2-(4-bromophenoxy)-5-methoxybenzoic acid | 1215864-17-7

• 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: 2-(4-bromophenoxy)-5-methoxybenzoic acid
• CAS: 1215864-17-7
• 化学式: C₁₄H₁₁BrO₄
• 分子量: 323.143
• InChiKey: VLRIVMWVPYALGL-UHFFFAOYSA-N

物化性质

• 沸点：
  422.3±40.0 °C(Predicted)
• 密度：
  1.518±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-bromophenoxy)-5-methoxybenzoic acid 在 3-溴甲基-3-甲基-1-氧杂环丁烷 、 硫酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 7-bromo-2-hydroxyxanthone
  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：

  4-溴苯酚 、 2-溴-5-甲氧基苯甲酸 在 copper (I) trifluoromethane sulfonate toluene complex potassium carbonate 、 盐酸 作用下， 以 乙酸乙酯 、 甲苯 、 水 为溶剂， 反应 20.66h， 生成 2-(4-bromophenoxy)-5-methoxybenzoic acid
  参考文献：
  名称：

  [EN] AMINO -DIHYDROOXAZINE AND AMINO - DIHYDROTHIAZINE SPIRO COMPOUNDS AS BETA - SECRETASE MODULATORS AND THEIR MEDICAL USE
  [FR] COMPOSÉS SPIRO DE L'AMINO-DIHYDROOXAZINE ET DE L'AMINO-DIHYDROTHIAZINE EN TANT QUE MODULATEURS DE LA BÉTA-SÉCRÉTASE ET UTILISATION MÉDICALE ASSOCIÉE

  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，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。在一个实施例中，这些化合物具有一般的化学式（I）：其中化学式（I）中的A1、A2、A3、A4、A5、A6、R2、R7、X、Y和Z在此处定义。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病况，包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症以及其他与大脑斑块的形成和/或沉积相关的中枢神经系统病症。该发明还包括化学式（I）的进一步实施例，中间体和有助于制备化合物的过程。

  公开号：

  WO2011115928A1

文献信息

• [EN] AMINO-OXAZINES AND AMINO-DIHYDROTHIAZINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE<br/>[FR] COMPOSÉS D'AMINO-OXAZINES ET D'AMINO-DIHYDROTHIAZINE COMME MODULATEURS DE SÉCRÉTASE BÊTA ET PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2013044092A1

  公开（公告）日：2013-03-28

  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 A1, A2, A3, A4, A5, A6, L, R2, R7, X, Y and Z 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β-分泌酶酶活性，并用于治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）及相关病症。在一个实施例中，这些化合物具有一般的化学式I，其中化学式I中的A1、A2、A3、A4、A5、A6、L、R2、R7、X、Y和Z在此处定义。该发明还包括将这些化合物用于制备用于治疗与β-分泌酶蛋白活性相关的疾病和病症的药物组合物，包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症以及与大脑斑块的形成和/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有用过程。
• [EN] SPIRO-TETRACYCLIC RING COMPOUNDS AS BETASECRETASE MODULATORS AND METHODS OF USE<br/>[FR] COMPOSÉS CYCLIQUES SPIRO-TÉTRACYCLIQUES UTILES EN TANT QUE MODULATEURS DE LA BÊTA-SÉCRÉTASE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2010030954A1

  公开（公告）日：2010-03-18

  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 A1, A2, A3, A4, A5, A6, T1, T2, W, X, Y and Z 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β-分泌酶酶活性，并用于治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）及相关疾病。在一种实施例中，这些化合物具有一般的化学式（I）；其中化学式（I）中的A1、A2、A3、A4、A5、A6、T1、T2、W、X、Y和Z在此处定义。该发明还包括将这些化合物用于制备用于治疗与β-分泌酶蛋白活性相关的疾病和症状的药物组合物。这些疾病包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症以及与大脑斑块的形成和/或沉积相关和/或由此引起的其他中枢神经系统疾病。该发明还涵盖了化学式I的进一步实施例、中间体和用于制备化合物的有用过程。
• [EN] AMINO-ISO-INDOLE, AMINO-AZA-ISO-INDOLE, AMINO-DIHYDROISOQUINOLINE AND AMINO-BENZOXAZINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE<br/>[FR] COMPOSÉS D'AMINO-ISO-INDOLE, D'AMINO-AZA-ISO-INDOLE, D'AMINO-DIHYDRO-ISOQUINOLÉINE ET D'AMINO-BENZOXAZINE EN TANT QUE MODULATEURS DE LA BÊTA-SÉCRÉTASE ET LEURS MÉTHODES D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2012019056A1

  公开（公告）日：2012-02-09

  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: (I). In another embodiment, the compounds have a general Formula II: (II). In another embodiment, the compounds have a general Formula III: (III). Variables A1, A2, A3, A4, A5, A6, R2, R7, V, W, X, Y and Z of Formulas I, II and III 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 Formulas I, II and III, intermediates and processes useful for the preparation of compounds of Formulas I, II and III.

  本发明包括一类新的化合物，用于调节Beta-分泌酶酶活性，并用于治疗Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）及相关病症。在一种实施方式中，这些化合物具有通用的化学式I：(I)。在另一种实施方式中，这些化合物具有通用的化学式II：(II)。在另一种实施方式中，这些化合物具有通用的化学式III：(III)。化学式I、II和III中的变量A1、A2、A3、A4、A5、A6、R2、R7、V、W、X、Y和Z在此处定义。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beta-分泌酶蛋白活性相关的疾病和病症，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/或沉积相关或由此引起的其他中枢神经系统病症。本发明还包括化学式I、II和III的进一步实施方式，以及用于制备化学式I、II和III化合物的中间体和工艺。
• [EN] 5-AMINO-OXAZEPINE AND 5-AMINO-THIAZEPANE COMPOUNDS AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE<br/>[FR] COMPOSÉS DE 5-AMINO-OXAZÉPINE ET 5-AMINO-THIAZÉPANE EN TANT QU'ANTAGONISTES DE LA BÊTA-SÉCRÉTASE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2012109165A1

  公开（公告）日：2012-08-16

  The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I); wherein variables A1, A3, A4, A5, A6, A8, R2, R7, X and Y of Formula (I) are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas (II) and sub-formula embodiments of Formula (I) and (II), intermediates and processes and methods useful for the preparation of compounds of Formulas (I)-(II).

  本发明提供了一类新的化合物，用于调节β-分泌酶（BACE）活性。这些化合物具有通式（I）；其中通式（I）中的变量A1、A3、A4、A5、A6、A8、R2、R7、X和Y在此处定义。本发明还提供包含这些化合物的药物组合物，并针对与A-beta斑块形成和沉积相关的疾病和/或症状的治疗，这些疾病和症状是由BACE的生物活性导致的。这种由BACE介导的疾病包括阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他中枢神经系统疾病。本发明还提供通式（II）的化合物和通式（I）和（II）的子式实施例，以及有用于制备通式（I）-（II）的化合物的中间体、过程和方法。
• [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。