(S)-7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (S)-7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine
• 英文别名: (4S)-7'-bromo-4'-fluoro-2'-methoxyspiro[5H-1,3-oxazole-4,9'-xanthene]-2-amine
• 化学式: C₁₆H₁₂BrFN₂O₃
• 分子量: 379.185
• InChiKey: DGQIPVRKRQJIKL-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  66.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine 在 三溴化硼 、 sodium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.52h， 生成 (S)-2-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthene]-7'-yl trifluoromethanesulfonate
  参考文献：
  名称：

  Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

  摘要：

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

  DOI：

  10.1021/jm501266w
• 作为产物：
  描述：

  2,5-二溴苯甲酸 在 (CuOTf)*toluene 、 二氧化碳 、 碘 、 caesium carbonate 、 二乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 、 甲苯 、 正戊烷 为溶剂， 反应 27.17h， 生成 (S)-7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine 、 (4R)-7'-bromo-4'-fluoro-2'-methoxyspiro[5H-1,3-oxazole-4,9'-xanthene]-2-amine
  参考文献：
  名称：

  Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

  摘要：

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

  DOI：

  10.1021/jm501266w

文献信息

• [EN] SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA - SECRETASE MODULATORS<br/>[FR] COMPOSÉS SPIRO TÉTRACYCLIQUES EN TANT QUE MODULATEURS DE LA BÉTA-SÉCRÉTASE
  申请人：AMGEN INC

  公开号：WO2011115938A1

  公开（公告）日：2011-09-22

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula (I) wherein A1, A2, A3, A4, A5, A6, R2, R7, X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.

  本发明涉及一类新的化合物，用于调节Beta-分泌酶酶活性，治疗由Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和其他相关疾病。在一个实施例中，这些化合物具有通用的化学式（I），其中化学式I中的A1、A2、A3、A4、A5、A6、R2、R7、X和Y已在此定义。该发明还包括将这些化合物用于制备药物组合物，用于治疗与β-分泌酶蛋白活性相关的疾病和症状，如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症以及与大脑斑块形成和/或沉积有关的其他中枢神经系统疾病。该发明还涉及化学式I的进一步实施例、中间体和用于制备化合物的过程。
• SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：CHENG Yuan

  公开号：US20110251190A1

  公开（公告）日：2011-10-13

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula I wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 2 , R 7 , X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.

  本发明涉及一类新的化合物，可用于调节β-分泌酶酶活性和治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）和其他相关疾病。在一种实施例中，所述化合物具有一般的I式，其中I式中的A1，A2，A3，A4，A5，A6，R2，R7，X和Y已在此定义。本发明还包括使用这些化合物于制备药物组合物，用于治疗与β-分泌酶蛋白活性相关的疾病和症状，包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他与大脑斑块形成和/或沉积相关和/或由此引起的中枢神经系统疾病。本发明还包括I式的进一步实施例、中间体和制备I式化合物的有用工艺。
• SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA - SECRETASE MODULATORS
  申请人：Amgen Inc.

  公开号：EP2547685A1

  公开（公告）日：2013-01-23
• US8883782B2
  申请人：——

  公开号：US8883782B2

  公开（公告）日：2014-11-11
• Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
  作者：Oleg Epstein、Marian C. Bryan、Alan C. Cheng、Katayoun Derakhchan、Thomas A. Dineen、Dean Hickman、Zihao Hua、Jason B. Human、Charles Kreiman、Isaac E. Marx、Matthew M. Weiss、Robert C. Wahl、Paul H. Wen、Douglas A. Whittington、Stephen Wood、Xiao Mei Zheng、Robert T. Fremeau、Ryan D. White、Vinod F. Patel

  DOI：10.1021/jm501266w

  日期：2014.12.11

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.