Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-08-22
1998-03-17
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514203, 514204, 514205, 514206, 514207, 544225, 544227, 544228, 544222, C07D50136, A61K 31545
Patent
active
057286914
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to quinolonylcarboxamidocephalosporin derivatives and to the pharmaceutical compositions having antibacterial activity which contain them.
The quinolonylcarboxamidocephalosporin derivatives of the invention are in particular derivatives of 7-aminoceph-3-em-4-carboxylic acid with 6-fluoroquinolone derivatives in which the cephem and 6-fluoroquinolone moieties are bound each other through a carboxamido bond. These compounds are also referred hereinafter as `cefaquinolone derivatives`.
A further object of the invention relates to the process for the preparation of said derivatives.
The 6-fluoroquinolonylcarboxamidocephalosporin derivatives, or cephaquinolone derivatives of the present invention possess striking potency against a wide range of microorganisms, either gram-negative or gram-positive of extra or intra-cellular type as well as an interesting growth promoting and probiotic action.
DESCRIPTION OF THE INVENTION
The object of the present invention relates to 6-fluoroquinolonylcarboxamidocephalosporin derivatives, herewith also referred as cephaquinolone derivatives, to the process for their preparation and to the antibacterial, growth promoting and probiotic pharmaceutical compositions containing said compounds.
The 6-fluoroquinolonylcarboxamidocephalosporin derivatives of the invention are endowed with a very high antimicrobial activity effective against a wide range of gram-negative and gram-positive microorganisms and with an interesting growth promoting and probiotic action which activities render the present compounds useful in human and veterinarian applications.
More particularly the cephaquinolone derivatives of the invention have structure formula: ##STR1## wherein R.sub.1 represents hydrogen, acetoxy, carbamyloxy, an heterocyclic group selected among pyridin-1-yl, 1H-1,2,3-triazol-5-ylthio, 1-methyl-1H-tetrazol-5-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-ylthio; C cycloalkyl radical; piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl.
As 1-4 C straight alkyl radical is intended methyl, ethyl, propyl and butyl, ethyl being preferred. As 1-4 C branched alkyl radical are intended isopropyl, sec.butyl and tert.butyl, isopropyl being preferred. As 3-5C cycloalkyl radical is intended cyclopropyl, cyclobutyl and cyclopentyl, cyclopropyl being preferred.
As halogen atom bromine, fluorine and chlorine are intended, chlorine being preferred.
Also included in the scope of the present invention are the alkaline metal salts and the ammonium salt of the compounds of formula (I) which may be obtained according to well known procedures. Particularly preferred are the sodium, potassium and ammonium salts of the compounds of formula (I).
The compounds (I) of the invention in which R.sub.3 represents a halogen atom are prepared by reacting the 6-fluoro-7-halo-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IV), in a suitable activated form (III), with the 7-aminoceph-3-em derivative (II) and optionally, when desired, introducing a substituent other than halide at position 7 of the quinolone moiety in compound (Ib).
In particular, in the case of an activated form represented by 6-fluoro-7-halo-1,4-dihydro-4-oxoquinoline-3-carbonyl chloride the process can be represented by the reaction scheme: ##STR2## wherein R.sub.1 and R.sub.2 have the above mentioned meaning and Hal represents a halogen atom.
The compounds of formula (I) in which R.sub.3 represents a piperazin-1-yl radical optionally 4-substituted with a methyl or ethyl radical are prepared from the corresponding 7-haloquinolonilcarboxamido-ceph-3-em derivative (Ia) by reacting with piperazine optionally 1-methyl or 1-ethyl-substituted according to the reaction: ##STR3## wherein Hal, R.sub.2 and R.sub.1 have the above mentioned meaning and R.sub.4 is selected among hydrogen, methyl and ethyl.
In alternative to the above indicated form as acyl chloride, compound (IV) may be in the form of mixed anhydride with a suitable acid: these compounds may be obtained accord
REFERENCES:
patent: 4404201 (1983-09-01), Haskell et al.
Arzneim.-Forsch./Drug. Res., vol. 29 (I), No. 2A, 1979, pp. 362-369. R. Compounds!.
J. Med.Chem., vol. 33, No. 1, 1990, pp. 77-86. H.A. Albrecht et al.
J. Antibiot., vol. 44, No. 2, 1991, pp. 200-209. T.P. Demuth et al. Esters!.
International Search Report dated Apr. 1, 1995 for PCT/IB94/00304.
Arrieta Munguia Judith Marcia
Ford John M.
Laboratorios Aranda S.A. De C.V.
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