1h-quinazoline-2,4-diones

Abstract

The present invention relates to 1H-Quinazoline-2,4-diones of formula (I) wherein R 1 and R 2 are as defined in the specification, their preparation, their use as pharmaceuticals, and pharmaceutical compositions containing them. Further, intermediates for the manufacture of compounds of formula (I) are and combinations comprising compounds of formula (I) are disclosed.

1 . Compounds of the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents CF 3 , CHF 2 , CH 2 F, CH 3 CHF—, CH 3 CF 2 —, ethyl or iso-propyl and 
         R 2  represents alkyl substituted by one or more substituents, the substituents being selected from the group consisting of halogen, nitro, cyano, acyl, hydroxy, oxo (═O), alkoxy, cycloalkoxy, acyloxy, alkoxycarbonyloxy, amino, alkylamino, dialkylamino, formyl, acylamino, alkoxycarbonylamino or 
         R 2  represents heterocyclylakyl substituted by one or more substituents, the substituents being selected from the group consisting of halogen, nitro, cyano, hydroxy, alkoxy, alkylcarbonyloxy, alkoxycarbonyloxy, amino, alkylamino, dialkylamino, alkoxycarbonylamino, or 
         R 2  represents phenyl substituted by one ore more substituents, the substituents being selected from the group consisting of cyano, hydroxy, alkanediyl, alkenediyl, alkoxy, hydroxyalkyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylamino, or 
         R 2  represents heterocyclyl optionally substituted by one ore more substituents, the substituents being selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, alkyl, hydroxalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxy, acyloxy, alkoxycarbonyloxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and whereby the heterocycle is bound to the phenyl-ring by a carbon-atom 
         and their salts. 
       
     
     
         2 . Compounds according to  claim 1 , wherein
 R 1  represents CF 3  or iso-Propyl and   R 2  represents (C 1 -C 4 )alkyl substituted by one to three substituents, the substituents being selected from the group consisting of halogen, nitro, cyano, HCO, (C 1 -C 4 )alkylcarbonyl, hydroxy, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylcarbonyloxy, (C 1 -C 4 )alkoxycarbonyloxy, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, acylamino, (C 1 -C 4 )alkoxycarbonylamino, except trifluoromethyl or   R 2  represents heterocyclyl(C 1 -C 4 )alkyl substituted by one to three substituents, the substituents being selected from the group consisting of halogen, nitro, cyano, hydroxy, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylcarbonyloxy, (C 1 -C 4 )alkoxycarbonyloxy, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkoxycarbonylamino and the heterocyclyl consist of 3 to 11 ring atoms of which 1-3 ring atoms are hetero atoms or   R 2  represents phenyl substituted by one to three substituents, the substituents being selected from the group consisting of cyano, hydroxy, alkanediyl, alkenediyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylcarbonyloxy, (C 1 -C 4 )alkoxycarbonyloxy, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkoxycarbonylamino or   R 2  represents heterocyclyl optionally substituted by one to three substituents, the substituents being selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyalkyl, amino(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, di(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, HCO, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )alkoxy, acyloxy, (C 1 -C 4 )alkoxycarbonyloxy, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, acylamino, (C 1 -C 4 )alkoxycarbonylamino; the heterocyclyl consist of 3 to 11 ring atoms of which 1-3 ring atoms are hetero atoms and whereby the heterocycle is bound to the phenyl-ring by a carbon-atom.   
     
     
         3 . Compounds according to  claim 1 , wherein
 R 1  represents CF 3 .   
     
     
         4 . Process for the manufacture of formula (I) according to  claim 1  which comprises
 conversion of a compound of formula (II) 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined in  claim 1  and R 3  represents C 1 -C 4 -alkyle, in the presence of with 4-chlorophenyl-chloroformate, optionally in the presence of a diluent, and optionally in the presence of a reaction auxiliary to a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         and conversion of compound of formula (IV) to a compound of formula (I) by cyclocondensation with sulfonylhydrazine H 2 N—NH—SO 2 —CH 3 , in an inert solvent, in the presence of or followed by addition of a base; 
         or 
         conversion of a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined in  claim 1  and R 3  represents C 1 -C 4 -alkyle in the presence of phosgene or triphosgene, optionally in the presence of a diluent and optionally in the presence of a reaction auxiliary to a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         and conversion of a compound of formula (III) to a compound of formula (I) by cyclocondensation with sulfonylhydrazine H 2 N—NH—SO 2 —CH 3 , optionally in an inert solvent, in the presence of or followed by addition of a base; 
         or 
         conversion of a compound of formula (XI) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is as defined in  claim 1 , by reduction, for example with hydrogen, optionally in the presence of a catalyst, and in the presence of acetic anhydride, optionally in the presence of a further diluent to a compound of formula (I′) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is as defined in  claim 1 , and conversion of a compound of formula (I′) to another compound of formula (I) by cyclisation, substitution, oxidation and/or reduction steps. 
       
     
     
         5 . Compounds according to  claim 1  for use as a pharmaceutical. 
     
     
         6 . Pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         7 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment of a condition mediated by the AMPA-receptor. 
     
     
         8 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment of epilepsy or schizophrenia. 
     
     
         9 . A method for the treatment of condition mediated by the AMPA-receptor, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         10 . A Compound of formula (II′) 
       
         
           
           
               
               
           
         
         wherein 
         R 2  has the meaning given above for compounds of formula (I) and 
         R 3  represents hydrogen or C 1 -C 4  alkyl. 
       
     
     
         11 . A compound of formula (III′) 
       
         
           
           
               
               
           
         
         wherein 
         R 2  has the meaning given above for compounds of formula (I) and 
         R 3  represents hydrogen or C 1 -C 4  alkyl. 
       
     
     
         12 . A compound of formula (IV′) 
       
         
           
           
               
               
           
         
         wherein 
         R 2  has the meaning given above for compounds of formula (I) and 
         R 3  represents hydrogen or C 1 -C 4  alkyl. 
       
     
     
         13 . A compound of formula (VII) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  has the meaning given above for compounds of formula (I) and 
         R 3  represents hydrogen or C 1 -C 4  alkyl. 
       
     
     
         14 . A compound of formula (IIX) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  has the meaning given above for compounds of formula (I) and 
         R 3  represents hydrogen or C 1 -C 4  alkyl. 
       
     
     
         15 . A compound of formula (IX) 
       
         
           
           
               
               
           
         
         wherein R 1  has the meaning given above for compounds of formula (I). 
       
     
     
         16 . A compound of formula (X) 
       
         
           
           
               
               
           
         
         wherein R 1  has the meaning given above for compounds of formula (I). 
       
     
     
         17 . A compound of formula (XI) 
       
         
           
           
               
               
           
         
         wherein R 1  has the meaning given above for compounds of formula (I). 
       
     
     
         18 . A Compound according to  claim 1 , wherein R 1  represents isopropyl.