4-((S)-2-benzyloxycarbonylamino-4-cyanobutyryl)piperazine-1-carboxylic acid ethyl ester | 1021703-32-1

• 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-((S)-2-benzyloxycarbonylamino-4-cyanobutyryl)piperazine-1-carboxylic acid ethyl ester
• 英文别名: ethyl 4-[(2S)-4-cyano-2-(phenylmethoxycarbonylamino)butanoyl]piperazine-1-carboxylate
• CAS: 1021703-32-1
• 化学式: C₂₀H₂₆N₄O₅
• 分子量: 402.45
• InChiKey: VHYFWBFGVVNKHA-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-((S)-2-benzyloxycarbonylamino-4-cyanobutyryl)piperazine-1-carboxylic acid ethyl ester 在 5%-palladium/activated carbon 作用下， 以 乙醇 为溶剂， 反应 24.0h， 以100%的产率得到4-((S)-2-amino-4-cyanobutyryl)piperazine-1-carboxylic acid ethyl 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
• 作为产物：
  描述：

  4-((S)-2-benzyloxycarbonylamino-4-carbamoylbutyryl)piperazine-1-carboxylic acid ethyl ester 在 吡啶 、 苯磺酰氯 作用下， 反应 1.0h， 以84%的产率得到4-((S)-2-benzyloxycarbonylamino-4-cyanobutyryl)piperazine-1-carboxylic acid ethyl ester
  参考文献：
  名称：

  2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR

  摘要：

  这项发明涉及2-苯基-6-氨基羰基嘧啶衍生物及其作为P2Y12受体拮抗剂在治疗和/或预防和/或治疗外周血管、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疾病或病况的用途，包括人类和其他哺乳动物中的血栓形成。公式（1）。

  公开号：

  US20090291962A1

文献信息

• 2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2079711A2

  公开（公告）日：2009-07-22
• US8044055B2
  申请人：——

  公开号：US8044055B2

  公开（公告）日：2011-10-25
• [EN] 2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES<br/>[FR] DÉRIVÉS DE 2-PHÉNYL-6-AMINOCARBONYL-PYRIMIDINE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2008050301A2

  公开（公告）日：2008-05-02

  [EN] The invention relates to 2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y₁₂ receptor antagonists in the treatment and/or prevention and/or treatment 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.
  [FR] La présente invention concerne des dérivés de 2-phényl-6-aminocarbonyl-pyrimidine et leur utilisation en tant qu'antagonistes de récepteur P2Y₁₂ dans le traitement et/ou la prévention et/ou le traitement de maladies et états vasculaires périphériques, viscéro-, hépato- et rénovasculaires, cardiovasculaires et cérébrovasculaires associés à l'agrégation plaquettaire, tels que la thrombose chez les êtres humains et autres mammifères.