benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate | 308845-81-0

• 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: benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate
• 英文别名: benzyl (3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate；benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1-yl)acetate
• CAS: 308845-81-0
• 化学式: C₁₉H₁₄Cl₂N₂O₃
• 分子量: 389.238
• InChiKey: OFCXVRAGHPWCCV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 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：

  benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate 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-(3-Azetidin-1-yl-5-chloro-2-oxo-6-phenyl-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：

  甘氨酸苄酯盐酸盐 在 盐酸 作用下， 以 二氯甲烷 、 乙酸乙酯 、 邻二氯苯 为溶剂， 反应 22.0h， 生成 benzyl 2-(3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate
  参考文献：
  名称：

  Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade

  摘要：

  这项发明涉及替代多环芳基和杂环芳基吡唑酮化合物，可用作凝血级联中丝氨酸蛋白酶的抑制剂，以及用于治疗和预防包括冠状动脉和脑血管疾病在内的各种血栓症状的抗凝治疗的化合物、组合物和方法。

  公开号：

  US06664255B1

文献信息

• 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。
• [EN] MASP-2 INHIBITORS AND METHODS OF USE<br/>[FR] INHIBITEURS DE MASP-2 ET PROCÉDÉS D'UTILISATION
  申请人：OMEROS CORP

  公开号：WO2021113686A1

  公开（公告）日：2021-06-10

  The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

  本公开提供了具有MASP-2抑制活性的化合物，这些化合物的组合物以及制备和使用这些化合物的方法。
• [EN] SUBSTITUTED POLYCYCLIC ARYL AND HETEROARYL PYRAZINONES USEFUL FOR SELECTIVE INHIBITION OF THE COAGULATION CASCADE<br/>[FR] ARYLE POLYCYCLIQUE SUBSTITUTE ET PYRAZINONES D'HETEROARYLE UTILISES DANS L'INHIBITION SELECTIVE DE LA COAGULATION
  申请人：PHARMACIA CORP

  公开号：WO2001087854A1

  公开（公告）日：2001-11-22

  The invention relates to substituted polycyclic aryl and heteroaryl pyrazinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

  本发明涉及替代的多环芳基和杂环芳基吡嗪酮类化合物，用作凝血级联反应中丝氨酸蛋白酶的抑制剂，以及用于治疗和预防各种血栓性疾病，包括冠状动脉和脑血管疾病的抗凝治疗的化合物、组合物和方法。
• Substituted monocyclic CGRP receptor antagonists
  申请人：Wood Michael R.

  公开号：US20080318927A1

  公开（公告）日：2008-12-25

  Compounds of formula I: (wherein variables A 1 , A 2 , A 2 , A 4 , m, n, J, Q, R 4 , E a , E b , E c , R 6 , R 7 , R e , R f , R PG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  公式I的化合物：（其中变量A1，A2，A3，A4，m，n，J，Q，R4，Ea，Eb，Ec，R6，R7，Re，Rf，RPG和Y如本文所述），这些化合物是CGRP受体拮抗剂，可用于治疗或预防CGRP参与的疾病，如偏头痛。本发明还涉及包含这些化合物的制药组合物以及在预防或治疗CGRP参与的这些疾病中使用这些化合物和组合物。
• SUBSTITUTED MONOCYCLIC CGRP RECEPTOR ANTAGONISTS
  申请人：Wood Michael R.

  公开号：US20100056498A1

  公开（公告）日：2010-03-04

  Compounds of formula I: (wherein variables A 1 , A 2 , A 3 , A 4 , m, n, J, Q, R 4 , E a , E b , E c , R 6 , R 7 , R e , R f , R PG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  式I的化合物：（其中变量A1，A2，A3，A4，m，n，J，Q，R4，Ea，Eb，Ec，R6，R7，Re，Rf，RPG和Y如本文所述）是CGRP受体拮抗剂，可用于治疗或预防CGRP参与的疾病，如偏头痛。本发明还涉及包含这些化合物的制药组合物以及这些化合物和组合物在预防或治疗CGRP参与的这些疾病中的应用。