Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-11-26
1996-05-21
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540350, C07D47700, A61K 3140
Patent
active
055190154
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00603.
The present invention relates to carbapenems and in particular to such compounds containing a carboxy substituted thienyl 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 against 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; further substituted by one or two substituents selected from halo, cyano, C.sub.1-4 alkyl, nitro, hydroxy, carboxy, C.sub.1-4 alkoxy, trifluoromethyl, C.sub.1-4 alkoxycarbonyl, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, sulfonic acid, C.sub.1-4 alkylS(O).sub.n --(wherein n is 0-2), C.sub.1-4 alkanoylamino, C.sub.1-4 alkanoyl(N-C.sub.1-4 alkyl)amino, carbamoyl, C.sub.1-4 alkylcarbamoyl, di-C.sub.1-4 alkylcarbamoyl and N-C.sub.1-4 alkanesulfonamido; or by a tetramethylene group attached to adjacent carbon atoms on the thienyl ring; or a 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. In particular R.sup.2 is methyl.
R.sup.3 is hydrogen or C.sub.1-4 alkyl for example methyl, ethyl, n-propyl, 1-methylethyl and n-butyl.
Preferably R.sup.3 is hydrogen or methyl. In particular R.sup.3 is hydrogen.
Suitable substituents for the thienyl ring include, for example: 2-methylpropyl; 2-methylpropoxy; propylcarbamoyl; methylethylamino; methylsulphonyl; propoxycarbonyl; N-ethylacetamido; N-ethanesulfonamido.
Preferably, when the thienyl ring is optionally substituted, the optional substituents are selected from halo, cyano, C.sub.1-4 alkyl, nitro, carboxy, hydroxy, C.sub.1-4 alkoxy, carbamoyl, amino, trifluoromethyl and tetramethylene.
Most preferably, the thienyl ring is not further substituted or further substituted by one hydroxy, methyl or tetramethylene group.
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 in three dimensions the bond would be going back into the paper. The compounds of the formula (I) have a number of other stereocentres, namely: within the group R.sup.1 (when R.sup.1 is 1-hydroxyethyl or 1-fluoroethyl); at the 6-position; at the 1-position (when R.sup.2 is C.sub.1-4 alkyl); and at t
REFERENCES:
patent: 4963544 (1990-10-01), Murata
patent: 5194624 (1993-03-01), Murata
patent: 5215983 (1993-06-01), Murata
Cook Rebecca
Zeneca Limited
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