combination of (a) methotrexate and (b) a nonhephototoxic dhodh inhibitor, use of a combination, product, kit, package and treatment method

摘要

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.