2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(pyridin-2-yl)oxazole | 1289564-86-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: 2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(pyridin-2-yl)oxazole
• 英文别名: tert-butyl-[2,3-dihydro-1H-inden-2-yl-(5-pyridin-2-yl-1,3-oxazol-2-yl)methoxy]-dimethylsilane
• CAS: 1289564-86-8
• 化学式: C₂₄H₃₀N₂O₂Si
• 分子量: 406.6
• InChiKey: GKXCNMFAHRYOIB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.21
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  48.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(pyridin-2-yl)oxazole 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以98%的产率得到(indan-2-yl)(5-(pyridin-2-yl)oxazol-2-yl)methanol
  参考文献：
  名称：

  Reversible Competitive α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Constraints in the Acyl Side Chain: Orally Active, Long-Acting Analgesics

  摘要：

  A series of alpha-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the alpha-ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (ip) or oral (po) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5 and 3 h, and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (> 6 h) and cold (> 9 h) allodynia for sustained periods consistent with its long-acting effects in raising the endogenous concentration of anandamide.

  DOI：

  10.1021/jm101597x
• 作为产物：
  描述：

  2-茚羧酸 在 咪唑 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 正丁基锂 、 硼烷四氢呋喃络合物 、 戴斯-马丁氧化剂 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.75h， 生成 2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(pyridin-2-yl)oxazole
  参考文献：
  名称：

  Reversible Competitive α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Constraints in the Acyl Side Chain: Orally Active, Long-Acting Analgesics

  摘要：

  A series of alpha-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the alpha-ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (ip) or oral (po) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5 and 3 h, and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (> 6 h) and cold (> 9 h) allodynia for sustained periods consistent with its long-acting effects in raising the endogenous concentration of anandamide.

  DOI：

  10.1021/jm101597x
• 作为试剂：
  描述：

  2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(tributylstannyl)oxazole 、 2-溴吡啶 在 2-((tert-butyldimethylsilyloxy)(indan-2-yl)methyl)-5-(pyridin-2-yl)oxazole 、 SiO2 作用下， 以Flash chromatography (SiO2, 30% EtOAc-hexanes) yielded the title compound (28.7 mg, 59%) as a colorless oil的产率得到
  参考文献：
  名称：

  ALPHA-KETOHETEROCYCLES AND METHODS OF MAKING AND USING

  摘要：

  本文披露了一些化合物，这些化合物能够有效地抑制脂肪酸酰胺水解酶，这种酶负责代谢内源性大麻素如阿那酰胺。这些化合物可用作镇痛化合物和催眠化合物，可以口服，并具有相对较长的作用时间。本文还提供了制备这些化合物的方法。这些化合物是杂环羰基酮（如噁唑基酮）的构象限制类似物。

  公开号：

  US20130338196A1

文献信息

• Reversible Competitive α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Constraints in the Acyl Side Chain: Orally Active, Long-Acting Analgesics
  作者：Cyrine Ezzili、Mauro Mileni、Nicholas McGlinchey、Jonathan Z. Long、Steven G. Kinsey、Dustin G. Hochstatter、Raymond C. Stevens、Aron H. Lichtman、Benjamin F. Cravatt、Edward J. Bilsky、Dale L. Boger

  DOI：10.1021/jm101597x

  日期：2011.4.28

  A series of alpha-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the alpha-ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (ip) or oral (po) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5 and 3 h, and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (> 6 h) and cold (> 9 h) allodynia for sustained periods consistent with its long-acting effects in raising the endogenous concentration of anandamide.
• ALPHA-KETOHETEROCYCLES AND METHODS OF MAKING AND USING
  申请人：Boger Dale L.

  公开号：US20130338196A1

  公开（公告）日：2013-12-19

  Compounds are disclosed that are effective in inhibition of fatty acid amide hydrolase, an enzyme responsible for catabolism of endogenous cannabinoids such as anandamide. The compounds are useful as analgesic compounds and as sleep-inducing compounds, that can be orally administered, and that can have a relatively long duration of effect. Methods of preparation of the compounds are also provided. The compounds are conformationally constrained analogs of heterocyclylketones such as oxazolylketones.

  本文披露了一些化合物，这些化合物能够有效地抑制脂肪酸酰胺水解酶，这种酶负责代谢内源性大麻素如阿那酰胺。这些化合物可用作镇痛化合物和催眠化合物，可以口服，并具有相对较长的作用时间。本文还提供了制备这些化合物的方法。这些化合物是杂环羰基酮（如噁唑基酮）的构象限制类似物。