2-(6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetic acid benzyl ester | 602280-43-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetic acid benzyl ester
• 英文别名: benzyl 2-(6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetate；benzyl 2-[6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl]acetate；Benzyl 2-(2-benzyl-3,5-dichloro-6-oxopyrazin-1-yl)acetate
• CAS: 602280-43-3
• 化学式: C₂₀H₁₆Cl₂N₂O₃
• 分子量: 403.265
• InChiKey: BMFVGDYJLOSDTE-UHFFFAOYSA-N

物化性质

• 沸点：
  528.3±60.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  59
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetic acid benzyl ester 在 氢氧化钾 、 三甲基氯硅烷 、 polymer-bound carbodiimide reagent 、 1-羟基苯并三唑 、 sodium iodide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.0h， 生成 2-(6-Benzyl-5-chloro-2-oxo-3-phenethylamino-2H-pyrazin-1-yl)-N-(4-carbamimidoyl-benzyl)-acetamide
  参考文献：
  名称：

  Design, Parallel Synthesis, and Crystal Structures of Pyrazinone Antithrombotics as Selective Inhibitors of the Tissue Factor VIIa Complex

  摘要：

  Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor Vlla (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S-1, S-2, and S-3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P-1, P-2, and P-3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/ VIIa with excellent selectivity over thrombin (Ha) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.

  DOI：

  10.1021/jm030131l
• 作为产物：
  描述：

  草酰氯 、 Benzyl 2-[(1-cyano-2-phenylethyl)amino]acetate 在 盐酸 作用下， 以 乙醚 、 乙二醇二甲醚 为溶剂， 反应 0.08h， 生成 2-(6-benzyl-3,5-dichloro-2-oxopyrazin-1(2H)-yl)acetic acid benzyl ester
  参考文献：
  名称：

  Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

  摘要：

  Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R-6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to K-i = 0.11 mu M were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  DOI：

  10.1021/jm301887f

文献信息

• Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1<i>H</i>)-pyrazinones
  作者：Anna Karin Belfrage、Johan Gising、Fredrik Svensson、Eva Åkerblom、Christian Sköld、Anja Sandström

  DOI：10.1002/ejoc.201403405

  日期：2015.2

  variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based

  自 2011 年第一个获批的丙型肝炎病毒 (HCV) NS3 蛋白酶抑制剂以来，许多直接作用抗病毒药物 (DAA) 已进入临床试验后期。今天，有几种基于不同 DAA 的联合疗法，无论是否需要注射聚乙二醇化干扰素-α，均可用于慢性 HCV 感染。已获批准的和晚期 HCV NS3 蛋白酶抑制剂的化学基础明显相似。这可以部分解释在 NS3 蛋白酶抑制剂的压力下出现的交叉耐药性。开发的第一代 NS3 蛋白酶抑制剂可有效抑制病毒的基因型 1，而对其他基因型的抑制作用较弱。 本论文的主要重点是设计和合成一类新的基于 2(1H)-吡嗪酮的 HCV NS3 蛋白酶抑制剂，在结构上与临床试验中评估或批准的抑制剂不同，可能具有独特的耐药性和广泛的基因型覆盖范围。围绕吡嗪酮核心结构依次进行修饰，阐明构效关系；发现 P3 尿素封端基团对抑制效力有价值，延长的 R6 残基可能指向 S2 口袋。与先前开发的抑制剂不同，P1'
• A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
  作者：Johan Gising、Pernilla Örtqvist、Anja Sandström、Mats Larhed

  DOI：10.1039/b905501k

  日期：——

  A rapid and versatile one-pot, 2 × 10 min microwave protocol for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones was developed. Comparable reaction sequences using classical conditions require about 1–2 days of heating. The α-aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as β-strand inducing core structures in a medicinal chemistry context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-containing Hepatitis C virus NS3 protease inhibitors is reported.

  开发了一种快速且多功能的单锅法2×10分钟微波协议，用于制备N-1和C-6修饰的3,5-二氯-2(1H)-吡嗪酮。使用经典条件进行的可比反应序列需要大约1-2天的加热时间。首先通过斯特雷克反应生成α-氨基腈，然后在微波加热下环化。所开发的微波方法提供了高效生成和利用功能化的3-氨基-5-氯-2(1H)-吡嗪酮-N-1-羧酸作为药物化学背景下β-链诱导核心结构的可能性。为了说明该方法的实用性，报道了两个新型含有2(1H)-吡嗪酮的丙型肝炎病毒NS3蛋白酶抑制剂的合成。
• Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
  作者：Anna Karin Belfrage、Eldar Abdurakhmanov、Eva Åkerblom、Peter Brandt、Hiba Alogheli、Johan Neyts、U. Helena Danielson、Anja Sandström

  DOI：10.1016/j.ejmech.2018.02.032

  日期：2018.3

  HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for

  在本文中，我们介绍了基于2（1 H）-吡嗪酮的HCV NS3蛋白酶抑制剂的设计和合成，并显示了延长的R 3尿素取代基与几种NS3蛋白变体的抑制能力增强相关。据信抑制剂依赖于模拟氢键的β-折叠，该氢键在不同的基因型和当前的抗药性变体上是相似的，并且对应于天然肽底物的β-折叠相互作用。例如，具有包括环状酰亚胺的尿素取代基的抑制剂36对基因型1a，野生型（K i  = 30 nM）和R155K（K i  = 2 nM）和基因型3a（Ki  = 5 nM）。
• Discovery of achiral inhibitors of the hepatitis C virus NS3 protease based on 2(1H)-pyrazinones
  作者：Pernilla Örtqvist、Johan Gising、Angelica E. Ehrenberg、Aparna Vema、Anneli Borg、Anders Karlén、Mats Larhed、U. Helena Danielson、Anja Sandström

  DOI：10.1016/j.bmc.2010.06.101

  日期：2010.9

  Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl-or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1' residues evaluated, an aromatic P1-P1' scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization. (C) 2010 Elsevier Ltd. All rights reserved.
• Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
  作者：Michael S. South、Brenda L. Case、Rhonda S. Wood、Darin E. Jones、Michael J. Hayes、Thomas J. Girard、Rhonda M. Lachance、Nancy S. Nicholson、Michael Clare、Anna M. Stevens、Roderick A. Stegeman、William C. Stallings、Ravi G. Kurumbail、John J. Parlow

  DOI：10.1016/s0960-894x(03)00410-4

  日期：2003.7

  Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.