Controlled Release of Phenolic Opioids

Abstract

A method of providing a patient with controlled release of a phenolic opioid using a prodrug capable, upon enzymatic activation, of releasing the phenolic opioid through intra-molecular cyclization leading to formation of a cyclic urea, carbamate or thiocarbamate.

1 - 57 . (canceled) 
     
     
         58 . A compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or a salt, hydrate or solvate thereof, wherein: 
         X is a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —N—(R 3 )(R 4 ); 
         Y is —NR 5 —; 
         n is 1 to 10; 
         each R 1 , R 2  and R 5  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1  and R 2  together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1  or R 2  groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 
         R 3  is H or (1-4C) alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 6  is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 7  is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; 
         p is an integer from 1 to 5; 
         each W is independently —NR 8 —, —O— or —S—; and 
         each R 8  is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 6  and R 8  independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 
       
     
     
         59 . The compound of  claim 58 , in which X is hydromorphone, morphine or oxymorphone. 
     
     
         60 . The compound of  claim 58 , in which X is hydromorphone. 
     
     
         61 . The compound of  claim 58 , in which X is morphine. 
     
     
         62 . The compound of  claim 58 , in which X is oxymorphone. 
     
     
         63 . The compound of  claim 58 , in which each of R 1 , R 2 , R 5 , and R 8  is independently hydrogen or alkyl. 
     
     
         64 . The compound of  claim 58 , in which R 5  is (1-4C) alkyl. 
     
     
         65 . The compound of  claim 58 , in which R 5  is methyl. 
     
     
         66 . The compound of  claim 58 , in which R 1  and R 2  are each hydrogen. 
     
     
         67 . The compound of  claim 58 , in which R 3  is hydrogen. 
     
     
         68 . The compound of  claim 58 , in which R 3  is methyl. 
     
     
         69 . The compound of  claim 58 , in which each R 6  is independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 6  and R 7  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 
     
     
         70 . The compound of  claim 58 , in which R 7  is hydrogen or an unsubstituted or substituted alkyl, acyl or alkoxycarbonyl group. 
     
     
         71 . The compound of  claim 58 , in which R 7  is a hydrogen atom, or an unsubstituted or substituted acyl group. 
     
     
         72 . The compound of  claim 58 , in which R 7  is an unsubstituted or substituted acyl group. 
     
     
         73 . The compound of  claim 58 , in which R 4  is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, lysine and valine; a residue of a dipeptide composed of two L-amino acids or a tripeptide composed of three L-amino acid residues, wherein the amino acids are selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, lysine and valine; or a residue of an N-acyl derivative thereof. 
     
     
         74 . The compound of  claim 58 , in which R 4  is arginine, N-acetylarginine, N-t-butanoylarginine, N-benzoylarginine, N-piperonylarginine, N-glycinylarginine, lysine, glutamic acid, aspartic acid, tyrosine, proline or N-glycinylproline. 
     
     
         75 . The compound of  claim 58 , in which R 4  is arginine, N-acetylarginine, N-t-butanoylarginine, N-benzoylarginine, N-piperonylarginine, N-glycinylarginine, lysine, glutamic acid, proline or N-glycinylproline. 
     
     
         76 . A process for the preparation of a compound of formula (I) or a salt, hydrate or solvate thereof as defined in  claim 58 , which comprises reacting a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       or a protected derivative thereof, with a compound of formula (IV) 
       
         
           
           
               
               
           
         
         in which M represents a leaving atom or group; 
         followed by removing any protecting groups and, if desired, acylating the compound of formula (I) and/or forming a pharmaceutically acceptable salt. 
       
     
     
         77 . A pharmaceutical composition, which comprises a compound of  claim 58  and a pharmaceutically acceptable carrier. 
     
     
         78 . A method of treating or preventing pain comprising administering an effective amount of a compound of  claim 58  to a patient in need thereof.