Details for Patent: 6,686,380

Title:	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: ##STR1## 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.
Inventor(s):	Lee; Francis Y. F. (Yardley, PA)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Filing Date:	Feb 08, 2002
Application Number:	10/072,123
Claims:	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: ##STR9## wherein: Q is selected from the group consisting of ##STR10## G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, ##STR11## W is O or NR.sub.15 ; X is O or H, H; Y is selected from the group consisting of O; H, OR.sub.16 ; OR.sub.17, OR.sub.17 ; NOR.sub.18 ; H, NHOR.sub.19 ; H, NR.sub.20 R.sub.21 ; H, H; and CHR.sub.22 ; wherein OR.sub.17, OR.sub.17 can be a cyclic ketal; each Z.sub.1 and Z.sub.2 is, independently, selected from the group consisting of CH.sub.2, O, NR.sub.23, S, and SO.sub.2, wherein only one of Z.sub.1 and Z.sub.2 can be a heteroatom; each B.sub.1 and B.sub.2 is, independently, selected from the group consisting of OR.sub.24, OCOR.sub.25, and O--C(.dbd.O)--NR.sub.26 R.sub.27, and when B.sub.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.sub.28 R.sub.29, NR.sub.30 COR.sub.31 and saturated heterocycle; each R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.13, R.sub.14, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22, R.sub.26 and R.sub.27 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R.sub.1 and R.sub.2 are alkyl can be joined to form a cycloalkyl, and when R.sub.3 and R.sub.4 are alkyl can be joined to form a cycloalkyl; each R.sub.9, R.sub.10, R.sub.16, R.sub.17, R.sub.24, R.sub.25 and R.sub.31 is, independently, selected from the group consisting of H, alkyl, and substituted alkyl; each R.sub.8, R.sub.11, R.sub.12, R.sub.28, R.sub.30, R.sub.32, and R.sub.33 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and each R.sub.15, R.sub.23 and R.sub.29 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R.sub.32 C.dbd.O, R.sub.33 SO.sub.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.sub.1, R.sub.2 and R.sub.7 are H; R.sub.3 R.sub.4 and R.sub.6 are methyl; R.sub.8 is H or methyl; Z.sub.1 and Z.sub.2 are CH.sub.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 ##STR12## X is O; Y is O; each Z.sub.1 and Z.sub.2 is, independently, CH.sub.2 ; and W is NR.sub.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-met hyl-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-tetramet lnrl-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-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-di one; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-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-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramet hyl-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-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-di one; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thizolyl)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-t hiazolyl)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-tetramet hyl-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-hex amethyl-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-pentam ethyl-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-m ethyl-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-penta methyl-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-pentame thyl-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-penta methyl-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-tetramet hyl-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-m ethyl-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-meth yl-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-hexa methyl-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-pentam ethyl-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-me thyl-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-8,8,10,12,16-penta methyl-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-tetramet hyl-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-m ethyl-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-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dio ne; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicycl o[14.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramet hyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6d ione; [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-meth yl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dio ne; [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-te tramethyl-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-penta methyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[1 4.1.0]heptadecane-5,9-dione; [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramet hyl-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-m ethyl-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: ##STR13## 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: ##STR14## 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: ##STR15## 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.