Histone deacetylase inhibitors
View Patent ↗The invention relates to hydroxamic acid derivatives having carbamate linkage with the structural formula that are inhibitors of histone deacetylase (HDAC), and are useful in the prevention and/or treatment of cellular proliferative diseases, for example cancer, autoimmune, allergic and inflammatory diseases, diseases of the central nervous systems (CNS) such as neurodegenerative diseases, and in the prevention and/or treatment of restenosis.
1. A compound represented by the following structural formula:
wherein
R 1 is unsubstituted or substituted and selected from phenyl, thiazolyl, C 2 -C 10 alkenyl, cycloalkyl, C 1 -C 10 alkyl-C 2 -C 10 alkenyl, C 1 -C 10 alkylcycloalkyl, C 1 -C 10 alkylheterocyclyl and C 1 -C 10 alkylheteroaryl;
R 2 is unsubstituted or substituted and selected from C 2 -C 10 alkenyl, cycloalkyl, heterocyclyl, heteroaryl, C 1 -C 10 alkyl-C 2 -C 10 alkenyl, C 1 -C 10 alkylcycloalkyl, C 1 -C 10 alkylheterocyclyl and C 1 -C 10 alkylheteroaryl;
R 3 and R 4 are independently hydrogen or C 1 -C 10 alkyl; and
n is 4-7;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 1 and R 2 are, independently of each other, unsubstituted or substituted with one, two or three substitutents selected from R sub ;
wherein
R sub is independently selected from C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 10 alkyl-C 2 -C 10 alkenyl, C 1 -C 10 alkylcycloalkyl, C 1 -C 10 alkylaryl, C 1 -C 10 alkylheterocyclyl, C 1 -C 10 alkylheteroaryl, halogen, hydroxy, C 1 -C 10 alkyloxy, C 1 -C 10 haloalkyloxy, aryloxy, nitro, oxo, —CN, —C(═O)H, —C(═O)OH, amino, N—C 1 -C 10 alkylamino, N,N-di C 1 -C 10 alkylamino, N-arylamino, N,N-diarylamino, N—C 1 -C 10 alkyl-N-arylamino, azido, and C(═O)OR wherein R is aryl or C 1 -C 10 alkyl;
and all other substituents and variables are as defined in claim 1 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein R 2 is unsubstituted or substituted and selected from cyclopropyl, cyclohexyl, thiazolyl, morpholinyl, and pyrrolidinyl;
and all other substituents and variables are as defined in claim 1 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein R 1 and R 2 are, independently of each other, unsubstituted or substituted with one, two or three substitutents selected from R sub ;
wherein
R sub is independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkyloxy, C 1 -C 4 alkyloxy, aryl, halogen and nitro;
and all other substituents and variables are as defined in claim 3 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , wherein R 3 and R 4 are hydrogen.
6. The compound according to claim 1 , represented by the structure of formula IA:
wherein
n is 5 or 6;
and all other substituents and variables are as defined in claim 1 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , represented by the structure of formula II:
wherein
R 2 and n are as defined in claim 1 ;
R sub is independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkyloxy, C 1 -C 4 alkyloxy, aryl, halogen and nitro; and
m is selected from 0, 1, 2 and 3;
and all other substituents and variables are as defined in claim 1 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 , represented by the structure of formula IIA:
wherein
n is 5 or 6;
and all other substituents and variables are as defined in claim 7 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
10. A compound which is selected from:
(S)-[6-Hydroxycarbamoyl-1-(4-phenyl-thiazol-2-ylcarbamoyl)-hexyl]-carbamic acid benzyl ester;
(S)-[6-Hydroxycarbamoyl-1-(4-phenyl-thiazol-2-ylcarbamoyl)-hexyl]-carbamic acid tert-butyl ester; and
(S)-(6-Hydroxycarbamoyl-1-phenylcarbamoyl-hexyl)-carbamic acid tert-butyl ester;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
11. A compound which is selected from:
(6-Hydroxycarbamoyl-1-phenylcarbamoyl-hexyl)-carbamic acid 2-morpholin-4-yl-ethyl ester;
(6-Hydroxycarbamoyl-1-phenylcarbamoyl-hexyl)-carbamic acid 2-pyridin-2-yl-ethyl ester; and
(6-Hydroxycarbamoyl-1-phenylcarbamoyl-hexyl)-carbamic acid 2-pyrrolidin-1-yl-ethyl ester;
or a stereoisomer or pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 10 , and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 11 , and a pharmaceutically acceptable carrier.