Cyclosporin derivatives wherein the mebmt sidechain has been cyclized

Abstract

The present invention relates to cyclosporin analogs that are potent inhibitors of cyclophilin D and have low immunosuppressive activity; processes for preparing them; pharmaceutical compositions containing them; and methods for using these analogs and compositions containing them for the treatment of medical conditions, including but not limited to ischemic conditions, such as ischemia-reperfusion (I/R) injury, including myocardial FR injury, cerebral I/R injury, and ocular or retinal I/R injury.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is 
       
       
         
           
           
               
               
           
         
         R 2  is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2  or —CH 2 CH 2 CH 3 , 
         R 3  is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 haloalkyl, —SC 1-6  alkyl, —CH 2 OH, —CH 2 OCH 3 , 
       
       
         
           
           
               
               
           
         
         R 4  is —CH 3 , —CH 2 CH 3  or —CH 2 CH 2 CH 3 ; 
         R 5  is —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ) or —CH 2 CH(R 7 )(CH 2 CH 3 ); 
         R 6  is —CH 3  or —CH 2 OH; 
         R 7  is —OC 1-6 alkyl; 
         R 8  is —H or —C 1-6 alkyl; 
         R 9  is —H or —C 1-6 alkyl; 
         R 10  is —H or —C 1-6 alkyl; 
         R 11  is —H or —C 1-6 alkyl; 
         R 12  is —H or —C 1-6 alkyl; 
         R 13  is —H or —C 1-6 alkyl; 
         X is O or NR 8 ; 
         Y is CR 9 R 10 ; CR 11  or C═O; 
         Z is (CH 2 ) m , CR 12 , NR 13  or 0; 
         W is (CH 2 ) n ; 
         m is 1, 2 or 3; 
         n is 0 or 1; and 
         the dashed line indicates that the bond joining Y and Z is a single or double bond; 
         provided that:
 (a) when the bond joining Y and Z is a single bond, then Y is CR 9 R 10  or C═O, and 
 
         Z is (CH 2 ) m , NR 13  or O; and
 (b) when the bond joining Y and Z is a double bond, then Y is CR 11  and Z is CR 12 ; 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9  and R 10  is H; m is 1; n is 0; and the bond joining Y and Z is a single bond. 
     
     
         3 . The compound of  claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; R 10  is H; m is 1; n is 0; and the bond joining Y and Z is a single bond. 
     
     
         4 . The compound of  claim 1 , wherein X is O; Y is CR 11 ; Z is CR 12 ; R 10  is H; R 11  is H; R 12  is H; m is 1; and n is 0, and the bond joining Y and Z is a double bond. 
     
     
         5 . The compound of  claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9  and R 10  is H; m is 2 or 3; n is 0; and the bond joining Y and Z is a single bond. 
     
     
         6 . The compound of  claim 1 , wherein X is NR 8 ; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9  and R 10  is H; m is 1; n is 0; and the bond joining Y and Z is a single bond. 
     
     
         7 . The compound of  claim 1 , wherein X is O; Y is C═O or CR 9 R 10 ; Z is NR 13 ; each of R 9  and R 10  is H; R 13  is —C 1-6 alkyl; n is 1; and the bond joining Y and Z is a single bond. 
     
     
         8 . The compound of  claim 1 , wherein X is O, m is 1 or 2, and n is 0. 
     
     
         9 . The compound of  claim 1 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein R 2  is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH) or —CH(CH 3 ) 2 . 
     
     
         11 . The compound of  claim 1 , wherein R 3  is H, —C 1-3 alkyl or —C 1-3 haloalkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 4  is —CH 3 ; R 5  is —CH 2 CH(CH 3 ) 2 ; and R 6  is —CH 3 . 
     
     
         13 . The compound of  claim 1 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 2  is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH) or —CH(CH 3 ) 2 ; 
         R 3  is H, —C 1-3 alkyl or —C 1-3 haloalkyl; 
         R 4  is —CH 3 ; 
         R 5  is —CH 2 CH(CH 3 ) 2 ; 
         R 6  is —CH 3 ; 
         R 8  is —H or —CH 3 ; 
         R 9  is —H or —CH 3 ; 
         R 10  is —H; 
         R 11  is —H; 
         R 12  is —H; 
         R 13 —CH 3 ; and 
         Z is (CH 2 ) m , CR 12  or NR 13 . 
       
     
     
         14 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.