COMPOUNDS AS INHIBITORS OF VLA-4 Russian patent published in 2005 - IPC

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C₁-C₆)-alkyl, halogen atom, (C₁-C₄)-alkoxy-group and halogen alkyl; W¹ means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C₁-C₆)-alkyl, halogen atom and (C₁-C₄)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C₁-C₆)-alkyl, halogen atom and (C₁-C₄)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH₂)_n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH₂-, -O- or -S-; R¹, R² and R³ are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH₂, mono- or dialkylamino-group, (C₁-C₆)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C₁-C₆)-alkylamine, (C₁-C₆)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C₁-C₄)-alkoxy-group; or two adjacent R¹, R² and R³ taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R⁴ means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C₂-C₈)-alkenylene group, (C₂-C₈)-alkynylene group, -C(O)-, -C(O)NH- and -(CH₂)_kY² wherein k is taken among 1, 2 and 3; Y² means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)₂- and -NY³- wherein Y³ is taken among hydrogen atom (H), lower alkyl; Z means (C₃-C₈)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A¹ means a direct bond, -(CH₂)_t-alkynyl wherein t is taken among 1, 2 and 3; R⁵ means -OH, lower alkoxy-group, , ; b) means wherein R¹¹ is taken among , -NR¹²- wherein R¹² is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z³ is taken among a direct bond, (C₁-C₁₂)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR¹³- wherein R¹³ means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R¹⁴ means hydrogen atom (-H), ; and when R¹¹ means NR¹² then Z³ is taken among: wherein ¹⁴Ra means hydrogen (H), halogen atom; , and ; Q² means wherein R¹⁷ and R¹⁸ mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L¹ means -COOH or -COOR¹⁹ wherein R¹⁹ means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex