(+/-)-[3,4-bis(difluoromethoxy)phenyl]-(2-bromopyridin-5-yl)methanol | 303165-20-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (+/-)-[3,4-bis(difluoromethoxy)phenyl]-(2-bromopyridin-5-yl)methanol
• 英文别名: [3,4-Bis(difluoromethoxy)phenyl]-(6-bromo-pyridin-3-yl)methanol；[3,4-Bis(difluoromethoxy)phenyl]-(6-bromo-3-pyridyl)methanol；[3,4-bis(difluoromethoxy)phenyl]-(6-bromopyridin-3-yl)methanol
• CAS: 303165-20-0
• 化学式: C₁₄H₁₀BrF₄NO₃
• 分子量: 396.136
• InChiKey: UTAUAGAGGSNWOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  51.6
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (+/-)-[3,4-bis(difluoromethoxy)phenyl]-(2-bromopyridin-5-yl)methanol 在 lithium hydroxide 、 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 、 二氯甲烷 为溶剂， 反应 19.08h， 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
• 作为产物：
  描述：

  2,5-二溴吡啶 、 3,4-双(二氟甲氧基)苯甲醛 在 正丁基锂 作用下， 以 乙醚 、 正己烷 为溶剂， 反应 2.75h， 以70%的产率得到(+/-)-[3,4-bis(difluoromethoxy)phenyl]-(2-bromopyridin-5-yl)methanol
  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

• Heterosubstituted pyridine derivatives as PDE 4 inhibitors
  申请人：Merck Frosst Canada & Co.

  公开号：US06316472B1

  公开（公告）日：2001-11-13

  The invention encompasses the novel compound of Formula I useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3′,5′-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4). The invention also encompasses pharmaceutical compositions and methods for treatment.

  本发明涵盖了公式I的新化合物，该化合物通过抑制磷酸二酯酶IV（PDE 4）提高环磷酸腺苷-3′，5′-单磷酸（cAMP）的水平，用于治疗包括哮喘在内的疾病。本发明还涵盖了制药组合物和治疗方法。
• Heterosubstituted pyridine derivatives as PDE4 inhibitors
  申请人：Merck Frosst Canada & Co.

  公开号：US06200993B1

  公开（公告）日：2001-03-13

  The invention encompasses the novel compound of Formula I useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3′,5′-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4). or a pharmaceutically acceptable salt or hydrate thereof. The invention also encompasses pharmaceutical compositions and methods for treatment.

  本发明涵盖了公式I的新化合物，其通过抑制磷酸二酯酶IV（PDE 4）提高环状腺苷酸-3'，5'-单磷酸（cAMP）水平，用于治疗包括哮喘在内的疾病，或其药物可接受的盐或水合物。本发明还涵盖了药物组合物和治疗方法。
• US6180650
  申请人：——

  公开号：——

  公开（公告）日：——
• Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors
  作者：Bernard Côté、Richard Frenette、Sylvie Prescott、Marc Blouin、Christine Brideau、Yves Ducharme、Richard W. Friesen、France Laliberté、Paul Masson、Angela Styhler、Yves Girard

  DOI：10.1016/s0960-894x(02)01030-2

  日期：2003.2

  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.
• US06180650B2
  申请人：——

  公开号：——

  公开（公告）日：——