Histone deacetylase inhibitors
View Patent ↗This invention relates to hydroxamic acid derivatives having a urea linkage, 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 system (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 and R 2 are, independently of each other, unsubstituted or substituted and selected from C 1 -C 10 alkyl, 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 and C 1 -C 10 alkylheteroaryl; and
R 3 , R 4 and R 5 are independently hydrogen or C 1 -C 10 alkyl; or
R 2 and R 5 together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic ring;
X is O or S; and
n is 5 or 6;
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.
3. The compound according to claim 1 , wherein R 1 and R 2 are, independently of each other, unsubstituted or substituted and selected from phenyl, naphthyl, fluorenyl, biphenyl, benzyl, —CH 2 CH 2 Ph, —CH 2 CH 2 CH 2 Ph, cyclopropyl, cyclohexyl, thiazolyl, phenylthiazolyl, quinolinyl, isoquinolinyl, —CH 2 -quinolinyl, —CH 2 -isoquinolinyl, CH(Ph) 2 and C 1 -C 10 alkyl.
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.
5. The compound according to claim 1 , wherein R 3 , R 4 and R 5 are independently hydrogen.
6. The compound according to claim 1 , represented by the structure of formula IA:
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , X and n 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 , R 3 , R 4 , R 5 , X 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;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 , wherein R 2 is substituted or unsubstituted phenyl, naphthyl, fluorenyl, biphenyl, benzyl, —CH 2 CH 2 Ph, —CH 2 CH 2 CH 2 Ph, cyclopropyl, cyclohexyl, thiazolyl, phenylthiazolyl, CH(Ph) 2 , cycloalkyl and C 1 -C 4 alkyl, wherein said optional substituent comprises one, two or three groups 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.
9. The compound according to claim 1 , represented by the structure of formula IIA:
wherein
R 2 , R 3 , R 4 , R 5 , X and n are as defined in claim 1 ;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 , wherein R 2 and R 5 together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic ring.
11. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
12. A compound which is selected from:
(S)-2-(3-Phenyl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Benzyl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Phenethyl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(3-Chloro-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(3-Trifluoromethyl-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Bromo-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Methoxy-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Trifluoromethyl-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(2-Phenyl-cyclopropyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Cyclohexyl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Naphthalen-1-yl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Nitro-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Phenoxy-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(3-Chloro-4-methyl-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Isopropyl-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Trifluoromethoxy-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Biphenyl-4-yl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-tert-Butyl-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(3-Phenoxy-phenyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(9H-Fluoren-2-yl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Benzhydryl-ureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(2-Biphenyl-4-yl-ethyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-{3-[2-(3,4-Dimethoxy-phenyl)-ethyl]-ureido}-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(3-Phenyl-propyl)-ureido]-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-(3-Phenyl-ureido)-octanedioic acid 8-hydroxyamide 1-[(4-phenyl-thiazol-2-yl)-amide];
(S)-2-(3-Benzyl-ureido)-octanedioic acid 8-hydroxyamide 1-[(4-phenyl-thiazol-2-yl)-amide];
(S)-2-(3-Phenethyl-ureido)-octanedioic acid 8-hydroxyamide 1-[(4-phenyl-thiazol-2-yl)-amide];
(S)-2-[3-(3-Phenyl-propyl)-ureido]-octanedioic acid 8-hydroxyamide 1-[(4-phenyl-thiazol-2-yl)-amide];
(S)-2-(3-Phenyl-thioureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
(S)-2-[3-(4-Methoxy-phenyl)-thioureido]-octanedioic acid 8-hydroxyamide 1-phenylamide; and
(S)-2-(3-tert-Butyl-thioureido)-octanedioic acid 8-hydroxyamide 1-phenylamide;
or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
13. The compound according to claim 12 that is 2-[(Piperidine-1-carbonyl)-amino]-octanedioic acid 8-hydroxyamide 1-phenylamide, or a stereoisomer, enantiomer, racemate, or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 12 , and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 13 , and a pharmaceutically acceptable carrier.