Pyridopyrimidinones

Synthesis from pyrido[7,2-a/pyrimidines. Reaction of the disubstituted pyridopyrimidinone 416 with hydrazine gives the aminopyrazole-fused product 417 (Equation 153) <1996FA781, 2003JIC311, 2004IJB1561>. Similarly, substituent interaction in the pyridopyrimidine 418 with amines in toluene at reflux gives, in various proportions, diastereomeric mixtures of the pyrrolopyridopyrimidines 419 and 420 (Equation 154) <2003T4581>. 

Apparently related to the aforementioned xanthine analogs, pyridopyrimidinone (X =X2=X3=CH or CR) and aza-pyridopyrimidinone (X1 or X3=N, X2=CH or CR) derivatives (M), exemplified by compounds 41 and 42 respectively, were discovered as GPR109A agonists [94,95]. So far no biological data has been provided for this class of molecules. The calculated pKa of the N-H group present in compounds 41 and 42 ranges from 8 to 9 [82]. 

Pyridopyrimidinone Template-Based Inhibitors PD180970, PD173955 and PD166326... 

The heats of formation of the lithiated derivatives 14 and 15 calculated by the semi-empirical Li/PM3 method indicated that the C-5-lithiated intermediate 15 is the more stable isomer. This was in agreement with the result obtained from their reaction with various electrophiles to give regioselectively the respective thermodynamically preferred 5-substituted pyridopyrimidinone at higher temperature and longer reaction time, while the second 8-substituted isomer needed milder conditions <2004T4107>. 

Ozone oxidation of 6-aryl-2-methylthiopyrido[2,3-methyl sulfone with /ra j-4-aminocyclohexanol afforded the amino pyridopyrimidinone derivative 176 <2002W02002018380>. Amination of 6-dimethoxyphenyl-8-ethyl-2-methylthiopyrido[2,3-t7 pyrimidin-7-one with 4-aminopyridine and LiNH2 in THF at 50°C produced the 2-[(4-pyridyl)amino] derivative 177 <2003W02003027110>. 

The final step in the synthesis ofthe pyridopyrimidinones (Scheme 7.10a) involved the release of the products from the solid support by intramolecular cyclisation, whereupon the pure products were obtained in solution. All reaction steps were carried out in a dedicated single-mode microwave instrument under sealed vessel conditions. 

Acetyl-4//-pyrido[ 1,2-a]pyrimidin-4-one 186 was formed in the reaction of ethyl iV-(2-pyridyl)formimidate 187 (R = H) and ketene in acetone at ambient temperature for 2 days in 12% yield (83H597). It was assumed that diketene formed first from ketene, then it reacted with the formimidate 187 (R = H). When excess ketene gas was passed over formimidates 187 (R = H and Me) at 75°C for 0.5-1.5 hours without solvent, 4//-pyrido[ 1,2-a]pyrimidin-4-ones 188 and 7V-(2-pyridyl)formamides were obtained in 25-85% and 0-45% yields, respectively. From the 5-methyl derivative of the formimidate 187 (R = 5-Me) only pyridopyrimidinone 188 (R = 7-Me) was obtained. It was proposed that both products were formed by 1,4-... 

The 2-hydroxyl group of 3-[4-(2-cyanophenyl)phenyl]-2-hydroxy-4//-pyrido[l,2-a]pyrimidin-4-ones were alkylated with various alkyl bromides (94MI2). O-Alkylation of 2-hydroxy-4//-pyrido[ 1,2-a]pyrimidin-4-ones 378 with 2-chloromethyl-4-isopropyl-6-methoxysaccharine 379 in dimeth-ylformamide in the presence of potassium tert-butoxide or sodium hydride for 1 hour or for 2.5 days, or in a mixture of methanol and dimethyl-formamide in the presence of cesium carbonate for 2 days at room temperature, gave proteolytic enzyme inhibitor pyridopyrimidinones 380 (93EUP547708). 

The 2-mercapto group of pyridopyrimidinone 121 (R = COOEt) was alkylated with ethyl bromide (81CCC2428). 

JMC1253]. In the first step of the reaction, 3-unsubstituted 9-dimethy-laminomethylene-6,7,8,9-tetrahydropyridopyrimidin-4-one formed and the electron-donating dimethylamino group activated position 3 of the pyridopyrimidinone ring for further reaction [83JCS(P1)369]. 

Pyridopyrimidinones 234 (Ar = Ph, 4-MeC6H4, 4-MeOC6H4, etc. R = Me, Ph, 4-BrC6H4, PhNH) exist in solution as mixtures of two chelate tautomers 234a and 234b. No non-chelated tautomers were detected. The tautomer 234a predominates for 234 (Ar = Ph R = Me, Ph) in DMSO-4 solution (91KG1397). 

Since the introduction of alkyl substituents into carbon positions by Friedel Crafts-type reactions is not feasible, the only ring positions available for alkylation reactions are the CONH functions of pyridopyrimidinones.420 463... 

Figure 6.15 Co-crystal structure of PF-04691502 bound to PI3K-y. The ring nitrogen of the pyridopyrimidinone forms the common H-bond hinge region interaction with the backbone NH of Val-882, while the exocyclic amine forms an additional interaction with the Val-882 backbone carbonyl. The pyridine nitrogen binds to Tyr-867 and Asp-841 through a conserved water molecule.

In an approach toward heterocycle synthesis two different three-step methods for solid-phase preparation of aminopropenones and aminopropenoates have been developed [29]. The first involved formation of the respective ester from N-protected glycine derivatives and Merrifield resin (Scheme 16.5) whereas the second used a different approach, use of simple aqueous methylamine solution for functionalization of the solid support [29]. The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the corresponding acetophenones, using N,N-dimethylformamide diethylacetal (DMEDEA) as reagent. The final step in the synthesis of the pyridopyrimidinones involved release of the products from the solid support by intramolecular cyclization. 

Pyridopyrimidinones la were made by the route shown in Figure 1. By a known thermal condensation method (P), aminopyridines of formula 6 were heated neat with substituted malonates (where generated ethanol was removed via distillation) to give intermediates of formula 7 (zwitterionic form shown). Alkylation of 7 in the presence of potassium carbonate in NJ4-... 

Substituents were also introduced on the pyridopyrimidinone ring via palladium-mediated cross-coupling reactions as outlined in Figure 2. Crosscoupling of 7-bromo-2-propoxy-3-propylpyridopyrimidinone la-1 (made by the method in Figure 1) with phenyl boronic acid, potassium cyanide or trimethylsilylacetylene (followed by desilylation with base) gave the phenyl, acetylenic and cyano substituted products la-2, la-3 and la-4, respectively. 

Pyridopyrimidinones of formulae lb (where W = S) and Ic (where W = NH) were significantly less active than the corresponding -propylthio and n-propylamino quinazolinones 2c and 2d. However, n-propoxy substitution generally gave higher activity than either n-propylthio or n-propylamino groups for a given heterocyclic system. 

Pyridopyrimidinones, quinazolinones and thienopyrimidinones were all evaluated in the field for powdery mildew control on wheat. Field candidates were applied early in the season as protectants (before substantial presence of the disease). Table 6 shows field efficacy of several substituted pyridopyrimidinones. Although highly active in greenhouse tests, these analogs were less effective than standards, e.g. flusilazole, under field conditions with only moderate levels of mildew control observed at 250-125 g/ha. 

Table 6. Field Activity of Substituted Pyridopyrimidinones as Protectants Against Wheat Powdery Mildew...

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