2-(Heterocyclylalkyl)phenyl carbapenem antibacterial agents

A compound of the formula:

• ##STR55## 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, R.sup.b, and R.sup.c are independently selected from the group consisting of
• (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;
• (d) a hydroxy group:
• --OH;
• (e) (C.sub.1 -C.sub.6 alkyl) carbonyloxy radical:
• ##STR56## (f) a carbamoyloxy radical which is unsubstituted or substituted on nitrogen with one or two C.sub.1 -C.sub.4 alkyl groups:
• ##STR57## where R.sup.y and R.sup.z are independently H or C.sub.1-4 alkyl, (g) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl radical or C.sub.1 -C.sub.6 alkylsulfonyl radical:
• ##STR58## alkyl where n.dbd.0-2, and the alkyl portion is optionally substituted by cyano;
• (h) a sulfamoyl group which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups:
• ##STR59## where R.sup.y and R.sup.z are as defined above;
• (i) an amino group, or a mono (C.sub.1 -C.sub.4 alkyl) amino or di(C.sub.1 -C.sub.4 alkyl)amino group:
• ##STR60## where R.sup.y and R.sup.z are as defined above;
• (j) a formylamino group:
• ##STR61## (k) (C.sub.1 -C.sub.6 alkyl)carbonylamino radical:
• ##STR62## (1) a (C.sub.1 -C.sub.4 alkoxy) carbonylamino radical:
• ##STR63## (m) a ureido group in which the terminal nitrogen is unsubstituted or substituted with one or two C.sub.1 -C.sub.4 alkyl groups:
• ##STR64## where R.sup.y and R.sup.z are as defined above;
• (n) a sulfonamido group:
• ##STR65## (o) a cyano group;
• --CN;
• (p) a formyl or acetalized formyl radical:
• ##STR66## (q) (C.sub.1 -C.sub.6 alkyl)carbonyl radical wherein the carbonyl is free or acetalized;
• ##STR67## (r) phenylcarbonyl;
• (s) a hydroximinomethyl radical in which the oxygen or carbonatom is optionally substituted by a C.sub.1 -C.sub.4 alkyl group;
• ##STR68## where R.sup.y and R.sup.z are as defined above;
• (t) a (C.sub.1 -C.sub.6 alkoxy)carbonyl radical;
• ##STR69## (u) a carbamoyl radical which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups;
• ##STR70## 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;
• ##STR71## where R.sup.y and R.sup.z are as defined above;
• (w) a thiocarbamoyl group:
• ##STR72## (x) an amidino group ##STR73## where R.sup.5, R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1 -C.sub.4 alkyl or wherein two of the alkyl groups together form a C.sub.2 -C.sub.6 alkylidene radical optionally interrupted by a heteroatom and joined together to form a ring;
• (y) a carboxamidino group ##STR74## where R.sup.5, R.sup.6 and R.sup.7 are as defined above;
• (z) a guanidinyl group where R.sup.6 in (a) above is NR.sup.8 R.sup.9 and R.sup.8 and R.sup.9 are as defined for R.sup.5 through R.sup.7 above;
• (aa) hydrogen;
• (ab) C.sub.2 -C.sub.6 alkenyl radical;
• (ac) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
• (ad) C.sub.3 -C.sub.7 cycloalkyl radical;
• (ae) C.sub.3 -C.sub.7 cycloalkyl methyl radical;
• (af) C.sub.5 -C.sub.7 cycloalkenyl radical;
• (ag) phenyl, except that only R.sup.c may be phenyl,
• (ah) C.sub.1 -C.sub.6 alkyl radical;
• (ai) C.sub.1 -C.sub.4 alkyl monosubstituted by one of the substituents (a)-(ag) above;
• (aj) an anionic function selected from the group consisting of:
• phosphono [P.dbd.O(OM.sup.c).sub.2 ];
• alkylphosphono {P.dbd.O(OM.sup.c) [O(C.sub.1 -C.sub.4 alkyl)]};
• alkylphosphinyl [P.dbd.O(OM.sup.c)--(C.sub.1 -C.sub.4 alkyl)];
• phosphoramido [P.dbd.O(OM.sup.c)N(R.sup.y)R.sup.z and P.dbd.O(OM.sup.c)NHR.sup.x ];
• sulfino (SO.sub.2 M.sup.c);
• sulfo (SO.sub.3 M.sup.c);
• acylsulfonamides selected from the structures CONM.sup.c SO.sub.2 R.sup.x, CONM.sup.c SO.sub.2 N(R.sup.y)R.sup.z, SO.sub.2 NM.sup.c CON(R.sup.y)R.sup.z ;
• and SO.sub.2 NM.sup.c CN, where
• R.sup.x and the phenyl is optionally mono substituted by R.sup.q ;
• M.sup.c is hydrogen or an alkali metal;
• R.sup.y and R.sup.z are as defined above;
• 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 ;
• --OC(O)N(CH.sub.3).sub.3).sub.2 ;
• --SO.sub.2 NH.sub.2 ;
• --SO.sub.2 N(CH.sub.3).sub.2 ;
• --SOCH.sub.3 ;
• --F;
• --CF.sub.3 ;
• tetrazolyl;
• and --COOM.sup.a, where M.sup.a is hydrogen, alkali metal, methyl or phenyl;
• R.sup.d is C.sub.1 -C.sub.4 alkyl, making the nitrogen atom of the N-heterocyclyl moiety to which it is attached quaternary;
• or it may be absent;
• A is para (p) or meta (m) with respect to the point of attachment of the phenyl ring to the carbapenem nucleus, and is (CH.sub.2).sub.m --Q--(CH.sub.2).sub.n, where m is 0 to 2 and n is 1 or 2;
• and Q is a covalent bond;
• Z is a member selected from the group consisting of CH.sub.2, O, S, SO, SO.sub.2, N(R') and .sup.+ N(R')(R"), where R' and R" are independently hydrogen, C.sub.1 -C.sub.4 alkyl, or oxo;
• provided that where R.sup.d is not absent, Z cannot be .sup.+ N(R')(R");
• m is 2 or 3;
• n is 1 or 2;
• and
• Y is selected from:
• (i) COOH or a pharmaceutically acceptable ester thereof;
• (ii) COOM wherein M is an alkali metal or other pharmaceutically acceptable salt;
• (iii) COOM wherein M is a negative charge in the case where a permanent positive charge exists elsewhere in the molecule.