Morpholino(4-phenylpiperazin-1-yl)methanone | 349118-82-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: Morpholino(4-phenylpiperazin-1-yl)methanone
• 英文别名: Morpholin-4-yl-(4-phenyl-piperazin-1-yl)-methanone；morpholin-4-yl-(4-phenylpiperazin-1-yl)methanone
• CAS: 349118-82-7
• 化学式: C₁₅H₂₁N₃O₂
• mdl: MFCD02029719
• 分子量: 275.351
• InChiKey: HYSVKZRGQBZLJC-UHFFFAOYSA-N

物化性质

• 沸点：
  435.0±45.0 °C(Predicted)
• 密度：
  1.204±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  36
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-吗啉碳酰氯 在 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 18.5h， 生成 Morpholino(4-phenylpiperazin-1-yl)methanone
  参考文献：
  名称：

  Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)

  摘要：

  Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50 similar to 100 nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.12.050

文献信息

• Achieving functional group diversity in parallel synthesis: solution-phase synthesis of a library of ureas, carbamates, thiocarbamates, and amides using carbamoylimidazolium salts
  作者：Justyna A. Grzyb、Robert A. Batey

  DOI：10.1016/j.tetlet.2008.06.096

  日期：2008.9

  A convenient protocol for the parallel solution-phase synthesis of a library of thiocarbamates, ureas, carbamates, and amides from carbamoylimidazolium salts has been developed. The crystalline carbamoylimidazolium salts are readily synthesized from secondary amines, CDI and iodomethane, and act as stable carbamoylation reagents. A common set of reaction conditions and a straightforward non-chromatographic

  已经开发了一种方便的方案，用于从氨基甲酰咪唑鎓盐中并行溶液相合成硫代氨基甲酸酯，脲，氨基甲酸酯和酰胺的库。结晶的氨基甲酰咪唑鎓盐很容易由仲胺，CDI和碘甲烷合成，并用作稳定的氨基甲酰化试剂。针对与硫醇，胺，酚和羧酸的反应，开发了一套通用的反应条件和一种简单的非色谱液-液萃取纯化方案，可提供高纯度和高收率的产品。最终的文库结合了多样性，这些多样性源于对反应伙伴的选择以及在偶联反应中产生的官能团的连接。
• Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)
  作者：Jack U. Flanagan、Graham J. Atwell、Daniel M. Heinrich、Darby G. Brooke、Shevan Silva、Laurent J.M. Rigoreau、Elisabeth Trivier、Andrew P. Turnbull、Tony Raynham、Stephen M.F. Jamieson、William A. Denny

  DOI：10.1016/j.bmc.2013.12.050

  日期：2014.2

  Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50 similar to 100 nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311. (C) 2013 Elsevier Ltd. All rights reserved.