Cyclopamine lactam analogs and methods of use thereof
The present invention relates to steroidal alkaloids useful in the treatment of hedgehog pathway related disorders, particularly cancer.
1. A compound of Formula 1:
or a pharmaceutically acceptable salt thereof;
wherein;
R 1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxyl, —SR 20 , —OR 20 , —N(R 20 )(R 20 ), —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —N(R 20 )S(O) 2 R 20 , —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , —[(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 ;
each of R 2 , R 7 and R 13 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxyl, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylseleno, aralkylseleno, arylseleno, alkylthio, aralkylthio, arylthio, heteroaryl, or heteroaralkyl;
R 3 is H; or R 2 and R 3 taken together form a bond;
each of R 4 and R 5 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl; or R 4 and R 5 taken together form ═O, ═S, ═N(R 20 ), ═N—OR 20 or ═N(N(R 20 ) 2 );
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl;
each of R 8 and R 12 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; or R 7 and R 8 taken together form a bond; or R 12 and R 13 taken together form a bond each of R 9 and R 16 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, heteroaryl, or heteroaralkyl; or R 9 and R 10 taken together form ═O, ═N(R 20 ), ═N—OR 20 , or ═S; R 11 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, —C(O)R 20 , —C(S)R 20 , —CO 2 R 20 , —SO 2 R 20 , —C(O)N(R 20 )(R 20 ), or —C(S)N(R 20 )(R 20 ); or has the formula) —[C(R 20 ) 2 ] q —R 21 ;
R 20 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[C(R) 2 ] q —R 21 , where each R is independently H or C1-C6 alkyl; or any two occurrences of R 20 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;
R 21 independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl; alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or a carbonyl-containing group;
R 22 independently for each occurrence is H, halide, ester, amide, or nitrile;
p is 0, 1, 2, 3, 4, 5, or 6;
q is 0, 1, 2, 3, 4, 5, or 6;
W is a diradical;
X is a bond or —C(R 22 ) 2 —;
and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.
2. The compound of claim 1 , wherein R 7 , R 8 , R 12 and R 13 are H.
3. The compound of claim 1 , wherein R 4 and R 5 are both H; or R 4 and R 5 taken together form ═O.
4. The compound of claim 1 , wherein R 2 and R 3 taken together form a bond.
5. The compound of claim 1 , wherein R 9 and R 10 are each H; or R 9 and R 10 taken together form ═O or ═S.
6. The compound of claim 4 , wherein R 4 and R 5 are both H.
7. The compound of claim 4 , wherein R 9 and R 10 taken together form ═O or ═S.
8. The compound of claim 4 , wherein R 7 , R 8 , R 12 and R 13 are H.
9. A compound of formula 9:
or a pharmaceutically acceptable salt thereof;
wherein;
R 1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxyl, —SR 20 , —OR 20 , —N(R 20 )(R 20 ), —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —N(R 20 )S(O) 2 R 20 , —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , —[(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 ;
each of R 4 and R 5 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl; or R 4 and R 5 taken together form ═O, ═S, ═N(R 20 ), ═N—OR 20 , or ═N(N(R 20 ) 2 );
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl;
each of R 9 and R 10 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, heteroaryl, or heteroaralkyl; or R 9 and R 10 taken together form ═O, ═N(R 20 ), ═N—OR 20 , or ═S;
R 11 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, —C(O)R 20 , —C(S)R 20 , —CO 2 R 20 , —SO 2 R 20 , —C(O)N(R 20 )(R 20 ), or —C(S)N(R 20 )(R 20 ); or has the formula) —[C(R 20 ) 2 ] q —R 21 ;
R 20 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[C(R) 2 ] q —R 21 , where each R is independently H or C1-C6 alkyl; or any two occurrences of R 20 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;
R 21 independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl; alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group; and
p is 0, 1, 2, 3, 4, 5, or 6;
q is 0, 1, 2, 3, 4, 5, or 6;
W is a diradical;
X is a bond or —CH 2 —;
and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.
10. The compound of claim 9 , wherein X is —CH 2 —.
11. The compound of claim 9 , wherein R 6 is H or alkyl.
12. The compound of claim 9 , wherein R 1 is H, optionally substituted C1-C6 alkyl, C(O)R 20 , SO 2 R 20 , or it is COOR 20 .
13. The compound of claim 9 , wherein R 9 and R 10 taken together form ═O or ═S.
14. A compound selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and at least one pharmaceutically acceptable excipient.
16. A method of treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute myelocytic leukemia, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, breast cancer, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, glioma, hepatocellular cancer, Hodgkin's disease, leukemia, lung cancer, medulloblastoma, melanoma, multiple myeloma, myelodysplastic syndrome, neuroectodermal tumors, non-Hodgkin's type lymphoma, osteogenic sarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and testicular cancer.
17. The method of claim 16 , wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, basal cell carcinoma, breast cancer, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, esophageal cancer, gastric cancer, glioma, hepatocellular cancer, lung cancer, medulloblastoma, multiple myeloma, non-Hodgkin's type lymphoma, osteogenic sarcoma, ovarian cancer, pancreatic cancer, and prostate cancer.
18. The method of claim 16 , wherein the cancer is pancreatic cancer.
19. The method of claim 16 , wherein the cancer is chondrosarcoma.
20. The method of claim 16 , wherein the cancer is lung cancer.
21. The method of claim 20 , wherein the lung cancer selected from the group consisting of small cell lung cancer and non- small cell lung cancer.
22. The method of claim 16 , wherein the cancer is basal cell carcinoma.
23. The method of claim 16 , wherein the cancer is medulloblastoma.
24. The method of claim 16 , wherein the cancer is ovarian cancer.
25. The method according to claim 16 , wherein the cancer is osteogenic sarcoma.
26. The method of claim 16 , wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's disease, leukemia, multiple myeloma, myelodysplastic syndrome, and non-Hodgkin's type lymphoma.
27. The method of claim 16 , wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia.
28. The method of claim 16 , wherein the compound or pharmaceutically acceptable salt thereof is used in combination with one or more chemotherapeutic or other anti-cancer agent.
29. The method of claim 28 , wherein the other anti-cancer agent is radiation.
30. The method of claim 16 , wherein the compound is administered locally to a tumor.
31. The method of claim 16 , wherein the compound is administered systemically.
32. The method of claim 16 , wherein the mode of administration of said compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intraperitoneal, epidural, subcutaneous, buccal, or nasal.
33. The method of claim 32 , wherein the mode of administration is oral, intravenous, or topical.
34. A method of inhibiting activation of a hedgehog pathway in a patient diagnosed with a hyperproliferative disorder, comprising administering to the patient a compound , or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in an amount sufficient to reduce the activation of the hedgehog pathway in a cell of the patient.
35. The method of claim 19 , wherein said hyper proliferative disorder is cancer.
36. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound , or a pharmaceutically acceptable salt thereof, as claimed in claim 1 .