Itraconazole analogues and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9839636-B2
Application number	US-201715481542-A
Country	US
Kind code	B2
Filing date	Apr 7, 2017
Priority date	Feb 1, 2014
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

Disclosed herein are analogues 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.

First claim

The invention claimed is:

1. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of Formula (I)

wherein
Q is O or CH 2 ;
each Ar is independently unsubstituted or substituted aryl;
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, pyrrole, or pyridinyl group;
R 2 is C 1-6 alkyl or unsubstituted or substituted aryl or heteroaryl;
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 method of claim 1 , wherein in Formula (I) Q is O; each Ar is phenyl, pyridine, pyrazine, or pyridazine; and J is O.

3. The method of claim 1 , wherein in Formula (I) each Ar is phenyl.

4. The method of claim 1 , wherein in Formula (I) R 1 is methyl optionally substituted with 1-pyrrole, 3-pyridine, 4-pyridine, phenyl, m-aminophenyl, p-aminophenyl, acetylamine, 1-pyrrolidine, amino, or dimethylamino; and R 2 is unsubstituted or substituted phenyl.

5. The method of claim 1 , wherein in Formula (I) R 1 is methyl and R 2 is 2,4-dichlorophenyl or 2,4-difluorophenyl.

6. The method of claim 1 , wherein in Formula (I) 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 method of claim 1 , wherein in Formula (I) 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 method of claim 1 , wherein the compound has 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 method 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 method of claim 1 , wherein the compound has 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 method of claim 10 , wherein R 6 and R 7 are each independently Cl or F.

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

13. The method of claim 1 , wherein the cancer is dependent upon the Hh signaling pathway.

14. The method of claim 13 , wherein the cancer is basal cell carcinoma (BCC) or medulloblastoma (MB).

15. The method of claim 13 , wherein the cancer is resistant to Vismodegib.

16. The method of claim 1 , wherein the cancer is chronic myeloid leukemia, lung cancer, prostate cancer, pancreatic cancer or bone cancer.

Assignees

• Univ Connecticut

Inventors

• Hadden Matthew Kyle
• Banerjee Upasana

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title