5-amino-2-methyl-<3,4'-bipyridin>-6(1H)-one | 80047-27-4

• 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: 5-amino-2-methyl-<3,4'-bipyridin>-6(1H)-one
• 英文别名: 3-amino-5-(pyridin-4-yl)-6-methylpyridin-2-one；3-amino-5-(4-pyridinyl)-6-methyl-2(1H)-pyridinone；3-amino-6-methyl-5-pyridin-4-yl-1H-pyridin-2-one
• CAS: 80047-27-4
• 化学式: C₁₁H₁₁N₃O
• 分子量: 201.228
• InChiKey: PODUQVUYRAXKPI-UHFFFAOYSA-N

物化性质

• 沸点：
  446.7±45.0 °C(Predicted)
• 密度：
  1.223±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  68
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-amino-2-methyl-<3,4'-bipyridin>-6(1H)-one 生成 6-Methyl-3-(dimethylamino)-5-(4-pyridinyl)-2(1H)-pyridinone
  参考文献：
  名称：

  LESHER, G. Y.;PHILION, R. E.

  摘要：

  DOI：
• 作为产物：
  描述：

  米力农 在 sodium hydroxide 、 硫酸 、 溴 作用下， 反应 3.25h， 生成 5-amino-2-methyl-<3,4'-bipyridin>-6(1H)-one
  参考文献：
  名称：

  Bipyridine cardiotonics: the three-dimensional structures of amrinone and milrinone

  摘要：

  The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile) is superior to its analogue amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) by virtue of its greater potency and reduced side effect profile. We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drugs had cumulative inotropic ED50's of 37 and 1891 micrograms/kg, respectively; relative effects on heart rate and blood pressure were comparable. There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone. We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone. A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms. Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography. The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 degrees. In marked contrast, the corresponding angle for milrinone was 52.2 degrees. Moreover, 1H NMR studies revealed conformational differences in solution. Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.

  DOI：

  10.1021/jm00155a009

文献信息

• 3-Substituted-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones, their
  申请人：Sterling Drug Inc.

  公开号：US04313951A1

  公开（公告）日：1982-02-02

  1-R.sub.1 -3-[amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino]-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. 1-R.sub.1 -3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting carbamyl to amino. The 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by reacting (pyridinylmethyl) lower-alkyl ketones with dimethylformamide di-(lower-alkyl) acetal to produce 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and reacting said ketones with N-R.sub.1 -.alpha.-cyanoacetamide to produce the 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones. Also shown are the conversions: of the 3-cyano compounds to the 3-H compounds; of the 3-H compounds to the 3-halo compounds; of the 3-halo compounds to the 3-[mono-(lower-alkyl)- or di-(lower-alkyl)-amino]compounds; and, of the 3-amino compounds to the 3-lower-acylamino or 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds.

  1-R.sub.1 -3-[氨基，氰基，氨基甲酰基，卤素，较低烷基氨基，双-(较低烷基)氨基或较低酰胺基]-6-(较低烷基)-5-(吡啶基)-2(1H)-吡啶酮或其药学上可接受的酸加合物或阳离子盐作为心力衰竭药物具有用途，其中R.sub.1为氢，较低烷基或较低羟基烷基。1-R.sub.1 -3-氨基-6-(较低烷基)-5-(吡啶基)-2(1H)-吡啶酮是通过水解相应的3-氰基化合物以产生相应的3-氨基甲酰基化合物并将后者与能将氨甲酰基转化为氨基的试剂反应而制备的。1-R.sub.1 -3-氰基-6-(较低烷基)-5-(吡啶基)-2(1H)-吡啶酮是通过将(吡啶基甲基)较低烷基酮与二甲基甲酰胺双-(较低烷基)缩醛反应以产生1-(吡啶基)-2-(二甲氨基)乙烯基较低烷基酮并将该酮与N-R.sub.1-.alpha.-氰基乙酰胺反应以产生1-R.sub.1 -3-氰基-6-(较低烷基)-5-(吡啶基)-2(1H)-吡啶酮制备的。还显示了以下转化：3-氰基化合物至3-H化合物的转化；3-H化合物至3-卤素化合物的转化；3-卤素化合物至3-[单-(较低烷基)-或双-(较低烷基)-氨基]化合物的转化；以及3-氨基化合物至3-较低酰胺基或3-[单-(较低烷基)-或双-(较低烷基)氨基]化合物的转化。
• Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition
  作者：Daren Fearon、Isaac M. Westwood、Rob L.M. van Montfort、Richard Bayliss、Keith Jones、Vassilios Bavetsias

  DOI：10.1016/j.bmc.2018.04.033

  日期：2018.7

  Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino 5 (1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity. (C) 2018 The Authors. Published by Elsevier Ltd.
• US4313951A
  申请人：——

  公开号：US4313951A

  公开（公告）日：1982-02-02
• US4365065A
  申请人：——

  公开号：US4365065A

  公开（公告）日：1982-12-21
• Bipyridine cardiotonics: the three-dimensional structures of amrinone and milrinone
  作者：David W. Robertson、E. E. Beedle、John K. Swartzendruber、Noel D. Jones、T. K. Elzey、Raymond F. Kauffman、Harve Wilson、J. Scott Hayes

  DOI：10.1021/jm00155a009

  日期：1986.5

  The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile) is superior to its analogue amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) by virtue of its greater potency and reduced side effect profile. We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drugs had cumulative inotropic ED50's of 37 and 1891 micrograms/kg, respectively; relative effects on heart rate and blood pressure were comparable. There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone. We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone. A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms. Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography. The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 degrees. In marked contrast, the corresponding angle for milrinone was 52.2 degrees. Moreover, 1H NMR studies revealed conformational differences in solution. Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.