5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid | 1403771-21-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid
• 英文别名: 5-((3-fluorophenyl)ethynyl)picolinic acid；VU0451326；5-(3-fluorophenylethynyl)pyridine-2-carboxylic acid；5-[2-(3-fluorophenyl)ethynyl]pyridine-2-carboxylic acid
• CAS: 1403771-21-0
• 化学式: C₁₄H₈FNO₂
• 分子量: 241.221
• InChiKey: RWBNWQJYOHIZQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid 在 sodium hydride 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.34h， 生成 (R)-5-((3-fluorophenyl)ethynyl)-N-(3-methoxy-3-methylbutan-2-yl)picolinamide
  参考文献：
  名称：

  Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

  摘要：

  Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu(5) PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu(5) PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift similar to 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu(5) PAMs.

  DOI：

  10.1021/jm401028t
• 作为产物：
  描述：

  1-乙炔基-3-氟苯 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 水 、 三乙胺 、 三苯基膦 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid
  参考文献：
  名称：

  [EN] ETHYNYL DERIVATIVES AS MODULATORS OF MGLUR5 RECEPTOR ACTIVITY
  [FR] DÉRIVÉS D'ÉTHYNYL UTILISÉS EN TANT QUE MODULATEURS DE L'ACTIVITÉ DES RÉCEPTEURS MGLUR5

  摘要：

  本发明涉及公式（I）的乙炔衍生物，其中Y为N或CH，R1为氟、氯或药学上可接受的酸加成盐，或其对映体和/或光学异构体和/或立体异构体的混合物。现已惊奇地发现，一般式（I）化合物是代谢型谷氨酸受体拮抗剂（负向变构调节剂），可用于治疗焦虑和疼痛、抑郁症、脆性X综合症、自闭症谱系障碍、帕金森病和胃食管反流病（GERD）。

  公开号：

  WO2014060384A1

文献信息

• PHENYL OR PYRIDINYL-ETHYNYL DERIVATIVES
  申请人：Jaeschke Georg

  公开号：US20120270852A1

  公开（公告）日：2012-10-25

  The present invention relates to ethynyl derivatives of formula I wherein Y is N or C—R 3 ; R 3 is hydrogen, methyl, halogen or nitrile; R 1 is phenyl or pyridinyl, each of which is optionally substituted by halogen, lower alkyl or lower alkoxy; R 2 /R 2′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen, or R 2 and R 2′ together with the N-atom to which they are attached form a morpholine ring, a piperidine ring or an azetidine ring, each of which is unsubstituted or substituted one or more substituents selected from lower alkoxy, halogen, hydroxy and methyl; R 4 /R 4′ are each independently hydrogen or lower alkyl, or R 4 and R 4′ together form a C 3-5 cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. Compounds of formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5).

  本发明涉及公式I的乙炔衍生物，其中Y为N或C—R3；R3为氢、甲基、卤素或腈基；R1为苯基或吡啶基，每个基团可选择地被卤素、低烷基或低烷氧基取代；R2/R2′各自独立地为氢、低烷基或被卤素取代的低烷基，或者R2和R2′与它们连接的N原子一起形成一个吗啉环、哌啶环或氮杂环，每个环未取代或取代一个或多个从低烷氧基、卤素、羟基和甲基中选取的取代基；R4/R4′各自独立地为氢或低烷基，或者R4和R4′一起形成一个C3-5环烷基、四氢呋喃环或噁唑环；或者形成药用可接受的酸盐、对映体混合物，或其对应的对映体和/或光学异构体和/或立体异构体。公式I的化合物是代谢型谷氨酸受体亚型5（mGluR5）的正向变构调节子（PAM）。
• [EN] 5-(PHENYL/PYRIDINYL-ETHINYL)-2-PYRIDINE/ 2-PYRIMIDINE-CARBORXAMIDES AS MGLUR5 MODULATORS<br/>[FR] 5-(PHÉNYL/PYRIDINYL-ÉTHINYL)-2-PYRIDINE/2 PYRIMIDINE-CARBOXAMIDES COMME MODULATEUR DE MGLUR5
  申请人：HOFFMANN LA ROCHE

  公开号：WO2012143340A1

  公开（公告）日：2012-10-26

  The present invention relates to ethynyl derivatives of formula (I), wherein, Y is N or C-R3;and R3 is hydrogen, methyl, halogen or nitrile; R1 is phenyl or pyridinyl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; R2/R2' are independently from each other hydrogen, lower alkyl or lower alkyl substituted by halogen, or R2 and R2' may form together with the N-atom to which they are attached a morpholine ring, a piperidine ring or an azetidine ring, which are unsubstituted or substituted one or more substituents selected from lower alkoxy, halogen, hydroxy or methyl; R4/R4' are independently from each other hydrogen or lower alkyl, or R4 and R4' form together a C3-5 cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. It has now surprisingly been found that the compounds of general formula (I) are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5).

  本发明涉及公式（I）的乙炔衍生物，其中，Y是N或C-R3；R3是氢、甲基、卤素或腈基；R1是苯基或吡啶基，可以选择地被卤素、低烷基或低烷氧基取代；R2/R2'分别是氢、低烷基或被卤素取代的低烷基，或者R2和R2'可以与它们连接的N原子一起形成吗啡啉环、哌啶环或氮杂环，该环未被取代或被一个或多个从低烷氧基、卤素、羟基或甲基中选择的取代基取代；R4/R4'分别是氢或低烷基，或者R4和R4'一起形成C3-5环烷基、四氢呋喃环或氧杂环；或者是药学上可接受的酸盐，或者是消旋混合物，或者是其对应的对映体和/或光学异构体和/或立体异构体。令人惊讶的是发现，通用公式（I）的化合物是代谢型谷氨酸受体亚型5（mGluR5）的阳性变构调节剂（PAM）。
• [EN] SUBSTITUED 5-(PROP-1-YN-1-YL)PICOLINAMIDE ANALOGS AS ALLOSTERIC MODULATORS OF MGLUR5 RECEPTORS<br/>[FR] ANALOGUES DE 5-(PROP-1-YN-1-YL)PICOLINAMIDE SUBSTITUÉ COMME MODULATEURS ALLOSTÉRIQUES DES RÉCEPTEURS DE MGLUR5
  申请人：UNIV VANDERBILT

  公开号：WO2013049255A1

  公开（公告）日：2013-04-04

  In one aspect, the invention relates to substituted 5-(prop-1-yn-1-yl)picolinamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. 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.

  在一个方面，该发明涉及替代的5-(丙炔基)吡啶甲酰胺类似物，其衍生物和相关化合物，这些化合物可用作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；以及使用这些化合物和组合物治疗与谷氨酸功能异常相关的神经和精神疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不打算限制本发明。
• Biotransformation of a Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Contributes to Seizure-Like Adverse Events in Rats Involving a Receptor Agonism-Dependent Mechanism
  作者：Thomas M. Bridges、Jerri M. Rook、Meredith J. Noetzel、Ryan D. Morrison、Ya Zhou、Rocco D. Gogliotti、Paige N. Vinson、Zixiu Xiang、Carrie K. Jones、Colleen M. Niswender、Craig W. Lindsley、Shaun R. Stauffer、P. Jeffrey Conn、J. Scott Daniels

  DOI：10.1124/dmd.113.052084

  日期：2013.9

  Activation of metabotropic glutamate receptor subtype 5 (mGlu5) represents a novel strategy for therapeutic intervention into multiple central nervous system disorders, including schizophrenia. Recently, a number of positive allosteric modulators (PAMs) of mGlu5 were discovered to exhibit in vivo efficacy in rodent models of psychosis, including PAMs possessing varying degrees of agonist activity (ago-PAMs), as well as PAMs devoid of agonist activity. However, previous studies revealed that ago-PAMs can induce seizure activity and behavioral convulsions, whereas pure mGlu5 PAMs do not induce these adverse effects. We recently identified a potent and selective mGlu5 PAM, VU0403602, that was efficacious in reversing amphetamine-induced hyperlocomotion in rats. The compound also induced time-dependent seizure activity that was blocked by coadministration of the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine. Consistent with potential adverse effects induced by ago-PAMs, we found that VU0403602 had significant allosteric agonist activity. Interestingly, inhibition of VU0403602 metabolism in vivo by a pan cytochrome P450 (P450) inactivator completely protected rats from induction of seizures. P450-mediated biotransformation of VU0403602 was discovered to produce another potent ago-PAM metabolite-ligand (M1) of mGlu5. Electrophysiological studies in rat hippocampal slices confirmed agonist activity of both M1 and VU0403602 and revealed that M1 can induce epileptiform activity in a manner consistent with its proconvulsant behavioral effects. Furthermore, unbound brain exposure of M1 was similar to that of the parent compound, VU0403602. These findings indicate that biotransformation of mGlu5 PAMs to active metabolite-ligands may contribute to the epileptogenesis observed after in vivo administration of this class of allosteric receptor modulators.

  代谢型谷氨酸受体亚型 5 (mGlu5) 的激活代表了一种治疗干预多种中枢神经系统疾病（包括精神分裂症）的新策略。最近，发现许多 mGlu5 正变构调节剂 (PAM) 在啮齿动物精神病模型中表现出体内功效，包括具有不同程度激动剂活性的 PAM (ago-PAM) 以及缺乏激动剂活性的 PAM。然而，之前的研究表明，ago-PAM 可以诱发癫痫发作和行为惊厥，而纯 mGlu5 PAM 不会诱发这些不良反应。我们最近发现了一种有效且选择性的 mGlu5 PAM，VU0403602，它可以有效逆转安非他明诱导的大鼠过度运动。该化合物还诱导时间依赖性癫痫发作，但与 mGlu5 拮抗剂 2-甲基-6-（苯乙炔基）吡啶合用可阻断该癫痫发作。与 ago-PAM 引起的潜在不良反应一致，我们发现 VU0403602 具有显着的变构激动剂活性。有趣的是，通过泛细胞色素 P450 (P450) 灭活剂抑制 VU0403602 体内代谢，可以完全保护大鼠免于诱发癫痫发作。发现 P450 介导的 VU0403602 生物转化可产生 mGlu5 的另一种有效的 ago-PAM 代谢物配体 (M1)。对大鼠海马切片的电生理学研究证实了 M1 和 VU0403602 的激动剂活性，并揭示 M1 可以以其促惊厥行为效应一致的方式诱导癫痫样活动。此外，M1 的未结合脑暴露与母体化合物 VU0403602 相似。这些发现表明，mGlu5 PAM 生物转化为活性代谢物配体可能有助于体内施用此类变构受体调节剂后观察到的癫痫发生。
• [EN] ETHYNYL DERIVATIVES AS MODULATORS OF MGLUR5 RECEPTOR ACTIVITY<br/>[FR] DÉRIVÉS D'ÉTHYNYLE COMME MODULATEURS DE L'ACTIVITÉ DES RÉCEPTEURS MGLUR5
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014060398A1

  公开（公告）日：2014-04-24

  The present invention relates to ethynyl derivatives of formula (I) wherein Y is N or CH R1 is fluoro or chloro R2 is hydrogen or methyl or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. It has now surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor antagonists (negative allosteric modulators) for use in the treatment of anxiety and pain, depression, Fragile-X syndrom, autism spectrum disorders, Parkinson's disease, and gastroesophageal reflux disease (GERD).

  本发明涉及公式（I）的乙炔衍生物，其中Y为N或CH，R1为氟或氯，R2为氢或甲基，或其药学上可接受的酸加盐，或其对映体和/或光学异构体和/或立体异构体。现已惊奇地发现，一般公式I的化合物是代谢型谷氨酸受体拮抗剂（负性变构调节剂），可用于治疗焦虑和疼痛，抑郁症，脆性X综合症，自闭症谱系障碍，帕金森病和胃食管反流病（GERD）。