methyl 6-hydroxy-3'-{4-[(3-methoxyphenyl)amino]-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl}biphenyl-3-carboxylate | 1345014-82-5

• 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: methyl 6-hydroxy-3'-{4-[(3-methoxyphenyl)amino]-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl}biphenyl-3-carboxylate
• 英文别名: methyl 4-hydroxy-3-[3-[4-(3-methoxyanilino)-5-oxo-7,8-dihydro-6H-1,6-naphthyridin-2-yl]phenyl]benzoate
• CAS: 1345014-82-5
• 化学式: C₂₉H₂₅N₃O₅
• 分子量: 495.535
• InChiKey: GDLQUSDYOPWASC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 6-hydroxy-3'-{4-[(3-methoxyphenyl)amino]-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl}biphenyl-3-carboxylate 在 水 、 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 72.0h， 以51%的产率得到6-hydroxy-3'-{4-[(3-methoxyphenyl)amino]-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl}biphenyl-3-carboxylic acid
  参考文献：
  名称：

  New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors

  摘要：

  揭示了具有化学结构式（I）的新的7,8-二氢-1,6-萘啶-5(6H)-酮衍生物衍生物；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：

  EP2380890A1
• 作为产物：
  描述：

  tert-butyl 3-[bis(methylthio)methylene]-2,4-dioxopiperidine-1-carboxylate 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium tert-butylate 、 ammonium acetate 、 caesium carbonate 、 溶剂黄146 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 19.5h， 生成 methyl 6-hydroxy-3'-{4-[(3-methoxyphenyl)amino]-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl}biphenyl-3-carboxylate
  参考文献：
  名称：

  4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships

  摘要：

  Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

  DOI：

  10.1021/acs.jmedchem.7b01751

文献信息

• New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors
  申请人：Almirall, S.A.

  公开号：EP2380890A1

  公开（公告）日：2011-10-26

  New 7,8-dihydro-1,6-naphthyridin-5(6H)-one derivatives derivatives having the chemical 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）的新的7,8-二氢-1,6-萘啶-5(6H)-酮衍生物衍生物；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。
• 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6<i>H</i>)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships
  作者：Richard S. Roberts、Sara Sevilla、Manel Ferrer、Joan Taltavull、Begoña Hernández、Victor Segarra、Jordi Gràcia、Martin D. Lehner、Amadeu Gavaldà、Miriam Andrés、Judit Cabedo、Dolors Vilella、Peter Eichhorn、Elena Calama、Carla Carcasona、Montserrat Miralpeix

  DOI：10.1021/acs.jmedchem.7b01751

  日期：2018.3.22

  Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.