Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

A compound or a pharmaceutically acceptable salt thereof represented by formula I:

• ##STR670## wherein:
• R.sup.1 represents H or methyl;
• CO.sub.2 M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
• P* represents H or a hydroxyl protecting group;
• Het has substituent groups which contain from one to three positively charged atoms and is selected from:
• ##STR671## wherein:
• A is O or S;
• D is O, S or NR.sup.a ;
• E, G, X, Y and Z represent CR or N;
• each R is independently selected from:
• --R*;
• hydrogen;
• halo;
• --CN;
• --NO.sub.2 ;
• --OR.sup.c ;
• --SR.sup.c ;
• --CONR.sup.a R.sup.b ;
• --COOR.sup.h ;
• --SOR.sup.c ;
• --SO.sub.2 R.sup.c ;
• --SO.sub.2 NR.sup.a R.sup.b ;
• --NR.sup.a SO.sub.2 R.sup.b ;
• --COR.sup.a ;
• --OCOR.sup.a ;
• --OCONR.sup.a R.sup.b ;
• --NR.sup.a CONR.sup.b R.sup.c ;
• --NR.sup.a CO.sub.2 R.sup.h ;
• --OCO.sub.2 R.sup.h ;
• --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.d groups;
• and --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to four R.sup.d groups,
• R.sup.a, R.sup.b and R.sup.c represent hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.d groups;
• --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to four R.sup.d groups;
• or -R *
• or R.sup.a and R.sup.b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR.sup.c, with R.sup.c as defined above, or --C(O)--, said ring being unsubstituted or substituted with one to four R.sup.i groups;
• or R.sup.b and R.sup.c taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR.sup.a, with R.sup.a as defined above, or --C(O)--, said ring being unsubstituted or substituted with one to four R.sup.i groups;
• each R.sup.d independently represents halo;
• --CN;
• --NO.sub.2 ;
• --NR.sup.e R.sup.f ;
• --OR.sup.g ;
• --SR.sup.g ;
• --CONR.sup.e R.sup.f ;
• --COOR.sup.g ;
• --SOR.sup.g;
• --SO.sub.2 R.sup.g ;
• --SO.sub.2 NR.sup.e R.sup.f ;
• --NR.sup.e SO.sub.2 R.sup.f ;
• --COR.sup.e ;
• --NR.sup.e COR.sup.f ;
• --OCOR.sup.e ;
• --OCONR.sup.e R.sup.f ;
• --NR.sup.e CONR.sup.f R.sup.g ;
• --NR.sup.e CO.sub.2 R.sup.h ;
• --OCO.sub.2 R.sup.h ;
• --C(NR.sup.e)NR.sup.f R.sup.g ;
• --NR.sup.e C(NH)NR.sup.f R.sup.g ;
• --NR.sup.e C(NR.sup.f)R.sup.g ;
• --R* or --Q;
• with the proviso that from 1 to 3 R groups are present which contain R* or Q, said R* and Q being defined below;
• R.sup.e, R.sup.f and R.sup.g represent hydrogen;
• --C.sub.1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R.sup.i groups, or --R*;
• or R.sup.e and R.sup.f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, --C(O)-- or NR.sup.g with R.sup.g as defined above, said ring being unsubstituted or substituted with one to four R.sup.i groups;
• each R.sup.i independently represents halo;
• --CN;
• --NO.sub.2 ;
• phenyl;
• --NHSO.sub.2 R.sup.h ;
• --OR.sup.h, --SR.sup.h ;
• --N(R.sup.h).sub.2 ;
• --N.sup.+ (R.sup.h).sub.3 ;
• --C(O)N(R.sup.h).sub.2 ;
• --SO.sub.2 N(R.sup.h).sub.2 ;
• heteroaryl;
• heteroarylium;
• --CO.sub.2 R.sup.h ;
• --C(O)R.sup.h ;
• --OCOR.sup.h ;
• --NHCOR.sup.h ;
• guanidinyl;
• carbamimidoyl or ureido;
• each R.sup.h independently represents H, a --C.sub.1-6 straight or branched-chain alkyl group, a --C.sub.3 -C.sub.6 cycloalkyl group or phenyl, or when two R.sup.h groups are present, said R.sup.h groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO.sub.2, --C(O)--, NH and NCH.sub.3 ;
• Q is selected from the group consisting of:
• ##STR672## wherein:
• a and b are 1, 2 or 3;
• L- is a pharmaceutically acceptable counterion;
• .alpha. represents O, S or NR.sup.s ;
• .beta., .delta., .lambda., .mu. and .sigma. represent CR.sup.t, N or N.sup.+ R.sup.s, provided that no more than one of .beta., .delta., .lambda., .mu. and .sigma. is N.sup.+ R.sup.s ;
• R* is selected from the group consisting of:
• ##STR673## wherein:
• each d independently represents O, S or NR.sup.k ;
• e, g, x, y and z represent CR.sup.m, N or N.sup.+ R.sup.k, provided that no more than one of e, g, x, y and z in any given structure represents N.sup.+ R.sup.k ;
• R.sup.k represents hydrogen;
• --C.sup.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• or --(CH.sub.2).sub.n Q where n=1, 2 or 3 and Q is as previously defined;
• each R.sup.m independently represents a member selected from the group consisting of:
• hydrogen;
• halo;
• --CN;
• --NO.sub.2 ;
• --NR.sup.n R.sup.o ;
• --OR.sup.n ;
• --SR.sup.n ;
• --CONR.sup.n R.sup.o ;
• --COOR.sup.h ;
• --SOR.sup.n ;
• --SO.sub.2 R.sup.n ;
• --SO.sub.2 NR.sup.n R.sup.o ;
• --NR.sup.n SO.sub.2 R.sup.o ;
• --COR.sup.n ;
• --NR.sup.n COR.sup.o ;
• --OCOR.sup.n ;
• --OCONR.sup.n R.sup.o ;
• --NR.sup.n CO.sub.2 R.sup.h ;
• --NR.sup.n CONR.sup.o R.sup.h ;
• --OCO.sub.2 R.sup.h ;
• --CNR.sup.n NR.sup.o R.sup.h ;
• --NR.sup.n CNHNR.sup.o R.sup.h ;
• --NR.sup.n C(NR.sup.o)R.sup.h ;
• --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to four R.sup.i groups;
• and --(CH.sub.2).sub.n Q where n and Q are as defined above;
• R.sup.n and R.sup.o represent hydrogen, phenyl;
• --C.sub.1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R.sup.i groups;
• each R.sup.s independently represents hydrogen;
• phenyl;
• --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• each R.sup.t independently represents hydrogen;
• halo;
• phenyl;
• --CN;
• --NO.sub.2 ;
• --NR.sup.u R.sup.v ;
• --OR.sup.u ;
• --SR.sup.u ;
• --CONR.sup.u R.sup.v ;
• --COOR.sup.h ;
• --SOR.sup.u ;
• --SO.sub.2 R.sup.u ;
• --SO.sub.2 NR.sup.u R.sup.v ;
• --NR.sup.u SO.sub.2 R.sup.v ;
• --COR.sup.u ;
• --NR.sup.u COR.sup.v ;
• --OCOR.sup.u ;
• --OCONR.sup.u R.sup.v ;
• --NR.sup.u CO.sub.2 R.sup.v ;
• --NR.sup.u CONR.sup.v R.sup.w ;
• --OCO.sub.2 R.sup.v ;heteroaryl;
• heteroarylium;
• --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• R.sup.u and R.sup.v represent hydrogen or --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• or R.sub.u and R.sup.v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR.sup.w or --C(O)--, said ring being unsubstituted or substituted with one to four R.sup.i groups;
• each R.sup.w independently represents hydrogen or --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
• C.sub.3-6 cycloalkyl optionally substituted with one to four R.sup.i groups;
• phenyl optionally substituted with one to four R.sup.i groups
• or R.sup.h and R.sup.w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO.sub.2, NH or NCH.sub.3 ;
• R.sup.x represents hydrogen or a C.sub.1-8 straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO.sub.2, NR.sup.w, N.sup.+ R.sup.h R.sup.w, or --C(O)--, said chain being unsubstituted or substituted with one to four of halo, CN, NO.sub.2, OR.sup.w, SR.sup.w, SOR.sup.w, SO.sub.2 R.sup.w, NR.sup.h R.sup.w, N.sup.+ (R.sup.h).sub.2 R.sup.w, --C(O)--R.sup.w, C(O)NR.sup.h R.sup.w, SO.sub.2 NR.sup.h R.sup.w, CO.sub.2 R.sup.w, OC(O)R.sup.w, OC(O)NR.sup.h R.sup.w, NR.sup.h C(O)R.sup.w, NR.sup.h C(O)NR.sup.h R.sup.w, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R.sup.i groups or with one to two C.sub.1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R.sup.i groups;
• R.sup.y and R.sup.z represent hydrogen;
• phenyl;
• --C.sub.1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R.sup.i groups, and optionally interrupted by O, S, NR.sup.w, N.sup.+ R.sup.h R.sup.w or --C(O)--;
• or R.sup.x and R.sup.y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO.sub.2, NR.sup.w , N.sup.+ R.sup.h R.sup.w or --C(O)--, unsubstituted or substituted with 1-4 Ri groups,
• and when R.sup.x and R.sup.y together represent a 4-6 membered ting as defined above, R.sup.z is as defined above or R.sup.z represents an additional saturated 4-6 membered ring fused to the ring represented by R.sup.x and R.sup.y taken together, optionally interrupted by O, S, NR.sup.w or --C(O)--, said rings being unsubstituted or substituted with one to four R.sup.i groups.