(3-cyclopropyloxy-4-difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy) methoxy)propane-2-yl]5-pyridyl}chloromethane | 290307-36-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (3-cyclopropyloxy-4-difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy) methoxy)propane-2-yl]5-pyridyl}chloromethane
• 英文别名: (3-Cyclopropyloxy-4-difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy)methoxy)propane-2-yl] 5-pyridyl}chloromethane；2-[2-[5-[chloro-[3-cyclopropyloxy-4-(difluoromethoxy)phenyl]methyl]pyridin-2-yl]propan-2-yloxymethoxy]ethyl-trimethylsilane
• CAS: 290307-36-7
• 化学式: C₂₅H₃₄ClF₂NO₄Si
• 分子量: 514.085
• InChiKey: CLMGYJGEQDMDFD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.12
• 重原子数：
  34
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3-cyclopropyloxy-4-difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy) methoxy)propane-2-yl]5-pyridyl}chloromethane 在 lithium hydroxide 、 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 、 二甲基亚砜 、 甲苯 为溶剂， 反应 22.0h， 生成 (+/-) 3-{2-(3-cyclopropyloxy-4-difluoromethoxyphenyl)-2-[2-(2-hydroxypropan-2-yl)5-pyridyl]ethyl}pyridine-N-oxide
  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：

  5-bromo-2-{1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}pyridine 在 吡啶 、 正丁基锂 、 氯化亚砜 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 反应 1.5h， 生成 (3-cyclopropyloxy-4-difluoromethoxyphenyl)-{2-[2-((2-trimethylsilylethoxy) methoxy)propane-2-yl]5-pyridyl}chloromethane
  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

• [EN] DI-ARYL-SUBSTITUTED-ETHANE PYRIDONE PDE4 INHIBITORS<br/>[FR] ETHANE PYRIDONE A SUBSTITUTION DIARYLE, INHIBITEURS D'ENZYME PDE4
  申请人：MERCK FROSST CANADA INC

  公开号：WO2004005258A1

  公开（公告）日：2004-01-15

  Di-aryl substituted ethane pyridones, particularly ethane pyridones substituted with i) a phenyl, ii) a pyridyl, iii) a thiazole, iv) a pyrimidinyl, v) a pyridazinyl, vi) a furyl, vii) a thienyl, viii) an oxazolyl, ix) an isoxazolyl, or x) an isothiazolyl moiety are phosphodiesterase-4 inhibitors useful in the treatment or prevention of asthma; chronic bronchitis; chronic obstructive pulmonary disease; adult respiratory distress syndrome; infant respiratory distress syndrome; cough; chronic obstructive pulmonary disease in animals; adult respiratory distress syndrome; ulcerative colitis; Crohn's disease; hypersecretion of gastric acid; bacterial, fungal or viral induced sepsis or septic shock; endotoxic shock; laminitis or colic in horses; spinal cord trauma; head injury; neurogenic inflammation; pain; reperfusion injury of the brain; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; osteoarthritis; inflammation; or cytokine-mediated chronic tissue degeneration. Formula (I) wherein X is phenyl, pyridinyl, thiazolyl, pyrimidinyl, pyridazinyl, furyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl.

  二芳基取代的乙烷吡啶酮，特别是取代有i) 苯基、ii) 吡啶基、iii) 噻唑基、iv) 嘧啶基、v) 吡啉基、vi) 呋喃基、vii) 噻吩基、viii) 噁唑基、ix) 异噁唑基或x) 异硫唑基基团的乙烷吡啶酮是磷酸二酯酶-4抑制剂，可用于治疗或预防哮喘；慢性支气管炎；慢性阻塞性肺疾病；成人呼吸窘迫综合征；婴儿呼吸窘迫综合征；咳嗽；动物慢性阻塞性肺疾病；成人呼吸窘迫综合征；溃疡性结肠炎；克罗恩病；胃酸过多；细菌、真菌或病毒引起的败血症或感染性休克；内毒素性休克；马的蹄受损或腹痛；脊髓创伤；头部受伤；神经源性炎症；疼痛；脑再灌注损伤；银屑病性关节炎；类风湿关节炎；强直性脊柱炎；骨关节炎；炎症；或细胞因子介导的慢性组织退化。式(I)中X为苯基、吡啶基、噻唑基、嘧啶基、吡啉基、呋喃基、噻吩基、噁唑基、异噁唑基或异硫唑基。
• Di-aryl-substituted-ethan pyridone pde4 inhibitors
  申请人：Cote Bernard

  公开号：US20060004056A1

  公开（公告）日：2006-01-05

  Di-aryl substituted ethane pyridones, particularly ethane pyridones substituted with i) a phenyl, ii) a pyridyl, iii) a thiazole, iv) a pyrimidinyl, v) a pyridazinyl, vi) a furyl, vii) a thienyl, viii) an oxazolyl, ix) an isoxazolyl, or x) an isothiazolyl moiety are phosphodiesterase-4 inhibitors useful in the treatment or prevention of asthma; chronic bronchitis; chronic obstructive pulmonary disease; adult respiratory distress syndrome; infant respiratory distress syndrome; cough; chronic obstructive pulmonary disease in animals; adult respiratory distress syndrome; ulcerative colitis; Crohn's disease; hypersecretion of gastric acid; bacterial, fungal or viral induced sepsis or septic shock; endotoxic shock; laminitis or colic in horses; spinal cord trauma; head injury; neurogenic inflammation; pain; reperfusion injury of the brain; psoriatic arthritis; rheumatoid arthritis; ankylosing spondylitis; osteoarthritis; inflammation; or cytokine-mediated chronic tissue degeneration.

  二芳基取代乙烯吡啶酮，特别是乙烯吡啶酮取代i）苯基，ii）吡啶基，iii）噻唑基，iv）嘧啶基，v）吡嗪基，vi）呋喃基，vii）噻吩基，viii）噁唑基，ix）异噁唑基，或x）异硫氰酰基基团是磷酸二酯酶-4抑制剂，可用于治疗或预防哮喘；慢性支气管炎；慢性阻塞性肺疾病；成人呼吸窘迫综合征；婴儿呼吸窘迫综合征；咳嗽；动物慢性阻塞性肺疾病；成人呼吸窘迫综合征；溃疡性结肠炎；克罗恩病；胃酸过多；细菌、真菌或病毒引起的败血症或感染性休克；内毒素性休克；马蹄褥疮或腹绞痛；脊髓创伤；头部损伤；神经源性炎症；疼痛；脑再灌注损伤；银屑病性关节炎；类风湿性关节炎；强直性脊柱炎；骨关节炎；炎症或细胞因子介导的慢性组织退化。
• 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.