New 4-substituted 3,5-dialkyl-isoxazole derivatives, useful as antiviral agents having strong activity against hepatitis B virus and low cytotoxicity

摘要

N-(Hetero)aryl-3,5-dialkylisoxazole-4-carboxamide derivatives (I) (including 4-thioamide, urea, thiourea or methylamine analogs) are new. Isoxazole derivatives of formula (I) are new. [Image] R 1, R 2alkyl (optionally substituted by one or more halo); X : -C(Y)-, -N(R 4)-C(Y)-, CH 2or (CH 2) nC(Y); n : 1-4; R 3, R 4H or optionally halo-substituted alkyl; Y : O or S; A : aryl or 6-membered heteroaryl (both optionally substituted by 1-3 of halo, alkyl, alkoxy, alkylthio, alkoxycarbonyl, NHCONH 2, mono- or dialkylamino, CN, NH 2or mono- or dialkylamino, provided that substituents in the ortho-position are halo, alkyl, alkoxy or alkylthio). Independent claims are included for: (i) the preparation of (I); and (ii) combinations of (A) at least one isoxazole (not restricted to (I)), (B) at least one other anti-hepatitis B virus (HBV) agent and optionally (C) at least one immunomodulator. ACTIVITY : Virucide; Hepatotropic; Antiinflammatory. In tests in HepG2.2.15 cells, 3,5-dimethylisoxazole-4-carboxylic acid N-(4-fluoro-3-methylphenyl)-amide (Ia) had IC 500.2 MicroM against hepatitis B virus and cytotoxicity CC 50more than 100 MicroM; the corresponding values for leflunomide were IC 50more than 70 MicroM and CC 5070 MicroM. MECHANISM OF ACTION : None given.