11-oxo-11H-pyrido<2,1-b>quinazoline-6-carboxylic acid | 4393-98-0

• 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: 11-oxo-11H-pyrido<2,1-b>quinazoline-6-carboxylic acid
• 英文别名: 11-oxopyrido[2,1-b]quinazoline-6-carboxylic acid；11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxylic acid
• CAS: 4393-98-0
• 化学式: C₁₃H₈N₂O₃
• 分子量: 240.218
• InChiKey: ILCIRAGSNQDBPD-UHFFFAOYSA-N

物化性质

• 熔点：
  221 °C
• 沸点：
  502.2±52.0 °C(Predicted)
• 密度：
  1.46±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  70
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  N,N-二乙基乙二胺 、 11-oxo-11H-pyrido<2,1-b>quinazoline-6-carboxylic acid 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.25h， 以44.7%的产率得到N-[2-(diethylamino)ethyl]-11-oxopyrido[2,1-b]quinazoline-6-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors

  摘要：

  RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Poll large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxidty. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies.

  DOI：

  10.1021/jm5004842
• 作为产物：
  描述：

  2-氯烟酸 、 邻氨基苯甲酸 在 N-甲基吡咯烷酮 、 铜 、 potassium carbonate 、 copper(II) oxide 作用下， 以57%的产率得到11-oxo-11H-pyrido<2,1-b>quinazoline-6-carboxylic acid
  参考文献：
  名称：

  潜在的抗肿瘤药。54.一般线性三环羧酰胺类中发色团对体内抗肿瘤活性的要求。

  摘要：

  报道了一般结构的许多不同实例（ac啶，吩嗪，蒽，a啶、,吨酮，噻吨酮，蒽醌，吡啶并喹唑啉，二苯并二恶英，噻吨，吩噻嗪，吩恶嗪，二苯并呋喃，咔唑和吡啶基吲哚的结构-抗肿瘤活性关系。 N- [2-（二甲基氨基）乙基]线性三环羧酰胺。仅包含共面发色团的化合物插入DNA。绝对需要羧酰胺周围的氧或芳族氮（可能是氢键受体），以及用于生物活性的平面环几何形状。除了进一步描述这类化合物的药效基团的性质外，该工作还确定了二苯并[1,4]二恶英是一种具有体内抗肿瘤活性的新型DNA嵌入发色团。

  DOI：

  10.1021/jm00399a003

文献信息

• Potential antitumor agents. 54. Chromophore requirements for in vivo antitumor activity among the general class of linear tricyclic carboxamides
  作者：Brian D. Palmer、Gordon W. Rewcastle、Graham J. Atwell、Bruce C. Baguley、William A. Denny

  DOI：10.1021/jm00399a003

  日期：1988.4

  thioxanthenone, anthraquinone, pyridoquinazoline, dibenzodioxin, thianthrene, phenothiazine, phenoxazine, dibenzofuran, carbazole, and pyridoindole) of the general class of N-[2-(dimethylamino)ethyl] linear tricyclic carboxamides. Only the compounds containing coplanar chromophores intercalated DNA. There is an absolute requirement for an oxygen or aromatic nitrogen (possibly as hydrogen-bond acceptors) peri to

  报道了一般结构的许多不同实例（ac啶，吩嗪，蒽，a啶、,吨酮，噻吨酮，蒽醌，吡啶并喹唑啉，二苯并二恶英，噻吨，吩噻嗪，吩恶嗪，二苯并呋喃，咔唑和吡啶基吲哚的结构-抗肿瘤活性关系。 N- [2-（二甲基氨基）乙基]线性三环羧酰胺。仅包含共面发色团的化合物插入DNA。绝对需要羧酰胺周围的氧或芳族氮（可能是氢键受体），以及用于生物活性的平面环几何形状。除了进一步描述这类化合物的药效基团的性质外，该工作还确定了二苯并[1,4]二恶英是一种具有体内抗肿瘤活性的新型DNA嵌入发色团。
• CARBOXYLIC ACID DERIVATIVES OF PYRIDOQUINAZOLINES USEFUL AS PROTEIN KINASE INHIBITORS
  申请人：ONCOSTELLAE, S.L.

  公开号：US20200079773A1

  公开（公告）日：2020-03-12

  The present invention relates to novel carboxylic acid derivatives of 11-oxo-11H-pyrido [2,1-b]quinazoline-6-carboxamide as potent inhibitors of protein kinase, to pharmaceutical compositions containing them and to the use of said compounds for the manufacture of a medicament for the treatment of pathological conditions or diseases which can be improved by the inhibition of protein kinase

  本发明涉及新型羧酸衍生物11-氧代-11H-吡啶并[2,1-b]喹唑啉-6-羧酰胺，作为蛋白激酶的有效抑制剂，以及含有它们的药物组合物，以及利用所述化合物制造用于治疗可以通过抑制蛋白激酶而改善的病理状况或疾病的药物。
• [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。
• Synthesis and Activity against Multidrug Resistance in Chinese Hamster Ovary Cells of New Acridone-4-carboxamides
  作者：Nerina Dodic、Bernard Dumaitre、Alain Daugan、Pascal Pianetti

  DOI：10.1021/jm00013a017

  日期：1995.6

  A number of tricyclic carboxamides have been synthesized and tested to evaluate their ability to reverse multidrug resistance in the (CHC)-C-R/5 cell line. Among them the acridone derivatives were the most potent, A key feature is the presence of a dimethoxybenzyl or phenethylamine cationic site, separated from the tricyclic lipophilic part by a carbamoylphenyl chain. Optimization led to compounds 2 orders of magnitude more active than the prototype inhibitors verapamil and amiodarone. On the basis of in vitro and in vivo activities, 9,10-dihydro-5-methoxy- 9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl)ethyl]phenyl]-4-acridinecarboxamide (84) has been selected for further development.