Neutral antagonists and use thereof in treating drug abuse

Abstract

The invention relates to the use of naltrexone and naloxone analogs, which are neutral antagonists at the μ opioid receptor, for the treatment of drug dependency in a drug-dependent individual. Surprisingly, it has been found that administration of a therapeutically effect amount of the naloxone or naltrexone analogs described herein for the treatment of a drug dependency, can result in reduction of undesirable side effects resulting from current treatments using naloxone and naltrexone. For example, the treatment described herein can result in a reduction in the withdrawal symptoms and aversion encountered in the use of naloxone and naltrexone in the treatment of drug dependency. In addition, the naltrexone and naloxone analogs of the invention can be used for the treatment of pain in an individual in need thereof by modulating opoid pain treatment using neutral antagonists, for example, reversing respiratory depression withough causing other adverse effects. In addition, during chronic use of opioid drugs for pain therapy, neutral antagonists can be used to diminish constipation peripherally without effecting the central analgesic effects.

What is claimed is:  
     
         1 . A method for the treatment of drug-dependency in an individual in need thereof comprising administering to the individual a therapeutically effect amount of a naloxone analog or naltrexone analog or a pharmaceutically acceptable salt thereof which is a neutral antagonist at the μ opioid receptor.  
     
     
         2 . The method of    claim 1   , wherein the naltrexone analog is represented by Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is cycloalkyl(alkyl) or cycloalkenyl (alkyl);  
 R 2  is H, OH or esters thereof;  
 R 3  is H, alkyl or (alkyl)C═O;  
 R 4  and R 5  are independently H, halogen, alkyl, alkoxy, nitro, amino, cyano, carboxyl or acyl which can be substituted for one or more hydrogens on the ring;  
 X is —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , —SR 11 ;  
 wherein,  
 R 6  and R 11  are independently selected from H, alkyl, substituted alkyl;  
 cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl,or aroyl;  
 R 7 , R 8  and R 10  are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;  
 R 9  and R 12  can be present or absent and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl and phamaceutically acceptable salts thereof.  
 
     
     
         3 . The method of    claim 2   , wherein the naltrexone analog is  
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof.  
     
     
         4 . The method of    claim 1   , wherein the naloxone analog is represented by Formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is alkenyl;  
         R 2  is H, OH or esters thereof;  
         R 3  is H, alkyl or (alkyl)C═O;  
         R 4  and R 5  are independently H, halogen, alkyl, alkoxy, nitro, amino, cyano, carboxyl or acyl which can be substituted for one or more hydrogens on the ring;  
         X is —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , —SR 11 ;  
         wherein, 
 R 6  and R 11  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, or aroyl, R 7 , R 8  and R 10  are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;  
 R 9  and R 12  can be present or absent and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl  
 and phamaceutically acceptable salts thereof.  
 
       
     
     
         5 . The method of    claim 4   , wherein the naloxone analog is  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.  
     
     
         6 . The method of    claim 1   , wherein the individual is in long-term therapy to prevent relapse to drug dependency.  
     
     
         7 . The method of    claim 1   , wherein the individual is undergoing drug overdose treatment.  
     
     
         8 . The method of    claim 1   , wherein the individual is undergoing active withdrawal treatment.  
     
     
         9 . A method for the treatment of drug-dependency in an individual in need thereof comprising administering to the individual a therapeutically effect amount of a sustained release composition comprising: 
 a) biocompatible polymer; and    b) an effective amount of a neutral antagonist selected from a naloxone analog or naltrexone analog or the pharmaceutically acceptable salts thereof which are neutral antagonist at the μ opioid receptor.    
     
     
         10 . The method of    claim 9   , wherein the naltrexone analog is represented by Formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is cycloalkyl(alkyl) or cycloalkenyl (alkyl);  
         R 2  is H, OH or esters thereof;  
         R 3  is H, alkyl or (alkyl)C═O;  
         R 4  and R 5  are independently H, halogen, alkyl, alkoxy, nitro, amino, cyano, carboxyl or acyl which can be substituted for any hydrogen on the ring;  
         X is —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , —SR 11 ;  
         wherein, 
 R 8  and R 11  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl,or aroyl, R 7 , R 8  and R 10  are independently selected from hydrogen alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl,  
 R 9  and R 12  can be absent or present and are independently selected from hydrogen alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted  
 aryl,  
 and phamaceutically acceptable salts thereof.  
 
       
     
     
         11 . The method of    claim 10   , wherein the naltrexone analog is  
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof.  
     
     
         12 . The method of    claim 9   , wherein the naloxone analog is represented by Formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1 is alkenyl;  
         R 2  is H, OH or esters thereof;  
         R 3  is H, alkyl or (alkyl)C═O;  
         R 4  and R 5  are independently H, halogen, alkyl, alkoxy, nitro, amino, cyano, carboxyl or acyl which can be substituted for one or more hydrogens on the ring;  
         X is —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , —SR 11 ;  
         wherein, 
 R 6  and R 11  are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, or aroyl, R 7 , R 8  and R 10  are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl,  
 R 9  and R 12  can be absent or present and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl  
 and phamaceutically acceptable salts thereof.  
 
       
     
     
         13 . The method of    claim 12   , wherein the naloxone analog is  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.  
     
     
         14 . The method of    claim 9   , wherein the individual is in long-term therapy to prevent relapse to drug dependency.  
     
     
         15 . The method of    claim 9   , wherein the individual is undergoing drug overdose treatment.  
     
     
         16 . The method of    claim 9   , wherein the individual is undergoing active withdrawal treatment.  
     
     
         17 . The method of    claim 9   , wherein the sustained release composition releases a therapeutically effective amount of the neutral antagonist for about 7 days.  
     
     
         18 . The method of    claim 1   , wherein the compounds act peripherally when administered peripherally.  
     
     
         19 . The method of    claim 1   , wherein the compounds act centrally when administered peripherally.