Bioisosteric hybrids of two anti-inflammatory agents, rutaecarpine and piroxicam

Bioisosteric replacements were accomplished by building the structural elements of piroxicam, an anti-inflammatory drug, into the pentacyclic system of rutaecarpine, a quinazolinocarboline alkaloid, in order to modify activity and selectivity on COX-isoenzymes. The pentacyclic compounds were synthesized efficiently by employing 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-benzothiazine 5,5-dioxide as a key intermediate, and prepared by alternative routes. Condensation of the tricyclic ketone with arylhydrazines and subsequent Fischer-indolization provided the first representatives of new heterocyclic ring systems 3 and 4.