Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase

Abstract

This invention comprises the novel compounds of formula (I) wherein R 1 , R 2 , R 3 , X and Y have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

1 - 12 . (canceled) 
     
     
         13 . A method of treating a disorder related to the abnormal growth of cells or the abnormal growth of transformed cells, in a mammalian subject in need of inhibition of such abnormal cell growth, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         each n is an integer with value 0, 1 or 2 and when n is 0 then a direct bond is intended; 
         each m is an integer with value 1 or 2; 
         each X is independently N or CH; 
         each Y is independently O, S, or NR 4 ; wherein 
         each R 4  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, phenylC 1-6 alkyl, —C(═O)—CHR 5 R 6  or —S(═O) 2 —N(CH 3 ) 2 ; wherein 
         each R 5  and R 6  is independently hydrogen, amino, C 1-6 alkyl or aminoC 1-6 alkyl; and 
         when Y is NR 4  and R 2  is on the 7-position of the indolyl then R 2  and R 4  together can form the bivalent radical
   —(CH 2 ) 2 —  (a-1), or
 
   —(CH 2 ) 3 —  (a-2);
 
 
         R 1  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl or mono- or di(C 1-6  alkyl)aminosulfonyl; 
         R 2  is hydrogen, hydroxy, amino, halo, C 1-6 alkyl, cyano, C 2-6 alkenyl, polyhaloC 1-6 alkyl, nitro, phenyl, C 1-6 alkylcarbonyl, hydroxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkyloxy, or mono- or di(C 1-6 alkyl)amino; 
         R 3  is hydrogen, C 1-6 alkyl, or C 1-6 alkyloxy; and 
         when R 2  and R 3  are on adjacent carbon atoms, they can form the bivalent radical —O—CH 2 —O—. 
       
     
     
         14 . The method of  claim 13  in which the abnormal growth of cells comprises cell growth independent of normal regulatory mechanisms, said mechanisms including the direct inhibition of tumour growth by growth arrest, terminal differentiation or apoptosis of cancer cells, and the indirect inhibition of tumour growth by inhibition of the neovascularization of tumours. 
     
     
         15 . The method of  claim 14  in which the abnormal growth of cells is c caused by histone deacetylase (HDAC) activity. 
     
     
         16 . A method of inhibiting abnormal cellular proliferative conditions caused by histone deacetylase (HDAC) activity, in a human subject in need of inhibition of histone deacetylase (HDAC) activity, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         each n is an integer with value 0, 1 or 2 and when n is 0 then a direct bond is intended; 
         each m is an integer with value 1 or 2; 
         each X is independently N or CH; 
         each Y is independently O, S, or NR 4 ; wherein 
         each R 4  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, phenylC 1-6 alkyl, —C(═O)—CHR 5 R 6  or —S(═O) 2 —N(CH 3 ) 2 ; wherein 
         each R 5  and R 6  is independently hydrogen, amino, C 1-6 alkyl or aminoC 1-6 alkyl; and 
         when Y is NR 4  and R 2  is on the 7-position of the indolyl then R 2  and R 4  together can form the bivalent radical
   —(CH 2 ) 2 —  (a-1), or
 
   —(CH 2 ) 3 —  (a-2);
 
 
         R 1  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl or mono- or di(C 1-6 alkyl)aminosulfonyl; 
         R 2  is hydrogen, hydroxy, amino, halo, C 1-6 alkyl, cyano, C 2-6 alkenyl, polyhaloC 1-6 alkyl, nitro, phenyl, C 1-6 alkylcarbonyl, hydroxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkyloxy, or mono- or di(C 1-6 alkyl)amino; 
         R 3  is hydrogen, C 1-6 alkyl, or C 1-6 alkyloxy; and 
         when R 2  and R 3  are on adjacent carbon atoms, they can form the bivalent radical —O—CH 2 —O—. 
       
     
     
         17 . A method of inhibiting tumor growth in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of formula (I), 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         each n is an integer with value 0, 1 or 2 and when n is 0 then a direct bond is intended; 
         each m is an integer with value 1 or 2; 
         each X is independently N or CH; 
         each Y is independently O, S, or NR 4 ; wherein 
         each R 4  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, phenylC 1-6 alkyl, —C(═O)—CHR 5 R 6  or —S(═O) 2 —N(CH 3 ) 2 ; wherein 
         each R 5  and R 6  is independently hydrogen, amino, C 1-6 alkyl or aminoC 1-6 alkyl; and 
         when Y is NR 4  and R 2  is on the 7-position of the indolyl then R 2  and R 4  together can form the bivalent radical
   —(CH 2 ) 2 —  (a-1), or
 
   —(CH 2 ) 3 —  (a-2);
 
 
         R 1  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl or mono- or di(C 1-6 alkyl)aminosulfonyl; 
         R 2  is hydrogen, hydroxy, amino, halo, C 1-6 alkyl, cyano, C 2-6 alkenyl, polyhaloC 1-6 alkyl, nitro, phenyl, C 1-6 alkylcarbonyl, hydroxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkyloxy, or mono- or di(C 1-6 alkyl)amino; 
         R 3  is hydrogen, C 1-6 alkyl, or C 1-6 alkyloxy; and 
         when R 2  and R 3  are on adjacent carbon atoms, they can form the bivalent radical —O—CH 2 —O—. 
       
     
     
         18 . The method of  claim 17  in which the tumor comprises lung cancer, adenocarcinoma lung cancer, non-small cell lung cancer, pancreatic cancer, exocrine pancreatic carcinoma, colon cancers, colon adenocarcinoma and colon adenoma, prostate cancer, advanced prostate cancer, hematopoietic tumours of lymphoid lineage, acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma, myeloid leukemias, acute myelogenous leukemia (AML), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal origin, fibrosarcomas, rhabdomyosarcomas, melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumours of the skin, keratoacanthomas, breast carcinoma, advanced breast cancer, kidney carcinoma, bladder carcinoma and epidermal carcinoma.