6-substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase 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 n, R 1 , R 2 , R 3 , R 4 and X 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
 n is 0, 1 or 2; 
 X is N or CR 5 , wherein R 5  is hydrogen or taken together with R 1  may form a bivalent radical of formula —CH═CH—CH═CH—; 
 R 1  is C 1-6 alkyl or thienyl; 
 R 2  is hydrogen or hydroxy or taken together with R 3  or R 4  may form ═O; 
 R 3  is a radical selected from
   —(CH 2 ) s —NR 6 R 7   (a-1),
 
   —O—H  (a-2),
 
   —O—R 8   (a-3),
 
   —S—R 9   (a-4), or
 
   —C≡N  (a-5),
 
 wherein 
 s is 0, 1, 2 or 3; 
 R 6  is —CHO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, piperidinyl, piperidinylC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, C 1-6 alkyloxy, thienylC 1-6 alkyl, pyrrolylC 1-6 alkyl, arylC 1-6 alkylpiperidinyl, arylcarbonylC 1-6 alkyl, arylcarbonylpiperidinylC 1-6 alkyl, haloindozolylpiperidinylC 1-6 alkyl, or arylC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl; 
 R 7  is hydrogen or C 1-6 alkyl; 
 R 8  is C 1-6 alkyl, C 1-6 alkylcarbonyl or di(C 1-6 alkyl)aminoC 1-6 alkyl; and 
 R 9  is di(C 1-6 alkyl)aminoC 1-6 alkyl; 
 
 or R 3  is a group of formula
   —Z—  (b-1),
 
 wherein 
 Z is a heterocyclic ring system selected from 
 
 
       
         
           
           
               
               
           
         
         
           wherein each R 10  independently is hydrogen, C 1-6 alkyl, aminocarbonyl, hydroxy, 
         
       
       
         
           
           
               
               
           
         
         
           C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylamino, arylC 1-6 alkyl, di(phenylC 2-6 alkenyl), piperidinylC 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-6 alkyl, aryloxy(hydroxy)C 1-6 alkyl, haloindazolyl, arylC 1-6 alkyl, arylC 2-6 alkenyl, morpholino, C 1-6 alkylimidazolyl, or pyridinylC 1-6 alkylamino; 
         
         R 4  is hydrogen, C 1-6 alkyl, furanyl, pyridinyl, arylC 1-6 alkyl or 
       
       
         
           
           
               
               
           
         
         aryl is phenyl or phenyl substituted with halo, C 1-6 alkyl or C 1-6 alkyloxy; 
         with the proviso that when
 n is 0, X is N, R 2  is hydrogen, R 3  is a group of formula (b-1), Z is the heterocyclic ring system (c-2) or (c-4) wherein said heterocyclic ring system Z is attached to the rest of the molecule with a nitrogen atom, and R 10  is hydrogen; then 
 R 4  is other than C 1-6 alkyl or pyridinyl. 
 
       
     
     
         2 . A compound as claimed in  claim 1  wherein
 n is 0 or 1; X is N or CR 5 , wherein R 5  is hydrogen; R 3  is a radical selected from (a-1), (a-2) or (a-3) or is a group of formula (b-1) i.e. —Z—; s is 0, 1 or 2; R 6  is —CHO, C 1-6 alkyl, piperidinylC 1-6 alkyl, arylcarbonylpiperidinylC 1-6 alkyl or arylC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl; R 8  is C 1-6 alkyl; when R 3  is a group of formula (b-1) then Z is a heterocyclic ring system selected from (c-2) or (c-4); and each R 10  independently is hydrogen, C 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkylamino 
 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         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 a compound as claimed in  claim 1  are intimately mixed. 
     
     
         8 . Use of a compound for the manufacture of a medicament for the treatment of a PARP mediated disorder, 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
 n is 0, 1 or 2; 
 X is N or CR 5 , wherein R 5  is hydrogen or taken together with R 1  may form a bivalent radical of formula —CH═CH—CH═CH—; 
 R 1  is C 1-6 alkyl or thienyl; 
 R 2  is hydrogen or hydroxy or taken together with R 3  or R 4  may form ═O; 
 R 3  is a radical selected from
   —(CH 2 ) s —NR 6 R 7   (a-1),
 
   —O—H  (a-2),
 
   —O—R 8   (a-3),
 
   —S—R 9   (a-4), or
 
   —C≡N  (a-5),
 
 wherein 
 s is 0, 1, 2 or 3; 
 R 6  is —CHO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, piperidinyl, piperidinylC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, C 1-6 alkyloxy, thienylC 1-6 alkyl, pyrrolylC 1-6 alkyl, arylC 1-6 alkylpiperidinyl, arylcarbonylC 1-6 alkyl, arylcarbonylpiperidinylC 1-6 alkyl, haloindozolylpiperidinylC 1-6 alkyl, or arylC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl; 
 R 7  is hydrogen or C 1-6 alkyl; 
 R 8  is C 1-6 alkyl, C 1-6 alkylcarbonyl or di(C 1-6 alkyl)aminoC 1-6 alkyl; and 
 R 9  is di(C 1-6 alkyl)aminoC 1-6 alkyl; 
 
 or R 3  is a group of formula
   —Z—  (b-1),
 
 wherein 
 Z is a heterocyclic ring system selected from 
 
 
       
         
           
           
               
               
           
         
         
           wherein each R 10  independently is hydrogen, C 1-6 alkyl, aminocarbonyl, hydroxy, 
         
       
       
         
           
           
               
               
           
         
         
           C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylamino, arylC 1-6 alkyl, di(phenylC 2-6 alkenyl), piperidinylC 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-6 alkyl, aryloxy(hydroxy)C 1-6 alkyl, haloindazolyl, arylC 1-6 alkyl, arylC 2-6 alkenyl, morpholino, C 1-6 alkylimidazolyl, or pyridinylC 1-6 alkylamino; 
         
         R 4  is hydrogen, C 1-6 alkyl, furanyl, pyridinyl, arylC 1-6 alkyl or 
       
       
         
           
           
               
               
           
         
         aryl is phenyl or phenyl substituted with halo, C 1-6 alkyl or C 1-6 alkyloxy. 
       
     
     
         9 . Use according to  claim 8  of a PARP inhibitor of formula (I) for the manufacture of a medicament for the treatment of a PARP-1 mediated disorder 
     
     
         10 . Use according to  claims 8  and  9  wherein the treatment involves chemosensitization. 
     
     
         11 . Use according to  claims 8  and  9  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
 n is 0, 1 or 2; 
 X is N or CR 5 , wherein R 5  is hydrogen or taken together with R 1  may form a bivalent radical of formula —CH═CH—CH═CH—; 
 R 1  is C 1-6 alkyl or thienyl; 
 R 2  is hydrogen or hydroxy or taken together with R 3  or R 4  may form ═O; 
 R 3  is a radical selected from
   —(CH 2 ) s —NR 6 R 7   (a-1),
 
   —O—H  (a-2),
 
   —O—R 8   (a-3),
 
   —S—R 9   (a-4), or
 
   —C≡N  (a-5),
 
 wherein 
 s is 0, 1, 2 or 3; 
 R 6  is —CHO, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, piperidinyl, piperidinylC 1-6 alkyl, piperidinylC 1-6 alkylaminocarbonyl, C 1-6 alkyloxy, thienylC 1-6 alkyl, pyrrolylC 1-6 alkyl, arylC 1-6 alkylpiperidinyl, arylcarbonylC 1-6  alkyl, arylcarbonylpiperidinylC 1-6 alkyl, haloindozolylpiperidinylC 1-6 alkyl, or arylC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl; 
 R 7  is hydrogen or C 1-6 alkyl; 
 R 8  is C 1-6 alkyl, C 1-6 alkylcarbonyl or di(C 1-6 alkyl)aminoC 1-6 alkyl; and 
 R 9  is di(C 1-6 alkyl)aminoC 1-6 alkyl; 
 
 or R 3  is a group of formula
   —Z—  (b-1),
 
 wherein 
 Z is a heterocyclic ring system selected from 
 
 
       
         
           
           
               
               
           
         
         
           wherein each R 10  independently is hydrogen, C 1-6 alkyl, aminocarbonyl, hydroxy, 
         
       
       
         
           
           
               
               
           
         
         
           C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylamino, arylC 1-6 alkyl, di(phenylC 2-6 alkenyl), piperidinylC 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-6 alkyl, aryloxy(hydroxy)C 1-6 alkyl, haloindazolyl, arylC 1-6 alkyl, arylC 2-6 alkenyl, morpholino, C 1-6 alkylimidazolyl, or pyridinylC 1-6 alkylamino; 
         
         R 4  is hydrogen, C 1-6 alkyl, furanyl, pyridinyl, arylC 1-6 alkyl or 
       
       
         
           
           
               
               
           
         
         aryl is phenyl or phenyl substituted with halo, C 1-6 alkyl or C 1-6 alkyloxy. 
       
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in  claim 2 . 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A method of treating in a subject a PARP mediated disorder, said method comprising administering to the subject a therapeutically effective amount of a compound of  claim 2 . 
     
     
         18 . A method for enhancing the effectiveness of chemotherapy comprising administration of a compound according to  claim 2 , in a therapeutically effective amount so as to increase sensitivity of cells to chemotherapy, prior to administration of said chemotherapy . 
     
     
         19 . A method for enhancing the effectiveness of radiotherapy comprising administration of a compound according to  claim 2 , in a therapeutically effective amount so as to increase sensitivity of cells to ionizing radiation, prior to administration of said radiotherapy. 
     
     
         20 .- 25 . (canceled) 
     
     
         26 . A combination of a compound with a chemotherapeutic agent wherein said compound is a compound of  claim 2 . 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . A product made by the process of  claim 13 . 
     
     
         30 . A pharmaceutical composition made by the process of  claim 13 . 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled)