A Convenient Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines Possessing Biological Activity

Abstract

S y n t h e s i s o f N o v e l 2 , 8 -D i s u b s t i t u t e d P y r i d o [ 3 , 4 -b ] p y r a z i n e sAbstract: A regioselective synthetic route to 2,8-disubstituted pyrido [3,4-b]pyrazines, by initial condensation reaction between suitable diaminopyridines and a-keto aldehydes equivalents, has been developed. Focusing on the functionalization on C-8, 2-aryl-8-bromo-and 8-amino-2-arylpyrido[3,4-b]pyrazines have been synthesized. Anilines, amides, and ureas have been introduced at the 8-position from key intermediates. 2,8-Disubstituted pyrido [3,4-b]pyrazines thus prepared were found to be of biological interest.In recent years, some pyrido[2,3-b]pyrazines and pyrido[3,4-b]pyrazines have been described in the literature as compounds with promising biological properties. In particular, 2,3,8-trisubstituted pyrido[2,3-b]pyrazines have been used for the treatment of malignant tumors and other diseases associated to pathological cell proliferations. 1 Other compounds bearing a pyridopyrazine scaffold have been described as vasculostatic agents (by inhibition of Src-family kinases: c-Src and Yes) and as inhibitors of FtsZ polymerization. 2 In addition, pyrido[3,4-b]pyrazine derivatives exhibited tubulin polymerization inhibition in the micromolar range. 3As part of our continuing efforts to identify new chemical classes of kinase inhibitors, we previously developed an efficient synthetic approach for the preparation of 2,3,8-trisubstituted pyrido[3,4-b]pyrazines, 4 but unfortunately they did not exhibit any kinase inhibitory activity (data not shown).A literature survey revealed that no example of 2,8-disubstituted pyrido[3,4-b]pyrazines targeting kinase pathway was described. To our knowledge, only a few papers have reported on the preparation of 2-or 2,8-disubstituted pyrido[3,4-b]pyrazines. 5-9 Thus, it was decided to synthesize new compounds with a pyrido[3,4-b]pyrazine scaffold bearing only one aryl group, in position 2, and an urea, an amide or an aniline in position 8, expecting to better interact with the target protein.In this paper, we present a regioselective synthetic route to 2,8-disubstituted pyrido[3,4-b]pyrazines obtained by initial condensation reaction between suitable diaminopyridines and a-keto aldehyde equivalents (Scheme 1). Scheme 1 Structures of synthesized 2,8-disubstituted pyrido[3,4-b]pyrazinesOur synthetic strategy was to functionalize directly 2-and 8-positions of the pyrido[3,4-b]pyrazine scaffold by ringclosing reaction. We envisioned to prepare our key intermediates, 2-aryl-8-bromo-and then 8-amino-2-arylpyrido [3,4-b]pyrazines by an initial condensation reaction between 3,4-diamino-5-bromopyridine and an a-dioxo partner.b-Oxosulfoxides or corresponding hemithioacetals were first used as 1,2-diketone equivalents. 6,10 The reaction was carried out in the past with 3,4-diaminopyridine and 2-aryl-2-oxoethyl methyl sulfoxides in a mixture of benzene and acetic acid to give selectively 2-arylpyrido [3,4-b]pyrazines. 6 This synthetic approach was applied to prepare 2-aryl-8-bromopyrido [...