(R)-3-azidoquinuclidine | 1403993-25-8

• 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: (R)-3-azidoquinuclidine
• 英文别名: (3R)-3-azido-1-azabicyclo[2.2.2]octane
• CAS: 1403993-25-8
• 化学式: C₇H₁₂N₄
• 分子量: 152.199
• InChiKey: GLWQAKJENGVGOU-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  17.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-乙炔噻吩 、 (R)-3-azidoquinuclidine 在 copper(ll) sulfate pentahydrate 、 sodium ascorbate 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以38%的产率得到(R)-3-(4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)quinuclidine
  参考文献：
  名称：

  Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies

  摘要：

  We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as alpha 7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for alpha 7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the alpha 4 beta 2 nicotinic receptor (up to 1 mu M) but interacted with the 5HT(3) receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.11.001
• 作为产物：
  描述：

  (3R)-1-氮杂双环[2.2.2]辛烷-3-胺盐酸盐(1:1) 在 1H-咪唑-1-磺酰叠氮盐酸盐 、 copper(ll) sulfate pentahydrate 、 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 6.0h， 生成 (R)-3-azidoquinuclidine
  参考文献：
  名称：

  1,4-DISUBSTITUTED 1,2,3-TRIAZOLES, METHODS FOR PREPARING SAME, AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF

  摘要：

  具有以下通式（I）的化合物：其中：X是氮原子，Y是碳原子；或者X是碳原子，Y是氮原子；Ar基团是芳基或杂芳基；RN和RN′基团，与其所连接的碳原子一起，形成单环或双环氮杂环烷基团。还描述了其药学上可接受的盐、水合物或多晶型晶体结构，以及其消旋体、非对映异构体或对映异构体。

  公开号：

  US20140030191A1

文献信息

• Selective α3β4 Nicotinic Acetylcholine Receptor Ligand as a Potential Tracer for Drug Addiction
  作者：Apinan Kanasuwan、Winnie Deuther-Conrad、Sumet Chongruchiroj、Jiradanai Sarasamkan、Chanisa Chotipanich、Opa Vajragupta、Kuntarat Arunrungvichian

  DOI：10.3390/ijms24043614

  日期：——

  α3β4 Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α3β4 nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2, for the development of an α3β4 nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p-hydroxyl motif for ligand-receptor binding affinity. Four (R)- and (S)-quinuclidine-triazole (AK1-AK4) were synthesized and the binding affinity, together with selectivity to α3β4 nAChR subtype, were determined by competitive radioligand binding assay using [3H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α3β4 nAChR with a Ki value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α3β4 nAChR in comparison to α7 nAChR. The α3β4 nAChR selectivity of AK3 was considerably higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 was shown to be a promising α3β4 nAChR tracer for further development as a radiotracer for drug addiction.

  α3β4烟碱乙酰胆碱受体（nAChR）已被认为是早期检测药物成瘾的新兴生物标记物。本文设计并合成了α3β4 nAChR配体，以提高两种先导化合物(S)-QND8和(S)-T2的结合亲和力和选择性，从而开发出一种α3β4 nAChR示踪剂。结构改造是通过保留关键特征并用一个苄氧基基团扩展分子结构来实现的，以增加亲脂性，促进血脑屏障渗透，并延长配体与受体的相互作用。保留的关键特征是一个用于放射性示踪剂开发的氟原子和一个用于配体与受体结合亲和力的对羟基基团。我们合成了四种(R)-和(S)-奎宁环-三唑（AK1-AK4），并以[3H]表巴蒂啶为放射性配体，通过竞争性放射性配体结合试验测定了它们的结合亲和力以及对α3β4 nAChR亚型的选择性。在所有修饰化合物中，AK3 与 α3β4 nAChR 的结合亲和力和选择性最高，Ki 值为 3.18 nM，与（S）-QND8 和（S）-T2 相当，与 α7 nAChR 相比，与 α3β4 nAChR 的结合亲和力高 3069 倍。AK3 的 α3β4 nAChR 选择性大大高于 (S)-QND8 （11.8 倍）和 (S)-T2 （294 倍）。研究结果表明，AK3是一种很有前途的α3β4 nAChR示踪剂，可进一步开发为药物成瘾的放射性示踪剂。
• Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds
  作者：Jiradanai Sarasamkan、Matthias Scheunemann、Nattayaporn Apaijai、Siripong Palee、Warisara Parichatikanond、Kuntarat Arunrungvichian、Steffen Fischer、Siriporn Chattipakorn、Winnie Deuther-Conrad、Gerrit Schüürmann、Peter Brust、Opa Vajragupta

  DOI：10.1021/acsmedchemlett.6b00146

  日期：2016.10.13

  The novel quinuclidine anti-1,2,3-triazole derivatives T1-T6 were designed based on the structure of QND8. The binding studies revealed that the stereochemistry at the C3 position of the quinuclidine scaffold plays an important role in the nAChR subtype selectivity. Whereas the (R)-enantiomers are selective to alpha 7 over alpha 4 beta 2 (by factors of 44-225) and to a smaller degree over alpha 3 beta 4 (3-33), their (S) -counterparts prefer alpha 3 beta 4 over alpha 4 beta 2 (62-237) as well as over alpha 7 (5-294). The (R)-derivatives were highly selective to alpha 7 over alpha 3 beta 4 subtypes compared to (RS)- and (R)-QND8. The (S)-enantiomers are S-10 times more selective to alpha 4 beta 2 than their (R) forms. The overall strongest affinity is observed for the (S)-enantiomer binding to alpha 3 beta 4 (K-i, 2.25-19.5 nM) followed by their (R)-counterpart binding to alpha 7 (K-i, 22.5-117 nM), with a significantly weaker (S)-enantiomer binding to alpha 4 beta 2 (K-i, 414-1980 nM) still above the very weak respective (R)-analogue affinity (K-i, 5059-10436 nM).
• 1,4-DISUBSTITUTED 1,2,3-TRIAZOLES, METHODS FOR PREPARING SAME, AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF
  申请人：Routier Sylvain

  公开号：US20140030191A1

  公开（公告）日：2014-01-30

  A compound having the following general formula (I): wherein: X is a nitrogen atom and Y is a carbon atom; or X is a carbon atom and Y is a nitrogen atom; the Ar group is an aryl or heteroaryl group; and the RN and RN′ groups, together with the carbon atoms to which they are bound, form a monocyclic or bicyclic azacycloalkane group. The pharmaceutically acceptable salts thereof, the hydrates or polymorphic crystalline structures thereof, and to the racemates, diastereoisomers, or enantiomers thereof are also described.

  具有以下通式（I）的化合物：其中：X是氮原子，Y是碳原子；或者X是碳原子，Y是氮原子；Ar基团是芳基或杂芳基；RN和RN′基团，与其所连接的碳原子一起，形成单环或双环氮杂环烷基团。还描述了其药学上可接受的盐、水合物或多晶型晶体结构，以及其消旋体、非对映异构体或对映异构体。
• Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies
  作者：Aziz Ouach、Frederic Pin、Emilie Bertrand、Johnny Vercouillie、Zuhal Gulhan、Céline Mothes、Jean-Bernard Deloye、Denis Guilloteau、Franck Suzenet、Sylvie Chalon、Sylvain Routier

  DOI：10.1016/j.ejmech.2015.11.001

  日期：2016.1

  We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as alpha 7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for alpha 7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the alpha 4 beta 2 nicotinic receptor (up to 1 mu M) but interacted with the 5HT(3) receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported. (C) 2015 Elsevier Masson SAS. All rights reserved.