methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4S)-4-methyl-N-((1S,4R)-4-((1r,4S)-4-methylcyclohexanecarbonyloxy)-4-(((S)-tetrahydrofuran-3-yloxy)methyl)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate | 1314795-30-6

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4S)-4-methyl-N-((1S,4R)-4-((1r,4S)-4-methylcyclohexanecarbonyloxy)-4-(((S)-tetrahydrofuran-3-yloxy)methyl)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate
• CAS: 1314795-30-6
• 化学式: C₃₉H₅₇NO₇S
• 分子量: 683.95
• InChiKey: SFXOJIIFHQBYIN-JYTVEGHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.95
• 重原子数：
  48.0
• 可旋转键数：
  9.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  91.37
• 氢给体数：
  0.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4S)-4-methyl-N-((1S,4R)-4-((1r,4S)-4-methylcyclohexanecarbonyloxy)-4-(((S)-tetrahydrofuran-3-yloxy)methyl)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 以36%的产率得到5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methylcyclohexanecarbonyloxy)-4-(tetrahydro-furan-3-yloxymethy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid
  参考文献：
  名称：

  Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

  摘要：

  Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

  DOI：

  10.1021/jm401420j
• 作为产物：
  描述：

  methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate 在 吡啶 、 盐酸 、 三乙基硅烷 、 iron(III) chloride 、 二丁基二氯化锡 、 potassium tert-butylate 、 sodium hydride 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 28.25h， 生成 methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4S)-4-methyl-N-((1S,4R)-4-((1r,4S)-4-methylcyclohexanecarbonyloxy)-4-(((S)-tetrahydrofuran-3-yloxy)methyl)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate
  参考文献：
  名称：

  Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

  摘要：

  Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

  DOI：

  10.1021/jm401420j

文献信息

• INHIBITORS OF FLAVIVIRIDAE VIRUSES
  申请人：Canales Eda

  公开号：US20110178129A1

  公开（公告）日：2011-07-21

  Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.

  提供的是式I的化合物及其药学上可接受的盐和酯。所提供的化合物、组合物和方法对于治疗黄热病毒感染，尤其是丙型肝炎感染非常有用。
• US8513298B2
  申请人：——

  公开号：US8513298B2

  公开（公告）日：2013-08-20
• US9321753B2
  申请人：——

  公开号：US9321753B2

  公开（公告）日：2016-04-26