New steroidal antiinflammatory antedrugs: steroidal [16 alpha,17 alpha-d]-3'-carbethoxyisoxazolines.
Novel steroidal antiinflammatory antedrugs, 11 beta,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)-isoxazolino[16,17 - d]pregna-1,4-diene (2a) and 9-fluoro-11 beta,20-dihydroxy-3,20-dioxo-3'-ethoxy- carbonylisoxazolino[16,17-d]pregna-1,4-diene (2b) were prepared in 97% yield via 1,3-dipolar cycloaddition of carbethoxyformonitrile (CEFNO) to 11 beta,21-dihydroxy-3,20-dioxopregna-1,4,-16-triene (1a) and 11 beta,21-dihydroxy-3,20-dioxo-9-fluoropregna-1,4,16-triene (1b), respectively, which were prepared via five steps from prednisolone and 9-fluoroprednisolone, respectively. The treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively, in 95% yield. Dose-response profiles of the croton oil-induced ear edema bioassay in rats were used to calculate the following ID50 values (nmol/ear resulting in a 50% reduction of edema): prednisolone (P), 540 nmol; 2b, 135 nmol; and 3b, 101 nmol. Inhibition of edema did not exceed 50% following application of either 2a or 3a. Relative potency calculations indicated that 2b was 4-fold and 3b 5.3-fold more potent than the parent compound P when applied topically. No significant adverse systemic effects were seen following treatments with 3b. These results suggest that C-9-fluorination, side-chain hydroxy group esterification, and [16 alpha,17 alpha-d]-3'-carbethoxyisoxazoline additions to the conventional steroid P improve topical antiinflammatory activity without concomitant increases in adverse systemic activity.
Kwon
T
T
Center for Anti-Inflammatory Research, College of Pharmacy, Florida A&M University, Tallahassee 32307.
Heiman
A S
AS
Oriaku
E T
ET
Yoon
K
K
Lee
H J
HJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003436:Croton Oil; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004431:Ear, External / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids
D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D013256:Steroids; D003436:Croton Oil