2-biphenyl-carbapenem antibacterial agents

Carbapenem compounds of the formula:

• ##STR256## wherein:
• R is H or CH.sub.3,
• R.sup.1 and R.sup.2 are independently 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 C(F)--;
• R.sup.a are independently selected from the group consisting of hydrogen and the radicals set out below, provided that one but not more than one R.sup.a is selected from type I substituents and not more than four R.sup.a radicals are other than hydrogen:
• I.
• (a) ##STR257## where is (CH.sub.2).sub.m --Q--(CH.sub.2).sub.n, where m is 0 to 6 and n is 1 to 6 and Q is a covalent bond, O, S, SO, SO.sub.2, NH, --SO.sub.2 NH--, --NHSO.sub.2 --, --CONH--, --NHCO--, --SO.sub.2 N(C.sub.1 -C.sub.4 alkyl)--, --N(C.sub.1 -C.sub.4 alkyl)SO.sub.2 --, --CON(C.sub.1 -C.sub.4 alkyl)--, --N(C.sub.1 -C.sub.4 alkyl)CO--, --CH.dbd.CH--, --CO--, --OC(O)--, --C(O)O-- or N(C.sub.1 --C.sub.4 alkyl) and (CH.sub.2).sub.m is attached to the biphenyl moiety;
• ##STR258## is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with attachment of the heterocycle to A by way of said first nitrogen and said first nitrogen is quaternary by virtue of the attachment and ring bonds, with the first ring containing 0 or 1 of either O or S, with the first ring containing 0 to 3 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4-membered moiety to form the optional second ring, with the the moiety containing at least one carbon atom, with the moiety containing 0 or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms, and with the moiety being saturated or unsaturated and the second ring aromatic or non-aromatic;
• is R.sup.a as defined under II below, hydrogen, or --NR.sup.y R.sup.z (where R.sup.y and R.sup.z are defined in II below), but independently selected from R.sup.a and from each other if more than one R.sup.c is present, and is attached to a carbon ring atom or a nitrogen heteroatom the valency of which is not satisfied by the ring bonds;
• (b) ##STR259## where ##STR260## is a 5 or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with said first nitrogen quaternary by virtue of a substituent R.sup.d in addition to the ring bonds thereto, with said first nitrogen neutral in the absence of a substituent R.sup.d, with attachment of the heterocycle to A' by way of a carbon atom of a ring, with the first ring containing 0 or 1 of either O or S, with the first ring containing 0 to 2 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4-membered moiety to form the optional second ring, with the moiety containing at least one carbon atom, with the moiety containing 0 or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms, and with the moiety being saturated or unsaturated and the second ring aromatic or non-aromatic;
• R.sup.c is defined above;
• R.sup.d is hydrogen, NH.sub.2, 0 or C.sub.1 -C.sub.4 alkyl (where the alkyl group is optionally mono-substituted with R.sup.q as defined under IIc below);
• A' is (CH.sub.2).sub.m --Q--(CH.sub.2).sub.n, where m is 0 to 6 and n is 0 to 6, Q is given above, and when m and n are 0 then Q is not a covalent bond;
• (c) --A.sub.p --N.sup.+ R.sup.y (R.sup.w).sub.(0-1) (R.sup.z)
• where
• R.sup.y and R.sup.z are as defined under II below.
• R.sup.y and R.sup.z may further be together a C.sub.2 -C.sub.4 alkylidene radical to form a ring (optionally mono-substituted with R.sup.q as defined below) interrupted by N(O)R.sup.e or N.sup.+ (R.sup.e).sub.2 (where R.sup.e is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkyl mono-substituted with R.sup.q as defined below),
• R.sup.w is hydrogen, C.sub.1-4 alkyl, O.sup.-, NH.sub.2 or absent in which case the N+ is neutral,
• R.sup.w, R.sup.y and R.sup.z may further together form a C.sub.5 -C.sub.10 tertiary alkylidene radical which with N.sup.+ forms a bicyclic ring, where the tertiary alkylidene radical is optionally mono-substituted with R.sup.q as defined below and where the tertiary carbon of the tertiary alkylidene radical is optionally replaced with nitrogen, N.sup.+ R.sup.e (where R.sup.e is defined above), or N.sup.+ --O.sup.-,
• p is 0 or 1, and
• A is as defined above;
• (d) ##STR261## where ##STR262## is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in a first ring, with the first ring saturated or unsaturated and non-aromatic, with the first nitrogen quaternary by virtue of one or two substituents R.sup.d in addition to the ring bonds thereto, with the first nitrogen alternatively neutral by virtue of zero or one substituents R.sup.d in addition to the ring bonds thereto, with attachment of the heterocycle to A' by way of a carbon atom or non-quaternary nitrogen atom of a ring, with the first ring containing in addition to carbon and the first nitrogen 0 to 1 of a member selected from the group consisting of the non-quaternary nitrogen of attachment, O, S, S(O), S(O).sub.2 and NR.sup.e where R.sup.e is defined above, with the first ring optionally fused to a 2-, 3- or 4-membered moiety to form the optional second ring, with the moiety optionally containing in addition to carbon the non-quaternary nitrogen of attachment, and with the moiety saturated or unsaturated and the second ring non-aromatic;
• R.sup.d is defined above and where more than one R.sup.d is present on a nitrogen, at least one R.sup.d is hydrogen or C.sub.1 -C.sub.4 alkyl;
• A' is defined above;
• and
• p is defined above;
• R.sup.q is defined below;
• II.
• (a) a trifluoromethyl group:
• --CF.sub.3 ;
• (b) a halogen atom:
• --Br, --Cl, --F, or --I;
• (c) C.sub.1 -C.sub.4 alkoxy radical:
• --OC.sub.1-4 alkyl, wherein the alkyl is optionally mono-substituted by R.sup.q, where
• R.sup.q is a member selected from the group consisting of --OH, --OCH.sub.3, --CN, 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, --COOM.sup.a (where M.sup.a is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma as defined above) and --SO.sub.3 M.sup.b (where M.sup.b is hydrogen or an alkali metal);
• (d) a hydroxy group:
• --OH;
• (e) a carbonyloxy radical:
• --O(C.dbd.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) a carbamoyloxy radical:
• --O(C.dbd.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), together a 3- to 5-membered alkylidene radical to form a ring (optionally substituted with R.sup.q as defined above) or together a 2- to 4-membered alkylidene radical, interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 --, to form a ring (where the ring is optionally mono-substituted with Rq as defined above);
• (g) a sulfur radical:
• --S(O).sub.n --R.sup.s where n=0-2, and R.sup.s is defined above;
• (h) a sulfamoyl group:
• --SO.sub.2 N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above.,
• (i) azido:
• N.sub.3
• (j) a formamido group:
• --N(R.sup.t)(C.dbd.O)H,
• where
• R.sup.t is is H or C.sub.1-4 alkyl, and the alkyl thereof is optionally mono-substituted by R.sup.q as defined above;
• (k) a (C.sub.1 -C.sub.4 alkyl)carbonylamino radical:
• --N(R.sup.t)(C.dbd.O)C.sub.1-4 alkyl, where R.sup.t is as defined above, and the alkyl group is also optionally mono-substituted by R.sup.q as defined above;
• (1) a (C.sub.1 -C.sub.4 alkoxy) carbonylamino radical:
• --N(R.sup.t)(C.dbd.O)OC.sub.1-4 alkyl, where R.sup.t is as defined above, and the alkyl group is also optionally mono-substituted by R.sup.q as defined above;
• (m) a ureido group:
• --N(R.sup.t)(C.dbd.O)N(R.sup.y)R.sup.z where R.sup.t, R.sup.y and R.sup.z are as defined above;
• (n) a sulfonamido group:
• --N(R.sup.t)SO.sub.2 R.sup.s, where R.sup.s and R.sup.t are as defined above;
• (o) a cyano group:
• --CN;
• (p) a formyl or acetalized formyl radical:
• --(C.dbd.O)H or --CH(OCH.sub.3).sub.2 ;
• (q) (C.sub.1 -C.sub.4 alkyl)carbonyl radical wherein the carbonyl is acetalized:
• --C(OCH.sub.3).sub.2 C.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
• (r) carbonyl radical:
• --(C.dbd.O)R.sup.s, where R.sup.s is as defined above;
• (s) a hydroximinomethyl radical in which the oxygen or carbon atom is optionally substituted by a C.sub.1 -C.sub.4 alkyl group:
• --(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) a (C.sub.1 -C.sub.4 alkoxy)carbonyl radical:
• --(C.dbd.O)OC.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
• (u) a carbamoyl radical:
• --(C.dbd.O)N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above;
• (v) an N-hydroxycarbamoyl or N(C.sub.1 -C.sub.4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a C.sub.1 -C.sub.4 alkyl group:
• --(C.dbd.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) a thiocarbamoyl group:
• --(C.dbd.S)N(R.sup.y)(R.sup.z) where R.sup.y and R.sup.z are as defined above;
• (x) carboxyl:
• --COOM.sup.b, where M.sup.b is as defined above;
• (y) thiocyanate:
• --SCN;
• (z) trifluoromethylthio:
• --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:
• phosphono [P.dbd.O(OM.sup.b).sub.2 ];
• alkylphosphono {P.dbd.O(OM.sup.b)--[O(C.sub.1 -C.sub.4 alkyl)]};
• alkylphosphinyl [P.dbd.O(OM.sup.b)--(C.sub.1 -C.sub.4 alkyl)];
• phosphoramido [P.dbd.O(OM.sup.b)N(R.sup.y)R.sup.z and P.dbd.O(OM.sup.b)NHR.sup.x ];
• sulfino (SO.sub.2 M.sup.b);
• sulfo (SO.sub.3 M.sup.b);
• acylsulfonamides selected from the structures CONM.sup.b SO.sub.2 R.sup.x, CONM.sup.b SO.sub.2 N(R.sup.y)R.sup.z, SO.sub.2 NM.sup.b CON(R.sup.y)R.sup.z ;
• and SO.sub.2 NM.sup.b CN, where
• 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, as defined above;
• M.sup.b is as defined above;
• and R.sup.y and R.sup.z are as defined above;
• (ac) 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 atom may be replaced by 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) 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) C.sub.2 -C.sub.4 alkynyl radical, optionally mono-substituted by one of the substituents (a) to (ac) above;
• (af) C.sub.1 -C.sub.4 alkyl radical;
• (ag) C.sub.1 -C.sub.4 alkyl 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;
• M is selected from:
• (i) hydrogen;
• (ii) a pharmaceutically acceptable esterifying group or removable carboxyl protecting group;
• (iii) an alkali metal or other pharmaceutically acceptable cation;
• or
• (iv) a negative charge which is balanced by a positively charged group.