N,O-bis(phenoxycarbonyl)-N-<4-<5-(4-fluorophenoxy)-2-furyl>-3-butyn-2-yl>hydroxylamine | 141598-93-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N,O-bis(phenoxycarbonyl)-N-<4-<5-(4-fluorophenoxy)-2-furyl>-3-butyn-2-yl>hydroxylamine
• 英文别名: N,O-Bis(carbophenoxy)-N-{4-[5-(4-fluorophenoxy)-2-furyl]-3-butyn-2-yl}hydroxylamine；[4-[5-(4-Fluorophenoxy)furan-2-yl]but-3-yn-2-yl-phenoxycarbonylamino] phenyl carbonate
• CAS: 141598-93-8
• 化学式: C₂₈H₂₀FNO₇
• 分子量: 501.468
• InChiKey: YEIUANBCSBSPAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  87.4
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N,O-bis(phenoxycarbonyl)-N-<4-<5-(4-fluorophenoxy)-2-furyl>-3-butyn-2-yl>hydroxylamine 在 氨 作用下， 以57%的产率得到1-[4-[5-(4-氟苯氧基)呋喃-2-基]丁-3-炔-2-基]-1-羟基脲
  参考文献：
  名称：

  Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

  摘要：

  Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connnecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)2-furyl]-1-methyl-2-propynyl]-N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.

  DOI：

  10.1021/jm00024a004
• 作为产物：
  描述：

  5-硝基糠醛 在 正丁基锂 、 偶氮二甲酸二异丙酯 、 sodium hydride 、 三苯基膦 、 锌 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 4.0h， 生成 N,O-bis(phenoxycarbonyl)-N-<4-<5-(4-fluorophenoxy)-2-furyl>-3-butyn-2-yl>hydroxylamine
  参考文献：
  名称：

  Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

  摘要：

  Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connnecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)2-furyl]-1-methyl-2-propynyl]-N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.

  DOI：

  10.1021/jm00024a004

文献信息

• J. Med. Chem. 1995, 38, 4768-4775
  作者：

  DOI：——

  日期：——
• ACETYLENE DERIVATIVES HAVING LIPOXYGENASE INHIBITORY ACTIVITY
  申请人：ABBOTT LABORATORIES

  公开号：EP0540673B1

  公开（公告）日：1996-10-16
• US5476873A
  申请人：——

  公开号：US5476873A

  公开（公告）日：1995-12-19
• US5516789A
  申请人：——

  公开号：US5516789A

  公开（公告）日：1996-05-14
• US5559144A
  申请人：——

  公开号：US5559144A

  公开（公告）日：1996-09-24