(3,4-Bis-difluoromethoxy-phenyl)-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-methanol | 192767-12-7

• 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: (3,4-Bis-difluoromethoxy-phenyl)-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-methanol
• 英文别名: [3,4-Bis(difluoromethoxy)phenyl]-[4-[1,1,1,3,3,3-hexafluoro-2-(2-trimethylsilylethoxymethoxy)propan-2-yl]phenyl]methanol；[3,4-bis(difluoromethoxy)phenyl]-[4-[1,1,1,3,3,3-hexafluoro-2-(2-trimethylsilylethoxymethoxy)propan-2-yl]phenyl]methanol
• CAS: 192767-12-7
• 化学式: C₂₄H₂₆F₁₀O₅Si
• 分子量: 612.537
• InChiKey: FZADKOJZSBUTME-UHFFFAOYSA-N

物化性质

• 沸点：
  499.8±45.0 °C(Predicted)
• 密度：
  1.308±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.62
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  57.2
• 氢给体数：
  1
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  (3,4-Bis-difluoromethoxy-phenyl)-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-methanol 在 吡啶 、 氯化亚砜 作用下， 以 甲苯 为溶剂， 反应 0.5h， 生成 2-[[2-[4-[[3,4-Bis(difluoromethoxy)phenyl]-chloromethyl]phenyl]-1,1,1,3,3,3-hexafluoropropan-2-yl]oxymethoxy]ethyl-trimethylsilane
  参考文献：
  名称：

  Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

  摘要：

  A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00615-7
• 作为产物：
  描述：

  4-二氟甲氧基-3-羟基苯甲醛 在 caesium carbonate 、 magnesium 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3,4-Bis-difluoromethoxy-phenyl)-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-methanol
  参考文献：
  名称：

  Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

  摘要：

  A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00349-9

文献信息

• Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor
  作者：Daniel Guay、Pierre Hamel、Marc Blouin、Christine Brideau、Chi Chung Chan、Nathalie Chauret、Yves Ducharme、Zheng Huang、Mario Girard、Tom R. Jones、France Laliberté、Paul Masson、Malia McAuliffe、Hanna Piechuta、José Silva、Robert N. Young、Yves Girard

  DOI：10.1016/s0960-894x(02)00190-7

  日期：2002.6

  Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (1 In) as a potent (HWB TNF-alpha = 0.67 muM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey. (C) 2002 Elsevier Science Ltd. All rights reserved.