2,7-Naphthyridinones

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

The intramolecular cyclizations of the cyanopyridines (253) and (254) using polyphos-phoric acid resulted in the formation of the 2,7-naphthyridinones (255) and (256) which were subsequently converted into the phenyl-substituted 2,7-naphthyridines (64JOC2298, 65JA5198). 

A palladium-catalyzed amidation of halo(hetero)aromatics substituted in the ortAo-position by a carbonyl function with a primary or secondary amine has been introduced as an alternative to the Friedlander condensation for the synthesis of naphthyridinones (and quinolinones) (Scheme 32) <2004OL2433>. 

The coupling of o-aroylbenzoic or nicotinic acids with phosphorylated amines using dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP) followed by deprotonation with potassium bis(trimethylsilylamide) and cyclization gave isoquinolines or naphthyridinones in good yields (Scheme 43) <1996T4433>. 

The adducts from the Diels-Alder reaction of 2(17/)-pyrazinones with 3-butynylaminomethyl side chains undergo thermolysis to give either [l,7]naphthyridinones or [2,7]naphthyridines <1996T9161>. The intramolecular... 

Another structurally related series is the 2-ary 1-1,8-naphthyridin-4-ones (37 to 48, see Table 6.7), which contain a second nitrogen in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or a-naphthyl groups at the C-2 position showed potent cytotoxicity in the NCI 60 human tumor cell line panel with GI50 values in the low micromolar to nanomolar range (Tables 6.7 and 6.8).51 The tumor cell line selectivity varies with the various substituents. 2-(3 -Methoxyphenyl)-naphthyridinone (37) was significantly more cytotoxic in several cancer cell lines than the corresponding 2-(3 -meth-oxyphenyl)-quinolone (36). Both compound classes were potent inhibitors of tubulin polymerization the 2-ary 1-1,8-naphthyridin-4-ones had activity nearly comparable with those... 

Ziegler and Noelken76 prepared the 1,5-naphthyridinone 28 by the following condensation. 

Two other modifications of quinoline syntheses which afford 1,7-naphthyridinones (62 and 64) have been successful.98 However, the starting materials, compounds 61 and 63 are not readily accessible. 

The reaction of 1,5-naphthyridine with methyl iodide gave, as expected, the monomethiodide (134). Oxidation of the salt, under basic conditions, with potassium ferricyanide, afforded the A-methyl naphthyridinone (135).16 Repetition of this sequence yielded,... 

Methylation of 2,4-dimethoxy-l,8-naphthyridine was shown to take place at N-8 [to give (140)], by potassium ferricyanide oxidation to the appropriate iV-methyl naphthyridinone.152 Similarly, treatment of the monomethiodide of 1,8-naphthyridine gave the expected naphthyridin-2-one (141).56... 

The reaction of 142 with hydrogen peroxide and acetic acid afforded a mono-A-oxide. However, the position of the A-oxide function was not established.70 The l,6-dimethyl-2-naphthyridinone (143) on similar treatment gave the 5-oxide (144).70... 

CoMFA Quinolones, naphthyridinones Analysis of the effects of substituents at different positions of the quinolone/naphthyridi-none scaffold [27]... 

CoMFA Thiocolchicinoids, allocolchici-noids, quinolones, naphthyridinones Identification of the portions of the scaffolds playing a key role on the activity of compounds [28]... 

The conversion of a tautomeric 1,5-naphthyridinone into the corresponding chloro- or bromo-l,5-naphthyridine is usually done by heating for several hours with neat phosphoryl chloride or phosphoryl bromide, respectively. A mixture of phosphoryl chloride and phosphorus pentachloride has been used for a few difficult cases. In addition, exceptional reactions have been reported in which a nontautomeric /V-alkyl-1,5-naphthyridinone or a hydroxymethyl-1,5-naphthyridine was used successfully as substrate. The following examples illustrate the foregoing possibilities. 

The term oxy-1,5-naphthyridine includes the tautomeric and nontautomeric 1,5-naphthyridinones, extranuclear hydroxy-l,5-naphthyridines, alkoxy-and aryloxy-... 

From an overwhelming mass of data on 7t-deficient nitrogenous heterocycles, it is usually considered axiomatic that (wherever possible) hydroxy-1,5-naphthyridines will exist predominantly as their respective 1,5-naphthyridinone tautomers for example, l,5-naphthyridin-2-ol (2) will exist as l,5-naphthyridin-2( 1 //)-one (3). This postulate has been strengthened by ionization constant, infrared spectral, and ultraviolet spectral measurements on simple 1,5-naphthyridinones 887,1026,1027,1035,1040 calculations have been less meaningful.1295... 

The mass spectra of 1,5-naphthyridin-2( 1 //)-one, 1,5-naphthyridin-4( 1 //)-one, and 4-hydroxy-l,5-naphthyridin-2(17f)-one have been compared with those of isomeric naphthyridinones.1253... 

Most such naphthyridinones have been made by primary synthesis (see Chapter 1) and some by hydrolysis of halogeno-1,5-naphthyridines (see Section 3.2.3). Other preparative routes are illustrated by the following examples. 

The reductive deoxygenation (Section 2.1.1) and halogenolysis (Section 3.1.2) of such naphthyridinones have been covered already. Their other reactions are illustrated in the following examples. 

Note The alkylation of tautomeric 1,5-naphthyridinones usually gives /V-alkyl derivatives, but (9-alkylation has been achieved by treatment of the substrate silver salt with an alkyl halide the other likely route to (9-alkylation, treatment with an diazoalkane, has not been used in this series. 

Note For their apparent rearrangement into C-alkyl-1,5-naphthyridinones, see Section 2.2.1 for their hydrolysis, see Section 4.1.1 and for other reactions, see the following examples. 

Reports on the chemistry of these naphthyridinones are scarce. Available information is summarized here. 

Note Most of these naphthyridinones have been made by either primary synthesis (see Chapter 1) or alkylation of tautomeric 1,5-naphthyridinones (see Section 4.1.2). A third route, involving direct oxylation, is illustrated here. 

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