Methods of use of cyclopamine analogs

1. A method for treating a hyperproliferative disorder, the method comprising administering to a subject an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein R 1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R 5 , —N(R 5 )C(O)R 5 , or a sugar;

R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;

or R 1 and R 2 taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR 2 ), or ═C(R) 2 ;

R 3 is H, alkyl, alkenyl, or alkynyl;

R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 5 , —C(O)R 5 , —CO 2 R 5 , —SO 2 R 5 , —C(O)N(R 5 )(R 5 ), —[C(R) 2 ] q —R 5 , —[(W)—N(R)C(O)] q R 5 , —[(W)—C(O)] q R 5 , —[(W)—C(O)O] q R 5 , —[(W)—OC(O)] q R 5 , —[(W)—SO 2 ] q R 5 , —[(W)—N(R 5 )SO 2 ] q R 5 , —[(W)—C(O)N(R 5 )] q R 5 , —[(W)—O] q R 5 , —[(W)—N(R)] q R 5 , —W—NR 5 3 + X − or —[(W)—S] q R 5 ;

wherein each W is, independently, a diradical;

each q is independently for each occurrence 1, 2, 3, 4, 5, or 6;

X − is a halide;

each R is independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

each R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 5 ; wherein p is 0-6; or any two occurrences of R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P; and

each R 6 is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR).

2. The method of claim 1 , wherein when R 2 , R 3 , and R 4 are H; R 1 is not hydroxyl or a sugar; and

when R 4 is hydroxyl, then R 1 is not a sugar or hydroxyl; and

when R 4 is hydroxyl, then R 1 and R 2 together are not C═O.

3. The method of claim 1 , wherein R 1 is sulfonamido.

4. The method of claim 1 , wherein the condition is selected from the group consisting of skin cancers, cancers of the central nervous system, cancers of the gastrointestinal tract, cancers of the pulmonary system, genitourinary cancers, breast cancer, hepatocellular cancer, brain cancers, and cancers of the hematopoietic system.

5. A method of treating a condition mediated by the hedgehog pathway, the method comprising administering to a subject an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein R 1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R 5 , —N(R 5 )C(O)R 5 , or a sugar;

R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;

or R 1 and R 2 taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR 2 ), ═C(R) 2 ;

R 3 is H, alkyl, alkenyl, or alkynyl;

R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 5 , —CO 2 R 5 , —SO 2 R 5 , —C(O)N(R 5 )(R 5 ),—[C(R) 2 ] q —R 5 , —[(W)—N(R)C(O)] q R 5 , —[(W)—C(O)] q R 5 , —[(W)—C(O)O] q R 5 , —[(W)—OC(O)] q R 5 , —[(W)—SO 2 ] q R 5 , —[(W)—N(R 5 ),SO 2 ] q R 5 , —[(W)—C(O)N(R 5 )] q R 5 , —[(W)—O] q R 5 , —[(W)—N(R)] q R 5 , —W—NR 5 3 + X − or —[(W)—S] q R 5 ;

wherein each W is independently for each occurrence a diradical;

each q is independently for each occurrence 1, 2, 3, 4, 5, or 6;

X − is a halide;

each R is independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

each R 5 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 6 ; wherein p is 0-6; or any two occurrences of R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P; and

each R 6 is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOK, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR).

6. The method of claim 5 , wherein when R 2 , R 3 , and R 4 are H; R 1 is not hydroxyl or a sugar; and

when R 4 is hydroxyl, then R 1 is not a sugar or hydroxyl; and

when R 4 is hydroxyl, then R 1 and R 2 together are not C═O.

7. The method of claim 5 wherein R 1 is sulfonamido.

8. The method of claim 5 wherein the condition is small cell lung cancer.

9. The method of claim 5 , wherein the condition is pancreatic cancer.

10. The method of claim 5 , wherein the condition is medulloblastoma.

11. The method of claim 5 , wherein the condition is selected from the group consisting of multiple myeloma, leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, and Hodgkin's disease.

12. The method of claim 5 , wherein the compound is administered orally.

13. The method of claim 5 , wherein the compound is administered intravenously.

14. The method of claim 5 , wherein the compound is administered topically.

15. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein R 1 is H, alkyl, —OR, amino, sulfonamide, sulfamido, —OC(O)R 5 , —N(R 5 )C(O)R 5 , or a sugar;

R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;

or R 1 and R 2 taken together form ═O, ═S, ═N(OR), ═N(R), ═N(NR 2 ), ═C(R) 2 ;

R 3 is H, alkyl, alkenyl, or alkynyl;

R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 5 , —C(O)R 5 , —CO 2 R 5 , —SO 2 R 5 , —C(O)N(R 5 )(R 5 ),—[C(R) 2 ] q —R 5 , —[(W)—N(R)C(O)] q R 5 , —[(W)—C(O)] q R 5 , —[(W)—C(O)O] q R 5 , —[(W)—OC(O)] q R 5 , —[(W)—SO 2 ] q R 5 , —[(W)—N(R 5 )SO 2 ] q R 5 , —[(W)—C(O)N(R 5 )] q R 5 , —[(W)—O] q R 5 , —[(W)—N(R)] q R 5 , —W—NR 5 3 + X − or —[(W)—S] q R 5 ;

wherein each W is independently for each occurrence a diradical;

each q is independently for each occurrence 1, 2, 3, 4, 5, or 6;

X − is a halide;

each R is independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

each R 5 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 6 ; wherein p is 0-6; or any two occurrences of R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P; and

each R 6 is independently hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR).

16. The method of claim 15 , wherein when R 2 , R 3 , and R 4 are H; R 1 is not hydroxyl or a sugar; and

when R 4 is hydroxyl, then R 1 is not a sugar or hydroxyl; and

when R 4 is hydroxyl, then and R 1 and R 2 together are not C═O.

17. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 5 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 15 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound having following structure:

or a pharmaceutically acceptable salt thereof;

wherein R 1 is H, alkyl, —OR, amino, sulfonamido, sulfamido, —OC(O)R 5 ,—N(R 5 )C(O)R 5 , or a sugar;

R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;

or R 1 and R 2 taken together form ═O, ═S, ═N(OR), ═N(R)—, ═N(NR 2 ), ═C(R) 2 ;

R 3 is H, alkyl, alkenyl, or alkynyl;

R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 5 , —C(O)R 5 , —CO 2 R 5 , —SO 2 R 5 , —C(O)N(R 5 )(R 5 ),—[C(R) 2 ] q —R 5 , —[(W)—N(R)C(O)] q R 5 , —[(W)—C(O)] q R 5 , —[(W)—C(O)O] q R 5 , —[(W)—OC(O)] q R 5 , —[(W)—SO 2 ] q R 5 , —[(W)—N(R 5 )SO 2 ] q R 5 , —[(W)—C(O)N(R 5 )] q R 5 , —[(W)—O] q R 5 , —[(W)—N(R)] q R 5 , —W—NR 5 3 + X − , or —[(W)—S] q R 5 ;

wherein each W is, independently, a diradical;

each q is, independently, 1, 2, 3, 4, 5, or 6;

X − is a halide;

each R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R) 2 ] p —R 6 ; wherein p is 0-6; or any two occurrences of R 5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

each R 6 is, independently, hydroxyl, —N(R)COR, —N(R)C(O)OR, —N(R)SO 2 (R), —C(O)N(R) 2 , —OC(O)N(R)(R), —SO 2 N(R)(R), —N(R)(R), —COOR, —C(O)N(OH)(R), —OS(O) 2 OR, —S(O) 2 OR, —OP(O)(OR)(OR), —NP(O)(OR)(OR), or —P(O)(OR)(OR);

wherein each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;

each of R 7 and R 7′ is H; or R 7 and R 7′ taken together form ═O;

R 8 and R 9 are H or R 8 and R 9 taken together form a bond; and

provided that when R 3 , R 4 , R 8 , R 9 are H and, R 7 and R 7′ taken together form ═O; R 1 cannot be hydroxyl and R 2 cannot be H;

provided that when R 3 , R 4 , R 8 , R 9 are H and, R 7 and R 7′ taken together form O; R 1 cannot be acetate and R 2 cannot be H;

provided that when R 3 , R 4 , R 8 , R 9 are H and, R 7 is H 2 ; R 1 and R 2 taken together cannot be ═O; and

provided that when R 3 , R 4 , R 8 , R 9 are H and, R 7 and R 7′ are H; R 1 and R 2 can not cannot be H.

21. The method of claim 20 , wherein R 1 is sulfonamido.

22. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

24. The method of claim 4 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

26. The method of claim 5 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

28. The method of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

29. The method of claim 28 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

30. The method of any one of claim 22 , 24 , 26 or 28 , wherein the compound is administered topically.