Treatment of refractory tumors using epothilone derivatives

Abstract

Methods of treating tumors in a mammal, especially a human that has demonstrated resistance to other chemotherapeutic agents, is disclosed. Specifically, methods of the present invention are effective in tumors that have initially been unresponsive to taxane therapy, or have developed resistance during the course of treatment. The methods of the present invention comprise administering epothilone derivatives selected from those represented by the formula: The subject epothilone derivatives are advantageous in addition to their enhanced potency and effectiveness against tumors that have demonstrated resistance to therapy with taxane oncology agents in that they are efficacious upon oral administration.

1. A method for treating a tumor in a mammal, said tumor having demonstrated resistance to oncology therapy, comprising administering to said mammal an effective amount of a composition comprising a pharmaceutically acceptable carrier and an epothilone compound of formula: 
                   
       wherein:
 Q is selected from the group consisting of 
                 
 
 G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
                 
 
 W is O or NR 15 ;  
 X is O or H, H;  
 Y is selected from the group consisting of O; H, OR 16 ; OR 17 , OR 17 ; NOR 18 ; H, NHOR 19 ; H, NR 20 R 21 ; H, H; and CHR 22 ; wherein OR 17 , OR 17  can be a cyclic ketal;  
 each Z 1  and Z 2  is, independently, selected from the group consisting of CH 2 , O, NR 23 , S, and SO 2 , wherein only one of Z 1  and Z 2  can be a heteroatom;  
 each B 1  and B 2  is, independently, selected from the group consisting of OR 24 , OCOR 25 , and O—C(═O)— NR 26 R 27 , and when B 1  is H and Y is OH, H, they can form a six-membered ring ketal or acetal;  
 D is selected from the group consisting of NR 28 R 29 , NR 30 COR 31  and saturated heterocycle;  
 each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26  and R 27  is, independently, selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R 1  and R 2  are alkyl can be joined to form a cycloalkyl, and when R 3  and R 4  are alkyl can be joined to form a cycloalkyl;  
 each R 9 , R 10 , R 16 , R 17 , R 24 , R 25  and R 31  is, independently, selected from the group consisting of H, alkyl, and substituted alkyl;  
 each R 8 , R 11 , R 12 , R 28 , R 30 , R 32 , and R 33  is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and  
 each R 15 , R 23  and R 29  is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R 32 C═O, R 33 SO 2 , hydroxy, O-alkyl or O-substituted alkyl;  
 and pharmaceutically acceptable salts thereof and any hydrates, solvates or geometric, optical and stereoisomers thereof,  
 with the proviso that compounds wherein W and X are both O; R 1 , R 2  and R 7  are H; R 3  R 4  and R 6  are methyl; R 8  is H or methyl; Z 1  and Z 2  are CH 2 ; G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and Q is as defined above, are excluded.  
 
     
     
       2. The method of  claim 1  wherein Q is 
                   X is O; Y is O; each Z 1  and Z 2  is, independently, CH 2 ; and    W is NR 15 .    
     
     
       3. The method of  claim 1  wherein said epothilone compound is selected from the group consisting of
 [1S-[1R*,3R*(E), 7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetrametlnrl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicycllo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;    [1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihdyroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptanedecane-5,9-dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6dione;    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;    [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;    [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;    [4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;    [4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;    [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; and    [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione;    and pharmaceutically acceptable salts, solvates and hydrates thereof.    
     
     
       4. The method of  claim 1  wherein said epothilone compound is of formula: 
                   
       
        
       
     
     
       5. The method of  claim 1  wherein said mammal is a human. 
     
     
       6. The method of  claim 1  wherein the composition containing said epothilone compound is administered parenterally. 
     
     
       7. The method of  claim 6  wherein said epothilone compound is of formula: 
                   
       
        
       
     
     
       8. The method of  claim 1  wherein the composition containing said epothilone compound is administered orally. 
     
     
       9. The method of  claim 8  wherein said epothilone compound is of formula: 
                   
       
        
       
     
     
       10. The method of  claim 1  wherein said tumor was initially not responsive to oncology therapy. 
     
     
       11. The method of  claim 1  wherein said tumor was initially responsive to oncology therapy, but developed resistance thereto during the course of treatment. 
     
     
       12. The method of  claim 1  wherein said compound is administered simultaneously or sequentially with a chemotherapeutic agent useful in the treatment of cancer or other proliferative diseases. 
     
     
       13. The method of  claim 1  wherein the oncology therapy is a taxane. 
     
     
       14. The method of  claim 1  wherein the oncology therapy is paclitaxel. 
     
     
       15. The method of  claim 1  wherein the tumor is of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid or skin. 
     
     
       16. A method for treating a tumor in a mammal, said tumor being resistant to oncology therapy with a taxane, comprising administering to said mammal an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound having the formula, 
                   
       
        
       
     
     
       17. The method of  claim 16  wherein said mammal is a human.  
     
     
       18. The method of  claim 17  wherein said tumor was initially not responsive to taxane therapy.  
     
     
       19. The method of  claim 17 , wherein said tumor was initially responsive to taxane therapy, but developed resistance thereto during the course of treatment.  
     
     
       20. The method of  claim 17 , wherein said tumor is innately resistant to taxane therapy.  
     
     
       21. The method of  claim 17 , wherein the taxane is paclitaxel.  
     
     
       22. The method of  claim 17  wherein the tumor is of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid or skin.  
     
     
       23. The method of  claim 22 , wherein the tumor is of the breast.  
     
     
       24. The method of  claim 22 , wherein the tumor is of the pancreas.  
     
     
       25. The method of  claim 23 , wherein the oncology therapy is paclitaxel.  
     
     
       26. The method of  claim 23  wherein said tumor was initially not responsive to taxane therapy.  
     
     
       27. The method of  claim 23  wherein said tumor was initially responsive to taxane therapy, but developed resistance thereto during the course of treatment.  
     
     
       28. The method of  claim 23 , wherein said tumor is innately resistant to taxane therapy.