2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸 | 454483-97-7

• 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: 2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸
• 英文名称: 3-(2,2-difluoro-2-(phenyl)ethylamino)-6-methylpyrazin-(1H)-2-one-1-acetic acid
• 英文别名: [3-(2,2-difluoro-2-phenylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]acetic acid；3-(2,2-Difluoro-2-phenylethylamino)-1-(hydroxycarbonylmethyl)-6-methyl-pyrazinone；2-[3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxopyrazin-1-yl]acetic acid
• CAS: 454483-97-7
• 化学式: C₁₅H₁₅F₂N₃O₃
• 分子量: 323.299
• InChiKey: ZGJNOOLKFXMTDI-UHFFFAOYSA-N

物化性质

• 沸点：
  491.5±55.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  82
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸 在 sodium hydroxide 作用下， 以 水 、 正丁醇 为溶剂， 反应 1.0h， 生成
  参考文献：
  名称：

  WO2007/146553

  摘要：

  公开号：
• 作为产物：
  描述：

  3-(2,2-Difluoro-2-phenylethylamino)-1-(ethoxycarbonylmethyl)-6-methylpyrazinone 在 水 、 sodium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.5h， 生成 2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸
  参考文献：
  名称：

  凝血酶抑制剂1- { N- [2-（mid氨基氨基氧基）乙基]氨基}羰基甲基-6-甲基-3- [2,2-二氟-2-苯基乙基氨基]吡嗪酮（RWJ-671818）的发现和临床评价氧胍P1基序

  摘要：

  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。

  DOI：

  10.1021/jm901802n
• 作为试剂：
  描述：

  [N,N'-di-(tert-butoxycarbonyl)]-2-ethoxyguanidine 、 2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸 在 2-(3-((2,2-二氟-2-苯基乙基)氨基)-6-甲基-2-氧亚基吡嗪-1(2H)-基)乙酸 作用下， 生成 1-(N-[2-(N',N"-bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]amino)carbonylmethyl-6-methyl-3-(2,2-difluoro-2-phenethylamino)pyrazinone
  参考文献：
  名称：

  J. Med. Chem. 2010, 53, 1843-1856

  摘要：

  DOI：

文献信息

• N-[2-[[(DIAMINOMETHYLENE)AMINO]OXY]ETHYL]-3-[(2,2-DIFLUORO-2-PHENYLETHYL)AMINO]-6-METHYL-2-OXO-1(2H)-PYRAZINEACETAMIDE
  申请人：Patel N. Mitul

  公开号：US20080021044A1

  公开（公告）日：2008-01-24

  The present invention is directed to N-[2-[[(diaminomethylene)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-s-oxo-1(2H)-pyrazineacetamide, pharmaceutical compositions containing said compound and methods of treatment comprising inhibiting a serine protease using said compound. The present invention is further directed to a process for the preparation of the N-[2-[[(diaminomethylene)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazineacetamide as a free base. The present invention is further directed to a process for the preparation of pharmaceutically acceptable salts of N-[2-[[(aminoiminomethyl)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazineacetamide.

  本发明涉及一种N-[2-[[(二氨基甲基)氨基]氧基]乙基]-3-[(2,2-二氟-2-苯乙基)氨基]-6-甲基-2-氧代-1(2H)-吡嗪乙酰胺化合物，含有该化合物的制药组合物以及使用该化合物抑制丝氨酸蛋白酶的治疗方法。本发明还涉及一种制备N-[2-[[(二氨基甲基)氨基]氧基]乙基]-3-[(2,2-二氟-2-苯乙基)氨基]-6-甲基-2-氧代-1(2H)-吡嗪乙酰胺自由碱的方法。本发明还涉及一种制备N-[2-[[(氨基亚甲基)氨基]氧基]乙基]-3-[(2,2-二氟-2-苯乙基)氨基]-6-甲基-2-氧代-1(2H)-吡嗪乙酰胺药用可接受盐的方法。
• Non-covalent thrombin inhibitors featuring p 3 -heterocycles with P 1 -monocyclic arginine surrogates
  作者：John E Reiner、Daniel V Siev、Gian-Luca Araldi、Jingrong Jean Cui、Jonathan Z Ho、Komandla Malla Reddy、Lala Mamedova、Phong H Vu、Kuen-Shan S Lee、Nathaniel K Minami、Tony S Gibson、Susanne M Anderson、Annette E Bradbury、Thomas G Nolan、J.Edward Semple

  DOI：10.1016/s0960-894x(02)00129-4

  日期：2002.4

  Investigations on P-2-P-3-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P-1-arginine derivatives. The design. synthesis. and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P-1-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydrox amidines, (2) 2-aminopyrazines. and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines. (C) 2002 Elsevier Science Ltd. All rights reserved.
• 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.
• [EN] N-[2-[[(DIAMINOMETHYLENE)AMINO]OXY]ETHYL]-3-[(2,2-DIFLUORO-2-PHENYLETHYL)AMINO]-6-METHYL-2-OXO-1(2H)-PYRAZINEACETAMIDE<br/>[FR] N-[2-[[(DIAMINOMÉTHYLÈNE)AMINO]OXY]ÉTHYL]-3-[(2,2-DIFLUORO-2-PHÉNYLÉTHYL)AMINO]-6-MÉTHYL-2-OXO-1(2H)-PYRAZINEACÉTAMIDE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2007146553A2

  公开（公告）日：2007-12-21

  [EN] The present invention is directed to N-[2-[[(diaminomethylene)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazineacetamide, pharmaceutical compositions containing said compound and methods of treatment comprising inhibiting a serine protease using said compound. The present invention is further directed to a process for the preparation of the N-[2-[[(diaminomethylene)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazineacetamide as a free base. The present invention is further directed to a process for the preparation of pharmaceutically acceptable salts of N-[2-[[(aminoiminomethyl)amino]oxy]ethyl]-3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazineacetamide.
  [FR] La présente invention concerne le N-[2-[[(diaminométhylène)amino]oxy]éthyl]-3-[(2,2-difluoro-2-phényléthyl)amino]-6-méthyl-2-oxo-1(2H)-pyrazineacétamide, les compositions pharmaceutiques le contenant et les méthodes de traitement comprenant l'inhibition d'une sérine protéase par l'emploi dudit composé. La présente invention concerne également un procédé de synthèse du N-[2-[[(diaminométhylène)amino]oxy]éthyl]-3-[(2,2-difluoro-2-phényléthyl)amino]-6-méthyl-2-oxo-1(2H)-pyrazineacétamide sous forme de base libre. La présente invention concerne en outre un procédé de synthèse de sels de qualité pharmaceutique du N-[2-[[(diaminométhylène)amino]oxy]éthyl]-3-[(2,2-difluoro-2-phényléthyl)amino]-6-méthyl-2-oxo-1(2H)-pyrazineacétamide.
• 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。