Quinazolinedione derivatives as parp inhibitors

Abstract

The present invention provides compounds of formula (I), their use as PARP inhibitors as well as pharmaceutical compositions comprising said compounds of formula (I) wherein R 1 , L 1 , L 2 , X, Y and Z have defined meanings.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         each X is independently 
       
       
         
           
           
               
               
           
         
       
       and when X is 
       
         
           
           
               
               
           
         
       
       then Y is 
       
         
           
           
               
               
           
         
         each Y is independently 
       
       
         
           
           
               
               
           
         
       
       except when X is 
       
         
           
           
               
               
           
         
       
       then Y is 
       
         
           
           
               
               
           
         
         L 1  is a direct bond or a bivalent radical selected from —C 1-6 alkanediyl-; 
         L 2  is a direct bond or a bivalent radical selected from carbonyl, —C 1-6 alkanediyl-,-(hydroxy)C 1-6 alkanediyl-, —C(O)—C 1-6 alkanediyl- or —C 1-6 alkanediyl-C(O)—; 
         R 1  is hydrogen or hydroxy; 
         Z is 
       
       
         
           
           
               
               
           
         
         with the proviso that 1-[1-[(2S)-2-[(2R)-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]-4-piperidinyl]-2,4 (1H, 3H)-quinazolinedione, 1-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H, 3H)-quinazolinedione, 1-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2,4-(1H, 3H)-quinazolinedione, 3-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H, 3H)-quinazolinedione and 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4-(1H, 3H)-quinazolinedione are not included. 
       
     
     
         2 . A compound as claimed in  claim 1  wherein
 each X is independently 
 
       
         
           
           
               
               
           
         
       
       each Y is independently 
       
         
           
           
               
               
           
         
       
       L 1  is a direct bond or a bivalent radical selected from —C 1-6 alkanediyl-; L 2  is a direct bond or a bivalent radical selected from carbonyl, or —C 1-6 alkanediyl-; and R 1  is hydrogen or hydroxy. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A compound as claimed in  claim 1  for use as a medicine. 
     
     
         6 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in  claim 1 . 
     
     
         7 . A process of preparing a pharmaceutical composition as claimed in  claim 6  wherein the pharmaceutically acceptable carriers and the compound as claimed in  claim 1  are intimately mixed. 
     
     
         8 . A method for the treatment of a PARP mediated disorder using a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4-(1H, 3H)-quinazolinedione 
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof 
       
     
     
         9 . (canceled) 
     
     
         10 . A method  claim 8  wherein the treatment involves chemosensitization. 
     
     
         11 . A method  claim 8  wherein the treatment involves radiosensitization. 
     
     
         12 . A combination of a compound with a chemotherapeutic agent wherein said compound is a compound of formula (I) 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         each X is independently 
       
       
         
           
           
               
               
           
         
       
       and when X is 
       
         
           
           
               
               
           
         
       
       then Y is 
       
         
           
           
               
               
           
         
         each Y is independently 
       
       
         
           
           
               
               
           
         
       
       except when X is 
       
         
           
           
               
               
           
         
       
       then Y is 
       
         
           
           
               
               
           
         
         L 1  is a direct bond or a bivalent radical selected from —C 1-6 alkanediyl-; 
         L 2  is a direct bond or a bivalent radical selected from carbonyl, —C 1-6 alkanediyl-,-(hydroxy)C 1-6 alkanediyl-, —C(O)—C 1-6 alkanediyl- or —C 1-6 alkanediyl-C(O)—; 
         R 1  is hydrogen or hydroxy; 
         Z is 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . A process for preparing a compound as claimed in  claim 1 , characterized by
 a) reacting an intermediate of formula (II) with an intermediate of formula (III), wherein W is an appropriate leaving group, with the formation of a compound of formula (I-a), wherein X is   
       
         
           
           
               
               
           
         
       
       in a reaction-inert solvent and with the addition of an appropriate base, or 
       
         
           
           
               
               
           
         
         b) reacting an intermediate of formula (IV) with an intermediate of formula (V), wherein W is an appropriate leaving group, with the formation of a compound of formula (I-b), wherein Y is 
       
       
         
           
           
               
               
           
         
       
       in a reaction-inert solvent and with the addition of an appropriate base. 
       
         
           
           
               
               
           
         
       
     
     
         14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and a compound of  claim 2 . 
     
     
         16 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and a compound of  claim 1 . 
     
     
         17 . (canceled) 
     
     
         18 . A process of preparing a pharmaceutical composition as claimed in  claim 15  wherein the pharmaceutically acceptable carriers and the compound of  claim 2  are intimately mixed. 
     
     
         19 . A process of preparing a pharmaceutical composition as claimed in  claim 16  wherein the pharmaceutically acceptable carriers and the compound of  claim 1  are intimately mixed. 
     
     
         20 . (canceled)