2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexyl)-5-fluoronicotinamide | 1197291-07-8

• 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: 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexyl)-5-fluoronicotinamide
• CAS: 1197291-07-8
• 化学式: C₃₀H₃₅FN₄O₄
• 分子量: 534.631
• InChiKey: XRHJDRFAPOTHSX-PSWAGMNNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.61
• 重原子数：
  39.0
• 可旋转键数：
  7.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  109.94
• 氢给体数：
  3.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  1,5-二甲基-1H-吡唑-3-羧酸 、 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexyl)-5-fluoronicotinamide 、 三氟乙酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 乙腈 为溶剂， 反应 0.17h， 以63%的产率得到2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-5-fluoronicotinamide trifluoroacetic acid salt
  参考文献：
  名称：

  Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD

  摘要：

  Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

  DOI：

  10.1021/jm5001216
• 作为产物：
  描述：

  tert-butyl N-[(1s,4s)-4-(2-chloro-5-fluoronicotinamido)cyclohexyl]carbamate 在 2-双环己基膦-2',6'-二甲氧基联苯 、 1,1'-双(二苯基膦)二茂铁 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 sodium sulfate 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 72.5h， 生成 2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-N-((1s,4s)-4-aminocyclohexyl)-5-fluoronicotinamide
  参考文献：
  名称：

  Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD

  摘要：

  Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

  DOI：

  10.1021/jm5001216