Bridged biphenyl carbapenem antibacterial compounds

A compound represented by formula I:

• ##STR180## wherein:
• m is an integer 0, 1, 2, 3, 4 or 5;
• n is an integer 0, 1, 2, 3 or 4;
• X represents (a) a bond;
• (b) --O--;
• (c) --S(O).sub.x -- with x equal to 0, 1 or 2;
• (d) --C(O)--;
• (e) --NR'--;
• (f) --CH.dbd.CH--;
• (g) --C(O)NR'--;
• (h)--NR'C(O)--;
• (i) --CO.sub.2 --;
• (j) --OC(O)--;
• (k) --SO.sub.2 NR'-- or (l) --NR'SO.sub.2 -- with R' representing H, C.sub.1 to C.sub.4 alkyl or acetyl;
• the values of m, n and X being selected such that ring B constitutes a 6 to 10 membered ring;
• Y represents H, a pharmaceutically acceptable ester, a biolabile ester, a carboxylate protecting group or a metal cation;
• R.sup.1 and R.sup.2 independently represent H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, (CH.sub.3).sub.2 CH--, HOCH.sub.2 --, CH.sub.3 CH(OH)--, (CH.sub.3).sub.2 C(OH)--, FCH.sub.2 CH(OH)--, F.sub.2 CHCH(OH)--, F.sub.3 CCH(OH)--, CH.sub.3 CH(F)--, CH.sub.3 CF.sub.2 -- or (CH.sub.3).sub.2 CF--;
• one of the R.sup.a groups represents H or W as defined below, and the other represents one of the groups (a) through (d):
• ##STR181## when one of the R.sup.a groups represents ##STR182## A represents --(CR.sup.3 R.sup.4).sub.r --Q-- (CR.sup.3 R.sup.4)s-- wherein r is 0-6, s is 1-6 and Q represents a member selected from the group consisting of:
• a covalent bond, --O--, --S(O).sub.x -- with x equal to 0, 1 or 2, --NR.sup.3 --, --SO.sub.2 NR.sup.3 --, --NR.sup.3 SO.sub.2 --, --C(O)NR.sup.3 --, --NR.sup.3 C(O)--, --CR.sup.3 .dbd.CR.sup.4 --, --C(O)-- and --OC(O)--;
• with R.sup.3 and R.sup.4 independently representing H or C.sub.1-4 lower alkyl, and (CR.sup.3 R.sup.4).sub.s -- being attached to the ring nitrogen;
• ##STR183## represents a 5 or 6 membered monocyclic heterocycle or an 8-10 membered bicyclic heterocycle, bonded to A through the ring nitrogen and having a substituent group R.sup.d optionally attached to the ring nitrogen, and having 0-3 R.sup.c groups attached to other atoms of the heterocyclic group, said ring nitrogen being tertiary or quaternary by virtue of A, the ring bonds and R.sup.d which may be optionally attached, said heterocyclic group being aromatic, partially aromatic or non-aromatic,
• said heterocycle also containing 0-3 additional nitrogen atoms and 0-1 oxygen or sulfur atom;
• each R.sup.c independently represents W as defined below or NR.sup.y R.sup.z, wherein R.sup.y and R.sup.z independently represent H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkyl substituted with R.sup.q, or R.sup.y and R.sup.z are taken together to represent either a 3- to 5-membered alkylidene radical to form a ring, optionally substituted with R.sup.q, or a 2- to 4-membered alkylidene radical interrupted by O or S(O).sub.x with x equal to 0, 1 or 2, to form a ring, said alkylidene being optionally substituted with R.sup.q ;
• R.sup.q is selected from the group consisting of:
• hydroxy, methoxy, cyano, --C(O)NH.sub.2, --OC(O)NH.sub.2, --CHO, --OC(O)N(CH.sub.3).sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 N(CH.sub.3).sub.2, --SOCH.sub.3, --SO.sub.2 CH.sub.3, --F, --CF.sub.3, --SO.sub.3 M.sup.b with M.sup.b representing H or alkali metal, --CO.sub.2 M.sup.a, where M.sup.a is H, alkali metal, methyl or phenyl;
• and tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by M.sup.a as defined above);
• each R.sup.d independently represents a member selected from the group consisting of:
• hydrogen, NH.sub.2, O-- or C.sub.1 to C.sub.4 alkyl, optionally mono-substituted with R.sup.q as defined above;
• when one R.sup.a group represents ##STR184## A' represents --(CR.sup.3 R.sup.4).sub.m '--Q--(CR.sup.3 R.sup.4).sub.m' -- with each m' independently equal to 0-6, and Q, R.sup.3 and R.sup.4 as defined above, except that when each m' is 0, Q is not a covalent bond, and --(CR.sup.3 R.sup.4).sub.m' attached to the phenyl ring;
• ##STR185## represents a 5 or 6 membered monocyclic heterocycle or an 8-10 membered bicyclic heterocycle, said heterocycle being aromatic, partially aromatic or non-aromatic, bonded to A' through an atom other than the ring nitrogen, and optionally having 0-2 R.sup.d substituent groups attached to the ring nitrogen, said nitrogen in the heterocycle being tertiary or quaternary by virtue of the ring bonds and the optional R.sup.d groups which may be attached;
• said heterocycle further containing 0-1 oxygen or sulfur atom and 0-2 additional nitrogen atoms therein;
• R.sup.c and R.sup.d are as defined above;
• when one R.sup.a group represents (c) --A.sub.p --NR.sup.10 R.sup.11 R.sup.12 (0-1);
• A is as defined above and p is an integer 0 or 1;
• R.sup.10, R.sup.11 and where present, R.sup.12, are independently H, C.sub.1-4 alkyl or C.sub.1-4 alkyl mono-substituted with R.sup.q ;
• or R.sup.10, R.sup.11 and R.sup.12 may be taken in combination to represent a C.sub.4 to C.sub.10 alkanetriyl group, optionally substituted with up to three W groups, with W as defined below;
• when one R.sup.a group represents (d), A', p, the N containing ring, R.sup.c and R.sup.d are as previously defined;
• each W independently represents a member selected from the group consisting of:
• a) --CF.sub.3 ;
• b) a halogen atom selected from the group consisting of:
• --Br, --Cl, --F, --I;
• c) --OC.sub.1-4 alkyl, wherein the alkyl is optionally mono-substituted by R.sup.q, where R.sup.q is as defined above;
• d) --OH;
• e) --OC(O)R.sup.s, where R.sup.s is C.sub.1-4 alkyl or phenyl, each of which is optionally mono-substituted by R.sup.q as defined above;
• f) --OC(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are independently H, C.sub.1-4 alkyl, (optionally mono-substituted by R.sup.q as defined above), or are taken together to represent a 3- to 5-membered alkylidene radical which forms a ring (optionally substituted with R.sup.q as defined above), or a 2- to 4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 -- which forms a ring, said ring being optionally mono-substituted with R.sup.q as defined above;
• g) --S(O).sub.n --R.sup.s, where n=O-2, and R.sup.s is defined above;
• h) --SO.sub.2 N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are as defined above;
• i) N.sub.3
• j) --N(R.sup.t)C(O)H, where R.sup.t is H or C.sub.1-4 alkyl, said alkyl group being optionally mono-substituted with R.sup.q as defined above;
• k) --N(R.sup.t)C(O)C.sub.1-4 alkyl, wherein R.sup.t is as defined above;
• l) --N(R.sup.t)C(O)OC.sub.1-4 alkyl, where R.sup.t is as defined above;
• m) --N(R.sup.t)C(O)N(R.sup.y R.sup.z where R.sup.t, R.sup.y and R.sup.z are defined above;
• n) --N(R.sup.t)SO.sub.2 .sup.R.sup.s, where R.sup.s and R.sup.t are as defined above;
• o) --CN;
• p) a formyl or acetalized formyl radical which is :--C(O)H or --CH(OCH.sub.3).sub.2 ;
• q) --C(OCH.sub.3).sub.2 C.sub.1 -C.sub.4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
• r) --C(O)R.sup.s, where R.sup.s is as defined above;
• s) --(C.dbd.NOR.sup.z)R.sup.y where R.sup.y and R.sup.z are as defined above, except they may not be joined together to form a ring;
• t) --C(O)OC.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
• u) --C(O)N(R.sup.y)R.sup.z, where R.sup.y and R.sup.z are as defined above;
• v) --C(O)N(OR.sup.y)R.sup.z, where R.sup.y and R.sup.z are as defined above, except they may not be joined together to form a ring;
• w) --C(S)N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above;
• x) --COOM.sup.a where M.sup.a is as defined above;
• y) --SCN;
• z) --SCF.sub.3 ;
• aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C.sub.1 -C.sub.4 alkyl optionally substituted by R.sup.q as defined above;
• ab) an anionic function selected from the group consisting of:
• P(O)(OM.sup.a).sub.2 ;
• P(O)(OM.sub.a)(OC.sub.1-4 alkyl);
• P(O)(OM.sup.a)(C.sub.1-4 alkyl);
• P(O)(OM.sup.a)NR.sup.y R.sup.z ;
• P(O)(OM.sup.a)NHR.sup.x ;
• SO.sub.2 M.sup.a ;
• SO.sub.3 M.sup.a ;
• SO.sub.2 NM.sup.a C(O)NR.sup.y R.sup.z and SO.sub.2 NM.sup.a CN wherein
• R.sup.x is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono-substituted by R.sup.q, said R.sup.q, M.sup.a, R.sup.y and R.sup.z being as defined above;
• ac) a C.sub.5 -C.sub.7 cycloalkyl group in which :one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, NH, or N(C.sub.1 -C.sub.4 alkyl) and in which one additional carbon may be replaced by the NH or N(C.sub.1 -C.sub.4 alkyl), and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen thus forming a carbonyl moiety and there are one or two carbonyl moieties present in the ring;
• ad) a C.sub.2 -C.sub.4 alkenyl radical, optionally mono-substituted by one of the substituents a) to ac) above and phenyl which is optionally substituted by R.sup.q as defined above;
• ae) a C.sub.2 -C.sub.4 alkynyl radical, optionally mono-substituted by one of the substituents a) to ac) above;
• af) a C.sub.1 -C.sub.4 alkyl radical;
• ag) a C.sub.1 -C.sub.4 alkyl group mono-substituted by one of the substituents a)-ac) above;
• ah) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from S and NR.sup.t (where R.sup.t is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the substituents a) to ag) above with the proviso that when R.sup.a contains a quaternary ammonium group Y represents a negative charge.