ANTIINFLAMMATORY 17-BETA-THIOALKYL-16-ALPHA,17-ALPHA-KETAL AND 17-BETA-THIOALKYL-16-ALPHA,17-ALPHA-ACETAL ANDROSTANES - A NEW CLASS OF AIRWAY SELECTIVE STEROIDS FOR THE TREATMENT OF ASTHMA

The synthesis and anti-inflammatory potencies of a new class of 17 bet a-tkioalkyl-16 alpha,17 alpha-ketal and -acetal androstanes are descri bed. This new class of steroids was made by fragmentation of 2-thioxo- 1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-r adical. The radical generated was trapped using a variety of radicophi lic disulfides, giving a steroidal D-ring having acetal or ketal funct ionality at C-16 and C-17, together with a sulfide link at C-17. Compo unds from this series bind to the glucocorticoid receptor with high po tency and are functional agonists as measured by their ability to indu ce tyrosine aminotransferase activity in a rat hepatic cell line in vi tro. These 17 beta-thioalkyl androstanes potently inhibit Sephadex-ind uced rat lung inflammation when administered directly into the airways . The high topical potency, together with a low propensity to induce s ystemic glucocorticoid-like side effects (rat thymus involution), prov ides the present compounds with a high degree of airway selectivity co mpared with currently available inhaled glucocorticoids. The presently described 17 beta-thioalkyl-16 alpha,17 alpha-ketal androstanes may b e useful for therapies for inflammatory diseases such as asthma.