Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-14
2000-07-18
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514204, 514206, 514242, 514365, 514369, 514396, A61K 31545, A61K 3153, A61K 31425, A61K 31415
Patent
active
060908017
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel antibacterial formulations, in particular to formulations including 6-(substituted-methylene) penems, and derivatives thereof, having .beta.-lactamase inhibitory and antibacterial properties.
The compound ceftriaxone (A): ##STR1## [6R-[6.alpha.,7.beta.(Z)]]-7 -[[(2-Amino4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[[(1,2,5,6-tetra hydro-2-methyl-5-6-dioxo-1,2,4-triazin-3-yl)thio]-methyl]-5-thia-1-azabicyc lo[4-2-O]oct-2-ene-2-carboxylic acid; (6R,7R)-7-[2-(2-amino4-thiazolyl)glyoxylamido]-3-[[2,5dihydro-6-hydroxy-2- methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]o ct-2-ene-2-carboxylic acid 7.sup.2 -(Z)-(O-methyloxime) is a known antibiotic compound. The term "ceftriaxone" as used herein includes all pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts and in-vivo hydrolysable esters. Although widely used it suffers the general problems of all cephalosporins in being less effective against anaerobes, and of generally rapid development of .beta.-lactamase mediated resistance by microorganisms.
To overcome the problem of lack of activity against anaerobes, ceftriaxone may be administered in combination with metronidazole. Recently, the activity of ceftriaxone against anaerobes such as Bacteroides fragilis has been reported to be enhanced by coadministration with the .beta.-lactamase inhibitor tazobactam (J. Antimicrobial Chemotherapy (1993), 32, 307-312). This combination suffers from a potential problem, however, because of the marked disparity in the serum half-lives of ceftriaxone (ca. 8 hours) and tazobactam (ca. 1 hour).
According to the present invention a pharmaceutical formulation comprises ceftriaxone in combination with a penem of formula (I): ##STR2##
in which: ##STR3##
wherein R.sup.4 and R.sup.5 are independently hydrogen or one or more substituents replacing hydrogen atoms in tile ring system shown; m is 2 or 3; p is zero, 1 or 2; and R.sup.3 is hydrogen, a pharmaceutically acceptable salt-forming cation or a pharmaceutically acceptable in-vivo hydrolysable ester-formig group; and the symbol =/= indicates that the double bond may be in either the E or Z configuration; and with a pharmaceutically acceptable carrier.
The compound of formula (I), its salts and esters, may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric formns are encompassed within the formulations of thle present invention.
The compounds of formula (I) may exist in two isomeric forms at the methylene group at thle 8-position, ie the E- and Z- isomeric forms. The Z-isomer is generally preferred as generally being the more active form.
Preferred forms of the compounds of formula (I) have the structure (IA): ##STR4##
In general formula (I), R.sup.1 denotes hydrogen (which is preferred) or an organic group, which may suitably be linked to the penem ring system through a sulphur or carbon atom. For example, R.sup.1 may represent hydrogen or a group of formula --R.sup.5 or --SR.sup.5, where R.sup.5 denotes an unsubstituted or substituted (C.sub.1-10) hydrocarbon or heterocyclyl group.
Preferably, R.sup.1 represents hydrogen, (C.sub.1-10)alkyl or (C.sub.1-10)alkylthio, or substituted (C.sub.1-10)alkyl or substituted (C.sub.1-10)-alkylthio, wherein the substituent may be hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)allanoyloxy; halogen, mercapto, (C.sub.1-6)alkylthio, heterocyclylthio, amino, (mono or di)-(C.sub.1-6)alkylamino, (C.sub.1-6)alkanoylamino, carboxy, or (C.sub.1-6)alkoxycarbonyl.
Examples of suitable organic groups R.sup.1 include methyl, ethyl, propyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, hydroxymethyl, methoxy-methyl, ethoxymethyl, acetoxymethyl, (1 or 2)-acetoxyethyl, aminomethyl, 2-aminoethyl, acetamidomethyl, 2-acetamidoethyl, carboxymethyl, 2-hydroxy-ethylthio, methoxymethylthio, 2-methoxyethylthio, acetoxymethylthio, 2-amino-ethylthio, acetamidomethylthio, 2-acetamidoethylthio, carboxymethylthio, 2-carboxyethylthio, aryl (especially phenyl), arylthio (especially p
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Coleman Kenneth
Neale Jane Elizabeth
Gimmi Edward R.
King William T.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Weddington Kevin E.
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