1-(4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2,2-dimethylpropan-1-one | 1557209-51-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 1-(4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2,2-dimethylpropan-1-one
• 英文别名: 1-[4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-yl]-2,2-dimethylpropan-1-one；1-[4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)spiro[2H-indole-3,4'-piperidine]-1'-yl]-2,2-dimethylpropan-1-one
• CAS: 1557209-51-4
• 化学式: C₂₄H₂₇BrFN₃O₄
• 分子量: 520.398
• InChiKey: KEORKCXRQDTGNE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  78.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2,2-dimethylpropan-1-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium carbonate 、 potassium carbonate 、 氯化铵 、 红铝 、 锌 作用下， 以 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 乙酸乙酯 、 1,2-二氯乙烷 为溶剂， 反应 70.5h， 生成 1-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-3-(2-(5-fluoro-4-(4-fluorophenyl)-7-methoxy-1'-neopentylspiro[indoline-3,4'-piperidin]-1-yl)phenyl)urea
  参考文献：
  名称：

  [EN] 7-HYDROXY-SPIROPIPIPERIDINE INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR
  [FR] ANTAGONISTES DE 7-HYDROXY-SPIROPIPIPÉRIDINE INDOLINYLE DU RÉCEPTEUR P2Y1

  摘要：

  本发明提供了如规范中定义的Formula (I)的化合物，以及包含任何此类新化合物的组合物。这些化合物是Ρ2Y1受体的拮抗剂，可用作治疗和/或预防血栓栓塞性疾病的药物。

  公开号：

  WO2014022349A1
• 作为产物：
  描述：

  (5-bromo-4-fluoro-2-methoxyphenyl)hydrazine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 16.17h， 生成 1-(4-bromo-5-fluoro-7-methoxy-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]-1'-yl)-2,2-dimethylpropan-1-one
  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-SPIROPIPIPERIDINE INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR<br/>[FR] ANTAGONISTES DE 7-HYDROXY-SPIROPIPIPÉRIDINE INDOLINYLE DU RÉCEPTEUR P2Y1
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014022349A1

  公开（公告）日：2014-02-06

  The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are antagonists of Ρ2Y1 receptor and may be used as medicaments in the treatment and/or prophylaxis of thromboembolic disorders.

  本发明提供了如规范中定义的Formula (I)的化合物，以及包含任何此类新化合物的组合物。这些化合物是Ρ2Y1受体的拮抗剂，可用作治疗和/或预防血栓栓塞性疾病的药物。
• 7-HYDROXY-SPIROPIPIPERIDINE INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150166538A1

  公开（公告）日：2015-06-18

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

  本发明提供了式(I)的化合物：如规范中定义的和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，可用作治疗和/或预防血栓栓塞性疾病的药物。
• US9428504B2
  申请人：——

  公开号：US9428504B2

  公开（公告）日：2016-08-30
• 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.