4-<5-<(4-fluorophenyl)methyl>-2-thienyl>-3-butyn-2-ol | 173095-30-2

• 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: 4-<5-<(4-fluorophenyl)methyl>-2-thienyl>-3-butyn-2-ol
• 英文别名: 4-[5-(4-Fluorophenylmethyl)-2-thienyl]-3-butyn-2-ol；4-[5-[(4-fluorophenyl)methyl]thiophen-2-yl]but-3-yn-2-ol
• CAS: 173095-30-2
• 化学式: C₁₅H₁₃FOS
• 分子量: 260.332
• InChiKey: QBVRHSKZOZYWLO-UHFFFAOYSA-N

物化性质

• 沸点：
  395.3±42.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  48.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-<5-<(4-fluorophenyl)methyl>-2-thienyl>-3-butyn-2-ol 在 ammonium hydroxide 、 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 N-{3-[5-(4-fluorophenylmethyl)-thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea
  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：

  2-(4-氟苄基)噻吩 在 哌啶 、 N-溴代丁二酰亚胺(NBS) 、 copper(l) iodide 、 四(三苯基膦)钯 、 溶剂黄146 、 三苯基膦 作用下， 以 氯仿 为溶剂， 反应 2.0h， 生成 4-<5-<(4-fluorophenyl)methyl>-2-thienyl>-3-butyn-2-ol
  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

• Substituted arylalkynyl-and heteroarylalkynl-N-hydroxyurea inhibitors of
  申请人：Abbott Laboratories

  公开号：US05616596A1

  公开（公告）日：1997-04-01

  The invention relates to compounds having activity to inhibit lipoxygenase enzyme activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treating. More particularly, this invention concerns certain substituted arylalkynyl- and ((heteroaryl)alkynyl)-N-hydroxy-ureas which inhibit leukotriene biosynthesis, to pharmaceutical compositions of these compounds and to a method of inhibiting leukotriene biosynthesis.

  本发明涉及具有抑制脂肪氧化酶酶活性的活性化合物，包括这些化合物的制药组合物，以及治疗的医疗方法。更具体地说，本发明涉及某些取代芳基炔基和((杂环)炔基)-N-羟基脲，这些化合物抑制白三烯生物合成，以及这些化合物的制药组合物和抑制白三烯生物合成的方法。
• SUBSTITUTED ARYLALKYNYL- AND HETEROARYLALKYNYL-N-HYDROXYUREA INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS
  申请人：ABBOTT LABORATORIES

  公开号：EP0667855A1

  公开（公告）日：1995-08-23
• EP0667855A4
  申请人：——

  公开号：EP0667855A4

  公开（公告）日：1996-02-21
• US5616596A
  申请人：——

  公开号：US5616596A

  公开（公告）日：1997-04-01
• [EN] SUBSTITUTED ARYLALKYNYL- AND HETEROARYLALKYNYL-N-HYDROXYUREA INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS<br/>[FR] ARYLALKANYL-N-HYDROXYUREES ET HETEROALKYLALKANYL-N-HYDROXYUREES SUBSTITUEES POUVANT INHIBER LA BIOSYNTHESE DE LEUCOTRIENES
  申请人：ABBOTT LABORATORIES

  公开号：WO1994011342A1

  公开（公告）日：1994-05-26

  (EN) The invention relates to compounds having activity to inhibit lipoxygenase enzyme activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treating. More particularly, this invention concerns certain substituted arylalkynyl- and ((heteroaryl)alkynyl)-N-hydroxy-ureas which inhibit leukotriene biosynthesis, to pharmaceutical compositions of these compounds and to a method of inhibiting leukotriene biosynthesis.(FR) L'invention concerne des composés pouvant inhiber l'activité de l'enzyme lipoxygénase, des compositions pharmaceutiques contenant ces composés, et un procédé de traitement médical associé. Plus particulièrement, cette invention concerne certaines arylalkanyl-N-hydroxyurées et((hétéroaryl)alkynyl)-N-hydroxyurées substituées qui inhibent la biosynthèse de leucotriènes, des compositions pharmaceutiques contenant ces composés, et un procédé d'inhibition de la biosynthèse de leucotriènes.