methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-N-((1s,4S)-4-hydroxycyclohexyl)-4-methylcyclohexanecarboxamido)thiophene-2-carboxylate | 1418215-07-2

• 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,4R)-N-((1s,4S)-4-hydroxycyclohexyl)-4-methylcyclohexanecarboxamido)thiophene-2-carboxylate
• CAS: 1418215-07-2
• 化学式: C₂₆H₃₇NO₄S
• 分子量: 459.65
• InChiKey: GNIBKVJTLKANCS-HKJRMUSSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  32.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  66.84
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-N-((1s,4S)-4-hydroxycyclohexyl)-4-methylcyclohexanecarboxamido)thiophene-2-carboxylate 在 sodium acetate 、 sodium hydride 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 12.5h， 生成 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(6-oxo-1,6-dihydropyridazin-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
• 作为产物：
  描述：

  methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(4-nitrobenzoyloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate 在 甲醇 、 potassium carbonate 作用下， 反应 4.0h， 以86%的产率得到methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-N-((1s,4S)-4-hydroxycyclohexyl)-4-methylcyclohexanecarboxamido)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：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。
• Thiophene analogues for the treatment or prevention of flavivirus infections
  申请人：Chan Chun Kong Laval

  公开号：US20080299080A1

  公开（公告）日：2008-12-04

  Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein R 1 , X, Y, and Z are as defined herein, are useful for treating flaviviridae viral infections.

  式I所代表的化合物，或其药用可接受的盐和溶剂化物，其中R1、X、Y和Z的定义如本文所述，可用于治疗黄病毒科病毒感染。
• THIOPHENE ANALOGUES FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
  申请人：Chan Chun Kong Laval

  公开号：US20120059170A1

  公开（公告）日：2012-03-08

  Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein R 1 , X, Y, and Z are as defined herein, are useful for treating flaviviridae viral infections.

  式I所代表的化合物或其药学上可接受的盐和溶剂合物，其中R1、X、Y和Z的定义如本文所述，可用于治疗黄病毒科病毒感染。
• Thiophene analogues for the treatment or prevention of Flavivirus infections
  申请人：Virochem Pharma Inc.

  公开号：EP2559691A1

  公开（公告）日：2013-02-20

  The present invention relates to compounds represented by formula IA or pharmaceutically acceptable salts and solvates thereof which are useful for treating flaviviridae viral infections wherein R1 is C1-6alkyl or C3-6 cycloalkyl; X is M is R5 is cyclohexyl which is unsubstituted or substituted one or more times by R13; R6 is or cyclohexyl which is substituted in the 4 position by R14; and Y, R14a and R14 are as defined herein.

  本发明涉及式 IA 所代表的化合物或其药学上可接受的盐和溶液，可用于治疗黄病毒科病毒感染，其中 R1 是 C1-6 烷基或 C3-6 环烷基；X 是 M 是 R5 是未被取代或被 R13 取代一次或多次的环己基；R6 是或在 4 位被 R14 取代的环己基；以及 Y、R14a 和 R14 如本文所定义。
• 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