Patent Evaluation: Pyrimidine Derivatives as Phospholipase A₂ Inhibitors

Summary

Novelty: 4-Substituted dihydropyrido[4,3-d]pyrimidines are disclosed as topically active antiinflammatory agents, potentially suitable for the treatment of dermatological conditions such as psoriasis, urticaria, contact dermatitis and other dermatitides. The compounds are said to inhibit the activity of phospholipase A₂ (PLA₂) and may have potential therapeutic use as analgesic agents, suitable for systemic use.

Biology: Inhibition of PLA₂ was demonstrated in a conventional in vitro assay; test compounds (0.01 M) showed a range of inhibition between 50–60%. In vivo activity was demonstrated in a variety of animal dermatitide models, including; PLA₂-induced paw oedema (0.1 M iv, inhibition range 36%), arachidonate-induced ear oedema (1.0 mg topical application, inhibition range 50–100%), and phorbol myristate acetate-induced ear oedema (10 μg topical application, inhibition range 30–50%). Analgesic activity was demonstrated by the suppression of phenylbenzoquinone-induced writhing in mice, where compounds at a dose of 20 mg/kg sc, inhibited writhing by between 20–80%.

Chemistry: Several preparative schemes are outlined. Seventeen compounds are exemplified and form a subsidiary part of the claim. Seven compounds are specifically claimed, including 4-cyclohexyl-1,4-dihydropyrido[4,3-d]pyrimidine.

Structure: