N-[2-(dimethylamino)ethyl]-N-methyl-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide | 1610978-65-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: N-[2-(dimethylamino)ethyl]-N-methyl-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide
• CAS: 1610978-65-8
• 化学式: C₂₂H₂₂N₄O₂
• 分子量: 374.442
• InChiKey: HHHOSJFOQVRKIN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  56.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-氨基-2-萘甲酸 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 82.25h， 生成 N-[2-(dimethylamino)ethyl]-N-methyl-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide
  参考文献：
  名称：

  [EN] COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE
  [FR] COMPOSÉS QUI INHIBENT L'ARN POLYMÉRASE, COMPOSITIONS COMPRENANT DE TELS COMPOSÉS, ET LEUR UTILISATION

  摘要：

  RNA聚合酶I（Pol I）是专门用于转录47S核糖体RNA前体的聚合酶，随后将其加工成成熟的5.8S、18S和28S核糖体RNA，并在核仁中组装成核糖体。Pol I活性在人类癌症中常常失调。基于引物分子BMH-21的发现，合成了一系列吡啶喹唑啉羧酰胺作为Pol I的抑制剂和RPA194的破坏激活剂，RPA194是Pol I的大催化亚基蛋白。本发明确定了一组生物活性化合物，包括纯化的立体异构体，它们能够有效地导致RPA194的降解，这些化合物在一个严格受限制的化学空间中发挥作用。还提供了包括这些化合物的药物组合物及其在癌症和其他与Pol I相关疾病中的用途。

  公开号：

  WO2015143293A1

文献信息

• [EN] COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE<br/>[FR] COMPOSÉS QUI INHIBENT L'ARN POLYMÉRASE, COMPOSITIONS COMPRENANT DE TELS COMPOSÉS, ET LEUR UTILISATION
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2015143293A1

  公开（公告）日：2015-09-24

  RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

  RNA聚合酶I（Pol I）是专门用于转录47S核糖体RNA前体的聚合酶，随后将其加工成成熟的5.8S、18S和28S核糖体RNA，并在核仁中组装成核糖体。Pol I活性在人类癌症中常常失调。基于引物分子BMH-21的发现，合成了一系列吡啶喹唑啉羧酰胺作为Pol I的抑制剂和RPA194的破坏激活剂，RPA194是Pol I的大催化亚基蛋白。本发明确定了一组生物活性化合物，包括纯化的立体异构体，它们能够有效地导致RPA194的降解，这些化合物在一个严格受限制的化学空间中发挥作用。还提供了包括这些化合物的药物组合物及其在癌症和其他与Pol I相关疾病中的用途。
• Compounds which inhibit RNA polymerase, compositions including such compounds, and their use
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US11001581B2

  公开（公告）日：2021-05-11

  RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

  RNA 聚合酶 I（Pol I）是一种专用聚合酶，用于转录 47S 核糖体 RNA 前体，随后加工成成熟的 5.8S、18S 和 28S 核糖体 RNA，并在核仁中组装成核糖体。在人类癌症中，Pol I 的活性通常会发生失调。在发现先导分子 BMH-21 的基础上，合成了一系列吡啶喹唑啉羧酰胺，作为 Pol I 的抑制剂和破坏 Pol I 大催化亚基蛋白 RPA194 的激活剂。本发明确定了一组生物活性化合物，包括纯化的立体异构体，它们能有效地导致 RPA194 降解，并在严格限制的化学空间中发挥作用。本发明还提供了包含这些化合物的药物组合物及其在癌症和其他 Pol I 相关疾病中的用途。
• COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE
  申请人：The Johns Hopkins University

  公开号：EP3119781B1

  公开（公告）日：2020-09-16
• COMBINATORY TREATMENT STRATEGIES OF CANCER BASED ON RNA POLYMERASE I INHIBITION
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20190247397A1

  公开（公告）日：2019-08-15

  Disclosed herein are compositions comprising a combination of at least one Pol I inhibitor, and at least one autophagy inhibiting compound, and/or at least one ACAT1 inhibiting compound, and/or at least one PARP inhibiting compound and their use in treating cancers and other related neoplastic diseases and which may also include additional chemotherapeutic agents.
• [EN] COMBINATORY TREATMENT STRATEGIES OF CANCER BASED ON RNA POLYMERASE I INHIBITION<br/>[FR] STRATÉGIES DE TRAITEMENTS COMBINÉS DU CANCER BASÉES SUR L'INHIBITION DE L'ARN POLYMÉRASE I
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2018057834A1

  公开（公告）日：2018-03-29

  Disclosed herein are compositions comprising a combination of at least one Pol I inhibitor, and at least one autophagy inhibiting compound, and/or at least one ACAT1 inhibiting compound, and/or at least one PARP inhibiting compound and their use in treating cancers and other related neoplastic diseases and which may also include additional chemotherapeutic agents.