3'-(5-(3-(3,5-dichloropyridin-4-yl)ureido)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,1'-biphenyl]-3-carboxylic acid | 1229439-08-0

• 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-(3-(3,5-dichloropyridin-4-yl)ureido)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,1'-biphenyl]-3-carboxylic acid
• 英文别名: 3'-[5-({[(3,5-dichloropyridin-4-yl)amino]carbonyl}amino)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl]biphenyl-3-carboxylic acid；3-[3-[5-[(3,5-Dichloropyridin-4-yl)carbamoylamino]-1-ethyl-6-oxopyridazin-3-yl]phenyl]benzoic acid
• CAS: 1229439-08-0
• 化学式: C₂₅H₁₉Cl₂N₅O₄
• 分子量: 524.363
• InChiKey: VDUNTICFHKEWCX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3'-(5-(3-(3,5-dichloropyridin-4-yl)ureido)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,1'-biphenyl]-3-carboxylic acid 、 金刚烷胺 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以49%的产率得到N-1-adamantyl-3'-[5-({[(3,5-dichloropyridin-4-yl)amino]carbonyl}amino)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl]biphenyl-3-carboxamide
  参考文献：
  名称：

  (3-oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors

  摘要：

  揭示了具有化学结构式（I）的新（3-氧代）吡啶并嘧啶-4-基脲衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为磷酸二酯酶IV（PDE4）抑制剂在治疗中的用途。

  公开号：

  EP2196465A1
• 作为产物：
  描述：

  1-(3-溴苯基)丁烷-1,3-二酮 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 lithium hydroxide monohydrate 、 氢溴酸 、 氢气 、 sodium 、 sodium hydride 、 potassium carbonate 、 caesium carbonate 、 一水合肼 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 130.0 ℃ 、96.53 kPa 条件下， 反应 34.33h， 生成 3'-(5-(3-(3,5-dichloropyridin-4-yl)ureido)-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)-[1,1'-biphenyl]-3-carboxylic acid
  参考文献：
  名称：

  Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure–Activity Relationships

  摘要：

  Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century Micro Sprayer Aerosolizer.

  DOI：

  10.1021/acs.jmedchem.6b00829

文献信息

• [EN] (3-OXO)PYRIDIN-4-YLUREA DERIVATIVES AS PDE4 INHIBITORS<br/>[FR] DÉRIVÉS DE (3-OXO)PYRIDIN-4-YLURÉE EN TANT QU'INHIBITEURS DE LA PDE4
  申请人：ALMIRALL SA

  公开号：WO2010069504A1

  公开（公告）日：2010-06-24

  New (3-oxo)pyridazin-4-ylurea derivatives having the chemcial structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).
• (3-oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors
  申请人：Almirall, S.A.

  公开号：EP2196465A1

  公开（公告）日：2010-06-16

  New (3-oxo)pyridazin-4-ylurea derivatives having the chemcial structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).

  揭示了具有化学结构式（I）的新（3-氧代）吡啶并嘧啶-4-基脲衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为磷酸二酯酶IV（PDE4）抑制剂在治疗中的用途。
• Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure–Activity Relationships
  作者：Jordi Gràcia、Maria Antonia Buil、Jordi Castro、Peter Eichhorn、Manel Ferrer、Amadeu Gavaldà、Begoña Hernández、Victor Segarra、Martin D. Lehner、Imma Moreno、Lluís Pagès、Richard S. Roberts、Jordi Serrat、Sara Sevilla、Joan Taltavull、Miriam Andrés、Judit Cabedo、Dolors Vilella、Elena Calama、Carla Carcasona、Montserrat Miralpeix

  DOI：10.1021/acs.jmedchem.6b00829

  日期：2016.12.8

  Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century Micro Sprayer Aerosolizer.