1.8- Naphthyridine-4-ones

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... 

Chart 3 General structure of 2-phenyl-4-quinolones (X=CH) and 2-phenyl-1,8-naphthyridin-4-ones (X=N) used by Weigt and Weise to generate their CoMFA model... 

Raltitrexed <1998MI423> can be used in the treatment of advanced colorectal cancer. Substituted 2-thienyl-1,8-naphthyridin-4-ones 25 < 1999JME4081 > exhibit cyctotoxicity and inhibit tubulin polymerization. Cyclopentathiophenes, for example, 26-29 <2002BMC2185>, have been successfully used against leukemia cell lines. 

Soskic, M. and Plavsic, D. (2001) QSAR study of 1,8-naphthyridin-4-ones as inhibitors of photosystem II./. Chem. Inf. Comput. Sci, 41, 1316-1321. 

Nalidixic acid is l-ethyl-7 methyl-1,8-naphthyridine-4-one-3-carbonic acid (C12H12N2O). It acts bacteriostatically and its optimal pH is 4.5--7.0. Solutions should not be kept in the refrigerator for more than 4 weeks. Eighty percent of orally administered nalidixic acid is absorbed. The half-life is 1 Vi-2 h and the protein binding of the serum 70%-94% 60%-80% is excreted by the kidneys, but only 20% of the dose is excreted in microbiologically active form, the rest being ineffective glucuronides and 3,7-dicarbonic acid. The antibacterial effect is limited to... 

Ethyl-7-methyl-1,4-dihydro-1,8-naphthyridine-4-one-3-carboxylic acid. See Naiidixic acid... 

CAS 389-08-2 EINECS/ELINCS 206-864-7 Synonyms 3-Carboxy-1 -ethyl-7-methyl-1,8-naphthidin-4-one 1,4-Dihydro-1 -ethyl7-methyl4-oxo-1,8-naphthyridine-3-carboxylic acid 1 -Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-Ethyl-7-methyl-1,4-dihydro-1,8-naphthyridine-4-one-3-carboxylic acid 1-Ethyl-7-methyl-1,8-naphthyridin-4-one-3-carboxylic acid 1-Ethyl-7-methyl-4-oxo-1,4-dihydo-1,8-naphthyridine-3-carboxylic acid Nalidic acid Nalidixin... 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

The relation of activation by para vs. ortho ring-nitrogen in bicy-clics is altered by these special cases. For example, 4-chloroquinazoline (4-Cl-l,3-diaza) is much more reactive than the 2-chloro isomer (2-Cl-l,3-diaza) for two reasons, one being the poor activation in 2-Le-3-aza compounds. 4-Chloro-l,8-naphthyridine will be decreased in reactivity relative to its 2-chloro isomer due to the very poor activation in 4-Le-8-aza compounds and it may be only slightly more reactive than the mono-aza analog 4-chloroquinoline. The greater reactivity at the 2-position of 2,4-dichloro-l,8-naphthyri-dine 3 can be ascribed to this 4-Le-8-aza effect. ... 

Several approaches to the synthesis of nitronaphthyridines and their derivatives are reported. Very common ones are those in which the construction of the nitronaphthyridine system was achieved by using nitro synthons (see Section II,A) or by nitration of the naphthyridine ring, although a successful nitration requires the presence of electron-donating substituents (see Section II,B). Furthermore, the oxidation of the amino group in aminonaphthyridines... 

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

According to the Friedlander method, the condensation of the readily available 2-aminoiiicotinic aldehyde (20a) (74JOC726) or its 6-phenyl derivative (20b) [66JCS(C)315] with nitroacetic acid (21) in boiling ethanol with piperidine as catalyst is another example of this method, which affords in fair yields the corresponding 3-nitro-l,8-naphthyridin-2(lFI)-ones (22a, 74%) and (22b, 47%), respectively [66JCS(C)315]. 

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315]. It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

Tlie presence of one or more electron-donating groups, such as the hydroxy substituent, is required to make easy nitration of the naphthyridines... 

Tlie 1,5-, 1,6-, 1,7-, and l,8-naphthyridin-4(lH)-ones (39a-39d) easily undergo nitration to afford the corresponding 3-nitro derivatives (40a-40d) in fair yields. 

Many reports deal with the preparation of numerous hydroxynitronaph-thyridones and nitronaphthyridinediones. By the nitration of 4-hydroxy-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) (51a-51d) using nitric acid in acetic acid, the corresponding 3-nitro substituted compounds (52a-52d) were obtained in reasonable-to-good yield (75JMC726 77MI1 96MI1). 

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