(S)-7-bromo-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-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-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine
• 英文别名: (S)-7-bromo-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4' oxazol]-2'-amine；(4S)-7'-bromo-3'-chloro-1'-fluorospiro[5H-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine
• 化学式: C₁₄H₈BrClFN₃O₂
• 分子量: 384.592
• InChiKey: KFCJSMDNVYRTLW-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.33
• 重原子数：
  22.0
• 可旋转键数：
  0.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  69.73
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (S)-7-bromo-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine 、 sodium methylate 在 水 、 Sodium sulfate-III 、 crude product 、 silica gel 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以to provide (S)-7-bromo-3-chloro-1-methoxy-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an amorphous off-white solid的产率得到(S)-7-bromo-3-chloro-1-methoxy-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine
  参考文献：
  名称：

  Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use

  摘要：

  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，化合物具有一般式I，其中式I中的A1，A2，A3，A4，A5，A6，R2，R7，X和Y的定义如本文所述。 本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，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的形成和/或沉积相关和/或由此引起的中枢神经系统疾病。本发明还包括式I的进一步实施例、中间体和制备式I化合物的有用工艺。

  公开号：

  US08883782B2
• 作为产物：
  描述：

  2-氯-6-氟吡啶 在 盐酸 、 正丁基锂 、 四丙基高钌酸铵 、 甲基溴化镁 、 碘 、 三溴化硼 、 potassium carbonate 、 N-甲基吗啉氧化物 、 二异丙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 正己烷 、 二氯甲烷 、 丙酮 为溶剂， 反应 17.92h， 生成 (S)-7-bromo-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine
  参考文献：
  名称：

  An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

  摘要：

  BACE1 inhibition to prevent A beta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain A beta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

  DOI：

  10.1021/ml500458t

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
• An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities
  作者：Yuan Cheng、James Brown、Ted C. Judd、Patricia Lopez、Wenyuan Qian、Timothy S. Powers、Jian Jeffrey Chen、Michael D. Bartberger、Kui Chen、Robert T. Dunn、Oleg Epstein、Robert T. Fremeau、Scott Harried、Dean Hickman、Stephen A. Hitchcock、Yi Luo、Ana Elena Minatti、Vinod F. Patel、Hugo M. Vargas、Robert C. Wahl、Matthew M. Weiss、Paul H. Wen、Ryan D. White、Douglas A. Whittington、Xiao Mei Zheng、Stephen Wood

  DOI：10.1021/ml500458t

  日期：2015.2.12

  BACE1 inhibition to prevent A beta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain A beta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.