5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid hydrochloride | 1402003-83-1

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid hydrochloride
• 英文别名: 5-(4-methylimidazol-1-yl)-6-oxo-1H-pyridine-2-carboxylic acid;hydrochloride
• CAS: 1402003-83-1
• 化学式: C₁₀H₉N₃O₃*ClH
• 分子量: 255.661
• InChiKey: SGJBAHKZPBZXBJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.99
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  84.2
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid hydrochloride 在 bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane 、 caesium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 25.33h， 生成 N-((S)-1-(4-fluoro-2-((R)-1,1,1-trifluoropropan-2-yl)phenoxy)propan-2-yl)-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide
  参考文献：
  名称：

  Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability

  摘要：

  Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione gamma-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain A beta 42 and A beta 40 were observed in a guinea pig time-course experiment.

  DOI：

  10.1021/acsmedchemlett.5b00070
• 作为产物：
  描述：

  6-甲氧基-5-(4-甲基-1H-咪唑-1-基)吡啶-2-羧酸甲酯 在 盐酸 作用下， 以 水 为溶剂， 反应 18.0h， 以98%的产率得到5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid hydrochloride
  参考文献：
  名称：

  [EN] NOVEL BICYCLIC PYRIDINONES AS GAMMA-SECRETASE MODULATORS
  [FR] NOUVELLES PYRIDINONES BICYCLIQUES UTILISÉES COMME MODULATEURS DE GAMMA-SÉCRÉTASE

  摘要：

  所述化合物及其药用可接受的盐已被披露，其中这些化合物具有规范中定义的 Formula I 的结构。相应的药物组合物、治疗方法、合成方法和中间体也已被披露。

  公开号：

  WO2015049616A1

文献信息

• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• [EN] CHROMENE AND 1,1 A,2,7B-TETRAHYDROCYCLOPROPA[C]CHROMENE PYRIDOPYRAZINEDIONES AS GAMMA-SECRETASE MODULATORS<br/>[FR] CHROMÈNE ET 1,1A,2,7B-TÉTRAHYDROCYCLOPROPA[C]CHROMÈNE PYRIDOPYRAZINEDIONES COMME MODULATEURS DE GAMMA-SÉCRÉTASE
  申请人：PFIZER

  公开号：WO2015150957A1

  公开（公告）日：2015-10-08

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I), wherein X, R1, R2a, R2b, R4a, R4b, R5a, R5b, R6, R7, y and z are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed. These compounds are γ-secretase modulators, useful for the treatment of neurodegenerative and/ or neurological disorders such as Alzheimer's disease and Down's syndrome.

  所述化合物及其药用可接受盐已被披露，其中所述化合物具有式（I）的结构，其中X、R1、R2a、R2b、R4a、R4b、R5a、R5b、R6、R7、y和z如规范中所定义。相应的药物组合物、治疗方法、合成方法和中间体也已被披露。这些化合物是γ-分泌酶调节剂，可用于治疗神经退行性和/或神经系统疾病，如阿尔茨海默病和唐氏综合征。
• Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin
  作者：Martin Pettersson、Douglas S. Johnson、John M. Humphrey、Christopher W. am Ende、Edelweiss Evrard、Ivan Efremov、Gregory W. Kauffman、Antonia F. Stepan、Cory M. Stiff、Longfei Xie、Kelly R. Bales、Eva Hajos-Korcsok、Heather E. Murrey、Leslie R. Pustilnik、Stefanus J. Steyn、Kathleen M. Wood、Patrick R. Verhoest

  DOI：10.1016/j.bmcl.2014.12.059

  日期：2015.2

  Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited

  在这里，我们描述了导致发现新颖的吡啶并吡嗪-1,6-二酮γ-分泌酶调节剂（GSMs）的设计策略，该调节剂结合了吲哚基序作为杂环取代了原来的铅9中存在的萘基。讨论了涉及平行药物化学和原位单体合成以制备重点文库的策略。优化的吲哚GSM 29表现出良好的体外药效和理化特性，在大鼠功效模型中以30 mg / kg口服时，脑Aβ42的适度降低。使用可点击的，吲哚衍生的GSM光亲和探针进行的标记实验表明，该系列与γ-分泌酶复合物的早老素N末端片段（PS1-NTF）结合。
• Bicyclic pyridinones
  申请人：Pfizer Inc.

  公开号：US09067934B2

  公开（公告）日：2015-06-30

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本文披露了化合物及其医药上可接受的盐，其中化合物的结构符合此处定义的公式I。同时还披露了相应的制药组合物、治疗方法、合成方法和中间体。
• Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
  申请人：Pfizer Inc.

  公开号：US08916564B2

  公开（公告）日：2014-12-23

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本文披露了化合物和药学上可接受的盐，其中化合物具有规范中定义的I式结构。同时还披露了相应的药物组合物、治疗方法、合成方法和中间体。