(2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-2-{[8-methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]-7-(methyloxy)-4-quinolinyl]oxy}-5,16-dioxo-6-({[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}amino)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide

• 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: (2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-2-{[8-methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]-7-(methyloxy)-4-quinolinyl]oxy}-5,16-dioxo-6-({[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}amino)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide
• 英文别名: (1S,4R,6S,14S,18R)-N-cyclopropylsulfonyl-18-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-2,15-dioxo-14-[(4-pyrrolidin-1-ylpiperidine-1-carbonyl)amino]-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxamide
• 化学式: C₄₈H₆₄N₈O₈S₂
• 分子量: 945.217
• InChiKey: AEAJJFLJXVBBLW-VWZOIZLJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  66
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  229
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  2-甲基-3-氨基-4-乙酰基苯甲醚 在 盐酸 、 偶氮二甲酸二异丙酯 、 potassium tert-butylate 、 N,N-二异丙基乙胺 、 三苯基膦 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 N,N'-羰基二咪唑 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 叔丁醇 为溶剂， 反应 76.33h， 生成 (2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-2-{[8-methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]-7-(methyloxy)-4-quinolinyl]oxy}-5,16-dioxo-6-({[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}amino)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide
  参考文献：
  名称：

  Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

  摘要：

  The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.

  DOI：

  10.1021/jm201278q

文献信息

• COMPOUNDS
  申请人：COOPER JOEL

  公开号：US20100196321A1

  公开（公告）日：2010-08-05

  The present invention features compounds of Formula (I) and (Ia), pharmaceutical compositions and use in the treatment of viral disease:

  这项发明涉及Formula (I)和(Ia)的化合物，药物组合物以及在治疗病毒性疾病中的应用。
• Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants
  作者：Wieslaw M. Kazmierski、Robert Hamatake、Maosheng Duan、Lois L. Wright、Gary K. Smith、Richard L. Jarvest、Jing-Jing Ji、Joel P. Cooper、Matthew D. Tallant、Renae M. Crosby、Katrina Creech、Amy Wang、Xianfeng Li、Suoming Zhang、Yong-Kang Zhang、Yang Liu、Charles Z. Ding、Yasheen Zhou、Jacob J. Plattner、Stephen J. Baker、Wei Bu、Liang Liu

  DOI：10.1021/jm201278q

  日期：2012.4.12

  The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.