1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid | 1144504-35-7

• 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: 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid
• 英文别名: 1-(4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4 H-quinolizine-3-carboxylic acid；PQCA；1-[(4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate；1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxoquinolizine-3-carboxylic acid
• CAS: 1144504-35-7
• 化学式: C₂₂H₂₀N₄O₃
• 分子量: 388.426
• InChiKey: RJTJRVASUFIDQM-UHFFFAOYSA-N

物化性质

• 沸点：
  708.5±60.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：10 mg/mL（25.75 mM；超声加热并加热至 80°C）

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  97.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid 在 氨 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 C₂₂H₂₁N₅O₂
  参考文献：
  名称：

  Identification of Amides as Carboxylic Acid Surrogates for Quinolizidinone-Based M₁ Positive Allosteric Modulators

  摘要：

  Selective activation of the M-1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M-1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.

  DOI：

  10.1021/ml300280g
• 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 、 水 、 溶剂黄146 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 17.08h， 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：

  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。
• [EN] HETEROARYL COMPOUNDS AS MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS HÉTÉROARYLE UTILISÉS EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE M1
  申请人：SUVEN LIFE SCIENCES LTD

  公开号：WO2019077517A1

  公开（公告）日：2019-04-25

  The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers or pharmaceutically acceptable salt (s) thereof as muscarinic M1 receptor positive allosteric modulators (M1 PAMs). The present invention describes the preparation, pharmaceutical composition and the use of compound formula (I).

  本发明涉及式(I)的化合物，或其同位素形式、立体异构体、互变异构体或其药学上可接受的盐，作为肌碱M1受体阳性变构调节剂（M1 PAMs）。本发明描述了化合物式(I)的制备、药物组合物以及使用方法。
• [EN] FLUOROINDOLE DERIVATIVES AS MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] DÉRIVÉS DE FLUOROINDOLE EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE M1
  申请人：SUVEN LIFE SCIENCES LTD

  公开号：WO2017042643A1

  公开（公告）日：2017-03-16

  The present invention relates to compound of formula (I), or stereoisomers and pharmaceutically acceptable salts as muscarinic M1 receptor positive allosteric modulators. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to muscarinic M1 receptor.(Formula I) (I)

  本发明涉及公式（I）的化合物，或其立体异构体和药用可接受的盐，作为肌胆碱M1受体阳性变构调节剂。本发明还涉及制备这类化合物的方法和包含这类化合物的药物组合物。本发明的化合物在治疗与肌胆碱M1受体相关的各种疾病中具有用途。(公式I) (I)
• 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。
• QUINOLIZIDINONE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
  申请人：Kuduk Scott D.

  公开号：US20120232076A1

  公开（公告）日：2012-09-13

  The present invention is directed to 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M1受体介导的疾病。