(E)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (S)-(2-oxoazepan-3-yl)amide | 372988-88-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (E)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (S)-(2-oxoazepan-3-yl)amide
• CAS: 372988-88-0
• 化学式: C₁₈H₂₃Cl₂N₃O₂
• 分子量: 384.306
• InChiKey: DJSJWZIKBHZZBW-WWMDUWORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.47
• 重原子数：
  25.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  70.23
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  3,5-双三氟甲基苯甲酰氯 、 (E)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (S)-(2-oxoazepan-3-yl)amide 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 N-[(E,2S)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3S)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide 、 N-[(E,2R)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3S)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide
  参考文献：
  名称：

  Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist

  摘要：

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.

  DOI：

  10.1021/jm030786m
• 作为产物：
  描述：

  2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester 在 盐酸 、 4-二甲氨基吡啶 、 正丁基锂 、 二异丁基氢化铝 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 27.33h， 生成 (E)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (S)-(2-oxoazepan-3-yl)amide
  参考文献：
  名称：

  Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist

  摘要：

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.

  DOI：

  10.1021/jm030786m