Histone deacetylase inhibitors

A compound of general formula (B1)

• in which:
• R1 is (C6 or C10) aryl, (C6 or C10) arylalkyl, a 6- or 10-membered ring system having one or more heteroatoms in the ring, (C6 or C10) heteroaryl, (C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl or a combination thereof to form a linked or fused ring system, the cyclic moiety being optionally substituted with (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10)alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, or (C1-C10) alkylsulfonyl,
• R3 is hydrogen, (C1-C12) alkyl, substituted (C1-C12) alkyl, or unsaturated (C2-C12) comprising one or more C═C bond or C≡C bond, (C6 or C10) aryl or (C6 or C10) heteroaryl, or a combination thereof to form a linked or fused ring system, or (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, cyano, nitro, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, or (C1-C10) alkylsulfonyl, in which the saturated or an unsaturated hydrocarbon chain is optionally interrupted by O, S, NR, CO, C(NR), N(R)SO2, SO2N(R), N(R)C(O)O, OC(O)N(R), N(R)C(O)N(R), OC(O), C(O)O, OSO2, SO2O, or OC(O)O, where R is independently hydrogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) hydroxylalkyl, hydroxyl, (C1-C10) halolalkyl, where each of the saturated or unsaturated hydrocarbon chains are optionally substituted with (C1-C10)alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, hydroxyl, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, amino, (C1 -C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, or (C1-C10) alkylsulfonyl,
• n is equal to 0, 1 or 2;
• X is hydroxyl (—OH), —OR, NHR, hydroxamate (—NHOH), NHOR, NROR, NRNHR, or SR, where each R is independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl;
• and
• Y is 0, 1 or 2 oxygen atoms;
• and
• Z is a one atom linkage of N, CH, or CR or a two-atom linkage of varying combinations of atoms of CH, CR, O, N, S, SO, SO2, wherein R is C1-C6 alkyl or substituted C1-C6 alkyl.

A compound of general formula:

• in which:
• R14 is hydrogen or (C1-C6)alkyl;
• n is equal to 1 or 2;
• and
• X is hydroxyl (—OH), —OR, or hydroxamate (—NHOH), where R is hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl.

A compound of general formula (C)

• in which:
• R3 is hydrogen, (C1-C12) alkyl, substituted (C1-C12) alkyl, or unsaturated (C2-C12) comprising one or more C═C bond or C≡C bond, (C6 or C10) aryl or (C6 or C10) heteroaryl, or a combination thereof to form a linked or fused ring system, or (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, cyano, nitro, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, or (C1-C10) alkylsulfonyl, in which the saturated or an unsaturated hydrocarbon chain is optionally interrupted by O, S, NR, CO, C(NR), N(R)SO2, SO2N(R), N(R)C(O)O, OC(O)N(R), N(R)C(O)N(R), OC(O), C(O)O, OSO2, SO2O, or OC(O)O, where R is independently hydrogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) hydroxylalkyl, hydroxyl, (C1-C10) halolalkyl, where each of the saturated or unsaturated hydrocarbon chains are optionally substituted with (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, hydroxyl, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, amino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, or (C1-C10) alkylsulfonyl;
• n is equal to 0, 1 or 2;
• X is hydroxyl (—OH), —OR, NHR, hydroxamate (—NHOH), NHOR, NROR, NRNHR, or SR, where each R is independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl;
• Y is 0, 1 or 2 oxygen atoms;
• and
• R4 and R5 are each independently hydrogen, unsubstituted or substituted C1-C10 alkyl, an unsaturated hydrocarbon chain of up to ten carbon atoms comprising one or more carbon-carbon double bonds, C6 or C10 aryl, a 5-to 10-membered heterocyclic group, C1-C10 alkoxy, C1-C10 thioalkoxy, hydroxyl, halo, cyano, nitro, amino, amido, (C1-C10 alkyl)carbonyloxy, (C1-C10 alkoxy)carbonyl, (C1-C10 alkyl)carbonyl, (C1-C10 alkyl)thiocarbonyl, (C1-C10 alkyl)suflonylamino, aminosulfonyl, C1-C10 a alkylsulfinyl, C1-C10 alkylsulfonyl, or a saturated or unsaturated C3-C12 hydrocarbon chain interrupted by O, S, NR, CO, C(NR), N(R)SO2, SO2N(R), N(R)C(O)O, OC(O)N(R), N(R)C(O)N(R), OC(O), C(O)O, OSO2, SO2O or OC(O)O, where R is as defined above and the saturated or unsaturated hydrocarbon chain is optionally substituted as defined above.

A compound of general formula (Ia)

• wherein:
• R2 and R3 are both Hydrogen (H);
• Y is two oxygen atoms;
• n is 1;
• R1 is
• and
• X is —OH, —CH3, —OC2H5 or NHOH.

A compound of general formula (B)

• wherein:
• R2 and R3 are both methyl (CH3);
• Y is zero oxygen atoms;
• R1 is
• and
• X is —OCH3, —OC2H5 or —OH.

A compound which is:

• 6-(4-Dimethylamino-phenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (6d),
• 6-(4-Methoxy-phenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (6e),
• 6-(4-Chloro-phenylsulfanyl)-hexa-2,4-dienoic acid hydroxyamide (7b),
• 6-(4-Dimethylamino-phenylsulfanyl)-hexa-2,4-dienoic acid hydroxyamide (7c),
• 6-(4-Chloro-benzenesulfinyl)-hexa-2,4-dienoic acid methyl ester (8c),
• 6-(4-Methoxy-benzenesulfinyl)-hexa-2,4-dienoic acid methyl ester (8c),
• 6-Benzenesulfinyl-hexa-2,4-dienoic acid (8d),
• 6-(4-Chloro-benzenesulfinyl)-hexa-2,4-dienoic acid hydroxyamide (9a),
• 6(4-Methoxy-benzenesulfinyl)-hexa-2,4-dienoic acid hydroxyamide (9b),
• 6-Benzenesulfonyl-hexa-2,4-dienoic acid (10a),
• 6-Benzenesulfonyl-hexa-2,4-dienoic acid methyl ester (10b),
• 6-Benzenesulfonyl-hexa-2,4-dienoic acid hydroxyamide (11a),
• 6-(Naphthalen-2-ylsulfanyl)-hexa-2,4-dienoic acid methyl ester (13b),
• 6-(Naphthalen-2-ylsulfanyl)-hexa-2,4-dienoic acid hydroxyamide (14a),
• 4-(4-Dimethylamino-phenylsulfanyl)-2-methyl-pent-2-dienoic acid methyl ester (21b),
• 6-(4-Dimethylamino-phenylsulfanyl)-4-methyl-hepta-2,4-dienoic acid ethyl ester (24c),
• 6-(4-Dimethylamino-phenylsulfanyl)-4-methyl-hepta-2,4-dienoic acid hydroxyamide (25c)
• 6-(4-Chloro-phenylsulfanyl)-hexanoic acid methyl ester (28b),
• 7-(4-Chloro-phenylsulfanyl)-heptanoic acid ethyl ester (28c),
• 6-(4-Dimethylamino-phenylsulfanyl)-hexanoic acid methyl ester (28e),
• 6-(4-((4-Chlorobenzyl)-methylamino)-phenylsulfanyl)-hexanoic acid methyl ester (28f),
• 6-(4-(4-Chlorobenzenesulfonylamino)-phenylsulfanyl)-hexanoic acid methyl ester (28g),
• 6-(4-Bromo-phenylylsulfanyl)-hexanoic acid methyl ester (28h),
• 6-(4′-Chloro-biphenyl-4-ylsulfanyl)-hexanoic acid methyl ester (28i),
• 6-(4-Chloro-phenylsulfanyl)-hexanoic acid hydroxyamide (29b),
• 6-(4-Dimethylamino-phenylsulfanyl)-hexanoic acid hydroxyamide (29c),
• 6-(4-(4-Chlorobenzenesulfonylamino)-phenylsulfanyl)-hexanoic acid hydroxamide (29g),
• 6-(4′-Chloro-biphenyl-4-ylsulfanyl)-hexanoic acid hydroxamide (29 i),
• 6-(4-Chloro-benzenesulfinyl)-hexanoic acid methyl ester (30b),
• 7-(4-Chloro-benzenesulfinyl)-heptanoic acid ethyl ester (30c),
• 6-(4-Dimethylamino-benzenesulfinyl)-hexanoic acid methyl ester (30e),
• 6-(4-((4-Chlorobenzyl)-methylamino)-benzenesulfinyl)-hexanoic acid methyl ester (30f),
• 6-(4′-Chloro-biphenyl-4-ylsulfinyl)-hexanoic acid methyl ester (30i),
• 6-(4-Chloro-benzenesulfinyl)-hexanoic acid hydroxyamide (31a),
• 7-(4-Chloro-benzenesulfinyl)-heptanoic acid hydroxyamide (31c),
• 6-(4-Dimethylamino-benzenesulfinyl)-hexanoic acid hydroxyamide (31e),
• 6-(4-((4-Chlorobenzyl)-methylamino)-benzenesulfinyl)-hexanoic acid hydroxamide (31f)
• 6-(4′-Chloro-biphenyl-4-sulfinyl)-hexanoic acid hydroxyamide (31i),
• (2E,4E)-5 -(5-Dimethylamino-benzo[b]thiophen-2-yl)-penta-2,4-dienoic acid ethyl ester (41a),
• (2E,4E)-5-(5-Dimethylaminobenzo[b]thiophen-2-yl)-penta-2,4dienoic acid hydroxamide (42a),
• (E)-3-(3-(4-Dimethylamino-phenylsulfanyl)-phenyl)-acrylic acid ethyl ester (51 a), or
• (E)-3-(3-(4-Dimethylamino-phenylsulfanyl)-phenyl)-N-hydroxy-acrylamide (52a).

A method of inhibiting HDAC activity in an individual comprising administering to said individual a therapeutically effective amount of a compound of general formula (I):

• in which:
• R1 is (C6 or C10) aryl, (C6 or C10) arylalkyl, a 6- or 10-membered ring system having one or more heteroatoms in the ring, (C6 or C10) heteroaryl, C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, (C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl or a combination thereof to form a linked or fused ring system, the cyclic moiety being optionally substituted with (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, or (C1-C10) alkylsulfonyl,
• R2 and R3 are each independently hydrogen, (C1-C12) alkyl, unsaturated (C2-C12) comprising one or more C═C bond or C≡C bond, (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, or (C1-C10) haloalkyl;
• or
• R2 and R3 optionally form a (C6 or C10) aryl, (C6 or C10) arylalkyl, a 6- or 10-membered ring system having one or more heteroatoms in the ring, (C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, (C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl linked or fused ring system, optionally containing up to 3 heteroatoms selected from oxygen, nitrogen, sulphur, and phosphorous;
• or
• R1 and R2 optionally form a (C6 or C10) aryl, (C6 or C10) arylalkyl, (C6 or C10) heteroaryl, (C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, (C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl linked or fused ring system, optionally the ring formed is further substituted with a group R1 as defined above, or the ring formed is fused to a further C6 aryl group which is optionally substituted with a group R1 as defined above, or a group R1R2N, with R1 and R2 as defined above;
• n is equal to 0, 1 or 2;
• X is hydroxyl (—OH), —OR, NHR, hydroxamate (—NHOH), NHOR, NROR, NRNHR, or SR, wherein each R is independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl;
• Y is 0, 1 or 2 oxygen atoms;
• Q represents
• wherein:
• m is an integer from 1 to 4;
• n is an integer from 1 to 8;
• and
• R4and R5 each independently represent hydrogen, or unsubstituted or substituted (C1-C10) alkyl;
• or a pharmaceutically acceptable salt thereof.

A compound of general formula (Ib)

• wherein:
• R1 is (C6 or C10) aryl, (C6 or C10) arylalkyl, a 6- or 10-membered ring system having one or more heteroatoms in the ring, (C6 or C10) heteroaryl, (C3-C8) heterocycloalkenyl, (C5-C8) cycloalkene ring, (C5-C8) cycloalkyl, (C5-C8) heterocycloalkyl or a combination thereof to form a linked or fused ring system, the cyclic moiety being optionally substituted with (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C1-C10) alkoxy, (C1-C10) thioalkoxy, hydroxyl, (C1-C10) hydroxylalkyl, halo, (C1-C10) haloalkyl, amino, amido, (C1-C10) alkylamino, (C1-C10) alkylcarbonyloxy, (C1-C10) alkoxycarbonyl, (C1 -C10) alkylcarbonyl, (C1-C10 ) alkylthiocarbonyl, (C1-C10) alkylsulfonylamino, aminosulfonyl, (C1-C10) alkylsulfinyl, or (C1-C10) alkylsulfonyl;
• R2 and R3 are each independently hydrogen or methyl, or R2 and R3 optionally form a (C6 or C10) aryl;
• n is 0, 1 or 2;
• X is hydroxamate (—NHOH);
• and
• Y is 0, 1 or 2 oxygen atoms;
• or a pharmaceutically acceptable salt thereof.