1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile | 1056381-96-4

• 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: 1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile
• 英文别名: 1-Cyclopropylmethyl-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile；1-(cyclopropylmethyl)-4-hydroxy-2-oxopyridine-3-carbonitrile
• CAS: 1056381-96-4
• 化学式: C₁₀H₁₀N₂O₂
• 分子量: 190.202
• InChiKey: OAUBYWATRFTIEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  64.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile 在 四(三苯基膦)钯 、 碳酸氢钠 、 三溴氧磷 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.17h， 生成 1-cyclopropylmethyl-4-[4-(2-methylpyridin-3-yloxy)-phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile
  参考文献：
  名称：

  Discovery of 1,4-Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

  摘要：

  The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

  DOI：

  10.1021/jm2016864
• 作为产物：
  描述：

  1-(环丙基甲基)-4-甲氧基-2-氧代-1,2-二氢吡啶-3-腈 在 水 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 5.0h， 生成 1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile
  参考文献：
  名称：

  三种新型放射性示踪剂在大鼠脑中对代谢型谷氨酸受体亚型2成像的合成及体外评价

  摘要：

  这项研究的目的是开发三种新的放射性示踪剂，1-（环丙基甲基）-4-（[[ 11 C / 18 F]取代的苯基）哌啶-1-基-2-氧-2-1,2-二氢吡啶-3-碳腈（[ 11 C] 1，[ 11 C] 2和[ 18 F] 4），并使用体外放射自显影法检查它们在大鼠脑切片中与代谢型谷氨酸受体亚型2（mGluR2）的特异性结合。发现这些化合物对大鼠脑匀浆中的mGluR2具有有效的体外结合亲和力（K i：8.0-34.1 nM）。[ 11 C] 1，[ 11 C] 2，和[ 18 F] 4通过相应的苯酚前体的[ 11 C / 18 F]烷基化与[ 11 C]甲基碘或[ 18 F]氟乙基溴化物进行化学合成，其化学纯度> 98％，且80-130 GBq /μmol合成结束时的比活。体外放射自显影显示这些放射性示踪剂在富含mGluR2的大脑区域（例如大脑皮层，纹状体，海马和小脑颗粒层）中显示出异质特异性结合。

  DOI：

  10.1016/j.bmcl.2017.05.029

文献信息

• Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[ 11 C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([ 11 C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain
  作者：Yufei Ma、Katsushi Kumata、Joji Yui、Yiding Zhang、Tomoteru Yamasaki、Akiko Hatori、Masayuki Fujinaga、Nobuki Nengaki、Lin Xie、Hui Wang、Ming-Rong Zhang

  DOI：10.1016/j.bmc.2016.12.011

  日期：2017.2

  1-(cyclopropylmethyl)-4-(4-[11C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([11C]CMDC) and evaluate its potential as a positron emission tomography (PET) radiotracer for imaging mGluR2 in the rat brain. CMDC, a positive allosteric modulator of mGluR2, showed potent functional activity (EC50: 98 nM) for human mGluR2 in vitro. [11C]CMDC was synthesized by O-[11C]methylation of 1-(c

  已经提出脑代谢型谷氨酸受体2（mGluR2）作为治疗因前脑中谷氨酸传递增加而引起的精神分裂症样症状的治疗靶标。但是，尚不存在用于在人类神经成像中研究mGluR2的可靠工具。这项研究的目的是放射性合成1-（环丙基甲基）-4-（4- [ 11 C]甲氧基苯基）哌啶-1-基-2-氧代-1,2-二氢吡啶-3-腈（[ 11 C] CMDC ），并评估其作为正电子发射断层扫描（PET）示踪剂对大鼠大脑中的mGluR2成像的潜力。CMDC，mGluR2的正变构调节剂，表现出有效的功能活性（EC 50：98 nM）的对人mGluR2的体外。[ 11 C] CMDC由O合成- [ 11 C] 1-（环丙基甲基）甲基-4-（4-羟基苯基）哌啶-1-基-2-氧代-1,2-二氢吡啶-3-甲腈（1）与[ 11 C]甲基碘。[ 11 C] CMDC（2.2±0.9 GBq; n  = 20）是从14.0–17.8 GBq的[
• 3-CYANO-4-(4-PHENYL-PIPERIDIN-1-YL)-PYRIDIN-2-ONE DERIVATIVES
  申请人：Cid-Núñez José Maria

  公开号：US20100063092A1

  公开（公告）日：2010-03-11

  The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate receptors 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. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and such compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

  本发明涉及新型化合物，特别是根据公式（I）的新型吡啶酮衍生物，包括其任何立体化异构体形式、药学上可接受的盐或其溶剂化物，其中所有基团在申请和权利要求中均有定义。本发明所述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mGluR2亚型的疾病。特别是，这些疾病是选择自焦虑、精神分裂症、偏头痛、抑郁症和癫痫等中枢神经系统疾病的一组。本发明还涉及制备这种化合物和这种组合物的制药组合物和过程，以及将这种化合物用于预防和治疗涉及mGluR2的这种疾病。
• 1,4-DISUBSTITUTED 3-CYANO-PYRIDONE DERIVATIVES AND THEIR USE AS POSITIVE MGLUR2-RECEPTOR MODULATORS
  申请人：Cid-Núñez José Maria

  公开号：US20100099715A1

  公开（公告）日：2010-04-22

  The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate receptors 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. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and such compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

  本发明涉及新型化合物，特别是公式（I）中的新型吡啶酮衍生物，包括其任何立体化异构体形式，或其药学上可接受的盐或溶剂，其中所有基团在申请和权利要求中都有定义。本发明所述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。特别是，这些疾病是选择自焦虑、精神分裂症、偏头痛、抑郁症和癫痫等中枢神经系统疾病。本发明还涉及制备这种化合物和这种组合物的制药组合物和过程，以及使用这种化合物预防和治疗涉及mGluR2的这种疾病。
• 3-CYANO-4-(4-TETRAHYDROPYRAN-PHENYL)-PYRIDIN-2-ONE DERIVATIVES
  申请人：Cid-Núñez José Maria

  公开号：US20100087487A1

  公开（公告）日：2010-04-08

  The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate receptors 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. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and such compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

  本发明涉及新型化合物，特别是根据公式（I）的新型吡啶酮衍生物，包括其任何立体化异构体形式，或其药学上可接受的盐或其溶剂化物，其中所有基团在申请和权利要求中均有定义。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。特别地，这些疾病是选择自焦虑、精神分裂症、偏头痛、抑郁症和癫痫等中枢神经系统疾病的。本发明还涉及制备这些化合物及其制剂的制药组合物和方法，以及使用这些化合物预防和治疗涉及mGluR2的这些疾病。
• 1,4-DISUBSTITUTED 3-CYANO-PYRIDONE DERIVATIVES AND THEIR USE AS POSITIVE MGLUR2-RECEPTOR
  申请人：Cid-Nunez Jose Maria

  公开号：US20130150412A1

  公开（公告）日：2013-06-13

  The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate receptors 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. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and such compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

  本发明涉及新颖化合物，特别是根据式（I）的新颖吡啶酮衍生物，包括其任何立体化异构体形式，或其药学上可接受的盐或溶剂化物，其中所有基团在申请和权利要求中都有定义。本发明所述化合物是代谢型谷氨酸受体亚型2（“mGluR2”）的正向变构调节剂，对于与谷氨酸功能障碍和mGluR2代谢型受体有关的神经和精神障碍以及疾病的治疗或预防是有用的。特别是，这些疾病是选择自焦虑、精神分裂症、偏头痛、抑郁症和癫痫的中枢神经系统疾病。本发明还涉及制备这些化合物和这些组合物的制药组合物和制备过程，以及使用这些化合物预防和治疗与mGluR2有关的这些疾病。