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The selective N-alkylation of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid has been achieved from 1,2-dihydro [1,4]oxazino[4,3-a]quinoline-4,6-dione by the 2-morpholinone ring opening. In the same time, we have developed a new methodology to obtain the 1,2-dihydro[1,4]oxazino[4,3-a]quinoline-4,6-dione that involves an intramolecular cyclization of the 2-chloroethyl 6-fluoro-4-oxo-1,4-dihydro-2-quinoline carboxylate.Quinolones, more known for their antibacterial activity, sometimes display hypoglycaemic activity. Indeed, according to Baker and Bramhall 1 in 1972, these molecules act on the glucose metabolic pathway.Recent work 2 has clearly shown the efficacy of some quinolones for inhibiting the activity of the ATP-K + channel of the b cell pancreatic membrane, thereby inducing the production of insulin. These quinolones act according to a mechanism similar to that found with sulfonylureas.Recently, we reported the in vivo activities of some quinolinoylguanidines, 3 and encouraged by these promising results, we therefore decided to investigate the structure / activity relationships of the N-[(2-quinolin)carbonyl]guanidines. We were interested in the selective introduction of a functional group at the nitrogen atom of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid.Historically N-alkyl quinoline-2-carboxylic acids have been obtained from N-alkyl anilines, using the method of Conrad and Limpach, 4 or from 2-amino acetophenones and derivatives, by condensation with diethyl oxalate using ethoxide as the base. 5 Nevertheless, these two methods only provide routes to derivatives with alkyl substituents such as isoamyl, propyl or ethyl because of the chemistry involved in the synthesis of the quinolinic skeleton and moderate yields are often obtained.Previously, by using standard alkylation methodology of the quinoline ring using sodium hydride and iodomethane, Jaen et al. 6 obtained a mixture of N-alkylated and O-alkylated products in 22% and 78% yield, respectively. This reaction revealed that a competitive alkylation takes place due to the prototropic equilibrium shown in Scheme 1.

The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine are described. The crystal structures and pKa values of these and related O6-methylguanine analogues are reported. All compounds display higher pKa values than O6-methylguanine with the sulfur-containing analogues being the more basic and exhibiting higher stability in aqueous solution. In a standard substrate assay with the human repair protein O6-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.

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