BE889151A - PENEME-3-CARBOXYLIC ACID DERIVATIVES, PREPARATION METHODS THEREOF AND THERAPEUTIC APPLICATION THEREOF - Google Patents

Description

       

    <EMI ID = 1.1>

  
both an interesting antibacterial activity and a relatively low toxicity, as well as processes for the preparation of these compounds.

  
Penicillins are a well-known class of antibiotics which ,. for many years have been used on a very large scale in human and animal therapy. In truth, benzyl-penicillin, which has been

  
  <EMI ID = 2.1>

  
general tick, is still widely used today.

  
Chemically, penicillins have in common a beta-lactam structure, commonly known as

  
  <EMI ID = 3.1>

  

  <EMI ID = 4.1>


  
However, although penicillins are still an interesting 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, attention has been paid to compounds having a penem structure, that is to say compounds having a double bond between the carbon atoms of positions 2 and 3 of the basic penam structure. The penem structure is as follows:

  

  <EMI ID = 5.1>
 

  
These pename and penema structures form the basis of a semi-systematic nomenclature of penicillin derivatives and this nomenclature is generally accepted by those skilled in the art, worldwide, and is used herein, the system numbering being that illustrated on the structures above

  
  <EMI ID = 6.1>

  
Various derivatives have been described in recent years, for example in the patent for

  
  <EMI ID = 7.1>

  
British Patent No. 2,013,674 (Cita Geigy) and British Patent No. 2,048,261 (Sankyo).

  
The compound described in the British patent

  
  <EMI ID = 8.1>

  
being of considerable interest to me, since it has excellent activity against a wide variety of bacteria and therefore considerable potential for use as an antibiotic. However, this compound was later found to have relatively high acute toxicity.

  
The Applicant has now surprisingly found a series of neighboring compounds which not only exhibit higher anti-bacterial activity, but which also have a much lower acute toxicity.

  
The compounds of the present invention respond

  
  <EMI ID = 9.1>
  <EMI ID = 10.1>
   <EMI ID = 11.1>
(in which :

  
R represents a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a <EMI ID = 12.1> lyloxyalkyl;

  
R <2> represents a hydrogen atom or an alkyl group;

  
  <EMI ID = 13.1>

  
protector of an amino group or a group of formula

  

  <EMI ID = 14.1>


  
(wherein R4 and R6, which are the same or different, each represents a hydrogen atom or an alkyl group);

  
A represents a branched chain alkylene group; and

  
R4 represents a carboxy group or a protected carboxy group.

  
The invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I).

  
The invention further relates to a method of

  
  <EMI ID = 15.1>

  
pharmaceutically acceptable, this process consisting in heating a phosphorus-ylide compound of formula (II):

  

  <EMI ID = 16.1>
 

  
  <EMI ID = 17.1>

  
  <EMI ID = 18.1>

  
alkyl, an alkoxy group, an acyloxyalkyl group, an alkylsulfonyloxyalkyl group, an arylsulfonyloxyalkyl group or a trialkylsilyloxyalkyl group;

  
  <EMI ID = 19.1>

  
eg amino;

  
R9 represents a protected carboxy group; and

  
Z + represents a trisubstituted phosphonio group

  
  <EMI ID = 20.1>

  
to obtain a compound of formula (III):

  

  <EMI ID = 21.1>


  
  <EMI ID = 22.1>

  
cited above).

  
This compound of formula (III) may be the desired end product, in which case it will be separated from the reaction mixture as described below. Furthermore, if necessary, it can be subjected to one or more of the steps

  
  <EMI ID = 23.1>

  
suitable house: <EMI ID = 24.1> carboxy to regenerate a free carboxy group; <EMI ID = 25.1>

  
and / or R, to regenerate a hydroxy group, an amino group or an alkylamino group;
(c) when the product obtained contains the group R <2> -NH-, converting it to a group of formula
  <EMI ID = 26.1>
(in which R5, R6 and R <2> are as defined above); and
(d) salification of the compound to produce a pharmaceutical salt <EMI ID = 27.1>

  
Another embodiment of the invention consists in a process for preparing the compounds of form

  
  <EMI ID = 28.1>

  
by reaction of an azetidine-2-one derivative, of formula (IV):

  

  <EMI ID = 29.1>


  
  <EMI ID = 30.1>

  
mentioned above and Y represents an oxygen atom or a sulfur atom) with a phosphorous acid triester or a phosphorous acid triamide, preferably of formula IV:

  

  <EMI ID = 31.1>


  
  <EMI ID = 32.1>

  
eg dialkylamino). If desired, any combination of steps (a) to (d) above can then be performed.

  
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or

  
a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.

  
We will now give a detailed description of the invention.

  
In the compounds of formula (I) and their salts

  
  <EMI ID = 33.1>

  
alkyl group, it is preferably a lower alkyl group which may be straight chain or branched chain

  
  <EMI ID = 34.1>

  
  <EMI ID = 35.1>

  
alkoxy group, this is preferably a lower alkoxy group, which may be straight or branched chain, for example a methoxy, ethoxy, propoxy, isopropcxy group,

  
  <EMI ID = 36.1>

  
droxyalkyl, this is preferably a hydroxy-

  
  <EMI ID = 37.1>

  
  <EMI ID = 38.1>

  
or 1-hydroxybutyl.

  
When R represents an acyloxyalkyl group,

  
  <EMI ID = 39.1>

  
laughing, which may be straight or branched chain, for example one of the alkyl groups illustrated above

  
while the acyl group is preferably a lower aliphatic acyl group or an aralkyloxycarbonyl group. Examples of such acyloxyalkyl groups include acetoxymethyl, 1-acetoxyethyl, 1-propionyloxy-

  
  <EMI ID = 40.1>

  
thyle or 1 - (&#65533; -nitrobenzyloxycarbonyloxy) butyl.

  
  <EMI ID = 41.1>

  
  <EMI ID = 42.1>

  
is preferably a lower alkyl group and examples of such alkylsulfonyloxyalkyl groups include:

  
  <EMI ID = 43.1>

  
pyle, 1-ethanesulfonyloxypropyle, 1-methanesulfonyloxy-1- <EMI ID = 44.1>

  
represents an arylsulfonyloxyalkyl group, the alkyl group is preferably a lower alkyl group and examples of such arylsulfonyloxyalkyl groups include

  
  <EMI ID = 45.1>

  
sulfonyloxybutyl. When R represents a trialkylsilyloxyalkyl group, the alkyl group cited last in this name is preferably a lower alkyl group,

  
  <EMI ID = 46.1>

  
  <EMI ID = 47.1>

  
alkyl, which may be a straight chain or branched chain group, preferably a lower alkyl group, for example a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.

  
  <EMI ID = 48.1>

  
amino group, it is preferably an aralkyloxycarbonyl group, for example a benzyloxycarbonyl group or

  
  <EMI ID = 49.1>

  
formula pe

  

  <EMI ID = 50.1>


  
  <EMI ID = 51.1>

  
an alkyl group, preferably a lower alkyl group such as a methyl, ethyl, propyl, isopropyl group.

  
A represents a branched chain alkylene group which is preferably a lower alkylene group, examples of such groups including 1-methylethylene, 1-ethylethylene, 1-propylethylene, 1-isopropylethylene, 1-butylethylene, 2-methylethylene, 2 -ethyl-

  
  <EMI ID = 52.1> <EMI ID = 53.1>

  
trimethylene, 2-isopropyltrimethylene, 2-butyltrimethylene, 3-methyltrimethylene, 3-ethyltrimethylene, 3-propyltrime-

  
  <EMI ID = 54.1>

  
thylene.

  
R4, which represents a carboxy group or a group

  
  <EMI ID = 55.1>
-COOR4, <EMI ID = 56.1>

  
protecting group of a carboxy group. Suitable examples of protecting groups for carboxy groups include: straight or branched chain lower alkyl groups, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; lower haloalkyl groups, such as 2-iodoethyl groups,

  
  <EMI ID = 57.1> <EMI ID = 58.1> phthalidyl.

  
Particularly preferred compounds of formula (I) are those, and their salts, in which:

  
R represents a methoxy group or a 1-hydroxyethyl group:

  
R2 represents a hydrogen atom or a group

  
  <EMI ID = 59.1>

  
  <EMI ID = 60.1>

  
eg formimidoyl or an acetimidoyl group;

  
A represents a group of ethylene, trimethylene or tetramethylene, the carbon chain of which comprises one or two methyl and / or ethyl substituents (for example the

  
  <EMI ID = 61.1>

  
tetramethylene, 4-methyltetramethylene, 1-ethyltetramethylene, 2-ethyltetramethylene, 3-ethyltetramethylene, 4-

  
  <EMI ID = 62.1> <EMI ID = 63.1>

  
The most preferred compounds of the invention are the compounds of formula (I), and their salts, in which:

  
R *] represents a hydroxyethyl group;

  
R represents a hydrogen atom or a

  
  <EMI ID = 64.1>

  
drogenic;

  
R <3> represents a hydrogen atom, a formimidoyl group or an acetimidoyl group, and better still-

  
  <EMI ID = 65.1>

  

  <EMI ID = 66.1>


  
in which R 4 "represents a hydrogen atom, a pivaloyloxymethyl group, a sodium atom or a potassium atom, preferably a hydrogen atom or a

  
  <EMI ID = 67.1>

  
A represents an ethylene or trimethylene group, preferably an ethylene group, the carbon chain of which comprises one or two, preferably one, methyl substituent in the alpha or beta positions, preferably the alpha position.

  
A list of preferred compounds according to the present invention is given below:

  
  <EMI ID = 68.1>

  
carboxylic.

  
  <EMI ID = 69.1>

  
thyl) penem-3-carboxylic.

  
(16) 2- (2-amino-1-methylpropylthio) -6- (1-hydroxy-) acid

  
thyl) penem-3-carboxylic.

  
  <EMI ID = 70.1>

  
peneme-3-carboxylic.

  
  <EMI ID = 71.1>

  
peneme-3-carboxylic.

  
(27) 2- (2-Formimidoylamino-1-methylethylthio) -6-metho- acid

  
xypenem-3-carboxylic.

  
  <EMI ID = 72.1>

  
thyl) penem-3-carboxylic.

  
(35) 2- (2-Formimidoylamino-1-ethylethylthio) -6- (1-

  
  <EMI ID = 73.1>

  
pivaloyloxymethyl carboxylate.

  
  <EMI ID = 74.1>

  
propylthio) penem-3-carboxylic.

  
(46) Acid 2- (3-ethylamino-1-methylpropylthio) -6- (1-hydro-

  
xyethyl) penem-3-carboxylic.

  
  <EMI ID = 75.1>

  
  <EMI ID = 76.1>

  
above, which are acids, i.e. compounds Nos. 1 to 8, No. 10, No. 12 to 37 and Nos. 43 to 46, sodium and potassium salts are also preferred. Compound No. 8 and its salts are most preferred, especially in the (5R, 6S) -1 '- (R) configuration.

  
Due to the presence of asymmetric carbon atoms in the compounds of the invention, these can exist in the form of various stereoisomers, both optical isomers and geometric isomers. All these isomers are represented here by a single formula, but it is obvious that the present invention covers both the individual isomers as well as the mixtures thereof. Preferred compounds are those in which the carbon atom in position 5 is in the same configuration as the corresponding atom of natural penicillins, i.e. the R configuration and, therefore, the (5R, 6S) isomers ) and (5R, 6R) are particularly preferred. When group R (in position

  
6 of the penem system) is an alkyl group substituted in po- <EMI ID = 77.1> butyldimethylsilyloxyethyl), the preferred configuration of the substituent is again configuration R.

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

  
Method A

  
In this process, compounds of formula (III) are prepared:

  

  <EMI ID = 78.1>


  
  <EMI ID = 79.1>

  
  <EMI ID = 80.1>

  
mule (II):

  

  <EMI ID = 81.1>


  
  <EMI ID = 82.1>

  
mentioned above).

  
The reaction can be carried out in the presence or in the absence of a solvent. When a solvent is used, its nature is not decisive provided that it does not have an adverse effect on the reaction. Suitable solvents include ethers, such as dioxane, and aromatic hydrocarbons, such as benzene, toluene or xylene. The temperature to which the phosphoreylide compound (II) is heated is also not critical, but the Applicant prefers to carry out this reaction at

  
  <EMI ID = 83.1>

  
an atmosphere of an inert gas such as nitrogen or argon.

  
When no solvent is used, the reaction can also be carried out in a reaction vessel under vacuum.

  
The time required for the reaction depends on the nature of the starting materials and the reaction temperature, but a time of about 5 to 12 hours is generally sufficient.

  
  <EMI ID = 84.1>

  
desired formula (III) can be extracted from the reaction mixture by conventional means. For example, a system

  
suitable recovery involves distilling the solvent under reduced pressure from the reaction mixture

  
  <EMI ID = 85.1>

  
to the resulting residue, the separation, by filtration, of the precipitates thus obtained and, finally, the elimination of the solvent from the filtrate, by distillation, to obtain the desired compound. If necessary, the compound of formula (III) thus obtained can be further purified by usual means, for example by recrystallization, thin layer chromatography or column chromatography. It is also possible to subject the compound of formula (III) to other reactions, as described below, to prepare other compounds of formula (I).

  
Method B

  
The compounds of formula (III), as defined above, and the corresponding compounds in which

  
  <EMI ID = 86.1>

  
react an azetidinone derivative of formula (IV):

  

  <EMI ID = 87.1>
 

  
with a phosphorous acid ester or amide of formula
(iT):

  

  <EMI ID = 88.1>


  
  <EMI ID = 89.1>

  
aforementioned information.

  
Suitable esters of phosphorous acid include trimethyl phcsphite and triethyl phosphite, while a suitable amide of acid

  
  <EMI ID = 90.1>

  
  <EMI ID = 91.1>

  
preferably from 2 to 20 equivalents per equivalent, of azetidinone derivative (IV).

  
The reaction is preferably carried out in the presence of a solvent, the nature of which is not decisive, provided that it does not produce an adverse effect on the reaction. Suitable solvents include: alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as tetrahydrofuran or dioxane; esters such as ethyl acetate or butyl acetate; aromatic hydrocarbons such as benzene or toluene; halogenated hydrocarbons such as chloroform or methylene chloride; dialkylamides of fatty acids such as dimethylformamide or dimethylacetamide; and nitriles such as acetonitrile. It is also possible to use only one of these solvents or a mixture of two or more of said solvents.

  
The reaction temperature is also not decisive, but the Applicant generally prefers to carry out the reaction at a temperature ranging from

  
room temperature at 150 [deg.] C, and better still 50 [deg.] C

  
at 150 "C. The time required for the reaction depends mainly on the nature of the starting materials and

  
the reaction temperature, this duration generally being from 5 hours to 4 days.

  
When this reaction temperature is relatively low, for example if it is between room temperature and 90 [deg.] C, the simple reaction of the azetidinone derivative (IV) with the ester or amide (V) da phosphorous acid can produce a ylide compound of the formula
(VI):

  

  <EMI ID = 92.1>


  
  <EMI ID = 93.1>

  
  <EMI ID = 94.1>

  
must then be heated, without requiring any intermediate purification, to give the desired derivative of penem-3-carboxylic acid. The heating temperature is preferably 100 to 150 [deg.] C and the time required for this reaction is generally 4 to 48 hours.

  
The compounds prepared as described by Methods A and B can then be subjected to any one or more of the following reactions:
removal of protecting groups from hydroxy groups, removal of protecting groups from amino groups, removal of protecting groups from carboxy groups, replacement

  
  <EMI ID = 95.1>

  
mule

  

  <EMI ID = 96.1>


  
and salification.

  
Removal of protecting groups from carboxy groups

  
The protected carboxy group represented by R9 in the compound obtained by Method A or B can be converted into a free carboxy group by conventional means. The reaction required to remove the protective group depends on the nature of the latter, but any method known in the art can be used.

  
For example, when the protecting group is a

  
  <EMI ID = 97.1>

  
raised by bringing the compound produced in Method A or B into contact with a reducing agent. In the case of halogenated alkyl groups, (for example 2,2-dibro-

  
  <EMI ID = 98.1>

  
preferred is a combination of zinc with acetic acid.

  
In the case of aralkyl groups (e.g. groups

  
  <EMI ID = 99.1>

  
preferred reducing agent is a catalytic reducing agent
(e.g. palladium on carbon), in the presence of hydrogen, or an alkali metal sulfide (e.g.

  
  <EMI ID = 100.1>

  
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 is normally

  
  <EMI ID = 101.1>

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

  
When the reaction is complete, the product can be extracted from the reaction mixture by usual means, for example by separation of the insolubles by filtration, washing with water of the phase constituted by the organic solvent and dehydration thereof, then separation. solvent by distillation. If necessary, the product can be further purified by conventional means such as recrystallization, thin layer chromatography or column chromatography.

  
Removal of protecting groups from hydroxy and amino groups <EMI ID = 102.1>

  
Method A or B, represents an acyloxyalkyl group or a

  
  <EMI ID = 103.1>

  
has a protecting group for an amino group, the protecting groups can, if necessary, be removed by usual means to regenerate a free hydroxy group, a

  
  <EMI ID = 104.1>

  
alkyl) a free alkylamino group. These reactions can take place before, after or at the same time as removal.

  
  <EMI ID = 105.1>

  
The compounds in which R represents a

  
  <EMI ID = 106.1>

  
on the compound of formula (III), the protecting group for a hydroxy group (for example an acyl group or a trialkylsilyl group). When the protected hydroxy group is a lower aliphatic acyloxy group (for example a group

  
  <EMI ID = 107.1>

  
presence of an aqueous solvent. There is no particular limiting condition as to the nature of this solvent and any solvent commonly used for hydrolysis can be used. However, the Applicant very particularly prefers water or a mixture of water and 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 alter other parts of the compound, in particular the beta-lactam nucleus. Preferred bases are alkali metal carbonates such as sodium carbonate.

  
  <EMI ID = 108.1>

  
is not decisive either, but the Application

  
  <EMI ID = 109.1>

  
room temperature to prevent side reactions. The time required for the reaction varies depending on the nature of the starting materials and <EMI ID = 110.1>

  
of the reaction temperature, but the reaction is normally complete after 1 to 6 hours.

  
  <EMI ID = 111.1>

  
aralkyloxycarbunyloxyalkyle group [pound] -for example a

  
  <EMI ID = 112.1>

  
  <EMI ID = 113.1>

  
can be removed by bringing the corresponding compound into contact with a reducing agent. The reducing agent and the reaction conditions which can be used are the same as those which can be used for the removal of aralkyl groups on the protected carboxy groups R9. Consequently, by choosing the appropriate protective groups, it is possible to remove

  
  <EMI ID = 114.1>

  
  <EMI ID = 115.1>

  
trialkylsilyloxyalkyl group (for example a 1-t- group

  
  <EMI ID = 116.1>

  
be removed by treating the corresponding compound with tetrabutylammonium fluoride in a suitable solvent, the nature of which is not decisive, provided that it does not produce an adverse effect on the reaction. Suitable solvents are ethers such as tetrahydrofuran or dioxane. The reaction is normally carried out near room temperature and normally requires 10 to 18 hours.

  
  <EMI ID = 117.1>

  
represents a hydrogen atom, i.e. the amino and alkylamino compounds, can be prepared by removing the aralkyloxycarbonyl group (for example the benzyloxycarbonyl or p-nitrobenzyloxycarbonyl group) represented by R in the compound of formula (III) . This removal is preferably carried out by reduction. The reducing agents and reaction conditions which are used can be the same as those which can be used for the removal of aralkyl groups on the protected carboxy group represented by R. Consequently, in <EMI ID = 118.1>

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

  
  <EMI ID = 119.1>

  
Conversion of the amino group to an imidoyl group

  
  <EMI ID = 120.1>

  
presents a group of formula

  

  <EMI ID = 121.1>


  
  <EMI ID = 122.1>

  
can be prepared by putting the corresponding compound in which R <3> represents a hydrogen atom, that is to say an amino or alkylamino compound, in contact with an imide-ester of formula (VII):

  

  <EMI ID = 123.1>


  
(in which R5 and R6 have the abovementioned meanings

  
  <EMI ID = 124.1>

  
methyl, ethyl, propyl or isopropyl).

  
The reaction is preferably carried out in the presence of a solvent, the nature of which is not decisive; however, when the starting substance is a

  
  <EMI ID = 125.1>

  
R represents a free carboxy group, the Applicant prefers to use, as solvent, a phosphate buffer solution which maintains the pH of the reaction mixture at a value of approximately 8. The reaction is preferably carried out at a relatively low temperature,

  
  <EMI ID = 126.1>

  
ambient, and the time required for the reaction is normally 10 minutes to 2 hours.

  
Salification

  
The carboxylic acids of formula (I), that is to say the compounds in which R4 represents a <EMI ID = 127.1> free carboxy group, can be transformed into their corresponding pharmaceutically acceptable salts. Examples of such salts include metal salts

  
(in particular lithium, sodium, potassium, calcium or magnesium salts), ammonium salts

  
and salts of organic amines (in particular the cyclohexylammonium, diisopropylammonium or triethylammonium salts), preferably the sodium or potassium salts. The salification reaction can be carried out by means of

  
  <EMI ID = 128.1>

  
after separation of the corresponding carboxylic acid within the reaction mixture.

  
The desired compound, prepared as described above, can be extracted from its reaction mixture by usual means and, if necessary, further purified by recrystallization, thin layer chromatography

  
  <EMI ID = 129.1>

PREPARATION OF STARTING SUBSTANCES

  
Starting substance for Process A

  
The phosphorus-ylide compound of formula (II), which is the starting material for Method A, can be prepared as described by the following reaction scheme, which also summarizes the preparation of the final products from this phosphorus-ylide compound.

  

  <EMI ID = 130.1>
 

  
In the formulas of this reaction scheme,

  
  <EMI ID = 131.1>

  
  <EMI ID = 132.1>

  
an acetoxy, propionyloxy or benzoyloxy group), a group

  
  <EMI ID = 133.1>

  
or ethanesulfonyl) or an arylsulfonyl group (for example a benzenesulfonyl or E-toluenesulfonyl group).

  
  <EMI ID = 134.1>

  
chlorine, bromine or iodine. Examples of groups re-

  
  <EMI ID = 135.1>

  
  <EMI ID = 136.1>

  
free hydroxy groups or free carboxy groups. Examples of groups represented by R, the

  
  <EMI ID = 137.1>

  
aralkyloxycarbonyl groups such as benzylo-

  
  <EMI ID = 138.1>

  
(e.g. tributylphosphonio group) or triarylphosphonio group (e.g. triphenylphos-

  
  <EMI ID = 139.1>

  
terified with a cation, it is preferably a diethylphosphono group accompanied by a lithium or sodium ion.

  
Step (a) of the above reaction scheme consists in reacting the compound of formula (VIII) with

  
  <EMI ID = 140.1>

  

  <EMI ID = 141.1>


  
(in which M represents an alkali metal atom,

  
  <EMI ID = 142.1>

  
  <EMI ID = 143.1>

  
tal alkaline trithiocarbonic acid can itself be prepared by reacting a mercaptan compound of formula (XIII):

  

  <EMI ID = 144.1>


  
  <EMI ID = 145.1>

  
  <EMI ID = 146.1>

  
alkali metal (for example sodium hydroxide or potassium hydroxide) or an alkali metal alcoholate (for example sodium methanolate, sodium ethanolate or potassium ethanclate).

  
  <EMI ID = 147.1>

  
formula (VIII) with the compound of formula (XII) is preferably carried out in the presence of a solvent, the nature of which is not decisive, provided that it does not produce any harmful effect on the reaction. Preferred solvents include: water; alcohols such as methanol, ethanol or propanol; ketones such as acetone or methyl ethyl ketone; fatty acid dialkylamides such as dimethylformamide or dimethylacetamide; and mixtures of one or more of said organic solvents with water. The molar ratio of the compound of formula (VIII) to the compound of formula (XII) is

  
  <EMI ID = 148.1>

  
tional is not critical, although the Applicant prefers to carry out this reaction at a temperature of -20 [deg.] C

  
at 50 [deg.] C. The time required for the reaction depends mainly on the nature of the starting materials and the reaction temperature, but this reaction is normally complete after 10 minutes to 2 hours.

  
The resulting compound of formula (IX) can be extracted from the reaction mixture by usual means, for example as follows: addition of an organic solvent immiscible with water (such as ethyl acetate) and water the reaction mixture; separation of the organic layer; washing the organic layer with water and then dehydrating the latter with a dehydrating agent; and finally separation, by distillation, of the solvent from the organic layer, to obtain the desired compound. The resulting compound can, if necessary, be further purified by usual means, for example by

  
  <EMI ID = 149.1>

  
column matography.

  
Step (b) of the above reaction scheme consists in reacting the compound of formula (IX) with an ester of glyoxylic acid of formula (XIV):

  

  <EMI ID = 150.1>


  
(in which R9 has the abovementioned meaning). This reaction is preferably carried out in the presence of a solvent, the nature of which is not decisive, provided that it does not produce an adverse effect on the reaction. Preferred solvents include: ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene; dialkylamides of fatty acids such as dimethylformamide or dimethylacetamide; and mixtures of these organic solvents. This addition reaction can optionally be accelerated by the presence of a base, for example an organic base (such as triethylamine, diisopropylethylamine or pyridine) or of a molecular sieve made of sodium alumino-silicate. The reaction temperature is not critical, but the Applicant generally prefers to use a time

  
  <EMI ID = 151.1>

  
a base is used, the reaction is preferably carried out near room temperature. Furthermore, if a base is not used, the reaction is preferably carried out at the reflux temperature of the solvent used and,

  
if necessary, in an atmosphere of an inert gas such as nitrogen. The time required for the reaction depends on the nature of the starting materials and the reaction temperature, but the reaction is generally complete after 1 to 6 hours.

  
  <EMI ID = 152.1>

  
When the reaction is complete, the desired compound can be extracted from the reaction mixture by usual means, for example by separating the insolubles from the reaction mixture by filtration, washing the filtrate with water and drying it over a drying agent, and, finally, by distilling off the solvent and the excess from the reactants, in order to obtain the desired compound which can, if necessary, be further purified by usual means such as recrystallization, thin layer chromatography or chromatography in column.

  
Step (c) of the reaction scheme consists of

  
  <EMI ID = 153.1>

  
obtain a compound of formula (XI). This reaction can be carried out simply by putting the compound of formula
(X) in contact with a halogenating agent in the presence of a solvent. The nature of the halogenating agent to be used is not decisive, but the Applicant prefers to use thionyl halides (such as thionyl chloride or thionyl bromide), oxyhalides

  
phosphorus (such as phosphorus oxychloride), phosphorus halides (such as phosphorus pentachloride or phosphorus pentabromide) or oxalyl halides (such as oxalyl chloride). The reaction is preferably carried out in the presence of a base, suitably an organic base, such as triethylamine, diisopropylethylamine, pyridine or lutidine.

  
There is no particular limiting condition as to the nature of the solvent to be used, provided that it does not produce an adverse effect on the reaction. Suitable solvents include ethers such as tetrahydrofuran or dioxane. The reaction temperature is also not critical, but it is preferred to carry out the reaction at a relatively low temperature (for example -15 [deg.] C up to around room temperature) in order to prevent side reactions. If necessary, the reaction can <EMI ID = 154.1>

  
te. The time required for the reaction depends on the nature of the starting materials and the reaction temperature, but the reaction is generally complete after 10 to 30 minutes. When the reaction is complete, the resulting compound of formula (XI) can be extracted from the reaction mixture by usual means, for example by separating, by distillation, the solvent and the excess of reagent; the resulting compound can be appropriately used in the next step without further purification.

  
The halogen atom represented by in the resulting compound of formula (XI) thus obtained can be converted into any other halogen atom by processes

  
  <EMI ID = 155.1>

  
in compound (XI) _7 can be transformed into compound

  
  <EMI ID = 156.1>

  
mineral or mineral iodide (for example lithium bromide or potassium iodide), in an organic solvent such as diethyl ether.

  
Step (d) consists in the preparation of the phosphorus-ylide compound of formula (II) by reaction of the compound of formula (XI) with a phosphine compound or with a phosphorous ester and a base in the presence of a solvent.

  
Suitable phosphine compounds which can

  
  <EMI ID = 157.1>

  
triarylphosphines (such as triphenylphosphine). Suitable phosphorous esters include tri (lower alkyl) phosphites (such as triethyl phosphite) and alkali metal salts of di (lower alkyl) phosphites such as sodium-dimethyl phosphite. When a phosphine compound is used, the base is preferably an organic base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine. Furthermore, when a phosphorous diester is used, the base is preferably an alkali metal hydride (such as sodium hydride) or a lower alkyllithium (such as butyllithium).

   There is no particular limiting condition as to the nature of the solvent to be used, provided that it does not produce an adverse effect on the reaction, the preferred solvents comprising: aliphatic hydrocarbons, such as hexane or cyclohexane; ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene;

  
and fatty acid dialkylamides such as dimethylformamide or dimethylacetamide. The reaction temperature is also not decisive and the Applicant generally prefers to carry out the reaction at a temperature of 30 to 100 [deg.] C, if necessary in an atmosphere of an inert gas such as nitrogen. The time required for the reaction depends on the nature of the starting materials and

  
  <EMI ID = 158.1>

  
1 to 50 hours.

  
When the reaction is complete, the desired phosphorus-ylide compound can be extracted from the reaction mixture.

  
  <EMI ID = 159.1>

  
an organic solvent immiscible with water (such as ethyl acetate) and water is added to the reaction mixture; the organic layer is separated, washed with water and dried with a dehydrating agent; and the solvent is then separated by distillation to obtain the desired compound. This compound can, if desired, be further purified by conventional means such as recrystallization, thin layer chromatography or column chromatography.

  
Steps (e) and (f) of the aforementioned reaction scheme involve the conversion of the phosphorus-ylide compound of formula (II) into the compound of formula (III) and, if desired, into the compound of formula (I), as described in the Process A paragraphs.

  
4-acyloxyazetidine-2-one or 4-sulfonylazetidine-2-one of formula (VIII), which is the starting material for the process illustrated in the above-mentioned reaction scheme, can be prepared, for example, as shown in the following reaction scheme:

  

  <EMI ID = 160.1>


  
In the above formulas, R <1> <2> represents a protecting group for a carboxy group, such as an alkyl group (for example methyl, ethyl or t-butyl) or a

  
  <EMI ID = 161.1>

  
protecting group for a hydroxy group, for example a group <EMI ID = 162.1>

  
silyl.

  
Following the reaction scheme given below-

  
  <EMI ID = 163.1>

  
  <EMI ID = 164.1>

  
(1969) _7 is treated with trimethyloxonium tetrafluoroborate and a base (such as hydrated alumina, of basic character), successively, to give the open-cycle compound of formula (XVI). This compound of formula (XVI)

  
  <EMI ID = 165.1>

  
me methylmagnesium bromide) or with a dialkylcivelithithium (such as dimethylcopper-lithium) to give the compound of formula (XVII). According to another embodiment, it is first treated with zinc in the presence

  
  <EMI ID = 166.1>

  
then reacted with acetaldehyde, to give the

  
  <EMI ID = 167.1>

  
compound (XVII) is then protected by usual means to give the compound (XVIII). This compound (XVIII) is either treated with mercuric acetate in acetic acid and oxidized by potassium permanganate to give one of the desired starting substances (Villa), or oxidized by potassium periodate, in the presence of permanga-

  
  <EMI ID = 168.1>

  
When the compound of formula (XVII) is prepared from the compound of formula (XVI) by the process defined

  
  <EMI ID = 169.1>

  
hydroxyethyl in position 3 of the azetidinone ring is mainly the S configuration. If the compound is treated with an organic acid in the presence of triphenylphospbine and diethyl azodicarboxylate, an acy compound is obtained.

  
  <EMI ID = 170.1>

  
  <EMI ID = 171.1>

  
has been reversed). This compound can then be reconverted into the hydrcxy compound by treatment with a solution of an alkali metal alcoholate in an alcohol (for example sodium methanolate in methanol) by usual procedures, in which case the position 1 'retains the configuration A. This compound of configuration R can then be used, in the following processes, to

  
  <EMI ID = 172.1>

  
It is also possible to react the compound of formula (XVI) with aliphatic aldehydes

  
  <EMI ID = 173.1>

  
both a 1-hydroxyalkyl group, other than the 1-hydroxyethyl group, in position 3 of the azetidinone ring. The preparation of other starting materials can be carried out in a similar manner.

  
Preparation of starting substances for Process B

  
The compound of formula (IV), which is the starting substance for Method B, can be prepared by reacting an azetidinone derivative of formula (XIX):

  

  <EMI ID = 174.1>


  
  <EMI ID = 175.1>

  
mentioned above, this derivative can be synthesized by the methods described in the following references from the literature: S. Oida, A. Yoshida, T. Hayashi, N. Takeda, T. Nishimura and E. Ohki, J. Antibiotics, 33, 107 (1980), I. Emest, J. Gosteli, CW Greengrass, W. Holick, DE Jack-

  
  <EMI ID = 176.1>

  
100, 8214 (1978) _7 with 1 to 4 equivalents of an alkoxalyl halide of formula (XX):

  

  <EMI ID = 177.1>
 

  
  <EMI ID = 178.1>

  
smells of a halogen atom, preferably chlorine or bromine), in the presence of a solvent and from 1 to 4 equivalents of an organic base. The product thus obtained can be extracted and, if desired, then purified by usual means.

  
The compounds of the invention have been found to exhibit excellent anti-bacterial activities vis-à-vis a wide range of pathogenic microorganisms. We

  
  <EMI ID = 179.1>

  
that they have an excellent antibacterial activity both towards Gram positive microorganisms (such as Staphylococcus aureus and Bacillus subtilis) as against

  
  <EMI ID = 180.1>

  
and Pseudomonas aeruginosa). The minimum inhibition concentrations of one of the compounds of the invention, except for

  
  <EMI ID = 181.1>

  
  <EMI ID = 182.1>

  
various microorganisms.

  
Board -

  

  <EMI ID = 183.1>


  
Compound A is the compound of the invention and

  
compound B is the known compound. It can be seen that the compound of the invention exhibits a much better activity than that of the known compound, even if the activity of the designed compound is itself extremely good. In addition, when compounds A and B are injected intravenously into mice, compound B kills them at a dose of

  
  <EMI ID = 184.1>

  
harmful effect at a dose of 1000 mg / kg, which shows

  
  <EMI ID = 185.1>

  
  <EMI ID = 186.1>

  
can be used for the treatment of provocative diseases

  
  <EMI ID = 187.1>

  
orally (e.g. in the form of tablets, capsules, granules, powders or syrups) or parenterally

  
  <EMI ID = 188.1>

  
  <EMI ID = 189.1>

  
the patient's body weight and condition, as well as <EMI ID = 190.1>

  
Compounds according to the invention can be administered at a daily dose of 250 to 3000 mg in the case of adults, either in a single dose or in elementary dose fractions.

  
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 following Preparations.

  
EXAMPLE 1

  
  <EMI ID = 191.1>

  
tion of <1> 2.5 mg (0.57 millimole) of metallic sodium in 4 ml of methanol at -10 [deg.] C and the mixture is then stirred for 5 minutes. 45 mg (0.59 millimole) of

  
  <EMI ID = 192.1>

  
temperature, then stir for 10 minutes. Then added to the solution, at the same temperature, 154

  
  <EMI ID = 193.1>

  
about 1 hour. When the reaction is complete, the reaction solution is made slightly acidic by adding a drop of acetic acid, diluted with α-

  
  <EMI ID = 194.1>

  
sodium chloride and dehydrated. After evaporation of the solvent, the resulting residue is subjected to column chromatography through 10 g of silica gel which

  
  <EMI ID = 195.1>

  
ethyl acetate in benzene, which gives 237 mg
(yield: 77%) of the desired product, in the form of a yellow oil.

  
Elementary analysis?

  

  <EMI ID = 196.1>


  
  <EMI ID = 197.1>

  

  <EMI ID = 198.1>


  
EXAMPLE 2

  
  <EMI ID = 199.1>

  
2-one

  
It is heated under reflux for 10 hours, a

  
  <EMI ID = 200.1>

  
  <EMI ID = 201.1>

  
benzyl and 5 ml of benzene. When the reaction is complete, the solvent is distilled off and the resulting residue is subjected to column chromatography through 10 g of silica gel, the elution being carried out with a 7-10% solution. , in volume / volume, of ethyl acetate in benzene, which gives 234 mg (yield:

  
  <EMI ID = 202.1>

  
Elementary analysis

  
  <EMI ID = 203.1>

  

  <EMI ID = 204.1>


  
Nuclear magnetic resonance spectrum (CHC13) S ppm:

  
  <EMI ID = 205.1>

  
0.08 (3H, singlet);

  
0.85 (9H, singlet);
1.18 (3H. Doublet, J = 6 Hz);

  
1.36 (3H, doublet, J = 7 Hz);

  
3.4 (3H, multiplet);

  
4.2 (3H, multiplet);

  
5.1 - 5.7 (6H, multiplet);

  
  <EMI ID = 206.1>

  
7.50 (2H, doublet);

  
7.55 (2H, doublet);

  
  <EMI ID = 207.1>

  
EXAMPLE 3

  
  <EMI ID = 208.1>

  
34 mg (0.31 millimole) of 2,6-lu- are successively added <EMI ID = 209.1>

  
  <EMI ID = 210.1>

  
the mixture is diluted with ethyl acetate / washed with water and dried. The solvent is distilled off and the resulting residue is subjected to. chromato-

  
  <EMI ID = 211.1>

  
  <EMI ID = 212.1>

  
volume, ethyl acetate in benzene, which gives

  
  <EMI ID = 213.1>

  
of a yellow oil.

  
Elementary analysis:

  

  <EMI ID = 214.1>


  
EXAMPLE 4

  
  <EMI ID = 215.1>

  
2-one, 10 mg of hydroquinone and 15 ml of xylene is heated under reflux at 130 [deg.] C in a stream of nitrogen, for 7.5 hours. When the reaction is complete, the solvent is distilled off under reduced pressure and the resulting residue is subjected to thin layer chromatography on silica gel, the development being carried out with a 3: 1 mixture (by volume) of benzene and ethyl acetate, <EMI ID = 216.1>

  
  <EMI ID = 217.1>

  
of oils. Nuclear magnetic resonance confirms that the two products obtained above are 1: 1 mixtures

  
  <EMI ID = 218.1>

  
triques of the substituents in position 2.

  
Elementary analysis:

  
  <EMI ID = 219.1>

  
Experimental values:

  
  <EMI ID = 220.1>

  
  <EMI ID = 221.1>

  
  <EMI ID = 222.1>

  

  <EMI ID = 223.1>


  
  <EMI ID = 224.1>

  
Isomer (5R):

  

  <EMI ID = 225.1>
 

  

  <EMI ID = 226.1>


  
EXAMPLE 5

  
  <EMI ID = 227.1>

  
benzyl

  
A mixture of 80 mg (0.109 millimole) of (5R, 6S) -

  
  <EMI ID = 228.1>

  
  <EMI ID = 229.1>

  
room temperature, for 24 hours. At the end of this period, the mixture is diluted with ethyl acetate and washed successively with water and with an aqueous solution of sodium bicarbonate. After dehydration of the mixture, the solvent is distilled off and the crystalline residue is washed with ethyl acetate, which

  
  <EMI ID = 230.1>

  
which melts at 195 - 198 [deg.] C. The washing liquors are concentrated and subjected to thin layer chromatography on <EMI ID = 231.1>

  
  <EMI ID = 232.1>

  
  <EMI ID = 233.1>

  
  <EMI ID = 234.1>

  
cipal.

  
The physical properties of the crystalline isomer A are as follows:

  
Elementary analysis:

  
  <EMI ID = 235.1>

  

  <EMI ID = 236.1>


  
  <EMI ID = 237.1>

  
tetrahydrofuran).

  
Nuclear magnetic resonance spectrum (dimethylformami-

  
  <EMI ID = 238.1>

  

  <EMI ID = 239.1>


  
The nuclear magnetic resonance spectrum

  
  <EMI ID = 240.1>

  
  <EMI ID = 241.1>

  

  <EMI ID = 242.1>


  
  <EMI ID = 243.1>

  
  <EMI ID = 244.1>

  
stereoisomers A and B, prepared in Example 5) in a mixture of 4 ml of tetrahydrofuran and 4 ml of a solution

  
  <EMI ID = 245.1>

  
palladium on carbon (10% w / w) and stirred

  
  <EMI ID = 246.1>

  
hours. At the end of this time, the reaction mixture is filtered and the catalyst is washed with 4 ml of the phosphate buffer solution mentioned above. The filtrate and

  
  <EMI ID = 247.1>

  
ethyl acetate. The aqueous layer is concentrated until

  
  <EMI ID = 248.1>

  
  <EMI ID = 249.1>

  
from Diaion HP20AG (product of Mitsubishi Chemical Industries

  
  <EMI ID = 250.1>

  
  <EMI ID = 251.1>

  
  <EMI ID = 252.1>

  
  <EMI ID = 253.1>

  
  <EMI ID = 254.1>
  <EMI ID = 255.1>
   <EMI ID = 256.1>

  

  <EMI ID = 257.1>

. "&#65533; &#65533; -T

  
  <EMI ID = 258.1>

  
following the same process as in Example 6, to remove the protective group and obtain the desired amino acid

  
  <EMI ID = 259.1>

  
  <EMI ID = 260.1>

  
251 (5200), 320 (6000).

  
  <EMI ID = 261.1>

  
3400, 1770, 1580.

  
Nuclear magnetic resonance spectrum (D20) # ppm:

  

  <EMI ID = 262.1>


  
EXAMPLE 8

  
  <EMI ID = 263.1>

  
azetidine-2-one

  
Following the same process as in Example 1, but reacting trithiocarboxylate from

  
  <EMI ID = 264.1>

  
methylsilyloxyethyl7azetidine-2-one, the desired product is obtained in the form of a yellow oil, with a ren-

  
  <EMI ID = 265.1>

  
  <EMI ID = 266.1>

  
3450, 3420, 1780, 1735.

  
EXAMPLE 9

  
  <EMI ID = 267.1>

  
Following the process described in Example 2, the title compound is obtained, with a yield of

  
  <EMI ID = 268.1>

  
3530, 3450, 1780, 1760, 1740.

  
EXAMPLE 10

  
  <EMI ID = 269.1>

  
tidine-2-one

  
Following the process described in Example 3, the title compound is obtained, with a yield of

  
  <EMI ID = 270.1>

  
  <EMI ID = 271.1>

  
3450, 1760, 1735, 1625.

  
  <EMI ID = 272.1>

  
  <EMI ID = 273.1>

  
Following the process described in the example

  
  <EMI ID = 274.1>

  
  <EMI ID = 275.1>

  
  <EMI ID = 276.1>

  
  <EMI ID = 277.1>

  

  <EMI ID = 278.1>


  
  <EMI ID = 279.1>

  
  <EMI ID = 280.1>

  
  <EMI ID = 281.1>

  

  <EMI ID = 282.1>
 

  

  <EMI ID = 283.1>


  
  <EMI ID = 284.1>

  
silyl, which gives the desired product with a roundness

  
  <EMI ID = 285.1>

  
  <EMI ID = 286.1>

  
3430, 1790, 1730, 1700.

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

  

  <EMI ID = 287.1>
 

  
  <EMI ID = 288.1>

  
  <EMI ID = 289.1>

  
desired, with a yield of 55%.

  
_ &#65533; *

  
  <EMI ID = 290.1>

  

  <EMI ID = 291.1>


  
  <EMI ID = 292.1>

  

  <EMI ID = 293.1>


  
  <EMI ID = 294.1>

  

  <EMI ID = 295.1>


  
EXAMPLE 14

  
  <EMI ID = 296.1>

  
To a solution of 518 mg of sodium (22.5 millimoles) in 100 ml of methanol, is added, at -10 [deg.] C, 6.61 g

  
  <EMI ID = 297.1>

  
nylamino) ethanethiol. The mixture is stirred for 5 minutes, then 1.76 g (23.1 millimoles) of carbon disulfide is added and stirring is continued for another 10 minutes. Then added at this same temperature, 6.46 g (22.5 millimoles) of (3R, 4R) -4-acetoxy-3-

  
  <EMI ID = 298.1>

  
  <EMI ID = 299.1>

  
in about 1 hour. Then added 300 mg of acid a- <EMI ID = 300.1>

  
sodium chloride. After dehydration of the solution, the solvent is removed by distillation under reduced pressure and the residue is purified by chromatography. column (200 g of silica gel), the ion elution eff-

  
  <EMI ID = 301.1>

  
te of ethyl in benzene, which gives the compound

  
  <EMI ID = 302.1>

  
3460, 3420, 1780, 1735.

  
  <EMI ID = 303.1>

  

  <EMI ID = 304.1>


  
EXAMPLE 15

  
  <EMI ID = 305.1> tidine-2-one <EMI ID = 306.1>

  
is complete, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography (150 g of silica gel), the elution is effected

  
  <EMI ID = 307.1>

  
  <EMI ID = 308.1>

  
  <EMI ID = 309.1>

  
3096 solution, by volume / volume, of acetone in hexane,

  
  <EMI ID = 310.1>

  
me with a yellow oil.

  
Elementary analysis:

  
  <EMI ID = 311.1>

  
  <EMI ID = 312.1>

  
Experimental values

  
  <EMI ID = 313.1>

  
  <EMI ID = 314.1>

  

  <EMI ID = 315.1>


  
  <EMI ID = 316.1>

  

  <EMI ID = 317.1>
 

  
  <EMI ID = 318.1>

  
  <EMI ID = 319.1>

  
of 2,6-lutidine and 2.11 g (17 7 millimoles) of thionyl chloride, after which the mixture is stirred at this

  
  <EMI ID = 320.1>

  
  <EMI ID = 321.1>

  
65 [deg.] C, under one. nitrogen flow, for an additional 35 hours. When the reaction is complete, the reaction mixture is diluted with ethyl acetate,

  
  <EMI ID = 322.1>

  
by distillation under reduced pressure and the residue is purified by column chromatography (250 g of silica gel). Elution is carried out with a solution at 15 -

  
  <EMI ID = 323.1>

  
  <EMI ID = 324.1>

  
the shape of a yellow oil.

  
Elementary analysis:

  
  <EMI ID = 325.1>

  

  <EMI ID = 326.1>


  
Experimental values:

  

  <EMI ID = 327.1>


  
  <EMI ID = 328.1>

  
  <EMI ID = 329.1>

  
EXAMPLE 17

  
  <EMI ID = 330.1> <EMI ID = 331.1>

  
methyl7azetidine-2-one and 570 mg of hydroquinone in

  
  <EMI ID = 332.1>

  
  <EMI ID = 333.1>

  
mined, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography, using 150 g of silica gel, eluting

  
  <EMI ID = 334.1>

  
volume of ethyl acetate in benzene, which gives

  
  <EMI ID = 335.1>

  
in the form of an oil, and then with a solution

  
  <EMI ID = 336.1>

  
  <EMI ID = 337.1>

  
  <EMI ID = 338.1>

  
which gives the pure product, which melts at 163 - 164 [deg.] C.

  
Elementary analysis:

  
  <EMI ID = 339.1>

  
C: 52.44%; H: 5.50%; N: 7.65%; S: 8.75..

  
Experimental values:

  
  <EMI ID = 340.1>

  
  <EMI ID = 341.1>

  
  <EMI ID = 342.1>

  
(cis isomer).

  
Infrared absorption spectrum:

  
  <EMI ID = 343.1>

  
3400 (large), 1785, 1735, 1690.

  
  <EMI ID = 344.1>

  
3450, 1798, 1735, 1700 (bearing).

  
  <EMI ID = 345.1>

  
CHC13) (trans isomer)

  
Nuclear magnetic resonance spectrum (CDC13) S ppm:

  
trans isomer:

  

  <EMI ID = 346.1>


  
  <EMI ID = 347.1>

  
  <EMI ID = 348.1>

  
p-nitrobenzyl

  
A solution of 3.39 g (4.63 millimoles) of

  
  <EMI ID = 349.1>

  
  <EMI ID = 350.1> <EMI ID = 351.1>

  
stirred at room temperature for 15 hours. When the reaction is complete, the reaction mixture is diluted with ethyl acetate and washed successively with water and. an aqueous solution of sodium bicarbonate. The solvent is distilled off under reduced pressure and the resulting crystalline residue is recrystallized from ethyl acetate, which gives the desired compound (1.98 g), which melts at 158 - 160 [deg.] C. The filtrate is subjected to column chromatography, which again gives 0.36 g of crystals of the desired compound, which melt at 158-160 [deg.] C. The overall yield is 2.43 g
(82%).

  
The nuclear magnetic resonance spectrum of the compound is in complete agreement with that of the B isomer in Example 5.

  
Elementary analysis:

  
Values calculated from C26H26N4010S2 '

  
  <EMI ID = 352.1>

  
Experimental values:

  
  <EMI ID = 353.1>

  
  <EMI ID = 354.1>

  
3520, 3330, 1780, 1710.

  
not

  
  <EMI ID = 355.1>

  
dimethylformamide).

  
EXAMPLE 19

  
  <EMI ID = 356.1>

  
200 ml of tetrahydrofuran and 200 ml of a 0.1 M phosphate buffer solution (pH: 7.1) is stirred under a stream of hydrogen for 5 hours, in the presence of 4 g of <EMI ID = 357.1>

  
the reaction is complete, the reaction mixture is filtered, the catalyst is washed with 50 ml of a solution.

  
  <EMI ID = 358.1>

  
of washing are gathered. The solution is washed twice with ethyl acetate and the aqueous layer is then concentrated to approximately 200 ml by evaporation at room temperature, under reduced pressure. The concentrate is purified by column chromatography

  
  <EMI ID = 359.1>

  
volume / volume of acetone in water and the eluate is lyophilized. The pulverulent substance thus obtained is again chromatographed, which gives 604 mg (56%) of the desired compound, in the form of a colorless powder.

  
  <EMI ID = 360.1>

  
H20)

  
  <EMI ID = 361.1>

  

  <EMI ID = 362.1>


  
EXAMPLE 20

  
  <EMI ID = 363.1>

  
droxyethyl7penem-3-carboxylic acid in 10 ml of a solution

  
  <EMI ID = 364.1>

  
tation and under ice cooling, dropwise, a 2N aqueous solution of sodium hydroxide, to adjust the pH to 8.5. Then added to the solution, in pe- <EMI ID = 365.1>

  
of methyl formimidate, over a period of 5 minutes, while maintaining the pH at 8.5 by adding, drop by drop, a 2N aqueous solution of sodium hydroxide. After stirring for 5 minutes, the pH of the solution is adjusted to 7.0 by adding 2N aqueous hydrochloric acid.

  
The solution is purified by column chromatography
(20 ml of Diaion HP2AG). After elution of mineral salts and impurities, the fractions eluted with solutions

  
  <EMI ID = 366.1>

  
picked and lyophilized, giving 17 mg (31%) of the desired compound, in the form of a colorless powder.

  
  <EMI ID = 367.1>

  
H20).

  
Nuclear magnetic resonance spectrum (D20) S ppm:

  

  <EMI ID = 368.1>


  
EXAMPLE 21

  
  <EMI ID = 369.1>

  
P-nitrobenzyl 3-carboxylate.

  
A 374 mg (0.48 millimole) solution of <EMI ID = 370.1>

  
475 mg (3.83 millimoles) of trimethyl phosphite in
40 ml of dioxane is stirred at 75 [deg.] C, under a stream of nitrogen, for 91 hours. The solvent is distilled off under reduced pressure and the residue is purified by thin layer chromatography, the elution being carried out

  
  <EMI ID = 371.1>

  
thyle, which is followed by further purification by thin layer chromatography and elution with an 8: 1 mixture by volume of chloroform and ethyl acetate, which gives 92 mg (26%) of the desired compound. This compound is recrystallized from benzene, which sleeps the pure substance, which melts at 163 - 164 [deg.] C. The physico-chemical properties of the compound are in complete agreement with those of the compound obtained in Example 17.

  
PREPARATION 1

  
  <EMI ID = 372.1>

  
thioazetidine-2-one and 843 mg (3 equivalents) of acetaldehyde in 20 ml of tetrahydrofuran. The resulting solution is added to a solution of 625 mg (1.5 equivalents)

  
  <EMI ID = 373.1>

  
weight / volume in hexane) of diethylaluminum chloride

  
  <EMI ID = 374.1>

  
over a period of 40 minutes, then the mixture is stirred for another 1 hour. The mixture is diluted successively with water and with ethyl acetate. The white precipitate produced is separated by filtration using Celite (trade name of a filter aid) and the filtrate is extracted with ethyl acetate. The extract is treated by a usual process to give 2.05 g of the crude product, in the form of an oil, which is subjected to column chromatography through silica gel (about 30 g), the development s '' performing with a 5: 1 mixture, by volume, of chloroform and ethyl acetate, which gives 1.04 g
(yield: 60%) of the desired product, in the form of a colorless oil. This product is a 4: 1 mixture of isomere-

  
  <EMI ID = 375.1>

  
position 3.

  
Elementary analysis

  
  <EMI ID = 376.1>

  
Experimental values:

  

  <EMI ID = 377.1>


  
  <EMI ID = 378.1>

  

  <EMI ID = 379.1>


  
  <EMI ID = 380.1>

  
  <EMI ID = 381.1>

  

  <EMI ID = 382.1>


  
PREPARATION 2

  
  <EMI ID = 383.1>

  
1-enyl) -4-methylthioazetidine-2-one, 201 mg (2 equivalents) of triphenylphosphine and 94 mg (2 equivalents) of benzoic acid in 2 ml of tetrahydrofuran. A solution of 134 mg is added little by little to the resulting solution.

  
(2 equivalents) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran, at 20 [deg.] C, in 10 minutes, then the mixture is stirred at this same temperature for 1.5 hours.

  
The solvent is then distilled off and the residue is dissolved in 3 ml of a 6: 1 mixture by volume of benzene and ethyl acetate, then left to stand in a refrigerator. The resulting precipitate is separated by filtration and the filtrate is subjected to thin layer chromatography, developing with a 5: 1 mixture by volume of benzene and ethyl acetate, which gives 119 mg (yield: 32 %) of the desired product,

  
  <EMI ID = 384.1>

  
Elementary analysis

  
  <EMI ID = 385.1>

  

  <EMI ID = 386.1>


  
Experimental values:

  

  <EMI ID = 387.1>


  
  <EMI ID = 388.1>

  

  <EMI ID = 389.1>


  
Nuclear magnetic resonance spectrum (CDC13) b ppm:

  
  <EMI ID = 390.1>

  

  <EMI ID = 391.1>
 

  

  <EMI ID = 392.1>


  
PREPARATION 3

  
  <EMI ID = 393.1>

  
To the resulting solution, or. add a solution of 7.17 mg (0.31 millimole) of sodium in 0.65 ml of methanol to

  
  <EMI ID = 394.1>

  
  <EMI ID = 395.1>

  
is complete, the mixture is made slightly acidic by addition of acetic acid, diluted with 20 ml of ethyl acetate and washed with water. After dehydration of the mixture, the solvent is removed by distillation. The resulting residue is subjected to thin layer chromatography on silica gel, the development being carried out with a 2: 1 mixture, by volume, of benzene and ethyl acetate, which gives 50 mg (yield: 74, 4%) of the pure product, in the form of an oil, which turns out to be cons

  
  <EMI ID = 396.1>

  
nuclear, of an approximately 4: 1 mixture of the 1'R isomers

  
  <EMI ID = 397.1>

  
Elementary analysis

  
  <EMI ID = 398.1>

  

  <EMI ID = 399.1>


  
Experimental values:

  

  <EMI ID = 400.1>


  
  <EMI ID = 401.1>

  

  <EMI ID = 402.1>
 

  
  <EMI ID = 403.1>

  
Main product (1'R isomer):

  

  <EMI ID = 404.1>


  
By-product (isomer S):

  

  <EMI ID = 405.1>


  
PREPARATION 4

  
  <EMI ID = 406.1>

  
2-one

  
Dissolve in 110 ml of dimethylformamide

  
  <EMI ID = 407.1>

  
ne-2-one, which was obtained in Preparation 3, and 2.54 g (37.3 millimoles) of imidazole. 5.33 g (35.3 millimoles) of t-butyldimethylchlorosilane are added to the solution.

  
  <EMI ID = 408.1>

  
room temperature for about 16 hours. When the reaction is complete, the mixture is diluted with 200 ml of benzene and washed with water. After dehydration of the mixture, the solvent is distilled off and the resulting residue is subjected to column chromatography on 10 times its volume of silica gel, the elution being carried out with a 10: 1 mixture, by volume, benzene and ethyl acetate, which gives 7.95 g (yield:
94%) of the desired product, in the form of a colorless oil

  
  <EMI ID = 409.1>

  
the starting substance. According to nuclear magnetic resonance spectroscopy, the product turns out to be an approximately 4: 1 mixture of the configuration isomers.

  
  <EMI ID = 410.1>

  
Elementary analysis:

  
  <EMI ID = 411.1>

  
C: 55.81%; H: 8.53%; N: 3.62%; S: 8.29%.

  
Experimental values:

  
  <EMI ID = 412.1>

  
  <EMI ID = 413.1>

  
1760, 1720

  
  <EMI ID = 414.1>

  
Main product (1'R isomer):

  

  <EMI ID = 415.1>
 

  

  <EMI ID = 416.1>


  
PREPARATION 5

  
  <EMI ID = 417.1>

  
1- (1-methoxycarbonyl-2-methylprop-1-enyl) azetidine-2-one

  
3.85 g are dissolved in 38 ml of acetic acid
(9.95 millimoles) of the product containing, as a

  
  <EMI ID = 418.1>

  
methylthioazetidine-2-one, which was obtained in Preparation 4, and 5.08 g (15.9 millimoles) of mercuric acetate. The solution is stirred under a stream of nitrogen, at a bath temperature of 95-100 [deg.] C, for 20 minutes.

  
When the reaction is complete, the acetic acid is distilled off under reduced pressure. A mix

  
  <EMI ID = 419.1>

  
t at 0 [deg.] C to the resulting white residue and the mixture is then stirred. The ethyl acetate layer is separated, washed with water and dried. The solvent is distilled off and the resulting residue is subjected to column chromatography through 30 g of silica gel, elution being carried out with a 5: 1 mixture by volume of benzene and acetate. ethyl, which gives 3.50 g (yield:

  
8896) of the desired product, in the form of an oil, which, according to nuclear magnetic resonance spectroscopy, appears to contain a small amount of isomer of confi-

  
  <EMI ID = 420.1>

  
Elementary analysis:

  
  <EMI ID = 421.1>

  

  <EMI ID = 422.1>


  
Experimental values:

  

  <EMI ID = 423.1>


  
  <EMI ID = 424.1>

  

  <EMI ID = 425.1>
 

  
  <EMI ID = 426.1>

J

  
  <EMI ID = 427.1>

  

  <EMI ID = 428.1>


  
PREPARATION 6

  
  <EMI ID = 429.1>

  
azetidine-2-one

  
Dissolve 3 g (7.5 millimoles) of the product containing, as main constituent, the (3R, 4R) -

  
  <EMI ID = 430.1>

  
was obtained in Preparation 5, in 300 ml of acetone. To the solution is added a solution of 6.43 g (30.1 millimoles) of sodium metaperiodate and 120 mg of potassium permanganate in a mixture of 150 ml of water and
150 ml of 0.1 M phosphate buffer solution (pH:
7.02) at around 18 [deg.] C, in 30 minutes, and then stirred <EMI ID = 431.1>

  
the reaction is complete, the precipitate obtained is separated by filtration and about 25 ml of the above buffer solution are added to the filtrate to adjust its pH to

  
  <EMI ID = 432.1>

  
lower temperature, under reduced pressure, and

  
the residue is extracted with benzene. The benzene layers are collected and dehydrated. The solvent is distilled off, which gives a solid

  
  <EMI ID = 433.1>

  
to obtain 0.934 g (43.3%) of the desired product in the form

  
  <EMI ID = 434.1>

  
Elementary analysis:

  
  <EMI ID = 435.1>

  

  <EMI ID = 436.1>


  
Experimental values:

  

  <EMI ID = 437.1>


  
Infrared absorption spectrum (Nujol-denomination com-

  
  <EMI ID = 438.1>

  
3175, 1783, 1743.

  
  <EMI ID = 439.1>

  
CHC13).

  
  <EMI ID = 440.1>

  

  <EMI ID = 441.1>


  
PREPARATION 7

  
  <EMI ID = 442.1> <EMI ID = 443.1>

  
of 172 mg (1.70 millimoles) of triethylamine in 10 ml of methylene chloride, cooled to -10 [deg.] C, 416 mg (1.71 is added with stirring and under a stream of nitrogen)

  
  <EMI ID = 444.1>

  
added to it. The mixture is extracted with chloroform, washed with water and dehydrated. After evaporation of the solvent under reduced pressure, the residue

  
  <EMI ID = 445.1>

  
silica gel (5 g), elution being carried out with a 15 l mixture by volume of benzene and ethyl acetate, which gives 385 mg (87%) of the desired compound, in the form d 'an oil.

  
  <EMI ID = 446.1>

  

  <EMI ID = 447.1>


  
  <EMI ID = 448.1>

  

  <EMI ID = 449.1>
 

CLAIMS

  
1) Compounds characterized in that they respond

  
  <EMI ID = 450.1>

  

  <EMI ID = 451.1>


  
  <EMI ID = 452.1>

  
  <EMI ID = 453.1>

  
alkyl, an alkoxy group, a hydroxyalkyl group, a

  
  <EMI ID = 454.1>

  
oxyalkyl;

  
  <EMI ID = 455.1>

  
eg alkyl;

  
R <3> represents a hydrogen atom, a protecting group for an amino group or a group of formula

  

  <EMI ID = 456.1>


  
  <EMI ID = 457.1>

  
each have a hydrogen atom or an alkyl group;

  
A represents a branched chain alkylene group: and

  
R4 represents a carboxy group or a protected carboxy group)

  
and pharmaceutically acceptable salts of these compounds.


    

Claims (1)

2) Compounds according to claim 1, characterized in that, in the above formula: R represents a methoxy group or a 1-hydroxyethyl group; R <2> represents a hydrogen atom or a group - <EMI ID = 458.1> R <3> represents a hydrogen atom, a formimidoyl group or an acetimidoyl group; A represents an ethylene, trimethylene or tetramethylene group having, in the carbon chain, one or two substituents chosen from methyl and ethyl groups; and R4 represents a carboxy group or a group  <EMI ID = 459.1> and pharmaceutically acceptable salts of these compounds. 3) Compounds according to claim 1, characterized in that, in the above formula:  <EMI ID = 460.1> R <2> represents a hydrogen atom or a C1-C2 alkyl group;  <EMI ID = 461.1> formimidoyl or an acetimidoyl group; A represents an ethylene or trimethylene group comprising, in its carbon chain, one or two substituents chosen from the methyl and ethyl groups; and R4 represents a carboxy group or a pivaloyloxymethoxycarbonyl group; and pharmaceutically acceptable salts of these compounds. 4) Compounds according to claim 1, cara &#65533; terized in that they are in the form of the sodium or potassium salt. 5) Compounds according to claim 3, characterized in that they are in the form of the sodium or potassium salt. 6) Compounds according to claim 1, characterized in that their configuration is a configuration (5R, 6S) or a configuration (5R, 6R). 7) Compounds according to claim 1, characterized in that R represents an alpha-substituted alkyl group in which the alpha substituent is of configuration R. 8) Process for the preparation of the compounds of formula (I):  <EMI ID = 462.1> (in which : R represents a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, an acyloxyalkyl group, an alkylsulfonyloxyalkyl group, an arylsulfonyloxyalkyl group or a trialkylsilyloxyalkyl group; R2 represents a hydrogen atom or an alkyl group;  <EMI ID = 463.1> protector of an amino group or a group of formula  <EMI ID = 464.1>  <EMI ID = 465.1> each has a hydrogen atom or an alkyl group); A represents a branched chain alkylene group; and  <EMI ID = 466.1> protected carboxy) and pharmaceutically acceptable salts of these compounds, characterized in that it consists in heating a phosphorus-ylide compound of formula (II):  <EMI ID = 467.1> (in which:  <EMI ID = 468.1> alkyl, an alkoxy group, an acyloxyalkyl group, an alkylsulfonyloxyalkyl group, an arylsulfonyloxyalkyl group or a trialkylsilyloxyalkyl group;  <EMI ID = 469.1> amino group; R9 represents a protected carboxy group;  <EMI ID = 470.1> and R <2> and A have the above meanings) to obtain a compound of formula (III):  <EMI ID = 471.1>  <EMI ID = 472.1> above) and, if necessary, to submit the said compound of formula (III) to a reaction chosen from the following: (a) removal of protecting groups from hydroxy groups; (b) removal of protecting groups from amino groups; (c) removal of protecting groups from carboxy groups; (d) conversion of an amino group or an alkylamino group represented by R <2> -NH- to a group of formula  <EMI ID = 473.1>  <EMI ID = 474.1> tees); (e) salification; and (f) a combination of two, three, four or five of said steps (a) to (e), in any order. 9) Method according to claim 8, characterized in that: R represents a methoxy group or a 1-hydroxyethyl group; R <2> represents a hydrogen atom or a  <EMI ID = 475.1> R <3> represents a hydrogen atom, a formimidoyl group or an acetimidoyl group; A represents an ethylene, trimethylene or tetramethylene group comprising, in the carbon chain, one or two substituents chosen from methyl and ethyl groups; and R4 represents a carboxy group, a group  <EMI ID = 476.1> to the corresponding pharmaceutically acceptable salts. 10) Method according to claim 8, characterized in that: R represents a 1-hydroxyethyl group; R <2> represents a hydrogen atom or a C1-C2 alkyl group;  <EMI ID = 477.1> formimidoyl or an acetimidoyl group; <EMI ID = 478.1> not having, in its carbon chain; one or two substituents selected from methyl and ethyl; and  <EMI ID = 479.1>  <EMI ID = 480.1> corresponding pharmaceutically acceptable salts. II) Method according to claim 8, characterized in that it is applied to the preparation of the sodium or potassium salt. 12) Method according to claim 10, characterized in that it is applied to the preparation of the sodium or potassium salt. 13) Method according to claim 8, characterized  <EMI ID = 481.1> or a configuration (5R, 6R). 14) Method according to claim 8, characterized in that R 1 represents an alpha-substituted alkyl group whose substituent in alpha position is of R configuration. 15) Process for the preparation of the compounds of formula (T) -  <EMI ID = 482.1> (in which :  <EMI ID = 483.1> alkyl, alkoxy group, hydroxyalkyl group, acyloxyalkyl group, alkylsulfonyloxyalkyl group, arylsulfonyloxyalkyl group or trialkylsilyloxyalkyl group; R <2> represents a hydrogen atom or a alkyl group; R <3> represents a hydrogen atom, a protecting group for an amino group or a group of formula  <EMI ID = 484.1>  <EMI ID = 485.1> each have a hydrogen atom or an alkyl group;  <EMI ID = 486.1> mified; and  <EMI ID = 487.1> protected carboxy) and  <EMI ID = 488.1> formula (IV):  <EMI ID = 489.1> (in which :  <EMI ID = 490.1> Y represents an oxygen atom or a sulfur atom;  <EMI ID = 491.1> eg amino; and R9 represents a protected carboxy group) with a phosphorous acid triester or a triamide phosphorous acid and, if necessary, subjecting the resulting product to a reaction chosen from the following: (a) removal of protecting groups from hydroxy groups; (b) removal of protecting groups from amino groups; (c) removal of protecting groups from carboxy groups; (d) conversion of an amino group or an alkylami- group <EMI ID = 492.1>  <EMI ID = 493.1>  <EMI ID = 494.1> cited); (e) salification; and <EMI ID = 495.1> <EMI ID = 496.1> 16) Method according to claim 15, characterized in that said triester of phosphorous acid or said triamide of phosphorous acid is a compound of formula (V)  <EMI ID = 497.1>  <EMI ID = 498.1> dialkylaminc group).  <EMI ID = 499.1> dried in that it is carried out at a temperature of 50 to 150 [deg.] C. 18) Method according to claim 15, characterized in that it is carried out at a temperature at most equal to 90 [deg.] C, which gives a ylide compound of formula (VI):  <EMI ID = 500.1>  <EMI ID = 501.1> in claim 15, Y represents an oxygen atom  <EMI ID = 502.1> amino), this ylide compound of formula (VI) then being heated to effect cyclization. 19) Method according to claim 15, characterized in that:  <EMI ID = 503.1> 1-hydroxyethyl; R <2> represents a hydrogen atom or a C1-C2 alkyl group;  <EMI ID = 504.1> formimidoyl or an acetimidoyl group; A represents an ethylene, trimethylene or tetramethylene group comprising, in the carbon chain, ur,  <EMI ID = 505.1> ethyl; and  <EMI ID = 506.1> pivaloyloxymethoxycarbonyl; this process also applies to corresponding pharmaceutically acceptable salts. 20) Method according to claim 15, characterized in that : R <1> represents a 1-hydroxyethyl group; R2 represents a hydrogen atom or a  <EMI ID = 507.1>  <EMI ID = 508.1> formimidoyl or an acetimidoyl group; A represents an ethylene or trimethylene group comprising, in its carbon chain, one or two substituents chosen from the methyl and ethyl groups; and R4 represents a carboxy group or a pivaloyloxymethoxycarbonyl group; this process also applies to corresponding pharmaceutically acceptable salts. 21) Method according to claim 15, characterized in that it is applied to the preparation of sodium salt or potassium. 22) Method according to claim 20, characterized in that it is applied to the preparation of the sodium or potassium salt. 23) Method according to claim 15, characterized in that the configuration is a configuration (5R, 6S) or a configuration (5R, 6R). 24) Method according to claim 15, characterized in that R represents an alpha-substituted alkyl group whose substituent in alpha position is of R configuration. 25) Pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable carrier or diluent, characterized in that it contains, as an antibiotic, a compound of formula (I):  <EMI ID = 509.1> (in which : R 1 represents a hydrogen atom, a group  <EMI ID = 510.1> acyloxyalkyl group, an alkylsulfonyloxyalkyle group, an arylsulfonyloxyalkyle group or a trialkylsilyloxyalkyle group;  <EMI ID = 511.1> eg alkyl; R <3> represents a hydrogen atom, a protecting group for an amino group or a group of formula  <EMI ID = 512.1>  <EMI ID = 513.1> each sense a hydrogen atom or an alkyl group; A represents a branched chain alkylene group; and R4 represents a carboxy group or a protected carboxy group) or a pharmaceutically acceptable salt of this compound. 26) Compound characterized in that it is chosen  <EMI ID = 514.1> 28) Compounds according to claim 1, characterized in that, in the above formula: R represents a 1-hydroxyethyl group; R <2> and R <3> represent hydrogen atoms; A represents an ethylene or trimethylene group comprising a methyl substituent in the alpha position of its carbon chain; and R4 represents a carboxy group, and pharmaceutically acceptable salts of these compounds.