6-[N-[(E)-(4-chlorophenyl)methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione | 32502-54-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-[N-[(E)-(4-chlorophenyl)methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
• 英文别名: 6-[(2E)-2-(4-chlorobenzylidene)-1-methylhydrazinyl]-3-methylpyrimidine-2,4(1H,3H)-dione；6-[[(E)-(4-chlorophenyl)methylideneamino]-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
• CAS: 32502-54-8
• 化学式: C₁₃H₁₃ClN₄O₂
• 分子量: 292.725
• InChiKey: WIEILEAIGWTWDX-OVCLIPMQSA-N

物化性质

• 熔点：
  194 °C(Solv: ethanol (64-17-5))
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-[N-[(E)-(4-chlorophenyl)methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione 以55%的产率得到
  参考文献：
  名称：

  YOUEDA F.; NAGAMATSU T., BULL. CHEM. SOC. JAP. , 1975, 48, NO 5, 1484-1489

  摘要：

  DOI：
• 作为产物：
  描述：

  6-氯-3-甲基尿嘧啶 以 乙醇 为溶剂， 反应 0.34h， 生成 6-[N-[(E)-(4-chlorophenyl)methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II

  摘要：

  The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAP.) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

  DOI：

  10.1021/jm400568p

文献信息

• Syntheses of 1,6-dimethylpyrimido(4,5-c)pyridazine-5,7(1H, 6H)-diones (4-deazatoxoflavins) and their use in the autorecycling oxidation of alcohols and amines.
  作者：FUMIO YONEDA、KEISHI NAKAGAWA、MITSUKO NOGUCHI、MASATSUGU HIGUCHI

  DOI：10.1248/cpb.29.379

  日期：——

  Treatment of 3-methyl-6-(1-methylhydrazino) uracil (I) with phenacyl bromides in ethanol afforded the corresponding 3-aryl-4, 8-dihydro-1, 6-dimethylpyrimido [4, 5-c]-pyridazine-5, 7 (1H, 6H)-diones (3-aryl-4, 8-dihydro-4-deazatoxoflavins) (II) and 3-aryl-1, 7-dimethyl-6, 8-dioxo-1, 4, 6, 7, 8-pentahydropyrimido [4, 3-c]-as-triazines (III). Oxidation of II with diethyl azodicarboxylate gave the corresponding 3-aryl-4-deazatoxoflavins (IV) in quantitative yields. The reaction of aryl aldehyde N-methyl-N-(3-methyluracil-6-yl)-hydrazones (VII) with triethyl orthoformate in dimethylformamide also gave the corresponding 3-aryl-4-deazatoxoflavins (IV). Compounds IV thus obtained oxidized alcohols under alkaline conditions in the dark to yield the corresponding carbonyl compounds, while they themselves were hydrogenated to compounds II. Under certain conditions, these oxidations were automatically recycled to give the corresponding carbonyl compounds in more than 100% yields.

  在乙醇中将 3-甲基-6-(1-甲基肼基)尿嘧啶(I)与苯乙酰溴处理，可得到相应的 3-芳基-4，8-二氢-1，6-二甲基嘧啶并[4，5-c]哒嗪-5、7(1H，6H)-二酮（3-芳基-4，8-二氢-4-脱氮恶黄素）（II）和 3-芳基-1，7-二甲基-6，8-二氧代-1，4，6，7，8-五氢嘧啶并[4，3-c]-as-三嗪（III）。用偶氮二甲酸二乙酯对 II 进行氧化，可以定量得到相应的 3-芳基-4-脱氮恶黄素（IV）。芳基醛 N-甲基-N-（3-甲基尿嘧啶-6-基）-肼（VII）与原甲酸三乙酯在二甲基甲酰胺中的反应也得到了相应的 3-芳基-4-脱氮恶黄素（IV）。这样得到的化合物 IV 在黑暗的碱性条件下氧化醇，生成相应的羰基化合物，而它们本身则氢化成化合物 II。在某些条件下，这些氧化反应会自动循环，生成相应的羰基化合物，收率超过 100%。
• YONEDA FUMIO; NAKAGAWA KEISHI; NOGUCHI MITSUKO; HIGUCHI MASATSUGU, CHEM. AND PHARM. BULL., 1981, 29, NO 2, 379-385
  作者：YONEDA FUMIO、 NAKAGAWA KEISHI、 NOGUCHI MITSUKO、 HIGUCHI MASATSUGU

  DOI：——

  日期：——
• Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II
  作者：Ali Raoof、Paul Depledge、Niall M. Hamilton、Nicola S. Hamilton、James R. Hitchin、Gemma V. Hopkins、Allan M. Jordan、Laura A. Maguire、Alison E. McGonagle、Daniel P. Mould、Mathew Rushbrooke、Helen F. Small、Kate M. Smith、Graeme J. Thomson、Fabrice Turlais、Ian D. Waddell、Bohdan Waszkowycz、Amanda J. Watson、Donald J. Ogilvie

  DOI：10.1021/jm400568p

  日期：2013.8.22

  The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAP.) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
• YOUEDA F.; NAGAMATSU T., BULL. CHEM. SOC. JAP. <BCSJ-A8>, 1975, 48, NO 5, 1484-1489
  作者：YOUEDA F.、 NAGAMATSU T.

  DOI：——

  日期：——