Pyrazinone ring

Substitution of a dipeptide unit by a cychc dipeptide derivative within a peptide chain can induce certain conformational restraints that may alter the biological response via changing receptor selectivity. A facile procedure for synthesis of pyrazinone ring-containing opioid mimetics [21] has been elaborated, based on the cycHzation of readily available dipep-tidyl chloromethyl ketones [22] (Scheme 6). This method affords 2(IH)-pyrazinone derivatives containing substituents with desired functional groups at positions 3 and 6 in high yield. 

Schemes Synthesis of pyrazinone ring-containing opioid mimetics...

It has been shown that cross-coupling reactions constitute a very mild method to introduce different alkyl and aryl groups to the most active C-3 position of the pyrazinone ring [26]. The broadly functionahzed 2-azadiene system of the title compounds was studied in cycloaddition reactions with various electron-reach and electron-poor dienophiles to provide highly substituted heterocycles [24]. 

Hirano K, Kubota T, Tsuda M, Watanabe K, Fromont J, Kobayashi J (2000) Ma edamines A and B, Cytotoxic Bromotyrosine Alkaloids with a Unique 2(lH)Pyrazinone Ring from Sponge Suberea sp. Tetrahedron 56 8107... 

A second example is evident from the work of Singh et al.68 on the pyrazinone-containing thrombin inhibitor 2, which is associated with irreversible incorporation of radioactivity to human microsomal tissue and in vivo in the rat. Visual inspection of the structure as well as analysis in the DEREK program does not raise any concern with regards to the presence of structural alerts. However, mechanistic studies on reactive metabolite formation depict de novo metabolic routes of bioactivation on the latent pyrazinone-ring system, leading to the formation of reactive metabolites that adduct to GSH (Figure 6.6). 

Singh R, Silva Elipe MV, Pearson PG, et al. Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation, rearrangement, and covalent binding to proteins. Chem Res Toxicol. 2003 16(2) 198-207. 

Ethyl 7-oxopteridine-6-carboxylate is synthesized from the diamine and diethyl mesoxalate [2299]. A substituted 2-quinoxalinone is obtained from A -methylphenylenediamine and DMAD [2678], but under slightly different conditions, two molar amounts of DMAD react with one of diamine [3252]. Stirring a diamine with the oxazolone (76.18) in acetic acid under mild conditions leads to the formation of a pyrazinone ring [3250]. 

Van der Eycken and coworkers have demonstrated an interesting solid-phase synthesis of 2(l//)-pyrazinones " based on the Strecker reaction" of the resin-bound amine with an appropriate aldehyde and a cyanide, allowing a wide diversity at the C6 position of the pyrazinone ring (Scheme 8.29). The authors investigated a number of interesting decorations on the resin-bound 2(lJ/)-pyrazinones, using a variety of microwave-assisted, transition metal-mediated cross-coupling reactions (Scheme 8.29). 

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