Synthesis of 6-(methoxycarbonyl)prednisolone and its derivatives as new antiinflammatory steroidal antedrugs.

The synthesis and pharmacological evaluation of 6-(methoxycarbonyl)prednisolone (11) (a 3:1 mixture of 6 alpha-isomer 11a and 6 beta-isomer 11b), its 21-ol acetates 13a (6 alpha-isomer) and 13b (6 beta-isomer), and 17,21-diol acetonide 14 (a 6:1 mixture of 6 alpha-isomer 14a and 6 beta-isomer 14b) as local antiinflammatory steroidal antedrugs are described. The lead compound 11 was prepared via 12 steps from hydrocortisone (1). In the croton oil-induced ear edema assay, the topical antiinflammatory activity of 13a was higher than that of its epimer 13b. Except for 13a, the compounds (11, 13b, and 14) showed less activity than prednisolone. The systemic activities were assessed after 5 days of consecutive administration of these compounds at equiactive doses. Neither 11 nor 14 depressed plasma corticosteroid levels or significantly altered adrenal weights. Thymic involution was absent for 14, 15% for 11, and 47% for prednisolone at the equiactive doses. Both 13a and 13b showed significant reduction of adverse systemic effects assessed as the increase of body weight and the decreases of adrenal and thymus weights. The putative metabolite, carboxylic acid 12, showed 26 times less topical antiinflammatory activity than prednisolone. These results suggest that introduction of a labile methoxycarbonyl group at the C-6 position of prednisolone results in retention of antiinflammatory activity while reducing systemic effects noted following topical application of the parent compound prednisolone.