butyl 4-[(2S)-2-amino-3-hydroxypropanoyl]piperazine-1-carboxylate | 1019929-42-0

• 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: butyl 4-[(2S)-2-amino-3-hydroxypropanoyl]piperazine-1-carboxylate
• CAS: 1019929-42-0
• 化学式: C₁₂H₂₃N₃O₄
• 分子量: 273.332
• InChiKey: MVZVNGNBRYWZPX-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  96.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  butyl 4-[(2S)-2-amino-3-hydroxypropanoyl]piperazine-1-carboxylate 、 6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 反应 0.25h， 生成 4-((S)-3-hydroxy-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

• QUINOLINE-CARBOXAMIDE DERIVATIVES AS P2Y12 ANTAGONISTS
  申请人：Nazaré Marc

  公开号：US20100135999A1

  公开（公告）日：2010-06-03

  The present invention relates to compounds of the formula I, in which R 1 ; R 2 ; R 3 ; R 4 ; R 5 ; R 6 ; Z; A; B; E; X; 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.

  本发明涉及公式I的化合物，其中R1; R2; R3; R4; R5; R6; Z; A; B; E; X; Q; J; V; G和M具有所述声明中指示的含义。公式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，从而具有抗血栓作用，适用于治疗和预防心血管疾病，如血栓栓塞病或再狭窄。它们是血小板ADP受体P2Y12的可逆拮抗剂，通常适用于存在不良激活血小板ADP受体P2Y12的情况，或者治愈或预防需要抑制血小板ADP受体P2Y12的情况。此外，本发明还涉及制备公式I化合物的方法，它们的用途，特别是作为药物中的活性成分，以及包含它们的制药制剂。
• 2-AMINOCARBONYL-PYRIDINE DERIVATIVES
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2081903A2

  公开（公告）日：2009-07-29
• US8669266B2
  申请人：——

  公开号：US8669266B2

  公开（公告）日：2014-03-11
• [EN] 2-AMINOCARBONYL-PYRIDINE DERIVATIVES<br/>[FR] DÉRIVÉS DE 2-AMINOCARBONYL-PYRIDINE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2008044217A2

  公开（公告）日：2008-04-17

  [EN] The present invention relates to 2-aminocarbonyl-pyridine derivatives and their use as P2Yi2 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.
  [FR] La présente invention concerne des dérivés de 2-aminocarbonyl-pyridine et leur utilisation en tant qu'antagonistes du récepteur de P2Yi2 dans le traitement et/ou la prévention de maladies ou d'affections vasculaires périphériques, viscéro-vasculaires, hépato-vasculaires et vasculaires rénales, cardiovasculaires et cérébro-vasculaires associées à l'agrégation des plaquettes, y compris la thrombose, chez les humains et d'autres mammifères.
• [EN] QUINOLINE-CARBOXAMIDE DERIVATIVES AS P2Y12 ANTAGONISTS<br/>[FR] DÉRIVÉS DE QUINOLÉINE-CARBOXAMIDE COMME ANTAGONISTES DE P2Y12
  申请人：SANOFI AVENTIS

  公开号：WO2008128647A1

  公开（公告）日：2008-10-30

  [EN] The present invention relates to compounds of the Formula (I), in which R¹; R²; R³; R⁴; R⁵; R⁶; Z; A; B; E; X; 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.
  [FR] La présente invention porte sur des composés de la Formule (I), dans laquelle R¹; R²; R³; R⁴; R⁵; R⁶; Z; A; B; E; X; Q; J; V; G et M ont les significations indiquées dans les revendications. Les composés de la formule I sont des composés pharmacologiquement actifs de valeur. Lesdits composés présentent un fort effet anti-agrégation sur des plaquettes ainsi qu'un effet anti-thrombotique et sont appropriés, par exemple, à la thérapie et à la prophylaxie de troubles cardio-vasculaires comme des maladies thrombo-emboliques ou des resténoses. Lesdits composés sont des antagonistes réversibles du récepteur de l'ADP des plaquettes P2Y12, et peuvent en général être appliqués dans des états dans lesquels une activation indésirée du récepteur de l'ADP des plaquettes P2Y12 est présente, ou des états dont la cure ou la prévention requiert le récepteur de l'ADP des plaquettes P2Y12. L'invention porte également sur des procédés de préparation de composés de la formule I, sur leur utilisation, en particulier comme principes actifs dans des produits pharmaceutiques, et sur des préparations pharmaceutiques les comprenant.