(+/-)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-bromo)pyridyl]ethyl}pyridine | 303165-22-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (+/-)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-bromo)pyridyl]ethyl}pyridine
• 英文别名: 4-[2-[3,4-Bis(difluoromethoxy)phenyl]-2-(6-bromo-3-pyridyl)ethyl]pyridine；5-[1-[3,4-bis(difluoromethoxy)phenyl]-2-pyridin-4-ylethyl]-2-bromopyridine
• CAS: 303165-22-2
• 化学式: C₂₀H₁₅BrF₄N₂O₂
• 分子量: 471.249
• InChiKey: DLBYYAVBMDFKID-UHFFFAOYSA-N

物化性质

• 沸点：
  498.6±45.0 °C(Predicted)
• 密度：
  1.472±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  44.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (+/-)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-bromo)pyridyl]ethyl}pyridine 在 MMPP 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 以93%的产率得到5-[1-[3,4-Bis(difluoromethoxy)phenyl]-2-(1-oxidopyridin-1-ium-4-yl)ethyl]-2-bromopyridine
  参考文献：
  名称：

  Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors

  摘要：

  The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue, The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 muM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2) = 2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%. early,,late, 0.5 mg/kg. iv). (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01030-2
• 作为产物：
  描述：

  3,4-双(二氟甲氧基)苯甲醛 在 lithium hydroxide 、 正丁基锂 、 氯化亚砜 、 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲醇 、 六甲基磷酰三胺 、 乙醚 、 正己烷 、 二氯甲烷 为溶剂， 反应 21.83h， 生成 (+/-)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-bromo)pyridyl]ethyl}pyridine
  参考文献：
  名称：

  Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors:  Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity

  摘要：

  A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.

  DOI：

  10.1021/jm0204542

文献信息

• Substituted 2-Pyridinemethanol derivatives as potent and selective phosphodiesterase-4 inhibitors
  作者：Yves Ducharme、Richard W Friesen、Marc Blouin、Bernard Côté、Daniel Dubé、Diane Ethier、Richard Frenette、France Laliberté、Joseph A Mancini、Paul Masson、Angela Styhler、Robert N Young、Yves Girard

  DOI：10.1016/s0960-894x(03)00314-7

  日期：2003.6

  synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.

  描述了2-吡啶甲醇衍生物的合成和磷酸二酯酶-4（PDE4）抑制活性。对这一系列新型PDE4抑制剂的构效关系（SAR）的评估导致了化合物9的鉴定，该化合物在支气管收缩动物模型中表现出优异的体外活性，理想的药代动力学参数和良好的功效。
• US6180650B1
  申请人：——

  公开号：US6180650B1

  公开（公告）日：2001-01-30
• US6200993B1
  申请人：——

  公开号：US6200993B1

  公开（公告）日：2001-03-13
• US6316472B1
  申请人：——

  公开号：US6316472B1

  公开（公告）日：2001-11-13
• Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors:  Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity
  作者：Richard W. Friesen、Yves Ducharme、Richard G. Ball、Marc Blouin、Louise Boulet、Bernard Côté、Richard Frenette、Mario Girard、Daniel Guay、Zheng Huang、Thomas R. Jones、France Laliberté、Joseph J. Lynch、Joseph Mancini、Evelyn Martins、Paul Masson、Eric Muise、Douglas J. Pon、Peter K. S. Siegl、Angela Styhler、Nancy N. Tsou、Mervyn J. Turner、Robert N. Young、Yves Girard

  DOI：10.1021/jm0204542

  日期：2003.6.1

  A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.