Synthesis of new antiinflammatory steroidal 20-carboxamides: (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4- pregnadiene.
The synthesis and antiinflammatory activities of new steroidal 20-carboxamides, (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene are described. These compounds were prepared from the respective isomer of 20-dihydroprednisolonic acid, (20R)- and (20S)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid, 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)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate to the known stereochemistry at C-20 of (20R)- and (20S)-11 beta,17,20,21-tetrahydroxy-3-oxo-1,4-pregnadiene 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.
Kim
H P
HP
Center for Anti-inflammatory Research, College of Pharmacy, Florida A&M University, Tallahassee 32307.
Bird
J
J
Heiman
A S
AS
Hudson
G F
GF
Taraporewala
I B
IB
Lee
H J
HJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D011246:Pregnadienetriols / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D011246:Pregnadienetriols; D011965:Receptors, Glucocorticoid