2-氨基-4-甲基嘧啶-5-羧酸甲酯 | 1023811-97-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 2-氨基-4-甲基嘧啶-5-羧酸甲酯
• 英文名称: methyl 2-amino-4-methylpyrimidine-5-carboxylate
• CAS: 1023811-97-3
• 化学式: C₇H₉N₃O₂
• mdl: MFCD09880929
• 分子量: 167.167
• InChiKey: TXAIGQFUQLUQJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.285
• 拓扑面积：
  78.1
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933599090

反应信息

• 作为反应物：
  描述：

  2-氨基-4-甲基嘧啶-5-羧酸甲酯 在 manganese(IV) oxide 、 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium tert-butylate 、 二异丁基氢化铝 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 生成 2-[(4-bromophenyl)amino]-4-methylpyrimidine-5-carbaldehyde
  参考文献：
  名称：

  Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication

  摘要：

  The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (RS) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.

  DOI：

  10.1021/jm401101p
• 作为产物：
  描述：

  盐酸胍 、 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 0.5h， 生成 2-氨基-4-甲基嘧啶-5-羧酸甲酯
  参考文献：
  名称：

  Efficient Assembly of 2,5,6-Substituted Pyrimidines via MgI₂-Mediated Morita−Baylis−Hillman Reaction

  摘要：

  A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substituted alpha-iodomethylene beta-keto ester intermediates obtained after oxidation of the MBH adducts, which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted pyrimidines-5-carboxylate libraries.

  DOI：

  10.1021/cc100001e

文献信息

• Discovery of Ureido-Based Apcin Analogues as Cdc20-specific Inhibitors against Cancer
  作者：Yiqin He、Xiangyang Le、Gaoyun Hu、Qianbin Li、Zhuo Chen

  DOI：10.3390/ph16020304

  日期：——

  Cdc20 is a promising drug target that plays an important role in the mid-anaphase process of cellular mitosis, and Apcin is the only reported core structure of the Cdc20-specific inhibitor. Some potent Apcin derivatives were obtained in our previous research, and a structure–activity relationship was determined. In this study, we designed and synthesized a series of ureido-based Apcin derivatives. The proliferation-inhibition experiments on four cancer-cell lines showed that ureido skeleton could promote the anti-proliferation activity of purine-substituted compounds, whereas the ureido analogues with pyrimidine substitutes showed no significant improvement in the inhibitory effect compared with the original ones. Further tests confirmed that ureido-based compounds can enhance the binding affinity to Cdc20 by increasing the levels of Cdc20 downstream proteins. Compound 27 revealed a remarkably antitumor activity pattern against Hela (IC50 = 0.06 ± 0.02 μM) and potent binding affinity to Cdc20. Moreover, compound 20 induced caspase-dependent apoptosis and cell-cycle arrest at the G2/M phase, and compound 27 induced caspase-dependent apoptosis and promoted microtubule polymerization. Finally, a molecular-docking simulation was performed for compounds 20 and 27 to predict the potential ligand–protein interactions with the active sites of the Cdc20 proteins.

  Cdc20在细胞有丝分裂的中期分裂过程中发挥着重要作用，是一个很有前景的药物靶点，而Apcin是目前唯一报道的Cdc20特异性抑制剂的核心结构。我们之前的研究获得了一些强效的 Apcin 衍生物，并确定了其结构-活性关系。在本研究中，我们设计并合成了一系列脲基 Apcin 衍生物。对四种癌细胞株的增殖抑制实验表明，脲基骨架能促进嘌呤取代化合物的抗增殖活性，而嘧啶取代的脲基类似物与原始化合物相比，抑制效果没有明显改善。进一步的测试证实，脲基化合物可以通过提高 Cdc20 下游蛋白的水平来增强与 Cdc20 的结合亲和力。化合物 27 揭示了对 Hela 的显著抗肿瘤活性模式（IC50 = 0.06 ± 0.02 μM）以及与 Cdc20 的强结合亲和力。此外，化合物20能诱导依赖于caspase的细胞凋亡并使细胞周期停滞在G2/M期，化合物27能诱导依赖于caspase的细胞凋亡并促进微管聚合。最后，对化合物 20 和 27 进行了分子对接模拟，以预测配体与 Cdc20 蛋白活性位点的潜在相互作用。
• Efficient Assembly of 2,5,6-Substituted Pyrimidines via MgI₂-Mediated Morita−Baylis−Hillman Reaction
  作者：Vasudha Sharma、Mark L. McLaughlin

  DOI：10.1021/cc100001e

  日期：2010.5.10

  A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substituted alpha-iodomethylene beta-keto ester intermediates obtained after oxidation of the MBH adducts, which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted pyrimidines-5-carboxylate libraries.
• Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication
  作者：Renato Skerlj、Gary Bridger、Yuanxi Zhou、Elyse Bourque、Ernest McEachern、Markus Metz、Curtis Harwig、Tong-Shuang Li、Wen Yang、David Bogucki、Yongbao Zhu、Jonathan Langille、Duane Veale、Tuya Ba、Michael Bey、Ian Baird、Alan Kaller、Maria Krumpak、David Leitch、Michael Satori、Krystyna Vocadlo、Danielle Guay、Susan Nan、Helen Yee、Jason Crawford、Gang Chen、Trevor Wilson、Bryon Carpenter、David Gauthier、Ron MacFarland、Renee Mosi、Veronique Bodart、Rebecca Wong、Simon Fricker、Dominique Schols

  DOI：10.1021/jm401101p

  日期：2013.10.24

  The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (RS) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.