4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)-2,3-dihydro-1H-indole | 1555701-57-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)-2,3-dihydro-1H-indole
• 英文别名: 4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)indoline；4-Bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)indoline；4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)-2H-indole
• CAS: 1555701-57-9
• 化学式: C₁₇H₁₇BrN₂O₃
• 分子量: 377.238
• InChiKey: VSSSKZPZRCQERE-UHFFFAOYSA-N

物化性质

• 沸点：
  494.1±45.0 °C(Predicted)
• 密度：
  1.427±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  58.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)-2,3-dihydro-1H-indole 在 四(三苯基膦)钯 、 叠氮磷酸二苯酯 、 sodium carbonate 、 氯化铵 、 三乙胺 、 锌 作用下， 以 甲醇 、 乙酸乙酯 、 甲苯 为溶剂， 反应 52.0h， 生成 1-(2-(4-(4-fluorophenyl)-7-methoxy-3,3-dimethylindolin-1-yl)phenyl)-3-(2-methylthiazol-4-yl)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-溴-2-甲氧基苯胺 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 硫酸 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium nitrite 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 18.75h， 生成 4-bromo-7-methoxy-3,3-dimethyl-1-(2-nitrophenyl)-2,3-dihydro-1H-indole
  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

文献信息

• [EN] 7-HYDROXY-INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR<br/>[FR] ANTAGONISTES DE 7-HYDROXY-INDOLINYLE DU RÉCEPTEUR P2Y1
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014022343A1

  公开（公告）日：2014-02-06

  The present invention provides compounds of Formula (I): Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are antagonists of P2Y1 receptor which may be used medicaments.

  本发明提供了Formula (I)的化合物：如规范中定义的Formula (I)，以及包含任何此类新化合物的组合物。这些化合物是P2Y1受体的拮抗剂，可用作药物。
• 7-HYDROXY-INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150259286A1

  公开（公告）日：2015-09-17

  The present invention provides compounds of Formula (I): Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are antagonists of P2Y 1 receptor which may be used medicaments.

  本发明提供了化合物(I)的公式：公式(I)如规范中定义的以及包含任何此类新型化合物的组成物。这些化合物是P2Y1受体的拮抗剂，可用作药物。
• US9540323B2
  申请人：——

  公开号：US9540323B2

  公开（公告）日：2017-01-10
• Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y₁ Antagonists as Novel Antiplatelet Agents
  作者：Wu Yang、Yufeng Wang、Amy Lai、Jennifer X. Qiao、Tammy C. Wang、Ji Hua、Laura A. Price、Hong Shen、Xue-qing Chen、Pancras Wong、Earl Crain、Carol Watson、Christine S. Huang、Dietmar A. Seiffert、Robert Rehfuss、Ruth R. Wexler、Patrick Y. S. Lam

  DOI：10.1021/jm5006226

  日期：2014.7.24

  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.