IE63171B1 - Derivatives of 1-dethia 2-thia cephalosporanic acid - Google Patents

Abstract

The following 1-dethia-2-thia-cephem cpds., within the scope of formula (I) of the parent patent, their internal salts and acid addn. salts are new: (1) 5-A-2-CF3-thiazolo (4,5-c)pyridinium (6S,7S,Z); A = (3-(7-(((2-amino-4-thiazolyl) (methoxyimino)acetyl) amino)-2-carboxy-8-oxo-4-thia-1- aza-bicyclo(4,2,0) -oct-2-en-3-yl)-2(E)-propenyl; (2) 7-(((2-amino-4-thiazolyl)(methoxy imino)acetyl)amino)-3-(3-(1,4-dihydro-3-formylamino -4-oxo-1-pyridyl)-1 (E).propenyl)8-oxo-4-thia -1-azabicyclo(4,2,O) -oct-2-ene-2-carboxylic acid (6S,7S,Z); (3) 5-8-thieno(3,2-c)pyridinium (6S,7S, Z); B is as A but difluromethoxyimino replaces methoxyimino; (4) 5-B-4-methyl-thieno (3,2-c)pyridinium (6S,7S,Z); (5) 5-C-thiazolo (4,5-c)pyridinium(6S,7S, Z); C is as A but fluoromethoxyimino replaces methoxyimino; (6) 5-C-4-methyl-thieno (3,2-c)pyridinium (6S,7S,Z); (7) 5-C-thieno(3,2-c)pyridinium (6S,7S,Z); (8) 5-A-thiazolo (4,5-c)pyridinium(6S,7S, Z); (9) 5-A-2-methyl -1H-imidazolo(4,5-c) pyridinium(6S,7S,syn); (10) 5-A-2-phenyl-oxazolo(4,5-c) pyridinium(6S,7S,syn); (11) 5-A-2-ethyl-thiazolo(4,5-c) pyridinium(6S,7S,syn); (12) 5-B-thiazolo(4,5-c)pyridinium(6S, 7S,syn); (13) 2-amino-5-B-thiazolo(4,5-c) pyridinium(6S,7S,syn); (14) 7-c-thieno(2,3-b)pyridinium; (15) 1-A-1-(2-(5-nitro -1H-imidazol-1-yl) ethyl)pyrrolidinium(6S,7S,Z); (16) 7-(3-(7-(((5-amino -1,2,4-thiadiazol -3-yl)(methoxyimino)acetyl) amino)-2-carboxy-8-oxo -4-thia-1-azabi cyclo(4,2,0)oct-2 -en-3-yl)-2(E) - propenyl)thieno(2,3-b) pyridinium(6S,7S,syn); (17) (2,2-dimethyl -1-oxopropoxy)methyl 7-(((2-amino-thiazol-4-yl) (methoxyimino)acetyl) amino)-8-oxo-3-(3- ((1,3,4-thiadiazol-2-yl) thio)-1(E)-propenyl) -4-thia-1-azabi cyclo-(4,2,O) oct-2-en-2-carboxylate.

Description

In Irish Patent Application No. 336/85, filed on 12 February, 1985 the Applicant Company described new derivatives of l-dethia-2-thia-cephalosporanlc acid, the process for their preparation and their use as medicaments.

Irish Patent Application No. 336/85 thus has as its subject products with the general formula (I): (i) ft in which R represents either a radical Ra-C-NH- in which Ra ft Rl. represents an organic radical, or a radical N»CH=N- In which Ri and Rj, identical or different, represent a hydrogen atom or an aliphatic or aromatic hydrocarbon radical, a heterocyclic radical, or Ri and Rj with the nitrogen atom to which they are attached, form a possibly substituted cyclic radical, or a radical Rb-NH- In which Rb represents a carbocyclic or heterocyclic aryl radical, possibly substituted.

R| represents, either : a) a radical -Z-R2 in which R2 is an alkyl, alkenyl or alkytnyl radical, possibly substituted or interrupted by a hetereoatom and Z represents a sulphur atom, possibly oxided, or a selenium or an oxygen atom, or -NH- , b) a radical Za-Rj In which R3 represents a carbocyclic or heterocyclic aryl radical, possibly substituted or a quaternary ammonium possibly substituted, and Zfl represents a methylene radical, an atom of sulphur, selenium or oxygen, or -NH-, or Za represents a simple bond, or Za represents a radical -CH2-Sc) an alkyl, alkenyl or alkynyl radical having from 2 to 8 carbon atoms, possibly substituted or interrupted by a heteroatom, d) a halogen atom, a nitrile, azido, thiocyanato or isothiocyanato radical, e) an azidomethyl, an amino or a mono- or disubstituted methylamino, a thlocyanatomethyl, Isothlocyanatomethyl, or carbamoyloxymethyl radical, represents a hydrogen atom or a methoxy radical, A represents a hydrogen atom, an equivalent of an alkali metal, alkaline-earth, magnesium, ammonium or of an aminated organic base, or A represents an ester group or CO2A represents a group CO2-· Π2 represents an integer, 0, 1 or 2, as well as the salts which are the products of formula (I) with mineral or organic acids.

The products with the formula (I) can appear in racemic or optically active form.

Among the products with the formula (I), the subject of Irish Patent Application No. 336/35, is more especially the products answering to the formula (I*): NH syn Isomer, in which R’ represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, possibly substituted, R’^ represents either : a) a radical Z'-R*2 in which R*2 represents an alkyl radical having from 1 to 4 carbon atoms, possibly Interrupted by a heteroatom and possibly substituted by an amino radical, a free, esterified or salified carboxy radical, or by an aryl or arylthio radical, possibly substituted, Z’ represents a sulphur or oxygen atom ; b) a radical Z’a-R’3 in which R’3 represents a phenyl radical, or a possibly substituted heterocyclic aryl radical, or a possibly substituted ammonium radical, and Z* represents a methylene radical, -CH2-S- or a sulphur, oxygen or selenium atom, or a simple bond ; c) an alkyl or alkenyl radical having from 2 to 4 carbon atoms, possibly interrupted by an oxygen atom or substituted by an aryl radical, d) an azidomethyl, aminomethyl or carbamoyloxymethyl radical ; represents the numeral 0 or 1 and A has the value Indicated above.

There is also described in the principal patent application a process for the preparation of the products with the general formula (1) as defined above, as well as variants of this process.

In the parent Irish Patent Application No. 2145/86, products are described coming within the general formula (I) of Patent Application No. 336/85, and corresponding to the general formula (IA): (Ia) in which R represents either a radical Ra-C-NH- in which Ra Ri. represents an organic radical, or a radical N-CH-N-, in Rj which Ri and Rj, identical or different, represent a hydrogen atom, an aliphatic or aromatic hydrocarbon radical or a heterocyclic radical, or R1 and Rj with the nitrogen atom to which they are bonded, form a cyclic radical, possibly substituted, or a Rb-NH- radical in which Rb represents a carbocyclic or heterocyclic aryl radical, possibly substituted, 'A'-R or a radical : Rl A-'-r R'a in which formulae R’A and R’g being identical or different, represent either a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, ZA represents a simple bond, a possibly oxided sulphur atom or an oxygen atom, R^A represents a possibly substituted carbocyclic or heterocyclic aryl radical, or a possibly substituted quaternary ammonium or an acetyl, carbamoyl, alkoxycarbonyl, alkyl or haloalkyl having 1 to 4 carbon atoms, nitrile or azido radical.

R^ represents a hydrogen atom or a methoxy radical.

A represents a hydrogen atom, an equivalent of alkali-metal, alkalineearth, magnesium, ammonium or of an organic amino base, or A represents an ester group or CO2A represents a group CO2", N2 represents an integer 0, 1 or 2, as well as the salts of the products with the formula (1^) with mineral or organic acids.

Among the acids with which the amino group or groups or the quaternary ammonium group of the products (IA) may be salified, there can be cited among others, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzene sulphonic, p-toluene sulphonic, trifluoromethanesulphonic, formic, phosphoric, sulphuric, hydrochloric, hydrobromic and hydriodic acids.

Among.the products with the formula (1^), the subject of the present application is more especially the products answering to the isomer syn, in which R* represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical having at the most 6 carbon atoms, possibly substituted, or an aryl radical, has the value indicated above and R*3A represents a phenyl radical, a possibly substituted heterocyclic aryl radical, a possibly substituted quaternary ammonium radical, or an acetyl or carbamoyl radical.

The subject of the parent Irish Patent Application No. 336/85 is also a process for the oreparation of the products witn the general formula (IA) as defined above, characterized in that a product with the formula (VII’) : OH (VII’) in which and A have the significance indicated above and R^ represents either an amino radical, free or protected by a mono- pr divalent protector group, or R^ represents the radical R, R having the significance indicatad above, is treated either with a halogenation agent or with a sulphonation agent and then with triphenylphosphine, or with a reagent with the formula PiOAlk)^ in which Aik represents an alkyl radical having from 1 t'o 4 carbon atoms, so as to obtain either a product with the formula (VIII S3 (VIII’A) in which R^, R^, and A have th& previous significance and X represents the residue of an anion, or a product with the formula (VIII^) : ' in which R^, R^, A and Aik have the previous significance, which products with the formulae (VIIIor (VIIIA) are, if desired, treated first with a strong base then with an alkyl halogenide with the formula hal-R^ in which hal represents a halogen atom and R^ has the values of R’^ other than a hydrogen atom, In order to obtain the products with the formulae (VIII*B) or (VIIIB) : in which formulae R’^ has the significance indicated above and which products with the formulae (VIII’β) and (VIII"B) are treated with a product with the formula : R’ Gp In which R’B has the value indicated above and Gp represents a protector group for the hydroxyl radical, in order to obtain a product with the formula (IX’) : (IX’) in the form of a mixture of the E and Z isomers or in the form of the E or Z isomer, on which product with the formula (IX*) the following reactions are carried out in any order : a) cutting off the protector group Gp : b) when R^ represents an amino radical protected by a mono- or divalent protector group, elimination of this protector group and treatment of the product in which R^ represents an amino radical, either by an acid with the formula (IVa) : RaC02. H (IVa) in which formula Ra represents an organic group, or by a functional’ derivative of this acid, or by a product with the formula (IVb): Ri N-CH=Xb (IVb) Rj/ In which Ri and Rj have the significance Indicated above and Xb represents a sulphur or oxygen atom, or by a product with the formula (IVc) : Rb-Xc (IVc) in which Rb has the significance indicated in the principal application and Xc represents a halogen atom : c) separation of the E and Z isomers : in order to obtain a product with the formula X’ : (X’) in which RA has the significance indicated above, on which product with the formula X', either a reactive derivative of the group is made to act in order to obtain a product with the formula (XI’A) : (XI’A) or a derivative of an activation group of the hydroxyl radical and then a derivative or a reactive derivative of the group RjA is made to act in order to obtain a product with the formula (XI*g) : or a derivative of an activation group of the hydroxyl radical then the product with the formula HS-R-j^ or a reactive derivative of this product is made to act, in order to obtain a product with the formula (XI’c) : KJ* which products with the formula (XI*A), (XI’g) or (XI'q), if necessary or if desired, are submitted to any one or more of the following reactions in any order : a) cutting off by hydrolysis, hydrogenolysis or by action of thiourea of all or part of the protector group or groups ; b) esterification or salification by a base of the carboxy or sulpho group or groups ; c) salification by an acid of the amino group or groups ; d) resolution of the molecuse in order to obtain an optically active product : e) oxidation of the sulphur atom in position 2 of the isocepheme ring.

The halogenation agent which is preferably used is thionyl chloride in a chlorated solvent such as methylene chloride or in dimethyl formamide. There is then obtained intermediately a product with the formula (VII’a) : <( (Vll’a) Other halogenation reagents can also be used such as phosphorus pentachloride, phosphorus oxychloride or tosyl chloride.

The sulphonation agent can, for example, be trifluoromethy1sulphonlc anhydride. The operation can then optionally be done In the presence of a base, preferably 2,6-dimethylpyridine or lutidine. In a general way, the sulphonation products are unstable and are not isolated.

The action of triphenylphosphine or of the reagent with the formula P(0Alk)3 in which Aik preferably represents an ethyl radical is realized in the usual conditions. The action of the triphenylphosphine or of the reagent with the formula P(0Alk)3 is preferably realized in the presence of silica on the halogenated product with the formula (VII^): In general the operation is done by heating a solvent such as toluene or chloroform to reflux. When operating on a product with the formula (VII*), the action of the triphenylphosphine or of the product with the formula P(0Alk)3 is preferably carried out at the same time as the sulphonation, because of the instability of the sulphonation products.

The strong base with which the products of formula (VIII*A) and (VIIIa) are possibly treated, can be chosen from potassium or lithium tertbutylate, lithium diisopropylamide, and lithium bis-trimethylsilyl amide.

The alkyl halogenlde with the formula hal-RA le preferably the chloride or the bromide.

The action of the product with the formula on the products with the formulae (Vlll’g) or (VIIIg) is preferably carried out in a chlorated solvent such as methylenechloride. The operation can be done in the presence of a relatively weak base such as triethylamine or the DBU (l,8-diazabicyclo[5,4,0]undec-7-ene) or the DBN (1,5-diazabicyclo(4,3,0]non-5-en^. The operation is then done at ambient temperature or on heating.

The operation can also be done in the presence of a strong base such as tert-butyl-lithium or an alcoholate such as lithium tertbuty late, lithium bis trimethylsilylamide or lithium dlisopropylamide. The operation is then done at a low temperature. The reaction can, for example, be conducted from -70°C to the ambient temperature.

The protector group which Gp represents can be a silyl group such as trimethylsilyl or tert-butyl dimethylsilyl. A group such as tetrahydropyranyl can however be used.

The cutting off of the protection group Gp is carried out in standard conditions. The operation is done, for example, in the presence of an acid or of a fluoride ion introduced by hydrofluoric acid or by tetrabutylammoniumfluoride.

When a product with the formula (IX*) is obtained in which represents an amino radical, In a preferred way of executing the process, the product with the formula (IX*) is treated with a functional derivative of a product with the formula (IVa). This functional derivative can be, for example, a halogenide, a symmetrical or mixed anhydride, an amide or an activated ester.

As an example of a mixed anhydride, there can be cited, for example, the one formed with isobutyl chloroformate and the one formed with pivaloyl chloride and the mixed carboxylic sulphonic anhydrides formed, for example, with paratoluenesulphonyl chloride. As an example of an activated ester, there can be mentioned the ester formed with 2,4-dinitrophenol and the one formed with hydroxybenzothiazole.

As an example of a halogenide, there can be cited the chloride or the bromide.

There can also be cited the acid azide or the acid amide.

The anhydride can be formed in situ by the action of NN’-dieubstituted carbodiimide, for example, Ν,Ν-dicyclohexylcarbodiimide.

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

When an acid halogenide ia used, and In a general way when a molecule of a hydrohalic acid is liberated in the course of the reaction, the reaction is preferably carried out In the presence of a base such as sodium or potassium hydroxide, the carbonates and acid carbonates of sodium or potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is in general lower than or equal to the ambient temperature.

In a preferred method of carrying out the process, the products with the formula (IV^) are converted into reactive derivatives such as the acid halogenides, which can be prepared by making the products with the formula (IVg) react with a halogenation agent such as phosgene, oxalyl chloride or thionyl chloride. Complexes can also be prepared with the dialkyl sulphates, preferably dimethyl sulphate.

The operational conditions for such reactions are known to an expert. Such reactions are described, for example, in the French Patent 2,073,338.

In a preferred way of carrying out the process, the halogens used in the products with the formula (IVC) are the chloride or the fluoride. It is preferred to use a derivative of pyridinium. The counter ion is then preferably an iodide, tosylate, bromide, or BF4 ion.

The preparation of the products with the formula (IVC) and the reaction of these products with the products of formula (IX’) are carried out in the conditions described, for example, in the Journal of Medicinal Chemistry 1982, Vol. 25, N° 4, p. 457-469.

The optional subsequent reaction of separation of the E and Z isomers is carried out according to the usual techniques. It is preferred to operate by chromatography on silica.

The conversion of the products with the formula X' into products with the formula XIA is also carried out according to standard methods.

The derivative of the group which is used can, for example, be a halogenide derived from a carbocyclic or heterocyclic aryl radical, possibly substituted., It is then preferred to use the fluoride when represents, for example, an acetyl or carbamoyl radical. The operation is done for preference in the presence of a reactive derivative such as an anhydride or a halogenlde.

The conversion of the products with the formula X* into products with the formula XI’g Is preferably carried out according to the following conditions : an activated derivative of the hydroxyl radical is prepared, for example, by the action of a derivative of a sulphonic acid such as the anhydride of trifluoromethyl sulphonic acid. The operation Is done at low temperature or at ambient temperature.

When R-ja does not represent a quaternary ammonium, it is . preferred to operate in the presence of a base.

The conversion of the products with the formula X’ into products with the formula XI’q Is carried out under similar conditions.

There Is first prepared an activated derivative of the hydroxyl group in the previously stated conditions, notably starting with trifluoromethyl sulphonic acid anhydride. The action of the product with the formula HSRj is preferably carried out in the presence of an organic base such as 2,6-dlmethylpyridine and of a soluble source of Iodide. The operation is then preferably done In the presence of tetra-alkylammonium Iodide.

The products with the formulae XI’A, XI’g and XIconstitute products with the formula IA when they do not include any protector group and when A does not represent, among the easily cleavable ester groups, one of those which it is desired to eliminate.

In the other cases, the action on the product with the formulae XI*A, XI’g or XI*β of one or more hydrolysis or hydrogenolysis agents or of thiourea has the object of eliminating the protector group or groups which the different products can include.

The nature of the reagents to be employed in all these cases is well known to an expert. Examples of such reactions are given further on in the experimental part.

A non-exhauetive enumeration is given further on of the means which can be employed to eliminate the different groups.

The elimination of the protector group or groups R’p can be effectuated by hydrolysis, the latter being acid, basic or utilizing hydrazine.

It Is preferred to use acid hydrolysis to eliminate the alkoxy and cycloalkoxycarbonyl groups, possibly substituted, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, the possibly substituted aralkoxycarbonyl groups such as benzyloxycarbonyl, the trityl, benzhydryl, tert-butyl or 4-methoxybenzyl groups.

The acid preferably used can be chosen from the group constituted by hydrochloric, benzene sulphonic or para-toluene sulphonic, formic or trifluoroacetic acids. Other mineral or organic acids can however be used.

Basic hydrolysis is preferentially used to eliminate acyl groups such as trifluoroacetyl.

The base preferably used is a mineral base such as sodium or potassium hydroxide. There can also be used magnesia, baryta or a carbonate or acid carbonate of an alkali metal such as the carbonates and acid carbonates of sodium or potassium or other bases.

Sodium or potassium acetate can also be used.

Hydrolysis utilizing hydrazine is used for preference to eliminate groups such as phthaloyl.

Certain groups can also be eliminated by the zinc-acetic acid system (for the trichloroethyl group); the benzhydryl and benzyloxyoxycarbonyl groups are preferably eliminated by hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiourea in a neutral or acid medium according to the type of reaction described by MASAKI, J.A.C.S., 90, 4508, (1958).

Other deprotection methods known in the literature can also be used.

Among the preferred groups, there can be cited the formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl, and trityl groups. The trityl and chloroacetyl radicals are particularly preferred.

The acid preferably used is trifluoroacetic acid.

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

The salification can, for example, be obtained by the action on a product in the form of an acid or on a solvate, for example the ethanol solvate or a hydrate of this acid, of a mineral base such as the hydroxide of sodium or potassium, the carbonate or acid carbonate of sodium or potassium. There can also be used the salts of mineral acids such as the tri-sodic phosphate. The salts of organic acids can also be called upon.

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

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

As examples of such organic acids, there can be mentioned formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproie, chloropropionic, crotonic, phenylacetic, 2-thienylacetic, 3-thienylacetlc, 4-ethylphenylacetic and glutaric acids, also the raonoethyl ester of adipic acid and hexanoic, heptanoic, decanolc, oleic, stearic, palmitic, 3-hydroxypropIonic, 3-methoxypropionic, 3-methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric, 3-phenoxybutyric, 4-ethylbenzoic and l-propylbenzolc acids.

However, the sodium salts used for preference are the acetate, the 2-ethylhexanoate or the diethylacetate.

The salification can also be obtained by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, Ν,Ν-dimethylethanolamine, tris(hydroxymethyl)amino methane, methylamine, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine and benzylamine.

It can also be obtained by the action of arginine, of lysine, of procaine, of histidine and of 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 the amorphous or the crystallized form according to the reactlonal conditions employed.

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

The salification of the products by mineral or organic acids is carried out in the usual conditions.

The optional esterification of the products Is carried out In standard conditions. The operation can In general be done by making the acid with the formula (1^) react with a derivative with the formula : Z’Rs in which Z represents a hydroxyl radical or a halogen atom such as chlorine, bromine or iodine, and Rg designates the ester group to be introduced, of which group a non-exhaustive list appears above. In certain cases, it can be advantageous to carry out an esterification on a product of which the amine Is blocked before removing the protector group of the amine.

The optional resolution of the compounds with the general formulae XI’A· XI’B, XI’c can be carried out by means of an optically active carboxylic or sulphonic organic acid, such as tartaric, dibenzoyltartarlc, camphosulphonic or glutamic acid, the decomposition of the salt so obtained being effectuated by means of a mineral base such as sodium bicarbonate or an organic base such as a tertiary amine such as triethylamine. Furthermore, It Is possible to use an optically active base .

The optional oxidation of the products with the formula XI’A, XI’B or XI’c can be effectuated by means of oxygen, peroxides, hydroperoxides, peracids or hydrogen peroxide. It is advantageous to sensitise the reaction by light. The reagents can be a mixture of organic and mineral acids. It is preferable to use metachloroperbenzoic acid. The reactional conditions are known to an expert. Such conditions are, for example, set out in the French Patent 2,387234.

The new compounds disclosed in the present application, which fall within the scope of formula (IA) of the parent Patent Application No. 2145/86 but are not disclosed therein, are as follows: The products corresponding to the general formula (I) of the principal patent of which the names follow : - 5— [3—[7—[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]-2-(trifluoromethyl)-thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 7- [ [ (2-amino-4-thiazolyl)(methoxyimino)-ace tyl]amino]-3-[3-[1,4dihydro-3-( formylamino)-4-oxo-l-pyridyl]-l(E)-propenyl]-8-oxo-4-thia1- azabicyclo^ .2.0]oct-2-ene-2-carboxylic acid (6S)(7S)(Z). - 5-[3-[7-[[(2-amino-4-thiazolyl)(difluoromethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-([(2-amino-thiazol-4-yl)(difluoromethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thla-l-azablcyclo (4.2.0]oct-2-eit-3-yl]-2(E)propenyl]-4-methylthleno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [( 2-amino-thiazol-4-yl)(fluorome'thoxyimino)-acetyl]-amino]l -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4.3.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [(2-amino-thiazol-4-yl)(fluorometHdxyimlno)-acetyl]-amino]| -2-carboxy-8-oxo-4-thia-l-azabicyclo (4.2.0]oct-2-en-3-yl]-2(E)propenyl]-4-methylthieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-([(2-amIno-thiazol-4-yl)(fluoromethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-(((2-amino-thiazol-4-yl)(me thoxyimino)-ace tyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-(((2-amino-thiazol-4-yl)(methoxyimino)-ace tyl]-amino]-2carboxy-8-oxo-4-thia-l-azablcyclo(4.2.0]oct-2-en-3-yl]-2(E)-propenyl]~ 2- methyl-lH-imldazolo[4.5.c] pyridinium (6S)(7S) syn. - 5-(3-(7-([(2-amlno-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2car boxy-8-ox 0-4-thia-1-azablcyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]~ 2-phenyl-oxazolo[4.5.c] pyridinium (6S)(7S) syn. - 5-(3-(7-([(2-amino-thiazol-4-yl)(raethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]~ 2-ethylthiazolo[4.5.c] pyridinium (6S)(7S) syn. - 5-(3- [7-( ((2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo(4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-aminothiazolo(4.5.c] pyridinium (6S)(7S) syn. - 5-(3-(7-([(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-25 carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S) syn. - 7-(3-(7-(((2-amino-4-thi azol)(fluorome thoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thieno[2.3.b] pyridinium. - l"[3-[7-[[(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-1-azablcyclo(4.2.0]oct-2-en-3-yl]-2(E)-propenyl]l-(2-(5-nitro-lH-imidazol-l-yl)-ethyl] pyrrolidinium (6S)(7S)(Z). - 7-(3-(7-( ((5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)-acetyl]amino ]-2-carboxy-8-oko-4-thia-l-*azablcyclo [4.2.0 ] oct-2-en-3-yl ] -2 (E )15 propenyl]-thieno[2.3.b] pyridinium. (6S)(7S). - .7-(((2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-8-oxo-3-(3((l,3,4-thiadiazol-2-yl)-thlo]-l(E)-propenyl]-4-thia-l-azabicyclo[4.2.0] oct-2-en-2-carboxylate of (2,2-dimethyl-l-oxo-propenyl)methyl (5S)(7S) syn (E). in the form of internal salt or of salt with the mineral or organic acids.

The invention has more particularly as its subject the products of which the names follow : - 5-(3-(7-(((2-amino-thiazo1-4-yl)(methoxyimino)-ace tyl]-amino]-225 carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 5-[3-[7-[[(2-amino-thiazol-4-yl)(d ifluorome thoxyimino)-acetyl]amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo(4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4.5.c] pyridinium (6S)(7S) syn. — 7-(3-(7-([(2-amino-4-thiazol)(fluoromethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azahicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thieno(2.3-b] pyridinium (6S)(7S) syn.

Finally, the invention has quite particularly as Its subject the product of which the name follows : — 5-(3-(7-(((2-amino-thiazol-4-yl)(difluoromethoxyimino)-acetyl]amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo (4.2.0] oct-2-en-3-yl]-2(E)propenyl]-thiazolo(4.5.c] pyridinium (6S)(7S) syn.

The products which are the subject of the present application for a Patent of addition can be prepared by the process described in the parent Application No. 2145/86, which process is recalled above.

Like the products with the general formula (I) described in Irish Patent Application No. 336/85, the products of the present application for a Patent of addition possess a very good antibiotic activity on gram(+) bacteria, such as the staphylococci, the streptococci and, In particular, on the penicillin-resistant staphylococci. Their efficacy on the gram(-)· bacteria, notably, on the coliform bacteria, the klebelella, salmonella and proteus is particularly remarkable.

These properties make the said products suitable to be used as medicaments in the treatment of affections by sensitive germs and, notably, in those of the staphylococci, such as staphylococcal septicaemia, facial or cutaneous malign staphylococcemia, pyodermatltis, septic or suppurating wounds, anthrax, phlegmons, erysipelas, primitive or poet-influenzal acute staphylococcemia, bronchopneumonia, pulmonary suppuration.

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

The present invention therefore also has as subject, as medicaments and particularly as antibiotic medicaments, the products corresponding to the general formula (I) of Patent Application No. 336/85, of which the names follow: - 5-(3-(7-([(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-(trifluoromethyl)-thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 7-(((2-amino-4-thiazolyl)(raethoxyimino)-acetyl]amino]-3-(3-[1,4dlhydro-3-(formylamino)-4-oxo-l-pyridyl]-l(E)-propenyl]-8-oxo-4-thia1-azabicyclo[4.2.0]oct-2-ene-2-carboxyllc acid (6S)(7S)(Z). - 5-(3-(7-(((2-amino-4-thiazolyl)(difluor omethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thleno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-[7-[[(2-amino-thiazol-4-yl)(difluoromethoxyimino)-acetyl]-amino ] -2-carboxy-8-oxo-4-thia-1-az abicyclo [ 4.2.0 ]o ct-2-en-3-yl]-2(E)propenyl]-4-methylthieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-[3-[7-[[(2-amino-thi azol-4-yl)(fluorome thoxyimino )-ace tyl]-amino] -2-carboxy-8-oxo-4-thia-l-azablcyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4.3.c] pyridinium (6S)(7S)(Z). - 5-[3-[7-[[(2-amino-thiazol-4-yl)(fluoromethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-. propenyl]-4-methylthieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-[3-[7-[[(2-amino-thi azol-4-yl)(fluorome thoxyimino)-ace tyl]-amino] -2-carboxy-8-oxo-4-thla-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thieno[3.2.c] pyridinium (6S)(7S)(Z). - 5—[3—[7-[[(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thlazolo[4.5.c] pyridinium (6S)(7S)(Z). - 5—[3—[7—[[(2-amino-thlazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-methyl-lH-imidazolo[4.5.c] pyridinium (6S)(7S) syn. - 5—[3—[7—[[(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thla-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-phenyl-oxazolo[4.5.c] pyridinium (6S)(7S) syn. - 5-[3-[7-[[(2-amino-thiazol-4-yl)(me thoxyimino)-ace tyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-ethylthiazolo[4.5.c] pyridinium (6S)(7S) syn. - 5—[3—[7—[[(2-amino-thiazol-4-yl)(raethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azablcyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-aminothlazolo[4.5.c] pyridinium (6S)(7S) syn. - 5—[3—[7—[[(2-amino-thiazol-4-yl)(raethoxyimlno)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S) syn. - 7—[3—(7—([(2-amino-4-thiazol)(fluororaethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thieno[2.3.b] pyridinium. - 1-[3-[7-[[(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]—2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]l-[2-(5-nitro-lH-imidazol-l-yl)-ethyl] pyrrolidinium (6S)(7S)(Z). - 7-(3-(7-(((5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)-acetyl]amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thieno[2.3.b] pyridinium. (6S)(7S). - 7-([(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-8-oxo-3-[3((1,3,4-thiadiazol-2-yl)-thio]-l(E)-propenyl]-4-thia-l-azabicyclo(4.2.0]oct-2-en-2-carboxylate of (2,2-diraethyl-l-oxo-propenyl)methyl (5S)(7S) syn (E). in the form of internal salt or of salt with the mineral or organic acids .

The invention has more particularly as its subject as medicaments the products : - 5-(3-(7-(((2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2ca r b oxy-8- oxo-4- thla-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]-thiazolo(4.5-c] pyridinium (6S)(7S)(Z). - 5-(3-(7-([(2-amino-thlazol-4-yl)(difluoromethoxyimino)-acetyljamino]-2-carboxy-8-oxo-4-thia-l-azabicyclo(4.2.0]oct-2-eo-3-yl]-2(E)propenyl]-thiazolo[4,5.c] pyridinium (6S)(7S) syn. - 7-(3-(7-(((2-amlno-4-thiazol)(fluoromethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azablcyclo(4.2.0]oct-2-en-3-yl]-2(E)-propenyl]thieno(2.3.b] pyridinium (6S)(7S) syn. and quite specially the product of which the name follows : - 5-(3-(7-([(2-amino-thIazol-4-yl)(difluoromethoxyimIno)-acetylJamino]-2-carboxy-8-oxo-4-thia-l-azabicyclo(4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thlazolo(4.5.c] pyridinium (6S)(7S) syn.

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

These compositions can be administered by oral, rectal, parenteral, intramuscular route, or by local route as topical application on the skin and the mucosa.

In particular, the products with the formula (I) in which A represents a cleavable ester such as the ester of propionyloxymethyl can be administered by oral route.

They can be solid or liquid and are presented in the pharmaceutical forms currently utilized in human medicine such, for example, as plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels : they are prepared according, to the usual methods. The active principles can be Incorporated with the excipients usually employed In these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty bodies of animal or vegetable origin, paraffin derivatives, glycols, the various wetting, dispersing or emulsifying agents, and preservatives.

These compositions can, in particular, be presented in the form of a powder Intended to be dissolved extemporaneously in an appropriate vehicle, for example, sterile apyrogenic water.

The dose administered is variable according to the affection treated, the subject concerned, the administration route and the product considered. It can for example, be between 0.500 g and 1 g three times per day, by Intramuscular route for the products of examples 8 or 12.

The products with the formula (IA) can also be used as disinfectants for surgical Instruments.

The products with the formula VII' used at the start of the preparation process for the products with the formula Ia can be prepared according to the process described in the principal patent.

In addition to the products described hereafter In the examples which illustrate the Invention, nevertheless without limiting it, the following products constitute products which can be obtained within the scope of the present invention.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION.

Activity in vitro, method of dilutions in liquid medium.

A series of tubes is prepared in each of which t.he same quantity of sterile nutritive medium is distributed. In each tube, increasing quantities of the product under study are distributed, then each tube is inoculated with a bacterial strain. After incubation in an oven at 37°C for twenty-four hours, the inhibition Of growth is evaluated by transillumination, which enables the minimal inhibiting concentrations (M.I.C) to be determined, expressed in ug/cm .

The following results were obtained : V* <1 STRAINS Product Example Product Example Product Example Product Example Product Example Product Example 1 2 3 4 5 6 STAPHYLOCOCCUS AUREUS SG511 1.200 2.500 0.150 0.080 0.300 0.150 STAPHYLOCOCCUS AUREUS SG511 S 5.000 2.500 0.150 0.150 0.600 0.300 STAPHYLOCOCCUS AUREUS 285 1.200 2.500 0.150 0.150 0.300 0.150 STAPHYLOCOCCUS AUREUS 54146 5.000 2.500 0.300 0.150 0.600 0.300 STREPTOCOCCUS PYOGENES A 561 0.020 <= 0.010 <= 0.010 <= 0.010 0.020 <= 0.010 STREPTOCOCCUS PYOGENES 77 A 0.020 <= 0.010 <= 0.010 <= 0.010 <= 0.010 <= 0.010 STREPTOCOCCUS FAECIUM M 78 L > 20.000 > 20.000 > 20.000 > 20.000 > 20.000 > 20.000 ESCHERICHIA COLI UC 1894 0.040 0.150 <= 0.010 <= 0.010 <= 0.010 <= 0.010 ESCHERICHIA COLI 0 78 0.150 1.200 <= 0.010 0.020 <= 0.010 <= 0.010 ESCHERICHIA COLI TEM 0.600 2.500 0.020 0.080 0.020 0.040 ESCHERICHIA COLI 1507 E 0.080 0.150 <= 0.010 <= 0.010 <= 0.010 <= 0.010 ESCHERICHIA COLI DC 0 0.600 2.500 0.040 0.080 0.020 0.040 ESCHERICHIA COLI DC 2 0.080 1.200 <= 0.010 <= 0.010 <= 0.010 <= 0.010 SALMONELLA TYPHIMURIUM MZ 11 0.150 1.200 <= 0.010 0.040 0.020 0.020 KLEBSIELLA PNEUMONIAE 52145 0.600 5.000 0.040 0.150 0.040 0.040 KLEBSIELLA AEROGENES 1082 E 20.000 > 20.000 0.150 1.200 5.000 2.500 KLEBSIELLA AEROGENES 1522 E 0.600 2.500 0.300 0.600 0.150 0.150 ENTEROBACTER CLOACAE P 99 > 20.000 > 20.000 2.500 2.500 5.000 5.000 ENTEROBACTER CLOACAE 1321 E 0.300 1.200 0.020 0.080 0.040 0.040 SERRATIA RG 2532 2.500 20.000 0.300 0.300 0.150 0.300 PROTEUS MIRABILIS A 235 0.300 0.600 0.020 0.040 0.040 0.080 PROTEUS VULGARIS A 232 2.500 2.500 0.040 0.040 0.020 0.080 PROVIDENCIA DU 48 2.500 5.000 0.600 0.300 0.600 0.150 STRAINS Product Example 7 Product Example o STAPHYLOCOCCUS AUREUS SG511 0.150 o 0.150 STAPHYLOCOCCUS AUREUS SG511 S 0.150 0.150 STAPHYLOCOCCUS AUREUS 285 0.150 0.150 STAPHYLOCOCCUS AUREUS 54146 0.150 0.300 STREPTOCOCCUS PYOGENES A 561 <= 0.010 <= 0.010 STREPTOCOCCUS PYOGENES 77 A <= 0.010 <= 0.010 STREPTOCOCCUS FAECIUM M 78 L > 20.000 20.000 ESCHERICHIA COLI UC 1894 <= 0.010 <= 0.010 ESCHERICHIA COLI 0 78 <= 0.010 <= 0.010 ESCHERICHIA COLI TEM 0.020 <= 0.010 ESCHERICHIA COLI 1507 E <= 0.010 <= 0.010 ESCHERICHIA COLI DC 0 0.020 <= 0.010 ESCHERICHIA COLI DC 2 <= 0.010 <= 0.010 SALMONELLA TYPHIMURIUM MZ 11 <= 0.010 <= 0.010 KLEBSIELLA PNEUMONIAE 52145 0.040 <= 0.010 KLEBSIELLA AEROGENES 1082 E 0.300 2.500 KLEBSIELLA AEROGENES 1522 E 0.080 0.040 ENTEROBACTER CLOACAE P 99 2.500 5.000 ENTEROBACTER CLOACAE 1321 E 0.020 <= 0.010 SERRATIA RG 2532 0.150 0.080 PROTEUS MIRABILIS A 235 0.020 0.020 PROTEUS VULGARIS A 232 0.020 0.020 PROVIDENCIA DU 48 0.300 0.300 Product Product Product Product Example Example Example Example 9 10 11 12 0.600 0.150 0.300 0.300 0.600 0.150 0.300 0.300 0.300 0.150 0.150 0.150 1.200 0.150 0.300 0.600 <= 0.010 <= 0.010 0.020 <= 0.010 <= 0.010 <= 0.010 <= 0.010 <= 0.010 > 20.000 > 20.000 > 20.000 10.000 0.080 <= 0.010 <= 0.010 <= 0.010 0.080 0.150 <= 0.010 <= 0.010 0.300 0.600 0.020 0.040 0.040 <= 0.010 <= 0.010 <= 0.010 0.300 0.600 0.040 0.040 0.040 <= 0.010 <= 0.010 <= 0.010 0.150 0.150 <= 0.010 0.020 0.300 0.300 0.040 0.040 20.000 10.000 0.600 1.200 1.200 1.200 0.080 0.150 > 20.000 5.000 5.000 2.500 0.600 0.150 0.040 0.040 2.500 2.500 0.300 0.300 0.300 0.300 0.040 0.040 0.300 0.300 0.150 0.040 1.200 5.000 0.600 1.200 <- Q STRAINS Product Example Product Example 13 14 STAPHYLOCOCCUS AUREUS SG511 0.300 0.150 STAPHYLOCOCCUS AUREUS SG511 S 0.300 0.150 STAPHYLOCOCCUS AUREUS 285 0.150 0.080 STAPHYLOCOCCUS AUREUS 54146 0.300 0.150 STREPTOCOCCUS PYOGENES A 561 <= 0.010 <= 0.010 STREPTOCOCCUS PYOGENES 77 A <= 0.010 <= 0.010 STREPTOCOCCUS FAECIUM M 78 L > 20.000 10.000 ESCHERICHIA COLI UC 1894 <= 0.010 <= 0.010 ESCHERICHIA COLI 0 78 0.020 <= 0.010 ESCHERICHIA COLI TEM 0.040 0.020 ESCHERICHIA COLI 1507 E <= 0.010 <= 0.010 ESCHERICHIA COLI DC 0 0.040 0.020 ESCHERICHIA COLI DC 2 <= 0.010 <= 0.010 SALMONELLA TYPHIMURIUM MZ 11 0.020 <= 0.010 KLEBSIELLA PNEUMONIAE 52145 0.150 0.040 KLEBSIELLA AEROGENES 1082 E 0.600 1.200 KLEBSIELLA AEROGENES 1522 E 0.150 0.150 ENTEROBACTER CLOACAE P 99 2.500 2.500 ENTEROBACTER CLOACAE 1321 E 0.080 0.020 SERRATIA RG 2532 0.300 0.040 PROTEUS MIRABILIS A 235 0.040 0.020 PROTEUS VULGARIS A 232 0.040 0.040 PROVIDENCIA DU 48 1.200 1.200 Product Example Product Example 15 16 0.300 0.300 0.300 0.600 <= 0.010 <= 0.010 > 20.000 0.150 0.300 0.150 0.300 <= 0.010 <= 0.010 10.000 <= 0.010 0.080 0.300 <= 0.010 0.300 0.020 0.080 0.600 10.000 0.600 5.000 0.150 1.200 0.300 2.500 5.000 <= 0.010 0.080 0.080 £ 0.020 0.040 0.040 0.040 0.080 > 20.000 0.150 20.000 0.080 0.300 0.080 0.600 0.300 Reference example : Trlfluoromethane sulphonate of 7-/3-/7-//(2-amino 4-thiazolyl) (methoxy imino) acetyl/ amino/ 2-carboxy 8-oxo 4-thia 1azabicyclo [4.2.0] zt-2-en-3-yl/ propen 2(E)-yl/thieno [2.3-b] pyridinium 6S,7S sy .

Stage A: 7-//2-(2-triphenyImethylamino thiazol-4-yl/ 2(Z) methoxy imino acetyl/amino 3-/3-/(1,1-dimethyl ethyl)dimethyl allyl oxy/ propen-l-yl/ 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of (1,1-dimethyl) ethyl 6S,7S. 1.89 g of 7-//2-(2-triphenylmethylamino thiazol-4-yl/ 2(Z) methoxy imino acetyl/amino/ 3-methyl triphenyl phosphonium 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of (1,1-dimethyl) ethyl hydrochloride, 30 cm of dichloromethane, 0.68 cur of 2/1,1dimethylethyl dimethylsilyl oxy/ acetaldehyde and 0.53 cmJ of triethylamine are mixed together and--agitated at +20°C for 14 hours» The solution is Chromatographed on &Xlica, eluting with a mixture o»f dichloromethane and ethyl acetate (9/1) and 1.305 g of the expected product—is isolated, containing a mixture of isomer E (2/3) and Z (4/3).

NMR Spectrum (CDCl^). 0.90 - 0.92 ppm SltBu ; 1.50 - Γ.53 ppm 002θ TBu ; 2.95 - 3.11 ppm CH2S ; 4.05 ppm 0CH3 ; 4.31 - 4.37 ppm CH2O ; 4.11 ppmH6 ; 5.4 - 5.5 ppmH7 5.75 - 5.87 ppm and 6.11 - 6.24 ppm Z(l/3) ; 6.17 - 6.34 ppm and 6.97 - 7.16 ppm E(2/3) ; 6.50 - 6.56 ppm thiazol 7.34 ppm 03 · Stage B : 7-//2-(2-triphenylmethylamino thiazol-4-yl/ 2(Z) methoxy imino acetyl/ amino/ 3-/3-hydroxy propen-l(E)-yl) 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of (1,1-dimethyl) ethyl, and 7-//2-(2-triphenylmethylamino thiazol-4-yl/ 2(Z) methoxy imino acetyl/ amino/ 3-/3-hydroxy propen-l(Z)-yl) 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of (1,1-dimethyl) ethyl. 1.305 g of the product obtained at stage A. of example 1 is dissolved in 15 cm of acetone, 2 cm of a mormal aqueous solution of hydrochloric acid is added and agitated for 2 hours 30 minutes. After concentrating to dryness by distilling under reduced pressure, bicarbonated water is added, and extraction is done with dichloromethane. The extracts are concentrated to dryness by distilling under reduced pressure, the residue is chromatographed on silica, eluting with a mixture-of dichloromethane-and ethyl acetate (1/1), and 536 mg of isomer E and 569 mg of isomer Z, of the expected product are isolated.

Checks of isomer E: I.R. Spectrum. (chloroform). 3607 cm1 OH ; 3405_cm"l amide NH ; Ϊ&84 cm"^ C=0 ; 1515 cm1 amide II~; 1772 cm1 beta lactame C=O ; 1595, 1544, 1527 cm^i : aromatic, thiazol, conjugated system ; 1700 cm1 tertbutyL ester ; 1370 cm1 CH^ ; 1154 cm"1 C-O-C ; 2820 cm1 OMe ; 1049 cm-1 C=N-0R.

U.V. Spectrum : ethanol.

Max. 231 nmE\ = 497- 6 = 32,200 Inflexion 258 nmE\ a 290 Inflexion 264 nme1i a 264 Inflexion 270 nmE\ = 240 Max. 320 nme11 a 245 e- 18,100 NMR Spectrum, (CDClj) 1.51 ppm tBu ; 3.05 ppm C^S ; 4.02 ppm OCH^ ; 4.28 ppm C^OH ; .48 ppm Hy ; 6.24 - 6.41 and 6.97 - 7.13 ppm ethylene H’s, delta E J = 15 Hz.; 7.29 ppm ; 6.53 ppm H^ thiazol syn".

Checks of isomer Z: I.R. Spectrum. (chloroform). 3605 cm-1 OH ; 3405 cm-1 amide NH ; 1685 cm-1 C=0 ; 1505 cm-1 amide II ; 1773 cm-1 beta lactame C=0 ; 1704 cm-1 tertbutyl ester ; 1368 cm1 Me ; 1154 cm1 C-O-C ; 1585, 1573, 1527, 1493 cm-1-, trityl, aromatics, thiazole, conjugated system, 2820 cm-1 C=N-0Me ; 1050 cm1 C=N-0R. U.V. Spectrum : ethanol.

Inflexion 230 nme1i = 411—; Inflexion 260 nm E1^ = 220 ; Inflexion 265 nme1i = 198 ; Inflexion 271 nm E1^ = 176 ; Max. 308 nme11 - 194 fc =· 14,300 NMR Spectrum, (CDClg) 1.49 ppm tBu ; 3.06 ppm S-CH2 ; 4.04 ppm OMe ; 4.27 ppm CHgOH ; .48 ppm Hy ; .85 - 5.98 and-6.21 - 6.34 ppm ethylene H’s, delta Z J » 11 Hz.; 6.56 ppm Hg thiazol syn"; 7.2-9 ppm 0 g.

Stage C : Trifluoromethane sulphonate of 7-/3-/7-//2-(2-triphenylmethyl amino thiazo1-4-yL) 2(Z) Cmexfthxy Imino) acetyl/ amino/ 2-//1,1-dimethyl ethyl/ oxy/ carbonyl / -8-oxo 4-thia 1- azabicyclo [4.2.0] oct-2-en-3-yl/ propen 2(E) yl/ thieno [2.2-b] pyridinium 6S,7S. 222 mg of isomer E obtained at stage B of example 1 is dissolved in 4.8 cm of dichloromethane, and 3 «1 of a solution comprising 536 mg of thieno pyridine for 10 cm of methylene chloride is added. q The mixture is cooled to -70eC, then, drop by drop, 2.7 cm of a solution of trifluoromethane sulphonic anhydride, comprising 0.42 cm'$ for 10 cm of methylene chloride is added. The temperature is taken slowly to +20°C, and the solution is concentrated to dryness by distilling under reduced pressure. Ethyl acetate is added to the residue which is then washed with water containing 0.7 cm of an N aqueous solution of hydrochloric acid, followed by decanting, washing with water and extracting with ethyl acetate. The extracts are concentrated to dryness by distilling under reduced pressure, and the residue is chromatographed on silica, eluting with a mixture of dichloromethane and methanol (92/8). 236 mg of the expected compound is isolated (Isomer E).

Stage C* : Trifluoromethane sulphonate of 7-/3-/7-//(2-triphenylmethyl amino thiazol-4-yl) 2(Z) (methoxy imino) acetyl/ amino/ 2-//1,1-dimethyl ethyl/ oxy/ carbonyl/ 8-oxo 4-thia 1-azablcyclo [4.2.0] oct-2-en-3-yl/ propen 2(Z) yl/ thieno [2.2-b] pyridinium 6S,7S. 145 mg of Isomer Z obtained at stage B of example 1 Is dissolved In 5 cm3 of dichloromethane, and 120 ul of thieno [2,3-b] pyridine is ο added. The mixture Is cooled to -70°C, then, drop by drop, 1.76 cm of a solution in methylene chloride of trifluoromethane sulphonic anhydride, comprising 0.42 cm for 10 cm of methylene chloride is added. The temperature is taken slowly to +20°C, and the solution is chromatographed on silica, -eluting with a mixture of dichloromethane and methanol (92/8). 157 mg of the expected compound is isolated.

Stage D : Trifluoromethane sulphonate of 7-/3-/7-//(2-amino 4-thiazolyl) (methoxy imino) acetyl/ amino/ 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl/ propen 2(E)-yl/ thieno [2.3-b] pyridinium 6S,7S syn. 221 mg of. isomer (E) obtained, at Stage C of example 1 and 2.5 cm of a 33 Z aqueous solution of formic acid are mixed together and heated to 65°C for 55 minutes, then cooled, diluted with water, filtered and washed with ether. The aqueous phase- ia concentrated to dryness by distilling under reduced pressure, wa£er is added, and after separating and drying, 93 mg of the expected product is obtained.

I.R. Spectrum (nujol). 1760 cm-1, aromatic + 1030 cm-1 U.V. Spectrum (ethanol) Max. 238 nm E11 = 625 ; fc = 44,200 Max. 307 nm E1^ » 251 ; £ = 17,700 Inflexion 318 nm E1^ = 232 ; Inflexion 338 nm E^ = 160 ; By formic hydrolysis, the isomer Z hydrolyses totally Into isomer E (isomerisation).

Preparation of the hydrochloride of 7[[(2-triphenyImethylamino thiazol 4-yl) 2(Z)-methoxy imino acetyl] amino] 2[(1,1-dimethylethyl) oxycarbonyl 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 3-yl] methyl triphenyl phosphonium (6S,7S). 2.182 g of 7-[[2-(2-tritylamino thiazol 4-yl) 2-(Z) methoxy imino acetyl] amino] 3-chloromethyl 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dimethyl ethyl (6S, 7S) and 1.679 g of q triphenyl phosphine are dissolved in 24 cm of tetrahydrofuran; 14.1 g of silica is added, and the tetrahydrofuran is distilled for 2 beta lactame ; 1660 cm ; 1550 and 1535 cm , amide II + thiazol + conjugated system. hours, followed by cooling and agitating for 26 hours at 20° C. After chromatographing on silica, eluting with a mixture of dichloromethane and methanol (90/10), 1.89 g of the product sought is obtained.

Example 1 : Trifluoroacetate of 5-(3-(7-([(2-amino-4-thlazolyl) (methoxy-imino)-acetyl]aminoJ2-carboxy 8-oxo 4-thia 1-azabicyclo # [4.2.0] oct-2-en-3-yl]-2(E) propenyl] 2-(trifluoromethyl) thlazolo [4.5.C] pyridinium (6S)(7S)(Z). 321 mg of 7-[(2-tritylamino thiazol 4-yl) (methoxy-imino) acetamido] 8-oxo 3-iodopropenyl 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dimethyl ethyl and 85 mg of trifluoromethyl thiazolo-pyridine are agitated—far 2 hours 30 minutes by centrifuging in 1 cm of dry dimethylsulphoxide. After distilling off as much as possible of the solvent and concentrating to dryness under pressure reduced to less than 1 mm Hg for 3 hours, the residue is chromatographed on silica, eluting with methylene chloride, then with mixtures of methylene chloride and acetone ¢91)-10) and methylene chloride an^ methanol (92-8), and 410 mg of the blocked iodide of the expected product is obtained.

To this latter, 2 cm3 of trifluoroacetic acid with 10 Z of anisole is added, with agitation for 20 miuutes. After cooling 3 slightly, 25 cm of isopropyl ether is added slowly, with agitation for 20 minutes. 137 mg of the expected product is isolated by centrifuging.

Example 2 : 7-fj(2-amino-4-thiazolyl) (methoxy-imlno) acetyl] amino] 3-(3-(1,4-dlhydro 3-(formylamino) 4-oxo 1-pyrldyl] 1 (E) propenyl 8-oxo 4-thla 1-azabicyclo [4.2.0] oct-2-ene 2-carboxylic acid (6S)(7S)(Z).

The operation is done as in example 1 with 85 mg of oxazola pyridine and 311 mg of trifluoroacetate of the expected product is obtained. 200 mg of this latter is chromatographed on silica in HPLC, in a mixture of acetonitrile and water (1-1), eluting successively with mixtures of water with 5, 10 and then 15 Z of acetonitrile. After lyophilisation, 48 mg of the expected product is obtained.

NMR Spectrum, DMSO, 250 MHz, in ppm : H^ of thiazol H of OCH3 6.81 3.85 . «7 h£ of the cephem H ethylenes Hg and Hg of pyridine Hg of the pyridine and H of the formyl.

: Iodide of 5-[3-[7-[[(2-amino-4-thiazolyl) (difluoromethoxy5.63 4.07 6.90 I 6.08 I 6.25-7.28 8.71-8.30 Example 3 imino)-acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azablcyclo [4.2.0] oct-2-en-3-yl]-2(E) propenyl] thieno [3.2.c] pyridinium, trifluoroacetate, (6S)(7S)(Z).

The operation is done as at example 1, starting with 200 mg of 7- [(2-tritylamino thiazol 4-yl) (difluoromethoxy imino) acetamido] 8- oxo 4-thia 3-Iodopropenyl 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dlmethyl ethyl and 38 mg ixf thieno [3,2-c] pyridine, and 44 mg of the expected product is obtained^ U.V. Spectrum, In EtOH : Max. 238 nm EXy = 620 ; Inflexion 24Gnm EX| < 232'; Max. 319 nm EJ 235 U.V. .Spectrum, in EtOH/HCJ Ό.1 N Max. 239 nm EJ Inflexion 260 nm EJ 566 286 g = 51,700 £ - 19,600 fc = 47,200 Inflexion 275 nm Ε^ - 249 ; Inflexion 284 nm EX^ = 226 ; Max. 327 nm EXn = 190 & = 15,900 Example 4 : Iodide of 5-[3-[7-[[(2-amlno-thiazol-4-yl) (difluoromethoxy imino)-acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2(E) propenyl] 4-methyl thieno [3.2.c] pyridinium, (trifluoroacetate), (6S)(7S)(Z).

The operation is done as at example 3, starting with 50 mg of methyl thieno [3.2.c] pyridine, and 59 mg of the expected product Is obtained.

U.V. Spectrum, in EtOH : Max.

Max. 212 nme1i = 438 fc = 37,200 238 nme1i 39 666 & ’ 56,600 260 nmE\ SI 233 317 nmE\ S 236 ε = 20.000 U.V. Spectrum, in EtOH/HCl 0.1 N fc = Max. 234 nmE\ a 619 Inflexion 259 nmE\ » 290 Inflexion 266 nmE\ = 277 Inflexion 280 nme1i 8 236 Inflexion 295 nme1l = 193 Max. 323 nme\ = 143 Inflexion 323 nme11 = 181 52,600 16,400 Example 5 : Iodide of 5-[3-[7-[[(2-amino-thiazol-4-yl) (fluoromethoxy imino)-acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azablcyclo [4.2.0] oct-2-en-3-yl]-2(E) propenyl] thiazolo [4.5.c] pyridinium, (trifluoroacetate), (65)(7S)(Z)« The operation is done as at example 1, starting with 200 mg of 7-[2-tritylamino thiazol 4-yl] fluoromethoxy imino acetamido] 8-oxo 4-thia 3-iodopropenyl 1-azabicyclo [4.2.0] oct-2-ene 2-carboxylate of 1,1-dimethyl ethyl and 35 mg of thiazolo [4.5.c] pyridine. mg of the expected product is obtained.

U.V. Spectrum, ta EtOH/HCl 0.1 N : Max. 224 nm E11 = 647 £ - 52,900 Max. 264 nm E11 »336 £ - 27,500 Max. 331 nm E11 = 190 6 = 15,500 NMR Spectrum, DMSO, 250 MHz, in ppm : 6.98 Hj of thiazol 7.14 CH=CH-CH2 .45 to 5.90 CHoF and CH2N+.

Example 6 : Iodide of 5-[3-[7-[[(2-amlno-thiazol-4-yl) (fluorome thoxy imino)-acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] 4-methyl thieno [3.2.c] pyridinium, (trifluoroacetate) (6S)(7S)(Z).

The operation is done as at example 5, starting with 38 mg of methyl thieno [3.2.c] pyridine, and 42 mg of the expected product is obtained .

U.V. Spectrum, in EtOH Max. 212 nm E1E 1 = 440 fc = 36,500 Max. 238 nmE\ = 642 fc - 53,300 Inflexion 260 nme1i = 231 Max. 317 nmE\ = 217 & = 18,000 U.V. Spectrum, in EtOH/HCl 0.1 N : Max. 239 nm E^y = 604 ζ = 50,200 Inflexion 257 nm E^ = 322 Inflexion 280 nm E^ · 249 Max. 324 nm = 181 .£ = 15,000 Example 7 : Iodide of 5-(3-(7-([(2-amino-thiazol-4-yl) (fluoromethoxy imino)-acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] thleno (3.2.c] pyridinium, (6S)(7S)(Z).

The operation is done as at example 5, starting with 52 mg of thieno [3.2.c] pyridine, and 77 mg of the blocked iodide of the product is obtained.

The 77 mg obtained and 0.924 cm of formic acid with 66 Z of water are agitated at 70°C for 2 hours 30 minutes. After cooling, the precipitate is separated and the filtrate Is evaporated to dryness. The residue Is taken up with 0.5 cm of ethanol and 1 cm of water and taken to dryness. It is taken up again with 5 cm of ethyl acetate, the solid product is triturated, separated, dried, and 47 mg of the expected product is obtained.

U.V. Spectrum, in EtOH Max. 238 nm = 440 E - 36,500 Inflexion 260 nm = 251 Max. 320 nm = 220 E- = 15,500 U.V. Spectrum, in EtOH/HCl 0.1 N : Max. 240 nm a 634 fc = 44,600 Inflexion 260 nm E^i = 304 Max. 325 nm E^ = 192 ε- 13,500 Example 8 : Internal salt of 5-(3-(7-([(2-amlno-thiazo1-4-yl) (methoxy imino) acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] thiazolo [4,5-c] pyridinium, (6S)(7S)(Z).

The operation is done as at example 1, starting with thiazolo [4,5-c] pyridine, and 151 mg of the trifluoroacetate of the expected product is obtained, which is dissolved in a (1-1) acetonitrile-water mixture, then chromatographed by HPLC on silica, eluting successively with mixtures of water with 5, 10 and 20 Z of acetonitrile. 46.5 mg of the expected product is obtained.

U.V. Spectrum, in EtOH Max. 225 nm = 870 & = 48,500 Inflexion 260 nm = 381 Max. 320 nm E^ - 305 έ = 17,000 U.V. Spectrum, in EtOH/HCl 0.1 N : Max. 225 nm E11 =782 £ = 43,600 Max. 268 nm E11 = 468 & = 26,100 Max. 330 nm E11 = 249 £ = 13,900 Example 9 : Internal salt of 5-(3-(7-([(2-amino-thiazo1-4-yl) (methoxy imino) acetylJ amino J 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] 2-methyl ΙΗ-imidazolo (4,5-c] pyridinium, (6S)(7S) syn.

The operation is done as at example 8, starting with 2-methyl 1Himidazolo [4,5-c] pyridine, and 50 mg of the expected product is obtained.

U.V. Spectrum, in EtOH/HCl 0.1 N : Max. 213 nm E^| » 856 £ = 47,400 Inflexion 242 nm E^ = 350 Max. 267 nm E^ = 454 £ = 25,200 Max. 330 nm E11 = 250 £ = 13,900 Example 10 : Internal salt of 5-(3-(7-([(2-amino-thiazo1-4-yl) (methoxy imino) acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] 2-phenyl oxazolo [4,5-c] pyridinium, (6S)(7S) syn.

The operation is done as at example 8, starting with 2-pheny1oxazolo [4,5-c] pyridine, and 90 mg of the expected product is is obtained.

U.V. Spectrum, in EtOH : Max. 239 nm eV 582 £ = 36,000 Inflexion 270 nme11 = 464 Inflexion 287 nme11 = 524 Max. 293 nm E^i = 555 £ = 34,300 Inflexion 304 nm£ll = 467 Inflexion 311 nme1i - 305 U.V. Spectrum, in EtOH/HCl 0 .1 N : Max. 241 nmE i - 508 5 = 31,400 Inflexion 278 nmE\ - 616 Max. Inflexion 284 nm E11 291 nm EX^ = 617 - 609 £= 38,100 Inflexion 305 nm EX^ = 403 Max. 330 nm e\ - 241 fc=* 14,900 Example 11 : Internal salt .of 5-(3-(7-([(2-amlno-thiazol-4-yl) 2(methoxy imino) acetyl] amino] 2-carboxy 8-oxo 4-thla 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] 2-ethyl thiazolo [4,5-c] pyridinium, (6S)(7S) syn.

The operation is done as at example 8, starting with 2-ethylthiazolo [4,5-c] pyridine, and 16 mg of the expected product is obtained.

NMR Spectrum, DMSO, 250 MHz, in ppm : 6.79 Hg of the thiazol .47 H7 I ol the cephem 3.96 Hfi I 7.33 I . ethylene Hof the propenyl 5.91 I 9.88 Hg of the pyridinium 8.86 Hg and Hg of the pyridinium 3.33 H of the CHg of the ethyl 1.43 H of the CHg of the ethyl Example 12 : Internal salt of 5-[3-[7-[[(2-amino-thiazol-4-yl) (dlfluoromethoxyimino) acetyl] amino] 2-carboxy 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] thiazolo [4,5-c] pyridinium, (6S)(7S) syn.

The operation Is done as at example 8, starting with 7-((-(2tritylamino thiazol 4-yl) (dlfluoromethoxyimino) acetyl] amino] 8-oxo 3-iodopropenyl 4-thia 1-azabicyclo [4.2.0] oct-2-ene 2-carboxylate of 1,1-dimethyl ethyl and 183 mg of the expected product is obtained.

U.V. Spectrum, in EtOH : Max. 225 nm E\- 855 fc = 50,800 Inflexion 253 nme11 - 355 Max. 320 nmE\ - 300 fc = 17,800 U.V. Spectrum, in EtOH/HCl 0 .1 N : Max. 22 6 nmE\ ’ 760 fc = 45,100 Max. 262 nmE\ " 400 fc = 23,700 Max. 330 nmE\ ’ 242 14,400 Example 13 : Trifluoroacetate of 2-amlno 5-(3-(7-([(2-amino-thlazol4-yl) (difluoromethoxyimino) acetyl] amino] 2-carboxy 8-oxo 4-thia— 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] thlazolo (4,5-c] pyridinium (6S)(7S)(Z).

The operation is done ~as In example 12, starting with 2-amino <, thiazolo [4.5.c] pyridine after agitation for 15 minutes of the 62 tag of trif luoroact’-^ce of the unblocked product In 0.3 cm of ethanol and 13 ul of pyridine, then centrifuging. 31 mg of the expected product is obtained.

U.V. Spectrum, In EtOH ; Inflexion 233 nm eV 494 Max. 249 nme11 = 782 £ = 57,600 Inflexion 291 nmSll = 195 Max. 323 xrz E1! - 285 6 = 21,000 U.V. Spectrum, in EtOH/HCl 0 .IN: Max. 248 nm E1! ’ 812 t - 59,800 Max. 273 nm E1! = 324 Max. 329 nm E1! " 240 6 -= 1-7,700 Example 14 : Trifluoromethane sulphonate of 7-(3-(7-([(2-amino-4thlazol) (fluoromethoxyimino) acetyl] amino] 2-carboxy 8-oxo 4-thla1- azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl] thleno [2,3-b] pyridinium (trifluoroacetate). 1°. Exchange : ί ~^~oxyl-base.

Under an inert atmosphere, 150 mg of 3-hydroxy (E) propenyl 7-[3-[7-[(2-tritylamino-4-thiazolyl] [(2-fluoro methyloxy) imino] acetyl] amino] 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 3-yl] 2- carboxylate of 1,1-dimethyl ethyl (6S)(7S)(Z), 5 cm3 of methylene chloride and 107 mg of thieno[2,3-b]pyridine are mixed together, and at -70°C over about 5 minutes, 1.34 cm of a 5 Z by volume solution of trifluoromethane sulphonic anhydride In methylene chloride is introduced, with agitation at -70°C for 15 minutes. The temperature Is raised to 0°C over 15 minutes, and the solution is concentrated to dryness under reduced pressure at 5°C. The residue is chromatographed on silica under nitrogen pressure, eluting with a mixture of methylene chloride and methanol (90/10), and 141 mg of the expected product is obtained. 2°. Detritylation, detertbutylatlon Under an inert atmosphere, the 141 mg of product obtained at 1‘ and 1.7 cm of a 66 Z aqueous solution of formic acid are mixed together and agitated at 66°C for 2 hours and 30 minutes, then cooled, and the precipitate formed is eliminated by filtering and washed with water. 20 cm of ethanol is added to the filtrate, which is then concentrated to dryness by distilling under reduced pressure. 1 cur of water and 1 cm of ethanol are added to the residue which is again concentrated to dryness; 5 cm of ethyl acetate is added to the residue which is then triturated, and the precipitate formed is separated, washed, dried, and 80 mg of incompletely unblocked product is obtained.

Under an inert atmosphere, the 80 mg of the preceding product and ‘320 ul of trifluoroacetic acid with 10 Z of water are mixed together and agitated at 2Q5C for 20 minutes; 5 cm of ether is added slowly, and after agitating, the precipitate formed is separated, washed, * dried, and 68 mg of the expected product is obtained.

Max. 238 nm E1^ a 497 £ = 41,700 Inflexion 260 nm E1^ = 190 Inflexion 300 nm E1^ = 191 Max. 308 nm E^| = 203 & = 17,000 Max. 323 nm E1^ a 195 16,400 U.V. Spectrum, (ethanol + HCl 0.1 N) : Max. 240 nm E1^ a 439 fc- - 36,800 Inflexion 262 nm E1^ = 240 Inflexion 260 nm E^ = 227 Inflexion 301 nm E^| a 176 Max. 331 nm E1^ = 170 c. = 14,300 Example 15 : Internal salt of l"(3-[7-[[( (methoxyimino) acetyl] amino] 2-carboxy 8-oxo 4-thla 1-azabicyclo [4.2.0] oct-2-en-3-yl]-2-(E) propenyl]-[2-(5-nitro-lH-imidazol-l-yl) ethyl] pyrrolidinium (6S)(7S)(Z).

The operation is done as at stage C of the reference example, starting with l-[5-nitro ΙΗ-imidazol 1-yl) ethyl] pyrrolidine, so as to obtain 77 mg of trifluorosulphonate of the blocked product. After treatment with trifluoroacetic acid with 10Z of anisole, and precipitation by isopropyl ether, as In example 8, the product obtained is chromatographed by HPLC with a water-acetonitrile mixture (85-15). mg of the expected product is obtained after lyophylisation.

NMR Spectrum (DMSO) 250 MHrv In ppm. 6.81H5 of the 5.52H7 1 1 of 3.96H6 1 7.48 (m) 1 .73 (d, J = 16 Hz) I of the cephem Delta E about 2.12 Hg and -H-^ pyrrolidine 3.10 to 4.87 Hg and Hg pyrrolidine, H of ethyl. 8.16 and 8.69 Hg and Hg imidazol.

Example 16 : Internal salt of 7-[3-[7-[[(5-amino-l,2,4-thiadlazol 3-yl) (methoxyimino) acetyl] amino] 2-=carboxy 8-oxo 4-thla 1-azabicyclo [4.2»0] oct-2-en—3-yl]-2-(E) propenyl] thieno [2.3-b] pyridinium (6S)(7S).

The operation is done as-ae-Example 14, starting with 7—[[2—(5— tritylamino 1,2,4-thiadiazol 3-yl) 2-methoxy imino) acetyl] amino] 2-[3-hydroxy propen (Z) 1-yl] 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dimethyl ethyl (prepared like the corresponding product obtained at stage B of the reference example), so as to obtain the trifluororaethylsulphonate of the blocked product.. The unblocking is done as at example 8, chromatographing in HPLC on lichrosorb with a mixture of water and acetonitrile (85-15) , and 52 mg of the expected product is obtained after lyophylisation.

U.V. Spectrum, (ethanol + HCl 0.1 N) : Max. 239 nm e\ = 780 £ = 43,500 Inflexion 270 nm EX^ = 302 £ = 16,800 Inflexion 294 and 304 nm, Max. 330 nm EX^ = 249 £ =* 13,900 Example 17 : 7-[[-(2-aminothlazol 4-yl) (methoxyimino) acetyl] amino] 8-oxo 3-[3-[(l,3,4-thladiazol 2-yl) thio] l-(E)-propenyl]~ 4-thla 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 2,2-dimethyl 1-oxo propoxy] methyl (6S)(7S) syn (E).

Stage A : Iodomethyl pivalate. o 1.55 g of potassium iodide is dissolved in 8 cm of acetone and 1.40 g of chloromethyl pivalate is added. This is agitated for minutes at +70°C, then for one hour at ambient temperature and filtered, so obtaining solution A.

Stage B : Potassium salt of 7-([-(2-aminothiazol 4-yl) (methoxyimino) acetyl] amino] 8-oxo 3-(3-((1,3,4-thiadiazol 2-yl) thio] 2-(E)propenyl]-4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylic acid. 0.129 g of anhydrous potassium carbonate Is agitated for one hour at ambient temperature in 5 cm of dimethylformamide and 0.500 g of the acid prepared like the product of the example described below, starting with 2-mercapto 1,3,4-thiadiazol, is added and agitated for for 5 minutes to obtain solution B.

Stage C : 7-([-(2-amlnothiazol 4-yl) (methoxyimino) acetyl] amino] 8-oxo 3-[3-[(1,3,4-thiadiazol 2-yl) thio] 2(E)-propenylJ 4-thia 1azabicyclo [4.2.0] oct-2-en 2-carboxylate of 2,2-dimethyl 1-oxo propoxy] methyl (6S)(7S) syn (Έ).

Solution A Is introduced rapidly into solution B and agitated for 30 minutes under an inert atmosphere.

The reactional mixture is poured into 70 g of water and ice, cur of ethyl acetate is ad-ded and after decanting is re-extracted. The organic phases are put together, washed with a 0.2 N solution of sodium thiosulphate, a solution of sodium bicarbonate and an aqueous solution of sodium chloride, followed by drying and evaporating to dryness. The residue is triturated in isopropyl ether, filtered, washed with a little petroleum ether (b,p. 60-80°C) , then with isopropyl ether. The dried product is chromatographed on silica, eluted with ethyl acetate, and 275 mg of the expected product is obtained.

U.V. Spectrum, in EtOH : Max. 238 nm e\ = 372 t = 24,300 Inflexion 250 nm E11 = 299 Max. 333 nm E11 = 234 £ = 15,300 U.V. Spectrum, in HCl 0.1 N : Inflexion 245 nm E1! = 317 Max. 265 nm E11 = 349 t = 22,800 Max. 335 nm E11 = 226 ζ, = 14,800 Preparation of 7-[[2-(2-amlno thiazol 4-yl) 2(Z) methoxy Imino acetyl] amino] 3-[[3-1-methyl 1H, 1,2,3,4-tetrazol 5-yl] thio] propen (E) yl] 8-oxo 4-thia-1-azabicyclo [4.2.0] oct-2-en 2-carboxylic acid 6S,7S syn.

Stage A : [7-[[2-(2-triphenyl methylamino thiazol 4-yl] 2(Z) methoxy imino acetyl] amino] 3-[[3-(l-methyl IH, 1,2,3,4-tetrazol 5-yl) thio] propen (E) yl] 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2- carboxylate of 1,1-dimethyl ethyl. mg of 7-[[2-(2-triphenyl methylamino thiazol 4-yl] 2(Z) methoxy imino acetyl] amino] 3-[[(3-hydroxy) propen 1(E) yl] 8-oxo 4-thia 1-azabicyclo [4.2.0] oct.-2-en 2-carboxylate of 1,1-dimethyl ethyl, o mg of tetrabutyl ammonium iodide, 0.8 cm of methylene chloride and 23 ul of 2,6-lutidine are mixed together and cooled to -70°C ; o 0.25 cm of a solution of trifluoromethane sulphonic anhydride, 3 titrating 0.42 cm of anhydride for 10 cm of methylene chloride, is added drop by drop, 14 mg of sodium salt of 1-methyl 5-mercapto 1,2,3,4-tetrazol and then 0.5 cm of dimethyl formamide are added, and the whole is agitated at 20°C. After concentrating to dryness, the residue is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate (9/1), and the expected product is isolated.

Stage B : 7-[[-(2-amino thiazol 4-yl) 2(Z) methoxyimino acetyl] amino] 3- [[3-[1-methyl IH, [(1,2,3,4-tetrazol 5-yl) thio] propen (E) yl] 8-oxo 4-thia 1-azabicyclo [4.2.0] oct-2-en 2-carboxylic acid. 329 mg of the compound obtained at stage A and 9.6 cmJ of a 33 Z aqueous solution of formic acid are mixed together and heated for one hour and 15 minutes at +65eC, then cooled, diluted with water, filtered, and concentrated to dryness by distilling under reduced pressure. The residue is triturated in water, the insoluble matter formed is eliminated by filtering,, and after concentrating to dryness, 142 mg of the expected compound is isolated.

Preparation of the 7-[[-(2-tritylamino thiazol 4-yl) (Z) (methoxyimino) acetyl] amino] 3-[3-lodopropen-l-(E)-yl] 8-oxo 4-thla 1-azabicyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dimethylethyl. 1.476 g of 7-[[-(2-tritylamino thiazol 4-yl) (Z) (methoxyimino) acetyl] amino] 3-[3-hydroxy propen-1(E)-yl] 8-oxo 4-thia 1-azablcyclo [4.2.0] oct-2-en 2-carboxylate of 1,1-dimethylethyl, ο 900 mg of tetrabutylammonium iodide in 25 cm of methylene chloride and 0.932 cm3 of lutidine are cooled to -70°C. At -65° to -70°C, and over 5 minutes, 8.52 cm of 0.5 cm of trifluoromethylsulphonic acid anhydride extended to 10 cm with methylene chloride is added, with agitation for 5 minutes.

At ambient temperature, 25 cm of a 0.2 N aqueous solution of sodium thiosulphate is added, with agitation for 5 minutes, then, after decanting, extraction is done with methylene chloride. The organic phases are dried and concentrated to dryness. The residue is chromato10 graphed on silica, eluting with a mixture of methylene chloride and ethyl acetate (80-20). The product is taken up in isopropyl ether, and 1.215 g of the expected product is obtained.

In the same way, the 2-(fluoromethoxyimino) or 2-(difluoromethoxy imino) derivatives can be obtained, starting with the corresponding alcohoIs.

Example 18 Preparations for injections have been made up with formula : A/. - Product of example 8 ........................... - sterile aqueous excipient, q.s. for ............

B/. - Product of example 12 .......................... - sterile aqueous excipient, q.s. for ............

C/. - Product of example 14 .......................... - sterile aqueous excipient, q.s. for ............ the following 500 mg 5 cm3 500 mg 5 cm3 500 mg 5 cm3. v

Claims (7)

1.) New derivatives of 1-dethia-2-thia cephalosporanic acid selected from the following: - 5-(3-(7-( [(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2carboxy-8-oxo-4-thia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-(trifluoromethyl)-thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 7-(((2- amino-4- thi azolyl)(me thoxyimino )- ace tyl ] amino ]-3-{3-[1,4dihydro-3-(foΓmylamino)-4-oxo-l-pyridyl]-l(E)-propenyl]-8-oxo-4-thia1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (6S)(7S)(Z). - 5-(3-(7-( [(2-amino-4-thiazolyl)(dif luoromethoxyimino)-acetyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [ ( 2-amino- thiazol-4-yl)(d if luorome thoxyimino )-ace tyl ]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-eo-3-yl]-2(E)propenyl]-4-raethylthieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [(2-amino-thiazol-4-yl)(fluoromethoxyimino)-acetyl)-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo(4.2.0]oct-2-en-3-yl]-2(E)propenylj-thiazolo[4.3.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [( 2-amino-thiazo 1-4-yl) (f luoromethoxyimino)-acetyl ]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4 .2.0]oct-2-en-3-yl]-2(E)propenyl]-4-methylthieno[3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [(2-ami no-thiazol-4-yl)(fluoromethoxyimino)-ace tyl]-amino] -2-carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)propenylj-thieno(3.2.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [(2-amino-thiazol-4-yl)(raethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0 Joct-2—en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-( [(2-amino-thiazo1-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2- methyl-lH-imidazolo(4,5.c] pyridinium (6S)(7S) syn. - 5-(3-(7-((( 2-amino- thiazol-4-yl)(me thoxyimino )-ace tyl ]-amino ] -2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-phenyl-oxazolo(4,5.c] pyridinium (6S)(7S) syn. - 5-(3-(7-( ((2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-ox0-4-thia-1-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]2-ethylthiazolo[4.5.c] pyridinium (6S)(7S) syn. - 43 difluoro - 5— [3— (7-[ [(2-amino-thiazol-4-yl)£faethoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]-2(E)-propenyl]« thiazolo[4.5.c] pyridinium (,6&)(7S) syn. 2-amino· difluoro j — 5— [ 3—[7—[[(2-amino-thiazol-4-yl) 0niethoxyimino)-acetyl]-amino]-25 carboxy-8-oxo-4-thia-l-azabicyclo [4 .2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5-c] pyridinium (6S)(7S) syn. - 7 - [3-[7-[[(2-amino-4-thiazol)(fluororaethoxyimino)-acetyl]-amino]-2 carboxy-8-oxo-4-chia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)-propenyl]— thieno[2.3.b] pyridinium. 10 - 1-(3-(7-(((2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-2carboxy-8-oxo-4-thia-l-azabicyclo[4 .2.0]oct-2-en-3-yl]-2(E)-propenyl]— l-[2-(5-nitro-lH-imidazol-l-yl)-ethyl] pyrrolidinium (6S)(7S)(Z). - 7-(3-(7-(((5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)-acetyl]amino]-2-carboxy-8-ox0-4-thia-l^azablcyclo [4.2.0]oct-2-ert-3-yl]-2(E)15 propenyl]-thieno[2.3.b] pyridinium. (6S)(7S) gy nt - 7- ([(2-amino-thiazol-4-yl)(methoxyimino)-acetyl]-amino]-8-oxo-3-[3((1,3,4-thiadiazol-2-yl)-thio]-1(E)-propenyl]-4-thia-1—azabicyclo [4.2.0]oct-2-en-2-carboxylate of (2,2-dimethyl-l-oxo-propenyl)methyl (5S)(7S) syn (E). 20 in the form of internal salt or of salt with the mineral or organic acids .

2. ) New derivatives of l-dethia-2-thia cephalosporanic acid, selected from the following: - 5-(3-(7-(((2-amino-thiazol-4-yl)(methoxyimino)-acetylJ-amino]-225 carboxy-8-oxo-4-thia-l-azabicyclo[4 .2.0]oct-2-en-3-yl]-2(E)-propenyl]thiazolo[4.5.c] pyridinium (6S)(7S)(Z). - 5-(3-(7-(((2-amino-thiazol-4-yl)(difluororaethoxyimino)-acetyl]amino]-2-carboxy-8~oxo-4-thia-l-azabicyclo [4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4.5.c] pyridinium (6S)(7S) syn. 30 - 7-(3-(7-( [(2-araino-4-thiazol)(fluoromethoxyimino)-acetyl]-amino]-2 — carboxy-8-oxo-4-thia-l-azabicyclo [4.2.0 ]oct-2-en-3-yl]-2(E)-propenyl]thieno[2.3.b] pyridinium (6S)(7S) syn. - 44

3. ) The compound: 5-(3-(7-( [(2-amino-thiazol-4-yl)(difluoromethoxyimino)-acetyl]amino]-2-carboxy-8-oxo-4-thia-l-azabicyclo (4.2.0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4.5.c] pyridinium (6S)(7S) syn.

4. ) , As medicaments, the products as defined in one of the Claims 1 or 5 2, as well as their salts of pharmacologically acceptable acids.

5. ) . As medicament, the product as defined in Claim 3, as well as its salts of pharmacologically acceptable acids.

6. ) . The pharmaceutical compositions containing, as active principle, one or more of the medicaments according to one of the Claims 4 or 5. 0 as defined in Claim 6,

7. ) A pharmaceutical composition/substantially as hereinbefore described with reference to Example 1