Patent EP-2210615-A1 (EP)
Inventor: GODESSART MARINA NURIA
IPC: A61K31/44
Filed: 2009-01-21
Abstract: The present invention provides a combination which comprises (a) methotrexate and (b) a non-hepatotoxic DHODH inhibitor of formula (I):   
wherein: 
R 1  is selected from the group consisting ofhydrogen atoms, halogen atoms, C 1-4  alkyl, C 3-4  cycloalkyl, -CF 3  and -OCF 3 , 
R 2  is selected from the group consisting of hydrogen atoms, halogen atoms and C 1-4  alkyl groups, 
R 3  is selected from the group consisting of -COOR 5 , -CONHR 5 , tetrazolyl, -SO 2 NHR 5  and -CONHSO 2 R 5  groups, wherein R 5  is selected from the group consisting of a hydrogen atom and linear or branched C 1-4  alkyl groups, 
R 4  is selected from the group consisting of a hydrogen atom and a C 1-4  alkyl group, 
R 9  is selected from the group consisting of a hydrogen atom and a phenyl group, 
G 1  represents a group selected from N and CR 6  wherein R 6  is selected from the group consisting ofhydrogen atoms, halogen atoms, C 1-4  alkyl, C 3-4  cycloalkyl, C 1-4  alkoxy, - CF 3 , -OCF 3 , monocyclic N-containing C 5-7  heteroaryl, monocyclic N-containing C 3-7  heterocyclyl groups and C 6-10  aryl groups which C 6-10  aryl groups are optionally substituted with one or more substituents selected from halogen atoms and C 1-4  alkyl groups, 
G 2  represents a group selected from: 
¢ a hydrogen atom, a hydroxy group, a halogen atom, a C 3-4  cycloalkyl group, a C 1-4  alkoxy group and NR a R b , wherein 
R a  represents a C 1-4  alkyl group and R b  is selected from a group consisting of C 1-4  alkyl group and C 1-4  alkoxy-C 1-4  alkyl group, or 
R a  and R b  together with the nitrogen atom to which they are attached form a saturated 6 to 8 membered heterocyclic ring optionally containing one oxygen atom as an additional heteroatom, 
¢ a monocyclic or bicyclic 5 to 10 membered heteroaromatic ring containing one or more nitrogen atoms which is optionally substituted by one or more substituents selected from halogen atoms, C 1-4  alkyl, C 1-4  alkoxy, C 3-4  cycloalkyl, C 3-4  cycloalkoxy, -CF 3 , -OCF 3 , and -CONR 7 R 8 , wherein R 7  and R 8  are independently selected from hydrogen atom, linear or branched C 1-4  alkyl groups, C 3-7  cycloalkyl groups, or R 7  and R 8  together with the nitrogen atom to which they are attached form a group of formula   
wherein n is an integer from 0 to 3, 
and 
¢ a phenyl group which is optionally substituted by one or more substituents selected from halogen atoms, C 1-4  alkyl, hydroxyl, C 1-4  alkoxy, C 3-4 cycloalkyl, C 3-4  cycloalkoxy, cyano, -CF 3 , -OCF 3 , -CONR 7 R 8 , oxadiazolyl, triazolyl, pyrazolyl and imidazolyl groups, which oxadiazolyl, triazolyl, pyrazolyl and imidazolyl groups are optionally substituted by C 1-4  alkyl or C 3-7  cycloalkyl groups and wherein R 7  and R 8  are independently selected from hydrogen atom, linear or branched C 1-4  alkyl groups, C 3-7  cycloalkyl groups, or R 7  and R 8  together with the nitrogen atom to which they are attached form a group of formula     
wherein n is an integer from 0 to 3 
or, when G' represents CR 6 , G 2  together with R 6  forms a non-aromatic C 5-10  carbocyclic group or a C 6-10  aryl group,  
and the pharmaceutically acceptable salts and N-oxides thereof.