N-substituted glycine derivatives: hydroxylase inhibitors

Abstract

The invention described herein relates to certain pyridazinedione N-substituted glycine derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.

What is claimed is: 
     
       1. A compound which is N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1 -methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a salt thereof. 
     
     
       2. A compound according to  claim 1  which is N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine. 
     
     
       3. A compound according to  claim 1  which is Na, K, Li, Ca, or Mg salt of N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine. 
     
     
       4. A method for treating anemia in a mammal, which method comprises administering an effective amount of N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a salt thereof to a mammal suffering from anemia which can be treated by inhibiting HIF prolyl hydroxylases. 
     
     
       5. A pharmaceutical composition comprising N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. 
     
     
       6. A compound which is N-{[2-[(3,4′-difluoro-4-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a pharmaceutically acceptable salt thereof. 
     
     
       7. A compound according to  claim 6  which is N-{[2-[(3,4′-difluoro-4-biphenylyl)methyl]-5-hydroxy-6-(1 -methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine. 
     
     
       8. A compound according to  claim 6  which is the Na, K, Li, Ca, or Mg salt of N-{[2-[(3,4′-difluoro-4-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine. 
     
     
       9. A method for treating anemia in a mammal, which method comprises administering an effective amount of N-{[2-[(3,4′-difluoro-4-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a salt thereof to a mammal suffering from anemia which can be treated by inhibiting HIF prolyl hydroxylases. 
     
     
       10. A pharmaceutical composition comprising N-{[2-[(3,4′-difluoro-4-biphenylyl)methyl]-5-hydroxy-6-(1 -methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. 
     
     
       11. A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is 2-fluoro-4-bromobenzyl, 4-bromobenzyl, 4-(halophenyl)benzyl, 2-fluoro-4-(halophenyl)benzyl, 2-fluoro-4-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, or 2-fluoro-4-(C 1 -C 4 alkoxyphenyl)benzyl; 
 R 2  is OH; 
 R 3  is H; and 
 R 4  is isopropyl, t-butyl or cyclohexyl; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
       12. A pharmaceutical composition comprising a compound of claim 11, or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents or excipients. 
     
     
       13. The compound: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       14. The compound: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       15. A pharmaceutical composition comprising a compound according to claim 13, and one or more of pharmaceutically acceptable carriers, diluents or excipients. 
     
     
       16. The compound: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       17. The compound: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       18. A pharmaceutical composition comprising a compound of claim 16, and one or more of pharmaceutically acceptable carriers, diluents or excipients. 
     
     
       19. A method for treating anemia associated with renal disease in a human, said method comprising administering a compound according to claim 13. 
     
     
       20. A method for treating anemia associated with renal disease in a human, said method comprising administering a compound according to claim 16. 
     
     
       21. A method for treating anemia associated with cancer chemotherapy in a human, said method comprising administering a compound according to claim 13. 
     
     
       22. A method for treating anemia associated with cancer chemotherapy in a human, said method comprising administering a compound according to claim 16. 
     
     
       23. A method for treating anemia associated with reduced erythropoietin production in a human, said method comprising administering a compound according to claim 13. 
     
     
       24. A method for treating anemia associated with reduced erythropoietin production in a human, said method comprising administering a compound according to claim 16. 
     
     
       25. A method for increasing erythropoietin production in a human, said method comprising administering a compound according to claim 13. 
     
     
       26. A method for increasing erythropoietin production in a human, said method comprising administering a compound according to claim 16.