Opiate analogs selective for the delta-opioid receptor

Abstract

Novel compounds which selectively bind to the δ-opioid receptor have been designed. These compounds have greater selectivity, improved water (blood) solubility, and enhanced therapeutic value as analgesics. Because agonists with selectivity for the δ-opioid receptor have shown promise in providing enhanced analgesis without the addictive properties, the compounds of the present invention are better than morphine, naltrindole (NTI), spiroindanyloxymorphone (SIOM), and other known μ-opioid receptor selectors as analgesics.

1 - 9 . (canceled)  
   
   
       10 . A method for treating disease mediated by the δ-opioid receptor comprising administering an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is O, NH, NR 6 , S, SH, or SR 6 ;  
       R 2  is H, ═O, t-butyl, phenoxy, diphenylamine, thiophenyl, phenyl, or cyclohexane;  
       R 3  is phenyl or phenoxy;  
       or wherein R 2  and R 3  comprise a ring system selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or wherein R 3  and R 4  comprise a ring system selected from:  
       
         
           
           
               
               
           
         
       
       R 4  is H or t-butyl; and  
       R 5  is CH 3 , methylcyclopropane, a linear alkyl, a branched alkyl, a substituted alkyl, or a substituted branched alkyl;  
       R 6  is H, CH 3 , a linear alkyl, a branched alkyl, a substituted alkyl, or a substituted branched alkyl; or  
       a pharmaceutically acceptable salt thereof.  
     
   
   
       11 . The method of  claim 10  wherein: 
 R 1  is O, or NH;    R 2  and R 3  comprise a ring system selected from:                                            R 4  is H;    R 5  is methylcyclopropane; or    a pharmaceutical acceptable salt thereof.    
   
   
       12 . The method of  claim 10  wherein: 
 R 1  is O, or NH;    R 2  is ═O;    R 3  and R 4  comprise a ring system selected from:                          R 5  is methyl; or    a pharmaceutically acceptable salt thereof.    
   
   
       13 . The method of  claim 10  wherein: 
 R 1  is O, or NH;    R 2  is H, or ═O;    R 3  is phenyl or phenoxy;    R 4  is H or t-butyl; and    R 5  is CH 3 , methylcyclopropane, a linear alkyl, a branched alkyl, a substituted alkyl, or a substituted branched alkyl; or    a pharmaceutically acceptable salt thereof.    
   
   
       14 . The method of  claim 10 , wherein R 5  is CH 3  or methylcyclopropane.  
   
   
       15 . The method of  claim 10 , wherein R 1  is NH or O.  
   
   
       16 . The method of  claim 10 , wherein R 2  is ═O.  
   
   
       17 . The method of  claim 10 , wherein 
 R 1  is O, or NH;    R 4  is H;    R 5  is methyl; and    R 2  and R 3  comprise:                          or a pharmaceutically acceptable salt thereof.    
   
   
       18 . The method of  claim 10 , wherein 
 R 1  is O, or NH;    R 2  is ═O;    R 3  and R4 comprise:                          R 5  is methylcyclopropyl; or    a pharmaceutically acceptable salt thereof.    
   
   
       19 . The method of  claim 10 , wherein the disease comprises an immune disorder, transplant rejection, allergy, inflammation, drug or alcohol abuse, diarrhea, cardiovascular disease, or respiratory disease.  
   
   
       20 . The method of  claim 10 , wherein treating of disease comprises treating pain, protecting brain cells, or decreasing gastric secretion.