2-Benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments

Abstract

The present invention relates to new 2-benzylaminodihydropteridinones of general formula (I) wherein the groups R 1 to R 7 , R 10 and R 11 have the meanings given in the claims and specification, the isomers thereof, methods of preparing these dihydropteridinones and their use as medicaments.

1 ) A compound of formula (I),  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1 , R 2  which may be identical or different, 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 1  and R 2  together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,  
 R 3  denotes hydrogen or a group selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, aryl, heteroaryl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl and C 5 -C 12 -spirocycloalkyl or  
 R 1  and R 3  or R 2  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms,  
 R 4  denotes optionally substituted aryl or heteroaryl,  
 R 5  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 6  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 7  denotes hydrogen or —CO—C 1 -C 4 -alkyl, —CO—NH—C 1 -C 4 -alkyl, —CO—X—C 1 -C 4 -alkyl, and  
 X in each case independently of one another denote O or S,  
 R 8  in each case independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, benzyl and phenyl,  
 R 10  and R 11  in each case independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl,  
 or R 10  and R 11  together denote a 2-5 membered alkyl bridge,  
 or the pharmacologically acceptable acid addition salt, solvate or hydrate thereof.  
 
   
   
       2 ) The compound according to  claim 1 ,  
     wherein 
 R 1  to R 4  have the meanings specified,  
 R 5  denotes methyl, and  
 R 6  and R 7  denote hydrogen,  
 R 10  and R 11  in each case independently of one another denote hydrogen or methyl, or  
 R 10  and R 11  together denote cyclopropyl.  
 
   
   
       3 ) The compound according to  claim 2 ,  
     wherein 
 R 3  to R 7 , R 10  and R 11  have the meanings specified and  
 R 1 , R 2  which may be identical or different, denote hydrogen or a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl, or  
 R 1  and R 2  together denote a 2- to 5-membered alkyl bridge.  
 
   
   
       4 ) The compound according to  claim 1 ,  
     wherein 
 R 1 , R 3  to R 7  , R 10  and R 11  have the meanings specified, and  
 R 3  is hydrogen or contains a group selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or a group selected from among optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl and C 5 -C 12 -spirocycloalkyl.  
 
   
   
       5 ) The compound according to  claim 4 ,  
     wherein 
 R 1  to R 3 , R 5  to R 7 , R 10  and R 11  have the meanings specified, and  
 R 4  denotes a group of formula  
                     
 R 9  which may be identical or different, denotes a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, 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, C 3 -C 6 -cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-cycloalkyl, and —O-heterocycloalkyl 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 , CF 3 , halogen, —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 -alkyl-Q 1  and CONR 8 O-Q 2 ,  
 R 8  in each case independently of one another denote 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,  
 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 and C 3 -C 8 -cycloalkyl group, and  
 n denotes 0,1, 2, 3, 4 or 5.  
 
   
   
       6 ) The compound according to  claim 1 ,  
     wherein 
 Q 1 , Q 2 , n, R 4  to R 8  have the meanings specified,  
 R 1 , R 2  which may be identical or different, denote hydrogen or a group selected from among methyl, ethyl, propyl, allyl and propargyl or  
 R 1  and R 2  together represent cyclopropyl  
 R 3  denotes hydrogen, or denotes optionally substituted C 1 -C 6 -alkyl or optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, and  
 R 10  and R 11  denote hydrogen.  
 
   
   
       7 ) The compound according to  claim 5 ,  
     wherein 
 Q 1 , Q 2 , n, R 1  to R 4 , R 6  to R 8 , R 10  and R 11  have the meanings specified, and  
 R 9  which may be identical or different, denote hydrogen or a group selected from among halogen, (C 1 -C 6 -alkyl) 2 N—, CF 3 , NH 2 SO 2 —, —CONH—C 6 -C 14 -aryl, —CONH—C 1 -C 4 -alkyl-C 6 -C 14 -aryl and —O—C 1 -C 4 -alkyl.  
 
   
   
       8 ) A method for the treatment and/or prevention of diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, characterised in that an effective amount of a compound of formula I according to  claim 1  is administered to a patient.  
   
   
       9 ) A pharmaceutical preparation comprising as active substance one or more compounds of formula (I) according to  claim 1  combined with one or more conventional excipients or carriers or both.