Azole analogues and methods of use thereof
Disclosed herein are analogues of itraconazole that are both angiogenesis and hedgehog signaling pathway inhibitors, formulations thereof, including liposome formulations thereof. The compounds are expected to be useful in the treatment of cell proliferation disorders such as cancer, particularly cancers that are dependent upon the hedgehog signaling pathway such as basal cell carcinoma and medulloblastoma.
1. A compound having the structure of Formula (I)
wherein
Q is O or CH 2 ;
each Ar is independently unsubstituted or substituted aryl;
R 1 is methyl;
R 2 is unsubstituted or substituted aryl;
R 3 is H or unsubstituted or substituted C 1-6 alkyl;
R 4 is —C(═O)—R 5 , C(═O)—O—R 5 , or —S(═O) n —R 5 , wherein R 5 is C 1-6 alkyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and n is 0, 1, or 2; or R 4 is H or unsubstituted or substituted C 1-6 alkyl; or R 3 and R 4 along with the nitrogen atom form a nitro (NO 2 ) group; or R 3 and R 4 join to form an unsubstituted or substituted 5- or 6-membered ring with the proviso that it does not contain a —N-(=J)-N— moiety where J is O or S;
wherein the substituted groups are substituted with 1, 2, or 3 substituents, each substituent is independently C 1-6 alkyl, halo, —OH, —COOH, cyano, nitro, amine, C 1-6 monoalkylamine, C 1-6 dialkylamine, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkanoyl, or C 1-6 alkoxcarbonyl;
a pharmaceutically acceptable salt, a stereoisomeric form thereof, or a combination thereof.
2. The compound of claim 1 , wherein Q is O; and each Ar is phenyl, pyridine, pyrazine, or pyridazine.
3. The compound of claim 1 , wherein each Ar is phenyl.
4. The compound of claim 1 , wherein R 2 is unsubstituted or substituted phenyl.
5. The compound of claim 1 , wherein is 2,4-dichlorophenyl or 2,4-difluorophenyl.
6. The compound of claim 1 , wherein R 4 is —C(═O)—R 5 or —S(═O) n —R 5 .
7. The compound of claim 6 , wherein R 5 is unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.
8. A compound having the structure of Formula (Ia)
wherein
Q is O or CH 2 ;
each Ar is independently unsubstituted or substituted aryl;
R 1 is methyl;
each R 2a independently is C 1-6 alkyl, halo, —OH, —COOH, cyano, nitro, amine, C 1-6 monoalkylamine, C 1-6 dialkylamine, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkanoyl, or C 1-6 alkoxcarbonyl;
m is 0, 1, 2, or 3;
R 3 is H or unsubstituted or substituted C 1-6 alkyl;
R 4 is —C(═O)—R 5 , —C(═O)—O—R 5 , or —S(═O) n —R 5 , wherein R 5 is C 1-6 alkyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and n is 0, 1, or 2; or R 4 is H or unsubstituted or substituted C 1-6 alkyl; or R 3 and R 4 along with the nitrogen atom form a nitro (NO 2 ) group; or R 3 and R 4 join to form an unsubstituted or substituted 5- or 6-membered ring with the proviso that it does not contain a —N-(=J)-N— moiety where J is O or S;
wherein the substituted groups are substituted with 1, 2, or 3 substituents, each substituent is independently C 1-6 alkyl, halo, —OH, —COOH, cyano, nitro, amine, C 1-6 monoalkylamine, C 1-6 dialkylamine, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkanoyl, or C 1-6 alkoxcarbonyl;
a pharmaceutically acceptable salt, a stereoisomeric form thereof, or a combination thereof.
9. A pharmaceutical composition comprising the compound of claim 1 and optionally a pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9 , wherein the composition is a solid dispersion of the compound and a polymer having acidic functional groups.
11. The pharmaceutical composition of claim 10 , wherein the polymer comprises a polycarboxylic acid.
12. The pharmaceutical composition of claim 10 , wherein the polymer comprises hydroxypropyl methylcellulose phthalate.
13. A method for the therapeutic treatment of a cell proliferation disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of claim 1 .
14. The method of claim 13 , wherein the cell proliferation disorder is dependent upon the Hh signaling pathway.
15. The method of claim 13 , wherein the cell proliferation disorder is a non-cancerous cell proliferation disorder.
16. The method of claim 13 , wherein the cell proliferation disorder is cancer.
17. The method of claim 16 , wherein the cancer is basal cell carcinoma (BCC) or medulloblastoma (MB).
18. The method of claim 16 , wherein the cancer is resistant to Vismodegib.
19. The method of claim 16 , wherein the cancer is chronic myeloid leukemia, lung cancer, prostate cancer, pancreatic cancer or bone cancer.
20. A liposome formulation comprising the compound of claim 1 or a compound having the structure of Formula (II):
wherein
Q is O or CH 2 ;
each Ar is independently unsubstituted or substituted aryl;
J is O or S;
R 10 is methyl;
R 20 is unsubstituted or substituted aryl;
R 30 is H or unsubstituted or substituted C 1-6 alkyl;
R 40 is H or unsubstituted or substituted C 1-6 alkyl; or R 30 and R 40 join to form an unsubstituted or substituted 5- or 6-membered ring with the —N-(=J)-N— moiety where R 30 and R 40 form a unsubstituted or substituted C 2-3 carbohydryl group or a unsubstituted or substituted C 1-2 carbohydryl group linked via a nitrogen to a nitrogen of the —N-(=J)-N— moiety;
R 50 is H, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkanoyl, C 1-6 alkoxcarbonyl, C 1-6 haloalkyl, wherein the substituted C 1-6 alkyl is substituted with 1, 2, or 3 substituents, each substituent is independently C 1-6 alkyl, —OH, —COOH, cyano, nitro, C 1-6 monoalkylamine, C 1-6 dialkylamine, C 1-6 haloalkyl, C 1-6 haloalkoxy;
a pharmaceutically acceptable salt, a stereoisomeric form thereof, or a combination thereof.
21. A method for the therapeutic treatment of a cell proliferation disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the liposome formulation of claim 20 .
22. The method of claim 21 , wherein the cell proliferation disorder is dependent upon the Hh signaling pathway.
23. The method of claim 22 , wherein the cell proliferation disorder is a non-cancerous cell proliferation disorder.
24. The method of claim 22 , wherein the cell proliferation disorder is cancer.
25. The method of claim 24 , wherein the cancer is basal cell carcinoma (BCC) or medulloblastoma (MB).
26. The method of claim 24 , wherein the cancer is resistant to Vismodegib.
27. The method of claim 24 , wherein the cancer is chronic myeloid leukemia, lung cancer, prostate cancer, pancreatic cancer or bone cancer.