2-[(6-methoxy-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one | 1260544-05-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-[(6-methoxy-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one
• 英文别名: 2-[(6-methoxy-1H-benzimidazol-2-yl)methyl]-4-morpholin-4-yl-1H-pyrimidin-6-one
• CAS: 1260544-05-5
• 化学式: C₁₇H₁₉N₅O₃
• 分子量: 341.37
• InChiKey: VFCLJXXMYKIMJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  91.8
• 氢给体数：
  2
• 氢受体数：
  6

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-[(6-methoxy-1H-benzimidazol-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

文献信息

• 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。
• 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

  公开号：EP2448932A1

  公开（公告）日：2012-05-09
• 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
• USE OF DIANHYDROGALACTITOL OR DERIVATIVES OR ANALOGS THEREOF FOR TREATMENT OF PEDIATRIC CENTRAL NERVOUS SYSTEM MALIGNANCIES
  申请人：DelMar Pharmaceuticals, Inc.

  公开号：US20180071244A1

  公开（公告）日：2018-03-15

  The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of malignancies of the central nervous system in pediatric patients, including glioblastoma multiforme (GBM) high grade glioma, and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N 7 methylation and that can induce double-stranded breaks in DNA. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents (e.g. cisplatin) and can possess additive or super-additive effects.
• US8507483B2
  申请人：——

  公开号：US8507483B2

  公开（公告）日：2013-08-13