Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-14
2002-10-29
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S114000
Reexamination Certificate
active
06472383
ABSTRACT:
This invention relates to novel antibacterial formulations, in particular to formulations including 6-(substituted-methylene) penems and derivatives thereof having &bgr;-lactamase inhibitory and antibacterial properties. The invention also relates to methods for the preparation of such formulations and to uses thereof.
The compound ceftazidime, [6R -[6&agr;,7&bgr;(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium hydroxide inner salt, is a known and much used cephalosporin antibiotic compound. Ceftazidime is normally administered by injection as its pentahydrate. The term “ceftazidime” as used herein includes all forms of ceftazidime including the free acid, hydrates, salts and ester thereof. Ceftazidime is susceptible to hydrolysis by &bgr;&bgr;-lactamase enzymes, for example those of
B.fragilis, S. aureus
and
enterobactenaceae
producing extended spectrum &bgr;&bgr;-lactamases or elevated levels of Class 1 enzymes.
The compound cefotaxime, [6R-[6&agr;,7&bgr;(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazoly)(syn-methoxyimoin)acetyl]amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is a known and much used cephalosporin antibiotic compound. Cefotaxime is normally administered by injection as its sodium salt. The term “cefotaaime” as used herein includes all forms of cefotaxime including the free acid, salts and ester thereof. Cefotaxime is susceptible to hydrolysis by &bgr;&bgr;-lactamase enzymes, for example those of
B.fragilis
, Group 1 enzymes (typically encountered in
Enterobacter Citrobacter
and Pseudomonas), or showing mutational changes around the active site of the Group 2 enzymes TEM-1 and SHV-1 (typically encountered in
E. coli
and Klebsiella.
The compound amoxycillin, 6-[D(−)-&agr;-amino-p-hydroxypheny-acetamido]penicillanic acid, is a known and much used antibiotic compound. Amoxycillin is normally administered orally in the form of amoxycillin trihydrate, or parenterally as sodium amoxycillin. The term “amoxycillin” as used herein includes all forms of amoxycillin including the free acid, salts and ester thereof. Amoxycillin is hydrolysed by a broad range of &bgr;&bgr;-lactamase enzymes, and is generally ineffective against organisms producing Group I and Group II &bgr;&bgr;-lactamases. Therefore amoxycillin is often administered together with a &bgr;&bgr;-lactamase inhibitor, for example clavulanic acid.
The compound piperacillin, 6-[[[[94-ethyl-2,3-dioxo-1-piperazinyl) carbonyl]amino]phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-azabicyclo [3.2.0]heptane-2-carboxylic acid, is a known and much used antibiotic compound. Piperacillin is normally administered parenterally as its sodium salt. The term “piperacillin” as used herein includes all forms of piperacillin including the free acid, salts and ester thereof. Piperacillin is hydrolysed by &bgr;&bgr;-lactamase enzymes.
It is an object of this invention to provide novel combinations of &bgr;&bgr;-lactam antibiotics with a &bgr;&bgr;-lactamase inhibitor, having improved characteristics compared with known combinations.
According to the present invention, a pharmaceutical formulation comprises, in combination with a penem of formula (I):
in which:
R
1
is hydrogen or an organic substituent group;
R
2
is a fused bicyclic heterocyclic ring system of general formula:
wherein R
4
and R
5
are independently hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown; m is 2 or 3; p is zero, 1 or 2; and R
3
is hydrogen, a salt-forming cation or an ester-forming group; and the symbol ═/═ indicates that the double bond may be in either the E or Z configuration; and a pharmaceutically acceptable carrier; a &bgr;&bgr;-lactam antibiotic selected from the group consisting of cefotaxime, amoxycillin, piperacillin and ceftazidime, and their pharmaceutically acceptable derivatives including salts and in vivo hydrolysable esters.
Compounds of formula (I) are disclosed in WO94/10178 the contents of which are incorporated herein by way of reference.
The compound of formula (I), its salts and esters, may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms are encompassed within the scope of the formulations of the present invention.
Moreover, the compounds of formula (I) may exist in two isomeric forms at the methylene group at the 8-position, ie the E- and Z-isomeric forms. The Z-isomer is generally preferred as generally being the more active form.
Consequently preferred forms of the compounds of the present invention have the structure (IA):
n general formula (1), R
1
denotes hydrogen or an organic group, which may suitably be linked through a sulphur or carbon atom. For example, R
1
may represent hydrogen or a group of formula —R
5
or —SR
5
, where R
5
denotes an unsubstituted or substituted (C
1-10
)hydrocarbon or heterocyclyl group.
Preferably, R
1
represents hydrogen, (C
1-10
)alkyl or (C
1-10
)alkylthio, or substituted (C
1-10
)alkyl or substituted (C
1-10
)-alkylthio, wherein the substituent may be hydroxy, (C
1-6
)alkoxy, (C
1-6
)alkanoyloxy, halogen, mercapto, (C
1-6
)alkylthio, heterocyclylthio, amino, (mono or di)-(C
1-6
)alkylamino, (C
1-6
)alkanoylamino, carboxy, or (C
1-6
)alkoxycarbonyl.
Examples of suitable organic groups R
1
include methyl, ethyl, propyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, (1 or 2)-acetoxyethyl, aminomethyl, 2-aminoethyl, acetamidomethyl, 2-acetamidoethyl, carboxymethyl, 2-hydroxyethylthio, methoxymethylthio, 2-methoxyethylthio, acetoxymethylthio, 2-aminoethylthio, acetamidomethylthio, 2-acetamidoethylthio, carboxymethylthio, 2-carboxyethylthio, aryl(especially phenyl), arylthio (especially phenylthio), pyridyl, pyrimidyl, isoxazolyl, pyrimidylthio, tetrazolylthio, and pyridylthio groups.
In particular, R
1
may be hydrogen.
Suitable groups R
2
include: 2,3-dihydroimidazo[2,1-b]thiazol-6-yl, 2,3-dihydro-1-(R,S)-oxoimidazo[2,1-b)thiazol-6-yl, 2,3-dihydro-1,1-dioxoimidazo[2,1-b]thiazol-6-yl, 6,7-dihydro-5H-imidazo[2,1-b]-thiazin-2-yl and 6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b][1,3]thiazin-2-yl.
Examples of suitable substituents R
4
and R
5
include(C
1-6
)alkanoyl, (C
1-6
)alkanoyloxy, heterocyclyl, amino, (C
1-6
)alkanoylamino, (mono or di)-(C
1-6
)alkylamino, hydroxy, (C
1-6
)alkoxy, sulpho, mercapto, (C
1-6
)alkylthio, (C
1-6
)alkylsulphinyl, (C
1-6
)alkyl-sulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters, arylcarbonyl, and heterocyclylcarbonyl groups, and also unsubstituted or substituted (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, aryl, and aryl(C
1-6
)alkyl groups.
Examples of suitable optional substituents for the above-mentioned (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, aryl and aryl(C
1-6
)alkyl substitutents include (C
1-6
)alkanoyl, (C
1-6
)alkanoyloxy, heterocyclyl, amino, (C
1-6
)alkanoylamino, (mono or di)-(C
1-6
)alkylamino, hydroxy, (C
1-6
)alkylsulphinyl, (C
1-6
)alkylsulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters,arylcarbonyl and heterocyclylcarbonyl groups.
Suitably R
4
and R
5
may both be hydrogen.
Suitable pharmaceutically acceptable salts of the 3-carboxylic acid group of the &bgr;&bgr;-lactam antibiotic or the compound of formula (I) or of other carboxylic acid groups which may be present as optional substituents include those in which R
3
is a metal ion e.g. aluminium salts, alkali metal salts (e.g. sodium, lithium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts, and substituted a
Coleman Kenneth
Neale Jane Elizabeth
Cook Rebecca
Gimmi Edward R.
Henderson Loretta J.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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