(E)-(R)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (R)-(2-oxoazepan-3-yl)amide | 583028-47-1

• 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)-(R)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (R)-(2-oxoazepan-3-yl)amide
• 英文别名: (E,4R)-5-(3,4-dichlorophenyl)-4-(methylamino)-N-[(3R)-2-oxoazepan-3-yl]pent-2-enamide
• CAS: 583028-47-1
• 化学式: C₁₈H₂₃Cl₂N₃O₂
• 分子量: 384.306
• InChiKey: DJSJWZIKBHZZBW-HDZMBNNRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  70.2
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-(R)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (R)-(2-oxoazepan-3-yl)amide 在 碳酸氢钠 、 锌 、 hydrazinium monoformate 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 2.0h， 生成 N-[(E,2R)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3R)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-3,5-diisothiocyanato-N-methylbenzamide
  参考文献：
  名称：

  Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes

  摘要：

  N-[(R, R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3, 5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK,/NKz receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK,/NK2 receptor antagonist activities (pK(b) = 8.4 for the NK1 receptors, pK(b) = 7.87 for the NK2 receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NKI and NK2 receptor antagonist activities. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.11.064
• 作为产物：
  描述：

  [(E)-(R)-1-(3,4-dichlorobenzyl)-3-((R)-2-oxoazepan-3-ylcarbamoyl)allyl]methylcarbamic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 (E)-(R)-5-(3,4-dichlorophenyl)-4-methylaminopent-2-enoic acid (R)-(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

文献信息

• Organic Compounds
  申请人：PORTMANN Robert

  公开号：US20110282053A1

  公开（公告）日：2011-11-17

  A process for preparing compounds of formula I or a solvate or hydrate thereof, where R, R 1 , R 2 , R 3 and R 5 have the meanings as indicated in the specification. Such compounds are useful in the treatment of a number of conditions associated with substance P and neurokinin.

  一种制备式I化合物或其溶剂化物或水合物的方法，其中R、R1、R2、R3和R5的含义如规范中所示。这些化合物在治疗与P物质和神经激肽相关的多种疾病方面具有用途。
• WO2007/118651
  申请人：——

  公开号：——

  公开（公告）日：——
• US8008479B2
  申请人：——

  公开号：US8008479B2

  公开（公告）日：2011-08-30
• Stereoselective Preparation of <i>N</i>-[(<i>R,R</i>)-(<i>E</i>)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-<i>N</i>-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist
  作者：Marc Gerspacher、Christine Lewis、Howard A. Ball、Colin Howes、Natarajan Subramanian、Karin Ryffel、John R. Fozard

  DOI：10.1021/jm030786m

  日期：2003.7.1

  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.
• Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes
  作者：Venkat Manoj Swarna、Bradley J. Undem、Vijaya L. Korlipara

  DOI：10.1016/j.bmcl.2006.11.064

  日期：2007.2

  N-[(R, R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3, 5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK,/NKz receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK,/NK2 receptor antagonist activities (pK(b) = 8.4 for the NK1 receptors, pK(b) = 7.87 for the NK2 receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NKI and NK2 receptor antagonist activities. (c) 2006 Elsevier Ltd. All rights reserved.