8-carboxamido-2,6-methano-3-benzazocines

Abstract

8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH 2 —OH, —CH 2 NH 2 , —NHSO 2 CH 3 , and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications. 8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 A is chosen from 
 
       
         
           
           
               
               
           
         
         Q is chosen from O, S and NR 17 ; 
         Y is chosen from O, S, NR 17  and NOH; 
         R 1  is chosen from hydrogen, lower alkoxy, phenyl and —NHR 8 ; 
         R 2  and R 2a  are both hydrogen or taken together R 2  and R 2a  are ═O; 
         R 3  is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl; 
         R 4  is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20  alkyl and C 1 -C 20  alkyl substituted with hydroxy or carbonyl; 
         R 5  is lower alkyl; 
         R 6  is lower alkyl; 
         R 7  is chosen from hydrogen and hydroxy; or together R 4 , R 5 , R 6  and R 7  may form from one to three rings, said rings having optional additional substitution; 
         R 8  is chosen from hydrogen, —OH, —NH 2  and —CH 2 R 15 ; 
         R 15  is chosen from hydrogen, alkyl, aryl, substituted aryl and alkyl substituted with alkoxy, amino, alkylamino or dialkylamino; 
         R 16  is chosen from hydrogen and NH 2 ; and 
         R 17  is chosen from hydrogen, alkyl, aryl and benzyl. 
       
     
     
         2 . A compound according to  claim 1  wherein A is chosen from the group consisting of: —COOCH 3 , —COOEt, —CONH 2 , —C(═S)NH 2 , —C(O)NHOH, —C(O)NHNH 2 , —CONHCH 3 , —CONHBn, —CONHCH 2 (4-MeOC 6 H 4 ), C(═NOH)NH 2 , C(═NOH)C 6 H 5 , —NHCHO and —NHCHS. 
     
     
         3 . A compound according to  claim 1  selected from: 
       
         
           
           
               
               
           
         
         wherein R 17  is selected from —CH 2 -c-C 3 H 5 , —CH 2 CH═CH 2 , —CH 2 CH═C(CH 3 ) 2 ,  - CH 3 ; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A method of treating a disease or condition selected from pain, pruritus, diarrhea, cough, drug addiction, hyperalgesia, respiratory depression, dyskinesia, gastrointestinal motility disorders, and irritable bowel syndrome comprising the step of administering to a subject in need thereof a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 A is chosen from 
 
       
         
           
           
               
               
           
         
         Q is chosen from O, S and NR 17 ; 
         Y is chosen from O, S, NR 17  and NOH; 
         Z is chosen from OH, SH, CN and NH 2 ; 
         R 1  is chosen from hydrogen, lower alkoxy, phenyl and —NHR 8 ; 
         R 2  and R 2a  are both hydrogen or taken together R 2  and R 2a  are ═O; 
         R 3  is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl; 
         R 4  is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20  alkyl and C 1 -C 20  alkyl substituted with hydroxy or carbonyl; 
         R 5  is lower alkyl; 
         R 6  is lower alkyl; 
         R 7  is chosen from hydrogen and hydroxy; or together R 4 , R 5 , R 6  and R 7  may form from one to three rings, said rings having optional additional substitution; 
         R 8  is chosen from hydrogen, —OH, —NH 2  and —CH 2 R 15 ; 
         R 15  is chosen from hydrogen, alkyl, aryl, substituted aryl and alkyl substituted with alkoxy, amino, alkylamino or dialkylamino; 
         R 16  is chosen from hydrogen and NH 2 ; and 
         R 17  is chosen from hydrogen, alkyl, aryl and benzyl. 
       
     
     
         5 . The method according to  claim 4  wherein A is chosen from the group consisting of: —COOCH 3 , —COOEt, —CONH 2 , —C(═S)NH 2 , —C(O)NHOH, —C(O)NHNH 2 , —CONHCH 3 , —CONHBn, —CONHCH 2 (4-MeOC 6 H 4 ), —C(═NOH)NH 2 , -C(=NOH)C 6 H 5 , —NHCHO and -NHCHS. 
     
     
         6 . The method according to  claim 4  wherein said compound is selected from: 
       
         
           
           
               
               
           
         
         wherein R 17  is selected from —CH 2 -c-C 3 H 5 , —CH 2 CH═CH 2 , —CH 2 CH═C(CH 3 ) 2 , —CH 3 ;