Substituted pteridines for the treatment of inflammatory diseases

Abstract

The invention relates to new pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions which contain these compounds.

1 . A compound of the formula 1,  
       
         
           
           
               
               
           
         
         wherein  
         R 1  denotes a saturated or unsaturated, five-, six- or seven-membered heterocyclic ring which may contain a nitrogen atom and another atom selected from among nitrogen, sulphur and oxygen;  
         R 2  denotes a five-, six- or seven-membered heterocyclic ring which may contain a nitrogen atom and another atom selected from among nitrogen, sulphur and oxygen;  
         R 3  denotes a group of formula 1a,  
         
           
             
             
                 
                 
             
           
           wherein  
           A denotes aryl;  
           X denotes NR 3.2 , S, O;  
           Y denotes C 1-4 -alkylene, substituted by one or more R 3.3    
           m denotes 0, 1, 2;  
           R 3.1  each independently of one another denote C 1-6 -alkyl, aryl, COOR 3.1.1 , CONR 3.1.1 R 3.1.2 , CN, NR 3.1.1 R 3.1.2 , NHCOR 3.1.1 , OR 3.1.1 , O—C 1-6 -haloalkyl, SO 2 R 3.1.1 , SO 2 NH 2 , halogen, C 1-6 -haloalkyl, C 1-6 -alkyl-CONH 2 , O—C 1-6 -alkyl-NH 2 , O—C 3-6 -cycloalkyl, O—C 1-4 -alkylene-C 3-6 -cycloalkyl; 
 R 3.1.1  denotes H, C 1-6 -alkyl;  
 R 3.1.2  denotes H, C 1-6 -alkyl; or  
 
           R 3.1  together with two atoms of A forms a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring which may contain one or more oxygen or nitrogen atoms;  
           R 3.2  denotes H, C 1-6 -alkyl;  
           R 3.3  each independently of one another denote C 1-6 -alkyl, C 1-6 -alkyl-OH, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-OH, O—C 1-6 -alkyl, COOH, COO—C 1-6 -alkyl, CONH 2 ;  
           R 3.3  together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 4, 5 or 6 carbon atoms  
         
         or a pharmacologically acceptable salt thereof.  
       
     
     
         2 . A compound of the formula 1, according to  claim 1  wherein 
 R 1  denotes a saturated or unsaturated, five- or six-membered heterocyclic ring which may contain a nitrogen atom and another atom selected from among nitrogen and sulphur;  
 R 2  denotes a five- or six-membered heterocyclic ring which may contain one or two nitrogen atoms;  
 or a pharmacologically acceptable salt thereof.  
 
     
     
         3 . A compound of the formula 1, according to  claim 1  wherein 
 R 1  denotes a saturated or unsaturated, five- or six-membered heterocyclic ring which may contain a nitrogen atom and optionally contains a further sulphur atom;  
 R 2  a six-membered heterocyclic ring which contains two nitrogen atoms;  
 or a pharmacologically acceptable salt thereof.  
 
     
     
         4 . A compounds of formula 1, according to  claim 1 , wherein 
 R 3  is a group of the formula 1a, wherein 
 A denotes phenyl;  
 X denotes NR 3.2 , S, O;  
 Y denotes C 1-4 -alkylene, substituted by one or more R 3.3    
 m denotes 0, 1 or 2;  
 R 3.1  each independently of one another denote C 1-4 -alkyl, aryl, COOR 3.1.1 , CONR 3.1.1 R 3.1.2  CN, NR 3.1.1 R 3.1.2 , NHCOR 3.1.1 , OR 3.1.1 , O—C 1-4 -haloalkyl, SO 2 R 3.1.1 , SO 2 NH 2 , halogen; 
 R 3.1.1  denotes H, C 1-6 -alkyl;  
 R 3.1.2  denotes H, C 1-6 -alkyl;  
 
 R 3.2  denotes H, C 1-6 -alkyl;  
 R 3.3  each independently of one another denote C 1-6 -alkyl, C 1-6 -alkyl-OH, C 3-6 -cycloalkyl, O—C 1-6 -alkyl, COOH, COO—C 1-6 -alkyl, CONH 2 ;  
 R 3.3  together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 5 or 6 carbon atoms  
   or a pharmacologically acceptable salt thereof.    
     
     
         5 . A compound of the formula 1, according to  claim 1 , wherein 
 R 3  is a group of the formula 1a, wherein 
 A denotes phenyl;  
 X denotes NR 3.2 ;  
 Y denotes C 1-2 -alkylene, substituted by one or more R 3.3    
 m denotes 0, 1 or 2;  
 R 3.1  each independently of one another denote C 1-4 -alkyl, aryl, COOH, COO—C 1-4 -alkyl, CONH 2 , CN, NH 2 , NHCO—C 1-4 -alkyl, OH, O—C 1-4 -alkyl, O—C 1-4 -haloalkyl, SO 2 —C 1-4 -alkyl, SO 2 NH 2 , halogen;  
 R 3.2  denotes H, C 1-4 -alkyl;  
 R 3.3  each independently of one another denote C 1-4 -alkyl, C 1-4 -alkyl-OH, C 3-6 -cycloalkyl, O—C 1-4 -alkyl, COOH, COO—C 1-4 -alkyl, CONH 2 ;  
 R 3.3  together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 5 or 6 carbon atoms  
   or a pharmacologically acceptable salt thereof.    
     
     
         6 . A compound of the formula 1, according to  claim 1 , wherein 
 R 3  is a group of the formula 1a, wherein 
 A denotes phenyl;  
 X denotes NR 3.2 ;  
 Y denotes C 1-2 -alkylene, substituted by one or more R 3.3    
 m denotes 0, 1 or 2;  
 R 3.1  each independently of one another denote methyl, ethyl, propyl, Ph, COOH, COOMe, CONH 2 , CN, NH 2 , NHCOMe, OH, OMe, OEt, OCF 3 , OCHF 2 , SO 2 Me, SO 2 NH 2 , F, Cl, Br;  
 R 3.2  denotes H, C 1-4 -alkyl;  
 R 3.3  each independently of one another denote methyl, ethyl, propyl, butyl, CH 2 OH, CH 2 CH 2 OH, C(CH 2 ) 2 OH, cyclopropyl, COOH, COOMe, COOEt, COOPr, CONH 2 , OMe, OEt, OPr;  
 R 3.3  together with one or two carbon atoms of Y forms a carbocyclic ring with 3, 5 or 6 carbon atoms  
   or a pharmacologically acceptable salt thereof.    
     
     
         7 . A compound of the formula 1, according to  claim 1 , wherein 
 R 3  is a group of the formula 1a, wherein 
 A denotes phenyl;  
 X denotes NR 3.2 ;  
 Y denotes C 1-2 -alkylene, substituted by one or more R 3.3    
 m denotes 0, 1 or 2;  
 R 3.1  each independently of one another denote methyl, iso-propyl, OMe, F, Cl, Br, CN,  
 R 3.2  denotes H;  
 R 3.3  each independently of one another denote methyl, cyclopropyl, CH 2 OH, CH 2 CH 2 OH, C(CH 2 ) 2 OH, COOH, COOMe, CONH 2 , OMe,  
 R 3.3  together with one or two carbon atoms of Y forms a carbocyclic ring with 3 carbon atoms  
   or a pharmacologically acceptable salt thereof.    
     
     
         8 . A pharmaceutical composition comprising a compound of the formula 1, in accordance with  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         9 . A method for treating a disease which can be treated by inhibiting the PDE4 enzyme which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1 .  
     
     
         10 . A method for treating respiratory or gastrointestinal complaints or diseases, and also inflammatory diseases of the joints, skin or eyes, cancers, as well as diseases of the peripheral or central nervous system which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1 .  
     
     
         11 . A method for treating respiratory or pulmonary diseases which are accompanied by increased mucus production, inflammation and/or obstructive diseases of the airways which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1 .  
     
     
         12 . A method for treating an inflammatory disease of the gastrointestinal tract which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1   
     
     
         13 . A method for treating COPD, chronic sinusitis, asthma, Crohn's disease or ulcerative colitis which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1 .  
     
     
         14 . A method for treating depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries to the brain caused by stroke, hypoxia or craniocerebral trauma which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1 .  
     
     
         15 . A method for treating acute lymphatic and acute myeloid leukaemia, chronic lymphatic and chronic myeloid leukaemia, osteosarcoma and gliomas which comprises administering a therapeutically effective amount of a compound of the formula 1 according to  claim 1.