Claims
- 1. 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.
- 2. A compound in accordance with claim 1 wherein A represents S.
- 3. A compound in accordance with claim 1 wherein A represents O.
- 4. A compound in accordance with claim 1 represented by formula Ia: ##STR674## wherein: CO.sub.2 M represents a carboxylic acid, a carboxylate anion or a pharmaceutically acceptable ester group;
- Het has substituent groups which contain from one to three positively charged atoms and is selected from: ##STR675## wherein: 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; OR.sup.e ; --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 ; --COR.sup.a ; --OCOR.sup.a ; --OCONR.sup.a R.sup.b ; --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; --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to four R.sup.d groups, with the proviso that one to three R groups contain R* or Q;
- and R* and Q are as defined above.
- 5. A compound in accordance with claim 4 represented by formula Ia: ##STR676## wherein: CO.sub.2 M represents a carboxylic acid or a carboxylate anion;
- Het has substituent groups which contain one or two positively charged atoms and is selected from: ##STR677## wherein: E, G, X, Y and Z represent CR or N;
- each R is independently selected from the group consisting of --R*; hydrogen; halo; --CN; --CONR.sup.a R.sup.u ; --COOR.sup.h ; --SOR.sup.c ; --SO.sub.2 R.sup.c ; --SO.sub.2 NR.sup.a R.sup.b ; --OC(O)R.sup.a ; --COR.sup.a ; --C.sub.1-6 straight-or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to three R.sup.d groups, with the proviso that one or two R groups contain R* or Q;
- R.sup.a, R.sup.b and R.sup.c independently represent --R*; 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.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;
- Q represents a member selected from the group consisting of: ##STR678## wherein: a and b are 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: ##STR679## 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 ;
- and R.sup.k is as previously defined.
- 6. A compound in accordance with claim 5 represented by formula Ic: ##STR680## wherein: Het has substituent groups which contain one or two positively charged atoms and is selected from the group consisting of: ##STR681## each R is independently selected from: hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; and --R*, with the proviso that one or two R groups contain R* or Q;
- R.sup.d represents --CN; --NR.sup.e R.sup.f ; --OR.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 ; --OCONR.sup.e R.sup.f ; --NR.sup.e CONR.sup.f R.sup.g ; --NR.sup.e CO.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;
- R.sup.e, R.sup.f and R.sup.g represent hydrogen; --C.sub.1-6 straight- or branched-chain alkyl or --R*;
- or R.sup.e and R.sup.f taken together represent a 4-6 membered saturated ring optionally interrupted by one or more 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.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 ;
- 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;
- Q is selected from: ##STR682## wherein: L- is as previously defined;
- 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.s represents hydrogen; phenyl; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- R.sup.t is selected from the group consisting of: 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 ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups, and the remaining R.sup.t groups are hydrogen;
- R* is ##STR683## wherein each R.sup.m is selected from the group consisting of: halo; --CN; --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 ; --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; or --(CH.sub.2).sub.n Q where n=1-3;
- 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;
- R.sup.u and R.sup.v independently represent hydrogen; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- or R.sup.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, and
- R.sup.w 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; or 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.
- 7. A compound in accordance with claim 1 represented by formula Ib: ##STR684## wherein: CO.sub.2 M represents a carboxylic acid, a carboxylate anion or a pharmaceutically acceptable ester group;
- and Het is as previously defined with respect to the compounds of formula I.
- 8. A compound in accordance with claim 7 represented by formula Ib: ##STR685## wherein: CO.sub.2 M represents a carboxylic acid or a carboxylate anion;
- Het has substituent groups which contain one to three positively charged atoms and is selected from the group consisting of: ##STR686## wherein: E, G, X, Y and Z independently represent CR or N;
- each R is selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to three R.sup.d groups; and --R*, with the proviso that one to three R groups contain R* or Q;
- Q is selected from the group consisting of: ##STR687## wherein: L- represents a pharmaceutically acceptable counterion;
- a and b independently represent 2 or 3;
- .alpha. represents O, S or NR.sup.s ;
- .beta., .delta., .lambda., .mu. and .sigma. independently 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: ##STR688## wherein: d represents O, S or NR.sup.k ;
- e, g, x, y and z independently represent CR.sup.m, N or N.sup.+ R.sup.k, provided that no more than one of e, g, x, y and z represents N.sup.+ R.sup.k ;
- R.sup.a, R.sup.b and R.sup.c independently 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; and
- 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;
- 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 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 ;
- R.sup.k represents hydrogen; --C.sub.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 and Q are as previously defined;
- each R.sup.m independently represents a member selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --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 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=1-3;
- R.sup.n and R.sup.o 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 : --NHR.sup.u ; --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 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.sup.u and R.sup.v together 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 or four R.sup.i groups;
- 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 --CO)--, said chain being unsubstituted 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)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 turn optionally substituted with from one to four R.sup.1 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;
- 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 are 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.
- 9. A compound in accordance with claim 8 represented by formula Ic: ##STR689## 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.sub.NR.sup.a R.sup.b ; --NR.sup.a SO.sub.2 R.sup.b ; --OCOR.sup.a ; --OCONR.sup.a R.sup.a R.sup.b ; --NR.sup.a CONR.sup.b R.sup.c ; --NR.sup.a CO.sub.2 R.sup.h ;--C.sub.1-6 straight- or branched-chained alkyl, unsubstituted or substituted with one or to four R.sup.d groups; and --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to four R.sup.d groups,
- with the proviso that from one to three positively charged atoms are contained in said R groups, and one to three R groups are present which contain R* or Q;
- Q is selected from the group consisting of: ##STR690## a and b are 1, 2 or 3; L.sup.- 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.30 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; ##STR691## 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.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.sup.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 ; --OCOR.sup.e R.sup.f ; --NR.sup.e CONR.sup.f R.sup.g ; --NR.sup.e CO.sup.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;
- 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 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 substituted or substituted with one to four R.sup.i groups;
- each R.sup.i independently represent 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.sup.2 N(R.sup.h).sub.2 ; heteroaryl; heteroarylium; --CO.sub.2 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 ;
- R.sup.k represents hydrogen; --C.sub.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 and Q are as previously defined;
- each R.sup.m independently represents a member selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --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.n ; --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=1-3;
- R.sup.n and R.sup.o represent hydrogen, phenyl; --C.sub.1-6 straight-- or branched-chain alkyl unsubstituted with one to four R.sup.i groups;
- 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 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 : --NHR.sup.u ; --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.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 represents hydrogen or --C.sub.1-6 straight-- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- or R.sup.u and R.sup.v together 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; R.sup.x represents hydrogen or a C.sub.1-8 straight-- or branched-chained 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; 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.2, N.sup.+R.sup.h R.sup.w or --C(O)--, and,
- when R.sup.x and R.sup.y together represent a 4-6 membered ring 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
- each R.sup.w independently represents hydrogen or --C.sub.1-6 straight-- branched-chain alkyl, unsubstituted with one to four R.sup.i groups, C.sub.3-6 cycloalkyl optionally substituted with one to four R.sup.i groups; or 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.
- 10. A compound in accordance with claim 9 represented by formula Id: ##STR692## wherein: (R).sub.4 contains from one to three positively charged atoms, and each R is selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; or --R*, with the proviso that from 1-3 R groups are present which contain R* or Q;
- R.sup.a, R.sup.b and R.sup.c independently represent hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, 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;
- 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;
- Q represents ##STR693## wherein L.sup.- is a pharmaceutically acceptable counterion; 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;
- 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 ;
- 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 ; --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;
- R.sup.w 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; or 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 or O, S, SO.sub.2, NH or NCH.sub.3 ;
- R* is selected from the group consisting of: ##STR694## wherein: d is O, S or NR.sup.k ;
- R.sup.k represents hydrogen; --C.sub.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;
- R.sup.m is selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --NR.sup.n R.sup.o ; --OR.sup.n ; --SR.sup.n ; --CONR.sup.n R.sup.o ; --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 ; --NR.sup.n CO.sub.2 R.sup.h ; --NR.sup.n CONR.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; and --(CH.sub.2).sub.n --Q;;
- R.sup.d represents --R* as defined above or Q; and
- 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.
- 11. A compound in accordance with claim 9 represented by formula Id: ##STR695## wherein: each R is selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; and --R*,
- with the proviso that one or two R groups contain R* or Q and --(R).sub.4 contains from one to two positively charged atoms;
- Q represents a member selected from the group consisting of: ##STR696## wherein: .alpha. represents O, S or NR.sup.s ;
- .beta., .delta., .lambda., .mu. and .sigma. independently represent CR.sup.t, N or N.sup.+ R.sup.s provided that no more than one of .beta., .delta., .lambda., .mu., and .sigma. may be N.sup.+ R.sup.S ;
- R* is selected from the group consisting of: ##STR697## wherein: d represents O, S or NR.sup.k ;
- R.sup.a, R.sup.b and R.sup.c independently represent hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, 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 --D(O)--, said ring being unsubstituted or substituted with one to four R.sup.i groups;
- R.sup.d represents --R* or --Q;
- 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 or O, S, SO.sub.2, --C(O)--, NH and NCH.sub.3 ;
- R.sup.k represents hydrogen; --C.sub.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;
- 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.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;
- R.sup.m is selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --NR.sup.n R.sup.o ; --OR.sup.n ; --SR.sup.n ; --CONR.sup.n R.sup.o ; --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 --NR.sup.n CO.sub.2 R.sup.h ; --NR.sup.n CONR.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; and --(CH.sub.2).sub.n --Q;
- 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;
- R.sup.n represents hydrogen; phenyl; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- R.sup.t represents hydrogen; halo; phenyl; --CN; --NHR.sup.u ; --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 ; --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.sup.u and R.sup.V together 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; or 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 or O, S, SO.sub.2, NH or NCH.sub.3.
- 12. A compound in accordance with claim 8 represented by formula Ie; ##STR698## wherein: Het has substituents which contain one to three positively charged atoms and is selected from the group consisting of: ##STR699## wherein: E, G, X, Y and Z independently represent CR or N;
- each R is selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to three R.sup.d groups, and --R*, with the proviso that one or two R groups are present which contain R* or Q;
- Q is selected from the group consisting of: ##STR700## wherein: L.sup.- represents a pharmaceutically acceptable counterion;
- a and b independently represent 2 or 3:
- .alpha. represents O, S or NR.sup.s ;
- .beta., .delta., .lambda., .mu. and .sigma. independently represent CR.sup.t, N or N.sup.+ R.sup.s provided that no more that one of .beta., .delta., .lambda., .mu., and .sigma. is N.sup.+ R.sup.s ;
- R* is selected from the group consisting of; ##STR701## wherein: O, S or NR.sup.k ;
- e, g, x, y and z independently represent CR.sup.m, N or N.sup.+ R.sup.k, provided that no more that one of e, g, x, y and z represents N.sup.+ R.sup.k ;
- R.sup.a, R.sup.b and R.sup.c independently 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; and
- 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 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;
- 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 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.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 ;
- 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;
- R.sup.k represents hydrogen; --C.sub.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;
- R.sup.s represents hydrogen; phenyl; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- R.sup.t represents hydrogen; halo; phenyl; --CN; --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 ; --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 branch-chain alkyl, unsubstituted or substituted with one to four R.sup.i groups;
- or R.sup.u and R.sup.v together 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, and
- 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; or phenyl optionally substituted with one to four R.sup.i groups.
- 13. A compound in accordance with claim 12 represented by formula Ie: ##STR702## wherein: Het has substituents which contain from one to three positively charged atoms and is selected from the group consisting of: ##STR703## wherein: E, G, X, Y and Z independently represent CR or N;
- each R is selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups; --C.sub.3-7 cycloalkyl, unsubstituted or substituted with one to three R.sup.d groups; and --R.sup.* ;
- with the proviso that one R group contains Q;
- R.sup.* is selected from the group consisting of: ##STR704## wherein: d is O, S or NR.sup.k ;
- Q represents ##STR705## wherein a and b are 2, L- is a pharmaceutically acceptable counterion, and
- 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.sub.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;
- each R.sup.h independently represents H, a --C.sub.1-6 straight or branch-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 ;
- 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;
- R.sup.k represents hydrogen; --C.sub.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, wherein n=1, 2 or 3 and Q is as defined above;
- R.sup.m is selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --NR.sup.n R.sup.o ; --OR.sup.n ; --SR.sup.n ; --CONR.sup.n R.sup.o ; --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 ; --NR.sup.n CO.sub.2 R.sup.h ; --NR.sup.n CONR.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; and --(CH.sub.2).sub.1-3 Q;
- R.sup.a, R.sup.b and R.sup.c independently represent hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one of four R.sub.d groups; or --R.sup.* ;
- 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;
- R.sup.d represents R.sup.* or Q;
- 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, and
- R.sup.w 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; or 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.
- 14. A compound in accordance with claim 12 represented by formula Ie: ##STR706## wherein Het has substituent groups which contain from one to three positively charged atoms and is selected from the group consisting of: ##STR707## wherein E, G, X, Y and Z independently represent CR of N;
- R represents a member selected from the group consisting of hydrogen; halo; --CN; --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 ; --COR.sup.a ; --C.sub.1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to three R.sup.d groups; and --R.sup.*, with the proviso that one or two R groups contain R.sup.* or Q;
- Q represents a member selected from the group consisting of: ##STR708## .alpha. represents O, S, or NR.sup.s ; .beta., .delta., .lambda., .mu. and .sigma. independently represent CR.sup.t, N or N.sup.+ R.sup.s provided that no more than one of .beta., .delta., .lambda., .mu., and .sigma. may be N.sup.+ R.sup.s ;
- R.sup.* is selected from the group consisting of: ##STR709## wherein: d represents O, S, or NR.sup.k ;
- R.sup.a, R.sup.b and R.sup.c independently represent hydrogen, --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R.sup.d groups; or --R.sup.* ;
- 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;
- R.sup.d represents --R.sup.* or --Q;
- 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 ;
- 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.sub.h ; --NHCOR.sup.h ; guanidinyl; carbamimidoyl or ureido;
- R.sup.k represents hydrogen; --C.sub.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, wherein n and Q are as previously defined;
- R.sup.m is selected from the group consisting of: hydrogen; halo; --CN; --NO.sub.2 ; --NHR.sup.n ; --NR.sup.n R.sup.o ; --OR.sup.n ; --SR.sup.n ; --CONR.sup.n R.sup.o ; --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 ; --NR.sup.n CO.sub.2 R.sup.h ; --NR.sup.n CONR.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; and --(CH.sub.2).sub.n --Q, wherein n and Q are as previously defined;
- 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;
- R.sup.s represents hydrogen; phenyl; --C.sub.1-6 straight- or branched-chain alkyl , unsubstituted or substituted with one to four R.sup.i groups;
- R.sup.t represents hydrogen; halo; phenyl; --CN; --NHR.sup.u ; --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 ; --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.sup.u and R.sup.v together 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; or phenyl optionally substituted with one to four R.sup.i groups.
- 15. A compound in accordance with claim 10 represented by the formula If: ##STR710## wherein: L- is a pharmaceutically acceptable counterion:
- n is 1-3;
- 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 of 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 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;
- each R is independently selected from: hydrogen; halo; --CN; .sub.[NO.sub.2 ; --OR.sup.c ; --SR.sup.c ; --CONR.sup.a R.sup.b ; --COOR.sup.h ; --SOR.sup.c j; --SO.sub.2 R.sup.c ; --SO.sub.2 NR.sup.a R.sup.b ; --NR.sup.a SO.sub.2 R.sup.b ; .sub.[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 of four R.sup.d 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 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 ; or --NR.sup.e C(NR.sup.f)R.sup.g ;
- R.sup.e, R.sup.f and R.sup.g 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.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.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 ;
- 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;
- R.sup.w 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; or 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.
- 16. A compound in accordance with claim 15 represented by formula Ig: ##STR711## wherein: L- is a pharmaceutically acceptable counterion;
- 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 .sub.[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, 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 of 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;
- 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 m --C(O)--NH and NCH.sub.3 ; p1 R.sup.w 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; or 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 at 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO.sub.2, NH or NCH.sub.3 ; and
- 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.
- 17. A compound in accordance with claim 15 represented by formula Ih: ##STR712## wherein: L- is a pharmaceutically acceptable counterion;
- 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;
- 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 ;
- R.sup.w 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; or 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, and
- 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.
- 18. A compound i accordance with claim 11 represented by formula Ii: ##STR713## wherein: each R independently represents a member selected from the group consisting of hydrogen or --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups;
- R.sup.d represents --Q;
- Q represents a member selected from the group consisting ##STR714## wherein: .alpha. represents O, S or NR.sup.s ;
- .beta., .delta., .lambda., .mu. and .sigma. independently represent CR.sup.t, N or N.sup.+ R.sup.s provided that no more than one of .beta., .delta., .lambda., .mu., and .sigma. may be N.sup.+ R.sup.s and further provided that from one to three positively charged atoms are contained in the R groups;
- R.sup.s represents hydrogen; halo; phenyl; .sub.[CN; --NHR.sup.u ; --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 ; --C.sub.1-6 straight- or branched-chain alkyl, 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 ;
- R.sup.u and R.sup.v represent hydrogen or --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted wit one to four R.sup.i groups;
- R.sup.u and R.sup.v together 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;
- and 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; or phenyl optionally substituted with one to four R.sup.i groups.
- 19. A compound in accordance with claim 13 represented by formula Ie: ##STR715## wherein: Het has substituent groups which contain from two to three positively charged atoms and is selected from the group consisting of: ##STR716## wherein: E, G and Y independently represent CR or N;
- X and Z independently represent CH or N;
- R represents a member selected from the group consisting of hydrogen; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with R.sup.d ;
- with the proviso that one R group is present which contains Q;
- R.sup.d represents Q: ##STR717## Q represents wherein L- is a pharmaceutically acceptable counterion;
- 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)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;
- 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 ;
- 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+(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, and
- R.sup.w 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; or 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.
- 20. A compound in accordance with claim 14 represented by formula Ie: ##STR718## wherein: Het has substituents which contain from one to three positively charged atoms and is selected from the group consisting of: ##STR719## wherein: E, G, X, Y and Z independently represent CR or N;
- R represents a member selected from the group consisting of hydrogen; --C.sub.1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R.sup.d groups;
- with the proviso that from one to three R groups are present which contains Q;
- R.sup.d represents Q;
- Q is selected from the group consisting of: ##STR720## wherein: .alpha. represents O, S or NR.sup.s ;
- .beta., .delta., .lambda., .mu. and .sigma. independently represent CR.sup.t, N or N.sup.+R.sup.s provided that no more than one of .beta., .delta., .lambda., .mu., and .sigma. may be N.sup.+ R.sup.s ;
- R.sup.s 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.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 ;
- R.sup.t represents hydrogen; halo; phenyl; --CN; --NHR.sup.u ; --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 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 ; --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.sup.u and R.sup.v together 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;
- and 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; or phenyl optionally substituted with one to four R.sup.i groups.
- 21. A compound in accordance with claim 16 wherein Het is selected from the group consisting of:
- __________________________________________________________________________ ##STR721## ##STR722## ##STR723## ##STR724## ##STR725## ##STR726## ##STR727## ##STR728## ##STR729## ##STR730## ##STR731## ##STR732## ##STR733## ##STR734##__________________________________________________________________________
- 22. A compound in accordance with claim 7 wherein Het is selected from the following:
- __________________________________________________________________________ ##STR735## ##STR736## ##STR737## ##STR738## ##STR739## ##STR740## ##STR741## ##STR742## ##STR743## ##STR744## ##STR745## ##STR746## ##STR747## ##STR748## ##STR749## ##STR750## ##STR751## ##STR752## ##STR753## ##STR754## ##STR755## ##STR756## ##STR757## ##STR758## ##STR759## ##STR760## ##STR761## ##STR762## ##STR763## ##STR764## ##STR765## ##STR766## ##STR767## ##STR768## ##STR769## ##STR770## ##STR771## ##STR772## ##STR773## ##STR774## ##STR775## ##STR776## ##STR777## ##STR778## ##STR779## ##STR780## ##STR781## ##STR782## ##STR783## ##STR784## ##STR785## ##STR786##__________________________________________________________________________
- 23. A compound in accordance with claim 1 wherein Het is selected from the group consisting of:
- ______________________________________ ##STR787## ##STR788## ##STR789## ##STR790## ##STR791## ##STR792## ##STR793## ##STR794## ##STR795## ##STR796## ##STR797## ##STR798## ##STR799## ##STR800## ##STR801## ##STR802## ##STR803## ##STR804## ##STR805## ##STR806## ##STR807## ##STR808## ##STR809## ##STR810## ##STR811## ##STR812## ##STR813## ##STR814## ##STR815## ##STR816## ##STR817## ##STR818## ##STR819## ##STR820## ##STR821## ##STR822## ##STR823## ##STR824## ##STR825## ##STR826## ##STR827## ##STR828## ##STR829## ##STR830## ##STR831## ##STR832## ##STR833## ##STR834## ##STR835## ##STR836## ##STR837## ##STR838## ##STR839## ##STR840## ##STR841## ##STR842## ##STR843## ##STR844## ##STR845## ##STR846## ##STR847## ##STR848## ##STR849## ##STR850## ##STR851## ##STR852## ##STR853## ##STR854## ##STR855## ##STR856## ##STR857## ##STR858## ##STR859## ##STR860## ##STR861## ##STR862## ##STR863## ##STR864## ##STR865## ##STR866## ##STR867## ##STR868## ##STR869## ##STR870## ##STR871## ##STR872## ##STR873##______________________________________
- wherein X.sup.- equals L.sup.- and L.sup.- represents a pharmaceutically acceptable counterion.
- 24. A compound represented by the formula: ##STR874## wherein L.sup.- represents a pharmaceutically acceptable counterion.
- 25. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
- 26. A pharmaceutical composition in accordance with claim 25 in the form of a tablet, capsule, solution or suspension.
- 27. A pharmaceutical composition in accordance with claim 25 in the form of an injectable liquid or lyophillized solid.
- 28. A pharmaceutical composition in accordance with claim 25, further comprised of a DHP inhibitor.
- 29. A pharmaceutical composition in accordance with claim 28 wherein the DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
- 30. A method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of claim 1 in an amount effective to treat said bacterial infection.
- 31. A method of treating a bacterial infection in accordance with claim 30 wherein the compound is administered orally.
- 32. A method of treating a bacterial infection in accordance with claim 30 wherein the compound is administered by injection.
- 33. A method of treating a bacterial infection in a mammalian subject in need of such treatment, comprising administering to such subject an antibacterially effective amount of a compound of claim 1 and an inhibitorily effective amount of a DHP inhibitor.
- 34. The method according to claim 33, wherein the DHP inhibitor is 7-(L-2-amino-2-carboxyethyl-thio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation in part of application Ser. No. 08/213,314, filed on Mar. 14, 1994, now abandoned, priority of which is claimed hereunder.
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Continuation in Parts (1)
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Number |
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Parent |
213314 |
Mar 1994 |
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