Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-10-06
1996-07-30
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540350, C07D47700, C07D20716, C07C22964, C07C22962
Patent
active
055411789
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/00588 filed Apr. 2, 1992.
The present invention relates to carbapenems and in particular to such compounds containing a carboxy substituted phenyl group. This invention further relates to processes for their preparation, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them. The compounds of this invention are antibiotics and can be used in the treatment of any disease that is conventionally treated with antibiotics for example in the treatment of bacterial infection in mammals including humans.
Carbapenems were first isolated from fermentation media in 1974 and were found to have broad spectrum antibacterial activity. Since this discovery substantial investigations have been made into new carbapenem derivatives and many hundreds of patents and scientific papers have been published.
The first, and so far the only, carbapenem to be commercially marketed is imipenem (N-formimidoyl thienamycin). This compound has a broad spectrum of antibacterial activity.
The present invention provides compounds with a broad spectrum of antibacterial activity including both Gram positive and negative, aerobic and anaerobic bacteria. They exhibit good stability to beta-lactamases. In addition representative compounds of this invention exhibit favourable pharmacokinetics.
The carbapenem derivatives referred to herein are named in accordance with the generally accepted semi-systematic nomenclature: ##STR2##
Accordingly the present invention provides a compound of the formula (I) ##STR3## wherein:
R.sup.1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R.sup.2 is hydrogen or C.sub.1-4 alkyl;
R.sup.3 is hydrogen or C.sub.1-4 alkyl; substituents selected from halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, trifluoromethyl, C.sub.1-4 alkoxycarbonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, sulphonic acid, C.sub.1-4 alkylS(O).sub.n --(wherein n is 0-2), N-C.sub.1-4 alkanesulphonamido, C.sub.1-4 alkanoylamino and C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino: pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
The term alkyl includes all straight and branched chain structures, for example, C.sub.1-4 alkyl includes n-butyl and 2-methylpropyl.
Preferably R.sup.1 is 1-hydroxyethyl.
R.sup.2 is hydrogen or C.sub.1-4 alkyl for example methyl, ethyl, n-propyl, 1-methylethyl and n-butyl.
Preferably R.sup.2 is hydrogen or methyl and in particular R.sup.2 is methyl.
R.sup.3 is hydrogen or C.sub.1-4 alkyl for example methyl, ethyl, n-propyl, isopropyl and n-butyl.
Preferably R.sup.3 is hydrogen or methyl.
R.sup.4 is hydroxy or carboxy.
Suitable substituents for the phenyl ring include, for example:
for halo: fluoro, chloro, bromo and iodo;
for C.sub.1-4 alkyl: methyl, ethyl, propyl, 1-methylethyl, butyl and 2-methylpropyl;
for C.sub.1-4 alkoxy: methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 2-methylpropoxy;
for C.sub.1-4 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
for C.sub.1-4 alkylcarbamoyl: methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl;
for C.sub.1-4 alkylamino: methylamino, ethylamino and propylamino;
for di-C.sub.1-4 alkylamino: dimethylamino, diethylamino and methylethylamino;
for C.sub.1-4 alkylS(O).sub.n --: methylthio, methylsulphinyl and methylsulphonyl;
for C.sub.1-4 alkanoylamino: acetamido and propionamido;
for N-C.sub.1-4 alkanesulphonamido: N-methanesulphonamido and N-ethanesulphonamido;
for C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino: N-methylacetamido and N-ethylacetamido.
The present invention covers all epimeric, diastereoisomeric and tautomeric forms of the compounds of the formula (I) wherein the absolute stereochemistry at the 5-position is as illustrated in formula (I). When a bond is represented as a wedge, this indicates that in three dimensions the bond would be coming forward out of the paper and when a bond is represented as hatched, this indicates that
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Betts Michael J.
Swain Michael L.
Cook Rebecca
Zeneca Limited
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