Claims
- 1. A compound of the formula: ##STR42## 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: ##STR43## f) a carbamoyloxy radical which is unsubstituted or substituted on nitrogen with one or two C.sub.1 -C.sub.4 alkyl groups: ##STR44## 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: ##STR45## where n=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: ##STR46## 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: ##STR47## where R.sup.y and R.sup.z are as defined above; j) a formylamino group: ##STR48## k) (C.sub.1 -C.sub.6 alkyl)carbonylamino radical: ##STR49## l) a (C.sub.1 -C.sub.4 alkoxy) carbonylamino radical: ##STR50## 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: ##STR51## where R.sup.y and R.sup.z are as defined above; n) a sulfonamido group: ##STR52## o) a cyano group: --CN; p) a formyl or acetalized formyl radical: ##STR53## q) (C.sub.1 -C.sub.6 alkyl)carbonyl radical wherein the carbonyl is free or acetalized: ##STR54## r) phenylcarbonyl: s) a hydroximinomethyl radical in which the oxygen or carbon atom is optionally substituted by a C.sub.1 -C.sub.4 alkyl group: ##STR55## where R.sup.y and R.sup.z are as defined above; t) a (C.sub.1 -C.sub.6 alkoxy)carbonyl radical: ##STR56## u) a carbamoyl radical which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups: ##STR57## 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: ##STR58## where R.sup.y and R.sup.z are as defined above; w) a thiocarbamoyl group: ##STR59## x) an amidino group ##STR60## 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 ##STR61## 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(OMc)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 is phenyl or heteroaryl, where heteroaryl is as defined below except that there is no quaternary nitrogen and attachment through nitrogen is optional, and the phenyl and heteroaryl are 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.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;
- 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; O; S; SO; SO.sub.2 ; NH; or N(C.sub.1 -C.sub.4 alkyl);
- Q.sup.+ is quinolinium ##STR62## or isoquinolinium ##STR63## 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.
- 2. A compound according to claim 1 wherein R.sup.1 /R.sup.2 is H-- and R.sup.2 /R.sup.1 is (R)--CH.sub.3 CH(OH)--.
- 3. A compound according to claim 1 wherein R.sup.1 /R.sup.2 is H-- and R.sup.2 /R.sup.1 is (R)--CH.sub.3 CH(OH)--; and A is --CH.sub.2 --.
- 4. A compound according to claim 1 wherein R.sup.1 /R.sup.2 is H-- and R.sup.2 /R.sup.1 is (R)--CH.sub.3 CH(OH)--; A is --CH.sub.2 --; and Q.sup.+ is quinolinium.
- 5. A compound according to claim 1 wherein R.sup.1 /R.sup.2 is H-- and R.sup.2 /R.sup.1 is (R)--CH.sub.3 CH(OH)--; A is --CH.sub.2 --; Q.sup.+ is quinolinium; and R.sup.c is selected from the group consisting of --NH.sub.2, --OH, --CH.sub.3, --CO.sub.2.sup.-, --CH.sub.2 SCH.sub.3, and --CH.sub.2 SOCH.sub.3.
- 6. A compound according to claim 1 wherein the compound is selected from the group consisting of ##STR64## where Q=quinolinium and IQ=isoquinolinium; and the other substituents are defined below:
- ______________________________________R' R R.sup.a R.sup.c A Q.sup.+______________________________________OH H H 2-NH.sub.2 4-CH.sub.2 -- QOH H 3-OH 2-NH.sub.2 5-CH.sub.2 -- QOH H 3-F 4-NH.sub.2 5-CH.sub.2 -- QOH H H 3-NH.sub.2 4-CH.sub.2 -- IQOH H 3-F 3-NH.sub.2 5-CH.sub.2 -- IQOH H H 3-CH.sub.2 SCH.sub.3 4-CH.sub.2 -- QOH H H 4-CH.sub.2 SCH.sub.3 4-CH.sub.2 -- IQOH H 3-OH 3-CH.sub.2 SCH.sub.3 5-CH.sub.2 -- QF H H 4-NH.sub.2 4-CH.sub.2 -- QF H H 3-CH.sub.2 SCH.sub.3 4-CH.sub.2 -- QOH CH.sub.3 H 4-NH.sub.2 4-CH.sub.2 -- QOH H H 4-NH.sub.2 4-CH.sub.2 SCH.sub.2 QOH H H 4-NH.sub.2 4-CH.sub.2 CH.sub.2 -- QOH H 3-OH 4-NH.sub.2 5-CH.sub.2 -- QOH H 3-CH.sub.3 4-NH.sub.2 --CH.sub.2 -- QOH H H 3-CH.sub.2 SCH.sub.3 4-CH.sub.2 -- QOH H 3-F 4-NH.sub.2 4-CH.sub.2 -- QOH H 3-SMe 4-NH.sub.2 4-CH.sub.2 -- QOH H H 4-NH.sub.2 4CH.sub.2 CH.sub.2 -- QOH H H 4-NH.sub.2 4-CH.sub.2 CH.sub.2 -- IQOH H 3-S(O)CH.sub.3 4-NH.sub.2 5-CH.sub.2 -- QOH H 3-CH.sub.2 CO.sub.2 K 4-NH.sub.2 4-CH.sub.2 -- QOH H 3-CH.sub.2 CO.sub.2 K 4-NH.sub.2 5-CH.sub.2 -- QOH H 3-CH.sub.2 SO.sub.3 -- 4-NH.sub.2 5-CH.sub.2 -- QOH H H 3-NH.sub.2 4-CH.sub.2 -- QOH H H 5-NH.sub.2 4-CH.sub.2 -- IQOH H H 6-OH 4-CH.sub.2 -- QOH H H 1-NH.sub.2 4-CH.sub.2 -- IQOH H H 3-CO.sub.2 4-CH.sub.2 -- QOH H H 3-CH.sub.3 4-CH.sub.2 -- QOH H H 4-NH.sub.2 4-CH.sub.2 -- QOH H H 3-NH.sub.2 4-CH.sub.2 -- QOH H H 5-NH.sub.2 4-CH.sub.2 -- IQOH H H 6-OH 4-CH.sub.2 -- QOH H H 1-NH.sub.2 4-CH.sub.2 -- IQOH H H 3-CO.sub.2.sup.- 4-CH.sub.2 -- QOH H H 3-CH.sub.3 4-CH.sub.2 -- QOH H H 4-NH.sub.2 4-CH.sub.2 -- Q______________________________________
- 7. A pharmaceutical composition for antibacterial use comprising an antibacterially effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier therefor.
- 8. A method of treating bacterial infections in human or animal subjects in need of such treatment comprising administering to such subject an antibacterially effective amount of a compound of claim 1.
- 9. The combination of a compound of claim 1 and a DHP inhibitor.
- 10. The combination of a compound of claim 6 and the DHP inhibitor 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
- 11. A pharmaceutical composition for antibacterial use comprising an antibacterially effective amount of a compound of claim 1, an inhibitorily effective amount of a DHP inhibitor, and a pharmaceutically acceptable carrier therefore.
- 12. A pharmaceutical composition according to claim 11 wherein the DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
- 13. A method of treating bacterial infections in human or animal subjects in need of such treatment comprising coadministering to such subject an antibacterially effective amount of a compound of claim 1 and an inhibitorily effective amount of a DHP inhibitor.
- 14. A method according to claim 13 wherein the DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
Parent Case Info
This is a continuation of application Ser. No. 395,854, filed Aug. 21, 1989, now abandoned.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
4680292 |
Christensen |
Jul 1987 |
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Continuations (1)
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Number |
Date |
Country |
Parent |
395854 |
Aug 1989 |
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