Histone deacetylase inhibitors
Compounds that may be used to inhibit histone deacetylase having the formula Z-Q-L-M or Z-L-M wherein M is a substituent capable of complexing with a deacetylase catalytic site and/or a metal ion; L is a substituent providing between 0-10 atoms separation between the M substituent and the remainder of the compound; and Z and Q are as defined herein.
1. A compound consisting of the formula:
Z-Q-L-M
wherein
Z-Q- is selected from the group consisting of
V is selected from the group consisting of C(R 12 ) 2 and NR 12 where only one V is NR 12 ;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, amino, thio, cyano, nitro, and a carbonyl group, each substituted or unsubstituted;
each R 12 is independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, amino, thio, cyano, nitro, and a carbonyl group, each substituted or unsubstituted, with the proviso that when the ring atom to which R 12 is bound is nitrogen, R 12 not halo, cyano, nitro, or thio;
M is selected from the group consisting of trifluoroacetyl (—C(O)—CF 3 ), —NH—P(O)OH—CH 3 , sulfonamides (—SO 2 NH 2 ), hydroxysulfonamides (—SO 2 NHOH), thiols (—SH), and carbonyl groups having the formula —C(O)—R 13 wherein R 13 is hydroxylamino, hydroxyl, amino, alkylamino, and an alkoxy group; and
L is a substituent providing between 2-10 atoms separation between the M substituent and the Q substituent, wherein the 2-10 atoms are all carbon atoms.
2. The compound according to claim 1 , wherein V are selected so that the ring is an N-substituted piperidin-3-yl moiety.
3. The compound according to claim 1 , wherein at least one of R 2 , R 3 , R 4 , or R 5 is fluoro.
4. The compound according to claim 1 , wherein M is selected from the group consisting of:
5. The compound according to claim 1 , wherein M is a hydroxamic acid moiety.
6. A compound according to claim 1 , wherein -L-M is
7. A compound comprising the formula:
Z-Q-L-M
wherein
Z-Q- is selected from the group consisting of
each V is selected from the group consisting of C(R 12 ) 2 and NR 12 where only one V is NR 12 ;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, cyano, and nitro;
each R 12 is independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, amino, thio, cyano, nitro, and a carbonyl group, each substituted or unsubstituted, with the proviso that when the ring atom to which R 12 is bound is nitrogen, R 12 is not halo, cyano, nitro, or thio;
M is selected from the group consisting of trifluoroacetyl (—C(O)—CF 3 ), —NH—P(O)OH—CH 3 , sulfonamides (—SO 2 NH 2 ), hydroxysulfonamides (—SO 2 NHOH), thiols (—SH), and carbonyl groups having the formula —C(O)—R 13 wherein R 13 is hydroxylamino, hydroxyl, amino, alkylamino, and an alkoxy group; and
L is selected from the group consisting of (E) isomer of —CH═CH—, (Z) isomer of —CHCH—, and mixtures of(E) and (Z) isomers of —CH═CH—.
8. The compound according to claim 7 , wherein V are selected so that the ring is an N-substituted piperidin-3-yl moiety.
9. The compound according to claim 7 wherein at least one of R 2 , R 3 , R 4 , or R 5 is fluoro.
10. The compound according to claim 7 , wherein M is selected from the group consisting of:
11. The compound according to claim 7 , wherein M is a hydroxamic acid moiety.
12. The compound according to claim 7 , wherein -L-M is
13. The compound according to claim 1 , wherein M is
14. The compound according to claim 1 , wherein M is
15. The compound according to claim 1 , wherein M is
16. The compound according to claim 1 , wherein M is
17. The comnound according to claim 1 , wherein M is
18. The compound according to claim 1 , wherein M is
19. The compound according to claim 1 , wherein M is
20. The compound according to claim 1 , wherein M is
21. The compound according to claim 1 , wherein M is
22. The compound according to claim 1 , wherein M is
23. The compound according to claim 7 , wherein M is
24. The compound according to claim 7 , wherein M is
25. The compound according to claim 7 , wherein M is
26. The compound according to claim 7 , wherein M is
27. The compound according to claim 7 , wherein M is
28. The compound according to claim 7 , wherein M is
29. The compound according to claim 7 , wherein M is
30. The compound according to claim 7 , wherein M is
31. The compound according to claim 7 , wherein M is
32. The compound according to claim 7 , wherein M is
33. The compound according to claim 1 , wherein -L-M is