BE887886A - Derived from 2-peneme-3-carboxylic acid, their preparation and their therapeutic application. - Google Patents

Description

       

    <EMI ID = 1.1>

  
and their therapeutic application.

  
The present invention relates to a series of new derivatives of 2-penem-3-carboxylic acid, their preparation and their use as antibiotics for the treatment of various diseases caused by both Gram positive and Gram negative bacteria.

  
Penicillins are a well-known class of antibiotics that have found very important use in human and animal therapy for many years.

  
  <EMI ID = 2.1>

  
is the first of the antibiotics to have been used in general therapy, is still widely used today. Chemically speaking, penicillins have in common a beta-lactam structure commonly known by the word "pename" which has the following formula:

  

  <EMI ID = 3.1>


  
However, although penicillins are still an effective weapon in the pharmaceutical arsenal, the development of new strains of pathogenic bacteria, often resistant to penicillin, has made it increasingly necessary to research new types of antibiotics. Recently, some interest has focused on compounds having a "penem" structure, that is to say compounds having a double bond between the carbon atoms located at positions 2 and 3 of the basic penam structure. The penem structure is as follows:

  

  <EMI ID = 4.1>
 

  
These pename and penem structures form the basis of the semi-systematic nomenclature of penicillin derivatives and this nomenclature is generally accepted by specialists in this field, on a global scale, and it is used in this thesis, the system of numbering being that illustrated on the structures above.

  
Among the penem derivatives discovered in recent years, a compound believed to have value

  
  <EMI ID = 5.1>

  

  <EMI ID = 6.1>


  
This compound and its extremely interesting antibiotic activity, in particular with respect to microorganisms resistant to most penicillins, in particular microorganisms of the genus Pseudomonas, is described in French patent application n [deg.] 80 08 137

  
filed on April 11, 1980. However, even if the activity

  
  <EMI ID = 7.1>

  
3-carboxylic is interesting, the Applicant has now found a series of neighboring or related compounds having an antibiotic activity, in particular against Gram negative bacteria, greater than that of this known compound; in addition, a certain number of facts indicate that the acute toxicities of the compounds of the invention are much lower than that of the compound of the prior art.

  
The new 2-penem-3-carboxylic acid derivatives of the present invention are the compounds of formula (I):

  

  <EMI ID = 8.1>


  
in which :

  
  <EMI ID = 9.1>

  
  <EMI ID = 10.1>

  
which R represents a bydroxy group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, a group

  
  <EMI ID = 11.1>

  
  <EMI ID = 12.1>

  
lorr &#65533; ule

  

  <EMI ID = 13.1>


  
  <EMI ID = 14.1>

  

  <EMI ID = 15.1>


  
  <EMI ID = 16.1> or more substituents chosen from aryl, heterocyclic or aralkyl groups, a hydroxy group, a group

  
  <EMI ID = 17.1>

  
eg hydrazino, a hydrazino group comprising one or more substituents chosen, for example, from alkyl groups,

  
  <EMI ID = 18.1>

  
alkoxyamino or a guan.idino group, and A 'represents a bivalent saturated aliphatic hydrocarbon group); and

  
  <EMI ID = 19.1>

  
xy protected.

  
In a neutral medium, the compounds of the invention in which R2 represents a hydrogen atom do not normally exist in the thiol form illustrated by the form

  
  <EMI ID = 20.1>

  
thioketone and correspond to formula (la):

  

  <EMI ID = 21.1>


  
  <EMI ID = 22.1>
  <EMI ID = 23.1>
 in the current one:

  
  <EMI ID = 24.1>

  
  <EMI ID = 25.1>

  
  <EMI ID = 26.1>

  
an alkylaulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, a group

  
  <EMI ID = 27.1>

  
finished above) <EMI ID = 28.1> <EMI ID = 29.1>

  
with a base; <EMI ID = 30.1> <EMI ID = 31.1>

  
  <EMI ID = 32.1>

  

  <EMI ID = 33.1>


  
  <EMI ID = 34.1>

  
  <EMI ID = 35.1>

  
  <EMI ID = 36.1>
  <EMI ID = 37.1>
  <EMI ID = 38.1>
  <EMI ID = 39.1>
(in which: X represents a halogen atom; 2 represents a halogen atom or an alkoxycarbonylo- group

  
  <EMI ID = 40.1>

  
alkyl group, an alkyl group having one or more halogen substituents, an aralkyl group or a group

  
  <EMI ID = 41.1>

  
kyle, an aryl group or an aralkyl group; and A 'has the abovementioned meaning);
(d) halogenating the product of step (c) to obtain a compound of formula (VII) or (VIIa):

  

  <EMI ID = 42.1>


  
  <EMI ID = 43.1>

  

  <EMI ID = 44.1>


  
  <EMI ID = 45.1>

  

  <EMI ID = 46.1>


  
  <EMI ID = 47.1>
  <EMI ID = 48.1>
 respectively;
(e) reacting this compound of formula (VII), (VIIa),

  
(VIII) or (X) with a base, to obtain a compound <EMI ID = 49.1>
  <EMI ID = 50.1>
  <EMI ID = 51.1>

  
formula group

  

  <EMI ID = 52.1>


  
in which A 'and R7' have the abovementioned meanings); or

  
(e ') reacting this compound of formula (VII)

  
with a compound of formula (XIII):

  

  <EMI ID = 53.1>


  
  <EMI ID = 54.1>

  
to give a compound of formula (XIV):

  

  <EMI ID = 55.1>


  
  <EMI ID = 56.1> above); or

  
(e ") reacting this compound of formula (IX) with a

  
compound of formula (XV):

  

  <EMI ID = 57.1>


  
  <EMI ID = 58.1>

  
  <EMI ID = 59.1>

  
alkyl group, an alkyl group having one or more subs-

  
  <EMI ID = 60.1>

  
protected amino or protected carboxy, an aryl group, a heterocyclic group, an aralkyl group, an amino group, an amino group having one or more substituents

  
  <EMI ID = 61.1>

  
hydroxy group, alkoxy group or amidino group, or

  
  <EMI ID = 62.1>

  
are connected, a nitrogen heterocyclic group which optionally contains one or more other hetero atoms) to give a compound of formula (XVI):

(XVI)

  

  <EMI ID = 63.1>


  
  <EMI ID = 64.1>

  
mentioned above); or

  
  <EMI ID = 65.1>

  
hydroxy compound of formula (XVII):

  
  <EMI ID = 66.1>

  
(in which R represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group) in the presence of a base to give a compound of formula (XVIII):

  

  <EMI ID = 67.1>


  
  <EMI ID = 68.1>

  
above);
(f) if necessary, removing the protecting group from any protected group and, if necessary, transforming a hydroxy group represents, by R4 into an acyloxy group,

  
  <EMI ID = 69.1>

  
or an alkylthio group;

  
  <EMI ID = 70.1> <EMI ID = 71.1> i.e. a compound of formula (XII):

  

  <EMI ID = 72.1>


  
before or after removal of the groups protecting the hydroxy groups and / or conversion of the hydroxy group represented by R in step (f), with a compound of formula (XIX):

  

  <EMI ID = 73.1>


  
  <EMI ID = 74.1>

  
eg alkyl, an alkyl group comprising one or more halogen substituents, an aralkyl group, an aryl group, an amino group, an alkylated amino group in which the alkyl group or groups optionally contain one or more substituents chosen from protected hydroxy groups, groups protected amino or protected carboxy groups, a cyclic amino group, an amino group comprising one or more substituents chosen from aryl, heterocyclic, aralkyl groups, a hydrazino group, a hydrazino group comprising one or more substituents chosen from <EMI ID = 75.1>

  
  <EMI ID = 76.1>

  
  <EMI ID = 77.1>

  
  <EMI ID = 78.1>

  
of formula (XX):

  

  <EMI ID = 79.1>


  
  <EMI ID = 80.1> <EMI ID = 81.1> the above-mentioned meanings) and, if necessary, to remove the protecting groups from all protected groups;

  
(h) optionally salifying the product of any preceding step.

  
The invention further provides a pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable diluent carrier, said antibiotic being a compound of formula (I) or a pharmaceutically acceptable salt thereof.

  
We will now give a detailed description of the invention.

  
In the compounds of the invention, when R represents an alkyl group, this can be a straight chain or branched chain group and, preferably, a lower alkyl group, for example a methyl, ethyl, propyl or isopropyl group , butyl, isobutyl, secondary butyl, t-butyl, pentyl or isopentyl. When R represents an alkoxy group, this group may be a straight chain or branched chain alkoxy group and it is preferably a lower alkoxy group, for example

  
a methoxy, ethoxy, propoxy, isopropoxy, butoxy group,

  
  <EMI ID = 82.1>

  
When R represents a group of formula R4A-, <EMI ID = 83.1>

  
or branched chain, preferably an alkoxy 'group

  
  <EMI ID = 84.1>

  
or isopropoxy. When R represents an acyloxy group, it may be a lower aliphatic acyloxy group
(for example an acetoxy, propionyloxy, butyryloxy or iaobutyryloxy group) or an aralkyloxycarbonyloxy group
(for example a benzyloxycarbonyloxy group or a group

  
  <EMI ID = 85.1>

  
alkylsulfonyloxy group, it is preferably a group

  
  <EMI ID = 86.1>

  
nesulfonyloxy, ethanesulfonyloxy or propanesulfonyloxy.

  
  <EMI ID = 87.1>

  
  <EMI ID = 88.1>

  
  <EMI ID = 89.1>

  
the alkyla groups are preferably lower alkyl groups, examples of such groups represented by R

  
  <EMI ID = 90.1>

  
it is preferably a lower alkylthio group, for example

  
  <EMI ID = 91.1>

  
  <EMI ID = 92.1>

  
  <EMI ID = 93.1>

  
Using a saturated aliphatic hydrocarbon group

  
  <EMI ID = 94.1>

  
  <EMI ID = 95.1>

  

  <EMI ID = 96.1>


  
  <EMI ID = 97.1>

  
denier may be a straight chain or branched chain alkyl group which preferably has 1 to 4 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl group.

  
  <EMI ID = 98.1>

  
aralkyl, it can be a benzyl, phenethyl or phenylpropyl group which can, if desired, contain one or more substituents in the aromatic ring. Such substituents include, for example, lower alkyl groups (e.g. methyl, ethyl, propyl or isopropyl groups), alkoxy groups (e.g.

  
  <EMI ID = 99.1>

  
  <EMI ID = 100.1>

  
  <EMI ID = 101.1>

  
  <EMI ID = 102.1>

  
  <EMI ID = 103.1>

  
  <EMI ID = 104.1>

  
  <EMI ID = 105.1>

  
  <EMI ID = 106.1>

  

  <EMI ID = 107.1>


  
and that R7 represents an alkyl group, the latter can be a straight chain or branched chain alkyl group and, preferably, a lower alkyl group, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl group , t-butyl, pentyl or isopentyl. When R7 represents a halogenated alkyl group, this group preferably comprises 1 to 3 halogen substituents, for example chlorine, bromine or fluorine atoms; examples of such halogenated alkyl groups include chloromethyl, 2-bromoethyl, 2-

  
  <EMI ID = 108.1>

  
an aralkyl group, it is preferably a group

  
  <EMI ID = 109.1>

  
tick may have one or more of the following substituents

  
  <EMI ID = 110.1>

  
  <EMI ID = 111.1>

  
When R represents an aryl group, it is preferably

  
  <EMI ID = 112.1> kyle of such alkylated amino groups can themselves be substituted by hydroxy groups ,,

  
protected amino, carboxy or carboxy. Examples of hydroxyalkylated amino groups include:

  
  <EMI ID = 113.1>

  
3-hydroxypropylamino and 4-hydroxybutylamino. As examples of aminoalkylated amino groups, mention may be made of:

  
  <EMI ID = 114.1>

  
4-carboxybutylamino. Examples of protected carboxyalkylated amino groups include groups in which the protecting group is a lower alkoxy group (e.g.

  
  <EMI ID = 115.1>

  
ethylamino and 3-ethoxycarbonylpropylamino) and groups in which the protecting group is an aralkylo- group

  
  <EMI ID = 116.1>

  
mino.

  
  <EMI ID = 117.1>

  
  <EMI ID = 118.1>

  
  <EMI ID = 119.1>

  
  <EMI ID = 120.1>

  
race 3 to 6 nuclear atoms; the cyclical mine group

  
  <EMI ID = 121.1>

  
  <EMI ID = 122.1> <EMI ID = 123.1>

  
propyl); lower alkoxy groups (for example methoxy, ethoxy or propoxy groups); and halogen atoms (for example fluorine, chlorine or bromine atoms).

  
When R7 represents an amino group comprising a heterocyclic substituent, it is preferably

  
  <EMI ID = 124.1>

  
phenylpropylamino, the aromatic nucleus of which may include one or more of the following substituents: lower alkyl groups (for example methyl, ethyl, propyl or isopropyl groups); lower alkoxy groups (for example methoxy, ethoxy, propoxy or isopropoxy groups);

  
and halogen atoms (for example fluorine, chlorine or bromine atoms).

  
  <EMI ID = 125.1>

  
preferably a lower alkoxy group, this group can be straight chain or branched chain. Examples of such alkoxy groups include methoxy, ethoxy, propoxy and isopropoxy groups.

  
When R7 represents an aryloxy group, it is preferably a phenoxy group the aromatic ring of which may contain one or more of the following substituents:
lower alkyl groups (for example methyl, ethyl, propyl or isopropyl groups); lower alkoxy groups (for example methoxy, ethoxy or propoxy groups); and halogen atoms (for example fluorine, chlorine or bromine atoms).

  
  <EMI ID = 126.1>

  
preferably a benzyloxy, phenethyloxy or phenylpropyloxy group which may have one or more of the following substituents in its aromatic ring: lower alkyl groups (for example methyl, ethyl, propyl or isopropyl groups); lower alkoxy groups (for example methoxy, ethoxy, propoxy or isopropoxy groups); nitrc groups; and halogen atoms (for example fluorine, chlorine or bromine atoms).

  
  <EMI ID = 127.1>

  
denier may contain one or more substituents selected from the alkyl, aralkyl or aryl groups. Examples of suitable alkylhydrazino groups include methylhydrazino, ethylhydrazino, propylhydrazino, isopropylhydrazino, N, N-dimethylhydrazino, N, N-diethylhy-

  
  <EMI ID = 128.1>

  
or phenylpropylhydrazino which optionally contain, in their aromatic ring, one or more of the following substituents: lower alkyl groups (for example methyl, ethyl, propyl or isopropyl groups);

  
lower alkoxy groups (for example methoxy, ethoxy, propoxy or isopropoxy groups); and halogen atoms (for example fluorine, chlorine or bromine). In the case of arylhydrazino groups, these are preferably phenylhydrazino groups in which the aromatic nucleus may contain one or more of the following substituents: lower alkyl groups (for example methyl, ethyl, propyl or isopropyl groups); lower alkoxy groups (for example methoxy, ethoxy, propoxy or isopropoxy groups); or halogen atoms
(for example fluorine, chlorine or bromine atoms).

  
When R7 represents an alkoxyamino group, the alkoxy group is preferably a lower alkoxy group and examples of such alkoxyamino groups include methoxyamino, ethoxyamino, propoxyamino or isopropoxyamino groups.

  
A 'represents a bivalent saturated hydrocarbon group and it can be an alkylene or alkylidene group, for example a methylene, ethylene, ethylidene, trimethylene, propylene or propylidene group.

  
  <EMI ID = 129.1>

  
the protecting group is preferably one of the following:
straight or branched chain lower alkyl groups
(for example methyl, ethyl, propyl, isopropyl, butyl t-butyl or isobutyl groups); halogenated lower alkyl groups (for example 2-iodoethyl, 2,2-dibromoethyl or 2,2,2-trichloroethyl); lower alkoxymethyl groups (e.g. methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or isobutoxymethyl); lower aliphatic acyloxymethyl groups (for example acetoxymethyl, propicnyloxymethyl, buty ryloxymethyl, isobutyryloxymethyl or pivaloyloxymethyl groups); groups 1- (alkoxy

  
  <EMI ID = 130.1>

  
thoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl or 1-isobutoxycarbonyloxyethyl); aralkyl groups (e.g. benzyl, E-metho-

  
  <EMI ID = 131.1>

  
benzhydryl; or the phthalidyl group.

  
Preferred compounds are those in which R represents a hydrogen atom, an ethyl group, an ethyl group comprising a substituent chosen from hydroxy, amino, C2-C4 aliphatic acyloxy or acylamino groups

  
  <EMI ID = 132.1>

  
(for example an alpha-hydroxyethyl, alpha-acetoxyethyl, alpha-propionyloxyethyl, alpha-butyryloxyethyl, alpha-aminoethyl, alpha-acetylaminoethyl, alpha-propionylaminoethyl or alpha-butyrylaminoethyl group) or a methoxy group.

  
It is also preferred that R2 is a hydrogen atom

  
or, when it is a group of formula
  <EMI ID = 133.1>
   <EMI ID = 134.1>

  
each represents a lower chain alkyl group

  
  <EMI ID = 135.1>

  
(propyl or isopropyl), an aralkyl group e (for example a benzyl group) or an aryl group (for example

  
  <EMI ID = 136.1>

  
the nitrogen atom to which they are linked represent a 1-pyrrolidinyl, piperidino, 4-hydroxypiperidino, morpholino or 1-piperazinyl group.

  
  <EMI ID = 137.1>

  
represents a group of formula

  

  <EMI ID = 138.1>


  
  <EMI ID = 139.1>

  
straight chain or branched chain (for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or t-butyl group), an amino group, an amino group substituted by one or more groups

  
  <EMI ID = 140.1>

  
substituted by a lower hydroxyalkyl group (for example a hydroxyethylamino, hydroxypropylamino or hydroxybutylamino group), an amino group substituted by a lower aminoalkyl group (for example a 2-aminoethylamino, 3-aminopropylamino or 4-aminobutylamino group), an amino group substituted by a lower carboxyalkyl group (for example a carboxyxnethylamino, carboxyethylamino, 3-carboxypropylamino or 4-carboxybutylamino group), an amino group substituted by a lower alkoxycarbonylalkyl group
(for example a methoxycarbonylmethylamino group, 2-methoxycarhonylethylamino, ethoxycarbonylmethylamino or pro-

  
  <EMI ID = 141.1> <EMI ID = 142.1>

  
dinyl, piperidino, 4-hydroxypiperidino, morpholino or 1-piperazinyl), an arylamino group (for example a

  
  <EMI ID = 143.1>

  
lino), an amino group substituted by a heterocyclic group (for example a 2-pyridylamino, 2-thiazolylamino or 1-methyl-5-tetrazoylamino group), a hydroxy group, a lower alkoxy group (for example a methoxy, ethoxy group, propoxy or isoproposy), a hydrazino group, a hydrazino group substituted by a lower alkyl group (for example a methylhydrazino, ethylhydrazino group, propylhydrazino or isopropylhydrazino), a hydroxyamino group, a lower alkoxyamino group (for example a methoxyamino, ethoxyamino group, propoxyamino or isopropoxyamino) or a guanidino group, and that A 'represents

  
  <EMI ID = 144.1>

  
straight chain or branched chain, comprising 1 to 3 carbon atones, for example a methylene group,

  
  <EMI ID = 145.1>

  
not.

  
  <EMI ID = 146.1>

  
  <EMI ID = 147.1> <EMI ID = 148.1>
  <EMI ID = 149.1>
  <EMI ID = 150.1>

  
  <EMI ID = 151.1>

  
A list of compounds according to the invention is given below, said compounds being identified in the present specification, when necessary, by the numbers assigned to them in this list.

  
1. 2-Thioxopenam-3-carboxylic acid.

  
2. p-nitrobenzyl 2-Thioxopenam-3-carboxylate.

  
  <EMI ID = 152.1>

  
of p-nitrobenzyl.

  
6. 2- (4-hydroxypiperidinocarbonylthio) penem-3carboxylic acid.

  
  <EMI ID = 153.1>

  
than.

  
  <EMI ID = 154.1>

  
  <EMI ID = 155.1>

  
  <EMI ID = 156.1>

  
carboxylic.

  
20. Sodium 2- (3,3,3-trifluoro-2-oxopropylthio) penem-3-carboxylate hydrate.

  
  <EMI ID = 157.1>

  
methyl late.

  
22. 2- (2-oxoethylthio) penetrates methyl -3-carboxylate.

  
  <EMI ID = 158.1>

  
benzyl.

  
24. 2- (2-Oxopentylthio) penem-3-carboxylic acid.

  
  <EMI ID = 159.1>

  
27. 2- (1-Methyl-2-oxopropylthio) penem-3-carboxylic acid.

  
  <EMI ID = 160.1>

  
carboxylic.

  
30. 2-Carbamoylmethylthiopenem-3-carboxylic acid.

  
  <EMI ID = 161.1>

  
  <EMI ID = 162.1>

  
38. 2- (2-Morpholino-2-oxoethylthio) penem-3-carboxylic acid.

  
  <EMI ID = 163.1>

  
carboxylic.

  
43. 2-carboxymethylthiopenem-3-carboxylic acid.

  
  <EMI ID = 164.1> me-3-carboxylic.

  
  <EMI ID = 165.1>

  
me-3-carboxylic.

  
56. 2-carbamoylmethylthio-6-ethylpenem-3-carboxylic acid.

  
  <EMI ID = 166.1>

  
peneme-3-carboxylic.

  
66. 2-hydrazinocarbonylmethylthio-6- (1-hydroxyethyl) penem-3-carboxylic acid.

  
  <EMI ID = 167.1>

  
70. 2- (2-Carbamoylethylthio) -6- (1-hydroxyethyl) penem-3-carboxylic acid.

  
  <EMI ID = 168.1>

  
me-3-carboxylic.

  
72. 2- (1-Carbamoylethylthio) -6-ethylpenem-3-carboxylic acid.

  
  <EMI ID = 169.1>

  
peneme-3-carboxylic.

  
75. 6- (1-t-Butyldimethylsilyloxyethyl) -2- (1-carbamoyl-

  
  <EMI ID = 170.1>

  
77. 2- (1-Carbamoylethylthio) -6- (1-hydroxyethyl) penem-

  
  <EMI ID = 171.1>

  
zyle.

  
80. 27-nitrobenzyl 2-Carbamoylmethylthiopenem-3-carboxylate.

  
81. 2- (N-methylcarbamoylmethylthio) penem-3-carboxylate

  
  <EMI ID = 172.1>

  
  <EMI ID = 173.1>

  
nitrobenzyl.

  
  <EMI ID = 174.1>

  
  <EMI ID = 175.1>

  
of &#65533; -nitrobenzyle.

  
  <EMI ID = 176.1>

  
nitrobenzyl.

  
  <EMI ID = 177.1>

  
97. 6-Methoxy-2- (2-oxopropylthio) penem-3-carboxylate

  
  <EMI ID = 178.1>

  
98. 6- (1-Hydroxyethyl) -2-methoxycarbonylmethylthio-

  
  <EMI ID = 179.1>

  
99. 2- (N-Methylcarbamoylmethylthio) -6-methoxypenem3-2-nitrobenzylcarboxylate.

  
Among these compounds, the compounds Nos 53, 65 and
74 are particularly appreciated, Compound No. 65 being the most interesting of all.

  
The compounds of the invention can exist in various stereoisomeric forms and, although all isomers are represented by a single formula in the description above, the invention includes both individual isomers and mixtures of two or more isomers. Particularly proffered are the compounds which have the configuration (5R, bS) or (5R, 6R) and,

  
  <EMI ID = 180.1>

  
alpha (for example an alpha-hydroxyalkyl, alpha-acetoxyalkyl, alpha-aminoalkyl or alpha-acetamidoalkyl group), it is preferred that the substituent at ^ on the

  
Those of the compounds of the invention where R <3> represents

  
  <EMI ID = 181.1>

  
carboxy group can form salts, in the same way as the usual carboxylic acids. The nature of the salt-forming cation is not critical, although, as is well known in the art, the cation should not render the resulting salt pharmaceutically unacceptable. Suitable salts include metal salts (such as lithium, sodium, potassium, calcium or magnesium salts), ammonium salts and organic amine salts (e.g. cyclohexylammonium, diisopropylammonium salts and triethylammonium). Among these, the sodium and potassium salts are particularly preferred.

  
The compounds of the invention can be prepared by the following methods.

  
Method A

  
  <EMI ID = 182.1>

  
of hydrogen can be prepared according to the following reaction scheme:

  

  <EMI ID = 183.1>
 

  
  <EMI ID = 184.1>

  
Step (a)

  
The first step of method A comprises the reaction of azetidinone (II) with carbon disulfide in the presence of a base and, then, the reaction of the resulting compound with a compound of formula (III):

  

  <EMI ID = 185.1>


  
(in which X represents a halogen atom).

  
The entire reaction is preferably carried out in the presence of a solvent; there is no particular condition as to the nature of the solvent used, provided that it does not have an adverse effect on the reaction. Preferred solvents include ethers (such as tetrahydrofuran or diethyl ether), dialkylamiaes

  
fatty chain (such as dimethylformamide or dimethylacetamide) and mixtures of these organic solvents. The

  
  <EMI ID = 186.1>

  
preferably lithium diisopropylamide or lithium hexamethyldisilazane. The reaction temperature is not critical, although the reaction is preferably carried out at a relatively low temperature, for example from -78 [deg.] C to -20 [deg.] C, to combat reactions

  
  <EMI ID = 187.1>

  
table to carry out the reaction under an inert gas atmosphere, such as nitrogen. The time required for the reaction with the base is generally 5 minutes to 1 hour, the time required for the reaction with carbon disulfide is generally 10 minutes to 2 hours and the time required for the reaction with carbonyl halide (III) is generally 10 minutes to 5 hours.

  
When the reaction is complete, the desired product of formula (XXI) can be extracted from the reaction mixture by conventional means. A suitable recovery process <EMI ID = 188.1>

  
separation of the organic phase; washing the

  
organic phase successively with aqueous sodium bicarbonate and water; the drying of the organic phase; and removing the organic solvent by distillation to obtain the desired product. If desired, the resulting product can be further purified by conventional means, such as recrystallization, thin layer chromatography or column chromatography ...,

  
According to another embodiment, instead of using the carbonyl halide (III), it is possible to use a carboxylic acid dihalide to prepare

  
a compound of formula (XXIa):

  

  <EMI ID = 189.1>


  
  <EMI ID = 190.1>

  
tees and B represents the residue of the dicarboxylic acid dihalide, XCO-B-COX, where X represents a halogen atom). Preferred dicarboxylic acid dihalides

  
are the dimethylmalonyl and phthaloyl dihalides, in particular the dichlorides. The reaction conditions and the subsequent recovery process are carried out only in the case of the use of a carbonyl (III) halide. Step (b)

  
In this step, the compound of formula (XXI) or
(XXIa) is reacted with a halogenating agent to give the compound of formula (VII) or (VIIa).

  
The halogenation reaction is preferably carried out

  
  <EMI ID = 191.1>

  
that it does not have an adverse effect on the reaction.

  
Preferred solvents include methylene chloride, chloroform, carbon tetrachloride and 1,2-dichlorethane. The nature of the halogenating agent is not particularly critical, provided that it does not attack other parts of the molecule. Suitable halogenating agents include chlorine, bromine, sulfuryl chloride and sulfuryl bromide. The reaction temperature is not critical, although relatively low temperatures are preferred in order to combat side reactions, and for this reason it is preferable to conduct the reaction at a temperature of -20 [deg.] C to 'around room temperature.

   The time required for the reaction varies depending on the nature of the starting materials and the reaction temperature, but the reaction is generally complete after 1 minute to 1 hour.

  
  <EMI ID = 192.1>

  
  <EMI ID = 193.1>

  
by usual means, for example simply by distillation of the solvent and any excess reagents. In general, the product can be used as a starting material for the next step without any purification.

  
If desired, the halogen represented by X in

  
the compound of formula (VII) or (VIIa) thus obtained can be converted into another halogen atom by known methods.

  
For example, the chlorinated compound can be transformed into the corresponding brominated or iodinated compound by treating the chlorinated compound with a bromide or an inorganic iodide (for example lithium bromide or potassium iodide) in

  
an organic solvent (for example diethyl ether or acetone).

  
Step (c)

  
In this step, the compound of formula (VII) or (Vlla) is treated with a base to cause the closure of the cycle

  
and thus give the compound of formula (XXII). The cycle closing reaction is preferably carried out in the presence of a solvent, although the nature of the solvent does not

  
is not particularly decisive, provided that it does not have an adverse effect on the reaction. Sol-

  
Suitable lights include: halogenated hydrocarbons

  
  <EMI ID = 194.1>

  
Carbon tetrachloride and 1,2-dichloroethane; alcohols such as methanol, ethanol and propanol; ethers such as diethyl ether, dioxane and

  
tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone and methyl ethyl ketone; dialkylamides

  
with fatty chain such as dimethylformamide and dimethylacetamide; esters such as methyl acetate and ethyl acetate; and mixtures of one or more of said organic solvents with water.

  
A wide variety of bases can be used to facilitate the ring closure reaction and any base capable of reacting with the thiocarbonyl bond, as a nucleophilic agent to remove said bond, can be used. Preferred organic bases include

  
  <EMI ID = 195.1>

  
thylamine; alkali metal alcoholates in alcohols, for example sodium methylate / methanol, sodium ethylate / ethanol and potassium t-butoxide /

  
  <EMI ID = 196.1>

  
moniac, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide and sodium hydroxide.

  
The reaction temperature is not critical and this reaction is preferably carried out at a temperature of -20 [deg.] C up to around ambient temperature. The time required for the reaction depends on the nature of the starting materials and the reaction temperature, but the reaction is normally complete after

  
  <EMI ID = 197.1>

  
When the reaction is complete, the desired product of formula (XXII) can be recovered from the reaction mixture by usual means, depending on the nature of the product and the reaction medium in which it was formed. A suitable recovery process includes: removing the solvent from the reaction by distillation under reduced pressure; diluting the mixture with a water-miscible organic solvent, washing the mixture with water; and separating the solvent by distillation to obtain the desired product.

  
The compound (XXII) thus obtained can, if ne-

  
  <EMI ID = 198.1>

  
example by recrystallization, thin layer chromatography or column chromatography.

  
Step (d)

  
If necessary, the compound of formula (XXII) can be converted into the corresponding free carboxylic acid by conversion of the protected carboxy group R 10 to a free carboxy group by usual means. The reaction required to remove the protective group depends on the nature

  
of this protecting group, but any method known in the art can be used.

  
For example, when the protecting group is a halogenated alkyl group, an aralkyl group or a benzhydryl group, it can be removed by bringing the compound of formula (XXII) into contact with a reducing agent. In the case of halogenated alkyl groups (for example the group

  
  <EMI ID = 199.1>

  
preferred reducing agent is a combination of zinc and acetic acid. In the case of aralkyl groups (e.g. benzyl group or p-nitrobenzyl group) or benzhydryl group, a preferred reducing agent is

  
a catalytic reducing agent (for example palladium on charcoal) in the presence of hydrogen, or an alkali metal sulfide (for example sodium sulfide or potassium sulfide). The reaction is normally carried out in the presence of a solvent, the nature of which is not decisive, provided that it does not have an adverse effect on the reaction. Preferred solvents are 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 temperature normally ranges from 0 [deg.] C to around ambient temperature.

   The time required for the reaction depends on the reactants and the reaction temperature, but the reaction is normally complete after 5 minutes to 12 hours.

  
When the reaction is complete, the product can be recovered from the reaction mixture by usual means, for example by removing the insolubles by filtration, washing the organic solution with water and drying it, and then separating the solvent by distillation. If necessary, the product can be further purified by conventional means such as recrystallization, thin layer chromatography or column chromatography.

  
  <EMI ID = 200.1>

  
formula (XXII) comprises a protected hydroxy group, a protected mercapto group or a protected amino group, the protective group can, if necessary, be removed by

  
  <EMI ID = 201.1>

  
capto or free amino. The regenerated free hydroxy group can then, if necessary, be converted to an acyloxy group, a halogen atom, an azido group, an amino group, an acylamino group or an alkylthio group. These reactions can be carried out before, after or simultaneously with the removal of the protective group from the carboxy group, in R <1> 0

  
  <EMI ID = 202.1>

  
  <EMI ID = 203.1>

  
hydroxy group can be prepared by removing the protecting group from the hydroxy group (eg an acyl group or a trialkylsilyl group) in the compound of formula (XXII). When the protected hydroxy group is a lower aliphatic acyloxy group (e.g. an acetoxy group), the protective group can be removed by treating the corresponding compound with

  
a base in the presence of an aqueous solvent. There is no particular condition as to the solvent and any solvent usually used in hydrolysis can be used. However, very particularly preferred is water or a mixture of water with an organic solvent such as an alcohol (for example methanol, ethanol or propanol) or an ether (for example tetrahydrofuran or dioxane). The base used is also not particularly decisive, provided that it does not affect

  
  <EMI ID = 204.1>

  
yau beta-lactam. Preferred bases are alkali metal carbonates such as sodium carbonate or potassium carbonate. The reaction temperature is not critical, but a temperature is preferred

  
  <EMI ID = 205.1>

  
te, to combat side reactions. The time required for the reaction depends on the nature of the starting materials and the reaction temperature, but the reaction is normally complete after 1 to 6 hours.

  
When the protected hydroxy group is an aralkyloxycarbonyloxy group (for example a benzyloxycar-

  
  <EMI ID = 206.1>

  
protecting group can be removed by bringing the corresponding compound into contact with a reducing agent. Reducing agents and reaction conditions which may

  
  <EMI ID = 207.1>

  
be used for the removal of aralkyl groups

  
  <EMI ID = 208.1>

  
choosing suitable protective groups, it is possible to remove the protective groups simultaneously

  
  <EMI ID = 209.1>

  
When the protected hydroxy group is a tri (lower alkyl) silyloxy group (for example the tbutyldimethylsilyloxy group), the protective group can be removed by treating the corresponding compound with the

  
  <EMI ID = 210.1>

  
the nature of which is not decisive provided that it does not have an adverse effect on the reaction. Suitable solvents are ethers such as tetrahydrofuran or dioxane. The reaction is preferably carried out near room temperature and normally requires 10 to 18 hours.

  
  <EMI ID = 211.1>

  
protected (for example an acylthio group), this can be converted into a mercapto group by removing the protective acyl group. Preferred acylthio groups are lower aliphatic acylthio groups (for example the acethylthio group) and, in this case, the acyl group can be removed by treating the corresponding compound with a base in the presence of an aqueous solvent.

  
The reagents and reaction conditions are the same as those used to remove acyl groups, when an acyl group is used as the protecting group for a hydroxy group.

  
  <EMI ID = 212.1>

  
has an azido group can be obtained by reacting the corresponding compound in which R4 represents a hydroxy group with hydrogen azide or diphenylphosphoric azide in the presence of a phosphine derivative and a dialkyl ester of azodicarboxylic acid. Preferred phosphine derivatives include

  
  <EMI ID = 213.1>

  
dialkyl esters of azodicarboxylic acids include dimethyl azodicarboxylate and diethyl azodicarboxylate. Preferred solvents include: halogenated hydrocarbons such as methylene chloride or chloroform; and ethers such as tetrahydrofuran or dioxane. Temperature

  
  <EMI ID = 214.1>

  
The time required for the reaction is generally 10 minutes to 2 hours.

  
  <EMI ID = 215.1>

  
present, an amino group can be prepared by reducing

  
  <EMI ID = 216.1>

  
feels an azido group. This reduction can be carried out by bringing the azido compound into contact with a reducing agent in the presence of a solvent. The reducing agents which can be used and the reaction conditions are similar to those described for the removal of aralkyl groups which are used as groups. <EMI ID = 217.1>

  
another embodiment, the reduction can be carried out at a temperature ranging from 0 [deg.] C to around room temperature using, as reducing agent, ammonium sulfide or sulfide d 'hydrogen / triethylamine. As a result, it is possible to simultaneously remove the protecting groups

  
  <EMI ID = 218.1>

  
  <EMI ID = 219.1>

  
  <EMI ID = 220.1>

  
represents an aralkyloxycarbonylamino group (for example a benzyloxycarbonylamino group or a p-nitrobenzyloxycarbonylamino group), the same reaction will remove the protective group and convert the group R <1> <2> to an amino group.

  
  <EMI ID = 221.1>

  
has an acyloxy group or an acylamino group can be prepared by acylation of the corresponding compound

  
  <EMI ID = 222.1>

  
an amino group, respectively. This reaction can be carried out by bringing the corresponding hydroxy or amino compound into contact with an acylating agent, in the presence of a solvent. there is no particular condition as to the nature of the solvent to be used, provided that it does not have an adverse effect on the reaction. Preferred solvents are: halogenated hydrocarbons such as chloroform or methylene chloride; and ethers such as tetrahydrofuran or dioxane. There is no special condition as to

  
the nature of the acylating agent to be used and all

  
  <EMI ID = 223.1>

  
tion of hydroxy or amino groups can be employed. Preferred acylating agents include: anhydrous fatty acids such as acetic anhydride or propionic anhydride; and fatty acid halides such as acetyl chloride, propionyl chloride, butyryl bromide, isobutyryl bromide or chloro <EMI ID = 224.1>

  
killed in the presence of a base, for example an organic base

  
  <EMI ID = 225.1>

  
alkali metal of a fatty acid (e.g. sodium acetate or potassium acetate). The reaction temperature is not critical, but it is preferred

  
  <EMI ID = 226.1>

  
up to around room temperature. The time required for the reaction varies depending on the nature of the acylating agent and the reaction temperature, but is usually 0.5 to 5 hours.

  
  <EMI ID = 227.1>

  
an alkylthio group can be prepared by halogenating the corresponding compound (Ib) in which R represents a hydroxy group and then reacting the halogenated compound with an alkali metal salt of an alkyl mercaptan, preferably the sodium or potassium salt . Suitable solvents for this reaction include alcohols such as methanol, ethanol or isopropanol.

  
  <EMI ID = 228.1>

  
room temperature and requires a period of 30 minutes to 5 hours.

  
Method B

  
Compounds of formula (Ib), tautomers of compounds of formula (Ia), can also be prepared by the following reaction scheme:

  

  <EMI ID = 229.1>
 

  
  <EMI ID = 230.1>

  
aforementioned gnifications).

  
Step (a)

  
The first step of process B comprises the reaction of azetidinone (II) with carbon disulfide in the presence of a base and the reaction of the resulting compound with a compound of formula (VI):

  

  <EMI ID = 231.1>


  
1

  
  <EMI ID = 232.1>

  
has the above meaning).

  
The reactions of this step can be carried out by bringing the azetidinone (II) into contact with the base, in the presence of a solvent, by reacting the compound with carbon disulfide and finally reacting the resulting product with the chloride. acyl (VI). The solvents and bases that can be used in this reaction, as well as the reaction temperature, the time required for the reaction

  
and the product recovery method are all similar to those described with regard to the corresponding reactions of step (a) of process A.

  
Step (b)

  
This reaction comprises bringing the compound of formula (XXIII), prepared in step (a), into contact with a halogenating agent. The solvents, reagents and reaction conditions are all similar to those described in step (b) of process A.

  
Step (c)

  
  <EMI ID = 233.1>

  
been prepared in step (b) is treated with a base to close the cycle. The reagents and the reaction conditions are similar to those described in step (c) of method A.

  
Step (d)

  
In this step, if necessary, the protecting groups are removed and, if desired, the hydroxy group represented by R4 in the product of formula (Ib) is transformed into an azido group, an amino group,

  
an acyloxy group, an acylamino group or an alkylthio group. The reagents and reaction conditions are as described in step (d) of method A.

  
Method C

  
Compounds of formula (Ic), i.e.

  
  <EMI ID = 234.1>

  
substituted carbamoyl group, can be prepared by the following reaction scheme:

  

  <EMI ID = 235.1>
 

  
  <EMI ID = 236.1>

  
aforementioned gnifications).

  
Step (a)

  
The first step in this reaction sequence comprises the reaction of the compound of formula (VII),

  
which can be prepared as described in steps (a) and

  
  <EMI ID = 237.1>

  

  <EMI ID = 238.1>


  
  <EMI ID = 239.1>

  
in the presence of a base, to give the compound of formula
(XIV). The solvents, bases, reaction conditions and the method of recovery of the desired product are similar to those described in step (a) of process A.

  
Step (b)

  
In this step, the protecting groups, if necessary, are removed, and the hydroxy group shown

  
  <EMI ID = 240.1>

  
ti to an azido group, an amino group, an acyloxy group, an acylamino group or an alkylthio group, as described

  
  <EMI ID = 241.1>

  
R6 contains a nitrogen atom (for example the nitrogen atom in position 4 of a piperazinyl group represented by R5 and R associated with the nitrogen atom to which they are linked), this group is preferably protected, for example by an acyl group or by an aralkyloxycarbonyl group during

  
  <EMI ID = 242.1>

  
be removed as described in step (d) of method A for the removal of acyl groups on the amino groups pro-

  
  <EMI ID = 243.1>

  
Method D

  
Compounds of formula (Id), i.e.

  
  <EMI ID = 244.1>

  
formula group
  <EMI ID = 245.1>
 can be prepared as illustrated by the following reaction scheme.

  

  <EMI ID = 246.1>
 

  
  <EMI ID = 247.1>

  
meanings given above).

  
Step (a)

  
The first step of this reaction sequence comprises the reaction of azetidinone (II) with carbon disulfide in the presence of a base and then the reaction of the resulting compound with a halogenated ketone of formula (IV):

  

  <EMI ID = 248.1>


  
(in which X represents a halogen atom, of pre-

  
  <EMI ID = 249.1>

  
A 'have the above meanings).

  
The reaction conditions, solvents, bases and recovery techniques are as described in step (a) of process A.

  
  <EMI ID = 250.1>

  
These steps consist, respectively, in the halogenation of the compound of formula (XXV) prepared in step (a)

  
  <EMI ID = 251.1>

  
re cycle this compound of formula (VIII) to obtain a compound of formula (XXVI) and finally, if necessary, removing the protective groups and converting a hydroxy group represented by R in the group represented by

  
  <EMI ID = 252.1>

  
an azido group. an amino group. an acylamino group or an alkylthio group. The reaction conditions used for all these steps are similar to those used for the corresponding step of method A.

  
Process E

  
Compounds of formula (I) in which R <2> represents a group of formula
  <EMI ID = 253.1>
   <EMI ID = 254.1>

  
  <EMI ID = 255.1>

  
  <EMI ID = 256.1>

  
compounds of formula (If) can be prepared as shown in the following reaction scheme:

  

  <EMI ID = 257.1>
 

  
  <EMI ID = 258.1>

  
  <EMI ID = 259.1>

  
  <EMI ID = 260.1>

  
  <EMI ID = 261.1>

  
in which the protecting groups have been removed.

  
Step (a)

  
In this step, the 4-alkylthio-2-azetidinone derivative of formula (II) is reacted with carbon disulfide in the presence of a base (the reactants and the reaction conditions are the same as those described for the corresponding step of process A) and the product is then reacted with a compound of formula (V):

  

  <EMI ID = 262.1>


  
in which . Z represents a halogen atom (for example a chlorine or bromine atom) or an alcohol group &#65533; lower xycarbonyloly (for example a methoxycarbonyloxy, ethoxycarbonyloxy or sec-butoxycarbonyloxy group); X represents a halogen atom (for example an atom

  
chlorine or bromine); and A 'has the above meaning.

  
The reaction conditions, the solvents, etc. used in the reaction with the compound of formula (V) are similar to those used in the corresponding reaction with the carbonyl halide in step
(a) of process A.

  
Step (b)

  
This step involves the halogenation of the compound of formula (XXVII), obtained in step (a), to obtain the corresponding halogenated derivative, of formula (IX). The halogenating agents and the solvents which can be used, as well as the reaction temperatures, the time required for the reaction and the method of recovery of the product are the same as those described in step (b) of process A.

  
  <EMI ID = 263.1>

  
In this step, a compound of formula (XVI) or
(XVIII) is obtained by reacting the compound of formula (IX), prepared in step (b), with a compound of formula (XV):

  

  <EMI ID = 264.1>


  
  <EMI ID = 265.1>

  
tees) or with a compound of formula (XVII):

  

  <EMI ID = 266.1>


  
(in which R has the abovementioned meaning). This reaction is carried out in the presence of a base. The reagents, the solvents, the reaction conditions and the method of recovery of the product are similar to those described with regard to step (c) of method A.

  
  <EMI ID = 267.1>

  
Finally, if desired, the protecting groups can be removed from the compounds of formula (XVI) and (XVIII), to obtain the desired compounds of formula
(le) and (If). The reagents, the reaction conditions and the methods for recovering the final products are as described with regard to step (d) of process A.

  
Method F

  
Compounds of formula (I) in which R <2> represents a group of formula

  

  <EMI ID = 268.1>


  
that is to say compounds of formula (Ig), can be prepared as illustrated by the following reaction scheme:

  

  <EMI ID = 269.1>


  
  <EMI ID = 270.1>

  
  <EMI ID = 271.1>

  
  <EMI ID = 272.1>

  
Step (a)

  
In this step, the compound of formula (XIIa), which could have been prepared as described in step (c) of method A, optionally after having removed the protective groups from group R, is reacted with an agent for alkylation of formula (XIX):

  

  <EMI ID = 273.1>


  
  <EMI ID = 274.1>

  
and Y represents a halogen atom (in particular a chlorine, bromine or iodine atom), an alkylsulfonyloxy group (in particular a methanesulfonyloxy group or

  
  <EMI ID = 275.1>

  
(in particular a benzenesulfonyloxy group or a p-toluenesulfonyloxy group).

  
The reaction is preferably carried out in the presence of a base and a solvent. There is no condition <EMI ID = 276.1>

  
since it does not have an adverse effect on the reaction,

  
  <EMI ID = 277.1>

  
logenes such as chloroform, methylene chloride or ethylene dichloride; ketones such as acetone or methyl ethyl ketone; ethers such as diethyl ether, tetrahydrofuran or dioxane;

  
aromatic hydrocarbons such as benzene or toluene; nitriles such as acetonitrile; esters such as ethyl formate or ethyl acetate; alcohols such as methanol or ethanol; amides such as dimethylformamide or dimethylacetamide;

  
dimethyl sulfoxide; nitromethane; or a mixture of two or more of the above solvents or a mixture of one or more of these solvents with water. There is no particular condition as to the nature of the base used in this reaction, provided that it does not

  
  <EMI ID = 278.1>

  
molecule, especially the beta-lactam nucleus. Preferred bases are acid coupling agents, in particular: organic bases such as triethylamine, py-

  
  <EMI ID = 279.1>

  
alkali metal bicarbonates such as sodium bicarbonate; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; and alkali metal hydrides such as hy-

  
  <EMI ID = 280.1>

  
Another way of carrying out this reaction consists in reacting the compound of formula (XIIa) with a silver salt of tetrafluoroboric acid, of acid

  
  <EMI ID = 281.1>

  
of an organic base, such as those illustrated above and then subjecting the resulting compound to alkylation with the alkylating agent of formula (XIX).

  
The reaction temperature is not critical although it is preferred to carry out the reaction at temperatures

  
  <EMI ID = 282.1>

  
is preferably from -10 [deg.] C to +100 [deg.] C. The time required for the reaction depends mainly on the reaction temperature and the nature of the starting material, but, in general, the reaction is complete after a time ranging from several minutes to 100 hours.

  
When the reaction is complete, the desired product of formula (XX) can be recovered from the reaction mixture by conventional means. A suitable recovery sequence includes: diluting the reaction mixture with an organic solvent immiscible with water;

  
washing the mixture with water; and separating the solvent by distillation to obtain the desired product.

  
If necessary, this product can be further purified by usual means, for example by recrystallization,

  
  <EMI ID = 283.1>

  
When the compound of formula (XX) prepared as described above is the 5S isomer, it can be easily converted to the corresponding 5R isomer by heating in an organic solvent such as toluene, xylene, dimethylformamide or dimethylacetamide .

  
Step (b)

  
In this step, if necessary, the protective groups are removed. The kidnapping reactions which,

  
  <EMI ID = 284.1>

  
can all be performed as described for the corresponding protecting groups in step
(d) of method A. Recovery of the desired compound from the resulting reaction mixture can also be carried out as described in step (d) of method A.

  
When the compound of formula (I), prepared as described by one of the above methods, comprises, in its group represented by R in formula (I), a secondary alcohol group (that is to say that R represents an alkyl group substituted by a hydroxy group), the configuration of the hydroxy group can, if necessary, be altered by reactions well known in the field of

  
  <EMI ID = 285.1>

  
  <EMI ID = 286.1>

  
droxyethyl of configuration S is treated with an organic acid in the presence of a phosphine derivative (such as

  
triphenylphosphine) and an azodicarboxylic acid diester (such as diethyl azodicarboxylate), it

  
it is possible to obtain the corresponding compound of formula (Ia) in which R <1> represents a 1-acyloxyethyl group of configuration R, the substituent in position 1

  
of the side chain of position 6 having been, in other words, reversed. Preferred organic acids include: lower fatty acids such as formic acid, acetic acid or propionic acid; aromatic carboxylic acids such as benzoic acid; and aralkanolic acids such as phenylacetic acid. The solvent used Pt the reaction conditions are similar to those described in step (d) above of method A, as regards the acylation reaction. The acyloxy compound thus obtained can then be converted

  
into various derivatives (including, if desired, the corresponding hydroxy compound) by combining various reactions described in step (d) of process A. When

  
these reactions are completed, the desired compound obtained in each step can be recovered by usual means, for example by removing the solvent by distillation under reduced pressure, having added water and an organic solvent immiscible with water to the residue , separating the organic layer and washing it with water, drying the resulting organic solution on a dehydrating agent and finally distilling the solvent out of this organic solution, to obtain the desired product which, if necessary, can be further purified by conventional means such as recrystallization, thin layer chromatography or column chromatography.

  
When the compound of formula (I) prepared by any of the above methods comprises a free carboxy group, for example when R <3> represents a carboxy group, it can be converted into a pharmaceutically acceptable salt, in particular one of the salts illustrated above, by methods well known in the art.

  
The 4-alkylthio-2-azetidinone compounds of formula
(II) which represent the starting substances used in most of the methods described above, can be synthesized by various routes, including those illustrated by methods G, H and I below.

  
Process G

  
The process of T. Kobayashi, Y. Twano and K. Hirai of Chem. Pharm. Bull., 26, 1761 (1978) can be summarized by the following equation:
  <EMI ID = 287.1>
  <EMI ID = 288.1> aforementioned meanings. By carrying out the process described in the aforementioned article, it is only possible to obtain, with very low yields, the compound of

  
  <EMI ID = 289.1>

  
trobenzyloxycarbonyl. However, this compound can be obtained, in higher yields, by reacting the compound of formula (XXVIII) with a [pound] -nitrobenzyl ester of a halogenated acetic acid, in the presence of powdered potassium hydroxide and a solvent consisting of a. ether, for example tetrahydrofuran.

  
Process H

  
Another route for the preparation of compounds

  
of formula (il) is illustrated by the following reaction scheme:

  

  <EMI ID = 290.1>


  
  <EMI ID = 291.1>

  
the above meanings.

  
In the first step of this reaction sequence, the compound of formula (XXVIII), which is a known compound, is reacted with an ester of glyoxylic acid, of formula (XXXI):

  
  <EMI ID = 292.1>

  
  <EMI ID = 293.1>

  
This reaction can be carried out by usual methods in the presence of a suitable solvent.

  
The second step of this reaction sequence comprises the reaction of the compound of formula (XXIX) thus obtained with a halogenating agent in the presence of a base. The halogenating agent used can be any of those usually used for the halogenation of azetidin-2-one derivatives.

  
The third step in this reaction involves reducing the compound of formula (XXX) to obtain the

  
  <EMI ID = 294.1>

  
be carried out by bringing the compound of formula (XXX) into contact with a reducing agent, in the presence of a solvent. There is no particular condition as to the nature of the solvent used, provided that it does not have an adverse effect on the reaction, preferred solvents being fatty chain dialkylamides (such as dimer

  
  <EMI ID = 295.1>

  
phosphoramide. Preferred reducing agents are boron compounds, such as sodium cyanoborohydride. When, in the compound of formula (XXX), X represents chlorine or bromine, the reduction can be favored by the presence of an inorganic iodine compound such as sodium iodide or potassium iodide. The reaction temperature is not critical and this reaction is normally carried out at a temperature of 0 [deg.] C to 100 [deg.] C. The time required for the reaction depends

  
the nature of the starting materials and the solvents, as well as the reaction temperature, but this reaction is normally complete after 10 minutes

  
at 10 o'clock.

  
When the reaction is complete, the desired compound of formula (II) can be recovered from the reaction mixture by conventional means. For example, the reaction mixture can be poured into melting ice and the precipitating compound can be collected by filtration. According to another embodiment, the mixture can be diluted with water and a non-target organic solvent in water (such as ethyl acetate), after which the organic layer is separated, washed with water and dried over a dehydrating agent, the solvent then being removed by evaporation to obtain the desired compound. The compound thus obtained can, if necessary. be purified by usual means, for example by recrystallization, thin layer chromatography or column chromatography.

  
Method I

  
  <EMI ID = 296.1>

  
illustrated by the following reaction scheme:

  

  <EMI ID = 297.1>


  
  <EMI ID = 298.1>

  
  <EMI ID = 299.1>

  
lower alkyl group.

  
The first step of this reaction scheme comprises reacting the compound of formula (XXXII) with an alkylating agent to obtain the Schiff base of formula (XXXIII). Any alkylating agent usually used to prepare thioformamide derivatives can be used in this reaction. Schiff's base
(XXXIII) is normally used in the next step without isolating it.

  
The second step of this reaction scheme comprises the reaction of the Schiff base (XXXIII) with an acid halide of formula (XXXV):

  

  <EMI ID = 300.1>


  
(in which R15 is as defined above and X represents a halogen atom) in the presence of a base, to give the desired azetidinone compound (XXXIV). This reaction can be carried out by the known method of preparation of the azetidinone derivatives which is described by A.K.

  
  <EMI ID = 301.1>

  
4091 (1972).

  
In the present specification, the expression "lower alkyl group *" refers to an alkyl group having 1 to 6 carbon atoms, the other "lower" groups being defined in an analogous manner.

  
The penem-3-carboxylic acid derivatives of the present invention are useful as antibacterial agents and as intermediates in the synthesis of other penem derivatives usable as antibacterial agents.

  
The activities of the compounds of the invention were evaluated by the agar plate dilution method

  
and some of the compounds according to the invention have been found to have a very potent antibacterial activity against a wide spectrum of pathogenic microorganisms, comprising both Gram positive microorganisms (such as Staphylococcus aureus and Bacillus subtilis) and Gram negative microorganisms (such as

  
  <EMI ID = 302.1>

  
niae, the species Proteus and Pseudomonas aeru &#65533; inosa). The minimum inhibition concentrations of certain compounds characteristic of the invention with respect to various microorganisms are given in the following table. In this table, the compounds subjected to the tests are identified as follows:

  
A: Isomer B of the sodium salt of compound n [deg.] 65: (5R, 6S) -

  
  <EMI ID = 303.1>

  
Sodium 3-carboxylate.

  
B: Sodium salt of compound n [deg.] 53: (5R, 6S) -2-carbamoyl-

  
  <EMI ID = 304.1>

  
sodium penem-3-carboxylate, that is to say the compound described in the previously mentioned French patent application.

  
Board

  

  <EMI ID = 305.1>


  
As can be seen from the examination of the table above, the compounds of the invention have antibacterial activities as good as or better than (and, with respect to certain microorganisms clearly better than) the activities of the known compound that is acid <EMI ID = 306.1>

  
boxylic. In addition, compound No. 65 has an acute toxicity in mice which is considerably more

  
  <EMI ID = 307.1>

  
that it is administered by intravenous injection in an amount of 500 to 1000 mg / kg of body weight, compound No. 65 does not cause harmful effects, even when injected intravenously in an amount of
1000 mg / kg.

  
Consequently, the compounds of the invention can be used for the treatment of diseases caused by numerous pathogenic microorganisms. For this purpose, the compounds of the invention can be administered orally (for example in the form of tablets, capsules, granules, powders or syrups) or parenterally (for example by intravenous injection or intramuscular injection). The dose varies depending on

  
  <EMI ID = 308.1> as well as the route and type of administration, but,

  
in general, the compounds of the invention can be administered at a daily dose of 250 to 3000 mg, in

  
in the case of adults, in the form of a single take or a plurality of takes.

  
The preparation of the compounds of the invention is further illustrated by the following examples, while the preparation of some of the starting materials used in these examples is illustrated by the "Preparations" which activate.

Example 1

  
  <EMI ID = 309.1>

  
  <EMI ID = 310.1>

  
in 12 ml of tetrahydrofuran, a solution of butyllithium in hexane (2.4 ml; 163 millimoles / ml) is added at room temperature, and the mixture is then stirred for 30 minutes. A solution of 620 mg of 2- (4-methylthio-2-azetidinon-1-yl) acetate is then added.
27 nitrobenzyl in 8 ml of tetrahydrofuran, after cooling the mixture to -78 [deg.] C, after which

  
  <EMI ID = 311.1>

  
  <EMI ID = 312.1>

  
mixing for 20 minutes. 198 mg solution

  
  <EMI ID = 313.1>

  
above solution and stirring is continued at -78 [deg.] C

  
  <EMI ID = 314.1>

  
reaction mixture. The resulting mixture is diluted with ethyl acetate, washed successively with water and with an aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography (eluent: 4: 1 mixture by volume of benzene and ethyl acetate), which gives 703 mg of the desired compound, under the form of a frothy substance.

  
  <EMI ID = 315.1>

  
  <EMI ID = 316.1>

  

  <EMI ID = 317.1>


  
  <EMI ID = 318.1>
  <EMI ID = 319.1>
  <EMI ID = 320.1>

  
p-nitrobenzyl (Compound No. 5)

  
A solution of 0.23 millimole of chlorine in carbon tetrachloride (522 1 1) is added to a solution of 95 mg (0.23 millimole) of 2- (4-methylthio-2-azé

  
  <EMI ID = 321.1>

  
cooling with ice and stirring. When the addition is complete, the mixture is stirred for 5 minutes and the solvent is then distilled off

  
  <EMI ID = 322.1>

  
is dissolved in 1.5 ml of methylene chloride, without purification. To the resulting solution is added a solution of 16.4 mg (0.23 millimole) of pyrrolidine and

  
  <EMI ID = 323.1>

  
ml of methylene chloride at 0 [deg.] C. After stirring at this temperature for one and a half hours, the reaction mixture is washed successively with water and

  
with an aqueous solution of sodium chloride. The organic layer is separated and is dried over anhydrous sodium sulfate, after which the solvent is distilled off. The resulting residue is purified by column chromatography (eluent: ethyl acetate), to give 30 mg of. desired compound.

  
  <EMI ID = 324.1>

  

  <EMI ID = 325.1>


  
  <EMI ID = 326.1>

  

  <EMI ID = 327.1>

Example 2

  
  <EMI ID = 328.1>

  
hydrofuran. To the solution is added a tam-

  
  <EMI ID = 329.1>

  
  <EMI ID = 330.1>

  
the mixture is stirred in a hydrogen atmosphere for 2 hours. The catalyst is filtered off and washed with water. The filtrate and the washing liquors are combined and concentrated by evaporation under reduced pressure. The concentrate is purified by column chromatography through a Diaion HP-20 resin (product of Mitsubishi Chemical Industries, Co .; particles from 0.074 mm to 0.149 mm; eluent: water and 5% v / v acetone aqueous solution ) and the fractions containing the desired compound are lyophilized, which gives 7 mg of the desired compound, in the form of a powder.

  
  <EMI ID = 331.1>

  

  <EMI ID = 332.1>


  
  <EMI ID = 333.1>

  

  <EMI ID = 334.1>


  
  <EMI ID = 335.1>

  

  <EMI ID = 336.1>

Example 3

  
P-nitrobenzyl 2-Thioxopenam-3-carboxylate (Compound No. 2)

  
Following the process of Example 1 (b), the corresponding 4-chloroazetidinone compound is obtained from 300 mg (0.726 millimole) of 2- (4-methylthio-2-

  
  <EMI ID = 337.1>

  
The resulting compound is dissolved in 4.5 ml of methylene chloride. To the resulting solution, a solution is added.

  
  <EMI ID = 338.1>

  
  <EMI ID = 339.1>

  
of triethylamine in 0.5 ml of methylene chloride, while cooling with ice. The mixture is stirred at this temperature for 1 hour, then the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography (eluent: mixture 97.5: 2.5 by volume of chloroform and methanol), which gives 155 mg of the desired compound.

  
  <EMI ID = 340.1>

  
  <EMI ID = 341.1>

  

  <EMI ID = 342.1>


  
  <EMI ID = 343.1>

  

  <EMI ID = 344.1>

Example 4

  
  <EMI ID = 345.1>

  
A solution of 1.04 ml of butyllithium (1.63 millimole / ml) in 6 ml of hexane is added to a solution of

  
  <EMI ID = 346.1>

  
ranne, at room temperature, and the mixture is then stirred for 30 minutes. A solution of 250 mg of 2- (4-methylthio-2-azetidinon-1-yl) p-nitrobenzyl acetate in 5 ml of tetrahydrofuran is added to the resulting solution, after cooling thereof

  
at -78 [deg.] C. The solution is stirred for 5 minutes and
73% of carbon disulfide are then added thereto, after which the mixture is stirred for 20 minutes. AT

  
  <EMI ID = 347.1>

  
cetyl, then stirred for 1 hour. After adding

  
  <EMI ID = 348.1>

  
with ethyl acetate and washed successively with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. The mixture is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: 10: 1 mixture by volume of benzene and ethyl acetate), which gives 303 mg of the desired product, in the form of crystals.

  
  <EMI ID = 349.1>

  

  <EMI ID = 350.1>


  
  <EMI ID = 351.1>
  <EMI ID = 352.1>
(b) p-nitrobenzyl 2-Thioxopenam-3-carboxylate
(Compose No. 2)

  
Following the process of Example 1 (b), a solution of carbon tetrachloride containing an equimolar amount of chlorine is added to a solution of

  
  <EMI ID = 353.1>

  
  <EMI ID = 354.1>

  
nitrobenzyl in 2 ml of methylene chloride, for

  
  <EMI ID = 355.1>

  
Crude 4-chloroazetidinone is dissolved in 3 ml of methylene chloride and 43 μl of triethylamine; then 135

  
  <EMI ID = 356.1>

  
30%) are added thereto, after which the mixture is stirred for 15 minutes. The solvent is distilled off under reduced pressure. The residue is purified by column chromatography (eluent: ethyl acetate), which gives 60 mg of the desired compound.

Example 5

  
  <EMI ID = 357.1>

  
1-yl) p-nitrobenzyl acetate

  
Following the process of Example 1 (a), 76 mg of the desired product is obtained from 100 mg (0.213

  
  <EMI ID = 358.1> <EMI ID = 359.1>

  

  <EMI ID = 360.1>


  
  <EMI ID = 361.1>
  <EMI ID = 362.1>
  <EMI ID = 363.1> p-nitrobenzyl carboxylate (Compound No. 11)

  
Following the process of Example 3, we obtain
46 mg of the desired compound, from 76 mg of 2- (4-oxo-

  
  <EMI ID = 364.1>

  
trobenzyle.

  
Nuclear magnetic resonance spectrum (CDC13) # ppm:

  

  <EMI ID = 365.1>

Example 6

  
  <EMI ID = 366.1>

  
benzyl

  
  <EMI ID = 367.1>

  
10 ml of tetrahydrofuran, a solution of butyllithium in hexane is added at room temperature
(2.08 ml; 163 millimoles / ml) and the resulting solution is stirred for 30 minutes. The solution is then cooled to -78 [deg.] C and a 500 mg solution of 2- (4-me-

  
  <EMI ID = 368.1>

  
10 ml of tetrahydrofuran is added to it. After stirring the solution for 20 minutes, it is added
324 mg of 2,2-dimethylmalonic acid dichloride, and the solution is stirred at -78 [deg.] C for 1 hour. 1.5 ml of acetic acid are then added to the reaction mixture which is then successively washed with water and with an aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography (eluent: 2: 1 mixture by volume of benzene and ethyl acetate), which gives 338 mg of the desired compound.

  
  <EMI ID = 369.1>

  

  <EMI ID = 370.1>


  
  <EMI ID = 371.1>
  <EMI ID = 372.1>
  <EMI ID = 373.1> posed No. 2)

  
Following the method of Example 4 (b), a solution containing an equimolar amount of chlorine in carbon tetrachloride is added to a solution of

  
  <EMI ID = 374.1>

  
ne) -2- (4-methylthio-2-azetidinon-1-yl) [pound] -nitrobenzyl acetate in 3 ml of methylene chloride, which gives <EMI ID = 375.1>

  
This crude 4-chloroazetidinone derivative is dissolved in 2 ml

  
  <EMI ID = 376.1>

  
after which a 30% solution is added to the mass

  
  <EMI ID = 377.1>

  
with ice, then stir the mixture for 15 minutes. The solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography (eluent: ethyl acetate), which gives 60 mg of the desired compound, which has the same properties as the product of Example 3 .

Example 7

  
  <EMI ID = 378.1>

  
benzyl

  
Following the processes of Example 6 (a), we

  
  <EMI ID = 379.1>

  
1.99 ml of hexamethyldisilazane, 5.82 ml of a solution

  
  <EMI ID = 380.1>

  
  <EMI ID = 381.1>

  
rify the reaction mixture by column chromatography on silica gel (eluent: methylene chloride), which gives 3.02 g of the desired compound.

  
  <EMI ID = 382.1>
  <EMI ID = 383.1>
   <EMI ID = 384.1>

  
(Compound No. 11)

  
3.0 g of 2- (1,5-dioxo-1,5-dihydro-2,4-benzo [ej-

  
  <EMI ID = 385.1>

  
thyl) -4-methylthio-2-azetidinon-1-yl7acetate of 2-nitrobenzyl are chlorinated with an equimolar amount of chlorine, in a similar manner to that described in Example 6 (b) and the product is then dissolved in
120 ml of diethyl ether. Then dissolved ammonia and diethyl ether are added to the reaction mixture for 10 minutes, while cooling with ice. The ether is distilled off and the residue is extracted with ethyl acetate. The extract is washed with a saturated aqueous solution of sodium chloride and the solvent is distilled off. The residue is purified by chromatography in a short column (eluent: ethyl acetate),

  
  <EMI ID = 386.1>

Example 8

  
  <EMI ID = 387.1>

  
  <EMI ID = 388.1>

  
  <EMI ID = 389.1>

  
36.9 mg of triethylamine and 165 mg of 2-iodopropionamide are added to a 165 mg solution of 6- (1-t-

  
  <EMI ID = 390.1>

  
resulting is stirred at room temperature for

  
6 hours and then left to stand for approximately

  
6 hours. The reaction mixture is washed with water and dried. The solvent is distilled off and the residue is purified by chromatography on silica gel (eluent: 1: 1 mixture by volume of benzene and ethyl acetate), which gives the desired compound (isomer A: 31 mg; isomer B: 32 mg).

  
Isomer A

  
  <EMI ID = 391.1>

  

  <EMI ID = 392.1>


  
  <EMI ID = 393.1>

  

  <EMI ID = 394.1>


  
Isomer B

  
  <EMI ID = 395.1>

  

  <EMI ID = 396.1>


  
  <EMI ID = 397.1>

  

  <EMI ID = 398.1>

Example 9

  
  <EMI ID = 399.1>

  
  <EMI ID = 400.1>

  
Isomer A <EMI ID = 401.1>

  
  <EMI ID = 402.1>

  
xylene and 2.5 mg of hydroquinone are added to the solution.

  
The mixture is stirred on an oil bath at 140 [deg.] C, in

  
a stream of nitrogen gas for 1 hour. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (eluent: 1: 1 mixture by volume of benzene and ethyl acetate), which gives the desired compound with sub-

  
  <EMI ID = 403.1>

  
The recovered part is again heated to give more of the desired compound. The total yield is

  
36 mg.

  
  <EMI ID = 404.1>

  

  <EMI ID = 405.1>


  
  <EMI ID = 406.1>

  

  <EMI ID = 407.1>


  
Isomer B

  
  <EMI ID = 408.1>

  
t-butyldimethylsilyloxyethyl) -2- (1-carbamoylethylthio) Z-nitrobenzyl penem-3-carboxylate in xylene, under the same conditions as those used for the preparation of the A isomer, which gives 39 mg of the desired compound.

  
  <EMI ID = 409.1>

  

  <EMI ID = 410.1>


  
  <EMI ID = 411.1>

  

  <EMI ID = 412.1>

Example 10

  
  <EMI ID = 413.1>

  
thylthio) p-nitrobenzyl penem-3-carboxylate (Compound No. 77)

  
Isomer A

  
38.9 l of acetic acid and 102 mg of tetrabutylammonium fluoride are added to a solution of 35 mg

  
  <EMI ID = 414.1>

  
p-nitrobenzyl in 1 ml of tetrahydrofuran. The mixture is left to stand at room temperature for 2 days. The reaction mixture is then diluted with ethyl acetate and washed successively with a saturated aqueous sodium chloride solution, a 5% w / v aqueous solution of sodium bicarbonate and a saturated aqueous sodium chloride solution. . The solvent is distilled off and the residue is purified by chromatography on silica gel (eluent: 10: 1 mixture by volume of chloroform and methanol), which gives 20 mg of the desired compound.

  
  <EMI ID = 415.1>

  

  <EMI ID = 416.1>


  
Nuclear magnetic resonance spectrum (dimethylfor-

  
  <EMI ID = 417.1>

  

  <EMI ID = 418.1>


  
Isomer B

  
38 mg of the B isomer of (5R, 6s) -6- / T- (R) -

  
  <EMI ID = 419.1>

  
p-nitrcbenzyl me-3-carboxylate in the same manner as isomer A above, to obtain 20 mg of the desired compound.

  
  <EMI ID = 420.1>

  
3430, 1788, 1685, 1655.

  
Nuclear magnetic resonance spectrum (heptadeuterated dimethylformamide) c &#65533; ppm:

  

  <EMI ID = 421.1>

Example 11

  
  <EMI ID = 422.1>

  
sodium penem-3-carboxylate (sodium salt of compound No. 65)

  
Isomer A

  
  <EMI ID = 423.1>

  
  <EMI ID = 424.1> <EMI ID = 425.1>

  
hydrofuran and phosphate buffer solution (pH

  
  <EMI ID = 426.1>

  
above, 38 mg of a catalyst consisting of palladium on charcoal (10% w / w palladium

  
  <EMI ID = 427.1>

  
gaseous for 1.5 hours. When the reaction is complete, the reaction mixture is filtered using a Celite filter aid (trade name), under reduced pressure, to remove the catalyst. The filtrate is extracted and washed with ethyl acetate;

  
  <EMI ID = 428.1>

  
  <EMI ID = 429.1>

  
of a mixture which is then purified by chromatography through Diaion HP-20AG resin (product of Mitsubishi Chemical Industries, Co .; particles from 0.074 mm to 0.149 mm), so as to obtain 10 mg of the desired compound.

  
  <EMI ID = 430.1>

  

  <EMI ID = 431.1>


  
Nuclear magnetic resonance spectrum (D20) # ppm:

  

  <EMI ID = 432.1>


  
Isomer B

  
20 mg of the B isomer of (5R, 6s) -6- / T- (R) -

  
  <EMI ID = 433.1>

  
above to obtain 10 mg of the desired compound.

  
  <EMI ID = 434.1>

  

  <EMI ID = 435.1>


  
  <EMI ID = 436.1>

  

  <EMI ID = 437.1>
 

  

  <EMI ID = 438.1>

Example 12

  
  <EMI ID = 439.1>

  
  <EMI ID = 440.1>

  
  <EMI ID = 441.1>

  
  <EMI ID = 442.1>

  
methyl tate in 3 ml of methylene chloride at room temperature, with stirring. After this addition, the solution is stirred for 3 minutes and the solvent is then distilled off to obtain

  
  <EMI ID = 443.1>

  
methyl acetate. This 4-chloroazetidinone compound is dissolved in 3 ml of methylene chloride, without purifying

  
  <EMI ID = 444.1>

  
whereupon the mixture is stirred at room temperature for 2 hours. The solvent is removed from the reaction mixture by distillation under reduced pressure. The resulting residue is dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride,

  
  <EMI ID = 445.1>

  
is distilled off under reduced pressure and the residue is purified by thin layer chromatography (eluent: 3: 2 mixture by volume of benzene and ethyl acetate), which gives 63 mg of the desired product, in the form of crystals .

  
  <EMI ID = 446.1>

  

  <EMI ID = 447.1>


  
  <EMI ID = 448.1>

  
  <EMI ID = 449.1>

  

  <EMI ID = 450.1>

Example 13

  
2- (3,3,3-trifluoro-2-oxopropylthio) p-nitrobenzyl penem-3carboxylate (compound No. 78)

  
Then following the process of Example 12, the desired product is obtained, in the form of crystals, from the

  
  <EMI ID = 451.1>

  
zyle.

  
  <EMI ID = 452.1>

  
  <EMI ID = 453.1>

  

  <EMI ID = 454.1>

Example 14

  
2- (2-Oxo-propylthio) p-nitrobenzyl penem-3-carboxylate
(Compound No. 79)

  
Following the process of Example 12. the desired product is obtained, in the form of crystals, from the

  
  <EMI ID = 455.1>

  

  <EMI ID = 456.1>


  
Nuclear magnetic resonance spectrum (tallow oxide

  
  <EMI ID = 457.1>

  

  <EMI ID = 458.1>

Example 15

  
  <EMI ID = 459.1>

  
(Compound No. 23)

  
By following the process of Example 12, the desired product is obtained from 2- (4-hydroxy-4-phe-

  
  <EMI ID = 460.1>

  

  <EMI ID = 461.1>


  
  <EMI ID = 462.1>

  

  <EMI ID = 463.1>

Example 16

  
  <EMI ID = 464.1>

  
28.5 mg (0.211 millimole) of sulfuryl chloride is added to a solution of 90 mg (0.211 millimole) of

  
  <EMI ID = 465.1>

  
2-ylidene) acetate -nitrobenzyl in 2 ml of methylene chloride, cooling with ice and stirring. When the addition is complete, the solution is stirred for 10 minutes and the solvent is then removed.

  
  <EMI ID = 466.1>

  
crude roazetidinone. This product is dissolved in 2 ml of <EMI ID = 467.1>

  
is stirred at this temperature for 1 hour. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography (eluent: ethyl acetate), which gives 17 mg of the desired product, in the form of crystals.

  
  <EMI ID = 468.1>

  

  <EMI ID = 469.1>


  
Nuclear magnetic resonance spectrum (dimethylfor-

  
  <EMI ID = 470.1>

  

  <EMI ID = 471.1>

Example 17

  
  <EMI ID = 472.1>

  
p-nitrobenzyl (Compound No. 81)

  
We. add a solution of 0.234 millimole of chlorine in carbon tetrachloride to a solution of 100 mg (0.234 millimole) of 2- (4-methylthio-2-azetidinon-1-yl) -2- (4-oxo-1,3 -dithiolan-2-ylidene) acetate <EMI ID = 473.1> while cooling with ice and stirring. When this addition is complete, the solution is stirred for 5 minutes and the solvent is then distilled off at 0 [deg.] C, which gives the crude 4-chloroazetidinone compound. This product, without purification,

  
  <EMI ID = 474.1>

  
and a solution of methylamine in methanol (corresponding to 0.468 millimole) is added to it. After acti- <EMI ID = 475.1>

  
solution is washed with water and dried over anhydrous sodium sulfate. The solvent is then removed by distillation under reduced pressure. The resulting residue is purified by column chromatography (eluent: methyl acetate), which gives 18 mg of the desired product.

  
  <EMI ID = 476.1>

  

  <EMI ID = 477.1>


  
Nuclear magnetic resonance spectrum (dimethylfor-

  
  <EMI ID = 478.1>

  

  <EMI ID = 479.1>

Example 18

  
  <EMI ID = 480.1>

  
benzyl; mixture of two isomers (Compound No.82)

  
Following the process of Example 17, the corresponding 4-chloroazetidinone compound is obtained from
80 mg (0.182 millimole) 2- (5-methyl-4-oxo-1,3-dithio-

  
  <EMI ID = 481.1>

  
with an excess of ammonia to give the desired product
(isomer A: 15 mg; isomer B: 18 mg).

  
Isomer A

  
  <EMI ID = 482.1>

  

  <EMI ID = 483.1>


  
Nuclear magnetic resonance spectrum (dimethylfor-

  
  <EMI ID = 484.1>

  

  <EMI ID = 485.1>
 

  

  <EMI ID = 486.1>


  
Isomer B

  
  <EMI ID = 487.1>

  

  <EMI ID = 488.1>


  
Nuclear magnetic resonance spectrum (heptadeuterated dimethylformamide) &#65533; ppm:

  

  <EMI ID = 489.1>

Example 19

  
  <EMI ID = 490.1>

  
p-nitrobenzyl; mixture of two isomers (Compound No.83)

  
Following the process of Example 18, but replacing the ammonia with methylamine, the desired product is obtained (isomer A: 13 mg, isomer B: 19 mg) from 80 mg (0.182 millimole) of 2- (5-methyl-4-oxo-

  
  <EMI ID = 491.1>

  

  <EMI ID = 492.1>


  
Nuclear magnetic resonance spectrum (heptadeuterated dimethylformamide) b ppm:

  

  <EMI ID = 493.1>
 

  

  <EMI ID = 494.1>


  
Isomer B

  
  <EMI ID = 495.1>

  

  <EMI ID = 496.1>


  
  <EMI ID = 497.1>

  

  <EMI ID = 498.1>

Example 20

  
  <EMI ID = 499.1>

  
p-nitrobenzyl (Compound No.84)

  
By following the process of Example 16, but replacing the ammonia with diethylamine, we obtain

  
17 mg of the desired product from 46.6 mg (0.109 millimole) of 2- (4-oxo-1,3-dithiolan-2-ylidene) -2- (4-methyl-

  
  <EMI ID = 500.1>

  

  <EMI ID = 501.1>


  
  <EMI ID = 502.1>

  

  <EMI ID = 503.1>
 

  

  <EMI ID = 504.1>


  
  <EMI ID = 505.1>

  
  <EMI ID = 506.1>

  
  <EMI ID = 507.1>

  
3380 (large), 3280, 1780, 1670, 1635.

  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 508.1>

  

  <EMI ID = 509.1>

Example 22

  
  <EMI ID = 510.1>

  
p-nitrobenzyl neme-3-carboxylate (Compound No. 86)

  
  <EMI ID = 511.1>

  
  <EMI ID = 512.1>

  
zyle, 89 mg of the desired product are obtained from 110 mg (0.258 millimole) of 2- (4-methylthio-2-azetidinon-1yl) -2- (4-oxo-1,3-dithiolan-2-ylidene) -Nitrobenzyl acetate.

  
  <EMI ID = 513.1>

  

  <EMI ID = 514.1>


  
Nuclear magnetic resonance spectrum (dimethylfor-

  
  <EMI ID = 515.1>

  

  <EMI ID = 516.1>

Example 23 -

  
  <EMI ID = 517.1>

  
p-nitrobenzyl (Compound No. 8 7)

  
By following the process of Example 16, but replacing the ammonia with morpholine, we obtain
27 mg of the desired product from 93.4 mg (0.219 milli-

  
  <EMI ID = 518.1>

  

  <EMI ID = 519.1>


  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 520.1>

  

  <EMI ID = 521.1>

Example 24

  
  <EMI ID = 522.1> p-nitrobenzyl thio7penem-3-carboxylate (Compound No. 37)

  
Following the process of Example 16, but

  
  <EMI ID = 523.1>

  
nyl) piperazine, 72 mg of the desired product are obtained, from 131 mg (0.307 millimole) of 2- (4-methylthio-2-azene)

  
  <EMI ID = 524.1>

  

  <EMI ID = 525.1>


  
  <EMI ID = 526.1>

  

  <EMI ID = 527.1>

Example 25

  
  <EMI ID = 528.1>

  
n.itrobenzyle (Compound No.88)

  
  <EMI ID = 529.1>

  
replacing methylamine with a solution of hydrazine in methanol, 20 mg of the desired product are obtained, starting from 100 mg (0.234 millimole) of 2- (4-methylthio-

  
  <EMI ID = 530.1>

  
3470, 3320 (large), 1785, 1675, 1650.

  
Nuclear magnetic resonance spectrum (dimethylformamide heptadeudety) S ppm:

  

  <EMI ID = 531.1>
 

  

  <EMI ID = 532.1>

Example 26

  
  <EMI ID = 533.1>

  
p-nitrobenzyl (Compound No. 89)

  
Following the process of Example 17, but replacing methylamine with a solution of hydroxylamine in methanol, 41 mg of the desired product is obtained, starting from 200 mg (0.468 millimole) of 2- (4-methylthio- 2-

  
  <EMI ID = 534.1>

  

  <EMI ID = 535.1>


  
Nuclear magnetic resonance spectrum (dimethylforma- <EMI ID = 536.1>

  

  <EMI ID = 537.1>

Example 27

  
  <EMI ID = 538.1>

  
Following the process of Example 17, but

  
  <EMI ID = 539.1>

  
droxylamine in methanol, 44 mg of the desired product are obtained, from 110 mg (0.258 millimole) of 2- (4-met

  
  <EMI ID = 540.1>

  
ne) p-nitrobenzyl acetate.

  
  <EMI ID = 541.1>

  
  <EMI ID = 542.1>

  

  <EMI ID = 543.1>


  
  <EMI ID = 544.1>

  

  <EMI ID = 545.1>

Example 28

  
  <EMI ID = 546.1>

  
  <EMI ID = 547.1>

  
Following the procedure of Example 16, 91 mg (0.207 millimole) of 2- (4-methylthio-2-az) are reacted.

  
  <EMI ID = 548.1>

  

  <EMI ID = 549.1>


  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 550.1>

  

  <EMI ID = 551.1>


  
co.....

Example 29

  
  <EMI ID = 552.1>

  
p-nitrobenzyl (Compound No.92)

  
  <EMI ID = 553.1>

  
react 150 mg (0.234 millimole) of 2- (4-methylthio-2-aza-

  
  <EMI ID = 554.1> <EMI ID = 555.1>

  
Crude 4-chloroazetidinone. This compound is dissolved in 1.5 ml of methylene chloride. 35.8 mg (0.234) is added to the solution, while cooling with ice.

  
  <EMI ID = 556.1>

  
millimole) of triethylamine, after which the mixture is stirred for 1.5 hours. When the reaction is complete, the reaction mixture is washed successively with water and with a saturated aqueous solution of sodium chloride. It is then dried over anhydrous sodium sulfate. The solvent is distilled off

  
  <EMI ID = 557.1>

  
column chromatography (eluent: 4: 1 mixture by volume of benzene and ethyl acetate), which gives 25 mg of the desired product.

  
  <EMI ID = 558.1>

  

  <EMI ID = 559.1>


  
  <EMI ID = 560.1>

  

  <EMI ID = 561.1>

Example 30

  
  <EMI ID = 562.1>

  
chloro-2-azetidinon-1-yl) -2- (4-oxo-1,3-dithiolan-2-ylidè-

  
  <EMI ID = 563.1>

  
21 is dissolved in 3 ml of methylene chloride. 30% methylamine solution is added to the solution.

  
  <EMI ID = 564.1> triethylamine in 0.5 ml of methylene chloride, while cooling with ice, after which the mixture is stirred at this temperature for 20 minutes. After removing the solvent by distillation under reduced pressure, ethyl acetate is added to the residue.

  
The resulting solution is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removal of the solvent by distillation, the resulting residue is purified by column chromatography through silica gel. We thus obtain
104 mg of the desired product from fractions eluted a-

  
  <EMI ID = 565.1>

  
ethyl acetate.

  
  <EMI ID = 566.1>

  
max

  

  <EMI ID = 567.1>


  
  <EMI ID = 568.1>

  

  <EMI ID = 569.1>


  
  <EMI ID = 570.1>

  

  <EMI ID = 571.1>

Example 31

  
  <EMI ID = 572.1> <EMI ID = 573.1>

  
14 mg of hydroquinone are added to the solution. The mixture is then heated on an oil bath at 125 [deg.] C, under

  
a stream of nitrogen for 4 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography

  
through silica gel. 54 mg of the desired product are obtained from fractions eluted with a 1: 1 mixture by volume of benzene and ethyl acetate. We recover

  
  <EMI ID = 574.1>

  

  <EMI ID = 575.1>

Example 32

  
  <EMI ID = 576.1>

  
  <EMI ID = 577.1>

  
tetrabutylammonium rure in a 54 mg solution of (5R,

  
  <EMI ID = 578.1>

  
1.5 ml of tetrahydrofuran, after which the mixture is stirred at room temperature for 52 hours. The reaction mixture is then diluted with ethyl acetate, washed successively with a saturated aqueous sodium chloride solution, a 5% w / v aqueous solution of sodium bicarbonate and a saturated aqueous sodium chloride solution. . The solvent is distilled off, which gives 39 mg of the desired product, in the form of crystals.

  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 579.1>

  

  <EMI ID = 580.1>


  
  <EMI ID = 581.1>

  

  <EMI ID = 582.1>


  
  <EMI ID = 583.1>

  

  <EMI ID = 584.1>

Example 33

  
  <EMI ID = 585.1>

  
p-nitrobenzyl (Compound No. 95)

  
By successively following the processes of the Pre-

  
  <EMI ID = 586.1>

  
  <EMI ID = 587.1>

  
benzyl to chlorination using an equimolar amount of chlorine and the resulting compound is treated with a mixture of a solution of ammonia in methanol and <EMI ID = 588.1>

  
The resulting crude product is purified by column chromatography with a silica gel. 101 mg of the desired methyl ester (compound No.95) are obtained from

  
fractions eluted with a 20: 1 volume mixture of benzene and ethyl acetate.

  
  <EMI ID = 589.1>

  

  <EMI ID = 590.1>


  
  <EMI ID = 591.1>

  

  <EMI ID = 592.1>


  
  <EMI ID = 593.1>

  

  <EMI ID = 594.1>


  
102 mg of the desired amide compound (Compound No. 58) are obtained from fractions eluted with a 2: 1 mixture by volume of benzene and ethyl acetate.

  
  <EMI ID = 595.1>

  

  <EMI ID = 596.1>
 

  
  <EMI ID = 597.1>

  

  <EMI ID = 598.1>


  
  <EMI ID = 599.1>

  

  <EMI ID = 600.1>

Example 34

  
  <EMI ID = 601.1>

  
(Compound No. 58)

  
Following the process of Example 31, we obtain
70 mg of the desired product from 95 mg of (5S, 6S) -6-

  
  <EMI ID = 602.1>

  

  <EMI ID = 603.1>


  
  <EMI ID = 604.1>

  

  <EMI ID = 605.1>

Example 35

  
  <EMI ID = 606.1>

  
(Compound No. 95)

  
Following the process of Example 31, we obtain
57 mg of the desired product from 91 mg of (5S, 6S) -

  
  <EMI ID = 607.1> <EMI ID = 608.1>

  

  <EMI ID = 609.1>


  
  <EMI ID = 610.1>

  

  <EMI ID = 611.1>


  
  <EMI ID = 612.1>

  
  <EMI ID = 613.1>

  
  <EMI ID = 614.1>

  
Following the process of Example 32, we obtain
40 mg of the desired product from 54 mg of (5R, 6S) -6-

  
  <EMI ID = 615.1>

  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 616.1>

  

  <EMI ID = 617.1>


  
  <EMI ID = 618.1>

  

  <EMI ID = 619.1>


  
  <EMI ID = 620.1>

  

  <EMI ID = 621.1>

Example 37

  
  <EMI ID = 622.1>

  
  <EMI ID = 623.1>

  
resulting product by thin layer chromatography (eluent:
mixture 1: 2 by volume of cyclohexane and ethyl acetate), the desired product was obtained.

  
  <EMI ID = 624.1>

  

  <EMI ID = 625.1>


  
  <EMI ID = 626.1>

  

  <EMI ID = 627.1>


  
  <EMI ID = 628.1>

  

  <EMI ID = 629.1>

Example 38

  
  <EMI ID = 630.1>

  
and 60 μl of acetic acid, 46 mg of the desired product are obtained.

  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 631.1>

  

  <EMI ID = 632.1>


  
  <EMI ID = 633.1>

  

  <EMI ID = 634.1>

Example 39

  
  <EMI ID = 635.1>

  
p-nitrobenzyl xvlate (Compound No. 99)

  
Following the procedure of Example 17, but using 108 mg of 2- (3-methoxy-4-methylthio-2-azetidi-

  
  <EMI ID = 636.1>

  
nitrobenzyl, a solution of chlorine in carbon tetrachloride at the rate of 2 moles of chlorine per mole

  
  <EMI ID = 637.1>

  
  <EMI ID = 638.1>

  
14 mg of the desired product, in the form of a powder.

  
Infrared absorption spectrum (methylene chloride)

  
  <EMI ID = 639.1>

  

  <EMI ID = 640.1>

Example 40

  
2- (Carbamoylmethylthio) sodium 3-carboxylate

  
(sodium salt of compound No. 30)

  
17 mg (0.043 millimole) of 2- (carbamoylmethylthio) penem-3-carboxylate of E-nitrobenzyl are dissolved in a mixture of 6 ml of tetrahydrofuran and 4 ml of a phosphate buffer solution (pH 7.10), after

  
which is suspended in this solution, 50 mg of a palladium catalyst on charcoal (10% by weight / palladium). The mixture is brought into contact with hydrogen gas for 2 hours. When the reaction is complete, the catalyst is filtered off using a filter aid consisting of Celite, under reduced pressure, and the filtrate is extracted and washed with ethyl acetate. The water is separated by distillation, which gives 1 ml of a residue

  
which is purified by chromatography through Diaion resin. HP-20AG (product of Mitsubishi Chemical Industries,

  
  <EMI ID = 641.1>

  
mg of the desired product.

  
  <EMI ID = 642.1>

  

  <EMI ID = 643.1>


  
Nuclear magnetic resonance spectrum (D20) # ppm:

  

  <EMI ID = 644.1>

Example 41

  
  <EMI ID = 645.1>

  
sodium (sodium salt of compound No. 33)

  
Following the process of Example 40, 4.8 mg of the desired product is obtained from 13 mg (0.0288 milli-

  
  <EMI ID = 646.1>

  
Infrared absorption spectrum (KBr) D max cm-1:

  

  <EMI ID = 647.1>


  
  <EMI ID = 648.1>

  

  <EMI ID = 649.1>
 

Example 42

  
  <EMI ID = 650.1>

  
sodium (Sodium salt of Compound No. 38)

  
Following the process of Example 40, we obtain
16 mg of the desired product, from 26 mg (0.0559 millimole) of 2- (2-morpholino-2-oxoethylthio) penem-3-carboxy-

  
  <EMI ID = 651.1>

  

  <EMI ID = 652.1>


  
  <EMI ID = 653.1>

  

  <EMI ID = 654.1>


  
  <EMI ID = 655.1>

  

  <EMI ID = 656.1>

Example 43

  
  <EMI ID = 657.1>

  
sodium (Sodium salt of Compound No. 36)

  
Following the process of Example 40, 8 mg of the desired product is obtained from 68 mg (0.106 millimole) of 2 - ((4-p-nitrobenzyloxycarbonyl-1-piperazinyl) -2-oxoethylthio7penem- P-nitrobenzyl 3-carboxylate.

  
Nuclear magnetic resonance spectrum (D20) # ppm:

  

  <EMI ID = 658.1>

Example 44

  
2- (2-Carbamoylethylthio) sodium penem-3-carboxylate
(Sodium salt of Compound No. 31)

  
Following the process of Example 40, 5.5 mg of the desired product is obtained from 20 mg (0.0488 millimole) of p-nitrcbenzyl 2- (2-carbamoylethylthio) penem-3-carboxylate.

  
  <EMI ID = 659.1>

  

  <EMI ID = 660.1>


  
  <EMI ID = 661.1>

  

  <EMI ID = 662.1>

Example 45

  
  <EMI ID = 663.1>

  
Following the process of Example 40, we obtain
12 mg of the desired product from 29 mg of (5R, 6s) -2-

  
  <EMI ID = 664.1>

  
  <EMI ID = 665.1>

  

  <EMI ID = 666.1>


  
  <EMI ID = 667.1>

  

  <EMI ID = 668.1>


  
  <EMI ID = 669.1>

  

  <EMI ID = 670.1>

Example 46

  
  <EMI ID = 671.1>

  
thio) sodium penem-3-carboxylate (sodium salt of Compound No. 54)

  
Following the process of Example 40, we obtain
12 mg of the desired product from 35 mg of (5R, 6S) -6-

  
  <EMI ID = 672.1> <EMI ID = 673.1>

  

  <EMI ID = 674.1>

Example 47

  
  <EMI ID = 675.1>

  
carbamoylethylthio) p-nitrobenzyl penem-3-carboxylate; mixture of isomers A and B (Compound No. 73)

  
An equimolar amount of chlorine is added to

  
  <EMI ID = 676.1>

  
in 4 ml of methylene chloride. To the resulting solution is added a mixture of an isopropanolic solution containing an excess of ammonia with an equimolar amount of triethylamine, and the mixture is then stirred.

  
  <EMI ID = 677.1>

  
is purified by chromatography on silica gel, elution being carried out with a 1: 1 mixture by volume of benzene and ethyl acetate, which gives the desired product (isomer A: 20 mg; isomer B: 13 mg).

  
Isomer A

  
  <EMI ID = 678.1>

  

  <EMI ID = 679.1>


  
  <EMI ID = 680.1>

  

  <EMI ID = 681.1>
 

  
Isomer B

  
  <EMI ID = 682.1>

  

  <EMI ID = 683.1>


  
  <EMI ID = 684.1>

  

  <EMI ID = 685.1>

Example 48

  
  <EMI ID = 686.1>

  
the; isomer A (Compound No. 73)

  
51 mg of the (5S, 6s) -6- / T- (R) - isomer is dissolved.

  
  <EMI ID = 687.1>

  
lene and then 2.5 mg of hydroquinone is added to the solution, after which the mixture is heated to 140 ° C. on an oil bath, with stirring, for 1 hour, under a

  
  <EMI ID = 688.1>

  
under reduced pressure and the residue is purified by chromatography on silica gel, the elution being carried out with a 1: 1 mixture by volume of benzene and ethyl acetate, which gives the desired product and a little unmodified starting material. The recovered starting material is again heated to give more of the desired product. The total yield is 36 mg.

  
  <EMI ID = 689.1>

  

  <EMI ID = 690.1>
 

  
  <EMI ID = 691.1>

  

  <EMI ID = 692.1>

Example 4 9

  
  <EMI ID = 693.1>

  
-Nirobenzyl 3-carboxylate in xylene, which gives 39 mg of the desired product.

  
  <EMI ID = 694.1>

  

  <EMI ID = 695.1>


  
  <EMI ID = 696.1>

  

  <EMI ID = 697.1>
 

  

  <EMI ID = 698.1>

Example 50

  
  <EMI ID = 699.1>

  
p-nitrobenzyl neme-3-carboxylate; isomer A (Compound No.77)

  
To a 35 mg solution of the A isomer of (5R, 6S) -

  
  <EMI ID = 700.1>

  
  <EMI ID = 701.1>

  
that and 102 mg of tetrabutylammonium fluoride. The mixture is kept at rest, at room temperature, for 2 days. The reaction mixture is then diluted with ethyl acetate, washed successively with a saturated aqueous solution of sodium chloride, an aqueous solution at 5% by weight / volume of sodium bicarbonate.

  
  <EMI ID = 702.1>

  
  <EMI ID = 703.1>

  
distillation and the resulting residue is purified by chromatography on silica gel, elution being carried out with a 10: 1 mixture by volume of chloroform and methanol, which gives 20 mg of the desired product.

  
  <EMI ID = 704.1>

  

  <EMI ID = 705.1>


  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 706.1>

  

  <EMI ID = 707.1>
 

Example 51

  
  <EMI ID = 708.1>

  
se No. 77)

  
Following the process described in Example 50,

  
  <EMI ID = 709.1>

  

  <EMI ID = 710.1>


  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 711.1>

  

  <EMI ID = 712.1>

Example 52

  
  <EMI ID = 713.1>

  
  <EMI ID = 714.1>

  
20 mg of the isomer A of (5R, 6S) - (1-

  
  <EMI ID = 715.1>

  
tetrahydrofuran and 4 ml of a phosphate buffer solution (pH 7.10). 38 mg of a catalyst consisting of palladium on charcoal (10% w / w palladium) are suspended in the above solution. The resulting mixture is brought into contact with hydrogen gas for 1.5 hours. The catalyst is separated by filtration under reduced pressure using Celite (filter aid). The filtrate is <EMI ID = 716.1>

  
  <EMI ID = 717.1>

  
of a mixture which is purified by chromatography through a Diaion HP-20AG resin (product of Mitsubishi Chemical Industries Ltd .; particles from 0.074 to 0.149 mm), this

  
which gives 10 mg of the desired product.

  
  <EMI ID = 718.1>

  

  <EMI ID = 719.1>


  
  <EMI ID = 720.1>

  

  <EMI ID = 721.1>

Example 53

  
  <EMI ID = 722.1>

  
sodium penem-3-carboxylate; isomer B (sodium salt of Compound No. 65)

  
Following the process described in Example 50,

  
20 mg of the isomer B of (5R, 6S) -2- (l-carbamoyl-

  
  <EMI ID = 723.1>

  

  <EMI ID = 724.1>


  
  <EMI ID = 725.1>

  

  <EMI ID = 726.1>

Example 54

  
  <EMI ID = 727.1>

  
  <EMI ID = 728.1>

  
purified by chromatography on a Lobar column (eluent:

  
  <EMI ID = 729.1>

  
  <EMI ID = 730.1>

  
Isomer A

  
Nuclear magnetic resonance speczre (CDC13) & ppm:

  

  <EMI ID = 731.1>


  
  <EMI ID = 732.1>

  

  <EMI ID = 733.1>


  
Isomer B

  
  <EMI ID = 734.1>

  

  <EMI ID = 735.1>
 

  

  <EMI ID = 736.1>


  
  <EMI ID = 737.1>

  

  <EMI ID = 738.1>

Example 55

  
  <EMI ID = 739.1>

  
isomers A and B (Compound No. 75).

  
90 mg of the isomer A and 124 mg of the is submitted

  
  <EMI ID = 740.1>

  
gives, respectively, 55 mg of isomer A and 95 mg of isomer B.

  
Isomer A

  
  <EMI ID = 741.1>

  

  <EMI ID = 742.1>
 

  

  <EMI ID = 743.1>


  
Isomer B

  
  <EMI ID = 744.1>

  

  <EMI ID = 745.1>


  
  <EMI ID = 746.1>

  

  <EMI ID = 747.1>

Example 56

  
  <EMI ID = 748.1>

  
p-nitrobenzyl penem-3-carboxylate; isomers A and B
(Compound No. 76)

  
55 mg of the isomer A and. 95 mg of the isomer

  
  <EMI ID = 749.1>

  
in a similar manner to that of Example 32, which gives, respectively, the desired isomers A (38 mg) and B

  
(51 mg).

  
Isomer A

  
Nuclear magnetic resonance spectrum (heptadeuterated dimethylformamide) S ppm:

  

  <EMI ID = 750.1>
 

  

  <EMI ID = 751.1>


  
  <EMI ID = 752.1>

  
Nuclear magnetic resonance spectrum (dimethylforma-

  
  <EMI ID = 753.1>

  

  <EMI ID = 754.1>


  
  <EMI ID = 755.1>

  

  <EMI ID = 756.1>

Example 57

  
  <EMI ID = 757.1> Sodium Compound No. 74)

  
Following the procedures described in Example 40 and using 38 mg of the isomer A and 50 mg of the isomer

  
  <EMI ID = 758.1>

  
p-nitrobenzyl thyl7penem-3-carboxylate, the desired isomers A (13 mg) and B (15 mg) are obtained.

  
Isomer A

  
  <EMI ID = 759.1>

  

  <EMI ID = 760.1>


  
  <EMI ID = 761.1>

  

  <EMI ID = 762.1>


  
  <EMI ID = 763.1>

  

  <EMI ID = 764.1>


  
Isomer B

  
Nuclear magnetic resonance spectrum (D20) ppm:

  

  <EMI ID = 765.1>


  
  <EMI ID = 766.1>

  

  <EMI ID = 767.1>


  
  <EMI ID = 768.1>

  

  <EMI ID = 769.1>


  
  <EMI ID = 770.1>

  
  <EMI ID = 771.1>

  
2.16 g (2.97 ml) of triethylamine are added and

  
  <EMI ID = 772.1>

  
  <EMI ID = 773.1> <EMI ID = 774.1>

  
reduced pressure, ethyl acetate is added to the residue and the mixture is washed successively with water

  
  <EMI ID = 775.1>

  
sodium rure. The mixture is then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: 1: 1 mixture by volume of benzene and ethyl acetate), which gives 6.3 g (57.0%) of the desired compound.

  
Preparation 1

  
  <EMI ID = 776.1>

  
nitrobenzyl; mixture of two isomers

  
1.11 g (4.86 millimoles) of p-nitrobenzyl glyoxylate monohydrate is added to a solution of 570 mg
(4.87 millimoles) of 4-methylthio-2-azetidinone in 30 ml of benzene and the resulting solution is heated while

  
that the water produced is removed by azeotropic distillation. After complete removal of the water by distillation, the mixture is concentrated and heated to a bath temperature of 100-110 [deg.] C for 12 hours. The solvent is then removed by distillation under reduced pressure, which gives 1.69 g of the desired compound, in the form of a viscous oil. This product can be used in subsequent reactions, without purification, although it contains a small amount of the starting compound.

  
  <EMI ID = 777.1>

  
2-Chloro-2- (4-methylthio-2-azetidinon-1-yl) acetate; mixture of two isomers

  
626 mg of 2,6-lutidine and 695 mg of thionyl chloride are successively added dropwise to a solution of 1.59 g of 2-hydroxy-2- (4-methylthio-2-azetidinon-1-yl ) p-nitrobenzyl acetate in 30 ml of tetrahydrofuran, while stirring at -20 [deg.] C. The reaction mixture is stirred at a temperature of -20 [deg.] To -15 [deg.] C for 30 minutes, diluted with ethyl acetate, washed with water (once), neutralized with a dilute aqueous solution of sodium bicarbonate and then washed with water.

  
The mixture is then dried over anhydrous sodium sulfate and the solvent is distilled off, which gives 1.79 g of the desired compound, in the form of a viscous oil. The product thus obtained can be used in subsequent reactions without purification.

  
Preparation 3

  
  <EMI ID = 778.1>

  
687 mg of sodium iodide and 576 mg of sodium cyanoborohydride are added to a solution of 1.58 g of

  
  <EMI ID = 779.1>

  
crude nitrobenzyl in 15 ml of hexamethylphosphoramide

  
and the resulting mixture is stirred at room temperature for one hour. The reaction mixture is then poured into melting ice and the precipitates produced are collected by filtration, washed with water, dried and recrystallized from ethyl acetate, to give 844 mg of the desired compound.

  
  <EMI ID = 780.1>

  

  <EMI ID = 781.1>


  
  <EMI ID = 782.1>

  

  <EMI ID = 783.1>


  
Preparation 4

  
  <EMI ID = 784.1>

  
36 mg (0.64 millimole) of hydroxide of po- <EMI ID = 785.1>

  
monium suspended in 3 ml of tetrahydrofuran.

  
Slowly added to the suspension, drop by drop,

  
a solution of 72.5 mg (0.62 millimole) of 4-methylthio2-azetidinone and 493 mg (1.25 millimole) of iodoacetate

  
  <EMI ID = 786.1>

  
under agitation. The temperature of the mixture is gradually increased to room temperature and the mixture is then stirred at this temperature for 1.5 hours. When the reaction is complete, the mixture is diluted with ethyl acetate and subjected to a

  
  <EMI ID = 787.1>

  
reduced pressure and the resulting residue is purified by

  
  <EMI ID = 788.1>

  
volume of ethyl acetate and benzene), which gives
49 mg of the desired compound, in the form of crystals.

  
Preparation 5

  
  <EMI ID = 789.1>

  
ml of a 15% w / v aqueous solution of sodium methyl mercaptate are added to a solution of 900 mg of 4-acetoxy-3- (1-t-butyldimethylsilyloxyethyl) -2-azetidinone in 15 ml of methylene chloride , while cooling with ice, and the mixture is stirred at room temperature for 3.5 hours. The methylene chloride layer is separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off and the residue is purified by chromatography on a column of silica gel (eluent: 10: 1 mixture by volume of methylene chloride and ethyl acetate), which gives 838 mg of the desired compound, in the form of colorless crystals melting at 84-86 [deg.] C.

  
  <EMI ID = 790.1>

  

  <EMI ID = 791.1>
 

  

  <EMI ID = 792.1>


  
  <EMI ID = 793.1>

  

  <EMI ID = 794.1>


  
Mass spectrum m / e: 218 (M + -t-Bu).

  
  <EMI ID = 795.1>

  
p-nitrobenzyl dinon-1-yl7-2-hydroxyacetate; mixture of two isomers

  
By following the Preparation 1 process, but by

  
  <EMI ID = 796.1>

  
methylthio-2-azetidinone and 250 mg of gly monohydrate

  
  <EMI ID = 797.1>

  
chromatography on a column of silica gel (eluent: 10: 1 mixture by volume of methylene chloride and ethyl acetate), 480 mg of the desired compound are obtained.

  
  <EMI ID = 798.1>

  

  <EMI ID = 799.1>


  
Preparation 7

  
  <EMI ID = 800.1>

  
two isomers

  
By following the Preparation 2 process, but by

  
  <EMI ID = 801.1>

  
  <EMI ID = 802.1>

  
thionyle, by purifying the product by chromatography on a column of silica gel and eluting with methylene chloride, 450 mg of the desired compound are obtained, in the form of an oil.

  
  <EMI ID = 803.1>

  

  <EMI ID = 804.1>


  
Preparation 8

  
  <EMI ID = 805.1>

  
p-nitrobenzyl azetidinon-1-yl7 acetate

  
By following the Preparation 3 process, but by

  
  <EMI ID = 806.1>

  
benzyl, 379 mg of sodium iodide and 314 mg of sodium cyanoborohydride, and by purifying the crude product by

  
  <EMI ID = 807.1>

  
being carried out with a 10: 1 mixture by volume of benzene and ethyl acetate, 785 mg of the desired compound are obtained.

  
  <EMI ID = 808.1>

  

  <EMI ID = 809.1>


  
  <EMI ID = 810.1>

  

  <EMI ID = 811.1>


  
Preparation 9

  
  <EMI ID = 812.1>

  
thylthio-2-azetidinon-1-yl) methyl acetate (mixture of two isomers

  
A solution of butyllithium in hexane (1.35 ml; 1.63 millimoles / ml) is added to a solution of <EMI ID = 813.1>

  
ranne at room temperature, then the mixture is stirred for 30 minutes. The solution is cooled to -78 ° C. and a solution of 189 mg of (4-methylthio-2-azetidinon-1yl) methyl acetate in 3 ml of tetrahydrofuran is added thereto, after which the mixture is agitated while

  
  <EMI ID = 814.1>

  
bone in the solution and the mixture is stirred for 1 hour.

  
  <EMI ID = 815.1>

  
hydrofuran is added to the resulting mixture, the mass then being stirred at -78 [deg.] C for 2 hours. The mixture

  
  <EMI ID = 816.1>

  
that and with ethyl acetate, washed successively with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and again an aqueous solution of sodium chloride, after which it is dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by thin layer chromatography (eluent: 2: 1 mixture by volume of benzene and ethyl acetate), which gives 290 mg of the desired product, under form of frothy substance.

  
Mass spectrum m / e: 321 (M +), 247 (base peak).

  
  <EMI ID = 817.1>

  

  <EMI ID = 818.1>


  
Nuclear magnetic resonance spectrum (CDC13) S ppm:

  

  <EMI ID = 819.1>


  
Preparation 10

  
  <EMI ID = 820.1> <EMI ID = 821.1>

  
(mixture of two isomers)

  
By following the Preparation 9 process, but by

  
  <EMI ID = 822.1>

  
ketone, 544 mg of the desired product is prepared, starting from
378 mg of (4-methylthio-2-azetidinon-1-yl) methyl acetate.

  
  <EMI ID = 823.1>

  
  <EMI ID = 824.1>

  

  <EMI ID = 825.1>


  
  <EMI ID = 826.1>

  

  <EMI ID = 827.1>


  
Preparation <1> 1

  
  <EMI ID = 828.1>

  
diaper of two isomers

  
Following the process of Preparation 9, 380 mg of the desired product is obtained from 310 mg of 2- (4-

  
  <EMI ID = 829.1>

  

  <EMI ID = 830.1>


  
  <EMI ID = 831.1>

  

  <EMI ID = 832.1>
 

  
Preparation 12

  
  <EMI ID = 833.1>

  
zyle; mixture of two isomers

  
By following the Preparation 10 process, 278 mg of the desired product are obtained from 250 mg of

  
  <EMI ID = 834.1>

  
  <EMI ID = 835.1>

  

  <EMI ID = 836.1>


  
Preparation 13

  
  <EMI ID = 837.1>

  
mixture of two isomers

  
Following the process of Preparation 11, but replacing bromacetone with phenacyl bromide, 110 mg of the desired compound are obtained from 310 mg of

  
  <EMI ID = 838.1>

  
  <EMI ID = 839.1>

  

  <EMI ID = 840.1>


  
Preparation 14

  
  <EMI ID = 841.1>

  
azetidinon-1-yl) p-nitrobenzyl acetate; mixture of two isomers

  
A solution of butyllithium in hexane (2.4 ml; <EMI ID = 842.1> <EMI ID = 843.1>

  
  <EMI ID = 844.1>
-78 [deg.] C and a solution of 620 mg of (4-methylthio-2-azéti- <EMI ID = 845.1>

  
hydrofuran is added to it, and the mixture is stirred

  
  <EMI ID = 846.1>

  
carbon to the resulting mixture which is then stirred for 1 hour. A solution of 503 mg of iodoacetaldehyde in tetrahydrofuran is added to the solution

  
  <EMI ID = 847.1>

  
  <EMI ID = 848.1>

  
  <EMI ID = 849.1>

  
thyle, then washed successively with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and again an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is dissolved in 4 ml of tetrahydrofuran. Add a drop of acid

  
  <EMI ID = 850.1>

  
stirred at room temperature for 1.5 hours.

  
The solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography (eluent: 1: 1 mixture by volume of benzene and ethyl acetate), which gives 733 mg of the desired product under the form of a frothy substance.

  
  <EMI ID = 851.1>

  

  <EMI ID = 852.1>


  
  <EMI ID = 853.1>

  

  <EMI ID = 854.1>
 

  

  <EMI ID = 855.1>


  
Preparation 15

  
  <EMI ID = 856.1>

  
By following the process of Preparation 11, but replacing the bromacetone with bromacetyl bromide, 800 mg of the desired product are obtained, from

  
  <EMI ID = 857.1>

  

  <EMI ID = 858.1>


  
  <EMI ID = 859.1>

  

  <EMI ID = 860.1>


  
Preparation 16

  
  <EMI ID = 861.1>

  
thio-2-azetidinon-1-yl) p-nitrobenzyl acetate

  
Following the process of Preparation 9, but replacing the bromoacetone with 2-bromopropionyl bromide, 160 mg of the desired product are obtained from 155 mg of (4-methylthio-2-azetidinon-1-yl) -

  
  <EMI ID = 862.1>

  
Mass spectrum m / e: 440 (M +).

  
  <EMI ID = 865.1>

  
  <EMI ID = 863.1>

  

  <EMI ID = 864.1>
 

  

  <EMI ID = 866.1>


  
Preparation 17

  
  <EMI ID = 867.1>

  
2-vlidene) p-nitrobenzyl acetate

  
121 mg of 2- (4-hydroxy-1,3-dithiolan-2- are dissolved

  
  <EMI ID = 868.1>

  
nitrobenzyl in 1 ml of tetrahydrofuran. A solution of 45.2 mg of bromine in carbon tetrachloride is added dropwise to the resulting solution, while cooling with ice. The mixture is stirred at this temperature for 10 minutes and the solvent is then removed by distillation under reduced pressure, the resulting residue being purified by column chromatography (eluent: mixture 1: 1 by volume of benzene and ethyl acetate ), which gives 130 mg of the desired product.

  
  <EMI ID = 869.1>

  

  <EMI ID = 870.1>


  
  <EMI ID = 871.1>

  

  <EMI ID = 872.1>


  
Preparation 18

  
  <EMI ID = 873.1> <EMI ID = 874.1>

  
Following the process of Preparation 17, but replacing the bromine with sulfuryl chloride, 38 mg of the desired product are obtained from 70 mg of 2- (4-hydroxy-1,3-dithiolan-2-ylidene) - 2- (4-methylthio-2azetidinon-1-yl) p_-nitrobenzyl acetate.

  
  <EMI ID = 875.1>

  

  <EMI ID = 876.1>


  
Nuclear magnetic resonance spectrum (CDC13) # ppm:

  

  <EMI ID = 877.1>


  
Preparation 19

  
2- (4-Methylthio-2-azetidinon-1-yl) -2- (4-oxo-1,3-dithian2-vlidene) p-nitrobenzyl acetate

  
Following the Preparation 11 process, but

  
by replacing bromacetone with 3-bromopropionyl chloride, the desired product is obtained (isomer A: 7 mg; isomer B: 96 mg) from 155 mg of (4-methylthio-2-

  
  <EMI ID = 878.1>

  
Isomer A

  
  <EMI ID = 879.1>

  

  <EMI ID = 880.1>


  
  <EMI ID = 881.1>

  

  <EMI ID = 882.1>
 

  
  <EMI ID = 883.1>

  
  <EMI ID = 884.1>

  

  <EMI ID = 885.1>


  
  <EMI ID = 886.1>

  

  <EMI ID = 887.1>


  
Preparation 20

  
  <EMI ID = 888.1>

  
p-nitrobenzyl tate

  
Following the process of Preparation 15, 274 mg of the desired product are obtained from 469 mg of

  
  <EMI ID = 889.1>

  

  <EMI ID = 890.1>


  
  <EMI ID = 891.1>

  

  <EMI ID = 892.1>


  
Preparation 21

  
  <EMI ID = 893.1> of p-nitrobenzyl

  
  <EMI ID = 894.1>

  
  <EMI ID = 895.1>

  
  <EMI ID = 896.1>

  
methylene, cooling with ice. The solution is stirred at this temperature for 30 minutes and the solvent is then removed by distillation, which gives the desired product quantitatively.

  
Nuclear magnetic resonance spectrum (CDC13) S ppm:

  

  <EMI ID = 897.1>


  
Preparation 22

  
  <EMI ID = 898.1>

  
nitrobenzyl; mixture of two isomers

  
Following the Preparation 9 process, but

  
  <EMI ID = 899.1>

  
  <EMI ID = 900.1>

  
holds 121 mg of the desired product, which is a mixture of two isomers. These isomers are isolated by chromatography on a column of silica gel (eluent: mixture

  
6: 1 by volume of methylene chloride and ethyl acetate).

  
Isomer with the lowest polarity:

  
  <EMI ID = 901.1>

  

  <EMI ID = 902.1>


  
  <EMI ID = 903.1>

  

  <EMI ID = 904.1>


  
Isomer with the highest polarity:

  
  <EMI ID = 905.1>

  

  <EMI ID = 906.1>


  
  <EMI ID = 907.1>

  

  <EMI ID = 908.1>


  
Preparation 23 <EMI ID = 909.1>

  
  <EMI ID = 910.1>

  
tyle, 108 mg of the desired product are obtained in the form of an oily substance.

  
  <EMI ID = 911.1>

  

  <EMI ID = 912.1>


  
  <EMI ID = 913.1>

  

  <EMI ID = 914.1>


  
Preparation 24

  
  <EMI ID = 915.1>

  
methyl

  
To a solution of 266 mg of methyl thioformylglycinate in 3 ml of methylene chloride is added

  
  <EMI ID = 916.1>

  
stirred at room temperature for 3 hours and re-

  
  <EMI ID = 917.1>

  
  <EMI ID = 918.1>

  
to the above mixture which is then stirred at this temperature for 45 minutes and then at room temperature for 30 minutes. The reaction mixture is extracted with ethyl acetate, washed with water and dried over magnesium sulfate.

  
The solvent is then separated by distillation. The re-

  
  <EMI ID = 919.1>

  
thin che, the Ion elution being effected: with a 4: 1 mixture by volume of methylene chloride and ethyl acetate; which gives 27 mg of the desired product.

  
  <EMI ID = 920.1>

  

  <EMI ID = 921.1>
 

  

  <EMI ID = 922.1>


  
  <EMI ID = 923.1>

  

  <EMI ID = 924.1>


  
Preparation 25

  
  <EMI ID = 925.1>

  
p-nitrobenzyl

  
Following the Preparation 24 process, but

  
  <EMI ID = 926.1>

  
  <EMI ID = 927.1>

  
holds 26 mg of the desired product.

  
  <EMI ID = 928.1>

  

  <EMI ID = 929.1>


  
  <EMI ID = 930.1>

  
A solution of butyllithium in hexane (1.27 ml; 1.61 millimoles / ml) is added to a solution of

  
  <EMI ID = 931.1>

  
ranne, at room temperature, and the mixture is stirred for 30 minutes. After the resulting solution has cooled to -78 [deg.] C, a solution is added.

  
  <EMI ID = 932.1>

  
zyle in 4 ml of tetrahydrofuran, and the mixture is stirred <EMI ID = 933.1>

  
carbon disulfide to the solution, then the mixture is stirred for 20 minutes. 2-Bromopropionyl bromide is added dropwise to the solution and the solution is then stirred at -78 [deg.] C for 1.5 hours. We have-

  
  <EMI ID = 934.1>

  
reaction with ethyl acetate, washed successively with water and with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off at reduced pressure and the residue is purified by column chromatography, the elution being carried out with a 10: 1 mixture by volume of benzene and ethyl acetate, which gives 457 mg of the product. desired, in the form of a frothy substance.

  
  <EMI ID = 935.1>

  

  <EMI ID = 936.1>


  
  <EMI ID = 937.1>

  

  <EMI ID = 938.1>


  
Preparation 27

  
  <EMI ID = 939.1>

  
  <EMI ID = 940.1>

  
Following the processes described in the example <EMI ID = 941.1>

  
1.23 ml (2.0 mmol) solution of butyllithium

  
  <EMI ID = 942.1>

  
ml of alpha-bromobutyl bromide, and the reaction mixture is purified by gel column chromatography

  
  <EMI ID = 943.1>

  
340 mg of the desired compound.

  
  <EMI ID = 944.1>

  

  <EMI ID = 945.1>



    

Claims (1)

CLAIMS <EMI ID = 946.1> intermediate chemicals, characterized in  <EMI ID = 947.1>  <EMI ID = 948.1> in which:  <EMI ID = 949.1> alkyl, an alkoxy group or a group of formula R 4 A- (in which R4 represents a hydroxy group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group,  <EMI ID = 950.1> an acylamino group or an azido group, and A represents a bivalent saturated aliphatic hydrocarbon group optionally comprising a substituent consisting of a trifluoromethyl and / or phenyl group); R2 represents a hydrogen atom, a group of formula  <EMI ID = 951.1>  <EMI ID = 952.1> each of them representing an alkyl group, an aralky-  <EMI ID = 953.1> association with the nitrogen atom to which they are linked, a nitrogen heterocyclic group) or a group of formula  <EMI ID = 954.1>  (in which R7 represents a hydrogen atom, an alkyl group, an alkyl group comprising one or more  <EMI ID = 955.1> an amino group, an alkylated amino group in which the alkyl group or groups optionally comprise one or more substituents chosen from hydroxy, amino groups,  <EMI ID = 956.1> an amino group comprising one or more substituents chosen from aryl, heterocyclic or aral.kyle groups, a hydroxy group, an alkoxy group, an aryloxy group, an aralkyloxy group, a hydrazino group, a hydrazino group comprising one or more substituents chosen from alkyl, aralkyl or aryl groups, a hydroxyamino group, an alkoxyamino group or a guanidino group, and A ′ represents a bivalent saturated aliphatic hydrocarbon group): and R <3> represents a carboxy group or a protected carboxy group; including the tautomers of said compounds in which R <2> represents a hydrogen atom; and the pharmaceutically acceptable salts of said compounds. 2) Compounds according to claim 1; characterized in that R represents a hydrogen atom, an ethyl group, an ethyl group comprising, in the alpha position, a substituent chosen from hydroxy, amino, C2-C4 aliphatic acyloxy or aliphatic acylamino groups in C2-C4, or a methoxy group. 3) Compounds according to claim 2, characterized in that R represents a hydrogen atom, an ethyl group, an alpha-hydroxyethyl group, an alphaacetoxy ethyl group, an alpha-propionyloxyethyl group, an alpha-butyryloxyethyl group, an alpha group -aminoethyl, an alpha-acetylaminoethyl group, an alphapropionylaminoethyl group, an alpha-butyrylaminoethyl group or a methoxy group. 4) Compounds according to one of claims 1 to 3, characterized in that R represents a hydrogen atom, a group of formula  <EMI ID = 957.1>  <EMI ID = 958.1> each of them representing a lower chain or branched chain lower alkyl group, an aralkyl group or an aryl group, or else R5 and R6, in association with the nitrogen atom to which they are attached, represents a group 1- pyrrolidinyl, piperidino, 4-hydroxypiperidino, morpholino or 1-piperazinyl  <EMI ID = 959.1>  <EMI ID = 960.1> straight chain or branched chain, an amino group, an amino group substituted by a lower alkyl group, an amino group substituted by a lower hydroxyalkyl group, an amino group substituted by a lower aminoalkyl group, an amino group substituted by a lower carboxyalkyl group, an amino group substituted by a lower alkoxycarbonylalkyl group, an amino group substituted by a lower aralkyloxycarbonylalkyl group,  <EMI ID = 961.1> amino substituted by a heterocyclic group, a hydroxy group, a lower alkoxy group, a hydrazino group, a hydrazino group substituted by a lower alkyl group, a hydroxyamino group, an alkoxyamino group or a guanidino group, and A 'represents a bivalent saturated aliphatic hydrocarbon group with a straight chain or with a branched chain containing 1 to 3 carbon atoms). 5) Compounds according to claim 4, characterized  <EMI ID = 962.1> of formula  <EMI ID = 963.1>  <EMI ID = 964.1> each of them representing a methyl, ethyl, propyl, isopropyl, benzyl or phenyl group, or else R5 and R, in association with the nitrogen atom to which they are linked, represents a 1-pyrrolidinyl, piperidino, 4- hydroxypiperidino, morpholino or 1-piperazinyl). 6) Compounds according to claim 4, characterized in that R2 represents a group of formula  <EMI ID = 965.1>  <EMI ID = 966.1> trimethylene, propylene, ethylidene or propylidene. 7) Compounds according to any one of claims 1 to 6, characterized in that R <3> represents a carboxy group, a pivaloyloxymethyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group. 8) Compounds according to claim 1, characterized in that: R <1> represents a 1-hydroxyethyl group; R2 represents a group of formula  <EMI ID = 967.1>  <EMI ID = 968.1> has a methylene group having a methyl or ethyl substituent); and R <3> represents a carboxy group. 9) Compounds according to any one of claims 1 to 8, characterized in that they consist of potassium or sodium salts. <EMI ID = 969.1> 1 to 9, characterized in that the compounds of formula (I) are of configuration (5R, 6S) or (5R, 6R). 11) Compounds according to claim 1, characterized in that they are: <EMI ID = 970.1> carboxylic; - 2- (1-carbamoylethylthio) -6- (1-hydroxyethyl) -penem3-carboxylic acid; or - 2- (1-carbamoylpropylthio) -6- (1-hydroxyethyl) -penem3-carboxylic acid; and their salts and esters. 12) Process for the preparation of a compound of formula (Ia):  <EMI ID = 971.1>  <EMI ID = 972.1> dication 1) and its tautomers as well as its pharmaceutically acceptable salts, characterized in that it comprises the stages consisting: (a) reacting a 4-alkylthio-azetidin-2-one of formula (II):  <EMI ID = 973.1> Which one: <EMI ID = 974.1> <EMI ID = 975.1>  <EMI ID = 976.1> <EMI ID = 977.1> oxy, a trialkylsilyloxy group, an acylthio group, an alkylthio group or an acylamino group, and A is as defined in claim 1); - R9 represents a lower alkyl group; and <EMI ID = 978.1> with a base; (b) reacting the product of step (a) with carbon disulfide; (c) reacting the product of step (b) with a compound of formula (III):  <EMI ID = 979.1> (in which X represents a halogen atom) or with a dicarboxylic acid dihalide; (d) halogenating the product of step (c); Ce) reacting the product of step (d) with a base to obtain a compound of formula (XII):  <EMI ID = 980.1>  <EMI ID = 981.1> <EMI ID = 982.1> protected group and, if necessary, convert a  <EMI ID = 983.1> an azido group, an amino group, an acylamino group or an alkylthio group; and  <EMI ID = 984.1> or (f) to obtain a pharmaceutically acceptable salt of this product. 13) Process for the preparation of a compound of formula  <EMI ID = 985.1>  <EMI ID = 986.1>  <EMI ID = 987.1> ceutically acceptable, characterized in that it comprises the stages consisting:  <EMI ID = 988.1> mule (II):  <EMI ID = 989.1> [where: <EMI ID = 990.1>  <EMI ID = 991.1>  <EMI ID = 992.1> acyloxy, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group or an acylamino group, and A is as defined in claim 1); - R9 represents a lower alkyl group; and - R represents a carboxy group protected / with a base; (b) reacting the product of step (a) with carbon disulfide; (c) reacting the product of step (b) with a compound of formula (VI):  <EMI ID = 993.1>   <EMI ID = 994.1> represents an alkyl group, an aryl group or an aralkyl group); (d) halogenating the product of step (c); (e) reacting the product of step (d) with a base to obtain a compound of formula (XII):  <EMI ID = 995.1>  <EMI ID = 996.1> (f) if necessary, removing any protecting group and, if necessary, converting a hydroxy group represented by R4 to an acyloxy group, an azido group, an amino group, an acylamino group or an alkylthio group; and (g) optionally salifying the product of step (e) or (f) to obtain a pharmaceutically acceptable salt of this product. 14) A method according to claim 12 or claim 13, characterized in that it comprises the additional step of reacting the compound of formula (XII), before or after removal of the protective groups and conversion of said hydroxy group in step (f), with a compound of formula (XIX):  <EMI ID = 997.1>  <EMI ID = 998.1> alkyl group, an alkyl group comprising one or more halogen substituents, an aralkyl group, an aryl group, an amino group, an alkylated amino group in which the alkyl group or groups optionally comprise one or more substituents chosen from hydroxy, protected amino or protected carboxy, a cyclic amino group, an amino group comprising one or more substituents chosen from aryl, heterocyclic or aralkyl groups, a hydrazino group, a hydrazino group comprising one or more substituents chosen from alkyl, aralkyl or aryl groups, a hydroxyamino group, an alkoxyamino group or a group guanidino, Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and A 'represents a bivalent saturated aliphatic hydrocarbon group) to obtain a compound of formula (XX):  <EMI ID = 999.1>  <EMI ID = 1000.1>  <EMI ID = 1001.1> the above-mentioned meanings) and, if necessary, to remove the protecting groups from all protected groups. 15) Method according to any one of claims 12, 13 and 14, characterized in that:  <EMI ID = 1002.1> thyle, an alpha-hydroxyethyl group, an alpha-acetoxyethyl group, an alpha-propionyloxyethyl group, an alpha-butyryloxyethyl group, an alpha-aminoethyl group, an alpha-acetylaminoethyl group, an alpha-propionylaminoethyl group, an alpha-butyrylaminoethyl group or a methoxy group; and R <3> represents a carboxy group, a pivotal group  <EMI ID = 1003.1> bonyle. 16) Process for the preparation of a compound of formula (I):  <EMI ID = 1004.1>   <EMI ID = 1005.1> di.cation 1 and R <2> represents a group of formula  <EMI ID = 1006.1> A 'and R7 being as defined in claim 1), characterized in that it comprises the stages consisting.  <EMI ID = 1007.1> formula (II):  <EMI ID = 1008.1> /in which: - R8 represents a hydrogen atom, an alkyl group, <EMI ID = 1009.1>  <EMI ID = 1010.1> loxy, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group or an acylamino group, and A is as defined in claim 1); - R9 represents a lower alkyl group; and - R10 represents a carboxy group protects / with a base; (b) reacting the product of step (a) with carbon disulfide; (c) reacting the product of step (b) with a compound of formula (IV):  <EMI ID = 1011.1> (in which A 'is as defined above and R7' represents a hydrogen atom, an alkyl group, an alkyl group comprising one or more halogen substituents, an aralkyl group or an aryl group); (d) halogenating the product of step (c); (e) reacting the product of step (d) with a base to obtain a compound of formula (XXVI):  <EMI ID = 1012.1>  <EMI ID = 1013.1> above); (f) if necessary, removing all protecting groups and, if necessary, converting a represented hydroxy group  <EMI ID = 1014.1>  <EMI ID = 1015.1> and, if necessary, transform any of the  <EMI ID = 1016.1> groups represented by R7; and (g) optionally salifying the product of step (e) or (f) to obtain a pharmaceutically acceptable salt of this product. 17) Method according to claim 16, characterized in that: R represents a hydrogen atom, an ethyl group, an ethyl group comprising, in the alpha position, a substituent chosen from hydroxy, amino, C2-C4 aliphatic acyloxy or C2-C4 aliphatic acylamino, or a methoxy group; R <2> represents a group of formula  <EMI ID = 1017.1>  <EMI ID = 1018.1> <EMI ID = 1019.1> amino group substituted with one. Lower alkyl group, an amino group substituted by a lower hydroxyalkyl group, an amino group substituted by a lower aminoalkyl group, an amino group substituted by a lower groucarboxyalkyl, an amino group substituted by a lower alkoxycarbonylalkyl group, an amino group substituted by a lower aralkyloxycarbonylalkyl group, a cyclic amino group, arylamino group, amino group substituted by heterocyclic group, hydroxy group, lower alkoxy group, hydrazino group, hydrazino group substituted by lower alkyl group, hydroxyamino group, lower alkoxyamino group or guanidino group, and A 'represents a bivalent saturated aliphatic straight chain or branched chain hydrocarbon group having 1 to 3 carbon atoms); and  <EMI ID = 1020.1> loyloxymethyloxycarbonyl or an E-nitrobenzyloxycarbonyl group. 18) Process for the preparation of a compound of formula (the):  <EMI ID = 1021.1>  <EMI ID = 1022.1>  <EMI ID = 1023.1>  <EMI ID = 1024.1> an alkyl group, an alkyl group comprising one or more substituents chosen from protected hydroxy, amino, carboxy or carboxy groups, an aryl group, a heterocyclic group, an aralkyl group, a group  <EMI ID = 1025.1> killing agents chosen from alkyl, aralkyl or aryl groups, a hydroxy group, an alkoxy group or an amidino group,  <EMI ID = 1026.1> to which they are linked, represents a nitrogen heterocyclic group) characterized in that it comprises the stages consisting of: (a) reacting a 4-alkylthio-azetidin-2-one of formula (II):  <EMI ID = 1027.1> / in which: <EMI ID = 1028.1> an alkoxy group or a group of formula R '' A- (in which R14 represents an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group or an acylamino group, and A is as defined in claim 1); - R9 represents a lower alkyl group; and <EMI ID = 1029.1> with a base; (b) reacting the product of step (a) with carbon disulfide; (c) reacting the product of step (b) with a compound of formula (V):  <EMI ID = 1030.1>  <EMI ID = 1031.1> as defined in claim 1 and Z represents a <EMI ID = 1032.1> <EMI ID = 1033.1>  <EMI ID = 1034.1> set of formula (XV):  <EMI ID = 1035.1>  <EMI ID = 1036.1>  <EMI ID = 1037.1> alkyl group, an alkyl group comprising one or more substituents chosen from hydroxy, protected amino or protected carboxy groups, an aryl group, a heterocyclic group, an aralkyl group, an amino group, an amino group comprising one or more substituents chosen from alkyl, aralkyl or aryl groups, a hydroxy group, an alkoxy group or an amidino group, or  <EMI ID = 1038.1> which they are connected, represent a nitrogen heterocyclic group) to obtain a compound of formula (XVI):  <EMI ID = 1039.1>  <EMI ID = 1040.1> mentioned above); (f) if necessary, remove the protecting group from any protected group and, if necessary, convert a group <EMI ID = 1041.1> azido, an amino group, an acylamino group or an alkylthio group; and  <EMI ID = 1042.1> (f) to obtain a pharmaceutically acceptable salt of this product. 19) Method according to claim 18, characterized in that:  <EMI ID = 1043.1>  <EMI ID = 1044.1>  <EMI ID = 1045.1>  <EMI ID = 1046.1> in C2-C4, or a methoxy group; and R <3> represents a carboxy group, a pivotal group  <EMI ID = 1047.1> carbonyl. 20) Process of a compound of formula (If):  <EMI ID = 1048.1>  <EMI ID = 1049.1>  <EMI ID = 1050.1> an alkyl group, an aryl group or an aralkyl group), characterized in that it comprises the stages consisting: (a) reacting a 4-alkylthio-azetidin-2-one of formula (II):  <EMI ID = 1051.1>  <EMI ID = 1052.1> <EMI ID = 1053.1> an alkoxy group or a group of formula R 14 A- (in  <EMI ID = 1054.1> acyloxy, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, an acylthio group, an alkylthio group or an acylamino group, and A is as defined in claim 1); <EMI ID = 1055.1>  <EMI ID = 1056.1> with a base; (b) reacting the product of step (a) with carbon disulfide; (c) reacting the product of step (b) with a compound of formula (V):  <EMI ID = 1057.1> (in which X represents a halogen atom, A 'is as defined above and Z represents a halogen atom or a lower alkoxycarbonyloxy group); (d) halogenating the product of step (c); (e) reacting the product of step (d) with a compound of formula (XVII):  <EMI ID = 1058.1>  <EMI ID = 1059.1> a base to obtain a compound of formula (XVIII):  <EMI ID = 1060.1>  <EMI ID = 1061.1> above); (f) if necessary, removing the protecting group from any protected group and, if necessary, converting a hydroxy group represented by R4 to an acyloxy group, an azido group, an amino group, an acylamino group or an alkylthio group; and (g) optionally salifying the product of step (e) or to obtain a pharmaceutically acceptable salt of this product. 21) Product according to claim 20, characterized in that:  <EMI ID = 1062.1> ethyl, an alpha-hydroxyethyl group, an alpha- group  <EMI ID = 1063.1> alpha-butyryloxyethyl group, alpha-aminoethyl group, alpha-acetylaminoethyl group, alphapropionylaminoethyl group, alpha-butyrylaminoethyl group or methoxy group; and  <EMI ID = 1064.1>  <EMI ID = 1065.1> carbonyl. 22) Process for the preparation of a compound of formula  <EMI ID = 1066.1>  <EMI ID = 1067.1> claim 1), characterized in that it comprises the steps consisting: (a) reacting a 4-alkylthio-azetidin-2-one of formula (II):  <EMI ID = 1068.1> / in which: <EMI ID = 1069.1>  <EMI ID = 1070.1> <EMI ID = 1071.1>  <EMI ID = 1072.1> trialkylsilyloxy group, acylthio group, group  <EMI ID = 1073.1> upper ; - R9 represents a lower alkyl group; and - R10 represents a protected carboxy group? with a base; (b) reacting the product of step (a) with carbon disulfide; <EMI ID = 1074.1> set of formula (III):  <EMI ID = 1075.1> (in which X represents a halogen atom); (d) halogenating the product of step (c); (e) reacting the product of step (d) with a compound of formula (XIII):  <EMI ID = 1076.1>  <EMI ID = 1077.1> dication 1); (f) if necessary, remove the protecting group from any protected group and, if necessary, transform a group <EMI ID = 1078.1> azido, an amino group, an acylamino group or an alkylthio group; and (g) optionally salifying the product of step (e) or (f) to obtain a pharmaceutically acceptable salt of this product. 23) Method according to claim 22, characterized in that: <EMI ID = 1079.1>  <EMI ID = 1080.1> alpha-butyryloxyethyl group, alpha-aminoethyl group, alpha-acetylaminoethyl group, alphapropionylaminoethyl group, alpha-butyrylaminoethyl group or methoxy group; R <3> represents a carboxy group, a pivotal group  <EMI ID = 1081.1> carbonyl; and  <EMI ID = 1082.1> of them represents a methyl, ethyl, propyl, iso- group  <EMI ID = 1083.1> tion with the nitrogen atom to which they are linked, represent a 1-pyrrolidinyl, piperidino, 4-hydroxypiperidino, morpholino or 1-piperazinyl group. 24) Method according to any one of claims 12 to 23, characterized in that the salification of step (g) gives a sodium or potassium salt. 25) Pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable carrier or diluent, characterized in that the antibiotic consists with one or more of the compounds of formula (I):  <EMI ID = 1084.1> in which: R represents a hydrogen atom, a group  <EMI ID = 1085.1> (in which R represents a hydroxy group, an alkoxy group, an alkoxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group, <EMI ID = 1086.1> an acylamino group or an azido group, and A represents a bivalent saturated aliphatic hydrocarbon group optionally comprising a substituent consisting of a trifluoromethyl and / or phenyl group); R <2> represents a hydrogen atom, a group of formula  <EMI ID = 1087.1> (in which R5 and R6 are identical or different, each of them representing an alkyl group, an aralkyl group or an aryl group or else R5 and R6 represent, in association with the nitrogen atom to which they are linked, a group heterocyclic nitrogen) or a group of formula  <EMI ID = 1088.1> (in which R7 represents a hydrogen atom, an alkyl group, an alkyl group comprising one or more halogen substituents, an aralkyl group, an aryl group, an amino group, an alkylated amino group in which the alkyl group or groups optionally contain a had several subs-  <EMI ID = 1089.1> or protected carboxy, a cyclic amino group, an amino group comprising one or more substituents chosen from aryl, heterocyclic or aralkyl groups, a  <EMI ID = 1090.1> aralkyloxy group, hydrazino group, hydrazino group having one or more substituents selected from alkyl, aralkyl or aryl groups, hydroxyamino group, alkoxyamino group or guanidino group, and A 'represents a bivalent saturated aliphatic hydrocarbon group); and R <3> represents a carboxy group or a protected carboxy group; including the tautomers of said compounds in which R2 represents a hydrogen atom; and the pharmaceutically acceptable salts of said compounds. 26) Composition according to claim 25, characterized in that the above-mentioned antibiotic is 2- (1-carbamoylethylthio) -6- (1-hydroxyethyl) penem-3-carboxylic acid or one of its salts or esters.