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Review
. 2019 Nov 16;24(22):4161.
doi: 10.3390/molecules24224161.

Pyrido[2,3- d]pyrimidin-7(8 H)-ones: Synthesis and Biomedical Applications

Guillem Jubete  1 , Raimon Puig de la Bellacasa  1 , Roger Estrada-Tejedor  1 , Jordi Teixidó  1 , José I Borrell  1
Affiliations
Review

Pyrido[2,3- d]pyrimidin-7(8 H)-ones: Synthesis and Biomedical Applications

Guillem Jubete et al. Molecules. .

Abstract

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

Keywords: 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones; biological activity; pyrido[2,3-d]pyrimidines; substitution pattern.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of the pyrido[2,3-d]pyrimidine ring system (1) and pyrido[2,3-d]pyrimidin-7(8H)-ones (2).
Figure 2
Figure 2
Synthesis of 2,4-diamino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (7) from 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (5).
Figure 3
Figure 3
Structure of palbociclib (8) approved for the treatment of breast cancer.
Figure 4
Figure 4
Number of pyrido[2,3-d]pyrimidin-7(8H)-ones (2) retrieved using an undefined bond (9), double bond (10) and single bond (11) between C5 and C6, respectively.
Figure 5
Figure 5
Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11) included in Scifinder.
Figure 6
Figure 6
Diversity analysis of the substituents present at positions C2, C4, C5, C6, and N8 of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Scifinder.
Figure 7
Figure 7
Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2): (a) from a preformed pyrimidine and (b) from a preformed pyridone.
Figure 8
Figure 8
Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed 4-amino-5-bromopyrimidine (12).
Figure 9
Figure 9
Synthetic approach for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed N-substituted pyrimidine-4-amine (13) bearing a carbon functional group G.
Figure 10
Figure 10
Synthesis of the palbociclib intermediate 19 from 5-bromo-2,4-dichloropyrimidine (15).
Figure 11
Figure 11
Synthesis of the pyrido[2,3-d]pyrimidin-7(8H)-one (23) from pyrimidine aldehyde (20).
Figure 12
Figure 12
Synthesis of the 5-hydroxy substituted pyrido[2,3-d]pyrimidin-7(8H)-one (26) from pyrimidine ester (24).
Figure 13
Figure 13
Synthesis of the 5-amino substituted pyrido[2,3-d]pyrimidin-7(8H)-one (29) from the nitrile substituted pyrimidine (27).
Figure 14
Figure 14
Synthesis of the 4-chloro substituted pyrido[2,3-d]pyrimidin-7(8H)-one (33) from the chloro substituted pyrimidine aldehyde (30).
Figure 15
Figure 15
Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (41) from the pyrimidinone 35.
Figure 16
Figure 16
Synthetic approaches for pyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a preformed pyridone.
Figure 17
Figure 17
Synthesis of the substituted pyrido[2,3-d]pyrimidin-7(8H)-one (44) from the pyridone 42.
Figure 18
Figure 18
Synthesis of 5,6-dihydropyrido[2,3-d]pyrimidin-7-(8H)-ones and pyrido[2,3-d]pyrimidin-7-(8H)-ones from α,β-unsaturated esters (45).
Figure 19
Figure 19
Synthesis of 6-aryl-2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (59) from α,β-unsaturated esters (45).
Figure 20
Figure 20
Pyrido[2,3-d]pyrimidin-7(8H)-ones with nM biological activities as BCR kinase inhibitor (62), DDR2 inhibitor (63), and HCV NS5B polymerase inhibitor (64).
Figure 21
Figure 21
Tasosartan (65).
Figure 22
Figure 22
Structures of pyrido[2,3-d]pyrimidin-7(8H)-ones (10) included in Drugbank which are in different phases of development.
See this image and copyright information in PMC

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