米力农杂质A | 80047-24-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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
• 中文名称: 米力农杂质A
• 中文别名: 米力农相关物质A；米力农相关化合物A(1,6-二氢-2-甲基-6-氧(3,4'-联吡啶)-5-甲酰胺)；米力农相关化合物A(50毫克)(1,6-二氢-2-甲基-6-氧(3,4'-联吡啶)-5-甲酰胺)；米力农相关化合物A(50毫克)(1,6-二氢- 2 -甲基- 6 -氧(3,4'-联吡啶)-5 -甲酰胺)；米力农相关化合物A(5毫克)(1,6-二氢- 2 -甲基- 6 -氧(3,4'-联吡啶)-5 -甲酰胺)
• 英文名称: 1,6-dihydro-2-methyl-6-oxo-<3,4'-bipyridine>-5-carboxamide
• 英文别名: 6-methyl-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide；5-(4-Pyridyl)-3-carbamoyl-6-methyl-pyridine-2(1H)-one；1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide；2-Methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-5-carboxamide；6-methyl-2-oxo-5-pyridin-4-yl-1H-pyridine-3-carboxamide
• CAS: 80047-24-1
• 化学式: C₁₂H₁₁N₃O₂
• 分子量: 229.238
• InChiKey: SWKVSFPUHCMFJY-UHFFFAOYSA-N

物化性质

• 熔点：
  >300 °C (decomp)
• 沸点：
  563.9±50.0 °C(Predicted)
• 密度：
  1.307±0.06 g/cm3(Predicted)
• 溶解度：
  酸水溶液（微溶）、DMSO（微溶、加热、超声处理）、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  85.1
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  室温下保存于惰性气体中

反应信息

• 作为反应物：
  描述：

  米力农杂质A 在 sodium hydroxide 、 溴 作用下， 以 盐酸 、 水 为溶剂， 生成 5-amino-2-methyl-<3,4'-bipyridin>-6(1H)-one
  参考文献：
  名称：

  3-Substituted-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones, their

  摘要：

  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。

  公开号：

  US04313951A1
• 作为产物：
  描述：

  米力农 在 硫酸 作用下， 反应 0.25h， 以72%的产率得到米力农杂质A
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2018.04.033

文献信息

• A process for preparing nicotinonitriles and intermediates used therein
  申请人：STERLING DRUG INC.

  公开号：EP0095152A1

  公开（公告）日：1983-11-30

  One aspect of the invention resides in the three step process for preparing cardiotonically active 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles or 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinamides which comprises reacting a pyridinylmethyl lower-alkyl ketone with tri-(lower-alkyl) orthoformate, acetic anhydride and acetic acid to produce 2-(lower-alkoxy)-1-(pyridinyl)-ethenyl lower-alkyl ketone reacting the latter with cyanoacetamide or malonamide in the presence of a basic condensing agent and neutralizing the reaction mixture, where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. Other aspects of the invention reside in the intermediate 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketones, their salts and their two step conversion, as described above, to 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)-nicotinonitriles or corresponding nicotinamides.

  本发明的一个方面是制备具有生物素活性的 1,2-二氢-6-(低级烷基)-2-氧代-5-(吡啶基)烟酰硝酸酯或 1,2-二氢-6-(低级烷基)-2-氧代-5-(吡啶基)烟酰胺的三步法，包括使吡啶甲基低级烷基酮与三-(低级烷基)原甲酸酯、乙酸酐和乙酸反应，生成 2-(低级烷氧基)-1-(吡啶基)乙烯基低级烷基酮，再使后者与氰乙酰胺或丙二酰酰胺反应、乙酸酐和乙酸反应，生成 2-(低级烷氧基)-1-(吡啶基)-乙烯基低级烷基酮，在碱性缩合剂存在下，使后者与氰乙酰胺或丙二酰胺反应，并中和反应混合物，其中吡啶基是 4-或 3-吡啶基或具有一个或两个低级烷基取代基的 4-或 3-吡啶基。本发明的其他方面在于中间体 2-(低级烷氧基)-1-(吡啶基)乙烯基低级烷基酮、它们的盐和它们的两步转化，如上所述，转化为 1,2-二氢-6-(低级烷基)-2-氧代-5-(吡啶基)-烟酰腈或相应的烟酰胺。
• Process for the preparation of 5-pyridyl-pyridine-2(1H)-ones
  申请人：FABRICA DE PRODUCTOS QUIMICOS Y FARMACEUTICOS ABELLO, S.A.

  公开号：EP0127756A1

  公开（公告）日：1984-12-12

  5-pyridyl-pyridine-2 (1H) -ones of general formula I in which R1 is an amino group, R2 is a hydrogen atom or a lower alkyl group and R3 is a 4-, 3- or 2-pyridyl group are prepared by reaction of 1-R2-1-oxo-2-R3-3-dimethyl- aminopropane (II) with malonamide undersolid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2-5-R3-nicotin-amide (IV), or by reaction of II with cyanoacetamide under solid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2-5-R3-nicotinonitrile (III) and partially hydrolizing III to yield IV; finally the carbamoyl group of IV is converted to amino and 1,2-dihydro-2-oxo-6-R2-5-R3-3-aminopyridin-2-ones are obtained.

  通式 I 的 5-吡啶基吡啶-2(1H)-酮 其中 R1 为氨基，R2 为氢原子或低级烷基，R3 为 4-、3-或 2-吡啶基，通过 1-R2-1-oxo-2-R3-3-dimethyl- aminopropane (II) 与丙二酰胺在固液或液液相转移催化条件下反应制备得到 1、2-二氢-2-氧代-6-R2-5-R3-烟酰胺（IV），或者在固液或液液相转移催化条件下，将 II 与氰乙酰胺反应，得到 1,2-二氢-2-氧代-6-R2-5-R3-烟腈（III），然后将 III 部分水解，得到 IV；最后将 IV 的氨基甲酰基转化为氨基，得到 1,2-二氢-2-氧代-6-R2-5-R3-3-氨基吡啶-2-酮。
• 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.
• HAGEN, VOLKER;KLAUSCHENZ, ERHARD;JANSCH, HANS-JOACHIM;NIEDRICH, HARTMUT;H+
  作者：HAGEN, VOLKER、KLAUSCHENZ, ERHARD、JANSCH, HANS-JOACHIM、NIEDRICH, HARTMUT、H+

  DOI：——

  日期：——
• LESHER, G. Y.;PHILION, R. E.
  作者：LESHER, G. Y.、PHILION, R. E.

  DOI：——

  日期：——