Novel compounds as histone deacetylase inhibitors

Abstract

The present invention is directed to compounds of the general formula (I) or pharmaceutical acceptable salts or physiologically functional derivatives thereof wherein: n is a non-aromatic ring system containing two to seven carbon atoms, wherein the ring system can contain one ore two double bonds; X is C, CH or CH 2 ; Y is selected from 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, halogene, haloalkyl, haloalkyloxy; R is H, an alkyl or cycloalkyl group; Z is CH, C, or P; p is 0 or 1.

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.