3-(环丙基甲基)-7-(4-苯基哌啶-1-基)-8-(三氟甲基)-[1,2,4]噻唑并[4,3-a]吡啶 | 1254977-87-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 3-(环丙基甲基)-7-(4-苯基哌啶-1-基)-8-(三氟甲基)-[1,2,4]噻唑并[4,3-a]吡啶
• 中文别名: 3-(环丙基甲基)-7-(4-苯基-1-哌啶基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶
• 英文名称: (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine)
• 英文别名: JNJ-42153605；NJ-42153605；3-(Cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine
• CAS: 1254977-87-1
• 化学式: C₂₂H₂₃F₃N₄
• 分子量: 400.447
• InChiKey: BQAVZGJJQFJSMW-UHFFFAOYSA-N

物化性质

• 密度：
  1.38±0.1 g/cm3(Predicted)
• 溶解度：
  DMF:30.0(最大浓度 mg/mL);74.92(最大浓度 mM)DMF:PBS (pH 7.2) (1:3):0.25(最大浓度 mg/mL);0.62(最大浓度. mM)DMSO:10.34(最大浓度 mg/mL);25.81(最大浓度 mM)乙醇:10.0(最大浓度 mg/mL);24.97(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  33.4
• 氢给体数：
  0
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性方面，JNJ-42153605是一种有效的、选择性mGlu2受体正向别构调节剂，其EC50值为17 nM。

靶点如下：

Target	Value
mGlu2 rECeptor	17 nM (EC50)

反应信息

• 作为反应物：
  描述：

  3-(环丙基甲基)-7-(4-苯基哌啶-1-基)-8-(三氟甲基)-[1,2,4]噻唑并[4,3-a]吡啶 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 以88.7%的产率得到3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine hydrochloride
  参考文献：
  名称：

  [EN] 1,2,4-TRIAZOLO [4,3-A] PYRIDINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OR PREVENTION OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS
  [FR] DÉRIVÉS DE 1,2,3-TRIAZOLO[4,3-A]PYRIDINE ET LEUR UTILISATION POUR LE TRAITEMENT OU LA PRÉVENTION DE TROUBLES NEUROLOGIQUES ET PSYCHIATRIQUES

  摘要：

  公开号：

  WO2010130424A9
• 作为产物：
  描述：

  2-氯-4-苯基甲氧基-3-(三氟甲基)吡啶 在 一水合肼 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 1.83h， 生成 3-(环丙基甲基)-7-(4-苯基哌啶-1-基)-8-(三氟甲基)-[1,2,4]噻唑并[4,3-a]吡啶
  参考文献：
  名称：

  Discovery of 3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

  摘要：

  Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED50 of 5.4 mg/kg sc, indicative of antipsychotic activity.

  DOI：

  10.1021/jm3010724

文献信息

• [EN] 6,7-DIHYDROPYRAZOLO[1,5-A]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS<br/>[FR] COMPOSÉS 6,7-DIHYDROPYRAZOLO[1,5-A] PYRAZIN-4(5H)-ONE ET LEUR UTILISATION COMME MODULATEURS ALLOSTÉRIQUES NÉGATIFS DES RÉCEPTEURS MGLUR2
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2016016395A1

  公开（公告）日：2016-02-04

  The present invention relates to novel 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR2"). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.

  本发明涉及新型的6,7-二氢吡唑[1,5-a]吡嗪-4(5H)-酮衍生物，作为代谢型谷氨酸受体2型("mGluR2")的负变构调节剂(NAMs)。该发明还涉及包含这些化合物的药物组合物，制备这些化合物和组合物的方法，以及使用这些化合物和组合物预防或治疗涉及代谢型受体mGluR2亚型的疾病。
• [EN] 6,7-DIHYDROPYRAZOLO[1,5-α]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS<br/>[FR] COMPOSÉS DE 6,7-DIHYDROPYRAZOLO[1,5-Α]PYRAZIN-4(5H)-ONE ET LEUR UTILISATION COMME MODULATEURS ALLOSTÉRIQUES NÉGATIFS DES RÉCEPTEURS MGLUR2
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2016087487A1

  公开（公告）日：2016-06-09

  The present invention relates to novel 6,7-dihydropyrazolo[1,5-α]pyrazin-4(5H)-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR2"). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.

  本发明涉及作为代谢型谷氨酸受体亚型2 ("mGluR2") 的负变构调节剂 (NAMs) 的新型6,7-二氢吡唑并[1,5-α]吡嗪-4(5H)-酮衍生物。该发明还涉及包含这种化合物的药物组合物，用于制备这种化合物和组合物的方法，以及用于预防或治疗涉及代谢型受体的 mGluR2 亚型的疾病的这种化合物和组合物的用途。
• [EN] COMBINATIONS COMPRISING POSITIVE ALLOSTERIC MODULATORS OR ORTHOSTERIC AGONISTS OF METABOTROPIC GLUTAMATERGIC RECEPTOR SUBTYPE 2 AND THEIR USE<br/>[FR] COMBINAISONS COMPRENANT DES MODULATEURS ALLOSTÉRIQUES POSITIFS OU DES AGONISTES ORTHOSTÉRIQUES DE SOUS-TYPE 2 DE RÉCEPTEUR GLUTAMATERGIQUE MÉTABOTROPE, ET LEUR UTILISATION
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2015110435A1

  公开（公告）日：2015-07-30

  The present invention relates to combinations comprising a positive allosteric modulator ("PAM") of metabotropic glutamatergic receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and a synaptic vesicle protein 2A ("SV2A") ligand.

  本发明涉及组合物，包括一种代谢型谷氨酸受体亚型2（"mGluR2"）的正向变构调节剂（"PAM"）或其药用可接受盐或溶剂，或一种代谢型谷氨酸受体亚型2的正交合激动剂化合物或其药用可接受盐或溶剂，以及突触囊泡蛋白2A（"SV2A"）配体。
• [EN] 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS<br/>[FR] COMPOSÉS 6,7-DIHYDROPYRAZOLO[1,5-A]PYRAZIN-4(5H)-ONE ET LEUR UTILISATION COMME MODULATEURS ALLOSTÉRIQUES NÉGATIFS DES RÉCEPTEURS MGLUR2
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2014195311A1

  公开（公告）日：2014-12-11

  The present invention relates to novel 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives of Formula (I) as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR2"). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved, especially CNS disorders.

  本发明涉及一种新型的Formula (I)的6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮衍生物，作为代谢型谷氨酸受体亚型2 ("mGluR2")的负变构调节剂（NAMs）。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及用于预防或治疗涉及代谢型受体亚型2的疾病的化合物和组合物的用途，特别是中枢神经系统疾病。
• [EN] 6,7-DIHYDROPYRAZOLO[1,5-A]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS<br/>[FR] 6,7-DIHYDROPYRAZOLO [1,5-A] PYRAZIN -4 (5H)-ONE COMPOSÉS ET LEUR UTILISATION COMME MODULATEURS ALLOSTÉRIQUES NÉGATIFS DES RÉCEPTEURS MGLUR2
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2016016381A1

  公开（公告）日：2016-02-04

  The present invention relates to novel 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR2"). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.

  本发明涉及一种新颖的6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮衍生物，作为代谢型谷氨酸受体亚型2（"mGluR2"）的负性别构调控剂（NAMs）。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及用于预防或治疗涉及代谢型受体亚型mGluR2的疾病的这些化合物和组合物的用途。