COMBINATIONS COMPRISING METHOTREXATE AND DHODH INHIBITORS

摘要

The present invention provides a combination which comprises (a) methotrexate and (b) a non-hepatotoxic DHODH inhibitor of formula (I): wherein: R1 is selected from the group consisting of hydrogen atoms, halogen atoms, C1-4 alkyl, C3-4 cycloalkyl, -CF3 and -OCF3, R2 is selected from the group consisting of hydrogen atoms, halogen atoms and C1-4 alkyl groups, R3 is selected from the group consisting of -COOR5, -CONHR5, tetrazolyl, -SO2NHR5 and -CONHSO2R5 groups, wherein R5 is selected from the group consisting of a hydrogen atom and linear or branched C1-4 alkyl groups, R4 is selected from the group consisting of a hydrogen atom and a C1-4 alkyl group, R9 is selected from the group consisting of a hydrogen atom and a phenyl group, G1 represents a group selected from N and CR6 wherein R6 is selected from the group consisting of hydrogen atoms, halogen atoms, C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, -CF3, -OCF3, monocyclic N-containing C5-7 heteroaryl, monocyclic N- containing C3-7 heterocyclyl groups and C6-10 aryl groups which C6-10 aryl groups are optionally substituted with one or more substituents selected from halogen atoms and C1-4 alkyl groups, G1 represents a group selected from N and CR6 wherein R6 is selected from the group consisting of hydrogen atoms, halogen atoms, C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, -CF3, -OCF3, monocyclic N-containing C5-7 heteroaryl, monocyclic N- containing C3-7 heterocyclyl groups and C6-10 aryl groups which C6-10 aryl groups are optionally substituted with one or more substituents selected from halogen atoms and C1-4 alkyl groups, G2 represents a group selected from:•a hydrogen atom, a hydroxy group, a halogen atom, a C3-4 cycloalkyl group, a C1-4 alkoxy group and -NRaRb, wherein Ra represents a C1-4 alkyl group and Rb is selected from a group consisting of C1-4 alkyl group and C1-4alkoxy-C1-4 alkyl group, or Ra and Rb 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, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, -CF3, -OCF3, and -CONR7R8, wherein R7 and R8 are independently selected from hydrogen atom, linear or branched C1-4 alkyl groups, C3-7 cycloalkyl groups, or R7 and R8 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, C1-4 alkyl, hydroxyl, C1-4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, cyano, -CF3, -OCF3, -CONR7R8, oxadiazolyl, triazolyl, pyrazolyl and imidazolyl groups, which oxadiazolyl, triazolyl, pyrazolyl and imidazolyl groups are optionally substituted by C1-4 alkyl or C3-7 cycloalkyl groups and wherein R7 and R8 are independently selected from hydrogen atom, linear or branched C1-4 alkyl groups, C3-7 cycloalkyl groups, or R7 and R8 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 CR6, G2 together with R6 forms a non-aromatic C5-10 carbocyclic group or a C6-10 aryl group, and the pharmaceutically acceptable salts and N-oxides thereof.