A class of 6-methoxy-.alpha.-carboxy penicillins have antibacterial activity against a wide range of Gram-negative organisms.

This invention relates to a class of penicillins which have antibacterial 
activity and are of value in the treatment of infections in animals, 
including man and poultry, caused by a wide range of Gram-negative 
organisms. In particular the invention relates to a class of 
6-methoxy-.alpha.-carboxy penicillins. The invention also relates to a 
process for the preparation of such compounds, and to pharmaceutical 
compositions comprising them. 
British Patent Specification No. 1,339,007 discloses inter alia a class of 
6-substituted acylamino penicillins of general formula (A) 
##STR1## 
where R.sub.A represents an acyl group, R.sub.B is a hydroxy or mercapto 
radical, a substituted or unsubstituted methoxy, ethoxy, methyl, ethyl, 
methylthio, or ethylthio radical, a carbamoyloxy, carbamoylthio, C.sub.1-6 
alkanoyloxy, C.sub.1-6 alkanoylthio, cyano or carboxy radical or a 
derivative of a carboxy radical such as carbamoyl and R.sub.C is a 
hydrogen atom or a pharmaceutically acceptable esterifying radical or 
cation. 
In abstract No. 368 of the "Program and Abstracts of the 14th Interscience 
conference on Antimicrobial Agents and Chemotherapy" held on 11th - 13th 
September, 1974 in San Francisco, Cal., U.S.A., a report is made of a 
single 6-methoxy penicillin within formula (A) above, namely 
6.alpha.-methoxy-6.beta.-(2-carboxyphenylacetamido)penicillanic acid. 
We have now found a small class of 6-methoxy .alpha.-carboxy penicillins 
which have a high level of antibacterial activity compared to the broad 
class of compounds disclosed in British Pat. No. 1,339,007 and also 
compared to the compound 
6.alpha.-methoxy-6.beta.-(2-carboxyphenylacetamido)penicillanic acid. 
According to the present invention there is provided a compound of formula 
(I): 
##STR2## 
wherein R is 2- or 3-thienyl, R.sup.1 is hydrogen or a pharmaceutically 
acceptable salting ion, and R.sup.2 is hydrogen, or a pharmaceutically 
acceptable salting ion or in vivo hydrolysable ester radical. 
Suitable salting ions for the groups R.sup.1 and R.sup.2 include metal ions 
e.g. aluminium, alkali metal ions such as sodium or potassium, alkaline 
earth metal ions such as calcium or magnesium, and ammonium or substituted 
ammonium ions for example those from lower alkylamines, such as 
triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, 
bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines 
such as bicyclohexylamine, or from procaine, dibenzylamine, 
N,N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, 
N-benzyl-.beta.-phenethylamine, dehydroabietylamine, 
N,N'-bis-dehydroabietylethylenediamine, or bases of the pyridine type such 
as pyridine, collidine or quinoline, or other amines which have been used 
to form salts with benzylpenicillin. 
In vivo hydrolysable pharmaceutically acceptable ester radicals for the 
group R.sup.2 are those which hydrolyse in the human body to produce the 
parent acid. Suitable examples include acyloxyalkyl groups such as 
acetoxymethyl, pivaloyloxymethyl, .alpha.-acetoxyethyl, 
.alpha.-acetoxybenzyl and .alpha.-pivaloyloxyethyl groups; 
alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and 
.alpha.-ethoxycarbonyloxyethyl; and lactone, thiolactone and dithiolactone 
groups, i.e. ester groups of formula: 
##STR3## 
wherein X' and Y' are oxygen or sulphur and Z' is an ethylene group or a 
1,2-phenylene group optionally substituted by lower-alkoxy, halogen or 
nitro. .delta. 
Preferred ester groups are the phthalide and 5,6-dimethoxyphthalide esters. 
Specific compounds within this invention include the following: 
6-.beta.-(2-carboxy-2-thien-3'-ylacetamido)-6-.alpha.-methoxy-penicillanic 
acid; 
6-.beta.-(2-carboxy-2-thien-2'-ylacetamido)-6-.alpha.-methoxy-penicillanic 
acid. 
The compounds of formula (I) may be prepared by reacting a compound of 
formula (III) or an N-silyl or N-phosphorylated derivative thereof: 
##STR4## 
wherein R.sup.x is hydrogen or a carboxyl blocking group; with an 
N-acylating derivative of an acid of formula (IV): 
##STR5## 
wherein R is as defined with respect to formula (I) above; and thereafter 
if necessary carrying out one or more of the following steps: 
i. removal of any silyl or phosphoryl groups by hydrolysis or alcoholysis; 
ii. removal of any carboxyl blocking groups; 
iii. converting the product to a salt or ester thereof. 
By the term "N-silyl derivative" of compound (III), we mean the product of 
reaction of the 6-amino group of compound (III) with a silylating agent 
such as a halosilane or a silazane of the formula: 
##STR6## 
wherein U is a halogen and the various groups L which may be the same or 
different, each represents hydrogen or alkyl, alkoxy, aryl, or aralkyl. 
Preferred silylating agents are silyl chlorides, particularly 
trimethylchlorosilane. 
The term "N-phosphorylated" derivative of compound (III) is intended to 
include compounds wherein the 6-amino group of formula (III) is 
substituted with a group of formula: 
EQU - P.R.sub.a R.sub.b 
wherein R.sub.a is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, 
aryloxy, aralkyloxy or dialkylamino group, R.sub.b is the same as R.sub.a 
or is halogen or R.sub.a and R.sub.b together form a ring. 
Suitable carboxyl-blocking derivatives for the group --CO.sub.2 R.sup.x in 
formulas (III) and (IV) include salts, esters, and anhydride derivatives 
of the carboxylic acid. The derivative is preferably one which may be 
readily cleaved at a later stage of the reaction. Suitable salts include 
tertiary amine salts, such as those with tri-loweralkylamines. 
N-ethyl-piperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine, 
dimethylpiperazine. A preferred salt is with triethylamine. 
Suitable ester groups of formula CO.sub.2 R.sup.x include the following: 
i. --COOCR.sub.c R.sub.d R.sub.e wherein at least one of R.sub.c, R.sub.d 
and R.sub.e is an electron-donor e.g. p-methoxyphenyl, 
2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy, methoxymethyl, benzyl 
or fur-2-yl. The remaining R.sub.c, R.sub.d and R.sub.e groups may be 
hydrogen or organic substituting groups. Suitable ester groups of this 
type include p-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxy 
carbonyl, bis-(p-methoxyphenyl)methoxycarbonyl, 
3,5-di-t-butyl-4-hydroxybenzyloxycarbonyl, methoxymethoxycarbonyl and 
benzyloxycarbonyl. 
ii. --COOCR.sub.c R.sub.d R.sub.e wherein at least one of R.sub.c, R.sub.d 
and R.sub.e is an electron-attracting group e.g. benzoyl, p-nitrophenyl, 
4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, 
ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethylsulphoniumethyl, 
o-nitrophenyl or cyano. The remaining R.sub.c, R.sub.d and R.sub.e groups 
may be hydrogen or organic substituting groups. Suitable esters of this 
type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 
4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 
2,2,2-tribromoethoxycarbonyl. 
iii. --COOCR.sub.c R.sub.d R.sub.e wherein at least two of R.sub.c, R.sub.d 
and R.sub.e are hydrocarbon such as alkyl e.g. methyl or ethyl, aryl e.g. 
phenyl and the remaining R.sub.c, R.sub.d and R.sub.e group, if there is 
one, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, 
t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl. 
iv. --COOR.sub.f wherein R.sub.f is adamantyl, phenyl, alkylsubstituted 
phenyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, 
tetrahydropyran-2-yl, pentachlorophenyl; 
v. Silyloxycarbonyl groups obtained by reaction of a silylating agent as 
described above with the carboxylic acid group; 
vi. CO.sub.2 P.R.sub.a R.sub.b, wherein R.sub.a and R.sub.b are as defined 
above; 
vii. An in vivo hydrolysable ester radical, such as defined above. 
The carboxyl group may be regenerated from any of the above esters by usual 
methods for example, acid -- the base -- catalysed hydrolysis, or by 
enzymically -- catalysed hydrolysis. 
Alternative methods of cleavage include: 
reaction with Lewis acids, such as trifluoroacetic acid, formic acid, 
hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous 
solutions or suspensions of mercuric compounds. (The reaction with the 
Lewis acid may be facilitated by addition of a nucleophile such as 
anisole); 
reduction with agents such as zinc/acetic acid, zinc/ formic acid, 
zinc/lower alcohol, zinc/pyridine, palladised-charcoal and hydrogen, and 
sodium and liquid ammonia; 
attack by nucleophiles, such as those containing a nucleophilic oxygen or 
sulphur atom for example alcohols, mercaptans and water; oxidative 
methods, for example, those which involve the use of hydrogen peroxide and 
acetic acid; and irradiation. 
A reactive N-acylating derivative of the acid (IV) is employed in the above 
process. The choice of reactive derivative will of course be influenced by 
the chemical nature of the substituents of the acid. 
Suitable N-acylating derivatives include an acid halide, preferably the 
acid chloride or bromide. Acylation with an acid halide may be effected in 
the presence of an acid binding agent for example tertiary amine (such as 
triethylamine or dimethylaniline), an inorganic base (such as calcium 
carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen 
halide liberated in the acylation reaction. The oxirane is preferably a 
(C.sub.2-6)-1,2-alkylene oxide - such as ethylene oxide or propylene 
oxide. The acylation reaction using an acid halide may be carried out at a 
temperature in the range -50.degree. to +50.degree.C, preferably 
-20.degree. to +30+C, in aqueous or non-aqueous media such as aqueous 
acetone, ethyl acetate, dimethylacetamide, dimethylformamide, 
acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof. 
Alternatively, the reaction may be carried out in an unstable emulsion of 
water-immiscible solvent, especially an aliphatic ester or ketone, such as 
methyl isobutyl ketone or butyl acetate. 
The acid halide may be prepared by reacting the acid (IV) or a salt thereof 
with a halogenating (e.g. chlorinating or brominating) agent such as 
phosphorus pentachloride, thionyl chloride or oxalyl chloride. 
Alternatively, the N-acylating derivative of the acid (IV) may be a 
symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic 
anhydrides, or anhydrides with, for example carbonic acid monoesters, 
trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, 
phosphorus acids (such as phosphoric or phosphor acids), sulphuric acid or 
aliphatic or aromatic sulphonic acids (such as p-toluenesulphonic acid). 
The mixed or symmetrical anhydrides may be generated in situ. For example, 
a mixed anhydride may be generated using 
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. When a symmetrical 
anhydride is employed, the reaction may be carried out in the presence of 
2,4-lutidine as catalyst. 
Alternative N-acylating derivatives of acid (IV) are the acid azide, or 
activated esters such as esters with cyanomethanol, p-nitrophenol, 
2,4-dinitrophenol, thiophenol, halophenol, including pentachlorophenol, 
monomethoxyphenol or 8-hydroxyquinoline; or amides such as 
N-acylsaccharins or N-acylphthalimides; or an alkylidene iminoester 
prepared by reaction of the acid (IV) with an oxime; or the ketene acid 
chloride of the malonic acid (IV), which gives the .alpha.-carboxy 
compound directly. 
Some activated esters, for example the ester formed with 
1-hydroxybenztriazole or N-hydroxysuccinimide, may be prepared in situ by 
the reaction of the acid with the appropriate hydroxy compound in the 
presence of a carbodimide, preferably dicyclohexylcarbodiimide. 
Other reactive N-acylating derivatives of the acid (IV) include the 
reactive intermediate formed by reaction in situ with a condensing agent 
such as a carbodiimide, for example N,N-diethyl-, dipropyl- or 
diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, or 
N-ethyl-N'-.gamma.-dimethylaminopropylcarbodiimide; a suitable carbonyl 
compound, for example N,N'carbonyldiimidazole or N,N'-carbonylditriazole; 
an isoxazolinium salt, for example N-ethyl-5-phenylisoxazolinium-3- 
sulphonate or N-t-butyl-5-methylisoxazolinium perchlorate; or an 
N-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such as 
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Other condensing agents 
include Lewis acids (for example BBr.sub.3 - C.sub.6 H.sub.6); or a 
phosphoric acid condensing agent such as diethylphosphorylcyanide. The 
condensation reaction is preferably carried out in an organic reaction 
medium, for example, methylene chloride, dimethylformamide, acetonitrile, 
alcohol, benzene, dioxan, or tetrahydrofuran. 
The compounds (III) may be prepared for example by the method described by 
Jen et al (J.Org. Chem. 1973, 38, 2857) from an ester of a compound of 
formula: 
##STR7## 
which compound may in turn be prepared from the corresponding 6-isocyano 
compound as described in our W. German Offenlegungsschrift No. 2,407,000. 
Compounds of formula (I) may also be prepared by reacting a compound of 
formula (VI): 
##STR8## 
wherein R.sup.x is as defined above with respect to formula (III) above; 
with an acid of formula (IV) or a carbanion of formula (VIA) R-CH-CO.sub.2 
R.sup.x ; and thereafter if necessary carrying out one or more of the 
following steps: 
i. removal of any carboxyl blocking group; 
ii. converting the product to a salt or ester thereof. 
This reaction is preferably carried out at a temperature in the range 
-10.degree. to +50.degree. C in an inert organic solvent, such as 
methylene dichloride, in the presence of a basic catalyst such as 
triethylamine, pyridine or a nitrogen-containing aromatic mono- or 
bi-cyclic compound such as 4-methoxy(dimethylamino)pyridine, 
1-methyl(benz)imidazole or imidazo [1,2-a]pyridine. 
A third method of preparation of the compounds of formula (I) comprises: 
a. protecting the 3-carboxylic acid group of a 
6-.alpha.-methoxy-6-.beta.-acylaminopenicillanic acid with a carboxyl 
blocking group. 
b. reacting the protected penicillanic acid to form an imino bond on the 
6-amido nitrogen atom; 
c. reacting the resulting compound to introduce a group QR.sub.f on the 
imino carbon atom, wherein Q is oxygen, sulphur or nitrogen and R.sub.f is 
an alkyl group of form 1 to 12 carbon atoms or an aralkyl group of from 7 
to 14 carbon atoms, to form an iminoether, iminothioether or amidine (when 
Q is O, S or N, respectively); 
d. reacting with an acylating derivative of an acid of formula (IV) above; 
e. treating with water or an alcohol; and 
f. thereafter if necessary carrying out one or more of the following steps: 
i. removal of any carboxyl blocking groups; 
ii. converting the product to a salt or ester thereof. 
In the above process, after protection of the 3-carboxylic acid group, the 
protected penicillanic acid is reacted with an agent to form an imino bond 
on the 6-amino nitrogen atom. Preferably an imino halide is formed of 
formula (VII): 
##STR9## 
wherein R.sup.o is the residue of an organic acylamino sidechain of a 
penicillin, R.sup.x is a carboxyl blocking group and Hal represents a 
halogen atom. A suitable agent for preparing an imino halide is an acid 
halide in the presence of an acid binding agent such as a tertiary amine, 
e.g. pyridine, triethylamine, or N,N,-dimethylaniline. Examples of 
suitable acid halides are phosphorus pentachloride, phosgene, phosphorus 
pentabromide, phosphorus oxychloride, oxalyl chloride and p-toluene 
sulphonic acid chloride. Phosphorus pentachloride and phosphorus 
oxychloride are preferred. The reaction may be conducted under cooling, 
preferably at temperatures from 0.degree. C to -30.degree. C when 
phosphorus pentachloride is employed. The amount of the tertiary amine is 
preferably 3-5 mols per mol of phosphorus pentachloride. It is also 
preferable to use the phosphorus halide in an amount slightly in excess of 
that of the starting material. 
The resulting imino compounds are then treated to introduce a--QR.sub.f 
grouping, onto the imino carbon atom, to produce a compound of formula 
(VIII): 
##STR10## 
wherein R.sup.o, Q, R.sub.f and R.sup.x are as defined above. 
This is preferably effected by reacting an imino halide with corresponding 
alcohol. Examples of suitable alcohols for reaction with the imino halide 
are aliphatic alcohols containing from 1 to 12 carbon atoms, preferably 1 
to 5 carbon atoms, such as methanol, ethanol, propanol, isopropyl alcohol, 
amyl alcohol and butyl alcohol, and aralkyl alcohols such as benzyl 
alcohol and 2-phenyl-ethanol-1. The reaction of the alcohol with the imino 
halide is preferably effected in the presence of an acid binding agent, 
such as a tertiary amine, preferably pyridine, and the reaction is usually 
carried out without isolating the imino halide from the reaction mixture. 
Thereafter the compound (VIII) is caused to react with an N-acylating 
derivative of an acid of formul (IV). The comments made above concerning 
such N-acylating derivative, and the conditions for carrying out 
acylations also apply in this case. In particular the presence of a 
tertiary amine such as pyridine or N,N-dimethylaniline in the reaction 
system is preferred. The product from such an acylation has formula (IX): 
##STR11## 
Finally, the addition compound (IX) is treated with water or alcohol. The 
water treatment may be conducted together with the isolation of the 
desired material. That is, water or a saturated aqueous solution of sodium 
chloride is added to the compound (IX) and then the aqueous layer formed 
is separated from the organic solvent layer. 
Alternatively a compound of formula (IX A): 
##STR12## 
wherein R, R.sup.o, and R.sup.x are as defined above and V is the residue 
of an N-acylating derivative of the acid (IV), (e.g. hydroxy, halogen, 
acyloxy, aryloxy, amino, cyano, azido);may be prepared by reaction of the 
corresponding N-acylating derivative of (IV) with the Schiff's base formed 
by reacting 6-.alpha.-methoxy-6-.beta.-aminopenicillanic acid (or a 
carboxyl protected derivative thereof) with an aldehyde R.sup.o.CHO. The 
compound (IXA) may be hydrolysed to a compound (I) with water optionally 
in the presence of acid or base. 
A further method for the preparation of compounds of formula (I) is by 
hydrolysis of an N-acylbenzyl-6-.alpha.-methoxy-penicillan of formula (X): 
##STR13## 
wherein R, and R.sup.x are as defined above. The hydrolysis may be an 
acid- or base-catalysed chemical hydrolysis or may be an enzymic 
hydrolysis with the aid of penicillin acylase. The compound (X) may be 
prepared either from an imino-halid compound of formula (VII) above by 
reaction with a salt of the acid (IV); or by the action of an acid halide 
of the acid (IV) with a 6-N-alkali metal derivative of benzyl 
6.alpha.-methoxypenicillin or alternatively with its 6N-trimethylsilyl 
derivative. 
A further method for the preparation of compounds of formula (I) comprises 
reacting a compound of formula (XIII): 
##STR14## 
wherein R, and R.sup.2 are as defined with respect to formula (I) and 
R.sup.3 is lower alkyl or benzyl: 
A. with chlorine or bromine at -25.degree. to 80.degree. C and subsequently 
decomposing the resultant halosulphonium halide with methanol and a base; 
or 
B. with methanol in the presence of a metal ion such as a tellurium (III), 
lead (IV), bismuth (V) mercury, lead, cadmium or thallium salts and 
subsequently removing the carboxyl protecting group. 
Preferably the reaction is carried out at -50.degree. to +25.degree. C in a 
solvent. 
Compounds (I) may also be prepared by reducing a compound of a formula 
(XV): 
##STR15## 
wherein R.sup.x is as defined above; and simultaneously or subsequently 
acylating with an N-acylating derivative of an acid of formula (IV) above 
and thereafter if necessary: 
i. removing any carboxyl blocking group; 
converting the product to a salt or ester thereof. 
Suitable N-acylating derivatives of the acid (IV) are as described above. 
Various methods of carrying out the reduction of the azido group may be 
used, but a preferred method is by catalytic hydrogenation using a noble 
metal catalyst such as platinum, palladium or oxides thereof. 
The intermediate of formula (XV) may be prepared as described in British 
Pat. No. 1,339,007. 
The antibiotic compounds according to the invention may be formulated for 
administration in any convenient way for use in human or veterinary 
medicine, by analogy with other antibiotics, and the invention therefore 
includes within its scope a pharmaceutical compositition comprising a 
compound of formula (I) together with a pharmaceutical carrier or 
excipient. 
The compositions may be formulated for administration by any route, 
although an oral administration is preferred. The compositions may be in 
the form of tablets, capsules, powders, granules, lozenges, or liquid 
preparations, such as oral or sterile parenteral solutions or suspensions. 
Tablets and capsules for oral administration may be in unit dose 
presentation form, and may contain conventional excipients such as binding 
agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or 
polyvinyl pyrolidone; fillers, for example lactose, sugar, maize-starch, 
calcium phosphate, sorbitol or glycine; tabletting lubricants, for example 
magnesium stearate, talc, polyethylene glycol or silica; disintegrants, 
for example potato starch; or acceptable wetting agents such as sodium 
lauryl sulphate. The tablets may be coated according to methods well known 
in normal pharmaceutical practice. Oral liquid preparations may be in the 
form of, for example, aqueous or oily suspensions, solutions, emulsions, 
syrups, or elixirs, or may be presented as dry product for reconstitution 
with water or other suitable vehicle before use. Such liquid preparations 
may contain conventional additives such as suspending agents, for example 
sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, 
hydroxyethylcellulose, carboxymethyl cellulose, alluminum stearate gel or 
hydrogenated edible fats, emulsifying agents, for example lecithin, 
sorbitan monooleate, or acacia; non-aqueous vehicles (which may include 
edible oils), for example almond oil, fractionated coconut oil oily esters 
such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for 
example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired 
conventional flavouring or colouring agents. 
Suppositories will contain conventional suppository bases, e.g. cocoa, 
butter or other glyceride. 
For parenteral administration, fluid unit dosage forms are prepared 
utilizing the compound and a sterile vehicle, water being preferred. The 
compound, depending on the vehicle and concentration used, can be either 
suspended or dissolved in the vehicle. In preparing solutions the compound 
can be dissolved in water for injection and filter sterilized before 
filling into a suitable vial or ampoule and sealing. Advantageously, 
adjuvants such as a local anesthetic, preservative and buffering agents 
can be dissolved in the vehicle. To enhance the stability, the composition 
can be frozen after filling into the vial and the water removed under 
vacuum. The dry lyophilized powder is then sealed in the vial and an 
accompanying vial of water for injection is supplid to reconstitute the 
liquid prior to use. Parenteral suspensions are prepared in substantially 
the same manner except that the compound is suspended in the vehicle 
instead of being dissolved and sterilization cannot be accomplished by 
filtration. The compound can be sterilized by exposure to ethylene oxide 
before suspending in the sterile vehicle. Advantageously, a surfactant or 
wetting agent is included in the composition to facilitate uniform 
distribution of the compound. 
The compositions may contain from 0.1% ot 99% by weight, preferably from 
10-60% by weight, of the active material, depending on the method of 
administration. Where the compositions comprise dosage units, each unit 
will preferably contain from 50-500 mg. of the active ingredient. The 
dosage as employed for adult human treatment will preferably range from 
100 to 3000 mg. per day, for instance 1500 mg. per day, depending on the 
route and frequency of administration. 
It will be clear that the side-chain of the penicillins of formula (I) 
contains a potentially asymmetric carbon atom. This invention includes all 
the possible epimers of compounds (I) as well as mixtures of them. 
The compounds of this invention have an unusual stability to Gram-negative 
.beta.-lactamases and are active against all the important Gram-negative 
pathogens with the exception of Pseudomonas aeraginosa. 
The following Examples illustrate the preparation of some of the compounds 
of this invention.