2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one | 1263413-73-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one
• 英文别名: 2-(Chloromethyl)-5-fluoroquinazolin-4(3H)-one；2-(chloromethyl)-5-fluoro-3H-quinazolin-4-one
• CAS: 1263413-73-5
• 化学式: C₉H₆ClFN₂O
• 分子量: 212.611
• InChiKey: LGBJRAIQFJBTSB-UHFFFAOYSA-N

物化性质

• 沸点：
  352.9±52.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  41.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 5-fluoro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)styryl)quinazolin-4(3H)-one
  参考文献：
  名称：

  Quinazolinones as γ-secretase modulators

  摘要：

  Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of gamma-secretase activity. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.11.111
• 作为产物：
  描述：

  氯乙腈 、 2-氨基-6-氟苯甲酸甲酯 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 以49%的产率得到2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one
  参考文献：
  名称：

  Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy

  摘要：

  环鸟苷酸腺苷酸合酶-干扰素基因刺激剂-TANK结合激酶1-干扰素调节因子3（cGAS-STING-TBK1-IRF3）轴现在被认为是先天免疫反应中的主要信号通路。然而，作为STING刺激剂的2'，3'-cGAMP容易被细胞外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）识别和降解，从而降低肿瘤免疫疗法的效果并促进转移进展。在这项研究中，采用基于结构的虚拟筛选策略，发现了八个含有结合锌的喹唑啉-4（3H）-酮骨架的ENPP1抑制剂候选化合物。随后，合成了这些新型抑制剂并通过NMR和高分辨质谱（HRMS）进行了表征。在生物测定中，7-氟-2-（（（5-甲氧基-1H-咪唑[4,5-b]吡啶-2-基）硫基）甲基）喹唑啉-4（3H）-酮（化合物4e）在分子和细胞水平上显示出对ENPP1的优异活性，IC50值分别为0.188μM和0.732μM。此外，与顺铂相比，化合物4e对转移性乳腺癌细胞（4T1）的选择性优于对正常细胞（LO2和293T）的选择性，表明化合物4e可能可用于转移性乳腺癌治疗。另一方面，化合物4e通过防止ENPP1水解cGAMP来刺激更强的先天免疫反应，在体内提高了IFN-β的表达水平。因此，这种化合物可能被应用于增强抗肿瘤免疫力的癌症免疫疗法。总的来说，我们的工作为开发针对ENPP1的有前途的药物候选剂提供了一种策略，用于肿瘤免疫疗法。

  DOI：

  10.3390/ijms23137104

文献信息

• PHARMACEUTICAL COMPOUNDS AS INHIBITORS OF CELL PROLIFERATION AND THE USE THEREOF
  申请人：ANDERSON MARK B.

  公开号：US20100068197A1

  公开（公告）日：2010-03-18

  Disclosed are compounds of Formula I effective as cytotoxic agents. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

  揭示的是作为细胞毒性剂有效的I式化合物。本发明的化合物在治疗多种临床病况中是有用的，这些病况中发生异常细胞的不受控制的生长和扩散。
• [EN] BENZOXAZINONE DERIVATIVES FOR THE TREATMENT OF GLYTL MEDIATED DISORDERS<br/>[FR] DÉRIVÉS DE BENZOXAZINONE POUR TRAITER DES TROUBLES INDUITS PAR GLYTL
  申请人：GLAXO GROUP LTD

  公开号：WO2011012622A1

  公开（公告）日：2011-02-03

  The present invention relates to benzoxazinone derivatives, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in treating disorders mediated by GlyT1, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.

  本发明涉及苯并噁唑酮衍生物，其制备方法，含有它们的药物组合物和药物，以及它们在治疗由GlyT1介导的疾病中的应用，包括神经系统和神经精神疾病，特别是精神病、痴呆或注意力缺陷障碍。
• Iridium-catalyzed intramolecular enantioselective allylation of quinazolin-4(3<i>H</i>)-one derivatives
  作者：Fei Peng、Hua Tian、Pengxiang Zhang、Haijun Yang、Hua Fu

  DOI：10.1039/c9ob01057b

  日期：——

  An efficient chiral cyclic phosphoramidite ligand-enabled iridium-catalyzed intramolecular allylation of quinazolin-4(3H)-one derivatives has been developed with high reactivity and high to excellent enantioselectivity.

  一种高效的手性环磷酰胺配体催化的铱催化的喹唑啉-4(3H)-酮衍生物内分子烯丙基化反应已经开发出来，其反应活性高，对映选择性高到极好。
• Quinazolinones as γ-secretase modulators
  作者：Christian Fischer、Sanjiv Shah、Bethany L. Hughes、George N. Nikov、Jamie L. Crispino、Richard E. Middleton、Alexander A. Szewczak、Benito Munoz、Mark S. Shearman

  DOI：10.1016/j.bmcl.2010.11.111

  日期：2011.1

  Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of gamma-secretase activity. (C) 2010 Elsevier Ltd. All rights reserved.
• Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy
  作者：Xiang Wang、Xing Lu、Daojing Yan、Yajun Zhou、Xiangshi Tan

  DOI：10.3390/ijms23137104

  日期：——

  The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes–TANK-binding kinase 1–interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2′,3′-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which reduces the effect of tumor immunotherapy and promotes metastatic progression. In this investigation, the structure-based virtual screening strategy was adopted to discover eight candidate compounds containing zinc-binding quinazolin-4(3H)-one scaffold as ENPP1 inhibitors. Subsequently, these novel inhibitors targeting ENPP1 were synthesized and characterized by NMR and high-resolution mass spectra (HRMS). In bioassays, 7-fluoro-2-(((5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)thio)methyl)quina-zolin-4(3H)-one(compound 4e) showed excellent activity against the ENPP1 at the molecular and cellular levels, with IC50 values of 0.188 μM and 0.732 μM, respectively. Additionally, compound 4e had superior selectivity towards metastatic breast cancer cells (4T1) than towards normal cells (LO2 and 293T) in comparison with cisplatin, indicating that compound 4e can potentially be used in metastatic breast cancer therapy. On the other hand, compound 4e upgraded the expression levels of IFN-β in vivo by preventing the ENPP1 from hydrolyzing the cGAMP to stimulate a more potent innate immune response. Therefore, this compound might be applied to boost antitumor immunity for cancer immunotherapy. Overall, our work provides a strategy for the development of a promising drug candidate targeting ENPP1 for tumor immunotherapy.

  环鸟苷酸腺苷酸合酶-干扰素基因刺激剂-TANK结合激酶1-干扰素调节因子3（cGAS-STING-TBK1-IRF3）轴现在被认为是先天免疫反应中的主要信号通路。然而，作为STING刺激剂的2'，3'-cGAMP容易被细胞外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）识别和降解，从而降低肿瘤免疫疗法的效果并促进转移进展。在这项研究中，采用基于结构的虚拟筛选策略，发现了八个含有结合锌的喹唑啉-4（3H）-酮骨架的ENPP1抑制剂候选化合物。随后，合成了这些新型抑制剂并通过NMR和高分辨质谱（HRMS）进行了表征。在生物测定中，7-氟-2-（（（5-甲氧基-1H-咪唑[4,5-b]吡啶-2-基）硫基）甲基）喹唑啉-4（3H）-酮（化合物4e）在分子和细胞水平上显示出对ENPP1的优异活性，IC50值分别为0.188μM和0.732μM。此外，与顺铂相比，化合物4e对转移性乳腺癌细胞（4T1）的选择性优于对正常细胞（LO2和293T）的选择性，表明化合物4e可能可用于转移性乳腺癌治疗。另一方面，化合物4e通过防止ENPP1水解cGAMP来刺激更强的先天免疫反应，在体内提高了IFN-β的表达水平。因此，这种化合物可能被应用于增强抗肿瘤免疫力的癌症免疫疗法。总的来说，我们的工作为开发针对ENPP1的有前途的药物候选剂提供了一种策略，用于肿瘤免疫疗法。