Novel Alpha-Hydroxy Carboxylic Acid And Derivatives And Other GRAS-Based Prodrugs Of Oxymorphone And Uses Thereof

Abstract

The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to the opioid oxymorphone, in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

What is claimed: 
     
         1 . An oxymorphone prodrug of the following formula where a prodrug moiety X is attached covalently to an oxymorphone molecule via a 6 position ketone enolate oxygen as an enolate ester, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein X is a monomeric alpha-hydroxy carboxylic acid or a derivative thereof. 
       
     
     
         2 . The oxymorphone prodrug according to  claim 1  wherein the alpha-hydroxy carboxylic acid is selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, pantothenic acid and poly-hydroxy carboxylic acids derived from sugars and carbohydrates. 
     
     
         3 . The oxymorphone prodrug compound according to  claim 1  wherein X is 
       
         
           
           
               
               
           
         
         wherein, 
         CZ═CH2, CHOR1, 
         R1=H, and 
         R=Me, Ph, CH2COR2, CHOR1COR2, and COR2 (when n is not zero), 
         where R2=OH, or O-alkyl (alkyl esters, where the alkyl group is selected from 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), and 
         n is an integer selected from 0 to 2. 
       
     
     
         4 . The oxymorphone prodrug compound according to  claim 1  which is represented by any one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A pharmaceutical composition comprising one or more of the oxymorphone prodrugs according to  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         6 . The pharmaceutical composition according to  claim 5  which is an oral pharmaceutical composition. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the compound is a pharmaceutically acceptable salt form. 
     
     
         8 . A method of treating pain comprising orally administering the composition of  claim 1  to a patient. 
     
     
         9 . An oxymorphone prodrug of the following formula where a prodrug moiety X is attached covalently to an oxymorphone molecule via a 6 position ketone enolate oxygen as an enolate ester, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein X is independently selected from alpha-hydroxy carboxylic acid homo-oligomers, alpha-hydroxy carboxylic acid hetero oligomers with another alpha-hydroxy carboxylic acid, alpha-hydroxy carboxylic acid hetero oligomers with dicarboxylic acids, alpha-hydroxy carboxylic acid hetero oligomers with fatty acids, and derivatives thereof. 
       
     
     
         10 . The oxymorphone prodrug compound according to  claim 9  wherein X is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein, 
         CZ═CH2, CHOR1, 
         CW═(CH2)q, CH═CH (both E and Z isomers), 
         R1=H, acyl groups from fatty acids, acyl groups from alpha-hydroxy acids, and acyl groups from dicarboxylic acids including, but not limited to, fumaric acid, maleic acid and succinic acid, 
         R=Me, Ph, CH2COR2, CHOR1COR2, and COR2 (when n is not zero), 
         R2=OH, or is part of an ester formed by the hydroxyl group of another alpha-hydroxy acid or O-alkyl (alkyl esters, where the alkyl group is selected from 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), 
         R3=Me, Ph, CH2COR2, CHOR1COR2, and COR2 (when n is not zero), 
         R6=OH or is part of an ester formed by the hydroxyl group of another alpha-hydroxy acid or R6 is part of an ester with an alkyl group (O-alkyl, where the alkyl group is selected from 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), 
         m is an integer selected from 0 to 4, and 
         n is an integer selected from 0 to 2, and q is an integer selected from 2 to 6. 
       
     
     
         11 . The oxymorphone prodrug according to  claim 9  wherein homo- and hetero-‘mers’ are linear or branched ‘mers’ wherein the hetero-‘mers’ are cross linked with other GRAS reagents. 
     
     
         12 . The oxymorphone prodrug according to  claim 9  wherein dicarboxylic acids of the hetero oligomers with alpha-hydroxy carboxylic acid are fumaric acid, maleic acid, or succinic acid. 
     
     
         13 . The oxymorphone prodrug according to  claim 9  wherein the alpha-hydroxy carboxylic acid is selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, pantothenic acid and poly-hydroxy carboxylic acids derived from sugars and carbohydrates. 
     
     
         14 . The oxymorphone prodrug according to  claim 9  which is represented by any one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The oxymorphone prodrug compound according to  claim 9  which is represented by any one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . A pharmaceutical composition comprising one or more of the oxymorphone prodrugs according to  claim 9  and one or more pharmaceutically acceptable excipients. 
     
     
         17 . The pharmaceutical composition according to  claim 16  which is an oral pharmaceutical composition. 
     
     
         18 . The pharmaceutical composition according to  claim 16 , wherein the compound is a pharmaceutically acceptable salt form. 
     
     
         19 . A method of treating pain comprising orally administering the composition of  claim 9  to a patient.