BENZIMIDAZOLE, BENZOTHIAZOLE AND BENZOXAZOLE DERIVATIVES AND USE THEREOF AS LTA4H MODULATORS Russian patent published in 2009 - IPC C07D417/12 C07D417/14 C07D277/68 C07D263/58 C07D471/10 C07D491/10 C07D235/26 C07D401/12 C07D413/12 A61K31/428 A61K31/4535 A61K31/4184 A61K31/423 A61P29/00 

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR⁵, O and S, where R⁵ is one of H and CH₃; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH₂ and CHR¹-CH₂, where R¹ is H or OH, and where the carbon group bonded to R¹ in the said CHR¹-CH₂ is not directly bonded to the nitrogen atom which is bonded to the said W; R⁴ is chosen from a group which consists of H, OCH₃ and Cl; R⁶ is H or F; and R^2' and R^3' are each independently chosen from a group which consists of: A) H, C_1-7alkyl, C_3-7cycloalkyl, C_3-7cycloalkyl-C_1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 R^Q, where each of said R^Q is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetR^a substitute; C) -C_1-7alkyl-C(O)R^x; H) -C_0-4alkyl-Ar⁵, where Ar⁵ is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NR^Y, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C_0-4alkyl-Ar^5' , where Ar^5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO₂C_1-4alkyl; alternatively, R^2' and R^3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetR^b, where the said 4-7-member heterocyclic ring HetR^b has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -R^Y, -CN, -C(O)R^Y, -C_0-4alkyl-CO₂R^Y, -C_0-4alkyl-C(O)CO₂R^Y, -C_0-4alkyl-OR^Y, -C_0-4alkyl-C(O)NR^YR^Z-, -C_0-4alkyl-NR^YC(O)R^Z-, -C(O)NR^ZOR^Y, -C_0-4alkyl-NR^YCO₂R^Y, -C_0-4alkyl-NR^YC(O)NR^YR^Y, -C_0-4alkyl-NR^YC(S)NR^YR^Z, -NR^YC(O)CO₂R^Y, -C_0-4alkyl-NR^WSO₂R^Y, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-R^Y-1H-tetrazol-5-yl, RY-triazolyl, 2-R^Y-2H-tetrazol- 5-yl, -C_0-4alkyl-C(O)N(R^Y)(SO₂R^Y), -C_0-4alkyl-N(R^Y)(SO₂)NR^YR^Y, -C_0-4alkyl-N(R^Y)(SO₂)NR^YCO₂R^Y, halogen, , ,; ii) 5-7-member heterocyclic ring HetR^C which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)₂ and >NR^M, where the said 5-7-member heterocyclic ring HetR^C has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)R^Y and R^Z; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C_0-4alkyl-R^Z, -C_0-4alkyl-CO₂R^Y; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetR^a is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NR^M group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C_1-4alkyl; R^L is chosen from a group which consists of -CO₂R^S; R^S is hydrogen; R^M is chosen from a group which consists of R^Z, -C(O)R^Y; R^N is chosen from a group which consists of OCH₃, CI, F, Br, I, OH, NH₂, CN, CF₃, CH₃ and NO₂; R^Q is chosen from a group which consists of -CN, -C_0-4alkyl-OR^Y, -C_0-4alkyl-CO₂R^Y, -C_0-4alkyl-NR^YR^Y, -C_0-4alkyl-NR^YCOR^Y, -C_0-4alkyl-NR^YCONR^YR^Z, -C_0-4alkyl-NR^YSO₂R^Y; R^W is chosen from a group which consists of R^Y; R^X is chosen from a group which consists of -OR^Y, -NR^YR^Z, -C_1-4alkyl and -C_1-4alkyl-R^Ar; R^Y is chosen from a group which consists of H, C_1-4alkyl, -C_0-4alkyl-R^Ar and -C_0-4alkyl-R^Ar', each of which is substituted with 1 or 2 R^N substitutes; R^Z is chosen from a group which consists of R^Y, -C_1-2alkyl-CO₂R^Y ; R^Ar is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 R^N or 0 or 1 ^RL; R^Ar' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NR^Y, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 R^K; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR⁵, O and S, where R⁵ is one of H and CH₃; Y is chosen from a group which consists of CH₂ and O, W is chosen from a group which consists of CH₂ and CHR¹-CH₂, where R¹ is H or OH, and where the carbon group bonded to R¹ in the said CHR¹-CH₂ is not directly bonded to a nitrogen atom; R⁴ is chosen from a group which consist of H, OCH₃, CI, F, Br, OH, NH₂, CN, CF₃ and CH₃; R⁶ is H or F; and R² and R³ are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex