DERIVATIVES OF BENZIMIDAZOL, BENZOTIAZOL AND BENZOXAZOL AND THEIR APPLICATION 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 A61K31/423 A61K31/428 A61K31/4184 A61K31/4535 A61P29/00 

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH₂ and O; R⁴ represents H; R⁶ represents H or F; and R^2' is determined as R², and R^3' is determined as R³, as follows: R² and R³, each, is independently selected from group that consists of A) H, C_1-7alkyl, C_3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 R^Q, and each of mentioned R^Q is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R² and R³, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetR^b, where specified (4-7)-member heterocyclic ring HetR^b has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -R^Y, -C(O)R^Y, -C_0-4alkylCO₂R^Y, -C_0-4alkylC(O)NR^YR^Z, -C_0-4alkylNR^YC(O)R^z, -C_0-4alkylNR^YC(O)CH₂OR^Y, -C_0-4alkylNR^YCO₂R^Y, -C₀-₄alkylNR^YC(O)NR^YR^z, -C_0-4alkylNR^yC(S)NR^yR^z, -NR^yC(O)CO₂R^y, -C_0-4alkylNR^wSO₂R^Y, tetrazol-5-yl, -C_0-4alkylN(R^Y)(SO₂)NR^YR^Y, -C_0-4alkylN(R^Y)(SO₂)NR^YCO₂R^Y, ii) (5-7)-member heterocyclic ring HetR^c, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)_0-2 and >NR^M, and where mentioned (5-7)-member heterocyclic ring HetR^c has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where R^K is selected from group that consists of H, -C_1-4alkyl, each not necessarily substituted by 1 substitute R^N; R^M is selected from group that consists of -SO₂R^Y, -C(O)R^Y, -C(O)C_1-4alkylOR^Y, each not necessarily substituted by 1 substitute R^N; R^N is selected from group that consists of OH, NH², CF₃; R^Q is selected from group that consists of -C_0-4alkylR^Ar', -C_0-4alkylCO₂R^Y, -C_0-4alkylNR^YR^z, -C_0-4alkylNR^YCOR^Y, -C_0-4alkylNR^yCONR^yR^z; R^w is selected from group that consists of R^Y and -C_3-7cycloalkyl; R^Y is selected from group that consists of H, -C_1-4alkyl, -C_0-4alkylR^Ar and -C_0-4alkylR^Ar', each not necessarily substituted by 1 substitute R^N; R^z is selected from group that consists of R^Y, -C_1-2alkylCO₂R^Y; R^Ar represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; R^Ar' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NR^Y, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 R^K; provided that (a) specified R^2' and R^3', moreover, satisfy the following requirements: (e1): specified R^2' and R^3', both, are not H, when Y represents O and X represents S; (e3): specified R^2' and R^3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH₂; (e4): specified R^2' and R^3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH₂; and (e5): specified R^2' and R^3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C_1-6alkyl, OSG represents O or S, and XR¹ and XR², taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR¹ and XR², taken independently, represent one of H, C_1-6alkyl, aryl, aralkyl, C_3-8cycloalkyl, C_3-8cycloalkyl-C_1-6alkyl, heteroalkyl, heteroaryl-C_1-6alkyl, heterocycloalkyl and heterocycloalkyl-C_1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C_1-6alkyl, C_1-6alkoxy, halogenated C_1-6alkyl, halogenated C_1-6alkoxy, nitro, cyano, amino, C_1-4alkylamino, di(C_1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R^2' and R^3' is not XCG, while the other represents C_1-6alkyl, where XCG represents group , where HC16 represents one of H, C_1-6alkyl, halogenC_1-6alkyl, allyl and C_1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex