Antibacterial penem compounds

Details Antibacterial penem compounds Antibacterial penem compounds

1993-02-19

1996-04-09

Rizzo, Nicholas

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514192, 540310, C07D49900, A61K 3143

Patent

active

055062253

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD The present invention relates to penem compounds, and more
specifically to penem compounds which are expected to find clinical utility as promising antibiotics.


BACKGROUND ART

The present inventors previously found that a group of penem compounds represented by the following formula: ##STR2## wherein R.sub.1 is a hydrogen atom or allyl group, gram-positive and gram-negative, aerobic or anaerobic bacteria (Japanese Patent Publication No. 207387/1986).
High safety of these compounds has been confirmed by safety test in which laboratory animals were used. Their development as medical drugs is now expected.
In the meantime, it has been found by the study on the correlation between structure and, antibacterial activities of these compounds [J. Antibiotics, 41, 1685 (1988)] that, among 2-substituents of penem, (R)-2-tetrahydrofuryl group provides the highest antibacterial activities while (S)-2-tetrahydrofuryl group, a diastereomer at its 2-side chain group, and (R) or (S)-3-tetrahydrofuryl group, a position isomer, provide weaker activities particularly against gram-negative bacteria.
For these reasons, compounds represented by the following formula (II): ##STR3## wherein R2 represents a hydrogen atom or a group capable of forming a pharmaceutically-acceptable salt, that they do not require any special chemical modification for oral absorption and they themselves can be developed as both injections and oral drugs.
Namely, the bioavailability of the above-described compounds per se in laboratory animal (rats) has been found by no means inferior to commercial drugs which are used clinically.
However, from the viewpoint of safety and economy further enhancement of their bioavailability upon oral administration is apparently more advantageous. As far as the above compounds are concerned, there is still a room for further improvement in this regard.
Regarding improvements in the absorption upon oral administration, extensive studies have been conducted on penicillin and cephalosporin antibiotics so that many of these antibiotics are used as curative medicines. There are, however, only a few study reports of this type on penem and carbapenem antibiotics [J. Antibiotics, 36, 983, (1983); Japanese Patent Laid-Open No. 6728/1990]. It has therefore been interested in determining whether or not the approaches used for penicillin and cephalosporin antibiotics are equally applicable to penem compounds.


DISCLOSURE OF INVENTION

The present inventors have carried out an extensive investigation on the compounds (II) with a view toward making an improvement in their bioavailability. As a result, it has been found that protection of their carboxyl group with an ester-forming group which can be hydrolyzed easily in vivo can significantly improve their bioavailability, leading to the completion of the present invention.
The present invention provides a penem compound represented by the following formula (I): ##STR4## wherein R represents certain physiologically-hydrolyzable, ester-forming group.
The physiologically hydrolyzable, ester-forming group useful in the penem compound of the present invention means a group which can be removed easily by in vivo hydrolysis. Examples include an acetyloxymethyl group, 1-(acetyloxy) ethyl group, pivaloyloxy-methyl group, 1-(ethoxycarbonyloxy) ethyl group, 1-(isopropyloxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyl)ethyl group and 3-phthalidyl group. When these groups contain an asymmetric carbon atom, it is preferable that they are optically active.


BEST MODE FOR CARRYING OUT THE INVENTION

The penem compound (I) of the present invention can be synthesized, for example, by reacting a halogenated alkyl compound (IV) with a penem compound (II') in accordance with the following formula: ##STR5## wherein X represents a halogen atom, and
When R.sub.3 in the compound (II') is an alkali metal atom or an amino residuum in the above reaction, the target product can be obtained by stirring the compound (II') together with the halogenated alkyl compound (IV) in an organic so

REFERENCES:
patent: 4952577 (1990-08-01), Alpegiani et al.
patent: 4997829 (1991-05-01), Ishiguro et al.
patent: 5089489 (1992-02-01), Alpegiani et al.
Bioreversible Carriers in Drug Design: Theory and Application, Pergamon Press, 1987, pp. 13-16, Hans Bundgaard, "Design of Bioreversible Drug Derivatives and The Utility of the Double Prodrug Concept".
The Journal of Antibiotics, vol. 41, No. 11, 1988, pp. 1685-1693, M. Ishiguro, et al., "Studies on Penem Antibiotics. 1. Synthesis and in Vitro Activity of Novel 2-Chiral Substituted Penems".

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