methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(7S)-2,2-difluoro-6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-6-azaspiro-[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate

• 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: methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(7S)-2,2-difluoro-6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-6-azaspiro-[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate
• 英文别名: methyl ((1S)-1-(((2S)-2-(4-(4'-(2-((7S)-2.2-difluoro-6-((2S)-3-methyl-2-(((methyloxy)carbonyl)amino)butanoyl)-6-azaspiro[3.4]oct-7-yl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate；methyl N-[(1S)-1-[(2S)-2-[5-[4-[4-[2-[2,2-difluoro-7-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-7-azaspiro[3.4]octan-6-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate；methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[2,2-difluoro-6-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-6-azaspiro[3.4]octan-7-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
• 化学式: C₄₃H₅₂F₂N₈O₆
• 分子量: 814.933
• InChiKey: BWDYLUOAHIYXDM-GONGHQDWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  59
• 可旋转键数：
  13
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  175
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  (2-(4-溴苯基)-2-氧代乙基)氨基甲酸叔丁酯 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 ammonium acetate 、 potassium acetate 、 碳酸氢钠 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.0h， 生成 methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(7S)-2,2-difluoro-6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-6-azaspiro-[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate
  参考文献：
  名称：

  Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical Compound

  摘要：

  [GRAPHICS]Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSIC2236805) supported high potency against genotypes la and lb as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.

  DOI：

  10.1021/jm4013104

文献信息

• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2011028596A1

  公开（公告）日：2011-03-10

  Disclosed are compounds of Formula III. Also disclosed are salts of the compounds, pharmaceutical composition comprising the compounds or salts, and methods for treating HCV infection by administration of the compounds or salts.

  揭示了III式化合物。还揭示了这些化合物的盐，包括这些化合物或盐的药物组合物，以及通过给予这些化合物或盐来治疗HCV感染的方法。
• Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical Compound
  作者：Wieslaw M. Kazmierski、Andrew Maynard、Maosheng Duan、Sam Baskaran、Janos Botyanszki、Renae Crosby、Scott Dickerson、Matthew Tallant、Rick Grimes、Robert Hamatake、Martin Leivers、Christopher D. Roberts、Jill Walker

  DOI：10.1021/jm4013104

  日期：2014.3.13

  [GRAPHICS]Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSIC2236805) supported high potency against genotypes la and lb as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.