Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-02-19
1998-11-03
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540310, C07D49932, A61K 3143
Patent
active
058308890
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 (V): ##STR3## wherein R.sub.3 is a hydrogen atom or allyl group, gram-positive and gram-negative, aerobic or anaerobic bacteria (Japanese Patent Publication No. 207387/1988).
High safety of these compounds has been confirmed by a 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 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.
From these reasons, compounds represented by the following formula (VI): ##STR4## wherein R.sub.4 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.
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 yet room for further improvement in this regard.
Regarding improvements on the absorption upon oral administration, active 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 No. 67287/1990!. There has therefore been interest 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 (VI) with a view toward making an improvement in their bioavailability. As a result, it has been found that protection of their carboxyl group with a particular ester-forming group 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): ##STR5## wherein R represents a group of the general formula (II), (III) or (IV): ##STR6## in which R.sub.1 is a hydrogen atom or a linear or branched C.sub.1 -C.sub.6 alkyl group; aryl group, a C.sub.7 -C.sub.11 aralkyl group, or a said R.sub.2 group substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl groups, C.sub.6 -C.sub.10 aryl groups, C.sub.7 -C.sub.11, aralkyl groups, hydroxyl groups, C.sub.1 -C.sub.6 alkoxyl groups and halogen atoms; and ##STR7## in which R.sub.1 has the same meaning as defined above; atoms in the ring thereof, or being a C.sub.1 -C.sub.6 alkyl group, a C.sub.6 -C.sub.10 aryl group, a C.sub.7 -C.sub.11 aralkyl group, or a said 5-substituent substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl groups, C.sub.6 -C.sub.10 aryl groups, C.sub.7 -C.sub.11 aralkyl groups, hydroxyl groups, C.sub.1 -C.sub.6 alkoxyl groups and halogen atoms.
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 (VII) with a penem compound (VI') in accordance with the following formula: ##STR8## wherein X represents a halogen atom, and
When R.sub.4 in the compound (IV') is an alkali metal atom or an amino residuum in this in
REFERENCES:
patent: 4479947 (1984-10-01), Christensen
patent: 4654331 (1987-03-01), Christensen
patent: 4997829 (1991-03-01), Shiguiro et al.
patent: 5036063 (1991-07-01), Lattrell et al.
Chem. Pharm. Bull., vol. 38, No. 4, Apr. 1990, pp. 1077-1078, I. Miyauchi, et al., "Studies on Penem and Carbapenem II. an Improved Synthesis of Orally Active Penem Antibiotic (5-Methyl-2-Oxo-1,3-Dioxol-4-Yl)Methyl (5R,6S)-2-(2-Fluoroethylthio)-6-{(1R)-1-Hydroxyethyl}Penem-3-Carboxylate".
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".
Budavari, S. et al. The Merck Index (Merck & Co., Whitehouse Station, N.J.), p. 1589 (1996).
Ishiguro Masaji
Iwata Hiromitsu
Nakatsuka Takashi
Tanaka Rie
Ford John M.
Suntory Limited
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