FR2684995A1 - Cephalosporins containing a ( alpha -carboxy-3,4-dihydroxybenzyloxyimino) group, preparation process and intermediates, application as medicaments and pharmaceutical compositions - Google Patents

Abstract

The subject of the invention is the products of general formula (I): syn isomer, in the R or S form or in the form of an R, S mixture, in which formula: R1, represents a quaternary ammonium radical, A and A', which are identical or different, represent a hydrogen atom or else one or each of the CO2A or CO2A' groups represents CO2<->. their process of preparation and the new intermediates obtained. These products have advantageous pharmacological properties which justify their use as medicaments.

Description

The present invention relates to new cephalosporins comprising on the chain in position 7, a radical (alpha-carboxy 3,4-dihydroxy benzyloxyimino) their preparation process, their application as medicaments, the compositions containing them and the new intermediates obtained.

isomère syn, sous forme R ou S ou d'un mélange R, S, formule dans laquelle
Ri représente un radical choisi parmi les radicaux suivants

ou encore l'un des radicaux

et A et A' identiques ou différents représentent un atome d'hydrogène, ou bien l'un ou chacun des CO2A ou CO2A' représente C02 ; le trait ondulé signifie que le groupement CH2R1 peut se trouver dans la position E ou Z ainsi que les sels des produits de formule (I) avec les acides minéraux ou organiques.The subject of the invention is the products of general formula (I):

syn isomer, in the form of R or S or a mixture of R, S, formula in which
Ri represents a radical chosen from the following radicals

or one of the radicals

and the same or different A and A 'represent a hydrogen atom, or one or each of CO2A or CO2A' represents CO2; the wavy line means that the CH2R1 group can be in the E or Z position as well as the salts of the products of formula (I) with mineral or organic acids.

The products of formula (I) can also be provided in the form of salts of organic or inorganic acids.

Among the acids with which the amino group (s) of the products (I) can be salified, mention may be made, inter alia, of acetic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, para-toluene sulfonic, phosphoric, sulfuric, hydrochloric acids, hydrobromic, hydroiodic.

The products can also be in the form of internal salts.

In a preferred embodiment of the invention, A 'represents a hydrogen atom and CO2A represents CO2-.

The expression in the form of quaternary ammonium indicates that the radical R1 is linked by the or one of the nitrogen atoms which it contains.

A particular subject of the invention is the products of general formula (I) as defined above in which the configuration of the double bond of the substituent -CH = CH-CH2-R1 is (E).

A more particular subject of the invention is the products of general formula (I) as defined above and whose names follow - the internal salt of (6R- (3 (E), 6alpha, 7béta (Z)]] 7 - (3- (7- [[(2-amino 4-thiazolyl) [(carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4 , 2,0] oct-2-en-3-yl] 2-propenyl] furo [2,3-b] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alpha, 7beta (Z)]] 7-E3- [7- [[(2-amino 4-thiazolyl) [(carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] furo [2,3-b] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of E6R-E3 (E), 6alpha, 7beta (Z))] 7- [3- [7- [[(2-amino 4- thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] thieno [2,3-b] pyridinium isomer (R) and isomer (S), - the internal salt of E6R-E3 (E), 6alpha, 7béta (Z)]) 1- [3- [7- [[(2-amino 4-thiazolyl) E (carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [ 4,2,0] oct-2-en-3-yl] 2-propenyl) 4-methoxy pyridinium (R) or (S) or a mixture (R + S), - the internal salt of E6R-E3 (E), 6alpha, 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2 -carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4- (methylthio) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alpha, 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) E Ecarboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 2- ( methylthio) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of E6R-E3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [ [(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2 -en-3-yl] 2-propenyl] 4- (amin ocarbonyl) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), = 6alpha, 7béta (Z)]] 1- [3- [ 7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 3- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E ), 6alpha, 7beta (Z)]] 3-amino 1- [3-7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2 -carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S) or a mixture (R + S) , - the internal salt of [6R- (3 (E), 6alpha, 7beta (Z)]] 6-amino 1- [3-7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4 -dihydroxyphenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) E (carboxy (3,4-dihydroxy phenyl) methoxy) imino] acetyl] amino) 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 3-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alpha, 7béta (Z)]) 1- [3- [7- [[(2-amino 4-thiazolyl ) E (carboxy (3,4-dihydroxy phenyl) methoxy) imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 -propenyl] 4-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- (3 (E), 6alpha, 7béta (Z)]] 1- [ 3- (7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2 , 0] oct-2-en-3-yl] 2-propenyl] 6-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 ( E), 6alpha, 7beta (Z)]) 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl) amino] 2- carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 6-chloro quinolinium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alph a, 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino] acetyl] amino] 2-carboxy 8- oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 6-methoxy quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl ) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] thiazolium (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alpha, 7béta (Z))] 1- [3- [7- [[(2-amino 4-thiazolyl ) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 -propenyl] 3-methyl imidazolium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 5- [3- [7 - [[( 2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en -3-yl] 2 (E) -propenyl] imidazo [1,2-b] pyridazinium ( R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl) ttcarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) - propenyl) imidazo (1,2-b] pyridazinium (R) or (S) or a mixture (R + S), - the internal salt of (#) (cis) (Z) l-t3-t7-tt (2-amino 4-thiazolyl) ttcarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl) amino] 2-carboxy 8-oxo 5-thia 1-azabicyclot4,2,0] oct-2-en-3- yl] 2 (E) -propenyl] imidazo [1,2-a] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 2-E3-E7- [E (2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4, 2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo (1,5-a] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of E6R-E3 (E), 6alpha, 7beta (Z)] 1- [3- [7 - [[(2-amino 4-thiazolyl) [(carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 6,7-dihydro 5H-pyrindinium isomer (R) and isomer (S), - the internal salt of (#) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo (4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 1-methyl pyrrolidinium (R) or (S) or a mixture (R + S), - internal salt of t6R-t3 (E), 6alpha, 7beta (Z)]] l-t3-t7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4-aza l-azoniabicyclo [2,2,2] octane (R) or (S) or a mixture (R + S), - the internal salt of (6R- (3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [ [(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2 -en-3-yl] 2-propenyl] 3-hydroxy 4-aza 1-azabicyclo [4,2,0] octane (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) ttcarb oxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N, N-trimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3R (E), 6alpha, 7béta (Z )]] 3- [7 - [[(2amino 4-thiazolyl) EEcarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2, 0] oct-2-en-3-yl] N, N-dimethyl N- (2-hydroxy ethyl) 2-propen 1-aminium (R) or (S) or a mixture (R + S), - (+) (cis) (Z) N- (2-amino 2-oxo ethyl) 3- [7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy internal salt ] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl 2 (E) -prooen-1aminium ( R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy ( 3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N- (cyanomethyl) N , N-dimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - ([(2-amino 4-thiazolyl) ((carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl N - [(2-methoxyimino) ethyl] 2 (E) -propen-1- aminium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-aza- bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4 - [(methoxyimino) methyl] quinolinium (R) or (S) or a mixture (R + S), - (+) (cis) (Z) 1- (3- (7 - [((2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino) internal salt 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-a] pyrimidin-4-ium ( R) or (S) or a mixture (R + S).

It is understood that the aforementioned products of formula (I) can exist in their 2-imino 2,3 dihydro thiazol-4-yl tautomeric form.

isomère syn, racémique ou optiquement actif ou un dérivé fonctionnel du produit de formule (II), dans laquelle Ra représente un atome d'hydrogène ou un groupement protecteur du radical amino, Rb et Rc identiques ou différents représentent un atome d'hydrogène ou un groupement protecteur du radical hydroxy, Rd représente un atome d'hydrogène ou le reste d'un groupement ester facilement éliminable, avec un produit de formule (III)

ou ses sels, dans laquelle Hal représente un atome d'halogène,
Rf représente un atome d'hydrogène ou le reste d'un groupement ester facilement éliminable et le trait ondulé signifie que le groupement CH2Hal peut se trouver dans la position E ou Z pour obtenir un produit de formule (IV)

que l'on fait agir avec un réactif capable d'introduire le radical R1 pour obtenir un produit de formule (V)

que, si désiré, l'on sépare en ses isomères E ou Z ou transforme les isomères Z en isomères E et produits de formule (V) que, si nécessaire ou si désiré, l'on soumet à une ou plusieurs des réactions suivantes, dans un ordre quelconque a) coupure par hydrolyse ou par action de la thiourée de tout ou partie des groupements esters ou des groupements de protection du radical amino ou des radicaux hydroxyles, b) estérification ou salification par une base du ou des radicaux carboxyliques, c) salification par un acide du radical amino, d) séparation des produits sous forme de mélange R,S en R ou S.A subject of the invention is also a process for preparing the products of formula (I) as defined above, characterized in that a product of formula (11) is made to act.

racemic or optically active syn isomer or a functional derivative of the product of formula (II), in which Ra represents a hydrogen atom or a protecting group for the amino radical, Rb and Rc which are identical or different represent a hydrogen atom or a protective group for the hydroxyl radical, Rd represents a hydrogen atom or the remainder of an easily removable ester group, with a product of formula (III)

or its salts, in which Hal represents a halogen atom,
Rf represents a hydrogen atom or the remainder of an easily removable ester group and the wavy line means that the CH2Hal group can be in the E or Z position to obtain a product of formula (IV)

which is made to act with a reagent capable of introducing the radical R1 to obtain a product of formula (V)

that, if desired, one separates into its E or Z isomers or transforms the Z isomers into E isomers and products of formula (V) which, if necessary or if desired, are subjected to one or more of the following reactions, in any order a) cleavage by hydrolysis or by the action of thiourea of all or part of the ester groups or of the protective groups of the amino radical or of the hydroxyl radicals, b) esterification or salification with a base of the carboxyl radical (s), c ) salification of the amino radical with an acid, d) separation of the products in the form of a mixture R, S into R or S.

By reagent capable of introducing the radical R1 is meant a reagent consisting of the radical R1 itself, the latter not being in the form of quaternary ammonium; in particular if it is desired to introduce a pyridinium radical, the easily removable ester groups which Rd er Rf may represent can be used with pyridine, for example, the ester formed with the butyl, isobutyl, tert-butyl, pentyl or hexyl radicals, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl.

Mention may also be made of the 2-iodoethyl, 2,2,2trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenylethyl, trityl, diphenylmethyl, 3,4-dimethoxyphenyl radicals.

Mention may also be made of the phenyl, 4-chlorophenyl, tolyl and tert-butylphenyl radicals.

Preferred is the diphenylmethyl radical for Rd and 4-methoxybenzyl or diphenylmethyl for Rf.

The protective group for the amino radical which Ra may represent may for example be an alkyl radical of 1 to 6 carbon atoms such as, preferably, tert-butyl or tert-amyl.

Ra can also represent an aliphatic, aromatic or heterocyclic acyl group or a carbamoyl group. Mention may be made of lower alkanoyl groups such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl.

Ra can also represent a lower alkoxy or cycloalkoxycarbonyl group such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tertbutyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, toloyoloylacarbonyl, hexyloxycarbonyl, toloyol-benzoyl group , phenylpropionyl, an aralkoxycarbonyl group, such as benzyloxycarbonyl.

The acyl groups can be substituted, for example, by a chlorine, bromine, iodine or fluorine atom. Mention may be made of chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals.

Ra can also represent a lower aralkyl group such as benzyl, 4-methoxybenzyl, phenylethyl, trityl, 3,4-dimethoxybenzyl or benzhydryl.

Ra can also represent a haloalkyl group such as trichloroethyl.

Ra can also represent a chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl or trichloroethoxycarbonyl group.

Ra can also represent a methyl carbamoyl, phenylcarbamoyl, naphthylcarbamoyl group, as well as the corresponding thiocarbamoyles.

The trityl group is preferred.

The above list is not limiting; it is obvious that other protective groups for amines, groups known in particular in peptide chemistry, can also be used.

The protective group for the hydroxyl radicals which Rb and Rc can represent can be chosen from the list below
Rb and Rc can represent an acyl group such as, for example, formyl, acetyl, propionyl, chloroacetyl, bromoacetyl, dichloro-acetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl groups. carbonyl, methoxycarbonyl, propoxycarbonyl, 2,2,2trichloro-ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzethyl-methyl-methyloxyhydropyrannyl, trityl, benzethyl-methyl-methyloxyhydropyrannyl, trityl, benzethyl-methyl-methyloxyhydropyranyl, trityl, benzethyl-methyl-methyloxyhydropyranny .

Mention may also be made of other acyls such as butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl.

Mention may also be made of the phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl radicals.

Mention may also be made of alkoxy alkoxy methyl radicals such as methoxy ethoxy methyl.

The Rb and R0 radicals can also together form a methylenedioxy, isopropylenedioxy, 1,1-cyclohexyl bis (oxy), diphenylmethylenedioxy, carbonate or hydroxy borannylbis (oxy) radical.

The methoxy ethoxy methyl group is preferred for the Rb and Rc substituents.

In one embodiment of the process, a functional derivative of the product of formula (II) is made to act. This functional derivative can be for example a halide, a symmetrical or mixed anhydride, the amide, the avid or an activated ester.

As an example of mixed anhydride, mention may be made, for example, of that formed with isobutyl chloroformate and that formed with pivaloyl chloride and the mixed carboxylic-sulfonic anhydrides formed, for example, with paratoluenesulfonyl chloride.

As an example of the activated ester, there may be mentioned the ester formed with 2,4-dinitrophenol and that formed with hydroxybenzothiazole.

As an example of a halide, mention may be made of chloride or bromide.

The anhydride can be formed in situ by the action of N, N'-disubstituted carbodiimide, for example N, N-dicyclohexylcarbodiimide or 1- (3-dimethylamino propyl) 3-ethyl carbodiimide (EDC).

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, other solvents such as tetrahydrofuran, chloroform or dimethylformamide can be used.

When an acid halide is used and in general when a hydrochloric acid molecule is released during the reaction, the reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydroxide and acid halide. sodium or potassium carbonates and acid carbonates, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is generally less than or equal to room temperature.

A product of formula (II) can also be made to act directly with a product of formula (III) in the presence of a carbodiimide such as diisopropylcarbodiimide or 1- (3-dimethylamino propyl) 3-ethyl carbodiimide (EDC). An example of such a preparation is given later in the experimental part.

The action of the reagents capable of introducing the radical RI on the product of formula (IV) is carried out under the following conditions
When Hal represents, for example, a chlorine atom, it is possible to carry out in situ or separately a substitution of the chlorine atom by an iodine atom in the presence of sodium iodide and then the desired reagent is then added, in the presence or not of d an organic solvent such as acetonitrile or tetrahydrofuran. Examples of such reactions are described below in the experimental part.

The desired reagent can also be made to act on the product of formula (IV) in which Hal represents a chlorine atom in the presence of silver tetrafluoroborate.

The isomerism of the products of formula (V) may be different from that of the products of formula (IV) used at the start. In the case where the Z isomer is isolated, this isomer can be converted into the E isomer according to the usual methods, in particular by the action of iodine.

The action on the product of formula (V) of one or more hydrolysis, hydrogenolysis or thiourea agents is aimed at eliminating the radical R a when the latter represents a radical protecting the amino radical, of eliminating the radicals Rb and Rc when these represent a protecting group for the hydroxyl radicals and / or of eliminating the radicals Rd and Rf when these represent, among the easily cleavable ester groups, one of those that the we want to eliminate.

Given the preferred protecting groups that are used: trityl for Ra, methoxy ethoxy methyl for Rb and Rc, diphenylmethyl for Rd and 4-metthoxybenzyl or diphenylmethyl for Rf, trifluoroacetic acid is preferably used without solvent or in a solvent. such as anisole or a mixture of solvents such as anisole / methylene chloride.

A salt is then obtained with trifluoroacetic acid. It is possible to return to the free base by the action of a base such as triethylamine carbonate.

The salification of the products can be carried out according to the usual methods.

Salification can, for example, be obtained by the action, on a product in acid form or on a solvate, for example, the ethanolic solvate or a hydrate of this acid, of an inorganic base such as sodium hydroxide or of potassium, sodium or potassium carbonate or hydrogen carbonate. It is also possible to use salts of mineral acids such as trisodium phosphate. It is also possible to use salts of organic acids.

As salts of organic acids, there may be mentioned, for example, the sodium salts of aliphatic, linear or branched, saturated or unsaturated carboxylic acids of 1 to 18 and preferably of 2 to 10 carbon atoms. The aliphatic chains of these acids can be interrupted by one or more heteroatoms such as oxygen or sulfur or substituted by aryl radicals, such as, for example phenyl, thienyl, furyl, by one or more hydroxyl radicals or by one or more halogen atoms such as fluorine, chlorine or bromine, preferably chlorine, with one or more carboxylic or lower alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, with one or more aryloxy radicals, preferably phenoxy.

In addition, sufficiently soluble aromatic acids such as, for example, benzoic acids substituted, preferably with lower alkyl radicals, can be used as organic acids.

As examples of such organic acids, there may be mentioned formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic, chloropropionic, crotonic, phenylacetic, 2-thienylacetic, 3 -thienylacetic, 4-ethylphenylacetic, glutaric, adipic acid monoethyl ester, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxypropionic, 3-methoxypropionic, 3-methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric, 3 -phenoxybutyric acids , 4-ethylbenzoic, 1-propylbenzoic.

However, sodium acetate, sodium 2-ethyl hexanoate or sodium diethyl acetate are preferably used as sodium salts.

Salification can also be obtained by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethyl ethanolamine, tris [(hydroxymethyl) amino] methane, methylamine, ethanolamine , pyridine, picoline, dicyclohexyl amine, morpholine and benzylamine.

It can also be obtained by the action of arginine, lysine, procaine, histidine, N-methyl glucamine.

This salification is preferably carried out in a solvent or a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone.

The salts are obtained in amorphous or crystalline form depending on the reaction conditions used.

The crystallized salts are preferably prepared by reacting the free acids with one of the salts of the aliphatic carboxylic acids mentioned above, preferably with sodium acetate.

The salification of the products with mineral or organic acids is carried out under the usual conditions.

The products of formula (I) contain several asymmetric carbons. In the cepheme nucleus, which has two asymmetric carbons, the two carbons are in the R configuration. Furthermore, the radical present on the oxyimino function also contains an asymmetric carbon which may be in the R or S form or in the form of an R mixture. , S. The separation of the two diastereoisomers can be carried out by means known to those skilled in the art, for example by chromatography.

The products of general formula (I) have very good antibiotic activity on gram (+) bacteria such as staphylococci, streptococci and in particular on penicillin-resistant staphylococci. Their effectiveness on gram (-) bacteria, in particular on coliform bacteria, klebsiella, salmonella, proteus and pseudomonas, is particularly remarkable.

These properties make said products and their pharmaceutically acceptable acid salts suitable for use as medicaments in the treatment of diseases with sensitive germs and in particular in that of staphylococci, such as staphylococcal septicemia, malignant staphylococci of the face or skin, pyoderma. , septic or suppurating wounds, anthrax, phlegmons, erepelas, primary acute or post-influenza staphylococci, bronchopneumonia, pulmonary suppurations.

These products can also be used as medicaments in the treatment of colibacillosis and associated infections, in proteus, klebsiella and salmonella infections and in other diseases caused by gram (-) bacteria.

A subject of the present invention is therefore also, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above as well as their pharmaceutically acceptable acid salts.

A specific subject of the invention is, as medicaments and in particular antibiotic medicaments, the products whose names follow - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 7- [3 - [7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino] acetyl] amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0 ] oct-2-en-3-yl] 2-propenyl] furo [2,3-b] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 7- [3- [7- [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] furo [2,3-b] pyridinium (R) or (S) or of a mixture (R + S), - the internal salt of [6R-E3 (E), 6alpha, 7béta (Z)]] 7-E3- [7- [((2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] thieno [ 2,3-b] pyridinium isomer (R) and isomer (S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z) ]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1- aza bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4-methoxy pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl ] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4- (methylthio) pyridinium (R) or (S) or of a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2- propenyl] 4- (methylthio) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2 , 0] oct-2-en-3-yl] 2-propenyl] 4- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [ 7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [4,2,0 ] oct-2-en-3-yl] 2-propenyl] 3- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R-E3 (E ), 6alpha, 7beta (Z)]] 3-amino 1 [3- [7 - [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2- carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 6-amino 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4 -dihydroxyphenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S ) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7 [[(2-amino 4-thiazolyl ) [[carboxy (3,4-dihydroxy phenyl) metho xy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 3-methyl quinolinium (R) or (S ) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6 &alpha;;, 7béta (Z)]] 1- [3- [7 [[(2-amino 4 -thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] -2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3- yl] 2-propenyl] 4-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3-t7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1aza-bicyclo [4 , 2,0] oct-2-en-3-yl] 2-propenyl] 6-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [ 3 (E), 6alpha, 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-yl] 2-propenyl] 6-chloro quinoleinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6 alpha, 7beta (Z)]] 1- [3- [7 [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino) 2-carboxy 8-oxo 5-thia 1-aza- bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 6-methoxy quinolinium (R) or (S) or a mixture (R + S) , - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z))] 3- [3- [7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl ) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] thiazolium (R) or (S) or a mixture (R + S), - the internal salt of [6R-E3 (E), 6alpha, 7béta (Z)]) 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2- propenyl] 3-methyl imidazolium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 5- [3- [7 - [[(2 -amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3 - yl] 2 (E) -propenyl] imidazoEl, 2-b] pyridaziniu m (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl ) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct2-en-3-yl] 2 (E ) -propenyl] imidazo [1,2-b] pyridazinium (R) or (S) or a mixture (R + S), - the internal salt of (#) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclot4,2,0] oct -2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-a] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (+ ) (cis) (Z) 2- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclot4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,5-a] pyridinium (R) or (S) or a mixture ( R + S), - the internal salt of [6R- [3 (E), 6 &alpha;, 7beta (Z) 1- [3- [7 - [[(2amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicycloE4, - 2,0] oct-2-en-3-yl] 2 (E) -propenyl] 6,7-dihydro 5H-pyridinium isomer (R) and isomer (S), - the internal salt of (#) (cis ) (Z) [1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclot4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 1-methyl pyrrolidinium (R) or (S) or a mixture (R + S), - the salt internal of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 4-aza l-azoniabicyclo [2, 2,2] octane (R) or (S) or a mixture (R + S), - the internal salt of [6R-t3 (E), 6 &alpha;, 7beta (Z)]] l-t3-t7 - [[(2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [4,2,0] oct -2-en-3-yl] 2-propenyl] 3-hydroxy 4-aza 1azoniabicyclo [2,2,2] octane (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[ carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N, N-trimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6 &alpha;;, 7béta (Z) 1- [3- [7 - [[(2amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4, - 2.0] oct-2-en-3-yl] N, N-dimethyl N- (2-hydroxy ethyl) 2-propen 1-aminium (R) or (S) or a mixture ( R + S), - the internal salt of (#) (cis) (Z) N- (2-amino 2-oxo ethyl) 3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S), - the internal salt of (#) (cis) (Z) 3- [7 - [[( 2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en- 3- yl] N- (cyanomethyl) N, N-dimethyl 2 (E) -propen-1-aminium (R ) or (S) or a mixture (R + S), - the internal salt of (#) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) E [carboxy (3 , 4-dihydroxy phenyl) methoxy] imino) acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl N- [(2-methoxyimino) ethyl) 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S),
It is understood that the aforementioned products of formula (I) may exist in their tautomeric form of 2-imino 2,3-dihydro thiazol-4-yl, - the internal salt of [6R-E3 (E), 6alpha, 7béta ( Z))] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia l -aza- bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4 - [(methoxyimino) methyl] quinolinium (R) or (S) or a mixture (R + S) ), - (#) (cis) (Z) l- [3- [7 - [[(2-amino 4-thiazolyl) [Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino salt ] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0) oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-a] pyrimidin-4-ium (R) or (S) or a mixture (R + S).

The invention extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments defined above.

These compositions can be administered by the buccal, rectal, parenteral, in particular intramuscular route or by the local route in topical application to the skin and the mucous membranes.

The products of formula (I) and in particular those in which A represents a cleavable ester can be administered orally.

The compositions according to the invention can be solid or liquid and be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active principle (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles. , fatty substances of animal or plant origin, paraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

These compositions may in particular be in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example sterile pyrogen-free water.

The dose administered is variable according to the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 0.250 g and 4 g per day, orally in humans, with the product described in Example 1 or also between 0.500 g and 1 g three times per day by the intramuscular route. .

The products of formula (I) can also be used as disinfectants for surgical instruments.

Finally, a subject of the invention is, as new industrial products and in particular as intermediate products necessary for the preparation of the products of formula (I) as defined above, the products of formula (IV) and the products of formula (V) in which Ra represents a protecting group for the amino radical, formulas (IV) and (V) being as defined above.

The products of formula (II) are known in the literature, in particular in European patent applications.
EP 0.238.061 or EP 0.266.060 or can be prepared according to the usual methods.

The products of formula (III) are also known in the literature, in particular in British patent applications GB 2,134,522 or German patent applications DE 3512225.

The following examples illustrate the invention without however limiting it.

EXAMPLE 1: The internal salt of [6R- [3 (E), alpha, 7beta (Z)]] 7 (3- E7- EL (2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl methoxy ] iminoj acetyl amino) 2-carboxy 8-oxo 5-thia 1-aza- bicycloC (, 2,0loct-2-en-3-yll 2-propenyl) furo (2,3-b) pyridiniun (R> or ( S) or a mixture (R + S),
Stage A: t6R- [3 (E), 6alpha, 7beta (Z)]] 7 - [[[(diphenylmethoxy carbonyl) E3,4-bisE (2-methoxy ethoxy) methoxy] phenyl methoxy] imino] [2- [(triphenylmethyl) amino] 4-thiazolyl] acetyl] amino] 3- (3-chloro 1-propenyl) 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl- P-methoxy benzyl 2-carboxylate.

A suspension comprising 3.75 g of [[(diphenylmethoxycarbonyl) [3,4-bis [(2-methoxyethoxy) methoxy] phenyl] methoxy] imino] t2-t (triphenylmethyl) amino] 4 is cooled to 0 ° C. -thiazolyl] acetic isomer syn (described in European patent EP 238061) and 1.81 g of 7-amino 3- (3-chloropropenyl) 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2 p-methoxybenzyl-en-2-carboxylate (prepared as indicated in European patent EP 0 333 154 in dichloromethane, and added 0.920 g of N- (dimethylaminopropyl) N'ethyl carbodiimide hydrochloride. The solution is maintained. obtained at 0 C with stirring for 30 minutes. The organic phase is washed with an aqueous solution of sodium chloride, dried and the solvents are removed. After chromatography of the residue on silica (eluent: methylene chloride-ether 85-15) and con cretion in isopropyl ether, 4.546 g of expected product is obtained.

NMR (CDCl3 400 MHZ in ppm) 5.10 to 5.32: CO2-CH2-Ar (Ar: aromatic ring) 3.80: Ar-O-CH3
Stage B: [6R- [3 (E), 6 &alpha;, 7beta (Z)]] 7 - [[[[(diphenylmethoxy carbonyl) [3,4-bis [(2-methoxy ethoxy) methoxy] phenyl] methoxy] imino] [2 - [(triphenylmethyl) amino] 4-thiazolyl] acetyl amino] 3- (3-iodo 1-propenyl) 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2- p-methoxy benzyl en-3-yl-2-carboxylate.

A mixture of product obtained in Stage A, 10 cm3 of acetone and 341 mg of sodium iodide and approximately 10 mg of iodine and approximately 10 mg of iodine is stirred for 1 hour at room temperature, the solvent is evaporated off and the residue is then taken up in 80 cm3 of dichloromethane.

The organic phase is washed with an aqueous solution of sodium thio sulfate and then with water. It is dried, the solvents are removed, chromatography on silica such as: ethyl dichloromethane acetate (8-2)] and 853 mg of expected product is obtained.

Proton NMR, (CDCl3 300MHz) 6.9 to 7.35: -CH = CH-CH2-I, Ar-H 6.13 (d, t J = 15 and 8): -CH = CH-CH2-I , E isomerism 4.0 (d): -CH = CH-CH2-I
Stage C: (#) (cis) (Z) 7- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl) amino ] 2-carboxy 8-oxo 5-thia 1-azabicycloE4,2,0) oct-2-en-3-yl] 2 (E) -propenyl] furo [2,3-b] pyridinium
1.928 g of the product prepared in Stage B, 0.365 g of furot2,3-b] pyridine and 2 cm3 of dichloromethane are stirred for two and a half hours, 40 cm3 of sulfuric ether are added, the precipitate is isolated, rinsed with ether, dried and chromatographed on silica, eluting with a dichloromethane-methanol mixture (928); 0.5106 g of the expected product is collected. Rf = 0.38
Proton NMR (CDCL3, 400 MHz, in ppm) 3.22 (s), 3.29 (s) and 3.35 (s): -O-CH2-O-CH2-CH2-O-CH3 3.79 (s): Ar-OCH3 3.10 to 3.9: -S-CH2-C (CH = CH-) and -O-CH2-O-CH2-CH2-O-CH3 5.00 (d) and 5 , 04 (d): -CO-NH-CH (C = O) -CH (N -) - S5.15 to 5.35: -O-CH2-O-CH2-CH2-O-CH3 5.32 (s ): - (C = O) -O-CH2-Ar 5.79 (dd) and 5.85 (dd): -CO-NH-Cfi (C = O) -CH (N -) - S- 5, 99 (resolved): Ar-CH (C = O) -O6.34 (m): -CH = CH-CH2-N + 6.77 (resolved): -S-CH-C (C = N -) - N = 6.84 to 7.45: Ar-H, -CH = CH-CH2-N + and the H in position 3 of furo E2.3 -b] pyridinium 7.87 (m): H in position 5 of furo [ 2,3-b] pyridinium 8.03 (m): H in position 2 of furo [2,3-b] pyridinium 8.35 (d): -NH8,66 (m): H in positions 4 and 6 furo [2,3-b] pyridinium
Stage D: the internal salt of E6R-E3 (E), 6alpha, 7beta (Z)]] 7 [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] furo [2,3-b ] pyridinium (R) or (S) or a mixture (R + S),
Stirred for one hour and fifteen minutes 0.516 g of the product prepared in the preceding stage 5.1 cm3 of a solution of trifluoroacetic acid 10% anisole; then added 30 cm3 of sulfuric ether, stirred again for an hour and a half, filter rinsed and dried.

0.261 g of the desired product is collected.

Proton NMR (DMSO, 400 MHz, in ppm) 3.50 to 3.78 (m): -S-CH2-C (CH = CH -) = C5.16 (resolved d): -CO-NH-CH (C = O) -CH (N -) - S- 5.31 (s): Ar-CH (C = O) -O- 5.58 (m): -CH = CH-CH2-N + 5.77 (m): -CO-NNH-CH (C = O) -CH (N -) - S- 6.32 (m): -CH = CH-CH2-N + 6.65 to 6.80 (m): Aromatics of (3,4-dihydroxy phenyl)
(Ar-H) 6.85 (s): -S-CH-C (C = N -) - N = 7.07 (d resolved): -CH = CH-CH2-N + 7.52 (d): H in position 3 of furot2,3-b] pyridinium 7.98 (dd): H in position 5 of furot2,3-b] pyridinium 8.61 (d): H in position 2 of furot2,3-b] pyridinium 8.89 (dl) and 8.93 (d): H in positions 4 and 6 of furo [2,3b] pyridinium 7.31 (sl) (2 H) and 9.04 (m) (2 H): H mobile 9.53 (d) and 9.61 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 2: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 7 [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxyjimino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-y] 2-propenyl] furo [3,2-b] pyridinium (R) or (S) or a mixture (R + S)
By operating in a manner analogous to that of Example 1, using furo [3,2-b] pyridine as quaternization agent, the desired product is obtained.

Proton NMR (DMSO, 400 MHz, in ppm) -S-CH2-C (CH = CH -) = C- masked 5.14 (split d): -CO-NH-CH (C = O) -CH ( N -) - S- 5.32 (s): Ar-CH (C = O) -O- 5.61 (m): -CH = CH-CH2-N + 5.76 (m): -CO-NNH -CH (C = O) -CH (N -) - S- 6.30 (m): -CH = CH-CH2-N + E isomer 6.6 to 6.78 (m): Ar-H 6.86 (s): -S-CH-C (C = N -) - N = 7.02 (split d): -CH = CH-CH2-N + 7.78 (sl): H in position 3 of furo [3 , 2-b] pyridinium 8.06 (dd): H in position 6 of furo [3,2-b] pyridinium 8.92 (d): H in position 2 of furo [3,2-b) pyridinium 8, 97 (d) to 9.04 (m): H in positions 5 and 7 of furo [3,2-b] pyridinium 9.0 (m): H mobile 9.48 (d) and 9.56 (d) : -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 3: the internal salt of (S) (cis) (Z) 7- [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyll amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl) thienoE2,3-b) pyridinium
Working in a manner analogous to that of Example 1, using as starting material the acid [[(S) - (diphenylmethoxycarbonyl) [3,4-bis [(2-methoxy ethoxy) methoxy] phenyl] methoxy] imino] [2 - [(triphenylmethyl) amino] 4-thiazolyl] acetic isomer syn (described in European patents
EP 0266060 and 0280521) and as thieno [2,3-b] pyridine as quaternization agent, the desired product is obtained.

Rf = 0.5 [Thin Layer Chromatography (TLC); eluent acetone-water (4-1)]
AlphaD = -11.5 [concentration (c) = 0.9 in DMSO),
Proton NMR (DMSO, 400 MHz, in ppm) 3.51 (m): -S-CH2-C (CH = CH-) 5.15 (d J = 5): -CO-NH-CH (C = O) -CH (N -) - S- 5.32 (s): Ar-CH (C = O) -O- 5.67 (d, J = 6): -CH = CH-CH2-N + 5, 8 (dd, sl after exchange): -CO-NH-CH (C = O) -CH (N -) - S- 6,27 (dt J = 16 and 6): -CH = CH-CH2-N + isomer E 6.6 to 6.87 (m): Ar-H and -S-CH-C (C = N -) - N = 7.13 (d J = 6): -CH = CH-CH2-N + 7 , 89 (d): H in position 3 of thieno [2,3-b] pyridinium 8,15 (dd): H in position 5 of thieno [2,3-b] pyridinium 8,28 (d): H in position 2 of thieno [2,3-b] pyridinium 9.08 (d): H in position 4 of thieno [2,3-b] pyridinium 9.22 (d): H in position 6 of thieno [2,3 -b] pyridinium 9.55 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 4: [6R- [3 (E), alpha, 7beta (Z)]] 1 (3- (7- (E (2-amino 4-thiazolyl)) [[carboxy (3,4-dihydroxy) internal salt phenyl) methoxyj iminoj acetyla amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 4-methoxy pyridinium (R) or (8 ) or a mixture (R + S)
By operating in a manner analogous to that of Example 1, using 4-nethoxy pyridine as quaternization agent, the desired product is obtained.

Proton NMR (DMSO, 400 MHz, in ppm) 3.72 (AB): -S-CH2-C (CH = CH -) = C- 4.10 (s): Ar-O-CH3 5.15 ( d): -CO-NH-CH (C = O) -CH (N -) - S- 5.22 (1): -CH = CH-CH2 -N + 5.32 (s): Ar-CH (C = O) -O- 5.77 (m): -CO-NH-CH (C = O) -CH (N -) - S- 6.25 (m): -CH = CH-CH2-N + isomer E 6.68 (dd), 6.74 (m) (2 H) and 6.86 (s) (1 H) =: Ar-H and
-S-CH-C (C = N -) - N = 6.95 (d J = 15.5): -CH = CH-CH2-N + 7.33: NH2 7.66 (d) and 8.83 (m): aromatic H of 4-MeO pyridiniun 9.0 (1), 9.5 (d) and 9.62 (d): mobile H
EXAMPLE 5: The internal salt of [6R- [3 (E), 6 &alpha;, 7beta (Z)]] 1 [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3,4- dihydroxy phenyl) methoxy] imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-aza- bicyclo [4,2,0] oct - 2en-3-yl] 2-propenyl) 4- (methylthio) pyridinium (R + S),
By operating in a manner analogous to that of Example 1, using 4- (methylthio) pyridine as quaternization agent, the desired product is obtained.

Proton NMR (DMSO, 300 MHz, in ppm) 2.72 (s): Ar-S-CH3 5.15 (d) and 5.18 (d): -CO-NH-CH (C = O) - CH (N -) - S- 5.22 (dl): -CH = CH-CH2-N + 5.32 (s): Ar-CH (C = O) -O5.77 (m, d split after exchange) : -CO-NH-CH (C = O) -CH (N -) - S- 6.26 (m): -CH = CH-CH2-N + E isomer 6.65 (dd) to 6.87 (m ) (4 H) =: Ar-H and -S-CH-C (C = N -) - N = 6.99 (d J = 15 Hz): -CH = CH-CH2-N + 7.96 (d ) and 8.70 (d): aromatic H of 4-MeS pyridinium 9.55 (d) and 9.62 (d): -CO-NH-CH (C = O) -CH (N -) - S7, 32 (m) and 9.06 (m): H movable
EXAMPLE 6: The internal salt of [6R- [3 (R), 6alpha, 7beta [Z- (R *)]]] 1- [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0joct-2-en-3-yl 2-propenyl) 4- 1- (me - thylthio) pyridinium,
The product obtained in Example 5 is purified by HPLC on a Microbondapack 18-300 column (registered trademark) of 10 microns and 0.019 m in diameter, eluting with acetonitrile at 0.025% trifluoroacetic acid and thus results in isomers ( R) and (S) (See following example).

Proton NMR (DMSO, 300 MHz, in ppm) 2.71 (s): Ar-S-CH3 3.54 (d) and 3.79 (d): -S-CH2-C (CH = CH-) = C5.17 (d): -CO-NH-CH (C = O) -CH (N -) - S5.22 (1): -CH = CH-CH2-N + 5.32 (s): Ar- CH (C = O) -O5.75 (d, d): -CO-NH-CH (C = O) -CH (N -) - S6.27 (m): -CH = CH-CH2-N + isomer E 6.72 (d): H in position 5 of (3,4-dihydroxy phenyl) 6.74 (s): -S-CH-C (C = N -) - N = 6.73 (d) : H at position 6 of (3,4-dihydroxy phenyl) 6.86 (d): H at position 2 of (3,4-dihydroxy phenyl) 6.98 (d J = 15.5 Hz): -CH = CH-CH2-N + 7.30 (1): -NH2 7.96 (d) and 8.71 (d): H aromatics of 4-MeS pyridinium 9.62 (d): -CO-NH-CH (C = O) -CH (N -) - S9.00 and 9.09: H mobile
EXAMPLE 7: The internal salt of [6R- [3 (E), alpha, 7betaEz- (S *)]]] 1- [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 4- ( methylthio) pyridinium,
Proton NMR (DMSO, 300 MHz, in ppm) 2.72 (s): Ar-S-CH3 3.54 [AB]: -S-CH2-C (CH = CH -) = C5.14 (d) : -CO-NH-CH (C = O) -CH (N -) - S 5.22 (dl): -CH = CH-CH2-N 5.32 (s): Ar-CH (C = O) -O5.79 (dd): -CO-NH-CH (C = O) -CH (N -) - S- 6.24 (dt): -CH = CH-CH2-N + isomer E 6.65 to 6 , 78 (m) (3H) and 6.87 (1H): Ar-H and -S-CH-C (C = N -) - N = 6.97 (d): -CH = CH-CH2 -N + 7.30 (1): -NH2 7.96 (d) and 8.70 (d): H aromatics of 4-MeS pyridinium 9.55 (d): -CO-NH-CH (C = O) -CH (N -) - S9.04 and 9.08: H movable
EXAMPLE 8: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1 [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl) amino] 2-carboxy 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 2- (methylthio) pyridinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 2.87 (s): Ar-S-CH3 5.16 (d, resolved): -CO-NH-CH (C = O) -CH (N-) -S5.78 (d, resolved after exchange): -CO-NH-CH (C = O) -CH (N -) - S6.13: -CH = CH-CH2-N + isomer E 6.65 to 6, 80: Ar-H 6.85: -S-CH-C (C = N -) - N = 6.85 (resolved d): -CH = CH-CH2-N + 7.32 and 9.05: -OH 7.84 (t) and 8.44 (t): Aromatic H in position 3 and 4 of the
2-MeS pyridinium 8.04 (d): aromatic H in position 5 of 2-MeS pyridinium 8.97 (d): aromatic H in position 2 of 2-MeS pyridinium 9.57 (split d): -CO-NH -CH (C = O) -CH (N -) - S-
EXAMPLE 9: The internal salt of [6R- [3 (E), alpha, 7beta (Z)]] 1 [3- [7 - [[(2-amino 4-thiazolyl] [[carboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-proenyl] 4- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.50 to 3.75 (m): -S-CH2-C (CH = CH -) = C5.17 (resolved d): CO-NH-CH ( C = O) -CH (N -) - S- 5.32 (s): Ar-CH (C = O) -O 5.44 (m): -CH = CH-CH2-N + 5.77 (m ): -cO-NH-CH (C = O) -CH (N -) - S- 6.29 (m): -CH = CH-CH2-N + E isomer 6.66 to 6.78 (m) ( 3H): Ar-H 6.86 (s): -S-CH-C (C = N -) - N = 7.06 (d, J = 15.5): -CH = CH-CH2-N + 8.44 (d): H in positions 3 and 5 of the pyridinium ring 8.67 (s) and 8.25 (s): (C = O) -NH2 not very mobile 9.20 (d): H in positions 2 and 6 of the pyridinium ring 9.47 (d) and 9.54 (d): -CO-NH-CH (C = O) -CH (N -) - S8.94 (m) (2 H) 7.24 (m) (2 H) and 12.85 (th.): mobile H
EXAMPLE 10: [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3-7 - [[(2-amino 4-thiazolyl) (Ecarboxy (3,4-dihydroxy phenyl) internal salt ) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 3- 3- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S)
Proton NMR (DMSO, 300 MHz, in ppm) 3.50 to 3.80 (m): -S-CH2-C (CH = CH -) = C- masked 5.17 (d split): -CO- NH-CH (C = O) -CH (N -) - S- 5.32 (s): Ar-CH (C = O) -O- 5.44 (m): -CH = CH-CH2-N + 5.77 (m): -CO-NH-CH (C = O) -CH (N -) - S- 6.30 (m): -CH = CH-CH2-N + E isomer 6.64 to 6, 90 (m) (4H): Ar-H and -S-CH-C (C = N -) - N = 7.08 (d J = 15): -CH = CH-CH2-N + 7.29 ( 3 H): = C-NH2 8.29 (t): H at position 5 of the pyridinium ring 8.36 (d): H at position 4 of the pyridinium ring 9.17 (d): H at position 6 of the pyridinium ring 9.47 (d): H in position 2 of the pyridinium ring 9.54 (d) and 9.62: -CO-NH-CH (C = O) -CH (N -) - S- 8.20 (s ) and 8.61 (s): H little mobile 9.02: H mobile
EXAMPLE 11: The internal salt of [6R- [3 (E), alpha, 7beta (Z)]] 6-amino 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3 , 4-dihydroxyphenyl methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 400 MHz, in ppm) 5.13: -CO-NH-CH (C = O) -CH (N -) - S5.31 (split d): Ar-CH (C = O) -O- 5.65 to 5.80: -CH = CH-CH2-N + and -CO-NH-CH (C = O) -CH (N -) - S- 6.32 (m): -CH = CH-CH2-N + E isomer 6.65-7.0 (m) (5H): Ar-11, -SCHC (C = N -) - N = and -CH = CH-CH2-N + 7.56 ( d split): H in position 7 of the quinolinium ring 7.88 (m): H in position 3 of the quinolinium ring 8.19 (m): ~ in position 8 of the quinolinium ring 8.80 (d): ~ in position 4 quinolinium ring 9.0 (s) 9.53 (d) and 9.61 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 12: The internal salt of [6R- [3 (E), alpha, 7beta (Z)]] 3-amino 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3 , 4-dihydroxy phenyl) methoxy) imino) acetyl] amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) quinolinium (R ) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 5.14: -CO-NH-CH (C = O) -CH (N -) - S5.31 (s) and 5.32 (s): Ar- CH (C = O) -O5.60 to 5.85 (m): -CH = CH-C-H2-N + and -CO-NH-CH (C = O) -CH (N -) - S6.33 (m): -CH = CH-CH2-N + E isomer 6.6 to 6.8 (m): Ar-H, 6.86 (s): -S-CH-C (C = N -) - N = 6.98 (split d): -CH = CH-CH2-N + 7.76 (m) (2H), 8.1 (m) (1H) and 8.25 (m) (1H): H in positions 5, 6, 7 and 8 of the quinolinium ring 8.03 (d): H in position 4 of the quinolinium ring 8.87 (sl): H in position 2 of the quinolinium ring 9.09 (m): H mobile 9.53 (d) and 9.61 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 13: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-yll 2-propenyl) 3-methyl quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 2.66 (s): -CH3 in position 3 of the quinolinium ring 3.50 (masked) and 3.75 (d): -S-CH2-C (CH = CH -) = C- 5.13 split: -CO-NH-CH (C = O) -CH (N -) - S- 5.31 (s): Ar-CH (C = O) -O5.78 (m): -CO-NH-CH (C = O) -CH (N -) - S- 5.85 (m): -CH = CH-C112-N + 6.36 (m): -CH = CH -CH2-N + E isomer 6.62 to 6.8 (m) (3 H): Ar-H 6.85 (s): -S-CH-C (C = N -) - N = 7.00 ( d split): -CH = CH-CH2-N + 8.01 (t) and 8.19 (t): H at 6 and 7 of the quinolinium ring 8.38 (d) and 8.50 (d): H at 5 and 8 of the quinolinium ring 9.14 (sl) and 9.54 (sl): H at 2 and 4 of the quinolinium ring 9.04 (m): mobile H 9.53 (d) and 9.59 (d) : -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 14: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy) imino] acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-yl 2-propenyl) 4-methyl quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.02 (s): -CH3 in position 4 of the quinolinium ring 3.45 to 3.80 (m): -S-Cil2-C (CH = CH-) = C- 5.13 (split d): -CO-NH-CH (C = O) -CH (N -) - S5.31 (s): Ar-Cil (C = O) -O- 5.75 (d, split after exchange): -CO-NH-CH (C = O) -CH (N -) - S5.80 (m): -CH = CH-CH2-N + 6.37 (m): -CH = CH-CH2-N + E isomer about 6.70 (m) (3 H): Ar-H 6.85 (s): -S-CH-C (C = N -) - N = 6.96 (d split j = 16Hz): -CH = CH-CH2-N + 8.06 (t) and 8.25 (t): H at 6 and 7 of the quinolinium ring 8.11 (d): H at 3 of the quinolinium ring 8 , 50 (2d): H at 5 and 8 of the quinolinium ring 9.43 (d): H at 2 of the quinolinium ring 7.30 (sl and 9.03 (sl): mobile H (-Nil2 and -OH) 9 , 51 (d) and 9.59 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 15: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicyclo4,2,0loct-2-en-3-ylI 2-propenyl) 6-methyl quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 2.62 (s): -CH3 in position 4 of the quinolinium ring 3.50 (masked) and 3.74 (d): -S-CH2-C (CH = CH -) = C- 5.13 (split d): -CO-NH-CH (C = O) -CH (N -) - S- 5.31 (s): Ar-CH (C = O) - O- 5.76 (d, resolved after exchange): -CO-NH-CH (C = O) -CH (N -) - S5.86 (m): -CH = CH-CH2-N + 6.35 ( m): -CH = CH-CH2-N + E isomer 6.85 (split s): -S-CH-C (C = N -) - N = 6.94 (split d j = 16Hz): -CH = CH-CH2-N + 8.10 to 8.45 (m) (4 H): H in 3, 5, 7 and 8 of the cycle
quinolinium 9.21 (d) (1 H): H at 4 of the quinolinium ring 9.50 (d): H at 2 of the quinolinium ring 9.03 (m): H mobile 9.50 (d) and 9.60 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 16: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy) imino) acetyll amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 6-chloro quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.60 (mask) and 3.75 (d): -S-Cil2-C (CH = CH -) = C- 5.14: -CO-NH- CH (C = O) -CH (N -) - S5.31 (s): Ar-CH (C = O) -O- 5.76 (m): -CO-NH-CH (C = O) - CH (N -) - S- 5.88 (m): -CH = CH-CH2-N + 6.34 (m): -CH = CH-CH2-N + E isomer 6.85 (s): -S- CH-C (C = N -) - N = 6.96 (resolved d): -CH = CH-CH2-N + 6.62 to 6.80 (m) (3H): Ar-H 8.29 ( m) and 8.59 (dd): il in 3, 7 and 8 of the quinolinium ring 8.69 (d): H in position 5 of the quinolinium ring 9.25 (d): il in position 4 of the quinolinium ring 9, 59 (d): H in position 2 of the quinolinium ring 9.04 (m): mobile H 9.52 (d) and 9.60 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 17: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy] imino) acetyl] amino) 2-carboxy 8-oxo 5-thia l-azabicyclot4,2,0loct-2-en-3-ylj 2-propenyl) 6-methoxy quinolinium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 400 MHz, in ppm) 3.45 to 3.75 (m): -S-CH2-C (CH = CH -) = C4.00 (s): -OCH3 at position 6 of the ring quinolinium 5.12 (resolved d): -CO-NH-CH (C = O) -CH (N -) - S- 5.31 (s): Ar-CH (C = O) -O- 5.74 (split dd): -CO-NH-CH (C = O) -CH (N -) - S5.84 (m): -CH = CH-CH2-N + 6.35 (m): -CH = CH- CH2-N + isomer E 6.65 to 6.80 (m): Ar-H 6.85 (s): -S-CH-C (C = N -) - N = 6.93 (d split J = 16Hz ): -CH = CH-CH2-N + 7.89 (dd): H at 7 of the quinolinium ring 7.90 (sl): H at 5 of the quinolinium ring 8.15 (dd): H at 3 of the quinolinium ring 8 , 46 (dd): H at 4 of the quinolinium ring 9.13 (d): H at 8 of the quinolinium ring 9.37 (d): H at 2 of the quinolinium ring 7.27 (m) (2 H) and 8 , 94 (m) (2 H): it mobile 9.45 (d) and 9.52 (d): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 18: [6R- [3 (E), 6alpha, 7beta (Z)]] 3- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl) methoxy] imino] acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-yll 2-propenyl) thiazolium (R) or (S) or d ' a mixture (R + S),
Proton NMR (DMSO, 400 MHz, in ppm) 3.40 to 3.80 (m): -S-CH2-C (CH = CH -) = C- 5.16 (d split): -CO-NH -CH (C = O) -CH (N -) - S- 5.33 (m) (3 H): Ar-CH (C = O) -O- and -CH = CH-CH2-N + 5.77 (m): -CO-NH-Cil (C = O) -CH (N -) - S- 6.26 (m): -CH = CH-CH2-N + isomer E 6.65 to 6.77 (m ): Ar-H 6.87 (s): -S-CH-C (C = N -) - N = 6.97 (split d): -CH = CH-CH2-N + 7.30 (s) ( 2 H): mobile H 8.36 (s) and 8.52 (s): H at 4 and 5 of the thiazolium ring 9.00 (s), 9.08 (s), 9.09 (s) and 9 , 64 (s): 2 H mobile 9.54 (d) and 9.62 (d): -CO-NH-CH (C = O) -CH (N -) - S10.21 (s): H in 2 of the thiazolium ring
EXAMPLE 19: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino 4-thiazolyl) E [carboxy (3,4- dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-ylI 2-propenyl) 3-methyl imidazolium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 400 MHz, in ppm) 3.50 to 3.80: -S-CH2-C (CH = CH -) = C- 3.86 (s): -CH3 at position 3 of the imidazolium ring 4.97 (d): -CH = CH-CH2-N + 5.16 (split d): -CO-NH-CH (C = O) -CH (N -) - S- 5.33 (s): Ar-CH (C = O) -O- 5.79 (m): -CO-NH-Ch (C = O) -CH (N -) - S- 6.18 (m): -CH = CH- CH2-N + E isomer 6.75-7.00 (m): Ar-H, -S-CH-C (C = N -) - N = and -CH = CH-CH2 7.28: NH2 7.71 (s) (2 H): H in 2 and 3 of the imidazolium ring 8.96 (broad), 12.81 (broad) and 13.68 (broad): 2 mobile H 9.12 (s): H in 5 of the imidazolium ring 9.47 (d) and 9.54 (d): -CO-NH-CH (C = O) -CH (N -) - S-
EXAMPLE 20: (#) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl internal salt ) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-b] pyridazinium (R ) or (S) or a mixture (R + S),
Proton NMR (DMSO, 400 MHz, in ppm) (1 H) masked and about 3.70 (d) (1 H): -S-Cil2-C (CH = CH -) = C- 5.15 (d split): -CO-NH-CH (C = O) -CH (N -) - S- 5.25 to 5.45 (m): -CH = CH-CH2 -N + and Ar-CH (C = O ) -O5.75 (m, d resolved after exchange): -CO-NH-CH (C = O) -CH (N -) - S- 6.25 (m): -CH = CH-CH2-N + isomer E 6.65 to 6.86 (m): Ar- and -S-CH-C (C = N -) - N = 6.96 (dl J = 16Hz): -CH = CH-CH2-N + 7, 34 (m) and 9.05 (m): H mobile 8.00 (dd): H in 3 of the imidazo [1,2-b] pyridazinium ring 8.54 (sl) and 8.88 (sl): H in 6 and 7 of the imidazo cycle
[1,2-b] pyridazinium 8.82 (d): H at 4 of the imidazoEl ring, 2-b] pyridazinium 9.12 (d): H at 2 of the imidazoEl ring, 2-b] pyridazinium 9.55 ( d) and 9.60 (d): -CO-NH-CH (C = O) -CH (N -) - S-
EXAMPLE 21: the internal salt of (#) (cis) (Z) 1- [3- [7 - [[(2-aminoi 4-thioazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl ) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-a] pyridinium (R ) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.55 (m) (masked): -S-CH2-C (CH = CH -) = C- 5.15 (m): -CO-NH-CH (C = O) -CH (N -) - S- 5.29 (m): -CH = CH-CH2-N + 5.32 (s): Ar-CH (C = O) -O- 5.74 (m): -CO-NH-CH (C = O) -CH (N -) - S- cis isomer 6.25 (m): -CH = CH-CH2-N + E isomer 6.68 to 6.92 : Ar-H, -S-CH-C (C = N -) - N = and -CH = CH-CH2-N + 7.33 (s), 9.03 (s), 9.56 (split d) and 12.80: mobile H 7.57 (t) (1 H), 8.06 (t) (1 H), 8.20 (d) (1 H), 8.29 (s) (1 H) , 8.45 (s) (1 H) and 8.97 (d) (1 H): H of the imidazo [1,2-b] pyridinium ring
EXAMPLE 22: (#) (cis) (Z) 2- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl internal salt ) amino] 2-carboxy 8-oxo 5-thia 1-azabicycldo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,5-a] pyridinium (R ) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.40 to 3.80: -S-CH2-C (CH = CH -) = C- 5.17 (m): -CO-NH-CH (C = O) -CH (N -) - S- 5.18 to 5.32: -CH = Ch-CH2-N + and Ar-CH (C = O) -O5.76 (m): -CO-NH- CH (C = O) -CH (N -) - S- cis isomer 6.28 (m): -CH = CH-CH2-N + E isomer 6.68 to 6.86: Ar-H and -S-CH -C (C = N -) - N = 7.04 (d J = 15.5): -CH = CH-CH2-N + 7.29, 9.0 to 9.08, 9.54 and 12.56 : Mobile H 7.19 (t) and 7.25 (t): it in 6 and 7 of the imidazo ring [1,5-a]
pyridazinium 7.86 (d): H in 8 of the imidazo [1,5-a] ring pyridazinium 8,23 (d): H in 1 of the imidazoEl, 5-a] pyridazinium 9,02 (d): H in 5 of the imidazo [1,5-a] pyridazinium ring 9.74 (s): H in 3 of the imidazoEl ring, 5-a) pyridazinium
EXAMPLE 23: The internal salt of [6R- [3 (E), 6alpha, 7beta [Z (R *)]]] 1- [3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-ylj 2 2 (E) -propenyl] 6,7dihydro 5H -pyrindinium,
Stage A: The internal salt of [6R- (3E), 6alpha, 7beta (Z)]] 1 [3- [7 - [[[[(diphenylmethoxycarbonyl) [3,4-bis [(2-methoxy ethoxy) methoxy ] phenyl] methoxy] imino] [2 - [(triphenylmethyl) amino] 4-thiazolyl] acetyl) amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3 -yl] 2 (E) -propenyl] 6,7-dihydro 5H-pyrindinium, (R + S)
1.33 g of the iodine derivative prepared in Stage B of Example 1, 0585 cm3 of cyclopentano [b] pyridine in a minimum amount of dimethylsulfoxide (DMSO), is stirred for 5 hours, the solvent is washed and chromatographed, eluting with the dichloromethane-methanol mixture (9-1) and thus obtains 1.07 g of the desired product
Stage B: The internal salt of E6R-E3 (E), 6alpha, 7beta (Z)]] 1 [3- [7 - [[2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 6,7-dihydro 5Hpyrindinium ,
By operating as in Stage D of Example 1, from 1.053 g of the product prepared in the preceding stage, 1.07 g of the expected product is obtained.

Stage C: The internal salt of [6R- [3 (E), 6alpha, 7beta [Z (R *)]]] 1- [3- [7 - [[2-amino 4-thiazolyl) t [carboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 6,7-dihydro 5H-pyrindinium,
The product obtained in Stage B is purified by HPLC on a column
Microbondapack C18-300 (registered trademark) of 10 microns and 0.0079 m in diameter, eluting with acetonitrile at 0.025% trifluoroacetic acid and thus results in the (R) and (S) isomers (see following example).

Proton NMR (DMSO, 400 MHz, in ppm) 2.24 (m): the H at 6 of the 6,7-dihydro 5H-pyrindinium ring 3.15 (m) and 3.38 (masked): the H at 5 and 7 of cycle 6,7
dihydro 5H-pyrindinium 3.54 (d, J = 17.5Hz) and 3.78 (d, J = 17.5Hz): -S-CH2-C (CH = CH -) = C- 5.17 (d , J = 5): -CO-NH-CH (C # O) -CH (N -) - S- 5.32 (m): -CH = CH-CH2-N + and Ar-CH (C # O) -O- 5.75 (dd, J = 5Hz and J = 7.5Hz): -CO-NH-CH (C # O) -CH (N -) - S- 6.24 (dt, J = 16 and J = 6.5 Hz): -CH = CH-CH2-N + E isomer 6.70 (d, J = 8Hz): H at 6 of 3,4-dihyroxyphenyl radical 6.74 (s): -S-CH -C (C = N -) - N = 6.75 (dd, J = 1.5 and J = 8Hz): H at 5 of the 3,4-dihydroxy radical
phenyl 6.86 (sl): H at position 2 of 3,4-dihydroxyphenyl 6,87 (d J = 16): -CH = CH-CH2-N + 7.25: mobile NH2 7.90 (dd, J = 6 and J = 7.5): H in 3 of the 6,7-dihydro 5H cycle
pyrindinium 8.41 (d, J = 7.5): H in 4 of the 6,7-dihydro 5H -pyrindinium 8.75 (d, J = 6): H in 2 of the 6,7-dihydro 5H- ring pyrindinium 9.53 (d, J = 7.5Hz): -CO-NH-CH (C = O) -CH (N -) - S- 8.92, 9.00, 12.76 and 13.72: H mobile
EXAMPLE 24: The internal salt of [6R- [3 (E), 6alpha, 7béta
Z (S *)]]] 1- [3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxyl imino) acetyll amino) 2-carboxy 8-oxo 5- thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 6,7dihydro SH-pyrindinium,
Proton NMR (DMSO, 400 MHz, in ppm) 2.24 (m): the H at 6 of the 6,7-dihydro 5H-pyrindinium ring 3.15 (m) and 3.40: the H at 5 and 7 of the 6,7-dihydro 5H cycle
pyrindinium 3.48 (d, J = 17.5Hz) and 3.63 (d, J = 17.5Hz): -S-CH2-C (CH = CH -) = C- 5.14 (d, J = 5): -CO-NH-CH (C = O) -CH (N -) - S- 5.32 (m): -CH = CH-C112 -N + and Ar-CH (C # O) -O- 5.78 (dd, J = 5Hz and J = 7.5Hz): -CO-NH-CH (C = O) -CH (N -) - S6.20 (dt, J = 16 and J = 6Hz): -CH = CH-CH2-Ns isomer E 6.68 (d, J = 8Hz): H at 6 of 3,4-dihyroxyphenyl radical 6.75 (dd, J = 2 and J = 8Hz): H at 5 of 3,4-dihydroxy radical
phenyl 6.78 (s): -S-CH-C (C = N) -N = 6.87 (d, J = 2Hz): H at 2 of the 3,4-dihydroxyphenyl radical 6.87 (d J = 16): -CH = CH-CH2-N + 7.25: mobile NH2 7.90 (dd, J = 6 and J = 7.5): H in 3 of the 6,7-dihydro 5H ring
pyrindinium 8.42 (d, J = 7.5): H at 4 of the 6,7-dihydro 5H -pyrindinium 8.75 ring (d, J = 6): H at 2 of the 6,7-dihydro 5H- ring pyrindinium 9.46 (d, J = 7.5Hz): -CO-NH-CH (C = O) -CH (N -) - S- 8.98 (2H), 9.00, 12.97 ( 1 H) and 13.69 (1 H): H mobile
EXAMPLE 25: [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[2-amino 4-thiazolyl) trcarboxy (3,4-dihydroxy phenyl) internal salt methoxy) imino) acetyl] amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4 - [(methoxyimino) methyll quinolinium ( R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.47 (m): -S-CH2-C (CH = CH -) = C- 4.19 (s): -CH = N-OCH3 at position 4 of the quinolinium ring 5.14 (m): -CO-NHCH (C = O) -CH (N -) - S- 5.31 (s): Ar-CH (C = O) -O- 5.75 ( m): -CO-NH-CH (C = O) -CH (N -) - S- 5.89 (m): -CH = CH-CH2-N + 6.36 (m): -CH = CH- CH2-N + isomer E 6.64 to 6.77 (m): Ar- 6.85 (s, d): -S-CH-C (C = N -) - N = 6.99 (split d j = 16Hz): -CH = CH-CH2-N + 7.31 (1): -NH2 8.09 (1) and 8.30 (t): H at 6 and 7 of the quinolinium ring 8.41 (d): H in 3 of the quinolinium ring 8.58 (d) and 8.96 (d): it in 5 and 8 of the quinolinium ring 9.33 (s): -CH = N-OCH3 in position 4 of the quinolinium ring
(isomer E) 9.52 (d, d): H at 2 of the quinolinium ring 9.03 (1) and 9.60 (d): mobile H
EXAMPLE 26: The internal salt of (#) (cis) (Z) 1- [3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 1-methyl pyrrolidinnium (R) or (S) d 'a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 2.10 (sl) and 3.45 (sl): H of the pyrrolidinium ring 2.99 (s): N ± CH3 3.9 (m): -S- Cil2-C (CH = CH -) = C- 4.11: -CH = CHG-CH2-N + 5.18 (m): -CO-NH-CGH (C = O) -CH (N -) - S - 5.33 (s): Ar-CH (C = O) -O- 5.79 (m): -CO-NH-CH (C = O) -CH (N -) - S6.17 (dt) : -CH = CH-CH2-N + isomer E 6.65 to 6.85: Ar-H and -S-CH-C (C = N -) - N = 7.05 (d, J = 15Hz): - CH = CH-CH2-N +
EXAMPLE 27: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- (7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxy phenyl methoxy imino) acetyl) amino) 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0loct-2-en-3-yl 2-propenyl) 4-aza l-azoniabicyclo [2,2,2] octane (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.14 and 3.35: H of the 4-aza ring 1-azoniabicyclo [2,2,2] octane 3.5 to 3.95: -S-CH2- C (CH = CH) = C- 4.06: -CH = CH-CH2-N + 5.20 (d, resolved): -CO-NH-CH (C = O) -CH (N -) - S- 5.34 (s): Ar-CH (C = O) -O5.80 (d, split): -CO-NH-CH (C = O) -CH (N -) - S6.11: -CH = CH-CH2-N + E isomer 6.7 to 6.90: Ar-H and -S-CH-C (C = N -) - N = 7.02 (d, resolved): -CH = CH-CH2- N + 9.10 (split d): -CO-NH-CH (C = O) -CH (N -) - S-
EXAMPLE 28: The internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl) 3-hydroxy 4-aza 1- azoniabicyclo [2,2,2] octane (R) or (S) or a mixture (R + s),
Rf = 0.5 (eluent: acetone-water (4-1))
EXAMPLE 29: The internal salt of (i) (cis) (Z) 3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl) amino) 2 -carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N, N, -trimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 2.99 (s) and 3.03 (s): -N + (CH3) 3 4.05: -CH = CH-CH2-N + 5.16 (d) : -CO-NH-CH) C = O = -CH (N -) - S- 5.33 (s): Ar-CH (C = O) -O5.75 (d): -CO-NH-CH (C = O) -CH (N -) - S- 6.04 (m): -CH = CH-CH2-N + E isomer 6.7 to 6.90: Ar-H and -S-CH-C ( C = N -) - N = 7.04 (d, resolved): -CH = CH-CH2-N + 9.08 (d resolved): -CO-NH-CH (C = O) -CH (N-) -S-
EXAMPLE 30: The internal salt of] 6R- [3 (E), 6alpha, 7beta (Z)]] 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl N- (2-hydroxy ethyl) 2-propen-1-aminium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.05 (s): -N + (CH3) 2-CH2-CH2-OH 3.38 and 3.87: -N + (CH3) 2-CH2-CH2- OH 4.14 (d): -CH = CH-C112-N + 5.19 (d, resolved): -CO-NH-CH (C = O) -CH (N -) - S- 5.80 (d , resolved): -CO-NH-CH (C = O) -CH (N -) - S6.14: -CH = CH-CH2-N + isomer E 6.87: -S-CH-C (C = N ) -N = 6.65 to 6.80: Ar-H 7.03 (d, resolved): -CH = CH-CH2-N + 7.36 and 9.05: -OH 9.59 (d resolved): -CO-NH-CH (C = O) -CH (N -) - S
EXAMPLE 31: The internal salt of (i) (cis) (Z) N- (2-amino 2-oxo ethyl) 3- [7 - [[2-amino 4-thiazolyl) ttcarboxy (3,4-dihydroxy phenyl methoxy ] imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl 2 (E) -propen-1aminium ( R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.19 (s): -N + (CH3) 2-CH2-CO-NH2 4.01 (s): -N + (CH3) 2-CH2-CO-NH2 4.27 (d): -CH = CH-CH2-N + 5.19 (d): -CO-NH-CH (C = O) -CH (N -) - S 5.34 (s): Ar-CH (C = O) -O- 5.85 (m): -CO-NH-CH (C = O) -CH (N -) - S6.13: -CH = CH-CH2-N + isomer E 6.72 at 6.80: Ar-H and -S-CH-C (C = N -) - N = 7.03: -CH = CH-CH2-N + 7.33, 7.70, 7.94 and 9, 04: H mobile 9.55 (d) and 9.62 (d): -NH
EXAMPLE 32: The internal salt of (i) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N- (cyanomethyl) N, N-dimethyl 2 (E) -propan-1-aminium ( R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.19 (s): -N + (CH3) 2-CH2-CN 4.24 (d): -CH2 = CH-CH2-N + 4.8 (s) : -N + (CH3) 2-CH2-CN 5.20 (d): -CO-NH-CH (C = O) -CH (N -) - S- 5.33 (s): Ar-CH (C = O) -O- 5.82 (m): -CO-NH-CH (C = O) -CH (N -) - S- 6.13 (m): -CH = CH-CH2-N + isomer E 6.65 to 6.80: Ar-H 6.87: -S-CH-C (C = N -) - N = 7.10: -CH = CH-CH2-N + 7.79 (2H), 9.07 (2H): mobile H 9.54 (d): -CO-NH-CH (C = O) -CH (N -) - S-
EXAMPLE 33: The internal salt of (i) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl N - [(2-methoxyimino) ethyl] 2 (E) -propen -l-aminium (R) or (S) or a mixture (R + S)
Proton NMR (DMSO, 300 MHz, in ppm) 3.19 (s): -N + (CH3) 2-CH2-CH = NO-CH3 3.89 (s): -N + (CH3) 2-CH2-CH = NO-CH3 4.10 to 4.30 (m): -CH = CH-CH2-N + and -N + (CH3) 2-CH2-CH = NO-CH3 5.20 (d): -CO-NH- CH (C = O) -CH (N -) - S- 5.35 (s): Ar-CH (C = O) -O- 5.81 (m, d split after exchange): -CO-NH- CH (CO) -CH (N -) - S- 6.14 (m): -CH = CH-CH2-N + E isomer 6.7 to 6.88: Ar-H and -S-CH-C (C = N -) - N = 7.04: -CH = CH-CH2-N + 7.77 (m): -N + (CH3) 2-CH2-CH = NO-CH3 9.57 and 9.65: -CO -NH-CH (C = O) -CH (N -) - S-
EXAMPLE 34: the internal salt of (i) (cis) (Z) 1- [3- [7 - [[(2-amino 4-thiazolyl) ttcarboxy (3,4-dihydroxy phenyl) methoxy] imino) acetyl) amino ) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-a] pyrimidin-4-ium (R) or (S) or a mixture (R + S),
Proton NMR (DMSO, 300 MHz, in ppm) 3.66 (m) (masked): -S-CH2-C (CH = CH -) = C- 5.14 (d, split): -CO-NH -CH (C = O) -CH (N -) - S- 5.24 (m): -CH = CH-CH2-N + 5.31 (s): Ar-CH (C = O) -O- 5 , 74 (m): -CO-NH-CH (C = O) -CH (N -) - S- cis isomer 6.23 (m): -CH = CH-CH2-N + E isomer 6.65 to 6 , 84 (4H): Ar-H, and -S-CH-C (C = N -) - N = 6.94 (d, split J = 16): -CH = CH-CH2-N + 7.31 (sl): -NH2 9.03 (m): mobile H 7.76 (dd) (1 H): H at 6 of the imidazo [1,2-a] pyrimdin-4-ium ring 8.39 (s) : H in 2 and 3 of the imidazo ring [1,2-a] pyrimdin-4-ium 9.14 (d, split) (1 H): H in 7 of the imidazo ring [1,2-a]
pyrimdin-4-ium 9.39 (d, split) (1 H): H at 5 of the imidazo ring [1,2-a]
pyrimdin-4-ium
Unless otherwise indicated, the products of Examples 7 to 34, previously cited, were prepared by the method described in Example 1, using the corresponding nitrogen base.

EXAMPLE 35: Preparations for injections of formula were produced - Product of Example 7 ........................ 500 mg - Sterile aqueous excipient qsp ................... 5 cm3
PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
In vitro activity, method of dilutions in a solid medium.

A series of dishes are prepared in which the same quantity of sterile nutrient medium is distributed, containing increasing quantities of the product to be studied, then each dish is inoculated with several bacterial strains.

After incubation for 24 hours in an oven at 37 ° C., the inhibition of growth is assessed by the absence of any bacterial development, which makes it possible to determine the minimum inhibitory concentrations (MIC) expressed in micrograms / cm3.

The results are expressed in CMI90 which is the minimum concentration of antibiotic making it possible to inhibit the growth of 90% of the strains studied.

The following results were obtained

Product <SEP> of <SEP> Enterobacteria <SEP> Staphylococci <SEP> Protenus <SEP> Pseudomonas
<tb> Example <SEP> Cloacae <SEP> 1321E <SEP> aureus <SEP> A <SEP> 235 <SEP> Aeroginosa
<tb><SEP> SG <SEP> 5 <SEP> 11 <SEP> 1771 <SEP> m
<tb><SEP> 5 <SEP> 0.08 <SEP> 0.15 <SEP> 0.04 <SEP> 0.3
<tb><SEP> 7 <SEP> 0.04 <SEP> 0.15 <SEP> 0.02 <SEP> 0.6
<tb><SEP> 1 <SEP> 0.15 <SEP> 0.15 <SEP> 0.02 <SEP> 0.15
<tb><SEP> 21 <SEP> 0.15 <SEP> 0.15 <SEP> 0.04 <SEP> 0.6
<tb>

Claims (9)

and the same or different A and A 'represent a hydrogen atom, or one or each of CO2A or CO2A' represents CO2; the wavy line means that the CH2R1 group can be in the E or Z position as well as the salts of the products of formula (I) with mineral or organic acids.

or one of the radicals

R1 represents a radical chosen from the following radicals syn isomer, in the form of R or S or a mixture of R, S, formula in which

CLAIMS 1) The products of general formula (I): 2) The products of formula (I) as defined in claim 1 in which A 'represents a hydrogen hydrogen atom and CO2A represents CO2 3) The products of general formula (I) as defined in any one of claims 1 or 2 in which the configuration of the double bond of the substituent -CH = CH-CH2 R1 is (E). 4) The products of general formula (I) as defined in any one of claims 1 to 3, the names of which follow - the internal salt of t6R- [3 (E), 6alpha, 7béta (Z)]] 7- E3-E7- [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2, 0] oct-2-en-3-yl] 2-propenyl] furo [2,3-b] pyri dinium (R) or (S) or a mixture (R + S), - the internal salt of [ 6R- [3 (E), 6alpha, 7beta (Z)]] 7- [3- [7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] furo [3,2-b] pyridinium (R) or (S ) or a mixture (R + S), - the internal salt of [6R-E3 (E), 6alpha, 7béta (Z)]] 7- [3- [7- [[(2-amino 4-thiazolyl ) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2- propenyl thieno [2,3b] pyridinium isomer (R) and isomer (S), - the internal salt of E6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7 [[2- at mino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3 -yl] 2-propenyl] 4-methoxy pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)] ] 1- [3- [7- [[2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [ 4,2,0] oct-2-en-3-yl] 2-propenyl] 4- (methylthio) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [ 6R- [3 (E), 6alpha, 7béta (Z)]] 1-E3- [7- [[(2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino ] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 2- (methylthio) pyridinium (R) or (S) or d ' a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7- [[2-amino 4-thiazolyl) E Ecarboxy ( 3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4- 4- (aminocarbonyl) p yridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1-E3- [7- [[ (2-amino 4-thiazolyl [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclof4,2,0] oct-2-en-3 -yl] 2-propenyl] 3- 3- (aminocarbonyl) pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3- (E), 6alpha, 7beta (Z)]] 3-amino 1- [3-E7-E [(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8- oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S) or a mixture (R + S), - the salt internal [[6R- [3 (E), 6alpha, 7beta (Z)]] 6-amino 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxyphenyl ) methoxy] imino] acetyl] amino) 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7 [[(2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] a cetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 3-methyl quinolinium (R) or (S) or d 'a mixture (R + S), - the internal salt of E6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4, 2, 0] oct-2-en-3-yl] 2-propenyl] 4 -methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [7 - [(<2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct -2-en-3-yl] 2-propenyl] 6-methyl quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha , 7beta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 6-chloro quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7bé ta (Z)]] 1- [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5 -thia l-azabicyclot4,2,0] oct-2-en-3-yl] 2-propenyl] 6-methoxy quinolinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 3-t3-t7- tt (2-amino 4-thiazolyl) E Ecarboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino ] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] thiazolium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z))] 1- [3- [7- [[2-amino 4-thiazolyl) [[carboxy (3,4- dihydroxyphenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 3-methyl imidazolium (R ) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 5- [3- [7 - [[(2-amino 4-thiazolyl) [[ carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3yl] 2 (E) -propenyl ] imidazo [1,2-b] pyridazinium (R) or (S) or a mixture (R + S), - the internal salt of (#) (cis) (Z) 1- [3- [7 - [[2-amino 4-thiazolyl) [[carboxy (3 , 4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] imidazo [1,2-b] pyridazinium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 1- [3- [7- [ [(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2 -en-3- yl] 2 (E) -propenyl] imidazo [1,2-a] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of (#) ( cis) (Z) 2- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5- thia 1-azabicyclo [4,2,0] oct-2-en-3 yl) 2 (E) -propenyl] imidazo [1,5-a] pyridinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z)] 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4 -dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4,2, 0] oct-2-en-3-yl] 2 (E) -propenyl] 6, 7-dihydro 5H-pyrindinium isomer (R) and isomer (S), - the internal salt of (#) (cis) (Z ) 1- [3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] 2 (E) -propenyl] 1-methyl pyrrolidinium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7beta (Z)]] 1- [3-t7- [[(2-amino 4-thiazolyl (((carboxy (3,4-dihydroxy phenyl) methoxy) imino) acetyl] amino] 2-carboxy 8-oxo 5-thia l-aza-bicyclo [4,2,0] oct-2-en-3-yl] 2-propenyl] 4-aza l-azoniabi cyclo [2,2 , 2] octane (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1- [3- [ 7 [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct -2-en-3-yl] 2-propenyl] 3-hydroxy 4-aza 1-azoniabicyclo [2,2,2] octane (R) or (S) or a mixture (R + S), - the (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carb oxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N, N-trimethyl 2 (E) -propen-1-aminium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3- (E), 6alpha, 7béta ( Z)]] 3- [7 - [[(2amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo [4 , 2,0] oct-2-en-3-yl] N, N-dimethyl N- (2-hydroxy ethyl) 2propen-1-aminium (R) or (S) or a mixture (R + S) , - the internal salt of (#) (cis) (Z) N- (2-amino 2-oxo ethyl) 3- [7 [[(2-amino 4-thiazolyl) E [carboxy (3,4-dihydroxy phenyl ) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl 2 (E) -propen- 1-aminium (R) or (S) or a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N- (cyanomethyl) N, N-dimethyl 2 (E) -propen-1-aminium (R) or (S) or of a mixture (R + S), - the internal salt of (+) (cis) (Z) 3- [7 - [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0] oct-2-en-3-yl] N, N-dimethyl N - [(2-methoxyimino) ethyl ] 2 (E) -propen-1aminium (R) or (S) or a mixture (R + S), - the internal salt of [6R- [3 (E), 6alpha, 7béta (Z)]] 1 - [3- [7- [[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl amino] 2-carboxy 8-oxo 5-thia 1-aza-bicyclo [ 4,2,0] oct-2-en-3-yl] 2-propenyl] 4 - [(methoxyimino) methyl] quinolinium (R) or (S) or a mixture (R + S), - the salt internal of (#) (cis) (Z) l- [3- [7 - [[(2-amino 4-thia zolyl) [[carboxy (3,4-dihydroxy phenyl) methoxy] imino] acetyl] amino] 2 -carboxy 8-oxo 5-thia l-azabicyclo [4,2,0] oct2-en-3-yl] 2 (E) -propenyl] imidazoEl, 2-a] pyrimidin-4-ium (R) or (S ) or a mixture (R + S). 5) Process for the preparation of the products of formula (I) as in claim 1, characterized in that a product of formula (II) is made to act

racemic or optically active syn isomer or a functional derivative of the product of formula (II), in which Ra represents a hydrogen atom or a protecting group for the amino radical, Rb and Rc which are identical or different represent a hydrogen atom or a protective group for the hydroxyl radical, Rd represents a hydrogen atom or the remainder of an easily removable ester group, with a product of formula (III)

or its salts, in which Hal represents a halogen atom, Rf represents a hydrogen atom or the remainder of an easily removable ester group and the wavy line means that the CH2Hal group can be in the E or Z position to obtain a product of formula (IV)

which is made to act with a reagent capable of introducing the radical R1 to obtain a product of formula (V):

that, if desired, one separates into its E or Z isomers or transforms the Z isomers into E isomers and products of formula (V) which, if necessary or if desired, are subjected to one or more of the following reactions, in any order a) cleavage by hydrolysis or by the action of thiourea of all or part of the ester groups or of the protective groups of the amino radical or of the hydroxyl radicals, b) esterification or salification by a base of the carboxyl radical (s), c ) salification of the amino radical with an acid, d) separation of the products in the form of a mixture R, S into R or S. 6) Application as medicaments of the products of formula (I) as defined in any one of claims 1 to 3. 7) Application, as medicaments, of the products of formula (I) as defined in claim 4. 8) Pharmaceutical composition containing, as active principle, at least drugs as defined in claims 6 and 7. 9) As industrial products, the products of formulas (IV) and (V) as defined in claim 5.