(2-Formyl-5-nitrophenyl) 2,2-dimethylpropanoate | 874676-60-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2-Formyl-5-nitrophenyl) 2,2-dimethylpropanoate
• CAS: 874676-60-5
• 化学式: C₁₂H₁₃NO₅
• 分子量: 251.239
• InChiKey: OPFJBMBSRPOBGS-UHFFFAOYSA-N

物化性质

• 沸点：
  387.5±37.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  89.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2-Formyl-5-nitrophenyl) 2,2-dimethylpropanoate 在 硫酸 、 sodium hydride 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 1.67h， 生成 (E)-3-[2-(2-methoxyethoxy)-4-nitrophenyl]acrylic acid methyl ester
  参考文献：
  名称：

  Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection

  摘要：

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

  DOI：

  10.1021/jm501532z
• 作为产物：
  描述：

  2-羟基-4-硝基苄醇 在 manganese(IV) oxide 、 三乙胺 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 5.92h， 生成 (2-Formyl-5-nitrophenyl) 2,2-dimethylpropanoate
  参考文献：
  名称：

  Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection

  摘要：

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

  DOI：

  10.1021/jm501532z

文献信息

• [EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE LA POLYMERASE VIRALE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2006007693A1

  公开（公告）日：2006-01-26

  A compound, represented by formula (I) or an enantiomer, diastereoisomer or tautomer thereof : wherein either A or B is nitrogen and the other B or A is C, and the radicals R1, R2, R3, R5, R6, R7, R9, and R10 are as defined herein, or a salt, ester or derivative thereof as viral polymerase inhibitors. The compound is used as an inhibitor of RNA dependent RNA polymerases, particulary those viral polymerases within the Flaviviridae family, more particulary to HCV polymerase.

  一种化合物，由化学式(I)表示，或其对映体、顺反异构体或互变异构体：其中A或B是氮，另一个是B或A是C，基团R1、R2、R3、R5、R6、R7、R9和R10如本文所定义，或其盐、酯或衍生物作为病毒聚合酶抑制剂。该化合物被用作RNA依赖性RNA聚合酶的抑制剂，特别是在黄病毒科家族中的病毒聚合酶，更具体地说是HCV聚合酶。
• Viral Polymerase Inhibitors
  申请人：BEAULIEU Pierre

  公开号：US20070249629A1

  公开（公告）日：2007-10-25

  A compound, represented by formula (I): wherein A, B, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , and R 10 are as defined herein, or an enantiomer, diastereoisomer or tautomer thereof, including a salt, ester or derivative thereof, as an inhibitor of HCV NS5B polymerase.

  一种化合物，用公式(I)表示：其中A，B，R1，R2，R3，R5，R6，R7，R9和R10如本文所定义，或其对映异构体、顺反异构体或互变异构体，包括其盐、酯或衍生物，作为HCV NS5B聚合酶的抑制剂。
• US7241801B2
  申请人：——

  公开号：US7241801B2

  公开（公告）日：2007-07-10
• Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection
  作者：Pierre L. Beaulieu、Paul C. Anderson、Richard Bethell、Michael Bös、Yves Bousquet、Christian Brochu、Michael G. Cordingley、Gulrez Fazal、Michel Garneau、James R. Gillard、Stephen Kawai、Martin Marquis、Ginette McKercher、Marc-André Poupart、Timothy Stammers、Bounkham Thavonekham、Dominik Wernic、Jianmin Duan、George Kukolj

  DOI：10.1021/jm501532z

  日期：2014.12.11

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.