Patent CA-2507607-A1 (CA)
Title: Heterocyclic compounds, their preparation and their use as medication, specifically as anti-bacterials and inhibitors of beta-lactamases
Inventor: MUSICKI BRANISLAV
IPC: C07D471/18
Filed: 2003-11-28
Abstract: Benzo- or heteroaromatic-fused azabicycloalkane derivatives (I) are new. Also new are some benzo- or heteroaromatic-fused azacycloalkane intermediates (A).  Azabicyclic compound derivatives of formula (I) and their salts with acids or bases are new.  Either (a) R1  =  H, COOH, COOR, CN, (CH2)pR5, CONR6R7 or C(NHR7)=NR8;  R  =  alkyl (optionally substituted (os) by one or more halo or by pyridyl), -CH2-(2-8C) alkenyl, 3-10C (poly)alkoxyalkyl (containing 1-4 O), or 6-10C aryl or 7-11C aralkyl (both os in the ring by OH, NH2, NO2, alkyl, alkoxy or one or more halo);  R5  =  COOH, COOR, CN, OH, NH2, CONR6R7 or OR;  R6, R7  =  H, alkyl, alkoxy, 6-10C aryl, 7-11C aralkyl or pyridyl-alkyl;  Qt = (CH2)n; p  =  1 or 2;  R3 + R4  =  group completing a fused phenyl ring or 5- or 6-membered heteroaromatic ring (containing 1-4 of N, O and/or S as heteroatoms), the rings being substituted by one or more groups R';  R'  =  -(O)a-(CH2)b-(O)a-CONR6R7, -(O)a-(CH2)b-OSO3H, -(O)a-(CH2)b-SO3H, -(O)a-SO2R, -(O)a-SO2-(trihalomethyl), -(O)a-(CH2)b-NR6R7, -(O)a-(CH2)b-NH-COOR, OR'', OH or -(CH2)b-Ar; provided that if R' = OH, then R1 = CONR6R7 in which R6 or R7 = alkoxy;  Ar  =  phenyl or 5- or 6-membered heteroaryl (containin g 1-4 of N, O and/or S as heteroatoms), both os by one or more halo, alkyl, alkoxy or CF3;  R''  =  alkyl substituted by one or more of OH, protected hydroxy, =O, halo, and CN;  a  =  0 or 1; and  b  =  0-6; or  (b) R4  =  H or -(CH2)q-R5;  q  =  0-2; and  R1 + R3  =  group completing a substituted phenyl or heteroaryl ring as defined in (a);  in both (a) and (b) R2  =  H, halo, R, S(O)mR, OR, NHCOR, NHCOOR or NHSO2R;  m  =  0-2;  X  =  -C(O)-B- (bonded to N via CO);  B  =  -O-(CH2)r (bonded to CO via O); or -NR8-(CH2)r- or -NR8-O- (bonded to CO via N);  r  =  0 or 1;  R8  =  H, OH, R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2-S(O)m-R, SiRaRbRc or OSiRaRbRc;  Ra, Rb, Rc  =  alkyl or aryl;  Y  =  CHO, COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CHFCOOH, CHFCOOR, CF2COOH, CF2COOR, CN, CH2CN, CH2CONHOH, CH2CONHCN, -CH2-(optionally protected tetrazolyl), CH2SO3H, CH2SO2R, CH2P(O)(OR)2, CH2P(O)(OR)OH or 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, NRSO2R or -CH2-Tet;  Tet  =  tetrazolyl (os by R);  n  =  1 or 2;  aklyl moieties have 1-6C unless specified otherwise.  Independent claims are included for: (a)  the preparation of (I); and  (b) new aza-cyclic intermediates of formulae (II)-(V) and their acid addition salts (specifically hydrochlorides and trifluoroacetates). R'1, R'2, R'4  =  as for R1, R2, R4 in (I), except that (i) R' is replaced by R10 and (ii) all OH, NH2 or COOH groups (excluding OH in R10) are protected;  R10  =  H; alkyl substituted by one or more OH, -O, halo or CN; 2-6C alkenyl, halo, protected hydroxy, OR, OR'', R'' or -(CH2)b-Ar;  ZH  =  HO-(CH2)r-, R'8-NH-(CH2)r- or R'8NH-O-;  Q3 = OH, R11, =N-R'8, NHR'8 or ONHR'8; R'8  =  as for R8, except that all OH, COOH, CONHOH, SO3H, tetrazolyl or squarate groups are protected;  X1  =  H and X2 = -Z-CO-X3; or  X1 = ZH and X2 = -CO-X3;  A  =  H or N-protecting group;  X3 = carboxy functional group; R11  =  leaving group;  provided that in the new compounds either (a) R10 is -(CH2)b-Ar or (b) R'1 is CONR6R7, in which R6 or R7 is 1-6C alkoxy.