3-[2-(7-methoxy-3,3-dimethyl-4-phenyl-2,3-dihydro-1H-indol-1-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]urea | 1617504-99-0

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 3-[2-(7-methoxy-3,3-dimethyl-4-phenyl-2,3-dihydro-1H-indol-1-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]urea
• CAS: 1617504-99-0
• 化学式: C₃₁H₂₈F₃N₃O₃
• 分子量: 547.577
• InChiKey: HYZNWRHMKUWVQA-UHFFFAOYSA-N

物化性质

• 沸点：
  585.9±50.0 °C(predicted)
• 密度：
  1.296±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.33
• 重原子数：
  40.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  62.83
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  3-[2-(7-methoxy-3,3-dimethyl-4-phenyl-2,3-dihydro-1H-indol-1-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]urea 在 三溴化硼-二甲基硫醚 三溴甲基硫化硼 、 盐酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 17.0h， 以14%的产率得到1-(2-(7-hydroxy-3,3-dimethyl-4-phenylindolin-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea
  参考文献：
  名称：

  Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y₁ Antagonists as Novel Antiplatelet Agents

  摘要：

  Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y(12) and P2Y(1). Blocking P2Y(12) receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y(1) antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y(12) inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y(1) antagonist, I. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y(12) antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y(1) antagonism as a promising new antiplatelet target.

  DOI：

  10.1021/jm5006226
• 作为产物：
  描述：

  (5-bromo-2-methoxyphenyl)hydrazine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 硫酸 、 sodium carbonate 、 氯化铵 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 锌 作用下， 以 乙醇 、 甲醚 、 二氯甲烷 、 甲苯 为溶剂， 反应 85.75h， 生成 3-[2-(7-methoxy-3,3-dimethyl-4-phenyl-2,3-dihydro-1H-indol-1-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]urea
  参考文献：
  名称：

  Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y₁ Antagonists as Novel Antiplatelet Agents

  摘要：

  Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y(12) and P2Y(1). Blocking P2Y(12) receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y(1) antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y(12) inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y(1) antagonist, I. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y(12) antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y(1) antagonism as a promising new antiplatelet target.

  DOI：

  10.1021/jm5006226