3-氯-6-氰基吡嗪-(1H)-2-酮-1-乙酸乙酯 | 312904-96-4

• 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
• 中文名称: 3-氯-6-氰基吡嗪-(1H)-2-酮-1-乙酸乙酯
• 英文名称: ethyl 3-chloro-6-cyanopyrazin-(1H)-2-one-1-acetate
• 英文别名: Ethyl 2-(3-chloro-6-cyano-2-oxopyrazin-1-yl)acetate
• CAS: 312904-96-4
• 化学式: C₉H₈ClN₃O₃
• 分子量: 241.634
• InChiKey: MAJCRFANKOMQFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  82.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-氯-6-氰基吡嗪-(1H)-2-酮-1-乙酸乙酯 在 lithium hydroxide 、 三乙胺 作用下， 以 乙二醇二甲醚 、 乙醇 、 甲苯 为溶剂， 反应 2.0h， 生成 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-cyanopyrazin-(1H)-2-one-1-acetic acid
  参考文献：
  名称：

  Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines

  摘要：

  Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the,modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

  DOI：

  10.1021/jm020311f
• 作为产物：
  描述：

  ethyl 6-cyano-3-hydroxypyrazin-(1H)-2-one-1-acetate 在 氯化铵 、 三氯氧磷 作用下， 反应 1.5h， 以415 mg的产率得到3-氯-6-氰基吡嗪-(1H)-2-酮-1-乙酸乙酯
  参考文献：
  名称：

  Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines

  摘要：

  Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the,modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

  DOI：

  10.1021/jm020311f

文献信息

• Discovery and Clinical Evaluation of 1-{<i>N</i>-[2-(Amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a Thrombin Inhibitor with an Oxyguanidine P1 Motif
  作者：Tianbao Lu、Thomas Markotan、Shelley K. Ballentine、Edward C. Giardino、John Spurlino、Kathryn Brown、Bruce E. Maryanoff、Bruce E. Tomczuk、Bruce P. Damiano、Umesh Shukla、David End、Patricia Andrade-Gordon、Roger F. Bone、Mark R. Player

  DOI：10.1021/jm901802n

  日期：2010.2.25

  prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, iv, respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully

  我们已经将RWJ-671818（8）鉴定为一种新型的低分子量人α凝血酶口服活性抑制剂（K i = 1.3 nM），对静脉和动脉血栓形成的急性和慢性治疗具有潜在的作用。在用于评估抗血栓形成功效的大鼠深静脉血栓形成模型中，口服30 mg / kg和50 mg / kg的8分别减少了87％和94％的血栓重量。在麻醉的大鼠抗血栓形成模型中，颈动脉的电刺激产生了血栓，8静脉注射分别延长了0.1和1.0 mg / kg的2倍和3倍的阻塞时间，在较高剂量下，活化凝血时间和活化部分凝血活酶时间延长了一倍以上。该化合物在狗中具有100％的优异口服生物利用度，估计半衰期约为3小时。根据其值得注意的临床前数据，有8项药物已进入人体临床试验，并顺利通过了1期研究。
• Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines
  作者：Christopher S. Burgey、Kyle A. Robinson、Terry A. Lyle、Philip E. J. Sanderson、S. Dale Lewis、Bobby J. Lucas、Julie A. Krueger、Rominder Singh、Cynthia Miller-Stein、Rebecca B. White、Bradley Wong、Elizabeth A. Lyle、Peter D. Williams、Craig A. Coburn、Bruce D. Dorsey、James C. Barrow、Maria T. Stranieri、Marie A. Holahan、Gary R. Sitko、Jacquelynn J. Cook、Daniel R. McMasters、Colleen M. McDonough、William M. Sanders、Audrey A. Wallace、Franklin C. Clayton、Dennis Bohn、Yvonne M. Leonard、Theodore J. Detwiler,、Joseph J. Lynch,、Youwei Yan、Zhongguo Chen、Lawrence Kuo、Stephen J. Gardell、Jules A. Shafer、Joseph P. Vacca

  DOI：10.1021/jm020311f

  日期：2003.2.1

  Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the,modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.