N-cyclopropyl-3-hydroxy-4-methylbenzamide | 796073-36-4

• 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: N-cyclopropyl-3-hydroxy-4-methylbenzamide
• CAS: 796073-36-4
• 化学式: C₁₁H₁₃NO₂
• mdl: MFCD11130688
• 分子量: 191.23
• InChiKey: BCIDUGSYSVTLOG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-cyclopropyl-3-hydroxy-4-methylbenzamide 、 4-Chloro-1-(2,4-difluorophenyl)-7-methylpyrazolo[3,4-b]pyridin-6-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 K₃PO₄ 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 生成 N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-4-methylbenzamide
  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

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。
• Pyrazole-amine compounds useful as kinase inhibitors
  申请人：Bristol-Myers Squibb Company

  公开号：EP2385041A1

  公开（公告）日：2011-11-09

  The present invention provides pyrazole derived compounds of formula (I) useful for treating p38 kinase-associated conditions, where W, X, R1, R2, R3, R4, R5, R6 and m are as defined herein. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention useful for treating p38 kinase-associated conditions, and methods of inhibiting the activity of p38 kinase in a mammal.

  本发明提供了式 (I) 的吡唑衍生化合物 其中 W、X、R1、R2、R3、R4、R5、R6 和 m 如本文所定义。本发明进一步涉及含有至少一种根据本发明的化合物的药物组合物，该组合物有助于治疗 p38 激酶相关病症，以及抑制哺乳动物体内 p38 激酶活性的方法。
• Part 2: 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、Bradley Henkle、Lisa Sherman、Matthew Plant、Kent Miner、Helen J. 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.2010.01.059

  日期：2010.3

  A novel class of pyrazolopyridazine p38 alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds 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 the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38 alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38 alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNF alpha production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.
• EP1620108A4
  申请人：——

  公开号：EP1620108A4

  公开（公告）日：2008-08-27