2-(4-bromophenoxy)-5-iodobenzoic acid | 1335218-45-5

• 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-iodobenzoic acid
• CAS: 1335218-45-5
• 化学式: C₁₃H₈BrIO₃
• 分子量: 419.013
• InChiKey: CEPIEYILIPYSAJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(4-bromophenoxy)-5-iodobenzoic acid 在 四(三苯基膦)钯 、 二氧化碳 、 二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II) 、 硫酸 、 碘 、 4-甲基苯磺酸吡啶 、 sodium carbonate 、 potassium carbonate 、 二乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.75h， 生成 (R)-2'-(3,6-dihydro-2H-pyran-4-yl)-7'-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9'-xanthen]-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
• 作为产物：
  描述：

  4-溴苯酚 、 2,5-二碘苯甲酸 在 caesium carbonate 作用下， 以 乙酸乙酯 、 甲苯 为溶剂， 反应 20.68h， 生成 2-(4-bromophenoxy)-5-iodobenzoic acid
  参考文献：
  名称：

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

  摘要：

  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。

  公开号：

  WO2013044092A1
• 作为试剂：
  描述：

  4-溴苯酚 、 2,5-二碘苯甲酸 、 Dicaesio carbonate 、 硫酸 、 2-(4-bromophenoxy)-5-iodobenzoic acid 在 乙酸乙酯 乙酸乙酯 、 水 、 Brine 、 Sodium sulfate-III 、 2-(4-bromophenoxy)-5-iodobenzoic acid 、 ice water 、 solution 、 sodium hydroxide 作用下， 以 甲苯 为溶剂， 反应 21.43h， 以to afford 2-bromo-7-iodo-9H-xanthen-9-one (23.4 g) as a tan solid that的产率得到2-bromo-7-iodo-9H-xanthen-9-one
  参考文献：
  名称：

  Amino-Oxazines and Amino-Dihydrothiazine Compounds as Beta-Secretase Modulators and Methods of Use

  摘要：

  本发明涉及一种新型化合物，用于调节Beta-分泌酶酶活性和治疗Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关疾病。在一种实施方式中，该化合物具有一般式I，其中式I中的A1、A2、A3、A4、A5、A6、R2、R7、X、Y和Z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beta-分泌酶蛋白活性相关的疾病和症状，包括阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他与大脑斑块形成和/或沉积有关和/或由此引起的中枢神经系统疾病。该发明还包括式I的进一步实施方式、中间体和制备式I化合物的有用过程。

  公开号：

  US20110251186A1

文献信息

• [EN] AMINO -DIHYDROOXAZINE AND AMINO - DIHYDROTHIAZINE SPIRO COMPOUNDS AS BETA - SECRETASE MODULATORS AND THEIR MEDICAL USE<br/>[FR] COMPOSÉS SPIRO DE L'AMINO-DIHYDROOXAZINE ET DE L'AMINO-DIHYDROTHIAZINE EN TANT QUE MODULATEURS DE LA BÉTA-SÉCRÉTASE ET UTILISATION MÉDICALE ASSOCIÉE
  申请人：AMGEN INC

  公开号：WO2011115928A1

  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 related conditions. In one embodiment, the compounds have a general Formula (I): wherein A1, A2, A3, A4, A5, A6, 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。
• AMINO-OXAZINES AND AMINO-DIHYDROTHIAZINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：AMGEN INC.

  公开号：US20140045828A1

  公开（公告）日：2014-02-13

  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 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, 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Beta-秘鲁酶酶活性和治疗Beta-秘鲁酶介导的疾病，包括阿尔茨海默病（AD）和相关疾病。在一种实施例中，该化合物具有通用的I式，其中I式中的A1、A2、A3、A4、A5、A6、R2、R7、X、Y和Z的定义在此处。本发明还包括将这些化合物用于制备用于治疗与Beta-秘鲁酶蛋白活性相关的疾病和病症的药物组合物，包括阿尔茨海默病、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。本发明还包括公式I的进一步实施例、中间体和用于制备公式I化合物的方法。
• Amino-Oxazine and Amino-Dihydrothiazine Compounds as Beta-Secretase Modulators and Methods of Use
  申请人：AMGEN INC

  公开号：US20140296226A1

  公开（公告）日：2014-10-02

  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 A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , L, R 2 , R 7 , 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.

  本发明涉及一种新型化合物类别，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）和相关疾病。在一个实施例中，该化合物具有一般式I，其中式I中的A1、A2、A3、A4、A5、A6、L、R2、R7、X、Y和Z在此定义。本发明还包括将这些化合物用于治疗与β-分泌酶蛋白活性相关的障碍和疾病的药物组合物，包括阿尔茨海默病、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。本发明还包括式I的进一步实施例、中间体和用于制备式I化合物的过程。
• Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
  申请人：Chen Jian J.

  公开号：US08497264B2

  公开（公告）日：2013-07-30

  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, 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-分泌酶酶活性和治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关疾病。在一种实施例中，所述化合物具有一般式I，其中式I中的A1、A2、A3、A4、A5、A6、R2、R7、X、Y和Z的定义如本文所述。本发明还包括使用这些化合物在药物组成物中治疗与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、精神分裂症和其他与大脑斑块形成和/或沉积相关和/或由其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。
• Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
  申请人：AMGEN INC.

  公开号：US09296759B2

  公开（公告）日：2016-03-29

  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Beta-分泌酶酶活性和治疗Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关疾病。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、L、R2、R7、X、Y和Z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Beta-分泌酶蛋白活性相关的障碍和疾病，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、中间体和用于制备I式化合物的有用工艺。