3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo-[h]quinazolin-4(3H)-one | 1227923-91-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo-[h]quinazolin-4(3H)-one
• 英文别名: Benzoquinazolinone 12；3-[(1S,2S)-2-hydroxycyclohexyl]-6-[[6-(1-methylpyrazol-4-yl)pyridin-3-yl]methyl]benzo[h]quinazolin-4-one
• CAS: 1227923-91-2
• 化学式: C₂₈H₂₇N₅O₂
• 分子量: 465.555
• InChiKey: SXJQBWJPNSOKQV-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  83.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-((6-chloropyridin-3-yl)methyl)-3-((1S,2S)-2-hydroxycyclohexyl)benzo[h]quinazolin-4(3H)-one 、 1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 以59%的产率得到3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo-[h]quinazolin-4(3H)-one
  参考文献：
  名称：

  基于新型融合芳基嘧啶酮的M 1毒蕈碱乙酰胆碱受体的变构调节剂

  摘要：

  Benzoquinazolinone 1是M的正变构调节剂（PAM）1毒蕈碱乙酰胆碱受体（的mAChR），这是比显著原型PAM更有效，1-（4-甲氧基苄基）-4-氧代-1,4-二氢喹啉-3- -羧酸（BQCA）。在这项研究中，我们探讨了结构决定因素，这些决定因素是1作为M 1 mAChR的PAM活性的基础。我们特别注意了化合物1的三环支架的重要性，用于分子的活性。外围稠合苯环的完全缺失导致与乙酰胆碱（ACh）的亲和力和结合协同作用显着降低。通过在喹唑啉-4（3H）-一个核心的7和/或8位添加一个或两个甲基来挽救这种亲和力的丧失。这些结果表明，该三环苯并[ ħ ]喹唑啉-4（3 H ^） -酮芯可以与喹唑啉-4（3代替ħ） -酮芯和保持功能性亲和力。这样，喹唑啉-4（3 H）一核代表了一种新型支架，可以进一步探索具有改善的理化性质的M 1 mAChR PAM。

  DOI：

  10.1021/acschemneuro.6b00018

文献信息

• [EN] ARYL METHYL BENZOQUINAZOLINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1 D'ARYLMÉTHYLBENZOQUINAZOLINONE
  申请人：MERCK SHARP & DOHME

  公开号：WO2010059773A1

  公开（公告）日：2010-05-27

  The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的苯并喹噁唑啉酮化合物，这些化合物是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• ARYL METHYL BENZOQUINAZOLININE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
  申请人：Kuduk Scott D.

  公开号：US20110224198A1

  公开（公告）日：2011-09-15

  The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的苯并喹唑啉酮化合物，它们是M1受体正向变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。本发明还涉及包括这些化合物的制药组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物的方法。
• ARYL METHYL BENZOQUINAZOLINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20150031713A1

  公开（公告）日：2015-01-29

  The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及公式（I）的苯并喹唑啉酮化合物，其为M1受体正向变构调节剂，并且在治疗M1受体参与的疾病，例如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍方面具有用途。该发明还涉及包含该化合物的制药组合物，以及使用该化合物和组合物治疗由M1受体介导的疾病方面的用途。
• Aryl Methyl Benzoquinazolinone M1 Receptor Positive Allosteric Modulators
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20140005182A1

  公开（公告）日：2014-01-02

  The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及公式（I）的苯并喹唑啉酮化合物，它们是M1受体正向变构调节剂，并且对于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍等具有用处。本发明还涉及包含这些化合物的制药组合物，以及使用这些化合物和组合物治疗M1受体介导的疾病。
• SCREENING METHOD
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP3627152A1

  公开（公告）日：2020-03-25

  The present invention provides a useful and efficient screening method for finding a cholinergic muscarinic M1 receptor positive allosteric modulator (M1PAM) with reduced cholinergic side effects. The present invention also provides a method for treating Alzheimer's disease and the like, a method for reducing cholinergic side effects, and the like which use M1PAM selected by the screening method and having a low α value, or the M1PAM and an acetylcholinesterase inhibitor.

  本发明提供了一种有用且高效的筛选方法，用于寻找具有降低胆碱能副作用的胆碱能毒蕈碱 M1 受体正性异位调节剂（M1PAM）。本发明还提供了一种治疗阿尔茨海默病等疾病的方法、一种减少胆碱能副作用的方法等，这些方法使用了通过筛选方法选出的具有低α值的M1PAM，或M1PAM和乙酰胆碱酯酶抑制剂。