Methods and compositions of novel triazine compounds

Abstract

The present invention relates to methods and compositions comprising compounds that treat pathophysiological conditions arising from inflammatory responses. In particular, the present invention is directed to compounds that inhibit or block glycated protein produced induction of the signaling-associated inflammatory response in endothelial cells. The present invention relates to compounds that inhibit smooth muscle proliferation. In particular, the present invention is directed to compounds that inhibit smooth muscle cell proliferation by modulating HSPGs such as Perlecan. The present invention further relates to the use of compounds to treat vascular occlusive conditions characterized by smooth muscle proliferation such as restenosis and atherosclerosis.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 G is NH or O;  
 E is CH;  
 X 1  is m-F or m-Cl;  
 X 2  is p-OCH 3 , p-OC(O)Me, p-NH 2 , or p-OH,  
 z is 0;  
 A is NH or O;  
 Y 1  is H  
                     
 B is NH, NMe, or O;  
                     
 
   
   
       2 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 1 .  
   
   
       3 . The pharmaceutical composition as claimed in  claim 2 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       4 . The pharmaceutical composition as claimed in  claim 2 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       5 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 G is selected from NH or O;  
 X 1  is selected from F or Cl;  
 A is selected from NR 1  or O;  
 Y 1  is selected from R 1 ,  
                     
 B is selected from NR 1  or O;  
 Y 2  is selected from: 
 a)  
                     
  wherein q is 0 or 1, E is selected from O or NR 2 , and R 2  is selected from R 1 , OR 1 , C(O)R 1 , C(O)OR 1 , C(O)NH 2 , or CH 2 NH 2 ; or  
 b)  
                     
  wherein R 3  is selected from R 1 , C(O)R 1 , C(O)OR 1 , or C(O)NH 2 ;  
 
 and  
 R 1  in each occurrence is independently selected from H; or a linear or branched alkyl with up to 10 carbon atoms.  
 
   
   
       6 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 5 .  
   
   
       7 . The pharmaceutical composition as claimed in  claim 6 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       8 . The pharmaceutical composition as claimed in  claim 6 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       9 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 G is selected from NH or O;  
 Z is selected from H or  
                     
 B is selected from NR 1  or O;  
 R 3  is selected from R 1 , C(O)R 1 , C(O)OR 1 , or C(O)NH 2 ; and  
 R 1  in each occurrence is independently selected from H, or a linear or branched alkyl with up to 10 carbon atoms.  
 
   
   
       10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 9 .  
   
   
       11 . The pharmaceutical composition as claimed in  claim 10 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       12 . The pharmaceutical composition as claimed in  claim 10 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       13 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 Q is selected from NH 2 , OC(O)R 1 , or OH;  
 X 1  is selected from F or Cl;  
 B is selected from NR 1  or O; and  
 Y 2  is selected from: 
 a)  
                     
  wherein q is 0 or 1, E is selected from O or NR 2 , and R 2  is selected from R 1 , OR 1 , C(O)R 1 , C(O)OR 1 , C(O)NH 2 , or CH 2 NH 2 ; or  
 b)  
                     
  wherein R 3  is selected from R 1 , C(O)R 1 , C(O)OR 1 , or C(O)NH 2 ;  
 
 and  
 R 1  in each occurrence is independently selected from H, or a linear or branched alkyl with up to 10 carbon atoms.  
 
   
   
       14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 13 .  
   
   
       15 . The pharmaceutical composition as claimed in  claim 14 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       16 . The pharmaceutical composition as claimed in  claim 14 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       17 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 GZ in combination is selected from NH 2 , OH,  
                     
 AY 1  in combination is selected from OH, NH 2 ,  
                     
 BY 2  in combination is selected from  
                     
 
   
   
       18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 17 .  
   
   
       19 . The pharmaceutical composition as claimed in  claim 18 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       20 . The pharmaceutical composition as claimed in  claim 18 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       21 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 GZ in combination is selected from NH 2 , OH,  
                     
 AY 1  in combination is selected from  
                     
 BY 2  in combination is selected from OH,  
                     
 
   
   
       22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 21 .  
   
   
       23 . The pharmaceutical composition as claimed in  claim 22 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       24 . The pharmaceutical composition as claimed in  claim 22 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.  
   
   
       25 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein: 
 GZ in combination is selected from  
                     
 AY 1  in combination is selected from OH, NH 2 ,  
                     
 BY 2  in combination is selected from OH,  
                     
 
   
   
       26 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to  claim 25 .  
   
   
       27 . The pharmaceutical composition as claimed in  claim 26 , further comprising at least one of the following: 
 a pharmaceutically acceptable auxiliary;    a pharmaceutically acceptable preservative;    a pharmaceutically acceptable excipient; or    any combination thereof.    
   
   
       28 . The pharmaceutical composition as claimed in  claim 26 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.