C-10 CARBAMATES OF TAXANES
First Claim
Patent Images
1. A compound of formula I:
- or pharmaceutically acceptable derivative thereof, wherein R1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or acyl;
R2 is alkyl or aryl, wherein the aryl group is optionally substituted with one to three electron withdrawing or electron donating groups;
R7 is H or OR7a where R7a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —
COR7b, —
CONR7cR7d or is hydroxyl protecting group, whereinR7b is alkyl, afkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, andR7c and R7b are each independently selected as follows;
a) R7c and R7d are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, orb) R7c and R7d together with the nitrogen atom form an optionally substituted 5-7 membered heterocyclic or heteroaryl ring;
R9 is ═
O, or —
OR7a;
X is NKxRy, where Rx is hydrogen or alkyl and Ry is carboxyalkyl, carboxyheteroalkyl, carboxyalkenyl, carboxyalkynyl, carboxycycloalkyl, carboxyheterocyclyl, carboxyaryl, carboxyheteroaryl or aminoheteroalkyl, wherein the amino group is optionally protected with a protecting group;
R14 is hydrogen, hydroxyl or alkoxy;
R3a is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or is hydroxyl protecting group;
R5a is —
COR7b, —
COOR7b, or CONR7cR7d; and
R1, R2, R3a, R4aR5a, R7a, R7b, R7c, R7d, Ry, and R14 are unsubstituted or substituted with 1-4 substituents Q1, wherein each Q1 is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, amino, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, aminoalkyl, diaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aralkyloxycarbonyl, aralkoxycarbonylamino, aminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, aralkoxy, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino or alkylarylamino.
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Accused Products
Abstract
Provided herein are C-10 taxane carbamates and pharmaceutically acceptable derivatives thereof. In certain embodiments, provided herein are compounds, compositions and methods for treating cancer and taupathy.
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Citations
37 Claims
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1. A compound of formula I:
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or pharmaceutically acceptable derivative thereof, wherein R1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or acyl; R2 is alkyl or aryl, wherein the aryl group is optionally substituted with one to three electron withdrawing or electron donating groups; R7 is H or OR7a where R7a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —
COR7b, —
CONR7cR7d or is hydroxyl protecting group, whereinR7b is alkyl, afkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and R7c and R7b are each independently selected as follows; a) R7c and R7d are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or b) R7c and R7d together with the nitrogen atom form an optionally substituted 5-7 membered heterocyclic or heteroaryl ring; R9 is ═
O, or —
OR7a;X is NKxRy, where Rx is hydrogen or alkyl and Ry is carboxyalkyl, carboxyheteroalkyl, carboxyalkenyl, carboxyalkynyl, carboxycycloalkyl, carboxyheterocyclyl, carboxyaryl, carboxyheteroaryl or aminoheteroalkyl, wherein the amino group is optionally protected with a protecting group; R14 is hydrogen, hydroxyl or alkoxy; R3a is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or is hydroxyl protecting group; R5a is —
COR7b, —
COOR7b, or CONR7cR7d; andR1, R2, R3a, R4aR5a, R7a, R7b, R7c, R7d, Ry, and R14 are unsubstituted or substituted with 1-4 substituents Q1, wherein each Q1 is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, amino, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, aminoalkyl, diaminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aralkyloxycarbonyl, aralkoxycarbonylamino, aminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, aralkoxy, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino or alkylarylamino. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)
R2 is alkyl or aryl group; R7 is H, OH or alkoxy; R9 is ═
O, OH or alkoxy;R14 is hydrogen; R3a is alkyl, alkenyl or aryl; R4a is hydrogen; and R5a is alkoxycarbonyl or arylcarbonyl.
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3. The compound of claim 1, wherein R1 is hydrogen.
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4. The compound of claim 1, wherein R2 is lower alkyl or aryl.
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5. The compound of claim 1, wherein R2 is phenyl.
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6. The compound of claim 1, wherein R7 is hydroxyl.
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7. The compound of claim 1, wherein R9 is ═
- O.
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8. The compound of claim 1, wherein R14 is hydrogen.
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9. The compound of claim 1, wherein R3a is aryl, alkyl, haloalkyl, alkenyl or haloalkenyl.
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10. The compound of claim 1, wherein R3a is phenyl.
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11. The compound of claim 1, wherein R5a is alkoxycarbonyl or arylcarbonyl.
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12. The compound of claim 1, wherein R5a is tert-butyloxycarbonyl or phenylcarbonyl.
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13. The compound of claim 1, wherein Rx hydrogen and Ry is carboxyalkyl or dicarboxyalkyl, optionally substituted with one to three groups selected from amino, araloxycarbonylaminoalkyl, aminoalkyl and cycloalkyl.
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14. The compound of claim 1, wherein X is:
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15. The compound of claim 1, wherein the compound has the formula
wherein X is -
16. The compound of claim 1, wherein X is:
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17. The compound of claim 1, wherein X is:
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27. The compound of claim 1, wherein the compound has formula 1b:
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28. The compound of claim 1, wherein the compound has formula 1c:
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29. The compound of claim 1, wherein the compound has formula 1d:
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30. The compound of claim 1, wherein the compound has formula 1f:
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31. A pharmaceutical composition comprising a compound of claim 1 or 18 in a pharmaceutically acceptable carrier.
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32. A method for inhibiting an action of P-glyocoprotein comprising administering a compound of claim 1 or 18 or a pharmaceutically acceptable derivative thereof.
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33. A method for treatment of taupathy, comprising administering a compound of claim 1 or 18 or a pharmaceutically acceptable derivative thereof.
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34. The method of claim 33, wherein the taupathy is associated with Alzheimer disease, Pick'"'"'s disease, corticobasal degeneration, progressive supranuclear palsy or frontotemporoparietal dementia.
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35. A method for treatment of cancer comprising administering a compound of claim 1 or 18 or a pharmaceutically acceptable derivative thereof.
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36. The method of claim 35, wherein the cancer is non-small cell lung cancer, small cell lung cancer, head and neck squamous cancer, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin'"'"'s lymphoma, brain tumor, cervical cancer, childhood cancer, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, cancer or small-cell lung cancer.
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37. An article of manufacture, comprising packaging material, the compound of claim 1 or 18, or a pharmaceutically acceptable derivative thereof, contained within packaging material, which is used for treatment, prevention or amelioration of one or more symptoms associated with a cancer or taupathy, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of one or more symptoms associated with a cancer or taupathy.
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18. A compound of formula Ia:
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or pharmaceutically acceptable derivative thereof, wherein X is glucosamine, or is NRxRy, where Rx is hydrogen or lower alkyl and Ry is alkyl substituted with one to three substitutents selected from hydroxy, amino, alkylaminocarbonyl, dialkylaminocarbonyl, aralkoxycarbonyl, alkoxycarbonyl, aralkoxycarbonylamino, and heterocyclylaminocarbonyl, wherein the heterocyclyl group contains a 5 to 7 membered ring containing one or two heteroatoms selected from N and O and is optionally substituted with 1 to 4 hydroxy or hydroxyalkyl groups, R3a is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or phenyl; R5a is —
COR7b, —
COOR7b or —
CONHR7b;R7b is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl; and R3a, R5a and R7b are unsubstituted or substituted with 1-4 substituents Q1, wherein each Q1 is independently is halo, pseudohalo, hydroxy, amino, nitro, alkyl, haloalkyl, aminoalkyl, diaminoalkyl, cycloalkyl, heterocycyl, stryl, heteroaryl, aralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aralkyloxycarbonyl or aralkoxycarbonylamino. - View Dependent Claims (19, 20, 21, 22, 23, 24, 25, 26)
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26. The compound of claim 18, wherein the compound has the formula:
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wherein X is;
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Specification