Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models

A group of derivatives of 7-methanesulfonylamino-6-phenoxychrome (1) at the pyrone and phenoxy rings was synthesized starting with 4-chloro-3-nitroani sole and evaluated against acute and chronic inflammations in oral administ ration in animals, Significant potency in the rat models of carrageenin-ind uced edema (CPE) and adjuvant-induced arthritis (AA) was realized with 2'-f luoro and 2',4'-difluoro derivatives (9a and 9d), and 3-formylamino derivat ive (19a) and its 2'-fluoro and 2',4'-diffuoro compounds (22a and 22d), dis playing AA therapeutic effect of ED40 = 2.5-7.1 mg/kg/d for 7 d and AA prop hylarrtic effect of 53-70% inhibition at the dosage of 3 mg/kg/d for 22 d. To identify a candidate for further pharmacological study, the five compoun ds, were subjected to evaluation of their gastro-ulcerogenic liability, lea ding to selection of the fluorine-free compound 19a which did not cause acu te ulceration at 300 mg/kg in oral administration in rats, Compound 19a (ED 40= 3.6 mg/kg in established AA) possessed good therapeutic efficacy agains t type II collagen-induced arthritis in DBA/1J mice with doses of 30 and 10 0 mg/kg, suggesting the development of 19a (designated T-614) as a prospect ive disease-modifying antirheumatic agent. In addition, a preparative-scale synthetic route to T-614 has been established.