(4S,6R)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine | 1432511-94-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (4S,6R)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine
• 英文别名: (4S,6R)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-1,3-oxazin-2-amine
• CAS: 1432511-94-8
• 化学式: C₁₂H₁₁F₄N₃O₃
• 分子量: 321.231
• InChiKey: GCMOKMVXBZGTFB-KOLCDFICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  93.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4S,6R)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine 在 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 20.5h， 生成 N-(3-((4S,6R)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide
  参考文献：
  名称：

  β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

  摘要：

  An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK(a) and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A beta 40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A beta 40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

  DOI：

  10.1021/jm400225m
• 作为产物：
  描述：

  2'-氟苯乙酮 在 盐酸 、 titanium(IV) tetraethanolate 、 硫酸 、 四丁基氟化铵 、 硝酸 、 二异丁基氢化铝 、 三氟乙酸 、 copper(l) chloride 、 锌 作用下， 以 四氢呋喃 、 乙醇 、 水 、 甲苯 为溶剂， 反应 5.0h， 生成 (4S,6R)-4-(2-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine
  参考文献：
  名称：

  β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

  摘要：

  An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK(a) and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A beta 40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A beta 40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

  DOI：

  10.1021/jm400225m

文献信息

• [EN] FLUOROMETHYL-5,6-DIHYDRO-4H-[1,3]OXAZINES<br/>[FR] FLUOROMÉTHYL-5,6-DIHYDRO-4H-[1,3]OXAZINES
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013110622A1

  公开（公告）日：2013-08-01

  The present invention provides a compound of formula (I) having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

  本发明提供了具有BACE1抑制活性的化合物(I)的公式，它们的制备，包含它们的药物组合物以及它们作为治疗活性物质的用途。本发明的活性化合物在治疗和/或预防治疗例如阿尔茨海默病等疾病方面是有用的。
• FLUOROMETHYL-5,6-DIHYDRO-4H-[1,3]OXAZINES
  申请人：F. Hoffmann-La Roche AG

  公开号：US20150031690A1

  公开（公告）日：2015-01-29

  The present invention provides a compound of formula (I) having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

  本发明提供了一种具有BACE1抑制活性的化合物（I）的制备方法，包括含有它们的制药组合物以及它们作为治疗活性物质的用途。本发明的活性化合物在治疗和/或预防例如阿尔茨海默病等疾病方面具有用途。
• US9067926B2
  申请人：——

  公开号：US9067926B2

  公开（公告）日：2015-06-30
• β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease
  作者：Hans Hilpert、Wolfgang Guba、Thomas J. Woltering、Wolfgang Wostl、Emmanuel Pinard、Harald Mauser、Alexander V. Mayweg、Mark Rogers-Evans、Roland Humm、Daniela Krummenacher、Thorsten Muser、Christian Schnider、Helmut Jacobsen、Laurence Ozmen、Alessandra Bergadano、David W. Banner、Remo Hochstrasser、Andreas Kuglstatter、Pascale David-Pierson、Holger Fischer、Alessandra Polara、Robert Narquizian

  DOI：10.1021/jm400225m

  日期：2013.5.23

  An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK(a) and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A beta 40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A beta 40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.