ethyl 5-acetamido-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate | 1148051-68-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-acetamido-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate
• 英文别名: ethyl 5-acetamido-1-(3-fluorophenyl)pyrazole-4-carboxylate
• CAS: 1148051-68-6
• 化学式: C₁₄H₁₄FN₃O₃
• 分子量: 291.282
• InChiKey: RAVPVSWVJVXCPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  73.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 5-acetamido-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate 、 alkaline earth salt of/the/ methylsulfuric acid 在 sodium hydride 、 lithium bromide 作用下， 以 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 1-(3-fluorophenyl)-5-(N-methylacetamido)-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

  摘要：

  A novel class of fused pyrazole-derived inhibitors of p38 alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED50 of 0.1 mg/kg while 10q was found to have an ED50 of 0.05-0.07 mg/kg. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.06.058
• 作为产物：
  描述：

  ethyl 5-diacetylamino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 反应 1.0h， 生成 ethyl 5-acetamido-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  [EN] PYRAZOLO-PYRIDINONE DERIVATIVES AND METHODS OF USE
  [FR] DÉRIVÉS DE PYRAZOLOPYRIDINONE ET PROCÉDÉS D'UTILISATION

  摘要：

  本发明涉及一种新型化合物类别，可用于预防和治疗炎症介导的前炎症因子性疾病，特别是p38活性介导的炎症和相关病症。该化合物具有一般式I（I），其中A1、A2、A3、A4、A5、R1、R2和R3在此被定义。本发明还涉及包括一种或多种I式化合物的药物组合物，使用这种化合物和组合物治疗炎症性疾病，包括类风湿性关节炎、牛皮癣和其他疾病，以及制备I式化合物的中间体和有用的过程。

  公开号：

  WO2009055033A1

文献信息

• [EN] PYRAZOLO-PYRIDINONE DERIVATIVES AND METHODS OF USE<br/>[FR] DÉRIVÉS DE PYRAZOLOPYRIDINONE ET PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2009055033A1

  公开（公告）日：2009-04-30

  The present invention comprises a new class of compounds useful for the prophylaxis and treatment of pro-inflammatory cytokine mediated diseases, and in particular, p38 activity mediated inflammation and related conditions. The compounds have a general Formula I (I) wherein A1, A2, A3, A4, A5, R1, R2 and R3 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of inflammatory diseases including rheumatoid arthritis, psoriasis and other disorders, as well as 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，可用于预防和治疗炎症介导的前炎症因子性疾病，特别是p38活性介导的炎症和相关病症。该化合物具有一般式I（I），其中A1、A2、A3、A4、A5、R1、R2和R3在此被定义。本发明还涉及包括一种或多种I式化合物的药物组合物，使用这种化合物和组合物治疗炎症性疾病，包括类风湿性关节炎、牛皮癣和其他疾病，以及制备I式化合物的中间体和有用的过程。
• Pyrazolo-pyridinone derivatives and methods of use
  申请人：Amgen Inc.

  公开号：US08080546B2

  公开（公告）日：2011-12-20

  The present invention comprises a new class of compounds useful for the prophylaxis and treatment of pro-inflammatory cytokine mediated diseases, and in particular, p38 activity mediated inflammation and related conditions. The compounds have a general Formula I wherein A1, A2, A3, A4, A5, R1, R2 and R3 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of inflammatory diseases including rheumatoid arthritis, psoriasis and other disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

  本发明涉及一类新的化合物，用于预防和治疗炎症介导的细胞因子相关疾病，特别是p38活性介导的炎症和相关病症。该类化合物具有一般的I式，其中A1、A2、A3、A4、A5、R1、R2和R3在此定义。本发明还包括含有一种或多种I式化合物的药物组合物，以及用于治疗炎症性疾病，包括类风湿性关节炎、牛皮癣和其他疾病的上述化合物和组合物的用途，以及用于制备I式化合物的中间体和方法。
• US8080546B2
  申请人：——

  公开号：US8080546B2

  公开（公告）日：2011-12-20
• Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase
  作者：Ryan P. Wurz、Liping H. Pettus、Shimin Xu、Bradley Henkle、Lisa Sherman、Matthew Plant、Kent Miner、Helen McBride、Lu Min Wong、Christiaan J.M. Saris、Matthew R. Lee、Samer Chmait、Christopher Mohr、Faye Hsieh、Andrew S. Tasker

  DOI：10.1016/j.bmcl.2009.06.058

  日期：2009.8

  A novel class of fused pyrazole-derived inhibitors of p38 alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED50 of 0.1 mg/kg while 10q was found to have an ED50 of 0.05-0.07 mg/kg. (C) 2009 Elsevier Ltd. All rights reserved.