(R)-N-(3-butyn-2-yl)-N-hydroxyurea | 154355-92-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物
• 英文名称: (R)-N-(3-butyn-2-yl)-N-hydroxyurea
• 英文别名: (R)-1-(but-3-yn-2-yl)-1-hydroxyurea；(R)-(+)-N-hydroxy-N-(3-butyn-2-yl)urea；(R)-N-hydroxy-N-(3-butyn-2-yl)urea；1-[(2R)-but-3-yn-2-yl]-1-hydroxyurea
• CAS: 154355-92-7
• 化学式: C₅H₈N₂O₂
• 分子量: 128.131
• InChiKey: IVSHIKQOYOZOFK-SCSAIBSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  9
• 可旋转键数：
  1
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  66.6
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-[(4-氟苯基)甲基]-5-碘噻吩 、 (R)-N-(3-butyn-2-yl)-N-hydroxyurea 在 双(乙腈)氯化钯(II) 、 copper(l) iodide 、 二乙胺 、 三苯基膦 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 以18%的产率得到1-[(2R)-4-[5-[(4-氟苯基)甲基]噻吩-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：

  [phenoxycarbonyl-[(2R)-4-trimethylsilylbut-3-yn-2-yl]amino] phenyl carbonate 在 ammonium hydroxide 作用下， 以 甲醇 为溶剂， 反应 48.0h， 生成 (R)-N-(3-butyn-2-yl)-N-hydroxyurea
  参考文献：
  名称：

  Synthesis of A-79175: a second generation 5-lipoxygenase inhibitor

  摘要：

  A convergent, high yielding, and scalable synthesis of A-79175, with a key step involving a mild and efficient Cu-Pd catalyzed coupling reaction of a terminal acetylene with a substituted 2-iodofuran is discussed. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0957-4166(97)00159-6

文献信息

• Asymmetric synthesis of (R)-N-3-butyn-2-yl-N-hydroxyurea, a key intermediate for 5-lipoxygenase inhibitors
  作者：Teodozyj Kolasa、Andrew O. Stewart、Clint D.W. Brooks

  DOI：10.1016/0957-4166(96)00068-7

  日期：1996.3

  An efficient asymmetric synthesis of (R)-N-3-butyn-2-yl-N-hydroxyurea from crotyl alcohol is described. The process involves asymmetric Sharpless epoxidation to establish the stereochemistry, formation of (S)-3-butynol and hydroxyl substitution with inversion by the masked N-hydroxyurea reagent N,O-bis(phenoxycarbonyl)hydroxylamine in a Mitsunobu reaction.

  描述了从巴豆醇有效地不对称合成（R）-N -3-丁炔-2-基-N-羟基脲。该方法涉及不对称的Sharpless环氧化，以建立立体化学，形成（S）-3-丁炔醇，并通过Mitsunobu反应中被掩蔽的N-羟基脲试剂N，O-双（苯氧基羰基）羟胺转化而进行羟基取代。
• Design, Synthesis, and Structure–Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase
  作者：Kerstin Hiesinger、Jan S. Kramer、Sandra Beyer、Timon Eckes、Steffen Brunst、Cathrin Flauaus、Sandra K. Wittmann、Lilia Weizel、Astrid Kaiser、Simon B. M. Kretschmer、Sven George、Carlo Angioni、Jan Heering、Gerd Geisslinger、Manfred Schubert-Zsilavecz、Achim Schmidtko、Denys Pogoryelov、Josef Pfeilschifter、Bettina Hofmann、Dieter Steinhilber、Stephanie Schwalm、Ewgenij Proschak

  DOI：10.1021/acs.jmedchem.0c00561

  日期：2020.10.22

  Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity

  花生四烯酸级联的多种酶的抑制导致协同的抗炎作用。5-脂氧合酶（5-LOX）和可溶性环氧化物水解酶（sEH）药效团的合并导致发现了双重5-LOX / sEH抑制剂，随后针对靶标和代谢稳定性进行了优化。优化的铅结构在人多形核白细胞中显示出细胞活性，口服生物利用度以及体内靶标结合，并且在小鼠单侧输尿管阻塞引起的肾脏损伤模型中显示出深远的抗炎和抗纤维化功效。这些结果为研究5-LOX / sEH双重抑制剂在其他炎症和纤维化相关疾病模型中的治疗潜力铺平了道路。
• [EN] DUAL INHIBITORS OF SOLUBLE EPOXIDE HYDROLASE AND 5-LIPOXYGENASE<br/>[FR] INHIBITEURS DOUBLES D'ÉPOXYDE HYDROLASE SOLUBLE ET DE 5-LIPOXYGÉNASE
  申请人：JOHANN WOLFGANG GOETHE UNIV FRANKFURT AM MAIN

  公开号：WO2021214048A1

  公开（公告）日：2021-10-28

  The invention pertains to a novel structure (I) that provides an activity as a dual inhibitor of the enzymes soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX). The invention pertains to multiple derivatives of the new class of dual inhibitors, their application in medicine, pharmaceutical compositions comprising them as well as to methods for synthesizing the new compounds.

  该发明涉及一种新型结构（I），作为可溶性环氧酰水解酶（sEH）和5-脂氧化酶（5-LOX）的双重抑制剂提供活性。该发明涉及新型双重抑制剂类的多个衍生物，它们在医学中的应用，包含它们的制药组合物，以及合成新化合物的方法。
• Hydroxyureas as Noncovalent Proteasome Inhibitors
  作者：Nerea Gallastegui、Philipp Beck、Marcelino Arciniega、Robert Huber、Stefan Hillebrand、Michael Groll

  DOI：10.1002/anie.201106010

  日期：2012.1.2

  Inhibitors with a new mechanism of action are needed for 20S proteasome (CP) inhibition owing to the ineffectiveness of current market drugs against some types of solid tumors. A novel class of nonpeptidic CP inhibitors has been developed, which display reversible and noncovalent binding. The structure‐based design of these highly active and site‐specific inhibitors revealed unexplored binding subpockets

  由于目前市场上的药物对某些类型的实体瘤无效，因此需要具有新作用机制的抑制剂来抑制20S蛋白酶体（CP）。已经开发出一类新型的非肽CP抑制剂，其表现出可逆的和非共价结合。这些高活性和位点特异性抑制剂的基于结构的设计揭示了未探索的结合亚型。
• 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。