4-氯-6-氟喹啉-3-羧酸 | 179024-67-0

• 物质功能分类: 医药中间体 - 杂环化合物 - 喹啉类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 4-氯-6-氟喹啉-3-羧酸
• 英文名称: 4-chloro-6-fluoroquinoline-3-carboxylic acid
• CAS: 179024-67-0
• 化学式: C₁₀H₅ClFNO₂
• 分子量: 225.607
• InChiKey: NEMDTRIVHUEXJW-UHFFFAOYSA-N

物化性质

• 沸点：
  355.6±37.0 °C(Predicted)
• 密度：
  1.550±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-氯-6-氟喹啉-3-羧酸 在 盐酸 、 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (4-(cyclopropanecarbonyl)piperazin-1-yl)(4-(4,4-difluoropiperidin-1-yl)-6-fluoroquinolin-3-yl)methanone
  参考文献：
  名称：

  Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

  摘要：

  Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDHIAI) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.

  DOI：

  10.1021/acs.jmedchem.8b00270

文献信息

• DIAZEPINO-INDOLES INHIBITEURS DE PHOSPHODIESTERASES IV
  申请人：INSTITUT DE RECHERCHE JOUVEINAL (I.R.J)

  公开号：EP0785789A1

  公开（公告）日：1997-07-30
• [EN] DIAZEPINO-INDOLES AS PHOSPHODIESTERASE IV INHIBITORS<br/>[FR] DIAZEPINO-INDOLES INHIBITEURS DE PHOSPHODIESTERASES IV
  申请人：INSTITUT DE RECHERCHE JOUVEINAL

  公开号：WO1996011690A1

  公开（公告）日：1996-04-25

  (EN) The use of diazepino-indole derivatives of formula (I), wherein R is hydrogen, lower alkyl or lower alkoxy, and A is mono- to trisubstituted aryl or heteroaryl, and racemic forms, enantiomers and pharmaceutically acceptable salts thereof, containing novel products, for preparing drugs useful for treating disorders requiring therapy using phosphodiesterase IV inhibitors.(FR) Application de dérivés de diazépino-indoles de formule (I), dans laquelle: R est hydrogène, alkyle inférieur, alcoxy inférieur; A est aryle ou hétéroaryle mono- à tribsubstitué, leurs formes racémiques, leur énantiomères, et leurs sels pharmaceutiquement acceptables, qui comprennent de nouveaux produits, pour la préparation de médicaments destinés au traitement des affections relevant d'une thérapie par les inhibiteurs de phosphodiestérases IV.
• Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity
  作者：Shyh-Ming Yang、Natalia J. Martinez、Adam Yasgar、Carina Danchik、Catrine Johansson、Yuhong Wang、Bolormaa Baljinnyam、Amy Q. Wang、Xin Xu、Pranav Shah、Dorian Cheff、Xinran S. Wang、Jacob Roth、Madhu Lal-Nag、James E. Dunford、Udo Oppermann、Vasilis Vasiliou、Anton Simeonov、Ajit Jadhav、David J. Maloney

  DOI：10.1021/acs.jmedchem.8b00270

  日期：2018.6.14

  Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDHIAI) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.