Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1984-12-07
1986-12-02
Marantz, Sidney
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540222, A61K 31545, C07D50146
Patent
active
046265333
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention is directed to novel cephalosporins of the formula (I), a process for their preparation, the pharmaceutical compositions containing compounds of the formula (I) as active ingredients and their use in therapy as antibiotics.
BACKGROUND OF THE INVENTION
The antibiotics of the cephalosporin-type play a prominent role in the treatment of human infectious diseases. Thus, e.g. Cephalotine, Cephaloglycine, Cephazoline and Cephalexine (c.f. Belgian patent specification No. 618,663; British patent specification No. 985,747; U.S. Pat. No. 3,516,997; Belgian patent specification No. 696,026, respectively) are widely known, valuable cephalosporin derivatives possessing antibacterial activity.
Presently great efforts are being made in order to prepare novel antibiotics suitable for the treatment of different infectious diseases.
Originally the semisynthetic cephalosporin derivatives were prepared by acylating the 7-amino group of 7-amino-cephalosporanic acid (further referred to as 7-ACA), but the later extensive experiments enabled the preparation of novel derivatives by changing the substituents in the positions 7 and/or 3 of the cephalosporin ring as well (Fortschritte der Chemie Organischer Naturstoff, 28, p. 343-403 (1970)).
A great number of cephalosporin derivatives as well as pharmaceutical compositions have been prepared up to now. Numerous scientific publications, technical books and patents relating to this subject are known (e.g. Flynn, E. H.: "Cephalosporin and Pennicillins", Academic Press, New York and London, 1972; Perlman, D.: "Structure-activity Relationship Among the Semisynthetic Antibiotics", New York, 1977; O'Callaghan, C. H.: Antimicrob. Chemother. 5, 635 (1979)).
SUMMARY OF THE INVENTION
The invention is directed to novel cephalosporins of the formula (I) and the pharmaceutically acceptable salts thereof ##STR2## wherein R.sup.1 is C.sub.1-4 alkyl; C.sub.2-4 alkenyl; phenyl; benzyl; phenyl substituted by one or more different or the same halo atom(s); or benzyl substituted by one or more different or the same halo atom(s); and b=1; halo if a=0 and b=1, 2, 3 and 4; and tetrazolyl, thiadiazolyl, thiazolyl, oxadiazolyl, oxazolyl, triazolyl, imidazolyl, pyrimidinyl, triazinyl or thiatriazolyl, all these groups being optionally substituted by halo, amino, nitro, alkyl, alkoxy, aryl, aralkyl, alkylamino, thioalkyl, furyl or thienyl if a=1 and b=1, same and their use as antibiotics.
The antibiotics according to the invention have not only a much broader spectrum of efficiency than the penicillins because the new compounds are effective not only against Gram-positive bacteria but they are effective against most Gram-negative bacteria as well and in vitro they are also stable against .beta.-lactamases produced by different microorganism strains.
The compounds of the formula (I) according to the invention structurally differ from the known cephalosporin derivatives in the feature that they comprise an acylaminomethyl group in position 3 of the dihydrothiazine moiety. The Japanese published patent application No. 56-140997 includes a method for the preparation of 7-amino-3-(substituted)methylceph-3-em-4-carboxylic acids of similar structure.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the formula (I) according to the invention are prepared by reacting a compound of the formula (I) ##STR3## wherein R.sup.1 and M are the same as set forth above, with an appropriately substituted isoxazole-carbonyl chloride, 2-thienylacetyl chloride or with a compound of the formula (III) ##STR4## in which formula X is a halo atom and b is equal to 1, 2, 3 or 4, in a mixture of water and an organic solvent, preferably in aqueous acetone, in the presence of an alkaline metal hydroxide as acid binding agent, at a pH 7 to 8 at a temperature of 0.degree. to 40.degree. C., preferably 0.degree. to 10.degree. C. After the reaction is accomplished, the products of the formula (I) are separated by known techniques, e.g. by evaporation of the solvent, addition of water, extract
REFERENCES:
patent: 3274186 (1966-09-01), Barker
patent: 3728342 (1973-04-01), Kukolja
patent: 3887549 (1975-06-01), Christensen
patent: 4258040 (1981-03-01), Christensen
Toyama (11/4/81) Derwent Abstract 92195.
Dunn, J. of Antimicrobial Chemotherapy (1982) 10, Suppl. C., 1-10.
Elek Sandor
Mihok Miklos
Mihok nee Borbely Ildiko
Benson Robert
Biogal Gyogyszergyar
Dubno Herbert
Marantz Sidney
Ross Karl F.
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