C-10 CARBAMATES OF TAXANES

• US 20090306014A1
• Filed: 12/27/2006
• Published: 12/10/2009
• Est. Priority Date: 12/28/2005
• Status: Active Grant

• Current Assignee: Acidophil, LLC, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Acidophil, LLC, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Ballatore, Carlo, Castellino, Angelo J., Sun, Chengzao, Aspland, Simon E., Smith, Amos B. III, Desharnais, Joel
• Granted Patent: US 8,138,361 B2
• Time in Patent Office: Days
• US Class Current: 514/63
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 493/10 Spiro-condensed systems

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.

Claims

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 OR^7a where R^7a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —

COR^7b, —

CONR^7cR^7d or is hydroxyl protecting group, wherein

R^7b is alkyl, afkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and

R^7c and R^7b are each independently selected as follows;

a) R^7c and R^7d are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or

b) R^7c and R^7d together with the nitrogen atom form an optionally substituted 5-7 membered heterocyclic or heteroaryl ring;

R⁹ is ═

O, or —

OR^7a;

X is NK^xR^y, where R^x is hydrogen or alkyl and R^y 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;

R^3a is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R^4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or is hydroxyl protecting group;

R^5a is —

COR^7b, —

COOR^7b, or CONR^7cR^7d; and

R¹, R², R^3a, R^4aR^5a, R^7a, R^7b, R^7c, R^7d, R^y, 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.

2. The compound of claim 1, wherein

R¹ is hydrogen or alkyl;

R² is alkyl or aryl group;

R⁷ is H, OH or alkoxy;

R⁹ is ═

O, OH or alkoxy;

R¹⁴ is hydrogen;

R^3a is alkyl, alkenyl or aryl;

R^4a is hydrogen; and

R^5a is alkoxycarbonyl or arylcarbonyl.

3. The compound of claim 1, wherein R¹ is hydrogen.

4. The compound of claim 1, wherein R² is lower alkyl or aryl.

5. The compound of claim 1, wherein R² is phenyl.

6. The compound of claim 1, wherein R⁷ is hydroxyl.

7. The compound of claim 1, wherein R⁹ is ═

O.

8. The compound of claim 1, wherein R¹⁴ is hydrogen.

9. The compound of claim 1, wherein R^3a is aryl, alkyl, haloalkyl, alkenyl or haloalkenyl.

10. The compound of claim 1, wherein R^3a is phenyl.

11. The compound of claim 1, wherein R^5a is alkoxycarbonyl or arylcarbonyl.

12. The compound of claim 1, wherein R^5a is tert-butyloxycarbonyl or phenylcarbonyl.

13. The compound of claim 1, wherein R^x hydrogen and R^y is carboxyalkyl or dicarboxyalkyl, optionally substituted with one to three groups selected from amino, araloxycarbonylaminoalkyl, aminoalkyl and cycloalkyl.

14. The compound of claim 1, wherein X is:

15. The compound of claim 1, wherein the compound has the formula

wherein X is

16. The compound of claim 1, wherein X is:

17. The compound of claim 1, wherein X is:

27. The compound of claim 1, wherein the compound has formula 1b:

28. The compound of claim 1, wherein the compound has formula 1c:

29. The compound of claim 1, wherein the compound has formula 1d:

30. The compound of claim 1, wherein the compound has formula 1f:

31. A pharmaceutical composition comprising a compound of claim 1 or 18 in a pharmaceutically acceptable carrier.

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.

33. A method for treatment of taupathy, comprising administering a compound of claim 1 or 18 or a pharmaceutically acceptable derivative thereof.

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.

35. A method for treatment of cancer comprising administering a compound of claim 1 or 18 or a pharmaceutically acceptable derivative thereof.

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.

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.

18. A compound of formula Ia:

or pharmaceutically acceptable derivative thereof, wherein X is glucosamine, or is NR^xR^y, where R^x is hydrogen or lower alkyl and R^y 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,

R^3a is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or phenyl;

R^5a is —

COR^7b, —

COOR^7b or —

CONHR^7b;

R^7b is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl; and

R^3a, R^5a and R^7b 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.

19. The compound of claim 18 wherein R^3a is alkyl, alkenyl or aryl;

and R^5a is alkoxycarbonyl or arylcarbonyl.

20. The compound of claim 18, wherein R^3a is aryl or alkyl.

21. The compound of claim 18, wherein R^3a is phenyl.

22. The compound of claim 18, wherein R^5a is alkoxycarbonyl or arylcarbonyl.

23. The compound of claim 18, wherein R^5a is tert-butyloxycarbonyl or phenylcarbonyl.

24. The compound of claim 18, wherein R^x is hydrogen and R^y is hydroxyalkyl, aminoalkyl, dialkylaminocarbonylalkyl, alkyloxycarbonylalkyl, or heterocyclylaminocarbonylalkyl, wherein the heterocyclyl group contains a 5 to 7 membered ring containing one or two heteroatoms that is N or O and is optionally substituted with 1 to 4 hydroxy or hydroxyalkyl groups.

25. The compound of claim 18, wherein X is:

26. The compound of claim 18, wherein the compound has the formula:

wherein X is;