2-氧代-5-(吡啶-4-基)-1,2-二氢吡啶-3-羧酸 | 62749-61-5

• 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: 2-氧代-5-(吡啶-4-基)-1,2-二氢吡啶-3-羧酸
• 英文名称: 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid
• 英文别名: 3-carboxy-5-(pyridin-4-yl)-(1H)-pyridin-2-one；2-oxo-5-(4-pyridinyl)nicotinic acid；6-oxo-1,6-dihydro-[3,4']bipyridinyl-5-carboxylic acid；2-Oxo-5-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxylic acid；2-oxo-5-pyridin-4-yl-1H-pyridine-3-carboxylic acid
• CAS: 62749-61-5
• 化学式: C₁₁H₈N₂O₃
• 分子量: 216.196
• InChiKey: WKDNSRJXCYJQBV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  79.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-氧代-5-(吡啶-4-基)-1,2-二氢吡啶-3-羧酸 在 三氯氧磷 作用下， 以 N-甲基乙酰胺 为溶剂， 生成 3-Carbamoyl-2-chlor-5-(pyrid-4-yl)pyridin
  参考文献：
  名称：

  2-Substituted amino-5-(pyridinyl)-nicotinamides and their cardiotonic use

  摘要：

  所示的是一种制备心力活性1,3-二氢-3-R-6-PY-5-Q-2H-咪唑[4,5-b]吡啶-2-酮的过程，其中Q是氢或低烷基，R是低烷基，低羟基烷基，低烷氧基烷基或Y-NB，其中Y是低烷基烯和NB是双-(低烷基)氨基或4-吗啉基，PY是4-或3-吡啶基或带有一个或两个取代基的4-或3-吡啶基，通过将2-RNH-5-PY-6-Q-烟酰胺与碱金属次氯酸盐反应来实现。还显示了心力活性组合物和一种利用2-RR'N-5-PY-6-Q-烟酰胺或其药用可接受的酸盐增加心脏收缩力的方法，其中R'是氢或甲基。还显示了通过将2-卤代-5-PY-6-Q-烟酰胺与RR'NH式胺反应制备所述2-RR'N-5-PY-6-Q-烟酰胺的过程。

  公开号：

  US04374141A1
• 作为产物：
  描述：

  3-cyano-5-(pyridin-4-yl)-(1H)-pyridin-2-one 在 硫酸 、 potassium carbonate 作用下， 以 水 为溶剂， 生成 2-氧代-5-(吡啶-4-基)-1,2-二氢吡啶-3-羧酸
  参考文献：
  名称：

  3-Cyano-5-(pyridinyl)-2(1H)-pyridinones

  摘要：

  作为心力衰竭药物有用的化合物是1-R-3-Q-5-PY-2(1H)-吡啶酮(I)，其中R是氢、较低的烷基或较低的羟基烷基，Q是氨基（首选）或NHAc，Ac是较低的烷酰基或较低的羧酰基，PY是带有一个或两个较低烷基取代基的4-、3-或2-吡啶基或4-、3-或2-吡啶基。相应的化合物中，Q为硝基、氨基甲酰基、氰基或氢的化合物可用作中间体，Q为氢或氰基的化合物也可用作心力衰竭药物。所述化合物通过以下方法制备：通过将α-PY-β-(R1R2N)丙烯醛(II)与马来酰胺反应，生成1,2-二氢-2-氧代-5-PY-烟酰胺(Ia)，然后将Ia与能够将氨基转化为氨基的试剂反应，生成3-氨基-5-PY-2(1H)-吡啶酮(Ib)；通过将II或α-PY-马隆醛(II')与α-氰基乙酰胺反应，生成1,2-二氢-2-氧代-5-PY-烟酰腈(III)，部分水解III生成Ia；通过将1,2-二氢-2-氧代-5-PY-烟酸(IV)与浓硫酸和浓硝酸混合加热，生成3-硝基-5-PY-2(1H)-吡啶酮(Ic)，然后将Ic还原生成Ib，或者首先将Ic与烷基化剂反应生成1-R'-3-硝基-5-PY-2(1H)-吡啶酮(Id)，再将Id还原生成1-R'-3-氨基-5-PY-2(1H)-吡啶酮(Ib)，其中R'是较低的烷基或较低的羟基烷基。

  公开号：

  US04004012A1

文献信息

• Lower-alkyl 2-halo-5-(pyridinyl)nicotinates, their preparation and use
  申请人：Sterling Drug Inc.

  公开号：US04264612A1

  公开（公告）日：1981-04-28

  Cardiotonic composition and method for increasing cardiac contractility using an effective amount of a cardiotonic lower-alkyl 2-halo-5-PY-6-Q'-nicotinate or pharmaceutically-acceptable acid-addition salt thereof, where halo is chloro or bromo, Q' is hydrogen or lower-alkyl and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. Also shown are novel lower-alkyl 2-halo-5-PY-6-(lower-alkyl)nicotinates or pharmaceutically-acceptable acid-addition salt thereof, useful as intermediates or cardiotonics and preparation thereof.

  心力衰竭组合物及增加心脏收缩力的方法，使用有效量的心力衰竭低烷基2-卤代-5-PY-6-Q'-烟酸盐或其药用可接受的酸盐，其中卤代是氯或溴，Q'是氢或低烷基，PY是4-或3-吡啶基或4-或3-吡啶基，具有一个或两个低烷基取代基。还显示了新型的低烷基2-卤代-5-PY-6-(低烷基)烟酸盐或其药用可接受的酸盐，可用作中间体或心力衰竭药物和其制备方法。
• 1,2-Dihydro-5-pyridinyl-3H-pyrazolo[3,4-b]pyridin-3-ones and their use
  申请人：Sterling Drug Inc.

  公开号：US04265895A1

  公开（公告）日：1981-05-05

  1,2-Dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-ones or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonic agents, are prepared by reacting lower-alkyl 2-halo-5-PY-6-Q-nicotinate with 1-R-hydrazine. Also disclosed are cardiotonic compositions and method for increasing cardiotonic contractility using said compounds or salts.

  1,2-二氢-1-R-5-PY-6-Q-3H-吡唑并[3,4-b]吡啶-3-酮或其药用可接受的酸盐，可用作心力增强剂，通过将低烷基2-卤代-5-PY-6-Q-烟酸酯与1-R-肼反应制备。还公开了心力增强剂组合物和使用所述化合物或盐增加心力增强性的方法。
• 3-Amino-5-(pyridinyl)-2(1H)-pyridinones
  申请人：Sterling Drug Inc.

  公开号：US04072746A1

  公开（公告）日：1978-02-07

  Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or .alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.

  作为强心药剂有用的化合物是1-R-3-Q-5-PY-2(1H)-吡啶酮（I），其中R是氢、低烷基或低羟基烷基，Q是氨基（首选）、低烷基氨基、二（低烷基）氨基或NHAc，Ac是低烷酰基或低羰基烷氧基，PY是4-或3-或2-吡啶基或带有一个或两个低烷基取代基的4-或3-或2-吡啶基。相应的化合物中，如果Q是硝基、氨基甲酰基、氰基、卤素或氢，则可用作中间体；其中Q是氢或氰基的化合物也可用作强心药剂。所述化合物的制备方法包括：通过将α-PY-β-(R1R2N)丙烯醛（II）与马来酰胺反应，生成1,2-二氢-2-氧-5-PY-烟酰胺（Ia），然后将Ia与能够将氨基甲酰转化为氨基的试剂反应，生成3-氨基-5-PY-2(1H)-吡啶酮（Ib）；通过将II或α-PY-马隆醛（II'）与α-氰基乙酰胺反应，生成1,2-二氢-2-氧-5-PY-烟酸腈（III），然后部分水解III，生成Ia；通过将1,2-二氢-2-氧-5-PY-烟酸（IV）与浓硫酸和浓硝酸的混合物加热，生成3-硝基-5-PY-2(1H)-吡啶酮（Ic），然后将Ic还原生成Ib，或者首先将Ic与烷基化剂反应，生成1-R'-3-硝基-5-PY-2(1H)-吡啶酮（Id），然后将Id还原生成1-R'-3-氨基-5-PY-2(1H)-吡啶酮（Ib），其中R'是低烷基或低羟基烷基。展示了Q是氨基的I的其他衍生物。
• 5-(Pyridinyl)-2(1H)-pyridinones
  申请人：Sterling Drug Inc.

  公开号：US04107315A1

  公开（公告）日：1978-08-15

  Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or .alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.

  有用作心脏强效药的化合物为1-R-3-Q-5-PY-2(1H)-吡啶酮（I），其中R为氢，低烷基或低羟基烷基，Q为氨基（首选），低烷基氨基，二（低烷基）氨基或NHAc，Ac为低烷酰基或低羧基烷基，PY为4-或3-或2-吡啶基或4-或3-或2-吡啶基，具有一个或两个低烷基取代基。当Q为硝基，氨基甲酰基，氰基，卤素或氢时，相应的化合物可用作中间体，当Q为氢或氰基时也可用作心脏强效药。所述化合物的制备方法为：通过将α-PY-β-(R1R2N)丙烯醛（II）与马隆酰胺反应以产生1,2-二氢-2-氧代-5-PY-烟酰胺（Ia），然后将Ia与能够将氨甲酰转化为氨基的试剂反应以产生3-氨基-5-PY-2（1H）-吡啶酮（Ib）；通过将II或α-PY-马隆醛（II'）与α-氰基乙酰胺反应以产生1,2-二氢-2-氧代-5-PY-烟酰腈（III），然后部分水解III以产生Ia；通过将1,2-二氢-2-氧代-5-PY-烟酸（IV）与浓硫酸和浓硝酸的混合物加热以产生3-硝基-5-PY-2（1H）-吡啶酮（Ic），然后将Ic还原以产生Ib，或首先将Ic与烷基化试剂反应以产生1-R'-3-硝基-5-PY-2（1H）-吡啶酮（Id），然后将Id还原以产生1-R'-3-氨基-5-PY-2（1H）-吡啶酮（Ib），其中R'为低烷基或低羟基烷基。还展示了Q为氨基的I的其他衍生物。
• Discovery and Structure−Activity Relationship of 3-Aminopyrid-2-ones as Potent and Selective Interleukin-2 Inducible T-Cell Kinase (Itk) Inhibitors
  作者：Jean-Damien Charrier、Andrew Miller、David P. Kay、Guy Brenchley、Heather C. Twin、Philip N. Collier、Sharn Ramaya、Shazia B. Keily、Steven J. Durrant、Ronald M. A. Knegtel、Adam J. Tanner、Kieron Brown、Adam P. Curnock、Juan-Miguel Jimenez

  DOI：10.1021/jm101499u

  日期：2011.4.14

  Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active. site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K-i of 7 nM and has a good selectivity profile across kinases.