Nitrogen-containing heterocyclic carboxamide derivatives or salts thereof and antiviral agents comprising the same

Abstract

Nitrogen-containing heterocyclic carboxamide derivatives represented by the following general formula: wherein ring A is a substituted or unsubstituted pyrazine, pyrimidine, pyridazine or triazine ring; R 1 is O or OH; R 2 is a hydrogen atom, an acyl group or a substituted or unsubstituted carbamoylalkyl or carboxyalkyl group; and the broken line represents a single bond or a double bond; or salts thereof are useful for preventing and treating virus infections and especially influenza virus infections.

1. A nitrogen-containing heterocyclic carboxamide compound represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein:
 each occurrence of R 3  R′ is independently a halogen atom, or a hydroxyl group, or an oxide group which is linked to a carbon atom of the nitrogen-containing heterocycle in said formula; 
 R 1  represents O or OH; 
 R 2  is selected from the group consisting of a hydrogen atom, an acyl group, an optionally substituted carbamoylalkyl group, and an optionally substituted carboxyalkyl group; 
 n is 1, or 2, 3, or 4; and 
 the broken line in the ring represents a single bond when R 1  is O and a double bond when R 1  is OH; and 
 the broken line between R 1  and the ring is a single bond when R 1  is OH and a double bond when R 1  is O; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. The nitrogen-containing heterocyclic carboxamide compound according to  claim 1  wherein:
 at least one occurrence of R 3 R′ is a halogen atom, which is linked to a carbon atom of the nitrogen-containing heterocycle in said formula; and 
 R 2  is a hydrogen atom. 
 
     
     
       3. A method of treating a viral condition infection associated with influenza virus, C-type hepatitis, rhino virus, or respiratory syncytial virus by administering, to a patient in need thereof, an effective amount of at least one compound or a pharmaceutically acceptable salt thereof, the compound having a structure according to a compound represented by the following formula 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring, a ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         wherein:
 the mark *1 expresses the position of substitution with R 1 ;   the mark *2 expresses the position of substitution with —C(═O)NHR 2 ;   
         ring A is optionally substituted with at least one of a halogen atom, a hydroxyl group, an oxide group, a phenyl group, a pyridinyl group, and a mercapto group, which is linked to a carbon atom of ring A; 
         R 1  represents O or OH; 
         R 2  is selected from the group consisting of a hydrogen atom, an acyl group, an optionally substituted carbamoylalkyl group, and an optionally substituted carboxyalkyl group; and 
         the broken line is one of a single bond and a double bond; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. The method according to  claim 3 , wherein:
 said ring A represents a pyrazine, pyrimidine, or triazine ring, ring A is optionally substituted with at least one of a halogen atom, a hydroxyl group, an oxide group, a phenyl group, a pyridinyl group, and a mercapto group.   
     
     
       5. The method according to  claim 4  claim 3, wherein:
 said ring A represents the following ring  
 
       
         
           
           
               
               
           
         
       
       a pyrazine ring, ring A is optionally substituted with at least one of a halogen atom, a hydroxyl group, an oxide group, a phenyl group, a pyridinyl group, and a mercapto group, which is linked to a carbon atom of ring A. 
     
     
       6. The method according to  claim 3 , wherein said viral condition infection is associated with influenza virus. 
     
     
       7. A pharmaceutical composition comprising:
 a therapeutically effective amount of a compound according to  claim 1 , and 
 a pharmaceutically acceptable carrier or diluent. 
 
     
     
       8. The method according to  claim 3 , wherein said viral condition infection is associated with C-type hepatitis. 
     
     
       9. The method according to  claim 3 , wherein said viral condition infection is associated with rhino virus. 
     
     
       10. The method according to  claim 3 , wherein said viral condition infection is associated with respiratory syncytial virus. 
     
     
       11. The method according to  claim 3 , wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 each occurrence of R 3  R′ is independently a halogen atom, or a hydroxyl group, or an oxide group which is linked to a carbon atom of the nitrogen-containing heterocycle in said formula; 
 R 1  represents O or OH; 
 R 2  is selected from the group consisting of a hydrogen atom, an acyl group, an optionally substituted carbamoylalkyl group, and an optionally substituted carboxyalkyl group; 
 n is 1 or 2; and 
 the broken line in the ring represents a single bond when R 1  is O and a double bond when R 1  is OH; and 
 the broken line between R 1  and the ring is a single bond when R 1  is OH and a double bond when R 1  is O; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. The method according to  claim 11 , wherein said viral condition infection is associated with influenza virus. 
     
     
       13. The method according to  claim 11 , wherein said viral condition infection is associated with C-type hepatitis. 
     
     
       14. The method according to  claim 11 , wherein said viral condition infection is associated with rhino virus. 
     
     
       15. The method according to  claim 11 , wherein said viral condition infection is associated with respiratory syncytial virus. 
     
     
       16. The method according to  claim 3 , wherein said ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring, a ring selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       ring A is optionally substituted with at least one of a halogen atom, a hydroxyl group, a phenyl group, a pyridinyl group, and a mercapto group, which is linked to a carbon atom of ring A. 
     
     
       17. The method according to  claim 4 , wherein ring A represents a pyrazine, pyrimidine, or triazine ring, ring A is optionally substituted with at least one of a halogen atom, a hydroxyl group, a phenyl group, a pyridinyl group, and a mercapto group. 
     
     
       18. The method according to claim  5  3, wherein said ring A represents a pyrazine ring the following ring,  
       
         
           
           
               
               
           
         
       
       ring A is optionally substituted with at least one of a halogen atom, or a hydroxyl group, and an oxide group which is linked to a carbon atom of ring A. 
     
     
       19. The compound of claim 1 wherein:
 R′ is fluorine, which is linked to a carbon atom of the nitrogen-containing heterocycle in said formula,   R 2  is hydrogen, and   n is 1.   
     
     
       20. A nitrogen-containing heterocyclic carboxamide compound represented by the following formula 
       
         
           
           
               
               
           
         
         wherein G 1  and G 4  are N, G 2  is C—F, G 3  is CH, and R 2  is hydrogen, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       21. A method of treating a viral infection associated with influenza virus, C-type hepatitis, rhino virus, or respiratory syncytial virus by administering, to a patient in need thereof, an effective amount of a compound represented by the following formula 
       
         
           
           
               
               
           
         
         wherein G 1  and G 4  are N, G 2  is C—F and G 3  is CH, and R 2  is hydrogen, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       22. The method according to claim 21, wherein said viral infection is associated with influenza virus. 
     
     
       23. The method according to claim 21, wherein said viral infection is associated with C-type hepatitis. 
     
     
       24. The method according to claim 21, wherein said viral infection is associated with rhino virus. 
     
     
       25. The method according to claim 21, wherein said viral infection is associated with respiratory syncytial virus. 
     
     
       26. A pharmaceutical composition comprising: a therapeutically effective amount of a compound according to claim 20, and a pharmaceutically acceptable carrier or diluent.