Methods of using dihydropteridinones

Abstract

Disclosed are dihydropteridinones of the formula (I): wherein the groups X, R 1 , R 2 , R 3 , R 4 , R 5 and R 7 have the meanings given in the claims and specification, the isomers thereof, processes and intermediates for preparing these dihydropteridinones as well as the use thereof as pharmaceutical compositions.

1 . A method of treating a disease or condition chosen from cancer, infections, inflammatory and autoimmune diseases said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I),  
       
         
           
           
               
               
           
         
         wherein  
         R 1  denotes a group selected from among hydrogen, NH 2 , XH, halogen and a C 1 -C 3 -alkyl group optionally substituted by one or more halogen atoms,  
         R 2  denotes a group selected from among hydrogen, CHO, XH, —X—C 1 -C 2 -alkyl and an optionally substituted C 1 -C 3 -alkyl group,  
         R 3 , R 4  are identical or different and denote a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR 8 -aryl, —NR 8 -heteroaryl, —NR 8 -cycloalkyl,- and —NR 8 -heterocycloalkyl, or  
         a group selected from among hydrogen, halogen, COXR 8 , CON(R 8 ) 2 , COR 8  and XR 8 , or  
         R 3  and R 4  together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,  
         R 5  denotes hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl and —C 3 -C 6 -cycloalkyl , or  
         R 3  and R 5  or R 4  and R 5  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms,  
         R 6  denotes optionally substituted aryl or heteroaryl, R 7  denotes hydrogen or —CO—X—C 1 -C 4 -alkyl, and  
         X in each case independently of one another denotes O or S, and  
         R 8  in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and phenyl,  
         or the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.  
       
     
     
         2 . A method of treating a disease or condition chosen from HIV, Kaposi's sarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis, conditions related to wound healing, bacterial, fungal and/or parasitic infections, leukaemias, lymphoma, solid tumours, psoriasis, bone diseases and cardiovascular disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  denotes a group selected from among hydrogen, NH 2 , XH, halogen and a C 1 -C 3 -alkyl group optionally substituted by one or more halogen atoms,  
 R 2  denotes a group selected from among hydrogen, CHO, XH, —X—C 1 -C 2 -alkyl and an optionally substituted C 1 -C 3 -alkyl group,  
 R 3 , R 4  are identical or different and denote a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR 8 -aryl, —NR 8 -heteroaryl, —NR 8 -cycloalkyl,- and —NR 8 -heterocycloalkyl, or  
 a group selected from among hydrogen, halogen, COXR 8 , CON(R 8 ) 2 , COR 8  and XR 8 , or  
 R 3  and R 4  together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,  
 R 5  denotes hydrogen or a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl and —C 3 -C 6 -cycloalkyl , or  
 R 3  and R 5  or R 4  and R 5  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms,  
 R 6  denotes optionally substituted aryl or heteroaryl,  
 R 7  denotes hydrogen or —CO—X—C 1 -C 4 -alkyl, and  
 X in each case independently of one another denotes O or S, and  
 R 8  in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and phenyl,  
 or the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.  
 
     
     
         3 . The methods according to claims  1  or  2  wherein for the formula (I) 
 R 1  denotes hydrogen,  
 R 2  denotes a group selected from among a CHO, OH, and CH 3  group,  
 R 3 , R 4  are identical or different and denote a group selected from among hydrogen, optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, or  
 R 3  and R 4  together denote a C 2 -C 5 -alkyl bridge,  
 R 5  denotes a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, C 3 -C 6 -cycloalkyl and C 3 -C 6 -cycloalkenyl, or  
 R 3  and R 5  or R 4  and R 5  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms, and  
 R 7  denotes hydrogen.  
 
     
     
         4 . The methods according to  claim 3 , wherein for the formula (I) 
 R 6  denotes a group of general formula                          wherein    n denotes 1, 2, 3 or 4,    R 9  denotes a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, —CONH—C 1 -C 10 -alkylene, —O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among —O—C 1 -C 6 -alkyl-Q 1 , —CONR 8 —C 1 -C 10 -alkyl-Q 1 , —CONR 8 —C 2 -C 10 -alkenyl-Q 1 , —CONR 8 —Q 2 , halogen, OH, —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —COR 8 , —COOR 8 , —N(R 8 ) 2 , —NHCOR 8 , CONR 8 OC 1 -C 10  alkylQ 1  and CONR 8 OQ 2 ,    Q 1  denotes hydrogen, —NHCOR 8 , or a group selected from among an optionally substituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl- and heterocycloalkyl group,    Q 2  denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, C 3 -C 8 -heterocycloalkyl, C 3 -C 8 -cycloalkyl- and C 1 -C 4 -alkyl-C 3 -C 8 -cycloalkyl group,    R 10  is identical or different and denotes a group selected from among optionally substituted C 1 -C 6 -alkyl , C 2 -C 6 -alkenyl and C 2 -C 6 -alkynyl, —O—C 1 -C 6 -alkyl, —O—C 2 -C 6 -alkenyl, —O—C 2 -C 6 -alkynyl, C 3 -C 6 -heterocycloalkyl and C 3 -C 6 -cycloalkyl, or a group selected from among hydrogen, —CONH 2 , —COOR 8 , —OCON(R 8 ) 2 , —N(R 8 ) 2 , —NHCOR 8 , —NHCON(R 8 ) 2 , —NO 2  and halogen, or    adjacent groups R 9  and R 10  together denote a bridge of the formula                          Y denotes O, S or NR 11 ,    m denotes 0, 1 or 2    R 11  denotes hydrogen or C 1 -C 2 -alkyl, and    R 12  denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, —C 1 -C 3 -alkyl-phenyl, —C 1 -C 3 -alkyl-pyridyl, —C 1 -C 3 -alkyl-pyrazinyl, —C 1 -C 3 -alkyl-pyrimidinyl and —C 1 -C 3 -alkyl-pyridazinyl, and    R 13  denotes C 1 -C 6 -alkyl.    
     
     
         5 . The methods according to  claim 4 , wherein for the formula (I) 
 R 1  denotes hydrogen,    R 2  denotes CH 3 , and    R 7  denotes hydrogen.    
     
     
         6 . A method of treating a disease or condition chosen from cancer, infections, inflammatory and autoimmune diseases said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (II),  
       
         
           
           
               
               
           
         
         wherein  
         R 1 -R 5  and X have the meanings given in  claim 1 .  
       
     
     
         7 . A method of treating a disease or condition chosen from HIV, Kaposi's sarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis, conditions related to wound healing, bacterial, fungal and/or parasitic infections, leukaemias, lymphoma, solid tumours, psoriasis, bone diseases and cardiovascular disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (II),  
       
         
           
           
               
               
           
         
         wherein  
         R 1 -R 5  and X have the meanings given in  claim 1.