3-[5-chloro-4-(2,4-difluorobenzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methylbenzoic acid | 773104-07-7

• 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: 3-[5-chloro-4-(2,4-difluorobenzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methylbenzoic acid
• 英文别名: 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid；3-[5-chloro-4-[(2,4-difluorophenyl)methoxy]-6-oxopyrimidin-1-yl]-4-methylbenzoic acid
• CAS: 773104-07-7
• 化学式: C₁₉H₁₃ClF₂N₂O₄
• 分子量: 406.773
• InChiKey: GEFBZDGWNJSLQF-UHFFFAOYSA-N

物化性质

• 沸点：
  603.7±65.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  79.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-[5-chloro-4-(2,4-difluorobenzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methylbenzoic acid 在 N-甲基吗啉 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 生成 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide
  参考文献：
  名称：

  Substituted N -aryl-6-pyrimidinones: A new class of potent, selective, and orally active p38 MAP kinase inhibitors

  摘要：

  A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (> 90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-alpha in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.05.006
• 作为产物：
  描述：

  3-氨基-4-甲基苯甲酸甲酯 在 二氯乙酸 、 N-氯代丁二酰亚胺 、 sodium methylate 、 potassium carbonate 、 柠檬酸 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 N,N-二甲基乙酰胺 、 1,2-二氯乙烷 为溶剂， 反应 33.0h， 生成 3-[5-chloro-4-(2,4-difluorobenzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methylbenzoic acid
  参考文献：
  名称：

  Substituted N -aryl-6-pyrimidinones: A new class of potent, selective, and orally active p38 MAP kinase inhibitors

  摘要：

  A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (> 90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-alpha in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.05.006

文献信息

• Substituted pyrimidinones
  申请人：——

  公开号：US20040242608A1

  公开（公告）日：2004-12-02

  Disclosed are compounds Formula I 1 and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , and R 5 are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.

  本发明涉及化合物I1及其药学上可接受的盐，其中R1、R2、R4和R5的定义如下。这些化合物可用于治疗由未调节的p38 MAP激酶和/或TNF活性引起或恶化的疾病和病况。本发明还涉及含有这些化合物的药物组合物、制备这些化合物的方法以及使用这些化合物进行治疗的方法。
• SUBSTITUTED PYRIMIDINONES
  申请人：Durley C. Richard

  公开号：US20070167621A1

  公开（公告）日：2007-07-19

  Disclosed are compounds Formula I and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , and R 5 are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.

  本发明涉及化合物I的公式及其药学上可接受的盐，其中R1、R2、R4和R5在此定义。这些化合物可用于治疗由未经调节的p38 MAP激酶和/或TNF活性引起或恶化的疾病和病况。本发明还涉及含有这些化合物的药物组合物、制备这些化合物的方法以及使用这些化合物的治疗方法。
• [EN] CRYSTALLINE FORMS OF 3-[5-CHLORO-4-[(2,4-DIFLUOROBENZYL) OXY]-6-OXOPYRIMIDIN-1(6H)-YL]-N-(2-HYDROXYETHYL)-4-METHYLBENZAMIDE<br/>[FR] FORMES CRISTALLINES DE 3-[5-CHLORO-4-[(2,4-DIFLUOROBENZYL) OXY]-6-OXOPYRIMIDIN-1(6H)-YL]-N-(2-HYDROXYETHYL)-4-METHYLBENZAMIDE
  申请人：PHARMACIA & UPJOHN CO LLC

  公开号：WO2006040649A1

  公开（公告）日：2006-04-20

  Crystalline forms of the p38 kinase inhibitor 3-[5-chloro-4-[(2,4­difluorobenzyl) oxy]-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide is provided. Also provided are combinations and pharmaceutical compositions comprising the crystalline forms and methods for the prophylaxis and/or treatment of a p38 kinase-mediated condition comprising administering to a subject a therapeutically effective amount of the crystalline forms.

  本发明提供了p38激酶抑制剂3-[5-氯-4-[(2,4-二氟苯基)氧基]-6-氧代嘧啶-1(6H)-基]-N-(2-羟乙基)-4-甲基苯甲酰的晶体形式。还提供了包含这些晶体形式的组合物和药物组成物，以及用于预防和/或治疗p38激酶介导的疾病的方法，包括向受试者施用治疗有效量的这些晶体形式。
• Crystalline Forms Of 3-[5-Chloro-4-[(2,4-difluorobenzyl) oxy]-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide
  申请人：Pharmacia & Upjohn Company LLC

  公开号：EP2708531A1

  公开（公告）日：2014-03-19

  Crystalline forms of the p38 kinase inhibitor 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide is provided. Also provided are combinations and pharmaceutical compositions comprising the crystalline forms, and methods for the prophylaxis and/or treatment of a p38 kinase-mediated condition comprising administering to a subject a therapeutically effective amount of the crystalline forms.

  提供了p38激酶抑制剂3-[5-氯-4-[(2,4-二氟苄基)氧基]-6-氧代嘧啶-1(6H)-基]-N-(2-羟乙基)-4-甲基苯甲酰胺的结晶形式。还提供了包含这些结晶形式的组合物和药物组合物，以及预防和/或治疗 p38 激酶介导的病症的方法，该方法包括向受试者施用治疗有效量的这些结晶形式。
• WO2008/153942
  申请人：——

  公开号：——

  公开（公告）日：——