Novel opiate compounds, methods of making and methods of use

Abstract

The present invention relates to a class of nitrogen-containing heterocyclic compounds which bind to opioid receptors. The inventive compounds can be used to treat a variety of disease states which involve the opioid receptors.

What is claimed as new and is desired to be secured by Letters Patent of the United States is:  
     
         1 . A compound represented by formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, an alkyl group, an aryl group, or an aralkyl group;  
 R 2  is hydrogen, an alkyl group, an aryl group, or an alkaryl group; and  
 R 3  is  
                     
 each X is, independently, halogen, —OH, —OR, an all group, an aryl group, —NH 2 , —NHR, —N(R) 2 , —CF 3 , —CN or —C(O)NH 2 , —C(O)NHR, or —C(O)N(R) 2 ;  
 each R is, independently, an alkyl group, an aryl group or an alkaryl group, wherein 
 when X is —N(R) 2  the R groups may, together, form a cyclic alkyl group;  
 n is 0 or an integer from 1 to 5; and  
 R a  is hydrogen or an alkyl group,  
 or a pharmaceutically acceptable salt thereof.  
 
 
     
     
         2 . The compound of  claim 1 , wherein 
 R 1  is hydrogen, a C 1-4  alkyl group, a phenyl group, or an aralkyl group;    R 2  is hydrogen or a C 1-4  alkyl group; and    n is 0, 1, 2, 3 or 4.    
     
     
         3 . The compound of  claim 2 , wherein 
 R 1  is hydrogen or a C 1-4  alkyl group; and    n is 0, 1, 2, 3 or 4.    
     
     
         4 . The compound of  claim 3 , wherein 
 R 1  is hydrogen or a C 1-3  alkyl group;    R 2  is hydrogen or a methyl group;    n is 1, 2, or 3, and at least one X is —OH, —OCH 3  or —F.    
     
     
         5 . The compound of  claim 4 , wherein at least one X is —OH.  
     
     
         6 . A compound represented by formula (II):  
       
         
           
           
               
               
           
         
         R 1  is an alkyl group or aralkyl group; and  
         R 3 , R 4 , R 5 , R 6  are each, independently, hydrogen, an alkyl group, —OH, —NHK, —NHR, —N(R) 2 , halogen, —OR, —CF 3 , —CN, —NO 2 , or —NHC(O)R, wherein when any of R 3 , R 4 , R 5 , or R 6  is N(R) 2  the R groups may, together, form a cyclic alkyl group;  
         each R is, independently, an alkyl group, an aryl group, or an alkaryl group; and  
         R 7  is hydrogen or an alkyl group,  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         7 . The compound of  claim 6 , wherein 
 R 1  is a C 1-8  alkyl group or an aryl-C 1-4  alkyl group;    at most three of R 3 , R 4 , R 5 , R 6  are each, independently, an alkyl group, —OH, —NH 2 , —NHR, —N(R) 2 , halogen, —OR, —CF 3 , —CN, —NO 2 , or —NHC(O)R; and    R 7  is hydrogen or a C 1-8  alkyl group.    
     
     
         8 . The compound of  claim 7 , wherein 
 R 1  is a C 1-8  alkyl group or a phenyl-C 1-4  alkyl group;    at most two of R 3 , R 4 , R 5 , and R 6  are each, independently, an alkyl group, —OH, —NH 2 , —NHR, —N(R) 2 , halogen, —OR, —CF 3 , —CN, —NO 2 , or —NHC(O)R;    R 7  is a C 1-8  alkyl group.    
     
     
         9 . The compound of  claim 8 , wherein 
 R 1  is a C 1-4  alkyl group or an aryl-C 1-3  alkyl group;    one of R 3 , R 4 , R 5 , or R 6  is an alkyl group, —OH, —NH 2 , —NHR, —N(R) 2 , halogen, —OR, —CF 3 , —CN, —NO 2 , or —NHC(O)R; and    R 7  is a C 1-4  alkyl group.    
     
     
         10 . The compound of  claim 9 , wherein R 3 , R 4 , R 5 , and R 6  are hydrogen.  
     
     
         11 . A compound represented by formula (III):  
       
         
           
           
               
               
           
         
       
       where 
 R 1  is an alkyl group or an aralkyl group;  
 R 2  is hydrogen, an alkyl group, an aralkyl group, ═O, —NH 2 , —NHR, —N(R) 2 , —NHC(O)R, —NRC(O)R, —NHC(O)R 5 , or —NRC(O)R 5 ;  
 R 3  and R 4  may be hydrogen or methyl, with the proviso that when R 3  is methyl then R 4  is hydrogen and when R 3  is hydrogen then R 4  is methyl;  
 each R is, independently, an alkyl group, an aryl group, or an alkaryl group; and  
 R 5  is  
                     
 each X is, independently, halogen, —OH, —OR, an alkyl group, an aryl group, —NH 2 , —NHR, —N(R) 2 , —CF 3 , —CN, —C(O)NH 2 , —C(O)NHR, or —C(O)N(R) 2 ;  
 each R is, independently, an alkyl group, an aryl group, or an alkaryl group;  
 n is 0 or an integer from 1 to 5; and  
 R a  is hydrogen or an alkyl group,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         12 . The compound of  claim 11 , wherein 
 R 1  is a C 1-8  alkyl group or an aryl-C 1-4  alkyl group;    R 3  is methyl; and    R 4  is hydrogen.    
     
     
         13 . The compound of  claim 12 , wherein R 1  is a C 1-8  alkyl group or an phenyl-C 1-4  alkyl group.  
     
     
         14 . The compound of  claim 11 , wherein 
 R 1  is a C 1-8  alkyl group or an aryl-C 1-4  alkyl group;    R 3  is hydrogen; and    R 4  is methyl.    
     
     
         15 . The compound of  claim 14 , wherein R, is a C 1-8  alkyl group or an phenyl-C 1-4  alkyl group.  
     
     
         16 . The compound of  claim 11 , wherein R 2  is ═O.  
     
     
         17 . A compound represented by formula (IV):  
       
         
           
           
               
               
           
         
       
       where 
 R a  and R b  are each, independently, hydrogen or an alkyl group, or R a  and R b , together, form a cycloalkyl group;  
 each X is, independently, an alkyl group;  
 ◯ is a five- or six-membered aryl or heteroaryl group;  
 each Z is, independently, an alkyl group, —OH, —OR, halogen, —CF 3 , —CN, —NH 2 , —NHR, or —N(R) 2 , wherein when Z is —N(R) 2  the R groups may, together, form a cyclic alkyl group;  
 each R is, independently, an alkyl group, an aryl group, or an alkaryl group;  
 each W is an alkyl group;  
 n is 0 or an integer from 1 to 4;  
 y is 0 or an integer from 1 to 5;  
 z is 0 or an integer from 0 to 8; and  
 R 5  is an alkyl group, alkenyl group, or aralkyl group,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         18 . The compound of  claim 17 , wherein 
 R a  and R b  are each, independently, hydrogen or a C 1-8  alkyl group, or R a  and R b , together, form a cycloalkyl group;    each X is, independently, a C 1-8  alkyl group;    ◯ is a five-membered heteroaryl group or a six-membered aryl or heteroaryl group;    each W is a C 1-8  alkyl group;    n is 0, 1 or 2;    y is 0 an integer from 1 to 3;    z is 0 an integer from 1 to 4; and    R 5  is a C 1-8  alkyl group, a C 3-8  alkenyl group, or an aryl-C 1-4  alkyl group.    
     
     
         19 . The compound of  claim 18 , wherein ◯ is a five-membered heteroaryl group containing up to 3 heteroatoms, a six-membered aryl group or a six-membered heteroaryl group containing up to three heteroatoms.  
     
     
         20 . The compound of  claim 19 , wherein the heteroatoms are each, independently, nitrogen, oxygen or sulfur.  
     
     
         21 . The compound of  claim 20 , wherein 
 R a  and R b  are each, independently, hydrogen or a C 1-4  alkyl group, or R a  and R b , together, form a cycloalkyl group;    each X is, independently, a C 1-4  alkyl group;    n is 0, 1 or 2;    y is 0, 1 or 2;    z is 0 an integer from 1 to 4; and    R 5  is a C 1-8  alkyl group, a C 3-8  alkenyl group, or a phenyl-C 1-4  alkyl group.    
     
     
         22 . The compound of  claim 21 , wherein 
 ◯ is a six-membered aryl group; and    z is an integer from 1 to 4.    
     
     
         23 . A method of binding opioid receptors, comprising administering an effective amount of the compound of  claim 1  to a mammalian subject in need thereof.  
     
     
         24 . A method of binding opioid receptors, comprising administering an effective amount of the compound of  claim 6  to a mammalian subject in need thereof.  
     
     
         25 . A method of binding opioid receptors, comprising administering an effective amount of the compound of  claim 11  to a mammalian subject in need thereof.  
     
     
         26 . A method of binding opioid receptors, comprising administering an effective amount of the compound of  claim 17  to a mammalian subject in need thereof.