methyl (3R,4R,5R)-3,4-(acetylepimino)-5-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate | 1234466-30-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吖庚因类
• 英文名称: methyl (3R,4R,5R)-3,4-(acetylepimino)-5-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate
• 英文别名: methyl (1R,5R,6R)-7-acetyl-5-pentan-3-yloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate
• CAS: 1234466-30-8
• 化学式: C₁₅H₂₃NO₄
• 分子量: 281.352
• InChiKey: NKJIUBCETDHTRO-QFBZGTDSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl (3R,4R,5R)-3,4-(acetylepimino)-5-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate 在 sodium azide 、 氯化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以68%的产率得到methyl (3S,4R,5R)-4-acetamido-3-azido-5-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate
  参考文献：
  名称：

  Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles

  摘要：

  We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (NI) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 x 10(-9) and 4.6 x 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 mu M vs 0.07 mu M) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.

  DOI：

  10.1021/jm100822f
• 作为产物：
  描述：

  methyl (1R,5R,6R)-5-pentan-3-yloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate 、 乙酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以75%的产率得到methyl (3R,4R,5R)-3,4-(acetylepimino)-5-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate
  参考文献：
  名称：

  [EN] COMPOUNDS AND METHODS FOR TREATMENT OF INFLUENZA
  [FR] COMPOSÉS ET MÉTHODES POUR LE TRAITEMENT DU VIRUS INFLUENZA

  摘要：

  本发明部分提供了一种化合物，其化学式为（I）或其药用盐或立体异构体：其中R1选自以下组：取代三唑基团、胍基团、脲基团、硫脲基团、酰胺基团和N3；R2选自以下组：H、Me、Et和氨基酸，以及其方法和用途。

  公开号：

  WO2010075636A1

文献信息

• [EN] COMPOUNDS AND METHODS FOR TREATMENT OF INFLUENZA<br/>[FR] COMPOSÉS ET MÉTHODES POUR LE TRAITEMENT DU VIRUS INFLUENZA
  申请人：UNIV FRASER SIMON

  公开号：WO2010075636A1

  公开（公告）日：2010-07-08

  The present invention provides in part a compound of Formula (I) or a pharmaceutically- acceptable salt or stereoisomer thereof: where R1 is selected from the group consisting of a substituted triazole group, a guanidine group, a urea group, a thiourea group, an amidine group, and N3; and R2 is selected from the group consisting of H, Me, Et and an amino acid, and methods and uses thereof.

  本发明部分提供了一种化合物，其化学式为（I）或其药用盐或立体异构体：其中R1选自以下组：取代三唑基团、胍基团、脲基团、硫脲基团、酰胺基团和N3；R2选自以下组：H、Me、Et和氨基酸，以及其方法和用途。
• Serendipitous Discovery of a Potent Influenza Virus A Neuraminidase Inhibitor
  作者：Sankar Mohan、Philip S. Kerry、Nicole Bance、Masahiro Niikura、B. Mario Pinto

  DOI：10.1002/anie.201308142

  日期：2014.1.20

  We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3‐pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki=0.46 nM; Ki (zanamivir)=0.16 nM) and in the viral replication inhibition assay

  我们以前曾报道过一种有效的神经氨酸酶抑制剂，该抑制剂包含扎那米韦的碳环类似物，其中亲水性甘油侧链被奥司他韦的疏水3-戊氧基取代。这种杂合抑制剂在神经氨酸酶抑制试验（K i = 0.46 n M ; K i（zanamivir） = 0.16 n M）和在10 -8  M的细胞培养中的病毒复制抑制试验中显示出优异的抑制性能。作为该前导优化的一部分，我们现在报告一种新的螺内酰胺，在细胞培养试验中，该螺内酰胺在10 -7  M时的抑制活性与我们的前导化合物相当。在尝试合成原始候选化合物的异硫脲衍生物期间偶然发现了该化合物。螺内酰胺的X射线晶体结构与N8亚型神经氨酸酶复合可提供抑制模式的见解。
• Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles
  作者：Sankar Mohan、Sarah McAtamney、Thomas Haselhorst、Mark von Itzstein、Brian Mario Pinto

  DOI：10.1021/jm100822f

  日期：2010.10.28

  We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (NI) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 x 10(-9) and 4.6 x 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 mu M vs 0.07 mu M) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.