(3R)-1-azabicyclo[2.2.2]oct-3-yl (2R)-cyclohexyl(hydroxy)phenylacetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: (3R)-1-azabicyclo[2.2.2]oct-3-yl (2R)-cyclohexyl(hydroxy)phenylacetate
• 英文别名: (R)-cyclohexyl-hydroxy-phenyl-acetic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester；(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic Acid (3R)-1-azabicyclo[2.2.2]oct-3-yl Ester；(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester；[(3R)-1-azabicyclo[2.2.2]octan-3-yl] (2R)-2-cyclohexyl-2-hydroxy-2-phenylacetate
• 化学式: C₂₁H₂₉NO₃
• 分子量: 343.466
• InChiKey: SWZDDEVSNRTITP-FPOVZHCZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3R)-1-azabicyclo[2.2.2]oct-3-yl (2R)-cyclohexyl(hydroxy)phenylacetate 在 乙醇 、 sodium hydroxide 作用下， 反应 7.0h， 生成 (R)-环己基羟基苯乙酸
  参考文献：
  名称：

  发现新型（3 R）-喹啉醇酯季铵衍生物作为强效和长效毒蕈碱类拮抗剂，吸入后具有最小的全身暴露潜力：（3 R）-3-{[羟基（二-2-噻吩基）的鉴定）乙酰基]氧基} -1-（3-苯氧基丙基）-1-氮杂双环[2.2.2]辛烷溴化物（Aclidinium Bromide）

  摘要：

  这项工作的目的是发现一种新型的长效毒蕈碱型M 3拮抗剂，用于吸入治疗慢性阻塞性肺疾病（COPD），与目前的抗毒蕈碱剂相比，具有潜在的改善的风险效益。合成并评价了一系列新的（3 R）-喹啉醇酯的季铵衍生物。根据其总体情况，（3 R）-3-{[羟基（二-2-噻吩基）乙酰基]氧基} -1-（3-苯氧基丙基）-1-氮杂双环[2.2.2]辛烷溴化物（溴化ac啶）成为每日维护一次的候选物治疗COPD。该化合物是有效的毒蕈碱拮抗剂，在体内具有长效作用，并且在人血浆中具有快速水解作用，从而最大程度地减少了诱发类相关的全身性副作用的可能性。溴化阿地铵目前处于III期开发中，用于维持治疗COPD患者。

  DOI：

  10.1021/jm900132z
• 作为产物：
  描述：

  D-扁桃酸 在 palladium on activated charcoal 氢氧化钾 、 硫酸 、 氢气 、 sodium hydride 、 对甲苯磺酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正戊烷 为溶剂， -80.0~25.0 ℃ 、500.0 kPa 条件下， 反应 27.75h， 生成 (3R)-1-azabicyclo[2.2.2]oct-3-yl (2R)-cyclohexyl(hydroxy)phenylacetate
  参考文献：
  名称：

  Stereoselective Synthesis and Biodistribution of Potent [¹¹C]-Labeled Antagonists for Positron Emission Tomography Imaging of Muscarinic Receptors in the Airways

  摘要：

  Quantitation of muscarinic receptors in the lungs in vivo with positron emission tomography (PET) is of clinical interest. For that purpose we decided to develop [C-11]-labeled ligands with a high affinity (K-D < 0.1 nM). Three quaternary muscarinic antagonists, racemic N-methylpiperidin-4-yl 2-cyclohexy-2-2-hydroxy-2-phenylacetate methiodide 1a (pK(B) = 10.39), its (R)-isomer 1b (pK(B) = 11.08), and (R,R)-quinuclidin-3-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 2 (pK(B) = 11.28), were labeled by reacting [C-11]CH3I With their tertiary amine precursors. The enantiomerically pure tertiary amine precursors were prepared by stereoselective synthesis starting from (R)-(-)-mandelic acid. In vitro binding assay of 1b and 2 demonstrated that both ligands bind with very high affinity to the muscarinic receptor subtypes M(1), M(2), and M(3). They are more potent than the muscarinic antagonist (R)-N-methylquinuclidinyl benzilate ((R)-MQNB). Distribution studies with la, 1b, and 2 in control and atropine-treated male Wistar rats demonstrated significant specific binding (90-99% of total issue uptake) in tissues containing cholinoceptors (heart, intestine, lung, pancreas, spleen, stomach, submandibular gland). Because the tissue/plasma concentration ratios of 1b are most favorable, this ligand was used for further evaluation. Analysis of plasma samples showed a very rapid clearance (t(1/2) = 0.3 min) of the radioligand 1b and a relatively slow appearance of a hydrophilic metabolite. At 15 min postinjection of 1b, analysis of heart, lungs, and liver showed that respectively 99%, 88%, and 8% of the tissue radioactivity corresponded with the parent compound. Ligand 1b appears to be an excellent candidate for PET studies of mAChR receptors in heart and lungs.

  DOI：

  10.1021/jm960374w

文献信息

• [EN] QUINUCLIDINE DERIVATIVES AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS DE QUINUCLIDINE ET LEUR UTILISATION COMME ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES
  申请人：ASTRAZENECA AB

  公开号：WO2009139710A1

  公开（公告）日：2009-11-19

  The invention provides compounds of formula (I) wherein R1, R2, R3, Het1, n, Y and X are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation

  本发明提供了公式(I)的化合物，其中R1、R2、R3、Het1、n、Y和X如说明书中所定义，一种制备它们的方法，包含它们的药物组合物，制备药物组合物的过程，它们在治疗中的用途以及用于它们制备的中间体。
• Organic Compounds
  申请人：Press Neil John

  公开号：US20090048281A1

  公开（公告）日：2009-02-19

  Compounds of Formula (I); in salt or zwitterionic form wherein R 1 , R 2 , R 3 and R 4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

  式（I）的化合物；以盐或双电离形式存在，其中R1，R2，R3和R4具有规范中指示的含义，可用于治疗由肌肉型M3受体介导的疾病，尤其是炎症性或阻塞性呼吸道疾病。还描述了含有该化合物的制药组合物和制备该化合物的过程。
• Quinuclidine derivatives and their use as muscarinic M3 receptor antagonists
  申请人：Novartis AG

  公开号：US08084463B2

  公开（公告）日：2011-12-27

  Compounds of Formula (I); in salt or zwitterionic form wherein R1, R2, R3 and R4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

  公式（I）的化合物；以盐或双离子形式存在，其中R1、R2、R3和R4的含义如规范中所示，可用于治疗由肌肉型M3受体介导的疾病，尤其是炎症性或阻塞性呼吸道疾病。还描述了包含这些化合物的制药组合物和制备这些化合物的过程。
• QUINUCLIDINE DERIVATIVES AND THEIR USE AS MUSCARINIC M3 RECEPTOR ANTAGONISTS
  申请人：Press Neil John

  公开号：US20100168132A1

  公开（公告）日：2010-07-01

  Compounds of Formula (I) ; in salt or zwitterionic form wherein R 1 , R 2 , R 3 and R 4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

  式(I)的化合物；以盐或双电离形式存在，其中R1，R2，R3和R4的含义如规范中所示，对于治疗由肌肉型M3受体介导的情况，特别是炎症性或阻塞性气道疾病是有用的。还描述了包含这些化合物的制药组合物和制备这些化合物的过程。
• Quinuclidine derivatives and their use as muscarinic m3 receptor antagonists
  申请人：Novartis AG

  公开号：US07723356B2

  公开（公告）日：2010-05-25

  Compounds of Formula (I); in salt or zwitterionic form wherein R1, R2, R3 and R4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor, especially inflammatory or obstructive airways diseases. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

  式(I)的化合物；以盐或双电离形式存在，其中R1、R2、R3和R4的含义如规范所示，可用于治疗由肌肉型M3受体介导的疾病，特别是炎症性或阻塞性呼吸道疾病。还描述了含有该化合物的制药组合物和制备该化合物的方法。