Rapamycin hydroxyesters

Abstract

A compound of the structure wherein R 1 and R 2 are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; R 3 and R 4 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, or —F; R 5 and R 6 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5 and R 6 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; R 7 is hydrogen, alkyl, alkenyl, alkynyl, —(CR 3 R 4- ) f OR 10 , —CF 3 , —F, or CO 2 R 11 ; R 8 and R 9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8 and R 9 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4- ) f OR 10 ; R 10 is hydrogen, alkyl, alkenyl, alkynyl, tri-(alkyl)silyl, tri-(alkyl)silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tri-(alkyl)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; R 11 is hydrogen, alkyl, alkenyl, alkynyl, or phenylalkyl; X is 5-(2,2-dialkyl)[1,3]dioxanyl, 5-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]dioxanyl, 4-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2dialkyl)[1,3]dioxalanyl, or 4-(2,2-dicycloalkyl)[1,3]dioxalanyl; b=0-6; d=0-6; and f=0-6 with the proviso that R 1 and R 2 are both not hydrogen and further provided that either R 1 or R 2 contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10 substituted cycloalkyl group, or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

What is claimed is: 
     
       1. A compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2--7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 —F, or—CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, 
         tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6 ; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound of  claim 1 , wherein R 2  is hydrogen or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound of  claim 2 , wherein b=0 and d=0 or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound of  claim 3 , wherein R 8  and R 9  are each, independently hydrogen, alkyl, or —(CR 3 R 4− ) f OR 10 , or are taken together to form X or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound of  claim 1  which is rapamycin 42-ester with (tetrahydropyran-2-yloxy)acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound of  claim 1  which is rapamycin 42-ester with hydroxyacetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound of  claim 1  which is rapamycin 42-ester with 2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound of  claim 1  which is rapamycin 42-ester with 3-hydroxy-2,2-dimethylpropionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound of  claim 1  which is rapamycin 42-ester with 2,2-dimethyl[1,3]dioxalane-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound of  claim 1  which is rapamycin 31,42-diester with 2,2-dimethyl[1,3]dioxalane-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound of  claim 1  which is rapamycin 42-ester with 2,3-dihydroxypropionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound of  claim 1  which is rapamycin 42-ester with 2,2-dimethyl[1,3]dioxane-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       13. The compound of  claim 1  which is rapamycin 42-ester with 3-hydroxy-2-hydroxymethylpropionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       14. The compound of  claim 1  which is rapamycin 42-ester with 2,2,5-trimethyl[1,3]dioxane-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       15. The compound of  claim 1  which is rapamycin 42-ester with 2,2-bis(hydroxymethyl)propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       16. The compound of  claim 1  Which is rapamycin 42-ester with 2,2-dimethyl-5-(2-trimethylsilanylethoxymethyl)[1,3]-dioxane-5-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       17. The compound of  claim 1  which is rapamycin 42-ester with 3-methyl-1,5-dioxa-spiro[5.5]undecane 3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       18. The compound of  claim 1  which is rapamycin 31,42-diester with 3-methyl-1,5-dioxa-spiro[5.5]undecane 3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
       19. A method of treating transplantation rejection or graft vs. host disease in a mammal in need thereof, which comprises administering to said mammal an antirejection effective amount of a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR  10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6 ; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       20. A method of treating a fungal infection in a mammal in need thereof, which comprises administering to said mammal an antifungal effective amount of a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 1− 0,—CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , or —F, —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6; and 
         d=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       21. A method of treating rheumatoid arthritis in a mammal in need thereof, which comprises administering to said mammal an antiarthritis effective amount of a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 )) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1, 3 ]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       22. A method of treating restenosis in a mammal in need thereof, which comprises administering to said mammal an antiproliferative effective amount of a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       23. A method of treating pulmonary inflammation in a mammal in need thereof, which comprises administering to said mammal an antiinflammatory effective amount of a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; 
         R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d=0-6; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof. 
     
     
       24. A pharmaceutical composition which comprises a compound of the structure 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each, independently, hydrogen or —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ; R 3  and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F; 
         R 5  and R 6  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 , or R 5  and R 6  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 7  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 , —F, or —CO 2 R 11 ; 
         R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR 3 R 4 ) f OR 10 , —CF 3 —F, or —CO 2 R 11 , or R 8  and R 9  may be taken together to form X or a cycloalkyl ring of 3-8 carbon atoms that is optionally mono-, di-, or tri-substituted with —(CR 3 R 4 ) f OR 10 ; 
         R 10  is hydrogen, alkyl of 1-6 carbon, atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri-(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; 
         R 11  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; 
         X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 5-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[1,3]dioxalanyl, or 4-(2,2-di-(cycloalkyl of 3-8 carbon atoms))[1,3]dioxalanyl; 
         b=0-6; 
         d =0-6; and 
         f=0-6 
       
       with the proviso that R 1  and R 2  are both not hydrogen and further provided that either R 1  or R 2  contains at least one —(CR 3 R 4 ) f OR 10 , X, or —(CR 3 R 4 ) f OR 10  substituted cycloalkyl of 3-8 carbon atoms group, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. 
     
     
       25. The compound of claim 1, wherein said compound is: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       26. The pharmaceutical composition of claim 24, wherein
 R 1  is —CO(CR 3 R 4 ) b (CR 5 R 6 ) d CR 7 R 8 R 9 ;   b=0;   d=0;   R 7  is methyl;   R 8  is —(CR 3 R 4 ) f OR 10 ;   R 9  is —(CR 3 R 4 ) f OR 10 ;   each R 3  is hydrogen;   each R 4  is hydrogen;   each R 10  is hydrogen;   each f=1; and   R 2  is hydrogen.