Oligomer-corticosteroid conjugates

Abstract

The invention provides corticosteroids that are chemically modified by covalent attachment of a water-soluble oligomer. A compound of the invention, when administered by any of a number of administration routes, exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the corticosteroid not attached to the water-soluble oligomer.

What is claimed is: 
     
         1 . A compound comprising a corticosteroid residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer. 
     
     
         2 . The compound of  claim 1 , wherein the linkage is a stable linkage. 
     
     
         3 . The compound of  claim 1 , wherein the linkage is a degradable linkage. 
     
     
         4 . The compound of  claim 1 , wherein the linkage is a hydrazone linkage. 
     
     
         5 . The compound of  claim 1 , wherein the weight average molecular weight of the water-soluble, non-peptidic oligomer is less than 400 Daltons. 
     
     
         6 . The compound of  claim 1 , wherein the corticosteroid residue is covalently attached at a position other than through the 16 or 17 positions of the corticosteroid residue to the water-soluble, non-peptidic oligomer. 
     
     
         7 . The compound of  claim 1 , wherein the corticosteroid residue is covalently attached at a position other than through D-ring atom positions of the corticosteroid residue to the water-soluble, non-peptidic oligomer. 
     
     
         8 . The compound of  claim 1 , wherein the corticosteroid residue is covalently attached at a position selected from the consisting of A-ring atom positions, B-ring atom positions, and C-ring atom positions of the corticosteroid residue to the water-soluble, non-peptidic oligomer. 
     
     
         9 . The compound of  claim 8 , wherein the corticosteroid residue is covalently attached at A-ring atom positions of the corticosteroid residue to the water-soluble, non-peptidic oligomer. 
     
     
         10 . The compound of  claim 1 , wherein the corticosteroid residue is covalently attached at the 3 position of the corticosteroid residue to the water-soluble, non-peptidic oligomer. 
     
     
         11 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         the dashed line represents an optional double bond; 
         R 1  is selected from the group consisting of halo and alkyl; 
         either 
         R 2  is selected from the group consisting of hydroxy and alkyl and R 3  is selected from the group consisting of hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, or 
         R 2  and R 3  combine to form a moiety selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 4  is selected from the group consisting 
       
       of —CH 3 , —CH 2 —OH, —CH 2 -halo, —S—CH 2 -halo, —CH 2 —O—C(O)—CH 3 , —CH 2 —O—C(O)—CH 2 —CH 3 , —CH 2 —PO 4 , —CH 2 —O—C(O)—C(CH 3 ) 3 , —CH 2 —O—C(O)—CH 2 —CH 2 —CH 2 —CH 3 , —CH 2 —C(O)—O—CH 3 , —CH 2 —O—C(O)—CH 2 —CH 2 —C(O)—OH;
 either 
 R 5  is —H and R 6  is selected from the group consisting of —H and hydroxy, or 
 R 5  and R 6  combine to form carbonyl; 
 R 7  is halo; 
 X is a spacer moiety; and 
 POLY is a water-soluble, non-peptidic oligomer. 
 
     
     
         12 . The compound of  claim 1 , wherein the corticosteroid residue is a residue of a corticosteroid having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 the dashed line independently represents an optional double bond; 
 R 1  is selected from the group consisting of halo and alkyl; 
 either 
 R 2  is selected from the group consisting of hydroxy and alkyl and R 3  is selected from the group consisting of hydroxy, alkyl, —OC(O)-alkyl, and —OC(O)-cyclo, or 
 R 2  and R 3  combine to form a moiety selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         R 4  is selected from the group consisting 
       
       of —CH 3 , —CH 2 —OH, —CH 2 -halo, —S—CH 2 -halo, —CH 2 —O—C(O)—CH 3 , —CH 2 —O—C(O)—CH 2 —CH 3 , —CH 2 —PO 4 , —CH 2 —O—C(O)—C(CH 3 ) 3 , —CH 2 —O—C(O)—CH 2 —CH 2 —CH 2 —CH 3 , —CH 2 —C(O)—O—CH 3 , —CH 2 —O—C(O)—CH 2 —CH 2 —C(O)—OH;
 either 
 R 5  is —H and R 6  is selected from the group consisting of —H and hydroxy, or 
 R 5  and R 6  combine to form carbonyl; and 
 R 7  is halo. 
 
     
     
         13 . The compound of  claim 1 , wherein the corticosteroid is a residue of a corticosteroid selected from the group consisting of desoxycorticosone, hydrocortisone, cortisone, methylprednisolone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, beclomethasone-17,21-dipropionate, budesonide, flunisolide, fludrocortisone, mometasone, fluticasone, alclometasone, clocortolone, flurandrenolide, fluocinonide, hydrocortisone acetate, fluorometholone, fluocinolone acetonide, diflucortolone valerate, paramethasone acetate, halcinonide, hydrocortisone phosphate, clobetasone butyrate, amcinonide, and prednisolone succinate. 
     
     
         14 . The compound of  claim 1 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide). 
     
     
         15 . The compound of  claim 14 , wherein the poly(alkylene oxide) is a poly(ethylene oxide). 
     
     
         16 . The compound of  claim 14 , wherein the water-soluble, non-peptidic oligomer has a number of repeating monomers in the range of from 1 to 30. 
     
     
         17 . The compound of  claim 14 , wherein the water-soluble, non-peptidic oligomer has a number of repeating monomers in the range of from 1 to 10. 
     
     
         18 . The compound of  claim 14 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety. 
     
     
         19 . The compound of  claim 1 , wherein the linkage is an ether linkage. 
     
     
         20 . The compound of  claim 1 , wherein the linkage is an ester linkage. 
     
     
         21 . A composition comprising a compound comprising (i) a corticosteroid residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, and (ii) optionally, a pharmaceutically acceptable excipient. 
     
     
         22 . A composition of matter comprising a compound comprising a corticosteroid residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form. 
     
     
         23 . A method comprising covalently attaching a water-soluble, non-peptidic oligomer to a corticosteroid. 
     
     
         24 . A method comprising administering to a subject a compound comprising a corticosteroid residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer.