Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 4. Synthesis and evaluation of 4-(4,10-dihydro-10-oxothieno[3,2-c] [1]benzoxepin-8-yl)butanol and -butyric acid and related derivatives.
4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid (6) was previously reported as a potent antiinflammatory-analgesic agent characterized by an impressive therapeutic ratio in comparison with indomethacin. With the goal of finding compounds that might display even more favorable therapeutic ratios and/or enhanced antiinflammatory/analgesic properties in comparison to 6, we synthesized 4-(4,10-dihydro-10-oxothieno [3,2-c][1]-benzoxepin-8-yl) butanol (4b) and -butyric acid (5a) and a series of related derivatives. All compounds were evaluated for potential analgesic activity in the phenylquinone-induced writhing (PQW) assay, for antiinflammatory activity in the carrageenan-induced paw edema (CPE) model and, where warranted, for gastric irritation (GI) liability. Of the compounds investigated, 4b (HP 573) displays moderate analgesic-like activity in PQW, is approximately half as potent as indomethacin or 6 as an antiinflammatory agent in the CPE, and is characterized by an extremely low propensity to induce GI as reflected by comparison of the therapeutic ratios (GI ED50/CPE ED50: 4b greater than 46, 6 = 9.9, indomethacin = 0.4). Compound 4b was selected for clinical evaluation.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D016227:Benzoquinones; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000627:therapeutic use; D002087:Butyrates / Q000138:chemical synthesis* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy; D011809:Quinones; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016227:Benzoquinones; D001584:Benzoxepins; D002087:Butyrates; D011809:Quinones; C029322:phenylbenzoquinone; C040560:4-(4,10-dihydro-10-oxothieno(3,2-c)(1)-benzoxepin-8-yl)butanol; C040562:4-(4,10-dihydro-10-oxothieno(3,2-c)(1)benzoxepin-8-yl)butyric acid