ethyl 4-[(4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl]-1-oxo-1,8a-dihydronaphthalene-2-carboxylate | 1144505-14-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹嗪类
• 英文名称: ethyl 4-[(4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl]-1-oxo-1,8a-dihydronaphthalene-2-carboxylate
• 英文别名: Ethyl 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxoquinolizine-3-carboxylate
• CAS: 1144505-14-5
• 化学式: C₂₄H₂₄N₄O₃
• 分子量: 416.48
• InChiKey: IWUQTVNIYIYDHW-UHFFFAOYSA-N

物化性质

• 沸点：
  669.8±55.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  86.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 4-[(4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl]-1-oxo-1,8a-dihydronaphthalene-2-carboxylate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 17.0h， 生成 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid
  参考文献：
  名称：

  [EN] QUINOLIZIDINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
  [FR] MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1 DE LA QUINOLIZIDINONE

  摘要：

  本发明涉及式(I)的螺环哌啶化合物，这些化合物是M1受体阳性变构调节剂，并且在治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍方面有用。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。

  公开号：

  WO2009051715A1
• 作为产物：
  描述：

  苄基N-[2-(N-(2-氨基-4-甲氧基-苯基)苯胺基)-2-氧代-乙基]氨基甲酸酯 在 盐酸 、 溶剂黄146 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 1.08h， 生成 ethyl 4-[(4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl]-1-oxo-1,8a-dihydronaphthalene-2-carboxylate
  参考文献：
  名称：

  Discovery of a Selective Allosteric M₁ Receptor Modulator with Suitable Development Properties Based on a Quinolizidinone Carboxylic Acid Scaffold

  摘要：

  One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M-1 muscarinic receptor. A number of nonselective M-1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M-2 to M-5 subtypes. One strategy to confer selectivity for M-1 is the identification of positive allosteric modulators, which would target an allosteric site on the M-1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have I been previously identified as highly selective M-1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.

  DOI：

  10.1021/jm200400m

文献信息

• [EN] QUINOLIZIDINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1 DE LA QUINOLIZIDINONE
  申请人：MERCK & CO INC

  公开号：WO2009051715A1

  公开（公告）日：2009-04-23

  The present invention is directed to spiropiperidine 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)的螺环哌啶化合物，这些化合物是M1受体阳性变构调节剂，并且在治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍方面有用。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。
• QUINOLIZIDINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
  申请人：Chang Ronald K.

  公开号：US20100222355A1

  公开（公告）日：2010-09-02

  The present invention is directed to spiropiperidine 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）的螺环吡啶化合物，它们是M1受体正向变构调节剂，并且在治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍方面有用。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由M1受体介导的疾病。
• US8258135B2
  申请人：——

  公开号：US8258135B2

  公开（公告）日：2012-09-04
• Discovery of a Selective Allosteric M₁ Receptor Modulator with Suitable Development Properties Based on a Quinolizidinone Carboxylic Acid Scaffold
  作者：Scott D. Kuduk、Ronald K. Chang、Christina N. Di Marco、Daniel R. Pitts、Thomas J. Greshock、Lei Ma、Marion Wittmann、Matthew A. Seager、Kenneth A. Koeplinger、Charles D. Thompson、George D. Hartman、Mark T. Bilodeau、William J. Ray

  DOI：10.1021/jm200400m

  日期：2011.7.14

  One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M-1 muscarinic receptor. A number of nonselective M-1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M-2 to M-5 subtypes. One strategy to confer selectivity for M-1 is the identification of positive allosteric modulators, which would target an allosteric site on the M-1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have I been previously identified as highly selective M-1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.