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    • 6. 发明申请
    • DIHYDRO-BENZO(1,4)OXAZINES AND TETRAHYDROQUINOXALINES
    • 二氢苯并(1,4)氧化合物和四氢喹啉酮
    • WO0039103B1
    • 2000-09-28
    • PCT/GB9904430
    • 1999-12-23
    • AVENTIS PHARMA LTDBOURZAT JEAN DOMINIQUECOMMERCON ALAINFILOCHE BRUNO JACQUES CHRISTOPHARRIS NEIL VICTORPALLIN THOMAS DAVIDSTUTTLE KEITH ALFRED JAMES
    • BOURZAT JEAN-DOMINIQUECOMMERCON ALAINFILOCHE BRUNO JACQUES CHRISTOPHARRIS NEIL VICTORPALLIN THOMAS DAVIDSTUTTLE KEITH ALFRED JAMES
    • A61P11/06A61P29/02C07D241/38C07D265/36A61K31/495A61K31/535
    • C07D241/38C07D265/36
    • The invention is directed to physiologically active compounds of formula (I) wherein R represents R -Z , R -L -R -Z -, R -L -Ar -L -Z - or R -L -Ar -L -R -Z -; R represents hydrogen, halogen, lower alkyl or lower alkoxy; A represents a straight chain C2-3alkylene linkage optionally substituted by one or more groups chosen from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, imino, oxo, thioxo, or alkyl substituted by -ZR , -NY Y , -CO2R or -C(=O)-NY Y ; L 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 , R , -C(=O)-R , -C(=O)-OR , -N(R )-C(=O)-R , -N(R )-C(=O)-OR , -N(R )-SO2-R , -NY Y or -[C(=O)-N(R )-C(R )(R )]p-C(=O)-NY Y , or by (b) alkyl substituted by an acidic functional group, or by S(O)mR , -C(=O)-NY Y or -NY Y ; a -[C(=O)-N(R )-C(R )(R )]p-linkage; a-Z -R -linkage; a -C(=O)-CH2-C(=O)-linkage; a -R -Z -R - linkage; a -C(R )(R )-[C(=O)-N(R )-C(R )(R )]p- linkage; or a -L -L -L - linkage; Z is NR or O; 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).
    • 本发明涉及式(I)的生理活性化合物,其中R 1表示R 3 -Z 3,R 3 -L 2 -R 4 -Z 3 - , R 3 -L 3 -Ar 1 -L 4 -Z 3 - 或R 3 -L 3 -Ar 1 -L 2 -R 4 -Z <3> - ; R 2表示氢,卤素,低级烷基或低级烷氧基; A 1表示任选被一个或多个选自烷基,芳基,芳基烷基,杂芳基,杂芳基烷基,亚氨基,氧代,硫代基或被-ZR 6,-NY取代的烷基的基团取代的直链C 2-3亚烷基键。 1→Y 2,-CO 2 R 6或-C(= O)-NY 1 Y 2; L 1表示直接键; 亚烷基,亚炔基,亚环烯基,亚环烷基,杂芳基二基,杂环亚烷基或亚芳基,各自任选被(a)酸性官能团,氰基,氧代,-S(O)m R 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)-SO 2 -R 9,-NY 4 Y 5或 - [C(= O) 10))-C(R 5)(R 11)] pC(= O)-NY 4 Y 5或(b)被酸官能团取代的烷基,或被S( O)m R 9,-C(= O)-NY 4 Y 5或-NY 4 Y 5; a - [C(= O)-N(R 10)-C(R 5)(R 11)] p - 键; A-Z <2> -R <12> - 键; -C(= O)-CH 2 -C(= O) - 链接; -R 12 -Z 2 -R 12 - 键; -C(R 4)(R 13) - [C(= O)-N(R 10)-C(R 5)(R 11)] p键; 或-L 5 -L 6 -L 7 - 键; Z 1是NR 17或O; Y是羧基或酸生物电子等排体; 和相应的N-氧化物及其前药; 和这些化合物及其N-氧化物和前药的药学上可接受的盐和溶剂化物。 这些化合物具有有价值的药物性质,特别是调节VCAM-1和纤连蛋白与整联蛋白VLA-4(α4β1)的相互作用的能力。