Novel Sulfonaminoquinoline Hepcidin Antagonists

Abstract

The present invention relates to novel hepcidin antagonists, pharmaceutical compositions comprising them and the use thereof as medicaments for the use in the treatment of iron metabolism disorders, such as, in particular, iron deficiency diseases and anemias, in particular anemias in connection with chronic inflammatory diseases.

1 . Compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , R 3 , R 4 , R 3  and R 6  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         nitro, 
         carboxyl, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted aminocarbonyl, 
         optionally substituted aminosulfonyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         R 7  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted alkyl, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted acyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; and 
         R 8  is selected from the group consisting of: 
         hydroxyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or wherein the substituents R′ to R 5  and R 7  have one of the above meanings and R 6  and R 8  together form a residue of the formula 
       
       
         
           
           
               
               
           
         
         wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         nitro, 
         carboxyl, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted aminocarbonyl, 
         optionally substituted aminosulfonyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted alkyl, 
         optionally substituted alkinyl, 
         optionally substituted alkenyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; and 
         R 14  and R 15  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         nitro, 
         carboxyl, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted aminocarbonyl, 
         optionally substituted aminosulfonyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof; 
         for use in the treatment of iron metabolism disorders. 
       
     
     
         2 . Compounds according to  claim 1 , wherein
 R 1 , R 2 , R 3 , R 4 , R 3  and R 6  are the same or different and are respectively selected from the group consisting of:   hydrogen,   hydroxyl,   halogen,   cyano,   nitro,   carboxyl,   optionally substituted sulfonyl (—SO 2 R),   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted acyl,   optionally substituted alkoxycarbonyl,   optionally substituted acyloxy,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted alkenyl,   optionally substituted aryl, and   optionally substituted heterocyclyl;   R 7  is selected from the group consisting of:   hydrogen,   optionally substituted alkyl,   optionally substituted alkenyl,   optionally substituted aryl, and   optionally substituted heterocyclyl; and   R 8  is selected from the group consisting of:   hydroxyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted aryl, and   optionally substituted heterocyclyl;   or wherein the substituents R 1  to R 3  and R 7  have one of the above meanings and R 6  and R 8  together form a residue of the formula   
       
         
           
           
               
               
           
         
         Wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         carboxyl, 
         halogen, 
         cyano, 
         nitro, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; and 
         R 14  and R 15  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         carboxyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof; 
       
     
     
         3 . Compounds according to  claim 1 , wherein
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are the same or different and are respectively selected from the group consisting of:   hydrogen,   hydroxyl,   halogen,   cyano,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl, optionally substituted acyl,   optionally substituted alkoxycarbonyl,   optionally substituted alkoxy, and   optionally substituted heterocycyl;   R 7  is selected from the group consisting of:   hydrogen and   optionally substituted alkyl,   R 8  is selected from the group consisting of:   optionally substituted amino,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted aryl, and   optionally substituted heterocyclyl;   or wherein the substituents R 1  to R 5  and R 7  have one of the above meanings and R 6  and R 8  together form a residue of the formula   
       
         
           
           
               
               
           
         
         wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         carboxyl, 
         halogen, 
         optionally substituted alkyl, and 
         optionally substituted alkoxy; 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted alkyl, and 
         optionally substituted aryl; and 
         R 14  and R 15  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         optionally substituted alkyl, 
         optionally substituted aryl and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         4 . Compounds according to  claim 1 , wherein:
 R 1  is selected from   hydrogen,   halogen and   optionally substituted alkyl;   R 2  is selected from   hydrogen and   optionally substituted alkyl;   R 3  is selected from   hydrogen,   halogen,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted alkoxycarbonyl,   optionally substituted alkoxy, and   optionally substituted heterocyclyl;   R 4  is selected from   hydrogen,   halogen,   cyano,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted acyl,   optionally substituted alkoxy and   optionally substituted heterocyclyl;   R 5  is selected from   hydrogen,   halogen,   optionally substituted alkyl, and   optionally substituted alkoxy;   R 6  is selected from   hydrogen,   hydroxyl,   halogen,   optionally substituted alkyl, and   optionally substituted alkoxy;   R 7  is selected from   hydrogen and   optionally substituted alkyl; and   R 8  is selected from   optionally substituted amino,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted aryl, and   optionally substituted heterocyclyl;   or pharmaceutically acceptable salts thereof.   
     
     
         5 . Compounds according to  claim 1 , having the general formula (Ia), 
       
         
           
           
               
               
           
         
         wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         carboxyl, 
         halogen, 
         cyano, 
         nitro, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         6 . Compounds according to  claim 5 , wherein
 R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of:   hydrogen,   halogen,   optionally substituted alkyl,   optionally substituted alkoxy;   or pharmaceutically acceptable salts thereof.   
     
     
         7 . Compounds according to  claim 1 , having the general formula (Ib), 
       
         
           
           
               
               
           
         
         wherein 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; and 
         R 14  and R 15  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         carboxyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted acyloxy, 
         optionally substituted alkenyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         8 . Compounds according to  claim 7 , wherein
 R 13  is selected from the group consisting of:   hydrogen,   optionally substituted alkyl, and   optionally substituted aryl; and   R 14  and R 15  are the same or different and are respectively selected from the group consisting of:   hydrogen,   optionally substituted alkyl,   optionally substituted aryl and   optionally substituted heterocyclyl.;   or pharmaceutically acceptable salts thereof.   
     
     
         9 . (canceled) 
     
     
         10 . Compounds according to  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         11 . Compounds according to  claim 1 , for use in the treatment of iron metabolism disorders selected from the group comprising iron deficiency diseases and/or anemias, in particular anemias in the case of cancer, anemia triggered by chemotherapy, anemia triggered by inflammation, anemias in the case of congestive cardiac insufficiency, anemia in the case of chronic renal insufficiency stage 3-5, anemia triggered by chronic inflammation, anemia in the case of rheumatoid arthritis, anemia in the case of systemic lupus erythematosus and anemia in the case of inflammatory bowel diseases. 
     
     
         12 . Composition, comprising one or more of the compounds according to  claim 1  and at least one of pharmaceutical carriers, auxiliary substances, and solvents. 
     
     
         13 . Combined preparation, comprising one or more of the compounds according to  claim 1  and at least one further pharmaceutically active compound, which is in particular a compound for the treatment of iron metabolism disorders and the symptoms associated therewith. 
     
     
         14 . Compounds according to  claim 1 , for use as a medicament for oral or parenteral administration. 
     
     
         15 . Compounds of the general formula (Ib), 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         nitro, 
         carboxyl, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted aminocarbonyl, 
         optionally substituted aminosulfonyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted alkinyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted sulfonyl (—SO 2 R), 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; and 
         R 14  and R 15  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         halogen, 
         cyano, 
         carboxyl, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted alkenyl, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         16 . Compounds according to  claim 15 , wherein
 R 13  is selected from the group consisting of:   hydrogen,   optionally substituted alkyl, and   optionally substituted aryl; and   R 14  and R 15  are the same or different and are respectively selected from the group consisting of:   hydrogen,   optionally substituted alkyl,   optionally substituted aryl and   optionally substituted heterocyclyl.;   or pharmaceutically acceptable salts thereof.   
     
     
         17 . Compounds according to  claim 15  for the use as a medicament. 
     
     
         18 . Compounds according to  claim 2 , wherein
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are the same or different and are respectively selected from the group consisting of:   hydrogen,   hydroxyl,   halogen,   cyano,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl, optionally substituted acyl,   optionally substituted alkoxycarbonyl,   optionally substituted alkoxy, and   optionally substituted heterocycyl;   R 7  is selected from the group consisting of:   hydrogen and   optionally substituted alkyl,   R 8  is selected from the group consisting of:   optionally substituted amino,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted aryl, and   optionally substituted heterocyclyl;   or wherein the substituents R 1  to R 5  and R 7  have one of the above meanings and R 6  and R 8  together form a residue of the formula   
       
         
           
           
               
               
           
         
         wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         carboxyl, 
         halogen, 
         optionally substituted alkyl, and 
         optionally substituted alkoxy; 
         R 13  is selected from the group consisting of: 
         hydrogen, 
         optionally substituted alkyl, and 
         optionally substituted aryl; and 
         R 14  and R′ are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         optionally substituted alkyl, 
         optionally substituted aryl and 
         optionally substituted heterocyclyl; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         19 . Compounds according to  claim 2 , wherein:
 R 1  is selected from   hydrogen,   halogen and   optionally substituted alkyl;   R 2  is selected from   hydrogen and   optionally substituted alkyl;   R 3  is selected from   hydrogen,   halogen,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted alkoxycarbonyl,   optionally substituted alkoxy, and   optionally substituted heterocyclyl;   R 4  is selected from   hydrogen,   halogen,   cyano,   optionally substituted aminocarbonyl,   optionally substituted amino,   optionally substituted alkyl,   optionally substituted acyl,   optionally substituted alkoxy and   optionally substituted heterocyclyl;   R 5  is selected from   hydrogen,   halogen,   optionally substituted alkyl, and   optionally substituted alkoxy;   R 6  is selected from   hydrogen,   hydroxyl,   halogen,   optionally substituted alkyl, and   optionally substituted alkoxy;   R 7  is selected from   hydrogen and   optionally substituted alkyl; and   R 8  is selected from   optionally substituted amino,   optionally substituted alkoxy,   optionally substituted aryloxy,   optionally substituted aryl, and   optionally substituted heterocyclyl;   
       or pharmaceutically acceptable salts thereof. 
     
     
         20 . Compounds according to  claim 2 , having the general formula (Ia), 
       
         
           
           
               
               
           
         
         wherein 
         X is C or N; 
         R 9 , R 10 , R 11  and R 12  are the same or different and are respectively selected from the group consisting of: 
         hydrogen, 
         hydroxyl, 
         carboxyl, 
         halogen, 
         cyano, 
         nitro, 
         optionally substituted amino, 
         optionally substituted alkyl, 
         optionally substituted acyl, 
         optionally substituted alkoxycarbonyl, 
         optionally substituted acyloxy, 
         optionally substituted alkoxy, 
         optionally substituted aryloxy, 
         optionally substituted aryl, and 
         optionally substituted heterocyclyl; 
       
       or pharmaceutically acceptable salts thereof. 
     
     
         21 . Compounds according to  claim 2  for use in the treatment of iron metabolism disorders selected from the group comprising iron deficiency diseases and/or anemias, in particular anemias in the case of cancer, anemia triggered by chemotherapy, anemia triggered by inflammation, anemias in the case of congestive cardiac insufficiency, anemia in the case of chronic renal insufficiency stage 3-5, anemia triggered by chronic inflammation, anemia in the case of rheumatoid arthritis, anemia in the case of systemic lupus erythematosus and anemia in the case of inflammatory bowel diseases.