5-(3,3-dimethylbut-1-ynyl)-3-((1R,2S,4R)-2-hydroxy-4-methyl-N-((1r,4R)-4-(tetrahydrofuran-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylic acid | 1263101-14-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 5-(3,3-dimethylbut-1-ynyl)-3-((1R,2S,4R)-2-hydroxy-4-methyl-N-((1r,4R)-4-(tetrahydrofuran-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylic acid
• CAS: 1263101-14-9
• 化学式: C₂₉H₄₁NO₆S
• 分子量: 531.714
• InChiKey: APLSYWRPVJPTPS-DPUUIYIISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.09
• 重原子数：
  37.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  96.3
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  5-(3,3-dimethylbut-1-ynyl)-3-((1R,2S,4R)-2-hydroxy-4-methyl-N-((1r,4R)-4-(tetrahydrofuran-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylic acid 在 potassium tert-butylate 、 sodium hydride 作用下， 以 N-甲基吡咯烷酮 、 二甲基亚砜 、 mineral oil 为溶剂， 反应 27.5h， 生成 methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1S,4r)-4-hydroxy-4-(((S)-tetrahydrofuran-3-yloxy)methyl)cyclohexylamino)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
• 作为产物：
  描述：

  methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate 在 盐酸 、 三乙基硅烷 、 iron(III) chloride 、 二丁基二氯化锡 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 生成 5-(3,3-dimethylbut-1-ynyl)-3-((1R,2S,4R)-2-hydroxy-4-methyl-N-((1r,4R)-4-(tetrahydrofuran-3-yloxy)cyclohexyl)cyclohexanecarboxamido)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

文献信息

• INHIBITORS OF FLAVIVIRIDAE VIRUSES
  申请人：Canales Eda

  公开号：US20110020278A1

  公开（公告）日：2011-01-27

  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I式化合物： 及其药用可接受的盐和酯。所提供的化合物、组合物和方法对于治疗黄病毒科病毒感染，特别是丙型肝炎感染，是有用的。
• 5-ALKINYLTHIEN-2-YLCARBOXYLIC ACIDS AS INHIBITORS OF FLAVIVIRIDAE VIRUSES
  申请人：Gilead Sciences, Inc.

  公开号：EP2475657B1

  公开（公告）日：2013-06-12
• US8569302B2
  申请人：——

  公开号：US8569302B2

  公开（公告）日：2013-10-29
• [EN] INHIBITORS OF FLAVIVIRIDAE VIRUSES<br/>[FR] INHIBITEURS DE VIRUS FLAVIVIRIDAE
  申请人：GILEAD SCIENCES INC

  公开号：WO2011011303A1

  公开（公告）日：2011-01-27

  Provided are compounds of Formula I: (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.