2-(1,2,3-triazolylsubstituted)phenyl carbapenem antibacterial agents

A compound of the formula I:

• ##STR71## 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, HOCH.sub.2 --, (R)--CH.sub.3 CH(OH)--, (CH.sub.3).sub.2 C(OH)--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, (R)--CH.sub.3 CH(F)--, CH.sub.3 CF.sub.2 --, or (CH.sub.3).sub.2 C(F)--;
• R.sup.a and R.sup.b are independently hydrogen or:
• 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:
• --OCl.sub.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 M.sup.a 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.2, 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)--, --S(O).sub.2 --or --NR.sup.e --, to form a ring (where R.sup.e is hydrogen, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkyl mono-substituted with R.sup.q and the ring is optionally mono substituted with R.sup.q 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,
• R.sup.t 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;
• l) 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) ];
• 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 where the phenyl is 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 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;
• R.sup.c is ##STR72## 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 ring carbon atom;
• R.sup.d is R.sup.a as defined hereinabove, hydrogen or --NR.sup.y R.sup.z (where R.sup.y and R.sup.z are defined hereinabove);
• ##STR73## is selected from the group consisting of ##STR74## A and A' are independently (CH.sub.2).sub.m --Q--(CH.sub.2).sub.n, where m is zero to 6 and n is zero 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);
• provided when m=n=zero that Q is not a covalent bond;
• Y is selected from:
• i) COOH or a pharmaceutically acceptable ester,
• ii) COOM wherein M is an alkali metal, or
• iii) COO.sup.- ;
• provided that when Y is other than iv) and a quaternary nitrogen heteroatom is present, a counterion Z.sup.- is provided,
• or the pharmaceutically acceptable salt thereof.