8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid | 1225377-90-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
• 英文别名: 8-fluoro-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carboxylic acid
• CAS: 1225377-90-1
• 化学式: C₁₂H₉FN₂O₃
• mdl: MFCD16325382
• 分子量: 248.213
• InChiKey: UMPRUWXPVHHQIF-UHFFFAOYSA-N

物化性质

• 沸点：
  497.6±45.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4-fluoro-3-(2-(8-fluoro-N-(3-fluorobenzyl)-1 -methyl-1,4-dihydrochromeno[4,3-c]pyrazole3-carboxamido)acetamido) benzoic acid TRIS salt
  参考文献：
  名称：

  Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

  摘要：

  Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

  DOI：

  10.1021/acs.jmedchem.9b01621
• 作为产物：
  描述：

  6-氟-4-二氢色原酮 在 sodium hexamethyldisilazane 、 溶剂黄146 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 9.5h， 生成 8-fluoro-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid
  参考文献：
  名称：

  Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

  摘要：

  Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

  DOI：

  10.1021/acs.jmedchem.9b01621

文献信息

• [EN] COMPOSITIONS AND METHODS FOR MODULATING FARNESOID X RECEPTORS<br/>[FR] COMPOSITIONS ET PROCÉDÉS POUR MODULER DES RÉCEPTEURS FARNESOÏDE X
  申请人：IRM LLC

  公开号：WO2015069666A1

  公开（公告）日：2015-05-14

  The present invention relates to compounds of Formula I, a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).

  本发明涉及公式I的化合物，其立体异构体，对映异构体，药用可接受的盐或其氨基酸结合物；其中变量如本文所定义；以及它们的药物组合物，其作为法尼索酸X受体（FXR）活性调节剂是有用的。
• [EN] TRICYCLIC COMPOUNDS AS GLUTAMATE RECEPTOR MODULATORS<br/>[FR] COMPOSÉS TRICYCLIQUES COMME MODULATEURS DES RÉCEPTEURS DE GLUTAMATES
  申请人：GLAXO GROUP LTD

  公开号：WO2010049366A1

  公开（公告）日：2010-05-06

  Disclosed herein are compounds that may be negative allosteric modulators of metabotropic receptors-subtype 5, and methods of making and using same.

  本文披露的是可能是代谢型受体亚型5的负性别构调节剂的化合物，以及制备和使用这些化合物的方法。
• [EN] FUSED TRICYCLIC PYRAZOLE DERIVATIVES USEFUL FOR MODULATING FARNESOID X RECEPTORS<br/>[FR] DÉRIVÉS DE PYRAZOLE TRICYCLIQUES FUSIONNÉS UTILES POUR MODULER DES RÉCEPTEURS FARNÉSOÏDES X
  申请人：NOVARTIS AG

  公开号：WO2016174616A1

  公开（公告）日：2016-11-03

  The present invention relates to compounds of Formula I, a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).

  本发明涉及公式I的化合物、立体异构体、对映体、药用可接受的盐或其氨基酸结合物；其中变量如本文所定义；以及它们的药用组合物，用作法尼索尔X受体（FXR）活性调节剂。
• TRICYCLIC COMPOUNDS AS GLUTAMATE RECEPTOR MODULATORS
  申请人：Bertinato Peter

  公开号：US20110263588A1

  公开（公告）日：2011-10-27

  The present invention relates to compounds that may be negative allosteric modulators of metabotropic receptors-subtype 5, and methods of making and using same.

  本发明涉及可能是代谢型受体亚型5的负向变构调节剂的化合物，以及制备和使用它们的方法。
• Compositions and methods for modulating farnesoid X receptors
  申请人：NOVARTIS AG

  公开号：US10077240B2

  公开（公告）日：2018-09-18

  The present invention relates to compounds of Formula I, a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).

  本发明涉及式 I 的化合物、 其立体异构体、对映体、药学上可接受的盐或氨基酸共轭物；其中变量如本文所定义；以及它们的药物组合物，可用作法尼类固醇 X 受体（FXR）活性的调节剂。