(+/-)-2exo-(3-methyl-isoxazol-5-yl)-7-azabicyclo[2.2.1]heptane | 188895-96-7

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (+/-)-2exo-(3-methyl-isoxazol-5-yl)-7-azabicyclo[2.2.1]heptane
• 英文别名: exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane；(+/-)-epiboxidine；epiboxidine；(+/-)epiboxidine；(+-)-Epiboxidine；5-[(1R,2S,4S)-7-azabicyclo[2.2.1]heptan-2-yl]-3-methyl-1,2-oxazole
• CAS: 188895-96-7
• 化学式: C₁₀H₁₄N₂O
• 分子量: 178.234
• InChiKey: GEEFPQBPVBFCSD-XHNCKOQMSA-N

物化性质

• 熔点：
  200-205 °C (decomp)
• 沸点：
  313.1±27.0 °C(Predicted)
• 密度：
  1.130±0.06 g/cm3(Predicted)
• 溶解度：
  H2O: 22 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  38.1
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• WGK Germany：
  3
• RTECS号：
  CL5446415
• 安全说明：
  S22,S24/25

制备方法与用途

Epiboxidine是一种有效且选择性的神经nAChR激动剂，其对大鼠和人α4β2nachr的Ki值分别为0.46纳摩尔和1.2纳摩尔。它是一种生物碱Epibatidine的甲基异恶唑类似物，并且类似于另一种nAChR激动剂ABT 418。

反应信息

• 作为产物：
  描述：

  托品酮 在 盐酸 、 正丁基锂 、 氢溴酸 、 溴 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 5.25h， 生成 (+/-)-2exo-(3-methyl-isoxazol-5-yl)-7-azabicyclo[2.2.1]heptane
  参考文献：
  名称：

  Synthesis and nicotinic activity of epiboxidine: an isoxazole analogue of epibatidine

  摘要：

  Synthetic (+/-)-epiboxidine (exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane) is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibiting [H-3]nicotine binding to alpha(4) beta(2) nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 alpha(3) beta(4(5)) nicotinic receptors in PCl2 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with alpha(1) beta(1) gamma delta nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice.

  DOI：

  10.1016/s0014-2999(96)00939-9

文献信息

• Aza-Prins-Pinacol Approach to 7-Azabicyclo[2.2.1]heptanes:  Syntheses of (±)-Epibatidine and (±)-Epiboxidine
  作者：Alan Armstrong、Yunas Bhonoah、Stephen E. Shanahan

  DOI：10.1021/jo701536a

  日期：2007.10.1

  and (±)-epiboxidine have been accomplished from commercial 2-methoxy-3,4-dihydro-2H-pyran. A recently developed aza-Prins-pinacol rearrangement was employed for the construction of the key 7-azabicyclo[2.2.1]heptane skeleton of these targets.

  （±）-表哌啶和（±）-表哌啶的合成已从商业的2-甲氧基-3，4-二氢-2 H-吡喃中完成。最近开发的aza-Prins-频哪醇重排用于构建这些靶标的关键7-氮杂双环[2.2.1]庚烷骨架。
• Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes
  作者：Luca Rizzi、Clelia Dallanoce、Carlo Matera、Pietro Magrone、Luca Pucci、Cecilia Gotti、Francesco Clementi、Marco De Amici

  DOI：10.1016/j.bmcl.2008.07.016

  日期：2008.8

  compounds were assayed for their binding affinity at neuronal alpha4beta2 and alpha7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity alpha4beta2 ligand (K(i)=0.4 nM) and, interestingly, evidenced a relevant affinity also for the alpha7 subtype (K(i)=6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K(i)=50 nM for alpha4beta2

  利用钯催化的Stille偶联作为反应顺序中的关键步骤，可以有效地制备外消旋的外表艾替丁烷3，内表艾替丁烷6和两种不饱和的与表甲替丁相关的衍生物7和8。分析了目标化合物对神经元α4beta2和α7烟碱乙酰胆碱受体的结合亲和力。Epiboxidine 3表现为高亲和力的alpha4beta2配体（K（i）= 0.4 nM），有趣的是，也证明了对alpha7亚型也有相关的亲和力（K（i）= 6 nM）。衍生物7，该组中最接近的类似物3，在两种受体亚型上均具有较低的亲和力（α4beta2的K（i = 50 nM，α7的K（i）= 1.6 microM））证明了alpha4beta2相对于alpha7选择性的提高与模型化合物比较时。
• Design and Synthesis of Isoxazole Containing Bioisosteres of Epibatidine as Potent Nicotinic Acetylcholine Receptor Agonists.
  作者：Satendra SINGH、Kwasi S. AVOR、Buddy POUW、Thomas W. SEALE、Garo P. BASMADJIAN

  DOI：10.1248/cpb.47.1501

  日期：——

  An efficient synthesis of isoxazole containing isosteres of epibatidine is described. The synthesis proceeded from N-tert-butoxycarbonyl (Boc)-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (9). Compound 9 was reacted with the dilithium salt of an appropriately substituted oxime in tetrahydrofuran (THF). Cyclodehydration of the resultant β-keto oxime and deprotection of the N-Boc group in 5N aqueous HCl afforded the isoxazole containing isosteres of epibatidine (6-8). The binding affinities of these compounds were determined at the nicotinic acetylcholine receptor for the displacement of [3H]cytisine. The unsubstituted isoxazole containing isostere (6) showed the lower binding potency compared to the 3'-methylisoxazole isostere (7). Substitution with a phenyl group at the 3'-position of the isoxazole significantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed. The LD50 of the analogs ranged in the order : Me>H>Ph.

  描述了一种高效合成含有异氧杂环的依比加丁等体的合成方法。合成从N-叔丁氧羧基（Boc）-exo-2-(甲氧羧基)-7-氮杂双环[2.2.1]庚烷（9）开始。化合物9与适当取代的肟类的锂二盐在四氢呋喃（THF）中反应。所得到的β-酮肟的环脱水反应和在5N盐酸水溶液中去保护N-Boc基团，得到了含有依比加丁等体的异氧杂环（6-8）。这些化合物在尼古丁乙酰胆碱受体上的结合亲和力通过[3H]细胞素的取代测定。与3'-甲基异氧杂环等体（7）相比，不带取代基的异氧杂环等体（6）显示出更低的结合活性。在异氧杂环的3'-位置用苯基取代显著降低了结合活性。这些类似物的体内毒理研究也进行了。类似物的LD50范围为：Me > H > Ph。
• [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 8. An Efficient Synthetic Strategy for Epiboxidine
  作者：Ganesh Pandey、Akhila K. Sahoo、Smita R. Gadre、Trusar D. Bagul、Usha D. Phalgune

  DOI：10.1021/jo9903757

  日期：1999.6.1
• COMPOSITIONS AND METHODS FOR TREATING COMPULSIVE-LIKE BEHAVIOR IN A SUBJECT
  申请人：UNIVERSITY OF THE SCIENCES

  公开号：US20190054067A1

  公开（公告）日：2019-02-21

  The present invention includes methods of treating obsessive-compulsive disorder and/or an obsessive-compulsive related disorder or disease. The present invention further includes methods of treating symptoms of a compulsive-like behavior, obsessive-compulsive related disorder, and/or compulsive-like behaviors in an autism spectrum disorder or disease. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a positive allosteric α4β2 nicotinic acetylcholine receptor modulator, alone or in combination with another positive allosteric α4β2 nicotinic acetylcholine receptor modulator or an additional agent known to treat the symptoms of obsessive-compulsive disorder, an obsessive-compulsive related disorder, and/or compulsive-like behaviors in autism spectrum disorder or disease.