(5R,6R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methyl-2,6-dihydro-1,4-oxazin-3-amine | 1443259-41-3

• 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: (5R,6R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methyl-2,6-dihydro-1,4-oxazin-3-amine
• CAS: 1443259-41-3
• 化学式: C₁₁H₁₁BrF₂N₂O
• 分子量: 305.122
• InChiKey: MSEBYOYZFVUOOX-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.49
• 重原子数：
  17.0
• 可旋转键数：
  1.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  47.61
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (5R,6R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methyl-2,6-dihydro-1,4-oxazin-3-amine 在 copper(l) iodide 、 sodium azide 、 sodium carbonate 、 N,N-二甲基乙二胺 、 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 、 二甲基亚砜 为溶剂， 反应 7.0h， 生成 N-{3-[(2R,3R)-5-amino-2-fluoro-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide
  参考文献：
  名称：

  1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

  摘要：

  1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pK(a) while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF A beta levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

  DOI：

  10.1021/acs.jmedchem.5b01101
• 作为产物：
  描述：

  (5R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methylmorpholine-3-thione 在 氨 作用下， 以 甲醇 为溶剂， 反应 36.0h， 以65%的产率得到(5R,6R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methyl-2,6-dihydro-1,4-oxazin-3-amine
  参考文献：
  名称：

  5-(3-AMINOPHENYL)-5-ALKYL-5,6-DIHYDRO-2H-[1,4]OXAZIN-3-AMINE DERIVATIVES

  摘要：

  本发明涉及一种新型5-(3-氨基苯基)-5-烷基-5,6-二氢-2H-[1,4]噁嗪-3-胺衍生物，作为β-分泌酶抑制剂，也被称为β-位点淀粉样蛋白裂解酶、BACE、BACE1、Asp2或memapsin2。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及将这些化合物和组合物用于预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、带有Lewy小体的痴呆、脑淀粉样血管病、多发性梗塞性痴呆、唐氏综合征、中风相关的痴呆、帕金森病相关的痴呆和β-淀粉样蛋白相关的痴呆。

  公开号：

  US20140364428A1

文献信息

• [EN] 5-(3-AMINOPHENYL)-5-ALKYL-5,6-DIHYDRO-2H-[1,4]OXAZIN-3-AMINE DERIVATIVES<br/>[FR] DÉRIVÉS DE 5-(3-AMINOPHÉNYL)-5-ALKYL-5,6-DIHYDRO-2H-[1,4]OXAZIN-3-AMINE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2013083556A1

  公开（公告）日：2013-06-13

  The present invention relates to novel 5-(3-aminophenyl)-5-alkyl-5,6-dihydro- 2H-[1,4]oxazin-3-amine derivatives as inhibitors of beta-secretase, also known as beta- site amyloid cleaving enzyme, BACE, BACE 1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid. (Formula I)

  本发明涉及一种新型的5-(3-氨基苯基)-5-烷基-5,6-二氢-2H-[1,4]噁嗪-3-胺衍生物，作为β-分泌酶抑制剂，也被称为β-位点淀粉样蛋白裂解酶、BACE、BACE 1、Asp2或memapsin2。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的工艺，以及利用这些化合物和组合物预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、带有Lewy小体的痴呆、脑淀粉样脉管病、多梗塞性痴呆、唐氏综合征、与中风相关的痴呆、与帕金森病相关的痴呆以及与β-淀粉样蛋白相关的痴呆等疾病的治疗和预防。（化学式I）