PT83174B1 - PROCESS FOR THE PREPARATION OF NEW DERIVATIVES OF 1-DETIA-2-TIA-CEFALOSPORANIC ACID - Google Patents

Description

A represents a hydrogen atom, an equivalent of alkali, alkaline earth metal, magnesium, ammonium or an amino-organic base where A represents an ester group where CC ^ A represents a C0 ₂ group, n ₂ represents a number integer equal to 0, 1 or 2.

Products corresponding to the general formula above can be presented in racemic or optically active form.

The requesting society has now discovered that a particular class of products has properties2

s.

particularly interesting pharmaceutical activities.

present yes request as a subject a process for the preparation of correspond to the general formula:

patent has a_s products which (I) in which R represents either a radical Ra-Ç-NH- in which R _& repreRi

X

N-CH = N- where z

Rj a hydrogen atom --------------- il sits an organic radical, wants a radical

Ri and Rj, the same or different, represent nio, an aliphatic or aromatic hydrocarbon radical or a radi. heterocyclic lime, or Ri and Rj form with the nitrogen atom to which they are attached, an optionally substituted cyclic radical, or an Rb-NH- radical in which Rb represents an optionally substituted carbocyclic or heterocyclic radical,

R ^ A represents

- wants a radical:

wants a radical:

formulas in which R'A and R'B, the same or different, represent either a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms. Z4 represents a single bond, an optionally oxidized sulfur atom or an oxygen atom, R4 represents an eventual carboxylic or heterocyclic aryl radical, possibly azido alkyl, hydrogen or substituted, or a quaternary ammonium possibly or an acetyl, carbamoyl radical, alkoxycarbonyl, haloalkyl having 1 to 4 carbon atoms, nitrile or represents a nio atom or a methoxy radical,

A represents a hydrogen atom, iJMíihri · iw] an equivalent of alkali, alkaline earth metal, magnesium, ammonium or an amino-organic base where A represents an ester group where CC ^ A represents a CC ^, n group ₂ represents an integer equal to 0, 1 or 2 as well as the salts of the products of formula (I) with mineral or organic acids.

Among the products of formula (I), in which Z & represents a sulfur or oxygen atom and R ^ _A represents a quaternary ammonium, products in which Z _{A is} not directly linked to the nitrogen atom are preferred.

The products of formula (I) can be presented in racemic or optically active form.

Among the values of R, a first class of products obtained in accordance with the present patent application, consists of products in which R represents an acylamino radical with the formula:

Ra-C-NHil

The one in which Ra represents an organic radical.

Among the values of Ra, the following values can be mentioned:

1) Ar- (CH _n ) Ar-CH-; Ar-CH _o 0-; Ar-OCH _o - Ar-S-CH ₀ -;

n | 2 2 2

R5

Ar-CH _O -S-; Ar-C ² «I

The formulas in which Ar represents an optionally mono or polysubstituted phenyl radical or a heterocyclic radical aromatic ring with 5, 6 or 7 rings comprising 1 to 4 heteroatoms chosen from sulfur, oxygen and nitrogen, n represents an integer from 0 to 4,

R ₅ can represent an amino radical, oxydryl, azido, hydrazine, free, esterified or salified carboxyl, free or salified sulfo, sulfoamino, halogeno, alkyl hydrazino, phenyl hydrazino, formyloxy.

Among the substituents of the phenyl or heterocyclic radicals, halogen atoms and the radicals C1-4 alkoxy, C1-4 alkylamino, preferably amino methyl, oxydryl, nitro, amino, trifluoromethyl or cyano, can be mentioned.

Among the aromatic heterocyclic radicals, thiazolyl, furyl, thienyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, morpholinyl, tetrazolyl radicals can be mentioned.

Furyl, amine-thiazolyl, amino halo thiazolyl, amino thiadiazolyl, amino pyrimidinyl radicals are preferred.

2) Ra may also represent an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl radical; each of these radicals may eventually be mono- or polysubstituted with one or more radicals such as alkylthio or cyanoalkylthio, mercapto, nitro, cyano, amino.

3) Ra can also represent a radical:

R -C ^c II N \ 0 \ Rd

Rc can have the same definition as Ar; among the preferred values of Rc, the following can be mentioned in particular: 2-amino-4-thiazolyl; 2-amino-5-nitro, 5-chlorine, 5-fluoro or 5-bromo thiazolyl;

5-amino-1,2,4-thiadiazolyl, 4-thiazolyl, 2-thienyl or 2-furyl; Rd can represent a hydrogen atom, an acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl optionally substituted, and possibly interrupted by an eventually oxidized oxygen or sulfur atom, or Rd can represent an optionally substituted carbamoyl radical.

Among the substituents of the radical Rd, there may be mentioned the radicals alkyl, halogen, acyl, carbon, carbamoyl, nitro, amino, hydroxy, alkylthio mercapto, oxo, alkoxy, a free, esterified or salified carboxyl radical

stayed.

Among the values of Rd, hydrogen, alkyl, alkenyl, possibly cyclic, alkynyl, aryl, mono or polycyclic heteroaryl, and

-Ch

-ch ₂ -ch = particular ch the values -CH ₃ , -CH ^ -CH

-chf ₂ , -ch ₀ -cf ₃ , -ch ₂ -o-ch ₃ ,

-CH „-SO ^ -CH„, -CH..CN, -CH.-CONH

^CH 2 (N0 „)

-CH ₂ -CSCH

Among the values of Rd, methyl, hydrogen, ethyl, allyl, 1-methyl-1-carboxyethyl, carboxymethyl or difluoromethyl are preferred.

4) Ra can also represent a radical:

PEOPLE;

Re-CHNH

C = O

RF

Re can represent the same values as Ar. The unsubstituted phenyl value is preferred.

Rf can represent an optionally substituted alkyl radical, or a -N = CH-Rg radical in which Rg can represent an aryl radical according to the above definition for Ra. Eth, phenyl or furyl values are preferred for Rf.

5) Ra can also represent a radical:

Re-CHNH

C = 0

Rk

Rh can have the values indicated for Ar; Rk can be a radical:

-N N - R1 in which RI can be a hydrogen atom, alkylsulfonyl, -N = CH-Rm where Rm has the same value as Ar, in particular furyl; Rk can be an optionally substituted aryl radical, for example an imidazolyl radical substituted by a carboxyl; Rk may also represent a substituted amino radical, for example an acylamido such as N-methyl benzoamido or furylcar bonilo or an amino substituted by an optionally substituted heterocycle; Rk may also represent an aryl radical eventually substituted and condensed; Rk can also represent7

where appropriate, an optionally substituted aralkyl.

In this first class of products, products in which Ra has the following values are preferred.

i

HO ₂ C-CH = CH-S-CH ₂ -

jikhikM

^Xx OCH ₃

Among the other values of R, a second class of products obtained in accordance with the present invention, preferably consists of products in which R represents a radical:

Laugh

X

X Rj

N-HC = In which Ri and Rj, the same or different, hydrogen or an alkyl radical with 1 represent an atom of 8 carbon atoms, that is, Ri and Rj form with the nitrogen atom to which they are attached, a cyclic amine eventually replaced.

Preferably, the radical

It does not represent a radical:

Among the other R values, a third class of preferred products obtained according to the present invention consists of products in which R represents a radical Rb-NH- in which Rb represents an optionally substituted carbocyclic or heterocyclic aryl radical. Among these preferred values of R, the following radicals can be mentioned:

H

Nh-mono- or polysubstituted in which Rp represents an alkyl radical having 1 to 4 carbon atoms, preferably methyl, isopropyl possibly interrupted by a heteroatom such as methoxy methyl, optionally substituted by one or more halogens such as methyl trichloroethoxy or methyl trifluoroethoxy; alkoxy as ethoxy. Rp can also represent an arylalkyl radical such as benzyl or phenylethyl optionally substituted by an alkyl radical such as methyl, al. coxy as methoxy, cyano, halogeno as fluoro. Rp can also represent a furfuryl radical, optionally substituted phenyl methoxy methyl.

Rq can represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms such as methyl, an alkoxycarbonyl radical such as methoxy carbonyl or tert-butoxy carbonyl.

Among these preferred values of R,

the value is preferred:

Among the values of R. ^ / ·, The radicals phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, tadiaiazolyl, tyriazolyl, pyridea, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, trazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, benzo xazole.

Among the different aryl radicals, thiazol-2-yl, 1,3,4-thiadiazol-5-yl and 1,2,4-thiadlazol-5-yl, imidazol-2-yl, 1,3 radicals are preferred , 4-triazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-5-yl, 1H-tetrazol-5-yl, pyridin-2-yl, 1, 3,4-triazin-2-yl, 1,3,5-triazin-4-yl, pyridinium, quinoline, isoquinoline, cyclopentylpyridinium, trimethylammonium.

The radicals may optionally be replaced by one or more radicals chosen from the alkyl radicals such as methyl, ethyl, propyl, isopropyl, linear or branched butyl. The alkyl radicals can in turn be replaced by an aryl radical like phenyl or thienyl, aryloxy like phenoxy, lower alkyloxy like methoxy, alkoxy carbonyl like ethoxy carbonyl, with a halogen like free or protected chlorine or hydroxyl bromine, free esterified carboxy or salified, amino, alkylamino or dialkylamino, acylamino.

The radicals can also be replaced by one or more alkenyl radicals such as vinyl, allyl, butenyl, an alkynyl radical such as ethynyl or propargyl, an aryl group such as phenyl, tolyl, a halogen such as chlorine, bromine, iodine, fluorine, an amino group or nitro, an alkoxy radical with 1 to 4 carbon atoms such as methoxy, alkylthio such as methylthio, a hydroxy radical, mercapto, amino, esterified or salified free carboxyl, carbamoyl, can also be substituted by two substituents that together form a cyclic radical such as cyclopentyl or cyclohexyl.

A particularly preferred category is the substituents R1 which comprise a quaternary ammonium, in particular the substituents:

the symbol being) representing the rest of a cycle.

^X SR can also preferably represent a non-cyclic quaternary ammonium radical.

Among the P ^ values are the following values:

Ν - Ν

CH

Λ

CH

-CHn-C-NH ^J II

NH-C-CH

II 0

Among the values of A, an equivalent of sodium, potassium, lithium, calcium, magnesium, ammonium or an organic base can be mentioned. Among the organic bases, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, Ν, Ν-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, can be mentioned. arginine, histidine, N-methylglucamine.

Among other residues of easily cleavable ester groups that A may represent, mention may be made of the methoxymethyl, ethoxymethyl, isopropyloxymethyl, ot-methoxyethyl, oC-ethoxyethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethylmethyl, valetylmethylmethyl, propionyl, butyl , isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadecanoyloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetyloxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-tert-butylcarbonyloxyethyl, 1-acetyloxyethyl, 1-acetyloxyethyl, 1-acetyloxypropyl, 1-acetyl ,

1-acetyloxybutyl, 1-acetyloxyethyl, 1-acetyloxyptyl, phthalidyl, 5,6-dimethoxyphthaloyl, tert-butylcarbonylmethyl, allyl, 2-chloroalyl, methoxycarbonylmethyl, benzyl or tert-butyl.

Among other residues of ester groups that A may represent, the groups methoxyethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butyloxycarbonylmethyl, 2,2-ethylenedioxyethyl, cyanoethyl, 2,2-dimethoxyethyl, 2-chloroethoxymethyl, 2-hydroxyethoxy, 2,3-epoxypropyl, 3-dimethylamino, 2-hydroxypropyl, 2-hydroxyethyl, 2-methylaminoethoxymethyl, 2-aminoethoxymethyl, 3-methoxy-2,4-thiadiazol-5-yl,

2-tetrahydropyranyl, 2-methoxyprop-2-yl, 1-hydroxyprop-2-yl, isc propyl, carbamoylmethyl, chloromethyl, 2-chloroethyl, acetylmethyl, 2-methylthioethyl or thiocyanomethyl.

Amongst other residues of ester groups that A may represent, the groups 2-chloro-1-acetyloxyethyl, 2-bromo-1-acetyloxyethyl, 2-fluoro-1-acetyloxyethyl, 2-methoxy-1-acetyloxyethyl , 2-methyl-1-acetyloxypropyl, 2-acetyloxyprop-2-yl, 1-methoxyacetyloxyethyl, 1-acetyl.

carbonyloxyethyl _r 1-hydroxyacetyloxyethyl, 1-formylcarbonyloxyethyl, 1- (2-thienyl) -carbonyloxyethyl, 1- (2-furyl) -carbonyloxyethyl, 1- (5-nitro-2-furyl) -carbonyloxyethyl, 1- (2-pyrrolyl ) -carbonyloxyethyl, 1- (propionyloxycarbonyloxy) ethyl, 1- (propyloxycarbonyloxy) ethyl, 1- (isopropyloxycarbonyloxy) ethyl, 1- (methoxyethoxycarbonyloxy) ethyl, 1- (allyloxycarbonyloxy) ethyl, 1- (2,3-epoxy) pro ethyl pyloxycarbonyloxy, 1- (2-furyl) methyloxycarbonyloxy ethyl, 1- (2-fluoro) ethyloxycarbonyloxy ethyl, 1- (methoxycarbonyloxy) propyl, (2-methoxycarbonyloxy) prop-2-yl, ((methoxycarbonyloxy) chloromethyl, 1- ( methoxycarbonyloxy) -2-chloroethyl, 1- (methoxycarbonyloxy) -2-methoxyethyl, 1- (methoxycarbonyloxy) -1-allyl. A can also represent the group:

CH ₃

Products with formula (I) may also be in the form of salts of organic or mineral acids.

Among the acids with which it is possible to salify the amino group (s) or the quaternary ammonium group of the products (I), we can mention, among others, acetic, trifluoroacetic, maleic, tartaric, methanesulfonic acids , sulfonic benzene, sulfonic p-toluene, formic, phosphoric, sulfuric, hydrochloric, hydrobromic, hydroiodic trifluoromethanes.

Among the values of A, esters groups with the formula can be mentioned in particular:

-CH-O-C-D

I II

B 0 in which B represents a hydrogen atom or an optionally substituted linear or branched alkyl radical containing 1 to 5 carbon atoms and D represents an optionally substituted linear or branched alkoxy or alkoxy radical which comprises 1 to 15 carbon atoms and in particular 1 to 5 carbon atoms, and more particularly the ester groups in which B repeats; _{and (} M- _A - j I, £ ¢¢ 0 β> firBii- - 5 has a hydrogen atom or a methyl or ethyl radical and D represents a methyl, ethyl, methoxy or ethoxy radical.

Among the values of A, we can also mention the radical -CH ₂ -C = CHRy in which Rx represents the values Rx hydrogen, alkyl, in particular methyl, ethyl, halogen, aryl, in particular phenyl, possibly substituted by methyl , methoxy or halogen, or Ry represents the alkyl value optionally substituted by acyloxy, alkoxycarbonyl or halogen.

Among the values of A, can be mentioned _n

X ¹

If the still -CH 2 -C = C radical in which R has the previous section significaRx alk ₂ and alk and alk ^ _2, identical or different, represent an alkyl radical containing 1 to 4 carbon atoms.

Currently, a process corresponding to the formula (1 ^) is used:

order has more special preparation of the products for the isomer sin

in which R represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical that has a maximum of 6 carbon atoms, optionally substituted or an aryl radical,

Z ^ has the value indicated above and R '^ represents a phenyl radical, an optionally substituted heterocyclic aryl, an optionally substituted quaternary ammonium radical or an acetyl or carbamoyl radical.

Among the products cited above with formula (1), products are preferred in which R 'represents a hydrogen atom, or a methyl or isopropyl radical, possibly substituted by a carboxy, carbamoyl, nitri radical21

J | SIXTY ¹ |? ESOUOOS:

lo, methylthino or methoxy, a difluoromethyl or trifluoro methyl radical, a phenyl radical, a cyclobutyl or cyclopropyl radical optionally substituted by a carboxy radical, an allyl radical possibly substituted by a chlorine or bromine atom and the products in which it represents a single bond and R '^ represents an optionally substituted pyridinium radical.

Preferred products include those described below in the examples, and in particular the following products:

- the internal salt of 7- / 3- / 7 - // (2-amino-4-thiazolyl) -2- / Z- (trifluoromethoxy) imino / -acetyl / amino / -2-carboxy-8-oxo-4 -thia-1-azabicyclo /4.2.0./ oct-2-en-3-yl / -2- (E) -propenyl / thieno /2.3.b/ pirj. domain (6S) (7S);

- the internal salt of 5- / 3- / 7 - // (2-amino-4-thiazolyl) (methoxyimino) acetyl / amino / 2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0 ./ oct-2-en-3-yl / -2- (E) -propenyl / -2-methyl thiazole / 4,5-c / pyridinium sin (6S) (7S);

- 7- / 3- / 7 - // (2-amino-4-thiazolyl) -2- (Z) - (methoxyimino) acetyl / amino / 2-carboxy-8-oxo-4-thia-1 internal salt -azabicycle /4.2.0./ oct-2-en-3-yl / propen-2- (E) -yl / thiene / 2,3-b / pyridinium (6S) (7S);

- 7 - // (2-amino-4-thiazole) (methoxyimino) acetyl / amino / 3-

- // 3- (1,3,4-thiadiazol-2-yl) thio / 1- (E) -propenyl / 8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-carboxylic sin (6S) (7S);

- 5- / 3 - / - // (2-amino-4-thiazolyl) (difluoromethoxy) imino salt / acetyl / amino / 2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0 . oct-2-en-3-yl / -2- (E) -propenyl / -2-methyl thiazole / 4,5-c / pyridinium (6S) (7S) Z.

The process of the present invention is characterized by treating a product with formula VII:

VII in which R ^ and A have the meanings indicated above and R &

represents either a free amino radical or protected by a mono or divalent protecting group, or R4 represents the radical R, having R the meaning indicated above, either by a halogenating agent or by a sulfonation agent and then by triphenylphosphine, or by a reactive with formula P (OAlk) 3 in which Alk represents an alkyl radical with 1 to 4 carbon atoms, to obtain either a product with formula VIII ^:

VIIIa in which R ^, R ^ and A have the previous meaning and X represents the

rest of an anion, or a product with formula VIII ' , ^R 4 VIII ' ^ - ^H x ^ \ / V ^Oalk, 2 THE ^c ° ₂ a

in which R &, R ^, A and Alk have the previous meaning, con products. formulas VIII ^ or VIII '^ which, if desired, are treated first with a strong base and then with an alkyl halogen with the formula hal-R _A in which hal represents a halogen atom and R ^ has the values of R ' _A other than a hydrogen atom

formulas in which R 'has the meaning indicated above, with products with the formulas νΐΙΙ _β and VIII' _{β representing} the set of starting products VIII ^ and VIII'and products obtained after t

with

- ΓβΟίΟΟ

í, SIXTY.] SHIELDS-.

of action on these products of the hal-R4 derivative, products of formulas VIII-, or VIII 'that are treated with a product OD the formula with which R'_ has the value indicated above and protective Gp of the oxydryl radical to obtain a la IX:

represents a product group with the

IX

Z or in the form of a mixture of the E isomers and the E or Z isomer, a product with formula IX on which the following reactions are carried out in any order:

A) cutting the protective group Gp;

B) when R & represents an amino radical protected by a mono or divalent protecting group, elimination of this protective group and treatment of the product in which R & represents an amino radical either by an acid of formula IVa:

(IVa)

RaCO ₂ H formula in which Ra represents an organic group, or by a functional derivative of this acid, either by a product with the formula

IVb:

Ri ^ N-CH-Xb

RJ in which Ri and Rj have the meaning indicated above and Xb represents a sulfur or oxygen atom, either for a product with the formula IVc:

Rb-Xc in which Rb has the meaning indicated above and Xc represents a hydrogen atom;

to get a product with

c) separation of the E and Z isomers; formula X:

in which R & has the meaning indicated above, product con. formula X on which either a reactive derivative of the group R ^ is acted to obtain a product with formula XI ^:

^XI A wants a derivative of a then a derivative to obtain a product with the oxydryl radical activation group and or a reactive derivative of the group Rg _A for formula ΧΙ _β :

^XI B wants a derivative of an activating group and then the product with the formula HS-R -, ^ or vo of it

3A product to obtain a product with the oxydryl radical and a reactivated derivative of formula XI _C :

cessary products

XI _C with formula XI which, if necessary or not, undergo any or several of the reactions if

following, in any order:

a) cutting by hydrolysis, hydrogenolysis or through the action of thiourea, of all or part of the protecting group or groups;

b) esterification or salification by a base of the carboxy or sulfo group or groups;

c) salification by an acid of the amino group or groups;

d) unfolding the molecule to obtain an optically active product;

e) oxidation of the sulfur atom at position 2 of the isocyte-female ring.

The halogenating agent which is preferably used is thionyl chloride in a chlorinated solvent such as methylene chloride or in dimethyl formamide. A product with formula VIIa is then obtained intermediate:

R Λ 1 in Villa 0 ^ co ₂ a They can also be used other re- halogenation assets like phosphorus pentachloride, oxychloride

phosphorus or tosyl chloride.

sulfonating agent can be for example trifluoromethylsulfonic anhydride. It is then optionally operated in the presence of a base, preferably 2,6-dimethylpyridine or lutidine. In general, sulfonation products are unstable and are not isolated.

The action of triphenylphosphine or the reactive with the formula P (OAlk) 3 in which Alk preferably represents an ethyl radical takes place under the usual conditions. The action of triphenylphosphine or the reactive with the formula P (OAlk) 3 is preferably carried out in the presence of silica on the halogenated product with the formula Vila, it is generally operated by refluxing a solvent such as toluene or chloroform. In the case where a sulfonation agent is • actuated on a product with fõrmu26

1 to VII, the action of triphenylphosphine or the product with the formula P (OAlk) 3 is preferably carried out at the same time, due to the instability of the sulphonation products.

The strong base with which products of formula VIII ^ and VIII ' _A may be treated may be chosen from potassium or lithium tert-butylate, lithium diisopropylamide, lithium bis trimethyl silyl amide.

alkyl halide of the form hal-RA is preferably chloride or bromide.

The action of the product of formula ^and _'b>> ^og p

Sobreι on products with the formulas νΐΙΙ _β or VIII ' _B is preferably carried out in a chlorinated solvent such as methylene chloride. Pc to operate in the presence of a relatively weak base, for example triethylamine or DBU (1,8-diabicyclo / 5,4,0 / undec-7-ene) or DBN (1,5-diazabicyclo / 4,3, 0 / non-5-ene). It is then operated at room temperature or heating.

It can also be operated in the presence of a strong base such as lithium tert-butyl or an alcoholate such as lithium tert-butylate, lithium bistrimethylsilyl amide or lithium diisopropylamide. It then operates at low temperature. The reaction can be carried out, for example, at a temperature from -70 ° C to room temperature.

protecting group represented by Gp can be a silyl group such as trimethylbusylyl or tert-butyl dimethylsilyl. However, a group such as tetrahydropyranyl can be used.

The cutting of the protection group is carried out under classical conditions. It operates, for example, in the presence of an acid or a fluoride ion provided by hydrofluoric acid or tetrabutylammonium fluoride.

When a product of formula IX is obtained in which R R represents an amino radical, in a preferred form of the process, the product is treated with formula (XI) with a functional derivative of a product with the formula

EWUOtfS -J (IV). This functional derivative can be, for example, a halogenide, symmetric or mixed anhydride, amide or activated ester.

As an example of mixed anhydride, one can mention, for example, that formed with isobutyl chloroformate and that formed with pivaloyl chloride and mixed sulfonic carboxylic anhydrides formed, for example, with paratoluenesulfonyl chloride. As an example of activated ester, the ester formed with 2,4-dinitrophenol and that formed with hydroxybenzothiazole can be mentioned.

As an example of halide, chloride or bromide can be mentioned.

Mention may also be made of acid azide or acid amide.

The anhydride can be formed in situ by the action of ΝΝ'-disubstituted carbodiimide, for example N, N-dicyclohexylcarbodiimide.

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

When an acid halide is used, and, in general, when a halohydric 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, carbonates and acidic sodium or potassium carbonates, sodium acetate, triethylamine, pyridine, morpholine or N-meylmorpholine.

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

In a preferred embodiment of the process, products of formula (IV ^) are transformed into reactive derivatives such as acid halides, which can be prepared by reacting products of formula (ΐν ^) with a cleaning agent. halogenation such as phosgene, oxalyl chloride, thionyl chloride. Complexes can also be prepared. with dialkyl sulfates, preferably dimethyl sulfate.

The operating conditions for these reactions are known to those skilled in the art. These reactions are described, for example, in French patent 2,073,338.

In a preferred embodiment of the process, the halogens used in the products of formula (IV) are chloride or fluoride. Preferably, a deri

Pyridinium cube. The counterion is then preferably an ion dide, tosylate, bromide, BF4.

The preparation of products with formula (IV) and the reaction of these products with products of formula (IX) are carried out under the conditions described, for example, in the Journal of Medicinal Chemistry 1982, Vol. 25, n9 4, p . 457-469.

The subsequent reaction of possible separation of the E and Z isomers is carried out according to the usual techniques. It is preferable to use chromatography on silica.

The transformation of products with formula X into products with formula XI ^ is also carried out according to classical methods.

The derivative of the group used may be, for example, a halide derived from an optionally substituted carboxylic or heterocyclic aryl radical. The fluoride is then preferably used when, for example, it represents an acetyl or carbamoyl radical. It preferably operates in the presence of a reactive derivative, such as, for example, an anhydride or halide.

The transformation of products with formula X into products with formula ΧΙ _β is preferably carried out according to the following conditions: an activated derivative of the oxhydryl radical is prepared by the action, for example, of an acid derivative sulfonic acid as the trifluoromethyl sulfonic acid anhydride. It operates at low temperature or at room temperature.

When R. ^ does not represent a quaternary ammonium, it is preferably operated in the presence of a base.

The transformation of products with formula X into products with formula XI _C takes place under conditions

analogous.

An activated derivative of the oxyhydryl group is first prepared under the conditions set out above, in particular from trifluoromethyl sulfonic acid anhydride. The action of the product with the formula HZR _3a is preferably carried out in the presence of an organic base such as 2,6-dimethylpyridine and a soluble source of iodide. It is then preferably operated in the presence of tetralguylammonium iodide.

Products with the formulas XI ^ z

ΧΙ _β and XIç constitute products with the formula 1 ^ when they do not include any protective group and when A does not represent, among the easily cleavable ester groups, one of those that is to be eliminated.

In other cases, the action on the product with the formula XI ^, ΧΙ _β or XI _C of one or more hydrolysis, hydrogenolysis or thiourea agents is intended to eliminate! define the protecting group or groups that the various products can comprise.

The nature of the reactants to be applied in all cases is known to those skilled in the art. Examples of these reactions are presented below, in the experimental part.

Below is a non-exhaustive list of the means that can be used to eliminate the various groups.

The elimination of the protecting group or groups can be done by hydrolysis, which is acidic, basic or using hydrazine.

Acid hydrolysis is preferably used to remove any substituted alkoxy and cycloalkoxycarbonyl groups, for example tert-pentyloxycarbonyl or tert-butyloxycarbonyl, the aralkoxycarbonyl groups possibly substituted as benzyloxycarbonyl, the trityl, benzhydryl, tert-butyl or 4-methoxybenzyl groups.

acid that is preferably used. can be chosen from the group consisting of hydrochloric, benzene sulfonic or para-toluene sulfonic, formic or

trifluoroacetic. However, other mineral or organic acids can be used.

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

The base that is preferably used is a mineral base, for example sodium or potassium hydroxide. Magnesia, barite or an alkali metal acid carbonate or carbonate, for example sodium or potassium acid carbonates or carbonates or other bases, may also be used,

Sodium or potassium acetate can also be used.

Hydrolysis using hydrazine is preferably used to eliminate groups such as phthaloyl,

Some groups can also be eliminated by the zinc-acetic acid system (for the trichloroethyl group), benzhydryl benzyloxycarbonyl groups are preferably eliminated by hydrogen, in the presence of a catalyst.

chloroacetyl group is eliminated by thiourea in neutral or acidic medium, according to the type of reaction described by MASAKI J.A.C.S., 90, 4508, (1968).

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

Preferred groups include formyl, acetyl, ethoxycarbonyl, mesyl, fluoroacetyl, chloroacetyl, trityl groups. Trityl and chloroacetyl radicals are especially preferred.

The acid that is preferably used is trifluoroacetic acid.

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

Salification can be achieved, for example, by acting on a product in the acid form or on a solvate, for example ethanolic solvate or a hydrate of this acid, from a mineral base such as sodium or potassium hydroxide, carbonate or sodium or potassium carbonate. They can also. use salts of mineral acids such as tri-sodium phosphate. Tam

well, organic acid salts can be used.

As salts of organic acids, mention may be made, among others, of the sodium salts of aliphatic, linear or branched, saturated or unsaturated carbohydrates, with 1 to 18 and preferably 2 to 10 carbon atoms. These aliphatic radicals can be interrupted by one or more heteroatoms such as oxygen or sulfur or replaced by aryl radicals, for example: phenyl, thienyl, furyl, or by one or more oxydryl radicals or by one or more halogen atoms such as fluorine, chlorine or bromine, preferably chlorine, by one or more lower carboxylic or alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, by one or more aryloxy radicals, preferably phenoxy.

In addition, sufficiently soluble aromatic acids, for example benzoic acids, preferably substituted by radical lower alkyls, can be used as organic acids.

Examples of such organic acids include: formic, acetic, acrylic, butyric, adipic, isobutyric, n-capranoic, isocaproic, chloropropyl, crotonic, phenylacetic, 2-thienylacetic, 3-thienylacetic, 4-ethylphenylacetic, glutanic, adipic acid monoethyl ester, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxypropionic, 3-methoxypropionic, 3-methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric, 4-phenoxy butyric butyric acid ethylbenzoic, 1-propylbenzoic.

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

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

Salification can also be achieved by • arginine, lysine, procaine, histidine, N-methyl glu. camina.

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

The salts are obtained in amorphous or crystallized 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.

Salification of products by mineral or organic acids is carried out under the usual conditions.

The eventual esterification of the products is carried out under the classic conditions. It is generally operated by reacting the acid with formula (I) with a derivative that has the formula:

ZR ^s in which Z represents an oxydryl radical or a halogen atom such as chlorine, bromine, iodine and R designates the ester group to be introduced, a group from which a non-exhaustive list is presented above. In some cases, it may be advantageous to perform an esterification on a product whose amine is blocked before removing the protecting group from the amine.

eventual unfolding of the compos. with general formulas XI ^, ΧΙ _β , ^XI and P ^o ^ ^{and be} effected by means of an optically active organic carboxylic or sulfonic acid such as tartaric, dibenzoyltartaric, camphosulfonic or glutamic acid, with the decomposition of the salt thus obtained carried out by means of a mineral base such as sodium bicarbonate or an organic base such as a tertiary amine, for example triethylamine. In addition, an optically active base may optionally be used.

The eventual oxidation of products with the formula XI &, ^XI B ^{or XI} C will ^be carried out by means of oxygen, peroxides, hydroperoxides, per acids or hydrogen peroxide. The action is advantageously sensitized to light. These reactive powder. mixed with organic or mineral acids. Uses33

preferably metachloroperbenzoic acid. The reaction conditions are known to those skilled in the art. These conditions are described, for example, in French patent 2,387,234.

The products of general formula (I) and their pharmaceutically acceptable salts have very good antibiotic activity on gram (+) bacteria such as staphylococci, streptococci and, in particular, on penicillin-resistant staphylococci. Its effectiveness on gram (-) bacteria, in particular on coliform, clebsiella, salmonella and proteus bacteria is particularly notable.

These properties make the products suitable to be used as medicines in the treatment of diseases of sensitive germs, and, in particular, in the treatment of staphylococci, for example staphylococcal septicemias, malignant facial or cutaneous staphylocysts, pyoderma, septic sores or suppurants, anthrax, phlegm, erysipelas, acute staphylococci, primitive or post-flu, brnopneumonia, pulmonary suppuration.

These products can also be used as medicines in the treatment of colibacillosis and associated infections, in infections of proteus, clebsiela and salmonella and in other conditions caused by bacteria with gram (-).

Among the medicaments according to the present invention, mention can be made more particularly of

in which R represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical with a maximum of 6 carbon atoms, optionally substituted or an aryl radical, Z & has the values indicated above and represents a phenyl radical,

optionally substituted heterocyclic aryl or an optionally substituted ammonium radical or an acetyl or carbamoyl radical.

Among these products, the products mentioned above that have the formula 1 can be mentioned, with products in which R * represents a hydrogen atom, or a methyl or isopropyl radical optionally substituted by a carboxy, carbamoyl, ni tryl, methylthio or methoxy, a difluoromethyl or trifluoromethyl radical, a phenyl radical, a cyclobutyl radical, or a cyclopropyl optionally substituted by a carboxy radical, an alkyl radical optionally substituted by a carboxy radical, an allyl radical optionally substituted by an atom of chlorine or bromine and Z _A represents a single bond and R ' _2A represents an optionally substituted pyridinium radical.

Among these products, mention can be made in particular of the products described below in the examples.

Products of formula I, as well as their pharmaceutically acceptable acid salts, can be used to prepare pharmaceutical compositions containing them as an active ingredient.

These compositions can be administered orally, rectally, parenterally, intramuscularly or locally via topical application on the skin and mucous membranes.

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

Said products can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, for example tablets, simple or dragee, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; ¹ are prepared by the usual procedures. The active principle or principles can be incorporated into said forms in excipients used. commonly used in these pharmaceutical compositions, for example * talc, gum arabic, lactose, starch, magnesium stearate, man35 -

^Γ 80 $ <3D

cocoa butter, aqueous vehicles or not, fatty bodies of animal or vegetable origin, paraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

These compositions can be presented, in particular, in the form of a powder, to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogenic water.

The dose administered varies with the condition treated, the patient in question, the route of administration and the product under consideration. The dose can be comprised, for example, between 0.500 g and 1 g three times a day, intramuscularly for the products of examples 1 or 2.

Products with formula (I) can also be used as disinfectants for surgical instruments.

Products with formula VII are used.

from the process of preparing products with formula I can be prepared by the process described in French patent 2,559,486.

An example of this preparation is presented below in the reference examples.

In addition to the products described below.

in the examples describing the present invention, without, however, limiting it, the following products constitute the products obtainable within the scope of the present invention.

The products correspond to the formula:

co ₂ a in which R, R ^, A and n2 have the same meaning as indicated in the tables that follow.

CM O u 8 8 = 8 CM ti O = = = *. Pí ®o 8 ° i ω CM CM U trj φ Μ K tó 1 ffl ! 3 The co The M O V <T = = CM O O φ _ CM - = = O U CM ti O = = = = = The uT to 1 CM K o 1 CM 0õ> 05 ^ Q5 ¹ Çcx ^x ÇcM Ç> ^§ ®y © j Pí 1 M 13 co the w O> J_ _ _ _ cm) = 13 ^

CM Ο O © CM o = = = = = U CM s o _ _s rt! r-H K CM U O III a φ CM i I OH θΰ · ^? © 5 ° ®> ®) ®J ®) ® \>>>>> 7 tó 1 The a ω the m the u \_ O CM O O V M Vm = S · CM _s s O uu CM P! O = = = = = 3 tó CM n _ co σ M © MW 0Ô- * ¢ 0-8 ÔA ⁸ OcV ^ ÔO * © v © X “© V“ Pí í M a o o _x o. o = = = = = CM> 2 ff

- 41 ϊ

1 βοφοο; ^; : ΞΞ3 Swj ç CM ο «Λ 5 = = = = = ο ο υ CM β ο = s = = AND cn (Ό ffl CM s M U W u ο there Ê \ r-ϊ tó 1½ THE H> > L> jL ÍÍN ίιΊ Ij ΠΊ 1Γ * easy liY <> 7 ~ ^ ι li s J vvz L! J ® \ ®> ®í eiT ) > 5> ) ) 1 Μ 3 cn Ο ίΰ Ο Ο Ρί V AND £ £ = = CM JS- / ” υ || ³ Λ3 CM Ο ο £ AND AND £ £ - υ ο CM β ο “ 1—1 tó ι <γ \ t ^ y Ç\ the .zx i ^ TT V r ϊιΛ í ^ r λ r ^ irP, 1 Ο Li // ; LJ k>. jJLcá ³ en 'cn> S> b © y jb® ^ / ο d ™ ( cn / 8 ( υ 7 7 w a 7 1 Μ 2 m Ο Μ 04 ο - _{= ç} CM> = W ^s s s ΝΗ Λ \ = Á - 46 -

ω Κ

[fiõÃOD) i taWj kJ ^ ií uIMll - ^ il ^ S4 ^s 3 &v'l - • kl & $ Sw-3 F ãBMmZSíCQjI "1 C4 Μ 04 (Ί _{= ε = = =} - ₌ - ο υ 04 β ο = - = = = = = = CXJ 03 rd Ρί Λ r ω f rn 3 υ ω ί Ν ® ^Μ ^ -? © _ζ 8 'V ω th ο Π Ο = ω * f S Ι3φ2ΚΠ ω 3 3 ϊ ϊ QC with W υ ^§ X V x3x 04 iH 3? dog 1 ] ι Μ 13 C0 FH ο \ A ο ^υ S = = = = = = ΖΓ Λ- ' << Μ ο r) ΟΙ r> = S S s Ε s = ο 04 β ο = = = = = = = 04 04 Ο 13 η M W O r-l 3 υ 3 <^> k-§0s ^κ - €><3 * γΖ ω ω W ^ω > 5 3 ⁵ ¾ f 'ΓΟ | I ffi w 1 · s -Ο S ^ sT 5 __ ο »ο 'Ff *? Τ ^{m 7} AX u. X η X 3η ^^ ° 3 K ω u > Ό $ >> > $ > 1 IH Β Μ r \ kJ \ -3 ^ζ f-CT _ζ ο ' 49 -

Ο) Ο υ Β _____ _ Ο Ο ΟΙ S Ο = = = = = = = Μ ftT ΟΙ (Ό Β Μ 5 U Μ ΟΙ ΟΙ Ο ΟΙ ΟΙ ___ Ο Ο Ο Ο ο οι sg ι υ υ g 7 ® Υ = | Γ = ί V ν = ι _β 4 = Ι _Β % ξ W _S J (γ γ y ν ν γ γ ω μ ^ω w ^ω co ^ω m] 1 ί 1 & Β 2 η ο a ο _υ ...... Η 3 <1 <Ν Ο Ο Β ο Ο ΟΙ β ο = = = == = = Η & ΓΌ ΟΙ ΟΙ pL | C0 Κ ΟΙ tyjSÍ (δζ4 tôfiôy ^ φ ^υ ω m S mmm ο ω uí 1 n MMM (4 The g m the a υ υ

ç CM O O M CM O U Θ CM O O w ('t υ 11 II II II II CM O _s you CM ffi N K CM QC CO ’τ * cn O u υ u O r — 1 toot K u 4 look ^Ζ Ύ i = r ω 1 ω ω ω \ ω \ ω \ > > $ 5 $ M S O tó L / CM> , x ^u AND AND AND £ AND £ «-Í3 m CM CM s ^{= = = AND s s} (J o U U CM O _s and, P; K K QC Fh ΓΩ co Ê4 <> O r) 0 u K r) m Q u Jt ,-THE. _ r * h t ί ° ν í> § _B ^ 5 έ®ξ i ^ S ω a ω ω \ ω \ ω \ ω \ ω ω \ 1 1 ) $ 1K B CM M u í <r

poo s fq U fq O co fq s u r = i r = / r = / ° __pT Ή 3rd o [= / co ¹ 1 κ ω o o ω V ω ω

co with co Eq M O U ω O THE THE 1 φ ω ω ω

M ffl o O O CM O ' O O u u 3 f \ r ^ \

Leatood 1 SIXTY; í SHIELDS1 Ç CM O O W CM o - - - - s O CM tí O = = = = = = = <ι — 1 tó IT) ffl CM o CM CM CM ™ & oss ο ω oosoo O £ Q-gQ- ^g v rnWWWCQWCQ W 1 Μ Μ M 1 tó ! U S cn The W the JU ífT ...... UT ç CM O o w CM - - O u CM β the _{ts t = =} = - r ^- 1 tó cn cn Μ tti _ ® ^u ° ffi CM CM CM cn CM OO Oh ® ο O Ο Ό O o H h Γί H Çs rò 0 v γ vyyuy '' ω ω ω ω ω ω ω ω Μ Μ Μ tó Cn 13 cn Ο Κ Ο J0 ν οΓ = = = = - = \ -43 ^ζ - 55 -

1 60 $ Ό0! CM Ο Ο M CM U CM d O - rH Pí m ffl CM the aF ίγ Q γ J] ω ω ω Μ tó 1 Μ s Ο Μ ο £ _ _, ν - - - k ζ ° cm> · | ζ; ^ζ CM O u Μ §Μ CM s ο. - ·. . = - rH Pí Μ CM ο υ ο CO CM CM Ο Κ Ο Μ ζ> ^η Q ΐζ> γ Ά ω ω ω ώ _ω ωυω Μ Μ ΠΊ tó 1 Μ S ω Ο Μ ου - - - ο '- CM ^§ <r - 56 -

go

ç (D M © ΓΜ ο O O ο ε 5 £ £ υ υ U υ CM O _ç you υ CO (XI 0 s K © Μ The ο u 5 ο CM CN CM CM ο II II Μ O O Ο s Μ ω s ç u u. υ ω 0 υ ο Ο υ Pí 2nd ®Ύ to ΙίΊ ^ Ι á ΘΛ Φ 11 Γ (ο W 5 5 7 < ί 1 > 1K m 13 M O U U O' - s £ £ £ s CM S MX CM K CM φ> O O - O ο s £ X s u u u ο CM faith O 5 * · * ^s κ ο ΓΠ CO 0 W £ ffl ffi ο II O O 1 Μ ç ο V 13 rH !P ° â ο Ά_ II Pí 0 O O ο Έύ 0 / κ Η Ο (O) ο Ά Θ ; © 5 5 > > > ? 1 K z co O tti O U Pí the ^x ε s £ s £ <n; = a ^x

CM O O Q ......... the o CM ti o = = = = === = Γ — 1 PÍ cm cm qn κ κ á κ g s 0 cm W o O 3 S O 1 u o o cm ο κ ta £ · £ * / ω Ο v 0-0 Pj Pi Η Η] Π Π 1 K & cn the ok O '° = = = = = air' Ç CM O o <R o = = = = = = = = O CM β o = = = = = = = = r * h t CM ta ta ta ta __ KJJ O CM CM s γ jm oOO ™? Õ) OS / õ; (cò ^ o) ° <o> W® \ 2A® \ _Z _to MôSaW ô ^V s © ^ -zQgjá o>)) 1>>>>'> Pi 1 ta g cn o ta op \ P = ⁵ = ^cs - CM Z = S χτ cX

eo <qb |

- ----- leoW® ^; 1 ^: ·; fr; SES «HTA; - es-juBas c CM O o = £ s £ £ s £ £ u O CM faith o = co Cl M K cn ci O U (D > K ffl ci cm CM VM O U O O O The m ω ω u U υ ΛΛ Si u i — i Pi / - (/ ~ \ u CM / O /-( _ ( ^ Õ> (O) <_o <o> <dog <0> -8 < ©) © * \ 7 7 'λ > 5 5 1 you S ω The ffi The U Pi \ P <N \ =! 3 s £ 5 £ £ £ £ κ ³ <'j CM O Φ O O u CM o = you ci n Sy M W w why QC U u ç Cl i — 1 Pi ®A \ (ok / q ^v ? ® M > (5 Γ® Φ \ you /- ° <o ®- ^δ ®) i i ) < J > 1 W Pi S co The ® O . O £ £ £ £ £ £ £ »R ^z <f - 63 -

«KíikU ·. - .-—— ΙΛ ..'..- SI ”« x ~ _ · _r . -, _a ^ -. 7 'W IUWW,] · ^ w / WW '* ··' · '' ·· '' ¹ tttjjadenWq ^ · ---- ^: - © J · i & dH '' c CM O The s U CM o = s = ^{s = 8 =} s Γ) r i CM M 'S U O 1 ω c K tz _y ω s " H pí ii! f XÔ 0 G w JL fGoú ^ω O © T ©) €) > ®> θΛ 7 7 > 7 > > κ 3 n \ _x ^u _{w w} w <! CD CM CM u CJ s u CM β The s = = = : - = = M K o CO u-u ώ r 'O (<' W O ω ω \) \ M < laughs \ tó <o> <o) - ° (õ> (o! f J í Ij ò íT / ifV ®®s 1 K S co the m u o \ P tó - _s s s CM cn ^. - 66

V

CM Ο Ο <D CM O O = AND AND K CM O υ © CM O u AND CM O AND s AND AND = = ^VT H ç 'Ç QÔC © f > 0 ®7 OCQ © T FRESH T <o-f Ph 1 iU S ω o st or \ ⁰ AND AND AND AND AND CM O υ (D CM O u = AND AND S £ = = CM £ O = = - E = = ⁵ Qôr © 1 d 03 ®y < O-x 1 S\ & 00 φΤ Pí - < 1 M 13 co The M υ u f = = = = = £ - 70 -

CM CM Ο O 5 £ O £ £ £ £ υ U u CM O _s you <k CL OH < the u _O ω ^ \ ο OJ jC 1 Π Pí ç frog * cn ίΓ ” ^> 0J li A / oh | J <btzUL xj <zJL n Λ | © \ ÍU / % ©? (£) © J O 4 I u y 1 M g cn O K U _Z O OK \ - g z ° = ^{= s = s 5} <N HJÍ Ç Θ W O ítá CM <D CM CM cM 5 CM XM £ O O O O O O O O U O O O CM ti O s = = = s = O (Ό O CM K O K O u g Π CM <% m ω -A ωΆ W 1 ^x ) I \\ /THE rH Pi í XjJ o ^ oo- ⁸ 03 The £ ίΓ zj & Φ ' © \ 1 K g cn O M u U Pi \ _ 0 ' - £ £ £ £ CM / —G M zg ^B - (UJ J - 71 -

Γβο $ οοΊ ^{; i} - ' | § | l CM Ο υ 0 CM O = O s = = - = - CM β o o = = = z = z r — 1 P4 M d '* PQ y Ί. <* θ / 53 \ J) <n ffl O ΪΙ ¹ 5® r = i ω * 3 vZ, ό © 1 [í Θ í = l 2 _χ ω xq zl <0 © J K υ íl u 1 co cm cn ® Μ K U U M, / ®) >> > Pí M Z m The ffi The Ό \ ° ω = = = = - = CM O o Θ CM s O U - ~ = = w (D S CN CM O O u u CM C O = - = s = - = I-1 cn K U O N M CM O O m K O CN O 2 O O co M U CM O U O Pí look j Vnr riT Hi [X • s -z X ^ ZS. k; Z r /> © © Λ ^v 5 Á cn λ / ^W / 7 7 7 K K g O cn υ w V o '° *> z- / “ ^s κΓ = = - = = =

CM (¾ u u ^Ç CM d O = = = = = = s N M CM rH The U 00 the u ΛΛ 0 Ô k z * ω k_> o .fxcyo ¢, 4.0 ® Y45 w ³ · ^ © pP> ® H>) ® 8 ^> ®s - f® 7 7 ')>>) Oa 1 ffi 13 o □ CO M ^f -d ~ ' ç CM ω CM o κ Φ CM CM u u = O O the o CM β O = = = = = = CD κ CM CM 00 00 O O mu u laugh i i rH tó Cq CO K U > 0 4 07 ® T ω k / 1 1 I CM 00 CM CM s_ m m m m co O co u u I | m i m z <> u —u 4 T i P4 m § u «Γ _{/ E} > ^a 'MJ CQ- ^. CO M y ° = = = = E

CM Ο Ο (¾ 8 8 CM Pi O = tf! r-d Pí 1 co O ω o 6 Pí m g CO O U _X O \ -g '° CM § <J' μ- ¹ ç CM O u the o CM Pi o = - - ~ c rH CM § U co K 1 34 NO co CM CM co UH ® TM \ Qg · Q _§ ® \ S ^ V 8 ^ ® 3 ^ ® © ^ Pí M g co The it <Λ *.

CM Ο Ο CM t — 1 tó Pl co "grandfather Z-b °? T CM O u Μ 1 u ¹ ™ ^u ~ * <. - = cm «0 = 0 S = o 8? ? the U 1 1 CM β <! Γ — 1 Pd td ™ ° § »r 4-, s Jy ° 7 r? 2 t ^ r n rU / r b i n \ \ P4 n KO | 3 O â = 3 ^Z = = = = = = CM KJ

CM O U CM O υ CM laughs O C rH tó i S-Ç Pí 1 § ™ n n ® ^U Λ * V ^ X ° = cm K 'J c CM The U CM O U = = = = = = = = = CM laughs O = = = = = = = = = C rd Pí CM co co M mum cm / g% J 2'3 U ^{^! at} <jaj! 3 ^'i5 \ ^{Ρ 2Ζ Λ} 2 5Λ ZRA SJS \ zf \ TJ TkJsUU ^1' J? · 9 ¹ JP ¹ 9 '^ kw mmWMWWWtQ CO ⁰ ) Π mm π Pí 1 M CM £ 3 OK υ u \ _ O = = = = = = = = = r <r

f õò * à & 1 j CM 1t K CM .. _s O <7 O u o CM O = = = 5 = = = κ M ΓΊ Ο Μ M m r 1 r i S-H. The & y $ <í co O ^ fco σ ,, Ϋ ω ο cn ω s U) P ω <1 ? g ω Ο Λ © \ ) ^w > > > i> í > ) > > 1 M K s o o A ° Λ } = S ^Z í-ZjT ω c CM Φ O O o = = u • “ “ “ CM tí The s = = = = = (Ό W r) rH tó Í * A I ω r ^ Y „UJ \ li Hi f | í ^z xy t * J * la ^ * c? teA y ✓J zj l x JJ H > 7 <l ®) ®) © ' λ © \ © p ) and ) 5> 5 1 5 1 > 1 S M ΓΊ <4 . LJ o Ao ^U \ _ c> s CM _ / “S ^z - 85 -

ί60 »ΟθΊ CM O o (b ® Q m CM = CM AND TM 5 5 CM O O O O υ υ υ ο CM tí 5 5 5 5 5 5 = = is the η - g m gB η co U _x Κ 1 1 Μ .— κ Va. ~ .___ a ^ zu Qr Q § = °> OdHQf OC ω The 1 π Μ π ° 8 / - ^υ CM O O % Q ΕΕ ΕΕΕΕΕ Ο CM tí Ο 5 £ 55 5 5 5 <rd Pí Π Μ υ I υ = ο φΗ © X © Η © Λ you I Μ Μ § Λ 8 ° _ν . .. ... §Xr - 87 -

CM ffl CM o Ο u the o O CM fí O = = = = s M O M ONE Εύ H x í ^ r s * nf cn K O u Π - u ω _F V ω ω ^e / ®p? R ) ) > THE > > > > > 1 pm a r) tó § u V. CM Z- / · g-O > o = 3 ' = = z = c CM QJ u kj υ CM tí O = = = z AND r — 1 toot 0 © \ it's the ®> a> G \ $ i 5 > > t-L The r ϊ P4 ⁸ ><ocm> ^{—z to} c / r = = £ - s

*

!; 5ESS «NTA

ESCUOOS-

CM O o K 0 CM = CM - O O O o CM tí O = = = cn M O 2 / r y ω í T J ω 1 l 1 í i a K u §> c CM The u Θ CM O = = = O CM o = = = <1 H tó CM cn M M S U 1 ω ω _ w J look at you 7 7 7 M § §> U ^z CM) = 5 - /] T ui

οι δλ κ οι ο Ο ⁼ ο L7 Ο οι β ο s = - ο = = Μ OK Μ ο Ο Μ Γ 1 Γ) γ — 1 fq Μ κ Μ _β ”Λ ° γ σ ο ζχ 0 Ρ 1 ω 2 ^ 25 υ ω ω 25 ω ζ ±> 2 φ 2 ^ω \ m Β Ο ) "0 ) 7 7 7 ? ) > C0NHχ> The ΟΥ ⁰ ω OJ % .. _{= 5} £ ε ₌ υ LJ ο ΟΙ ο = β Μ Μ Γ — 1 tó ο οο 00 & (Γ L ^ ³ <Δ 0 1 ^ 1 0 ω- ^ & ®) © \ $ ® \ <b \ 7 7 5 5 - · 4 >) ) The § Γ Β <Γ = = £ S S = <51 ^§ <Γ

Csosoo ι

Sessmt * · ₃ , j

© j . ! gi & OUDOS < CM Ο ο M © CM cM The s o s O O CM Ρί The s s = = <rd Pí Μ Co co O O W M 2.  O U O U 9 2 A ç <g “A u w ω ω ω 2 'Ί 1 i m P4 g Ο S_ Ο '' - 'ípf ω-- ⁴ ç CM O u _ Μ <%. = = = = - -. 0 'ο υ ο CM β ο = = S = = = Ο rd CM Μ co 2 Ο - J co ω ωνω “fq μ» 'co ό && Φ çmjí οζ-Ύ' ^δ Pi 1 Μ - 9 \ _ ο '' f <r 1 1

j 6Q $ O0 ~ | rtj CM O u © ok Hm s = = = cm = = O O The U cm β o = = = == = = <rH M m cm okay ο ω § ° o / w ^u -4 ω za ig i S RT RT ^r "Γ Μ Z RTR toaw nf ^Ύ XGR JJE z ^ C / I> x * <· Λ μ ω UW ω 1 b 7; ®; ⁵ j -j OK OK 1 CM So g ° 8> ==== = w / K <! CM O υ <D Hm O = = = = = = = O CM β O = = = = = = = rtí Ok ΠΊ're ω λ f = \ | j | ^ω y ³ ^ ô Οοπ α π ò o ® | ® | © 5 OK M 1 CM M o to 8> ......

..... Q 6Q * 0 G> / M Φ CM CM O O 5 CM = = S £ 5 ο LJ o CM fí O = = = = = s = H tó cn ω o SO ³ co M O U = O O 0 wire co $ J ^ i jO ôr U 1 > © X © X © X © \ > > > >> >> M 8 hU CO CM δ 8 Xcn Q £ Pí = = = = = = O rtj Θ CM CM O O CM tí O = =  - c s = = cn W m M O w r j 1 III 0 = 0 r-4 1 w LOL 1 w Pí cn ffi n ω OKO _v 1 _X O O O Ui z * Ò 00 ζΜ The © í © í © 5 © 5 ® | ”G ³ · ^ ® > 7 7 7 Pí 1 IT § O M m cm W O O O Xcn \ ,OK Ui ^ 97

Γ i Q0 $ 00 | & -7 | I1ÍU JFOCe · 1  xC ^ ** · Ehi ; W HM · ^ QjUh 13; _the v <! CM f> AND CM E _ç Θ CM _ç u The υ kJ υ CM £ o = = ^and = = AND AND THE E ΓΊ Μ Γ1 r) There F * f u ^z 'η ω ω “) 1 fA z = f ω % cn IT'S THE ço > UJ >> > r ') Μ M ο r> r) AND \ J vJ 8 X η \ δ - . _{= =} <N C CM Φ CM AND CM The υ O = u “ “ O o CM P! O = ^s • = and AND and = CM E pT * 'l ⁶ -1 E 1 υ ω _ ω — 1 ó áfáror <SÔ ©} © ^ :> ®9 ^ ^g <K>>> cn E ç * V \, u ω AND 1 co CM E AND O s υ υ 8 Xn AND g g g _{= s} \ __ kJ H-H θ '° 1 38

βο $ οοΊ j®S | Í ϊϊςχ ^j S> 3 HO SCSSCNT * I ^J WUP0S-- j c CM O Λ K (D ^0X1 Ά ee eeO if OO U CM laughs Ο Ε = E E S s E C Η KO with KO tti CM QOU MI ^o // la Λ · ^K a ·, a ^ω χ> 4 co fw ο α - ο ϊ w, 4 to 4> aA ^m ω Θ | S j tó CM 1 W aa § 8. W ⁼ ''' CM The U 0 í ~ M OE = BESEE u CM Pi E E S E = E S H tó CO m ω-λ rt = \ r <> “ Ô ÇQ 05 ff O ô KT ©) ®) ® \ ®) © 7 @ \ © J ©) ) 7 7 7 7 7 7 7 CM i m w a to O <J . W ...... §- <Tf ω - 99 -

- 100 -

C CM The u 0 © CM = E = CM = O O The u CM £ o = = = = = r — 1 Μ M The cn ju s-g · The Q Μ The Jr í 13 J3 'J3 T ζΡ z & Z * ω „'T -3: s oo P4 1 m cn 13 The u % o> - '- í <r I C CM O o Φ K CM CM O = = = E E = O u u CM The E = S = = = = <rd tó CM 4 is it? $ To _the TO Tm ®7 ®5 ® ©} ^ ® @ 5) 8 1 tti <n! 3 OO O <-? \ OES 5 S = = / = ^ ^Z tzf CO- ⁴

105

60S00 I mjCT / ΏγμΙ - CM 8 © M cM CM o s = = = o S = O O CM £ O O = = = = = = rj ^K S O co cm Μ O M- KOOU _T ⁿ ts fX X> íV W / TX «. J LaO Ç JX H <j k. JL · ω u “© ^ ® ^ O ia | \ tó 1 M § U / = = = = = = 5 \ __ O CM y ⁼ g 'S ^ ef Ui rfj, CM 1 O 1 o o o CM £ O = = = = = s = r-i CO h ^- * U CQ 0 (COCOíP ^ uÔ & © T ®j © T ®j <® ^ T © ^ tó I ffi § ^ - (' \) -. ...... X- o CM 'ω-J - 106 -

- 111 -

; 60 »oo | 3 igiii 8JrJ) r * ã γ * Ρ * kfe 11 Í'Z gMgJ | r «ss < | - · E8 & U CM ffi CM = CM The υ Ο u U CM c O = = = = = M Hi The ffl K u u ç <—1 P4 K 3 kX ΐΛ Π m 01 a * / * Y ffl O ω ω )) % A> z >> >> > 1 m ® ffi 3 U tó % O* = = = = <! CM © « M CM O O And £ X s = O 1st u u CM tí O _ s = 8 = = = CM M a w u ω ω -a ω "d 00 M & = a χ è V \ n ω K Γ rH tó 2nd & fy 05 ô; Wn (c U X © Λ © Λ © Λ © Λ © Λ ©) ► ^u ? 7 Z 7 y) > 1 01 m k 8 O* you And £ £ z £ £ w cn **

113

1 $ 0 ι $ Χ3 0 1 1¾¾ CM Ο υ © CM O = υ s z z W CM o = = U CM C5 ο = = z z = = = 3 01 CM Μ £ > ^§ VçC mu K O cn MOM O OR p = ç aA ^ °} = <YpY ² V ^B ω ο ο ω ω -7 l 01 í (u /, J = B '° §-e j Μ- * z = = z z z CM Ο υ 1 © CM O = u = = = z z z CM 0! The s = = = z z z 3 01 Q G ΦΛ Φλ ω-λ / ^ \ \ ÍiY ÍÍM _b / Ιζχ -Ax.y <xl cn K \ ω ) to Λ> Ô tó 1 s V ⁸ x> ^M 'taZ ^' ⁰ §- (T ω— ' z z : = = - 114 -

pasci οΊ | ·] - λ CM Ο Ο CM CM = 5 5 S Ο Ο ο υ CM β Ο = = 5 5 5 3 Ρη <Ό W υ ί υ-ο ω »Ο ço δ οο air © ^ © jp « 1 Μ § Ζζ ^c ') - -. ω- ⁴ <1 <Ν Ο Ο W © CM CN 0 = 0 = = = = 5 υ ο CN β ο = = = = = = = « C0 Κ υ η κ ί Η &. Ο Ο Ο // Ζ 111 1 πί ι £ ί 31 ο cm μ; ζ: β \ <3 \ Ί ^{1 ω} Γ = Λ ^υ 1 'Τ 11 ω CM Ο / rn \'> 0 Μ ⁰⁰ J1 / 7¾ * L> 1 / ^ χ ¹ k υ Α ⁰⁰ χ ^ ζ ³ ω ω ε ^ zkZ JSlzAn> 3 ϊ) j η “1 ®ν} « ί ® h 'Κ </ ο) ο / \ _ Ο 5 5 5 = = = CM .β · '/ § <'] ω

-115

116

σι Μ CM Q. Ο Ο £ Ο - £ s = s Ο Ο ο <Μ Ο __ _{Β w} _ β Γ — ί Ά C0 η Μ Ο fj <γ · γ ^ \ ί Μ χγ 0 = 0 ο II ' ^ω Χ /> U Π xl H ) J2 » > ) © Θ Θ) ) 5 ? ) > s ω 1 Μ κ Ο 3 σι Ο Μ Ο Ο £ £ £ s £ Ε V Ο §Ό & σι Ο Θ ο _s - - £ s = S U ο CM 'ο β ω Μ W Μ ο Ο Μ I 1 ο ο 0 = 0 III 1 I ο CM Μ ι Μ Ο ί σι Ο Γ ~~ \ ο Μ η | ω VQ Κ Ο H ό ό . ^ω J0 O ο > & Ο \ ο © ^ © ί Θ) ν ω 'κ / > ^υ | ω 1 m m ο σι ο Μ ο Ο \ _ Ο ' £ 5 s £ = = σι Κ J W- ⁴ «R · 120 -

<CM O O the CD CM CM O = = = o - υ o CM Pi The 5 = = S = <rd tó K cn cn ffi O ffi a g. o OU U // ¾ 1Y K ϊΑ u -f * ^S Y τ g qhr \ ί ΐ ΐ ®Ι ι The <Ό 1 Μ Β Ο a οι ο a νΧ = = = = <ν to ~ v ~ ij < CM O u φ ^κ ^ CM ΟΙ Ο = = = = 5 = 0 υ u CM Pi Ο = = '= = = 5 = <rd ok CM CQ to aa ο | ω ω ω ϋ, β ° ώ # & 9 ^ 'θ'ÇC-'ν®>®>®>®> ®5 ®5 ³ > The (Ό ι a a ο a οι ο a UU = = = = = = \ _ο ^s <f - 121 -

1 ™ ο ο «Λ ο υ ΟΙ β ο = = Η 1 Β Cf ÇO Í? θΛ ^ω © ί Ρί Μ Ο η η Ο ...- / Κ Μ Μ μ g, ΖΓΆ κ g υιυ s-gJL # y_o ο = χ_ CT ^ O οι J = g “<Ί Ο] Ο υ φ κ ΧΝ ΟΙ ο ο = - = = = υ υ Ο] β ο = = = = = = 3 tí Β Ο en cn, η ^ = ia: ψ. = ^ υ ® η]]] ίΉ Ρί ίϋ I Τι ™ ο = ι> § OJ 1 Μ κ. “F. ϊ «*» ° Λ & Π = ο Í-C?

- 122 -

ç CM O O Θ © 1 © M CM CM CM CM O == O = OO = o o o o CM laughs The S 8 s s s = rd Pí co ffl co O OK 1 P W OS —2 XJ '1? ¹ 'V * ç mo mo çoW Pí ¹ _P ^M ? - © - ° 0 = 0 «0 = 0 1 J / oim ω_ο / z = = = x? G rw • P o O Η 1 M ç CM o O Bm = = CM = = = O O O O CM laughs O = = = SB = r — 1 Pí K co OO A Λ X ^Βγ8χ P 11 JL 0! L / · m ^! ow ω μ o X? οΧλ ow co; the co ω Ί í 1 Γ -Μ Ί Pí 1 1 M K zr \ M .ri O ? © ° 7 ffia © g © g O 1 O o 1 o -p the -PO Μ 1 to 1

- 123 ίι

Μ Q K CN ο Ο O O ο υ O O CN ο ₌ s Μ 2 7Ί K u cn the cn Pi ^s v \ _m ^ f ^a 2 ο CQ U CO W (! ΰ O (í , ✓) the cn \ Μ \ © Θ \ Θ \ and \ / J / 5 s >> > THE > 2 2 K 2 ο-ο ω Μ Ο 0 = 0 w Ρί s = 1 co = ^{= =} X- • cn ο 0 2 CN Q, M CN © * ΎΝ w CN Ο ο O Ο O O s Ο ο u O O u CN β ο “ * ^s Γ-4 Ρί Ç0 2 = ^ ώ 00 Tf í ] 3 ço @2 1 @2 Μ 2 2 κ 2 r \ * 1 = o 1 M you CN o <4 Ο ο ρ © a = φ ” u 5 g - 124

125

Γ8QÍ0ÕJ:

EXAMPLE OF REFERENCE A; 7- / 2- (2-Aminothiazol-4-yl) -2-methoxyimino acetamido / 8-oxo-4-thia-3-methoxymethyl-1-azabiclclo / 4-2-0 / oct-2-eno- 2-carboxylic sin racemic cis.

PHASE A: methoxyacetaldehyde.

100 cm of methoxyacetaldehyde dimethyl ketal, 100 cm of water and 3.2 cm of concentrated hydrochloric acid are refluxed and then several fractional distillations are carried out and 8.7 g of the expected product are obtained.

PHASE B; 1,1-dimethyl ethyl 2-chloro-3-methoxymethyl oxirane carboxylate.

A mixture consisting of 2.106 g of methoxyacetaldehyde, 3.8 cm of terbutyl dichloride and 25 cm of tetrahydrofuran is cooled to -20 ° C. 29 cm of potassium terbutyl in tetrahydrofuran (0.9 M / l) are introduced for 15 minutes and left in contact for 1 hour and 20 minutes. Add 25 cm of ether and 25 cm of water and extract with ether. Wash the organic phase with saturated sodium chloride water, dry and concentrate to dryness under reduced pressure. The residue obtained is chromatographed on silica, eluted with methylene chloride and 1.44 g of the expected product are obtained.

PHASE C: 7- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-2-hydroxy-3-methoxymethyl-4-thia-1-azabicycle / 4-2-0 1,1-dimethyl ethyl / octane-2-carboxylate.

1.38 g of 1,1-dimethyl ethyl 2-chloro-3-methoxymethyl oxirane carboxylate, 2,736 g of 4-mercaptomethyl-3- / 2- (2-tritylamino-thiazol-4-yl) -2 -petoxyimino ace tamido / -2-oxo-1-azetidine cis racemic prepared by the process described in Belgian patent 894,795 and 12 cm of dimethylformamide. After 10 minutes of contact, 458 mg of lithium carbonate are added and stirred for 2 hours and 50 minutes. The reaction mixture is poured into 100 cm of water and 60 cm of ethyl acetate. Extract with ethyl acetate, wash the organic phase with water, dry and concentrate to dryness under reduced pressure, the residue is taken up in ether and 3.058 g of the expected product are obtained.

- 126 -

Analysis: 0-, _ο Η _Λn 0-, N _r S _o : 743.91

-------- 38 41 7 5 2 Calculated C% 61.35 H% 5.56 N% 9.41 S% 8.62 Found 61.1 5.7 8.9 8.4

PHASE D: 7- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-3-methoxy methyl-4-thia-1-azabicyclo / 4-2-o / - 1,1-dimethyl ethyl oct-2-ene-2-carboxylate.

4.44 g of diphosphorus tetraiodide is suspended in 35 cm of pyridine, stirred for 5 minutes and 3.058 g of 7- / 2- (2-tritylamino-thiazole) are added in one portion. 1,1-dimethyl 4-yl) -2-methoxyimino acetamido / -8-oxo-2-hydroxy-3-methoxymethyl-4-thia-1-azabicyclo / 4-2-0 / -octane-2-carboxylate ethyl and stir for 2 hours and 40 minutes. Distillation

pyridine is taken up, the residue is taken up with 50 cm of ethyl acetate, filtered, 50 cm of hydrochloric acid N are added to the filtrate, vigorously stirred and the organic phase is decanted, washed with water , dry, concentrate to dryness under reduced pressure. The residue is chromatographed on silica using a mixture of methylene chloride-ethyl acetate (85-15). The fractions of interest are concentrated to dryness, recrystallized from methanol and 703 mg of the expected product are obtained.

Analysis: C _nn H ™ 0 ^ N, -S _o : 725.89

---- 3839652 Calculated C% 62.88 H% 5.41 N% 9.65 S% 8.83 Found 62.7 5.4 9.6 8.8

PHASE E: 7- / 2- (2-Aminothiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-4-thia-3-methoxymethyl-1-azabicyclo / 4-2-0 / -oct- acid 2-ene-2-carboxylic sin racemic cis.

246 mg of 7- / 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino acetamido-8-oxo-3-methoxymethyl-4-thia-l-azabicycle / 4-2-0 / -oct 1,1-dimethylethyl -2-ene-2-carboxylate in 1 cm of trifluoroacetic acid and left in contact for 50 minutes at room temperature. 12 cm of isopropyl ether are added, the precipitate formed is filtered and 176 mg of crude trifluoroacetate are obtained, which are dissolved in ethanol. Add 2 drops of pyridine, allow to crystallize for 1 hour and obtain 88 mg of the expected product.

127

Analysis: ^c i5 ^H q7 ° 6 ^N 5 ^S 2 ^{: 42} 7.46

Calculated C% 42.15 H% 4.01 N% 16.38 S% 15.00

Found 42.2 4.0 16.2 15.0

REFERENCE EXAMPLE B: 7- / 2- (2-Aminothiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-3 - / (1-methyl-1H-tetrazol-5-yl) -thio methyl acid ] / / 4-thia-1-azabicyclo / 4-2-0 / -oct-2-ene-2-carboxylic sin cis racemic.

PHASE A: 2- (1,1-dimethyl ethyl) dimethyl-silyloxy / ethanol.

At 209C, they are mixed in an atmosphere [of nitrogen:

I- 18 g of tert-butyl methylsilyl chloride, r 150 cm of dichloromethane,

- 17,5 cm of dimethyl formamide,

- 33.6 cm of ethylene glycol.

After complete dissolution, 20.1 cm of triethylamine is added for 5 minutes and then 1.8 g of 4-dimethyl amino pyridine are added. After 2 hours and 45 minutes of stirring, the solution is poured into 120 cm of water 3 and neutralized with N hydrochloric acid (approximately 40 cm) in order to obtain a pH of 3. Decant, extract again to fc *

if aqueous with 20 cm of pentane, then the organic phase is washed with 60 cm of water which is extracted again with 20 cm of pentane. The organic phase is dried and distilled under reduced pressure. After rectification, 13.9 g of the expected product are isolated. Eb 16 mm / Hg = 829-869C

PHASE B: 2 - / (1,1-dimethyl ethyl) dimethyl silyloxy / acetaldehyde.

Keeping stirring in an atmosphere

3 of nitrogen, 4.71 cm of oxalyl chloride is dissolved in 120 cm of dichloromethane. Cool to a temperature of -70 ° C and introduce for 12 minutes keeping the temperature at -65 ° C, a solution of ~ 3-3 cm comprising 8 cm of dimethyl sulfoxide and 26 cm of dichloroethane. Then, after 10 minutes of contact with this temperature, the next solution at -65 ° C is introduced for 12 minutes. C comprising 8.81 g of 2 / (1,1-dimethyl ethyl) dimethyl silyloxy / ethanol obtained in phase A, 50 cm of dichloromethane and 8.86 cm of

128 βΜ

pyridine. After 15 minutes of contact at this temperature, 3 joins in 8 minutes at -65 ° C _Z 35 cm of triethylamine. At -13C, neutralize with hydrochloric acid N, in order to obtain a pH of 4. Decant, extract again with 50 cm of dichloromethane, dry the organic phase and distillate. if under reduced pressure. The crude product is chromatographed on silica eluting with dichloromethane. Finally, 7.95 g of the expected product are isolated.

PHASE C; 1,1-dimethyl ethyl 2-chloro-3- (tertbutyl dimethyl silyloxy methyl) oxirane carboxylate.

It operates as in phase B of reference example A, taking care to introduce at the same time the solutions of potassium tertbutylate and 7.95 g of aldehyde obtained in phase B at -20 ° C, in a solution of dichloro acetate of 1,1-dimethyl ethyl and, after chromatography on silica (eluent: hexane-dichloromethane 6-4), 9.4 g of the expected product are obtained.

PHASE D: 7- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-2-hydroxy-3 - / (1,1-dimethyl ethyl) dimethyl silyl xi methyl / - 1,1-dimethyl ethyl 4-thia-1-azabicyclo / 4-2-0 / octane-2-carboxylate.

It operates as in step C of reference example A, with a reaction time of 16 hours. After chromatography on silica and elution with dichloromethane-ethyl acetate (75-25), isolate from 8.31 g of 4-mercaptomethyl-3- / 2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino acetamido / 2-pxp-1-azetidine cis sin racemic, and, from the product obtained above, 9.09 g of cyclized product.

PHASE E; 7- / 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino acetamido / -8-OXO-3 - / (1,1-dimethyl ethyl) dimethyl silyloxy methyl / -4-thia-l-azabicyclo / 4 1,1-dimethyl ethyl -2-0 / oct-2-ene-2-carboxylate.

It operates as before in reference example A, phase D. The contact is reduced to 55 minutes. The reaction mixture is poured into water, acidified with

129

; -60 $ 00 2N hydrochloric acid up to pH 1.4 and extracted with ethyl acetate.

Starting from 9.09 g of product obtained above, they are isolated, after chromatography, 4 g of product expected. UV spectrum - in ethanol infl: 233 nm 364 infl: 265 nm 1 ^E i 173 max: 302 nm 1 ^AND 1 229 ê = 18900

PHASE F; 7- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-3-hydroxy methyl-4-thia-1-azabicyclo / 4-2-0 / oct-2-ene 1,1-dimethyl ethyl -2-carboxylate.

A suspension of 2.595 g of silylated derivative obtained in phase E is prepared in 30 cm of acetone and 4.7 cm of hydrochloric acid N. The solution becomes clear little by little, and after 3 hours of stirring, 7.7 cm of saturated bicarbonated water are added and the acetone is distilled under reduced pressure. Add 20 cm of dichloromethane, stir, decant, extract again and dry the organic phase and distillate under reduced pressure. The residual gum is dissolved with 5.5 cm of ethyl acetate, to which is added 43 cm of ether. After 3 hours and 15 minutes of stirring, the crystals formed are filtered, rinsed and dried. 2.232 g of the expected product are thus isolated.

PHASE G; 7- / 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino acetamido / · -8-oxo-3-chloromethyl-4-thia-1-azabicyclo / 4-2-0 / -oct-2-ene 1,1-dimethyl ethyl -2-carboxylate.

623 mg of alcohol obtained 3 in phase F is dissolved in 8 cm of dichloromethane with 834 mg of tosyl chloride and the following solution is introduced for 20 minutes, which contains 534 mg of 4-dimethyl amino pyridine and 5 cm of dichloromethane. After 1 hour of stirring, 2.2 cm of hydrochloric acid N is added, stirring, decanting, drying the organic phase. After distillation under reduced pressure, the residue is chromatographed on silica eluting with dichloromethane-ethyl acetate, (9-1). The expected product crystallizes from ether; 245 mg is obtained

*. this product.

130

UV spectrum

- in EtOH

infl: infl: 224 264 nm nm E-]: ^X 1 ^Ε 1 _ί ^: 441 179 £ = 38200 infl: max: 271 306 nm nm ^E 1 ^: 1 ^E 1 ^: 164 222 is = 19200

PHASE H; 7- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-3 - / (1-methyl-1H-tetrazol-5-yl) thiomethyl / -8-oxo-4 1,1-dimethyl ethyl thia-1-azabicyclo / 4-2-0 / -oct-2-ene-2-carboxylate.

301 mg of the product obtained in phase G, 114 mg of the sodium salt of l-methyl-5-mercapto-1,2,

3,4-tetrazole in 3 cm of dimethylformamide. After 1 hour and

40 minutes of stirring, pour the solution into 30 cm of water and extract with ethyl acetate. The organic phase is dried and distilled under reduced pressure. The obtained gum is dissolved in ethyl acetate (2 cm) and ether is added up to the limit of solubility. The crystals obtained after 45 minutes are filtered, rinsed with ether, dried and obtained twice. 283 mg of the sought derivative.

PHASE I: 7- / 2- (2-Aminothiazol-4-yl) -2-methoxyimino acetamido / · -8-OXO-3 - / (1-methyl-1H-tetrazol-5-yl) -thiomethyl / 4 -thia-1-azabicyclo / 4-2-0 / -oct-2-ene-2-carboxylic.

It operates as in example 1, phase E, but the impure product is dissolved in bicarbonated water and acidified to pH 4, then filtered after having distilled one. much of the water. From 371 mg of product obtained in phase H, 61 mg of the expected product are isolated.

UV spectrum

1) in EtOH max: 302 nm: 295

2) in EtOH / HCL N / 10 infl: 273 nm: 304 max: 285 nm: 318 infl: 292 nm: 312 infl: 309 nm E- ^: 245

6 = 15100

16300

16000

6 = 12500

131.

The corresponding optically active products and in particular 7- (2- (2-tritylamino thiazol-4-yl) -2-methoxy imino acetamido / -8-oxo-3-hydroxymethyl-4-thia-1- 1,1-dimethyl ethyl sin 6S, 7S azabicycle / 4,2,0 / -oct-2-ene-2-carboxylate operating as in reference example A starting from 4-mercaptomethyl-3- / 2- (2-tritylamino thiazol-4-yl) -2-methoxyimiacetamido / -2-oxo-1-azetidine cis sin 3S, 4S described in French patent application RF 2,538,389.

The product obtained has the following physicochemical properties:

D = 1809C.

Ultra violet: 1) of the characteristics ηο

2)

In ethanol: inf. • • • • • • 222 237 302 nm nm nm inf. max. In ethanol and HCl 0 , 1N inf. 221 nm inf. • 263 nm inf. • • 285 nm max. • • 293 nm inf. • 300 nm inf. • • 310 nm

^ε 4 ^Ε 1 ^Ε 1

444

352 β = 15900 ^Ε ν ^Ε 1 ⁼

Ε =

Ε ι = ^Ε κ = ^Ε 1 =

464

204

294

340

299

230 έ = 22000

REFERENCE EXAMPLE C: / 7 // (2-Triphenylmethylamino thiazol-4-yl) -2- (Z) -methoxyimino acetyl / amino / -2 - / (1,1-dimethyl ethyl) -oxycarbonyl chloride 8-oxo-4-thia-1-azabicyclo / 4,2,0 / -oct-ene-3-yl / methyl / triphenyl phosphonium 6S, 7S.

2.182 g of 7/2 (2-trityl. Amino thiazol-4-yl) -2-methoxyimino acetamido / -8-oxo-3-chloromethyl-4-thia-1-azabicyclo / 4,2,0 / 6S, 7S 1,1-dimethyl ethyl -oct-2-ene-2-carboxylate prepared as in step G of the reference example. B and 1,679 g of triphenyl phosphine in 24 cm of tetrahydrofuran, add 14.1 g of silica, distill the tetrahydrofuran under reduced pressure for 2 hours, cool and stir for 26 hours at 20 ° C, chromatographed. on silica (eluent dichloromethane-methanol 9-1) and 1.89 g of the desired product are obtained.

132

.....

Example 1: 7- / 3/7 - // 2-amino-4-thiazyl) trifluoromethane sulfonate (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 sin.

Phase A: 7 - // 2- (2-triphenylmethylamino thiazol-4-yl / -2 (Z) -methoxy imine in acetyl / amino-3- / 3 - / (1,1-dimethyl ethyl) dimethyl silyl / oxy (1,1-dimethyl) ethyl 6S, 7S /-propen-l-il/-8-oxo-4-tia-l-azabicyclo/4.2.0/-oct-2-en-2-carboxylate.

1.89 g of 7 - // 2- (2-triphenylmethyl amino thiazol-4-yl / -2 (Z) -methoxy iminoacetyl / amino / -3-methyl triphenyl phosphonium-8-oxo-4 hydrochloride are mixed -thia-1-azabicyclo / ethyl (1,1-dimethyl) ethyl 2.0 / -oct-2-en-2-carboxylate, 30 cm of dichloromethane, 0.68 cm of 2 / 1,1-dimethylethyl dimethylsilyl oxy / ether q taldehyde, 0.53 cm of triethylamine, stir at + 20 ° C for 14 hours, chromatograph the solution on silica eluting with a mixture of dichloromethane and ethyl acetate (9/1) and isolate 1.305 g of the expected product contains a mixture of isomer E (2/3) and Z (1/3).

NMR spectrum (CDC1 ₃ )

0.90 - 0.92 ppm SitBu; 1.50 - 1.53 ppm CC ^ tBu; 2.95 - 3.11 ppm CH3 S; 4.05 ppm OCH3; 4.31 - 4.37 ppm CH2 O 4.11 ppm Hg; 5.4 to

5.5 ppm 5.75 - 5.87 ppm and 6.11 - 6.24 ppm ΔΖ (1/3); 6.17 -

- 6.34 ppm and 6.97 - 7.16 ppm E (2/3); 6.50 - 6.56 ppm Hg thiazole sin; 7.34 ppm 0 ^.

FAse B: 7 - // 2- (2-triphenylmethylamino thiazol-4-yl) 2 (Z) methoxyimino acetyl / amino / -3 - / (3-hydroxy propen-1 (E) -yl) -8-oxo- (1,1-dimethyl ethyl) 4-thia-1-azabicyclo /4.2.0/ oct-2-en-2-carboxylate,

7 - // 2- (2-triphenylmethylamino thiazol-4-yl) -2 (Z) -methoxyimino acetyl / amino / -3- / 3-hydroxy propen-1 (Z) -yl / -8-oxo-4- (1,1-dimethyl ethyl) thia-1-azabicyclo4.2.0/ oct-2-en-2-carboxylate.

1.305 g of product obtained are dissolved

3 in phase A of example 1 in 15 cm of acetone, add 2 cm of normal aqueous hydrochloric acid solution, stir for 2 hours and 30 minutes, concentrate until drying by distillation under reduced pressure, if bicarbonated water is extracted with di133

chloromethane, concentrated to dryness under reduced pressure, chromatograph the residue on silica, eluting with a mixture of dichloromethane and ethyl acetate (1/1) and isolate:

536 mg of E isomer and,

369 mg of Z isomer of the expected product.

Isomeric controls (E).

I.V. spectrum (chloroform)

3607 ^Cm_1 OH; 3405 NH amide; 1684 C = O;

1515 ^cm_1 amide II; 1772 ^cm_1 lactam C = O; 1595 ^ ^1-1 , 1544; 1527 ^cm-1 · aromatic, thiazole, conjugated system;

1700 ^Cm terbutyl ester; 1370 ^cm ; CHg;

1154 ^cm_1 COC; 2820 ^cm_1 OMe; 1049 ^cm-1 C = N-OR.

U.V. : ethanol

Max. 231 nm Inflection 258 nm Inflection 264 nm Inflection 270 nm Max. 320 nm

- = 497 f = 32 200. 1 = 290 • / E ¹ = 264 • l ^And i  = 240 r AND: ^: = 245 ·, E = is 100.

NMR spectrum (CDC1 ₃ )

1.51 ppm tBu; 3.05 ppm C3 S; 4.02 ppm OCH ^, 4.28 ppm C ^OH;

5.48 ppm: H ·? ; 6.24 - 6.41 and 6.97 - 7.13 ppm H ethylene ΔE J = 15 Hz; 7.29 ppm 0 ^; 6.53 ppm H ^ thiazole sin. Z isomer controls.

I.V. spectrum (chloroform)

3605 ^{cm -1} OH; 3405 ^cm_1 NH amide; 1685 ^{cm -1} C = O;

1505 ^cm_1 amide II; 1773 Lactame C = O;

1704 θ ” ^{1 1 terbutyl} ester, · 1368 ^031-1 Me, · 1154 ^cm-1 COC;

1585 ^cm_1 , 1573 ^cm_1 , 1527 ^cm_1 , 1493 ^cm-1 , trityl, aromatics, thiazole, conjugate system; 2820 ^{Cm 1} C = N-OMe; 1050 ^Cm_1 C = N-OR.

U.V. (ethanol)

Inflection 230 nm E ¹ = 411; Inflection 260 nm E ^ = 220;

Inflection 265 nm E ¹ = 198; Inflection 271 nm E ^ = 176;

Max. 308 nm E ¹ = 194 = 14 300.

'NMR spectrum (CDCl _n ) • —— .. - □ • 1.49 ppm tBu; 3.06 ppm S-CH ₂ ; 4.04 ppm OMe; 4.27 ppm CH ₂ OH;

134 βΟ $ ΟΟ

5.48 ppm; 5.85 - 5.98 ppm and 6.21 - 6.34 ppm ethylenic Z J = 11 Hz; 6.56 ppm thiazole sin; 7.29 ppm 0 ^.

Phase C; 7- / 3- / 7- / 2- (2-triphenylmethyl amino thiazol-4-yl) -2 (Z) -methoxy imino) acetyl / amino / 2 - // 1,1-dimethyl ethyl / oxy trifluoromethane sulfonate /carbonil/-8-oxo-4-tia-l-azabiciclo/4.2.0/-oct-2-en-3-il/propen-2(E)-il/tieno/2,3-b/piridínio 6S , 7S.

222 mg of E3 isomer obtained in phase B of example 1 are dissolved in 4.8 cm of dichloromethane, add 3

3 cm of solution containing 536 mg of thiene pyridine to 10 cm of methylene chloride, cool to -70 ° C, add 2.7 g of trifluoromethane sulfonic anhydride solution containing 0 drops dropwise, 42 cm to 10 cm of methylene chloride, take slowly to + 20 ° C, concentrate until drying by distillation under reduced pressure, add ethyl acetate, wash with water containing 0.7 cm of aqueous solution N of hydrochloric acid, decant, wash with water, extract with ethyl acetate, concentrate to dryness under reduced pressure, chromatograph the residue on silica, eluting with a mixture of dichloromethane and methanol (92/8) and 236 mg of expected compound (E-isomer) are isolated.

Phase C ¹ ; 7- / 3/7 // (2-triphenylmethylamino thiazol-4-yl) -2 (Z) -methoxyimino) acetyl / amino / -2 - // 1,1-dimethyl ethyl / oxy / carbonyl / trifluoromethane sulfonate / -8-oxo-4-thia-1-azabicyclo /4.2.0/ oct-2-en-3-yl / propen-2 (Z) -yl / thiene / 2,3-b / pyridinium 6S, 7S.

145 mg of Z isomer obtained in phase B of example 1 are dissolved in 5 cm of dichloromethane,

120 1 of thiene / 2,3-b / pyridine, cool to -70C, add 3 ~

1.76 cm of solution of trifluoromethane sulfonic anhydride in methylene chloride containing 0.42 cm of anhydride 3 to 10 cm of methylene chloride are added dropwise, the temperature is slowly brought to + 20 ° C, chromatographed the solution on silica eluting with a mixture of dichloromethane and methanol (92/8) and 15 mg of expected compound are isolated.

. Phase D: 7- / 3/7 - // 2-amino-4-thiazolyl) (methoxy imino) acetyl / amino / -2-carboxy-8-oxo-4-thia-1-azabicyclo trifluoromethane sulfonate

135 /4.2.0/ oct-2-en-3-yl / propen 2 (E) -yl / thiene / 2,3-b / pyridinium 6S, 7S sin.

221 mg of isomer (E) obtained in phase C of example 1 are mixed, 2.5 cm of 33% formic acid (aqueous solution), heated to 65 ° C for 55 minutes, cooled, diluted with water, filter, wash with ether, concentrate the aqueous phase until drying by distillation under reduced pressure, add water, dry, dry and obtain 93 mg of expected product.

I.V. Spectrum (nujo1)

1760 (Lactama C); 1660 ^Cm_1 ; 1550 and 1535 ^Cm_1 aromatic 'h + amide II + 0 tiazole + conjugate system; 1030 ^{cm 1} cf ₃ so ₃ Spectrum U.V. (ethanol) • Max. 238 nm E * = 625 = 44,200 Max. 307 nm E ¹ = 1 251 = 17,700 Inflection 318 nm ^E 1 = 232 Inflection 338 nm = 166 Spectrum NMR (DMSO) 3.83 ppm : OCH ₃ ; ; 5.55 at 6.44 ppm CH ^ N®; 107: Ethylenic 1H; 6.81 ppm : H ₅ tiazolo ; 7.23 ppm NH ₂ ; 7, 84 to 9 , 24 ppm

aromatic.

The Z isomer by formic hydrolysis is totally hydrolyzed to E isomer (isomerization).

Example 2: 7 - // 2- (2-Amino thiazol-4-yl) -2- (Z) -methoxy imino acetyl / amino / -3 - // 3- / 1-methyl-1H acid, 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 6S, 7S sin .

Phase A; / 7 - // 2- (2-triphenyl methylamino thiazol-4-yl) -2 (Z) -methoxy imino acetyl / amino / 3 - // 3- (1-methyl-1H, 1,2,3,4 1,1-dimethyl ethyl -tetrazol-5-yl) thio / propen- (E) -yl / -8-oxo-4-thia-1-azabicyclo /4.2.0/ oct-2-en-2-carboxylate .

37 mg of 7 - // 2- (2-triphenyl methyl amino thiazol-4-yl / -2 (Z) -methoxy imino acetyl / amino / 3136 are mixed

Λ

Γ BõfqOj:

| θί ^ Ι ’.71.

- // 1,1-Dimethyl ethyl (3-hydroxy) propen-1 (E) -yl / -8-oxo-5-thia-1-azabicyclo /4.2.0/ oct-2-en-2-carboxylate , 24 mg of tetrabutyl ammonium iodide, 0.8 cm of methylene chloride, 23 ul of 2.6-3

-lutidine, cool to -70 ° C, add 0.25 cm of trichloromethane sulfonic anhydride solution dropwise with the title

3

0.42 cm of anhydride to 10 cm of methylene chloride, 14 mg of sodium salt of l-methyl-5-mercapto-1,2,3-tetrazole and then 0.5 cm of dimethyl formamide are added, stir at 20 ° C, concentrate to dryness, chromatograph the residue on silica eluting with a mixture of methylene chloride and ethyl acetate (9/1) and isolate the expected product.

Phase B; Acid 7 - // 2- (2-amino 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.

329 mg of compound obtained in phase A of example 2 are mixed, 9.6 cm of 33% aqueous formic acid solution, heated for one hour and 15 minutes at + 65 ° C, cooled, diluted it is water, filtered, concentrated to dryness by distillation under reduced pressure, the residue is pasted in water, the insoluble formed is filtered off, concentrated to dryness and 142 mg of compound are isolated expected.

/ vC / = -99 (ç = 0.8% DMSO).

I.V. Spectrum (nujo1)

3410; 3300 ^cm_1 ; 3210 ^cm_1 OH / NH absorption. 1775

1770 ^Cm 1 $ Lactama C; 1665 ^{cm with} another carbonyl; 1626 J ||

O

1556 ^cm ”l aromatic NE ^ conjugate system.

U.V. (HCL, O, 1N ethanol).

Max. 239 nm And? · = 390 21 ooo; Max. 266 nm 414 22 300; Infl. 280 nm 1 ^AND 1 = 390 • / Max. 329 nm hey = ^Λ 1 304 a = 16 300. NMR spectrum (DMSO) 3.86 and 3.94 ppm NCH 3 ^and OMe

4.03 - 4.10 ppm = C-CH ₂ S

5.56 to 5.73 ppm H _{? Lactoma (cis)}

137

6.07

6.88

Η

6.84 ppm Η ,, thiazole sin

7.2 ppm: NH ^

9.17 - 9.27 ppm NHCO

Example 3: 7- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / 2-carboxy-8-oxo-4-thia-1-azabicium salt /4.2.0/ oct-2-en-3-yl / propen-2- (E) -yl / thieno / 2,

3-b / pyridinium sin (6S) (7S).

281 mg of product obtained in step C of example 1 are dissolved in 3.17 cm of 66% formic acid, a3 are heated at 65 ° C for 2 hours. Dilute with 3.2 cm of water, filter and concentrate the filtrate to dryness under reduced pressure 3 ~, The residue is dissolved in 1.3 cm of a 1M 3 aqueous solution of triethylamine carbonate and 1.3 cm of acetonitrile, chromatograph on silica (eluent: water-acetonitrile 9-1 then 85-15). 77 mg of expected product are obtained.

NMR spectrum. (DMSO) ’

3.83 ppm (s): OCHg

5.49 ppm: H? p-Lactama cis

5.88-7.48 ppm: ethylene H

6.80 ppm (s): thiazole sin.

IR spectrum (new)

NH / OHj'-Lactama C = 0: 1760 ^cm_1 starch C = 0: 1665 ^cm

NH ₂ def, aromatic, COO, starch II thiazole: 1635 ^cra 1600 ^cm \

1558 ^to111 ” ¹ , 1540 ^cm_1 .

C = N 0R: 1035 ^Cm_1 .

Example 4: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3 - / (3-acetoxy) -1- (E) -propenyl / -8-oxo trifluoroacetate -4-tia-l-azabiciclo /4.2.0/ oct-2-en-2138

δ r ·, 1

Iβο $ οοΊ

- - ·

Phase A: 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyimino acetamido / -3 - / (3-acetoxy) propen-1- (E) -yl / -8-oxo -4 — thia-l-azabicyclo / 1,1-dimethyl ethyl -4.2.0./-oct-2-en-a-carboxylate.

300 mg of the E isomer obtained in example 1, phase B, are stirred for 2 hours at room temperature,

1.5 cm of pyridine and 0.75 cm of acetic anhydride. 20 cm of water and 10 cm of hydrochloric acid N are added and extracted with methylene chloride. 395 mg of crude product are obtained, which are chromatographed on silica eluting with a methylene chloride-ethyl acetate (6-4) mixture. 255 mg of expected product are obtained.

F -1709C.

Phase B: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3 - / (3-acetoxy) -1- (E) -propenyl / -8-oxo trifluoroacetate -4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

210 mg of the product obtained above and 1.05 cm of the trifluoroacetic acid are stirred for 55 minutes at room temperature with 10% water. Add 5 cm of ether, stir for an additional 1 hour, dry and obtain 133 mg of expected duct.

NMR Spectrum (DMSO)

6.92 ppm

9.27-9.37 ppm

5.63 to 5.68 ppm

4.02-4.08 ppm

6.22 to 6.3 and 7.09-6.93 ppm: H

2.07 ppm: H

IR Spectrum (NUJ o1) region Absorption OH / NH lactam J. H _c thiazole 5 H starch: _H? ethylenics of acetyl.

C = O: 1767 ^Cm_1 ,

1698 ^0111- ^ 1640 ^Cm_1 .

i-l f

1740 ^{cin Σ} , l ₆₆₇ em-l, ãci pro

Strong absorption UV spectrum : 1140 ^cm 1) EtOH max. 236 nm eJ = 387 & = 23100 inf 1. 260 nm eJ = 256 max. 320 E ^ = 260 ¢ = 15500

1250 ^αΙΪ1-1

139

2) EtOH + HCL O, 1N

max. 238 nm E ^ = 291 g = 17300 max. 266 nm E * = 331 ê = 19700 inf 1. 283 nm E ^ = 289 max. 324 nm E ^ = 234 β = 13900

Example 5: 3- / 7- / 2-aminothiazole-4-i]) -2-methoxyimino acetamido / -2-carboxy-8-oxo-4-thia-l-aza bicycle /4.2.0/ oct trifluoromethane sulfonate /4.2.0/ oct -2-en-3-yl-2- (Z) -propenyl trimethyl ammonium sin (6S) (7S) and the (E) propenyl isomer.

Phase A; 3- / 7- / 2- (2-tritylqminothiazol-4-yl) -2-methoxyimino acetamido / -2 - / (1,1-dimethylethoxy) carbonyl / -8-oxo-4-thia-l- trifluoromethane sulfonate azabicycles /4.2.0./ oct-2-en-3-yl / propen-2- (E) -yl-trimethylammonium sin (6S) (7S) and the isomer (propen-2- (Z) -il) dissolve 282 mg of 7- / 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino) acetamido-3- / 3-hydroxy-1 (E + Z) propenyl / -S-oxo-4-thia- 1-azabicyclo /4.2.0./-oct-2-en terbutyl carboxylate in 3 cm of methylene chloride. Cool to ~

-70 ° C and 1.6 cm of a 1.53 mmol of trimethyl 3 amine solution are added. 0.094 cm of trifluoromethane sulfonic anhydride are added dropwise and stirred at -70 ° C for 30 minutes. 7 cm of methylene chloride and 5 cm of 0.1 N hydrochloric acid are added. The mixture is allowed to warm up, the organic phase is separated, dried and chromatographed on silica. After elution with a methylene chloride-methanol (95-5) mixture, the expected products are obtained 108 mg Z isomer (30%), 117 mg E isomer (33%) and 53 mg E mixture and Z.

Phase B; 3- / 7- / 2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido / 2-carboxy-8-oxo-4-thia-l-azabicyclo /4.2.0./-oct- trifluoromethane sulfonate /4.2.0./-oct- 2-en-3-yl-2- (Z) -propenyl trimethylammonium sin (6S) (7S) and the 2 (E) propenyl isomer.

108 mg of the product obtained (Z-isomer) are dissolved in 2 cm of 66% formic acid and stirred for 2 hours at 65 ° C. Cool and dilute with 2 cm of water. Wash the reaction mixture with ether and then with methyl chloride

- 140 i? Wg?

at the. The aqueous phase is evaporated. The residue is taken up 3 times, with 5

3 * cm of acetonitrile and 1 cm of methanol. Add 3 3 cm of methylene chloride to the residue, stir for 1 hour, dry and

55 mg of expected product are obtained. NMR Spectrum (DMSO) ffi 3.06 ppm (s): N (CH ^) ^ 3.86 ppm (s): OCH_ -4.10 ppm (m): C ^ -In 3.02 to 3.27 ppm: S-CH ^ 6.72 ppm: - @ = CH-CH ₂ ΔΖ 6.81 ppm: thiazole sin 9.3 ppm: NHCO

UV spectrum

1) EtOH

max. 231 nm Λ = 336 έ - 21200 max. 302 nm Λ = 202 € = 12700 2) EtOH 4  HCL 0, lN max. 232 nm ^E \ = 257 £ = 16200 max. 261 nm THE = 250 £ = 15800 max. 284 nm = 237 £ = 14900 infl • 310 nm THE = 179 Leaving the isomer (E) obtained in if A , operates as above and get up 56 mg expected product Spectrum NMR (DMSO) 3.02 ppm : (Me) ₃ 3.87 ppm (s) : OMe 3 4.11 ppm : CH ₂ -N® 5.61 to 5, 78 ppm : H _? (cis) 6.73 ppm : H ₅ tiazolo sin 5.94 to 6, 22 ppm Ethylene H âE 7.11- -7.28 ppm Spectrum UV 1) EtOH max. max. 235 nm 325 nm ^E \ 1 = 381. = 244 is = £. = 24000 15400

141 -

2) EtOH + HCL O, 1N

inf 1. 245 nm ^E u ⁼ 299 max. 263 nm ^E 1 - 318 20100 max. 332 nm E _χ = £ 212 = 13400 Example 6: Salt internal of 3 - // 3 - // 7- (2-aminothiazol-4-yl) -2-metho

xiimino acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-3-yl / -2- (E) -propenyl / oxycarbonyl / -1-methyl pyridinium sin (6S) (7S).

Phase A; 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido-3- / 3- (nicotindloxy) -1- (E) -propen.il/-8-oxo~ 1,1-dimethylethyl (6S) 4-thia-1-azabici clo /4.2.0./-oct-2-en-2-carboxylate (6S).

Heat to reflux 1.5 g of nicotinic acid in 1.8 cm of thionyl chloride for 1.5 hours. Take up with toluene, evaporate, crush the residue with ether, dry and obtain se2.12 g of nicotinoyl chloride hydrochloride. 258 mg of the E isomer obtained in phase B of example 1 are dissolved in 1 cm of pyridine and 93 mg of the solution (0.525 mM) of freshly prepared nicotinoyl chloride hydrochloride are added and stirred for 2 hours in a inert atmosphere. Dilute with 10 cm of methylene chloride, wash with 1N hydrochloric acid and then with sodium bicarbonate solution. Dry, evaporate, chromatograph the residue on silica, elute with a methylene chloride-acetone mixture (9-1) and obtain 232 mg of expected product.

Phase B; 3-3- / 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) -imino methoxy / acetamido / -2- (1,1-dimethylethoxycarbonyl) -8-oxo-4- tia-l-azabicyclic /4.2.0./-oct-2-en-3-il/-l-(E)-propenyloxycarbonyl-1-methyl pyridinium (6S) (7S) £ E.

225 mg of the product obtained above is dissolved in 1 cm of dimethyl sulfoxide, 0.168 cm of methyl iodide is added and stirred for 5 hours. The dimethyl sulfoxide is evaporated under reduced pressure at 40 ° C, the residue is chromatographed on silica (eluent: methylene chloride-methanol 92-8) and 187 mg of expected product is obtained.

- 142 -

Phase C: Internal salt of 3 - // 3 - // 7- (2-aminothiazol-4-yl) -2-methoxyimino acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2. 0./-oct-2-en-3-il/-2-(E)-propenyl/ oxycarbonyl / -1-methyl pyridinium sin (6S) (7S).

187 mg of product obtained in phase B are dissolved in 1 cm of trifluoroacetic acid and left to stand at room temperature for 10 minutes. Precipitates the

- «r product with 10 cm of isopropyl ether. Dry, dissolve the residue in 5 cm of hot ethanol, concentrate to approximately 1 cm, redissolve the product by heating and add 3

0.05 cm of pyridine. Cool, stir for 10 minutes, dry, wash with ethanol, with ether and 34 mg of expected product are obtained.

NMR spectrum (DMSO).

3.78-4.86 ppm (s) och ₃ 4.05 ppm (m) V 4.37-4.44 ppm N®-CH ₃ 5.05 ppm -ch ₂ 0- 5.66 ppm (m) ^H 7 6.24 ppm (t, d) = @ - CH ₂ 7.15 ppm (d) - @ ^ = CH-CH ₂ 6.82 ppm tiazolo sin 7.23 ppm NH ₂ 8.06 to 9.57 ppm pyridine and mobile H

Example 7: 1- / 3-7 - // 2- (2-aminothiazol -4-yl) -2- (methoxyimino) acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo trifluoromethane sulfonate /4.2.0./-oct-2-en-3-il/-2-(Z)-propenil/-l,4-diazabicyclo octane (6S, 7S) trifluoroacetate.

Phase A: 7- / 2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3- (1,4-diazabicyclo octane) -1 (Z) -propenyl / trifluoromethane sulfonate / -8-oxo-4-thia-1-azabicyclo / 1,1-dimethyl ethyl (6S) (7S) -4.2.0./-oct-2-en- carboxylate.

300 mg of 7 - // 2- (2-trityl aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3-hydroxy-l- (Z) - • propenyl / -8- oxo-4-thia-l-azabicycle /4.2.0./-oct-2-en-carboxylate • 3

-of 1,1-dimethyl ethyl (6S) (7S), 6 cm of methylene chloride and 179

- 143 -

1,4-diazabicyclooctane mg. Cool to -70 ° C and add 0.114 cm of trifluoromethane sulfonate anhydride 3 dropwise, stirring for 25 minutes at this temperature. Leave to stand at -15 ° C for 15 minutes, stir and then pour 20 cm of water and 6 cm of 0.1N hydrochloric acid. 'Extract with methylene chloride, dry and concentrate to dryness and 350 mg of crude product are obtained, which is chromatographed on silica, eluted with a methylene chloride-methanol mixture (9-1). Harvest

240 mg of expected product.

Phase B: 1- / 3- / 7 - // 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -2-carboxy-8 - * - oxo-4-thia- trifluoromethane sulfonate l-azabicycles /4.2.0./-oct-2-en-3-il/-2-(Z)-propenil/-l,4-diazabicycles octane, (6S, 7S) trifluoroacetate.

190 mg of the product obtained above and 1 cm of trifluoroacetic acid are stirred for 60 minutes with 10% water. Precipitate with 6 cm of ether, filter, dry and obtain 146 mg of expected product.

F = 1909C.

NMR Spectrum (DMSO)

6.88 ppm

9.3-9.4 ppm

5.58 to 5.73

6.73-6.87 ppm

5.86 to 6.11 ppm: from thiazole: H from starch ^H 6

Ethylene IH AZ

UV spectrum

max. 231 nm max. 303 nm 2) EtOH + HCL max. 233 nm max. 261 nm inf 1. 283 nm infl. 291 nm infl. 311 nm

: D

0, lN

EtOH 236 G = 18800 150 è = 12000 176 14000 177 £ = 14000 164 157 119

Example 8; 4- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / 2-carboxy-8-oxo-4-thia-1-azabici clo /4.2. 0./-oct-2-en-3-il/-2-(E)-propenil/-2-methyl

144 ι

thiazole / 5,4-b / pyridinium sin (6S) (7S).

βΟ $ ΟΟ ^Ί

- j Sixty

- SHIELDS

Phase A: 4 - // 7- (2- (2-tritylaminothiazol-4-yl) -2- (Z) -methoxyimino) acetamido / -2- (1,1-dimethylethyloxycarbonyl / -8-oxo-4 trifluorosulfonate -tia-l-azabicyclo /4.2.0./-oct-2-en-3-il/-2-(E)-propenil/-2-methyl thiazole / 5,4-b / pyridinium sin (6S) ( 7S).

Cool to -70 ° C 350 mg of Z isomer obtained in step B of example 1 in 10 cm of methylene chloride and 356 mg of methylthiazolopyridine. 2.34 cm of a solution consisting of 0.5 cm of trifluorosulphonic anhydride in 10 cm of methylene chloride are introduced. Stir for 5 minutes at -70 ° C in a nitrogen atmosphere, then allow the temperature to rise to 209 ° C, dilute with methylene chloride, wash with water, dry under reduced pressure . The residue is chromatographed on silica (eluent: methylene chloride-acetone 9-1 and then methylene chloride-methanol 92-8). 347 mg of expected product are obtained.

Phase B: 4- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2- (methoxy imino) acetamido / -2-carboxy-8-oxo-4-thia-l- azabicyclo /4.2.0./ oct-2-en-3-yl / -2- (E) -propenyl / -2-methyl thiazole / 5,4-b / pyridinium sin (6S) (7S).

It operates as in example 3 from 330 mg of product obtained above. Elute with distilled water containing 5% acetonitrile, then 10% and finally 20%. The acetonitrile is evaporated, the residue is taken up in 1 cm of acetone, isolated and rinsed with a minimum of acetone by centrifugation and 98 mg of expected product are obtained.

NMR Spectrum (DMSO)

3.84 ppm : OCH ₃ 6.80 ppm : H, - do tiazolo 5 5.58 ppm : H? ^ -Cis lactam 5.93 and 7.41 ppm: ethylenic H £ E

UV spectrum

1) EtOH max. 225 nm infl. 260 nm infl. 295 nm

E ¹ ₁ = 598 ê, = 34200

E ¹ ₁ = 332

E ¹ , = 306

145 max. 304 nm E ¹ ^ 333 ê = 19000 infl. 320 nm E ³ ^ = 256 & 2) EtOH + HCL O, 1N max. 220 nm E ³ ^ = 52630100 max. 265 nm E ³ ^ = 413 <^ = 23600 infl. 280 nm E ³ ^ = 381 infl. 289 nm E ³ ^ = 357 infl. 299 nm E ³ ^ = 316 max. 331 nm E ³ ^ = 200 ê = 11400

Example 9; 1- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido / -2-carboxy-8-oxo-4-thi-1-az abi-cycle /4.2 .0 ./- oct-2-en-3-yl / -2- (E) -propenyl / 5,6,7,8-tetra ·· idroquinolinein (6S) (7S).

Phase; A: 1- / 3- / 7- / 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino acetamido / -2- (1,1-dimethylethyloxycarbonyl) -8-oxo-4 trifluoromethane sulfonate -thia-1-azabicyclo /4.2.0./ oct-2-en-3-yl / -2- (E) -propenyl / 5,6,7,8-tetrahydroquinoline sin (6S) (7S).

Operate as in step A of example 8 using 162 μΐ of 2,3-cyclohexenopyridine and 73 mg of expected product are obtained.

Phase B; Internal salt of 1- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0. / oct -2-en-3-yl / -2- (E) -propenyl / 5,6,7,8-tetrahydroquinoline sin (6S) (7S).

136 mg of product obtained as described above are dissolved in 1.5 cm of 66% formic acid and run as in example 3 to obtain 25 mg of expected product. NMR spectrum (DMSO) 3.84 ppm: OCHg

5.46 ppm: Η ^ / 5-lactam (cis)

6.8 ppm: from tiazolo sin

7.09 ppm: Ethylene H & E

UV spectrum EtOH 'max. 232 nm E ³ ^ = 411 ê = 22800 infl. 264 nm E ³ ^ = 290

I - 146 - βο $ οο; -infl. 274 nm E ³ ^ = 269 infl. 282 nm E ³ ^ = 239 max. 317 nm E ³ ^ = 277 é = 15400

Example 10; 7- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2-difluoromethoxyimino acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0. / oct-2-en-3-yl / -2- (E) -propenij / thieno / 2,3-b / pyridinium sin (6S) (7S).

It operates as in example 5 from 2.527 g of 7- / 2- (2-tritylaminothiazol-4-yl-2- (Z) -difluoromethoxyimino acetamido / -3- (3-hydroxy (E + Z)) 1,1-dimethyl ethyl l-yl) -8-oxo-4-thia -1-azabicyclo /4.2.0./ oct-2-en-2-yl-2-carboxylate prepared by the usual methods and 1.89 cm of thiene / 2,3-b / pyridine and are obtained after hydrolysis with formic acid 813 mg of expected product.

/ c </ _D = 132.59 + 29 (c = 1% in I ^O-CHgCM mixture (1-1).

NMR Spectrum (DMSO)

2.89 to 3.06 ppm: S-CH ^

5.51 ppm: H ^ jS-Lactama (cis)

7.06 ppm: thiazolosin H ₅

7.48 ppm ϋ ethylene d E

UV ethanol spectrum - HCL 0, lN max. 240 nm E ³ ·. = £ 614 · = 36400 infl. 260 nm E = 316 infl. 280 nm E ³ ^ = 296 infl. 300 nm E ³ ^ = 258 max. 329 nm E ³ ^ = 238 £ = 14 100

Example 11; 4- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2-difluoromethoxyimino acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2.0. / oct-2-en-3-yl / -2- (E) -propenyl / thieno / 3,2-b / pyridinium (6S) (7S).

It operates as in example 5 from 300 mg of 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) -difluoromethoxyimino acetamido / -3- / 3-hydroxy- (E) -propen 1,2-dimethyl ethyl and 210 mg thiene-210-thi-1-oxo-4-thia-1-azabicyclo / -.2-oxo-4-thia-1-azabicyclo / 210 mg of thiene / 3,2-b / pyridine. After treatment, 147 -

with formic acid and then with trifluoroacetic acid, 117 mg of product are obtained which is taken up with 0.5 cm of acetonitrile and 0.5 cm of triethylamine carbonate, chromatographed on silica, eluted with a mixture of acetonitrile with 5% water, then with 10% and finally with 15% water. 43 mg of expected product are obtained.

UV spectrum EtOH - HCL O, 1N max. 239 nm E ^3- ^ = 569 £ = 33700 infl. 260 nm E ³ ^ = 274 max. 290 nm E ³ ' ₁ = 260 = 15400 max. 327 nm E ³ ^ = £ 254 = 15 100

Example 12: 7- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2- (propenyloxyimino) acetamido / -2-carboxy-8-oxo-4-thia-l-azabicyclo trifluoromethane sulfonate /4.2.0./ oct-2-en-3-yl / -2- (E) -propenyl thieno / 2,3-b / pyridinium sin (6S (7S).

It operates as in example 5 from 160 mg of 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) -propenyloxy minametamido-3- (3-hydroxy-E) -propenyl) -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-3-yl / -2-carboxylate of 1,1-dimethyl ethyl and 2.2 cm of a thienylpyridine solution (266 mg / 5 cm CH ₂ C _{1 2} ). After hydrolysis with formic acid, 53 mg of expected product are obtained.

NMR spectrum (DM50).

6.80 ppm ~ 6.33 ppm

-7.18 ppm

Hz- do tiazolo

H ethylenic trans

5.95 ppm: -CH = CH ₂

7.88 ppm:

8.27 ppm: H

8.14 ppm: Hg> aromatic bicycle

9.08 ppm: H ₅ |

9.22 ppm: H - ,. 1

UV spectrum

1) EtOH max. 239 nm infl. 260 nm

E ¹ ₁ = £ 686 = 50 600

E ³ ^ = 263

- 148 -

max. 306 nm inf 1. 322 nm 2) EtOH + HCL max. 240 nm max. 270 nm infl. 280 nm infl. 291 nm infl. 301 nm max. 330 nm

Ε ¹ , = 264

Ε ³ ^ = 244 Ο, ΙΝ

Ε ¹ , = 612

Ε ¹ ₁ = 363

Ε ¹ ₁ = 333

Ε ¹ ₁ = 288

Ε ¹ , = 237

Ε ³ ^ = 218 β = £ 19500 = £ 45200 = 25500

Example 13: 7 - // 2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl / amino / -3- / 3 / 5- (methyl) -1,3,4-thiadiazol-2-yl / acid thio / -l- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

Phase A: 7 - // (2-triphenylmethylaminothiazol-4-yl) -2- (methoxyimino) acetylamino / -3 - // 5- (methyl) 1,3,4-thiadiazol-2-yl / uncle / -l - 1,1-Dimethyl ethyl sin (6S) (7S) (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en carboxylate.

| Cool to -70 ° C, 184.5 mg of the> 3 isomer E obtained in step B of example 1 in 4 cm of anhydrous methylene chloride, 120 mg of tetrabutylammonium iodide and 116 µl of 2,6-lutidine. 620 µl of a solution (0.609 M / l) of sulfonic trifluoromethane anhydride in methylene chloride is added dropwise. After 10 minutes at -709C _z let the temperature rise to 209C, the solvent was evaporated under reduced pressure and nam Add Your successively, with stirring, 66.1 mg of 5-methyl

1,3,4-thiadiazole, 2.5 cm of dimethylformamide and 104 mg of anhydrous potassium carbonate. Stir for half an hour at 20-25 ° C and pour over 10 cm of hydrochloric acid N and extract with ethyl acetate. Wash with a 5% aqueous solution of sodium bicarbonate, then with water, dry and evaporate to dryness under reduced pressure. The residue is chromatographed on silica, eluted with an ethyl acetate-methylene chloride (15-85) mixture and 147 mg of expected product is collected.

* Phase B; 7 - // 2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl / ami / no / -3- / 3 / 5- (methyl) 1,3,4-thiadiazol-2-yl / uncle / -l- (E) -propenyl / -8I

I

I ♦

I - 149 -

-οχο-4-tia-1-azabiciclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

118 mg of product obtained above and 2.3 cm of trifluoroacetic acid are stirred for 20 minutes at room temperature. 25 cm of anhydrous ether are added dropwise, centrifuged, the funnel is taken up with 5 cm of ether twice in a row, centrifuging each time, then dried ~ 3 under reduced pressure. The product is taken up in 1.5 cm of ethanol and 100 µl of a solution (1M / 1) of pyridine in ethanol, centrifuged, the funnel is taken up twice with 1 cm of centrifuged ether each time. After drying, 52 mg of expected product are obtained.

NMR Spectrum (DMSO)

6.81 ppm • • H, - from tiazolo 5.64 ppm • • * 7 4.01 ppm • ^H 6 6.96 and 6.19 ppm : Ethylene H 7.23 ppm • • Amino amino 3.85 ppm • H of methoxy 2.68 ppm • H of thiadiazole methyl

UV Spectrum EtOH - HCL O, 1N

inf 1. 243 nm E ¹ ₁ = 430 max. 267 nm And ¹ ! = £ 580 = 29300 max. 329 nm E ¹ , = £ 340 = 18800

Spectrum IV (nujol)

General absorption NH / OH ^ 3-Lactam C = O: 1759 ^{cm 1} other C = 0: 1660 ^CItl region C = C; C = N \ 1630 ^cm starch II J 1540 ^cm

Example 14: 7- / 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido / 3- / 3- (1H-tetrazol-l-yl) -1- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic (6S) (7S) and 7- / 2- (2-aminothiazole-4- yl) -2- (Z) - (methoxyimino) acetamido / 3- / 3- (2H-tetrazol-2-yl) -1- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo / 4.2.0./

150

oct-2-en-2-carboxylic (6S) (7S).

Phase A: 7- / 2- (2-tritylaminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido / -3- / 3- (1H-tetrazol-1-yl) -1- (E) -propenyl / -8-oxo-4 — thia-1-azj bicycle /4.2.0./ oct-2-en-2-carboxylate of 1,1-dimethyl ethyl and 7- / 2- (2-tritylaminothiazole-4 -yl) -2- (Z) -methoxyimino) acetamido / -3 ~ / 3- (2H-tetrazol-2-yl) -1- (E) -propenyl / -8-oxo-4 “thia-l-azabicyclo /4.2.0./ 1,1-dimethyl ethyl oct-2-en-2-carboxylate.

230 mg of the isomer obtained in phase B of example 1 are dissolved, 149 mg of tetrabutylammonium iodide, 33

0.143 cm of 2,6-lutidine in 5 cm of dichloroethane. Cool · * 3 ~ to -70 ° C and add 1.7 cm of a trifluoromethyl sulfonic anhydride solution (0.42 cm qsp 10 cm EC ^ Cl ^) drop by dropping the temperature to 20 ° C, evaporate the solvent and add 44 mg of 1H-tetrazole, 131 mg of potassium carbonate 3 sodium and 3 cm of dimethylformamide. After 1 hour and 10 minutes of stirring, the solution is poured into water containing 1 , 5 cm of 2N hydrochloric acid and extracted with ethyl acetate Wash the organic phase with water containing excess 0.2N thiosulfate, dry, concentrate to dryness and chromatograph the residue on silica , elute with a methylene chloride-ethyl acetate mixture first (75-25) and then (50-50), 90 mg of the isomer (position 2) and 99 mg of the isomer (position 1) are isolated.

Phase B: Acid 7- / 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido / -3- / 3- (1H-tetrazol-l-yl) -1- (E ) -propenyl / -8-oxo-4-thia-1-az-a bicycle /4.2.0./ oct-2-en-2-carboxylic (6S) (7S).

The 99 mg of the isomer (position 1) is dissolved in 1.2 cm of 66% formic acid. Heat to 65 ° C for 2 hours, cool, dilute with 1.5 cm of water, filter, concentrate to dry the filtrate, put the residue in water, filter, rinse with water, then with ether and 49 mg of expected product are obtained.

NMR Spectrum (DMSO)

3.87 ppm: H OCH ₃

6.11 to 6.41 and 6.84 to 7.0 ppm: H ethylene AE * 6.84 ppm: from thiazole to 5.61 to 5.76 ppm; H ^ (3-cis lactam)

151

UV spectrum EtOH- + HCL O, 1N max. 238 nm E ^ = 377 t = 18500 max. 263 nm E ^ = 419 β = 20600 infl. 280 nm E ^ = 356 max. 325 nm = £ 299 = 14700

Phase C: 7- / 2- (2-Aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido / -3- / 3- (2H-tetrazol-2-yl) -1- (E ) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic (6S) (7S).

It is operated as in phase B from the mg of isomer (position 2) and 31 mg of expected product is obtained.

NMR Spectrum (DMSO)

3.88 ppm: H of OCH ^

6.11 to 6.44 and 6.9-7.07 ppm: ethylenic H ^ E

6.87 ppm: from tiazolo sin

5.7 ppm: (S-Lactama cis

UV Spectrum EtOH

max. 234 nm E ¹ ₁ = 470 - and - 23400 infl. 260 nm E ¹ , = 302 max. 320 nm l ¹ E i = 303 e = 15100

Example 15: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamide / -3- / 3- (2-methyl-1H-imidazol-l-yl) -1- (E ) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-boxyl sin (6S) (7S).

Phase A: 7- / 2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3- (2-methylimidazol-l-yl) -1- (E) -propenyl / - 1,1-dimethyl ethyl sin (6S) 8-oxo-4-thia-1-azabicyclo /4.2.0./-oct-2-en-2- carboxylate (7S).

It is operated as in step A of example 13 from 62 mg of 2-methylimidazole and 82 mg of expected product is obtained.

Phase B: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3- (2-methyl-1H-imidazol-l-yl) -1- (E ) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

- 152 -

Heat for 3 hours at 60-659C,

- -

80.5 mg of product obtained above and 1 cm of 66% formic acid, evaporate to dryness at 30 ° C under reduced pressure, the residue is taken up twice in succession with 5 cm of water, evaporated to dryness. The residue is taken up with 7 cm of ether, stirred for half an hour, dried and 41.5 mg of expected product are obtained.

NMR Spectrum (DMSO)

3.85 ppm (s)

6.55-6.61 ppm (d - J = 16)

5.58 to 5.64 ppm (m)

7.13 ppm

UV spectrum EtOH + HCL O, 1N: OCH ₃ : H ethylene ZL E: β-cis lactam: H _c thiazole

infl. 217 nm max. 238 nm e = 17300 max. 264 nm e = i9ioo infl. 281 nm max. 327 nm e = i3ioo

Example 16: 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3 - // (5-methylthio) 1,3,4-thiadiazol-2-yl / thio / -1- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

As in Example 13, using 2-mercapto-5-methylthio 1,3,4-thiadiazole, eluting the chromatography with a methylene chloride-ethyl acetate mixture (95-5) then (9-1) . After unblocking the functions and purifying, 69 mg of expected product are obtained.

NMR Spectrum (DMSO)

6.81 ppm

3.85 ppm

5.64 ppm

6.18 and 6.98 ppm

2.74 ppm

UV spectrum

1) EtOH + (1 cm ³ DMSO) max. 298 nm E ^ • jinfl. 320 nm E ³ : of thiazole sin: OCH ₃ : -Trans ethylene cis-H lactam; S-CH ₃ = £ 378 = 22 100 = £ 350 = 20 500

153

/ SC5SENTA I j 'E-SCUDOSl- ί

2) EtOH - HCL O, 1N max. 280 nm ^E 1 ⁼ max. 330 nm E ³ ^ = 310 £ = 27500 β = 18200

Example 17; 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3 - / (5-methylthio) 1,3,4-thiadiazol-2-yl / thio / - 1- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ o <t -2-carboxylic sin (6S) (7S).

It is operated as in example 13 from 184.5 mg of the isomer E obtained in step B of example 1 and employing 66.6 mg of 2-amino-5-mercapto 1,3,4-thiadiazole in dimethylformamide. Chromatography on silica is eluted with a methylene chloride-ethyl acetate (1-1) mixture. Functions blocked with trifluoroacetic acid are released and 60.5 mg of expected product are obtained.

Spectrum NMR (DMSO) 6.82 ppm : H _c of tiazolo □ 3.86 ppm : OCH ₃ 5.64 ppm ; -Cis lactam 6.90 ppm (d = J = 1.5) \ ( Ethylene H / J ^E 6.15 Ppm (d- + J = 7.5 and 15) J

UV spectrum

1) EtOH

max. infl. 287 282 nm nm E ³ ^ = 411 Ε ¹ _ί = 309 e = 22800 l ¹ max. 322 nm E _Σ = 312 e = 17300 2) EtOH - HCL 0, lN max. max. 271 330 nm nm E ¹ ^ = 472 E ¹ ₁ = 285 - e. = 26200 15800

Example 18; 7- / 2- (2-aminothiazol-4-yl ·) -2- (methoxyimino) acetamido / -3- / 3 - / (9H-purin-6-yl) thio / -l- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

It is operated as in example 13, using 76 mg of 6-mercaptopurine. The product is chromatographed on silica, eluting first with a methylene chloride-acetate mixture

- 154 -

Ethyl I (75-25) then only ethyl acetate and finally with a methylene chloride-methanol mixture (95-5). Unblocking and purification are performed and 76 mg of expected product are obtained.

NMR Spectrum (DMSO) 6.82 ppm (s) ^{: H} 5 thiazole 5.64 ppm: H ^^ - Lactama cis 6/26 ppm ethylene _H ^ E 7.06 ppm

UV spectrum

1) EtOH + 2 cm ³ DMSO max. 240 nm max. 2 9 2 nm max. 320 nm infl. 257,410 nm

2) EtOH infl. 240 infl. 264 max. 287 max. 323

HCL O, 1N nm nm nm nm

E ¹ ₁ = 401

E ¹ = 423 l ¹

E _T = 311

E ¹ ₁ = 319

E ¹ = 375 ι ±

E ^± ₁ = 475

E ¹ ₁ = 286

6 = £ 23000 = 24300

E = 17800 = 27200

16400

Example 19: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxylimino) acetamido / -3 - // 3- (1,3,4-thiadiazol-2-yl) thio / -l - (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

Operate as indicated in example 13, using 59.1 mg of 5-mercapto 1,3,4-thiadiazole and 47 are obtained.]

mg of expected product. NMR Spectrum (DMSO) 6.85 ppm (s) : Tiazolo Hg 3.87 ppm (s) : OCH ₃ 5.65 ppm : (Ô-Lactama cis 6.01 ppm (d - J = 15.5)] 7.06 ppm (d - J = 15.5 and 7) i H ethylene A E Spectrum UV

EtOH - HCL 0, lN • infl. 241 nm E ^3- ^ = 335 • max. 269 nm E ¹ ^ = £ 425 = 22900

155

I

60 $ 00

E ¹ ₁ = 278 6 = 15000

; .. max. 329 nm

Example 20: 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3 - // 3- (1,2,3-triazol-5-yl) thio / -l - (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

It is operated as in example 13 using sodium thiolate, without the addition of potassium carbonate. Chromatography is carried out by eluting with a methyl chloride-ethyl acetate (75-25) mixture. The functions are unlocked with formic acid: 2 cm at 66% for 149 mg of blocked product. Stir at 60-65 ° C for 3 hours, formic acid at 30 ° C under reduced pressure, take up twice with water, evaporating each time. The residue is crushed with ether, dried and 89 mg of product is obtained which is dissolved in 6 cm of tetrahydrofuran and 1 cm of methanol. This solution is introduced dropwise in 100 cm of ether keeping a strong agitation, dried and 69.5 mg of expected product are obtained.

NMR Spectrum (DMSO)

6.81

3.85

5.63

6.76

6.08

Spectrum max.

Thiazole Hg sin och ₃ Ηγ ^ -Cyl ethylene lactam â E ppm ppm ppm PPm PPm

UV EtOH max.

infl.

max.

240

266

282

328 nm nm nm nm è = 20700

21700 = 16700

Example 21: 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3 // 4-methyl-5-trifluoromethyl-4H-1,2,4-triazole- 3-yl / thio / -1- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

It is operated as in example 13, using 90 mg of 4-methyl-5-trifluoromethyl 4H-1,2,4-triazole-3-thione. Chromatograph on silica, elute with a chloride mixture of

156

methylene-ethyl acetate (75-25). After treatment with 66% formic acid, 78 mg of expected product are obtained.

NMR Spectrum (DMSO)

3.67 and 3.85 ppm

5.64 ppm

6.2 and 6.89 ppm: N-CH ₃ and O-CH ₃ : Ηγ ^ -Cis lactam: ethylene H âE

6.81 ppm: Thiazole Hg

UV spectrum EtOH - HCL O, 1N infl. 240 nm E ^ = 328 max. 260 nm E ^^ = 345 & = 20900 infl. 280 nm E ^^ = 303 max. 326 nm E ^ = 215 £ L = 13000

Example 22;

7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3 - / (thiazole / 5,4-b / pyridin-2-yl) thio / -l- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

It is operated as in example 13 using 205 mg of 2-mercapto thiazole / 5,4-b / pyridine. Chromatograph and elute with a methylene chloride-acetone mixture (9-1). The functions are released by formic acid on 150 mg of product obtained and 67 mg of impure product are obtained. A 45 mg portion of this crude product is chromatographed on silica, eluted with ethyl acetate, and then with an acetone-ethyl acetate-water mixture (5-4-1). 17 mg of expected product are obtained.

NMR Spectrum (DMSO)

6.79 ppm

3.84 ppm

5.54 ppm

5.98 and 7.27 ppm

Spectrum IV (nujol)

General absorption OH / NH region> C = O β-Lactama maxillary parapet region -C = C> C = N: Hg of thiazole; OCH ₃ : H ^ -Lactam: H ethylene

1754

1660

1650 cm-1 f

cm-1 f

cm-1 f

wide absorption

- 157 -

_____________ - -4 region

aromatic 1 158O ⁰¹¹¹ ” ¹ , 1620 ^cm_1 , NH def, amide II J 1535 ^Cm_1 . -CH = CH-: gvscm-i.

Example 23; 7- / 2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido / -3- / 3 - // 1H-1,2,4-triazol-3-yl / thio / -l- (E) -propenyl / -8-oxo-4-thia-1-azabicyclo /4.2.0./ oct-2-en-2-carboxylic sin (6S) (7S).

It is operated as in example 21 using 50 mg of 1H-1,2,4 — triazole-3-thione, 62 mg of expected product are obtained.

NMR Spectrum (DMSO)

5.56 to 5.71 ppm

6.04 to 6.4 ppm and 6.84-7.02 ppm

6.84 ppm

UV spectrum EtOH max. 234 nm max. 320 nm: H_ / 3-cis lactam /?

Ethylenic JH Λ E: H ₅ from tiazolo sin

E ³ ^ = £ 481 = 25 100

E ¹ ₁ = 323 C = 16900

Example 24; 2- / 3- / 7- / 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido / -2-carboxy-8-oxo-4-thia-1-azabicyclo /4.2. 0. / oct-2-en-3-yl / -2- (E) -propenyl / isoguinolein sin (6S) (7S).

It is operated as in example 21 starting from 148 mg of isomer E obtained in step B of example 1. After the addition of trifluorolethane sulfonic anhydride and distillation of the solvent, 5 cm of acetonitrile and 52 µl of isoquinoline are added. After 1 hour and 15 minutes, acetonitrile is expelled, the residue is dissolved in ethyl acetate, washed with water containing excess 0.2N sodium thiosulfate, washed with water, dried and concentrates until dry. The residue is chromatographed on silica, eluted with a methylene chloride-methanol (92-8) mixture and 83 mg of blocked intermediate is isolated. After treatment with 66% formic acid, filtration and evaporation of the solvent, the residue obtained is taken up in 1 cm of acetonitrile and cm of a 1M triethylamine solution and chromatographed on

- 158 -

silica, eluent: water-acetonitrile (9-1) then (85-15). 16.76 mg of expected product are obtained.

NMR Spectrum (DMSO)

3.83 ppm

- 5.45 ppm

6.79 ppm

5.91-7.42 ppm

UV Spectrum EtOH

max. 224 nm infl. 232 nm inf 1. 262 nm infl. 277 nm max. 289 nm max. 323 nm

E ³ ^ = 951

E ^{* 1} ₁ = 840

E ¹ ₁ = 296

E ¹ ₁ = 252

E ¹ ₁ = 226 = 280 och ₃

H _? and thiazole CH ₂ -tP

Ethylene H âE £> 52400 = £ 12400 = 15400

Examples 25 to 39:

The products indicated in the tables that follow were also obtained by the process according to the present invention.

----------------------- Γ

CO ₂ A}

I I I I I I

I

I

I

I

I I I

I I I I 1

I

I I I

I

I I

I • I. I

I • I - I

I

I

CO ~ H ΐ ^Z I

I

I

C ° ₂ ® I

I

I

I

I

Ο ° ₂ Θ]

I

I

I ^C0 2 ^H !

!

I

I

C0 _o H i

1

I

I

159

ΝΗ _Ο

Α \ = 4 ^ 0ΝΗΥ: η ₃

II

II νη ₉

Λ

S Ν

C0NHΝ '0 ^V CHF ₂

Ϊ ^Η 2 (j = O ^H 3 ^C -Ç- °

Ο

HCC-0 ³ II Ο

Ν-Ν sA _s > 7 c = o

H ₃ C- ©

3®®

II

II

II

00 ₂ η co ₂ ^h

160

I

R ^R 1 co ₂ a ^ 2, CF ₃ CO ₂ H

Vzl ^ CONHN o

^V CH -CO ₂ H

CO ₂ H

NH

Λ

Y N

CONHN Y) 'CH'

Ο ^X CH

N-N

II

CO ₂ H nh ₉

'S' n l = ^^ know

N

Y) ^K ch ₃

N-N p ·

II

C0 ₂ h

I 1

I I

I

I I

I

I I

I

I I

I I

I

I

I I

I I

I I

I I

I

I

I

I

I

I I

I I I

I I

I

Example 40;

Preparations were made for injections that have the formula:

- 7- / 3- / 7 - // (2-amino-4-thiazole) -2- (Z) - (trifluoromethoxy) imino salt / 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) ..... ...................... 500mg

-Aqueous sterile aqueous container q.s.p .................... 5cm

161 -

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

I60 $ 00, ιαιΙΛΜ

In vitro activity, liquid dilution method.

A series of tubes is prepared in which the same amount of sterilized nutrient medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain. After incubation of twenty-four to forty-eight hours in the oven at 37 ° C, growth inhibition is appreciated by transillumination, which allows the determination of the minimum inhibitory concentrations (C.M.I.) expressed in ug / cm.

The following results are obtained:

STREETS

I J

I

I

I

I

I T

I

Prod. Ex. 3 j Prod. Ex. 1

------------- _T ------------- ι

H: 48 H> 24 H: 48 H ι --------------------------------------- --------------1----------------------------------- ---------------------- I

• Staphylococcus aureus SG ⁵¹ l 0.08 : 0.15 } 0.08 : 0.15 ! Staphylococcus aureus 285 1 1 | 0.15 : 0.3 ! 0.08 1 : 0.15 j Staphylococcus aureus 541 46} 0.15 : 0.15 I 0.15 : 0.3 ! Streptococcus pyogènes THE 561 x < 0.01 : <0.01 ! <0.01 : <0.01 ΐ Streptococcus pyogènes 77 THE ! 0.01 : <0.01 } <0.01 : <0.01 j Escherichia Coli 1894 1 1 1 4 0.01 : <0.01 | | <0.01 : <0.01 } 078 1 1 t x < 0.01 : <0.01 ! <o, hi : <0.01 j HAS 1 1 s < 0.01 : 0.04 | ’0.04 : 0.08 } 1507 AND I x < 0.01 : <0.01 '<0.01 | : <0.01 | I DCO 1 1 x < 0.01 : 0.02 ; 0.02 : 0.04 'DC2 I 1 1 1 0.01 : <0.01 í <0.01 : <0.01 1 | Salmonella typhimurium MZ u 0.01 : <0.01 ; o, o4 : 0.04 Klebsiella pneumoniae 521 45 i | 0.04 : 0.04 í 0.04 : 0.04 * Klebsiella aerogênes 1 522 Hey 0.08 : 0.08 ! o, 15 : 0.15 ! Enterobacter cloacae 1 | 321 1 AND 1 1 x < 0.01 : <0.01 í 0.02 : 0.02 ΐ Proteus mirabilis A 23 1 Proteus vulgaris A 232 5 1 1 0.02 : 0.02 ! 0.04 : 0.04 1 1 0.08 : 0.3 1 0.08 : 0.08

I I

162

STREETS 1 1 1 ! Prod, 24 H . Ex. 30 : 48 H -! --------- } Prod. -1-------- 1 } 24 H I 1 Ex. 19} ---------1 1 : 48 Η 1 1 1 Staphylococcus aureus SG 51Í I 0.3 : 0.3 i 1 | 0.6 : 0.6 1 Staphylococcus aureus 285 1 0.3 : 0.3 1 1 0.6 : 0.6} Staphylococcus aureus 541 46 1 | 0.3 : 0.6 1 0.6 : 1.2 1 Streptococcus pyogènes THE 561} <0.01 : <0.01 1 c 0.01 : <0.01 1 Streptococcus pyogènes 77 1 TO 1 1 <0.01 ; <0.01 ! * 0.01 : <0.01} Escherichia Coli 1894 1 <0.01 : <0.01 1 0.01 : <0.01 ' ”078 l 1 <0.01 : <0.01 1 1 1 0.04 : 0.04 {  HAS 1 1 0.02 : 0.02 1 1 0.15 : 0.15 1  1507 AND 1 1 1 <0.01 : <0.01 1 < 0.01 : <0.01 |  DCO 1 1 0.04 : 0.04 1 1 0.15 : 0.15 1  DC2 1 1 <0.01 : <0.01 k 0.01 : <0.01 1 Salmonella typhimurium MZ useful I 0.02 : 0.02 1 | 0.15 : 0.15 1 Klebsiella pneumoniae 521 45} 0.02 : 0.02 1 1 0.3 : 0.3} Klebsiella aerogènes 1 522 E 1 I 0.04 : 0.04 1 0.3 : 0.3 j Enterobacter cloacae 1 321 AND } <0.01 : <0.01 1 I 0.04 : 0.08 1 Proteus mirabilis A 23 5 1 | 0.02 : 0.04 1 1 0.08 : 0.08 { Proteus vulgaris A 232 1 0.02 : 0.04 1 0.04 : 0.04 1

163

I

Process for the preparation of compounds of general formula (I):

(°) ⁿ ₂ (I)

Ri and Rj, the same or different, represent nio,

V

N-CH = N-, in which ^R j_ an aliphatic or aromatic hydrocarbon radical hydrogen atom or a heterocyclic radical in which Ri and Rj form with the nitrogen atom to which they are attached, a cyclic radical that can be substituted, either a Rb-NH- radical in which Rb represents a substituted arocyclic or heterocyclic aryl radical,

, equals

-any radical:

or different, represent alkyl having 1 to 4 atoms a sulfur atom with formulas in which a hydrogen atom or a carbon radical, represents a single bond, possibly oxidized or an oxygen atom, R4 is a carboxylic aryl radical or substituted heterocyclic, or substituted quaternary ammonium or an acetyl, carbamoyl alkoxycarbonyl, alkyl or haloalkyl radical

lo with 1 to 4 carbon, nitrile or azido atoms, r ₄ represents a hydrogen atom or a methoxy radical,

A represents a hydrogen atom, an alkali, alkaline earth metal, magnesium, ammonium equivalent or an organic amino base where A represents an ester group where CC ^ A represents a COjD group, n ₃ represents an integer equal to 0, 1 or 2, as well as their salts with mineral or organic acids, since it is a product with the formula characterized by pe (VII):

(VII) in which R ₄ and A have the previous meanings and R 4 represents either a free amino radical or protected by a mono or divalent protecting group, or the radical R, having R the meaning indicated above, or with an halogenation either with a sulfonating agent, then with triphenylphosphine or with a reagent of the formula P (OAlq) ₃ in which Alq represents an alkyl radical with 1 to 4 carbon atoms, to obtain a pro

(VIII _A ) in which R ^, R ^ and A have the previous meaning and represent the residue of an anion, or a product with the formula VIII

165

(VIII ¹ _Α ) in which R, R ₄ and Alq have the previous meaning, products with the formulas VIII ^ or VIII ' _A which, if desired, are treated first with a strong base and then with an alkyl halide which has the formula hal-R _A in which hal represents a halogen atom and R _A has values of R ' _A different from a hydrogen atom, to obtain products with formulas VIII _B or VIII' _β

VIII 'formulas in which R' has the meaning indicated above and products with formulas VIII _B or VIII ' _B which are treated with a product with the formula:

in which R ' _B has the value indicated above and G _p represents a protecting group against the oxydryl radical, to obtain a product with formula IX:

(IX) in the form of a mixture of the E and Z isomers or in the form of

166 E or Z isomer, which product has formula IX, on which the following reactions are carried out in any order:

a) cutting the protective group G _p ;

b) when R ^ represents an amino radical protected by a mono or divalent protecting group, elimination of this protecting group and treatment of the product in which R &'represents an amino radical with either an acid of formula IV _at :

RaCO ₂ H (IVa) formula in which R _& represents an organic group or with a functional derivative of this acid, either with a product with formula IV _b :

Laugh

X

N-CH-Xb

RJ (iVb) in which Ri and Rj have the meaning indicated above and X _b represents a sulfur or oxygen atom, either with a product with formula IV:

V ^X C ^(IV c>

in which R4 has the meaning indicated above and X _c represents a halogen atom;

c) separation of E and Z isomers;

to obtain a product with formula X:

in which R has the meaning indicated above, which product has formula X on which it is acted either a reactive derivative of the group R _3a to obtain a product with formula XI,:

167

< ^XI A>

either a derivative of a next a derivative group or an activating oxydryl radical and reactive derivative of the group R _3A Para

(XI _B ) either a derivative of an oxydryl radical activating group and then the product with the formula HS-R _3A or a reactive derivative of this product, to obtain a product with the formula XI _C ;

(XI _C) these products having formula XI ^, ^{X or XI} b C ^ ^u ^ ^s ^ ^su ° ^{methylphenoxy} of, if necessary or desired, any one or more of the following reactions, in any order:

a) cutting by hydrolysis, hydrogenolysis or by thiourea action, of all or part of the protecting group or groups;

b) esterification or salification by means of a base of the carboxy or sulfo group or groups;

c) salification with an acid of the amino group or groups;

d) unfolding the molecule to obtain an optically active product;

168

e) oxidation of the sulfur atom at position 2 of the isocephe cycle.

Process according to claim 1, for the preparation of products corresponding to the formula

sin isomer, ^(I A>

in which R 'represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical having a maximum of 6 carbon atoms, optionally substituted or an aryl radical has the value in claim 1 and R' _3A represents a pheni radical. lo, optionally substituted heterocyclic aryl or an optionally substituted quaternary ammonium radical or an acetyl or carbamoyl radical, characterized in that the product with formula (VII) is treated:

(VII) in which A has the meaning indicated in claim 1 and R _c represents either a free amino radical or protected by a mono or divalent protecting group, or R represents the radical c

169 eosoo

optionally protected, either by a halogenating agent or by a sulphonating agent, then by triphenylphosphine or by a reagent of the formula P (AAlq) ₃ in which Alq represents an alkyl radical having 1 to 4 carbon atoms, to obtain a product

(VIII _A ) in which Ρθ and A have the previous meaning and represent the residue of an anion,

(VIII ') in which R, A and Alq have the previous meaning,

The products that have the formulas VIII ^ or VIII * _A that are treated with a product with the formula:

in which G _p represents an oxydryl protecting group, to obtain a product of formula IX ':

170

(IX ') in the form of a mixture of the E and Z isomers or in the form of the E or Z isomer, a product having the formula IX', on which the following reactions are carried out in any order:

a) cutting the protective group G _p ;

b) when R represents an amino radical protected by a group c

mono or divalent protector, elimination of this protecting group and treatment of the product in which R represents an amino radical by means of an acid of formula IV ':

or through a functional derivative of this acid,

c) separation of E and Z isomers;

to obtain a product with the formula X ':

(X ') in which R has the meaning indicated in claim 1, which product has the formula X' on which either a reactive derivative of the group R '' is acted to obtain a product with the formula XI ':

171

(XI · _Α ) or a derivative of an oxydryl radical activating group and then a reactive derivative or derivative of this group R '. ^ To obtain a product with the formula XI' _β :

(XI ' _B ) either a derivative of an oxydryl radical activating group and then the product with the formula HS-R' ^ or a reaction derivative of this product, to obtain a product with the formula XI ' _c :

(XI

products with formula XI 'dos, if necessary or desired, following reactions, in any order:

a) cutting by hydrolysis, hydrogenolysis or by the action of thiourea of all or part of the protecting group or groups;

b) esterification or salification by means of a base of the carboxy or sulfo group or groups;

c) salification by means of an acid of the amino group or groups;

d) unfolding the molecule to obtain an optically active product.

XI 'or XI * that are subjected to any or more of the

172

Process according to claim 2, characterized in that a compound of formula VII or a compound of formula IV 'is used in the first instance in which CL

R 'represents a hydrogen atom or a methyl or iso propyl radical, which can be replaced by a carboxy, carbamoyl, nitrile, methylthio or methoxy radical, a difluoromethyl or trifluoromethyl radical, a phenyl radical, a cyclobutyl or cyclopropyl radical that can be replaced by a carboxy radical, an allyl radical that can be replaced by a chlorine or bromine atom.

- 4- -

Process according to claim 2 or 3, characterized in that the product having the formula X 'is treated with a derivative of an oxydryl radical activation group and then a derivative or a reactive derivative of a pyridinium radical substituted.

- 5- -

Process according to claim 1, characterized in that any one of the compounds of formula I is obtained whose names are indicated below: - the internal salt of 7- / 3- / 7 - // (2-amino-4 -thiazolyl) 2- / 7- (trifluoroethoxy) -imino / acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /4.2.0./ oct-2-en-3-yl / 2- ( E) -propenyl / thieno / 2,3-b / pyridinium (6S) (7S).

• j- the internal salt of 5- / 3- / 7 - // (2-amino 4-thiazolyl) (methoxyimino). acetyl / - amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /4.2.0./ oct173

-2-en-3-yl / 2- (E) -propenyl / 2-methyl thiazole / 4,5-c / pyridinium sin (6S) (7S);

- the internal salt of 7- / 3- / 7 - // (2-amino 4-thiazolyl) 2- (Z) - (methoxymino) -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);

- 7 - // (2-amino 4-thiazolyl) (methoxyimino) acetyl / amino / 3 - // 3- (1,3,4-thiadiazol-2-yl) thio / 1- (E) -propenyl acid / 8-oxo 4-thia 1-azabicyclo- / 4.2.0. / Oct-2-en-2-carboxylic sin (6S) (7S);

- the internal salt of 5- / 3- / 7 - // (2-amino 4-thiazolyl) (difluoromethoxy) imino / -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / 4. 2.0./ oct-2-en-3-yl / -2- (E) -propenyl / 2-methyl thiazole / 4,5-c / pyridinium (6S) (7S) Z.

Process for the preparation of pharmaceutical compositions, characterized in that at least one of the compounds of formula I is incorporated as an active ingredient when prepared according to the preceding claims, or at least one of its addition salts with the pharmaceutical acids acceptable, in a form intended for this use.

Process for the preparation of pharmaceutical compositions, characterized in that at least one of the compounds of formula Ia is incorporated as an active ingredient when prepared according to claim 2, or at least one of its salts by addition with the pharmaceutically acids acceptable, in a form intended for this use.

- 8- 174

Process for the preparation of pharmaceutical compositions, characterized in that at least one of the compounds of formula Ia is incorporated as an active ingredient when prepared according to claim 5, or at least one of its addition salts with the pharmaceutically acids acceptable, in a form intended for this use.

The applicant declares that the first application for this patent was filed in France on August 9, 1985, under the number. 85-12218.

Lisbon, August 8, 1986

175

Λ ^ βτζ; '· SUMMARY

PROCESS FOR THE PREPARATION OF NEW 1-DETIA ACID DERIVATIVES

2-CEPHALOSPORAN AUNT

The invention relates to a process for the preparation of products corresponding to the general formula (I):

with (I) mineral or organic acids, which, as well as their salts, includes in particular treating a product that has the formula (VII):

(VII) either with a tying agent, then with triphenylphosphine or mule P (OAlq) ₃ to obtain a product with the formula halogenation or with a sulfone agent reagent with the form

VIII _A :

6¾ ⁵ (vn _A ) or a product with formula VIII ' _A :

formulas (OAlq) ₂ (VIII * _A ) products these are treated first

VIII _A or VIII ' _A which, if desired;

with a strong base and then with a halo

the formula hal-R ^, to obtain the alkyl genet products which have

6 ^H 5 ^} 3 the formulas νΐΙΙ _β

(OAlq) ₂ or VIII 'and products with a

VIII _B these with the formulas VIII_ Already product with the formulation

to obtain a product with formula IX:

VIII 'which are treated in the form of a mixture of the E and Z isomers or in the form of the E or Z isomer, a product with formula IX, on which the following reactions are carried out in any order:

a) cutting the protective group G _p ;

b) when R ^ represents an amino radical protected by a mono or divalent protecting group, elimination of this protecting group and treatment of the product in which it represents an amino radical with either an acid of formula IV:

Raco ₂ H (IVa) in which formula R represents an organic functional or a decl Rivado this acid group, or with a product of formu la _fo IV:

N-CH-Xb

(IVb)

I either with a product with formula IV:

Rj-X bc (iv _c )

c) separation of the E and Z isomers;

to get a product with the formula

X:

if that product with formula X on which

group one one acts either a product with the form ^XI A or a derivative, then a derivative obtains a product with the oxhydryl radical and activates a reactive derivative of the group R _3A for or a formula XI „:

^XI B wants a derivative of an oxydryl radical activating group and then the product with the formula HS-R ^ or a reactive derivative of this product, to obtain a product with the formula XI ^:

^XI C products that have the formula XI ^, XI _B or XI _C that are subjected, if necessary or desired, to any one or more of the following reactions, in any order:

a) cutting by hydrolysis, hydrogenolysis or by thiourea action, of all or part of the protecting group or groups;

b) esterification or salification by means of a base of the carboxy or sulfo group or groups;

60 $ 00

ΙΪΠΪ

ç)

d)

e) salification with an acid of the amino group or groups; unfolding the molecule to obtain an optically active product;

oxidation of the sulfur atom at position 2 of the isocephe cycle.

Description referring to the addition to ROUSSEL-UCLAF patent No. 83 174, to the French, industrial and commercial anonymous company, with headquarters at 35 Bd des Invalides, 75007 Paris, France, (inventors: «Toszef Aszodi, Solange Goin D'Ambrieres and Jean-Georges Teutsch, residing in France), for: PROCESS FOR THE PREPARATION OF NEW 1-DETIA 2-TIA-CEPHALOSPORANIC ACID DERIVATIVES ¹¹

Description

In the patent application filed on February 13, 1984 under No. 84.02138 and published under No. 2,559,846, the applicant described a process for the preparation of new derivatives of 1-detia, 2-cephalosporanic acid further referring to their application as medicines.

This request therefore had as its object the preparation of products of general formula (I):

P

(I) in which

The same or different Ri and Rj represent a hydrogen atom or an aliphatic or aromatic hydrocarbon radical, a heterocyclic radical or Ri and Rj form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic radical, or an Rb radical -NHemque Rb represents an optionally substituted carbocyclic or heterocyclic aryl radical.

represents either:

a) a radical -ZR ₂ , where R ₂ is an alkyl, alkenyl or alkynyl radical optionally substituted by a heteroatom and Z represents an optionally oxidized sulfur, selenium, or oxygen atom or -NH-

b) a radical Z -R_, where R_ represents an aryl radical - the possibly substituted carbocyclic or heterocyclic J

or an optionally substituted quaternary ammonium and Z_ represents a methylene radical, a sulfur atom,

O.

selenium, oxygen or -NH-, or Z _a represents a single bond, or Z represents a -CH „-S- radical

c) an alkyl, alkenyl or alkynyl radical with 2 to 8 carbon atoms possibly substituted or interrupted by a hetero atom

d) a halogen atom, a nitrile radical, azido, thiocyanate or isothiocyanate

e) an azidomethyl, amino or mono- or disubstituted methyl radical, methyl thiocyanate, methyl isothiocyanate, carbamoyloxymethyl,

R ₄ represents a hydrogen atom or a methoxy radical,

A represents a hydrogen atom, or an equivalent of alkali, alkaline earth metal, magnesium, ammonium or an amine organic base or A represents an ester group or GO2 ^ar ®P ^res ®n a C0 ₂ group.

n ₂ represents an integer equal to 0, 1 or 2 as well as the salts of the products of formula (i) with mineral or organic acids.

The products of formula (I) can be in racemic or optically active form.

Among the products of formula (i), the aforementioned patent application concerned more specifically products which comply with formula (I ·) s

(I ¹ ) sin isomer, in which

R * represents a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms optionally substituted, R represents quers

a) a radical Z'-R ' ₂ in which R' ₂ represents an alkyl radical containing 1 to 4 carbon atoms, eventually interrupted by a heteroatom and eventually replaced by an amino radical, esterified or salified free arboxy or by a radical aryl or eventyl arylthio; replaced,

2 ‘represents a sulfur or oxygen atom,

b) a radical Z ' _to -R · ^ in which R' ^ represents a phenyl radical, an optionally substituted heterocyclic aryl or an optionally substituted ammonium radical and Z'_ represents a methylene radical, -CH ₂ -S- or an atom of sulfur, oxygen, selenium or a single bond,

c) an alkyl or alkenyl radical containing 2 to 4 carbon atoms that may be interrupted by an oxygen atom or replaced by an aryl,

d) an azidomethyl, aminomethyl or carbamoyloxymethyl radical, n'2 represents the numbers 0 or 1 and A has the value indicated above.

Said patent application also describes a process for the preparation of products of general formula I as defined above as well as variants of that process.

Main patent application 83 83 174 filed on August 8, 1986 describes products with general formula I of the main patent and corresponding to general formula I, s

(IA) in which

R represents either a radical Ra-C-Níl- where Ra

II

Represents an organic radical, either a radical

Ri \ N-CH = NRj where Ri and Rj, the same or different, represent a hydrogen atom, an aliphatic or aromatic hydrocarbon radical

or a heterocyclic radical, or Ri and Rj form with the nitrogen atom to which they are attached, an optionally substituted cyclic radical, or an Rb-NH- radical in which Rb represents an optionally substituted carbocyclic or heterocyclic radical.

Rj.A represents

want a radical s

formulas in which the same or different R'_ and R * represent either a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms. Z _A represents a single bond, an optionally oxidized sulfur atom or an oxygen atom, R _3a represents an optionally substituted carbocyclic or heterocyclic radical, or an optionally substituted quaternary ammonium or an acetyl, carbamoyl, alkoxycarbonyl, alkyl or haloalkyl radical with 1 to 4 carbon, nitrile or azide atoms,

- 6 £ _ί ,, 1 ... -. .

y

r ₄ represents a hydrogen atom or a methoxy radical,

A represents a hydrogen atom, an alkali metal, alkaline earth metal, magnesium, ammonium or amine organic base equivalent or A represents an ester or CO ₂ group A represents a CO ^ _t n _{2 group} represents an integer equal to 0, 1 or 2 as well as the salts of the products of formula (i ^) with mineral or organic acids.

The products of formula (1) can also be in the form of salts of organic or mineral acids.

E _n tre acids with which it may or salifying the amino group or quaternary ammonium group of the formula # products may be mentioned, among others, acetic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p toluenesulfonic, trifluoromethanesulfonic, formic, phosphoric, sulfuric, hydrochloric, hydrobromic, hydroiodic.

Among the products of formula (I,), the / 1 of this application is more specifically concerned with products with the formula ^:

sin isomer in which R 'represents a hydrogen atom or an alkyl, alkenyl, alkynyl or cycloalkyl radical containing a maximum of 6 carbon atoms, optionally substituted or a radical

aryl, Z _A has the value indicated above, and R * _3A represents a phenyl radical, optionally substituted heterocyclic aryl, an optionally substituted quaternary ammonium radical or an acetyl or carbamoyl radical.

The application for a second certificate of addition also concerns a process for the preparation of products of general formula I _A as defined above, characterized in that it is a product of formula VII ':

(VII ') in which R ₄ and A have the meaning defined above and R _A represents either a free amino radical or protected by a mono or divalent group, or R & represents the radical R, having R the meaning indicated above, either with a halogenating agent either with a sulfonating agent and then with triphenylphosphine, or with a reagent of formula P (OAlk) 3 in which Alk represents an alkyl radical having 1 to 4 carbon atoms, to obtain either a product of formula VIII ¹ j

c ° ₂ a in which ^R A * ^R 4 ' ^{and A has the} previous 4? nification and X represents the rest of an anion, or a product of the formula VHI ^H _A :

P (OAlk) ₂

II in which R _A , R ₄ , A and Al have the previous meaning, products of formula VIII ' _A or VI1'I _A which, if desired, are treated first with a strong base and then with an alkyl halide of formula hal-R “ _A in which hal represents a halogen atom and R _A has values of R ' _A different from a hydrogen atom, to obtain products of formulas VIII' _B or VIII _B

VIII ‘B

SAW formulas where R _A has the above meaning and products of formulas VIII * _B and VIII ^U _B that are treated with a product of formula

The in which

R ' _b has the value indicated above and Gp represents a hydroxyl protecting group to obtain a product of formula IX':

in the form of a mixture of the E and Z isomers or in the form of an E or Z isomer, product of formula IX * with which the following reactions are carried out in any order *

a) cutting the protective group Gp;

b) when R ^ represents an amino radical protected by a mono or divalent protecting group, elimination of this protecting group and treatment of the product in which R & 'represents an amino radical or with an acid of formula IVat

RaCOgH (IVa) formula where Ra represents an organic group, or with a functional derivative of this acid, or with a product of formula ivbx

Laughs \

N-CH »Xb (iVb) ** z

RJ in which

Ri and Rj have the above meaning and Xb represents a sulfur or oxygen atom, or with a product of formula ivc *

Rb-Xc (iVc) in which

Rb has the meaning indicated in the main application and Xc represents a halogen atom;

c) S _and stop the Z and E isomers;

to obtain a product of formula X *

in which

R _a has the above meaning, product of formula X with which it is reacted or a reactive derivative of the group ^R 3A P ^{to obtain a} product of formula XI * _A :

either a derivative of a hydroxyl radical activating group and then a derivative or a reactive derivative of the group R _3a to obtain a product of formula XI · _β t

either a derivative of a hydroxyl radical activating group and then with a product of formula HS-R2, or a reactive derivative of this product to obtain a product of formula XI * q ·

products of formulas XI ^or XI XI'q ^undergoing if necessary or desired, any one or more of the following reactions, in any order:

a) cutting by hydrolysis, hydrogenolysis or by the action of thiourea of all or part or of the protecting groups;

b) esterification or salification of a base of the carboxy or sulfo groups;

c) salification with an acid of the amino group (s)

d) unfolding the molecule to obtain an optically active product;

e) oxidation of the sulfur atom at position 2 of the isocepheme cycle.

The halogenating agent used is preferably thionyl chloride in a chlorinated solvent such as methylene chloride or in dimethylformamide. A product of formula VII’a is thus obtained intermediate:

You may also use other halogenating reagents such as phosphorus pentachloride, phosphorus oxychloride or tosyl chloride ₀ sulfonating agent may be for example trifluorometilssulfónico anhydride. It is then possible to proceed in the presence of a base preferably 2,6-dimethylpyridine or lutidine. In general, sulfonation products are unstable and are not isolated.

The action of triphenylphosphine or the reagent of formula P (0Alk) 5 in which Alk preferably represents an ethyl radical is carried out under the usual conditions. The action of triphenylphosphine or the reagent of formula P (0Alk) 3 is preferably carried out in the presence of silica in the halogenated product of formula VII, it is generally operated by refluxing a solvent such as toluenc or chloroform. When operating on a product of formula VII ', the action of triphenylphosphine or product of formula P (0Alk) 5 is preferably carried out at the same time as

solfunation, given the instability of sulfonation products.

The strong base with which the products of formulas VIII and VIII ^ may be treated may be chosen from potassium or lithium t-butylate, lithium disopropylamide, lithium bistrimethylsilyl amide.

alkyl halide of the formula hal-RA is preferably chloride or bromide.

The action of the formula product

OGp in products of formulas VIII'-θ or VIIIVg is preferably carried out in a chlorinated solvent such as methylene chloride. It can be operated in the presence of a relatively weak base such as triethylamine or DBU-diabiciclo / ”5,4,0J undec-7-eno) or DBN (1,5-diababiciclo /” 4,3,07non- 5-ene). It then operates at room temperature or by heating.

It can also be operated in the presence of a strong base such as lithium t-butyl or an alcoholate such as lithium t-butylate, lithium bistrimethylsilyl amide or lithium diisopropyl amide. So it operates at low temperature. The reaction can be carried out, for example, between -70 ° C and room temperature.

protecting group that Gp represents can be a silyl group such as trimethylsilyl or t-butyldimethylsilyl. However, one can use

group such as tetrahydropyranyl.

cutting of the protection group G-p is carried out under classical conditions. It is carried out, for example, in the presence of a suitable acid or fluoride ion obtained by hydrofluoric acid or tetrabutylammonium fluoride.

When a product of formula IX 'is obtained in which it represents an amino radical, in a preferred mode of carrying out the process, the product of formula (IX') is treated with a functional derivative of a product of formula (IV _& ). This functional derivative can be, for example, a halide, a symmetric or mixed anhydride, an amine or an activated ester.

As an example of mixed anhydride, for example, those formed with isobutyl chloroformate and those formed with pivaloyl chloride and mixed sulfonic carboxylic anhydrides formed, for example, with paratoluenesulfonyl chloride. As an example of activated ester, the ester formed with 2,2-dinitrophenol and the one formed with hydroxybenzothiazole can be mentioned.

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

Mention may also be made of acid azide or acid amide.

anhydride can be formed in situ by the action of ΝΝ'-disubstituted carbodiimide, for example M, N-dicyclohexylcarbodiimide.

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 molecule of halohydric acid is released during the reaction, the reaction is preferably carried out in the presence of a base such as caustic soda, caustic potash, carbonates and acidic carbonates sodium or potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine ₀

The reaction temperature is generally less than or equal to the ambient temperature.

In a preferred method of carrying out the process. the products of formula (IV · ^) are transformed into reactive derivatives such as acyl halides, which can be prepared by reacting the products of formula (IV ^) with a halogenating agent such as phosgene, chloride oxalyl, thionyl chloride. They can also prepare complexes with dialkyl sulfates, preferably with dimethyl sulfate.

The operating conditions for these reactions are known to those skilled in the art. Such reactions are described for example in French patent 2,075,338.

In a preferred mode of carrying out the process, the halogens used in the products of formula (IV) are chloride or fluoride. Preferably, a pyridinium derivative is used. The counter ion is therefore preferably an iodide, tosylate, bromide, BP4 ion.

The preparation of the products of formula (IV) and the reaction of those products with the products of formula (IX ') are carried out under the conditions described for example in the Journal of Medicinal Ghemistry 1982, Vol 25, ns 4,

pg. 457-469

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

The transformation of the products of formula X 'into products of formula XI ^ is also carried out according to the classical processes.

derived from the R groups

5A used, for example, may be a halide derived from an optionally substituted carbocyclic or heterocyclic aryl radical. It is used then preferably fluoride when R ^ _A is for example , a carbamoyl radical or aoetilo. It is preferably operated in the presence of a reactive derivative such as an anhydride or halide.

The transformation of products of formula X * into products of formula XI ' _B is preferably carried out according to the following conditions: an activated derivative of the hydroxyl radical is prepared by the action, for example, of a sulfonic acid derivative such as trifluoromethylsulfonic acid anhydride. Operates at low temperature or at room temperature.

quaternary

When R ^ does not represent one, preferably a base is operated in the presence of ammonium.

The transformation of products of formula X 'into products of formula ΧΙ2θ is carried out under similar conditions.

An activated derivative of the hydroxyl group is prepared in the first place under the conditions set out above, namely from trifluorome acid anhydride18 -

tilsulfonic.

The reaction of the product of formula HSR4 is preferably carried out in the presence of an organic base such as 2,6-dimethylpyridine and a soluble source of iodide. It is then preferably operated in the presence of tetraalkylammonium iodide.

The products of formulas XI ¹ ^, XI'g and XI'θ are products of formula 1 ^ when they do not contain any protecting groups and when A does not represent, among the easily cleavable ester groups, one of those to be eliminated.

In other cases, the action on the products of formulas XI'XI'g or XI'θ of one or more hydrolysis, hydrogenolysis or thiourea agents is intended to eliminate the protecting group (s) that may contain the different products.

The nature of the reagents that go into all of these cases is well known to those skilled in the art. Examples of these reactions are given later in the experimental part.

Below is a non-exhaustive list of the means that can be used to eliminate the different groups.

The elimination of the protecting group or groups R'p can be carried out by hydrolysis, which is acidic, basic or using hydrazine.

Acid hydrolysis is preferably used to eliminate any substituted alkoxy and cycloalkoxycarbonyl groups, such as, for example, t-pentyloxycarbonyl or t-butyloxycarbonyl, aralkoxycarbonyl groups

optionally substituted, for example, benzyloxycarbonyl, the trityl, benzhydryl, t-butyl or 4-methoxybenzyl groups, _the acid that is preferably used can be chosen from the group consisting of hydrochloric, benzenesulfonic or para-toluenesulfonic, formic or trifluoroacetic acids. However, other mineral or organic acids can be used.

Basic hydrolysis is preferably used to remove acyl groups such as trifluoroacetyl.

The base that is preferably used is a mineral base such as sodium or potassium hydroxide. Magnesium, barite or an alkali metal acid carbonate such as sodium or potassium or other acidic carbonates or other bases may also be used.

You can also use sodium or potassium acetate.

Hydrolysis using hydrazine is preferably used to eliminate groups such as phthaloyl.

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

chloroacetyl group is unlimited by the action of thiourea in neutral or acidic medium according to the reaction described by MASAKI J, ACS, 90, 4508, (1968) ₀

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

Preferred groups include formyl, acetyl, ethoxyarbonyl, mesyl, trifluoroacetyl, chloroacetyl, trityl groups. Trityl and chloroacetyl radicals are particularly preferred. The acid which is preferably used is trifluoroacetic acid.

Salification of the products can be carried out according to the usual procedures.

Salification can, for example, be achieved by acting on a product in acid form or in a solvate, for example ethanolic solvate or a hydrate of this acid, of a mineral base such as sodium or potassium hydroxide, carbonate or acid carbonate sodium or potassium. Mineral acid salts such as trisodium phosphate can also be used. Organic acid salts can also be used.

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

ν '· ”, -

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

As examples of these organic acids, the following can be mentioned: formic, acetic, acrylic, butyric, adipose, isobutyric, n-capranoic, isocaproic, chloropropionic, crotonic, phenylacetic, 2-thienylacetic, 3-thienylacetic, 4-ethylphenylacetic, glutaric acids , the monoethyl ester of adipic acid, hexanoic, heptanoic, deoanoic, oleic, stearic, palmitic, 3-hydroxypropionic, 3-methoxypropionic, J-methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric, 3-phenoxybutyric, 4-phenoxybutyric, 4-phenoxybenzyl, 4-phenoxybenzoic, 4 1-propylbenzoic.

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

Salification can also be achieved by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, I, H-dimethylethanolamine, tris (hydroxymethyl) amino methane, methylamine, ethanolamine, pyridine, pieolin, diciolohexylamine, 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 an amorphous or crystallized form according to the reaction conditions used 22 -

used.

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

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

The eventual esterification of the products is carried out in the classic categories. It is generally operated by reacting the acid of formula (1 ^) with a derivative of formula:

nosal Z represents a hydroxyl radical or a halogen atom such as chlorine, bromine, iodine and Rg designates the ester group to be introduced, a group of which is given a non-exhaustive list below. In certain cases, it may be advantageous to perform an esterification on a product in which the amine is blocked before removing the amine protecting group.

eventual splitting of compounds of general formulas XI'ΧΙ'ρ, ΧΙ'θ can be carried out by means of an optically active organic oarboxyl or sulfonic acid, such as tartaric, dibenzoyl-tartaric, camphosulfonic or glutamic acid, with the decomposition of salt thus obtained carried out by means of a mineral base such as sodium bicarbonate or an organic base such as, for example, a tertiary amine, such as triethylamine. In addition, an optically active base can eventually be used.

The possible oxidation of products of formula ΣΙ ¹ XI'-g or ΧΙ'θ can be carried out with the help of

oxygen, peroxides, hydroperoxides, peracids or hydrogen peroxide. The reaction is advantageously sensitized by light. These reagents can be used in mixtures containing organic or mineral acids. Preferably, metachloroperbenzoic acid is used. Reaction conditions are known to experts. These conditions are found, for example, in the French application B.F. 2,387,254.

The purpose of this addition application is to illustrate, with new examples, the general formula I of the main application. These new examples also enter formula 1 of the main patent.

The new examples described in this application for addition have the following formulas: Products corresponding to general formula I of the main application of which the following names are given:

5 - / “3 - / - 7 - /” / ”(2-amino 4-thiazolyl) (methoxy imino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycloig /4.2.07 oct- 2-en-3 — yl / —2 (e) propenyl / 2- (trifluoromethyl) (thiazole /icando4.5.07 pyridinium (6S) (7S) (2).

7 - // (2-amino 4-thiazolyl) (methoxy imino) acetyl / amino7 3 - / ”5 - /” 1,4-dihydro 3- (formylamino) 4-oxo 1-pyridyl / 1 (E) propenyl / 8-oxo 4-aunt 1-azabicycles / 7.2.27 oct-2-ene

2-carboxylic (6S)) 7S) (2).

5-Z3-Z'7-ZZ “( ^2- amino 4-thiazolyl) (difluoromethoxyimino) -aoethyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycles /4.2.0/ oct-2-en 5- 117 2 (E) propenyl / thieno / gea3.2.ç7 pyridinium (6S) (7S) (2).

5-Z'3-Z'7-Z · £ (2-amino thiazol-4-yl) (difluoromethoxyimino) -aoethyl / amino7 2-carboxy 8-oxo 4-thia 1-azabicyclo / 4. <. 07 oct- 2-en 5-iJ / 2 (E) propenyl / 4-methylthene Z ”3.2.c / pyridinium (6S) (7S) (2).

5 - / - 3 - / - 7 - / - / - '(2-aminothiazol-4-yl) (fluoromethoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / 4.2.07 oct- 2-en 3yl / 2 (E) -propenyl / thiazole / 4.5.c / pyridinium (6S) (7S) (2).

^ -α-ΰ-FC ^ -amino thiazol-4-yl) (fluoromethoxyimino) -acetyl7aniino7 2-carboxy 8-oxo 4-thia 1-azabicyclo /ada4.2.0__7 oct-2-en 5-I17 2 (E) propenyl7 4-methylthiene /3.2.cJ pyrinium (6S) (7S) (Z).

5 - / ^ 3 - / ^ 7 - / ^ / ^ (2-amino thiazol-4-yl) (fluormethoxyimino) acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycle /4.2.0_7 oct-2- en 5-yl7 2 (e) propenyl7 thieno / where3.2.cJ pyridinium (6S) (7S) (Z).

5 - / ”3- / 7 - / '£' (2-amino thiazol-4-yl) (methoxyimino) -acetyl / amino / 2-caÈoxy 8-oxo 4-thia 1-azabicycles / as4.2.O__7 oct- 2-en J-1117 2 (E) -propenyl7 thiazole /.44.cJ pyridinium (6S) (7S) (Z).

5-Z ^_ 3-Z'7-ZZ '( ^2- amino thiazol-4-yl) (methoxyimino) -acryl] / amino / 2-carboxy 8-oxo 4-thia 1-azabicycles / where4.2.0J oct -2-en 5-1717 2 (E) -propenyl7 2-methyl ΙΗ-imidazole / “4,5-cJ pyridinium (6S) 7S) sin.

δ-Ζ ^ -Ζ'τ-Ζ'Ζ (2-amino thiazol-4-yl) (methoxyimino) -scetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycles / ^_ 4.2.0_ / oct- 2-en 5-117 2 (E) -propenyl 2-phenyl oxazole / accounting4.5cJ pyridinium (6S) (7S) sin.

_ / “3 ../- 7 _ /“ / “(2-amino thiazol-4-yl) (methoxyimino) acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycle /^.2.0^ oct-2 -en 3-I17 2- (E) propenyl72-ethyl thiazole k k * 5 ** pyridinium (6S) (7S) sin.

5-Z'3-Z'7-Z'Z '( ^2- amino thiazol-4-yl) (difluoromethoxyimino) aceti] / - amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo oct-2-en 5 yl / 2- (E) propenyl / thiazole / panto4.5.c/ pyridinium (6S) (7S) sin.

2-amino 5 - / ”3- / ^- 7 - /” / ^_ (2-amino thiazol-4-yl7 (difluoromethoxy imino) acetyl7 aming7 2-carboxy 8-oxo 4-thia 1-azabicycle

..., ......, -. ·:

/Ath4.2.0/ oct -2-en 3-yl / 2- (Ξ) propenyl / thiazole / like4.5.c/ pyridinium (6S) (7S) sin.

7-Z-3-Z-7-Z - / - (2-amino 4-thiazol) (fluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /.4.2.0/ oct-2 -en 3-yl / 2- (E) propenyl / thieno / where2.3.b/ pyridinium.

1-Z'3-Z'7-Z'Z '(2-amino thiazol-4-yl) (methoxyimino) acetyl / amino7 2-carboxy 8-oxo 4-thia 1-azabicycle / as4.2.0J oct-2 -en 3-yl / 2 (E) -propenyl / 1 - / ”2- (5-nitro ΙΗ-imidazol 1-yl) -ethyl-7 pyrrolidinium (6S) (7S) (2).

7-Z “3-Z'7-Z'Z · (5-anino 1,2,4-thiadiazol-3-yl) (methoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / "4.2.0_ / oct-2-en 3-yl / 2 (E) propenyl / thieno /" 2,3-b / pyridinium (6S) (7S).

7- / 7 // (2-2-amino thiazol-4-yl) (methoxyimino) (acetyl / amino /

8- oxo 3 - / ”3 - /” (1,3,4-thiadiazol 2-yl) thiol 1 (E) -propenyl /

4- (2,2-dimethyl 1-oxo propoxj / methyl 6S, 7S sin (E) 1-azabicyclo / gated4.2.0__/ oct-2-en 2-carboxylate in a form of internal salt or salt obtained with mineral or organic acids.

The present invention is more particularly concerned with the following products:

5- Z “5-Z7-ZZ ^_ (2-amino thiazol-4-yl) (methoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycl / /4.4.0J oct-2-en 3 -il / 2 (E) -propenyl / thiazole / like4.5.oJ pyridinium (6S) (7S) (Z).

5 - / “3 - /” 7 - / “/“ (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / where4.2.0/ oct -2-en 3-yl / 2 (E) propenyl / thiazole / as4.5.C_J pyridinium (6S) (7S) sin.

aminçy 2-carboxy 8-oxo 4-tia 1-azabicycle //4.2.07

-amino 4-thiazole) (fluoromethoxy) imino) acetyl7amino7 2-carboxy 8-oxo 4-thia 1-azabicycl / /4.2.O_7 oct-2-en 3-117 2 (E) propenyl7 thieno / where2,5.b_7 pyridinium (6S) (7S) sin.

Finally, it is particularly concerned with the following product:

5-Γ 3-Z7-Z'Z (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl / oct-2-en 3-yl7 2 (E) -propenyl7 thiazole, / Ύ? · ⁰ J pyridinium (6S ) (78) sin.

The products which are the subject of the present application for addition can be prepared by the process of the main patent, a process which has been mentioned above.

Like the products of general formula (I) described in the main application, the products of the present addition application have very good antibiotic activity in gram (+) bacteria such as staphylococci, streptococcus and, in particular, in penicillin-resistant staphylococci . Its effectiveness in gram (-) bacteria, namely in coliform, cebsiela, salmonella and proteus bacteria is particularly remarkable.

These properties make the products particularly suitable for use as medicines in the treatment of diseases caused by sensitive germs and, in particular, in the case of staphylococci, such as staphylococcal septicemias, malignant facial or cutaneous staphylococci, pyoderma, septic or suppurative sores, anthrax , phlegm, erizipelas, acute primitive staphylococci or flu-feet, bronchopneumonia, pulmonary suppuration.

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

The present invention also has as its object, as medicines and in particular as antibiotic medicines, the products corresponding to the general formula I of the main application, the names of which are given below:

ίΟΖΤ-ΓΓί ² -amino 4-thiazolyl) (methoxy imino) -acetyl7 amino 2-carboxy 8-oxo 4-thia 1-azabicyclo /γ4.2.0oct-2-en-5-il7-2(E) propenyl7 2- (trifluoromethyl) thiazole /.4-.5.c7 pyridinium (6S) (7S) (Z).

7 - / “/ (2-amino 4-thiazolyl) (methoxy imino) aceti / Z amino 3 - /” 3- / 1,4-dihydro 3- (formylamino) 4-oxo 1-pyridyl / 1 (E ) propenyl7 8-oxo 4-thia 1-azabicyclo / as4.2.0J oct-2-ene

2-carboxylic (6S) (7S) (Z).

5 - / “3 - /” 7 - // ”(2-amino 4-thiazolyl) (difluoromethoxyimino) -acetyl7-arnino7 2-carboxy 8-oxo 4-thia 1-azabicyclo /made4.2.0J oct-2-en 3-117 2 (E) propenyl7 ϋθπθ /icando3.2.c/7pyridinio (6S) (7S) (Z).

5-Z'3-ZV-ZV- (2-amino thiazolo-4-yl) (difluoromethoxyimino) -acetyl7 amino7 2-carboxy 8-oxo 4-thia 1-azabioiclo / 4.2.0J oct-2-en 3-117 ² (E) propenyl / 4-methylthiene / peat3.2.c__7 pyridinium (6S) (7S) (Z).

5-Z'3-Z'7-Z'Z '(2-amino thiazol-4-yl) (fluoromethoxyimino) -acetyl7 amino7 2-carboxy 8-oxo 4-thia 1-azabicyclo Z-4.2.0J, oct- 2-en 3-117 2 (E) propenyl 7 thiazole /.44.c_7 pyridinium (6S) (7S) (Z).

-amino thiazol-4-yl) (fluoromethoxyimino) -acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycle Z ~ 4.2 _o 0 _> _7 -oct-2-en 3-yl7 2 (B) propenyl7 4- methyl thieno / 7.2.3.c_7 pyridinium (6S) (7S) (Z).

5-Ζ'3-Γ7-ζΓΖ · (2-amino thiazol-4-yl) (fluoromethoxyimino) -acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / used4.2.07 oct-2-en 3 -I17 2 (E) -propenyl7 thieno / as3.2.ç7 pyridinium (6S)) 7) (Z).

5-Z'3-Z'7-rZ '(2-amino thiazol-4-yl) z (methoxyimino) acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo4.2.07 oct-2- en 3-117 2 (E) -propenyl7thiazole ^ 4.5. pyridinium (68) (7S) (Z).

537- / 7C (2-amino thiazol-4-yl) (methoxyimino) -acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycl / /4.2.0/ oct-2-en 3-yl72 (E) -propenyl7 2-methyl IH-imidazole /.4.5.c_7 pyridinium (6S)) 7S) sin.

5- / ~ 3- / 7 - / ”/ ^_ ( ² “ ^amino thiazol-4-yl) (methoxyimino) -acetyl7 'amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / as4.2.0_J7 oct- 2-en 3-117 2 (E) -propenyl7 2-phenyl azololo /4.5.g7 pyridinium (6S) (7S) sin.

5-Z '? - Z'7-Z'Z' (2-amino thiazol-4-yl) (methoxyimino) acetyl7 amino / 2-carboxy 8-oxo 4-thia 1-azabicycloal / /4.2.0__7 oct-2 -en 3-117 2- (E) propenyl7 2-ethyl thiazole // 4.5.o_7 pyridinium (6S) (7S) sin.

5-Z'3-Z'7-Z'Z ^_ (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl7amino7 2-carboxy 8-oxo 4-thia 1-azabicycle /4.2.07 oct-2-en 3 -117 2- (E) propenyl / thiazole /icando4.5.c_J7 pyridinium (6S)) 7S) sin.

2-amino-5 - / ”3- / 7 - // (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl7 amino7 2-carboxy 8-oxo 4-thia 1-azabicyclo

/ Ash4.2.07 oct-2-en 3-117 2- (E) propynyl / thiazole / either4.5.ç/ pyridinium (6S) (7S) sin.

7-Z-3-Z'7-Z7- (2-amino 4-thiazol) (fluoromethoxy) i [nino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabioiclo Z-4.2.07 oct- 2-en 3-yl / 2- (E) propenyl / thieno / ”2,3-b7 pyridinium.

iZ- ₃ -Z-7-Z "Z '(2-amino thiazol-4-yl) (methoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /.4.2.07 oct-2- en 3-yl / 2 (E) -propenyl / -l - / “2- (5-nitro ΙΗ-imidazol 1-yl) ethyl / pyrrolidinium (6S) (7S) (Z).

7_ / 5 - / “7-./madeZ“ (5-amino 1,2,4-thiadiazol-3-yl) (methoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / “ 4.2.07 oct-2-en 3-yl / 2 (E) -propenyl / thieno / ”2,3-1 / pyridinium (6S) (7S).

7- Z'Z '(2-amino thiazol-4-yl) (methoxyimino) acetyl / amino /

8- oxo 3- / ~ 3 - / ”(1,3,4-thiadiazol 2-yl) thiol-l- (E) propenyl 4-thia 1-azabicyclo /ã4.2.07 oct-2-en 2-carboxylate of (2,2-dimethyl 1-oxo propoxy / methyl 6S, 7S sin (E).

in the form of an internal salt or a salt formed with mineral or organic acids.

The invention has more particularly as its object, as medicines, the products:

5-Ζ'3-Ζ · 7-Ζ'Ζ · '(2-amino thiazol-4-yl) (methoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / 4.2.0 / oct -2-en 3-yl / 2 (E) -propenyl / thiazole /icando4.5.ç7 pyridinium (6S) (7S) (Z).

5-Ζ-3-Γ7-Ζ-Ζ '' (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabieiclo / 4.2.0 / oct-2 -en 3-yl / 2 (E) -propenyl / thiazole / as4.5 Phasic / pyridinium (6S) (7S) sin.

ι-Ci-ir-CC (2-amino 4-thiazol) (fluoromethoxy) imino) aceti.17 amino7 2-carboxy 8-oxo 4-thia 1-azabioiclo / according4.2.0J oct-2-en 3-i 17 2 (E) -propenyl7 thieno /2.3- ^ 7 pyridinium (6S) (7S) sin.

the product with the following name is very special:

5-Z3-Z7-Z ^- Z- (2-amino thiazol-4-yl) (difluoromethoxyimino) acetyl / amino7 2-carboxy 8-oxo 4-thia 1-azabioiclo / where4.2.0/ oct-2-en 3 -117 2 (E) -propenyl7thiazole / as4.5.ç7 pyridinium (6S)) 7S) sin.

The invention comprises pharmaceutical compositions containing as an active principle at least one of the compounds defined above.

These compositions can be administered orally, rectally, parenterally, intramuscularly or locally via topical application to the skin and mucous membranes.

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

They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as tablets, simple or dragee, jellies, granules, suppositories, injectable preparations, ointments, creams, gels; and are prepared according to the usual procedures. The active principles or principles can be incorporated with excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty bodies of animal origin or vegetable, paraffinic derivatives, glycols, various wetting agents, dispersing 31 1

preservatives or emulsifiers.

These compositions can, in particular, be in the form of a powder intended to be dissolved out of time in a suitable vehicle, for example sterile pyrogenic water.

The administrative dose varies according to the condition treated, patient concerned, route of administration and the product under consideration. It can, for example, be between 0.500 g and 1 g three times a day, intramuscularly for the products of Examples 8 or 12.

The products of formula (1) can also be used as disinfectants for surgical instruments.

The products of formula VII 'used in the process for the preparation of the products of formula 1 may be prepared according to the process described in the main patent.

In addition to the products described below in the Examples which illustrate the present addition without limiting it. The following products are products that can be obtained as part of this addition.

Example 18

Injection formulations were prepared:

THE/. - Product of Example 8 500mg

- sterile aqueous excipient q.b.p ...... 5om3

B/. - Product of Example 12 500mg

- sterile aqueous excipient q.b.p ...... 5om3

0 /. - Product of Example 14 500mg

- sterile aqueous excipient q.b.p ..... 5cm3.

-

PHARMACOLOGICAL STUDY OF PRODUCTS

In vitro activity, liquid dilution method

A series of tubes are prepared in which the same amount of sterile nutrient medium is introduced. Increasing quantities of the product to be studied are distributed in each tube, and then each tube is inseminated with a bacterial strain. After incubation for 24 hours in an oven at 37 ° C, growth inhibition is evaluated by transillumination, which allows the determination of the minimum inhibitory concentrations (C.M.I.) expressed in yUg / cmJ.

The following results are obtained:

- © --- * ο \ ο + ³ I— | d Α Ό s Ο φ Í4 X Α Α

οοοοο ιηοιηο - - - 03 - 03 ο Ο οοοοοοο ο -Ρ φ ο

Í4

Α

Ο γ — 4

Α

S φ X

Α

Ο + ³

Α ο

Α 'ο + ³

Α ο

Fh

Α ο

Α

Α ο

Α ο

rH

Α <Τ

Φ

X W ο

Α

Α

AND

Φ ΚΛ

X W

8888828 «3 03 ΙΟ ο ο ο ό 6 6 6 ό ò d 0 <

I I I

I | · I

I I

I I οοοοο «ιηιηιη - - Ο --- ΟΟ

Ο Ο Ο Ο Ο Ο Ο οοοοο ιηιηιηο - - - - - οο ο ο οοοοοοοο

8888 ^ 23 ιη ιη ιη ιη ο ο ο

04 04 04 ο ο ο

I 1 I I I I I I I I I

I

I

OOOOOOO-NiDinomOOm dddddddo— doióóódd

II V

Φ Ο Ο ΟΟΟΟΜΟΟΟΟΟ οο ιη ο - 04

Ο - 04004 - - U3 Ο 04 Ο - Ο Ο 04 m

04 04

Ο Ό ο ‘Ο —4 • Ρ 3. Α Ε B Φ ο X Ρ Α Α '

ι

OOQιΟΟΟΟΟΟΟ οι 04 ο ι ιη ο αο ο <x> ιη ΟΟΟ I Ο - 100 (00 -

- ΙΟ - tnooo ι OCOOOOOOOOOO04O0404 04 I 0404 · '· .Γ

Α-I-Α

I

1· .

I <Λ -I m φ Α

É4 • rd Ρ ω

Η

- - (Ο (Ο <03 ιη uj uj ui - - μ · ιη γ- <τ ιο ιη ιη - Γ— Ν - 04 04 Ο - ο ο ω ν <r— s V S 04 C0 04 0) 04 ιη ιη 04 ιη σι tu ιη ο ιη 03 ΙΟ 04 ιη <η 03 2 - - CL - 03 03 ιη ιη ιη ιη χι χι s - 03 Γ— Ο 04 Ο 111 04 04 Ο □ 2 Ο ζ ζ Ο γ- S Ο - <ιη ιη XI χι XI UJ χ | XI XI XI - < ο χιιηοοαί — ιχιχι <<<< cc cc tr χ ο ο ο ο ο 3- - ααζζζζ Ο <_> OOOOOOiU 2 Ο tu χι <<l / l CD <<<< >> < α. α. u. J J-J J J JI3OO _J _1 03 —J - * ιη ιη ιη ιη ΟΟΟΟΟΟιωκα uuin-a: 2 Σ3 13 X) d <✓) ιη <ζ> υυυυυυυ> ζωιι 04 03 <d UUUUO33 'ρ α. <<. CC X <O UUUUUUU <(<<<<< UJ XI C> CC —1 < οοοουυυ 1— 3— X - d · - < οοοοοο ΙΙΙΙΙΙJJJj O O 2> U3 οοοουυυ UUUUUUJJJJ <<<Z -1 _Ι _ι _Ι ο ο ο -> - · - _ χι UJ χ, UJ 03 os · -> cn <n xi > -> -> -> · 1— 1— 3— orcxaraiíxaiz - -. - O O 3- D D d I X II α. α. α. xixiujximujOininin (X X <UJ XI α. α. □. α. m ιιι χι ΙΙΙΙΙΙί m os <η XI XI X 3- 3-> <<<. <χ χ α OU (_3OQ (J_JUJXIUJ i- 3- tr o o o l ~ 3—) - 1— Η * 3— < tnini / i <z) (/> cn <_j_j_i z z xi x x x ιη ιη ιη ιη <η <η ιη ι χιχιχιχιχιχιπκ: ^^: uj uj in cl o. cl

► ►

_ Γ Ο ο Η + ³ Ρ < ι $ s φ 0J ο κ ρ Η J ' F4 ο | .'d ο ο ι — 1 ρ < -ρ s • d φ V τ5 Μ V ο Η Ρ Α Ο π3 ο γ-Η ! Ο Ρ. Ρ s 3 ο Ο: X X ν ' Ο Η Ρ Pd ! ο <ϋ ο ο r-4 Pd Ρ β d φ σλ | ^r d Μ ο Μ 1 Ρ 1 Pd 1 1

ο X ο ί — 1 Ο Ρι Ρ s Ρ φ X X ο Ή Ρ Pd

ο X Ο 1—1 Ο Ρ < Ρ s ρ φ X X Ο Η Ρ Pd

V) _J - r- (D (Ο <00 - · - v m r- ιη ιη ιη - μ cd ο ® ν <2 <λ <λ cm ιη ΚΓ 0) UJ NJ £ in uj uj uj T - CM CM CD rCM 00 CM CD CM UO O LÍ0 C0 in cm ui υο 09 2 r ~ f · τ— ’ poo ΙΛ (Λ <Λ <0 XI LL1 2 - 00 t * ~ Q CM X UJ CN ÇN • X X X X Ζ Ζ X XI LU XI XI XI LU t— > ί Ο ο ω ιη <_> ω * - <X <</) ΟΊ UJ UJ UJ UJ << << χ χ χ χ cd cd υ X X X X Ο Ο ω 2θμ-αα X 2 ζ ζ ζ ω o Ο XI XI << cn CD <<<< >> < Η Η Μ »Η Μ Η 1— < 5 000004 > - <<ZJ ’Τ χ χ χ -J —1 _1 _ι _ι _ | X x o O _i _i cn «J F-4 C0 1 /> ΟΠ G0 ο ο ο ο ο ο X iu χ x cj cd in μ- * Qí 79 X χ χ χ υο ιη is> cd ο cd cd ω <_> > Z UJ UJ CM OD < Q υυυυχχχ υυυυυυυυ <<<<<< B- O. <<r α UJ UJ o <The cr _i < οοοουυυ > <* ► — 1 Ι-Μ < <<<> - j— cr · - '79 υ ο ο ο ο ο α X X X X X X -J -J -J -J o u 5E> O . οαοουυυ υυυυυυ -1 -1 -1 _J <<< Z J JJJOOO ►Μ μ-1 Μ * - · · - » you lu uj uj ca co - · (✓) UJ >>>> Η- Η μ. X X X X X X z · - <- · —ι O O H · 79 Z> Q j X I Ζ I χ χ χ LU UJ UJ UJ UJ LU (~ Ί tz> cn σι cr cr < UJ UJ f-m 1 χ α χ χ χι χι ω ιιιιιι jpj m m <n lu lu α μ- t- l <<<<χ α α UUUUUU J uj xi χι μ-1- x α α o Η— μ— t— μ— »- ί— ι— (Ζ) (/) 4ΖΊ (Ζ) (Ζ) (Ζ) < -J _1 _J z Z UJ cr cr cr ι (Ζ) (Ζ) (Ζ) (Ζ) (Ζ) L0 ΙΖ) 1 UJ UJ UJ UJ UJ LU 00 x ϋ X uj uj cn X X X 1

Reference Example: Srifluorometano sulfonate 7- / ~ 3 / 7_ ~ / ~ y ~ 2- _am i _in 4-thiazolyl) (methoxy imino) acetyl / amino7

2-carboxy 8-oxo 4-thia 1-azabicyclo / g4.2.07 oct-2-en-3-yl7 propen 2 (E) -yl7thene / “2,3-b / pyridinium 6S, 7S sin.

Base A: 7-Z ^_ / '2- (2-triphenylmethylamino thiazol-4-yl / 2 (Z) methoxy imino acetyl / amino 3-Z “3-Z” (1,1-dimethyl ethyl) dimethyl silyl όχι / propen-1-yl / 8-oxo 4-thia 1-azabicyclo Z ~ 4.2.p7 (1,1-dimethyl ethyl) 6S, 7S oct-2-en 2-carboxylate.

1.89 g of 7-cc '2- (2-triphenylmethylamino thiazol-4- 117 2 (Z) methoxy iminoacetyl / amine / 3-methyl triphenyl phosphonium 8-oxo 4-thia 1-azabicycle Z) ^_ 4.2.07 oct-2-ene-2-carboxylic acid (1,1-dimethyl) ethyl, 30 cm3 of dichloromethane, 0.68 OM3 2-Ζ'Ι, Ι dimethyl dimethylsilyl oxy / acetaldehyde, 0.53 cm3 triethylamine, stir at + 20 ° C for 14 hours, chromatograph the solution on silica eluting with a mixture of dichloromethane and ethyl acetate (9/1) and separate 1.305 g of the desired product containing a mixture isomer E (2/3) and 2 (1/3) the

NMR spectrum (CD01 ₅ )

0.90 - 0.92 ppm SitBu; 1.50 - 1.53 ppm COgtBu; 2.95 - 3.11 ppm CHgS; 4.05 ppm OCH3; 4.31 - 4.37 ppm OHgO 4.11 ppm Hg; 5.4 to 5.5 ppm Ηγ 5.75 - 5.87 ppm and 6.11 - 6.24 ppm Z (1/3); 6.17 - 6.34 ppm and 6.97 - 7.16 ppm E (2/3); 6.50 -6.56 ppm thiazole sin; 7.34 ppm 0 ^.

Base B: 7- ZT ² - (2-triphenylmethylamino thiazol-4-yl) 2 (Z) methoxy imino acetyl / amino7 3-Z ”(3-hydroxy propen-1 (E) yl) 8-oxo 4-thia 1 -azabicycloZ “4.2.07 (1,1-dimethyl ethyl) oct-2-en 2-carboxylate and,

7 - / ”/“ 2- (2-triphenylmethylamino thiazol-4-yl) 2 (Z) methoxy imino acetyl / amino7 3-Z3-hydroxy propen-1 (Z) yl7 8-oxo 4-thia 1-azabicycle / “ 4.2.07 (1,1-dimethyl ethyl) oct-2-en 2-carboxylate.

1.505 g of the product obtained in step A of Example 1 are dissolved in 15 cm3 of acetone, 2 cm3 of normal aqueous hydrochloric acid solution are added, stirred for 2.5 hours, concentrated to dryness by distillation at reduced pressure, bio-carbonated water is added, the dichloromethane is extracted, it is distilled under reduced pressure, the residue is chromatographed on silica, eluting with a mixture of dichloromethane and ethyl acetate (1/1) and separate up;

536 mg of isomer E and,

369 mg of the Z isomer of the desired product. Isomeric controls (E).

I.V. spectrum (chloroform)

3607 cm ¹ OH; 3405 cm ” ¹ NH amide: 1684 cm ^-1 0 = 0;

1515 cm ¹ amide II, 1772 with ¹ lactam 0 = 0; 1595 cm ¹ ;

-1 -1

1544 cm; 1527 cm: aromatic, thiazole, conjugated system;

1700 cm ¹ terbutyl ester; 1370 cm ^-1 ; ;

1154 cm ¹ COC; 2820 cm ¹ OMe; 1049 ^cm-1 0 = 0R C.

U.V. : ethanol.

Max 231 nm E ¹ = £ 497 = 32 200.

Inflection 258 nm E ¹ = 290;

Inflection 264 E ¹ = 264;

Inflection 270 nm E ¹ = 240;

Max. 320 nm E ¹ = 245; £ = 18 100.

NMR spectrum (CDCl ^)

1.51 ppm tBu; 3.05 ppm 0H ₂ S; 4.02 ppm Ol · ^; 4.28 ppm CH ^OH;

5.48 ppm: Ηγ; 6.24 - 6.41 and 6.97 - 7.13 ppm ethylenic H A E J = 15 Hz; 7.29 ppm 0 ^; 6.53 ppm H ^ thiazole sin.

Z isomer controls.

I.V. spectrum (chloroform)

3605 cm ¹ OH; 3405 cm ¹ araide NH; 1685 cm ^-1 0 = 0;

1505 cm ¹ amide II; 1773 cm ¹ Q lactam 0 = 0;

1704 cm ” ¹ terbutyl ester; 1368 cm ¹ Me; 1154 cm ¹ COC:

1585 cm ¹ , 1573 cm ¹ , 1527 cm ¹ , triethyl, —1 aromatics, thiazole, conjugate system; 2820 cm C = N-0Me; 1050 cm ¹ CN-OR.

U.V spectrum, (ethanol)

1

Inflection 250 nm E = 411; Inflection 260 nm E = 220;

1

Inflection 265 nm E = 198; Inflection 271 nm Ξ = 176;

1

Max. 308 nm E = £ 194 = 14 300.

NMR spectrum (CDCl ^)

1.49 ppm tBu; 3.06 ppm S-OH ₂ ; 4.04 ppm OMe; 4.27 ppm CHgOE;

5.48 ppm Ηγ; 5.85 - 5.98 ppm and 6.21 - 6.34 ppm ethylenic H Δ z J = 11 Hz; 6.56 ppm H ^ thiazole sin; 7.29 ppm 0

Phase 0: 7-Z ”3- / 7 - /” / 2- (2-triphenylmethylamino thiazol-4-yl) 2 (Z) methoxyimino) acetyl7 aminu / 2 - / “Zl, l-dimethyl-ethyl7oxy7carbonyl7 8-Z”, trifluoromethane sulfonate 8 -oxo 4-thia 1-azabicyclo /4.2.07 oct-2-en 3-17 propen 2 (E) yl / thieno Z2,2, b7 pyridinium 6S, 7S.

222 mg of the E isomer obtained in step B of Example 1 are dissolved in 4.8 cm of dichloromethane,

3 cm3 of solution containing 536 mg of thiene pyridine are added for each 10 cm3 of methylene chloride, cooled to -70 ° C, 2.7 cm3 of 0.42 sulfonic trifluoromethane anhydride solution are added dropwise cm3 for each 10 cm3 of methylene chloride, bring slowly to +20 ° C, concentrate to dryness under reduced pressure, add ethyl acetate, wash with water containing 0.7 cm3 of solution aqueous hydrochloric acid N, decant, wash with water, extract with ethyl acetate, concentrate to dryness under reduced pressure, chromatograph the residue on silica, eluting with a mixture of dichloromethane and methanol (92/8) and 236 mg of the desired compound (E-isomer) are separated.

Phase C: 7- / 3- / ~ 7 - / “/“ (2-triphenylmethylamino thiazol-4-yl) 2 (z) methoxy imino) acetyl? amino? 2- / ~ / ~ 1,1-dir-ethyl ethyl 7 oxy? carbonyl? 8-oxo 4-thia 1- azabicyclo /4.2.07 oct-2-en 3-17 propen 2 (Z) 11 / thieno / * 2, 3-b? pyridinium 6S, 7S.

145 mg of the Z isomer obtained in step B of Example 1 are dissolved in 5 cm3 of dichloromethane, 120 µl of thiene / ~ 2,3-b? pyridine, cool to -70 ° C, add 1.76 cm3 of trifluoromethane sulfonic anhydride solution in methylene chloride containing 0.42 cm3 of anhydride for each 10 cm3 of methylene chloride, add slowly at + 20 ° C, the solution is chromatographed on silica, eluting with a mixture of dichloromethane and methanol (92/8) and 157 mg of the desired compound are isolated.

Phase D - 7 - / "3- / 7 - /" / "2-amino 4-thiazolyl) (methoxy imino) acetyl? Amino? Trifluoromethane sulfonate 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 sin.

221 mg of the isomer (E) obtained in step 0 of Example 1 are mixed, 2.5 cm3 of 33% formic acid (aqueous solution), heated to 65 ° C for 55 minutes, cooled, diluted if it is filtered with water, washed with ether, the aqueous phase is concentrated to dryness by distillation under reduced pressure, water is added, drained, dried and 93 mg of the desired product are obtained.

I.V. Spectrum (nujol)

1760 cm ¹ β Lactama C; 1660 cm ^-1 ; 1550 and 1535 cm ¹

Aromatic It + amide II + thiazole + conjugated system; 1030 cm ¹ C? ₃ SO ₅

U. V. spectrum (ethanol).

Max. 238 nm Ξ = £ 625 = 44,200 _r

Max. 307 nm E = £ 251 = 17,700

Inflection 318 nm E = 232

Inflection 338 nm E = 166 isomer 2 by formic hydrolysis of totally E hydrolysis (isomerization).

Preparation of 7 - // (2-triphenylmethylamino thiazol 4-yl) 2 (2) -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

1,1-dimethyl ethyl 2-carboxylate (6S, 7S) and 1,679 g of triphenyl phosphine in 24 cm3 of tetrahydrofuran, 14.1 g of silica are added, the tetrahydrofuran is distilled for 2 hours, cooled, stir for 26 hours at 2 ° C, chromatograph on silica eluting with a mixture of dichloromethane and methanol (90/10) and 1.89 g of the expected product are obtained.

Example 1

5 - / '3- / ~ 7- / ^_ /''(2-amino-4-thiazolyl) (methoxy imino) -acetyl7amino7 2-carboxy 8-oxo 4-thia 1-azabicycle /~4.2.o7 oct -2-en-3-yl7-2 (E) propenyl7 2- (trifluoromethyl) thiazole /~4.5.C7 pyridinium (6S) (7S) (Z),

Stir for 2 hours and 30 minutes at 20 ° C 321 mg of 7 - / “(2-tritylamino thiazol 4-yl) (methoxyimino) acetamido7 8-oxo 3-iodopropenyl 4-thia 1-azabiciole /4.2.07 oct -2-ene 1,1-dimethyl ethyl 2-oarboxylate and 85 mg trifluoromethyl thiazole pyridine by centrifugation in 1 cm 3 of dry dimethyl sulfoxide. The maximum solvent is distilled off, concentrated to dryness under reduced pressure <1 mm Hg for 3 hours, the residue is chromatographed on silica, eluting with methylene chloride and then with methylene chloride-acetone mixtures (90- 10) and methylene chloride-methanol (92-8) and 410 mg of blocked blocked product iodide is obtained.

2 cm 3 of 10% trifluoroacetic acid are added to this product, stirred for 20 minutes, cooled slightly to add 25 cm3 of isopropyl ether slowly and stirred for 20 minutes. 137 mg of the desired product are isolated by centrifugation.

- 42 Example 2:

7- / ~ / ~ (2-amino 4-thiazolyl) (methoxy imino) acetyl / amino7 3- / ~ 3- / ~ 1,4-dibidro 3- (formylamino) 4-oxo 1-pyridyl7 1 (E) propenyl7 8-oxo 4-thia 1-azabioiclo /~4.2,o7 oot-2-ene 2-carboxylic 6 (S) (78) (Z).

It is operated as in Example 1 with 85 mg of oxazole pyridine and 311 mg of trifluoroacetate of the desired product is obtained. Chromatograph on silica on HPLC 200 mg of the latter product in a mixture of acetonitrile-water (1_1), eluting successively with mixtures of water and 5, 10 and then 15% acetonitrile. 48 mg of the desired product is obtained after lyophilization

250 MHz DMSO NMR spectrum in ppm:

b, 81 Hg

3.85 H

5.63 H _?

4.07 H ₆

6.90

6.08

6.25-7.28

OCEL thiazole 8.71-8.30) 3 of ethylene cefeme

J

Pyridine Hg and Hg

H2 to pyridine and H of formyl

Example 3:

5- / ~ 3- / ~ 7- / ~ / '~ (2-amino 4-thiazolyl) (difluoromethoxyimino) -acetyl7 amino7 2-oarboxy 8-oxo 4-thia 1-azabicycle /~4.2.o7 oot- 2-en 3-yl7 2 (E) -propenyl7 thieno /~3.2.c7 pyridinium, trifluoroacetate (6S) (7S) (Z).

It is operated as in Example 1 starting from 200 mg of 7-Z ~ 2-tritylamino thiazol 4-11 / difluoromethoxy imino7 acetamido / 8-oxo 4-thia 3-iodopropenyl 1-azabicycl Z 4.2.07 oct-2-en 1,1-dimethyl ethyl 2-carboxylate and 38 mg of thiene z-3.2.07 pyridine and 44 mg of the product are obtained

intended.

U.V.

Π /. in EtOH:

max 258 nm E ^ 620 £ 51 700 infl. 260 nm E 252 max. 519 nm E 255 t 19 600 & /. in EtOH / HCL 0.1 H:

_c max. 259 nm E 566 C 47 200 infl. 260 nm E 286 infl. 275 nm E 249 infl. 284 nm E 226 max. 527 nm E 190 í 15 900

Example 4:

5- / ~ 3 - / '7 /' / ~ '(2-amino-thiazol-4-yl) (difluoromethoxy imino) acetyl7 amino7 2-carboxy 8-oxo 4-thia-1-azabicycle /~4.2. 07 oct-2-en-3-yl7 2- (E) propenyl7 4-methylthiene /~3.2.c7 pyridinium (trifluoroacetate) (6S) (7S) (2).

It is operated as in Example 5 from 50 mg of methyl thieno / powd5.2.ç7 pyridine and 59 mg of the desired product are obtained.

- 44 i

U.V.í Spectrum

1 ^ /. in : EtOH: _T £ 37 200 infl. 212 nm AND 1 438 max 238 nm 1 AND 1 666 6 56 600 infl. 260 nm 1 AND 1 233 max. 317 nm 1 AND 1 236 £ 20,000 2 ^ /. max. in EtOH / HOL 1 234 nm E 1 0.1 619 N: £ 52 600 infl. 259 nm 1 AND 1 290 infl. 266 nm 1 AND 1 277 infl. 280 nm 1 AND 1 236 infl. 295 nm 1 AND 1 193 max 323 nm 1 AND 1 143 16 400 infl. 332 nm 1 AND 181

Example 5:

5- / 3 - / '~ 7- / ~' / ~~ (2-amino-thiazol-4-yl) (imino fluoromethoxy) acetyl7 amino7 2-oarboxy 8-oxo 4-thia 1-azabiciolo /*4.2 .0 / oct-2-en-3-yl7 2- (E) propenyl · / thiazole /~4.5.c7 pyridinium (trifluoroacetate (6S)) 7S) (Z).

- 45 4

It is operated as in Example 1 from 200 mg of 7 - / ”2-tritylamino thiazol 4- 117 fluoromethoxy imino acetamido / 8-oxo 4-thia 3-iodopropenyl 1-azabicyclo Z'4.2.07 oct-2-eno 1,1-dimethylethyl 2-carboxylate and 35 mg thiazole Z4.5.o7 pyridine.

82 mg of the desired product is obtained.

UV spectrum:

in EtOH / HCL Ο, ΙΝ _χ t52 900 max. 224 nm AND 1 647 1 £ 27 500 max. 264 nm AND 1 1 336 max 331 nm AND 1 190 The 15 500

250 MHz DMSO NMR spectrum in ppm:

6.98 .Htj tiazole

7.14 0H = CH-0H ₉

5.45 to 5.90 CH ₂ F and CH ₂ N

Example 6:

5 - / ^ 3 - / ^ 7 - // (2-amino-thiazol-4-yl) (fluoromethoxy imino) acetyl7 amino7 2-carboxy 8-oxo 4-thia 1-azabioiol /4.2.07 oct-2 -en-3-yl7 2- (E) propenyl7 4-methylthene / ~ 3.2 _o c7 pyridinium (trifluoroacetate) (6S) (7S) (Z).

It is operated as in Example 5 from 38 mg of methyl thiene /3.2.c7 pyridine and 42 mg of the desired product are obtained.

- 46 UV spectrum í

I ^a /. in EtOH

max. 212 nm E 440 1 6 36 500 max. 258 nm 1 E 642 1 r, 53 300 inf 1. 260 nm 1 E 231 1 max. 317 nm 1 E 217 1 ç. 18 000 2 ^ /. max. in EtOH / 0.1 ICL 259 nm Ξ ¹ 604 1 ’6 50 200 inf 1. 257 nm 1 E 322 1 inf 1. 280 nm 1 E 249 1 max. 324 nm 1 E 181 r D 15 000

Example 7

5- / ~ '3- / ~ 7 - /' / ~ '(2-amino-thiazol-4-yl) (fluoromethoxyimino) acetyl7 amino7 2-carboxy 8-oxo 4-thia 1-azabicycle /4.2.07 oot-2-en-3-yl7 2- (E) propenyl7 thieno / pyridinium (6S) (7S) (Z).

It is operated as in Example 5 from 52 mg of thien Z 3.2, c7 pyridine and 77 mg of iodide of the desired product are obtained.

The obtained 77 mg and 0.924 cm3 of formic acid are stirred at 70 ° C for 2 hours and 30 minutes with

66% water. Cool, drain the precipitate, evaporate the filtrate to dryness. The residue is taken up in 0.5 cm3 of ethanol and 1 cm3 of water and brought to dryness. Take up with 5 cm3 of ethyl acetate, crush the solid product, drain, dry and obtain 47 mg of the desired product.

UV spectrum: 1 £ 7 /. max. in EtOH 238 nm '1 AND 1 669 and c 47 000 infl. 260 nm 1 AND 1 251 max. 320 nm 1 AND 1 220 £ 15 500 2 © /. in EtOH / HCL 0.1 N J max. 240 nm E ^X 1 634 £ 44 600 infl. 260 nm 1 AND 1 304 max. 325 nm 1 AND 192 6 13 500

Example 8:

Internal salt of 5- _/ ^/ ~ 3-z ^/ ~ 7 - / ^/ ~ / '' (2 ~ amino-thiazol-4-yl) (imino methoxy) acetyl7 amino? 2-carboxy 8-pxo 4-thia 1-azabicyclo /4.2.o7 oct-2-en-3-yl7 2- (E) propenyl? thiazole /~4.5-c7 pyridinium (6S) (7S) (Z).

It is operated as in Example 1 from thiazole /~4.5,ç7 pyridine and 151 mg of trifluoro acetate of the desired product is obtained, which is dissolved in a mixture of acetonitrile-water (1-1), chromatographed by HPLC in silica and successively eluted with water mixtures with 5, 10 and 20%

- 48 ~ acetonitrile

46.5 mg of the desired product are obtained.

Spectrum 1 D /. max.

UV x in E-fcOH

225 nm * 1

AND

870 to 48 500 infl.

260 nm

381 max.

320 nm

305

000

2#/.

max.

in EtOH-HCL 0.1

225 nm

E ¹

782

600 max.

268 nm

468

100 max.

330 nm

249

900

Example 9

Internal salt of 5 - / ^ 3 - / "7 - //" (2-amino thiazol-4-yl) (methoxy iminp) acetyl? amino? 2-carboxy 8-oxo 4-thia 1-azabicyclo / ~ 4.2.0? oct-2-en-3-yl? 2- (E) propenyl? .2-methyl 1H-imidazole /4.5-c? pyridinium (6S) (7S) sin

It is operated as in Example 8 from 2-methyl 1H-imidazole /4.5.C? pyridine and 50 mg of the desired product is obtained.

UV spectrum s

D /. in E _t OH-nCL 0.1 N s

max. 213 nm E ¹ 1 856 í 47 400 infl. 242 nm 1 AND 1 350 is ^: 19,400 max. 267 nm 1 AND 1 454 i í 25 200 max. 330 nm 1 AND 1 250; 900 13 900 Example 10:

Internal salt of 5 - / ^ 3- / ^- 7 - // (2-amino thiazol-_4-yl) ..... (methoxy imino) acetyl? amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /**4,2.θ7 oct-2-en-3-yl7 2- (E) propenyl / 2-phenyl oxal /*4.5-ç7 pyridinium (6S ) (7S) sin

It is operated as in Example 8 from 2-phenyloxal / pand4.5-c7 pyridine and 90 mg of the desired product is obtained.

UV spectrum t 1 Π /. in EtOH '1 £ 582 max. 239 nm AND 1 1 36,000 infl. 270 nm AND 1 1 464 infl. 287 nm AND 1 1 524 max. 293 nm AND 1 1 555 C / 34 500 infl. 304 nm AND 1 467

infl. 311 nm E 305

Π /. in EtOH / 0.1 N HCL s

max. 241 nm E ¹ 1 508 £ 31 400 infl. 278 nm 1 AND 1 616 max. 284 nm 1 AND 1 617 6 38 100 infl. 291 nm 1 AND 1 609 infl. 305 nm 1 AND 1 403 max. 330 nm 1 AND 1 241 £ 14 900

Example 11

5- / ~ 3- / 7 - // (2-amino-thiazol-4-yl) 2- (methoxy imino) acetyl? amino? 2-carboxy 8-oxo 4-thia 1- azabicyclo / 4.2 4.2? oct-2-en-3-yl? 2- (E) propenyl? 2-ethyl thiazole /4.5.07 pyridinium (6S) (7S) sin

Do you operate as in Example 8 from 2-ethyl thiazole /4.5.c? pyridine and 16 mg of the desired product is obtained.

250 MHz DMSO NMR Spectrum in ppps

6.79 Thiazole Hg 5.47 »7 Λ cephe 3.96 ^H 6 ' 7.33 Ethylenic H of propenyl 5.91

9.88 Hg of pyridinium

8.86 H ₅ and Hg of pyridinium

3.33 H of ethyl CHg

1.43 H of ethyl CH ₃

Example 12:

Internal salt of 5 ~ / 3- / ~ 7 - // (2-ammonium-thiazol-4-yl) (difluoromethoxyimino) acetyl? amino? 2-carboxy 8-oxo 4-thia 1-azabicycle /~4.2.0? oct-2-en-3-117 2- (E) propenyl) thiazole / p4a4.5-c7 pyridinium. (6S) (7S) sin

It operates as in Example 8 from 7 - / '/ ~ (2-tritylamino thiazol 4-yl' (difluoromethoxyimino) acetyl / amino 8-oxo 3-iodopropenyl 4-thia 1-azabicyclo / where4.2.0? Oct 1,1-dimethyl ethyl -2-en 2-carboxylate and 183 mg of the desired product is obtained

Spectrum 1O /. max UV · in EtOH: _Ί 225 nm AND 1 855 í 50 800 infl. 253 nm 1 AND 355 max. 320 nm 1 1 AND 300 € 17 800 1

£> /. in EtOH-HCL 0.1 N s

max. 226 nm 1 AND 1 760 and 45 100 max. 262 nm 1 AND 400 ε 23 700 max. 330 nm 1 1 AND 242 6 14 400 1

Example 13 s

2-amino 5- / ~ 3- / 7 - / “/ (2-amino thiazol-4-yl) trifluoroacetate. (difluoromethoxyimino) (acetyl7 amino7 2-carboxy 8-oxo 4-thia-1-azabicyclo / ~ 4. 2,27 oct-2-en-3-yl / 2- (E) propenyl7 thiazole /~4.5.c7 pyridinium ( 6S) (7S) (Z).

It is operated as in Example 12 from 2-amino thiazole /4.5.c7 pyridine after stirring 62 mg of trifluoroacetate of the deblocked product in 0.3 cm3 of ethanol and 13/11 of pyridine for 15 minutes after centrifugation.

31 mg of the desired product is obtained.

UV spectrum t

lz? /. in : EtOH • *1 infl. 233 nm E 494 1 max 249 nm 1 z E 782 t 1 57 600 infl. 291 nm 1 E 195 1 max. 323 nm 1 E 285 i 1 S 21 000 2 £ 7 /. in EtOH- -IICL 0, 1 N max. 248 nm E ¹ 812 t 1 l 59 800 max. 273 nm 1 E 324 1 max. 329 nm 1 E £ 240 17 700

Example 14

7- / 3 - / ^ 7 - / ^ / ^ trifluoromethane sulfonate (2-amino 4-thiazole)

/ (fluoromethoxyffin) acetyl7amino7 2-carboxy 8-oxo 4-thia

1-azabicycles / “4.2.07 oct-2-en 3-1717 2- (B) propenyl7 thieno /2.3-b7 pyridinium (trifluoroacetate)

1- / · Hydroxyl-base exchange:

150 mg of 3-hydroxy (E) propenyl 7 - / ”3 - /“ 7 - / ”(2-trityl amino) are mixed under an inert atmosphere

1,1-dimethyl ethyl 4-thiazolyl7 / (2-fluoromethyloxy) imino7 acetyl7 amino7 8-oxo 4-thia 1-azabicyclo /4.2.07 oct-2-en-3-yl7 2-carboxylate (6S) (7S) (Z), 5 cm3 is methylene eloride, 107 mg of thiene / 2,3-b7 pyridine, introduce at -70 ° C in a period of 5 minutes about 1.34 cm3 of a solution of sulfonic trifluoromethane at 5% by volume in methylene chloride, stir at -70 ° C for 15 minutes, raise the temperature to 0 ° C for 15 minutes, concentrate to dryness under reduced pressure at 5 ° C, chromatograph remove the residue on silica, under nitrogen pressure, eluting with a mixture of methylene chloride and methanol (90/10) and 141 mg of the desired product are obtained.

2s /. D ^ stritilation, desterbutilation:

The 141 mg of the product obtained in 1 °, 1.7 cm3 of 66% aqueous formic acid solution are mixed in an inert atmosphere, stirred at 66 ° C for 2 hours and 30 minutes, cooled, the precipitate formed is filtered off, washed with water, 20 cm3 of ethanol are added to the filtrate, the filtrate is concentrated to dryness by distillation under reduced pressure, 1 cm3 of water, 1 cm3 is added to the residue. of ethanol, concentrate again to dryness, 5 cm3 of ethyl acetate are added to the residue, crushed, the precipitate formed is drained off, washed, dried and 80 mg of incompletely unlocked product.

80 mg of the previous product, 320 jal of trifluoroacetic acid are mixed in an inert atmosphere

with 10% water, stir at 20 ° C for 20 minutes, slowly add 5 µm of ether, stir, drain off the formed precipitate, wash, dry and obtain 68 mg of the desired product.

UV spectrum (ethanol) and 41 700 max 238 nm AND 1 497 infl. 260 nm 1 AND 1 190 infl. 300 nm 1 AND 1 191 max. 308 nm 1 AND 1 203 ε 17 000 max 323 nm 1 AND 195 16 400

UV spectrum (ethanol + 0.1 N HOL) max. 240 nm E ¹ 439 f 36 800 infl. 262 nm and 240 infl. 260 nm E 227 infl.

max.

301 nm E 176

331 nm E 170 ζ 14 300

Example 15

Internal salt of 1 - / ^ 3 - / ^ 7 - / ^^ (2-amino-thiazol-4-yl) (taetoxyimino) aoethyl / amino / 2-carboxy 8-oxo 4-thia 1-azabioiclo

/Ath4.2.θ7 oct-2-en-3-117 2- (Ξ) propenyl7 1- / ~ 2- (5-nitro ΙΗ-imidazol 1-yl) ethyl7 pyrrolidinium (6S) (7S) (Z)

It is operated as in the Reference Example phase G, starting from 1 - / “5-nitro IH-imidazol 1-yl) ethyl 7 pyrrolidine to obtain 77 mg of trifluorosulfonate of the blocked product. After treatment with trifluoroacetic acid with 10% anisole, precipitation with isopropyl ether, as in Example 8, the product obtained by HPLC is chromatographed as a water-acetonitrile mixture (85-15), and 19 mg of the desired product is obtained. after lyophilization.

Spectrum 31 * 0 (DMSO) 250 MHz in ppm:

6.81 ppm Hp; of tiazol

5.52 efγ of the head ~ 5.96 H ₆ J

7.48 (ra) x

5.73 (d, J = 16 Hz) / A ^E

- 2.12 and pyrrolidine from 3.10 to 4.87 Hg and pyrrolidine H from ethyl

8.16 and 8.69 and imidazole

Example 16:

7- / ~ “3 - /“ 7- / ~ / '~ (5-amino 1,2,4 thiadiazol 3-yl) (methoxyimino) acetyl7 amino7 2-oarboxy 8-oxo 4-thia 1-azabicycle /~4.2.07 oct-2-en-3-yl7 2- (E) propenyl7 thieno / “2,3-67 pyridinium (6S) (7S)

It operates as in Example 14 from 7-fZ '(2- (5-tritylamino 1,2,4-thiadiazol 3-yl) (2-methoxy imino) acetyl7 amino / 2 - / “3-hydroxy propen ( Z) 1,1-dimethyl ethyl 1-yl / 8-oxo 4-thia 1-azabicyclo / 1,14.2.07 oct-2-en 2-carboxylate (prepared as the corresponding product obtained in step B of the Reference Example ) to obtain the trifluoromethylsulfonate of the blocked product. Unlocking is carried out as in Example 8 by

lichosorb with a water-acetonitrile mixture (85-15) and 52 mg of the desired product is obtained after lyophilization.

UV spectrum;

In EtOH-HCli 0.1 N!

max. 239 nm E ^ 780 £ 45 500 r

infl. 270 nm E 302 £ 16 800 infl. 294 and 304 nm max 330 nm E 249 L 13 900 1

Example 17

7- / ~~ / - (2-aminothiazol 4-yl) (methoxyimino) acetyl / amino7

8- oxo 3- / ~ 3 - / (1,3,4-thiadiazol 2-yl) thio7 1- (E) -propenyl7 4-thia 1-azabicyclo /4.2.07 oct-2-en 2-oarboxylate ( 2,2dimethyl 1-oxo propoxy / methyl 6 (S) 78 sin (E)

Phase A: Iodomethyl pivalate:

1.55 g of potassium iodide are dissolved in 8 cm3 of acetone and 1.40 g of chloromethyl pivalate are added. Stir for 45 minutes at + 70 ° G, then for 1 hour at room temperature, filter and obtain solution A.

Phase B: Potassium salt of acid / 7-ll- (2-amino thiazol 4-yl) (methoxyimino) acetyl / amino / 8-oxo 3-thiadiazol 2-yl) thio7 2- (13) propenyl / 4-thia 1-azathioniole Z'4.2.07 oct 2-en-2-carboxylic).

Stir for an hour at room temperature • 0.129 g of anhydrous potassium carbonate in 5 - cm3 of dimethylformamide and 0.500 g of pre-

stopped as product of the Example described below from 2-mercapto 1,3,4-thiadiazole, then stirred for 5 minutes to obtain solution B.

Phase C s 7 - / "/" (2-aminothiazol 4-yl) (methoxyimino) acetyl? amino? 8-oxo 3- / ~ 3- / ~ (1,3,4-thiadiazol 2-yl) thio) 2 (E) -propenyl? 4-tia 1-azabiciclo (2,2-dimethyl 1-oxo propoxy-methyl (6S), (7S) sin (E) oct-2-en 2-carboxylate.

Solution A is rapidly introduced into solution B and stirred for 30 minutes in an inert atmosphere.

The reaction mixture is poured into 70 g of water plus ice, 50 cm @ 3 of ethyl acetate acetate are added, decanted and re-extracted. Combine the organic phases, wash with a 0.2 N solution of sodium thiosulfate, a solution of sodium bicarbonate, then an aqueous solution of sodium chloride. S _and ca up and evaporated to dryness. _R t itura up the residue in isopropyl ether, filtered, washed with a little CIE petroleum ether (60-80 ° C b), and then with isopropyl ether. The dry product is chromatographed on silica, eluted with ethyl acetate and 275 mg of the desired product are obtained.

UV spectrum:

1 ° /. in EtOH s max. 238 nm 1 AND 1 372 ε 24 300 infl. 250 nm 1 AND 1 299 ma £. 333 nm 1 AND 1 234 ε 15 300

2 0 /. in EtOH, 0.1 N HCL s 1 infl. 245 nm E 317 1

„,„ ........... 1 max. 265 nm AND 1 1 349 t 22 800 max. 335 nm AND 1 226 £ 14 800

Preparation of 7 - // 2- (2-amino thiazol 4-yl) 2 (Z) methoxy imino aoethyl7 amino7 3- / ~ / ~ 3-1 methyl 1H, 1,2,3,4-tetrazole 5-117 thio7 propen (E) yl7 8-oxo 4-thia 1-azabiciolo /4.2.07 oct-2-en 2-carboxyl 6S, 7S sin.

Phase A: Z'7-rZ'2- (2-triphenyl methylamino thiazol 4-1117 2 (z) methoxy imino acetyl / amino / 3 - /// ~ 3- (1-methyl 1H, 1,2,3, 4-. -Tetrazol 5-yl) thio7 propen (E) yl / 8-oxo 4-thia 1-azabicyclo /4.2.07 oct-2-en 2-carboxylate 1,1-dimethyl ethyl.

37 mg of 7 - /// 2- (2-triphenyl methyl amino thiazol 4-yl / 2 (Z) methoxy imino acetyl / amino /

3- // (3-hydroxy) propen 1 (E) yl7 8-oxo 4-thia 1-azabicyclo /4.2.07 oct-2-en 1,1-dimethyl ethyl 2-carboxylate, 24 mg tetrabutylammonium iodide , 0.8 cm3 of methylene chloride, 23 ul of 2,6-lutidine, cool to -70 ° 0, 0.25 cm3 of sulfonic trichloromethane anhydride solution is added dropwise, titrating 0.42 cm3 of anhydride per 10 cm3 of methylene chloride, add 14 mg of sodium salt of 1-methyl 5-mercapto 1,2,3,4-tetrazole, and then 0.5 cm3 of dimethyl formamide, stir 20 ° C, concentrate to dryness, chromatograph the residue on silica, eluting with a mixture of methylene chloride and ethyl acetate (9/1) and isolate the desired product.

Phase B í Acid 7- Z “Z“ (2-aminothiazol 4-yl) 2 (Z) methoxyimino acetyl / amino / 3- / ~ / ^_ 3- / 1-methyl 1H, / (1,2,3,4 -tetrazol 5-yl) thio / propen (Ξ) yl / θ-oxo 4-thia 1-azabicyclo /ada4.2.07 oct-2-en 2-carboxylic.

329 mg of the compound obtained in phase A, 9.6 cm3 of 33% aqueous formic acid solution are mixed,

~ heat for 1 hour and 15 minutes at + 65 ° O, cool, dilute with water, filter, concentrate to dryness under reduced pressure, paste the residue in water, remove the insoluble solid formed is filtered off, concentrated to dryness and 142 mg of the desired compound is isolated.

Preparation of 7- / ~ / ~ - (2-tritylamino thiazol 4-yl / (Z) (methoxyimino) acetyl7 amino7 3- / ~ 3-iodopropen-l- (E,) - yl · / 8-oxo

4-thia-1-azabicyclo / gado4.2.0/ oct-2-en 2-carboxylate of * 1.l-methylimethyl.

Heat to -70 ° C 1.476 g of 7-ΖΎ '' - (2-tritylamino thiazole 4- 117 (2) (methoxyimino) acetyl / amino7 3- / ^_ 3- ^ idroxypropenyl-l- (E) -yl / 8-oxo 4-thia 1-aza $ iciclo /ada4.2.0/ oct-2-en 2-carboxylate 1,1-dimethyl ethyl 900 mg of tetrabutylammonium iodide in 25 cm3 of methylene chloride and 0.932 cm3 of At -65 ° C, -70 ° C in 5 minutes, 8.52 cm3 of 0.5 cm3 of trifluoromethylsulfonic acid anhydride taken to 10 cm3 with methylene chloride was added and stirred for 5 minutes.

I Add at room temperature, cm3 of 0.2 N aqueous sodium thiosulfate solution, stir for 5 minutes, decant and reextract with methylene chloride. The organic phases are dried and concentrated to dryness. The residue is chromatographed on silica, eluted with a mixture of methylene chloride-ethyl acetate (80-20). The product is taken up in isopropyl ether and 1.215 g of the expected product is obtained.

Similarly, derivatives 2- (fluoromethoxyimino) or 2- (difluoromethoxyimino) can be obtained from the corresponding alcohols.

Claims (5)

- Process for the preparation of compounds of general formula I according to the process of the main patent characterized by obtaining, in particular, the following compounds: > - 5-Z ’? - Z7Z 'Z' ( - - (2-Amino 4-thiazole) (fluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /ado4.2.0/ oct-2-en 3-yl / 2- (E) propenyl / thieno / "2,3-b / pyridinium. - lZ ^- 3-Z'7Z'Z '(2 — animate oiazo 1—4 ~ yl) (methoxyimino) ace ui 1 / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / where4.2.0/ oct -2-en 3-yl / 2 (E) -propenyl / 1 - / “2- (5-nitro IH-imidazol 1-yl) ethyl / pyrrolidinium (6S) (78) (Z). - 7-Ζ · 3-Ζ'7-Ζ'Ζ · (5-amino 1,2,4-thiadiazol-3-yl) (methoxyimino) ¹ acetyl / amino / 2-carboxy 8-oxo 4-thia 1- azabicycles zx.2.07 oct-2-en 3-117 2 (E) -propenyl7 thieno 2 ”2 · 3- £ 7 pyridinium (68) (7S) sin. - 7-Z'Z (2-amino thiazol-4-yl) (methoxyimino) acetyl / amino / 8-oxo 3-Z-3-Z '(1,3,4-thiadiazol 2-yl) thio / 1- (E) -propenyl / - 2-amino-5 - / ”3- /” 7 - / ”/ (2-amino thiazol-4-yl) (difluoromethoxyimino) aoethyl / amino / 2-carboxy 8-oxo 4-thia l-trimicycle / as4.2 .0 / oct-2-en 3-yl / 2- (E) propenyl / 2-ethyl thiazole /4.5.0/ pyridinium (6S) (7S) sin. 2-ammo 4-thiazolyl) (methoxyimino) -acetyl / amino7 2-carboxy 8-oxo 4-thia 1-azabicyclo /4.2.07 oct-2-en-3-yl7 -2- (E) propenyl / 2- ( trifluoromethyl) thiazole / pyridinium (6S) (78) (Z). - 7- Z'Z '' 2-Amino 4-thiazolyl) (methoxyimino) acetyl / amino / 3- / ~ 3- / ~ K4-dihydro 3- (formylamino) 4-oxo 1-pyridyl / 1 (E) propenyl_7 8-oxo 4-thia 1-azabicyclo / ad4.2.0/ oct-2 * and ene 2-oarboxylic (63) (78) (Z). - 5-Z'3-Z'7Z'Z ^- (2-ammo 4-thiazolyl) (difluoromethoxyimino) - -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycles / · 2 · θΖ) oct-2-en J-Í17 2 (E) -propenyl7 -thene Ζ ^- 3 · 2.ο7 pyridinium (6S) (78) (Z). - 5-Z'3-Z'Z '(2-amino thiazol-4-yl) (difluoromethoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / where4.2.0) oct-2 -en 3-yl / 2 (E) -propenyl / 4-methylthene /3.2.ç/ pyridinium (63) (7S) (Z). - 5-Z'3-Z'7Z'Z · '(2-amino thiazolyl-4-yl) (fluoromethoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / as4.2.0/ oct-2-en 3-yl / 2 (E) -propenyl / thiazole / used4.5.c/ pyridinium (6S) (7S) (Z). - 5-Z3-Z-7Z'Z '(2-amino thiazol-4-yl) (fluoromethoxyimino) -. -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / as4.2.0/ 1 oct-2-en 3-117 2 (Ξ) -propenyl / 4-methyl thieno / where3.2.c/ pyridinium - 61 __,? ______ A-ÀL. (6S) (7S) (Z). - 5 - / - 3 - / - 7 / - 7 (2-amino thiazol-4-yl / (fluoromethoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / where4.2.0/ oct -2-en 3-yl / 2 (E) -propenyl / thiene / ad3.2.c/ pyridinium (6S) (68 / (Z). - 'idC ^ CC (2-amino thiazolyl-4-yl) (methoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / around4.2.0/ oct-2-en 3-yl / 2 (E) -propenyl / thiazole /4.5.c/ pyridinium (68) (78) (Z). - 5-Z3-Z ~ ^_ 7ZZÍ <2-amino thiazol-4-yl) (methoxyimino) -aoetil / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo /"4.2.0/ oct-2 -en 3-I17 2 (E) -propenyl / thiazole /icando4.5.c/piridinio (68) (7S) (Z) _o - 5-Z ”3-Z” 7-Z'Z ^- ( ^2- amino 4-thiazol) (difluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / 4.2.0 / oot-2 -en-3-íl / 2 (E) -propenyl / thiazole /icando4.5.ç/ pyridinium (6S) (7S) sin. . - 7-r3-Z'7-Z'Z '(2-amino 4-thiazole) (fluoromeoxyimino) acetyl /. amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / 4.2.0 / oct-en-3- -yl / 2 (E) -propenyl / thieno / 2.4.b / pyridinium (68) (78) sin . - already. Process according to any of claims 1 and 2 of the main patent, characterized in that the following compound is obtained: 3-yl72 (E) -propenyl_ / 2-phenyl oxazole Γ4.5.Ο7 pyridinium (6S) (7S) sin. - 5 - / - 3 - / - 7 / - / - (2-amino thiazol-4-yl) (methoxyimino) aoethyl / amino / 2-earboxy 8-oxo 4-thia 1-azabicycle / as4.2.0/ oct -2-en 3 yl / 2- (E) propens 1/7 2-ethyl thiazole //4.5. w / pyridinium (6S) (7S / sin. - 5 - / - 3-J / - / - '(2-amino thiazol-4-yl) (difluoromethoxyimino) aoethyl / amino / 2-carboxy 8-oxo 4-thia 1-azabiciolo / where4.2.0/ oct- 2-en 3- 117 2- (E) propenyl / thiazole /4.5.ç7 pyridinium (6S) (7S) sin. 3-117 2 (E) -propenyl / 2-methyl ΙΗ-imidazole /~4.5.c/ pyridinium (6S) (7S) sin. - 5 - / - 3- / 7- (2-amino thiazol-4-yl) (methoxyimino) -acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicyclo / wing4.2.0/ oct-2- en (2,2-dimethyl 1-oxo propoxy / methyl 6S, 78, sin (E)) 4-thia 1-azabiciolo /ada4.2.0/ oct-2-en 2-carboxylate. in the form of internal salt or salt formed with mineral or organic acids. 2. A process according to claim 1 of the main patent characterized by obtaining the following compounds: - 5 <3-Ζ · 7-Ζ ~ Ζ · (2-amino thiazol-4-yl) (methoxyimino) acetyl · / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / 4.2.0 / oct- 2-en - 5-Γ3-Γ7-Ζ - / - (2-amino thiazott-yl) (difluoromethoxyimino) acetyl / amino / 2-carboxy 8-oxo 4-thia 1-azabicycle / where4.2.0/ oct-2-en 3 -yl / 2 (E) -propenyl / thiazole / like4.5.o/ pyridinium (6S) (78) sin. Process for the preparation of a pharmaceutical composition characterized by incorporating, as an active ingredient, at least one of the compounds mentioned above when prepared according to any of the preceding claims, in association with pharmaceutically acceptable vehicles and excipients. The applicant declares that the first application for this addition patent was filed in France on February 6, 1987, under no. 87.01456.