Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-02-19
1997-12-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540310, C07D49900, A61K 3143
Patent
active
057030685
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/JP91/01100, Aug. 16, 1991.
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 (IV): ##STR3## in which R.sub.4 is a hydrogen atom or allyl group, oxygen atoms in the ring thereof activities against both gram-positive and gram-negative, aerobic or anaerobic bacteria (Japanese Patent Publication No. 162694/1988).
Of these compounds, compounds represented by the following formula (V): ##STR4## have high antibacterial activities and their high safety has been confirmed by their safety test in which laboratory animals were used. Their development as medical drugs is therefore expected.
The bioavailability of the compounds (V) is, however, not sufficient, so that their use as oral preparations requires improvements in their oral absorption.
DISCLOSURE OF INVENTION
The present inventors have carried out an extensive investigation on the compounds (V) with a view toward making improvements 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 of the following formula (I): ##STR5## wherein R represents a group of the following formula (II) or (III): ##STR6## in which R.sub.1 is a hydrogen atom or a linear or branched, C.sub.1 -C.sub.6 alkyl group or together with R.sub.2 ; forms an o-phenylene 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.3 represents 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 R.sub.3 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, 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 (VI) with a penem compound (V') in accordance with the following formula: ##STR8## wherein X represents a halogen atom, and
When R.sub.5 in the compound (V') is an alkali metal atom or an amino residuum in the present invention, the target product can be obtained by stirring the compound (V') with the halogenated alkyl compound (VI) in an organic solvent.
When R.sub.5 in the compound (V') is a hydrogen atom, on the other hand, the compound (V') is first reacted with an alkali metal hydroxide, an alkali metal salt or an amine compound in an organic solvent to form a salt, and the reaction mixture is then reacted with the halogenated alkyl compound (VI).
The halogenated alkyl compound represented by the formula (VI) can efficiently esterify the carboxyl group of the compound (V') with the group R to produce the target compound of the formula (I). Examples of the compound (VI) include those employed for the preparation of prodrugs of the penicillin or cephalosporin type: Described more specifically, there are those containing, as the group R, an acetyloxymethyl group, a 1-(acetyloxy)ethyl group, a pivaloyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy) group, a 3-phthalidyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or the like and, as the halogen atom represented by X, a chlorine, bromine or iodine atom.
No particular limitation is imposed on the alkali metal insofar as it forms a salt with the compound (V'). Examples of the alka
REFERENCES:
patent: 4479947 (1984-10-01), Christensen
patent: 4654331 (1987-03-01), Christensen
patent: 5036063 (1991-07-01), Lattrell et al.
patent: 5116832 (1992-05-01), Ishiguro 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".
Chem. Pharm. Bull. vol. 38, No. 4, 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".
Ishiguro Masaji
Iwata Hiromitsu
Nakatsuka Takashi
Tanaka Rie
Shah Mukund J.
Suntory Limited
Wong King Lit
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