6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid | 1159501-69-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid
• 英文别名: (S)-6-(3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid；6-[(3S)-3-methoxypyrrolidin-1-yl]-2-phenylpyrimidine-4-carboxylic acid
• CAS: 1159501-69-5
• 化学式: C₁₆H₁₇N₃O₃
• 分子量: 299.329
• InChiKey: QGYHTJSIWLWSRN-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  75.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid 在 lithium hydroxide monohydrate 、 5% palladium on barium sulphate 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 1.33h， 生成 4-((S)-3-(3-hydroxyisoxazol-5-yl)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}propionyl)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-氯-6-(甲氧基甲基)-2-苯基嘧啶 在 potassium permanganate 、 三溴化硼 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 3.5h， 生成 6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid
  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
• 作为试剂：
  描述：

  4-((R)-2-amino-3-diethoxyphosphorylpropionyl)piperazine-1-carboxylic acid butyl ester hydrochloride 、 6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid 在 6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid 作用下， 生成 butyl 4-((R)-3-(diethoxyphosphoryl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carboxamido)propanoyl)piperazine-1-carboxylate
  参考文献：
  名称：

  Phosphonic acid derivates and their use as P2Y12 receptor antagonists

  摘要：

  本发明涉及含有磷酸基团的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疾病或情况，包括人类和其他哺乳动物中的血栓形成的用途。 (I)。

  公开号：

  US08518912B2

文献信息

• [EN] PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS D'ACIDE PHOSPHONIQUE ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DU RÉCEPTEUR P2Y12
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2009069100A1

  公开（公告）日：2009-06-04

  The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 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).

  这项发明涉及含有膦酸基团的2-苯基嘧啶衍生物，以及它们作为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疾病或状况中的使用，包括人类和其他哺乳动物中的血栓形成。（I）。
• [EN] CRYSTALLINE FORMS<br/>[FR] FORMES CRISTALLINES
  申请人：IDORSIA PHARMACEUTICALS LTD

  公开号：WO2018055016A1

  公开（公告）日：2018-03-29

  The invention relates to crystalline forms of 4-((R)-2-[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y12 receptor antagonist.

  该发明涉及4-((R)-2-[6-((S)-3-甲氧基吡咯啉-1-基)-2-苯基嘧啶-4-羰基]-氨基}-3-磷酸-丙酰)-哌嗪-1-羧酸丁酯盐的结晶形式，其制备方法，包括所述结晶形式的药物组合物，由这些结晶形式制备的药物组合物及其作为药物的用途，特别是作为P2Y12受体拮抗剂。
• [EN] SUBCUTANEOUS ADMINISTRATION OF A P2Y12 RECEPTOR ANTAGONIST<br/>[FR] ADMINISTRATION SOUS-CUTANÉE D'UN ANTAGONISTE DU RÉCEPTEUR P2Y12
  申请人：IDORSIA PHARMACEUTICALS LTD

  公开号：WO2018167139A1

  公开（公告）日：2018-09-20

  The present invention relates to a P2Y12 receptor antagonist selected from the group consisting of4-((R)-2-[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, (1S,2S,3R,5S)-3- [7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, and (1S,2R,3S,4R)-4-[7- [(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol, or a pharmaceutically acceptable salt thereof, for use as a medicament by subcutaneous or intradermal administration.

  本发明涉及一种P2Y12受体拮抗剂，所述拮抗剂选自以下组合物：4-((R)-2-[6-((S)-3-甲氧基吡咯烷-1-基)-2-苯基嘧啶-4-羰基]-氨基}-3-磷酸基丙酰基)-哌嗪-1-羧酸丁酯，(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙基氨基]-5-(丙基硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-5-(2-羟乙氧基)环戊烷-1,2-二醇，以及(1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙基氨基]-5-(丙基硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基]环戊烷-1,2,3-三醇，或其药学上可接受的盐，用于皮下或皮内给药的药物。
• 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)。
• Crystalline forms
  申请人：IDORSIA PHARMACEUTICALS LTD

  公开号：US10730896B2

  公开（公告）日：2020-08-04

  The invention relates to crystalline forms of 4-((R)-2-[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4 carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y12 receptor antagonist.

  本发明涉及 4-((R)-2-[6-((S)-3-甲氧基-吡咯烷-1-基)-2-苯基-嘧啶-4-羰基]-氨基}-3-膦酰基丙酰基)-哌嗪-1-羧酸丁酯盐酸盐的结晶形式、其制备工艺、包含上述结晶形式的药物组合物、由上述结晶形式制备的药物组合物及其作为药物（尤其是作为 P2Y12 受体拮抗剂）的用途。