8-(trifluoromethyl)-3-(cyclopropylmethyl)-7-[(4-(2,4-difluorophenyl)-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine | 1254979-76-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 8-(trifluoromethyl)-3-(cyclopropylmethyl)-7-[(4-(2,4-difluorophenyl)-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine
• 英文别名: 3-(cyclopropylmethyl)-7-((4-(2,4-difluorophenyl)piperidin-1-yl)-methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine；3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine；3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)piperidin-1-yl]methyl]-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine
• CAS: 1254979-76-4
• 化学式: C₂₃H₂₃F₅N₄
• 分子量: 450.454
• InChiKey: CRUGMDQKVDVGOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  33.4
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  7-vinyl-3-(cyclopropylmethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine 在 sodium periodate 、 四氧化锇 作用下， 以 1,4-二氧六环 、 水 、 1,2-二氯乙烷 、 叔丁醇 为溶剂， 反应 6.0h， 生成 8-(trifluoromethyl)-3-(cyclopropylmethyl)-7-[(4-(2,4-difluorophenyl)-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine
  参考文献：
  名称：

  Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM)

  摘要：

  Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders: We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in Solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.

  DOI：

  10.1021/acs.jmedchem.6b00913

文献信息

• [EN] MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR 2<br/>[FR] MODULATEURS DU RÉCEPTEUR MÉTABOTROPIQUE DU GLUTAMATE 2
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2021155196A1

  公开（公告）日：2021-08-05

  The present application provides a compound of Formula: or a pharmaceutically acceptable salt thereof, wherein ring B, L1, ring A, L2, n, R1, R2, R3, R4, and X1 are as described herein. Pharmaceutical compositions comprising the compound, as well as the methods of making and using the compound, are also provided.

  本申请提供了一种化合物的公式：或其药用可接受的盐，其中环B、L1、环A、L2、n、R1、R2、R3、R4和X1如本文所述。还提供了包含该化合物的药物组合物，以及制造和使用该化合物的方法。
• 1,2,3-TRIAZOLO [4,3-A] PYRIDINE DERIVATIVES AND THIER USE FOR THE TREATMENT OF PREVENTION OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS
  申请人：Cid-Nunez Jose Maria

  公开号：US20120184525A1

  公开（公告）日：2012-07-19

  The present invention relates to novel triazolo[4,3- a ]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

  本发明涉及一种新型的三唑并[4,3-a]吡啶衍生物，其化学式为（I），其中所有基团均如权利要求中所定义。本发明中的化合物是代谢型谷氨酸受体亚型2（“mGluR2”）的正向变构调节剂，可用于治疗或预防与谷氨酸功能障碍有关的神经和精神障碍以及涉及代谢型受体的mGluR2亚型的疾病。本发明还涉及包含这些化合物的制药组合物，制备这些化合物和组合物的过程，以及使用这些化合物预防或治疗涉及mGluR2的神经和精神障碍和疾病的方法。
• 1,2,4-Triazolo [4,3-A] Pyridine Derivatives and Their Use For The Treatment of Prevention of Neurological and Psychiatric Disorders
  申请人：JANSSEN PHARMACEUTICALS, INC.

  公开号：US20150141403A1

  公开（公告）日：2015-05-21

  The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

  本发明涉及一种新型的三唑并[4,3-a]吡啶衍生物，其化学式为（I），其中所有基团如权利要求所定义。本发明的化合物是代谢型谷氨酸受体亚型2（“mGluR2”）的正向变构调节剂，可用于治疗或预防与谷氨酸功能障碍相关的神经和精神障碍以及涉及代谢型受体亚型mGluR2的疾病。本发明还涉及包含这种化合物的制药组合物、制备这种化合物和组合物的过程，以及使用这种化合物预防或治疗涉及mGluR2的神经和精神障碍和疾病的方法。
• Design, Synthesis, and Characterization of [¹⁸F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2
  作者：Gengyang Yuan、Maeva Dhaynaut、Nicolas J. Guehl、Sepideh Afshar、Dalena Huynh、Sung-Hyun Moon、Suhasini M. Iyengar、Manish Kumar Jain、Julie E. Pickett、Hye Jin Kang、Mary Jo Ondrechen、Georges El Fakhri、Marc D. Normandin、Anna-Liisa Brownell

  DOI：10.1021/acs.jmedchem.2c00593

  日期：2022.7.28

  An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8–10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds

  合成了一系列基于 JNJ-46356479 ( 6 ) 的三唑并吡啶，作为代谢型谷氨酸受体 2 (mGluR2) 的潜在正电子发射断层扫描放射性示踪剂。在 cAMP GloSensor 测定中，与化合物6相比，选定的候选物8-10具有增强的正变构调节剂 (PAM) 活性（最多 20 倍）和 mGluR2 激动剂活性（最多 25 倍）。化合物8和9 (mG2P026) 的放射性标记是通过 Cu 介导的放射性氟化实现的，放射化学收率令人满意，>5%（未衰变校正）；高摩尔活性，>180 GBq/μmol；以及优异的放射化学纯度，>98%。[ 18 F] 8和[ 18 F] 9在大鼠中的初步表征证实了它们优异的脑通透性和结合动力学。对非人灵长类动物中的[ 18 F] 9的进一步评估证实了其在mGluR2图谱方面具有优越的脑异质性，并且比[ 18 F] 6具有更高的亲和力。在大鼠和灵长类动物中使用不同类别的
• 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
  申请人：JANSSEN PHARMACEUTICALS, INC.

  公开号：US10071095B2

  公开（公告）日：2018-09-11

  The present invention relates to methods of treating various central nervous system disorders using novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

  本发明涉及使用式 (I) 的新型三唑并[4,3-a]吡啶衍生物治疗各种中枢神经系统疾病的方法 其中所有基团如权利要求中定义。根据本发明的化合物是代谢型谷氨酸受体亚型 2（"mGluR2"）的正异位调节剂，可用于治疗或预防与谷氨酸功能障碍相关的神经和精神疾病以及代谢型受体 mGluR2 亚型参与的疾病。本发明还涉及包含此类化合物的药物组合物、制备此类化合物和组合物的工艺，以及使用此类化合物预防或治疗涉及 mGluR2 的神经和精神障碍及疾病。