Itraconazole analogues and methods of use thereof
Disclosed herein are analogs of itraconazole that are both angiogenesis and hedgehog signaling pathway inhibitors. The compounds are expected to be useful in the treatment of 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 or heteroaryl;
J is O or S;
R 1 is C 1-6 alkyl optionally substituted with an amino, a C 1-6 alkylamino, a C 1-6 dialkylamino, an N-acylamino, —COOH, an aryl, a heterocycloalkyl, pyrrolidine or pyrrole, group;
R 2 is C 1-6 alkyl or unsubstituted or substituted aryl;
R 3 is H or unsubstituted or substituted C 1-6 alkyl;
R 4 is H or unsubstituted or substituted C 1-6 alkyl; or R 3 and R 4 join to form an unsubstituted or substituted 5- or 6-membered ring with the —N-(=J)-N— moiety where R 3 and R 4 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 5 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.
2. The compound of claim 1 , wherein Q is O; each Ar is phenyl, pyridine, pyrazine, or pyridazine; and J is O.
3. The compound of claim 1 , wherein each Ar is phenyl.
4. The compound of claim 1 , wherein R 1 is methyl optionally substituted with, 1-pyrrole, phenyl, m-aminophenyl, p-aminophenyl, acetylamine, 1-pyrrolidine, amino, or dimethylamino; and R 2 is unsubstituted or substituted phenyl.
5. The compound of claim 1 , wherein R 1 is methyl and R 2 is 2,4-dichlorophenyl or 2,4-difluorophenyl.
6. The compound of claim 1 , wherein R 3 and R 4 join to form an unsubstituted or substituted 5- or 6-membered ring with the —N-(=J)-N— moiety where R 3 and R 4 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.
7. The compound of claim 1 , wherein R 5 is propyl; 2′-sec-butyl, the R isomer, the S isomer, a racemate or any enantiomerically enriched form; 2-hydroxypentan-3-yl, the 2R,3R-isomer, the 2S,3S, isomer, the 2R,3S, isomer, the 2S,3R isomer, or any diastereomerically enriched form; 2-hydroxyprop-2-yl; or 2-hydroxyprop-1-yl, the R isomer, the S isomer, a racemate, or any enantiomerically enriched form.
8. The compound of claim 1 , having the Formula (Ia)
wherein
each one of X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 independently is CH, CCH 3 , or N.
9. The compound of claim 8 , wherein in Formula (Ia)
X 1 is N and Y 1 , Z 1 , X 2 , Y 2 , and Z 2 are CH;
Y 1 is N and X 1 , Z 1 , X 2 , Y 2 , and Z 2 are CH;
X 1 and Y 1 are N and Z 1 , X 2 , Y 2 , and Z 2 are CH;
X 1 and Z 1 are N and Y 1 , X 2 , Y 2 , and Z 2 are CH;
X 2 is N and X 1 , Y 1 , Z 1 , Y 2 , and Z 2 are CH;
Y 2 is N and X 1 , Y 1 , Z 1 , X 2 , and Z 2 are CH;
X 2 and Y 2 are N and X 1 , Y 1 , Z 1 , and Z 2 are CH; or
X 2 and Z 2 are N and X 1 , Y 1 , Z 1 , and Y 2 are CH.
10. The compound of claim 1 , having Formula (Ib)
wherein
R 6 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkanoyl, C 1-6 alkoxcarbonyl, —NH 2 , —OH, —COOH, cyano, nitro, C 1-6 monoalkylamine, C 1-6 dialkylamine, C 1-6 haloalkyl, or C 1-6 haloalkoxy.
11. The compound of claim 10 , wherein R 6 and R 7 are each independently Cl or F.
12. The compound of claim 1 , which is
13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.