N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide | 1260544-11-3

• 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: N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide
• 英文别名: N-(2-hydroxy-4-methylphenyl)-2-(4-morpholin-4-yl-6-oxo-1H-pyrimidin-2-yl)acetamide
• CAS: 1260544-11-3
• 化学式: C₁₇H₂₀N₄O₄
• 分子量: 344.37
• InChiKey: JFTRLBFKWKIOQE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide 在 对甲苯磺酸 作用下， 以 邻二甲苯 为溶剂， 以105 mg的产率得到2-[(6-methyl-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one
  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
• 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 N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide
  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

• 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：US08507483B2

  公开（公告）日：2013-08-13

  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.

  本发明涉及公式(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地被取代；R2和R3代表H、Hal或烷基，可选地被一个或多个卤素原子取代；R4代表H。这些产品以所有异构体形式和盐的形式作为药物，特别是作为AKT（PKB）磷酸化抑制剂。
• NOUVEAUX DERIVES DE 6-MORPHOLIN-4-YL-PYRIMIDIN-4-(3H)-ONE, LEUR PREPARATION PHARMACEUTIQUE COMME INHIBITEURS DE PHOSPHORYLATION D'AKT(PKB)
  申请人：SANOFI

  公开号：EP2448932B1

  公开（公告）日：2014-03-05
• US8507483B2
  申请人：——

  公开号：US8507483B2

  公开（公告）日：2013-08-13
• [EN] NOVEL 6-MORPHOLIN-4-YL-PYRIMIDIN-4-(3H)-ONE DERIVATIVES, AND THE PHARMACEUTICAL PREPARATION THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS<br/>[FR] NOUVEAUX DERIVES DE 6-MORPHOLIN-4-YL-PYRIMIDIN-4- ( 3H ) -ONE, LEUR PREPARATION PHARMACEUTIQUE COMME INHIBITEURS DE PHOS PHORYLAT I ON D ' AKT ( PKB )
  申请人：SANOFI AVENTIS

  公开号：WO2011001115A1

  公开（公告）日：2011-01-06

  L'invention concerne les nouveaux produits de formule (I): dans laquelle Z représente –O-, -NH, Ncycloalkyle,Nalkou N-phényl éventuellement susbtitués; n représente 0 à 4; R1 représente H, Hal,hydroxyle, alkyle ou alcoxy; les radicaux alkyle et alcoxy étant éventuellement substitués; R1 pouvant représenter un reste phényle fusionné avec le phényl qui porte R1 pour former naphtyle; R2 et R3 représentent H, Hal ou alkyle éventuellement substitué par un ou plusieurs atomes d'halogène; R4 représente H; ces produits étant sous toutes les formes isomères et les sels, à titre de médicaments notamment comme inhibiteurs de phosphorylation d'AKT(PKB).
• Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
  作者：Victor Certal、Frank Halley、Angela Virone-Oddos、Cécile Delorme、Andreas Karlsson、Alexey Rak、Fabienne Thompson、Bruno Filoche-Rommé、Youssef El-Ahmad、Jean-Christophe Carry、Pierre-Yves Abecassis、Pascale Lejeune、Loic Vincent、Hélène Bonnevaux、Jean-Paul Nicolas、Thomas Bertrand、Jean-Pierre Marquette、Nadine Michot、Tsiala Benard、Peter Below、Isabelle Vade、Fabienne Chatreaux、Gilles Lebourg、Fabienne Pilorge、Odile Angouillant-Boniface、Audrey Louboutin、Christoph Lengauer、Laurent Schio

  DOI：10.1021/jm300241b

  日期：2012.5.24

  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.