Treatment of refractory tumors using epothilone derivatives
First Claim
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 NR15;
X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H, NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
each Z1 and Z2 is, independently, selected from the group consisting of CH2, O, NR23, S, and SO2, wherein only one of Z1 and Z2 can be a heteroatom;
each B1 and B2 is, independently, selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27, and when B1 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 NR28R29, NR30COR31 and saturated heterocycle;
each R1, R2, R3, R4, R5, R6, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
each R9, R10, R16, R17, R24, R25 and R31 is, independently, selected from the group consisting of H, alkyl, and substituted alkyl;
each R8, R11, R12, R28, R30, R32, and R33 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and
each R15, R23 and R29 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R32C═
O, R33SO2, 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;
R1, R2 and R7 are H;
R3 R4 and R6 are methyl;
R8 is H or methyl;
Z1 and Z2 are CH2;
G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and
Q is as defined above, are excluded.
2 Assignments
0 Petitions
Accused Products
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.
58 Citations
15 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:
-
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 NR15;
X is O or H, H;
Y is selected from the group consisting of O;
H, OR16;
OR17, OR17;
NOR18;
H, NHOR19;
H, NR20R21;
H, H; and
CHR22;
wherein OR17, OR17 can be a cyclic ketal;
each Z1 and Z2 is, independently, selected from the group consisting of CH2, O, NR23, S, and SO2, wherein only one of Z1 and Z2 can be a heteroatom;
each B1 and B2 is, independently, selected from the group consisting of OR24, OCOR25, and O—
C(═
O)—
NR26R27, and when B1 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 NR28R29, NR30COR31 and saturated heterocycle;
each R1, R2, R3, R4, R5, R6, R7, R13, R14, R18, R19, R20, R21, R22, R26 and R27 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R1 and R2 are alkyl can be joined to form a cycloalkyl, and when R3 and R4 are alkyl can be joined to form a cycloalkyl;
each R9, R10, R16, R17, R24, R25 and R31 is, independently, selected from the group consisting of H, alkyl, and substituted alkyl;
each R8, R11, R12, R28, R30, R32, and R33 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and heterocyclo; and
each R15, R23 and R29 is, independently, selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R32C═
O, R33SO2, 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;
R1, R2 and R7 are H;
R3 R4 and R6 are methyl;
R8 is H or methyl;
Z1 and Z2 are CH2;
G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and
Q is as defined above, are excluded.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
X is O; - Y is O;
each Z1 and Z2 is, independently, CH2; and
W is NR15.
-
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-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-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-dihydroxy-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]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]-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.
-
Specification