Rapamycin derivatives

Abstract

Rapamycin derivatives; pharmaceutical compositions comprising such rapamycin derivatives and pharmaceutically acceptable carriers or diluents; and methods of using such derivatives to inhibit pathogenic fungi growth, inhibit immunosuppression or treat carcinogenic tumors are disclosed.

What is claimed is:  
     
       1. A compound of the formula                    
       wherein: 
       R 1  is selected from the group consisting of ═O, (—OR 6 , H) and (H,H);  
       R 2  is selected from the group consisting of ═O, (H,H), and (H,OH);  
       R 3  and R 6  are independently selected from the group consisting of —H, —C(═O)R 7 , —C(═O)OR 7 , —C(═O)NHR 7 , and —C(═S)OR 7 ;  
       R 4  is selected from the group consisting of ═O and  (H,OR 6 ); or R 3  and R 4  can be taken together to form a bridge of the formula A—C(R 8 )(R 9 )—O—B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position;  
       R 5  is selected from the group consisting of —H and C 1 -C 4  alkyl;  
       R 7  is selected from the group consisting of C 1 -C 10  alkyl, C 3 -C 6  cycloalkyl, phenyl and naphthyl optionally substituted by from one to five members selected from the group consisting of C 1 -C 6  alkyl, phenyl, naphthyl, hydroxyl, C 1 -C 6  alkoxyl, acyloxy, amino, N-acylamino, nitro, cyano and halogen and heterocyclic groups selected from the group consisting of piperidyl, piperidinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furyl, and thienyl optionally substituted in a manner such that carbon atoms attached to a heteroatom are not directly substituted by a heteroatom, by from one to four members selected from the group consisting of C 1 -C 6  alkyl, phenyl, naphthyl, hydroxyl, C 1 -C 6  alkoxyl, acyloxy, amino, N-acylamino, nitro, and halogen;  
       R 8  and R 9  are independently selected from the group consisting of H, C 1  to C 6  alkyl, or R 8  and R 9  taken together are ═O;  
       provided that:  
       (a) when R 4  is ═O, then R 2  is (H,OH); and  
       (b)  when R 1  is (—OH, H), R 2  is ═O, R 3  is (—H), R 4  is (H, OH), then R 5  is not —H, and all pharmaceutically acceptable salts, hydrates or solvates thereof.  
     
     
       2. A compound of claim  1  where R 1  is (H, OH). 
     
     
       3. A compound of claim  1  where R 2  is (H, OH). 
     
     
       4. A compound of claim  1  where R 3  is H. 
     
     
       5. A compound of claim  1  where R 4  is selected from the group consisting of ═O and  (H, OH). 
     
     
       6. A compound of claim  1  where R 5  is H. 
     
     
       7. The compound of claim  1  wherein: 
       (a) R 1  is (H,OH), R 2  is (H,OH), R 3  is —H, R 4  is (H,OH), and R 5  is —H;  
       (b) R 1  is (H,OH), R 2  is (H,OH), R 3  is —H, R 4  is ═O, and R 5  is —H;  
       (c) R 1  is (H,OH), R 2  is (H, OH), R 3  is H, R 4  is (H,OH), and R 5  is —CH 3 ; or  
       (d) R 1  is (H, OH), R 2  is (H,H), R 3  is H, R 4  is (H, OH), and R 5  is H.  
     
     
       8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and an effective therapeutic or prophylatic amount of one or more compounds of claim  1 . 
     
     
       9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of one or more compounds of claim  2 . 
     
     
       10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of one or more compounds of claim  3 . 
     
     
       11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of one or more compounds of claim  4 . 
     
     
       12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of a compound of claim  5 . 
     
     
       13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of a compound of claim  6 . 
     
     
       14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective therapeutic or prophylactic amount of a compound of claim  7   20 . 
     
     
       15. A method of inhibiting the growth of pathogenic fungi in a human or other animal in need thereof which comprises administering to such human or other animal an effective, non-toxic amount of a compound of claim  1 . 
     
     
       16. A method of inducing immunosuppression in a human or other animal in need thereof which comprises administering to such human or other animal an effective, non-toxic amount of a compound of claim  1 . 
     
     
       17. A method of treating carcinogenic tumors in a human or other animal comprising administering to such human or animal an effective, non-toxic amount of a compound of claim  1 . 
     
     
       18. A method of preparing a compound of claim  1  wherein R 4  is (H,OH) comprising contacting a compound of the formula                    
       wherein: 
       R 1  is selected from the group consisting of ═O, (—OR 6 , H) and (H,H);  
       R 2  is selected from the group consisting of ═O, (H,H), and (H,OH);  
       R 3  and R 6  are independently selected from the group consisting of —H, —C(═O)R 7 , —C(═O)OR 7 , —C(═O)NHR 7 , and —C(═S)OR 7 ;  
       R 5  is selected from the group consisting of —H and C 1 -C 4  alkyl;  
       R 7  is selected from the group consisting of C 1 -C 10  alkyl, C 3 -C 6  cycloalkyl, phenyl and naphthyl optionally substituted by from one to five members selected from the group consisting of C 1 -C 6  alkyl, phenyl, naphthyl, hydroxyl, C 1 -C 6  alkoxyl, acyloxy, amino, N-acylamino, nitro, cyano and halogen and heterocyclic groups selected from the group consisting of piperidyl, piperidinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furyl, and thienyl optionally substituted in a manner such that carbon atoms attached to a heteroatom are not directly substituted by a heteroatom, by from one to four members selected from the group consisting of C 1 -C 6  alkyl, phenyl, naphthyl, hydroxyl, C 1 -C 6  alkoxyl, acyloxy, amino, N-acylamino, nitro, and halogen;  
       R 8  and R 9  are independently selected from the group consisting of H, C 1  to C 6  alkyl, or R 8  and R 9  taken together are ═O;  
       with a mixture of cerium trichloride and sodium cyanoborohydride.  
     
     
       19. A compound of claim  1  wherein R 3    and R   4    taken together form a bridge of the formula A—C ( R   8 )( R   9 ) —O—B, where A is a bond to the oxygen bonded to the carbon at the  28   - position and B is a bond to the carbon at the  30   - position; and    
       
         R 
         8  
         and R 
         9  
         are independently selected from the group consisting of H, and C 
         1  
         to C 
         6  
         alkyl, or R 
         8  
         and R 
         9  
         taken together are ═O. 
       
     
     
       20. A compound of claim  1  wherein: 
       ( a )  R   1    is  ( H, OH ) , R   2    is  ( H, OH ) , R   3    is —H, R   4    is  ( H, OH ) , and R   5    is —H;    
       ( b )  R   1    is  ( H, OH ) , R   2    is  ( H, OCH   3 ) , R   3    is H, R   4    is  ( H, OH ) , and R   5    is H;    
       ( c )  R   1    is  ( H, OH ) , R   2    is ═O, R   3    and R   4    are —C—C ( CH   3 ) 2   —O—, and R   5    is H;    
       ( d )  R   1    is  ( H, OH ) , R   2    is  ( H, H ) , R   3    is H, R   4    is  ( H, OH ) , and R   5    is H;    
       ( e )  R   1    is  ( H, OH ) , R   2    is ═O, R   3    and R   4    are —C—C ( O ) O—, and R   5    is H; or    
       ( f )  R   1    is  ( H, OH ) , R   2    is  ( H, OH ) , R   3    is H, R   4    is  ( H, OH ) , and R   5    is —CH   3 .