申请人:Bristol-Myers Squibb Company
公开号:US05846998A1
公开(公告)日:1998-12-08
A method of inhibiting the proliferation of B cells by using inhibitors of phosphotyrosine phosphatase can be used to regulate the immune response and to treat diseases such as leukemias or lymphomas marked by malignant proliferation of B cells or T cells. Antitumor activity is seen in vivo against tumors and against tumor cell lines. The use o such inhibitors can be combined with radiation, which produces a synergistic effect. Several types of inhibitors can be used, including: (1) compounds comprising a metal coordinate-covalently bound to an organic moiety that can form a five- or six-membered ring, in which the metal is preferably vanadium (IV); (2) compounds in which vanadium (IV) is coordinate-covalently bound to an organic moiety such as a hydroxamate, .alpha.-hydroxypyridinone, .alpha.-hydroxypyrone, .alpha.-amino acid, hydroxycarbonyl, or thiohydroxamate; (3) coordinate-covalent complexes of cysteine or a derivative thereof; (4) nonhydrolyzable phosphotyrosine analogues; (5) dephostatin; (6) 4-(fluoromethyl)phenyl phosphate and esterified derivatives; and (7) coordinate-covalent metal-organic compounds containing at least one oxo or peroxo ligand bound to the metal, in which the metal is preferably vanadium (V), molybdenum (VI), or tungsten (VI).
使用磷酸酪氨酸酶抑制剂抑制B细胞增殖的方法可用于调节免疫反应并治疗由B细胞或T细胞恶性增殖标记的白血病或淋巴瘤等疾病。在体内观察到对肿瘤和肿瘤细胞系的抗肿瘤活性。这些抑制剂的使用可以与放射线结合使用,产生协同作用。可以使用几种类型的抑制剂,包括:(1)包含金属配位共价结合到可以形成五元或六元环的有机基团的化合物,其中金属最好是钒(IV);(2)钒(IV)与羟肟酸,α-羟基吡啶酮,α-羟基吡酮,α-氨基酸,羟基羰基或硫羟肟酸等有机基团共价结合的化合物;(3)半胱氨酸或其衍生物的配位共价络合物;(4)不可水解的磷酸酪氨酸类似物;(5)去磷酸酯酶;(6)4-(氟甲基)苯磷酸和酯化衍生物;(7)含有至少一个氧或过氧配体与金属结合的配位共价金属-有机化合物,其中金属最好是钒(V),钼(VI)或钨(VI)。