New benzo or heterocyclo fused aza-bicycloalkane derivatives, are antibacterial agents effective against Gram positive and Gram negative bacteria e.g. Staphylococcus aureus and Escherichia coli

摘要

Benzo or heterocyclo fused aza-bicycloalkane derivatives (I) are new. Also new are seven classes of intermediates. Benzo or heterocyclo fused aza-bicycloalkane derivatives of formula (I) and their salts with acids or bases are new. Either (i) R1 = H, COOH, CN, COOR, (CH2)pR5, CONR6R7 or -C(=NR6)NHR7; and R3+R4 = group completing a fused phenyl or 5 or 6-membered heterocyclic ring containing 1-4 of N, O and S as heteroatom(s), both optionally substituted (os) by one or more R'; or (ii) R1+R3 = group completing a fused ring as defined above; and R4 = H or (CH2)qR5; R = 1-6C alkyl (os by pyridyl); CH2-alkenyl having a total of 3-9C; or 6-10C aryl or 7-11C aralkyl (both os in the ring by OH, NH2, NO2, 1-6C alkyl, 1-6C alkoxy or one or more halo); R5 = COOH, CN, OH, NH2, CONR6R7, COOR, OR, OCHO, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOR, NHCHO, NHSO2R, NHCOOR, NHCONHR or NHCONH2; R6, R7 = H, 1-6C alkyl, 6-10C aryl, 7-11C aralkyl or pyridyl-(1-6C) alkyl; p = 1 or 2; q = 0-2; R' = H, 1-6C alkyl, 2-6C alkenyl, halo, NH2, OH, OR, NHCHO, NHCOR, NHCOOR, COOH, COOR, C(Ph)3 or -CH2CH2S(O)mR; m = 0-2; R2 = H, halo, R, S(O)mR, OR, NHCOR, NHCOOR or NHSO2R; X = CO-B- (bonded to N via CO); B = O-(CH2)r- (bonded to CO via O), NR8(CH2)r, NR8-O (bonded to CO via N); r = 0-1; R8 = H, OH, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2S(O)mR, SiRaRbRc, or OSiRaRbRc; Ra, Rb, Rc = 1-6C alkyl or 6-10C aryl; Y = CHO, COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN, optionally protected tetrazolylmethyl, CH2SO3H, CH2SO2R, CH2P(O)(OR)2, CH2P(O)(OR)(OH), CH2P(O)(R)(OH) or CH2P(O)(OH)2; Y1 = SO2R, SO2NHCHO, SO2NHCOR, SO2NHCOOR, SO2NHCONHR, SO2NHCONH2 or SO3H; Y2 = P(O)(OH)2, P(O)(OR)2, P(O)(OH)(OR) or P(O)(OH)(R); Y3 = Tet, squarate, NH-Tet, NR-Tet, NHSO2R or NRSO2R; Tet = tetrazolyl (os by R); n = 1 or 2. Independent claims are also included for: (1) preparation of (I); and (2) piperidine or homopiperazine derivative intermediates of formulae (II)-(VIII), their acid-addition salts (specifically the hydrochlorides or trifluoroacetates) and N-protected derivatives of (II). R'1-R'4, R'8 = R1-R4, R8, except that any OH, NH2, NHR, CONHOH, free carboxylic, sulfonic or phosphoric/phosphonic acid, tetrazolyl or squarate groups are protected; Z'H = HO(CH2)r, HNR'8(CH2)r or HNR8O; either X1 = H; and X2 = Z'-CO-X3; or X1 = CO-X3; and X2 = Z'H; X3 = carbonylating agent residue; A = H or protecting group.