1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone | 308846-10-8

• 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: 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone
• 英文别名: benzyl 2-[3,5-dichloro-2-(3-nitrophenyl)-6-oxopyrazin-1-yl]acetate
• CAS: 308846-10-8
• 化学式: C₁₉H₁₃Cl₂N₃O₅
• 分子量: 434.235
• InChiKey: RPKLNFAELHVWEE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 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：
  105
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 、 乙腈 为溶剂， 生成 2-[2-(3-Aminophenyl)-3-chloro-5-(cyclobutylamino)-6-oxopyrazin-1-yl]acetic acid
  参考文献：
  名称：

  Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(03)00410-4
• 作为产物：
  描述：

  草酰氯 、 三甲基氰硅烷 、 甘氨酸苄酯盐酸盐 、 间硝基苯甲醛 以 二氯甲烷 、 邻二氯苯 为溶剂， 生成 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone
  参考文献：
  名称：

  Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(03)00410-4

文献信息

• Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
  申请人：Pharmacia Corporation

  公开号：US06664255B1

  公开（公告）日：2003-12-16

  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.

  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。
• [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 polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
  申请人：Warner-Lambert Company

  公开号：US07119094B1

  公开（公告）日：2006-10-10

  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.

  本发明涉及取代的多环芳基和杂环芳基吡唑酮化合物，其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化合物、组合物和抗凝治疗方法。
• Design, Parallel Synthesis, and Crystal Structures of Pyrazinone Antithrombotics as Selective Inhibitors of the Tissue Factor VIIa Complex
  作者：John J. Parlow、Brenda L. Case、Thomas A. Dice、Ricky L. Fenton、Michael J. Hayes、Darin E. Jones、William L. Neumann、Rhonda S. Wood、Rhonda M. Lachance、Thomas J. Girard、Nancy S. Nicholson、Michael Clare、Roderick A. Stegeman、Anna M. Stevens、William C. Stallings、Ravi G. Kurumbail、Michael S. South

  DOI：10.1021/jm030131l

  日期：2003.9.1

  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.
• SUBSTITUTED POLYCYCLIC ARYL AND HETEROARYL PYRAZINONES USEFUL FOR SELECTIVE INHIBITION OF THE COAGULATION CASCADE
  申请人：Pharmacia Corporation

  公开号：EP1202975A1

  公开（公告）日：2002-05-08