[6,7-二氢-2-(苯氧基甲基)恶唑并[5,4-c]吡啶-5(4H)-基](氟苯基)甲酮 | 1363281-27-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: [6,7-二氢-2-(苯氧基甲基)恶唑并[5,4-c]吡啶-5(4H)-基](氟苯基)甲酮
• 英文名称: (4-fluorophenyl)-[2-(phenoxymethyl)-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl]methanone
• 英文别名: (4-fluorophenyl)(2-(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridin-5(4H)-yl)methanone；VU0409551/JNJ-46778212；5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine；(4-fluorophenyl)-[2-(phenoxymethyl)-6,7-dihydro-4H-[1,3]oxazolo[5,4-c]pyridin-5-yl]methanone
• CAS: 1363281-27-9
• 化学式: C₂₀H₁₇FN₂O₃
• 分子量: 352.365
• InChiKey: QUZLMKNNIUSREV-UHFFFAOYSA-N

物化性质

• 沸点：
  545.8±50.0 °C(Predicted)
• 密度：
  1.308±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶；乙醇：可溶

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  5

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

JNJ-46778212 (VU 0409551) 是一种 mGlu5 正变构调节剂，其 EC50 值为 260 nM。

靶点

mGlu5 Receptor EC50: 260 nM

体内研究

在口服脑组织/血浆的研究中，JNJ-46778212 展现出优秀的中枢神经系统穿透性。它能增强 NMDAR 功能，并在 SR−/− 小鼠分离的海马切片中恢复长期强化作用。向 SR−/− 小鼠给予 JNJ-46778212 可逆转其多种神经可塑性信号通路的缺陷，并改善它们的条件恐惧记忆。

反应信息

• 作为反应物：
  描述：

  [6,7-二氢-2-(苯氧基甲基)恶唑并[5,4-c]吡啶-5(4H)-基](氟苯基)甲酮 在 偶氮二甲酸二叔丁酯 、 三溴化硼 、 三苯基膦 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 0.33h， 生成 5-(4-fluorobenzoyl)-2-[(2-fluorophenoxy)methyl]-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine
  参考文献：
  名称：

  Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound

  摘要：

  This Letter describes the progress and challenges in the continued optimization of the mGlu(5) positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c] pyridine-5(4H)-yl(aryl) methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.06.096
• 作为产物：
  描述：

  6,7-dihydro-2-(hydroxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester 在 偶氮二甲酸二叔丁酯 、 水 、 三乙胺 、 三苯基膦 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 90.58h， 生成 [6,7-二氢-2-(苯氧基甲基)恶唑并[5,4-c]吡啶-5(4H)-基](氟苯基)甲酮
  参考文献：
  名称：

  [EN] BICYCLIC OXAZOLE AND THIAZOLE COMPOUNDS AND THEIR USE AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
  [FR] COMPOSÉS BICYCLIQUES D'OXAZOLE ET DE THIAZOLE ET LEUR UTILISATION EN TANT QUE MODULATEURS ALLOSTÉRIQUES DES RÉCEPTEURS MGLUR5

  摘要：

  在一个方面，该发明涉及新型的双环氧唑和噻唑化合物，它们是代谢型谷氨酸受体亚型5（"mGluR5"）的阳性变构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；使用这些化合物和组合物治疗与谷氨酸功能障碍相关的神经和精神疾病的方法；以及治疗或预防与谷氨酸功能障碍相关的疾病以及mGluR5受体亚型参与的疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不意味着对本发明的限制。

  公开号：

  WO2012031024A1

文献信息

• BICYCLIC OXAZOLE AND THIAZOLE COMPOUNDS AND THEIR USE AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS
  申请人：Conn P. Jeffrey

  公开号：US20130261107A1

  公开（公告）日：2013-10-03

  In one aspect, the invention relates to novel bicyclic oxazole and thiazole compounds which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (“mGluR5”); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions; and methods for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  该发明涉及一种新型双环氧唑和噻唑化合物，它们是代谢型谷氨酸受体亚型5（“mGluR5”）的正向变构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；使用这些化合物和组合物治疗与谷氨酸功能失调相关的神经和精神障碍的方法；以及用于治疗或预防与谷氨酸功能失调相关的疾病和mGluR5受体亚型参与的疾病的方法。本摘要旨在作为搜索特定技术领域的扫描工具，并不限制本发明。
• Bicyclic oxazole and thiazole compounds and their use as allosteric modulators of mGluR5 receptors
  申请人：Conn P. Jeffrey

  公开号：US09090632B2

  公开（公告）日：2015-07-28

  In one aspect, the invention relates to novel bicyclic oxazole and thiazole compounds which are positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (“mGluR5”); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions; and methods for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptors is involved. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及新型双环氧唑和噻唑化合物，它们是代谢型谷氨酸受体亚型5（“mGluR5”）的正向变构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；使用这些化合物和组合物治疗与谷氨酸功能障碍相关的神经和精神障碍的方法；以及治疗或预防与谷氨酸功能障碍相关的疾病和涉及mGluR5受体亚型的疾病的方法。本摘要旨在作为扫描工具，用于在特定领域搜索，不旨在限制本发明。
• Discovery of VU0409551/JNJ-46778212: An mGlu₅ Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia
  作者：Susana Conde-Ceide、Carlos M. Martínez-Viturro、Jesús Alcázar、Pedro M. Garcia-Barrantes、Hilde Lavreysen、Claire Mackie、Paige N. Vinson、Jerri M. Rook、Thomas M. Bridges、J. Scott Daniels、Anton Megens、Xavier Langlois、Wilhelmus H. Drinkenburg、Abdellah Ahnaou、Colleen M. Niswender、Carrie K. Jones、Gregor J. Macdonald、Thomas Steckler、P. Jeffrey Conn、Shaun R. Stauffer、José Manuel Bartolomé-Nebreda、Craig W. Lindsley

  DOI：10.1021/acsmedchemlett.5b00181

  日期：2015.6.11

  Herein, we report the structure activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu(5)) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
• US9090632B2
  申请人：——

  公开号：US9090632B2

  公开（公告）日：2015-07-28
• Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound
  作者：Ya Zhou、Chrysa Malosh、Susana Conde-Ceide、Carlos Manuel Martínez-Viturro、Jesus Alcázar、Hilde Lavreysen、Claire Mackie、Thomas M. Bridges、J. Scott Daniels、Colleen M. Niswender、Carrie K. Jones、Gregor J. Macdonald、Thomas Steckler、P. Jeffrey Conn、Shaun R. Stauffer、José Manuel Bartolomé-Nebreda、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2015.06.096

  日期：2015.9

  This Letter describes the progress and challenges in the continued optimization of the mGlu(5) positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c] pyridine-5(4H)-yl(aryl) methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies. (C) 2015 Elsevier Ltd. All rights reserved.