Benzobchromenonapthyridin-7-one and pyrano2',3':7,8quino2,3-bQuinoxalin-7-one derivatives, process of synthesis, pharmaceutical compositions and their antitumoral properties for the treatment of cancer

摘要

Benzo[b]chromeno[g]naphthyridone or pyrano[2',3':7,8]quinolino[2,3-b]quinoxalinone derivatives (I) are new. Benzo[b]chromeno[g]naphthyridone or pyrano[2',3':7,8]quinolino[2,3-b]quinoxalinone derivatives of formula (I) and their isomers, N-oxides and salts are new: B 1, B 2C or N, at least one being N; X, Y : H, halo, OH, 1-6C alkoxy, NO 2, CN, 1-6C alkyl, 2-6C alkenyl, 1-6C polyhaloalkyl or NR aR b; R a, R bH, COCF 3, CONH 2 or 1-6C alkyl optionally substituted with NR' aR' b or NR aR b is a 5- to 7-membered ring optionally containing another heteroatom (O or N); R' a, R' bH or 1-6C alkyl, or NR' aR' b is a 5- to 7-membered ring optionally containing another heteroatom (O or N); X 1, Y 1X and Y or are absent when B 1, B 2 is N; R 1H or 1-6C alkyl; R 2H, 1-6C alkyl, OR" a, NR' aR' b, OT aOR" a, NR" aT aNR' aR' b, NR" aCOT aH, OCOT aH, OT aNR' aR' b, NR" aT aOR" a, NR" aT aCOOR" a or NR" aCOT aNR' aR' b; T a1-6C alkylene; R" aH or 1-6C alkyl; R 3, R 4H or 1-6C alkyl or together form a 3- to 6-membered ring; A : CHR 5CHR 6, CH=CR 7, CR 7=CH, COCHR 8 or CHR 8CO; R 5, R 6H, OR c, NR cR d, SR c, W 1C(W 2)U'V', W 1C(W 2)W 3T 1, W 1SO nW 3T 1, W 1SO nT 1 or C(W 2)T 1, or together form OC(Z)O, NHC(Z)O, OC(Z)NH, NHC(Z)NH, O(CH 2) mO, OCOB'COO, NHCOB'COO or OCOB'CONH, or CR 5R 6 is an oxirane or optionally N-substituted aziridine group; R c, R dH, 1-6C alkyl, aryl, aryl(1-6C)alkyl or COR e; R eH, aryl or NR"' aR"' b; R"' a, R"' bH or NR"' aR"' b is a 5- to 7-membered ring optionally containing another heteroatom (O or N); W 1O, S or NR c; W 2O or S; U' : 1-8C alkylene or 2-8C alkenylene, or is a bond when W 2 is not O and V' is not H, aryl or NH 2; V' : H, aryl, OR c, COOR c, COR c, CONR' aR' b, NR cR d, N(R c)COOR' c or N(R c)COR' c; R' c1-6C alkyl, aryl or aryl(1-6C)alkyl; W 3O, S or NR c; T 1H, 1-6C alkyl, 2-6C alkenyl, aryl, aryl(1-6C)alkyl, or 1-6C alkyl or 2-6C alkenyl substituted with OR c or NR' aR' b; n : 1 or 2; Z : O or S; m : 1-4; B' : bond, 1-6C alkylene or 2-6C alkenylene; R 7H, OR" a, W 1C(W 2)U'V', W 1C(W 2)W 3T 1, W 1SO nW 3T 1, W 1SO nT 1 or C(W 2)T 1; and R 8H, 2-7C alkanoyloxy or OR" a. An independent claim is also included for the preparation of (I). [Image] ACTIVITY : Cytostatic. cis-1,2-Acetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one had IC50 values of 0.32 mu M against L1210 murine leukemia cells and 0.037 mu M against KB-3-1 human epidermoid carcinoma cells. MECHANISM OF ACTION : Cell cycle blocker.