Materials And Methods For Treating Coagulation Disorders

Abstract

This invention is drawn to compounds which are more easily metabolized by the metabolic drug detoxification systems. Particularly, warfarin analogs which have been designed to include esters within the structure of the compounds are taught. The invention teaches methods of reducing the toxicity of drugs comprising the introduction of ester groups into drugs during the synthesis of the drug. This invention is also drawn to methods of treating coagulation disorders comprising the administration of compounds which have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the ester containing warfarin, analogs are also taught.

1 . An anticoagulant compound having the following formula:  
       Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is hydrogen, alkyl, cycloalkyl, halogen, heterocyclyl, hydroxy, alkoxy, R 2 , heteroaryl or aryl optionally substituted with halogen or COOR 1 ;  
 R 1  is independently in each occurrence hydrogen, alkyl or alkylaryl, all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
 R 2  is  
                     
 Y is (CHR 3 ) n COOR 4  or aryl optionally substituted with COOR 5  wherein n=1-3;  
 R 3  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
 R 4  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy; and  
 R 5  is independently in each occurrence hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy.  
 
     
     
         2 . A pharmaceutical composition comprising an anticoagulant compound having the following formula:  
       
         
           
           
               
               
           
         
         wherein:  
         X is hydrogen, alkyl, cycloalkyl, halogen, heterocyclyl, hydroxy, alkoxy, R 2 , heteroaryl or aryl optionally substituted with halogen or COOR 1 ;  
         R 1  is independently in each occurrence hydrogen, alkyl or alkylaryl, all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
         R 2  is  
         
           
             
             
                 
                 
             
           
         
         Y is (CHR 3 ) n COOR 4  or aryl optionally substituted with COOR 5  wherein n=1-3;  
         R 3  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
         R 4  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy; and  
         R 5  is independently in each occurrence hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy.  
       
     
     
         3 . A method for providing anticoagulant activity to a patient in need of such activity wherein said method comprises administering to said patient an anticoagulant compound having the following formula:  
       
         
           
           
               
               
           
         
         wherein:  
         X is hydrogen, alkyl, cycloalkyl, halogen, heterocyclyl, hydroxy, alkoxy, R 2 , heteroaryl or aryl optionally substituted with halogen or COOR 1 ;  
         R 1  is independently in each occurrence hydrogen, alkyl or alkylaryl, all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
         R 2  is  
         
           
             
             
                 
                 
             
           
         
         Y is (CHR 3 ) n COOR 4  or aryl optionally substituted with COOR 5  wherein n=1-3;  
         R 3  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy;  
         R 4  is hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy; and 
 R 5  is independently in each occurrence hydrogen, alkyl or alkylaryl, aryl all optionally substituted with lower alkyl, hydroxy, halogen, or alkoxy.