AZA-BICYCLES WHICH MODULATE THE INHIBITION OF CELL ADHESION

摘要

The invention is directed to physiologically active compounds of formula (I) wherein R<1> represents R<3>-Z<3>-, R<3>-L<2>-R<4>-Z<3>-, R<3>-L<3>-Ar<1>-L<4>-Z<3>- or R<3>-L<3>-Ar<1>-L<2>-R<4>-Z<3>-; R<2> represents hydrogen, halogen, lower alkyl or lower alkoxy; A<1> represents a straight chain C1-3alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR<6>, -NY<1>Y<2>, -CO2R<6> or -C(=O)-NY<1>Y<2>; L<1> represents a direct bond; an alkenylene, alkylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, -S(O)mR<9>, R<3>, -C(=O)-R<3>, -C(=O)-OR<3>, -N(R<8>)-C(=O)-R<9>, -N(R<8>)-C(=O)-OR<9>, -N(R<8>)-SO2-R<9>, -NY<4>Y<5> or -[C(=O)-N(R<10>)-C(R<5>)(R<11>)]p-C(=O)-NY<4>Y<5>, or by (b) alkyl substituted by an acidic functional group, or by S(O)mR<9>, -C(=O)-NY<4>Y<5> or -NY<4>Y<5>; a -[C(=O)-N(R<10>)-C(R<5>)(R<11>)]p- linkage; a -Z<2>-R<12>- linkage; a -C(=O)-CH2-C(=O)- linkage; a -R<12>-Z<2>-R<12>- linkage; a -C(R<4>)(R<13>)-[C(=O)-N(R<10>)-C(R<5>)(R<11>)]p- linkage; or a -L<5>-L<6>-L<7>- linkage; Z<1> is C(R<7>)(R<7a>), C(=O) or CH(OH); Y is carboxy or an acid bioisostere; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs. Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 ( alpha 4 beta 1).