N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[8-bromo-2-(bromoacetyl)-7-methoxyquinolin-4-yl]oxy}-N-[(1R,2S)-2-ethenyl-1-(methoxycarbonyl)cyclopropyl]-L-prolinamide | 1240791-87-0

• 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: N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[8-bromo-2-(bromoacetyl)-7-methoxyquinolin-4-yl]oxy}-N-[(1R,2S)-2-ethenyl-1-(methoxycarbonyl)cyclopropyl]-L-prolinamide
• 英文别名: methyl (1R,2S)-1-[[(2S,4R)-4-[8-bromo-2-(2-bromoacetyl)-7-methoxyquinolin-4-yl]oxy-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate
• CAS: 1240791-87-0
• 化学式: C₃₆H₄₄Br₂N₄O₉
• 分子量: 836.575
• InChiKey: AGFRCTZGCQCTLA-RRZCTFDUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  51
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  163
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-异丙基羰基硫脲 、 N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[8-bromo-2-(bromoacetyl)-7-methoxyquinolin-4-yl]oxy}-N-[(1R,2S)-2-ethenyl-1-(methoxycarbonyl)cyclopropyl]-L-prolinamide 在 2-异丙基羰基硫脲 作用下， 生成 methyl (1R,2S)-1-((2S,4R)-4-((8-bromo-2-(2-isobutyramidothiazol-4-yl)-7-methoxyquinolin-4-yl)oxy)-1-((S)-2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylate
  参考文献：
  名称：

  [EN] HEPATITIS C INHIBITOR COMPOUNDS
  [FR] COMPOSES INHIBITEURS DE L'HEPATITE C

  摘要：

  式(I)的化合物：其中B、X、R3、L0、L1、L2、R2、R1和RC的定义详见文中。这些化合物可用作HCV NS3蛋白酶抑制剂，用于治疗丙型肝炎病毒感染。

  公开号：

  WO2004103996A1
• 作为产物：
  描述：

  methyl (1R,2S)-1-[[(2S,4R)-4-[8-bromo-2-(2-diazoacetyl)-7-methoxyquinolin-4-yl]oxy-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate 生成 N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[8-bromo-2-(bromoacetyl)-7-methoxyquinolin-4-yl]oxy}-N-[(1R,2S)-2-ethenyl-1-(methoxycarbonyl)cyclopropyl]-L-prolinamide
  参考文献：
  名称：

  [EN] HEPATITIS C INHIBITOR COMPOUNDS
  [FR] COMPOSES INHIBITEURS DE L'HEPATITE C

  摘要：

  式(I)的化合物：其中B、X、R3、L0、L1、L2、R2、R1和RC的定义详见文中。这些化合物可用作HCV NS3蛋白酶抑制剂，用于治疗丙型肝炎病毒感染。

  公开号：

  WO2004103996A1

文献信息

• Hepatitis C virus serine protease: synthesis of radioactive and stable isotope-labeled potent inhibitors
  作者：Bachir Latli、Matt Hrapchak、Vida Gorys、Montse Llinàs-Brunet、Scot S. Campbell、Jinhua Song、Chris H. Senanayake

  DOI：10.1002/jlcr.3187

  日期：2014.5.15

  protease inhibitors related to BILN 2061 and BI 201335 labeled with radioactive and stable isotopes. Synthetic efforts were focused on the common substituted thiazole moiety, which is easily accessible via a Hantzsch's reaction of α-bromoketones and mono-substituted thioureas. In the radioactive synthesis, commercially available carbon-14 thiourea was utilized to prepare mono-substituted thioureas, which

  吸收、分布、代谢和排泄 (ADME) 研究、药代动力学、放射自显影、生物分析和其他研究活动需要用放射性和稳定同位素标记的候选药物。这些研究的结果对于开发候选药物及其批准供人类使用至关重要。在此，我们报告了与放射性稳定同位素标记的 BILN 2061 和 BI 201335 相关的强效选择性丙型肝炎病毒丝氨酸蛋白酶抑制剂的合成。合成工作集中在常见的取代噻唑部分，它很容易通过 α-溴酮和单取代硫脲的 Hantzsch 反应获得。在放射性合成中，利用市售的碳 14 硫脲制备单取代硫脲，在异丙醇中与 α-溴酮缩合，然后酯水解，得到所需的碳 14 标记的蛋白酶抑制剂。使用相同的策略来制备这些用稳定同位素标记的抑制剂。从市售的氘标记中间体获得单取代硫脲，然后与 α-溴酮缩合，然后酯水解得到氘标记抑制剂。
• Discovery of a Potent and Selective Noncovalent Linear Inhibitor of the Hepatitis C Virus NS3 Protease (BI 201335)
  作者：Montse Llinàs-Brunet、Murray D. Bailey、Nathalie Goudreau、Punit K. Bhardwaj、Josée Bordeleau、Michael Bös、Yves Bousquet、Michael G. Cordingley、Jiamin Duan、Pat Forgione、Michel Garneau、Elise Ghiro、Vida Gorys、Sylvie Goulet、Ted Halmos、Stephen H. Kawai、Julie Naud、Marc-André Poupart、Peter W. White

  DOI：10.1021/jm100690x

  日期：2010.9.9

  C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a CS methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotypel NS3 protease with a promising PK profile in rats.
• J. Med. Chem. 2010, 53, 6466-6476
  作者：

  DOI：——

  日期：——