Class of mu-opioid receptor agonists

Abstract

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt or ester thereof.

1 .- 35 . (canceled) 
     
     
         36 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         A is an aryl or heteroaryl, with or without substitution; 
         R 1  is —H or -(alkyl); 
         R 2  is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole); 
         R 3  is —H or -(alkyl); 
         R 5  is Br; 
         R 4 , R 6  and R 7  are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and 
         Y 1 , Y 2 , Y 3  and Y 4  are each independently N or C,
 wherein when Y 1  is N, then R 4  is absent, and when Y 1  is C, then R 4  is present; when Y 2  is N, then R 5  is absent, and when Y 2  is C, then R 5  is present; when Y 3  is N, then R 6  is absent, and when Y 3  is C, then R 6  is present; when Y 4  is N, then R 7  is absent, and when Y 4  is C, then R 7  is present, 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The compound of  claim 36 , wherein
 R 2  is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole).   
     
     
         38 . The compound of  claim 36  having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         A is an aryl or heteroaryl, with or without substitution; 
         R 1  is —H or -(alkyl); 
         R 2  is -(alkyl)-CO 2 H or -(alkyl)-C(O)—NH 2 ; 
         R 3  is —H or -(alkyl); 
         R 5  is Br; 
         R 4 , R 6  and R 7  are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and 
         Y 1 , Y 2 , Y 3  and Y 4  are each independently N or C,
 wherein when Y 1  is N, then R 4  is absent, and when Y 1  is C, then R 4  is present; when Y 2  is N, then R 5  is absent, and when Y 2  is C, then R 5  is present; when Y 3  is N, then R 6  is absent, and when Y 3  is C, then R 6  is present; when Y 4  is N, then R 7  is absent, and when Y 4  is C, then R 7  is present, 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The compound of  claim 38 , wherein
 A is   
       
         
           
           
               
               
           
         
         
           wherein R 8 , R 9 , R 10  and R 11  are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl), -(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); 
           Y 5 , Y 6 , Y 7  and Y 8  are each independently N or C,
 wherein when Y 5  is N, then R 8  is absent, and when Y 5  is C, then R 8  is present; when Y 6  is N, then R 9  is absent, and when Y 6  is C, then R 9  is present; when Y 7  is N, then R 10  is absent, and when Y 7  is C, then R 10  is present; when Y 8  is N, then R 11  is absent, and when Y 8  is C, then R 11  is present. 
 
         
       
     
     
         40 . The compound of  claim 36  having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole); 
         R 5  is —Br; 
         R 4 , R 6  and R 7  are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl); and 
         R 8 , R 9 , R 10  and R 11  are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl), -(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl), 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The compound of  claim 36  having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is -(alkyl)-CO 2 H or -(alkyl)-C(O)—NH 2 ; 
         R 5  is —Br; 
         R 4 , R 6  and R 7  are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl); and 
         R 8 , R 9 , R 10  and R 11  are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl), -(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl), 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The compound of  claim 41 ,
 wherein   R 4 , R 6  and R 7  are each independently —H, —Cl, —Br, —F or —I, or a pharmaceutically acceptable salt thereof.   
     
     
         43 . The compound of  claim 41 ,
 wherein   R 2  is -(alkyl)-CO 2 H or -(alkyl)-C(O)—NH 2 ,
 wherein each alkyl is unsubstituted and unbranched, 
   
       or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The compound of  claim 36  having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is -(alkyl)-CO 2 H; 
         R 5  is —Br; 
         R 4 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are each —H, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The compound of  claim 44 ,
 wherein   R 2  is -(alkyl)-CO 2 H,
 wherein the alkyl is unsubstituted and unbranched, 
   
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The compound of  claim 44 ,
 wherein   R 2  is —(C 1 -C 12  alkyl)-CO 2 H,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The compound of  claim 46 ,
 wherein   R 2  is —(C 1 -C 12  alkyl)-CO 2 H,
 wherein the alkyl is unsubstituted and unbranched, 
   
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The compound of  claim 36 , wherein
 A is a thiophene or phenyl, with or without substitution,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The compound of  claim 36 , wherein
 A is a thiophene or phenyl, with or without substitution;   R 4 , R 6  and R 7  are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl); and   Y 1 , Y 2 , Y 3  and Y 4  are each C,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The compound of  claim 36 , wherein
 A is a thiophene or phenyl, with or without substitution;   R 4 , R 6  and R 7  are each independently —H, —Cl, —Br, —F or —I; and   Y 1 , Y 2 , Y 3  and Y 4  are each C,   or a pharmaceutically acceptable salt thereof.   
     
     
         51 . The compound of  claim 36 , wherein
 A is a thiophene or phenyl, with or without substitution;   R 4 , R 6  and R 7  are each —H; and   Y 1 , Y 2 , Y 3  and Y 4  are each C,   or a pharmaceutically acceptable salt thereof.   
     
     
         52 . The compound of  claim 36  having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         53 . A pharmaceutical composition comprising the compound of  claim 36  and a pharmaceutically acceptable carrier. 
     
     
         54 . A method of treating a subject afflicted with pain, a depressive disorder or a mood disorder comprising administering an effective amount of the compound of  claim 36  to the subject so as to thereby treat the subject. 
     
     
         55 . A method of activating a mu-opioid receptor or delta-opioid receptor comprising contacting the mu-opioid receptor or delta-opioid receptor with an effective amount of the compound of  claim 36  so as to thereby activate the mu-opioid receptor or delta-opioid receptor.