1-[(2-bromo-3-cyclopentyl-1-methyl-lH-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid | 866096-48-2

• 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: 1-[(2-bromo-3-cyclopentyl-1-methyl-lH-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid
• 英文别名: 1-[(3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid；1-[(3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carbonyl)amino]cyclobutane-1-carboxylic acid
• CAS: 866096-48-2
• 化学式: C₂₅H₂₇N₃O₃
• 分子量: 417.508
• InChiKey: VACZUFQDYQLMPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  84.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-[(2-bromo-3-cyclopentyl-1-methyl-lH-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid 在 乙酸酐 、 溶剂黄146 作用下， 以 甲苯 为溶剂， 反应 0.67h， 生成 methyl (E)-3-[4-[[1-[(3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carbonyl)amino]cyclobutanecarbonyl]amino]-2-ethoxyphenyl]prop-2-enoate
  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：

  3-cyclopentyl-1-methyl-2-tributylstannanyl-1H-indole-6-carboxylic acid methyl ester 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 sodium hydroxide 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.22h， 生成 1-[(2-bromo-3-cyclopentyl-1-methyl-lH-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid
  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] PROCESS FOR CROSS COUPLING INDOLES<br/>[FR] PROCEDE DE COUPLAGE CROISE D'INDOLES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2005092855A1

  公开（公告）日：2005-10-06

  The present invention provides a process for making a compound of general formula (I) wherein: R = H or C1-8 alkyl X = C3 -C8 cycloalkyl, C3 -C8 aryl or C3 -C8 alkyl; Y = heteroaryl or aryl; Z = H, HO2C-, C1-8 alkyl O2C-, C1-6 alkyl HNC(O)- and as described herein.

  本发明提供了一种制备通式(I)化合物的方法，其中：R = H或C1-8烷基；X = C3-C8环烷基，C3-C8芳基或C3-C8烷基；Y = 杂芳基或芳基；Z = H，HO2C-，C1-8烷基O2C-，C1-6烷基HNC(O)-，以及如本文所述。
• Process for cross coupling indoles
  申请人：Khodabocus Ahmad

  公开号：US20050234242A1

  公开（公告）日：2005-10-20

  The present invention provides a process for making a compound of general formula I: wherein: R=H or C 1-8 alkyl X=C 3 -C 8 cycloalkyl, C 3 -C 8 aryl or C 3 -C 8 alkyl; Y=heteroaryl or aryl; Z=H, HO 2 C—, C 1-8 alkyl O 2 C—, C 1-6 alkyl HNC(O)—, and as described herein.

  本发明提供了一种制备通式I化合物的过程：其中：R = H或C1-8烷基，X = C3-C8环烷基，C3-C8芳基或C3-C8烷基; Y = 杂环芳基或芳基; Z = H，HO2C—，C1-8烷基O2C—，C1-6烷基HNC（O）—，并如本文所述。
• PROCESS FOR CROSS COUPLING INDOLES
  申请人：Boehringer Ingelheim Pharmaceuticals Inc.

  公开号：EP1727797B1

  公开（公告）日：2012-05-30
• US7332614B2
  申请人：——

  公开号：US7332614B2

  公开（公告）日：2008-02-19
• 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.