4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1(2H)-one | 1297285-26-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1(2H)-one
• 英文别名: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1-one；4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1-one
• CAS: 1297285-26-7
• 化学式: C₁₉H₂₃BF₃NO₃
• 分子量: 381.203
• InChiKey: BYEXJDRQYKUJGG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.64
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-(5-fluoro-3-iodo-2-methyl-1H-indol-1-yl)acetate 、 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1(2H)-one 在 potassium phosphate monohydrate 、 palladium diacetate 、 2-二环己基磷-2,4,6-三异丙基联苯 、 sodium hydroxide 作用下， 以 水 、 正丁醇 、 四氢呋喃 、 甲醇 为溶剂， 反应 18.33h， 生成
  参考文献：
  名称：

  Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

  摘要：

  Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).

  DOI：

  10.1021/jm401509e
• 作为产物：
  描述：

  1-羟基异喹啉 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 silver trifluoromethanesulfonate 、 碘 、 potassium acetate 、 caesium carbonate 、 溶剂黄146 、 potassium hydroxide 作用下， 以 乙醚 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4,4,4-trifluorobutyl)isoquinolin-1(2H)-one
  参考文献：
  名称：

  Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

  摘要：

  Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).

  DOI：

  10.1021/jm401509e

文献信息

• Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases
  作者：Neelu Kaila、Bruce Follows、Louis Leung、Jennifer Thomason、Adrian Huang、Alessandro Moretto、Kristin Janz、Michael Lowe、Tarek S. Mansour、Cedric Hubeau、Karen Page、Paul Morgan、Susan Fish、Xin Xu、Cara Williams、Eddine Saiah

  DOI：10.1021/jm401509e

  日期：2014.2.27

  Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).