Synthesis of new antiinflammatory steroidal 20-carboxamides: (20R)- and (20S)-21-(N-substituted amino)-11β,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene

Article abstract of DOI:10.1021/jm00395a011

The synthesis and antiinflammatory activities of new steroidal 20-carboxamides, (20R)- and (20S)-21-(N-substituted amino)-11β,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene (5-8) are described. These compounds were prepared from the respective isomer of 20-dihydroprednisolonic acid, (20R)- and (20S)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid (4a and 4b), by coupling with primary amines after the activation of the steroid acid with N,N¹-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole. Confirmation of the configurational assignment at C-20 of the 20-carboxamides was achieved by reduction of methyl (20R)- and (20S)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate (3a and 3b) to the known stereochemistry at C-20 of (20R)- and (20S)-11β,17,20,21-tetrahydroxy-3-oxo-1,4-pregnadiene (2a and 2b). The topical antiinflammatory activities of these steroidal 20-carboxamides were assessed by the croton oil induced ear edema assay and their local and systemic antiinflammatory activities by the cotton pellet granuloma bioassay. Results of these investigations suggest a structure-activity relationship where carboxamide derivatives with the 20(R)-hydroxy configurations exhibit higher potency than those with the 20-(S)-hydroxy configurations. The amides of steroidal 21-oic acids with high local antiinflammatory potency exhibited systemic activities unlike the corresponding esters of steroidal 21-oic acids, which are devoid of systemic activities.