Methods of treating factor VIIa-associated conditions with compounds having an amine nucleus

Abstract

Methods of treating Factor VIIa-associated conditions in a mammal are described, comprising administering to the mammal in need of treatment thereof an effective amount of at least one compound having the formula (I), or a pharmaceutically-acceptable salt, hydrate or prodrug thereof.

1 . A compound having the formula (II),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt, or hydrate, or prodrug thereof, wherein 
 A is selected from phenyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and pyrazolyl, said ring A being optionally substituted with up to two groups selected from halogen, NO 2 , C 1-4 alkyl, haloalkyl, haloalkoxy, OH, C 1-4 alkoxy, C 1-4 alkylcarbonyl, CN, NH 2 , NH(C 1-4 alkyl), and N(alkyl) 2 ;  
 R 3  is selected from hydrogen, halogen, C 1-4 alkyl, hydroxy(C 0-4 alkyl), CF 3 (C 0-4 alkyl), OCF 3 (C 0-4 alkyl), cyano(C 0-4 alkyl), amino(C 0-4 alkyl), C 1-3 alkoxy(C 0-4 alkyl), and C 1-6 alkylamino(C 0-4 alkyl);  
 R 11  is selected from hydrogen, halogen, C 1-4 alkyl, hydroxy(C 0-4 alkyl), CF 3 (C 0-4 alkyl), OCF 3 (C 0-4 alkyl), cyano(C 0-4 alkyl), amino(C 0-4 alkyl), C 1-3 alkoxy(C 0-4 alkyl), and C 1-6 alkylamino(C 0-4 alkyl), or two R 11  groups may be taken together, or one of R 11  may be taken together with R 11a  to form a fused benzo, heteroaryl, or heterocyclic ring, wherein said ring in turn is optionally substituted with a group A or one to two of C 1-4 alkyl, oxo(═O), halogen, cyano, trifluoromethyl, or trifluoromethoxy;  
 R 11a  is selected from hydrogen, halogen, C 1-4 alkyl, hydroxy(C 0-4 alkyl), CF 3 (C 0-4 alkyl), OCF 3 (C 0-4 alkyl), cyano(C 0-4 alkyl), and C 1-4 alkoxy(C 0-4 alkyl), or R 11a  may be taken together with R 11  to form a fused benzo, heteroaryl, or heterocyclic ring, wherein said ring in turn is optionally substituted with a group A or one to two of C 1-4 alkyl, oxo(═O), halogen, cyano, trifluoromethyl, or trifluoromethoxy;  
 a is 0 or 1; and  
 n is 0, 1, 2, 3, or 4; and said compound of formula (II) is effective in inhibiting Factor VIIa in a mammal with an IC 50  of less than 1 μM.  
 
   
   
       2 . A compound according to  claim 1 , having the formula,  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof, wherein said compound is effective in inhibiting Factor VIIa in a mammal with an IC 50  of less than 500 nM.  
   
   
       3 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1 .  
   
   
       4 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 2 .  
   
   
       5 . A method of treating a disorder selected from myocardial infarction, unstable angina, thromboembolic stroke, venous thrombosis, pulmonary embolism, peripheral occlusive arterial disease, atherosclerotic vascular disease, athersclerotic plaque rupture, and/or thromboembolic consequences of surgery, interventional cardiology, and immobility, in a mammal comprising administering to the mammal in need of treatment thereof an effective amount of at least one compound of  claim 1 .  
   
   
       6 . A method of treating a disorder selected from myocardial infarction, unstable angina, thromboembolic stroke, venous thrombosis, pulmonary embolism, peripheral occlusive arterial disease, atherosclerotic vascular disease, athersclerotic plaque rupture, and/or thromboembolic consequences of surgery, interventional cardiology, and immobility, in a mammal comprising administering to the mammal in need of treatment thereof an effective amount of at least one compound of  claim 2.