methyl 3-amino-6-chloro-5-(dimethylamino)pyrazine-2-carboxylate | 1458-21-5

• 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: methyl 3-amino-6-chloro-5-(dimethylamino)pyrazine-2-carboxylate
• CAS: 1458-21-5
• 化学式: C₈H₁₁ClN₄O₂
• 分子量: 230.654
• InChiKey: CIJAOZNANCPBRB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  81.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 3-amino-6-chloro-5-(dimethylamino)pyrazine-2-carboxylate 在 palladium on activated charcoal sodium hydroxide 、 氢溴酸 、 氢气 、 溴 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 溶剂黄146 为溶剂， 反应 48.5h， 生成 6-氯-5-二甲氨基-吡嗪-2-羧酸
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006
• 作为产物：
  描述：

  二甲胺 、 3-氨基-5,6-二氯-2-吡嗪羧酸甲脂 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以83%的产率得到methyl 3-amino-6-chloro-5-(dimethylamino)pyrazine-2-carboxylate
  参考文献：
  名称：

  使用基于亚胺的动态组合化学进行模板指导的RNA配体选择。

  摘要：

  这项研究建立了基于亚胺的动态组合化学发现RNA靶标的非共价配体的适用性。我们阐明了芳基胺反应性的基础性质，并证明了基于阿米洛利的动态库中目标导向的紧密结合剂的扩增。

  DOI：

  10.1039/d0cc00266f

文献信息

• Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR
  作者：Neeraj N. Patwardhan、Laura R. Ganser、Gary J. Kapral、Christopher S. Eubanks、Janghyun Lee、Bharathwaj Sathyamoorthy、Hashim M. Al-Hashimi、Amanda E. Hargrove

  DOI：10.1039/c6md00729e

  日期：——

  dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.

  RNA靶向支架的多样化为寻找治疗相关RNA（例如HIV-1 TAR）的选择性配体提供了广阔的前景。我们在此报告了阿米洛利作为一种新型的RNA结合支架，以及合成的C（5）-和C（6）-多样化途径的合成途径的建立。在C（5）-和C（6）位置的迭代修饰产生衍生物24，在肽置换试验中，其活性比母体二甲基阿米洛利提高了100倍。使用2D SOFAST- [ 1 H- 13C] HMQC NMR方法，可以轻松快速地评估所有文库成员的结合模式。化学信息学分析揭示了选择性配体和非选择性配体之间的明显差异。在这项研究中，我们通过合成方法和分析技术的新颖结合，将二甲基阿米洛利从弱的TAR配体演化为迄今为止报道的结合最紧密的选择性TAR配体之一。我们希望这些方法能够快速扩增文库并调整阿米洛利支架的RNA靶标范围，并对SOFAST NMR进行前所未有的小分子与RNA相互作用的评估。
• Pyrazinecarboxamides and processes for preparing same
  申请人：Merck & Co., Inc.

  公开号：US04085211A1

  公开（公告）日：1978-04-18

  The case involves novel pyrazinecarboxamides and processes for preparing same. The pyrazinecarboxamides are excellent eukalemic agents possessing diuretic and natriuretic properties.

  本案涉及新型吡嗪羧酰胺及其制备方法。这些吡嗪羧酰胺是优秀的利尿剂和钠利尿剂。
• US4085211A
  申请人：——

  公开号：US4085211A

  公开（公告）日：1978-04-18
• Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands
  作者：Arun K. Ghosh、Wayne J. Thompson、M. Katharine Holloway、Sean P. McKee、Tien T. Duong、Hee Yoon Lee、Peter M. Munson、Anthony M. Smith、Jenny M. Wai、Paul L. Darke、Joan A. Zugay、Emilio A. Emini、William A. Schleif、Joel R. Huff、Paul S. Anderson

  DOI：10.1021/jm00068a006

  日期：1993.8.1

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.
• Template-guided selection of RNA ligands using imine-based dynamic combinatorial chemistry
  作者：Aline Umuhire Juru、Zhengguo Cai、Adina Jan、Amanda E. Hargrove

  DOI：10.1039/d0cc00266f

  日期：——

  This study establishes the applicability of imine-based dynamic combinatorial chemistry to discover non-covalent ligands for RNA targets. We elucidate properties underlying the reactivity of arylamines and demonstrate target-guided amplification of tight binders in an amiloride-based dynamic library.

  这项研究建立了基于亚胺的动态组合化学发现RNA靶标的非共价配体的适用性。我们阐明了芳基胺反应性的基础性质，并证明了基于阿米洛利的动态库中目标导向的紧密结合剂的扩增。