Fluorinated integrin antagonists

Abstract

The present invention relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing the fluorinated compounds of the invention, and methods of treating macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is 
 
       
         
           
           
               
               
           
         
         R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring; 
         Q is 
       
       
         
           
           
               
               
           
         
       
       and
 R 2  and R 3  are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2  and R 3  is not H, 
 
       provided that the compound of formula (I) contains at least one fluorine atom. 
     
     
         2 . A method of treating or preventing a disease or condition mediated by an αv integrin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is 
 
       
         
           
           
               
               
           
         
         R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring; 
         Q is 
       
       
         
           
           
               
               
           
         
         X is CH or N; 
         Y is CH or N; 
         R 1  is C 1 -C 4  alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; and 
         R 2  and R 3  are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2  and R 3  is not H, 
       
       provided that the compound of formula (I) contains at least one fluorine atom.