Synthesis of substituted benzamides as anti-inflammatory agents that inhibit preferentially cyclooxygenase 1 but do not cause gastric damage.

Parsalmide [5-amino-N-butyl-2-(2-propynyloxy)benzamide] is a non-steroidal anti-inflammatory drug (NSAID), commercialized in Italy until 1985 with the brand name of Synovial, that has been widely used to treat arthritic patients. In addn., it was shown to spare gastric mucosa. Here we have synthesized a series of novel substituted benzamides related to Parsalmide and have evaluated their activity in vitro on COX-1 and COX-2 as well as in vivo in the carrageenin-induced rat paw edema anti-inflammatory assay. Compds. I (R = CH2CH:CMe2, cyclohexyl, Ph), which showed a favorable profile in vitro and in vivo, were screened in comparison with Parsalmide for gastrointestinal (GI) tolerability in vivo in the rat. Results obtained showed that Parsalmide and compd. I (R = Ph) inhibited both COX-1 and COX-2 in vitro and were active in vivo. Both compds. were devoid of gastric effect at the efficacious dose. In addn., both prevented indomethacin-induced gastric damage. Thus, these compds. may guide the definition of a new leading structure with anti-inflammatory activity that may allow designing new safer NSAIDs.