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 15:
or a pharmaceutically acceptable salt thereof;
wherein;
each of A and B independently is —N(R 13 )—, —(C═O)—, or —(C═S)—;
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 10 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; or R 6 and R 10 taken together form a bond;
each of R 11 , R 12 , R 14 and R 15 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; or R 11 and R 12 taken together form a bond; or R 7 and R 14 taken together form a bond;
R 13 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;
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;
provided that when A is —N(R 13 )—; B must be —(C═O)—, or —(C═S)—; and
provided that when A is —(C═O)—, or —(C═S)—; B must be —N(R 13 )—.
2. The compound of claim 1 , wherein A is —N(R 13 )— and B is C═O.
3. The compound of claim 1 , wherein R 11 and R 12 are each H.
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 7 and R 10 are each H.
6. The compound of claim 1 , wherein B is —N(R 13 )— and A is C═O.
7. A compound of formula 21:
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)] pR 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;
R 7 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylseleno, aralkylseleno, arylseleno, alkylthio, aralkylthio, arylthio, heteroaryl, heteroaralkyl, or nitrile;
R 13 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 14 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; or R 7 and R 14 taken together form a bond;
R 20 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[C(R 20 ) 2 ] q —R 21 ; 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;
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
Y is O or S;
and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.
8. The compound of claim 7 , wherein X is —CH 2 —.
9. The compound of claim 7 , wherein said compound has formula 23:
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 ;
R 13 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 20 ) 2 ] q —R 20 ; 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;
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
Y is O or S;
and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.
10. A compound selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
11. A pharmaceutical composition comprising Compound or salt as claimed in claim 1 , and at least one pharmaceutically acceptable excipient.
12. A method of inhibiting activation of a hedgehog pathway in a patient diagnosed with a hyperproliferative disorder, comprising administering to said patient the compound or salt as claimed in claim 1 in an amount sufficient to reduce the activation of the hedgehog pathway in a cell of said patient.
13. The method of claim 12 , wherein said hyperproliferative disorder is cancer.
14. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of the compound or salt as claimed in claim 1 .
15. A method of treating a hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1 , wherein the hematological cancer is selected from multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myelodysplastic syndrome.
16. A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1 , wherein the leukemia is selected from acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia.
17. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1 , wherein the cancer is selected from pancreatic cancer, medulloblastoma, multiple myeloma, myeloid leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, Hodgkin's disease, and acute lymphocytic leukemia.
18. A method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1 .
19. A method of treating chondrosarcoma comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1 .