DIOXOISOQUINOLINE-4-CARBOXANILIDES, NOVEL NONSTEROIDAL ANTI-INFLAMMATORY AGENTS WITH A SPECIES-SPECIFIC EFFECT ON BASAL METABOLISM

¹ Medical Research Laboratories, Chas. Pfizer & Co., Inc., Groton, Connecticut

Dioxoisoquinoline-4-carboxanilides have anti-inflammatory activities in animals with potencies from 0.3 to 3.4 times that of phenylbutazone. The plasma halflife of these compounds ranges from 1.0 to 6.0 hours (rat), 2.0 to 35.0 hours (dog), 6.0 to 10.0 hours (monkey) and 8.5 to 22.0 hours (man). Those analogs carrying a methyl moiety on position 2 of the isoquinohine nucleus elicited a pronounced stimulation of basal metabolism in the dog, but not in the rat, monkey or man. This phenomenon was correlated with a species-specific displacement of thyroxine from the binding plasma -globulin in the dog. No manifestations of toxicity were observed in the rat or monkey treated chronically with these compounds at doses up to 100 mg/kg/day. N-p-chlorophenyl-1,3(2H,4H)-dioxoisoquinoline-4-carboxamide increased phenol red retention time in rats, and this indication of uricosuric activity was confirmed in man.