BENZIMIDAZOLE DERIVATIVES, SYNTHESIS METHODS THEREOF, USE THEREOF AS FARNESOID X RECEPTOR (FXR) AGONIST AND PHARMACEUTICAL PREPARATIONS CONTAINING SAID DERIVATIVES Russian patent published in 2011 - IPC C07D235/18 C07D409/10 C07D409/04 C07D403/04 C07D403/10 A61K31/4184 A61P3/00 A61P25/00 A61P35/00 

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R¹ denotes C_1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R² denotes hydrogen or lower alkyl; R³ denotes lower alkyl, C_3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)₂; R⁴ denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)₂, oxo group, NH₂, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH₂, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)₂, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R³ denotes cycloalkyl and R¹ denotes cycloalkyl, then R⁴ can also denote phenyl; R⁵, R⁶, R⁷ and R⁸ independently denote H, halogen, lower alkoxy group or lower alkyl, or R⁶ and R⁷, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex