Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents

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Abstract
A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione (see, for instance, Table III), is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.