Melanocortin receptor ligands modified with hydantoin

Abstract

The present invention relates to peptide ligands of the melanocortin receptors, in particular the melancortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and sexual dysfunction.

1 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 X is selected from the group consisting of —CH 2 —S—S—CH 2 —, —C(CH 3 ) 2 —S—S—CH 2 —, —CH 2 —S—S—C(CH 3 ) 2 —, —C(CH 3 ) 2 —S—S—C(CH 3 ) 2 —, —(CH 2 ) 2 —S—S—CH 2 —, —CH 2 —S—S—(CH 2 ) 2 —, —(CH 2 ) 2 —S—S—(CH 2 ) 2 —, —C(CH 3 ) 2 —S—S—(CH 2 ) 2 —, —(CH 2 ) 2 —S—S—C(CH 3 ) 2 , —(CH 2 ) t —C(O)—NR 8 —(CH 2 ) r — and —(CH 2 ) r — NR 8 —C(O)—(CH 2 ) t —; 
 R 1  and R 2  each is, independently for each occurrence thereof, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl; 
 R 3  is —OH or —NH 2 ; 
 R 4  and R 5  each is, independently for each occurrence thereof, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl; 
 X 1  is 
 
       
         
           
           
               
               
           
         
         A 1  is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or deleted; 
         A 2  is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe; 
         A 3  is Arg, hArg, Dab, Dap, Lys or Orn; 
         A 4  is Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp; 
         R 6  and R 7  each is, independently for each occurrence thereof, H, 
       
       (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl or R 6  and R 7  may be joined together form a cyclic moiety;
 R 8  is H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl; 
 r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and 
 t is, independently for each occurrence thereof, 1 or 2; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         2 - 50 . (canceled)