Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-04-09
1996-01-02
Lovering, Richard D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540310, A61K 3143, C07D49900
Patent
active
054808804
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/01396.
The present invention relates to penem compounds, to a process for their preparation, and to pharmaceutical and veterinary compositions containing them.
There is a continuing need for new antibiotics. Because of the confirmed wide scale use of known antibiotics, resistant strains of pathogens are selected. Accordingly, there is no constant effectiveness for any given antibiotic. Additionally, known antibiotics suffer from the disadvantage of being effective against only certain types of microorganisms, or they may produce undesired side-effects. There is thus a strongly felt need for new antibiotics which do not suffer from the above disadvantages.
Penem compounds are promising antibiotics, in particular the quaternary ammonium penems. In the past, several penem antibiotics featuring a quaternary ammonium at the C-2 sidechain have been investigated: E. Perrone et al., 2-(Quaternary ammonio)methyl penems, J. Antibiotics 39:1351 (1986): E. Perrone et al., Novel quaternary ammonium penems: the [(pyridino)methyl]phenyl derivatives, J. Antibiotics 40:1636 (1987); M. Alpegiani et al , 2-(Heteroatom-substituted)methyl penems. III. Nitrogen derivatives, Heterocycles 27:1329 (1988); G. Franceschi et al., 6-Hydroxyethyl penems--Ten years after, Recent Advances in the Chemistry of .beta.-Lactam Antibiotics, P. H. Bently ed., The Royal Society of Chemistry, London 1989, p. 223-246. Unfortunately, these penems showed as unexpected side effect a high acute toxicity.
The present invention provides quaternary ammonium penems which did not display acute toxicity in mice up to the highest dose tested (2000-3000 mg/kg i.v.), and showed the following advantages:
The compounds of the invention are quaternary ammonium penems of the following formula (I): ##STR3## wherein R.sub.1 is a hydrogen atom, a negative charge or an ester residue; R is --(CH.sub.2).sub.n --A--PO.sub.3 H.sub.2, E or Z), --OCH.sub.2 --, --SCH.sub.2 -- or --CHOH--; NHCN, --(CH.sub.2).sub.n NHSO.sub.3 H, --(CH.sub.2).sub.n CONHSO.sub.2 CH.sub.3 or --(CH.sub.2).sub.n CONHSO.sub.2 CF.sub.3, wherein n is as defined above; group or a heterocyclediyl group, m is 0 or 1, n is as above defined, and Z represents CO.sub.2 H, PO.sub.3 H.sub.2, SO.sub.2 NHCN, NHSO.sub.3 H, CONHSO.sub.2 CH.sub.3 or CONHSO.sub.2 CF.sub.3 ; ##STR4## wherein Y is O or NH and X is NH, N--OH or N--O--(CH.sub.2).sub.n+1 COOH wherein n is as defined above; or convertible into an anion at physiological pH and m is as defined above; and the pharmaceutically acceptable salts thereof.
The term arylene preferably encompasses a phenylene or naphthylene group.
A heterocyclediyl group is preferably an optionally substituted five- or six-membered unsaturated or saturated heterocyclic ring containing at least one nitrogen, oxygen or sulphur atom, and is more preferably a furanediyl, thiophenediyl, tetrazolediyl, thiazolediyl, isothiazolediyl, oxazolediyl, isoxazolediyl, thiadizaolediyl or a pyrrolediyl group.
A heterocyclyl group is preferably an optionally substituted five- or six-membered unsaturated or saturated heterocyclic ring containing at least one nitrogen, oxygen or sulphur atom. Preferred substituents are hydroxy, C.sub.1 -C.sub.4 alkyl and an oxo group. More preferably, "heterocyclyl" represents a furanyl, thiophenyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl or triazinyl group, and most preferably a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl group, a 2,5-dihyrdo-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-yl group, or a 1,2,3,4-tetrazol-5-yl group.
Pharmaceutically or veterinarily acceptable salts of the compounds of formula I are included in the present invention. These salts may be prepared from the compounds of formula I and any pharmaceutically or veterinarily acceptable base. The last include either inorganic bases such as, e.g., alkali or alkaline-earth metal hydroxides, in particular sodium or potassium hydroxides, or organic bases, such as, e.g., triethylamine, including aminoacids such as
Alpegiani Marco
della Bruna Costantino
Jabes Daniela
Perrone Ettore
Visentin Giuseppina
Farmitalia Carlo Erba S.r.l.
Kilby Scalzo Catherine S.
Lovering Richard D.
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