Serine protease inhibitors

Abstract

Compounds having the structure shown below are useful to inhibit serine protease enzymes, such as TF/factor VIIa, factor Xa, thrombin and kallikrein. These compounds may be used in methods of preventing and/or treating clotting disorders.

1 . A method of inhibiting a serine protease comprising contacting a serine protease inhibitor compound with a serine protease wherein the serine protease inhibitor compound has the structure:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is C═O or CH 2 ;  
 R 1  is selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, naphthyl, benzyl and heteroaryl, wherein heteroaryl has 5 or 6 ring carbon atoms and 1 or 2 heteroatoms, where the heteroatoms are N, S, or O, and where the heteroaryl group is linked to the sulfonamide group by a carbon atom; and where R 1  is optionally substituted with 1-3 substituents selected from halo, nitro, C 1 -C 6  alkyl, NR 7 R 8 , OR 7 , SR 7 , C 1 -C 6  alkyl-C(O)OR 7 , C 1 -C 6  alkyl-OC(O)R 7 , C 1 -C 6  alkyl-C(O)R 7 , C 1 -C 6  alkyl-OR 7 , C 1 -C 6  haloalkyl, C 1 -C 6  alkyl-NR 7 R 8 , C(O)OR 7 , OC(O)R 7 , C(O)NR 7 R 8 , OC(O)NR 7 R 8 , NHC(O)R 7 , and NHC(O)NR 7 R 8 ;  
 Q is phenyl optionally substituted with one or more groups selected from halo, nitro, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, NR 7 R 8 , OR 7 , SR 7 , C 1 -C 6  alkyl-C(O)OR 7 , OC 1 -C 6  alkyl-C(O)OR 7 , C 1 -C 6  alkyl-OR 7 , OC 1 -C 6  alkyl-OR 7 , C 1 -C 6  alkyl-NR 7 R 8 , OC 1 -C 6  alkyl-NR 7 R 8 , C 1 -C 6  alkyl-C(O)NR 7 R 8 , OC 1 -C 6  alkyl-C(O)NR 7 R 8 , C 1 -C 6  alkyl-C(O)R 7 , OC 1 -C 6  alkyl-C(O)R 7 , C 1 -C 6  haloalkyl, O-aralkyl, C(O)OR 7 , C(O)NR 7 R 8 , OC(O)NR 7 R 8 , NHC(O)R 7 , NHC(O)NR 7 R 8 , NR 7 S(O) 2 R 1 , NR 7 S(O) 2 R 7 , NR 7 S(O) 2  C 1 -C 6  alkyl-C(O)OR 7 , S(O) 2 R 7 , and S(O) 2 NR 7 R 8 ;  
 R 6  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  alkyl-OR 7 , C 1 -C 6  alkyl-N R 7 R 8 , C 1 -C 6  haloalkyl, halo, cyano, OR 7 , SR 7 , NR 7 R 8 , C(O)OR 7 , C(O)R 7  and OC(O)R 7 ; and  
 R 7  and R 8  are independently H, C 1 -C 6  alkyl, or phenyl; and  
 acid and base addition salts thereof.  
 
     
     
         2 . A method of inhibiting clotting comprising collecting blood in a blood collection tube wherein the tube contains an amount of a compound of  claim 1  sufficient to prevent or inhibit the formation of a clot.  
     
     
         3 . The method of  claim 2  wherein 2 to 10 ml of mammalian blood is collected in the tube and the concentration of the compound is 10-1000 nM.  
     
     
         4 . A method of inhibiting thrombus formation comprising administering a compound of  claim 1  to a mammal following angioplasty.  
     
     
         5 . A method of antithrombolytic treatment comprising administering a compound of  claim 1  to a mammal in combination with an antithrombolytic agent selected from tissue plasminogen activator, streptokinase, urokinase, and derivatives thereof.  
     
     
         6 . A method of treating thromboembolic disorders comprising administering a compound of  claim 1  to a mammal in combination with an anticoagulant agent selected from aspirin, heparin and warfarin.  
     
     
         7 . The method of  claim 4 ,  5 , or  6  wherein a dose of 0.01-100 mg/kg body weight of the compound is administered.  
     
     
         8 . The method of  claim 7  wherein the dose is 0.1 to 20 mg/kg of body weight.  
     
     
         9 . The method of  claim 7  wherein the dose is 0.3 to 15 mg/kg of body weight.