5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester | 1163792-09-3

• 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: 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester
• 英文别名: 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester；(2S)-1-[2-(5-ethoxycarbonyl-2-phenylpyrazol-3-yl)oxyacetyl]pyrrolidine-2-carboxylic acid
• CAS: 1163792-09-3
• 化学式: C₁₉H₂₁N₃O₆
• 分子量: 387.392
• InChiKey: AXEUSGWMEKNMMT-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester 在 水 、 1-羟基苯并三唑 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 sodium hydroxide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 46.67h， 生成 4-[(S)-4-carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester
  参考文献：
  名称：

  Identification of High-Affinity P2Y₁₂ Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

  摘要：

  A series of novel, highly potent P2Y(12) antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure-activity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y(12) antagonists displaying not only low nanomolar binding affinity to the P2Y(12) receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC50 values below 50 nM. Using a homology and a three-dimensional quantitative structure-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.

  DOI：

  10.1021/jm300771j
• 作为产物：
  描述：

  ethyl 3-oxo-2-phenyl-1H-pyrazole-5-carboxylate 在 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 caesium carbonate 、 1,2-二氯乙烷 、 N,N-二异丙基乙胺 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、300.01 kPa 条件下， 反应 43.0h， 生成 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester
  参考文献：
  名称：

  Identification of High-Affinity P2Y₁₂ Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

  摘要：

  A series of novel, highly potent P2Y(12) antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure-activity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y(12) antagonists displaying not only low nanomolar binding affinity to the P2Y(12) receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC50 values below 50 nM. Using a homology and a three-dimensional quantitative structure-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.

  DOI：

  10.1021/jm300771j

文献信息

• Heterocyclic pyrazole-carboxamidesas P2Y12 antagonists
  申请人：Nazaré Marc

  公开号：US08426420B2

  公开（公告）日：2013-04-23

  The present invention relates to compounds of the formula I, wherein R1; R2; Z; A; B; D; Q; J; V; G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong anti-aggregating effect on platelets and thus an anti-thrombotic effect and are suitable, e.g., for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible antagonists of the platelet ADP receptor P2Y12, and can in general be applied in conditions in which an undesired activation of the platelet ADP receptor P2Y12 is present or for the cure or prevention of which an inhibition of the platelet ADP receptor P2Y12 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

  本发明涉及式I的化合物，其中R1; R2; Z; A; B; D; Q; J; V; G和M具有声明中指示的含义。式I的化合物是有价值的药理活性化合物。它们表现出强烈的抗血小板聚集作用，因此具有抗血栓作用，适用于治疗和预防心血管疾病，如血栓栓塞性疾病或再狭窄。它们是血小板ADP受体P2Y12的可逆拮抗剂，通常可应用于存在血小板ADP受体P2Y12的不良激活或预防其抑制的情况的治疗或预防。本发明还涉及制备式I化合物的过程，它们的使用，特别是作为药物中的活性成分，以及包含它们的制药制剂。
• HETEROCYCLIC PYRAZOLE-CARBOXAMIDESAS P2Y12 ANTAGONISTS
  申请人：Nazaré Marc

  公开号：US20110021537A1

  公开（公告）日：2011-01-27

  The present invention relates to compounds of the formula I, wherein R1; R2; Z; A; B; D; Q; J; V; G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong anti-aggregating effect on platelets and thus an anti-thrombotic effect and are suitable, e.g., for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible antagonists of the platelet ADP receptor P2Y12, and can in general be applied in conditions in which an undesired activation of the platelet ADP receptor P2Y12 is present or for the cure or prevention of which an inhibition of the platelet ADP receptor P2Y12 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

  本发明涉及式I的化合物，其中R1；R2；Z；A；B；D；Q；J；V；G和M具有所述声明中指示的含义。式I的化合物是有价值的药理活性化合物。它们对血小板具有强烈的抗聚集作用，因此具有抗血栓作用，适用于治疗和预防心血管疾病，如血栓栓塞性疾病或再狭窄。它们是血小板ADP受体P2Y12的可逆拮抗剂，并且通常适用于存在不希望的血小板ADP受体P2Y12激活的情况，或者用于治疗或预防需要抑制血小板ADP受体P2Y12的情况。此外，本发明还涉及式I化合物的制备方法，它们的用途，特别是作为药物中的活性成分，以及包含它们的制剂。
• [EN] HETEROCYCLIC PYRAZOLE-CARBOXAMIDES AS P2Y12 ANTAGONISTS<br/>[FR] PYRAZOLE-CARBOXAMIDES HÉTÉROCYCLIQUES UTILISÉS EN TANT QU'ANTAGONISTES DU RÉCEPTEUR P2Y12
  申请人：SANOFIS AVENTIS

  公开号：WO2009080226A3

  公开（公告）日：2009-08-27
• HETEROCYCLIC PYRAZOLE-CARBOXAMIDES AS P2Y12 ANTAGONISTS
  申请人：Sanofi-Aventis

  公开号：EP2238128A2

  公开（公告）日：2010-10-13
• US8426420B2
  申请人：——

  公开号：US8426420B2

  公开（公告）日：2013-04-23