Dipeptide apoptosis inhibitors and the use thereof

Abstract

The present invention is directed to novel dipeptides thereof, represented by the general Formula I: where R 1 -R 3 and AA are defined herein. The present invention relates to the discovery that compounds having Formula I are potent inhibitors of apoptotic cell death. Therefore, the inhibitors of this invention can retard or block cell death in a variety of clinical conditions in which the loss of cells, tissues or entire organs occurs.

1 - 39 . (canceled)  
     
     
         40 . A method of treating or ameliorating hepatitis in an animal in need thereof, comprising administering to said animal an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 AA is a residue of an amino acid selected from the group consisting of valine (Val), isoleucine (Ile), and leucine (Leu);  
 R 1  is an N-terminal protecting group selected from the group consisting of Cbz, Ac and Boc;  
 R 2  is H or CH 2 R 4 , where R 4  is an electronegative leaving group; and  
 R 3  is alkyl or H.  
 
     
     
         41 . The method of  claim 40 , wherein R 3  is methyl or H.  
     
     
         42 . The method of  claim 40 , wherein said compound is Cbz-Val-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         43 . The method of  claim 40 , wherein said compound is Cbz-Leu-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         44 . The method of  claim 40 , wherein said compound is Cbz-Ile-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         45 . The method of  claim 40 , wherein said compound is Ac-Val-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         46 . The method of  claim 40 , wherein said compound is Ac-Leu-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         47 . The method of  claim 40 , wherein said compound is Ac-Ile-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         48 . The method of  claim 40 , wherein said compound is Boc-Val-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         49 . The method of  claim 40 , wherein said compound is Boc-Leu-Asp-CH 2 F or a pharmaceutically acceptable salt thereof  
     
     
         50 . The method of  claim 40 , wherein said compound is Boc-Ile-Asp-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         51 . The method of  claim 40 , wherein said compound is Cbz-Val-Asp(OMe)-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         52 . The method of  claim 40 , wherein said compound is Cbz-Leu-Asp(OMe)-CH 2 F or a pharmaceutically acceptable salt thereof.  
     
     
         53 . The method of  claim 40 , wherein said compound is Cbz-Ile-Asp(OMe)-CH 2 F or a pharmaceutically acceptable salt thereof.