.beta.-Lactam antibiotics their preparation and their use

The present invention provides a process for inversion of the absolute stereochemistry at the .alpha.-carbon atom of a C-6 substituent of a bicyclic carbapenem antibiotic via a phosphorus - azodicarboxylate mediated reaction. Novel azides, amines and formates are described as useful intermediates and as antibacterial agents.

This invention relates to substituted carbapenems, to processes for their 
preparation and their use. 
European Patent Application Publication Nos. 0001627 and 0001628 discloses 
a group of synthetic antibacterial agents of the formula (I): 
##STR1## 
wherein R.sup.a, R.sup.b, R.sup.c may be selected from a wide range of 
substituents. However all compounds described in that specification were 
racemic and could only be prepared by a lengthy synthetic sequence. A new 
process has been discovered that enables new antibacterial agents to be 
prepared by a relatively short reaction sequence and these new 
antibacterial agents are produced as a single optical isomer. 
This present invention provides a process for inverting the absolute 
stereochemistry at the C-8 position (that is, the .alpha.-carbon atom of 
the C-6 substituent). 
Accordingly this invention provides a process for the preparation of a 
compound of the formula (II): 
##STR2## 
and salts and esters thereof wherein R.sup.1 is an azido, amino or hydroxy 
group, or is a group of the sub-formula (a): 
EQU --OCOR.sup.3 (a) 
wherein R.sup.3 is a hydrogen atom or a C.sub.1-6 alkyl, aryl or aryl 
C.sub.1-6 alkyl group; and R.sup.o is hydrogen or an organic group: which 
process comprises the reaction of an ester of a compound of the formula 
(III): 
##STR3## 
wherein the stereochemistry of C-8 is inverted compared to that at C-8 of 
the compound of the formula (II), with 
(a) a compound of the formula (IV): 
EQU R.sup.4 --H (IV) 
wherein R.sup.4 is azido or a group of the sub-formula (a) OCOR.sup.3, 
wherein R.sup.3 is hydrogen, C.sub.1-6 alkyl, aryl or aryl C.sub.1-6 
alkyl; 
(b) a compound of the formula (V): 
EQU R.sup.5 O.CO.N.dbd.N.CO.OR.sup.6 (V) 
wherein R.sup.5 and R.sup.6 are independently C.sub.1-6 alkyl, aryl 
C.sub.1-6 alkyl or aryl; and 
(c) a compound of the formula (VI): 
##STR4## 
wherein l, m and n are independently zero or one and R.sup.7, R.sup.8 and 
R.sup.9 are independently a C.sub.1-6 alkyl, aryl C.sub.1-6 alkyl or aryl 
group; and thereafter if necessary: 
(i) converting a compound of the formula (II) wherein R.sup.1 is an azido 
group to a compound of the formula (II) wherein R.sup.1 is an amino group; 
(ii) converting a compound of the formula (II) wherein R.sup.1 is a group 
of the sub-formula (a) to a compound of the formula (II) wherein R.sup.1 
is a hydroxy group. 
If the stereochemical configuration at C-8 in the compound of the formula 
(III) is R, then the stereochemical configuration at C-8 in the product of 
the formula (II) is S. If the stereochemical configuration at C-8 in the 
compound of the formula (III) is S, then the stereochemical configuration 
at C-8 in the product of the formula (II) is R. 
Suitable compounds of the formula (IV) are hydrazoic acid and formic acid. 
Suitable compounds of the formula (V) include those wherein R.sup.5 and 
R.sup.6 are independently selected from methyl, ethyl, propyl, butyl, 
phenyl, and benzyl. It is generally convenient that R.sup.5 and R.sup.6 
each represent the same moiety. 
Particularly suitable compounds of the formula (V) include those wherein 
R.sup.5 and R.sup.6 each represent an ethyl, t-butyl group or isopropyl 
group. 
Suitable compounds of the formula (VI) include those wherein the R.sup.7, 
R.sup.8 and R.sup.9 groups are selected from methyl, ethyl, n-propyl, 
n-butyl, benzyl, phenyl and methoxyphenyl groups. It is generally 
convenient that R.sup.7, R.sup.8 and R.sup.9 each represent the same 
moiety. 
Favoured compounds of the formula (VI) include tri-aryl phosphines and 
tri-alkyl phosphites. Particularly suitable compounds of the formula (VI) 
include triphenylphosphine, trimethylphosphite and triethylphosphite, of 
these triphenylphosphine is preferred. 
Suitably R.sup.o is an optionally substituted hydrocarbon group of 1 to 20 
carbon atoms. 
More suitably R.sup.o is an etherified or acylated mercapto group, the 
sulphur atom of which is optionally oxidised so that the moiety may be in 
the form of a sulphide or sulphoxide. Most suitably R.sup.o is a group 
S(O).sub.x R.sup.2 wherein x is zero or one, and R.sup.2 is C.sub.1-6 
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl (C.sub.1-6) alkyl, 
C.sub.1-6 alkanoyl, aryl C.sub.1-6 alkanoyl, aryloxy (C.sub.1-6) alkanoyl, 
arylcarbonyl, aryl or a heterocyclyl, heterocyclyl (C.sub.1-6) alkyl, 
heteroaryl (C.sub.1-6) alkyl or heteroaryl group wherein the hetero atom 
or hetero atoms in the above named heteroaryl and/or heterocyclyl moieties 
are selected from 1-4 oxygen, nitrogen or sulphur atoms; any of such 
R.sup.2 groups being optionally substituted. Preferably x is zero. 
When R.sup.2 is a C.sub.1-6 alkyl group suitable substituents include 
amino, di-(C.sub.1-6)alkylamino, C.sub.1-6 alkylamino, acylamino, hydroxy, 
C.sub.1-6 alkanoyloxy, C.sub.1-6 alkoxy, benzoyl, C.sub.1-6 alkanoyl or 
carboxy or an ester or salt thereof. 
More suitably such alkyl groups contain up to 4 carbon atoms, for example 
R.sup.2 aptly may be methyl, ethyl, propyl, butyl, aminomethyl, 
aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, 
hydroxybutyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 
propoxypropyl, methoxypropyl, methoxybutyl, acetoxymethyl, acetoxyethyl, 
propionoxymethyl, propionoxyethyl, phenacyl, acetylmethyl, acetylethyl, 
propionylmethyl, propionylethyl, carboxymethyl or pharmaceutically 
acceptable salt thereof, methoxycarbonylmethyl, ethoxycarbonylmethyl, 
methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, 
ethoxycarbonylethyl, carboxyethyl or pharmaceutically acceptable salt 
thereof, carboxypropyl or pharmaceutically acceptable salt thereof, 
carboxybutyl or pharmaceutically acceptable salt thereof, acetamidoethyl 
and propionamidoethyl. Of these values methyl, ethyl, propyl, butyl, 
2-aminoethyl and acetamidoethyl are preferred. 
When R.sup.2 is a C.sub.2-6 alkenyl group wherein the double bond is not 
present on the carbon adjacent to the sulphur atom, suitable substituents 
include carboxy or an ester or pharmaceutically acceptable salt thereof, 
or hydroxy or C.sub.1-6 alkoxy. 
When R.sup.2 is a C.sub.2-6 alkenyl group wherein the double bond is 
present on the carbon adjacent to the sulphur atom, suitable substituents 
include carboxy or an ester or pharmaceutically acceptable salt thereof. 
More suitably R.sup.2 is propenyl, butenyl and CH.dbd.CH--CO.sub.2 H or a 
pharmaceutically salt or ester thereof, for example the sodium or 
potassium salt or the methyl, ethyl, propyl, aminoethyl, aminopropyl, 
benzyl or p-nitrobenzyl ester. 
In another aspect preferred values for R.sup.2 include the acetamidoethenyl 
and propionamidoethenyl groups. 
Suitable aryl, heteroaryl and heterocyclyl groups for use in the 
substituent R.sup.2 include phenyl, naphthyl, pyrrolyl, furyl, tetrazolyl, 
thienyl, indolyl, thionaphthyl, benzofuryl, imidazolyl, thiazolyl, or any 
of such groups substituted by one or more groups selected from C.sub.1-3 
alkyl, phenyl, nitro and amino; or a phenyl group optionally substituted 
by halogen atom or a C.sub.1-3 alkoxy, nitro or acetamido group. 
When R.sup.2 is an aryl C.sub.1-6 alkyl, heteroaryl C.sub.1-6 alkyl or 
heterocyclyl C.sub.1-6 aryl group, more suitably the alkyl moiety is a 
methylene or ethylene divalent radical. Suitable examples of such aryl and 
heteroaryl moieties are phenyl optionally substituted by one or more 
substituents selected from a halogen atom or a C.sub.1-3 alkoxy, nitro or 
acetamido group; pyrrolyl optionally substituted by a phenyl or C.sub.1-3 
alkyl group; thienyl optionally substituted by a phenyl or C.sub.1-3 alkyl 
group; furyl optionally substituted by a phenyl or C.sub.1-3 alkyl group; 
tetrazolyl optionally substituted by phenyl or a C.sub.1-3 alkyl group; 
imidazolyl optionally substituted by one or more groups; selected from 
phenyl, nitro, amino, C.sub.1-3 alkyl; and thiazolyl optionally 
substituted by one or more groups selected from phenyl, nitro, amino and 
C.sub.1-3 alkyl. 
More suitably R.sup.2 is a benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl, 
methoxybenzyl, nitrobenzyl, acetamidobenzyl, thiazolylmethyl, 
aminothiazolylmethyl, nitrothiazolylmethyl or phenylthiazolylmethyl group. 
Suitably also R.sup.2 is phenethyl, pyrrolylethyl or optionally substituted 
tetrazolylethyl or imidazolylethyl. In a suitable aspect the imidazolyl 
ring may be substituted at the C-2 position (that is the carbon atom 
.alpha. to the two nitrogen atoms) by a C.sub.1-3 alkyl or phenyl group. 
In another aspect the imidazolyl ring may be further substituted at the 
C-4 position or the C-5 position by a C.sub.1-3 alkyl, phenyl, nitro or 
amino groups; preferably such substituents are on the C-4 position and the 
C-5 position is unsubstituted; alternatively such substituents are on the 
C-5 position and the C-4 position is substituted. 
In a further aspect R.sup.2 is a C.sub.1-6 alkanoyl, aralkanoyl, 
aroxyalkanoyl or aroyl group, for example acetyl, phenylacetyl, 
phenoxyacetyl or benzoyl. Of these acetyl is preferred. 
Suitably R.sup.2 is phenyl optionally substituted by a halogen atom or a 
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, nitro or acetamido group. Suitably 
R.sup.2 is a 5- or 6-membered aromatic heterocyclic group containing 1 or 
2 nitrogen atoms such as the pyridyl, pyrimidyl, pyrrolyl and imidazolyl 
ring systems, for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 
4-pyrimidinyl, 5-pyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl and 
4-imidazolyl. Of these the pyridyl and pyrimidinyl ring systems are 
favoured, the pyrimidinyl ring being preferred and in particular the 
2-pyrimidinyl and 4-pyrimidinyl ring systems. Suitably such aromatic 
heterocyclic ring systems are optionally substituted by one or more 
C.sub.1-4 alkyl or C.sub.1-4 alkanoyloxy groups. 
The compounds of the formula (II) wherein R.sup.1 is azido are 
antibacterially active in their own right but are primarily envisaged as 
intermediates in the preparation of compounds of the formula (II) wherein 
R.sup.1 is amino. 
When the compounds of the formula (II) and salts and esters thereof are 
intended for use as antibacterial agents, then suitably the compound is in 
the form of an in-vivo hydrolysable ester or pharmaceutically acceptable 
salt. Suitable pharmaceutically acceptable salts include those of the 
alkali and alkaline earth metals, of these the sodium and potassium salts 
are preferred. 
Suitably for use as an intermediate, for example in the preparation of a 
compound of the formula (II) or a salt thereof, the compound of the 
formula (II) is provided in the form of a cleavable ester at the C-2 
carboxyl. Apt cleavable esters include those cleavable by chemical methods 
such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and 
biological methods such as in-vivo hydrolysis and enzymatic hydrolysis. 
Suitably the esterifying group is an alkyl, alkenyl, aryl or aralkyl, group 
which may be substituted if desired. Preferably the alkyl, alkenyl and 
alkynyl groups and the alkyl portion of the aralkyl group contain up to 6 
carbon atoms. Suitable substituents which may be included in the 
esterifying group include halogen atoms and C.sub.1-6 alkoxy, C.sub.1-6 
alkanoyl, hydroxy, C.sub.1-6 acyloxy for example C.sub.1-6 alkanoyloxy, 
C.sub.1-6 alkylamino and di(C.sub.1-6) alkylamino groups. 
More suitably the carboxylic acid is esterified by a group of the 
sub-formula (b), (c), (d), (e), (f) or (g): 
##STR5## 
wherein A.sup.1 is a hydrogen atom, C.sub.1-6 alkanoyl or an C.sub.1-5 
alkyl group optionally substituted by C.sub.1-7 alkoxy or C.sub.1-7 
carboxylic acyloxy, or an alkenyl or alkynyl group of up to 5 carbon 
atoms; A.sup.2 is a hydrogen atom or a methyl group; A.sup.3 is a phenyl 
group or a phenyl group substituted by a fluorine, chlorine or bromine 
atom or a nitro, C.sub.1-3 alkyl or C.sub.1-3 alkoxy group; A.sup.4 is a 
hydrogen atom or a phenyl group or phenyl group substituted by a fluorine, 
chlorine or bromine atom or a nitro, C.sub.1-3 alkyl or C.sub.1-3 alkoxy 
group; A.sup.5 is a hydrogen atom or a methyl group; A.sup.6 is a 
C.sub.1-6 alkyl, phenyl, phenoxy, phenyl (C.sub.1-3) alkyl, phenyl 
(C.sub.1-3) alkoxy or C.sub.1-6 alkoxy group or A.sup.5 is joined to 
A.sup.6 to form a phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl 
group; A.sup.7 is a C.sub.1-4 alkyl, phenyl, chlorophenyl or nitrophenyl 
group; A.sup.8 is a C.sub.1-4 alkyl or phenyl group; A.sup.9 is a 
C.sub.1-4 alkyl or phenyl group; A.sup.10 is C.sub.1-4 alkyl; and A.sup.11 
is C.sub.1-4 alkyl: or CHA.sup.1 A.sup.2 is a phenacyl or bromophenacyl 
group. 
Favourably A.sup.1 is a hydrogen atom or a methyl, ethyl, vinyl or ethenyl 
group. Favourably A.sup.2 is a hydrogen atom. Favourably A.sup.3 is a 
phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group. Favourably 
A.sup.4 is a hydrogen atom. Favourably A.sup.6 is a methyl, t-butyl or 
ethoxy group or is joined to A.sup.5. Favourably A.sup.7 is a methyl 
group. Favourably A.sup.5 is a hydrogen atom. 
Preferred groups of the sub-formula (b) include the methyl, ethyl and 
acetonyl groups. 
Preferred groups of the sub-formula (c) include the benzyl and 
p-nitrobenzyl groups. 
When A.sup.5 is hydrogen, suitably A.sup.6 is selected from methyl, ethyl, 
n-propyl, iso-propyl, n-butyl, tert-butyl, phenyl, benzyl, methoxy, 
ethoxy, n-propyloxy and iso-propyloxy. Preferably A.sup.6 is tert-butyl. 
Preferred groups of the sub-formula (d) include the acetoxymethyl, 
pivaloyloxymethyl, ethoxycarbonyloxymethyl, phthalidyl, 
.alpha.-ethoxycarbonyloxyethyl and .alpha.-acetoxyethyl groups. These 
esterifying groups are favoured as they tend to form in-vivo hydrolysable 
esters. 
A preferred group of the sub-formula (e) is the methoxymethyl group. 
Preferred groups of the sub-formula (f) include the trimethylsilyl, 
tert-butyldimethylsilyl and tert-butyldiphenylsilyl groups. 
A preferred group of the sub-formula (g) is p-methoxycarbonylbenzyl. 
Particularly preferred esterifying groups are the p-nitrobenzyl and 
phthalidyl groups. 
The in-vivo hydrolysable nature of the ester may be confirmed by 
administration to an animal such as a mouse or rat and determination of 
the presence of a compound of the formula (II) or a salt thereof in the 
blood or urine of the animal. Alternatively hydrolysis in human blood or 
serum may be determined. 
In general any convenient ester of the compound of the formula (III) may be 
used in the process of this invention. Suitable esters include those of 
the subformulae (b)-(g) as hereinbefore specified. 
In general it has proved convenient to use one equivalent of the compound 
of the formula (III), approximately two equivalents of the compounds of 
the formulae (V) and (VI), and from two to five equivalents of the 
compound of the formula (IV). 
The reaction is performed in an inert organic solvent which should be 
aprotic and unreactive towards the reagents involved. Suitable solvents 
include tetrahydrofuran, dioxan, 1,2-dimethoxyethane, benzene, toluene and 
mixtures of such solvents. Preferably the solvents used are substantially 
anhydrous. Preferred solvents include tetrahydrofuran, benzene, toluene 
and mixtures thereof. 
The reaction is normally carried out at a non-extreme temperature such as 
-60.degree. to +100.degree. C., more suitably from about -10.degree. to 
+50.degree. C. and most conveniently at ambient temperature (approximately 
+20.degree. C.). 
In the process of this invention any amino group present can be 
conveniently protected in conventional manner, for example as a 
p-nitrobenzyloxycarbonylamino group. Any hydroxy group present in the 
ester group or in the substituent R.sup.o should be protected in 
conventional manner, for example as a p-nitrobenzyloxycarbonyloxy group. 
A compound of the formula (II) wherein R.sup.1 is an azido group may be 
converted to a compound of the formula (II) wherein R.sup.1 is an amino 
group by standard reduction methods, such as catalytic hydrogenation, for 
example using a transition metal catalyst such as palladium suitably 
palladium on carbon. 
A compound of the formula (II) wherein R.sup.1 is a group of the 
sub-formula (a) may be converted to a compound of the formula (II) wherein 
R.sup.1 is a hydroxy group by standard hydrolysis methods, for example 
using an alkali or alkaline earth metal salt in aqueous solution. Suitable 
salts include sodium hydroxide, sodium bicarbonate, potassium bicarbonate, 
sodium carbonate, potassium carbonate and potassium hydroxide. Of these 
sodium hydroxide is preferred when the C-2 carboxyl group is esterified, 
and sodium bicarbonate is preferred when the C-2 carboxyl group is 
salified. 
The compounds of the formula (III) may be obtained from natural sources or 
may be obtained by synthetic methods, see for example the disclosures of 
European Patent Application Publication Nos. 0001627 and 0024832 and 
Belgian Patent No. 864,570. 
Methods of removing protecting groups, cleaving any ester moiety to a free 
acid or salt, and converting a free acid or salt to a pharmaceutically 
acceptable salt or ester are as detailed in the above European Patent 
Applications which are incorporated herein by reference. 
Certain compounds produced by this process are novel and as such form part 
of this invention. 
Accordingly, the present invention provides the compounds of the formula 
(IX): 
##STR6## 
and salts and esters thereof, wherein R.sup.2 and x are as herein above 
defined, and R.sup.10 is an azido or amino group. 
In one aspect --S(O).sub.x R.sup.2 is as hereinabove defined with the 
proviso that --S(O).sub.x R.sup.2 is not SCH.sub.2 CH.sub.2 NH.sub.2, 
SCH.sub.2 CH.sub.2 N.dbd.CHNH.sub.2, SCH.sub.2 CH.sub.2 
N.dbd.C(CH.sub.3)NH.sub.2 or SCH.sub.2 CH.sub.2 N.dbd.C(NH.sub.2)NH.sub.2. 
Suitable and apt values for R.sup.2 in the compounds of the formula (IX) 
are as described hereinbefore in relation to the compound of the formula 
(III). Favourably in the compounds of the formula (IX), x is zero. 
The present invention further provides the compounds of the formula (X): 
##STR7## 
and salts and esters thereof, wherein R.sup.2 and x are as hereinabove 
defined, with the proviso that --S(O).sub.x R.sup.2 is not 
2-aminoethylthio. Suitable and apt values for R.sup.2 in the compounds of 
the formula (X) are as described hereinbefore in relation to the compound 
of the formula (III). Favourably in the compounds of the formula (X), x is 
zero. 
The compounds of the formulae (IX) and (X) and their pharmaceutically 
acceptable salts and in-vivo hydrolysable esters may be employed in the 
treatment of bacterial infections such as those due to Staphylococcus 
aureus, Escherichia coli and Klebsiella aerogenes. Thus the present 
invention provides a pharmaceutical composition which comprises a compound 
of the formulae (IX) or (X) in the form of its pharmaceutically acceptable 
salt or in-vivo hydrolysable ester and a pharmaceutically acceptable 
carrier. 
The compositions of this invention may be prepared by conventional methods 
of preparing antibiotic compositions and in conventional manner may be 
adapted for oral, topical or parenteral administration. 
Aptly, the compositions of this invention are in the form of a unit-dose 
composition adapted for oral administration. 
Alternatively the compositions of this invention are in the form of a unit 
dose composition adapted for administration by injection. 
Unit-dose forms according to this invention will normally contain from 50 
to 500 mgs of a compound of this invention, for example about 62.5, 100, 
125, 150, 200, 250 or 300 mgs. Such compositions may be administered from 
1 to 6 times a day or more conveniently 2, 3 or 4 times a day so that the 
total daily dose for a 70 kg adult is about 200 to 2000 mg, for example 
about 400, 600, 750, 1000 or 1500 mg. 
The compositions of this invention may be used to treat infections in 
humans and animals, for example infections of the respiratory tract, 
urinary tract or soft tissues in humans or mastitis in cattle. 
The carriers used in the compositions of this invention may include 
diluents, binders, disintegrants, lubricants, colours, flavouring agents 
or preservatives in conventional manner. Thus suitable agents include 
lactose, starch, sucrose, calcium phosphate, sorbitol, 
polyvinylpyrrolidone, acacia, gelatin, tragacanth, potato starch or 
polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate. 
Orally administrable forms of the compositions of this invention are most 
suitably in the form of unit-dose units such as tablets or capsules. 
The present invention also provides synergistic pharmaceutical compositions 
which comprise a pharmaceutical composition as hereinbefore described 
which also contains a penicillin or a cephalosporin. 
Suitable penicillins for inclusion in the compositions of this invention 
include benzyl penicillin, phenoxymethylpenicillin, ampicillin or a 
pro-drug therefor, amoxycillin or a pro-drug therefor, carbenicillin or a 
pro-drug therefor, ticarcillin or a pro-drug therefor, suncillin, 
sulbenicillin, azlocillin or mezlocillin. 
Particularly suitable penicillins for inclusion in orally administrable 
compositions of this invention include ampicillin and its orally 
administrable pro-drugs, amoxycillin and its orally administrable 
pro-drugs and orally administrable pro-drugs of carbenicillin. Thus 
particularly suitable penicillins include ampicillin anhydrate, ampicillin 
trihydrate, sodium ampicillin, talampicillin hydrochloride, pivampicillin 
hydrochloride and bacampicillin hydrochloride; amoxycillin trihydrate, 
sodium amoxycillin; and the sodium salts of the phenyl and 5-indanyl 
.alpha.-esters of carbenicillin. 
A preferred penicillin for inclusion in the orally administrable 
compositions of this invention is amoxycillin trihydrate. A further 
preferred penicillin for inclusion in the orally administrable 
compositions of this invention is ampicillin trihydrate. 
Particularly suitable penicillins for inclusion in injectably administrable 
compositions of this invention include injectable salts such as the sodium 
salt of ampicillin, amoxycillin, carbenicillin and ticarcillin. 
A preferred penicillin for inclusion in the injectably administrable 
compositions of this invention is sodium amoxycillin. A further preferred 
penicillin for inclusion in the injectably administrable compositions of 
this invention is sodium ampicillin. 
Particularly suitable cephalosporins for inclusion in the compositions of 
this invention include cephaloridine, cephalexin, cephradine, cefazolin 
and cephalothin. 
A particularly suitable cephalosporin for inclusion in the orally 
administrable compositions of this invention is cephalexin. 
Particularly suitable cephalosporins for inclusions in the injectably 
administrable compositions of this invention include cephaloridine, 
cefazolin and cephradine, generally as their pharmaceutically acceptable 
salt. 
The weight ratio between compound of this invention and penicillin or 
cephalosporin is generally from 10:1 to 1:10, more usually from 5:1 to 1:5 
and normally from 3:1 to 1:3. 
The penicillin or cephalosporin is generally utilised in its conventionally 
administered amount. 
Suitable methods of formulation include those described in the 
aforementioned European Patent Applications.