New 2,4-dianilinopyrimidine derivatives are kappa B kinase inhibitors, useful to treat or prevent e.g. inflammatory diseases, diabetes, cancer resistant to cytotoxic agents, solid or liquid tumors and in cancer chemotherapy

摘要

2,4-Dianilinopyrimidine derivatives (I) and their isomers, enantiomers, diastereomers and addition salts with mineral and organic acids, are new. 2,4-Dianilinopyrimidine derivatives of formula (I) and their isomers, enantiomers, diastereomers and addition salts with mineral and organic acids, are new. R2-R4 : halo, H, alkyl or alkoxy; R5 : H or halo; R1 : alkyl (optionally substituted by 5 membered heterocyclic radical (optionally substituted by halo, alkyl or alkoxy) or T), cycloalkyl, alkenyl, alkynyl (all optionally substituted by T) or H; T : halo, OR8 or NR8R9; A : single bond, -CH 2-CO- or NR6; R6 : R1; ring Y1 : 4-8 membered ring containing Y1; Y1 : O or S (optionally oxidized by 2O, N-R7, C=O or dioxolane as protective group of carbonyl, CF 2, CH-OR8 or CH-NR8R9); R7 : alkyl (optionally substituted by phosphonate, alkylthio (optionally oxidized by sulfone or by optionally substituted heterocycloalkyl)), cycloalkyl, CH 2-alkenyl, CH 2-alkynyl (all optionally substituted by naphthyl, halo, OH, alkoxy, phenyl or heteroaryl) or H; either R8 : alkyl (optionally substituted by alkylthio, phenyl or heterocyclic group), (hetero)cycloalkyl (all optionally substituted by halo, OH, alkoxy, NH 2, NHalkyl or N(alkyl) 2); NR8R9 : cyclic amine (containing 1-2 heteroatoms e.g. O, S, N or NR10, optionally substituted by alkyl); and R10 : H or alkyl. The heterocyclic, heterocycloalkyl and heteroaryl radicals contain 4-10 membered ring and 1-3 heteroatoms e.g. O, S, N and NR10. The radicals of naphthyl, phenyl, heterocyclic, heterocycloalkyl and heteroaryl are optionally substituted by halo, OH, alkoxy, alkyl, OH-alkyl, CN, CF 3, NH 2, NHalkyl or N(alk) 2. Provided that at least one of R2-R4 is halo. Provided that when Y1 is NR7, the ring can contain a 1-3C bridging group. An independent claim is also included for the preparation of (I). [Image] ACTIVITY : Antiinflammatory; Antidiabetic; Cytostatic; Antiarthritic; Antirheumatic; Osteopathic; Ophthalmological; Uropathic; Antipsoriatic; Neuroprotective; Antiasthmatic; Respiratory-Gen.; Antiallergic; Muscular-Gen.; Immunosuppressive; Dermatological; Immunomodulator; Antibacterial; Cardiant; Antiarteriosclerotic; Anti-HIV; Anorectic; Gynecological; Hypotensive; Cardiovascular-Gen.; Analgesic; Antianginal; Nephrotropic; Virucide; Vasotropic; Cerebroprotective; Antiarrhythmic; Hepatotropic; Antianemic; Antiangiogenic. MECHANISM OF ACTION : Kappa B kinase inhibitor; Apoptosis modulator; Tumor cell proliferation inhibitor. The ability of (I) to inhibit kappa B kinase was tested using biological assays. The results showed that the IC 50 value of (I) was less than 10 mu M.