(S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine | 1415914-96-3

• 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: (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine
• 英文别名: (4S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-1,3-oxazin-2-amine
• CAS: 1415914-96-3
• 化学式: C₁₁H₁₂F₃N₃O
• 分子量: 259.231
• InChiKey: WHYVUNIQQDJJIE-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  73.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine 、 5-氰基-2-吡啶羧酸 在 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 、 sodium carbonate 作用下， 以 甲醇 、 水 为溶剂， 反应 16.5h， 以73.2%的产率得到(S)-N-(3-(2-amino-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide
  参考文献：
  名称：

  [EN] HALOGEN-ALKYL-1,3 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS
  [FR] HALOGÉNO-ALKYL-1,3 OXAZINES EN TANT QU'INHIBITEURS DE BACE1 ET/OU BACE2

  摘要：

  本发明提供具有BACE1和/或BACE2抑制活性的式(I)化合物，它们的制备方法，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可用于治疗和/或预防例如阿尔茨海默病和2型糖尿病等疾病。

  公开号：

  WO2012168164A1
• 作为产物：
  描述：

  1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone 在 盐酸 、 titanium(IV) tetraethanolate 、 锂硼氢 、 硫酸 、 palladium 10% on activated carbon 、 氢气 、 硝酸 、 sodium acetate 、 三氟乙酸 、 copper(l) chloride 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 异丙醇 为溶剂， 反应 1.0h， 生成 (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-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

• HALOGEN-ALKYL-1,3 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS
  申请人：Siena Biotech S.p.A.

  公开号：US20140080819A1

  公开（公告）日：2014-03-20

  The present invention provides compounds of formula (I) having BACE1 and/or BACE2 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 and type 2 diabetes.

  本发明提供具有BACE1和/或BACE2抑制活性的化合物(I)的公式，它们的制备，含有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和2型糖尿病方面是有用的。
• Halogen-alkyl-1,3 oxazines as BACE1 and/or BACE2 inhibitors
  申请人：Woltering Thomas

  公开号：US08987255B2

  公开（公告）日：2015-03-24

  The present invention provides compounds of formula (I) having BACE1 and/or BACE2 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 and type 2 diabetes.

  本发明提供了具有BACE1和/或BACE2抑制活性的式（I）化合物，它们的制造方法，包含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可用于治疗和/或预防例如阿尔茨海默病和2型糖尿病等疾病。
• US8987255B2
  申请人：——

  公开号：US8987255B2

  公开（公告）日：2015-03-24
• 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.
• [EN] HALOGEN-ALKYL-1,3 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS<br/>[FR] HALOGÉNO-ALKYL-1,3 OXAZINES EN TANT QU'INHIBITEURS DE BACE1 ET/OU BACE2
  申请人：HOFFMANN LA ROCHE

  公开号：WO2012168164A1

  公开（公告）日：2012-12-13

  The present invention provides compounds of formula (I) having BACE1 and/or BACE2 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 and type 2 diabetes.

  本发明提供具有BACE1和/或BACE2抑制活性的式(I)化合物，它们的制备方法，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可用于治疗和/或预防例如阿尔茨海默病和2型糖尿病等疾病。