6-o-tolylquinolin-2-amine | 1308869-78-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-o-tolylquinolin-2-amine
• 英文别名: 6-(2-methylphenyl)quinolin-2-amine
• CAS: 1308869-78-4
• 化学式: C₁₆H₁₄N₂
• 分子量: 234.301
• InChiKey: CGNIKISUVFSKGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  38.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-o-tolylquinolin-2-amine 在 palladium diacetate 、 三(邻甲基苯基)磷 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醚 、 正己烷 为溶剂， 反应 14.0h， 生成 N-(3-(2-(6-cyclopentenylpyrimidin-4-yl)cyclopent-2-enyl)-6-o-tolylquinolin-2-yl)pivalamide
  参考文献：
  名称：

  [EN] AMINO HETEROARYL COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  [FR] COMPOSÉS AMINO HÉTÉROARYLIQUES COMME MODULATEURS DE BÊTA-SÉCRÉTASE ET PROCÉDÉS D'UTILISATION

  摘要：

  本发明涉及一类新的化合物，用于调节Beta-分泌酶酶活性以及治疗由Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关病症。在一种实施例中，这些化合物具有一般的化学式I，其中化合物的环A、B1、B2、B3、L、R1、R4、环Z、m和p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beta-分泌酶蛋白活性相关的疾病和症状，如阿尔茨海默病（AD）、认知缺陷、认知障碍、精神分裂症以及与大脑上的斑块形成和/或沉积相关的其他中枢神经系统病症。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工艺。

  公开号：

  WO2011063272A1
• 作为产物：
  描述：

  6-溴-2-氯喹啉 在 potassium carbonate 、 三氟乙酸 作用下， 以 乙二醇二甲醚 、 乙醇 、 甲苯 为溶剂， 反应 2.42h， 生成 6-o-tolylquinolin-2-amine
  参考文献：
  名称：

  From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)

  摘要：

  Using fragment-based screening of a focused fragment library, 2-aminoquinoline I was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 mu M). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC50 value of 11 nM on BACE1 and cellular activity of 80 nM, This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of A beta levels in cerebrospinal fluid (CSF).

  DOI：

  10.1021/jm200544q

文献信息

• Amino Heteroaryl Compounds as Beta-Secretase Modulators and Methods of Use
  申请人：Paras Nick A.

  公开号：US20130018064A1

  公开（公告）日：2013-01-17

  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 related conditions. In one embodiment, the compounds have a general Formula I, wherein ring A, B 1 , B 2 , B 3 , L, R 1 , R 4 , ring Z, m and p 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 (AD), 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.

  本发明涉及一类新型化合物，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）和相关病症。在一种实施方式中，所述化合物具有通式I，其中通式I中的环A、B1、B2、B3、L、R1、R4、环Z、m和p在此定义。本发明还包括这些化合物在药物组合物中的使用，用于治疗与β-分泌酶蛋白活性相关的疾病和病症的预防或治疗，例如阿尔茨海默病（AD）、认知缺陷、认知障碍、精神分裂症和其他与脑部斑块形成和/或沉积相关和/或由其引起的中枢神经系统病症。本发明还包括通式I的进一步实施方式、中间体和有用于制备通式I化合物的方法。
• AMINO HETEROARYL COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：Amgen Inc.

  公开号：EP2504330A1

  公开（公告）日：2012-10-03
• US8822485B2
  申请人：——

  公开号：US8822485B2

  公开（公告）日：2014-09-02
• From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
  作者：Yuan Cheng、Ted C. Judd、Michael D. Bartberger、James Brown、Kui Chen、Robert T. Fremeau、Dean Hickman、Stephen A. Hitchcock、Brad Jordan、Vivian Li、Patricia Lopez、Steven W. Louie、Yi Luo、Klaus Michelsen、Thomas Nixey、Timothy S. Powers、Claire Rattan、E. Allen Sickmier、David J. St. Jean、Robert C. Wahl、Paul H. Wen、Stephen Wood

  DOI：10.1021/jm200544q

  日期：2011.8.25

  Using fragment-based screening of a focused fragment library, 2-aminoquinoline I was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 mu M). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC50 value of 11 nM on BACE1 and cellular activity of 80 nM, This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of A beta levels in cerebrospinal fluid (CSF).
• [EN] AMINO HETEROARYL COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE<br/>[FR] COMPOSÉS AMINO HÉTÉROARYLIQUES COMME MODULATEURS DE BÊTA-SÉCRÉTASE ET PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2011063272A1

  公开（公告）日：2011-05-26

  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 related conditions. In one embodiment, the compounds have a general Formula I, wherein ring A, B1, B2, B3, L, R1, R4, ring Z, m and p 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 (AD), 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-分泌酶酶活性以及治疗由Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关病症。在一种实施例中，这些化合物具有一般的化学式I，其中化合物的环A、B1、B2、B3、L、R1、R4、环Z、m和p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beta-分泌酶蛋白活性相关的疾病和症状，如阿尔茨海默病（AD）、认知缺陷、认知障碍、精神分裂症以及与大脑上的斑块形成和/或沉积相关的其他中枢神经系统病症。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工艺。