2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide | 1260583-42-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide
• 英文别名: 2-[4-(Morpholin-4-Yl)-6-Oxo-1,6-Dihydropyrimidin-2-Yl]-N-Phenylacetamide；2-(4-morpholin-4-yl-6-oxo-1H-pyrimidin-2-yl)-N-phenylacetamide
• CAS: 1260583-42-3
• 化学式: C₁₆H₁₈N₄O₃
• 分子量: 314.344
• InChiKey: FPFCFOIMTFHSNY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  23
• 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：
  83
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate 在 吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 64.0h， 生成 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide
  参考文献：
  名称：

  Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

  摘要：

  Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

  DOI：

  10.1021/jm300241b

文献信息

• Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors
  作者：Victor Certal、Frank Halley、Angela Virone-Oddos、Fabienne Thompson、Bruno Filoche-Rommé、Youssef El-Ahmad、Jean-Christophe Carry、Cécile Delorme、Andreas Karlsson、Pierre-Yves Abecassis、Loic Vincent、Hélène Bonnevaux、Jean-Paul Nicolas、Renaud Morales、Nadine Michot、Isabelle Vade、Audrey Louboutin、Sébastien Perron、Gilles Doerflinger、Bernadette Tric、Sylvie Monget、Christoph Lengauer、Laurent Schio

  DOI：10.1016/j.bmcl.2012.08.072

  日期：2012.10

  From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a

  从HTS活动中，已鉴定出一系列新的以化合物1为代表的嘧啶酮酐，对PI3Kβ亚型具有良好的抑制活性。解析了PI3Kγ中化合物1的结构，揭示了与PI3Kβ上观察到的SAR一致的结合方式。这些化合物在生化分析中显示出在纳摩尔范围内的抑制作用，并且在PTEN缺陷型PC3前列腺癌细胞系中也是有效的p-Akt抑制剂。体外药物动力学特性的优化导致化合物25在小鼠中表现出52％的生物利用度，并在一项急性PK / PD研究中与靶标结合。
• NOVEL 1H-PYRIMIDIN-2-ONE DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF AS INHIBITORS OF AKT (PKB) PHOSPHORYLATION
  申请人：CERTAL Victor

  公开号：US20120172360A1

  公开（公告）日：2012-07-05

  The invention relates to the novel products of formula (I): in which Z represents —O—, —NH or Nalk; n represents 0 to 4; R1 represents Hal, hydroxyl, alkyl or alkoxy; the alkyl and alkoxy radicals being optionally substituted; R2 and R3 represent H, Hal or alkyl optionally substituted with one or more halogen atoms; R4 represents H; these products being in all the isomer forms and the salts, as medicaments, in particular as inhibitors of AKT(PKB) phosphorylation.

  这项发明涉及公式(I)的新产品：其中Z代表—O—、—NH或Nalk；n代表0至4；R1代表Hal、羟基、烷基或烷氧基；烷基和烷氧基基团可选择性取代；R2和R3代表H、Hal或烷基，可选择性取代一个或多个卤素原子；R4代表H；这些产品在所有异构体形式和盐中作为药物，特别是作为AKT(PKB)磷酸化抑制剂。
• NOVEL (6-OXO-1,6-DIHYDROPYRIMIDIN-2-YL)AMIDE DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS
  申请人：CARRY Jean-Christophe

  公开号：US20120270867A1

  公开（公告）日：2012-10-25

  The invention relates to the novel materials of formula (I), where: R1 is an optionally substituted aryl or heteroaryl; R is an H or, when formed with R1, a 5- or 6-member ring fused with an aryl or heretoaryl group optionally containing one or more of O, S, N, NH, and Nalk, being optionally substituted; R2 and R3 are, independently, an H, Hal, or alkyl optionally substituted by one or more Hal; R4 is H; and R5 is an H or alkyl optionally substituted by one or more halogen atoms. Said materials being in any isomeric form and the salts thereof, and are intended for drugs, particularly AKT(PKB) phosphorylation inhibitors.

  本发明涉及公式（I）的新型材料，其中：R1是可选择取代的芳基或杂环芳基；R是H或与R1形成的5-或6-成员环，与可选择含有O、S、N、NH和Nalk中的一种或多种的芳基或杂环芳基团融合，可选择取代；R2和R3分别为H、卤素或可选择取代的1个或多个卤素的烷基；R4为H；R5为H或可选择取代的1个或多个卤素原子的烷基。所述材料以任何异构形式及其盐的形式存在，用于药物，特别是AKT（PKB）磷酸化抑制剂。
• (6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives, preparation thereof and pharmaceutical use thereof as AKT(PKB) phosphorylation inhibitors
  申请人：Carry Jean-Christophe

  公开号：US08791255B2

  公开（公告）日：2014-07-29

  The invention relates to the novel materials of formula (I), wherein each of the substituents R, R1, R2, R3, R4 and R5 is as defined herein. The materials are useful as inhibitors of AKT(PKB) phosphorylation.

  本发明涉及式(I)的新型材料，其中取代基R、R1、R2、R3、R4和R5的定义如本文所述。该材料可用作AKT（PKB）磷酸化抑制剂。
• JP5680638
  申请人：——

  公开号：——

  公开（公告）日：——