4-((R)-3-(bis-((isopropoxy)carbonyloxymethoxy)phosphoryl)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}propionyl)piperazine-1-carboxylic acid butyl ester | 1159501-31-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-((R)-3-(bis-((isopropoxy)carbonyloxymethoxy)phosphoryl)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}propionyl)piperazine-1-carboxylic acid butyl ester
• 英文别名: 1-Piperazinecarboxylic acid, 4-((2R)-2-(((6-((3S)-3-methoxy-1-pyrrolidinyl)-2-phenyl-4-pyrimidinyl)carbonyl)amino)-10-methyl-4-((((1-methylethoxy)carbonyl)oxy)methoxy)-4-oxido-1,8-dioxo-5,7,9-trioxa-4-phosphaundec-1-yl)-, butyl ester；butyl 4-[(2R)-3-[bis(propan-2-yloxycarbonyloxymethoxy)phosphoryl]-2-[[6-[(3S)-3-methoxypyrrolidin-1-yl]-2-phenylpyrimidine-4-carbonyl]amino]propanoyl]piperazine-1-carboxylate
• CAS: 1159501-31-1
• 化学式: C₃₈H₅₅N₆O₁₄P
• 分子量: 850.86
• InChiKey: ZDPYSJCPGHHDID-SMCANUKXSA-N

物化性质

• 沸点：
  865.0±65.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  59
• 可旋转键数：
  24
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  224
• 氢给体数：
  1
• 氢受体数：
  17

制备方法与用途

ACT-281959（ACT281959）是ACT-246475的前体药物，后者是一种强效、选择性且可逆的P2Y12受体拮抗剂，其结合IC50值为1.0纳摩尔。

反应信息

• 作为产物：
  描述：

  butyl 4-((R)-3-(diethoxyphosphoryl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carboxamido)propanoyl)piperazine-1-carboxylate 在 N,N-二甲基丙烯基脲 、 三甲基溴硅烷 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 0.17h， 生成 4-((R)-3-(bis-((isopropoxy)carbonyloxymethoxy)phosphoryl)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}propionyl)piperazine-1-carboxylic acid butyl ester
  参考文献：
  名称：

  4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y₁₂ Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel

  摘要：

  Recent post hoc analyses of several clinical trials with P2Y(12) antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y(12) antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.

  DOI：

  10.1021/acs.jmedchem.5b00933

文献信息

• PHOSPHONIC ACID DERIVATES AD THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
  申请人：Caroff Eva

  公开号：US20100261678A1

  公开（公告）日：2010-10-14

  The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y 12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. (I).

  本发明涉及含有膦酸基团的2-苯基嘧啶衍生物及其作为P2Y12受体拮抗剂在治疗和/或预防外周血管、内脏、肝脏和肾脏血管、心血管和脑血管疾病或与血小板聚集有关的病症，包括人类和其他哺乳动物的血栓形成中的应用。(I)。
• PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2225253B1

  公开（公告）日：2012-06-27
• US8518912B2
  申请人：——

  公开号：US8518912B2

  公开（公告）日：2013-08-27