PYRAZOLOTHIAZOLOPYRIMIDINE DERIVATIVES AS A NOVEL CLASS OF ANTIINFLAMMATORY OR ANTINOCICEPTIVE AGENTS - SYNTHESIS, STRUCTURAL CHARACTERIZATION AND PHARMACOLOGICAL EVALUATION

As a part of a research program on anti-inflammatory-analgesic compounds, pyrazolothiazolopyrimidines 5a-f and 5g-i were prepared by cyclodehydration in 98% H2SO4 or PPA of the corresponding 6-thioketomethylene-substituted-4-hydroxy-pyrazolo[3,4-d]pyrimidines 2a-i and 2g-i. The results of the pharmacological in vivo screening indicate an interesting dissociation of the analgesic from the anti-inflammatory activity depending on aromatic or aliphatic substitution at the C4 of the thiazole ring. Analgesic activity was not associated with any narcotic effect; in addition, all the active compounds showed a remarkable systemic and gastric tolerance. This indicated a mode of action different from that of the classical nonsteroidal anti-inflammatory drugs, acting on prostaglandin biosynthesis. To clarify the mechanism or the mechanisms underlying the pharmacological activity of these and other closely related compounds, we initiated a 'file chemical approach' to various systems involved in the inflammatory process. At present, some of the more active in vivo compounds tested as substance P antagonists showed a moderate and possibly non-specific effect on NK1 and NK2 receptors.