Compounds of formula (I): ##STR1## wherein: one or both of R.sup.1 and R.sup.2 are selected from a variety of organic groups; PA1 R.sup.3 is an optionally substituted heterocycle; and PA1 R.sup.4 is hydrogen or optionally substituted alkyl or alkoxy. and salts and esters thereof have valuable antibiotic activity.

The present invention relates to a series of new carbapenem compounds and 
to compositions containing the compounds, and provides a process for 
preparing these compounds. 
The penicillins form a well known class of antibiotics, which have found 
considerable use in human and animal therapy for many years. Chemically, 
the penicillins have in common a .beta.-lactam structure, commonly 
referred to as "penam", which may be represented by the following formula: 
##STR2## 
However, although the penicillins still form a valuable weapon in the 
pharmaceutical armory, the development of new, and often 
penicillin-resistant, strains of pathogenic bacteria has increasingly made 
it necessary to search for new types of antibiotic. 
In recent years, great interest has been shown in compounds having a 
carbapenem structure, that is compounds having a carbon atom in place of 
the sulfur atom at the 1-position and having a double bond between the 
carbon atoms in the 2- and 3-positions of the basic penam structure. The 
carbapenem structure may be represented by the following formula 
##STR3## 
These penam and carbapenem structures form the basis for the 
semi-systematic nomenclature of the penicillin derivatives in accordance 
with the recommendations of the International Union of Pure and Applied 
Chemistry (IU), and this nomenclature is generally accepted by those 
skilled in the art throughout the world and is used herein. The numbering 
system employed herein is that illustrated on the above formulae. 
Of the known carbapenem derivatives, the best known is a compound called 
"thienamycin", whose semi-systematic name is 
2-(2-aminoethylthio)-6-(1-hydroxyethyl)carbapen-2-em-3-carboxylic acid. 
Although thienamycin is known to have remarkably potent and broad 
antibacterial activity, its chemical stability in the human body is poor, 
which restricts its practical use. Various attempts have, therefore, been 
made to modify the chemical structure of thienamycin in order to improve 
its chemical stability whilst maintaining or improving its superior 
activity. 
In recent years, as interest in the carbapenem compounds has increased, a 
large number of carbapenem derivatives has been proposed in a variety of 
publications in an attempt to overcome various of the problems associated 
with thienamycin, and, in particular, in order to improve stability and 
improve antibacterial activity. 
Of the prior art, the closest prior art to the present invention is 
believed to be European Patent Publication No. 10,317, which discloses a 
series of carbapenem compounds in which substituents at the 1-, 2- and 6- 
positions are chosen from an extremely long list of groups and atoms, 
whose general terms cover some of the appropriate substituents on the 
compounds of the invention. Also U.S. Pat. 4,552,873 which issued on 
application Ser. No. 407,914, filed 13th Aug. 1982 is close prior art. It 
discloses a limited class of carbapenem derivatives having a 
heterocyclyl-thio group at the 2-position; the compounds of this prior 
art, however, differ from those of the present invention in that they lack 
a substituent at the 1-position. Also relevant prior art, in that they 
disclose compounds having substituents at the 1-position, are U.S. Pat. 
Nos. 4,206,219 and No. 4,260,627; the compounds disclosed in these U.S. 
patents, however, differ from those of the present invention in that, 
respectively, they lack a substituent at the 2-position or, whilst having 
a wide range of substituents at the 2-position, do not contemplate a 
heterocyclyl-thio substituent. 
We have now discovered a class of compounds, of which those compounds 
investigated have been found to exhibit far better absorption and 
metabolic stability (as evidenced by improved recovery rates in the urine) 
than the compounds of U.S. Pat. No. 4,552,873 and which have a broader 
antibacterial spectrum, stronger activity and greater stability than 
thienamycin. 
BRIEF SUMMARY OF INVENTION 
The compounds of the invention are those compounds which may be represented 
by the formula (I): 
##STR4## 
wherein: 
R.sup.1 and R.sup.2 are independently selected from the group consisting of 
hydrogen, provided that R.sup.1 and R.sup.2 are not both hydrogen, halogen 
atoms, C.sub.2 -C.sub.7 alkoxycarbonyl groups and substituted and 
unsubstituted C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, 
C.sub.3 -C.sub.8 cycloalkyl, C.sub.6 -C.sub.10 carbocyclic aryl, aralkyl, 
aralkenyl and aralkynyl groups wherein, in said aralkyl, aralkenyl and 
aralkynyl groups, the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl 
group and the alkyl, alkenyl or alkynyl part contains up to 6 carbon 
atoms, and wherein the substituents on said alkyl, alkenyl, alkynyl, 
alkoxy, alkylthio, cycloalkyl, aryl, aralkyl, aralkenyl and aralkynyl 
groups are selected from the group consisting of: 
(a) halogen atoms, C.sub.1 -C.sub.6 alkyl or haloalkyl groups but only on 
said aryl groups or the aryl part of said aralkyl, aralkenyl or aralkynyl 
groups, C.sub.1 -C.sub.6 alkoxy groups, C.sub.1 -C.sub.6 alkylthio groups, 
hydroxy groups and phenyl groups, 
or R.sup.1 and R.sup.2, together with the carbon atom to which they are 
attached, form a C.sub.3 -C.sub.8 alicyclic ring; 
R.sup.3 represents a heterocyclic ring having from 4 to 8 ring atoms, of 
which from 1 to 3 ring atoms are selected from the group consisting of 
oxygen, sulfur and nitrogen atoms, which heterocyclic ring is 
unsubstituted or has from 1 to 3 substituents selected from the group 
consisting of: 
(b) oxo groups, C.sub.1 -C.sub.6 alkyl groups, alkoxyalkyl groups where the 
alkyl part and the alkoxy part both have from 1 to 6 carbon atoms, 
cyanoalkyl groups where the alkyl part has from 1 to 6 carbon atoms, 
C.sub.1 -C.sub.6 haloalkyl groups, C.sub.1 -C.sub.6 alkoxy groups, hydroxy 
groups, amino groups, halogen atoms, C.sub.1 -C.sub.7 aliphatic acyloxy 
groups, C.sub.1 -C.sub.7 aliphatic acylamino groups, cyano groups, azido 
groups, carboxy groups, C.sub.2 -C.sub.7 alkoxycarbonyl groups, carbamoyl 
groups, thiocarbamoyl groups, C.sub.1 -C.sub.6 alkylthio groups, C.sub.1 
-C.sub.6 alkylsulfinyl groups, C.sub.1 -C.sub.6 alkylsulfonyl groups, 
nitro groups, C.sub.2 -C.sub.6 alkenyl groups, cycloalkylalkyl groups 
where the cycloalkyl part has from 3 to 8 carbon atoms and the alkyl part 
has from 1 to 6 carbon atoms, C.sub.6 -C.sub.10 carbocyclic aryl groups, 
C.sub.1 -C.sub.7 aliphatic acyl groups, C.sub.4 -C.sub.9 
cycloalkanecarbonyl groups, cycloalkylalkanoyl groups where the cycloalkyl 
part has from 3 to 8 carbon atoms and the alkanoyl part has from 2 to 7 
carbon atoms, aromatic carbocyclic acyl groups, araliphatic acyl groups 
where the aryl part is C.sub.6 -C.sub.10 carbocyclic aryl and the 
aliphatic acyl part is C.sub.2 -C.sub.7, heterocyclic acyl groups, 
heterocyclic-substituted C.sub.2 -C.sub.7 aliphatic acyl groups, aromatic 
acyl-substituted C.sub.1 -C.sub.6 alkyl groups, sulfo groups, C.sub.1 
-C.sub.6 alkoxysulfonyl groups, C.sub.1 -C.sub.6 alkenylsulfonyl groups, 
C.sub.1 -C.sub.6 alkynylsulfonyl groups, C.sub.3 -C.sub.8 
cycloalkylsulfonyl groups, cycloalkylalkylsulfonyl groups where the 
cycloalkyl part has from 3 to 8 carbon atoms and the alkyl part has from 1 
to 6 carbon atoms, C.sub.6 -C.sub.10 carbocyclic arylsulfonyl groups, 
aralkylsulfonyl groups where the aryl part is C.sub.6 -C.sub.10 
carbocyclic aryl and the alkyl part is C.sub.1 -C.sub.6 alkyl, 
heterocyclyl-sulfonyl groups, heterocyclic-substituted C.sub.1 -C.sub.6 
alkylsulfonyl groups, aliphatic, carbocyclic aromatic and heterocyclic 
acyl imidoyl groups of formula --C(R.sup.5).dbd.N--R.sup.6, wherein: 
R.sup.5 and R.sup.6 are the same or different and each represents hydrogen, 
a C.sub.1 -C.sub.6 alkyl group, a C.sub.1 -C.sub.6 alkyl group having from 
1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.6 
alkoxy, cyano, phenyl and halogen substituents, a phenyl group or an 
aromatic heterocyclic group, 
alkylcarbamoyl, alkylthiocarbamoyl, dialkylcarbamoyl and 
dialkylthiocarbamoyl groups where each alkyl part has from 1 to 6 carbon 
atoms, amidino groups, mono-, di- and tri-(C.sub.1 -C.sub.6 alkyl)amidino 
groups, aralkoxycarbonyl groups where the aryl part is C.sub.6 -C.sub.10 
carbocyclic aryl and the alkoxy part is C.sub.1 -C.sub.6 alkoxy, aliphatic 
acyl groups having at least one amino substituent, aliphatic acyloxyalkyl 
groups where the acyl part is C.sub.1 -C.sub.7 and the alkyl part is 
C.sub.1 -C.sub.6, aralkyl groups where the aryl part is C.sub.6 -C.sub.10 
carbocyclic aryl and the alkyl part is C.sub.1 -C.sub.6 alkyl, C.sub.1 
-C.sub.6 hydroxyalkyl groups, arylcarbamoyl and aryl(thiocarbamoyl) groups 
where the aryl part is C.sub.6 -C.sub.10 carbocyclic aryl, 
cycloalkylcarbamoyl and cycloalkyl(thiocarbamoyl) groups where the 
cycloalkyl part is C.sub.3 -C.sub.8 cycloalkyl, and alkoxycarbonylalkyl 
groups where the alkoxy and alkyl parts are both C.sub.1 -C.sub.6. 
R.sup.4 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl or alkoxy 
group which is unsubstituted or has from 1 to 3 substituents selected from 
the group consisting of: 
(c) hydroxy groups, aryloxycarbonyloxy groups where the aryl part is 
C.sub.6 -C.sub.10 carbocyclic aryl and is unsubstituted or substituted, 
alkenyloxycarbonyloxy groups where the alkenyl part is C.sub.2 -C.sub.6 
and is unsubstituted or substituted, alkoxycarbonyloxy groups where the 
alkoxy part is C.sub.1 -C.sub.6 and is unsubstituted or substituted, 
trialkylsilyloxy groups where each alkyl is C.sub.1 -C.sub.6, C.sub.1 
-C.sub.6 alkoxy groups, C.sub.1 -C.sub.7 aliphatic acyloxy groups, C.sub.1 
-C.sub.6 alkylsulfonyloxy groups, arylsulfonyloxy groups where the aryl 
part is C.sub.6 -C.sub.10 carbocyclic aryl and is unsubstituted or 
substituted, mercapto groups, C.sub.1 -C.sub.6 alkylthio groups, amino 
groups and C.sub.1 -C.sub.7 aliphatic acylamino groups, the substituents 
on said aryl, alkenyl and alkoxy parts being as defined in (a) above; 
and pharmaceutically acceptable salts and esters thereof. 
The invention also provides a pharmaceutical composition comprising an 
effective amount of an antibacterial agent in admixture with a 
pharmaceutically acceptable carrier or diluent, wherein the antibacterial 
agent is selected from the group consisting of compounds of formula (I) 
and pharmaceutically acceptable salts and esters thereof.

DETAILED DESCRIPTION OF INVENTION 
In the compounds of the invention, one of R.sup.1 and R.sup.2, but not 
both, may be hydrogen and the other may be selected from the groups and 
atoms defined below, or both may be selected from these groups and atoms. 
R.sup.1 and R.sup.2 may represent alkyl groups having from 1 to 10 carbon 
atoms, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 2-methylbutyl, 
hexyl, isohexyl, 2-methylpentyl, heptyl, octyl, 2-ethylhexyl, nonyl or 
decyl groups, preferably the C.sub.1 -C.sub.3 alkyl groups (i.e. the 
methyl, ethyl, propyl and isopropyl groups) and more preferably the methyl 
group. 
R.sup.1 or R.sup.2 may also represent alkenyl groups having from 2 to 6 
carbon atoms, for example the vinyl, allyl, methallyl, 1-propenyl, 
1-butenyl, 2-butenyl, 3-butenyl, pentenyl (1,2,3 or 4) or hexenyl (1,2,3,4 
or 5) groups, preferably a C.sub.2 or C.sub.3 alkenyl group and more 
preferably a vinyl or allyl group. 
R.sup.1 and R.sup.2 may also represent alkynyl groups having from 2 to 6 
carbon atoms, for example the ethynyl, propargyl, 1-propynyl, 1-butynyl, 
2-butynyl 3-butynyl, pentynyl (1,2,3 or 4) or hexynyl (1,2,3,4 or 5) 
groups. Of these, we prefer C.sub.2 and C.sub.3 alkynyl groups, 
particularly the ethynyl and propargyl groups. 
Where R.sup.1 or R.sup.2 represents an alkoxy group, this has from 1 to 6 
carbon atoms and may be a straight or branched chain group. Examples 
include the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, 
hexyloxy and isohexyloxy groups, of which the C.sub.1 -C.sub.3 alkoxy 
groups (methoxy, ethoxy, propoxy and isopropoxy) are preferred. 
Where R.sup.1 or R.sup.2 represents an alkylthio group, this has from 1 to 
6 carbon atoms and may be a straight or branched chain group. Examples 
include the methylthio, ethylthio, propylthio, isopropylthio, butylthio, 
isobutylthio, sec-burylthio, t-butylthio, pentylthio, isopentylthio, 
neopentylthio, t-pentylthio, hexylthio and isohexylthio groups, of which 
the C.sub.1 -C.sub.3 alkylthio groups (i.e. methylthio, ethylthio, 
propylthio and isopropylthio) are preferred. 
Where R.sup.1 or R.sup.2 represents a cycloalkyl group, this has from 3 to 
8 carbon atoms and examples include the cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, particularly 
the C.sub.3 -C.sub.6 cycloalkyl groups (cyclopropyl, cyclobutyl, 
cyclopentyl and cyclohexyl). 
Where R.sup.1 or R.sup.2 represents an aryl group, this is a carbocyclic 
aromatic group, which may have from 6 to 10 carbon atoms, for example a 
phenyl, 1-naphthyl or 2-naphthyl group, preferably a phenyl group. 
Where R.sup.1 or R.sup.2 represents an aralkyl, aralkenyl or aralkynyl 
group, the aryl part of this group is as defined above where R.sup.1 or 
R.sup.2 is itself an aryl group and is preferably a phenyl group, and the 
alkyl, alkenyl or alkynyl part is as defined above where R.sup.1 or 
R.sup.2 is itself an alkyl, alkenyl or alkynyl group, and is preferably a 
methyl, ethyl, vinyl, allyl, ethynyl or propargyl group, more preferably a 
methyl group. 
Alternatively, R.sup.1 and R.sup.2, together with the carbon atom to which 
they are attached, may represent an alicyclic ring system having from 3 to 
8, preferably from 3 to 6, carbon atoms and more preferably R.sup.1 and 
R.sup.2 together represent an ethylene, trimethylene, tetramethylene or 
pentamethylene group. 
Where R.sup.1 or R.sup.2 represents an alkyl, alkenyl, alkynyl, alkoxy, 
alkylthio, cycloalkyl, aryl, aralkyl, aralkenyl, or aralkynyl group, they 
may be unsubstituted or they may be substituted. If substituted, they have 
from 1 to 3 substituents, which are selected from the group consisting of 
the following: 
halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, 
particularly fluorine, chlorine or bromine atoms; where there are 2 or 3 
halogen substituents, these may be all on the same carbon atom or they may 
be on different carbon atoms, preferably on the same carbon atom; 
hydroxy, mercapto, nitro, cyano and amino groups; 
alkoxy groups, preferably having from 1 to 3 carbon atoms and more 
preferably being the methoxy or ethoxy groups; 
alkylthio groups, preferably having from 1 to 3 carbon atoms and more 
preferably being the methylthio or ethylthio groups; 
carbocyclic aryl groups, for example as exemplified above in relation to 
R.sup.1 and R.sup.2, particularly the phenyl group; 
except where the substituent is on an alkyl, alkenyl, alkynyl, alkoxy or 
alkylthio group, an alkyl group preferably having from 1 to 3 carbon atoms 
and more preferably being the methyl or ethyl group; and 
except where the substituent is on an alkyl, alkenyl, alkynyl, alkoxy or 
alkylthio group, a haloalkyl group having from 1 to 6, preferably 1 to 3, 
more preferably 1 or 2 and most preferably 1, carbon atoms and from 1 to 3 
halogen, e.g. fluorine, chlorine, bromine or iodine, atoms; examples 
include the fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 
trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl and 
2,2,2-trifluoroethyl groups. 
R.sup.3 represents a heterocyclic group having from 4 to 8 ring atoms, of 
which from 1 to 3 are hetero-atoms selected from the group consisting of 
nitrogen, oxygen and sulfur atoms, the remainder being carbon atoms. The 
heterocyclic ring may be saturated or partially saturated. In the 
heterocyclic groups represented by R.sup.3, the atom through which the 
heterocyclic group is attached to the sulfur atom of --SR.sup.3 is 
preferably a carbon atom. Examples of such heterocyclic ring systems which 
may be represented by R.sup.3 include the 2-azetidinyl, 3-azetidinyl, 
2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 
hexahydro-1H-azepin-4-yl, octahydroazocin-5-yl, oxazolidin-5-yl, 
thiazolidin-5-yl, 2-morpholinyl, 1,4-thiazin-2-yl, 
hexahydropyrimidin-5-yl, hexahydropyridazin-4-yl, perhydroazocin-3-yl, 
perhydroazepin-3-yl and 3, 4, 5, 6-tetrahydropyrimidin-5-yl 
These heterocyclic ring systems may be substituted or unsubstituted and a 
wide range of substituents are possible on the carbon, nitrogen and 
possibly sulfur atoms of the heterocyclic ring. The nature of permissible 
substituents will, of course, depend upon the atom of the heterocyclic 
ring to which they are attached. 
Examples of substituents which may be attached to ring carbon atoms 
include: 
C.sub.1 -C.sub.6 alkyl groups, which may be straight or branched chain 
groups, particularly the methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, sec-butyl, t-butyl, pentyl and isopentyl groups; 
alkoxyalkyl groups where both the alkoxy and the alkyl parts have from 1 to 
6 carbon atoms, for example the methoxymethyl, ethoxymethyl, 
propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxyethyl, 
1-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl and 4-ethoxybutyl groups; 
cyanoalkyl groups where the alkyl part is C.sub.1 -C.sub.6 alkyl, such as 
the cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl 
and 4-cyanobutyl groups; 
C.sub.1 -C.sub.6 haloalkyl groups (preferably having 1, 2 or 3 halogen 
atoms, such as the chlorine, fluorine, bromine or iodine atoms), for 
example the trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 
2,2,2-trichloroethyl, 2 chloroethyl, 2-bromoethyl, 3-fluoropropyl, 
2-fluoropropyl, 4-chlorobutyl and 3-fluorobutyl groups; 
C.sub.1 -C.sub.6 alkoxy groups, which may be straight or branched chain 
groups, for example the methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
isobutoxy, sec-butoxy and t-butoxy groups 
halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms; 
C.sub.1 -C.sub.7, preferably C.sub.2 to C.sub.5, aliphatic acyloxy groups, 
such as the acetoxy, propionyloxy, butyryloxy and isobutyryloxy groups; 
C.sub.1 -C.sub.7, preferably C.sub.2 to C.sub.5, aliphatic acylamino 
groups, such as the acetamido, propionamido, butyramido and isobutyramido 
groups; 
the hydroxy, amino, cyano, nitro, azido, carbamoyl and carboxy groups; 
alkoxycarbonyl groups where the alkoxy part is C.sub.1 -C.sub.6 alkoxy, 
such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl 
and t-butoxycarbonyl groups; 
C.sub.1 -C.sub.6 alkylthio groups, which may be straight or branched chain 
groups, such as the methylthio, ethylthio, propylthio, isopropylthio, 
butylthio and isobutylthio groups; 
C.sub.1 -C.sub.6 alkylsulfinyl groups, which may be straight or branched 
chain groups, such as the methylsulfinyl, ethylsulfinyl, propylsulfinyl, 
isopropylsulfinyl, butylsulfinyl and isobutylsulfinyl groups; 
C.sub.1 -C.sub.6 alkylsulfonyl groups, which may be straight or branched 
chain groups, such as the methylsulfonyl, ethylsulfonyl, propylsulfonyl, 
isopropylsulfonyl, butylsulfonyl and isobutylsulfonyl groups; and 
the oxo group (i.e. a doubly bonded oxygen atom, forming, with the carbon 
atom to which it is attached, a carbonyl group). 
Examples of substituents which may be attached to ring nitrogen atoms 
include the following: 
C.sub.1 -C.sub.6 alkyl groups, which may be straight or branched chain 
groups, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, t-butyl, pentyl and isopentyl groups; these alkyl groups may be 
unsubstituted or may have one or more substituents selected from the group 
consisting of those substituents listed above as possible substituents on 
ring carbon atoms, particularly hydroxy groups and halogen (especially 
fluorine) atoms; C.sub.2 -C.sub.6 alkenyl groups, which may be straight or 
branched chain groups, such as the vinyl, allyl, 1-propenyl, isopropenyl, 
2-butenyl and 2-pentenyl groups; 
C.sub.2 -C.sub.6 alkynyl groups, such as the ethynyl, 1-propynyl, 
propargyl, 2-butynyl and 4-pentynyl groups; 
C.sub.3 -C.sub.8 cycloalkyl groups, such as the cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl and cycloheptyl groups; 
cycloalkylalkyl groups, in which the cycloalkyl part is C.sub.3 -C.sub.8 
cycloalkyl and the alkyl part (which may be straight or branched chain) is 
C.sub.1 -C.sub.6 alkyl, such as the cyclopropylmethyl, cyclobutylmethyl, 
cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 
2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopentylpropyl, 
2-cyclopentylpropyl. 3-cyclohexylpropyl, 2-cyclohexylpropyl, 
4-cyclopentylbutyl and 3-cyclohexylbutyl groups; 
carbocyclic aryl groups, preferably having from 6 to 10 ring carbon atoms, 
such as the phenyl, 1-naphthyl and 2-naphthyl groups; 
aralkyl groups, of which the alkyl part preferably has from 1 to 6, more 
preferably from 1 to 3, carbon atoms and the aryl part is a carbocyclic 
aryl group preferably having from 6 to 10 ring carbon atoms, for example 
the benzyl, phenethyl and 3-phenylpropyl groups; 
C.sub.1 -C.sub.7 aliphatic acyl groups, of which the aliphatic part may be 
saturated or have carbon-carbon unsaturation, such as the formyl, acetyl, 
propionyl, butyryl, isobutyryl, acryloyl, methacryloyl, crotonoyl, 
propioloyl and methylpropioloyl groups, and may be unsubstituted or may 
have one or more substituents selected from the group consisting of those 
substituents listed above as possible substituents on ring carbon atoms, 
particularly amino groups; 
cycloalkanecarbonyl groups, where the cycloalkane part is C.sub.3 -C.sub.8 
cycloalkane, such as the cyclopropanecarbonyl, cyclobutanecarbonyl, 
cyclopentanecarbonyl and cyclohexanecarbonyl groups; 
cycloalkylalkanoyl groups, where the cycloalkane part is C.sub.3 -C.sub.8 
cycloalkane and the alkanoyl part is C.sub.2 -C.sub.7 alkanoyl, such as 
the cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, 
cyclohexylacetyl, 3-cyclopentylpropionyl, 3-cyclohexylpropionyl, 
4-cyclopentylbutyryl and 4-cyclohexylbutyryl groups; 
aromatic carbocyclic carboxylic acyl groups, wherein the aryl part 
preferably has from 6 to 10 ring carbon atoms, such as the benzoyl, 
1-naphthoyl and 2-naphthoyl groups; 
carbocyclic aromatic-substituted aliphatic carboxylic acyl groups wherein 
the aromatic part preferably has from 6 to 10 ring carbon atoms and the 
aliphatic acyl part preferably has from 2 to 7 carbon atoms and may be 
saturated or unsaturated, for example the phenylacetyl, 1-naphthylacetyl, 
3-phenylpropionyl, hydratropoyl, cinnamoyl and phenylpropioloyl groups; 
heterocyclic carboxylic acyl groups, such as the furoyl, thenoyl, 
nicotinoyl, isonicotinoyl, 4-thiazolecarbonyl, 5-pyrimidinecarbonyl, 
2-pyridinecarbonyl, 1-aziridinecarbonyl, 1-azetidinecarbonyl, 
3-azetidinecarbonyl, 1-pyrrolidinecarbonyl, 2-pyrrolidinecarbonyl, 
3-pyrrolidinecarbonyl, 1-piperidinecarbonyl, 2-piperidinecarbonyl, 
4-piperidinecarbonyl and 1-morpholinecarbonyl groups; 
heterocyclic-substituted aliphatic acyl groups, wherein the aliphatic acyl 
part preferably has from 2 to 7, and more preferably from 2 to 4 carbon 
atoms, and the heterocyclic part, which may be saturated, unsaturated or 
partially saturated, preferably has from 3 to 8 ring atoms of which from 1 
to 3 are hetero-atoms selected from the group consisting of oxygen, sulfur 
and nitrogen atoms, such as the 2-thienylacetyl, 3-(2-thienyl)propionyl, 
4-thiazolylacetyl, 2-pyridylacetyl, 4-pyridylacetyl, 5-pyrimidylacetyl, 
1-aziridinylacetyl, 1-azetidinylacetyl, 3-azetidinylacetyl, 
1-pyrrolidinylacetyl, 2-pyrrolidinylacetyl, 3-pyrrolidinylacetyl, 
3-(2-pyrrolidinyl)propionyl, piperidinoacetyl, 2-piperidylacetyl, 
4-piperidylacetyl and morpholinoacetyl groups; 
aromatic acyl-substituted alkyl groups, where the acyl part is an aromatic 
carbocyclic carboxylic acyl group and is preferably selected from those 
groups listed above and the alkyl part is C.sub.1 -C.sub.6 alkyl and is 
preferably selected from those groups listed above, particularly methyl or 
ethyl, e.g. the phenacyl group; 
the sulfo group; 
C.sub.1 -C.sub.6 alkoxysulfonyl groups, such as the methoxysulfonyl, 
ethoxysulfonyl, propoxysulfonyl and isopropoxysulfonyl groups; 
C.sub.1 -C.sub.6 alkylsulfonyl groups, which may be straight or branched 
chain groups, such as the methylsulfonyl, ethylsulfonyl, propylsulfonyl, 
isopropylsulfonyl, butylsulfonyl and isobutylsulfonyl groups; 
C.sub.2 -C.sub.6 alkenylsulfonyl groups, such as the allylsulfonyl, 
isopropenylsulfonyl and 2-butenylsulfonyl groups; 
C.sub.2 -C.sub.6 alkynylsulfonyl groups, such as the ethynylsulfonyl, 
propargylsulfonyl and 2-butynylsulfonyl groups; 
C.sub.3 -C.sub.8 cycloalkylsulfonyl groups, such as the 
cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and 
cyclohexylsulfonyl groups; 
cycloalkylalkylsulfonyl groups, where the cycloalkyl part is C.sub.3 
-C.sub.8 cycloalkyl and the alkyl part (which may be straight or branched 
chain) is C.sub.1 -C.sub.6 alkyl, such as the cyclopropylmethylsulfonyl, 
cyclobutylmethylsulfonyl, cyclopentylmethylsulfonyl, 
cyclohexylmethylsulfonyl, 2-cyclopentylethylsulfonyl, 
2-cyclohexylethylsulfonyl, 3-cyclopentylpropylsulfonyl and 
2-cyclopentylpropylsulfonyl groups; 
arylsulfonyl groups, wherein the aryl part is a carbocyclic aromatic group 
preferably having from 6 to 10 ring carbon atoms, such as the 
phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl groups; 
aralkylsulfonyl groups, in which the aryl part is a carbocyclic aromatic 
group preferably having from 6 to 10 ring carbon atoms and the alkyl part 
is a C.sub.1 -C.sub.6 alkyl group, which may be a straight or branched 
chain group, for example the benzylsulfonyl, phenethylsulfonyl, 
3-phenylpropylsulfonyl and 2-phenylpropylsulfonyl groups; 
aromatic heterocyclic-sulfonyl groups, such as the 2-thiophenesulfonyl, 
4-thiazolesulfonyl, 2-pyridinesulfonyl and 4-pyridinesulfonyl groups; 
(aromatic heterocyclic)-substituted alkylsulfonyl groups, in which the 
alkyl part, which may be straight or branched chain, preferably has from 1 
to 6, more preferably from 1 to 3, carbon atoms, for example the 
2-thienylmethylsulfonyl, 3-(2-thienyl)propylsulfonyl, 
4-thiazolylmethylsulfonyl, 2-pyridylmethylsulfonyl and 
4-pyridylmethylsulfonyl groups; 
aliphatic, substituted aliphatic, aromatic or heterocyclic acyl imidoyl 
groups which may be represented by the formula 
--(R.sup.5)C.dbd.N--R.sup.6, in which R.sup.5 and R.sup.6 are the same or 
different and each represents hydrogen, a C.sub.1 -C.sub.6, preferably 
C.sub.1 -C.sub.3, alkyl group (for example a methyl, ethyl, propyl or 
isopropyl group), an alkoxyalkyl group where the alkoxy and alkyl parts 
both have from 1 to 6, preferably 1 to 3 more preferably 1 or 2, carbon 
atoms (for example a methoxymethyl or ethoxymethyl group), a cyanoalkyl 
group where the alkyl part (which may be straight or branched chain) has 
from 1 to 6 carbon atoms (for example a cyanomethyl, 1-cyanoethyl or 
2-cyanoethyl group), an aromatic heterocyclic group (such as a pyridyl, 
furyl or thienyl group), a phenyl group, a benzyl group or a C.sub.1 
-C.sub.6 haloalkyl group (such as a chloromethyl or fluoromethyl group), 
particularly the formimidoyl, acetimidoyl, N-methylformimidoyl, 
N-methylacetimidoyl, propionimidoyl, .alpha.-methoxyacetimidoyl, 
.alpha.-fluoroacetimidoyl, nicotinimidoyl and benzimidoyl groups; 
carbamoyl, thiocarbamoyl and amidino groups and alkyl-substituted 
derivatives thereof of formula --(Z:)C--NR.sup.7 R.sup.8, in which R.sup.7 
and R.sup.8 are the same or different and each represents hydrogen or a 
C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, alkyl group (such as a 
methyl, ethyl, propyl or isopropyl group) and Z represents an oxygen or 
sulfur atom, an imino group or a C.sub.1 -C.sub.6 alkylimino group (such 
as the methylimino, ethylimino, propylimino or isopropylimino group); 
alkoxycarbonyl groups, where the alkoxy part is C.sub.1 -C.sub.6 alkoxy, 
such as the methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl and 
isobutoxycarbonyl groups; and 
aralkyloxycarbonyl groups, in which the aryl part is a carbocyclic aromatic 
group preferably having from 6 to 10 ring carbon atoms and the alkyl part 
is a C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, alkyl group, for 
example the benzyloxycarbonyl and phenethyloxycarbonyl groups. 
Where the sulfur atom of the heterocyclic ring represented by R.sup.3 is 
substituted, the substituents are preferably 1 or 2 oxygen atoms, so as to 
form, with the sulfur atom, a sulfinyl or sulfonyl group. 
R.sup.4 represents hydrogen, or a C.sub.1 -C.sub.6 alkyl or C.sub.1 
-C.sub.6 alkoxy group. Where R.sup.4 represents an alkoxy group, this may 
be a straight or branched chain group and is preferably a C.sub.1 -C.sub.4 
alkoxy group, particularly a methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
isobutoxy or t-butoxy group. Where R.sup.4 is an alkyl group, this may be 
a straight or branched chain group and is preferably a C.sub.1 -C.sub.5 
alkyl group, for example a methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, t-butyl, pentyl or isopentyl group. These alkyl and alkoxy 
groups may be unsubstituted or may have one or more, preferably from 1 to 
3, substituents which may be selected from the group consisting of the 
following: hydroxy groups (which may, if desired, be protected by any 
conventional protecting group, for example a benzyloxycarbonyl, 
4-nitrobenzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 
2,2,2-tribromoethoxycarbonyl, aryloxycarbonyl, trimethylsilyl or 
t-butyldimethylsilyl group); alkoxy groups (preferably having from 1 to 6, 
more preferably from 1 to 3, carbon atoms, for example methoxy, ethoxy, 
propoxy or isopropoxy groups); carboxylic acyloxy groups (preferably 
C.sub.2 -C.sub.7 alkanoyloxy groups, such as the acetoxy and propionyloxy 
groups); alkylsulfonyloxy and arylsulfonyloxy groups (particularly C.sub.1 
-C.sub.6, preferably C.sub.1 -C.sub.4, alkylsulfonyloxy and C.sub.6 
-C.sub.10 carbocyclic arylsulfonyloxy groups, such as the 
methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, 
benzenesulfonyloxy, naphthalenesulfonyloxy and p-toluenesulfonyloxy 
groups); the mercapto group; C.sub.1 -C.sub.6, preferably C.sub.1 
-C.sub.3, alkylthio groups (for example the methylthio, ethylthio, 
propylthio or isopropylthio groups); the amino group; and carboxylic 
acylamino groups (particularly alkanoylamino groups preferably having from 
2 to 7 carbon atoms, for example the acetamido, propionamido, butyramido 
or isobutyramido groups). 
The compounds of the invention, being acids, are capable of forming salts 
and esters. The nature of such salts and esters is not critical to the 
present invention and the compounds of formula (I) are capable of forming 
salts and esters with any cations and ester-forming alcohols, 
respectively, which are known for the formation of salts and esters with 
compounds of this type. The only restriction on the nature of such salts 
and esters is that they should be "pharmaceutically acceptable" which 
means to those skilled in the art that the salt-forming cation or 
ester-forming alcohol should not, or should not to an unacceptable extent, 
reduce the activity of the compounds of formula (I), nor should they 
increase, or increase to an unacceptable extent, the toxicity of those 
compounds. However, the formation of salts and esters and the application 
of these criteria to the choice of salt-forming cations or ester-forming 
alcohols is so well-known to the man skilled in the art as to require no 
further definition here. 
Examples of suitable esters include: C.sub.1 -C.sub.6 preferably C.sub.1 
-C.sub.4, alkyl esters, such as the methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl and t-butyl esters; C.sub.1 -C.sub.6, preferably C.sub.1 
-C.sub.4, haloalkyl esters, which may have one or more halogen atoms (the 
maximum number of halogen atoms being dictated by the number of carbon 
atoms in the alkyl group, but preferably being from 1 to 3), such as the 
2-iodoethyl, 2,2-dibromoethyl and 2,2,2-trichloroethyl esters; 
alkoxymethyl esters, wherein the alkoxy part has from 1 to 6, preferably 
from 1 to 4, carbon atoms, for example the methoxymethyl, propoxymethyl, 
isopropoxymethyl, butoxymethyl and isobutoxymethyl esters; aliphatic 
carboxylic acyloxymethyl esters, wherein the acyl part which may have 
saturated or unsaturated carbon-carbon bonds, preferably all saturated, 
has from 2 to 7, preferably from 2 to 5, carbon atoms, for example the 
acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl 
and pivaloyloxymethyl esters; 1-alkoxycarbonyloxyethyl esters, where the 
alkoxy part has from 1 to 6, preferably from 1 to 4, carbon atoms, for 
example the 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 
1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 
1-butoxycarbonyloxyethyl and 1-isobutoxycarbonyloxyethyl esters; aralkyl 
esters, where the aryl part has from 6 to 10 ring carbon atoms and is 
unsubstituted or has one or more (preferably from 1 to 3) substituents 
selected from the group consisting of those substituents listed above as 
possible substituents on ring carbon atoms (and preferably C.sub.1 
-C.sub.3 alkoxy groups, nitro groups, C.sub.1 -C.sub.3 alkyl groups, 
hydroxy groups and halogen atoms), for example the benzyl, 
p-methoxybenzyl, o-nitrobenzyl and p-nitrobenzyl esters; benzhydryl 
esters; (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters; and phthalidyl 
esters. 
Esters of compounds of formula (I) which contain a suitable 
nitrogen-containing heterocyclic group represented by R.sup.3 or in which 
any of the groups represented by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 has 
a suitable amino substituent are capable of forming acid-addition salts. 
As with the salts and esters defined above, the nature of the acids 
employed to form these salts is not critical and is only limited, where 
the compounds of the invention are intended for pharmaceutical use, by the 
requirement that the resulting acid-addition salts should be 
pharmaceutically acceptable. Accordingly, a wide range of acids can be 
employed to form such acid-addition salts. Examples include: such mineral 
acids as hydrochloric acid and hydrobromic acid; and such organic acids as 
oxalic acid, tartaric acid and citric acid, preferably hydrochloric acid. 
The compounds of formula (I) can also form salts with a wide variety of 
cations. Examples of salts which may be employed in the present invention 
include: metal salts, particularly alkali metal or alkaline earth metal 
salts, such as the lithium, sodium, potassium, calcium or magnesium salts; 
salts with basic amino acids, such as lysine or arginine; ammonium salts; 
and salts with organic amines, such as cyclohexylamine, diisopropylamine 
or triethylamine. Of these, the alkali metal, particularly sodium and 
potassium, salts are preferred. 
The compounds of the invention can also exist in the form of hydrates and 
these likewise form part of the present invention. 
Preferred compounds of the invention are those in which R.sup.3 represents 
a ring-saturated nitrogen-containing heterocyclic group having from 4 to 8 
ring atoms and having, in addition to the nitrogen atom specified, 0, 1 or 
2 additional hetero-atoms selected from the group consisting of nitrogen, 
oxygen and sulfur atoms; or R.sup.3 represents a group of formula: 
##STR5## 
in which: 
R.sup.10 represents hydrogen or a C.sub.1 -C.sub.6 alkyl group, preferably 
a C.sub.1 -C.sub.3 alkyl group, for example a methyl or ethyl group; 
R.sup.11 represents hydrogen, a C.sub.1 -C.sub.6, preferably C.sub.1 
-C.sub.4, alkyl group (such as a methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, sec-butyl or t-butyl group). an alkoxyalkyl group, in which the 
alkoxy part and the alkyl part each have from 1 to 6, preferably from 1 to 
4, and more preferably 1 or 2, carbon atoms (for example the 
methoxymethyl, 1-ethoxyethyl and 2-ethoxyethyl groups), a C.sub.1 
-C.sub.6, preferably C.sub.1 -C.sub.3 and more preferably C.sub.1 or 
C.sub.2, cyanoalkyl or haloalkyl group (for example a cyanomethyl or 
chloromethyl group), an aralkyl group where the aryl part is C.sub.6 
-C.sub.10 carbocyclic aryl and the alkyl part is C.sub.1 -C.sub.6, 
preferably C.sub.1 -C.sub.3, alkyl (for example a benzyl group) or a 
C.sub.3 -C.sub.8 cycloalkyl group (for example a cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group); 
R.sup.12 represents: hydrogen; a C.sub.1 -C.sub.6, preferably C.sub.1 
-C.sub.4, alkyl group (for example a methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, sec-butyl or t-butyl group); a C.sub.3 -C.sub.8, 
preferably C.sub.3 or C.sub.4, cycloalkyl group (for example a 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group); an 
alkoxyalkyl group, in which the alkoxy part and the alkyl part each have 
from 1 to 6, preferably from 1 to 3, carbon atoms (for example a 
methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, 
1-methoxyethyl or 2-methoxyethyl group); a cyanoalkyl group, in which the 
alkyl part is C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, alkyl (for 
example a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanopropyl or 
1-methyl-2-cyanoethyl group); an alkoxycarbonylalkyl group in which the 
alkoxy part and the alkyl part each have from 1 to 6, preferably from 1 to 
3, carbon atoms (for example a methoxycarbonylmethyl, 
ethoxycarbonylmethyl, 2-methoxycarbonylethyl or 2-ethoxycarbonylpropyl 
group); a C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, haloalkyl group 
(for example a chloromethyl, fluoromethyl, 2-fluoroethyl, 2-fluoropropyl, 
1-methyl-2-fluoroethyl, trifluoromethyl or 2,2,2-trifluoroethyl group); an 
aromatic heterocyclic group having from 4 to 8 ring atoms, of which from 1 
to 3 are hetero atoms selected from the group consisting of nitrogen, 
oxygen and sulfur atoms (for example a pyridyl, preferably 2-pyridyl or 
3-pyridyl, thiazolyl, thienyl or oxazolyl group); or a phenyl group; and 
m is 0, 1, 2 or 3, more preferably 1 or 2 and most preferably 1, and n is 
1, 2 or 3, more preferably 1 or 2 and most preferably 1, provided that 
(m+n) is an integer from 1 to 4. 
The nitrogen-containing heterocyclic groups defined above for R.sup.3 may 
be unsubstituted or may have one or more substituents selected from the 
group consisting of the substituents defined above for attachment to ring 
nitrogen atoms and the substituents defined above for attachment to ring 
carbon atoms. Particularly preferred nitrogen-containing heterocyclic 
groups include the 2-azetidinyl, 3-azetidinyl, 2-pyrrolidinyl, 
3-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-morpholinyl, 
5-thiazolidinyl, 1,4-thiazin-2-yl, hexahydropyrimidin-5-yl and 
hexahydropyridazin-4-yl groups, which may be substituted or unsubstituted. 
More particularly, we prefer compounds in which R.sup.3 represents an 
azetidinyl (more preferably 3-azetidinyl) group or a pyrrolidinyl (more 
preferably 3-pyrrolidinyl) group, which may be unsubstituted or 
substituted as defined above, or a group of formula: 
##STR6## 
in which R.sup.10, R.sup.11, R.sup.12, m and n are as defined above. 
Most preferably, R.sup.3 represents an unsubstituted or substituted 
3-pyrrolidinyl group. 
A preferred class of compounds of the present invention are those in which: 
R.sup.1 represents a methyl, ethyl, hydroxymethyl, methoxymethyl, 
methylthiomethyl, fluoromethyl, chloromethyl, methoxy, methylthio or 
trifluoromethyl group or a fluorine, chlorine or bromine atom; 
R.sup.2 represents a hydrogen, fluorine, chlorine or bromine atom or a 
methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, 
fluoromethyl, chloromethyl or trifluoromethyl group; or 
R.sup.1 and R.sup.2 together with the carbon atom to which they are 
attached form a 3- or 4-membered alicyclic ring; 
R.sup.3 represents a ring-saturated nitrogen-containing heterocyclic group 
having from 4 to 8 ring atoms, and having, in addition to the specified 
nitrogen atom, 0, 1 or 2 additional hetero atoms selected from the group 
consisting of nitrogen, oxygen and sulfur atoms and being unsubstituted or 
having from 1 to 3 substituents selected from the group consisting of (a) 
substituents attached to ring carbon atoms and (b) substituents attached 
to ring nitrogen atoms and (c) substituents attached to ring sulfur atoms: 
(a) C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, alkyl groups, 
particularly the methyl, ethyl, propyl and isopropyl groups; alkoxyalkyl 
groups, in which the alkoxy part and the alkyl part each have from 1 to 6, 
preferably from 1 to 4, carbon atoms, particularly the methoxymethyl, 
ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 
1-methoxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl and 
4-ethoxybutyl groups; cyanoalkyl groups where the alkyl part has from 1 to 
6, preferably from 1 to 4, carbon atoms, particularly the cyanomethyl, 
1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl and 4-cyanobutyl 
groups; C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.3, haloalkyl groups, 
particularly the trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl 
groups; C.sub.1 -C.sub.6, particularly C.sub.1 -C.sub.3, alkoxy groups, 
particularly the methoxy, ethoxy, propoxy and isopropoxy groups; the 
hydroxy group; halogen atoms, particularly the fluorine atom; C.sub.2 
-C.sub.7, particularly C.sub.2 -C.sub.5 and more particularly C.sub.2 
-C.sub.3, aliphatic carboxylic acyloxy groups, particularly the acetoxy 
and propionyloxy groups; C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, 
alkylthio groups, particularly the methylthio, ethylthio, propylthio and 
isopropylthio groups; C.sub.1 -C.sub.6, particularly C.sub.1 -C.sub.4, 
alkylsulfonyl groups, particularly the methylsulfonyl, ethylsulfonyl, 
propylsulfonyl and isopropylsulfonyl groups; C.sub.1 -C.sub.6, 
particularly C.sub.1 -C.sub.4, alkylsulfinyl groups, particularly the 
methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl 
groups; cyano groups; and carbamoyl groups; 
(b) C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, alkyl groups, e.g. the 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, 
pentyl, isopentyl and hexyl groups, particularly the methyl and ethyl 
groups; C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, hydroxyalkyl 
groups, particularly the 2-hydroxyethyl, 3-hydroxypropyl and 
2-hydroxypropyl groups; C.sub.1 -C.sub.6, particularly C.sub.1 -C.sub.3, 
haloalkyl groups, such as the trifluoromethyl, 2-fluoroethyl and 
2,2,2-trifluoroethyl groups; C.sub.1 -C.sub.7 aliphatic acyl groups and 
their amino-acid analogs, such as the formyl, acetyl, propionyl, butyryl, 
isobutyryl, glycyl, alanyl and .beta.-alanyl groups; aromatic-substituted 
aliphatic acyl groups, wherein the aromatic part is a C.sub.6 -C.sub.10 
carbocyclic aryl group and the aliphatic acyl part, which may be saturated 
or unsaturated is a C.sub.2 -C.sub.7 aliphatic carboxylic acyl group, for 
example the phenylacetyl and cinnamoyl groups; the phenacyl group; the 
sulfo group; C.sub.1 -C.sub.6, particularly C.sub.1 -C.sub.4, 
alkylsulfonyl groups, particularly the methylsulfonyl, ethylsulfonyl, 
propylsulfonyl and isopropylsulfonyl groups; groups of formula 
--(R.sup.5)C.dbd.N--R.sup.6, in which R.sup.5 and R.sup.6 are the same or 
different and each represents hydrogen, a C.sub.1 -C.sub.6, preferably 
C.sub.1 -C.sub.3, alkyl group (particularly methyl or ethyl), the phenyl 
group, an aromatic heterocyclic group (particularly a pyridyl or furyl 
group), the methoxymethyl group, the cyanomethyl group, the benzyl group, 
the fluoromethyl group or the chloromethyl group); or the carbamoyl group; 
(c) oxygen atoms; 
or a group of formula: 
##STR7## 
in which: 
R.sup.10 represents hydrogen or methyl; 
R.sup.11 represents hydrogen; a C.sub.1 -C.sub.3 alkyl group (i.e. methyl, 
ethyl, propyl or isopropyl), a C.sub.3 -C.sub.6 cycloalkyl group 
(preferably cyclopropyl or cyclobutyl), an alkoxyalkyl group wherein the 
alkoxy part and the alkyl part both have from 1to 3 carbon atoms 
(particularly methoxymethyl, 1-ethoxyethyl or 2-ethoxyethyl), cyanomethyl, 
chloromethyl, fluoromethyl or benzyl; 
R.sup.12 represents hydrogen, a C.sub.1 -C.sup.3 alkyl group (i.e. methyl, 
ethyl, propyl or isopropyl), a C.sub.3 -C.sub.6 cycloalkyl group 
(preferably cyclopropyl or cyclobutyl), an alkoxyalkyl group wherein the 
alkoxy part and the alkyl part both have from 1 to 3 carbon atoms 
(preferably methoxymethyl or ethoxymethyl), a cyanoalkyl group, wherein 
the alkyl part has from 1 to 3 carbon atoms (preferably cyanomethyl, 
1-cyanoethyl or 2-cyanoethyl), phenyl or an aromatic heterocyclic group 
(preferably 2-pyridyl or 3-pyridyl) and 
m and n are each 1 or 2; 
R.sup.4 represents hydrogen, ethyl, ethyl having at its .alpha.-position a 
substituent selected from the group consisting of: 
hydroxy groups, amino groups, C.sub.1 -C.sub.7 aliphatic acyloxy groups and 
C.sub.1 -C.sub.7 aliphatic acylamino groups; 
(for example .alpha.-hydroxyethyl, .alpha.-acetoxyethyl, 
.alpha.-propionyloxyethyl, .alpha.-butyryloxyethyl, .alpha.-aminoethyl, 
.alpha.-acetamidoethyl, .alpha.-propionamidoethyl or 
.alpha.-butyramidoethyl), isopropyl, isopropyl having at its 
.alpha.-position a substituent selected from the group consisting of: 
hydroxy groups, amino groups, C.sub.1 -C.sub.7 aliphatic acyloxy groups and 
C.sub.1 -C.sub.7 aliphatic acylamino groups; 
(for example 1-hydroxy-1-methylethyl, 1-acetoxy-1-methylethyl, 
1-propionyloxy-1-methylethyl, 1-butyryloxy-1-methylethyl, 
1-amino-1-methylethyl, 1-acetamido-1-methylethyl, 
1-propionamido-1-methylethyl or 1-butyramido-1-methylethyl) or methoxy and 
pivaloyloxymethyl and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters 
thereof and hydrochloric acid addition salts of said esters; and 
sodium and potassium salts thereof. 
The most preferred compounds of the present invention are those in which: 
R.sup.1 represents methyl, ethyl, trifluoromethyl, fluoromethyl, 
chloromethyl, methoxymethyl, methylthio, hydroxymethyl, phenyl, benzyl, 
fluorine, chlorine or bromine; 
R.sup.2 represents hydrogen, methyl, fluorine or chlorine; or 
R.sup.1 and R.sup.2, together with the carbon atom to which they are 
attached, form a cyclopropane ring; 
R.sup.3 represents a 3-pyrrolidinyl or 3-azetidinyl group which is 
unsubstituted or has from 1 to 3 substituents selected from the group 
consisting of (a) substituents on ring carbon atoms and (b) substituents 
on ring nitrogen atoms; 
(a) methyl, methoxy, fluorine, methylthio, methylsulfinyl, methylsulfonyl, 
hydroxymethyl, C.sub.2 -C.sub.7 alkoxycarbonyl, cyano, carbamoyl or 
acyloxymethyl wherein the acyl part is C.sub.1 -C.sub.5 aliphatic acyl; 
(b) formyl, acetyl, glycyl, alanyl, formimidoyl, acetimidoyl, 
propionimidoyl or .alpha.-methoxyacetimidoyl; 
or a 3,4,5,6-tetrahydropyrimidin-5-yl group having at its 3-position 
hydrogen or methyl and having at its 2-position hydrogen, methyl, ethyl, 
isopropyl, methoxymethyl, cyanomethyl, fluoromethyl, pyridyl or benzyl; 
and 
R.sup.4 represents .alpha.-hydroxyethyl. 
The compounds of the present invention can exist in the form of various 
optical isomers and stereoisomers due to the presence of asymmetric carbon 
atoms. Although all of these isomers are represented herein by a single 
formula, it should be understood that the present invention envisages both 
the individual isolated isomers, as well as mixtures of isomers. Preferred 
compounds are those in which the carbon atom at the 5-position is in the 
same configuration as in thienamycin, that is to say the R-configuration. 
In particular, we prefer compounds having the (5R, 6S) or (5R, 6R) 
configuration and, when the group represented by R.sup.4 has a substituent 
at its .alpha.-position (for example a hydroxy, acetoxy, amino or 
acetamido group), the preferred configuration of this group is the 
R-configuration. 
In the preferred compounds of the invention, R.sup.1 represents one of the 
groups defined above, most preferably a methyl group, whilst R.sup.2 
represents a hydrogen atom. In this case, the group, particularly methyl 
group, represented by R.sup.1 is preferably in the R-configuration (also 
known as the ".beta. configuration"). We have found that those compounds 
having a 1-methyl group in the R-configuration have surprisingly superior 
activity. 
Examples of preferred compounds of the invention are given in the following 
list; in this list, the configuration of substituents is not specified and 
each of the compounds given in this list may be in any of the possible 
configurations or may be a mixture of isomers; however, the listed 
compounds are preferably (5R, 6S) or (5R, 6R), more preferably (1R, 5R, 
6S) or (1R, 5R, 6R) and, where R.sup.4 (the group at the 6-position) has 
an .alpha.-substituent, this is preferably in the R-configuration. 
1. 
2-(1-formylazetidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3-c 
arboxylic acid 
2. 
2-(1-formylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylic acid 
3. 
2-(1-formylpiperidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3- 
carboxylic acid 
4. 
2-(1-acetylazetidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3-c 
arboxylic acid 
5. 
2-(1-acetylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylic acid 
6. 
2-(1-acetylpiperidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3- 
carboxylic acid 
7. 
2-(1-glycylazetidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3-c 
arboxylic acid 
8. 
2-(1-glycylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylic acid 
9. 2-[1-(.beta.-alanyl)pyrrolidin-3-ylthio]-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
10. 
2-(1-alanylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylic acid 
11. pivaloyloxymethyl 
2-(1-formylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylate 
12. pivaloyloxymethyl 
2-(1-acetylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylate 
13. pivaloyloxymethyl 
2-(1-glycylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylate 
14. 
6-(1-hydroxyethyl)-1-methyl-2-(pyrrolidin-3-ylthio)carbapen-2-em-3-carboxy 
lic acid 
15. 
6-(1-hydroxyethyl)-2-[1-(2-hydroxyethyl)pyrrolidin-3-ylthio]-1-methylcarba 
pen-2-em-3-carboxylic acid 
16. 
2-[1-(2-fluoroethyl)pyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-1-methylcarbap 
en-2-em-3-carboxylic acid 
17. 6-(1-hydroxyethyl)-1-methyl-2-(1-phenylacetylpyrrolidin- 
3-ylthio)carbapen-2-em-3-carboxylic acid 
18. 
6-(1-hydroxyethyl)-1-methyl-2-(1-sulfopyrrolidin-3-ylthio)carbapen-2-em-3- 
carboxylic acid 
19. 
6-(1-hydroxyethyl)-2-(1-methanesulfonylpyrrolidin-3-ylthio)-1-methylcarbap 
en-2-em-3-carboxylic acid 
20. 
2-(1-carbamoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-e 
m-3-carboxylic acid 
21. 
6-(1-hydroxyethyl)-1-methyl-2-(1-phenacylpyrrolidin-3-ylthio)carbapen-2-em 
-3-carboxylic acid 
22. 
2-(1-formimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2 
-em-3-carboxylic acid 
23. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2 
-em-3-carboxylic acid 
24. 
6-(1-hydroxyethyl)-2-(4-methoxypyrrolidin-3-ylthio)-1-methylcarbapen-2-em- 
3-carboxylic acid 
25. 
2-(1-formyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarba 
pen-2-em-3-carboxylic acid 
26. 2-(1-acetyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
27. 
2-(1-formimidoyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylic acid 
28. 
2-(1-acetimidoyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylic acid 
29. 
6-(1-hydroxyethyl)-1-methyl-2-(5-methylpyrrolidin-3-ylthio)carbapen-2-em-3 
-carboxylic acid 
30. 
2-(1-formyl-5-methylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbap 
en-2-em-3-carboxylic acid 
31. 
2-(1-acetyl-5-methylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbap 
en-2-em-3-carboxylic acid 
32. 
2-(1-acetimidoyl-4-methylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylc 
arbapen-2-em-3-carboxylic acid 
33. 
2-(4-acetoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em- 
3-carboxylic acid 
34. 2-(4-acetoxy-1-acetylpyrrolidin-3-ylthio)-6-( 
1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylic acid 
35. 
2-(1-acetimidoyl-4-acetoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylic acid 
36. 
2-(4-fluoropyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylic acid 
37. 
2-(1-acetyl-4-fluoropyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbap 
en-2-em-3-carboxylic acid 
38. 
2-(1-acetimidoyl-4-fluoropyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylc 
arbapen-2-em-3-carboxylic acid 
39. 
6-(1-hydroxyethyl)-1-methyl-2-(4-methylthiopyrrolidin-3-ylthio)carbapen-2- 
em-3-carboxylic acid 
40. 
2-(1-acetyl-4-methylthiopyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylca 
rbapen-2-em-3-carboxylic acid 
41. 
2-(1-acetimidoyl-4-methylthiopyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-met 
hylcarbapen-2-em-3-carboxylic acid 
42. 
6-(1-hydroxyethyl)-2-(4-methanesulfinylpyrrolidin-3-ylthio)-1-methylcarbap 
en-2-em-3-carboxylic acid 
43. 
2-(1-acetyl-4-methanesulfinylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-met 
hylcarbapen-2-em-3-carboxylic acid 
44. 
2-(1-acetimidoyl-4-methanesulfinylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
45. 
6-(1-hydroxyethyl)-2-(4-methanesulfonylpyrrolidin-3-ylthio)-1-methylcarbap 
en-2-em-3-carboxylic acid 
46. 
2-(1-acetyl-4-methanesulfonylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-met 
hylcarbapen-2-em-3-carboxylic acid 
47. 
2-(1-acetimidoyl-4-methanesulfonylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
48. 
6-(1-hydroxyethyl)-2-(4-hydroxypyrrolidin-3-ylthio)-1-methylcarbapen-2-em- 
3-carboxylic acid 
49. 
2-(1-acetyl-4-hydroxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarba 
pen-2-em-3-carboxylic acid 
50. 
2-(1-acetimidoyl-4-hydroxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylic acid 
51. pivaloyloxymethyl 
2-(1-acetyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarba 
pen-2-em-3-carboxylate 
52. pivaloyloxymethyl 
2-(1-acetimidoyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylate 
53. pivaloyloxymethyl 
6-(1-hydroxyethyl)-1-methyl-2-(pyrrolidin-3-ylthio)carbapen-2-em-3-carboxy 
late 
54. pivaloyloxymethyl 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2 
-em-3-carboxylate 
55. pivaloyloxymethyl 
2-(1-acetyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarba 
pen-2-em-3-carboxylate 
56. pivaloyloxymethyl 
2-(1-acetimidoyl-4-methoxypyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methyl 
carbapen-2-em-3-carboxylate 
57. 
2-(1-acetimidoyl-5-chloromethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-m 
ethylcarbapen-2-em-3-carboxylic acid 
58. 
2-(1-acetimidoyl-5-fluoromethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-m 
ethylcarbapen-2-em-3-carboxylic acid 
59. 
2-(5-carbamoyl-1-formimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-meth 
ylcarbapen-2-em-3-carboxylic acid 
60. 
2-(1-formimidoyl-5-methoxycarbonylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
61. 
2-(5-acetoxymethyl-1-formimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1- 
methylcarbapen-2-em-3-carboxylic acid 
62. 
6-(1-hydroxyethyl)-2-(4-methoxypiperidin-3-ylthio)-1-methylcarbapen-2-em-3 
-carboxylic acid 
63. 
2-(1-acetyl-4-methoxypiperidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbap 
en-2-em-3-carboxylic acid 
64. 
6-(1-hydroxyethyl)-2-(4-methoxyperhydroazocin-3-ylthio)-1-methylcarbapen-2 
-em-3-carboxylic acid 
65. 
6-(1-hydroxyethyl)-2-(4-methoxyperhydroazepin-3-ylthio)-1-methylcarbapen-2 
-em-3-carboxylic acid 
66. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2 
-em-3-carboxylate 
67. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 
2-(1-acetylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3 
-carboxylate 
68. 
6-(1-hydroxyethyl)-1-methyl-2-[1-(N-methylformimidoyl)azetidin-3-ylthio]ca 
rbapen-2-em-3-carboxylic acid 
69. 
6-(1-hydroxyethyl)-1-methyl-2-[1-(N-methylacetimidoyl)azetidin-3-ylthio]ca 
rbapen-2-em-3-carboxylic acid 
70. 
6-(1-hydroxyethyl)-1-methyl-2-[1-(N-methylformimidoyl)pyrrolidin-3-ylthio] 
carbapen-2-em-3-carboxylic acid 
71. 
6-(1-hydroxyethyl)-1-methyl-2-[1-(N-methylacetimidoyl)pyrrolidin-3-ylthio] 
carbapen-2-em-3-carboxylic acid 
72. 6-(1-hydroxyethyl)-2-(5-methoxycarbonylpyrrolidin-3-ylthio) 
1-methylcarbapen-2-em-3-carboxylic acid 
73. 
6-(1-hydroxyethyl)-2-(5-hydroxymethylpyrrolidin-3-ylthio)-1-methylcarbapen 
-2-em-3-carboxylic acid 
74. 
2-(5-acetoxymethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen 
-2-em-3-carboxylic acid 
75. 
2-(5-carbamoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-e 
m-3-carboxylic acid 
76. 
2-(1-acetimidoyl-5-methoxycarbonylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
77. 
2-(1-acetimidoyl-5-hydroxymethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1- 
methylcarbapen-2-em-3-carboxylic acid 
78. 
2-(1-acetimidoyl-5-acetoxymethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1- 
methylcarbapen-2-em-3-carboxylic acid 
79. 
2-(1-acetimidoyl-5-carbamoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-meth 
ylcarbapen-2-em-3-carboxylic acid 
80. 
6-(1-hydroxyethyl)-1-methyl-2-(1-propionimidoylpyrrolidin-3-ylthio)carbape 
n-2-em-3-carboxylic acid 
81. 
6-(1-hydroxyethyl)-2-[1-(.alpha.-methoxyacetimidoyl)azetidin-3-ylthio]-1-m 
ethylcarbapen-2-em-3-carboxylic acid 
82. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-trifluoromethylc 
arbapen-2-em-3-carboxylic acid 
83. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1-ethyl-6-(1-hydroxyethyl)carbapen-2- 
em-3-carboxylic acid 
84. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methoxycarbapen- 
2-em-3-carboxylic acid 
85. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylthiocarbap 
en-2-em-3-carboxylic acid 
86. 
6-(1-hydroxyethyl)-2-[1-(.alpha.-fluoroacetimidoyl)azetidin-3-ylthio]-1-me 
thylcarbapen-2-em-3-carboxylic acid 
87. 
6-(1-hydroxyethyl)-1-methyl-2-(3,4,5,6-tetrahydropyrimidin-5-ylthio)carbap 
en-2-em-3-carboxylic acid 
88. 
6-(1-hydroxyethyl)-1-methyl-2-(2-methyl-3,4,5,6-tetrahydropyrimidin-5-ylth 
io)carbapen-2-em-3-carboxylic acid 
89. 
2-(2-ethyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-6-(1-hydroxyethyl)-1-meth 
ylcarbapen-2-em-3-carboxylic acid 
90. 
6-(1-hydroxyethyl)-2-(2-methoxymethyl-3,4,5,6-tetrahydropyrimidin-5-ylthio 
)-1-methylcarbapen-2-em-3-carboxylic acid 
91. 
2-(2-cyanomethyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-6-(1-hydroxyethyl)- 
1-methylcarbapen-2-em-3-carboxylic acid 
92. 
2-(2-benzyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-6-(1-hydroxyethyl)-1-met 
hylcarbapen-2-em-3-carboxylic acid 
93. 
2-(2,3-dimethyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-6-(1-hydroxyethyl)-1 
-methylcarbapen-2-em-3-carboxylic acid 
94. 
6-(1-hydroxyethyl)-2-(2-isopropyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-1- 
methylcarbapen-2-em-3-carboxylic acid 
95. 
6-(1-hydroxyethyl)-2-(2-methoxymethyl-3-methyl-3,4,5,6-tetrahydropyrimidin 
-5-ylthio)-1-methylcarbapen-2-em-3-carboxylic acid 
96. 
2-(2-fluoromethyl-3,4,5,6-tetrahydropyrimidin-5-ylthio)-6-(1-hydroxyethyl) 
-1-methylcarbapen-2-em-3-carboxylic acid 
97. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1,1-dimethylcarbap 
en-2-em-3-carboxylic acid 
98. 
6-(1-hydroxyethyl)-1,1-dimethyl-2-(1-propionimidoylpyrrolidin-3-ylthio)car 
bapen-2-em-3-carboxylic acid 
99. 
6-(1-hydroxyethyl)-2-[1-(.alpha.-methoxyacetimidoyl)pyrrolidin-3-ylthio]-1 
,1-dimethylcarbapen-2-em-3-carboxylic acid 
100. 
2-(1-formimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1,1-dimethylcarbap 
en-2-em-3-carboxylic acid 
101. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1,1-dichloro-6-(1-hydroxyethyl)carbap 
en-2-em-3-carboxylic acid 
102. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1-chloro-6-(1-hydroxyethyl)carbapen-2 
-em-3-carboxylic acid 
103. 
6-(1-hydroxyethyl)-1-methyl-2-(1-nicotinimidoylpyrrolidin-3-ylthio)carbape 
n-2-em-3-carboxylic acid 
104. 6-(1-hydroxyethyl)-1,1-dimethyl-2-(2-methyl 
3,4,5,6-tetrahydropyrimidin-5-ylthio)carbapen-2-em-3-carboxylic acid 
105. 
2-(1-acetimidoylpyrrolidin-3ylthio)-6-(1-hydroxyethyl)-(carbapen-2-em)-1-s 
piro-1'-cyclopropane-3-carboxylic acid 
106. 
6-(1-hydroxyethyl)-1-methyl-2-(1-methylpyrrolidin-3-ylthio)carbapen-2-em-3 
-carboxylic acid 
107. 
2-(1-ethoxycarbonylmethylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylc 
arbapen-2-em-3-carboxylic acid 
108. 
2-(5-carbamoyl-1-methylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-1-methylcar 
bapen-2-em-3-carboxylic acid 
109. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1-fluoro-6-(1-hydroxyethyl)carbapen-2 
-em-3-carboxylic acid 
110. 
6-(1-hydroxyethyl)-1-methoxy-2-(pyrrolidin-3-ylthio)carbapen-2-em-3-carbox 
ylic acid 
111. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1-cyano-6-(1-hydroxyethyl)carbapen-2- 
em-3-carboxylic acid 
112. 1-ethoxycarbonyl-6-(1-hydroxyethyl)-2-(pyrrolidin- 
3-ylthio)carbapen-2-em-3-carboxylic acid 
113. 
2-(1-acetimidoylpyrrolidin-3-ylthio)-1,1-difluoro-6-(1-hydroxyethyl)carbap 
en-2-em-3-carboxylic acid 
114. 
1,1-difluoro-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)carbapen-2-em-3-car 
boxylic acid 
115. p-nitrobenzyl 
6-(1-hydroxyethyl)-1-methyl-2-[1-(N-p-nitrobenzyloxycarbonylacetimidoyl)py 
rrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
116. p-nitrobenzyl 
6-(1-hydroxyethyl)-1-methyl-2-[1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl 
thio]carbapen-2-em-3-carboxylate 
117. p-nitrobenzyl 
2-[5-carbamoyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]-6-(1-hydro 
xyethyl)-1-methylcarbapen-2-em-3-carboxylate 
118. p-nitrobenzyl 
6-(1-hydroxyethyl)-1-methoxy-2-[1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-y 
l]carbapen-2-em-3-carboxylate 
119. p-nitrobenzyl 
6-(1-hydroxyethyl)-1-methoxy-2-[1-(N-p-nitrobenzyloxycarbonylacetimidoyl)p 
yrrolidin-3-ylthio]carbapen- 2-em-3- carboxylate 
120. p-nitrobenzyl 
1-fluoro-6-(1-hydroxyethyl)-2-[1-(N-p-nitrobenzyloxycarbonylacetimidoyl)py 
rrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
121. p-nitrobenzyl 
2-[5-carbamoyl-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidin-3-ylthi 
o]-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3- carboxylate 
122. p-nitrobenzyl 
6-(1-hydroxyethyl)-1,1-dimethyl-2-[1-(p-nitrobenzyloxycarbonyl)pyrrolidin- 
3-ylthio]carbapen-2-em-3-carboxylate 
123. 
6-(1-hydroxyethyl)-1,1-dimethyl-2-pyrrolidin-3-ylthio)carbapen-2-em-3-carb 
oxylic acid 
124. p-nitrobenzyl 
1-methyl-2-[1-(p-nitrobenzyl-oxycarbonyl)pyrrolidin-3-ylthio]-6-[1-(trimet 
hylsilyloxy)ethyl]carbapen-2-em-3-carboxylate 
125. p-nitrobenzyl 
1-methyl-2-{1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio 
}-6-[1-(trimethylsilyloxy)ethyl]carbapen-2-em-3-carboxylate 
126. 2-(1-acetimidoyl-5-cyanopyrrolidin-3-ylthio)-6-C.sub.1 
-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylic acid 
Of the compounds listed above, the preferred compounds are Compounds Nos. 
23 and 79, and particularly those isomers of these Compounds having the 
6-[1(R)-hydroxyethyl] and (5R, 6S) or (5R, 6R) configurations, more 
preferably (1R, 5R, 6S) or (1R, 5R, 6R) configurations, as well as 
pharmaceutically acceptable salts and esters thereof. 
The compounds of the invention may be prepared by: 
(a) reacting a compound of formula (II): 
##STR8## 
(in which R.sup.1a, R.sup.2a R.sup.4a represent any one of the groups or 
atoms defined for R.sup.1, R.sup.2 and R.sup.4, respectively, or any such 
group in which any reactive group is protected, and R.sup.20 represents a 
carboxy group or a protected carboxy group) with a compound of formula 
(IIa) 
EQU R.sup.21 OH (IIa) 
(in which R.sup.21 represents an alkanesulfonyl group, an arylsulfonyl 
group, a dialkylphosphoryl group or a diarylphosphoryl group) or with an 
active derivative (e.g. anhydride or halide) of said compound (IIa), to 
give a compound of formula (III): 
##STR9## 
(in which R.sup.1a, R.sup.2a, R.sup.4a, R.sup.20 and R.sup.21 are as 
defined above); 
(b) reacting said compound of formula (III) with a compound of formula 
(IIIa): 
EQU R.sup.3a SH (IIIa) 
(in which R.sup.3a represents any one of the groups represented by R.sup.3 
or any such group in which any active group is protected) to give a 
compound of formula (IV): 
##STR10## 
(c) reacting said compound of formula (III) with a compound of formula (V): 
##STR11## 
(in which m, n, R.sup.10 and R.sup.11 are as defined above and R.sup.22 
and R.sup.23 are nitrogen-protecting groups) to give a compound of formula 
(VI): 
##STR12## 
(in which R.sup.1a, R.sup.2a, R.sup.4a, R.sup.10, R.sup.11, R.sup.20, 
R.sup.22, R.sup.23, m and n are as defined above): 
(d) removing from said compound of formula (VI) the protecting groups 
represented by R.sup.22 and R.sup.23 and reacting the product thereof with 
a compound of formula (VIa): 
EQU R.sup.24 O--C(R.sup.12).dbd.NH (VIa) 
(in which R.sup.12 is as defined above and R.sup.24 represents an alkyl or 
aralkyl group); to give a compound of formula (XIV): 
##STR13## 
(in which R.sup.1a, R.sup.2a, R.sup.4a, R.sup.10, R.sup.11, R.sup.12, 
R.sup.20, m and n are as defined above: 
(e) if necessary, removing protecting groups from said compounds of 
formulae (IV) and (XIV) to give a compound of formula, respectively, (I) 
or (Ia): 
##STR14## 
(in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10, R.sup.11, 
R.sup.12, m and n are as defined above) 
or an ester thereof; and 
(f) if necessary, salifying or esterifying said compound of formula (I) or 
(Ia). 
Alternatively, the compounds of the invention may be prepared by the 
following process: 
(a) reacting a compound of formula (VIII): 
##STR15## 
(in which R.sup.4a is as defined above, R.sup.25 represents an aliphatic 
acyloxy group, preferably an acetoxy group, and R.sup.26 represents a 
leaving group, preferably a trimethylxilyl group) with a compound of 
formula (VIII): 
##STR16## 
(in which R.sup.1a and R.sup.2a are as defined above and R.sup.27 
represents a leaving group, preferably a trimethylsilyl group), to give a 
compound of formula (IX): 
##STR17## 
(in which R.sup.1a, R.sup.2a, R.sup.4a and R.sup.26 are as defined above): 
(b) reacting said compound of formula (IX) first with water and then with a 
hydrogenating agent (preferably hydrogen in the presence of a 
hydrogenation catalyst, such as palladium-on-charcoal) to give a compound 
of formula (X): 
##STR18## 
(in which R.sup.1a, R.sup.2a and R.sup.4a are as defined above): 
(c) reacting said compound of formula (X) with a compound of formula 
(IIIa): 
EQU R.sup.3a --SH (IIIa) 
(in which R.sup.3a is as defined above) or with an active derivative, such 
as an alkali metal salt thereof, to give a compound of formula (XI): 
##STR19## 
(in which R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a are as defined above): 
(d) reacting said compound of formula (XI) with an oxalic acid derivative 
of formula (XIa): 
EQU R.sup.20 --C(.dbd.O)--Hal (XIa) 
(in which R.sup.20 is as defined above and Hal represents a halogen atom, 
preferably a chlorine atom) to give a compound of formula (XII): 
##STR20## 
(in which R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a and R.sup.20 are as 
defined above): 
(e) reacting said compound of formula (XII) with a compound of formula 
(XIIa): 
EQU P(R.sup.27).sub.3 (XIIa) 
(in which R.sup.27 represents an alkoxy group, preferably a C.sub.1 
-C.sub.6 alkoxy group, an aralkoxy group, in which the aryl part is 
preferably a C.sub.6 -C.sub.10 carbocyclic aryl group which is 
unsubstituted or has one or more substituents selected from the group 
consisting of the substituents listed above as possible substituents on 
carbon atoms, a dialkylamino group, in which each alkyl part has from 1 to 
6 carbon atoms, or a diarylamino group, in which each aryl part is a 
C.sub.6 -C.sub.10 carbocyclic aryl group which is unsubstituted or has one 
or more substituents selected from the group consisting of those 
substituents listed above as possible substituents on ring carbon atoms) 
to give a compound of formula (XIII): 
##STR21## 
(in which R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a and R.sup.27 are as 
defined above): 
(f) cyclizing said compound of formula (XIII) to give a compound of formula 
(IV): 
##STR22## 
(in which R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a and R.sup.20 are as 
defined above); 
(g) if necessary, removing protecting groups from said compound of formula 
(IV); 
(h) if necessary, salifying or esterifying the product of step (f) or (g). 
Preparation of the compounds of the invention is described in more detail 
in the following Methods. 
METHOD A 
In this Method, compounds of formula (I) are prepared as illustrated in the 
following reaction scheme: 
##STR23## 
In the above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.1a, 
R.sup.2a, R.sup.3a, R.sup.4a, R.sup.20 and R.sup.21 are as defined above. 
R.sup.4a represents any one of the groups or atoms represented by R.sup.4 
or any such group in which any active group is protected. In particular, 
R.sup.4a preferably represents a hydrogen atom, a C.sub.1 -C.sub.6 alkyl 
group or a group of formula R.sup.30 A-- (in which R.sup.30 represents a 
hydroxy group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy 
group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio 
group, an alkylthio group, an acylamino group or an aralkylamino group; 
and A represents a C.sub.1 -C.sub.6 alkylene group optionally having a 
trifluoromethyl or phenyl substituent). 
Where any of the substituents on the compound of formula (II) is or 
includes a hydroxy, mercapto, amino or carboxy group, such groups may be 
left unprotected, but are preferably protected prior to carrying out any 
other reactions; such protection has no significance in the overall 
reaction scheme, in that protecting groups are normally removed at the end 
of the reaction sequence, but does have the substantial practical 
advantage that it improves overall yields by reducing the possibility of 
side-reactions. Accordingly, the nature of the protecting groups employed 
is in no way critical to the present invention and a very wide range of 
protecting groups may be used, the nature of such protecting groups being 
dependent on the nature of the group which it is intended to protect. Such 
protecting groups are extremely well-known to those skilled in this art 
and require no specific definition here. However, examples of suitable 
protecting groups are discussed hereafter in relation to step A3, where 
the protecting groups are removed. 
In step A1 of this reaction scheme, the compound of formula (II) is reacted 
with a compound of formula (IIa): 
EQU R.sup.21 OH (IIa) 
(in which R.sup.21 is as defined above). R.sup.21 is preferably a C.sub.1 
-C.sub.6 alkanesulfonyl group, a benzenesulfonyl, naphthalenesulfonyl or 
p-toluenesulfonyl group, a dialkylphosphoryl group in which each alkyl 
part has from 1 to 6 carbon atoms or a diarylphosphoryl group in which 
each aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl group, preferably 
phenyl or naphthyl. However, the nature of the group represented by 
R.sup.21 is of no overall significance in the process of the invention, in 
that this group is removed in the course of the reactions and plays no 
part in the final product. 
Instead of using the compound of formula (IIa) as such, it is possible to 
employ an active derivative of such a compound. Suitable active 
derivatives include anhydrides and halides, particularly chlorides. In 
particular, we prefer to employ an anhydrous alkanesulfonic acid, an 
anhydrous arylsulfonic acid, a dialkylphosphoryl halide or a 
diarylphosphoryl halide. Preferred alkanesulfonic acids include 
methanesulfonic acid and ethanesulfonic acid. Preferred arylsulfonic acids 
include benzenesulfonic acid and p-toluenesulfonic acid. Preferred 
dialkylphosphoryl halides include dimethylphosphoryl chloride and 
diethylphosphoryl chloride. Preferred diarylphosphoryl halides include 
diphenylphosphoryl chloride and diphenylphosphoryl bromide. In particular, 
we prefer to employ anhydrous p-toluenesulfonic acid or diphenylphosphoryl 
chloride. 
The reaction is preferably effected in the presence of a base, the nature 
of which is not critical, provided that it has no adverse effect on the 
reaction or upon the reagents, in particular the .beta.-lactam ring. 
Preferred bases are organic bases, particularly triethylamine, 
diisopropylethylamine and 4-dimethylaminopyridine. 
The reaction is preferably effected in the presence of a solvent, the 
nature of which is likewise not critical, provided that it has no adverse 
effect upon the reaction. Suitable solvents include: halogenated 
hydrocarbons, such as methylene chloride, 1,2-dichloroethane and 
chloroform; nitriles, such as acetonitrile; and amides, such as 
dimethylformamide or dimethylacetamide. 
The reaction may be carried out over a wide range of temperatures, the 
reaction temperature not being critical, but we prefer to employ a 
relatively low temperature, in order to reduce or control side reactions. 
Accordingly, we prefer to employ a temperature of from -20.degree. C. to 
40.degree. C. The time required for the reaction will vary depending upon 
many factors, but particularly on the reaction temperature and the nature 
of the reagents; however, a period of from 10 minutes to 5 hours will 
normally suffice. 
The resulting compound of formula (III) is then reacted in step A2 with a 
mercaptan of formula (IIIa): 
EQU R.sup.3a SH (IIIa) 
(in which R.sup.3a is as defined above), preferably without intermediate 
isolation of the compound of formula (III). This reaction, like the 
reaction in step A1, is preferably effected in the presence of a base, the 
nature of which is not critical, provided that it does not adversely 
affect the reaction or adversely affect the reagents, particularly the 
.beta.-lactam ring. Suitable bases include: organic amines, such as 
triethylamine or diisopropylethylamine; and inorganic bases, particularly 
alkali metal carbonates, such as sodium carbonate or potassium carbonate. 
The reaction temperature is not critical, but, in order to reduce or 
control side reactions, a relatively low temperature is preferably 
employed. A suitable temperature is from -20.degree. C. to room 
temperature. The time required for the reaction will vary depending upon 
many factors, but primarily upon the reaction temperature and the nature 
of the reagents. However, a period of from 30 minutes to 8 hours will 
normally suffice. 
After completion of the above reactions, the resulting product of formula 
(IV) may, if desired, be recovered from the reaction mixture by 
conventional means. For example, one suitable recovery procedure 
comprises: distilling the reaction solvent from the reaction mixture; 
adding a water-immiscible organic solvent to the residue; washing the 
mixture with water and, if necessary, drying it; and distilling off the 
solvent to give the desired product. If necessary, the resulting product 
may be further purified by a variety of conventional means adapted to the 
precise nature of the product; suitable further purification techniques 
include recrystallization, reprecipitation and the various chromatographic 
techniques, for example column chromatography or preparative thin layer 
chromatography. 
Step A3 of the reaction scheme is optional and involves a variety of 
possible reactions, any one or more of which may be employed, in any 
suitable order, if desired. 
Thus, if the compound of formula (IV) obtained as described above contains 
a carboxy-protecting group, for example if the group represented by 
R.sup.20 is a protected carboxy group, the carboxy-protecting group may be 
removed to leave a free carboxy group; the reactions employed to do this 
are conventional and depend upon the nature of the protecting group. 
If the protecting group is removable by reduction, for example if it is a 
haloalkyl group, an aralkyl group or a benzhydryl group, it may be removed 
by contact with a reducing agent. In the case of haloalkyl groups, such as 
the 2,2-dibromoethyl or 2,2,2-trichloroethyl groups, the preferred 
reducing agent is a combination of zinc with acetic acid. If the 
protecting group is an aralkyl group (such as a benzyl or p-nitrobenzyl 
group) or a benzhydryl group, we prefer that the reduction should be 
either: catalytic reduction using hydrogen and a suitable catalyst, such 
as platinum- or palladium-on-charcoal; or reduction with an alkali metal 
sulfide, such as sodium sulfide or potassium sulfide. Whatever the 
reduction technique, the reduction process is preferably effected in the 
presence of a solvent, the nature of which is not critical, provided that 
it has no adverse effect upon the reaction. Suitable solvents include: 
alcohols, such as methanol or ethanol; ethers, such as tetrahydrofuran or 
dioxane; fatty acids, such as acetic acid; or a mixture of one or more of 
these organic solvents with water. The reaction may be carried out over a 
wide temperature range, although we generally find it convenient to carry 
out the reaction at a temperature in the range from 0.degree. C. to room 
temperature. The time required for the reaction will vary, depending upon 
the nature of the starting materials and reducing agents, as well as upon 
the reaction temperature, but a period of from 5 minutes to 12 hours will 
normally suffice. 
After completion of the reaction, the desired compound, which will contain 
a free carboxy group, may be recovered by conventional means from the 
reaction mixture. For example, a suitable recovery technique comprises: 
separating off any insolubles; washing the organic solvent layer with 
water and, if necessary, drying it; and then distilling off the solvent to 
give the desired product. This may, if necessary, be further purified by 
conventional means, for example recrystallization or the various 
chromatography techniques, such as preparative thin layer chromatography 
or column chromatography. 
If the group represented by R.sup.4a in the compound of formula (IV) 
contains an acyloxy group, a trialkylsilyloxy group, an acylamino group or 
an aralkylamino group, the protecting groups may, if desired, be removed 
by conventional means, as described below, to restore a hydroxy group or 
an amino group. Removal of these hydroxy-protecting or amino-protecting 
groups may be carried out prior to, simultaneously with or after removal 
of any carboxy-protecting group in a protected carboxy group represented 
by R.sup.20. 
For example, if the protecting group, for example any such group in the 
group represented by R.sup.4a, is a lower (e.g. C.sub.1 -C.sub.7) 
aliphatic acyloxy group, such as an acetoxy group, this may be removed by 
treating the corresponding compound with a base in the presence of an 
aqueous solvent. The nature of the solvent is not critical and any such 
solvent commonly used for hydrolysis reactions may be employed. However, 
we normally prefer to use water or a mixture of water with an organic 
solvent, such as an alcohol (e.g. methanol, ethanol or propanol) or an 
ether (e.g. tetrahydrofuran or dioxane). The nature of the base is also 
not critical to the process, provided that it does not adversely affect 
any other part of the compound, notably the .beta.-lactam ring; preferred 
bases are alkali metal carbonates, such as sodium carbonate or potassium 
carbonate. The reaction temperature is not critical, but we normally 
prefer to employ a temperature of from 0.degree. C. to about room 
temperature, in order to reduce or control side reactions. The time 
required for the reaction will vary, depending upon many factors, 
including the nature of the starting materials and the reaction 
temperature, but a period of from 1 to 6 hours will normally suffice. 
If the hydroxy-protecting group is an aralkyloxycarbonyl group (such as a 
benzyloxycarbonyl or p-nitrobenzyloxycarbonyl group), this may be 
eliminated to restore a free hydroxy group by contacting the compound with 
a reducing agent. The nature of the reducing agent and the reaction 
conditions are precisely the same as those employed for removing a 
carboxy-protecting group where this carboxy-protecting group is an aralkyl 
group; accordingly, if the compound contains both an aralkyloxycarbonyl 
group (as hydroxy-protecting group) and an aralkyl group (as 
carboxy-protecting group), these will be removed simultaneously. 
Similarly, the same reaction can be employed to remove amino-protecting 
groups, where these are aralkyloxycarbonyl groups (such as 
benzyloxycarbonyl or p-nitrobenzyloxycarbonyl groups), aralkyl groups or 
benzhydryl groups, to restore a free amino group. 
Where the compound contains a trialkylsilyloxy group in which each alkyl 
group has from 1 to 6 carbon atoms (for example a t-butyldimethylsilyloxy 
group) as a protected hydroxy group, the protecting group may be 
eliminated by treating the compound with tetrabutylammonium fluoride. The 
reaction is preferably effected in the presence of a solvent, the nature 
of which is not critical, provided that it has no adverse effect upon the 
reaction; suitable solvents include ethers such as tetrahydrofuran or 
dioxane. The reaction is preferably effected at about room temperature and 
the period required for the reaction, which will vary depending upon the 
reagents and reaction temperature, will normally be from 10 to 18 hours. 
If the compound of formula (IV) contains a haloacetyl group (such as a 
trifluoroacetyl or trichloroacetyl group) as a hydroxy-protecting or 
amino-protecting group, this may be eliminated by treating the compound 
with a base in the presence of an aqueous solvent. The nature of the bases 
and the reaction conditions are the same as are employed for removal of 
lower aliphatic acyl groups when employed as hydroxy-protecting groups in 
the group represented by R.sup.4a. 
Also at this stage, where R.sup.3 in the resulting compound of formula (I) 
or R.sup.3a in the compound (IV) represents a heterocyclic group having a 
ring nitrogen atom attached to a hydrogen atom, this hydrogen atom may be 
replaced by an imidoyl group of formula: 
EQU --(R.sup.5)C.dbd.N--R.sup.6 
(in which R.sup.5 and R.sup.6 are as defined above). This may be achieved 
by reacting the corresponding compound of formula (I) or (IV) with an 
imidoester of formula (XV): 
EQU R.sup.31 O--C(R.sup.5).dbd.N--R.sup.6 
(in which R.sup.5 and R.sup.6 are as defined above and R.sup.31 represents 
a C.sub.1 -C.sub.6 alkyl group, preferably a methyl, ethyl, propyl or 
isopropyl group). 
The reaction is preferably effected in the presence of a solvent, the 
nature of which is not critical, provided that it has no adverse effect 
upon the reaction. A suitable solvent is an aqueous phosphate buffer 
solution whose composition is such as to maintain a pH value of about 8. 
Although the reaction will take place over a wide range of temperatures, 
in order to reduce or control side reactions, we prefer to employ a 
relatively low temperature, for example a temperature of from 0.degree. C. 
to about room temperature. The time required for the reaction will vary, 
depending upon many factors, including the nature of the reagents and the 
reaction temperature, but a period of from 10 minutes to 2 hours will 
normally suffice. 
After completion of this reaction, the desired product may be recovered 
from the reaction mixture by conventional means and, if necessary, further 
purified by such conventional techniques as recrystallization, preparative 
thin layer chromatography and column chromatography. 
Where the compound of formula (IV) or (I) obtained as described above 
contains a heterocyclic group having a ring nitrogen atom attached to a 
hydrogen atom, this hydrogen atom may be replaced by an acyl group by 
reacting the compound of formula (IV) or (I) with a carboxylic acid 
corresponding to the acyl group which it is desired to introduce or with 
an active derivative of such a carboxylic acid, for example the acid 
halide, acid anhydride or active ester. Suitable acid halides include acid 
chlorides (such as acetyl chloride or propionyl chloride). Suitable acid 
anhydrides include carboxylic acid anhydrides (such as acetic anhydride) 
or mixed acid anhydrides (for example those of a carboxylic acid with 
ethyl chloroformate). Suitable active esters include, for example, the 
p-nitrobenzyl ester, the 2,4,5-trichlorophenyl ester, the cyanomethyl 
ester, the N-phthaloylimido ester and the N-hydroxysuccinimido ester of 
the carboxylic acid. 
If the carboxylic acid itself is employed, we prefer that the reaction 
should be carried out in the presence of a dehydrating agent (such as 
dicyclohexylcarbodiimide or carbonyldiimidazole) or of a Vilsmeyer reagent 
(prepared from dimethylformamide and phosphorous oxychloride or thionyl 
chloride). 
The reaction between the compound of formula (IV) or (I) and one of the 
above-mentioned acylating agents is preferably effected either in a 
suitable buffer solution (for example a phosphate buffer solution 
formulated to maintain a pH value of from 8.0 to 8.5) or in the presence 
of an inert organic solvent and a base. Where an organic solvent is 
employed, the nature of the solvent is not critical, provided that it has 
no adverse effect upon the reaction. Suitable solvents include: 
halogenated hydrocarbons, such as methylene chloride, 1,2-dichloroethane 
or chloroform; nitriles, such as acetonitrile; ethers, such as diethyl 
ether, tetrahydrofuran or dioxane; and amides, such as dimethylformamide 
or dimethylacetamide. The nature of the base is likewise not critical, 
provided that it does not have any adverse effect upon other parts of the 
molecule and most notably on the .beta.-lactam ring; organic bases are 
preferred, for example triethylamine, diisopropylethylamine, pyridine or 
2,6-lutidine. 
The reaction may be carried out over a wide range of temperatures and hence 
the reaction temperature is not critical; however, in order to reduce or 
control side reactions, a relatively low temperature is preferred, for 
example a temperature from -20.degree. C. to about room temperature. The 
time required for the reaction will vary, depending upon many factors, but 
particularly on the reaction temperature and the nature of the reagents; 
however, a period of from 10 minutes to 5 hours will normally suffice. 
After completion of the reactions described above, the desired product may 
be recovered from the reaction mixture by conventional means. For example, 
when the reaction is carried out in a buffer solution, the desired product 
is preferably separated by column chromatography, for example through a 
column of Diaion (trade mark) HP-20AG (a product of Mitsubishi Chemical 
Industries Co Ltd). On the other hand, if the compound is obtained by 
reaction in an organic solvent, the solution is washed with water (if 
necessary, after transferring the product into solution in a 
water-immiscible organic solvent), the solution is, if necessary, dried, 
and then the solvent is distilled off to give the desired product. This 
product may, if necessary, be further purified by conventional techniques, 
for example by recrystallization, reprecipitation or the various 
chromatography techniques, such as preparative thin layer chromatography 
or column chromatography. 
METHOD B 
Compounds of formula (I) in which R.sup.3 represents a 
tetrahydropyrimidinyl or similar group, that is to say compounds of 
formula (Ia) may be prepared as illustrated in the following reaction 
scheme: 
##STR24## 
In the above formulae, R.sup.1, R.sup.2, R.sup.4, R.sup.1a, R.sup.2a, 
R.sup.4a, R.sup.10, R.sup.11, R.sup.12, R.sup.20, R.sup.21, R.sup.22, 
R.sup.23, m and n are as defined above. Examples of amino-protecting 
groups which may be represented by R.sup.22 and R.sup.23 include the 
aralkyloxycarbonyl groups (e.g. the benzyloxycarbonyl or 
p-nitrobenzyloxycarbonyl groups), the benzhydryloxycarbonyl group, 
aryloxycarbonyl groups, aralkyl groups, the benzhydryl group and 
haloacetyl groups (such as the trifluoroacetyl or trichloroacetyl groups). 
The compound of formula (III), shown as the starting material in this 
reaction scheme, may be, and preferably is, prepared as described in step 
A1 of Method A. 
In step B1 of this reaction, the compound of formula (III) and the 
mercaptan of formula (V) are reacted together to give the compound of 
formula (VI). This reaction is precisely the same as the reaction employed 
in step A2 of Method A and may be carried out using the same solvents and 
under the same conditions. 
Step B2 of this reaction scheme comprises first eliminating the 
amino-protecting groups represented by R.sup.22 and R.sup.23 and then 
reacting the resulting diamino compound with an imino ether to give the 
compound of formula (XIV). 
Removal of the amino-protecting groups may be carried out by conventional 
means: the precise nature of the reaction depending upon the nature of the 
protecting group. For example, where the protecting group is an 
aralkyloxycarbonyl group (e.g. benzyloxycarbonyl or 
p-nitrobenzyloxycarbonyl), it may be removed by catalytic reduction, using 
hydrogen and a catalyst, such as platinum or palladium-on-charcoal; under 
these conditions, hydroxy-protecting groups, amino-protecting groups or 
carboxy-protecting groups in the groups represented by R.sup.4a, R.sup.1a, 
R.sup.2a, and R.sup.20 may occasionally also be eliminated. The product of 
this reaction is preferably then reacted with an imino ether of formula 
(VIa): 
EQU R.sup.24 O--C(R.sup.12).dbd.NH (VIa) 
(in which R.sup.12 and R.sup.24 are as defined above), preferably without 
intermediate isolation. The reaction is preferably effected in the 
presence of a suitable solvent, for example a phosphate buffer solution 
having a composition such as to maintain a pH value of about 8.0. The 
reaction is preferably effected at relatively low temperature, for example 
from 0.degree. C. to about room temperature and the time required for this 
reaction will normally vary from 10 minutes to 2 hours. 
After completion of the reaction, the desired product of formula (XIV) may 
be recovered from the reaction mixture by conventional means and, if 
necessary, further purified by such conventional techniques as 
recrystallization, preparative thin layer chromatography or column 
chromatography. 
In step B3, which is an optional step, protecting groups may be removed and 
other reactions may be carried out, as illustrated in relation to the 
corresponding reaction in step A3. 
METHOD C 
As an alternative to Methods A and B, compounds of the invention may be 
prepared by the method illustrated by the following reaction scheme. 
##STR25## 
In the above formulae, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.20, 
R.sup.25, R.sup.26 and R.sup.27 are as defined above. 
In step C1 of this reaction scheme, the compound of formula (VII) is 
reacted with a compound of formula (VIII), to give a compound of formula 
(IX). This compound of formula (IX) is reacted in step C2 first with water 
and then with hydrogen in the presence of a catalyst, for example 
palladium-on-charcoal, to give the compound of formula (X). If any of the 
groups represented by R.sup.1a, R.sup.2a or R.sup.4a contains a protecting 
group removable by reduction, then this may be removed during this step. 
In step C3, the compound of formula (X) is reacted with a mercaptan of 
formula R.sup.3a SH, to give the compound of formula (XI). This reaction 
is precisely the same as the corresponding reaction in step A2 and may be 
carried out using the same reagents and under the same conditions. 
The compound of formula (XI) is then reacted in step C4 with an oxalyl 
halide derivative of formula (XIa): 
EQU R.sup.20.CO.Hal (XIa) 
to give the compound of formula (XII). 
This compound of formula (XII) is reacted, in step C5, with a phosphorus 
compound of formula P(R.sup.27).sub.3. Particularly preferred phosphorus 
compounds are the trialkyl phosphites, of which triethyl phosphite, 
tripropyl phosphite and triisopropyl phosphite are the most preferred. 
This reaction is preferably effected in the presence of an inert solvent, 
for example: an aliphatic or aromatic hydrocarbon, such as hexane, 
benzene, toluene or xylene; a halogenated hydrocarbon, such as chloroform, 
methylene chloride or 1,2-dichloroethane; an ester, such as ethyl acetate; 
an ether, such as tetrahydrofuran or dioxane; a nitrile, such as 
acetonitrile; or an amide, such as dimethylformamide. 
The reaction of step C5 is preferably effected with heating, for example at 
a temperature within the range from 50.degree. to 150.degree. C. The time 
required for the reaction will vary depending upon many factors, including 
the nature of the reagents and the reaction temperature, but a period of 
from 1 to 10 hours will normally suffice. At the end of this time, the 
solvent and other substances are distilled off under reduced pressure, 
giving the compound of formula (XIII). Depending upon the reaction 
temperature and the time allowed for the reaction, the compound of formula 
(XIII) may already have undergone cyclization to convert some or all of 
that compound into the compound of formula (IV). Thus, if the reaction in 
step C5 was carried out at a temperature within the range of from 
80.degree. to 150.degree. C. for a period of from 10 hours to 5 days, 
without isolation of the compound of formula (XIII), the compound (IV) is 
obtained directly. If, however, the compound has not undergone 
cyclization, then it is preferably heated, e.g. at a temperature within 
the range from 80.degree. to 150.degree. C. for a period of from 10 hours 
to 5 days, to give the desired compound of formula (IV) as step C6. 
If desired, the resulting compound of formula (IV) may be subjected to any 
of the reactions heretofore described in step A3 of Method A to give the 
compound of formula (I) or a salt or ester thereof. 
The compounds obtained by any of the above Methods may, if desired, be 
salified and/or esterified by conventional means, to give salts and/or 
esters thereof, examples of such salts and esters being given previously. 
Some of the compounds of formula (I) have, in themselves, outstanding 
antibacterial activity, whilst others, although generally exhibiting some 
antibacterial activity, are of more value as intermediates for the 
preparation of other compounds having good antibacterial activity. Those 
compounds having antibacterial activity exhibit this effect against a wide 
range of pathogenic microorganisms, including both gram-positive bacteria 
(such as Staphylococcus aureus and Bacillus subtilis) and gram-negative 
bacteria (such as Escherichia coli, Shigella flexneri, Klebsiella 
pneumoniae, Proteus vulgaris, Serratia species e.g. Serratia marcescens, 
Enterobacter species e.g. Enterobacter cloacae, Salmonella enteritidis and 
pseudomonas aeruginosa) and are thus useful for the treatment of diseases 
caused by such microorganisms. 
Certain of the compounds of the invention were investigated for their 
activities against various microorganisms. The compounds tested were: 
A: 
(5R)-6(S)-[1(R)-hydroxyethyl]-1(R)-methyl-2-[(3S)-pyrrolidin-3-ylthio]carb 
apen-2-em-3-carboxylic acid; 
B: 
(5R)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6(S)-[1(R)-hydroxyethyl]-1( 
R)-methylcarbapen-2-em-3-carboxylic acid; 
C: 
(5R)-2-[(3S)-5(S)-carbamoylpyrrolidin-3-ylthio]-6(S)-[1(R)-hydroxyethyl]-1 
(R)-methylcarbapen-2-em-3-carboxylic acid; and 
D: thienamycin. 
The activities of the test compounds of the invention, identified by the 
letters assigned to them above, against various bacteria are shown in the 
following Table, in terms of their minimal inhibitory concentrations 
(.mu.g/ml). 
______________________________________ 
Compound No. 
Microorganism 
A B C D 
______________________________________ 
Staphylococcus 
.ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
aureus 209P 
Staphylococcus 
.ltoreq.0.01 
.ltoreq.0.01 
0.02 .ltoreq.0.01 
aureus 56 
Escherichia .ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
0.1 
coli NIHJ 
Escherichia .ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
0.1 
coli 609 
Shigella .ltoreq.0.01 
0.02 .ltoreq.0.01 
0.1 
flexneri 2a 
Pseudomonas 0.8 6.2 0.8 6.2 
aeruginosa 
Klebsiella .ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
0.1 
pneumoniae 806 
Klebsiella .ltoreq.0.01 
.ltoreq.0.01 
.ltoreq.0.01 
0.1 
pneumoniae 846 
Proteus 0.4 0.2 0.05 3.1 
vulgaris 
Salmonella 0.02 .ltoreq.0.01 
.ltoreq.0.01 
0.2 
enteritidis G. 
Serratia 0.02 0.02 .ltoreq.0.01 
-- 
marcescens 
Enterobacter 0.2 0.2 0.1 -- 
cloacae 
______________________________________ 
As can be seen from the above Table, the activities of the compounds of the 
invention, in the in vitro test, are comparable with or better than the 
activities of the known compound, thienamycin and are also generally 
better than the compounds of U.S. Ser. No. 407,914. However, as already 
noted, the compounds of the invention show much greater stability in the 
body than does thienamycin and thus the compounds of the invention exhibit 
much better activities than thienamycin when tested in vivo. 
It is well known in the art that compounds having a low minimal inhibitory 
concentration, and which are, as a result, expected to be valuable in 
chemotherapy, sometimes fail to show a good antibacterial effect when they 
are administered to humans or other animals. This may be due to various 
causes, for example chemical or physiological instability of the 
compounds, poor distribution of the compounds in the body or binding of 
the compounds to blood serum. The compounds of the invention, however, do 
not seem to exhibit such problems and thus are expected to show a 
remarkable in vivo activity. 
The compounds of the invention may be administered either orally or 
parenterally for the treatment of diseases in humans and other animals 
caused by pathogenic microorganisms. The compounds may be formulated into 
any conventional forms for administration. For example, for oral 
administration, suitable formulations include tablets, granules, capsules, 
powders and syrups, whilst formulations for parenteral administration 
include injectable solutions for intramuscular or, more preferably 
intravenous, injection. 
The compounds of the invention are preferably administered parenterally, 
particularly in the form of an intravenous injection. 
The dose of the compound of the invention will vary, depending upon the 
age, body weight and condition of the patient, as well as upon the form 
and times of administration. However, in general the adult daily dose is 
from 200 to 3000 mg of the compound, which may be administered in a single 
dose or in divided doses. 
The preparation of compounds of the invention is further illustrated by the 
following Examples. 
EXAMPLE 1 
p-Nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3R)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 115) 
0.174 ml of diisopropyl(ethyl)amine and 0.245 ml of diphenylphosphoryl 
chloride were added, under a nitrogen atmosphere and with ice-cooling, to 
5 ml of an acetonitrile solution containing 363 mg of p-nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate. 
The mixture was stirred for 2 hours at the same temperature, and then a 
further 0.2 ml of diisopropyl(ethyl)amine and 330 mg of 
3(R)-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were 
added to the mixture, which was then stirred for one hour. The reaction 
mixture was then diluted with ethyl acetate, washed with water and with a 
saturated aqueous solution of sodium chloride and dried over anhydrous 
magnesium sulfate. The solvent was then distilled off. The resulting 
residue was then subjected to chromatography through a short column packed 
with silica gel to remove impurities, giving 450 mg of the title compound 
as an oily substance which had partly crystallized. 
Nuclear Magnetic Resonance Spectrum 
(60 MHz, CDCl.sub.3 +sufficient CD.sub.3 OD to dissolve the test compound) 
.delta. ppm: 
1.3 (3H, doublet); 
1.4 (3H, doublet); 
1.8-2.4 (3H, multiplet); 
2.3 (3H, singlet); 
3.0-4.3 (8H, multiplet); 
5.15 (2H, singlet); 
5.32 (2H, AB); 
7.3, 8.1 (A.sub.2 B.sub.2); 
7.5, 8.1 (A.sub.2 B.sub.2). 
EXAMPLE 2 
(1S,5R,6S)-2-[(3R)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]- 
1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 23) 
80 ml of water and 1.6 g of 10% w/w palladium-on-carbon were added to 50 ml 
of a tetrahydrofuran solution containing 450 mg of p-nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3R)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (obtained 
as described in Example 1) and the mixture was stirred for 2 hours in a 
hydrogen atmosphere. The catalyst was filtered off, the tetrahydrofuran 
was distilled off under reduced pressure and the residue was washed with 
ethyl acetate. The aqueous layer was condensed by evaporation under 
reduced pressure to a volume of approximately 50 ml, and then subjected to 
column chromatography using Diaion CHP-20P (a trade name for a product of 
Mitsubishi Chemical Industries). 62 mg of the desired compound were 
obtained from the fraction eluted with 5% v/v aqueous acetone. 
Nuclear Magnetic Resonance Spectrum (90 MHz, D.sub.2 O) .delta. ppm: 
1.02 (3H, doublet); 
1.06 (3H, doublet); 
2.03 (3H, singlet); 
1.8-2.3 (2H, multiplet); 
3.0-4.2 (9H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1760, 1675. 
EXAMPLE 3 
p-Nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 115) 
The procedure described in Example 1 was repeated, but using 365 mg of 
p-nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate 
and 390 mg of 
3(S)-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine, to 
give 360 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 
1.3 (3H, doublet); 
1.4 (3H, doublet); 
2.29 (3H, singlet); 
1.6-2.5 (3H, multiplet); 
2.9-4.5 (8H, multiplet); 
5.21 (2H, singlet); 
5.28, 5.44 (2H, AB); 
7.59, 8.20 (4H, A.sub.2 B.sub.2); 
7.67, 8.24 (4H, A.sub.2 B.sub.2). 
EXAMPLE 4 
(1S,5R,6S)-2-[(3S)-1-Acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]- 
1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 23) 
The catalytic hydrogenation process described in Example 2 was repeated, 
but using 360 mg of p-nitrobenzyl 
(1S,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (obtained 
as described in Example 3), to give 60 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
1.09 (3H, doublet, J=6.4 Hz); 
1.16 (3H, doublet, J=6.8 Hz); 
1.7-2.0 (1H, multiplet); 
2.07, 2.08 (each 1.5H, singlet); 
2.1-2.3 (1H, multiplet); 
3.1-3.95 (8H, multiplet); 
4.0-4.2 (1H, multiplet). 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
289 (4790). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1760, 1675. 
EXAMPLE 5 
p-Nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3R)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 115) 
The procedure described in Example 1 was repeated, but using 363 mg of 
p-nitrobenzyl (1R,5R,6S)-6-[1(R)-hydroxyethyl]-1 
methyl-2-oxocarbapenam-3-carboxylate and 430 mg of 
3(R)-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine, to 
give 430 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl.sub.3 +sufficient 
CD.sub.3 OD to dissolve the compound) .delta. ppm: 
1.3 (3H, doublet); 
1.4 (3H, doublet); 
1.8-2.4 (3H, multiplet); 
2.3 (3H, singlet); 
3.0-4.3 (8H, multiplet); 
5.20 (2H, singlet); 
5.35 (2H, AB); 
7.5, 8.2 (4H, A.sub.2 B.sub.2); 
7.6, 8.2 (4H, A.sub.2 B.sub.2). 
EXAMPLE 6 
(1R,5R,6S)-2-[(3R)-1-Acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]- 
1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 23) 
The catalytic hydrogenation process described in Example 2 was repeated, 
but using 430 mg of p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3R)-1-(N-p-nitrobenzyloxycar 
bonylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (prepared 
as described in Example 5), to give 110 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
1.04 (3H, doublet, J=6.8 Hz); 
1.10 (3H, doublet, J=6.4 Hz); 
1.85-2.05 (1H, multiplet); 
2.08 (1.5H, singlet); 
2.09 (1.5H, singlet); 
2.2-2.35 (1H, multiplet); 
3.2-3.75 (6H, multiplet); 
3.8-3.95 (1H, multiplet); 
4.0-4.25 (2H, multiplet). 
Ultraviolet Absorption Spectrum (H.sub.2 O) .nu..sub.max nm(.epsilon.): 
298 (7960). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1760, 1675. 
EXAMPLE 7 
p-Nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-1-(p-nitrobenzyloxycarbo 
nyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 116) 
The process described in Example 1 was repeated, but using 1.35 g of 
p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate and 1.43 g 
of 3(S)-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine, to give 1.8 g of 
the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.30 (3H, doublet, J=6 Hz); 
1.38 (3H, doublet, J=6 Hz); 
1.6-2.5 (2H, multiplet); 
3.1-4.4 (10H, multiplet); 
5.17 (1H, doublet, J=15 Hz); 
5.20 (2H, singlet); 
5.52 (1H, doublet, J=15 Hz); 
7.47 (2H, doublet, J=9 Hz); 
7.62 (2H, doublet, J=9 Hz); 
8.20 (4H, doublet, J=9 Hz). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1770, 1705. 
EXAMPLE 8 
(1R,5R,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[(3S)-pyrrolidin-3-ylthio]carba 
pen-2-em-3-carboxylic acid 
(Compound No. 14) 
The catalytic hydrogenation process described in Example 2 was repeated, 
but using 0.8 g of p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-1-(p-nitrobenzyloxycarbo 
nyl)pyrrolidin-3-ylthio)]carbapen-2-em-3-carboxylate (prepared as described 
in Example 7), to give 0.25 g of the title compound. 
Nuclear Magnetic Resonance Spectrum (D.sub.2 O) .delta. ppm: 
1.03 (3H, doublet, J=7 Hz); 
1.10 (3H, doublet, J=6 Hz); 
1.7-1.9 (1H, multiplet); 
2.2-2.4 (1H, multiplet); 
3.0-4.1 (9H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1760, 1590. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
296.8 (8460). 
EXAMPLE 9 
(1R,5R,6S)-2-[(3S)-1-Acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]- 
1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 23) 
100 mg of 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-pyrrolidin-3-ylthio]carb 
apen-2-em-3-carboxylic acid (prepared as described in Example 8) were 
dissolved in 1.2 ml of a phosphate buffer (pH 7.1), and the pH of this 
solution was then adjusted to a value of 8.5 by adding a 1N aqueous 
solution of sodium hydroxide, whilst ice-cooling. 200 mg of ethyl 
acetimidate hydrochloride were added to the resulting solution, and the pH 
of the mixture was again adjusted to a value of 8.5 by adding a 1N aqueous 
solution of sodium hydroxide; the mixture was then stirred for 30 minutes, 
whilst ice-cooling. The pH of this solution was adjusted to a value of 7 
by adding dilute hydrochloric acid, and the mixture was then purified by 
chromatography through a column of Diaion Hp 20 AG. The fraction which was 
eluted with 3% v/v aqueous acetone was lyophilized to yield 102 mg of the 
title compound. 
Nuclear Magnetic Resonance Spectrum (D.sub.2 O) .delta. ppm: 
1.04 (3H, doublet, J=7 Hz); 
1.10 (3H, doublet, J=6 Hz); 
1.8-2.0 (1H, multiplet); 
2.05 (1.5H, singlet); 
2.09 (1.5H, singlet); 
2.2-2.4 (1H, multiplet); 
3.1-4.2 (9H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1755, 1680, 1635, 1590. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
297.2 (8660). 
EXAMPLE 10 
p-Nitrobenzyl 
(1R,5R,6S)-2-[(3S,5S)-5-carbamoyl-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3 
-ylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate 
(Compound No. 117) 
1 g of p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate 
and 898 mg of 
(2S,4S)-2-carbamoyl-4-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine 
were reacted and treated as described in Example 1, to give 385 mg of the 
title compound. 
Nuclear Magnetic Resonance Spectrum (CD.sub.3 COCD.sub.3) .delta. ppm: 
1.25 (6H, doublet, J=7 Hz); 
2.90 (2H, singlet); 
1.7-4.7 (1H); 
5.22 (2H, singlet); 
5.30, 5.48 (2H, AB-quartet, J=14 Hz); 
7.60, 8.13 (2H, AB-quartet, J=8 Hz); 
7.76, 8.20 (2H, AB-quartet, J=8 Hz). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3450, 3350, 1770, 1700. 
EXAMPLE 11 
(1R,5R,6S)-2-[(3S,5S)-5-Carbamoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl] 
-1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 75) 
225 mg of p-nitrobenzyl 
(1R,5R,6S)-2-[(3S,5S)-5-carbamoyl-1-p-nitrobenzyloxycarbonyl)pyrrolidin-3- 
ylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (prepared 
as described in Example 10) were subjected to the catalytic hydrogenation 
procedure described in Example 2, to give 51 mg of the title compound 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
1.02 (3H, doublet, J=7.3 Hz); 
1.10 (3H, doublet, J=6.3 Hz); 
1.62 (1H, multiplet); 
2.55 (1H, multiplet); 
2.85 (1H, quartet); 
3.17-3.25 (2H, multiplet); 
3.56-3.64 (1H, multiplet); 
3.78 (1H, triplet, J=8 Hz); 
4.00-4.10 (2H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3270, 3200, 1750, 1670, 1590. 
EXAMPLE 12 
p-Nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-[(3S)-1-(p-nitrobenzyloxycarbony 
l)pyrrolidin-3-yl]-carbapen-2-em-3-carboxylate 
(Compound No. 118) 
1 g of p-nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-oxocarbapenam-3-carboxylate and 
820 mg of 3(S)-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine were 
reacted and then treated as described in Example 1, to give 392 mg of the 
title compound. 
Nuclear Magnetic Resonance Spectrum (60 MHz, CDCl.sub.3) .delta. ppm: 
1.35 (3H, doublet, J=6 Hz); 
1.8-2.4 (2H, multiplet); 
3.40, 3.45 (together 3H, each singlet); 
3.2-4.4 (9H, multiplet); 
5.18 (2H, singlet); 
5.18, 5.46 (2H, AB, J=14 Hz); 
7.46, 8.13 (4H, A.sub.2 B.sub.2, J=9 Hz); 
7.57, 8.13 (4H, A.sub.2 B.sub.2, J=9 Hz). 
EXAMPLE 13 
(5R,6S)-6-[1(R)-Hydroxyethyl]-1-methoxy-2-[(3S)-pyrrolidin-3-ylthio]carbape 
n-2-em-3-carboxylic acid 
(Compound No. 110) 
150 mg of p-nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-[(3S)-1-(p-nitrobenzyloxycarbony 
l)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (prepared as described in 
Example 12) were subjected to the catalytic hydrogenation procedure 
described in Example 2, to give 13 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
1.04, 1.16 (together 3H, each doublet, J=6.4 Hz); 
1.85-1.95 (2H, multiplet); 
2.2-2.35 (4H, multiplet); 
3.13-3.5 (2H, multiplet); 
3.31 (3H, singlet); 
3.8-3.9 (1H, multiplet); 
4.05, 4.07 (each 1H, doublet, J=3.4 Hz); 
4.08-4.18 (1H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3450, 1765, 1610. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
278 (7320). 
EXAMPLE 14 
p-Nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-[(3S)-1-(N-p-nitrobenzyloxycarbo 
nylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 119) 
270 mg of p-nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-oxocarbapenam-3-carboxylate and 
292 mg of 
3(S)-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were 
reacted and treated as described in Example 1, to give 670 mg of the title 
compound, in an impure form. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.2-1.5 (3H, multiplet); 
2.36 (3H, singlet); 
2.9-3.5 (2H, multiplet); 
3.0-4.4 (9H, multiplet); 
3.47 (3H, singlet); 
5.20, 5.46 (2H, AB, J=13 Hz); 
5.25 (2H, singlet); 
7.4-8.2 (8H, A.sub.2 B.sub.2 .times.2). 
EXAMPLE 15 
(5R,6S)-2-[(3S)-1-Acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1-m 
ethoxycarbapen-2-em-3-carboxylic acid 
(Compound No. 84) 
670 mg of p-nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1-methoxy-2-[(3S)-1-(N-p-nitrobenzyloxycarbo 
nylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (prepared as 
described in Example 14) were subjected to the catalytic hydrogenation 
procedure described in Example 2, to give 74 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
1.13-1.18 (3H, multiplet); 
1.87-2.02 (1H, multiplet); 
2.05, 2.07, 2.09, 3.00 (together 3H, each singlet); 
3.29, 3.31 (together 3H, each singlet); 
3.4-4.15 (9H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3330, 1765, 1675, 1590. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
202.8 (16800), 296.6 (5490). 
EXAMPLE 16 
p-Nitrobenzyl 
(5R,6S)-1-fluoro-6-[1(R)-hydroxyethyl]-2-[(3S)-1-(N-p-nitrobenzyloxycarbon 
ylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 120) 
800 mg of p-nitrobenzyl 
(5R,6S)-1-fluoro-6-[1(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate and 
756 mg of 
3(S)-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were 
reacted together and treated as described in Example 1, to give 1.2 g of 
the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.1-1.3 (3H, multiplet); 
2.25 (3H, singlet); 
2.0-2.3 (2H, multiplet); 
3.0-4.4 (9H, multiplet); 
5.15 (2H, singlet); 
5.22, 5.42 (2H, AB, J=15 Hz); 
7.3-8.3 (8H, A.sub.2 B.sub.2 .times.2). 
EXAMPLE 17 
(5R,6S)-2-[(3S)-1-Acetimidoylpyrrolidin-3-ylthio]-1-fluoro-6-[1(R)-hydroxye 
thyl]carbapen-2-em-3-carboxylate 
(Compound No. 109) 
670 mg of p-nitrobenzyl 
(5R,6S)-1-fluoro-6-[1(R)-hydroxyethyl]-2-[(3S)-1-(N-p-nitrobenzyloxycarbon 
ylacetimidoyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate (prepared as 
described in Example 16) were subjected to the catalytic hydrogenation 
procedure described in Example 2, to give 16 mg of the title compound. 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3250, 1750, 1680. 
EXAMPLE 18 
p-Nitrobenzyl 
(1R,5R,6S)-2-[(3S,5S)-5-carbamoyl-1-(N-p-nitrobenzyloxycarbonylacetimidoyl 
)pyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxy 
late 
(Compound No. 121) 
264 mg of p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate 
and 311 mg of 
(2S,4S)-2-carbamoyl-4-mercapto-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)py 
rrolidine were treated in the same manner as described in Example 1, to 
give 839 mg of the title compound in a crude state. This crude product was 
used without purification in Example 19. 
EXAMPLE 19 
(1R,5R,6S)-2-[(3S,5S)-1-Acetimidoyl-5-carbamoylpyrrolidin-3-ylthio]-6-[1(R) 
-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 79) 
839 mg of the crude product obtained as described in Example 18 were 
treated in the same manner as in Example 2 to give 67 mg of the title 
compound. 
Nuclear Magnetic Resonance Spectrum (270 MHz, D.sub.2 O) .delta. ppm: 
1.00 (3H, doublet, J=6.0 Hz); 
1.09 (3H, doublet, J=6.0 Hz); 
2.06, 2.17 (together 3H, each singlet); 
1.97-2.25 (1H, multiplet); 
2.58-2.86 (2H, multiplet); 
3.06-3.22 (1H, multiplet); 
3.24-3.40 (2H, multiplet); 
3.77-3.94 (2H, multiplet); 
3.94-3.96 (2H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
1755, 1690, 1590. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm: 
298. 
EXAMPLE 20 
p-Nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1,1-dimethyl-2-[(3S)-1-(p-nitrobenzyloxycarb 
onyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 122) 
1 g of p-nitrobenzyl 
(5R,6S)-6-[1(R)-hydroxyethyl]-1,1-dimethyl-2-oxocarbapenam-3-carboxylate 
and 840 mg of 3(S)-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine were 
reacted and treated in the same manner as in Example 1 to give 390 mg of 
the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.08 (3H, doublet, J=5 Hz); 
1.28 (3H, singlet); 
1.33 (3H, doublet, J=4 Hz); 
1.7-2.6 (3H, multiplet); 
3.0-4.5 (8H, multiplet); 
5.15 (2H, singlet); 
5.20, 5.40 (2H, AB-quartet, J=14 Hz); 
7.47, 8.12 (2H, AB-quartet, J=9 Hz); 
7.59, 8.12 (2H, AB-quartet, J=9 Hz). 
EXAMPLE 21 
(5R,6S)-6-[1(R)-Hydroxyethyl]-1,1-dimethyl-2-[(3S)-pyrrolidin-3-ylthio]carb 
apen-2-em-3-carboxylic acid 
(Compound No. 123) 
300 mg of the product obtained as described in Example 20 were treated in 
the same manner as in Example 2 to give 49 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (400 MHz, D.sub.2 O) .delta. ppm: 
0.93 (3H, singlet); 
1.09 (3H, doublet, J=6.3 Hz); 
1.14 (3H, singlet); 
1.82-1.88 (1H, multiplet); 
2.03 (1H, singlet); 
2.16-2.26 (1H, multiplet); 
3.13 (1H, doublet of doublets, J=12.7 & 3.9 Hz); 
3.19-3.24 (1H, multiplet); 
3.27 (1H, doublet of doublets, J=5.9 & 2.9 Hz); 
3.32-3.39 (2H, multiplet); 
3.68 (1H, doublet, J=2.4 Hz); 
3.88-3.95 (1H, multiplet); 
4.03-4.09 (1H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3300, 1765, 1600. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
279 (5750). 
EXAMPLE 22 
(5R,6S)-2-[(3S)-1-Acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-1,1 
-dimethylcarbapen-2-em-3-carboxylic acid 
(Compound No. 97) 
190 mg of 
(5R,6S)-6-[1(R)-hydroxyethyl]-1,1-dimethyl-2-[(3S)-pyrrolidin-3-ylthio]car 
bapen-2-em-3-carboxylic acid (prepared as described in Example 21) and 560 
mg of ethyl acetimidate hydrochloride were reacted in the same manner as 
in Example 9 to give 120 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (90 MHz, D.sub.2 O) .delta. ppm: 
0.92 (3H, singlet); 
1.09 (3H, doublet, J=6.0 Hz); 
1.13 (3H, singlet); 
2.06 (3H, singlet); 
1.56-2.58 (2H, multiplet); 
3.06-4.25 (8H, multiplet). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3350, 3250, 1755, 1670, 1630, 1600. 
Ultraviolet Absorption Spectrum (H.sub.2 O) .lambda..sub.max nm(.epsilon.): 
280 (5250). 
EXAMPLE 23 
(1R,5R,6S) 
6-[1(R)-Hydroxyethyl]-2-(2-methoxymethyl-3,4,5,6-tetrahydropyrimidin-5-ylt 
hio)-1-methylcarbapen-2-em-3-carboxylic acid 
(Compound No. 90) 
(a) 1.0 g of p-nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate 
and 2.0 g of 1,3-bis(p-nitrobenzyloxycarbonylamino)-2-mercaptopropane were 
reacted in the same manner as described in Example 1 to give 1.7 g of 
p-nitrobenzyl 
(1R,5R,6S)-1-methyl-2-[1,3-bis-(p-nitrobenzyloxycarbonylamino)propan-2-ylt 
hio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.3 (6H, doublet); 
2.9-3.8 (7H, multiplet); 
5.1 (4H, singlet); 
5.1, 5.4 (2H, AB-quartet, J=13 Hz); 
7.4, 8.1 (4H, A.sub.2 B.sub.2, J=9 Hz); 
7.5, 8.1 (4H, A.sub.2 B.sub.2, J=9 Hz). 
Infrared Absorption Spectrum (KBr) .delta..sub.max cm.sup.-1 : 
3400, 1770, 1705. 
(b) 0.8 g of the product obtained as described in step (a) above was 
dissolved in 80 ml of tetrahydrofuran, and then 80 ml of a phosphate 
buffer solution (pH 6.0) and 0.45 g of platinum oxide-on-carbon were 
added. The mixture was stirred for 2.5 hours under a hydrogen stream. At 
the end of this time, the catalyst was filtered off and the solvent was 
distilled off at below 20.degree. C. under reduced pressure. The residue 
was extracted twice with ethyl acetate. The aqueous layer was filtered to 
remove insoluble matter. The filtrate was ice-cooled and adjusted to a pH 
value of 8.5 by the addition of an aqueous solution of sodium hydroxide. 
1.7 g of ethyl methoxyacetimidate hydrochloride were then added and the pH 
value of the mixture was again adjusted to 8.5. The mixture was stirred 
for 20 minutes, and then its pH value was adjusted to 7.0 by the addition 
of dilute hydrochloric acid. The mixture was concentrated by evaporation 
under reduced pressure at a temperature below 20.degree. C. to a volume of 
about 70 ml. The concentrate was subjected to column chromatography 
through Diaion CHP-20P and eluted with 10% v/v aqueous acetone. The eluate 
was lyophilized to give 0.1 g of the title compound. 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3350, 1755, 1660, 1580. 
EXAMPLE 24 
p-Nitrobenzyl 
(1R,5R,6S)-1-methyl-2-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthi 
o]-6-[1(R)-(trimethylsilyloxy)ethyl]carbapen-2-em-3-carboxylate 
(Compound No. 124) 
980 .mu.l of triethyl phosphite and 10 mg of hydroquinone were added to a 
solution of 746 mg of 
(3S,4R)-4-{1(R)-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carb 
onylethyl}-1-(p-nitrobenzyloxyoxalyl)-3-[1(R)-(trimethylsilyloxy)ethyl]-2-a 
zetidinone in 50 ml of toluene, and the mixture was refluxed for 1 day. The 
toluene was distilled off and the residue was dissolved in 80 ml of 
xylene. The solution was refluxed for 1 day, after which the solvent was 
distilled off under reduced pressure. The residue was purified by column 
chromatography through silica gel, eluted with a 1:2 by volume mixture of 
cyclohexane and ethyl acetate, to give 415 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
0.10 (9H, singlet); 
1.25 (6H, doublet, J=6 Hz); 
1.7-2.4 (2H, multiplet); 
3.1-4.4 (9H, multiplet); 
5.11 (1H, doublet, J=14 Hz); 
5.15 (2H, singlet); 
5.24 (1H, doublet, J=14 Hz); 
7.43 (2H, doublet, J=9 Hz); 
7.57 (2H, doublet, J=9 Hz); 
8.14 (2H, doublet, J=9 Hz). 
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 
1765, 1700. 
EXAMPLE 25 
p-Nitrobenzyl 
(1R,5R,6S)-1-methyl-2-{(3S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyr 
rolidin-3-ylthio}-6-[1(R)-(trimethylsilyloxy)ethyl]carbapen-2-em-3-carboxyl 
ate 
(Compound No. 125) 
550 mg of 
(3S,4R)-4-{1(R)-[(3S)-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidin- 
3-ylthio]carbonylethyl}-3-[1(R)-(trimethylsilyloxy)ethyl]-2-azetidinone 
were reacted and treated in the same manner as in Example 24 to give 204 
mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
0.12 (9H, singlet); 
1.26 (6H, doublet, J=7 Hz); 
1.7-2.6 (2H, multiplet); 
2.28 (3H, singlet); 
3.0-4.4 (9H, multiplet); 
5.13 (1H, doublet, J=14 Hz); 
5.15 (2H, singlet); 
5.27 (1H, doublet, J=14 Hz); 
7.48 (2H, doublet, J=9 Hz); 
7.58 (2H, doublet, J=9 Hz); 
8.15 (4H, doublet, J=9 Hz). 
EXAMPLE 26 
p-Nitrobenzyl 
(1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[(3S)-1-(p-nitrobenzyloxycarbo 
nyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylate 
(Compound No. 115) 
279 mg of the product obtained as described in Example 24 were dissolved in 
3 ml of acetonitrile, and then a solution of 65 mg of potassium fluoride 
in 1 ml of water was added, followed by 130 .mu.l of acetic acid, and the 
whole mixture was stirred at room temperature for 1 hour. At the end of 
this time, ethyl acetate was added to the reaction mixture, and the whole 
mixture was washed with water. The solvent was removed by evaporation 
under reduced pressure, and then the residue was purified by short column 
chromatography through silica gel, eluted with a 10:1 by volume mixture of 
ethyl acetate and methanol, to give 237 mg of the title compound. 
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 
1.30 (3H, doublet, J=6 Hz); 
1.38 (3H, doublet, J=6 Hz); 
1.6-2.5 (2H, multiplet); 
3.1-4.4 (10H, multiplet); 
5.17 (1H, doublet, J=15 Hz); 
5.20 (2H, singlet); 
5.52 (1H, doublet, J=15 Hz); 
7.47 (2H, doublet, J=9 Hz); 
7.62 (2H, doublet, J=9 Hz); 
8.20 (4H, doublet, J=9 Hz). 
Infrared Absorption Spectrum (KBr) .nu..sub.max cm.sup.-1 : 
3400, 1770, 1705.