DERIVATIVES OF 1'-(2-HYDROXY-3-ARYLOXYPROPYL-1-YL)-SUBSTITUTED SPIRO[BENZOFURAN-PIPERIDINES], SPIRO[BENZOFURAN-PYRROLIDINES] AND SPIRO[CHROMEN-PIPERIDINES], METHOD FOR THEIR PREPARING, INTERMEDIATE COMPOUND AND METHOD FOR ITS PREPARING, PHARMACEUTICAL COMPOSITION, USING Russian patent published in 2008 - IPC C07D491/10 C07D471/10 C07D221/20 C07D209/54 

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R¹ means halogen atom; X, Y and Z represent independently a bond, -CH₂- or -O-, or X and Y form in common -CH=C(CH₃)- or -C(CH₃)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R² represents halogen atom, or (C₁-C₆)-alkyl; q = 0 or 1; R³ represents -NHC(O)R¹⁰, -C(O)NR¹¹R¹² or -COOR^12a; each radical among R⁴, R⁵, R⁶, R⁷ and R⁸ represents independently hydrogen atom (H) or (C₁-C₆)-alkyl; t = 0, 1 or 2; R⁹ represents halogen atom, -OH, -COOH, (C₁-C₆)-alkoxy group, (C₁-C₆)-alkoxycarbonyl; R¹⁰ represents group (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, or R¹⁰ represents -NR¹⁴R¹⁵; each R¹¹ and R¹² represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C₁-C₆)-alkyl, (C₁-C₆)-hydroxyalkyl; (3) (C₁-C₆)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C₁-C₆)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C₁-C₆)-alkylsulfonyl, or R¹¹ and R¹² in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C₁-C₆)-alkyl, (C₁-C₆)-hyroxyalkyl, (C₁-C₆)-halogenalkyl, (C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R^12a represents H or (C₁-C₆)-alkyl; each radical among R¹⁴ and R¹⁵ represents independently H or (C₁-C₆)-alkylsulfonyl, or R¹⁴ and R¹⁵ in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R³ represents -NHC(O)R¹⁰ and L¹ represents a leaving group is subjected for interaction with L¹C(O)R¹⁰; by other variant, compound of the formula (VIII): wherein R³ represents -C(O)NR¹¹R¹² and L² represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R^1a is chosen from F, Cl, -CH₃ and -CF₃; s = 1 or 2; q = 0 or 1; w = 0 or 1; R^2a represents F, and when q and s = 1 and w = 0 then R^1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R²⁰ represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R²⁰.

EFFECT: improved methods of synthesis.

25 cl, 236 ex