Histone deacetylase (HDAC) inhibitors targeting prostate tumors and methods of making and using thereof
Compounds of Formula (I), and methods of making and using thereof, are described herein; wherein AR is an aryl group, ZBG is a Zinc Binding Group, and other substituents are as defined herein. The compounds can be administered as a pharmaceutically acceptable salt, prodrug, or solvate. The compounds may be useful to treat and/or prevent hyperproliferative disorders which may include hormone sensitive and hormone refractory prostate cancers. The compounds can be formulated with a pharmaceutically acceptable carrier and, optionally one or more pharmaceutically acceptable excipients, for enteral or parenteral administration.
1. A compound of Formula I:
wherein:
AR is an aryl group or covalent bond;
B′ is absent or consists of a C 1-6 group, optionally containing one or more heteroatoms, wherein the carbon atoms and/or heteroatoms are in a linear arrangement;
A is a linking group connected to AR, wherein A is selected from the group consisting of:
B is C 1 -C 11 linear alkyl optionally containing one or more double or triple bonds and/or —CH 3 and/or CH 2 CH 3 branching;
ZBG is selected from the group consisting of
R 1 and R 2 are independently selected from of hydrogen or C 1 to C 8 alkyl or together form a group comprising 3-8 carbon atoms that is selected from cycloalkyl or substituted cycloalkyl;
R 3 is H or a salt counter ion;
R 4 is acyl or alkyl;
R 5 is alkyl; and
R 6 and R 7 are independently H or alkyl;
W is selected from the group consisting of O and S;
X is selected from the group consisting of cyano and nitro;
Y is selected from the group consisting of trifluoromethyl and iodo;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein B′ is absent.
3. The compound of claim 1 , wherein B′ is C1 to C6 linear alkyl.
4. The compound of claim 1 , wherein AR is a covalent bond.
5. The compound of claim 1 , wherein AR is selected from the group consisting of:
where
indicates optional connecting points to A and B′, or to A and the nitrogen atom of the hydantoin group when B′ is absent.
6. The compound of claim 1 , wherein B is C1 to C8 linear alkyl.
7. The compound of claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of H and C1 to C8 alkyl; or R 1 and R 2 together form a C3 to C8 cycloalkyl.
8. The compound of claim 1 , wherein:
B′ is present or absent, and when present is C1 to C6 linear alkyl;
AR is an aryl group or covalent bond, and when an aryl group, and when present is selected from the group consisting of:
where
indicates optional connecting points to A and B′, or to A and the nitrogen atom of the hydantoin group when B′ is absent;
A is selected from the group consisting of:
B is C1 to C8 linear alkyl;
ZBG is selected from the group consisting of
R 1 and R 2 are each independently selected from the group consisting of H and C1 to C8 alkyl;
or R 1 and R 2 together form a C3 to C8 cycloalkyl;
R 3 is H or a salt counter ion;
R 4 is acyl or alkyl;
R 5 is alkyl; and
R 6 and R 7 are independently H or alkyl.
9. The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
10. The compound of claim 1 , wherein ZBG is hydroxamic acid.
11. The compound of claim 1 , wherein ZBG is hydroxamic acid and W is S.
12. A pharmaceutical composition comprising an effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable diluent, excipient, or carrier.
13. A method of treating prostate cancer in a human or animal subject comprising administering said subject an effective amount of a compound of claim 1 .
14. The method of claim 13 , wherein ZBG is hydroxamic acid.
15. The method of claim 13 , wherein and ZBG is hydroxamic acid and W is S.
16. The method of claim 13 , wherein the prostate cancer is selected from hormone sensitive prostate cancer and hormone refractory prostate cancer.
17. The method of claim 13 , wherein the compound is administered enterally or parenterally.