Melanocortin Receptor-Specific Peptides

Abstract

The invention relates to melanocortin receptor-specific cyclic peptides of Formula (I) or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , x and y are as defined in the specification. These compounds are particularly useful in the treatments of energy homeostasis and metabolism related (e.g. diabetes), food intake related and/or energy balance and body weight related diseases, disorders and/or conditions, including obesity, overweight and diseases, disorders and/or conditions associated with obesity and/or overweight, such as type 2 diabetes and metabolic syndrome.

1 .- 17 . (canceled) 
     
     
         18 . A method of treating a disease, disorder and/or condition responsive to MC4 receptor activation in a mammal comprising administering to mammal in need thereof a therapeutically effective amount of a cyclic peptide of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is —NH—C(═O)— or —C(═O)—NH—; 
         R 2  is —H or —CH 2 —, wherein if R 2  is —CH 2 —, then R 2  forms with R 3  a pyrrolidine ring, wherein the pyrrolidine ring optionally substituted with —OH; 
         R 3  is —(CH 2 ) 2 — if R 2  is —CH 2 —, and otherwise R 3  is selected from the group consisting of: —(CH 2 ) 1-4 NH 2 , —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 CONH 2 , —CH 2 (imidazole), —(CH 2 ) 1-2 CO 2 H, —CH 2 OBz, —CH(CH 3 )OBz, —CH 2 Ph(CONH 2 ), —(CH 2 ) 2 NHCOCH 3 , —(CH 2 ) 3 NHC(═NH)NH 2  and —(CH 2 ) 2 SO 2 CH 3 ; 
         R 4a , R 4b  and R 4c  are each independently selected from the group consisting of —H, —Cl, —F, —CN, —OH, —CF 3 , —CH 3 , —OCH 3 , —NO 2 , —Ph and —NH 2 , with the proviso that at least one of R 4a , R 4b  and R 4c  is not hydrogen and that R 4a , R 4b  and R 4c  cannot all be —Cl, —CH 3  or —OCH 3 ; 
         R 5  is —OH or —N(R 6a )(R 6b ); 
         R 6a  and R 6b  are each H; 
         x is 1 to 4; and 
         y is 1 to 4. 
       
     
     
         19 . The method according to  claim 18 , wherein the disease, disorder and/or condition is diabetes, obesity and conditions associated with obesity. 
     
     
         20 . A method of reducing food intake, body weight and/or body weight gain in a mammal comprising administering to a mammal a therapeutically effective amount of a cyclic peptide of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is —NH—C(═O)— or —C(═O)—NH—; 
         R 2  is —H or —CH 2 —, wherein if R 2  is —CH 2 —, then R 2  forms with R 3  a pyrrolidine ring, wherein the pyrrolidine ring optionally substituted with —OH; 
         R 3  is —(CH 2 ) 2 — if R 2  is —CH 2 —, and otherwise R 3  is selected from the group consisting of: —(CH 2 ) 1-4 NH 2 , —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 CONH 2 , —CH 2 (imidazole), —(CH 2 ) 1-2 CO 2 H, —CH 2 OBz, —CH(CH 3 )OBz, —CH 2 Ph(CONH 2 ), —(CH 2 ) 2 NHCOCH 3 , —(CH 2 ) 3 NHC(═NH)NH 2  and —(CH 2 ) 2 SO 2 CH 3 ; 
         R 4a , R 4b  and R 4c  are each independently selected from the group consisting of —H, —Cl, —F, —CN, —OH, —CF 3 , —CH 3 , —OCH 3 , —NO 2 , —Ph and —NH 2 , with the proviso that at least one of R 4a , R 4b  and R 4c  is not hydrogen and that R 4a , R 4b  and R 4c  cannot all be —Cl, —CH 3  or —OCH 3 ; 
         R 5  is —OH or —N(R 6a )(R 6b ); 
         R 6a  and R 6b  are each H; 
         x is 1 to 4; and 
         y is 1 to 4. 
       
     
     
         21 . The method according to  claim 18  or  claim 20 , wherein the cyclic peptide is of Formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 1  is C(═O)—NH; x is 2; and y is 3. 
     
     
         23 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 1  is NH—C(═O)—; x is 3; and y is 2. 
     
     
         24 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide,
 R 2  is H or —CH 2 —, wherein if R 2  is —CH 2 —, then R 2  forms with R 3  a pyrrolidine ring, wherein the pyrrolidine ring is optionally substituted with —OH; and 
 R 3  is —(CH 2 ) 2 — if R 2  is —CH 2 —, and otherwise R 3  is selected from the group consisting of: —(CH 2 ) 1-4 NH 2 , —CH 3 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 CONH 2 , —(CH 2 ) 2 NHCOCH 3 , —(CH 2 ) 3 NHC(═NH)NH 2  and —(CH 2 ) 2 SO 2 CH 3 . 
 
     
     
         25 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 2  is H; and R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 2  and R 3  together form an unsubstituted pyrrolidine ring. 
     
     
         27 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 4a  is in the 4-position and is —C≡N; and R 4b  and R 4c  are each —H. 
     
     
         28 . The method according to  claim 18  or  claim 20 , wherein for the cyclic peptide, R 4a  is in the 4-position and is —F; and R 4b  and R 4c  are each —H. 
     
     
         29 . The method according to  claim 18  or  claim 20 , wherein the cyclic peptide is selected from the group consisting of: 
       
         
           
                 
               
                   (SEQ ID NO: 48) 
                 
                   Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 51) 
                 
                   Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 74) 
                 
                   Ac-Arg-cyclo(Glu-Asn-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 90) 
                 
                   Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-OH; 
                 
                     
                 
                   (SEQ ID NO: 91) 
                 
                   Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-OH; 
                 
                     
                 
                   (SEQ ID NO: 97) 
                 
                   Ac-Arg-cyclo(Glu-Gln-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 44) 
                 
                   Ac-Arg-cyclo(Glu-Pro-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 72) 
                 
                   Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 ; 
                 
                   and 
                 
                     
                 
                   (SEQ ID NO: 107) 
                 
                   Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-OH; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         30 . The method according to  claim 19 , wherein the disease, disorder and/or condition is selected from the group consisting of: insulin resistance, impaired glucose tolerance, type 2 diabetes, metabolic syndrome, dyslipidemia, hyperlipidemia, hypertension, heart disorders, cardiovascular disorders, non-alcoholic fatty liver disease, joint disorders, secondary osteoarthritis, gastroesophageal reflux, sleep apnea, atherosclerosis, stroke, macro- and micro-vascular diseases, steatosis and gall stones.