Novel compounds as histone deacetylase inhibitors

1 . A compound of formula (I):

or pharmaceutically acceptable salts or physiologically functional derivatives thereof wherein:

n denotes a non-aromatic ring system containing two to seven carbon atoms, wherein the ring system can contain one crc or two double bonds;

X is C, CH or CH 2 ;

Y is selected from the group consisting of C, CH, CH 2 , S, NR, CH 2 -CH 2 ,

H 2 C—CH, HC—CH 2 , C—CH 2 , H 2 C—C, or C—C; one or more of the hydrogen atoms

can optionally be substituted by one or more substituents R′;

each of the dotted lines means a single, a double or triple bond with the exclusion of a combination of a triple with triple bond and a double with a triple bond;

R′ is independently H, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy;

R is H, an alkyl or cycloalkyl group;

z is CH, C, or P;

p is 0 or 1;

with the provisio that the following compounds are excluded:

2 . The compound of claim 1 , wherein n=cyclopentyl or cyclohexyl.

3 . The compound of claim 1 , wherein n=cyclopentyl or cyclohexyl and Z is CH.

4 . A pharmaceutical composition comprising a compound as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt or a physiologically functional derivative and a pharmaceutically acceptable excipient.

5 - 18 . (canceled)

19 . A method of inhibiting enzymes, comprising:

administering an effective amount of the compound of claim 1 to a subject thereby inhibiting enzymes having histone deacetylase activity in the subject.

20 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby treating a disease or a therapeutic indication in which inhibition of histone deacetylase activity is effective in treating the condition.

21 . The composition of claim 4 , wherein the human histone deacetylase is selected from the group consisting of HDACs 1-10 or a member of the SIR2 protein family.

22 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby inducing the differentiation of cells.

23 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby inducing the differentiation of transformed cells.

24 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby inducing apoptosis of transformed cells.

25 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby inhibiting proliferation of transformed cells.

26 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, for the treatment of a disease or a therapeutic indication in which the induction of hyperacetylation of histones would be therapeutically effective.

27 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby treating a disease or a therapeutic indication selected from the group consisting of skin cancer, melanoma, estrogment receptor-dependent and independent breast cancer, ovarian cancer, prostate cancer, renal cancer, colon and colorectal cancer, pancreatic cancer, head and neck cancer, small cell and non-small lung carcinoma, leukemias and other types of blood cell cancer and endocrine disease based on aberrant recruitment of histone deacetylase.

28 . The method according to claim 27 , wherein aid endocrine disease is thyroid resistance syndrome.

29 . A method of therapeutically treating a subject, comprising:

administering an effective amount of the compound of claim 1 to a subject, thereby inhibiting abnormal gene expression characteristic of inflammatory disorders, diabetes, thalassemia, cirrhosis or protozoal infection.

30 . A process for the preparation of a compound according to claim 1 , which comprises:

reacting an acid of formula (II)

wherein n, X, Y, Z, and p are defined in claim 1 ,

or an acid chloride of formula (III)

wherein n, X, Y, Z, and p are defined in claim 1 , with hydroxylamine.

31 . A method of treatment or prophylaxis, comprising:

administering an effective amount of the composition of claim 4 to a subject in whom there is an advantage in inhibiting hyperacetylation of histones.