12,13-modified epothilone derivatives
First Claim
Patent Images
1. A compound of the formula wherein Q is G is alkyl;
- substituted alkyl;
aryl;
subsitituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
W is O or NR16;
X is O, S, CHR17 H, or R18;
Y is O;
H, H;
OR22;
OR23, OR23;
NOR24;
H, NOR25;
H, NR26R27;
NHNR28,R29;
H,NHNR30R31;
or CHR32;
where OR23, OR23 can be a cyclic ketal;
B1 and B1 are H, OR33, OCOR34, OCONR35R36, NR37R38 or NR39CONR40R41;
D is NR42R43 or a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
M is S, C═
O, S═
O, SO2, or NR44;
R1, R2, R3, and R4, are H, or lower alkyl;
R5, R8, R9, R10, and R11 are H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl;
or a 4 to 7 membered moniocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R17, R18, R22 and R23 are H, alkyl, or substituted alkyl;
R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are H, alkyl, substituted alkyl, aryl or substituted aryl;
R12, R16, R27, R29, R31, R38, R43, and R44, are H;
alkyl;
substituted alkyl;
substituted aryl;
cycloalkyl;
a 4 to 7 membered moniocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R51C═
O;
R52OC═
O;
R53SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
when X is O then R16 is not R51C═
O, R52OC═
O, and R53SO2 and wherein R44 is further amino and and any salts, solvates or hydrates thereof.
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Abstract
The present invention relates to 12,13-position modified epothilone derivatives, methods of preparation of the derivatives and intermediates therefor.
93 Citations
7 Claims
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1. A compound of the formula
wherein Q is G is alkyl; - substituted alkyl;
aryl;
subsitituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
W is O or NR16;
X is O, S, CHR17 H, or R18;
Y is O;
H, H;
OR22;
OR23, OR23;
NOR24;
H, NOR25;
H, NR26R27;
NHNR28,R29;
H,NHNR30R31;
or CHR32;
where OR23, OR23 can be a cyclic ketal;
B1 and B1 are H, OR33, OCOR34, OCONR35R36, NR37R38 or NR39CONR40R41;
D is NR42R43 or a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
M is S, C═
O, S═
O, SO2, or NR44;
R1, R2, R3, and R4, are H, or lower alkyl;
R5, R8, R9, R10, and R11 are H;
alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl;
or a 4 to 7 membered moniocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R17, R18, R22 and R23 are H, alkyl, or substituted alkyl;
R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are H, alkyl, substituted alkyl, aryl or substituted aryl;
R12, R16, R27, R29, R31, R38, R43, and R44, are H;
alkyl;
substituted alkyl;
substituted aryl;
cycloalkyl;
a 4 to 7 membered moniocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R51C═
O;
R52OC═
O;
R53SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
when X is O then R16 is not R51C═
O, R52OC═
O, and R53SO2 and wherein R44 is further amino andand any salts, solvates or hydrates thereof. - View Dependent Claims (2, 4, 6, 7)
and X is O or S and Y is O. -
4. The compound of claim 2, wherein M is S or NR44.
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6. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1.
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7. A method of treating a cancer responsive to microtubule stabilization in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 2.
- substituted alkyl;
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3. A compound selected from the group consisting of:
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[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]-5,9-dioxo-4-oxa-17-azabicyclo[14.1.0]heptadecane-17-carboxylic acid, 1,1-dimethylethyl ester;
[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]-5,9-dioxo-4-oxa-17-azabicyclo[14.1.0]heptadecane-17-carboxylic acid phenyl ester;
[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]-5,9-dioxo-4-oxa-17-azabicyclo[14.1.0]heptadecane-17-carboxylic acid phenylmethyl ester;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-N,N,8,8,10,12-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-5,9-dioxo-4-oxa-17-azabicyclo[14.1.0]heptadecane-17-sulfonamide;
[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]-17-(2-thienylsulfonyl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-17-[1-methyl-1H-imidazol-4-yl)sulfonyl]-3-[1-methyl-2-(2methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[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]-17-(propylsulfonyl)-4-oxa-17-azabicyclo[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-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16*]]-17-Benzoyl-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazoly)ethenyl]-4oxa-17-azabicyclol[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dhydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazoly)ethenyl]-17-(2-thienylcarbonyl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-17-(methoxyacetyl)-8, 8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazoly)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-17-(2-Oxopropanoyl)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione; and
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-]1-methyl-2-(2-methyl-4-thiazoly)ethenyl]-5,9-dioxo-4-oxa-17-azabicyclo[14.1.0]heptadecane-17-carboxylic acid ethyl ester.
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5. A method of treating breast cancer, ovary cancer, colon cancer, head and neck cancer, lung cancer, melanoma, gynecological cancers, brain cancer, germ cell cancer, urothelial cancer, esophageal cancer, non-Hodgkin'"'"'s lymphoma, multiple myeloma, prostrate cancer, bladder cancer, pancreatic cancer and Karposi'"'"'s sarcoma in a patient which comprises providing, to said patient an effective amount of a compound of the formula
G is alkyl; - substituted alkyl;
aryl;
subsitituted aryl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogcn, oxygen and sulfur atoms;
W is O or NR16;
X is O, S, CHR17 H, or R18;
Y is O;
H, H;
OR22;
OR23, OR23;
NOR24;
H, NOR25;
H, NR26R27;
NHNR28R29;
H,NHNR30R31;
or CHR32;
where OR23, OR23 can be a cyclic ketal;
B1 and B1 H, OR33, OCOR34, OCONR35R36, NR37R38 or NR39CONR40R41;
D is NR42R43 or a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
M is S, C═
O, S═
O, SO2, or NR44;
R1, R2, R3, and R4, are H, or lower alkyl;
R5, R8, R9, R10 and R11 are H, alkyl;
substituted alkyl;
aryl;
substituted aryl;
cycloalkyl;
or a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R17, R18, R22 and R23 are H, alkyl, or substituted alkyl;
R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are H, alkyl, substituted alkyl, aryl or substituted aryl;
R12, R16, R27, R29, R31, R38, R43, and R44, are H;
alkyl;
substituted alkyl;
substituted alkyl;
aryl or substituted aryl;
cycloalkyl;
a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems having between 1 and 3 heterotaoms selected from nitrogen, oxygen and sulfur atoms;
R51C═
O;
R52OC═
O;
R53SO2;
hydroxy;
O-alkyl or O-substituted alkyl;
when X is O then R16 is not R51C═
O, R52OC═
O, and R53SO2 and wherein R44 is further amino andand any salts, solvates or hydrates thereof.
- substituted alkyl;
Specification