9-((R)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one | 1260585-26-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 9-((R)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
• 英文别名: (8s)-9-[(2r)-2-Hydroxy-2-Phenylethyl]-2-(Morpholin-4-Yl)-8-(Trifluoromethyl)-6,7,8,9-Tetrahydro-4h-Pyrimido[1,2-A]pyrimidin-4-One；(8S)-9-[(2R)-2-hydroxy-2-phenylethyl]-2-morpholin-4-yl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one
• CAS: 1260585-26-9
• 化学式: C₂₀H₂₃F₃N₄O₃
• 分子量: 424.423
• InChiKey: PZFUMOISBVVUGC-HOTGVXAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  68.6
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-三氟甲基-2-氨基嘧啶 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 正庚烷 、 水 、 1,2-二氯乙烷 为溶剂， 反应 29.75h， 生成 9-((R)-2-hydroxy-2-phenylethyl)-2-morpholin-4-yl-8-(S)-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

  摘要：

  Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

  DOI：

  10.1021/jm5013352

文献信息

• NOVEL 1,2,3,4-TETRAHYDRO-PYRIMIDO(1,2-A)PYRIMIDIN-6-ONE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF
  申请人：Bacque Eric

  公开号：US20120208810A1

  公开（公告）日：2012-08-16

  The invention relates to the novel materials of formula (I), where: R 1 is an optionally substituted L-aryl or L-heteroaryl, such that L is a single bond, alkyl, CO, or CO-alk, or L-X, with L□ being an alkyl and X being O or S; R 2 is H or alkyl; R 3 is an alkyl optionally substituted by Hal; and R 4 is Hou Hal, wherein said materials are in any isomeric form and the salts thereof, to be used as drugs.

  本发明涉及式(I)的新型材料，其中：R1是可选取的取代的L-芳基或L-杂环基，L是单键、烷基、CO或CO-烷基，或L-X，其中L□是烷基，X是O或S；R2是氢或烷基；R3是烷基，可选取卤素取代；R4是氢或卤素，所述材料以任何同分异构体形式及其盐形式作为药物。
• JP5655070
  申请人：——

  公开号：——

  公开（公告）日：——
• NOUVEAUX DERIVES DE 1,2,3,4-TETRAHYDRO-PYRIMIDO{1,2-a}PYRIMIDIN-6-ONE,LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE
  申请人：SANOFI

  公开号：EP2448940A2

  公开（公告）日：2012-05-09
• Dérivés de 6,7,8,9-tétrahydro-pyrimido{1,2-a} pyrimidin-4-one, leur préparation et leur utilisation pharmaceutique
  申请人：SANOFI

  公开号：EP2448940B1

  公开（公告）日：2014-05-21
• US8846670B2
  申请人：——

  公开号：US8846670B2

  公开（公告）日：2014-09-30