Synthesis of 6-(Methoxycarbonyl)prednisolone and Its Derivatives as New Antiinflammatory Steroidal Antedrugs

New Steroidal Antiinflammatory Antedrugs: Steroidal [16.alpha.,17.alpha.-d]-3'-Carbethoxyisoxazolines

“…To a solution of 2a (185 mg, 0.41 mmol) in 1 mL of pyridine was added 0.2 mL of acetic anhydride. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with 5% HC1 solution, washed with saturated NaCl solution, dried (Na2S04), and evaporated in vacuo to give 220 mg of white solid, which was purified by flash column chromatography on silica gel (1:2 mixture of hexane-EtOAc) to give 192 mg (95%) of compound 3a: mp 181-183 °C; NMR (CDC13) <5 7.22 (d, 1 ,J= 10.3, 1-CH), 6.26 (dd, 1, J = 10.3, 2.2, 2-C.if). 6.00 (br s, 1, 4-CH), 4.99 (d, 1, J = 17.6, one of 21-CH2), 4.71 (d, 1,J= 17.6, one of 21-CH2), 4.51 (m, 1, 11-Cff), 4.31 (q, 2, J = 7.0, 3z-C02Cff2-CH3), 4.15 (dd, 1 ,J= 9.6, 2.9,16-Cff), 2.15 (s, 3, 21-OCOCff3), 1.43 (s, 3, 18-Cffa), 1.33 ll/?,20-Dihydroxy-3,20-dioxo-3'-carboxyisoxazolino-…”

“…In an effort to circumvent the adverse clinical systemic effects, new steroidal antiinflammatory antedrugs that act locally at the site of application but are easily transformed into inactive metabolites upon entry into the systemic circulation are being synthesized and tested. [1][2][3][4][5][6][7] Our most recent efforts toward acheiving this goal include the synthesis of ll/3,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)isoxazolino [16,17-d]pregna-l,4-diene (2a) and 9-fluoro-ll/3,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)isoxazolino[l6,17-<¿]prednisolone (2b), respectively. Treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively.…”

“…The prototypic steroidal antedrugs, ester derivatives of steroid-21-oic acids, prepared by modifying the 17/3-ketol side chain of prednisolone have been shown to retain the significant local antiinflammatory activity seen following application of the parent compound but are devoid of prednisolone-like adverse systemic effects.8-10 The antedrug concept has been further applied by incorporating a metabolically labile group such as a carboxy ester or carboxamide at strategic positions on the steroid nucleus. 1,2,6 Syntheses of the steroidal [ 16 , 17a-d]-3'-carbethoxyisoxazolines and results of their pharmacologic screening using single-and multiple-dose paradigms of the croton oil-induced ear edema bioassay in rats are presented in this report.…”

Synthesis and Pharmacology of Anti-Inflammatory Steroidal Antedrugs

“…Scheme 849 shows the 10-step synthesis of prednisolone-6-carboxylate ester ( 48 ) from hydrocortisone ( 1 ). The 21-OH and 17-OH groups of hydrocortisone were protected as bismethylene dioxyether ( 41 ) by treating with formaldehyde and conc.HCl in CHCl 3 and the 3-keto function was converted to corresponding cyclic ketal, with the spontaneous shift of the 4,5-double bond to the 5,6-position giving 42 .…”

“…Incorporation of the carboxylate ester function at C6 of the steroid nucleus slightly reduced the overall potency; however, the potency was comparable to that of prednisolone when its 21-OH was esterified ( 48 with 21-O-Acyl) or 17,21-OH functions were ketalized (e.g., 78 ) 49. The ω-methoxycarbonyl group at 17 α -ester function ( 52 ) where the 21-OH is replaced with a Cl-group furnished potent topical anti-inflammatory agent (1.3-fold over parent steroid) with reduced thymolytic activity and thus excellent separation of systemic thymus involution from topical anti-inflammatory activity (the ration of topical/systemic >130).…”