Compositions having c-17 and c-3 modified triterpenoids with hiv maturation inhibitory activity

Abstract

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-17 and C-3 modified triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II and III: These compounds are useful for the treatment of HIV and AIDS.

What is claimed is: 
     
         1 . A pharmaceutical composition which comprises an HIV ameliorating amount of one or more of the compounds which are selected from the group consisting of:
 a compound of formula I   
       
         
           
           
               
               
           
         
         a compound of formula II 
       
       
         
           
           
               
               
           
         
       
       and
 a compound of formula III 
 
       
         
           
           
               
               
           
         
         wherein R 1  is isopropenyl or isopropyl; 
         J and E are independently —H or —CH 3 , and E is absent when the double bond is present; 
         X is a phenyl or heteroaryl ring substituted with A, wherein A is at least one member selected from the group of —H, -halo, -hydroxyl, —C 1-6  alkyl, —C 1-6  alkoxy, and —COOR 2 ; 
         R 2  is —H, —C 1-6  alkyl, -alkyl substituted C 1-6  alkyl or -aryl substituted C 1-6  alkyl; 
         Y is selected from the group of —COOR 2 , —C(O)NR 2 SO 2 R 3 , —C(O)NHSO 2 NR 2 R 2 , —NR 2 SO 2 R 2 , —SO 2 NR 2 R 2 , —C 3-6  cycloalkyl-COOR 2 , —C 2-6  alkenyl-COOR 2 , —C 2-6  alkynyl-COOR 2 , —C 1-6 alkyl-COOR 2 , —NHC(O)(CH 2 ) n —COOR 2 , —SO 2 NR 2 C(O)R 2 , -tetrazole, and —CONHOH, 
         wherein n=1-6; 
         R 3  is —C 1-6  alkyl or -alkyl substituted C 1-6  alkyl; 
         R 4  is selected from the group of —H, —C 1-6  alkyl, —C 1-6 alkyl-C(OR 3 ) 2 —C 3-6 cycloalkyl, —C 1-6  substituted alkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 1-6  alkyl-Q 1 , —C 1-6  alkyl-C 3-6  cycloalkyl-Q 1 , aryl, heteroaryl, substituted heteroaryl, —COR 6 , —COCOR 6 , —SO 2 R 2 , —SO 2 NR 2 R 2 , 
       
       
         
           
           
               
               
           
         
         wherein Q 1  is selected from the group of heteroaryl, substituted heteroaryl, halogen, —CF 3 , —OR 2 , —COOR 2 , —NR 8 R 9 , —CONR 10 R 11  and —SO 2 R 7 ; 
         R 5  is selected from the group of —H, —C 1-6  alkyl, —C 3-6  cycloalkyl, —C 1-6  alkyl substituted alkyl, —C 1-6 alkyl-NR 8 R 9 , —COR 10 , —COR 6 , —COCOR 6 , —SO 2 R 2  and —SO 2 NR 2 R 2 ; 
         with the proviso that only one of R 4  or R 5  can be selected from the group of —COR 6 , —COCOR 6 , —SO 2 R 7  and —SO 2 NR 2 R 2 ; 
         or R 4  and R 5  are taken together with the adjacent N to form 
       
       
         
           
           
               
               
           
         
         R 6  is selected from the group of —H, —C 1-6  alkyl, —C 1-6  alkyl-substituted alkyl, —C 3-6  cycloalkyl, —C 3-6  substituted cycloalkyl-Q 2 , —C 1-6  alkyl-Q 2 , —C 1-6  alkyl-substituted alkyl-Q 2 , —C 3-6  cycloalkyl-Q 2 , aryl-Q 2 , —NR 13 R 14 , and —OR 15 ; 
         wherein Q 2  is selected from the group of aryl, heteroaryl, substituted heteroaryl, —OR 2 , —COOR 2 , —NR 8 R 9 , SO 2 R 2 , —CONHSO 2 R 3 , and —CONHSO 2 NR 2 R 2 ; 
         R 7  is selected from the group of —C 1-6  alkyl, —C 1-6  substituted alkyl, —C 3-6 cycloalkyl, aryl, and heteroaryl; 
         R 8  and R 9  are independently selected from the group of —H, —C 1-6  alkyl, —C 1-6  substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, —C 1-6  alkyl-Q 2 , and —COOR 3 , 
         or R 8  and R 9  are independently selected from the group of 
       
       
         
           
           
               
               
           
         
         or R 8  and R 9  are taken together with the adjacent N to form a cycle selected from the group of: 
       
       
         
           
           
               
               
           
         
         with the proviso that only one of R 8  or R 9  is —COOR 3 ; 
         R 10  and R 11  are independently selected from the group of —H, alkyl, —C 1-6  substituted alkyl and —C 3-6  cycloalkyl, 
         or R 10  and R 11  are taken together with the adjacent N to form the cycle 
       
       
         
           
           
               
               
           
         
         R 12  is selected from the group of —C 1-6  alkyl, —NR 2 R 2 , —C 1-6  alkyl-OH, —C 1-6  alkyl, —C 1-6  substituted alkyl, —C 3-6  cycloalkyl, —COR 7 , —COONR 22 R 23 , —SOR 7 , and —SONR 24 R 25 ; 
         R 13  and R 14  are independently selected from the group of —H, —C 1-6  alkyl, —C 3-6  cycloalkyl, —C 1-6  substituted alkyl, —C 1-6  alkyl-Q 3 , alkyl-C 3-6  cycloalkyl-Q 3 , C 1-6  substituted alkyl-Q 3  and 
       
       
         
           
           
               
               
           
         
         or R 13  and R 14  are taken together with the adjacent N to form a cycle selected from the group of: 
       
       
         
           
           
               
               
           
         
         Q 3  is selected from the group of heteroaryl, substituted heteroaryl, —NR 20 R 21 , —CONR 2 R 2 , —COOR 2 , —OR 2 , and —SO 2 R 3 ; 
         R 15  is selected from the group of —C 1-6  alkyl, —C 3-6  cycloalkyl, —C 1-6  substituted alkyl, —C 1-6  alkyl-Q 3 , —C 1-6  alkyl-C 3-6  cycloalkyl-Q 3  and —C 1-6  substituted alkyl-Q 3 ; 
         R 16  is selected from the group of —H, —C 1-6  alkyl, —NR 2 R 2 , and —COOR 3 ; 
         R 17  is selected from the group of —H, —C 1-6  alkyl, —COOR 3 , and aryl; 
         R 18  is selected from the group of —COOR 2  and —C 1-6  alkyl-COOR 2 ; 
         R 19  is selected from the group of —H, —C 1-6  alkyl, —C 1-6  alkyl-Q 4 , —COR 3 , —COOR 3 , wherein Q 4  is selected from the group of —NR 2 R 2  and —OR 2 ; 
         R 20  and R 21  are independently selected from the group of —H, —C 1-6  alkyl, —C 1-6  substituted alkyl, —C 1-6  substituted alkyl-OR 2 , and —COR 3 , 
         or R 20  and R 21  are taken together with the adjacent N to form a cycle selected from the group of 
       
       
         
           
           
               
               
           
         
         with the proviso that only one of R 20  or R 21  can be —COR 3 , 
         R 22  and R 23  are independently selected from the group of H, —C 1-6  alkyl, —C 1-6  substituted alkyl, and —C 1-6 cycloalkyl, 
         or R 22  and R 23  are taken together with the adjacent N to form a cycle selected from the group of 
       
       
         
           
           
               
               
           
         
         R 24  and R 25  are independently from the group of H, —C 1-6  alkyl, —C 1-6  substituted alkyl, —C 1-6  alkyl-Q 5 , —C 1-6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 
         and Q 5  is selected from the group of halogen and SO 2 R 3 ; including pharmaceutically acceptable salts thereof; 
         together with one or more pharmaceutically acceptable carriers, excipients or diluents. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , useful for ameliorating infection by HIV, which additionally comprises an HIV ameliorating amount of an AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; and (d) another HIV entry inhibitor.