BE875054A - COMPOUNDS ANALOGUE TO CEPHALOSPORINS - Google Patents

Description

       

  Cephalosporin-like compounds

  
The present invention relates to acids

  
  <EMI ID = 1.1>

  
by the general structural formula (I) below, and its derivatives:

  

  <EMI ID = 2.1>


  
formula in which X represents an acyl group, R represents a hydrogen atom or a protecting group

  
  <EMI ID = 3.1>

  
of hydrogen, a lower alkyl group or a lower acyloxy group.

  
  <EMI ID = 4.1>

  
Journal of the American Chemical Society Vol. 96, 7584,
1974.

  
Among the compounds of the carbacephem type, those which have a methyl group substituted in position 3,

  
  <EMI ID = 5.1>

  
following formula:

  

  <EMI ID = 6.1>
 

  
are known and are indicated as having antibacterial activity (the same reference as that indicated

  
  <EMI ID = 7.1>

  
State of numerous studies carried out with the aim of discovering new analogues of cephalosporins possessing a powerful antibacterial activity, the Applicant had previously discovered compounds analogous to cephalosporins, represented by the following general structural formula (II), that is to say - to say of the carbacephems substituted on the carbon atom in position 4 or the carbon atom in position 5 (the numbering being carried out in the present specification according to the mode indicated in formula (II) below) and salts of these carbacephemes (Japanese patent application N [deg.] 34696/78).

  

  <EMI ID = 8.1>


  
  <EMI ID = 9.1>

  
hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, an acyloxy group, a lower alkyl sulfonyloxy group, an arylsulfonyloxy group, a lower alkyl thio group, a group arylthio, an aralkylthio group, a lower alkyl sulfinyl group,

  
  <EMI ID = 10.1>

  
sulfonium group represented by the general formula <EMI ID = 11.1> or different and represent an alkyl group, an aryl group or an aralkyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, a quaternary ammonium group represented by

  
  <EMI ID = 12.1>

  
may be the same or different and each represents a lower alkyl group, an aryl group, an aralkyl group, an arylseleno group or a group

  
  <EMI ID = 13.1>

  
lower alkyl substituted by halogens, an azido group, a nitrile group or an amino group shown

  
  <EMI ID = 14.1>

  
may be the same or different and each represents a hydrogen atom, a lower alkyl, aryl or aralkyl group and R3 represents a hydrogen atom, a silyl, aralkyl, aryl or substituted or unsubstituted alkyl group, as well as the salts of compounds in question.

  
As a result of further research, the Applicant has also discovered that it is possible to obtain cephalosporin-like compounds possessing potent antibacterial activity by acylating a compound represented by the general formula (II)
  <EMI ID = 15.1>
   <EMI ID = 16.1>

  
A more particular subject of the present invention is compounds represented by the general formula (I)

  

  <EMI ID = 17.1>


  
in which X denotes an acyl group represented by

  
  <EMI ID = 18.1>

  
following groups:

  
1) a cyanomethyl group or a group represented by

  
  <EMI ID = 19.1>

  

  <EMI ID = 20.1>


  
  <EMI ID = 21.1>

  
unsaturated, such as cyclohexenyl, cyclohexadiene, phenyl, etc., or a five- or six-membered heterocyclic group, such as furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrinidinyl, pyrazinyl, pyridazinyl,

  
  <EMI ID = 22.1>

  
feels one of the substituents chosen from hydrogen atoms, hydroxyl and lower alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, nitro, amino, aminomethyl, methylsulfamido, lower acyloxy groups having from 1 to 4 'carbon atoms,

  
n is a number whose value varies from 0 to 5 and A2 represents a hydrogen atom, an amino, hydroxyl, carboxyl or sulfoxyl group,

  
2) a group represented by the following general formula:

  

  <EMI ID = 23.1>


  
in which A1, B and n have the meanings previously indicated, A3 and A4 are the same or different and each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a group represented by the general formula

  
0

  
yew <EMI ID = 24.1> of 1 to 4 carbon atoms) or a group represented by

  
the general formula

  

  <EMI ID = 25.1>


  
  <EMI ID = 26.1>

  
identical or different each represent a hydrogen atom, a lower alkyl group having

  
1 to 4 carbon atoms or an alkali metal) and

  
also designates a group represented by the

  

  <EMI ID = 27.1>


  
general formula

  

  <EMI ID = 28.1>


  
  <EMI ID = 29.1>

  
identical or different and denote hydrogen atoms or lower alkyl radicals having from 1 to 4 carbon atoms) or a group represented by

  
the general formula

  

  <EMI ID = 30.1>


  
(where Ag represents a

  
hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a methylsulfonyl group or

  
  <EMI ID = 31.1>

  
hydrogen or a lower alkyl group having

  
1 to 4 carbon atoms),

  
3) a group represented by the following general formula:

  

  <EMI ID = 32.1>


  
  <EMI ID = 33.1>

  
substituted or a substituted mono-, bi- or tricyclic heterocyclic radical, such as a group represented by one of the following formulas:

  

  <EMI ID = 34.1>


  
, (Y is an oxygen or sulfur atom).

  

  <EMI ID = 35.1>


  
and a naphthylidinyl group such as

  

  <EMI ID = 36.1>


  
which may contain substituents such as those represented

  
  <EMI ID = 37.1>

  
4) a group represented by the following general formula:

  

  <EMI ID = 38.1>
 

  
  <EMI ID = 39.1>

  
a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkinyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an aryl group, these groups not being substituted or being substituted by one or more suitable substituents, such as carboxyl radicals, cyano, halogen atoms, carbamoyl or lower alkyl oxycarbonyl radicals possessing 1 to 4 carbon atoms,

  
5) a group represented by the following general structural formula:

  

  <EMI ID = 40.1>


  
  <EMI ID = 41.1>

  
a cyanomethyl group or a group represented by

  
  <EMI ID = 42.1>

  
cations than those previously indicated) and Z represents an oxygen or sulfur atom;

  
R1 represents a hydrogen atom or a protective ester group conventionally employed in the field of penicillin and cephalosporin chemistry, that is to say an alkyl group having 1 to 5 carbon atoms, such as a methyl radical, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., a halogenated alkyl group having 1 to 5 carbon atoms,

  
such as chloromethyl, 2,2,2-trichlorethyl, 2,2,2-trifluoroethyl, etc., an arylmethyl group having 7 to 20 carbon atoms, such as benzyl, diphenylmethyl, triphenylmethyl, etc. ., an arylmethyl group having 7 to 20 carbon atoms and having a methoxy radical, a nitro group, etc., on the phenyl ring, a substituted silyl group, such as a trimethylsilyl or triphenylsilyl radical or an enzymatically or not group enzymatically easily removable in vivo, for example a group represented by

  
  <EMI ID = 43.1>

  
R3

  
a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R4 represents a lower alkyl group having 1 to 6 carbon atoms,

  
a lower alkoxy group having 1 to 6 carbon atoms or a phenyl group, etc. and R2 has the same meanings as those previously indicated.

  
In the case where R in the general formula (I) represents a hydrogen atom or in that where X represents an acyl group having a free amino or carboxyl group, the compounds represented by the general formula (I) may be salts of Pharmaceutically acceptable organic or inorganic acids or bases.

  
Compounds represented by general formula (I) include all stereoisomers at positions 6, 7 and 4 and mixtures thereof. Among the stereoisomers, those which have the cis configuration at the 6 and 7 positions have higher antibacterial activities than the trans isomers, so the cis isomers are more useful as antibiotics. The = NOR group in the acyl radical has two geometric isomers, namely the syn and anti isomers.

  

  <EMI ID = 44.1>


  
Since the syn isomer is superior to the anti isomer in antibacterial activity, the syn isomer is more valuable as an antibiotic. In general, it is known that the thiazolyl group represented

  
by the formula

  

  <EMI ID = 45.1>


  
demonstrates interconversion

  
reversible with the thiazolinyl group, as shown below, and these two forms are usually considered to be the same. In the present specification, the two isomers are represented by the thiazolyl group:

  

  <EMI ID = 46.1>


  
The compounds represented by the general formula (I) are produced by acylating the compounds (II ') represented by the general formula (II) in which

  
X is NH2, R1 is H, R2 is H, a lower alkyl group or a lower acyloxy group having 1 to 5 atoms

  
  <EMI ID = 47.1>

  
below.

  
  <EMI ID = 48.1>

  

  <EMI ID = 49.1>


  
  <EMI ID = 50.1>

  
same meanings as indicated above.

  
The acylation reaction (condensation) is carried out by carrying out a conventional acylation process used in the field of penicillin and cephalosporin chemistry.

  
The compounds represented by the general formula
(I) are prepared by the condensation of the compound (II ') represented by the general formula (II'), a salt of this compound or a compound which is functionally equivalent thereto (these compounds will be called "7-amino compounds" in the continuation of this specification) and a carboxylic acid represented by the general formula (III)

  

  <EMI ID = 51.1>


  
or a reactive derivative of such an acid and, if this proves necessary, the condensation is followed by deprotection, i.e. by removal of the protective group in the radical X <2> - or -COOR <1>, this abduction being carried out

  
  <EMI ID = 52.1>

  
  <EMI ID = 53.1> above or the group X suitably protected in case X has one or more groups capable of being acylated, such as hydroxyl, amino, carboxyl or mercapto radicals.

  
X <2> concretely represents the following five groups:

  
le) a cyanomethyl group or a group represented by

  
the following general formula:

  

  <EMI ID = 54.1>


  
in which B has the same meanings as those

  
  <EMI ID = 55.1>

  
substituents which are selected from a group consisting of a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, a nitro group, a group protected amino, a protected aminoethyl group, a methylsulfamido group, a lower acyl oxy group having 1 to 4 carbon atoms,

  
  <EMI ID = 56.1>

  
represents a hydrogen atom, a protected amino group, a hydroxyl group, a protected hydroxyl group, a carboxyl group, a protected carboxyl group, a sulfoxyl or protected sulfoxyl group,

  
2 ') a group represented by the general formula

  
next :

  

  <EMI ID = 57.1>
 

  
  <EMI ID = 58.1>

  
meanings than those previously indicated, 3 ') a group represented by the general formula

  
next :

  

  <EMI ID = 59.1>


  
  <EMI ID = 60.1>

  
fications than those previously indicated,

  
4 ') a group represented by the general formula

  
next :

  

  <EMI ID = 61.1>


  
  <EMI ID = 62.1>

  
than those previously indicated and A12 represents

  
a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkinyl group having 2 to 6 carbon atoms,

  
a cycloalkyl group having 3 to 6 carbon atoms

  
or an aryl group, these groups not being substituted or being substituted by appropriate substituents, such as

  
a protected carboxyl group, a cyano group, a halogen atom, a carbamoyl group or a lower alkyl oxycarbonyl group having from 1 to 4 carbon atoms,

  
5 ') a group represented by the general formula

  
next :

  

  <EMI ID = 63.1>
 

  
  <EMI ID = 64.1>

  
meanings that, those previously indicated) and Z represents an oxygen atom or a sulfur atom.

  
As protecting groups for amino group, hydroxyl group, carboxyl group, etc., in group X <2>, one uses those which one employs in chemistry of cephalosporins or penicillins and

  
those listed below.

  
As salts of compound (II '), mention may be made of inorganic salts and organic salts, such as hydrochlorides, sulfates, carbonates, phosphates, formates, trifluoroacetates, malates, etc. Moreover, as examples, there may be mentioned sodium, potassium, calcium, ammonium salts, salts with organic amines, etc., of the carboxylic acid represented by the general formula (II ') in which R represents a hydrogen atom. These salts are prepared by carrying out a conventional process.

  
As compound functionally equivalent to compound (II '), there may be mentioned as examples the derivatives

  
of the 7-monosilyl- or 7-disilyl-amino type of compound (II ').

  
As reactive derivatives of carboxylic acids

  
  <EMI ID = 65.1>

  
mention may be made of 1) acid halides, 2) anhydrides, 3) mixed anhydrides, 4) active esters,

  
5) active thioesters, 6) acid azides, etc.

  
The condensation (acylation) reactions using the aforementioned derivatives are explained below:

  
1) Process using an acid halide

  
A 7-amino compound and an acid halide are subjected to a condensation reaction in an inactive solvent, preferably in the presence of a proton acceptor. The acid halide is prepared in a conventional manner.

  
As proton acceptor, inorganic and organic bases are used, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N-methylmorpholine, pyridine. , etc.

  
As the solvent, any inactive solvent is used which does not affect the reaction, preferably.

  
water, an ether, such as tetrahydrofuran, dimethoxyethane, etc., an ester, such as ethyl acetate, etc., an amide, such as dimethylacetamide, hexamethylphosphoric triamide, etc. or a sulfoxide, such as

  
dimethyl sulfoxide, etc., which is used alone

  
or in combination.

The reaction is carried out at a temperature of

  
  <EMI ID = 66.1> ambient.

  
2) Process using an acid anhydride

  
A 7-amino compound and an acid anhydride are subjected to a condensation reaction in an inactive solvent.

  
The acid anhydride is prepared in a conventional manner.

  
As the solvent, any solvent which does not affect the reaction is used, preferably the same solvents as those used in the above-mentioned process. The temperature range of the reaction is the same as that indicated in the above process.

  
The typical process using a carbodiimide, such as dicyclohexylcarbodiimide, can be exemplified as an anhydride process.

  
3) Process using a mixed anhydride

  
A 7-amino compound and a mixed anhydride are subjected to a condensation reaction in an inactive solvent.

  
The mixed anhydride is prepared in a conventional manner, for example the method according to which a corresponding carboxylic acid is reacted, X <2> COOH and a chloroformic ester, such as ethyl chloroformate, isobutyl chloroformate, etc., in the presence of a base.

  
As the solvent, any inactive solvent is used which does not affect the reaction, generally a water-free solvent or a mixture of water and a water-free solvent, preferably the same solvent as that mentioned above in the aforementioned processes.

  
The temperature range for carrying out the reaction is the same as that indicated in the aforementioned processes.

  
4) Process using an active ester

  
A 7-amino compound and an active ester are subjected to a condensation reaction in an inactive solvent.

  
The solvents and the reaction temperature are the same as those used in the processes

  
1 to 3 above.

  
As active ester, there may be mentioned, as examples. a phenyl ester, such as p-nitrophenyl ester, trichlorophenyl ester, etc., a methyl ester having an electronegative group, such as cyanomethyl ester, etc. and an N-oxydiacylimidic ester, such as N-hydroxysuccinimidic ester, etc.

  
The active ester is prepared by carrying out a conventional process such as reacting a corresponding carboxylic acid and a hydroxyl compound in the presence of a dehydrating condensation reagent, such as dicyclohexylcarbodlimide, etc.

  
5) Process using an active thioester

  
This process is carried out in a similar way

  
to that described in method 4).

  
As the most advantageous thioester, mention may be made, for example, of the p-nitrothiophenyl ester which is prepared according to a mixed anhydride process or according to a dicyclohexylcarbodiimide process.

  
6) Process using an acid azide

  
A 7-amino compound and an acid azide are subjected to a condensation reaction in an inactive solvent, in a manner similar to that described in the above-mentioned methods 1 to 5.

  
The acid azide is prepared by a method such as reacting the hydrazide of a corresponding carboxylic acid with nitrous acid at a temperature.

  
  <EMI ID = 67.1>

  
In the case where the reactive derivatives of the aforementioned carboxylic acid have a group, such as an amino group, a hydroxyl group, a carboxyl group or a mercapto group which is capable of acylation, these groups are preferably protected. with a suitable protecting group in a conventional manner before carrying out the condensation reaction with the compounds of the amino type.

  
As suitable protecting groups, there may be mentioned those used in the field of synthetic chemistry of penicillins and cephalosporins.

  
Mention may be made, as group protecting the amino function, of the most advantageous examples, of the following groups: t-butyloxycarbonyl (Boc), benzyloxycarbonyl
(Cbz), trichlorethyloxycarbonyl, trityl, formyl, chloracetyl, trialkylsilyl, protone, &#65533; -diketone, p-ketoester, etc. As compound protected by a proton, there may be mentioned as an example the compound represented by the following formula:

  

  <EMI ID = 68.1>


  
As compound protected by a P-ketoester group, there may be mentioned, as an example, the compound represented by the following formula:

  

  <EMI ID = 69.1>


  
As groups protecting the hydroxyl function, mention may be made, as examples, of the benzyl, benzyloxycarbonyl, trityl, tetrahydropyranyl, t-butyl, etc. radicals. Since the reactivity (nucleophilic activity) of most amino groups is greater than that of the hydroxyl group, the protection

  
of the hydroxyl group is not necessarily essential and depends on the acylation process used.

  
As groups protecting the carboxyl function, mention may be made of t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl, etc. radicals.

  
As groups protecting the mercapto function, mention may be made of benzyl, trityl, benzyloxycarbonyl, p-nitrobenzyl, etc. radicals.

  
The deprotection of the aforementioned protective groups is carried out according to a method conventionally used in the field of synthetic chemistry of penicillins and cephalosporins.

  
As methods of deprotection, that is to say of removal of the groups protecting the amino function, the following illustrative methods may be mentioned.

  
The Boc group is removed by a method using an acid, such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, etc.

  
The Cbz group is removed by catalytic reduction or a process using a mixture of hydrobromic acid and acetic acid, etc.

  
The trityl group is removed by catalytic reduction or a process using an acid, such as trifluoroacetic acid, etc.

  
The formyl group is removed by hydrolysis using an acid or an alkali.

  
The chloroacetyl group is removed by carrying out a process using a thiourea.

  
The trialkylsilyl group is removed by hydrolysis.

  
The adduct with -diketone or-ketoester is removed by acid hydrolysis.

  
As methods of removing groups protecting the hydroxyl function, the following may be mentioned as examples.

  
The benzyl group is removed by catalytic reduction or a process using hydrofluoric acid.

  
The Cbz group is removed by catalytic reduction or a process using a mixture of hydrobromic acid and acetic acid.

  
The trityl group is removed by carrying out catalytic reduction or a process using trifluoroacetic acid, etc.

  
The tetrahydropyranyl group is removed by acid hydrolysis.

  
The t-butyl group is removed by a method using an acid, such as trifluoroacetic acid,

  
a mixture of hydrobromic acid and acetic acid, hydrochloric acid, etc.

  
As methods of removing groups protecting the carboxyl function, the following may be mentioned as examples.

  
The t-butyl group is removed by carrying out a process using an acid such as trifluoroacetic acid.

  
The benzyl group or the p-nitrobenzyl radical is removed by carrying out a process or a catalytic reduction using a Lewis acid, such as

  
  <EMI ID = 70.1>

  
Benzhydryl group or p-methoxybenzyl group is removed by catalytic reduction or a process using a mixture of hydrobromic acid and acetic acid, hydrochloric acid and methanol, trifluoroacetic acid, etc.

  
As a method for removing the groups protecting the mercapto function, the following can be cited as examples.

  
The benzyl group is removed by a method using hydrofluoric acid, etc.

  
The Cbz group is removed by a method using a mixture of hydrobromic acid, acetic acid, trifluoroacetic acid, etc.

  
The p-nitrobenzyl group is removed by catalytic reduction. The above-mentioned deprotection can be carried out concomitantly with the conversion of the group R <1> into a hydrogen atom, that is, deesterification.

  
If desired, the acylation reaction

  
is preferably promoted by the silylation of the starting compound (II) with a silylating agent, such as trimethylchlorosilane-base, hexamethyldisilazane. N, O-bistrimethylsilylacetamide, etc., so as to solubilize the starting material in organic solvents and activate the amino group.

  
The starting compounds represented by the general formula (II ') can be produced according to the process described in Japanese Patent Application No. [deg.] 34696/78.

  
An example of such a preparation is given in

  
  <EMI ID = 71.1>

  
  <EMI ID = 72.1>

  

  <EMI ID = 73.1>
 

REFERENCE DIAGRAM (II ')

  

  <EMI ID = 74.1>
 

  
  <EMI ID = 75.1>

  
described in the following reference examples.

  
The compound (II) represented by the general formula (I) in which R represents a hydrogen atom can be produced by removing the group protecting the carboxyl function, according to the process outlined in scheme (II).

DIAGRAM (II)

  

  <EMI ID = 76.1>


  
In the above formulas, R represents a group

  
  <EMI ID = 77.1>

  
have the meanings previously indicated.

  
The deesterification reaction is carried out according to a conventional process used in the field of synthetic chemistry of penicillins and cephalosporins.

  
As a reaction which converts -COOR group to -COOH group, 1) catalytic reduction, 2) acidolysis, 3) cleavage reaction using Lewis acid, 4) hydrolysis, 5) reduction other than reduction catalytic using reducing agents and 6) a process using an esterase. Each process in question will be explained in more detail below.

  
1) Catalytic reduction

  
We convert the COOR group into a COOH group

  
in the presence of a catalyst in a hydrogen atmosphere, in an inactive solvent. As a solvent, there may be mentioned, as examples, any solvent which does not affect the reaction, preferably ethanol, water, tetrahydrofuran, dioxane, ethyl acetate or acetic acid. , alone or in combination. As catalyst, there may be mentioned, as examples, the carbon supporting. palle.dium, platinum oxide, palladium-bearing calcium carbonate and Raney nickel. The reaction is generally carried out at a pressure of 1 to 5 atmospheres and a temperature of 0 to 100 [deg.] C, preferably at atmospheric pressure and at room temperature.

  
Preferably, this method is carried out

  
  <EMI ID = 78.1>

  
benzyl, diphenylmethyl, p-methoxybenzyl, etc.

  
2) Acidolysis

  
The COOR group is converted to the COOH group with an acid in an inactive solvent. As the acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. are used. As solvent, any solvent is used which does not affect the reaction medium, preferably ethyl acetate, benzene, ethanol, acetic acid, dioxane, methylene chloride or chloroform, etc., alone

  
or in combination.

The reaction is carried out at a temperature of

  
-15 to 50 [deg.] C, preferably 0 to 25 [deg.] C, for a period which fluctuates from 10 minutes to 5 hours, preferably 30 minutes to 3 hours.

  
This process is preferably used in the

  
case where R represents a t-butyl group, a trityl group, etc.

  
3) Scission reaction using a Lewis acid

  
We convert the COOR group to the COOH group by

  
a scission reaction in the presence of a Lewis acid

  
in an inactive solvent. As the solvent, any solvent is used which does not affect the reaction, preferably a mixture of a nitroalkane, such as nitromethane, and a haloalkane, such as methylene chloride. As the Lewis acid, there may be mentioned aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, etc. We use acid

  
in an amount of 1.0 to 1.5 molar equivalents based on the compound (II). The reaction is preferably carried out in the presence of a carbonium cation binding agent, such as anisole. The reaction is carried out at a temperature of

  
0 to 50 [deg.] C, preferably at room temperature, for a period which varies from 1 to 10 hours.

  
Preferably, this method is used in the

  
case where R represents a p-nitrobenzyl group, etc.

  
4) Hydrolysis

  
We convert the COOR group <1> to a COOH group by hydrolysis in the presence of an acid or an alkali in an inactive solvent. As an acid, we can mention

  
  <EMI ID = 79.1>

  
acetic, etc. As the solvent, there can be mentioned any solvent which does not affect the reaction, preferably a 2% aqueous solution of methanol, N, N-dimethylformamide or a mixture of acetic acid, water and tetrahydrofuran, etc. We perform the reaction

  
  <EMI ID = 80.1>

  
for a period which fluctuates from 10 minutes to 2 hours.

  
Preferably, this process is used by resorting to acids in the case where R represents a t-butyldimethylsilyl group.

  
As alkali, calcium carbonate is preferably used in an amount which varies from 1 to 6 molar equivalents with respect to the compound (In). As the solvent, preferably any solvent is used which does not affect the reaction, preferably a mixture of tetrahydrofuran and water, dioxane and water or acetone and water. The reaction is generally carried out at a temperature of 0 to 30 [deg.] C, for a time which fluctuates from 30 minutes to 24 hours.

  
Preferably, this process is used, which uses alkalis in the case where R represents a methyl group, an ethyl group, etc.

  
5) Reduction using reducing agents (other

  
than catalytic reduction)

  
The COOR group is converted to the COOH group by reduction in an inactive solvent. As the reduction, a process involving a mixture of zinc and acid is used. As the solvent, acetone, water, dioxane, tetrahydrofuran, ethanol, acetonitrile, N.N-dimethylformamide and acetic acid are used, alone or in combination.

  
As the acid, there may be mentioned hydrochloric acid, formic acid and acetic acid.

  
The reaction is carried out at a temperature of 0 to 100 [deg.] C, preferably 0 to 40 [deg.] C, for a period which varies from 1 to 10 hours.

  
The amount of zinc used for the reaction usually varies from 1 to 10 molar equivalents.

  
If suitable reagents are used, the protecting group in group X can be removed simultaneously with deesterification.

  
The compounds in accordance with the present invention

  
  <EMI ID = 81.1>

  
represents a hydrogen atom, have, as mentioned in the example below, activities

  
  <EMI ID = 82.1>

  
Gram-positive and Gram-negative ries that they constitute valuable anti-infective or antibacterial agents against these bacteria. The compounds represented by the general formula (I) in which R has a meaning other than hydrogen can also be used as a starting material for the compounds represented.

  
by the general formula (I) in which R represents

  
a hydrogen atom.

  
The invention therefore also has for; subject of pharmaceutical compositions comprising, as active ingredient, compound (I) or a pharmaceutical salt; only acceptable of such a compound, in combination with

  
a pharmaceutical diluent or vehicle. The compounds according to the invention are administered parenterally
(intramuscular, intraperitoneal, intravenous or subcutaneous injection), oral or rectal and can be presented in dosage forms suitable for each mode of administration.

  
Preparations according to the invention suitable for parenteral administration include emulsions, suspensions, aqueous solutions or

  
non-aqueous, sterile. As examples of vehicles or non-aqueous solvents, mention may be made of propylene glycol,

  
polyethylene glycol, vegetable oils, such as olive oil and injectable organic esters,

  
such as ethyl oleate. Such dosage forms

  
may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. We can sterilize them,

  
for example, by filtration through a retaining filter

  
bacteria, by incorporating sterilizing agents

  
in the compositions, by irradiating the compositions or

  
by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or in any other

  
other sterile injectable medium, immediately before use.

  
We can present the suitable compositions

  
for oral administration in a form suitable for absorption from the gastrointestinal tract.

  
Tablets and capsules suitable for oral administration may be presented in unit dosage form and may contain conventional excipients, such as binding agents, for example, syrup,

  
acacia gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants, for example, magnesium stearate,

  
talc, polyethylene glycol, silica; disintegrating agents, for example, potato starch

  
or acceptable wetting agents, such as sodium lauryl sulfate. Tablets can be coated

  
according to methods well known to those skilled in the art. Liquid preparations to be absorbed by the

  
oral route may be in the form of syrups, emulsions, solutions, oily or aqueous suspensions, etc. or they can be presented in the form of a dry product, intended to be reconstituted with water

  
or with any other suitable vehicle before use.

  
Such liquid preparations may contain

  
conventional additives, such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose, sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, agents emulsifiers, for example, lecithin or sorbitan mono-oleate; non-aqueous vehicles which may include edible oils, for example, almond oil, coconut oil,

  
  <EMI ID = 83.1>

  
of propyl or sorbic acid.

  
Compositions suitable for rectal administration are preferably suppositories which may contain, in addition to the active substance, excipients, such as cocoa butter or a suppository wax.

  
The dose of active ingredient in the compositions according to the invention can vary; however, it is necessary that the amount of active ingredient be such that a suitable dosage form is obtained. The dose chosen depends on the therapeutic effect, the mode of administration and the duration of treatment. In general, doses which vary from 5 to 350 mg / kg of body weight per day are administered to mammals, so

  
to achieve an antibiotic effect.

  
As pharmaceutically acceptable salts of compounds (I), mention may be made of inorganic salts and organic salts, such as hydrochlorides, sulphates, carbonates, phosphates, formates, malates, etc. In addition, there may be mentioned; by way of example, the sodium, potassium, calcium, ammonium, organic amine, etc. salts of the carboxylic acids represented by formula (I) in which R denotes a hydrogen atom. The "salts

  
are prepared according to a conventional process.

  
The following examples illustrate shapes

  
practical embodiments of the preparation of the compounds according to the invention.

  
EXAMPLE 1

  
  <EMI ID = 84.1>

  
next :

  

  <EMI ID = 85.1>


  
In this example, 88 mg (0.489 mmol) of

  
amino compound as obtained by carrying out the process described in Reference Example 8, are dissolved in

  
2 ml of deionized water and 1 ml of acetone and then 84 mg of an aqueous solution of sodium bicarbonate are added thereto. To the mixture is added, dropwise and under ice-cooling, 78 mg of 2-thienylacetyl chloride dissolved in 0.5 ml of acetone. The mixture is then stirred for 30 minutes and washed with ethyl acetate. The pH of the resulting aqueous layer is adjusted to 2.0 with hydrochloric acid. We extract

  
the white suspension thus obtained three times with

  
5 ml of ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily yellow product. The product is introduced into a

  
  <EMI ID = 86.1>

  
  <EMI ID = 87.1> same silica gel in the following examples and the reference examples) and the elution is carried out with chloroform. The syrup obtained is treated with a mixture of chloroform and ethanol so as to obtain 30 mg

  
of crystals. The comae crystals constituting the desired compound are identified on the basis of the following properties:

  
  <EMI ID = 88.1>

  
melting point: 181 - 183 [deg.] C

  

  <EMI ID = 89.1>


  
EXAMPLE 2

  
The anti-

  
  <EMI ID = 90.1>

  
obtained in Example 1. The method of regular dilution in agar, at a pH of 7.0 is used.

  

  <EMI ID = 91.1>
 

  
i EXAMPLE 3

  
  <EMI ID = 92.1>

  

  <EMI ID = 93.1>


  
Method a)

  
In this example, 73 mg (0.307 mmol) of

  
  <EMI ID = 94.1>

  
oct-2-en-8-one as obtained in Reference Example 9 and 135.9 mg (0.307 mmol) of 2- (2-tritylamino-4thiazolyl) -2-anti-methoxyiminoacetic acid are dissolved in 2 ml of anhydrous methylene chloride and added

  
69.6 mg (0.307 mmol) of dicyclohexylcarbodiimide dissolved in 1 ml of anhydrous methylene chloride, with stirring under ice-cooling. The mixture was stirred for 3 hours and allowed to react at a temperature of 10 [deg.] C overnight. The reaction mixture is washed with 1% aqueous phosphate solution, saturated aqueous bicarbonate solution.

  
of sodium and a saturated aqueous solution of sodium chloride. The wash liquor was dried with magnesium sulfate and concentrated under reduced pressure to obtain 257 mg of a crude product. The product is purified by column chromatography using

  
12 g of silica gel and a solvent consisting of n-hexane and ethyl acetate (1: 1) so as to obtain 73 mg
(35.9%) of the desired compound as a pale yellow glass.

  
-1

  
  <EMI ID = 95.1>

  
Method b)

  
In this example, 524.9 mg (1.18 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetic acid are dissolved in 10 ml of dried tetrahydrofuran. To the solution is added 1.18 ml (1.18 mmol) of N-methylmorpho-

  
  <EMI ID = 96.1>

  
temperature of -30 [deg.] C and the mixture was stirred for 40 minutes. A solution of 235 mg is added dropwise.

  
  <EMI ID = 97.1>

  
of anhydrous methylene to the reaction mixture. The mixture is left to react for 30 minutes and then stirred

  
  <EMI ID = 98.1>

  
10 ml of ethyl acetate are added and the mixture is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution.

  
The wash liquor was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 865 mg of a crude product. By chromatography on silica gel using 40 g of silica gel <EMI ID = 99.1>

  
of the desired compound. The infrared and re spectra. nuclear magnetic sonance of the product are compatible with those of the compound prepared according to process a). EXAMPLE 4

  
  <EMI ID = 100.1>

  

  <EMI ID = 101.1>


  
In this example, 500 mg (0.754 mmol,

  
  <EMI ID = 102.1>

  
in a mixture of 5 ml of trifluoroacetic acid, 2.5 ml of anhydrous methylene chloride and 2.5 ml

  
  <EMI ID = 103.1>

  
3 hours and 40 minutes and then concentrated under reduced pressure. 5 ml of an aqueous solution of acetic acid are added to the concentrate. The mixture is stirred at room temperature for 3 hours and then concentrated under reduced pressure. The concentrate is suitably triturated with ether and filtered to give 244 mg of a crude product. The product is purified by column chromatography with 10 ml of Diaion HP-1C and a solvent consisting of methanol and water (2: 5 by volume the same will apply in the remainder of this present document).

  
  <EMI ID = 104.1>

  
pale yellow.

  
-1

  
  <EMI ID = 105.1>

  

  <EMI ID = 106.1>


  
Method a)

  
In this example, 81 mg (0.34 mmol) are dissolved

  
  <EMI ID = 107.1>

  
(R) -N-t-butyloxycarbonyl-phenylglycine in 2 ml of anhydrous methylene chloride. We add a solution of
77 mg (0.34 mmol) of dicyclohexylcarbodiimide in 1 ml of anhydrous methylene chloride in solution, under cooling with ice and sodium chloride.

  
The mixture is allowed to react under cooling with ice for 2 hours and then two drops of acetic acid are added thereto. The mixture is stirred for 20 minutes and filtered under reduced pressure.

  
The cake is washed with 20 ml of ethyl acetate. The filtrate and the washing liquor are combined and then added.
20 ml of ether. The mixture is washed with a 1% aqueous solution of phosphoric acid, a saturated solution of sodium bicarbonate and a saturated solution of chlorine.

  
  <EMI ID = 108.1>

  
anhydrous sodium sulfate and concentrated under reduced pressure to obtain 187 mg of a crude product. The product is purified by chromatography on silica gel with 9 g of silica gel and a solvent consisting of n-hexane and ethyl acetate (1: 1) so as to obtain
104 mg (64.9%) of the desired compound as a colorless glass.

  
  <EMI ID = 109.1>

  
Method b)

  
In this example, 297.3 mg (1.18 mmol) of (R) -N-t-butyloxycarbonylphenylglycine are dissolved in

  
5 ml of anhydrous tetrahydrofuran and 1.18 ml are added
(1.13 mmol) of N-methylmorpholine IN-tetrahydrofuran and 1.18 ml (1.18 mmol) of i-Bu-1Ntetrahydrofuran chloroformate at -30 [deg.] C. The mixture is stirred for
30 minutes and add 234 mg (0.983 mmol) of

  
  <EMI ID = 110.1>

  
oct-2-en-8-one dissolved in 5 ml of anhydrous methylene chloride. The mixture is left to react at a <EMI ID = 111.1>

  
4 hours and 15 minutes. The reaction mixture is diluted with 15 ml of methylene chloride and washed successively with water, 1N hydrochloric acid, water and saturated sodium chloride solution. The wash liquor was dried over anhydrous sodium sulfate and concentrated to afford 588 mg of a crude acyl compound. Purification by chromatography on silica gel with 28 g of silica gel, carried out

  
  <EMI ID = 112.1>

  
of the desired compound in the form of a colorless glass. The infrared and nuclear magnetic resonance spectra of the product are compatible with those of the compound prepared by carrying out process a).

  
EXAMPLE 6

  
  <EMI ID = 113.1>

  
carboxylic:

  

  <EMI ID = 114.1>


  
In this example, 280 mg (0.59 mmol) are dissolved

  
  <EMI ID = 115.1>

  
oct-2-en-8-one obtained in Example 5 in 2.5 ml of anhydrous methylene chloride and 2.5 ml of anisole and

  
5.0 ml of trifluoroacetic acid is added under ice cooling. The mixture was allowed to stand for 4 hours and 50 minutes under ice cooling and concentrated. To the concentrated residue is added
10 ml of ether and the mixture is stirred at room temperature for 1 hour to form a precipitate. The precipitate is collected by filtration. obtaining 202 mg (70.9%) of the desired compound as a pale yellow powder.

  
_1

  
  <EMI ID = 116.1>

  
7.51 (d, 5H), 6.31 (m, 1H), 4.95 (d, 1H), 3.8-3.5 (m, 1H), 2.6-2.9 (m, 4H)

  
Separation of diastereomers from acid

  
  <EMI ID = 117.1>

  
The compound (50 mg) obtained by carrying out the process described above is dissolved in 150 ml of water and the solution is subjected to high speed liquid chromatography using Bondapak C-18.
(product of Waters Co.) as the vehicle and a solvent consisting of 7% methanol and 0.2N hydrogenated potassium phosphate, the operation being repeated eight times. The isolation of two fractions is monitored by spectroscopic analysis at a wavelength of 254 nm. After removal of the methanol under reduced pressure, each fraction is lyophilized. The dried material was dissolved in water and adsorbed on a 20 ml column packed with Diaion HP-10 (product of Mitsubishi Kasei Kogyo Co., Ltd.). The column is washed with 200 ml.

  
  <EMI ID = 118.1>

  
The ninhydrin positive fractions were collected and lyophilized to obtain 14.0 mg of isomer A and 24.6 mg of isomer B as a white powder of the potassium salt.

  
A: the most polar fraction

  
  <EMI ID = 119.1>

  
Taking into consideration the relationship between the structure and activity of cephalosporins, the absolute configuration 6 (R) 7 (S) is assigned to the less polar isomer which possesses rotational power.

  
  <EMI ID = 120.1>

  
stronger than the more polar isomer, as shown in the following table.

  
EXAMPLE 7

  
  <EMI ID = 121.1>

  

  <EMI ID = 122.1>


  
Method a)

  
In this example, 68 mg (0.286 mmol) are dissolved

  
of (+) - cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo-

  
  <EMI ID = 123.1>

  
carbonylamino) -acetic in 2 ml of anhydrous methylene chloride and 70 mg (0.315 mmol) of dicyclohexylcarbodiimide dissolved in 1 ml of anhydrous methylene chloride are added, under cooling in ice. The mixture was stirred for 6 hours and then stirred at a temperature of 10 ° C. overnight. The reaction mixture is filtered and the cake washed with methylene chloride. The filtrate and the washing liquor are combined and the whole is washed successively with phosphoric acid 1, saturated sodium bicarbonate solution and saturated sodium chloride solution. The wash liquor was dried with anhydrous sodium sulfate and concentrated to afford 189 mg of a crude acyl compound.

   The product is purified by chromatography on silica gel using 9 g of silica gel and a solvent consisting of n-hexane and ethyl acetate.

  
  <EMI ID = 124.1>

  
20 mg of a less polar isomer and 11.1 mg of a mixture

  
  <EMI ID = 125.1>

I

  
most polar isomer
-1

  
  <EMI ID = 126.1>

  
2.6-0.7 (m, 4H), 1.50 (s, 9H), 1 20 (t, 3H) least polar isomer

  
_-1

  
  <EMI ID = 127.1>

  
Method b)

  
Process In this example, 428.5 mg ( <1>, <1> <3>

  
mmol) of (R) -2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperidinylcarbonylamino) -acetic acid in 10 ml of dried tetrahydrofuran and 1.25 ml (1, 25 mmol)

  
of N-methylmorpholine 1N-tetrahydrofuran and 1.25 ml

  
(1.25 mmol) of 1N isobutyl chloroformate-tetrahydrofuran at a temperature of -30 [deg.] C. The mixture is stirred for 30 minutes and 235 mg (1.13 mmol) of

  
  <EMI ID = 128.1>

  
oct-2-en-8-one dissolved in 5 ml of anhydrous methylene chloride. The mixture is left to react for

  
1 hour and stirred at 10 [deg.] C overnight. The reaction mixture is diluted with 20 ml of ethyl acetate and washed successively with

  
water, 0.1 N hydrochloric acid, saturated sodium bicarbonate solution and water. We dry

  
washing liquor over anhydrous sodium sulfate

  
and concentrated to obtain 570 mg of a crude acyl compound. The product is purified and fractionated according to method a), except that 27 g is used.

  
of silica gel so as to obtain 73 mg of a more polar isomer and 61 mg of a less polar isomer (total yield: 65.4%). The infrared and nuclear magnetic resonance spectra of the isomers are compatible with those of the isomers obtained in accordance with method a). EXAMPLE 8

  
  <EMI ID = 129.1>

  
carboxylic:

  

  <EMI ID = 130.1>


  
In this example, 103 mg (0.248

  
  <EMI ID = 131.1> less polar) as obtained in Example 7 in a mixture of 5 ml of trifluoroacetic acid, 5 ml of methylene chloride and 2 drops of anisole. We let

  
  <EMI ID = 132.1>

  
center under reduced pressure. To the concentrate, we add

  
dry benzene and the mixture is again concentrated to obtain an oily product. To the product is added ether and the mixture is stirred at room temperature to obtain a yellow precipitate. The crude product (104 mg) is collected by filtration as a yellow powder. The crude product is dissolved in ethyl acetate and extracted with 5 ml of saturated sodium bicarbonate solution, the extraction being carried out three times. The extracts are washed with ethyl acetate. The pH of the wash liquor is adjusted to 2.5 with 0.5N hydrochloric acid, under ice-cooling and extracted three times with 5 ml of ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure of

  
  <EMI ID = 133.1>

  
1.27 (t, 3H)

  
Based on the potent microbial activity as indicated in the following table, this compound is assigned the absolute configuration 6 (R) 7 (S).

  
EXAMPLE 9

  
  <EMI ID = 134.1>

  

  <EMI ID = 135.1>


  
In this example, 132 mg (0.53 mmol) of (R) -Nt-butyloxycarbonylphenylglycine is dissolved in 5 ml of anhydrous tetrahydrofuran and 0.53 ml (0.53 mmol) of 1N and 0 N-methylmorpholine is added thereto, 53 ml (0.53 mmol) of 1N isobutyl chloroformate, at a temperature of 0 [deg.] C. The mixture is stirred for 15 minutes and then 0.07 ml (0.5 mmol) of triethylamine and 1.44 mg are added thereto.

  
  <EMI ID = 136.1>

  
as obtained in Reference Example 12. The

  
  <EMI ID = 137.1>

  
The mixture is diluted with 10 ml of ethyl acetate and washed successively with citric acid at
10%, saturated sodium bicarbonate solution and saturated sodium chloride solution. The wash liquor was dried with anhydrous sodium sulfate and concentrated to obtain a crude acyl compound. The product is purified by column chromatography

  
of 30 g of silica gel and using a solvent consisting of n-hexane and ethyl acetate (3: 1 in

  
  <EMI ID = 138.1>

  
in the form of a powder.

  
-1.

  
  <EMI ID = 139.1>

  
event, J = 7.5Hz)

  
EXAMPLE 10

  
Preparation of (+) - cis- trifluoroacetate

  
  <EMI ID = 140.1>

  

  <EMI ID = 141.1>


  
In this example, 100 mg (0.21 mmol) are dissolved

  
  <EMI ID = 142.1>

  
in 1 ml of anhydrous methylene chloride and then 1 ml of trifluoroacetic acid is added thereto, under cooling on an ice bath. Let the mixture stand

  
at a temperature of 0 to 5 [deg.] C for 3.5 hours with occasional stirring. The reaction mixture is concentrated under reduced pressure. The concentrate is triturated with 5 ml of anhydrous ethyl ether and the ethereal layer is separated by decantation. This treatment is repeated three times and the cake thus obtained is dried under reduced pressure so as to obtain 70 mg (75%) of the desired compound in the form of a powder.

  
  <EMI ID = 143.1>

  
partially overlapping with DMSO-d6 signal), 1.82 (2H, broad), 1.14, 0.91 (3H, d, respectively,

  
  <EMI ID = 144.1>

  

  <EMI ID = 145.1>


  
In this example, the same procedure is repeated as that described in Example 9, except that we

  
  <EMI ID = 146.1>

  
as obtained in Reference Example 11 as the starting compound. 140 mg (57.6%) of the desired compound are thus obtained.

  
  <EMI ID = 147.1>

  
(3H, d respectively, J = 7Hz)

  
EXAMPLE 12

  
  <EMI ID = 148.1>

  
oct-2-en-8-one:

  

  <EMI ID = 149.1>


  
In this example, the same procedure is repeated as that carried out in Example 10, except that we

  
  <EMI ID = 150.1>

  
Example 11 as the starting compound. 73 mg (100%) of the desired compound are thus obtained.

  
  <EMI ID = 151.1>

  
(3H, d respectively, J = 7.5Hz) The above-mentioned compound is dissolved (30 mg)

  
  <EMI ID = 152.1>

  
High speed liquid phase tography using Bondapak C-18 (product of Waters Co.) as support and a solvent consisting of 7% methanol and 0.2N hydrogenated potassium phosphate, the operation proceeds repeating five times. The isolation of two fractions is monitored by spectroscopic analysis at a length

  
  <EMI ID = 153.1>

  
reduced pressure, each fraction is lyophilized. The dried material was dissolved in water and adsorbed onto a column packed with 20 ml of Diaion HP-10. The column is washed with 200 ml of water and the elution is carried out with 20% ethanol. The eluate is taken up in fractions of 20 ml. We collect the fractions that are positive

  
ninhydrin test and lyophilized so as to

  
  <EMI ID = 154.1>

  
first during liquid chromatography

  
at high speed and 11.4 mg (yield 38%) of isomer D which then elutes. The specific rotational powers of isomers are as follows:

  
  <EMI ID = 155.1>

  
Isomer D

  
IR (KBr): 3420, 1760, 1695, 1633

  
  <EMI ID = 156.1>

  
5.47 (1H, d, J = 4.7), 5.19 (1H, s),

  
3.89 (1H, m), 2.45 (1H, m), 1.44-1.04 (2H, m), 1.00 (3H, d, J = 7.4) The absolute configuration is assigned 6 (R) 7 (S) to the D isomer which possesses more microbial activity

  
  <EMI ID = 157.1>

  
shown in the following table.

  
EXAMPLE 13

  
  <EMI ID = 158.1>

  

  <EMI ID = 159.1>


  
Method A

  
In this example, 88 mg (0.35 mmol) are dissolved

  
  <EMI ID = 160.1>

  
anhydrous methylene ride and 155 mg (0.35 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetic acid are added. Then 1.5 ml of anhydrous dioxane is added to the mixture in order to make it more homogeneous. To the mixture is added 80 mg (0.39 mmol) of dicyclohexylcarbodiimide dissolved in 1 ml of dioxane and the mixture is stirred at

  
  <EMI ID = 161.1>

  
the white precipitate obtained by filtration and 10 ml of ethyl acetate and 5 ml of ether are added to the filtrate. We wash

  
mixing successively with 5 ml of phosphoric acid

  
  <EMI ID = 162.1>

  
of sodium bicarbonate. The wash liquor is dried with anhydrous sodium sulfate and concentrated.

  
under reduced pressure so as to obtain 290 mg of the desired crude compound in the form of a semi-solid. The crude compound is introduced into a column packed with 27 g of silica gel and elution is carried out with a mixture of n-hexane and ethyl acetate (2: 1). The eluate is concentrated under reduced pressure so as to obtain 170 mg.
(7290 of the desired compound.

  
Melting point (recrystallization from n-hexane and

  
  <EMI ID = 163.1>

  
Method B

  
In this example, 243.9 mg (0.05 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-antimethoxyiminoacetic acid is dissolved in 5 ml of anhydrous tetrahydrofuran and 0.55 ml (0, 55 mmol) of N-methyl-

  
  <EMI ID = 164.1>

  
the mixture is then stirred for 15 minutes. Triethylamine (0.11 ml - 0.5 mmol) is added to the mixture, followed by the addition of <EMI ID = 165.1>

  
reduced pressure. Ethyl acetate (10 ml) was added to the concentrate and the mixture thus obtained was washed successively with 5% hydrochloric acid, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The wash liquor was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The product is introduced into a column packed with 25 g of silica gel and the elution is continued with n-hexane and ethyl acetate (5: 3). The eluate is concentrated under reduced pressure to obtain 250 mg (74.0%) of the desired compound. The physical properties of the compound are compatible with those of the compound prepared by carrying out method A. EXAMPLE 14

  
  <EMI ID = 166.1>

  

  <EMI ID = 167.1>
 

  
In this example, 70 mg (0.103

  
  <EMI ID = 168.1>

  
in Example 13 in 0.5 ml of anhydrous methylene chloride and 0.1 ml of anisole. The mixture is cooled to 0 ° C. and then this cooling is followed by the addition of 0.5 ml of trifluoroacetic acid. The mixture thus obtained is left to stand in an ice bath for 3.5 hours.

  
The reaction mixture is concentrated under reduced pressure. The concentrate is triturated with 5 ml of anhydrous ethyl ether and filtered to obtain a white powder. The powder is dissolved in 2 ml of acid

  
  <EMI ID = 169.1>

  
room temperature for 2.5 hours and then at 5-10 [deg.] C overnight. The solution is still left to stand at room temperature.
(25 [deg.] C) for 6 hours and then concentrated under reduced pressure so as to obtain a glassy product. The glassy product is suitably triturated with ether and the whole is filtered. The filtrate is dried

  
  <EMI ID = 170.1>

  
J = 7.5Hz) EXAMPLE 15

  
  <EMI ID = 171.1>

  

  <EMI ID = 172.1>


  
In this example, the same operating mode is repeated as that described in method B of example 13, except

  
  <EMI ID = 173.1>

  
2-ene-8-one as the starting compound. In this way 251 mg (53%) of the desired compound is obtained.

  
Melting point: 201.0 - 202.0 [deg.] C
-1 <EMI ID = 174.1>

  

  <EMI ID = 175.1>


  
In this example, the same procedure is repeated as that described in Example 14, except that 70 mg of (+) - cis- is used as starting material.

  
  <EMI ID = 176.1>

  
2-ene-8-one obtained in Example 15. This gives 22 mg
(56%) 'of the desired compound.

  
-1

  
  <EMI ID = 177.1>

  
6 10 (1H, d, J = 2Hz), 5 47 (lH, m), 4.00 (3 / 2H, s), 3 85 (3 / 2H, s), 2.60 (wide, partially overlapping with DMSO-dg signal), 1.91 (2H, m), 1.12 (3H, dd, J = 7.5Hz)

  
EXAMPLE 17

  
  <EMI ID = 178.1>

  

  <EMI ID = 179.1>
 

  
In this example, 172 mg (0.62 mmol) of (2-chloroacetylamino-4-thiazolyl) -2-syn-methoxyiminoacetic acid is suspended in 3.6 ml of anhydrous dichloromethane and 68.9 mg is added thereto. (0.68 mmol) of triethylamine so as to make the solution homogeneous. Under cooling in an ice bath and sodium chloride, 129 mg (0.62 mmol) of phosphorus pentachloride was added to the mixture with stirring and the mixture thus obtained was stirred for 1.5 hours. N-hexane (13.8 mL) is added to the mixture and the supernatant layer is separated by decantation. Anhydrous tetrahydrofuran is added to the residue so as to obtain a hydrochloric acid solution.

  
On the other hand, 160 mg (0.52 mmol) of the

  
  <EMI ID = 180.1>

  
of reference 13 in 1 ml of a 50% mixture of tetrahydrofuran and water and then 209 mg are added thereto

  
(2.06 mmol) of triethylamine.

  
Or add the mixture to the hydrochloric acid solution under ice cooling and stirring. After stirring the whole at the same temperature for 1.5 hours, the pH of the mixture is adjusted to a value which varies from 4 to 5 with 1N hydrochloric acid and

  
it is extracted with 10 ml of ethyl acetate three times. The ethyl acetate extracts were washed with sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

  
so as to obtain 147 mg (52.1%) of the desired compound.

  
-1

  
  <EMI ID = 181.1>

  

  <EMI ID = 182.1>


  
In this example, 147 mg (0.321 mmol) of the chloroacetyl compound as obtained in Example 17 are dissolved in 0.5 ml of dimethyl sulfoxide and 2.5 ml of dimethylformamide and then 47 mg (0, 64 mmol) of thiourea at room temperature and with stirring.

  
The mixture is stirred for 14 hours. After addition of ether, the supernatant layer is separated by decantation and the residue is dissolved in a small amount of dimethyl sulfoxide. The solution is adsorbed on a column packed with 10 ml of Diaion HP-10. The column is washed with 240 ml of water and the elution is carried out with a solvent consisting of methanol and water (1:10 to 1: 2). The eluates are collected and the methanol is removed under reduced pressure. The residue is adsorbed again on

  
a column packed with 10 ml of Diaion HP-10 and the column was washed with 500 ml of water. Elution is carried out with a solvent consisting of methanol and water (1: 1). We

  
collect the eluates and concentrate them under pressure

  
  <EMI ID = 183.1>

  
wish.

  
-1

  
  <EMI ID = 184.1>

  
J = 8Hz)

  
EXAMPLE 19

  
  <EMI ID = 185.1>

  

  <EMI ID = 186.1>


  
In this example, we put 54.2 mg (0.195 mmol)

  
; 2-Chloroacetylamino-4-thiazolyl-2-syn-methoxy- acid

  
  <EMI ID = 187.1>

  
anhydrous methylene chloride and add 23.48 mg

  
(0.195 mmol) of triethylamine. Phosphorus pentachloride (40.3 mg - 0.195 mmol) is added to the reaction mixture under ice cooling. After a commotion

  
20 minutes, 3.92 ml of n-hexane are added to the mixture

  
and the supernatant layer is separated by decantation. The residue is dissolved in 1.96 ml of tetrahydrofuran so as to obtain an acid chloride solution.

  
On the other hand, 45.9 mg (0.155 mmol) are dissolved

  
  <EMI ID = 188.1>

  
(0.469mmol) of triethylamine. To the solution, we add

  
the above-mentioned acid chloride solution under ice cooling and the mixture stirred for 2 hours. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid and triple extracted with ethyl acetate. The extracts are washed with saturated sodium chloride solution. The wash liquor was dried with anhydrous sodium sulfate and concentrated to obtain 80 mg of the desired compound.

  
as a pale yellow powder.

  
-1

  
  <EMI ID = 189.1>

  

  <EMI ID = 190.1>
 

  
In this example, 80 mg of the compound are dissolved

  
  <EMI ID = 191.1>

  
To the solution is added 27.5 mg of thiourea at room temperature with stirring and the mixture is stirred for 14 hours. After addition of ether, the supernatant layer is separated by decantation so as to obtain a red oily residue. The residue is purified by chromatography using Diaion HP-10 so as to obtain
19.2 mg of the desired compound.

  
-1

  
  <EMI ID = 192.1>

  
one-2-carboxylic:

  

  <EMI ID = 193.1>


  
In this example, 126 mg of acid are dissolved

  
  <EMI ID = 194.1>

  
2-en-8-one-2-carboxylic acid obtained in Reference Example 14 in 3.0 ml of dioxane and 4.0 ml of water. The solution is cooled on a bath of ice and sodium chloride. To the solution are added 105 mg of sodium bicarbonate and 84 mg of 2-thienylacetyl chloride dissolved in 1 ml of dioxane. The mixture is stirred for 1 hour. The pH of the reaction mixture is then adjusted to 2.0 with 1N hydrochloric acid and

  
  <EMI ID = 195.1>

  
The extracts are combined and washed with saturated sodium chloride solution. The wash liquor was dried with anhydrous sodium sulfate and subjected to filtration. The filtrate is concentrated and the concentrated product is introduced into a column packed with 20 g of silica gel. Elution is continued with a mixture of chloroform and ethanol (20: 1 by volume). The fractions containing the desired compound are combined and concentrated to dryness so as to obtain 89.1 mg of the desired compound as a pale yellow powder. Make it-

  
  <EMI ID = 196.1>

  
quées below:
-1

  
  <EMI ID = 197.1>

  
The antibacterial activities of the compounds obtained in Examples 4, 6, 8, 10, 12,
14, 16, 18, 20 and 21 by an extract dilution process

  
  <EMI ID = 198.1>

  
are shown in the following table. Cefazolin is used as a reference compound.

  

  <EMI ID = 199.1>
 

  
  <EMI ID = 200.1>

  
2: Staphylococcus aureus Smith 3 ': Staphylococeus epidermidis 4: Escherichia coli NIHJC-2 5: Escherichia coli Juhl

  
6: Klebsiella pneumoniae 8045 7: Klebsiella pneumoniae Y-60 8: Serratia marcescens T-26

  
9.:- Serratia marcescens T-55
10 Proteus mirabilis 1287
11: Proteus vulgaris 6897
12: Proteus morganii KY4298
13: Proteus rettgeri KY4289
14: Pseudomonas aeruginosa 145

  
  <EMI ID = 201.1>

  
a: The compound obtained in Example 4

  
  <EMI ID = 202.1>

  
c: isomer A obtained in example 6 d: isomer B obtained in example 6 e: the compound obtained in example 8

  

  <EMI ID = 203.1>


  
g ': isomer D obtained in Example 12 EXAMPLE 22

  
  <EMI ID = 204.1>

  

  <EMI ID = 205.1>


  
In this example, 50.1 mg (0.28

  
  <EMI ID = 206.1>

  
oct-2-en-8-one-2-carboxylic acid as obtained in Reference Example 16 (or 8) in 1 ml of water and 2 ml of acetone and 55.5 mg of sodium hydrogencarbonate.

  
To the mixture, 0.3 ml of a solution of 1 N phenylacetyl chloride - methylene chloride at a temperature of -20 [deg.] C is added and the mixture is stirred at the same temperature for 20 minutes. After raising the temperature to room temperature, the reaction mixture is stirred for 2 hours. The mixture was then adjusted to pH 1.5 with 10% hydrochloric acid under ice-cooling and extracted three times with 5 ml of ethyl acetate. The extract is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated.

  
under reduced pressure. The crystals thus obtained are recovered by filtration and washed with a small amount of ethyl acetate so as to obtain 39.7 mg.

  
  <EMI ID = 207.1>

  
properties of the compound.

  
  <EMI ID = 208.1> <EMI ID = 209.1>

  
lique:

  

  <EMI ID = 210.1>


  
In this example, 399 mg (1.28 mmol) are dissolved

  
  <EMI ID = 211.1>

  
the manner described in Example 18 (or 13) in 6.4 ml of water and 12.8 ml of acetone and 432 mg (5.14 mmol) of sodium hydrogencarbonate are added thereto. The mixture is stirred under ice cooling. After addition of 258.5 mg
(5.14 mmol) of acetyl chloride, the mixture is left to react for 3 hours under ice-cooling. The pH of the reaction mixture is adjusted to 3 with 0.1N hydrochloric acid and extracted five times with
10 ml of ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ether is added to the concentrated product and the crystals formed are collected by filtration. We obtain
242.7 mg of the desired compound.

  
The aqueous layers obtained in the above-mentioned ethyl acetate extraction were re-extracted five times with 10 ml of ethyl acetate. The crystallization process described above is repeated so as to obtain 27.6 mg of the desired compound. To the remaining aqueous layers, saturated sodium chloride solution is added and the mixture is extracted five times with 10 ml of ethyl acetate. The crystallization process described above is repeated so as to obtain 21.3 mg of the desired compound. The total quantity

  
  <EMI ID = 212.1>

  
The properties of the compound are shown below.

  
  <EMI ID = 213.1>

  

  <EMI ID = 214.1>


  
In this example, 42.5 mg (0.5 mmol) of cyanoacetic acid and 57.5 mg (0.5 mmol) of N-hydroxysuccinimide are dissolved in 2.5 ml of dry dioxane and added
103.3 mg (0.5 mmol) of N, N-dicyclohexylcarbodiimide in solution. The mixture is stirred at room temperature for 1 hour. The crystals thus obtained are separated by filtration and the filtrate is concentrated under reduced pressure. To the residue obtained, 5 ml of dried dichloromethane is added and an insoluble material is filtered off so as to obtain a solution of the succinimidic ester of cyanoacetic acid.

  
On the other hand, 123 mg (0.45 mmol) of (+) - cis-7-amino-2-t-butyloxycarbonyl- hydrochloride is dissolved.

  
  <EMI ID = 215.1>

  
of the present specification amino compound) and 0.077 ml of triethylamine in 5 ml of dry dichloromethane. To the solution is added the above solution of cyanoacetic acid succinimidic ester. The mixture is stirred at room temperature for 4 hours and then concentrated under reduced pressure. The oily product thus obtained was subjected to chromatography on a column of silica gel using a mixture of chloroform and methanol (15: 1). The fractions containing the desired compound are combined and concentrated under reduced pressure to obtain 112 mg of the desired compound. Yield:
73.4%.

  
  <EMI ID = 216.1> EXAMPLE 25

  
  <EMI ID = 217.1>

  

  <EMI ID = 218.1>


  
The same procedure is repeated as that described in Example 24, except that 158 mg is used.

  
  <EMI ID = 219.1>

  
instead of cyanoacetic acid and 247 mg
(0.9 mmol) of the amino compound. We thus obtain 313 mg

  
  <EMI ID = 220.1>
--1

  
  <EMI ID = 221.1>

  
3.78 (1H, m), 2.19 (4H, m), 1.50 (9H, s)

  
EXAMPLE 26

  
  <EMI ID = 222.1>

  
oct-2-en-8-one:

  

  <EMI ID = 223.1>
 

  
The same procedure is repeated as that described in Example 24, except that 65.6 mg is used.
(0.5 mmol) of cyanomethylthioacetic acid instead of cyanoacetic acid. 136.5 mg of the desired compound are thus obtained. Yield: 86.3%.

  
-1

  
  <EMI ID = 224.1>

  
3.72 (5H, m), 2.18 (4H, m), 1.51 (9H, s) EXAMPLE 27

  
  <EMI ID = 225.1>

  
oct-2-en-8-one:

  

  <EMI ID = 226.1>


  
The same procedure is repeated as that described in Example 24, except that 156 mg is used.

  
(1 mmol) of 2- (2-furyl) -2-hydroxyiminoacetic acid instead of cyanoacetic acid and which is used 137 mg
(0.5 mmol) of the amino compound. In this way, we get

  
  <EMI ID = 227.1>

  
  <EMI ID = 228.1> EXAMPLE 28

  
  <EMI ID = 229.1>

  

  <EMI ID = 230.1>


  
The same procedure is repeated as that described in Example 24, except that 85.6 mg is used.
(0.5 mmol) of 2- (2-thienyl) -2-hydroxyiminoacetic acid instead of cyanoacetic acid and which 137 mg is used
(0.5 mmol) of the amino compound. In this way, 103 mg of the desired compound are obtained. Yield: 52.6. %.

  
'-1

  
  <EMI ID = 231.1>

  
5.37 (1H, m), 3.78 (1H, m), 2.09 (4H, m), 1.46 (9H, s)

  
EXAMPLE 29

  
  <EMI ID = 232.1>

  
oct-2-en-8-one:

  

  <EMI ID = 233.1>
 

  
In this example, 79 mg (0.55 mmol) are dissolved

  
  <EMI ID = 234.1>

  
1N sodium nate. The crystals obtained are separated by filtration and the filtrate is extracted twice with 50 ml.

  
  <EMI ID = 235.1>

  
ethyl, dried over magnesium sulfate and

  
  <EMI ID = 236.1>

  
oily product thus obtained by chromatography on silica gel so as to obtain 157 mg of the desired compound.

  
  <EMI ID = 237.1>

  
  <EMI ID = 238.1>

  
EXAMPLE 30

  
Preparation of (&#65533;) - cis-7- (2-tetrazolyl) -

  
  <EMI ID = 239.1>

  
oct-2-en-8-one:

  

  <EMI ID = 240.1>
 

  
The same procedure is repeated as that described in Example 29 except that 79 mg (0.55 mmol) of (2-tetrazolyl) -acetic acid are used instead of acid.
(1-tetrazolyl) -acetic. 142 mg of

  
  <EMI ID = 241.1>

  
  <EMI ID = 242.1>

  
1.50 (9H, s)

  
  <EMI ID = 243.1>

  
  <EMI ID = 244.1>

  
oct-2-en-8-one:

  

  <EMI ID = 245.1>


  
The same procedure is repeated as that described in Example 29, except that 181 mg is used.
(0.725 mmol) of 4-pyridylthioaceti- acid hydrobromide

  
  <EMI ID = 246.1>

  
Thus, 148.6 mg of the desired compound are obtained. Yield: 76.3%.

  
-1

  
  <EMI ID = 247.1> EXAMPLE 32

  
  <EMI ID = 248.1>

  

  <EMI ID = 249.1>


  
In this example, 3 ml of tri-

  
  <EMI ID = 250.1>

  
of the present specification ester compound) obtained in Example 30. The solution is stirred for 10 minutes and concentrated.

  
  <EMI ID = 251.1>

  
To the extremely viscous substance thus obtained, 10 ml of ether are added. The mixture is stirred for 20 minutes and then filtered to obtain a solid product. The product is dissolved in 2 ml of methanol and the mixture is allowed to stand on an ice bath for 1 hour. The crystals thus obtained were filtered off and dried so as to obtain 111.5 mg of the desired compound. Yield: 87.3%.

  
  <EMI ID = 252.1>

  
8-one:

  

  <EMI ID = 253.1>


  
The same procedure is repeated as that described in Example 32, except that 70 mg is used.

  
  <EMI ID = 254.1>

  
obtained in Example 29 instead of the ester compound. In this way, 53.6 mg of the desired compound are obtained.

  
  <EMI ID = 255.1>

  
max

  
EXAMPLE 34

  
  <EMI ID = 256.1>

  

  <EMI ID = 257.1>


  
The same procedure is repeated as that described in Example 32, except that 105 mg are used.

  
  <EMI ID = 258.1>

  
obtained in Example 31 instead of the ester compound. In this way, 70 mg of the desired compound are obtained. Yield: 78.096.

  
  <EMI ID = 259.1>

  
max EXAMPLE 35

  
Preparation of (&#65533;) - cis-7-cyanoacetamido-2-

  
  <EMI ID = 260.1>

  

  <EMI ID = 261.1>


  
The same procedure is repeated as that described in Example 32, except that 112 mg is used.

  
  <EMI ID = 262.1>

  
obtained in Example 24 instead of the ester compound. In this way, 81 mg of the desired compound are obtained. Yield: 88.6%.

  
-1

  
  <EMI ID = 263.1>

  
  <EMI ID = 264.1>

  
  <EMI ID = 265.1>

  
oct-2-en-8-one:

  

  <EMI ID = 266.1>


  
The same procedure is repeated as that described in Example 32 except that 131 mg is used.

  
  <EMI ID = 267.1>

  
oct-2-en-8-one obtained in Example 25 instead of the ester compound. 78 mg of the desired compound are thus obtained.

  
  <EMI ID = 268.1>
-1

  
  <EMI ID = 269.1>

  

  <EMI ID = 270.1>


  
The same procedure is repeated as that described in Example 32, except that 136 mg are used.

  
  <EMI ID = 271.1>

  
In this way, 100 mg of the desired compound are obtained.

  
  <EMI ID = 272.1>

  
  <EMI ID = 273.1>

  
oct-2-en-8-one:

  

  <EMI ID = 274.1>
 

  
The same procedure is repeated as that described in Example 32, except that 115 mg is used.

  
  <EMI ID = 275.1>

  
oct-2-en-8-one as obtained in Example 27 instead of the ester compound. In this way, 92 mg of the desired compound are obtained. Yield: 69%.

  
-1

  
  <EMI ID = 276.1>

  
oct-2-en-8-one:

  

  <EMI ID = 277.1>


  
The same procedure is repeated as that described in Example 32, except that 103 mg is used.

  
  <EMI ID = 278.1>

  
instead of the ester compound. In this way, we get

  
  <EMI ID = 279.1>

  
  <EMI ID = 280.1> EXAMPLE 40

  
  <EMI ID = 281.1>

  
oct-2-en-8-one:

  

  <EMI ID = 282.1>


  
In this example, 176 mg (1 mole) are dissolved

  
  <EMI ID = 283.1>

  
carbodiimide to solution. The mixture is stirred at room temperature for 2 hours. The crystals thus obtained are separated by filtration and the filtrate is concentrated. The residue obtained is dissolved in 6 ml of dried dichloromethane.

  
On the other hand, 109 mg of hydrochloride is dissolved

  
  <EMI ID = 284.1>

  
ene-8-one according to the same process as that carried out in Reference Example 16 and 0.21 ml of

  
  <EMI ID = 285.1>

  
solution, the above-mentioned solution of dichloromethane is added and the mixture is stirred at room temperature for 10 hours and then concentrated under reduced pressure. To the residue thus obtained, 10 ml of water is added and an insoluble material is filtered off. The pH of the filtrate is adjusted to 2.5 with 2N hydrochloric acid. After cooling, the solution is filtered off and dried thoroughly. obtain 120 mg of the desired compound. Yield: 70.5%.

  
  <EMI ID = 286.1>

  
EXAMPLE 41

  
  <EMI ID = 287.1>

  
2-en-8-one:

  

  <EMI ID = 288.1>


  
The same procedure is repeated as that described in Example 40, except that 152 mg is used.

  
  <EMI ID = 289.1>

  
1,4-dithianyl) acetic. We get in this way

  
  <EMI ID = 290.1>
-1

  
  <EMI ID = 291.1>

  
one:

  

  <EMI ID = 292.1>
 

  
In this example, 90 mg (0.5 mole) of phenylmalonic acid is dissolved in a mixed solution of 5 ml of dry ether and 61 mg (0.51 mmol) of chloride

  
  <EMI ID = 293.1>

  
amide to the solution and the mixture is heated under reflux for 2 hours. The material is then concentrated under reduced pressure. To the residue thus obtained, 5 ml of dried benzene is added and the mixture is again concentrated.

  
The residue thus obtained is dissolved in dry ether and to the solution is added a solution in which

  
  <EMI ID = 294.1>

  
  <EMI ID = 295.1>

  
0.5 N sodium bonate and 1 ml of ether, under ice cooling. The mixture is stirred at room temperature for 1 hour and then the pH is adjusted.

  
  <EMI ID = 296.1>

  
times the mixture with 20 ml of ethyl acetate. The extract is evaporated to dryness and the solid obtained is completely suspended in 5 ml of ether. We filter

  
the suspension and dried to obtain 100 mg

  
  <EMI ID = 297.1>

  
1

  
  <EMI ID = 298.1> EXAMPLE 43

  
Preparation of the triethylamine salt of <EMI ID = 299.1>

  

  <EMI ID = 300.1>


  
In this example, 109 mg (0.5 mmol) are dissolved

  
  <EMI ID = 301.1>

  
  <EMI ID = 302.1>

  
195 mg (0.5 mmol) of α-triethylammoniumsulfophenylacetic ethyl carbonic anhydride are added, under ice-cooling. The mixture was stirred for 1.5 hours and the solvent was removed by distillation. The residue thus obtained is dissolved in 5 ml of water and the pH of the solution is adjusted to 1.5 with 1N hydrochloric acid. The solution is then extracted twice with
10 ml of n-butanol. The layers are combined with n-butanol and concentrated under reduced pressure. We wash it

  
  <EMI ID = 303.1>

  
dry it so as to obtain 196 mg of the desired compound.

  
  <EMI ID = 304.1>

  
  <EMI ID = 305.1> The antibacterial activities of the compounds of Examples 32, 33, 34, 36, 38, 41 and 42 are determined by the dilution method with heart extract-agar
(pH 7.2). The results obtained appear in the following table.

  

  <EMI ID = 306.1>
 

  
1: Staphylococcus aureus 209-p 2: Staphylococcus aureus Smith 3: Staphylococcus epidermidis 4: Escherichia coli NIHJC-2 5; Escherichia coli Juhl

  
6: Klebsiella pneumoniae 8045 7: Klebsiella pneumoniae Y-60 8: Serratia marcescens T-26 9: Serratia marcescens T-55
10: Proteus mirabilis 1287
11: Proteus vulgaris 6897
12: Proteus morganii KY4293
13: Proteus rettgeri KY4289
14: Pseudomonas aeruginosa 145
15: Pseudomonas putrida F264 m: The compound obtained in Example 32

  

  <EMI ID = 307.1>


  
t: Cefazolin

  
  <EMI ID = 308.1>

  
  <EMI ID = 309.1>

  
oct-2-en-8-one-2-carboxylic

  
  <EMI ID = 310.1>

  
  <EMI ID = 311.1>

  
than that described in Example 12, except that we

  
  <EMI ID = 312.1>

  
  <EMI ID = 313.1>

  
  <EMI ID = 314.1>

  
the less polar isomer of the desired compound.

  
  <EMI ID = 315.1>

  
presented in the following table.

  
EXAMPLE 45

  
  <EMI ID = 316.1>

  
lique:

  

  <EMI ID = 317.1>


  
In this example, the same procedure is repeated as that described in Example 8, except that 55 mg of (&#65533;) - cis- is used as starting material.

  
  <EMI ID = 318.1>

  
polar) obtained by carrying out the same process as that described in Example 7. This gives 35.7 mg
(72%) of a white powder.

  
  <EMI ID = 319.1> This compound was assigned the absolute configuration 6 (R) 7 (S) based on the potent antimicrobial activity shown in the following table.

  
EXAMPLE 46

  
  <EMI ID = 320.1>

  
2-carboxylic:

  

  <EMI ID = 321.1>


  
In this example, the same procedure is repeated as that described in Example 8, except that one uses

  
  <EMI ID = 322.1>

  
by carrying out the same process as that described in Example 7. 40 mg (78%) of a white powder are thus obtained.

  
  <EMI ID = 323.1> <EMI ID = 324.1>

  
This compound was assigned the absolute configuration 6 (R) 7 (S) based on the potent antimicrobial activity shown in the following table.

  
EXAMPLE 47

  
  <EMI ID = 325.1>

  

  <EMI ID = 326.1>


  
In this example, the same procedure is repeated as that described in Example 6, except that we

  
  <EMI ID = 327.1>

  
2-ene-8-one obtained by carrying out the same process as that described in Example 5. In this way 29.5 mg is obtained.
(80%) of an isomer of the desired compound.

  
  <EMI ID = 328.1>

  
1.62 (1H, m), 1.12 (1H, m)

  
Absolute configuration 6 (R) 7 (S) has been assigned

  
to this compound from the potent antimicrobial activity

  
  <EMI ID = 329.1>

  
The antibacterial activities of the compounds of Examples 44, 45, 46 and 47 are determined by the method

  
  <EMI ID = 330.1>

  
results obtained appear in the following table.

  

  <EMI ID = 331.1>
 

  
1: Staphylococcus aureus 209-p 2: Staphylococcus aureus Smith 3: Staphylococcus epidermidis 4: Escherichia coli NIHJC-2 5: Escherichia coli Juhl

  
6: Klebsiella pneumoniae 8045 7 Klebsiella pneumoniae Y-60 8: Serratia marcescens T-26 9: Serratia marcescens T-55
10: Proteus mirabilis 1287
11: Proteus vulgaris 6897
12: Proteus morganii KY4298
13: Proteus rettgeri KY4289
14: Pseudomonas aeruginosa 145
15: Pseudomonas putrida F264

  
w to z: The compounds obtained in Examples 44 to 47

  
respectively.

  
The following reference examples show practical embodiments of the preparation of the compounds used in the examples.

  
REFERENCE EXAMPLE 1

  
Preparation of (+) - cis-2-t-butyloxycarbonyl-

  
  <EMI ID = 332.1>

  
cis represented by the following formula):

  

  <EMI ID = 333.1>


  
The compound in question is produced according to the procedures described in Methods 1 and 2 which follow. In the remainder of this brief, cis and

  
trans will relate to stereochemistry at position 3 or

  
4 of the 2-azetidinone ring or in position 6 or 7 of the ring

  
  <EMI ID = 334.1>

  
In this example, 447 mg (1.78

  
mmol) t-butyl α-aminodiethylphosphonoacetate

  
  <EMI ID = 335.1>

  
  <EMI ID = 336.1>

  
anhydrous and 164 mg (1.96 mmol) of 4-pentene-1-al is added to the solution. The solution is stirred at room temperature for 1 hour and to this solution is added
200 mg of a molecular sieve (4A - product of the company

  
  <EMI ID = 337.1>

  
The reaction mixture is subjected to filtration under reduced pressure and the filtrate is concentrated under reduced pressure to obtain a pale yellow oily product. Anhydrous benzene is added to the product and

  
the mixture is concentrated under reduced pressure so

  
to obtain a pale yellow oily product. The presence of Schiff's base in the product is confirmed by the nuclear magnetic resonance spectrum. The product

  
is dissolved in 12.5 ml of cyclohexane and 12.5 ml of anhydrous benzene and 0.369 ml (2.66 mmol) of

  
  <EMI ID = 338.1>

  
solution. Azidoacetyl chloride (319 mg, 2.66 mmol), dissolved in 12.5 ml of cyclohexane, is added dropwise to the mixture, with stirring, at room temperature, over a period of 1.5. hour. We agitate more

  
the reaction mixture for 30 minutes and diluted with 10 ml of benzene. The reaction solution is washed

  
  <EMI ID = 339.1>

  
sodium bicarbonate, deionized water and a

  
  <EMI ID = 340.1>

  
anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily product which is identified as the crude product of the desired compound. The oily product is introduced into a column packed with 45 g of silica gel. Elution is carried out with a mixture of n-hexane and ethyl acetate (1: 2) so as to obtain two types of isomers. The properties of the isomers are shown below and these products are identified as the isomers at positions 3 and 4, i.e. 345 mg of cis isomer are obtained and

  
58 mg of trans isomer. The total yield is 54.2%. cis isomer
-1

  
  <EMI ID = 341.1>

  
trans isomer

  
  <EMI ID = 342.1>

  
t-butyl yl7-2-diethylphosphonoacetate obtained above in 8.5 ml of dioxane and 2.5 ml of deionized water and 30 mg of osmium tetroxide are added thereto. The solution is stirred for 30 minutes. Powdered sodium periodate (496 mg, 2.32 mmol) was added to the black reaction mixture over 20 minutes. After stirring for 1.5 hours, the reaction solution is extracted with three times 50 ml of ether. The ethereal extracts are combined and washed with saturated sodium chloride solution. The solution thus obtained is dried with anhydrous sodium sulfate and concentrated under reduced pressure so as to obtain a black-brown oily product. The product is introduced into a column packed with 5 g of silica gel and the elution is continued with a solvent formed from benzene and ethyl acetate (1: 2).

   The fractions which are positive on reaction with 2,4-dinitrophenylhydrazine are collected and concentrated so as to obtain 235 mg of an oily product which is the cis isomer of the aldehyde compound. The oily product is dissolved in 15 ml of anhydrous acetonitrile. Hydride is added

  
  <EMI ID = 343.1>

  
a stream of nitrogen, with stirring and at room temperature.

  
After stirring for 20 minutes, the reaction mixture is poured into 20 ml of an aqueous solution.

  
  <EMI ID = 344.1>

  
50 ml of ether, the extraction being repeated four times. The ethereal extracts are combined and washed with saturated sodium chloride solution. The solution thus obtained is dried with anhydrous sodium sulfate and concentrated under reduced pressure so as to obtain
180 mg of an oily product which is identified as being a crude product of the desired cis compound.

  
The oily product is introduced into a column packed with 5 g of silica gel and the procedure is carried out.

  
  <EMI ID = 345.1>

  
Ethyl acetate (3.5: 1 by volume). White crystals (91 mg) of the desired compound are obtained. Yield.

  
  <EMI ID = 346.1>

  
Melting point: 64.5 - 65.5 [deg.] C
-1

  
  <EMI ID = 347.1>

  
trans represented by the following formula):

  

  <EMI ID = 348.1>


  
In this example, 767 mg (1.84 mmol) are dissolved

  
  <EMI ID = 349.1>

  
dioxane and 6.5 ml of deionized water and 100 mg

  
of osmium tetroxide. The mixture is stirred for 30 minutes. Powdered sodium periodate (1.5 7.04 mmol) is added to the black reaction solution over 30 minutes.

  
After stirring for 1 hour, the reaction mixture is extracted three times with 150 ml of ether.

  
  <EMI ID = 350.1>

  
anhydrous sodium sulfate. The solution thus obtained is concentrated under reduced pressure so as to obtain a product

  
;

  
oily. The oily product is introduced into a column packed with 20 g of silica gel and the elution is carried out.

  
with a solvent consisting of benzene and ethyl acetate
(1: 2). The oily product (561 mg) is obtained from the fractions which are positive on the reaction with 2,4dinitrophenylhydrazine. This product is the trans compound

  
of the aldehyde compound. The product is dissolved in 6 ml of anhydrous acetonitrile and 61.4 mg (2.56 mmol) are added thereto.

  
  <EMI ID = 351.1>

  
nutes. The reaction mixture is poured into 6 ml of a 2% aqueous solution of acetic acid and extracted.

  
four times with 50 ml of ether. The ether extracts are combined and dried over anhydrous sodium sulphate. The solution thus obtained is concentrated under pressure

  
reduced so as to obtain an oily product. The oily product is introduced into a column packed with 20 g

  
of silica gel and the elution is carried out with a solvent consisting of n-hexane and ethyl acetate (3.5: 11). White crystals (218 mg) of the desired compound are obtained. The compound is identified as the compound

  
trans of the desired substance. The properties of the product! are as follows: Melting point: 80.5 - 81.5 [deg.] C
-1

  
  <EMI ID = 352.1> REFERENCE EXAMPLE 3

  
  <EMI ID = 353.1>

  
represented by the following formula):

  

  <EMI ID = 354.1>


  
In this example, 55 mg (0.224

  
  <EMI ID = 355.1>

  
Reference 1 in 2 ml of trifluoroacetic acid and the solution is allowed to stand at room temperature for 10 minutes. The solution is concentrated under reduced pressure. Benzene is added to the concentrate and the solution thus obtained is concentrated under reduced pressure so as to obtain 51 mg of a yellow semi-solid. The properties of the semi-solid are as follows and the semi-solid is identified as consisting of the desired carboxylic acid. Yield: 100%.

  
  <EMI ID = 356.1>

  
(the cis compound represented by the following formula):

  

  <EMI ID = 357.1>


  
In this example, 50 mg (0.203 mmol) are dissolved

  
  <EMI ID = 358.1>

  
in 2 ml of anhydrous chloroform and add 36.0 mg
(0.202 mmol) of N-bromosuccinimide and a catalytic amount of azobisisobutyronitrile. The mixture was heated under reflux with stirring for 30 minutes and diluted with 5 ml of chloroform. The diluted solution was washed with 3 ml of water and 3 ml of saturated sodium chloride solution and dried with anhydrous sodium sulfate. The solution thus obtained is concentrated under reduced pressure so as to obtain 53 mg of an oily product.

  
The product is introduced into a column packed with 4.0 g of silica gel and the elution is continued with

  
  <EMI ID = 359.1>

  
An oily product (23 mg) is thus obtained. The product is identified as the desired cis compound from the following properties:

  
Efficiency: 33%

  
  <EMI ID = 360.1>

  
(2H, m), 1.52 (9H, s) REFERENCE EXAMPLE 5

  
  <EMI ID = 361.1>

  
(the trans compound represented by the following formula):

  

  <EMI ID = 362.1>


  
In this example, 100 mg (0.407

  
  <EMI ID = 363.1>

  
Reference 2 in 5 ml of anhydrous carbon tetrachloride and 72.4 mg of N-bromosuccinimide are added thereto. The mixture is heated to reflux with stirring for 30 minutes.

  
Then 10 ml of methylene chloride are added to the reaction mixture and the mixture thus obtained is washed with

  
5 ml of deionized water and 5 ml of a saturated solution of sodium chloride. The solution thus obtained is dried with anhydrous sodium sulfate and concentrated under reduced pressure so as to obtain 102 mg of an oily product. The oily product is introduced into a column packed with 5 g of silica gel and the elution is continued with a solvent consisting of n-hexane and ethyl acetate.
(3.5: 1). An oily product (24 mg) is obtained. the product is identified as being the desired trans compound having the following properties:

  
  <EMI ID = 364.1>

  
  <EMI ID = 365.1>

  
1.50 (9H, s)

  
REFERENCE EXAMPLE 6

  
  <EMI ID = 366.1>

  
(the cis compound represented by the following formula):

  

  <EMI ID = 367.1>


  
In this example, 75 mg (0.219 mmol) are dissolved

  
  <EMI ID = 368.1>

  
as described in Reference Example 4) in 2 ml of acetic acid.

  
Protecting the reaction system from light, 39.4 mg (0.241 mmol) of silver acetate is added to the mixture and the mixture is stirred for 2 hours and 20 minutes. The reaction mixture is subjected to filtration and concentrated under reduced pressure to obtain a crude acetoxylated product of the desired compound. The product is introduced into a column packed with 3.5 g of silica gel and the elution is continued with a solvent consisting of n-hexane and ethyl acetate (3.5: 1), so as to obtain 51 mg of an oily product. The product is identified as the desired cis compound from the following properties:

  
  <EMI ID = 369.1>

  
(the cis compound represented by the following formula):

  

  <EMI ID = 370.1>


  
The present compound is produced according to the following methods 1 and 2.

  
  <EMI ID = 371.1>

  
tert-butyl.

  
In this example, 2.13 g (8 mmol) of t-butyl α-amino-diethylphosphonoacetate is dissolved in 80 ml of anhydrous ether and 902 mg (9.2 mmol) of 3-methyl-4- are added. pentenal with stirring. The mixture is stirred at room temperature for 1 hour and added
900 mg of a 4A molecular sieve and 700 mg of sulfate

  
magnesium. After stirring for 1.5 hours, the reaction mixture is subjected to filtration under reduced pressure. The filtrate thus obtained is concentrated so

  
to obtain a pale yellow oily product. Anhydrous benzene (30 ml) was added to the product and the solution thus obtained was again concentrated to collect 2.82 g of an oily product. The presence of a Schiff's base in the product is confirmed by the nuclear magnetic resonance spectrum. The oily product was dissolved in 56 ml of dried cyclohexane and 56 ml of anhydrous benzene and 900 mg of a 4A molecular sieve and 1.67 ml (12 mmol) of triethylamine were added. To the mixture is added, dropwise, 1.43 g (12 mmol) of azidoacetyl chloride dissolved in 56 ml of dried cyclohexane over 1.5 hours at room temperature with stirring. The mixture is further stirred for 30 minutes and 30 ml of benzene is added thereto. The mixture is transferred to a separating funnel and washed with

  
30 ml of 10% citric acid, 30 ml of saturated sodium chloride solution, 30 ml of saturated sodium bicarbonate solution and 30 ml of saturated sodium chloride solution, in order indicated. The solution thus obtained is dried with anhydrous sodium sulfate and concentrated under reduced pressure so as to obtain 2.8 g of an oily product. We check the presence of a mixture of two major isomers in the product

  
by thin layer chromatography [pound] -silica gel, n-hexane - ethyl acetate (1: 1) _7. The product is introduced into a column packed with 300 g of silica gel and the elution is carried out with a mixed solvent consisting of n-hexane and ethyl acetate (1: 1) so as to obtain
380 mg (yield 11.0%) of the less polar isomer of the desired compound, 570 mg (yield 16.7%) of the more polar isomer of the desired compound and 201 mg
(yield 5.8%) of a mixture of the two isomers.

  
The properties of each isomer are shown below. From the data, the more polar isomer is identified as the cis isomer of the desired compound.

  
less polar isomer
-1 <EMI ID = 372.1>

  
J = 6, OHz)

  
more polar isomer (cis compound)

  
  <EMI ID = 373.1>

  
1.50 (9H, s), 1.33 (6H, t), 1.08 (3H, d)

  
2) Preparation of (+) - cis-2-t-butyloxycarbonyl-

  
  <EMI ID = 374.1>

  
(the cis compound represented by the following formula):

  

  <EMI ID = 375.1>
 

  
  <EMI ID = 376.1>

  
obtained as described in the example reference

  
  <EMI ID = 377.1>

  
deionized. Osmium tetroxide (20 mg) is added and the mixture is stirred for 10 minutes. We add per-

  
  <EMI ID = 378.1>

  
small fractions, to the black reaction solution, over 30 minutes. After stirring for 40 minutes,

  
  <EMI ID = 379.1>

  
  <EMI ID = 380.1>

  
  <EMI ID = 381.1>

  
sodium, dried over anhydrous sodium chloride and concentrated to obtain 230 mg of an oily product. The oily product is introduced into a column packed with 6 g of silica gel and the elution is continued.

  
  <EMI ID = 382.1>

  
(1: 2). The fractions which are positive at the

  
  <EMI ID = 383.1>

  
center so as to obtain 185 mg of an oily product

  
'at

  
  <EMI ID = 384.1>

  
immediately the product in 8 ml of anhydrous acetonitrile

  
  <EMI ID = 385.1>

  
  <EMI ID = 386.1>

  
tion and at room temperature. After a commotion

  
  <EMI ID = 387.1>

  
of a 2% aqueous solution of acetic acid and

  
  <EMI ID = 388.1>

  
ether. The ethereal layers are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily product. The product thus obtained is identified as being a crude product of the compound.

  
  <EMI ID = 389.1>

  
ethyl tate (3.5: 1 by volume). The desired compound (70 mg) is obtained in the form of a colorless oily product which crystallizes on standing. The properties of the product are described below:

  
  <EMI ID = 390.1>

  
The obtained crystals were identified as being a mixture of the 4 "-methyl isomer and the 4p-methyl isomer in a ratio of about 4: 1, according to the nuclear magnetic resonance data mentioned above.

  
REFERENCE EXAMPLE 8

  
Preparation of (&#65533;) - cis-2-carboxy-7-amino-1-

  
  <EMI ID = 391.1>

  

  <EMI ID = 392.1>


  
In this example, 91 mg of (+) - cis- are dissolved

  
  <EMI ID = 393.1>

  
obtained as described in Reference Example 3 in 6.5 ml of ethanol and 26 mg of carbon supporting 10% palladium are added thereto. The mixture is then stirred at room temperature and at atmospheric pressure in a stream of hydrogen for 2 hours. The mixture is subjected to filtration so as to separate the catalyst therefrom and the filtrate is concentrated under reduced pressure. The concentrate is dissolved again in 10 ml of methanol and 26 mg of carbon supporting 10% palladium are added thereto. The mixture was subjected to catalytic reduction at room temperature and atmospheric pressure for 3 hours and 50 minutes, and then carried out.

  
  <EMI ID = 394.1>

  
as a filter aid. The filtrate is concentrated under reduced pressure so as to obtain 88 mg (100%) of a semi-solid product. The product was identified as the desired amino compound on the basis of the following data:

  
  <EMI ID = 395.1> REFERENCE EXAMPLE 9

  
Preparation of (&#65533;) - cis-7-amino-2-t-butyloxy-

  
  <EMI ID = 396.1>

  

  <EMI ID = 397.1>


  
In this example, 178 mg (0.67 mmol) are dissolved

  
  <EMI ID = 398.1>

  
reference 1 in 10 ml of ethanol and 25 mg of a catalyst consisting of carbon supporting 10% palladium are added thereto. The mixture is stirred at room temperature in a stream of hydrogen for 50 minutes. The reaction solution is subjected to filtration to separate the catalyst therefrom, and the filtrate is concentrated under reduced pressure to obtain the desired compound as a yellow oily product.

  
Quantity of product obtained: 159.5 mg

  
Yield: 100 #

  
  <EMI ID = 399.1>

  
In the case where the catalytic reduction is carried out in ethanol containing an equivalent amount of hydrochloric acid, the hydrochloride of the desired compound is obtained.

  
REFERENCE EXAMPLE 10

  
  <EMI ID = 400.1>

  
represented by the following formula:

  

  <EMI ID = 401.1>


  
The compound in question is produced by carrying out methods 1 and 2.

  
  <EMI ID = 402.1>

  
t-butyl:

  

  <EMI ID = 403.1>


  
In this example, we dissolve 2.13 g (a large)

  
  <EMI ID = 404.1>

  
of absolute ether and 902 mg (9.2 mmoles) of 3-methyl4-pentenal are added, with stirring. The mixture was stirred at room temperature for 1 hour, and 900 mg of 4A molecular sieve and 700 mg of magnesium sulfate were added thereto. The mixture is stirred for 1.5 hours and subjected to filtration under reduced pressure. We focus

  
the filtrate so as to obtain a pale yellow oily product. To the product is added 30 ml of anhydrous benzene and

  
the mixture is concentrated again so as to obtain 2.82 g of an oily product. The presence of a Schiff base is confirmed by the nuclear magnetic resonance spectrum. The oily product is dissolved in 56 ml of dried cyclohexane and 56 ml of anhydrous benzene and

  
add 900 mg of 4A molecular sieve and 1.67 ml

  
(12 mmol) of triethylamine. Azidoacetyl chloride (1.43 g, 12 mmol) dissolved in 56 ml of dried cyclohexane was added dropwise to the mixture, with stirring, at room temperature over 1.5 hours and stirred. the mixture for 30 minutes. The reaction mixture is transferred to a separatory funnel along with 30 ml of benzene. We wash the diaper

  
  <EMI ID = 405.1>

  
saturated sodium chloride solution, 30 ml

  
of a saturated solution of sodium bicarbonate and 30 ml of a saturated solution of sodium chloride. We dry

  
the solution thus obtained with anhydrous sodium sulfate and concentrated under reduced pressure so as to obtain 2.8 g of an oily product. The presence of two isomers in the product is detected by thin layer chromatography [pound] ¯ silica gel, n-hexane and ethyl acetate

  
  <EMI ID = 406.1>

  
of 300 g of silica gel and the elution is carried out with n-hexane and ethyl acetate (1: 1). The less polar isomer is obtained (380 mg, yield: 11.0%)

  
  <EMI ID = 407.1>

  
  <EMI ID = 408.1>

  
of a mixture of the two isomers.

  
The properties of each isomer are given below. The more polar isomer is identified as the cis isomer of the desired compound.

  
Least polar isomer (trans isomer)

  
  <EMI ID = 409.1>

  
Most polar isomer (cis isomer)

  
  <EMI ID = 410.1>

  
Reference Example 10-1) in 6.6 ml of dioxane and 2 ml of deionized water and 20 mg of osmium tetroxide are added thereto. The mixture is stirred for 10 minutes and 390 mg (1.82 mmol) of powdered sodium periodate are added in small portions to the black reaction mixture over 30 minutes. After stirring for 40 minutes, the reaction solution is triple extracted with 30 ml of ether. The extracted ethereal layers are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain

  
230 mg of an oily product. The oily product is introduced into a column packed with 6 g of silica gel

  
and elution is continued with a solvent consisting of benzene and ethyl acetate (1: 2). The fractions which are positive on reaction with 2,4-dinitrophenylhydrazine are combined and concentrated so as to obtain
185 mg of an oily product, namely the aldehyde compound of the desired compound. The product is immediately dissolved in 8 ml of anhydrous acetonitrile and added thereto.

  
  <EMI ID = 411.1>

  
room temperature, with stirring, in a stream of nitrogen. After stirring for 30 minutes, the reaction mixture is poured into 15 ml of an aqueous solution of

  
  <EMI ID = 412.1>

  
taken up with 20 ml of ether. The ethereal layers obtained are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily product. The product is introduced into a column packed with 20 g of silica gel and the elution is carried out with a solvent consisting of n-hexane and ethyl acetate.
(3.5: 1 by volume). The desired product (70 mg) is obtained in the form of a colorless oily product with a yield of 48.1%. The product crystallizes on standing.

  
The properties of the product are as follows:
-1

  
  <EMI ID = 413.1>

  
On the basis of nuclear magnetic resonance data, the crystals obtained are identified as being a mixture of the 4a-methyl isomer and the 40-methyl isomer in the ratio of approximately 4: 1. The compounds can be separated by gel chromatography

  
silica using a solvent consisting of n-hexane and ethyl acetate (3: 1). The most polar isomer

  
  <EMI ID = 414.1>

  
following respective priities:

  

  <EMI ID = 415.1>


  
  <EMI ID = 416.1>

  
Melting point: 84.0 - 86.5 [deg.] C
-1

  
  <EMI ID = 417.1>

  
one:

  

  <EMI ID = 418.1>
 

  
In this example, 255 mg (0.67 mmol) are dissolved

  
  <EMI ID = 419.1>

  
reference 10 -2) in the form of a less polar isomer in 10 ml of ethanol and 100 mg of carbon supporting 10% palladium are added thereto. We submit the mixture

  
to catalytic hydrogenation for 1.5 hours and filtration to separate the catalyst. The catalyst is washed with methanol. The filtrate and the washing liquors are combined and concentrated under reduced pressure to obtain a pale yellow oily product. The product is dissolved in 8 ml of ethyl acetate and the solution is subjected to quintuple extraction with 3 ml of 10% citric acid. The aqueous layer is adjusted to a pH of 6 to 7 with potassium carbonate. so as to obtain a white suspension. The suspension was extracted twice with 5 ml of ethyl acetate and washed with saturated sodium chloride solution. The wash liquors were dried with anhydrous sodium sulfate to give 177 mg (76.6%) of an oily product.

  
  <EMI ID = 420.1>

  
(2H, broad), 1.80 - 1.60 (2H, m), 1.50 (9H, s), 1.31 (3H, d, J - 7, OHz) In the case where 1 'is carried out Catalytic hydrogenation with one equivalent of hydrochloric acid yields the hydrochloride of the desired compound.

  
REFERENCE EXAMPLE 12

  
  <EMI ID = 421.1>

  

  <EMI ID = 422.1>


  
In this example, 655 mg (2.35 mmol) are dissolved

  
  <EMI ID = 423.1>

  
reference 10 - 2) as the more polar isomer in 6 ml of ethanol and 0.79 ml (2.37 mmol) of 3N HCl is added thereto. The mixture is subjected to hydrogenation with
200 mg of carbon supporting 10% palladium for

  
70 minutes. Methanol is added to the mixture thus obtained in order to dissolve the deposited salt of the desired compound. The catalyst is filtered off and the filtrate is concentrated to give a crude product. The product is suitably triturated with ether and filtered. The filtrate is dried so as to obtain 512 mg (75.4%)

  
hydrochloride of the desired compound.

  
Melting point: 216 - 221 [deg.] C (dec.)

  
1

  
  <EMI ID = 424.1> REFERENCE EXAMPLE 13

  
  <EMI ID = 425.1>

  
8-one:

  

  <EMI ID = 426.1>


  
In this example, 196 mg (0.78 mmol) are dissolved

  
  <EMI ID = 427.1>

  
Reference 11 in 4.2 ml of anhydrous dichloromethane and 1.8 ml of trifluoroacetic acid are added thereto, at room temperature and with stirring. After 1.5 hours, the mixture is concentrated under reduced pressure. We submit

  
the concentrate to azeotropic distillation with anhydrous benzene so as to obtain an oily product. The product is triturated with ether and filtered from

  
  <EMI ID = 428.1>

  
wish.

  
-1

  
  <EMI ID = 429.1> REFERENCE EXAMPLE 14

  
  <EMI ID = 430.1>

  
lique:

  

  <EMI ID = 431.1>


  
In this example, 179 mg of (&#65533;) - cis7 &#65533; -azido-4a-acetoxy-2-t-butyloxycarboayl-1-azabicyclo- are dissolved.

  
  <EMI ID = 432.1>

  
in 3 ml of methylene chloride and 3 ml of trifluoroacetic acid. The solution is left to stand at room temperature for 2 hours and concentrated to obtain 145 mg of the desired compound, as

  
  <EMI ID = 433.1>

  
compound are shown below:

  
1

  
  <EMI ID = 434.1>

  
lique:

  

  <EMI ID = 435.1>
 

  
In this example, 145 mg of acid are dissolved

  
  <EMI ID = 436.1>

  
reference example 14 - 1) in 14 ml of ethanol and

  
40 mg of carbon supporting 10% palladium are added thereto. The mixture is subjected to catalytic hydrogenation,

  
atmospheric pressure, with stirring, for 1 hour. The reaction mixture is subjected to filtration and the filtrate is concentrated to obtain 126 mg of the desired compound.

  
REFERENCE EXAMPLE 15

  
  <EMI ID = 437.1>

  
(the cis compound represented by the following formula):

  

  <EMI ID = 438.1>


  
  <EMI ID = 439.1>

  
8-one obtained as described in Reference Example 1 in 8.8 ml of carbon tetrachloride and

  
134.9 mg of N-bromosuccinimide and a quantity

  
  <EMI ID = 440.1>

  
mixing at reflux for 30 minutes. After cooling, the reaction mixture is diluted with 5 ml of chloroform and washed with 3 ml of water and 3 ml of saturated sodium chloride solution. The wash liquor is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated so as to obtain an oily brominated compound which is the same oily product as that obtained in Example 4. The product is immediately dissolved in 10 ml of acetone and 50 mg of silver carbonate and is added thereto. 50 μl of water. The mixture is stirred at

  
  <EMI ID = 441.1>

  
reaction and concentrated to obtain a crude product. The product is introduced into a column packed with 20 g of silica gel and the elution is continued with a mixture of n-hexane and ethyl acetate (2: 1). The eluates are concentrated so as to obtain 86.4 mg of the desired compound in the form of crystals of pale yellow tint. Yield: 40.7%. The properties of the crystals obtained appear below:

  
  <EMI ID = 442.1>

  

  <EMI ID = 443.1>
 

  
In this example, 300 mg of

  
  <EMI ID = 444.1>

  
oct-2-en-8-one obtained as described in Reference Example 9 in 3.0 ml of methylene chloride and 3.0 ml of trifluoroacetic acid is added thereto. The mixture is left to stand at room temperature for 1 hour and 20 minutes. The reaction mixture is concentrated and benzene is added to the residue. The solution is concentrated again so as to obtain 250 mg of the trifluoroacetate

  
of the desired compound as a yellow powder. The product properties are shown below:

  
1

  
  <EMI ID = 445.1>

  
The above-mentioned trifluoroacetate is dissolved

  
  <EMI ID = 446.1>

  
with saturated sodium bicarbonate solution so as to generate crystals. Thus, 129 mg of the desired compound are recovered by filtration. The properties of the product are compatible with those of the product of Reference Example 8.

  
REFERENCE EXAMPLE 17

  
  <EMI ID = 447.1>

  

  <EMI ID = 448.1>
 

  
In this example, 4 ml of trifluoroacetic acid is added to 238 mg (0.703 mol) of (+) - cis-7 &#65533; -

  
  <EMI ID = 449.1>

  
Reference 10 and the mixture is allowed to stand at room temperature for 10 minutes. The reaction mixture is concentrated at 25 [deg.] C under reduced pressure. The concentrate is double extracted with 5 ml of dry benzene. 255 mg of the oily product obtained are then dissolved in 5 ml of ethyl acetate. The solution is subjected to a double extraction with each time 2 ml of a 10% solution of potassium carbonate and the pH of the aqueous layer is adjusted to approximately 3 with 0.5 N HCl. The solution is extracted twice. with 5 ml of ethyl acetate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure so as to obtain 166 mg of the desired compound in the form of a

  
  <EMI ID = 450.1>

  
read by rest.

  
The properties of the product obtained are shown below:

  
  <EMI ID = 451.1>

  
1.11 (3H, d, J = 7.2) REFERENCE EXAMPLE 18

  
Preparation of (+) - cis- acid trifluoroacetate

  
  <EMI ID = 452.1>

  
carboxylic:

  

  <EMI ID = 453.1>


  
In this example, 200 mg of (&#65533;) - cis-

  
  <EMI ID = 454.1>

  
then 75 mg of carbon supporting 10% palladium are added.

  
The mixture is stirred in a stream of hydrogen gas at atmospheric pressure. After 20 hours, the reaction mixture is filtered under reduced pressure. To the filter cake, 2 ml of trifluoroacetic acid is added. After having separated the catalyst by filtration, the filtrate is concentrated under reduced pressure, then the addition of 10 ml of dry ether is carried out. The crystals formed are recovered by filtration so as to obtain

  
  <EMI ID = 455.1>

  
The properties of the compound thus obtained are compatible with those of Reference Example 13.


    

Claims (1)

1. Cephalosporin-like compounds represented by the following general formula: <EMI ID = 456.1> (wherein X represents an acyl group represented by the general formula X <1> CO wherein X1 represents one of the following five groups: 1) a cyanomethyl group or a group represented by following general formula: <EMI ID = 457.1> wherein B represents a six-membered unsaturated carbocyclic group which is selected from cyclohexenyl, cyclohexadienyl and phenyl radicals or five- or six-membered heterocyclic radicals, <EMI ID = 458.1> halogens, hydroxyl, lower alkoxy having 1 to 4 carbon atoms, nitro, amino, aminomethyl, methylsulfamido and lower acyloxy having 1 to 4 carbon atoms, n is a number <EMI ID = 459.1> hydrogen atom, an amino, hydroxyl, carboxyl or sulfoxyl group, 2) a group represented by the following general formula: <EMI ID = 460.1> <EMI ID = 461.1> <EMI ID = 462.1> or different, represent hydrogen atoms, lower alkyl radicals having 1 to 4 carbon atoms, groups represented by the formula general <EMI ID = 463.1> (where A5 represents a group lower alkyl having 1 to 4 carbon atoms) or a group represented by the general formula <EMI ID = 464.1> <EMI ID = 465.1> different represent hydrogen atoms, lower alkyl radicals having 1 to 4 carbon atoms or alkali metals) and <EMI ID = 466.1> <EMI ID = 467.1> the general formula <EMI ID = 468.1> <EMI ID = 469.1> <EMI ID = 470.1> hydrogen atoms or lower alkyl radicals having 1 to 4 carbon atoms) or a group represented by the general formula <EMI ID = 471.1> (wherein A9 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a methylsulfonyl or furfurylidene group- <EMI ID = 472.1> lower alkyl group having 1 to 4 carbon atoms), 3) a group represented by the following general formula: <EMI ID = 473.1> <EMI ID = 474.1> mono-, bi- or tri-cyclic heterocyclic or a group, substituted aryl, 4) a group represented by the following general formula: <EMI ID = 475.1> in which A1, B and n have the meanings <EMI ID = 476.1> hydrogen, a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkinyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an aryl group, these groups not being substituted or being substituted by one or more suitable substituents which are chosen from carboxyl, cyano, halogen, carbamoyl and lower alkyl oxycarbonyl radicals having from 1 to 4 carbon atoms, 5) a group represented by the following general formula: <EMI ID = 477.1> wherein B1 represents a trifluoromethyl or cyanomethyl group, a group represented by the formula gene- <EMI ID = 478.1> meanings indicated above and 2 represents an oxygen atom or a sulfur atom, R represents a hydrogen atom or a group protecting the carboxylic acid function which is chosen from alkyl radicals having from 1 to 5 carbon atoms, halogenated alkyl radicals having from 1 to 5 carbon atoms, arylmethyl radicals having from 7 with 20 carbon atoms which can be substituted on the phenyl ring, the substituted silyl radicals and the radicals easily removable in vivo enzymatically or by <EMI ID = 479.1> a lower alkyl radical possessing from 1 to 5 carbon atoms or a lower acyl oxy radical possessing from 1 to 5 carbon atoms), as well as their pharmaceutically acceptable salts. 2. Compounds according to claim 1, characterized in that the hydrogen atoms in positions 6 and 7 in formula (I) have the configuration <EMI ID = 480.1> 3. Compounds according to any one of claims 1 and 2, characterized in that R1 represents a hydrogen atom. 4. Compounds according to any one of claims 1 and 2, characterized in that R represents an alkyl group having from 1 to 5 carbon atoms. 5. Compounds according to claim 4, characterized in that R represents a t-butyl group. 6. Compounds according to any one of claims 1 and 2, characterized in that the arylmethyl group represents a benzyl group, a diphenylmethyl or triphenylmethyl group. 7. Compounds according to any one of claims 1 and 2, characterized in that the group which can be easily removed in vivo by the enzymatic route or by the non-enzymatic route is a group represented by the general formula: <EMI ID = 481.1> wherein R 1 represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, a lower alkoxy group having 1 to 5 carbon atoms or a phenyl group and R4 represents a lower alkyl group having 1 having 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or a phenyl group. 8. Compounds according to any one of <EMI ID = 482.1> a hydrogen atom. 9. Compounds according to any one of claims 1 to 7, characterized in that R <2> represents an alkyl group having from 1 to 5 carbon atoms. <EMI ID = 483.1> <EMI ID = 484.1> 11. Compounds according to claim 10, <EMI ID = 485.1> 12. Compounds according to any one of <EMI ID = 486.1> an acetoxy group. 13. Compounds according to any one of claims 1 to 12, characterized in that B represents a phenyl group. <EMI ID = 487.1> claims 1 to 12, characterized in that B represents a thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, <EMI ID = 488.1> zinyl, pyridazinyl, triazinyl or 5,6-dihydro-1,4-dithin-2-yl. 15. Compounds according to claim 14, characterized in that B represents a furyl group. 16. Compounds according to claim 14, characterized in that B represents a thiazolyl group. 17. Compounds according to any one of <EMI ID = 489.1> smells of a hydrogen atom. 18. Compounds according to any one of <EMI ID = 490.1> feels a group which is selected from halogens, hydroxyl, amino, aminomethyl and methylsulfamido radicals <EMI ID = 491.1> 19. Compounds according to claim 13, <EMI ID = 492.1> and n is equal to 1. 20. Compounds according to claim 16, <EMI ID = 493.1> and n is equal to 1. 21. Compounds according to any one of claims 13 to 20, characterized in that A2 represents a hydrogen atom. 22. Compounds according to any one of claims 13 to 20, characterized in that A2 represents a hydroxyl group. 23. Compounds according to any one of claims 13 to 20, characterized in that A2 represents an amino group. 24. Compounds according to any one of claims 13 to 20, characterized in that the group represented by the general formula <EMI ID = 494.1> is a group represented by the general formula <EMI ID = 495.1> <EMI ID = 496.1> previously indicated. 25. Compounds according to claim 24, <EMI ID = 497.1> <EMI ID = 498.1> 26. Compounds according to any one of claims 13 to 20, characterized in that the group represented by the general formula <EMI ID = 499.1> <EMI ID = 500.1> <EMI ID = 501.1> <EMI ID = 502.1> as indicated. 27. Compounds according to claim 25, <EMI ID = 503.1> <EMI ID = 504.1> furfurylidene-imino. 28. Compounds according to any one of <EMI ID = 505.1> is a mono-, bi- or tri-cyclic heterocyclic group. 29. Compounds according to claim 28, characterized in that the mono-, bi or tri-cyclic heterocyclic group is chosen from those represented by the following formulas: <EMI ID = 506.1> (Y is an oxygen or sulfur atom), a substituted or unsubstituted 2-oxo-2H-1-benzopyran-3-yl group or a substituted or unsubstituted naphthidyl group, the substituent (s) of which are chosen from among groups <EMI ID = 507.1> 30. Compounds according to claim 29, characterized in that the substituted naphthidyl group is a group represented by the following formula: <EMI ID = 508.1> 31. Compounds according to any one of <EMI ID = 509.1> smells of a hydrogen atom. 32. Compounds according to any one of <EMI ID = 510.1> means a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. 33. Compounds according to claim 32, <EMI ID = 511.1> 34. Compounds according to any one of <EMI ID = 512.1> means a substituted or unsubstituted alkenyl group having 2 to 4 carbon atoms. 35. Compounds according to claim 34, <EMI ID = 513.1> or an allyl group. 36. Compounds according to any one of claims 31 to 35, characterized in that the group <EMI ID = 514.1> 2-carboxylic acid and its para-hydroxy compound. <EMI ID = 515.1> oct-2-en-8-one-2-carboxylic. <EMI ID = 516.1> one-2-carboxylic. 57. A process for the production of cephalosporin-like compounds represented by the general formula (I): <EMI ID = 517.1> (in which X represents an acyl group represented <EMI ID = 518.1> one of the following five groups: 1) a cyanomethyl group or a group represented by following general formula: <EMI ID = 519.1> wherein B represents a six-membered unsaturated carbocyclic group which is selected from radicals <EMI ID = 520.1> five- or six-membered heterocyclic radicals., A1 represents a substituent selected from hydrogen, halogens, hydroxyl, lower alkoxy having 1 to 4 carbon atoms, nitro, a &#65533; ino, aminomethyl, methylsulfamido and lower acyloxy having 1 to 4 carbon atoms , n is a number whose value varies from zero to 5 and A2 represents a <EMI ID = 521.1> or sulfoxyl, 2) a group represented by the following general formula: <EMI ID = 522.1> <EMI ID = 523.1> or different, represent hydrogen atoms, lower alkyl radicals having 1 to 4 carbon atoms, groups represented by the formula general <EMI ID = 524.1> <EMI ID = 525.1> lower alkyl having 1 to 4 carbon atoms) or a group represented by the general formula <EMI ID = 526.1> <EMI ID = 527.1> different represent hydrogen atoms, lower alkyl radicals having 1 to 4 carbon atoms or alkali metals) and / A3 <EMI ID = 528.1> <EMI ID = 529.1> the general formula <EMI ID = 530.1> <EMI ID = 531.1> <EMI ID = 532.1> having 1 to 4 carbon atoms) or a group represented by the general formula <EMI ID = 533.1> (where A9 represents a hydrogen atom, a lower alkyl group having 1 to 4 atoms of <EMI ID = 534.1> carbon), 3) a group represented by the following general formula: <EMI ID = 535.1> <EMI ID = 536.1> mono-, bi- or tri-cyclic heterocyclic or a substituted aryl group, 4) a group represented by the following general formula: <EMI ID = 537.1> <EMI ID = 538.1> hydrogen, a lower alkyl group having from 1 to 6 carbon atoms, a lower alkenyl group <EMI ID = 539.1> lower having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an aryl group, these groups not being substituted or being substituted by one or more suitable substituents which are chosen from carboxyl radicals, cyano, halogens, carbamoyl and alkyl radicals lower oxycarbonyl having 1 to 4 carbon atoms, 5) a group represented by the following general formula: <EMI ID = 540.1> <EMI ID = 541.1> cyanomethyl, a group represented by the general formula <EMI ID = 542.1> meanings indicated above and Z represents an oxygen atom or a sulfur atom, R1 represents a hydrogen atom or a group protecting the carboxylic acid function which is chosen from alkyl radicals having from 1 to 5 carbon atoms, halogenated alkyl radicals having from 1 to 5 carbon atoms, arylmethyl radicals having from 7 with 20 carbon atoms which may be substituted on the phenyl ring, the substituted silyl radicals and the radicals easily removable in vivo enzymatically or non-enzymatically and R <2> represents a hydrogen atom, a lower alkyl radical possessing 1 to 5 carbon atoms or a lower acyl oxy radical having 1 to 5 carbon atoms) and of their pharmaceutically acceptable salts, characterized in that one acylates compounds analogous to cephalosporins represented by the general formula (II ') : <EMI ID = 543.1> (in which R <2> and R 'have the meanings indicated above) or a functionally equivalent compound (the latter is called "7-amino compound" in the following), on a carboxylic acid represented by the general formula (III) <EMI ID = 544.1> <EMI ID = 545.1> fronts: <EMI ID = 546.1> the following general formula: <EMI ID = 547.1> in which B and n have the meanings <EMI ID = 548.1> substituents which are chosen from hydrogen atoms, hydroxyl radicals, protected hydroxyl radicals, lower alkoxy radicals possessing from 1 to 4 carbon atoms, halogens, radi- <EMI ID = 549.1> methylsulfamido and lower acyl oxy having <EMI ID = 550.1> of hydrogen, a protected amino, hydroxyl, protected hydroxyl, carboxyl, protected carboxyl, sulfoxyla or protected sulfoxyl group. 2 ') a group represented by the following general formula: <EMI ID = 551.1> <EMI ID = 552.1> previously indicated instructions, 3 ') a group represented by the following general formula: <EMI ID = 553.1> <EMI ID = 554.1> previously indicated cations, 4 ') a group represented by the following general formula: <EMI ID = 555.1> <EMI ID = 556.1> hydrogen, a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms carbon atoms or an aryl group, these groups not being substituted or being substituted by one or more suitable substituents which are chosen from a protected carboxyl group, cyano, halogens, carbamoyl and lower alkyl oxycarbonyl radicals having 1 to 4 carbon atoms, <EMI ID = 557.1> <EMI ID = 558.1> <EMI ID = 559.1> have the meanings previously indicated and Z represents an oxygen atom or a sulfur atom) or a reactive derivative of such a compound and, if necessary, the protecting group is removed in the group <EMI ID = 560.1> As necessary, the compound is converted to a pharmaceutically acceptable salt in a conventional manner. 58. The method of claim 57, characterized in that the hydrogen atoms in positions 6 and 7 in formula (I) have the "cis" configuration. 59. Process according to any one of <EMI ID = 561.1> means an alkyl group having 1 to 5 carbon atoms. 60. The method of claim 59, characterized in that R. represents a t-butyl group. 61. A method according to any one of claims 57 and 58, characterized in that the arylmethyl group is a benzyl, diphenylmethyl or triphenylmethyl group. 62. A method according to any one of claims 57 and 58, characterized in that the group easily eli &#65533; in vivo enzymatically or non-enzymatically is a group represented by the following general structural formula: <EMI ID = 562.1> in which R represents a hydrogen atom or a <EMI ID = 563.1> bone, 'a lower alkoxy group having 1 to 5 carbon atoms or a phenyl group and R4 represents a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms or a group phenyl. 63. A method according to any one of claims 57 and 58, characterized in that R in the compound represented by the general formula (II *) is a hydrogen atom and, if necessary, we <EMI ID = 564.1> classic. 64. Method according to any one of claims 57 and 58, characterized in that one removes the protecting group in the -COOR &#65533; in a conventional manner and, if necessary, remove the <EMI ID = 565.1> if that. 65. Process according to any one of claims 57 to 64, characterized in that R <2> represents a hydrogen atom. 66. Process according to any one of claims 57 to 64, characterized in that R <2> represents an alkyl group having from 1 to 5 carbon atoms. 67. The method of claim 66, <EMI ID = 566.1> 68. The method of claim 67, <EMI ID = 567.1> 69. Process according to any one of <EMI ID = 568.1> an acetoxy group. 70. A method according to any one of claims 57 to 69, characterized in that B represents a phenyl group. 71. Process according to any one of claims 57 to 69, 'characterized in that B represents a thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyra group - <EMI ID = 569.1> 2-yle. 72. The method of claim 71, characterized in that B represents a furyl group. 73. A method according to claim 71, characterized in that B represents a thiazolyl group. 74. Process according to any one of <EMI ID = 570.1> smells of a hydrogen atom. 75. Process according to any one of <EMI ID = 571.1> <EMI ID = 572.1> hydroxyl, protected hydroxyl, protected amino, protected aminomethyl and methylsulfamido radicals and n is equal to 1 or 2. 76. The method of claim 70, <EMI ID = 573.1> <EMI ID = 574.1> protected xyle. 77. The method of claim 73, <EMI ID = 575.1> <EMI ID = 576.1> 78. Process according to any one of <EMI ID = 577.1> represent hydrogen atoms. 79. Process according to any one of <EMI ID = 578.1> represents a hydroxyl group and A'2 represents a hydroxyl group or a protected hydroxyl group. 80. Process according to any one of claims 70 to 77, characterized in that A2 represents <EMI ID = 579.1> protected. 81. A method according to any one of claims 70 to 77, characterized in that the group represented by the general formula <EMI ID = 580.1> is a group represented by the general formula <EMI ID = 581.1> <EMI ID = 582.1> previously indicated. 82. The method of claim 83, <EMI ID = 583.1> <EMI ID = 584.1> 83. A method according to any one of claims 70 to 77, characterized in that the group represented by the general formula <EMI ID = 585.1> is a group represented by the general formula <EMI ID = 586.1> <EMI ID = 587.1> previously indicated. 84. The method of claim 83, <EMI ID = 588.1> <EMI ID = 589.1> idene-imino. 85. Process according to any one of <EMI ID = 590.1> means a mono-, bi- or tri-cyclic heterocyclic radical. 86. The method of claim 35, characterized in that the mono- heterocyclic radical, bi- or tri-cyclic is chosen from the group formed by those which correspond to the following formulas: <EMI ID = 591.1> (Y represents an oxygen atom or a sulfur atom), the substituted or unsubstituted 2-oxo-2H-1-benzopyran-3-yl radicals and the substituted or unsubstituted naphthidyl radicals, the substituent (s) of which are chosen <EMI ID = 592.1> 87. The method of claim 86, characterized in that the naphthidyl group is the group represented by the following formula: <EMI ID = 593.1> 88. Process according to any one of <EMI ID = 594.1> represent hydrogen atoms. 89. Process according to any one of <EMI ID = 595.1> represent substituted or unsubstituted alkyl radicals having from 1 to 6 carbon atoms. 90. The method of claim 89, <EMI ID = 596.1> methyl. 91. Process according to any one of the <EMI ID = 597.1> represent substituted or unsubstituted alkenyl groups having from 2 to 4 carbon atoms. 92. The method of claim 91, <EMI ID = 598.1> vinyl or allyl. 93. A method according to any one of claims 88 to 92, characterized in that the groups <EMI ID = 599.1> "syn" configuration.