and conditions either alone or in combination with other therapeutically-active compounds or substances, processes and intermediates used to prepare them, uses of them as medicaments for therapy, uses of them in the manufacture of medicaments and uses of them for diagnostic and analytic purposes.

  公式I的化合物及其药用可接受盐，其中Q、Ar1、A和Ar2的定义如规范中所述，包含它们的药物组合物和制剂，使用它们单独或与其他治疗活性化合物或物质联合治疗疾病和症状的方法，用于制备它们的过程和中间体，将它们用于治疗的药物用途，将它们用于制造药物的用途以及将它们用于诊断和分析目的的用途。
• Nicotinic Acetylcholine Receptor Ligands
  申请人：Chapdelaine Marc

  公开号：US20080113983A1

  公开（公告）日：2008-05-15

  Acetylcholine receptor ligands of formula I wherein A, Ar 1 and Ar 2 are as described in the specification, diastereoisomers, enantiomers, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

  公式I中的乙酰胆碱受体配体，其中A、Ar1和Ar2如规范所述，对映异构体、对映体、药学上可接受的盐，制备方法，含有药物的制剂以及使用方法。
• Oxazolidinone nicotinic acetylcholine receptor agonists
  申请人：AstraZeneca AB

  公开号：US07514567B2

  公开（公告）日：2009-04-07

  Compounds of formula I: and pharmaceutically-acceptable salts thereof, wherein Q, Ar1, A and Ar2 are as defined in the specification, pharmaceutical compositions and formulations containing them, methods of using them to treat diseases and conditions either alone or in combination with other therapeutically-active compounds or substances, processes and intermediates used to prepare them, uses of them as medicaments for therapy, uses of them in the manufacture of medicaments and uses of them for diagnostic and analytic purposes.

  公式I的化合物及其药用可接受盐，其中Q、Ar1、A和Ar2如规范所定义，含有它们的药用组合物和配方，使用它们治疗疾病和病况的方法，可以单独使用或与其他治疗活性化合物或物质结合使用，用于制备它们的过程和中间体，将它们用作治疗药物的用途，将它们用于制造药物的用途以及将它们用于诊断和分析目的的用途。
• (<i>R</i>)-3‘-(3-Methylbenzo[<i>b</i>]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5‘-oxazolidin]-2‘-one, a Novel and Potent α7 Nicotinic Acetylcholine Receptor Partial Agonist Displays Cognitive Enhancing Properties
  作者：Ryo Tatsumi、Masakazu Fujio、Shin-ichi Takanashi、Atsushi Numata、Jiro Katayama、Hiroyuki Satoh、Yasuyuki Shiigi、Jun-ichi Maeda、Makoto Kuriyama、Takashi Horikawa、Takahiro Murozono、Kenji Hashimoto、Hiroshi Tanaka

  DOI：10.1021/jm060249c

  日期：2006.7.1

  Recent studies have suggested that the alpha 7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha 7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha 7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K-i) 3 nmol/L) toward the alpha 7 receptor but also showed agonistic activity even at a concentration of 0.1 mu mol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha 7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.