Combinations that include methotrexate and a dihydroorotate dehydrogenase inhibitor

Abstract

The present invention provides a combination comprising (a) methotrexate and (b) a non-hepatotoxic dihydroorotate dehydrogenase (DHODH) inhibitor of formula (I): wherein: R1 consists of a hydrogen atom, a halogen atom, C1-4 alkyl, C3-4 cycloalkyl, -CF3 and -OCF3; R2 is selected from the group consisting of hydrogen atom, halogen atom and C1-4 alkyl; R3 Selected from the group consisting of -COOR5, -CONHR5, tetrazolyl, -SO2NHR5 and -CONHSO2R5 groups, wherein R5 is selected from the group consisting of hydrogen atoms and straight-chain 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 a group consisting of a hydrogen atom and a phenyl group; G1 represents a group selected from N and CR6, wherein R6 is composed of a hydrogen atom, Halogen atom, C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, -CF3, -OCF3, N-containing monocyclic C5-7 heteroaryl, N-containing monocyclic C3-7 heterocyclic And selected from the group consisting of C6-10 aryl groups, said C6-10 aryl groups may be optionally substituted by one or more substituents selected from halogen atoms and C1-4 alkyl groups; G2 means selected from the following Groups in the group: hydrogen atom, hydroxyl, halogen atom, C3-4 cycloalkyl, C1-4 alkoxy and -NRaRb, wherein Ra represents C1-4 alkyl and Rb consists of C1-4 alkyl and C1 - selected from the group consisting of 4 alkoxy-C1-4 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 6 to 8 which may optionally contain an oxygen atom as another heteroatom membered heterocyclic ring; monocyclic or bicyclic 5 to 10 membered heteroaryl ring containing one or more nitrogen atoms, which may be optionally replaced by one or more members selected from halogen atoms, C1-4 alkyl, C1-4 alkoxy Substituents of radical, C3-4 cycloalkyl, C3-4 cycloalkoxy, -CF3, -OCF3 and -CONR7R8, wherein R7 and R8 are independently selected from hydrogen atom, straight chain or branched chain C1-4 alkane group, C3-7 cycloalkyl group, or R7 and R8, together with the nitrogen atom to which they are attached, form a group of the following formula: wherein n is an integer from 0 to 3; and phenyl, which may optionally be replaced by one or more One selected from halogen atom, C1-4 alkyl, hydroxyl, C1-4 alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, cyano, -CF3, -OCF3, -CONR7R8, oxadiazole Substituents of diazolyl, triazolyl, pyrazolyl and imidazolyl, said diazolyl, triazolyl, pyrazolyl and imidazolyl can be optionally replaced by C1-4 alkyl or C3-7 cycloalkyl Substituted and wherein R7 and R8 are independently selected from a hydrogen atom, a straight or branched C1-4 alkyl group, a C3-7 cycloalkyl group, or R7 and R8 together with the nitrogen atom to which they are attached form a group of the following 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 its pharmaceutical Pharmaceutically acceptable salts and N oxides.

Description

【Technical field】 [0001] The present invention relates to novel combinations of methotrexate and dihydroorotate dehydrogenase (DHODH) inhibitors. These combinations are suitable for the treatment, prevention or inhibition of diseases and conditions known to be ameliorated by methotrexate and / or by inhibition of dihydroorotate dehydrogenase, such as autoimmune diseases, immune and inflammatory diseases, destructive Destructive bone disorder, malignant neoplastic disease, angiogenic-related disorder, viral disease, and infectious disease. 【Background technique】 [0002] Methotrexate (MTX) is an antimetabolite and immunomodulator that affects many intracellular pathways of purine metabolism. It is effective in reducing the signs and symptoms of rheumatoid arthritis (RA) and slowing or stopping radiation damage. Due to its efficacy, ease of administration, and relatively low cost, MTX has become the first-line oral therapy in most RA patients. In patients with an incomplete r...

AI Technical Summary

Problems solved by technology

Therefore, hepatotoxicity has been identified as an adverse effect directly arising from the mechanism of action of DHODH-inhibitors, which hampers the development of this class of compounds

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