6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-naphthyridine | 207279-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-naphthyridine
• 英文别名: 6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-napthyridine；Trifluoro-methanesulfonic acid 8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl ester；[8-(3-cyanophenyl)-1,7-naphthyridin-6-yl] trifluoromethanesulfonate
• CAS: 207279-19-4
• 化学式: C₁₆H₈F₃N₃O₃S
• 分子量: 379.319
• InChiKey: CWZPJPLVHJFENV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ethyl 4-iodocyclohexanecarboxylate 、 6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-naphthyridine 在 三甲基氯硅烷 、 1,2-二溴乙烷 、 锌 、 1,1'-双(二苯基膦)二茂铁 、 四丁基碘化铵 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 为溶剂， 反应 1.5h， 生成 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester
  参考文献：
  名称：

  Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

  摘要：

  The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

  DOI：

  10.1021/jm300459a
• 作为产物：
  描述：

  3-吡啶乙腈 在 氢溴酸 、 双氧水 、 溶剂黄146 、 二甲氨基甲酰氯 、 sodium nitrite 作用下， 以 甲苯 为溶剂， 反应 4.5h， 生成 6-trifluoromethylsulfonyloxy-8-(3-cyanophenyl)-1,7-naphthyridine
  参考文献：
  名称：

  Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

  摘要：

  The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

  DOI：

  10.1021/jm300459a

文献信息

• Naphthyridine derivatives
  申请人：Novartis AG

  公开号：US06136821A1

  公开（公告）日：2000-10-24

  Novel 8-aryl-1,7-naphthyridines, in free or salt form, are PDE IV inhibitors and are thus useful as pharmaceuticals, e.g. for asthma therapy. Preferred compounds include compounds of formulae (I and II) wherein the R groups are as defined. Pharmaceutical compositions comprising the compounds, processes for preparation of the compounds and novel intermediates for use in the processes are disclosed.

  8-芳基-1,7-萘啶类的小说，以自由形式或盐形式存在，是PDE IV抑制剂，因此可用于制药，例如用于哮喘治疗。首选化合物包括式（I和II）中的R基团定义的化合物。揭示了包含该化合物的制药组合物，制备该化合物的过程以及用于该过程的新型中间体。
• Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines:  A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors
  作者：Rene Hersperger、Katharine Bray-French、Lazzaro Mazzoni、Thomas Müller

  DOI：10.1021/jm991094u

  日期：2000.2.1

  Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein; we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC50 values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D T-Vith an IC50 value of 1 nM. Thus, compound II was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, sind PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1.,7-naphthyridine class have the potential as an oral therapy for treating asthma.
• US6136821A
  申请人：——

  公开号：US6136821A

  公开（公告）日：2000-10-24