HU211871A9 - New cephalosporins containing a substituted benzyloxyimino group in position 7, process of preparation thereof and their application as medicaments - Google Patents

Description

The present invention relates to novel cephalosporin derivatives bearing the 7-substituted benzyloxyimino group, their preparation, their use as medicaments, pharmaceutical compositions containing them and novel intermediates.

The present invention relates to compounds of formula I in color isomeric forms, either in the (R) or (S) form or in the mixture (R, S) or in the form of salts or inner salts with mineral or organic acids. In the formula (I), R ₁ , R ₂ , R ₃ and R ₅ are each independently hydrogen or halogen, or hydroxy, C 1-4 alkoxy, mercapto, C 1-4 alkylthio, nitro, cyano. , amino, C 1-4 alkylamino, C 2-8 dialkylamino, carbamoyl, C 2-5 (alkylamino) carbonyl, C 3-9 (dialkylamino) carbonyl, , carboxy, (C2-C5) alkoxycarbonyl, (C1-C8) acyloxy,

R ₄ is hydroxy or C 1 -C 8 alkoxy, provided that when R ₃ is hydroxy or C 1 -C 8 acyloxy, then R 1, R ₂ and R ₅ at the same time are other than hydrogen,

And A is independently A'egymástól hydrogen, one equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base, or -CO ₂ A ₂ or -CO only one of the 'groups on one or both of -CO ₂ group means the wavy line indicates that the -CH ₂ R ₆ group may be in the E or Z position and

R _b is a quaternary ammonium group (XV), (XVI), (XVII), (XVIII). Groups represented by the general formula (XIX), (XX), (XXI), (XXII) or (XXIII) and in these groups

X is oxygen or sulfur or methylene or imino.

QJ Y, TU V, W and Z each independently represents a methyl group or a nitrogen atom, provided that each of these ring groups contains from 1 to 5 heteroatoms and at least one of these heteroatoms is nitrogen and one or more of these ring groups are They may be substituted with R or R ', wherein R and R' are independently halogen or (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, cyano, OC ₂ -C 7 -CONQ, (Q ₂ ), -NQ, (Q _2), SO ₂ NQI (Q _2), - CS-NH _2, -NH-CO-Qi, -CH = NOH, -CH = NOQ), -CH ₂ CN or CH ₂ group -SQi means, and in these groups Qi and _Q2 are independently hydrogen or C1-4 alkyl;

P _b P ₂ and P ₃ each independently represent an alkyl group containing up to 4 carbon atoms, optionally substituted with R and R ', and the dotted line is P | and P ₂ indicate that P and P ₂ may optionally form a 5- or 6-membered heterocyclic group with the nitrogen atom to which they are attached.

C 1-4 alkyl is understood to mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

C 1-4 alkoxy is understood to mean methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy.

C 1-4 alkylthio is understood to mean methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio or tert-butylthio.

C 1-4 alkylamino is methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino or tert-butyl. is an amino group.

Dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ethylmethylamino, propylmethylamino, butylmethyl in the C2-C8 dialkylamino group. is meant amino or propylethylamino.

C2 -C5 alkylamino-carbonyl, (methylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl, (isopropylamino) carbonyl, or ( butylamino) carbonyl.

C2-C5 alkoxycarbonyl is understood to mean, for example, methoxycarbonyl or ethoxycarbonyl.

C 3-9 (dialkylamino) carbonyl is, for example, (dimethylamino) carbonyl, (diethylamino) carbonyl or (dipropylamino) carbonyl.

C 1-8 acyloxy means, for example, acyloxy, propionyloxy or benzoyloxy.

By halogen is meant fluorine, chlorine, bromine or iodine.

When P 1 and P ₂ form a heterocyclic group with the nitrogen atom to which they are attached, this group may be, for example, pyrrolidine, morpholine or piperidine.

When R4 represents an alkoxy group, it may be, for example, acetoxy, propionyloxy or benzoyloxy.

Examples of A 'include an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Examples of suitable organic bases include methylamine, propylamine, trimethylamine, triethylamine, Ν, Ν-dimethyl ethanolamine, tris [(hydroxymethyl) amino] methane, ethanolamine, pyridine. , picolines. dicikohexil added. morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine.

The compounds of formula (I) may be in the form of a pure inner salt, an acid salt or a combination thereof. Examples of salts that form salts with the compounds of formula I include acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrobromic acid, hydrogen iodide.

Preferred compounds of formula I are those wherein A 'is hydrogen and -CO ₂ A is -COf. The term "quaternary ammonium form" used in the definition of substitution means that the substituent R ₆ is

A9 is attached through a nitrogen atom or one of the nitrogen atoms it contains.

Of the compounds of formula (I), particular mention is made of those having the following claims: (XXIV), (XXV), (XXVI), (XXVD), (XXVID), (XXIX), (XXX), (XXXI) , (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVHI), (XXXIX), (XL), (XLI), (XLII), (XLHI), (XLIV), ( XLV), (XLVI), (XLVII), (XLVHI), or (XLIX) or (L), (Ll), (LD), (Lili), (LIV), (LV), (LVI), (LVII), (LVIII), (LIX), (LX), (LXI), (LXII), (LXIII), (LXIV), (LXV), (LXVI), (LXVII) or (LXVIII).

Especially preferred are compounds of formula (I) wherein R ₆ represents a quinolinium, izokinolinium-, 4- (methylthio) pyridinium, thieno [3,3-b] pyridinium, imidazo [l, 2- a) pyridinium or 6,7-dihydro-5H-pyridinium, wherein R ₃ and R 4 are both hydroxy, and wherein R 1 and R ₅ are both chloro or fluoro, and wherein R 1 and R ₂ are fluoro, and wherein R _{2 is} methoxy and one of R ₁ or R ₅ is chloro.

Particularly preferred compounds of formula I are the following:

(6R- (3- (E) octyl, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-difluoro-4, 5-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-3-yl) -2-propenyl) imidazo [1,2-a] pyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) imidazo (1,2a) pyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-4,5- dihydroxy-3-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-ene-3 -yl) -2-propenyl) quinolinium inner salt;

(6R- (3- (E) octyl, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3, 4-Dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3 yl) -2-propenyl) -6,7-dihydro-5H-pyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z (S *)))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro) 3,4-dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct- 2-en-3-yl) -2-propenyl) quinolinium inner salt;

[6R- (3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (2-chloro-3,4- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (3-cyano-4,5- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-aza-bicikIo- [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-fluoro-4,5- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3- ii) the inner salt of -2-propenyl] quinolinium in the (R) - or (S) - or (R + S) -form;

[6R- [3- (E) octyl, 7beta [Z (S *)]]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-cyano-4) 5-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3 yl) -2-propenyl] -thieno [2,3-b] pyridinium inner salt;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3 il) -2-propenyl] isoquinolinium inner salt in the (R) - or (S) - or (R + S) -form; [6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3 yl) -2-propenyl] -4- (methylthio) pyridinium inner salt in the (R) or (S) or (R + S) form.

The invention further relates to a process for the preparation of compounds of formula (I). According to the present invention, this is the case. optionally protecting one of the reactive functional groups of an aromatic aldehyde of formula (II) wherein R 1, R ₂ , R ₃ , R ₄ and R ₅ are as defined above, and then obtaining the aromatic aldehyde of formula (kapott) _ρ aldehyde - wherein _{R] p,} R _2p, R _3p, R _4p and R _5p are as R ,, R _2, R _3, R ₄ and R ₅ or represents a protected by an α-hydroxyacid of the formula (III) homologated and an acid of formula (III) thus obtained is esterified to an alpha-hydroxy ester of formula (IV) wherein R ₇ is a residue of an easily cleaved ester, and the compound of formula (IV) thus obtained is reacted with N-hydroxyphthalimide, reducing a compound of formula (V) to an O-substituted hydroxylamine of formula (VI), a compound of formula (VI) to a (2-aminothiazolol) -glyoxide of formula (VII) with an ilic acid derivative in which R _g is hydrogen or a protecting group, the resulting alpha-hydroxyiminoacetic acid derivative of formula VIII is prepared with a 7-amino-3- (3-chloro) of formula IX -1-propenyl) -8-oxo-5-thiaazabicyclo [4,2,0] oct-2-ene-2-carboxylic acid hydrochloride ester or one of its salts - wherein Rg is a readily cleaved ester residue amide diffusion followed by the preparation of 7- (N-substituted amido) -3- (3-chloro-1-propenyl) -8-oxo-5-thialazabicyclo [4,2,0] oct-2 (X) the ene-2-carboxylic acid derivative is converted to the analogous 3- (3-iodo-propenyl) derivative of formula XI, which is treated with a base corresponding to R 1 and, if desired, from the product of formula XII (E)

The A9 or (Z) isomer is isolated or the (Z) isomer is converted to the (E) isomer, or a product of formula (XII) is subjected to one or more of the following steps in any order:

a) protecting the amino and / or hydroxy protecting groups and all or part of the ester groups by hydrolysis or exposure to thiourea;

b) esterifying the carboxyl group or carboxyl groups or reacting it with a base to form a salt,

c) forming an acid salt at the amino group,

d) separating the products of the (R, S) mixture form into the products of the (R) and (S) forms.

Alternatively, the present invention may be carried out by condensing an O-substituted hydroxylamine derivative of formula (VI) with a compound of formula (XIII) to obtain one of the aforementioned compounds of formula (XII).

In R _{) p} , R _2p , R _3p , R _4p and R _5p, the protected hydroxy group may be an acyloxy group such as formyloxy, acetoxy, propionyloxy, chloroacetoxy, bromoacetoxy, dichloro -acetoxy, trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, benzoyloxy, benzoyl formoxy or p-nitrobenzoyloxy. The following groups may also be mentioned: ethoxycarbonyloxy, methoxycarbonyloxy. propoxy-carbonyloxy. 2,2,2-trichloroethoxycarbonyloxy, benzyloxycarbonyloxy, tert-butoxycarbonyloxy. 1-cyclopropylethoxycarbonyloxy, phthaloyloxy, butyryloxy, isobutyryloxy. valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy, pivaloyloxy, phenylacetoxy, phenylpropionyloxy. mesyloxy. chlorobenzoyloxy, para-nitrobenzoyloxy, para-tert-butylbenzoyloxy, capryloxy, acryloxy, methylcarbamoyloxy, phenylcarbamoyloxy or naphthylcarbamoyl -oxicsoport.

The following groups may also be mentioned: phenoxy, 4-chlorophenoxy, tolyloxy, tert-butylphenoxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, methoxy-tetrahydropyranyloxy, trityloxy. , benzyloxy, 4-methoxybenzyloxy, benzhydryloxy. trichloroethoxy, 1-methyl-1-methoxyethoxy or alkoxyalkoxymethyl groups such as methoxyethoxymethyl.

Two adjacent hydroxy groups can be protected by forming a methylenedioxy, isopropylenedioxy, 1,1-cyclohexylbis (oxy), diphenylmethylenedioxy, carbonate or hydroxyboranyl bis (oxy) group. Who.

R _p, R _2p, R _3p, R _4p and R _5p report the hydroxyl group is preferably protected by one of the following groups: methoxy, ethoxy-methoxy, propionyloxy, methoxy, acetoxy, methoxy, butoxy, isobutoxy, tert butoxy, pentoxy, hexyloxy, butyryloxymethoxy, valeryloxymethoxy, pivaloyloxymethoxy, 2-acetoxyethoxy, 2-propionyloxyethoxy,

2-butyryloxyethoxy, 2-iodoethoxy, 2,2,2-trichloroethoxy, vinyloxy, allyloxy, ethynyloxy, propynyloxy, benzyloxy -

4-methoxybenzyloxy, 4-nitrobenzyloxy, trityloxy, diphenylmethoxy or 3,4-dimethoxyphenoxy.

The 2-methoxyethoxy-methoxy group (commonly abbreviated as MEM-O) is particularly preferred.

As the remainder of the easily cleavable ester groups, R ₇ and R ₉ include butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxymethyl, ethoxymethyl, isopropyloxymethyl, amethoxyethyl, α-ethoxyethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadecanoyloxymethyl, pivaloyloxy- methyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-propionyloxyethyl,

2-propionyloxyethyl, 1-butyryloxyethyl, 2-butyryloxyethyl,

1- (tert-butylcarbonyloxy) ethyl, 1-acetoxypropyl, 1hexadecanoyloxyethyl, 1-propionyloxypropyl, 1-methoxycarbonyloxyethyl, methoxycarbonyl -oxymethyl, 1-acetoxy-butyl, 1-acetoxy-hexyl, 1-acetoxy-heptyl, phthalidyl,

5,6-dimethoxyphthalidyl, tert-butylcarbonylmethyl, vinyl, allyl, 2-chloroallyl, ethynyl, propynyl, methoxycarbonylmethyl, benzyl, 4-methoxybenzyl -, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, phenyl, 4-chlorophenyl, tolyl, tert-butylphenyl, 3,4-dimethoxyphenyl, methoxy ethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butoxycarbonylmethyl, 2,2-ethylenedioxyethyl, cyanoethyl, 2,2-dimethoxy ethyl, 2-chloroethoxymethyl, (2-hydroxyethoxy) ethyl, 2,3-epoxypropyl, 3- (dimethylamino) -2-hydroxypropyl,

2-hydroxyethyl, 2- (methylamino) ethoxymethyl, (2-aminoethoxy) methyl, 3-methoxy-2,4-thiadiazol-5-yl, tetrahydropyran-2-yl- , 1-methoxy-1-methylethyl, 2-hydroxy-1-methylethyl, isopropyl, carbamoylmethyl, chloromethyl, 2-chloroethyl,

2,2,2-trichloroethyl, 2-iodoethyl, acetyl, methyl, 2- (methylthio) ethylthiocyanate methyl, 2-chloro-1-acetoxyethyl, 2-bromo- 1-acetoxyethyl, 2-fluoro-1-acetoxyethyl, 2-methoxy-1-acetoxyethyl. 2-methyl-1-acetoxypropyl, 1-methyl-1-acetoxyethyl, 1- (methoxyacetoxy) ethyl, 1- (acetylcarbonyloxy) ethyl, 1- (hydroxyacetoxy) ) ethyl, 1- (2-thienylcarbonyloxy) ethyl, 1- (2-furylcarbonyloxy) ethyl, 1- (5-nitro-2-furylcarbonyloxy) ethyl, 1- (2-pyrrolylcarbonyloxy) ethyl, 1- (propionyloxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxy) carbonyloxy) ethyl, 1- (methoxyethoxycarbonyloxy) ethyl, 1- (allyloxycarbonyloxy) ethyl, isopropoxycarbonylmethyl, 1 - [(2,3-epoxy) propyl) oxycarbonyloxy] ethyl, 1 - [(2-furyl) methoxycarbonyloxy] ethyl, 1 - [(2-fluoroethoxy) carbonyloxy] ethyl, 1- (methoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) -1-methyl-ethyl, (methoxycarbonyloxy) chloromethyl, 1- (methoxy- carbonyloxy) -2-chloroethyl, 1- (methoxycarbonyloxy) -2-methoxyethyl, 1- (methoxycarbonyloxy) allyl or 5-methyl-2-oxo-1, 3-dioxol-4-yl.

Diphenylmethyl is preferred for R ₇ , while 4-methoxybenzyl or diphenylmethyl is preferred for R ₉ .

R _g is an amino protecting group such as carbamoyl, methylcarbamoyl, phenylcarbamoyl or naphthylcarbamoyl, or the corresponding thiocarbamoyl group, and optionally substituted C 1 -C 4 alkyl, such as, for example, trichloroethyl, tert-butyl - or a t-amyl group; aralkyl groups such as benzyl, 4-methoxybenzyl, phenethyl, trityl,

3,4-dimethoxybenzyl or benzhydryl; optionally substituted aliphatic, aromatic or heterocyclic acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromo; acetyl, trifluoroacetyl, benzoyl, toluoyl, naphthoyl, chlorobenzoyl, para-nit4

HU 211 871 A9 ro-benzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, decanoyl, acryloyl, phthaloyl, mesyl, phenylacetyl, phenylpropynyl, oxalyl , succinyl, pivaloyl, lower alkoxycarbonyl or cycloalkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl -, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl or trichloroethoxycarbonyl; aralkoxycarbonyl such as benzyloxycarbonyl.

The trityl group is preferred.

The above list is not to be construed as limiting the skilled artisan, so other amino protecting groups well known in the art of peptide chemistry may be utilized.

Reactive derivatives of the acids of formula (VIII) include, for example, a halide, a symmetric or mixed anhydride, an amide, an azide or a reactive ester.

Examples of mixed anhydrides are esters with isobutyl chloroformate or pivaloyl chloride, and mixed anhydrides with carboxylic and sulfonic acids, such as para-toluenesulfonyl chloride.

Examples of reactive esters include esters with 2,4-dinitrophenol or hydroxybenzothiazole.

Suitable acid halides include, for example, acid chlorides or acid bromides.

The acid anhydrides may be prepared in situ from an N, N-disubstituted carbodiimide. For example, using N, N-dicyclohexylcarbodiimide.

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

If an acid halide is used and a hydrogen halide molecule is liberated in the usual manner during the reaction, the reaction is preferably carried out with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium carbonate. in the presence of bicarbonate, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is usually about room temperature or below.

Compounds of formula (VIII) may be prepared directly using compounds of formula (IX) using a carbodiimide such as diisopropylcarbodiimide or 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) presence. An example of such a reaction will be mentioned in the experimental section.

Reaction of R _{6 into the} intermediates of formula (IV) is carried out as follows:

if Hal is, for example, a chlorine atom, the chlorine atom is first substituted with an iodine atom in the presence of sodium iodide in situ or in a separate step, followed by the addition of a reagent corresponding to R 1, optionally an organic solvent such as dichloromethane, in the presence of tetrahydrofuran.

The reagent corresponding to R 1 may be reacted directly with an intermediate of formula X in the presence of silver tetrafluoroborate.

The isomers of the products of formula (ΧΠ) may be different from those of the compounds of formula (X) or (XI) used as starting materials. If the Z-isomer is isolated, this isomer can be converted to the E-isomer by conventional means, in particular by treatment with iodine.

R ₇ , R e, R 9. Depending Rip, R2p>R3p> R4p and R _P is of formula (ΧΠ) tenméket having the formula with one or more hidrolizáló- or hidrogenizálószerrel or thiourea to eliminate the R _g group, when A is the latter amino-protecting group to give R _lp , R _2p , R _3p , R 4p and R _5p are converted to R ₂ , R ₃ , R ₄ and R ₅ when these are hydroxy protecting groups and / or R ₇ and R 8 are removed if they are readily cleaved are an ester group and one of them is desirable.

Of course, the group R _{g can be} removed and the groups R _1p , R _2p , R _3p , R 4,, and R _{5p can} be converted to R ₁ , R ₂ , R ₃ , R ₄ and R ₅ (unless they represent a hydroxy protecting group). that the R ₇ and R _g substituents would undergo change if desired to be retained. In such cases, reagents that can be used will be selected by one of ordinary skill in the art. Examples of reactions of this type will be described in the experimental section. Methods for deprotecting various protecting groups are described, for example, in French Patent Publication No. 2,499,955.

When a protecting group is preferred for R _g is trityl, one or more of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are hydroxyfunctional protecting groups, 2-methoxyethoxymethyl, R ₇ is diphenylmethyl and R In the case of ₉ , when 4-methoxybenzyl or diphenylmethyl is used, it is preferable to use trifluoroacetic acid in the absence of a solvent or in the presence of a solvent such as anisole or mixtures of anisole and methylene chloride as the solvent. In this case, a salt is formed with trifluoroacetic acid. The free base can be liberated from this salt by treatment with a base such as triethylamine or a carbonate.

The salts of the compounds of formula I according to the invention may be prepared in conventional manner; for example, a product in acid form or a solvate thereof, such as ethanol, or a hydrate thereof with a mineral base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate reaction with hydrogen carbonate. Salts of mineral acids such as trisodium phosphate may also be used. It is also possible to use salts of organic acids, such as saturated or unsaturated, straight or branched chain aliphatic carboxylic acids having from 1 to 18 carbon atoms, preferably from 2 to 10 carbon atoms. The aliphatic chains of these acids may be interrupted by one or more heteroatoms, such as oxygen or sulfur, or may be substituted with aryl groups such as phenyl, thienyl or furyl; one or more hydro5

HU 211 871 A9 xyl; one or more halogen atoms such as fluorine, chlorine or bromine, preferably chlorine; one or more carboxyl or lower alkoxycarbonyl groups such as methoxycarbonyl or propoxycarbonyl; or one or more aryloxy groups, preferably phenoxy groups.

Suitable organic acids are suitably soluble aromatic acids, such as, for example, benzoic acid derivatives which are preferably substituted by lower alkyl groups.

Examples of such organic acids include formic acid, acetic acid, acrylic acid, butyric acid, adipic acid, isobutyric acid, caproic acid, isocaproic acid, chloropropionic acid, crotonic acid, phenylacetic acid, 2-thienylacetic acid, 3-thienylacetic acid, acetic acid, glutaric acid, monoethyl ester of adipic acid, hexane carboxylic acid, heptane carboxylic acid, decanoic acid, oleic acid, stearic acid, palmitic acid, 3-hydroxypropionic acid, 3-methoxypropionic acid, 3-methylthio-butyric acid, 4-chlorobutyric acid 4-phenylbutyric acid, 3-phenoxybutyric acid, 4-ethylbenzoic acid or 1-propylbenzoic acid.

However, sodium acetate, sodium 2-ethylhexanoate or sodium diethyl acetate is preferably used as the sodium salt.

The salt formation may be carried out with an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethyl ethanolamine, tris [(hydroxymethyl) amino] methane, methylamine, ethanolamine, pyridine, picoline, dicyclohexylamine. morpholine or benzylamine.

Alternatively, arginine, lysine, procaine, histidine or N-methylglucamine may be used to form the salt.

The salt formation is preferably carried out in a solvent or solvent mixture, such as water, diethyl ether, methanol. ethanol or acetone.

The resulting salts may be in amorphous or crystalline form, depending on the reaction conditions.

Crystalline salts are preferably prepared by reacting the free acids with the salts of the aforementioned aliphatic carboxylic acids, preferably sodium acetate.

The salt formation with mineral or organic acids is carried out under standard conditions.

Optional esterification of the target compounds can also be carried out under conventional conditions. Usually, an acid of formula I or a reactive derivative thereof is reacted with a compound of formula Z-Re, wherein Z is hydroxy or a halogen atom, for example chlorine, bromine or iodine, and Re is as indicated above. exemplifies the ester group already mentioned - reaction. In some cases, it may be advantageous to carry out the esterification on a product in which the amino and / or other functional groups attached to the oxyimino moiety are protected by a protecting group, followed by removal of the amino protecting group and reactive group attached to the oxyimino group.

The compounds of formula I contain a number of asymmetric carbon atoms. In a cephem core containing two asymmetric carbon atoms, the two carbon atoms have the R configuration. Further, the oxyimino moiety also contains an asymmetric carbon atom, which may be in the R or S form or as a mixture of the two forms. Separation of the two diastereoisomers may be accomplished by conventional means, for example, chromatography.

The compounds of formula I according to the invention have very good antibiotic activity against Gram-positive bacteria such as staphylococci and streptococci, in particular penicillin-resistant staphylococci. Particularly noteworthy is the efficacy of the compounds of the formula I according to the invention in Gram-negative bacteria, in particular Coliform bacteria, as well as in Klebsiella, Salmonella, Proteus and Pseudomonas strains.

In view of these properties, the compounds of the present invention and their pharmaceutically acceptable acid addition salts can be used as active ingredients in pharmaceutical formulations for the treatment of bacterial diseases, in particular staphylococcal diseases such as staphylococcal haemorrhagic disorders, or for the treatment of purulent skin infections, anthrax, purulent connective tissue inflammation, stinging, acute primary or post-influenza staphylococcal infections, bronchial and pulmonary inflammation and pneumonia. The pharmaceutical compositions of the present invention can be used to treat infections caused by colibacilli and related infections, infections caused by Proteus, Klebsiella and Salmonella, as well as other diseases caused by Gram-negative bacteria.

The present invention also relates to compounds of the formula I and their pharmaceutically acceptable acid salts as medicaments, in particular antibiotics.

The pharmaceutical compositions of the invention as active ingredient are preferably used as compound (I) of formula wherein _R6 kinolinum-, izokinolinum-, 4- (methylthio) pyridinium, 6,7-dihydro-5H-imidazo pyridinium or [l, 2-a] thieno [2,3-b] pyridinium group.

Among the active compounds of the pharmaceutical compositions according to the invention, the following compounds and their pharmaceutically acceptable salts are particularly preferred:

(6R- (3- (E) octyl, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-difluoro-4, 5-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) imidazo [1,2-a] pyrpyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3, 4-Dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3 yl) -2-propenyl) imidazo (1,2a) pyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-4,5- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl) quinolinium inner salt;

EN 211 871 A9 (6R- (3- (E) 6alpha, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy (2,5- dichloro-3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2- en-3-yl) -2-propenyl) -6,7-dihydro-5H-pyridinium inner salt;

(6R- (3- (E) octyl, 7beta (Z (S ')))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy) 5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- il) -2-propenyl) quinolinium inner salt;

[6R- (3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (2-chloro-3,4- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (3-cyano-4,5- dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- (3- (E) -alpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-fluoro-4,5- dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-3-yl) -2-propenyl] quinolinium inner salt in (R) - or (S) - or (R + S) form;

[6R- [3- (E) octyl, 7beta [Z (S ')]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-cyano-4) 5-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl] -thieno [2,3-b] pyridinium inner salt;

[6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-3-yl) -2-propenyl] -isoquinolinium inner salt in (R) - or (S) - or (R + S) form; [6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl] -4- (methylthio) pyridinium inner salt in the (R) or (S) or (R + S) form.

The present invention also relates to pharmaceutical compositions comprising as active ingredient one or more therapeutic compounds as defined above.

The pharmaceutical compositions of the invention may be administered, for example, buccally, rectally or parenterally, particularly by intramuscular or topical application, applied to the skin and mucous membranes.

The compounds of the formula I can be administered orally, in particular the compounds having an ester group which can be cleaved by A.

The pharmaceutical compositions of the present invention may be in solid or liquid form or may be in the form commonly used in human pharmaceuticals. For example, they may be in the form of uncoated or sugar coated tablets, capsules, granules, suppositories, injectables, ointments, creams or gels. Pharmaceutical compositions of this type may be prepared in conventional manner by admixing one or more active ingredients with excipients and / or other excipients conventionally used in the preparation of such compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols and various wetting, dispersing or emulsifying agents and preservatives. These compositions may also be in the form of a powder which is reconstituted with a suitable vehicle, for example sterile water, free of antipyretic agents, before use.

It will be appreciated by those skilled in the art that the dosage of the compounds of the present invention will depend on a number of factors, such as the particular compound, the disease to be treated, the patient and the route of administration. However, in general, for example, the daily dose of the product of Example 1, for example, is 0.250 g to 4 g daily, and the intramuscular dose is 0.500 g to 1 g three times daily in humans.

The compounds of formula (I) of the present invention may also be used as surgical disinfectants.

The compounds of formula (III), (IV), (V), (VI), (VIII), (X), (XI), (XII) and (XIII) used as intermediates in the process of the invention are novel compounds. The invention also relates to these.

The compounds of formula II are well known compounds; most of them are commercially available, while others can be prepared from commercially available compounds by the methods referred to below. For example, the so-called Rosemund reduction, reduction of benzoic acids or formylation of aromatic rings, such as the Vilsmeier Haack reaction, the Gatterman-Koch reaction, the ReimerTiemann reaction or the reaction with formyl fluoride [J. Chem. Soc. 82, 2380 (1960)].

Compounds of formula (VII) and (IX) are also known in the art, more particularly in Belgian Publication No. 874,828 and European Publication No. 333,154.

The following examples are intended to illustrate the invention.

Reference Example I

2-chloro-3,4-bis [(2-methoxyethoxy) methoxy] benzaldehyde

Step A: 2-Chloro-3,4-dihydro-benzaldehyde

27.62 g are commercially available

A solution of 3,4-dihydroxybenzaldehyde in 450 ml of acetic acid was bubbled through room temperature at room temperature until 4.48 dm ^{3 was} consumed. The reaction mixture was stirred for 16 hours, then concentrated, the concentrate cooled to 0 ° C, and the activated precipitate was filtered off, washed and dried. so

HU 211 871 A9

7.5 g of the title compound are obtained, m.p. 160 'C, which is crystallized from ethyl acetate.

Step B: 2-Chloro-3,4-bis [2-methoxyethoxy) methoxy] benzaldehyde

To a suspension of 11.42 g of the product obtained in the preceding step in 120 ml of methylene chloride are added 46 ml of diisopropylethylamine, and the reaction mixture is cooled to -10 ° C and 30.14 ml of chloro- (2- methoxyethoxy) methane is added. The reaction mixture was stirred for one hour and then diluted with water (100 mL). The layers were separated and the aqueous layer was washed, dried and evaporated. and also to give the the title compound 22.6 g, tlc _Rf 0.6, using ethyl acetate as eluent.

1 H-NMR (CDCl ₃ , 250 MHz, ppm)

3.36 (s) and 3.38 (s): -OCtf,

3.58 (m) (4H), 3.84 (m) (2H) and 4.06 (m) (2H):

O-CH ₂ -CW ₂ -O

5.29 (s) (2H) and 5.38 (s) (2H): _O-CH2 -O

7.21 (d) and 7.71 (d): aromatic protons (Ατ-ff)

10.36 (s): -CH = O

2. Reference Example

3-Formyl-5,6-bis [(2-methoxyethoxy / methoxy) -benzonitrile

Step A: 3-Formyl-6-hydroxy-5-methoxybenzonitrile

A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 9.3 g of copper (I) cyanide and 140 ml of dimethylacetamide (abbreviated as DMA) is heated under reflux for 2 hours, then cool and pour over ice. The ice mixture was extracted with ethyl acetate: methanol (90:10 by volume), and the extract was washed, dried and evaporated. The resulting crude product (18 g) was used in the next step. Melting point: 180 ° C.

Step B: 3-Formyl-5,6-dihydroxybenzonitrile

18 g of the product obtained in the preceding step and 400 ml of dichloromethane are stirred under a nitrogen atmosphere, and the mixture is cooled to 0 ° C and 1M boron tribromide solution in 150 ml of dichloromethane is added. The resulting mixture was then allowed to stand at room temperature over a north, then concentrated, cooled to 0 ° C and treated with 250 ml of 1 N aqueous hydrochloric acid. The crystallized product is then isolated, washed with water and recrystallized from a 1: 2 by volume mixture of isopropanol and water. 12 g of the title compound are obtained.

IR spectrum (Nujol):

strong and complex absorption in the -NH / OH region

2245 cm -1: CsN

1700 cm ^-1 : C = O

1602, 1597, 1520 cm ^-1 : @ 1 H-NMR spectrum of the aromatic nucleus (DMSO, 250 MHz, ppm)

7.45 (d) (J = 2): Ar-H

7.73 (d) (J = 2): Ar-H

9.74: CH = O

11.15: Mobile absorption

Step C: 3-Formyl-5,6-bis [(2-methoxyethoxy / methoxy / benzonitrile)

To a suspension of 12.6 g of the product obtained in the preceding step in 500 ml of dichloromethane is added 53.6 ml of diisopropylamine, the reaction mixture is cooled to -10 ° C and then 35.3 ml of chloro- (2- methoxyethoxy) methane is added. The reaction mixture was stirred for one hour, diluted with water (100 mL) and the phases were separated. The resulting organic phase is washed, dried and evaporated. 21.4 g of the title compound of this step are obtained.

IR (CHC1 _3):

OH absence

2235 cm -1: CsN

1702 and 2730 cm @ -1: CH = 0

1592, 1582 and 1485 cm-1: 1 H-NMR spectrum of the aromatic nucleus (CDCl ₃ , 250 MHz, ppm)

3.37 (s): -OC //,

3.38 (m) (4H), 3.85 (m) (2H) and 4.06 (m) (2H): o-ch ₂ -ch ₂ -o

5.39 (s) (2H) and 5.49 (s) (2H): -O-CW ₂ -O

7.76 (d) (1H) and 7.92 (d) (1H): Ar-H

9.90 (s): -CH = O

3. Reference Example

3-Fluoro-4,5-bis [(2-methoxyethoxy / methoxy / benzaldehyde)

Step A: 3-Fluoro-4-hydroxy-5-methoxybenzaldehyde

Under nitrogen atmosphere at 0 DEG C., 30.4 g of 4-hydroxy-5-methoxybenzaldehyde (vanillin), 100 ml of acetonitrile and 250 ml of freon were bubbled with 10% by volume of fluorine for 2.5 hours and then the reaction mixture was bubbled through sodium thiosulfate was added and the reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried, evaporated and purified by chromatography on silica gel using dichloromethane as eluent. 2.1 g of the title compound are obtained with an R _r of 0.3.

Analysis: Calculated for C ₇ H ₇ FO ₃ : C, 56.47; H, 4.14; F, 11.16;

Found: C, 56.4; H, 4.1; F, 11.0;

Step B: 3-Fluoro-4,5-dihydroxybenzaldehyde

3.72 g of the product obtained in the preceding step and 60 ml of dichloromethane are stirred under a nitrogen atmosphere, and the resulting mixture is cooled to 0 ° C and 32 ml of a 1M solution of boron tribromide in dichloromethane are added. . The reaction mixture was allowed to stand at room temperature for 1 hour, then concentrated, cooled to 0 ° C and acidified. The precipitated crystalline product is isolated, washed with water and dried. This gives 2.83 g of the title compound in crude form which is used without further purification.

EN 211 871 A9 We are in the next step. _Rf value of the product 1 of acetone and methylene chloride as eluent 0.2: 9 by volume as the eluant.

Step C: 3-Fluoro-4,5-bis [(2-methoxyethoxy-methoxy) -benzaldehyde

To a suspension of 2.8 g of the product obtained in the preceding step in 5.6 ml of dichloromethane is added 17 ml of diisopropylethylamine, and the reaction mixture is cooled to -10 ° C and 6.5 ml of chlorine are added. (2-methoxy-ethoxy) methane. The reaction mixture was stirred for 1 hour and then diluted with water (100 mL). The phases are separated and the organic phase is washed, dried and evaporated. 5.5 g of the title compound are obtained in the same manner as in the title. Rf = 0.5 using a 9: 1 by volume mixture of dichloromethane and acetone as eluent. IR (CHC1 _3):

the absence of a hydroxyl group

1696 and 2730 cm ^-1: CH = conjugated 0 Ή-NMR (CDC1 _3, 200 MHz, ppm)

3.36 (s) and 3.37 (s): _OCH3

603.38 (m) (4H), 3.85 (m) (2H) and 3.96 (m) (2H):

O-CH ₂ -CH ₂ -O

5.33 (s) and 5.36 (s): -0-Ctf ₂ -0

7.32 (dd), 7.51 (m): Ar-H

9.90 (m): -CH = O

4. Reference Example

3-Chloro-4,5-bis [(2-methoxyethoxy) methoxy]

Step A: 3-Chloro-4,5-dihydroxybenzaldehyde

Under nitrogen atmosphere, 37.2 g of commercially available 5-chloro-vanillin and 800 ml of dichloromethane are mixed. the resulting mixture was cooled to 0 ° C and 300 ml of a 1M solution of boron tribromide in dichloromethane were added. The reaction mixture was allowed to stand at room temperature overnight, then concentrated, cooled to 0 ° C and acidified. The precipitated crystalline product is isolated, washed with water, dried and finally recrystallized from a 1: 2 by volume mixture of isopropanol and water. 26.6 g of the title compound are obtained, m.p.> 260 ° C.

IR spectrum (Nujol)

3425 cm ^-1 : -OH + general absorption

1672-1660 ^cm-1: C = O

1595, 1588, 1534, 1500 cm ^-1 : Ή NMR spectrum of the aromatic ring (DMSO, 250 MHz, ppm)

7.24 (d J = 2 Hz) and 7.44 (d J = 2 Hz) Ar-H

9.90 (m): -CH = O

10.40: Mobile absorption

Step B: To a suspension of 3-chloro-4,5-bis (2-methoxyethoxy) methoxy] benzaldehyde g, prepared in the preceding step, in dichloromethane (150 mL) was added diisopropylethylamine (60.5 mL). and the resulting mixture was cooled to -10 ° C and 39.7 ml of chloro- (2-methoxyethoxy) ethane was added over 45 minutes. The reaction mixture was stirred for half an hour and then diluted with water (100 mL). The phases are separated and the organic phase is washed, dried and evaporated. The residue was purified by chromatography on silica gel (eluent: dichloromethane: methanol = 99: 1). 15.9 g of the title compound are obtained in the same manner as in the title.

IR (CHC1 _3):

1698 and 2735 cm ^-1 : conjugated CH = O

1591.1579, 1498 cm ^-1: aromatic ring H-NMR (CDC1 _3, 250 MHz, ppm)

3.38 (s): _OCH3

3.57 (m) (4H), 3.87 (m) (2H) and 4.03 (m) (2H):

O-CH ₂ -CH ₂ -O

5.36 (s) and 5.38 (s): // ₂ -O OC

7.59 (d) 7.62 (d): Ar-H

9.85 (s): -Ctf = O

5. Reference Example

3-Nitro-4,5-bis [(2-methoxyethoxy) methoxy] benzaldehyde

Step A: 3-Nitro-4,5-dihydroxybenzaldehyde

Under nitrogen atmosphere, 35 g of commercially available 5-nitro-vanillin and 1200 ml of dichloromethane are mixed and the resulting mixture is cooled to 0 ° C and 533 ml of a 1M solution of boron tribromide in dichloromethane are added. The reaction mixture was allowed to stand at room temperature for 2 days and then concentrated. The residue was taken up in 300 ml of 2N hydrochloric acid while cooling in an ice-methanol bath and stirred at the same temperature for 2-3 hours. The solution was allowed to stand at room temperature for 16 hours and then extracted with ethyl acetate. The extract was washed, dried and evaporated. 18 g of the title compound are obtained, m.p. 260 ° C.

IR spectrum (Nujol):

general absorption in NH / OH region 1682 cm @ ^-1 : C = O

1620, 1590, 1580, 1548 and 1525 cm @ ¹ : aromatic ring + NO

Step B: To a suspension of 3-Nitro-4,5-bis (2-methoxyethoxy) methoxy] benzaldehyde, the product obtained in the previous step, in dichloromethane (50 ml) was added diisopropylethyl ethyl (13.6 ml). and the resulting mixture was cooled and 39.6 ml of chloro- (2-methoxyethoxy) methane was added over 45 minutes. The reaction mixture was stirred at 0 ° C for 2 hours and then diluted with water (100 mL). The phases are then separated and the organic phase is washed, dried and evaporated. The residue was purified by chromatography on silica gel using dichloromethane: acetone (9: 1 v / v) as the eluent. This gives 22.1 g of the title compound of this step, together with the title compound, having an R _r of 0.3.

HU 211 871 A9

IR (CHC1 _3):

1704 cm ^-1 : CH = O

1608, 1578, 1546, 1496 cm ^-1 : aromatic ring + ₁ H NMR (CDCl ₃ , 300 MHz, ppm)

3.6 and 3.38: -OCtf ₃

3.55 (m), 3.87 (m): OC // ₂ -Ctf ₂ -O

5.41: -0-C // ₂ -0

7.92: Ατ-Η

9.93: -CH = O

6. Reference Example

3-Iodo-4,5-bis [(2-methoxy-ethoxy) -methoxy] -benzaldehyde

Step A: 3-Iodo-4,5-dihydroxybenzaldehyde

After stirring under nitrogen atmosphere, commercially available 5-iodo-vanillin (37.2 g) and dichloromethane (360 ml) were cooled to 0 ° C and 135 ml of a 1M solution of boron tribromide in dichloromethane were added. . The resulting reaction mixture was allowed to stand at room temperature for 16 hours, then concentrated, cooled to 0 'C and acidified. The crystalline product which precipitated out was collected, washed with water, dried and then recrystallized from a 1: 2 by volume mixture of isopropanol and water. 23.4 g of the title compound are obtained.

IR spectrum (Nujol):

general absorption NH / OH 1662 (m) 1640 (F) cm-1: CH = O 1588, 1578, 1516 cm-1: aromatic ring 1 H-NMR spectrum (DMSO, 250 MHz, ppm)

7.25 (sl) and 7.44 (sl): Ατ-Η

9.68 (m): -C / 7 = O

10.46, 10.43 cm ^-1 : mobile absorption

Step B: 3-Iodo-4,5-bis (2-methoxyethoxy) methoxy] benzaldehyde

To a suspension of 25.4 g of the product obtained in the preceding step in 640 ml of dichloromethane is added 67 ml of diisopropylethylamine, and the resulting mixture is cooled to 10 ° C and 44 ml of chloro- (2-methoxy) is added over 45 minutes. ethoxy) methane is added. The reaction mixture was stirred for half an hour and then diluted with water (100 mL). The phases are separated and the organic phase is washed, dried and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1: 1). Yield: 25.5 g of the title compound of this step and of the title compound.

IR _(CHCl3):

OH absence

1698 and 2730 cm @ -1: C = O

1588, 1562 cm-aromatic ring H-NMR (CDC1 _3, 250 MHz, ppm)

3.38 (sl) (6H). -OCH, '

3.58 (m) (4H), 3.84 (m) (2H) and 4.05 (m) (2H):

O-CH ₂ -CH ₂ -O

5.33 (ski) and 5.39 (sl): -0-Ctf ₂ -0

7.68 (sl) and 7.96 (sl): Ατ-Η

9.82: -CW = O

7. Reference Example

To a suspension of 3.4.5-tris [(2-methoxyethoxy) methoxy] benzaldehyde g, commercially available 3,4 ml of trihydroxybenzaldehyde in 160 ml of dichloromethane was added 52 ml of diisopropylethylamine and the resultant The mixture was cooled to 0-5 ° C and chloro (2-methoxyethoxy) methane (35 ml) was added over 1.5 hours. After stirring, the reaction mixture was diluted with water (100 mL), the layers were separated, and the organic layer was washed, dried, and evaporated. 21.75 g of the title compound are obtained as a crude product which is used without further purification.

IR (CHC1 _3):

OH absence

1696cm- ': C = O

1590, 1498 cm-aromatic ring Ή-NMR (CDC1 _3, 250 MHz, ppm)

3.36 and 3.38 (9H): -OCH,

3.57 (m) (6H), 3.85 (mj (4H) and 3.99 (m) (2H):

O-CH ₂ -CH ₂ -O

5.31 (s) (2H) and 5.34 (s) (4H): -O-CH.-O

7.43 (s): Ατ – Η

9.82: -CH-0

8. Reference Example

2.5-Dichloro-3,4-bis (2-methoxyethoxy) methoxy] benzaldehyde

Step A: 2,5-Dichloro-3,4-dihydroxybenzaldehyde

27.6 g of commercially available 3,4-dihydroxybenzaldehyde were dissolved in 300 ml of acetic acid, and chlorine gas was bubbled through the resulting solution at room temperature until 31.24 g was consumed. After stirring for 42 hours, the reaction mixture was evaporated, the concentrate was cooled to 0 ° C and the precipitate was filtered off, washed and dried. so

13.7 g of the title compound are obtained, m.p. 176-178 ° C. _Rf value 0.1, eluant ethyl acetate: cyclohexane 5: 5, v: v.

1 H NMR (CDCl ₃ , 250 MHz, ppm)

7.24 (d J = 2 Hz) and 7.44 (d J = 2 Hz): Al-H

9.90 (m): -Ctf = O

10.40: Mobile absorption

Step B: 2,5-Dichloro-3,4-bis [(2-methoxyethoxy) methoxy] benzaldehyde

To a solution of the product obtained in the preceding step (6.83 g) in acetonitrile (265 ml) was added diisopropylethylamine (60.5 ml) followed by chloro (2-methoxyethoxy) methane (11.27 ml), followed by the reaction mixture. Stir at 35 ° C for 2 hours. The reaction mixture is evaporated to dryness and the residue is taken up in dichloromethane. The solution thus obtained is washed, dried and evaporated. The residue was purified by chromatography on silica gel using a 6: 4 by volume mixture of ethyl acetate and cyclohexane as the eluent. and also to give the the title compound was 10.9 g, melting point of 50 ° C and _Rf 0.3.

HU 211 871 A9

IR spectrum (PE580):

1690 cm ': CH.dbd.O

1572, 1551 cm ^-1: aromatic ring Ή-NMR (CDC1 _3, 250 MHz, ppm)

3.37 and 3.38: -OC // ₃

3.59 and 4.01 (m) (2H): OC // _2- C _22- O

5.29 and 5.36 (s): -OC // ₂ -O

7.78 (s): Ar - //

10.36 (s): -CH = O

9. Reference Example

To a suspension of 3-methoxy-4,5-bis [(2-methoxyethoxy) methoxy] benzaldehyde commercially available 3,4-dihydroxy-5-methoxybenzaldehyde in 80 ml dichloromethane was added 34 ml diisopropylethyl and the resulting reaction mixture was cooled to -5 ° C to 10 ° C. Chloro (2-methoxyethoxy) methane (23 mL) was added over half an hour, and the reaction mixture was stirred for 16 hours. The organic phase is then separated, washed, dried, filtered and evaporated. The residue was purified by chromatography on silica gel using a 50:50 by volume mixture of hexane and ethyl acetate as eluent. to yield the title compound, _Rf value of 0.4 using a gel plate using hexane: ethyl acetate 30:70 mixture. IR (CHC1 ₃ and PE580):

OH absence

1696 cm @ ^-1 : CH = O

1588, 1498 cm ^-1: aromatic ring H-NMR _(CDCl3, 250 MHz, ppm)

3.37 (s) (3H) and 3.38 (s) (3H): OC // ₂ -C // ₂ -OC // ₃

3.57 (m) (4H), 3.87 (m) (2H) and 4.00 (m) (2H):

O-CH ₂ -CH ₂ -O

3.90 (s) (3H): Ar-OC // ₃

Also 5.31) Í2H) and 5:35 (s) (2H): // ₂ -O OC

7.19 (d. J = 2Hz) (1H) and 7.38 (d. J * = 2Hz) (1H):

Ar - // Meta ... position

9.80 (s) (1H): - CH = O

10. Reference Example

J- [3- [7-beta - [[oxo [2 - [(triphenylmethyl) -amino] -thiazol-4-yl) -2 - [(4-methoxy-benzyloxy) carbonyl} - 8-oxo-5-thia-1-aza-bicyclo [4,2,0] [oct-2-en-3-yl] -2-propenyl] -thieno- [2,3-b] pyridinium iodide

Step A: 4-Methoxybenzyl 7beta- [oxo [2 - [(triphenylmethyl) amino] -thiazol-4-yl] -acetyl] amino] -3] (Z + E) -3-chloro 1-Propenyl} -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylate In a nitrogen atmosphere, 5 g of the compound of European Patent Application 333,154 were used. methoxybenzyl 7-beta-amino-3 - [(Z) -2-chloro-1-propenyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylate hydrochloride and a solution of 0.72 g of oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid in 200 ml of dichloromethane described in Belgian Application No. 874 828 are cooled to 0 ° C. and then 2,315 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (abbreviated as EDC) are added. After stirring for 40 minutes, the reaction mixture was washed and dried. After evaporation of the solvents, the residue obtained is chromatographed using 9: 1 dichloromethane: diisopropyl ether as eluent. to give the title compound, 5.51 g, whose R value of 0.3 _r.

Step B: 4-Methoxybenzyl 7beta- [oxo [2 - [(triphenylmethyl-famino] -thiazol-4-yl] -acetyl] -amino] -3] (Z + E) -3-iodo-1-p-phenyl -8-oxo-5-thia-1-azabicyclo [4,2,0] [oct-2-ene-2-carboxylate

To a solution of 5.5 g of the product obtained in the preceding step in 110 ml of acetone is added 3.094 g of sodium iodide and the resulting mixture is stirred at 20 ° C for 1.5 hours. The solvent was evaporated and the residue was taken up in 350 ml of dichloromethane. The solution thus obtained is washed, dried, filtered and evaporated to dryness. The resulting foam was filtered off and purified by chromatography using a 90:10 by volume mixture of dichloromethane and diisopropyl ether as eluent. to give the title compound, 3.93 g, whose R value of 0.3 _r.

IR (CHC1 _3):

1786, 1721, 1701 and 1663 cm @ ^-1 : C = O and beta-lactam

1613, 1586, 1535, 1516 ^cm-1: aromatic conjugated system + H-NMR (CDC1 _3, 330 MHz, ppm)

3.57: -SC // ₂ -C (C = CH -) = C3.82 (s): Ar-OC // ₃

3.98 (d, J = 8), -CH = CH-C // ₂ -I

5.03 (d, J = 5) ppm; CO-NH-CH (C = O) C // (N -) - S5,25 (AB, J = 12): CO-OC // ₂ -Ar

5.75: CO-NH-C H (C = O) -CH- (N -) - S 6.14 (dt, J = 16 and 8) ppm: -CH = C H - CH ₂ -I ( E) isomerism

6.8-7.4 (M): -S-C // = C (C = N -) - N = C (NH-trityl) and Ar - part of trityl group

8.19 (d): CO-CO-N 1 -CH (C = O) -CH- (N -) - SC. Step 1- [3- [7-Beta - [[oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] -2 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] [oct-2-en-3yl] -2-propenyl] -thieno- [2,3-b] pyridinium iodide

3.93 g of the iodine derivative prepared as described in the previous step are mixed with 6 g of thieno [2,2,3-b] pyridine at 20 'C for 1.5 hours, and 400 ml of diethyl ether are added to the resulting precipitate. filtered and dried in vacuo. This gives 4.12 g of the title compound of the title compound, which has an R _r of 0.1 using a 92: 8 by volume mixture of dichloromethane and methanol as the eluent.

Analytical results according to the formula C ₄ 9 H ₄₀ IN ₅ O ₆ S ₃ :

Calculated: C, 57.81; H, 3.96;

1% = 12.46, N% = 6.87, S% = 9.44;

Found: C, 57.3; H, 3.9;

I, 11.7, N, 6.7, S, 9.6;

HU 211 871 A9 1 H NMR Spectrum (CDCl ₃ , 300 MHz, ppm)

5.02 (d): CO-NH-CH (C = O} -C // (N -) - S5,27 (S) -CO-OC / 7 ₂ -Ar

5.6 (dd): -CH = CH-CH ₂ -N ⁺

5.74 (dt): H7 CO / CH (C = O) CH (N -) - S6,56 (d) -CH = CH-CH ₂ -N ⁺ (E) -izoméria

7.3: Ar-77 portion of trityl group

8.3: CTF = -S-C (C = N -> - N = C (NH _2), 7.89 (d): H of the thieno [2,3-b] piridiniumrész position 2; 7.71 ( d): H in the 3-position of the thieno [2,3-b] pyridinium moiety 8.8 (d): H in the thieno [2,3-b] pyridinium moiety

4-position; 8.10 (m): H at position 5 of the thieno [2,3-b] pyridinium moiety.

Reference Example 77 [4-Fluoro (2,3-bis-hydroxy) -phenyl] -hydroxy-acetic acid Dissolve 3 g of 3-fluoronirocatechin and 36.8 g of glyoxylic acid in 160 ml of water, and then After cooling to 0 ° C, a solution of 34.8 g of sodium carbonate in 400 ml of water was added. The reaction mixture was then cooled to 0 ° C and adjusted to pH 4.6 by addition of concentrated hydrochloric acid. 14.7 g of the starting 9-fluoropyrocatechin are distilled off and the residue is extracted with diethyl ether. The pH of the aqueous phase was then adjusted to 1.8 with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated from the extract to give 47.7 g of the title compound as a mixture of isomers, 2,3-bis-hydroxy-4-fluoro-isomer, 3,4-bis-hydroxy-5-fluoro-isomer and a mixture of -fluoro-3,4-bis-hydroxy isomer is formed. This mixture of isomers is utilized in Example 16, Step A, below.

Example 7 [6R-13- (E) 6alpha, 7beta (Z)] -] - [3- [7 - [[(2-Amino-4-thiazolyl)] [[carboxy- (2-chloro-3,4- dihydroxyphenyl) methoxy] imino acetyl] amino] -2-carboxy-8-oxo-5-thia -] - azabicyclic l4,2,0] oct-2-en-3-yl) -2- propenyl] quinolinium inner salt;

Step A: [2-Chloro-3,4-bis [(2-methoxy-ethoxy) -methoxy] -phenyl] -hydroxy-acetic acid is dissolved in 30 ml of water at 2.42 g of lithium chloride and 7.02 of potassium carbonate (10 g), then add 10 g of 2-chloro-3,4-bis [(2-methoxyethoxy) methoxy] benzaldehyde (2.8 ml) in bromoform and 38 ml of dioxane, prepared as described in Reference Example I. mixture. The reaction mixture was stirred at 0 ° C for 24 hours, followed by addition of additional 2.8 ml of bromoform. The resulting mixture was allowed to stand for 16 hours, then diluted with water (100 mL), washed with diethyl ether, decanted, cooled to 0 ° C, acidified to pH 2.5 to 3 and extracted with diethyl ether. The extract was washed with water, dried and the solvent was evaporated. to give the title compound as an oil, 11.4 g, having _Rf value of 0.1, methylene chloride, methanol and acetic acid as eluent 89: 1 by volume mixtures of: 10th

IR (CHC1 _3):

General Absorption in the -OH Region (Acid + Associated OH) 1726 cm ^-1 Complex: C = O Part of Acid Function

1598-1489 cm @ ^-1: aromatic nucleus Ή-NMR (CDC1 _3, 250 MHz, ppm)

3.37 (s 1) (6H): -OC77 ₃

3.57 (m) (4H), 3.81 (m) (2H) and 4.01 (m) (2H):

O-C77 ₂ -C77 ₂ -O

5.25 (m) (4H) and 5.52 (s 1) (1H): -O-CT / ₂ -O and

Ar-C / 7 CO

7.11 (s 1) (2H): Ar-77

Step B: Diphenylmethyl [2-chloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] hydroxyacetate under nitrogen atmosphere at room temperature

Dissolve 11.4 g of the acid obtained in Step A above in 120 ml of dichloromethane and add 120 ml at 15 ° C. 0.3M diphenyl diazomethane in dichloromethane. After stirring at room temperature for 16 hours, water (30 ml) was added, decanted, acetic acid (30 ml) was added for acidification, washing with a saturated aqueous sodium bicarbonate solution, drying and distilling off the solvent. The resulting residue was purified by chromatography on silica gel using a 60:40 by volume mixture of ethyl acetate and hexane as the eluent. 8.1 g of the title compound are obtained. IR (CHC1 _3):

3528 cm ^-1 : non-phenolic -OH

1734 cm ': C = 0

1702 cm ^-1 : C = O part of ester function

1597, 1496, 1487 cm ^-1 : aromatic core ^! 1 H-NMR (CDCl ₃ , 300 MHz, ppm)

3.36 (s): -OC77,

3.55 (s) (4H), 3.82 (s) (2H) and 4.03 (s) (2H): OC77 ₂ -C77 ₂ -O

5.27 (s) and 5.29 (s): -O-C77 ₂ -O

5.67 (after d exchange): Ar-C77 (C = O) -O

6.88 (S): CO-O-C77Ar ₂

7.0 (masked) and 7.08 (d): linked Ar-H (ortho position of the tetrasubstituted ring) 7.00 (2H)

7.18 (3H) and 7.30 (s) (5H): Ar-H

Step C: Diphenylmethyl [2-chloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] phthalimidoxyacetate

To a solution of 8.1 g of the ester prepared in Step B above in 90 ml of tetrahydrofuran is added 2.47 g of N-hydroxyphthalimide and 7.55 g of triphenylphosphine. the reaction mixture was cooled to 10 ° C and then diethyl azodicarboxylate (abbreviated as DEAD) (3.88 ml) was added. The reaction mixture was stirred for 16 hours, then the solvent was evaporated and the residue was purified by chromatography on silica gel using ethyl acetate / hexane (60: 4) as the eluent. Thus 6.27 g of the title compound as an oil having an _Rf value of 0.25.

IR (CHC1 _3):

HU 211 871 A9

1739, 1755 (shoulder) and 1795 cm @ ^-1 : C = O

1597, 1489 cm ^-1: aromatic nucleus

1 H NMR (CDCl ₃ , 300 MHz, ppm)

3.33 and 3.37: -OC // ₃

3.54 (m) (4H), 3.82 (m) (2H) and 3.92 (m) (2H):

O-CH ₂ -CH ₂ -O

5.22 (AB sys) and 5.30 (AB sys): -OC // ₂ -O

6.50: Ar-C // (C = O) -0

6.93 (s) ppm: CO-OC // - Ar ₂

7.09 (d) 7.41 (d): linked Al-H (ortho position of the tetrasubstituted ring)

7.44 (d) (4H): Ar - // part of phthalimido 7.05-7.33: Ar - // part of aromatic ring

Step D: Diphenylmethylamino-oxy [2-chloro-3,4-bis [(2-methoxy-ethoxy) -methoxy] -phenyl] -acetate

6.27 g of a solution of the compound prepared in Step C above in 65 ml of ethanol are cooled to 5 ° C and 0.47 ml of hydrazine hydrate are added. The resulting mixture was then heated at 5 ° C for half an hour. then allow to stand at room temperature for 2 hours. After filtration, the solvent was evaporated and the resulting residue was purified by chromatography on silica gel using ethyl acetate as the eluent. Thus 3.64 g of the title compound as an oil having an _Rf value of 0.3.

Analysis results for C ₂₉ H ₃₄ ClNO ₉ :

Found: C, 60.46; H, 5.95; N, 2.43; Found: C, 60.1; H, 6.1; N, 2.6;

IR (CHC1 _3):

3235 cm ^-1 : -NH ₂

1738 cm ⁴ : C = O part of the ester function

1598, 1572, 1490 cm ^-1: aromatic nucleus + NH _second

Step E: [[] - [Chloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxyimino [2 -I (triphenylmethyl) -amino] -thiazol-4-yl] -acetic acid

Under a nitrogen atmosphere, 0.69 g of the compound prepared as described in Step D above and 0.496 g of oxo [2 - [(triphenylmethyl) amino] thiazol4-yl] acetic acid described in Belgian Patent Application 864,828. A solution of methanol (7 ml) was stirred at room temperature for 3 hours, then the solvent was removed and the residue was purified by chromatography on silica gel using a 95: 5 by volume mixture of methylene chloride and methanol as eluent. to give the title compound 0.726 g, having a value of _Rf 0.3, eluent methylene chloride: methanol 90:10 as eluent.

Analysis results based on the formula Cs ^ jqCH ^ OhS:

H, 5.18 Found: C, 65.45;

N, 2.43; S, 3.29; Cl, 3.64;

Found: C, 63.7; H, 5.1;

N, 4.2; S, 3.2; Cl, 3.1;

Step E: 4-Methoxy-benzyl 7-beta - [[[[[1- [2-chloro-3,4-bis [(2-methoxy-ethoxy) -methoxy] -phenyl] -2-oxo-2- (diphenylmethyl) oxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) -amino) -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro-propenyl ] -8-oxo-5-thia -] - azabicyclo [4,2,0] oct-2-ene-2-carboxylate

0,322 g of 4-methoxybenzyl 7-beta-amino-3 - ((Z) -3-chloro-1-propenyl) -8-oxo-5-thia-1-azabicyclo [4-methoxybenzyl] described in European Patent Application Publication No. 333,154. , 2.0] -oct-2-ene-2-carboxylate hydrochloride and 0.72 g of the compound prepared in Step E above in 10 ml of dichloromethane are cooled to 5 ° C with stirring and then added. 0.1803 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (abbreviated as EDC). The reaction mixture was stirred for half an hour and then a solution of potassium hydrogen phosphate (10 mL) in methylene chloride (10 mL) was added. Decanting, washing, drying and evaporation of the solvent is carried out, to give the title compound 0.670 g with _Rf value of 0.43 using a developing agent; methylene chloride: ethyl acetate 80:20 mixture.

Step G: 4-Methoxybenzyl 7beta - [[[[[[1- [2-chloro-3,4-bisK-2-methoxyethoxy] methoxy] phenyl] -2-oxo-2- (diphenylmethyl) oxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino) thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo-propenyl] - 8-Oxo-5-thia-J-azabicyclo [4,2,0] oct-2-ene-2-carboxylate

A mixture of 0.67 g of the compound prepared in Step F above and 0.223 g of sodium iodide in 10 ml of acetone is stirred at room temperature for 1 hour in the presence of an iodine crystal, and the solvent is distilled off and the residue is taken up in methylene chloride. The resulting organic solution was washed, dried and the solvent was evaporated. The resulting residue was recrystallized from diisopropyl ether to give the title compound 0.579 g with _Rf value of 0.27 using a developing agent; methylene chloride: methanol 90:10 as eluent.

Step H: J-13- [7beta- [1 - [[[1- [2-Chloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) - methyloxy) ethyl N-oxy J-imino] - [2 - [(triphenylmethyl) amino) thiazol-4-yl N-acetyl] amino] -2 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-3-yl] -2-propenyl] quinolinium iodide

To a solution of 0.572 g of the compound prepared in Step G above in 6 ml of methylene chloride is added 0.234 g of quinoline and the resulting mixture is stirred for 1 hour. The solvent was distilled off and the residue was taken up in diethyl ether. To give the title compound 0.235 g (1 by volume mixture of methylene chloride and methanol 9 as eluant) after which the value of _Rf 0.27, using methylene chloride and methanol 90:10 by volume mixture of crystallization, separation and chromatography on silica gel.

HU 211 871 A9 1 H NMR Spectrum (CDCl ₃ , 250 MHz, ppm)

3.31-3.34: -OCtf ₃

3.73 (s): Ar-O-CH ₂ 3.42-4.01: CW ₂ -S and O-CH ₂ -Ctf ₂ -O

4.92 (m): -CH (N -) - S 5.84 (m): -NH-CH-C

5.20-5.30: _-O-CH2 - and COO-CH ₂ -Ar 5.93 to 6.15: = _C-CH2 -N ⁺

6.40-6.55: = CH-CH ₂ - (E) isomerism and O-CH-Ar separated 6.76: H at position 5 of the thiazole ring 6.86-7.42: -CH-Ar, COO- CHAR ₂ , = C-CH = CH (E) isomerism

8.05-8.25 (3H), 8.37 (m) (1H), 8.92 (d, separated) (1H) and 10.4 (d): hydrogen atoms of the quinoline ring

7.83 and 8.27: -CO-Ntf /. Step 6: [6R- [3- (E), halpha, 7beta (Z)]] - 1- [3- [7 [[(2-amino-4-thiazolyl)] [[carboxy (2-chloro-4, 5-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-N-aza-bicyclo [4,2,0] oct-2-ene- 3-yl) 2-propenyl] -quinolinium inner salt - (R) -isomer and (S) -isomer

A mixture of 0.235 g of the compound prepared in Step H above and 5 ml of 10% anisole in trifluoroacetic acid was stirred at room temperature for 1.5 hours, and then diethyl ether was added. The resulting mixture was subjected to ultrasound, filtered, washed and dried at room temperature under vacuum for 16 hours. Yield: 0.118 g of the title compound of this step and of the title compound.

HPLC (Micro Bondapac C ₁₈ column 25 cm) solvent: water / acetonitrile (85/25) pH 2.7 Retention time: S isomer 13.5 min

Isomer R: 18.2 min

Analysis results for C ₃₂ H ₂₅ C1N ₆ O9S ₂ ·

According to the formula 1.5 C ₂ HF ₃ O ₂ O, 5 Hl (molecular weight 1014):

Calculated: C, 43.81. H, 2.88; N, 8.28.

Cl% = 3.49, S% = 6.32, F% = 8.42, 1% = 6.25;

Found: C, 44.1; H, 2.7; N, 8.5.

Cl% = 4.1, S% = 6.7, F% = 8.5, 1% = 6.0.

1 H NMR (DMSO, 300 MHz, ppm)

Masked by DMSO aqueous -S-CH ₂ C (C = C H -) = C5,15 (d of d) ppm CO-NH - (= O) CH (N -) - S5,72-5,89 ( 4H): CO-NH-CH (C = O) -CH (N -) - S-,

Ar-CH (CO-O) -O- and -CH = CH-CH ₂ -N ⁺

6.38 (m) ppm: -CH = CH-CH ₂ -N ⁺ (E) -isomer

6.7-6.82: -S-CH = C (C = N-) -N = C (NH ₂ ) - and the Ατ-H part of the pyrocatechin

6.98 ppm (d, J = 15.5) -CH = CH-CH ₂ -N ⁺ (E) isomerism

7.30: NH ₂

8.06 (t) (1H), 8.25 (m) (2H), 8.54 (m) (2H) and 9.34 (d) (1H): Ar-H portion of quinoline

9.29 (s 1) and 9.49 (s 1): mobile hydrogens

9.47 (d) and 9.58 (d): ττ-H and -CO-NH-CH (C = O) CH (N -) - S2. Example 6 [6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-cyano-4,5-dihydroxy) -phenyl) methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia] - azabicyclo [4,2,0] oct-2-en-3-yl) -2 - Inner salt of (-propenyl) quinolinium, (R) -isomer or (S) -isomer or a mixture thereof

Step A: [3-Cyano-4,5-bis [(2-methoxy-ethoxy) -methoxy] -phenyl-hydroxy-acetic acid

In the same manner as in Example 1, Step A, starting from 6.2 g of the compound prepared in Reference Example 2, Step C, 4.4 g of potassium carbonate, 3.15 g of lithium bromide, 1.7 g of the title compound. g of bromoform and 15 ml of dichloromethane. After stirring at -5 ° C for 48 hours, 7.2 g of crude acid are obtained, which product is purified by chromatography on silica gel using dichloromethane: methanol: acetic acid (90: 7: 3) as the eluent. 3.42 g of the title compound are obtained with an Rj of 0.3 using a 90: 7: 3 mixture of methylene chloride, methanol and acetic acid as the eluent. IR (CHC1 _3):

overall absorption in the -OH region (acid + associated OH)

1721 cm ¹ (max) + 1750 cm '(shoulder): acid function

C.dbd.O of 2235 ^cm-first

1602-1586-1489 cm ': aromatic core

Step B: Diphenylmethyl [3 cyano-4,5-bis [(2-methoxyethoxy) methoxy] hydroxyacetate 8.5 g of the acid prepared in Step A above are dissolved in 100 ml of dichloromethane under nitrogen atmosphere at room temperature. 75 ml of a 0.3 M solution of diphenyl diazomethane in diethyl ether are added at 15 ° C. The reaction mixture was stirred at room temperature for 16 hours and water (30 mL) was added. Then decantation followed by acidification with 30 ml of acetic acid. The reaction mixture was then washed with a saturated aqueous sodium bicarbonate solution, dried and the solvents were evaporated. The residue was purified by chromatography on silica gel using a 50:50 by volume mixture of methyl acetate and hexane as the eluent. 4.2 g of the title compound are obtained with an R _r of 0.3. IR (CHC1 _3):

3525 cm <^-1> : non-phenolic -OH

2235 cm ': C = N

1732 and 1750 cm ': C = O part of the ester function

1600, 1585, 1495, 1490 cm-1: 1 H-NMR spectrum of the aromatic nucleus (CDCl ₃ , 300 MHz, ppm)

3.32-3.47: _-OCH3

3.58 and 3.72: O-CH ₂ -CH ₂ -O

5.15 to 5.40: O-CH ₂ -O and Ar-CH (C = O) -OH

6.89 (s): CO-O-CHAr ₂

7.24-7.50: Ar-H

Step C: Diphenylmethyl [3-cyano-4,5-bis [2- (methoxyethoxy) methoxy] phenyl] phthalimidoxyacetate

0.430 g is obtained as described in Step B above14

To a solution of the esterified ester in tetrahydrofuran (10 mL) was added N-hydroxyphthalimide (0.134 g) and triphenylphosphine (0.409), and the reaction mixture was cooled to -10 ° C and DEAD (0.24 mL) was added. After stirring for 16 hours, the solvents were evaporated. The residue was purified by chromatography on silica gel using dichloromethane: acetone (95: 5, v / v) as the eluent. Thus 0.2 g of the title compound as an oil having an _Rf value of 0.25, eluent dichloromethane-acetone 97: 3 as the eluant.

IR (CHCl ₃ ): 1792 (m), 1775 (shoulder), 1760 (shoulder) and 1738 (max) cm ^-1 : C = O

2230cm -1: C = N

1604, 1586, 1490 cm ^-1 : aromatic core

Step D: Diphenylmethylamino-oxy [3-cyano-4,5-bis (2-methoxy-ethoxy) -methoxy] -phenyl] -acetate Under nitrogen atmosphere, 2.7 g of the compound prepared in the preceding step C 80 A solution of ethanol (ml) was cooled to -2 ° C and 0.2 ml of hydrazine hydrate was added. The resulting reaction mixture was maintained at -2 'C for half an hour and then allowed to warm to room temperature over 1 hour. After filtration and evaporation of the solvent, the residue obtained is purified by chromatography on silica gel using a 7: 3 by volume mixture of ethyl acetate and hexane as the eluent. so

1.8 g of the title compound as an oil having an _Rf value of 0.25.

Analysis calculated for C ₃₀ H ₃₄ N 2 O ₉ : C, 63.53; H, 6.04; N, 4.94.

Found: C, 63.3; H, 6.4. N, 4.6.

IR (CHC1 _3):

3335 cm ^-1 : O-NH,

2230cm - ': C = N

1748 cm ^-1 : C = O part of the ester function

1600, 1588, 1488 cm ^-1 : aromatic core + NH ₂

Step E: [[1- [3-Cyano-4,5-bis [(2-methoxyethoxy) methoxy) phenyl] -2-oxo (diphenylmethoxy) ethyl] oxy) imino- [2- [triphenylmethyl) amino] thiazole} acetic acid under nitrogen atmosphere at room temperature

0.650 g of the compound prepared as described in Step D above and 0.428 g of the compound described in Belgian Patent Application 864 828 can be prepared as oxo [2 [(triphenylmethyl) amino] thiazol-4-yl] acetic acid methanol (2 ml) was stirred for 2 hours and then the solvent was removed. The residue was taken up in diethyl ether, and the resulting solution was filtered and the filtrate was purified by chromatography on silica gel using a 95: 5 by volume mixture of methylene chloride and methanol as eluent. 0.841 g of the title compound is obtained, m.p. 158 'C.

IR (CHC1 _3):

3402 cm-1: -C-NH general absorption OH / NH 2235 cm-1: C = N

1755 (shoulder), 1740 (max) and 1717 (shoulder) cm ^-1 : C = O

1587, 1531, 1509 and 1490 cm @ ^-1 : aromatic, heterocyclic, conjugated system @ 1 H-NMR spectrum (ppm)

3.36 (s) and 3.43 (s) - OCtf ₃

3.55-3.90 (m) (6H), and 4.05 (m) (2H): OC ₂ // C // ₂ -0

5.03 (d), 5.12 (d) and 5.33 (d) _-O-CH2 -O

5.85 (s): Ar-CH (C = O) -O6.68 (s): CO-OC // Ar ₂

6.87 (s): -S-Ctf = C (C = N) -N

7.10-7.36 (massive) (27h), 7.67 (d) (1H): Ar-H

Step E: 4-Methoxybenzyl 7beta - [[[[[1- [3-cyano-4,5-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2 (diphenylmethoxy)] ethyl] oxy] imino [2-triphenylmethyl) amino] -thiazol-4-yl] acetyl] -amirto] -3 - [(Z) -3-chloro-1-phenyl] -8-oxo- 5-Thia-1-aza-bicyclo [4,2,0] oct-2-ene-2-carboxylate

0.160 g of 7-beta-amino-3 - [(Z) -3-chloro-1-propenyl] -8-chloro-5-thia-1-azabicyclo [4,2,0] oct. Disclosed in European Patent Application 333 154 A mixture of -2-ene-2-carboxylate hydrochloride and 0.36 g of the compound prepared in Step E above in 5 ml of dichloromethane was cooled to 5 ° C and 0.0893 g of EDC was added. The reaction mixture was stirred for 15 minutes and then a solution of potassium hydrogen phosphate (15 ml) in dichloromethane (8 ml) was added. Thereafter, decantation, washing, drying and distillation of the solvents were carried out. The residue was purified by chromatography on silica gel, eluting with dichloromethane: ethyl acetate (8: 2). to give the title compound 0.349 g, having a value of _Rf 0.4, eluent methylene chloride: ethyl acetate 8: 2 as the eluant.

Step G: 4-Methoxybenzyl 7-beta [[[[[1- [3-cyano-4,5-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2 (diphenylmethoxy) ) ethyl] oxy] imino [2- [triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo-propenyl] -8-oxo -5-Thia-J-aza-bicyclo [4,2,0] oct-2-ene-2-carboxylate

A mixture of 0.573 g of the compound prepared in Step F above and 0.192 g of sodium iodide in 7 ml of acetone is stirred at room temperature for 1 hour in the presence of an iodine crystal. After evaporation of the solvent, the residue is taken up in dichloromethane and the resulting solution is washed, dried and evaporated. The residue was finally crystallized from diisopropyl ether to give the title compound 0.463 g with _Rf 0.30, eluent dichloromethane-methanol 9: 1 as eluent.

Step H: 3-13- [7beta - [[[[[1- [3-Cyano-4,5-bis (<2-methoxyethoxy-flmethoxy] -phenyl] -2-oxo-2- (diphenylmethoxy)) ethyl] oxy] imino [2- [triphenylmethylamino] -azol-4-yl] acetyl] amino] -3 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5 -thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl] -2-propenyl] quinolinium iodide

To a solution of 0.463 g of the compound prepared in Step G above in 4 ml of dichloromethane

Quinoline (0.191 g) was added and the reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was taken up in diethyl ether. After crystallization, the precipitated crystals were collected and purified by chromatography on silica gel using dichloromethane: methanol (97: 3, v / v) as the eluent. to give the title compound 0.241 g with _Rf value of 0.27.

1 H-NMR (CDCl ₃ , 400 MHz, ppm)

3.25 (s), 3.27 (s) and 3.34: -OCW ₃

3.26-4.04: CH ₂ -S and O-CH ₂ -CH ₂ -O

3.98 (s): Ar-O-C / ή,

4.90-5.08 and 5.15-5.40: -C (N -) - S-, = C-Ctf ₂ N ⁺ , -O-CH ₂ -O and COO-CH ₂ -Ar.

5.75-6.05: N-C (C = O) -CN- (N -) - S and -OC (C = O) -Ar

6.38 (m) and 6.56 (m): C = - CH - (E) -isomer

6.73 (m): S-CH- (C = N) -N

6.80-7.50: trityls, COO-C (7Ar ₂

7.9-8.56 (5H) (d) and 8.87 (d) separated (1H), 10.27 (d) and 10.83 (d): Hydrogen of the quinoline ring and -N / 7

Step I: [6R- [3- (E) halo]. 7beta (Z)]] - 1- [3- [7 - [[(2 amino-4-thiazolyl) [[carboxy- (3-cyano-4,5-dihydroxyphenyl) methoxy] amino] acetyl] amino -2-Carboxy-8-thio-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl] -quinolinium, inner salt of (R) -isomer or (S) ) isomer

A mixture of 0.241 g of the compound prepared in Step H above and 5 ml of 10% anisole in trifluoroacetic acid was stirred at room temperature for 1.5 hours and then diethyl ether was added. After crystallization, filtration, washing and drying at room temperature in vacuo for 16 hours, 0.128 g of the title compound is obtained.

Analysis results for C ₃₃ H ₂₅ N ₇ O ₉ S ₂ ·

1.4 C ₂ HF ₃ O ₂ according to the formula 0,4 Hl:

H, 2.87; N, 10.43 Found: C, 45.83; H, 2.87;

S, 6.83; F, 8.5; 1%, 5.4;

Found: C, 44.1. H, 2.7; N, 8.5.

S, 7.0, F, 8.4, I, 4.1. 1 H NMR (DMSO, 300 MHz, ppm)

3.53 (d) and 3.74 (d): -SC // _2- C (C = CH -) = C5.14 (linked d) ppm: CO-NH- (C = O) -CH (N -) - S 5.40 (s): Ar-CW (CO-O -) - O 5.76 (m): O-NH-CW (C = O) -CH (N -) - S5.89 (m) : -CH = CH-Ctf ₂ -N ⁺

6.34 (m): CH ₂ = CW-CH-N ⁺ (E) -izoméria

6.76 (s) and 6.79 (s): CW = -S-C (C = N -) - N = C (NH _2), 6.98 ppm (d, J = 16): -Ctf = CH-CH ₂ - N ⁺ (E) isomerism

7.11-7.15 (m) (2H): Ar-W

7.30 (m) and 10.38 (m): mobile hydrogens

8.06 (t) (1H), 8.26 (m) (2H), 8.53 (m) (2H), 9.33 (d) and 9.58 (d): Ar-W

9.60 (d) and 9.65 (d): -CO-NW-CH (C = O) CH (N -) - S3. Example 6 [6R- [3- (E) -alpha, 7beta (Z)] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-fluoro-4,5-dihydroxy) -phenyl) methoxy] -imino-J-acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2 - Internal salt of (-R) -propenyl-quinolinium, (R) -isomer or (S) -isomer, or mixtures thereof

Step A: [3-Fluoro-4,5-bis [(2-methoxy-ethoxy) -methoxy] -phenyl] -hydroxy-acetic acid is dissolved in 13 ml of water at 0.662 g of lithium bromide and 3.6 g of potassium carbonate and 5.5 g of 3-fluoro-4,5-bis [(2-methoxyethoxy) methoxy] benzaldehyde, 285 ml of bromoform and ml of dioxane. The resulting reaction mixture was stirred at 0 ° C for 24 hours, then an additional 2.85 ml of bromoform was added and then allowed to stand overnight. After dilution with water and washing with diethyl ether, decantation was carried out, and the residue was cooled to 0 ° C, acidified to pH 2.5-3 and extracted with diethyl ether. The extract was washed with water, dried and evaporated. 5.3 g of the title compound are obtained in the form of an oil.

IR (CHC1 _3):

3600 cm ¹ : -OH region (acid + associated OH)

1715 cm ¹ complex: C = O part of the acidic function

1616, 1595 and 1510 cm ^-1: aromatic nucleus

Step B: Diphenylmethyl [3-fluoro-4,5-bis ((2-methoxyethoxymethoxy) phenyl] hydroxyacetate

To a solution of 5.3 g of the acid prepared in Step A above in 66 ml of dichloromethane is added 46 ml of a solution of diphenyl diazomethane in diethyl ether at a density of 6.5 g / cm ^3. and the resulting mixture was stirred at room temperature for 16 hours. Water was added followed by decantation and acidification with acetic acid. washing, drying and evaporation with a saturated aqueous sodium bicarbonate solution. The residue was purified by chromatography on silica gel using a 50:50 by volume mixture of ethyl acetate and hexane as the eluent. 4.0 g of the title compound are obtained with an R _r of 0.17.

IR (CHC1 _3):

3520 cm @ ¹ : non-phenolic -OH

1735 cm- ¹ : C = O part of the ester function

1615, 1595 and 1509 cm ^-1: aromatic nucleus Ή-NMR (CDC1 _3, 250 MHz, ppm)

3.33 (s) and 3.37 (s): -OCtf,

3.45 (m), 3.57 (m), 3.78 (m) and 3.98 (m): O-CH ₂ c / o y ₂

5.19 to 5.30: -0-Ar-CW and CW ₃ -0 (C = OO) -O6,87 (s): CO-OC / 7aR ₂

6.87 (m) (1H), 6.97 (m) (2H), 7.07 (m) (1H), 7.21 (m) (3H) and 7.32 (m) (5H): Price-//

Step C: Diphenylmethyl [3-fluoro-4,5-bis [(2-methoxyethoxy) methoxy] phenyl] phthalimidoxyoxyacetate

To a solution of the ester (2.6 g, prepared as described in Step B above) in tetrahydrofuran (28 mL) was added N-hydroxyphthalimide (0.77 g) and tri16 (2.42 g).

A9 phenylphosphine was added and the resulting mixture was cooled to -10 ° C and 1.4 ml of DEAD was added dropwise. After the addition was complete, the reaction mixture was stirred at 0 ° C for 1.5 hours and the solvent was evaporated. The residue was purified by chromatography on silica gel using dichloromethane: acetone (95: 5, v / v) as the eluent. Thus 2.56 g of the title compound as an oil, having a value _Rf of 0.6 using a developing agent; dichloromethane: acetone 85:15 as eluent.

IR (CHC1 _3):

1794, 1752 and 1738 (max) cm -1: C = O 1 H-NMR (CDCl ₃ , 250 MHz, ppm)

3.34 (s) and 3.33 (s): -OC / ₃

3.48 (m) (2H), 3.56 (m), 3.77 (m) (2H) and 3.96 (m) (2H): OC ₂ // C // ₂ -O

5.22 (d) (4H): -0-C -0 // ₂

5.92 (s): Ar-C // (C = OO) -O6.92 (s): CO-OC // Ar ₂ 7.00-7.35 (m): Ar-H

7.75 (m) (4H): Ar-H portion of phthalimide

Step D: Diphenylmethylamino-oxy [3-fluoro-4,5-bis (2-methoxy-ethoxy / methoxy] -phenyl / acetate Under nitrogen atmosphere, 2.4 g of the compound prepared in Step C above with 25 ml of ethanol. The reaction mixture was cooled to -5 ° C and 0.38 ml of hydrazine hydrate were added, the reaction mixture was kept at -5 ° C for 2 hours, then filtered and the solvent was evaporated, and the residue was purified by chromatography on silica gel. 3 by volume as eluant to give 1.67 g of the title compound as an oil having an _Rf value of 0.3 IR (CHC1 _3): 7 ethyl acetate and hexane as eluent..:

3,340 cm -1: O-NH ₂

1747 cm ⁴ : C = O part of the ester function

1616, 1596, 1581, 1508 and 1497 cm ^-1 : aromatic core + NH _{2 1} H-NMR spectrum (CDCl ₃ , 300 MHz, ppm)

334 and 3.36: -OC // ₃

3.48, 3.56, 3.77 and 3.97: O-CH ₂ -CH ₂ -O

5.17 (s): Ar-C // (C = OO) -O5.20 and 5.21: -OC // _2- O

5.79 (s): O-NH ₂

6.82 (dd): Ar-H at F ortho

6.91 (s): CO-OC // Ar ₂ 7.02: Ar - // at F para 7.05-7.40: Ar-H

Step E: [[[1- [3-Fluoro-4,5-bis [(2-methoxyethoxy / methoxy / phenyl / oxo-2- (diphenylmethyloxy) -ethyl) -oxy] -imino] [ 2 - [(triphenylmethyl / amino / thiazol-4-yl / acetic acid

Nitrogen gas at ambient temperature

0.640 g. A mixture of the compound prepared in the above step and 0.474 g of oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid described in Belgian Application 864 828 in 20 ml of methanol. After stirring for 1 hour, the solvent was distilled off. The residue was purified by chromatography on silica gel using dichloromethane: methanol (95: 5, v / v) as the eluent. to give the title compound 0.612 g, whose R value _r 9 mixture of dichloromethane and methanol, 0.35, eluent: 1 by volume as the eluant. Spetkrum IR (CHC1 _3):

3400 cm ^-1 : = C-NH

1755 (shoulder), 1736 (max) cm ^-1 : C = O

1695, 1527, 1509 and 1496 cm ^-1 : aromatic, heterocyclic

1635cm -1 ': C = O' 1 H-NMR (CDCl ₃ , ppm)

3.39 (s) and 3.22 (s): _OCH3

3.30 (m), 3.55 (m), 3.60 (m), 3.92: OC // ₂ -C // ₂ -O

5.15 (s), 5.10 (d) and 5.20 (d) _-O-CH2 -O

5.81 (s): Ar-C // (C = O) -O6.56 (s): CO-OC // Ar ₂

6.74 (s): -S-C H = C (C = N) -N

7.10-7.33 (m): Ar - //

Step F: 4-Methoxybenzyl 7beta [[[[[1- [3-Fluoro-4,5-bis [(2-methoxyethoxy / methoxy) phenyl] 2-oxo-2- (diphenylmethyloxy) (ethyl) oxyimino [2 - [(triphenylmethyl / amino] thiazol-4-yl] acetyl} amino] -3 - [(Z) -3-chloro-propenyl] -8-oxo 5-thia-azabicyclo [4,2,0] oct-2-ene-2-carboxylate

0.289 g of 7-beta-amino-3 - [(Z) -3-chloro-1-propenyl] -8-oxo-5-thiaazabicyclo [4,2,0] octane, prepared as described in European Patent Application 333,154, are obtained. A mixture of -2-ene-2-carboxylate hydrochloride and 0.641 g of the compound prepared in Step E above in dichloromethane (6 ml) was cooled to 5 ° C with stirring, and 0.160 g of EDC was added and the reaction mixture was stirred for half an hour. A solution of potassium hydrogen phosphate in dichloromethane is then added to the reaction mixture, followed by decantation, washing, drying and distilling off the solvents. The residue was purified by chromatography on silica gel, eluting with dichloromethane: ethyl acetate (8: 2). 0.678 g of the title compound is obtained, Rf 0.4, eluting with dichloromethane: ethyl acetate (8: 2).

Step G: 4-Methoxybenzyl 7beta [[[[[1- [3-Fluoro-4,5-bis [(2-methoxyethoxy) methoxy / phenyl] -2-oxo-2- (diphenylmethyloxy) ) ethyl] oxy] imino] - [2- (1-triphenylmethyl / amino] -thiazol-4-yl] -acetyl] -amino] -3 - [(Z / 3-iodo-propenyl) -8 oxo-5-thia-azabicyclo [4,2,0] oct-2-ene-2-carboxylate

A mixture of 0.678 g of the compound prepared in Step F above and 0.228 g of sodium iodide in 7 ml of acetone is stirred at room temperature for 1 hour in the presence of an iodine crystal, and the solvent is distilled off. The residue was taken up in dichloromethane and the resulting solution was washed, dried and evaporated. This gives 0.501 g of the title compound of the step, having R _r of 0.2, as the starting material

A9 was used as a 97: 3 by volume mixture of dichloromethane and methanol.

Step H: 1- [3-7beta [[[[[1- [3-Fluoro-4,5-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxy-benzyloxy) carbonyl ] -8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl] -2-propenyl] quinolinium iodide

Quinoline (0.226 ml) was added to a solution of 0.500 g of the compound prepared in Step G above in 2 ml of dichloromethane, then part of the solvent was evaporated, and the concentrate was stirred at room temperature for 1 hour and then 2 ml of dichloromethane was added. Subsequently, the product is precipitated by addition of diethyl ether and the crude product is purified by chromatography on silica gel, eluting with a 97: 3 mixture of dichloromethane and methanol. to give the title compound 0.220 g with _Rf value of 0.20.

Step I: [6R- [3- (E) 6alpha, 7beta (Z)]] - 1- [3- [7 - [[(2 amino-4-thiazolyl)] [[carboxy (3-fluoro-4, 5-dihydroxyphenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-thio-1-aza-bicyclo [4,2,0-oct-2-en-3-yl] - 2-propenyl] quinolinium inner salt, (R) -isomer or (S) -isomer

A mixture of 0.220 g of the compound prepared in Step H above and 5 ml of 10% anisole in trifluoroacetic acid was stirred at room temperature for 1.5 hours and then 15 ml of diethyl ether was added. The precipitate was washed and dried. This gives 0.0994 g of the title compound of the step and of the title compound.

Analytical results for C, ₂ H ₂₅ FN ₆ O _g S ₂ +

According to the formula 1,4 C ₂ HF, O ₂ + 0,5 Hl:

Calculated: C, 44.8; H, 2.89; N, 9.12

S% = 6.95, F% = 9.48, 1% = 6.88;

Found: C, 44.7. H, 2.8. N, 8.8.

S, 6.6; F, 9.1; I, 6.6;

1 H NMR (DMSO, 300 MHz, ppm)

3.5 and 3.8: (masked by solvent water)

5.14 (separated d) ppm: CO-NH-CH (C = O) CH- (N -) - S5.34 (separated s): Ar-CH (CO-O -) - O5.77 (separated dd) and d, resolved): -CO-NH (C = O) CH (N -) - S5,80-6,0: -CH = CH-CW ₂ -N ⁺

6.37 (m): -CH = CH-CH, -N ⁺

6.7-6.8: -S-CH = C (C = N -) - N = C (NH ₂ ) - and Ar-H at F ortho and para

6.98 ppm (separated d): -CH = CH-CH ₂ -N ⁺ (E) isomer

8.07 (t), 8.29 (t): H at the 6- and 7-positions of the quinolinium

8.24 (dd): H at 3-position of quinolinium 8.53: If 5-position and 8-position of quinolinium

9.34 (d): H at position 4 of the quinolinium

9.58 (d): When in quinolinium 2 position

7.31-9.19 and 9.5-9.7: mobile hydrogens

Example 4 [(±) (cis) (Z)] 7- [3- [7 - [[(2-Amino-4-thiazolyl) - [[carboxy- (3-chloro-4,5-dihydroxyphenyl) ) -methoxy] -imino] -acetyl] -amino-2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-3-yl] -2 ( E) -propenyl] -thieno [2,3-b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof

Step A: [3-Chloro-4,5-bis - [(2-methoxy-ethoxy) -methoxy] -phenyl] -hydroxy-acetic acid

To a solution of 3.34 g of lithium chloride and 9.64 g of potassium carbonate in 36 ml of water at 0 ° C is added 13.77 g of 3-chloro-4,5-bis [- (prepared as described in Reference Example 3). 2-methoxyethoxy) methoxy] benzaldehyde, 3.74 mL; bromoform and 34 ml of dioxane. The resulting reaction mixture was stirred at 0 ° C for 24 hours and then an additional 3.74 ml of bromoform was added. After stirring for 16 hours, the reaction mixture was diluted with water (100 mL), washed with diethyl ether, decanted, cooled to 0 ° C, then acidified to pH 2.520 and extracted with diethyl ether. The extract was washed with water, dried and the solvent was evaporated. 13.95 g of the title compound are obtained in the form of a yellow oil. IR spectrum (CHCl3):

1700 (max) and 1730 (shoulder) cm ^-1 : C = O

1599, 1578, 1489 cm @ ^-1 : @ ¹ H-NMR spectrum of the aromatic nucleus (CDCl3, 250 MHz, ppm).

3.38 (m) (6H): -OCH, '

5.09-5.35 (m): -O-CH ₂ -O and Ar-CH (C = O) -O

7.05-7.78 p.p.m. (m) (2H); Ar-H

Step B: Diphenylmethyl [3-chloro-4,5-bis [(2-methoxyethoxy) methoxy] hydroxyacetate At room temperature under a nitrogen atmosphere

13.95 g of the acid prepared as described in Step A above are dissolved in 150 ml of diethyl ether and 150 ml of a 0.3 M solution of diphenyl diazomethane in dichloromethane are added at 15 ° C. . The resulting mixture was stirred at room temperature for 16 hours and water (30 mL) was added. After decantation and acidification with 30 ml of acetic acid, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, dried, and the solvent was distilled off. The residue was chromatographed on silica gel, eluting with a 99: 1 mixture of dichloromethane and methanol. 10 g of the title compound are obtained. IR spectrum (CHCl3):

3535 cm ^-1 : non-phenolic -OH

1738 cm &^lt; -1 &gt;: is the functional C = O portion of the ester

1600, 1580. 1489 cm ^-1: aromatic nucleus H-NMR (CDC1 _3, 250 MHz, ppm)

3.59 (m) and 3.47 (m) (4H), 3.75 (m) (2H) and 4.04 (m) (2H): O-CH ₂ -CH ₂ -O

3.38, 3.33 and 3.25 (m) (6H): -OCH,

5.02 to 5.30 (m): 0-CH ₂ -0-CH and Ar (C = 0) -0

6.8-7.35 (m): Ar-H

Step C: Diphenylmethyl [3-chloro-4,5-bis [(2-methoxyethoxymethoxy) phenyl] phthalimidoxyacetate

1 g, prepared as described in Step B above

To a solution of the ester A9 in 35 ml of tetrahydrofuran was added 1 g of N-hydroxyphthalimide and 1.54 g of triphenylphosphine, and the resulting reaction mixture was cooled to 10 ° C and then 1.58 g of DEAD was added dropwise. The reaction mixture was stirred for 16 hours and the solvent was evaporated. The residue was purified by chromatography on silica gel (eluent: dichloromethane: methanol = 99: 1). Thus 3.09 g of the title compound as a colorless oil having an _Rf value of 0.3.

IR (CHC1 _3):

1738, 1755 (shoulder) and 1795 cm -1: C = O 1600, 1578, 1488 cm ^-1 : ¹ H-NMR spectrum of the aromatic nucleus (CDCl ₃ , 250 MHz, ppm)

3.34 (s) and 3.36 (s): -OCT / ₃

3.49 (m) (2H), 3.57 (m) (2H), 3.77 (m) (2H) and 4.02 (m) (2H): O-CH ₂ -CH ₂ -Q

5.22 (s) and 5.27 (s): _O-CH2 -O

5.91 (s) and 5.92 (s) ppm: Ar-C (C = O) -O

6.92 (s) ppm: CO-O-Ctf-Ar ₂

7.75 (s) p.p.m .: Ar-H part of phthalimido

7.11 (m) and 7.21-7.33 ppm: the other aromatic hydrogen atoms

Step D: Diphenylmethylamino-oxy [3-chloro-4,5-bisH-2-methoxy-ethoxy] -methoxy] -phenyl] -acetate Under nitrogen atmosphere, 3 g of the compound prepared in Step C above are 40 ml. ethanol solution was cooled to 5 ° C and 0.224 ml of hydrazine hydrate was added. The resulting reaction mixture was kept at 5 ° C for half an hour and then allowed to warm to room temperature over 2 hours. After filtration and solvent evaporation, the title compound as an oil with a _Rf value of 0.3, developed in acetone: hexane 3: 7 as the eluant.

IR (CHC1 _3):

3330 cm ³ : -NH ₂ 1745 cm -1: C = O

1600, 1578, 1488 cm ^-1 : aromatic core + NH _{2 1} H-NMR (CDCl ₃ , 250 MHz, ppm)

3.34 (s) and 3.38 (s): -OC / 7 ₃

3.48 (m), 3.58 (m), 3.76 (m) and 4.02 (m): _{O-CH2 CH2} -0

5.17: Ar-C / 7 (C = O) -0

5.19 (s) and 5.25 (s): -OC // ₂ -O 5.80: mobile NH ₂

6.91 (s): CO-OC // - Ar ₂

7.10 (m) (4H) and 7.21-7.33 (8H): Ar-H

Step E: 7- [3- {7beta - [[[[[1- [3-chloro-4,5-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) -amino] -thiazol-4-yl] acetyl] -2 - [(4-methoxy-benzyloxy ) carbonyl] -8-oxo-5-thia -] - aza-bicyclo [4,2,0] - [oct-2-ene-3-yl) -2-propenyl] thieno [3,2-b] pyridinium iodide

Under nitrogen atmosphere, 0.441 g of D. above.

A mixture of 24 ml of methanol and 145 mg of para-toluenesulfonic acid, prepared in the same manner as in Step 1a, is stirred for 5 minutes and then 0.65 g of

Prepared as described in Reference Example 10

1- [3- [7-beta - [[oxo [2 - [(triphenylmethyl) amino] thiazol4-yl] acetyl] amino] -2 - [(4-methoxybenzyloxy) -carbonyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] [oct-2-en-3-yl] 2-propenyl] -thieno- [2,3, -b] pyridinium iodide solution. The reaction mixture was stirred for 16 hours and the solvent was distilled off. The residue is taken up in diethyl ether and the precipitate is filtered off, washed and dried. to give the title compound 0.730 g, having a melting point of 135 is' C (resin), _Rf 0.3, eluent dichloromethane-methanol 9: 1 as eluent.

Step F: [(±) (Cis) (Z) - 7- [3- [7 - [[(2-Amino-4-thiazolyl) - [[carboxy- (3-chloro-4,5-dihydroxyphenyl) methoxy) ] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia] - azabicyclo [4,2,0-octeno-3-yl] -2 (E) -propenyl] - thieno [2,3-b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof at 0.69 mg, prepared as described in Step E above, in a mixture of 17 ml of dichloromethane and 3 ml of anisole a mixture of trifluoroacetic acid (31 ml) and dichloromethane (8.5 ml) was added and the mixture was stirred at the same temperature for 1 hour. The solvents were then distilled off, and the residue was crystallized, filtered, washed, dried and chromatographed using a 1: 1 by volume mixture of acetonitrile and water. This gives 0.22 g of the title compound of the step and of the example.

1 H NMR (DMSO, 300 MHz, ppm)

3.19: C = C-CH ₂ -S5.01 (d) and 5.07 (d): CO-NH-CH (C = O) -CW (N -) - S 5.12 (s) and δ. , 17 (s): Ατ-CH (CO-O -) - O.5.52 (1): -CH (CH-CH ₂ -N ⁺

5.60: CO-NH-C H (C = O) -CH (N -) - S- (cis / H

6-position)

5.87 (m) -CH = C / 7-CH ₂ -N ⁺ E isomerism

6.78-6.86: -S-CH = (C = N -) - N = C (NH ₂ ) - and Ar-H at the ortho and para position of the chlorine atom

7.21 and 7.41: -HH ₂

7.87 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium, 8.10 (1): hydrogen at the 5-position of thieno [2,3-b] pyridinium, 8.26 (d): hydrogen at the thieno [2,3-b] -b] pyridinium at the 2-position, 9.03 (1): hydrogen at the thieno [2,3-b] pyridinium at the 4-position, 9.23 (1): hydrogen at the thieno [2,3-b] pyridinium 6- 9.74 (d): CO-NH-CH (C = O) CH (N -) - SA as described in Example 4, respectively.

1-12. using the starting compounds prepared as described in the Reference Examples, the following target compounds can be prepared:

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Example 5 [(6R- [3- (E), 6alpha, 7beta (Z))] 7- [3- [7 - [[(2-Amino-4-thiazolyl) - {[carboxy- (3,4-dihydroxy) -5-nitro-phenyl) -methoxy-imino-Pacetyl-J-amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl] -2 ( E) -propenyphtheno [2,3-b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof 1 H-NMR spectrum (DMSO, 300 MHz, ppm)

3.49 to 3.9 (m): C = _C-CH2 -S3,14 (d) and 5.18 (d): CO-NH-CH (C = O) -C77- (N -) - S5.47 (s) and 5.50 (s), 5.60 (s), 5.63 (s): Ar-C77 (CO-O -) - O5.67 (d): -CH = CH- C // ₂ -N ⁺

5.77: -CO-NH-C77 (C = O) CH (N -) - S6.29 (m) -CH = C // - CH ₂ -N ⁺

6.80 (s), 6.83 (s),

76.4 (s) and 7.66 (s): -SC // (C = N -) - N = C (NH ₂ ) 7.42 (d) and 7.47 (d): Ατ-H in nitro para -position

7.1-7.2 (m): C7 / = CH-CH ₂ N ⁺ H, and the Ax-nitro para position

7.89 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium, 8.15 (dd): hydrogen at the 5-position of thieno [2,3b] pyridinium,

8.29 (d): hydrogen at the 2-position of thieno [2,3-b] pyridinium, 9.09 (d): hydrogen at the 4-position of thieno [2,3b] pyridinium, 9.23 (d): hydrogen at the thieno [2.3 -b] pyridinium at position 6, 9.65 (d) and

9.69 (d): CO-N77-CH (C = O) -CH (N -) - S

10.42 (m): mobile hydrogens.

Example 6 1 (±) (cis) (Z) - 7- (3- (7 - ([(2-Amino-4-thiazolyl)) - [carboxy- (3,4-dihydroxy-5-iodophenyl) ) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-azabicyclo [4.2.0] oct-2-en-3-yl] -2 (E) - propenyl] -thiene (2,3bjpyridinium inner salt, mixture of (R) or (S) isomer desirers

Analysis results for C ₃₀ H ₂₃ IN ₆ O ₉ S ₃ +

According to the formula C ₂ HF ₃ O ₂ + 1 APTS:

Calculated: C, 41.78; H, 2.85. N% = 7.5,

S, 11.43; I, 11.3;

Found: C, 46.6; H, 2.8; N, 7.8;

S, 16.0; I, 10.9.

1 H-NMR Spectrum (DMSO, 300 MHz, ppm)

3.70: C = _C-CH2 -S5,11 (s) and 5.17 '(s) (1 H) CO-NH-CH (C = O) CH (N -) - S5.29 ( s) and 5.32 (s): Ar-CW (CO-O -) - O 5.67 (d): -CH = CH-CW ₂ -N ⁺

5.75 (m): CO-NH-C // (C = O) CH (N -) - S6.29 (m): C7 / = CH-CH ₂ -N ⁺ E isomerism

6.77 (resolved) 1H) -S-CW = C (C = N) N = C (NH _2), 6.90 (2H): Ax-H in the ortho and one para-position

7.89 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium. 8.15 (d): hydrogen at the 5-position of thieno [2,3-b] pyridinium, 8.29 (d): hydrogen at the 2-position of thieno [2,3-b] pyridinium, 9.08 (d): hydrogen at the thieno [2,3-b] pyridinium at the 4-position, 9.13 (d): hydrogen at the thieno [2,3-b] pyridinium at the 6-position, 9.37 (sl): CO-NH-CH (C = O); ) CH (N -) - S

Example 7 [(±) (cis) (Z)] 7- [3- [7 - [[(2-Amino-4-thiazolyl) - [[carboxy (3,4,5-trihydroxyphenyl) methoxy] - imino] -acetyl] -amino-2-carboxy-8-oxo-5-thia] - aza-bicyclo [4,2,0] oct-2-en-3-yl] -2 (E) -propenyl-thiene [2,3- inner salt of pyridinium, (R) or (S) isomer or a mixture thereof

1 H NMR (DMSO, 300 MHz, ppm)

5.15 (d) and 5.17 (d) (1H): CX10QH-CH (O = O) -C1 - (N -) - S [2/5 (R / S) 3/5 ]

5.22 (s) and 5.34 (2H): Ar-C77 (C0-O -) - 05,67 (d) -CH = CH-C77 ₂ -N ⁺

5.76 (m), 6.20-6.40 (m): CO-NH-C H (C = O) CH (N -) - S -, C H = CH-CH ₂ -N ⁺ and triphenol Ar-77 6.75, 6.77, 6.87 and 6.90 (1H): -S-CH = C (C = N-) N = C (NH ₂ ) 7.74 ( d): hydrogen at position 5 of thieno [2,3-b] pyridinium, 7.89 (d) and 8.28 (d): hydrogen at position 5 of thieno [2,3-b] pyridinium, 8.29 (d): hydrogen at the 4- and 3-positions of thieno [2,3-b] pyridinium, 8,10-8,27, 9,09 and 9.23: hydrogen at the thieno [2,3-b] pyridinium 2- and 6- position

9.6-9.85: CO-N77-CH (C = O) -CH (N -) - S

Example 8 [(±) (cis) (Z) 7- [3- [7 - [[(2-Amino-4-thiazolyl)] - [[carboxy (2-chloro-3,4-dihydroxyphenyl) ) methoxy] -iminojacetilj anunoj-2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl] -2 (Eppropenil] thieno [2.3b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof

Analysis results for C ₃₀ H ₂₃ IN ₆ O ₉ S ₃ + 2 APTS:

Found: C, 46.8. H, 2.55; N, 8.53.

S, 9.76; Cl, 3.59.

1 H-NMR Spectrum (DMSO, 300 MHz, ppm)

3.5-3.9 (m) C = _C-CH2 -S5,17 (m) (1 H) CO-NH-CH (C = O) -C / 7- (N -) - S5 67 (dl): -CH = CH-C 77 ₂ -N ⁺

5.70-5.90 (2H): CO-NH-C (C = O) -CH (N -) - S- + Hydrogen

6.33 (m): C / 7 = CH-CH ₂ -N ⁺ E isomerism

6.79 (m) and 6.96 (m) (4H): 47 /

7.89 (d) and 8.29 (d): hydrogen at the 2 and 3 positions of thieno [2,3-b] pyridinium, 8.14 (m): hydrogen at the thieno [2,3-b] pyridinium At 5, 9.08 (d): hydrogen at the 4-position of thieno [2,3-b] pyridinium, 9.26 (d): hydrogen at the 6-position of thieno [2,3-b] pyridinium.

Example 9 [6R- (3- (E) halpha, 7beta (Z) j] 7- (3- [7- [1- (2-amino-4-thiazolyl)) ([carboxy (2,5-dichloro-3, 4-Dihydroxyphenyl Pmethoxy j-imino Pacetyl j-amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo- (4,2,0] oct-2-en-3-yl) -2 -propenyl] -thieno [2,3-b] pyridinium inner salt of (R) or (S) isomer or a mixture thereof

1 H NMR (DMSO, 300 MHz, ppm)

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5.20: chlorine at the Ar - / ortho position

5.79: Ar-C // (CO-O -) - O 5.78 (m): -CH = CH-C // _2- N ⁺

6.31: -CH = C 1 - -CH ₂ -N ⁺

7.88: hydrogen at the 3-position of thieno [2,3-b] pyridinium, 8.15 (m): hydrogen at the 5-position of thieno [2,3b] pyridinium, 8.98 (m): hydrogen at the thieno [2, 3-b] pyridinium at the 2-position, 9.08 (d): hydrogen at the thieno [2,3-b] pyridinium at the 4-position, 9.13 (d): hydrogen at the thieno [2,3-b] pyridinium 6 -position.

/ 0th Example 6 [6R- [3- (E) 6alpha, 7beta (Z)]] 7- [3- [7 - [[(2-Amino-4-thiazolyl)] [[carboxy (3-cyano-4,5-dihydroxy) phenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2- propenyl] thieno [2,3-b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof

HPLC (MicroBondapac 100 column, 25 cm) solvent: water / acetonitrile (85/15) retention time: S isomer: 14 min

Isomer R: 18 min 1 H NMR (DMSO, 300 MHz, ppm):

3.19: C = C-CH ₂ -S5.15 (d) and 5.20 (d): CO-NH-CH (C = O) -C (N -) - S 5.40 (s) : Ar-CH (CO-O -) - O5.67 (d): -CH = CH-CH ₂ -N ⁺

5.81: CO-NH-CH (C = O) -CH (N -) - S6.67 (s): -S-CH = C (C = N -) - N = C (NH ₂ ) 7.10- 7.20 (m) (3H): Ar-H and CH =

7.34 (m), 10.27-10.42 (m): mobile hydrogens

7.89 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium. 8.15 (dd): hydrogen at the 5-position of thieno [2,3-b] pyridinium, 8.28 (d): hydrogen at the 2-position of thieno [2,3-b] pyridinium, 9.09 (d): hydrogen at the thieno In the 4-position of [2,3-b] pyridinium. 9.23 (d): hydrogen at the 6-position of thieno [2,3-b] pyridinium.

9.52 (d) and 9.62 (d): CO-N-CH (C =) - CH (N -) -. Example 6 [6R- [3- (E) octyl, 7beta (Z) J] 7-13- [7 - [[(2-amino-4-thiazolyl) [[carboxy- (3,4-dihydroxy-5-methoxyphenyl) (methoxy] -imino] -acelyl] -amino] -2-carboxy-8-oxo-5-thia] -azabicyclo-1,4,2,0] oct-2-en-3-yl) -2-propenyl] thieno [2,3-b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof

(R) - and (S) isomers were separated by HPLC using Microbondapack brand cartridge _C18 column: or using water-acetonitrile 85:15 as eluent.

(S) -isomer 1 H-NMR (DMSO, 300 MHz, ppm):

3.71 (s): Ar-OC // ₃

5.32 (s): CO-NH-CH (C = O) -C // - (N -) - S5.32 (s): Ar-C // (CO-O -) - O5.68 ( d) -CH = CH-C // ₂ -N ⁺

5.79 (dd J = 5 and 7.5): CO-NH-C // (C = O) CH (N -) - S6.29 (m): -CH = C //-CH _2- N ⁺

6.55 (s) (2H): Ar - // at the ortho and para position of -OMe

6.78 (s): -SC // = C (C = N -) - NC (NH ₂ ) 7.11 (d): -C // = CH-CH ₂ -N ⁺

7.29 (m), 8.38 (m), 8.99 (m): mobile hydrogens

7.88 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium, 8.15 (dd): hydrogen at the 5-position of thieno [2,3b] pyridinium, 8.29 (d): hydrogen at the thieno [2,3 -b] pyridinium at the 2-position, 9.08 (d): hydrogen at the thieno [2,3-b] pyridinium at the 4-position, 9.22 (d): hydrogen at the thieno [2,3-b] pyridinium 6- position.

9.55 (d): CO-N //-CH (C = O) -CH (N -) - S (R) -isomer

1 H NMR (DMSO, 300 MHz, ppm):

3.50 (s) (partly masked): C = _C-CH2 -S3,72 (s): Ar-OC // ₃

5.19 (d J = 5): CCL-NH-CH (C = O) -C // - (N -) - S5.32 (s): Ar-C // (CO-O -) - O5 68 (d, J = 6) -CH = CH-C // ₂ -N ⁺

5.76 (dd J = 5 and 7.5): CO-NH-C // (C = O) CH (N -) - S6.29 (m): -CH = C //-CH _2- N ⁺

6.55 (s) and 6.57 (s) (2H): Ar-H at the ortho and para positions of OMe

6.74 (s): -SC // = C (= N -) - N = C (NH ₂ ) 7.15 (d): -C // = CH-CH ₂ -N ⁺

7.30 (m) (2H), 8.39 (s) (1H), 8.96 (s) (1H): mobile hydrogen

7.89 (d): hydrogen at the 3-position of thieno [2,3-b] pyridinium, 8.15 (dd): hydrogen at the 5-position of thieno [2,3b] pyridinium, 8.29 (d): hydrogen at the thieno [2,3 -b] pyridinium at the 2-position, 9.08 (d): hydrogen at the thieno [2,3-b] pyridinium at the 4-position, 9.23 (d): hydrogen at the thieno [2,3-b] pyridinium 6- position.

9.62 (d): CO-N //-CH (C = O> -CH (N -) - S)

Example 12 [6R- [3- (E) 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-amino-4-thiazolyl) [[carboxy (2,5-dichloro-3)] 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt, (R) or (S) isomer or a mixture thereof

Example 13 [6R- [3- (E) -alpha-alpha, 7beta (Z) J] 2- [3- [7 - [[(2-amino-4-thiazolyl) [[carboxy-1,2,5-dichloro-3, 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt, (R) or (S) isomer or a mixture thereof

_Rf value = 0.6, developed in acetone-water 8: 2 as the eluant.

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Example 14 [6R- [3- (E) 6alpha, 7beta (Z)]] 1- [3- [7 - [[(2-Amino-4-thiazolyl) [[carboxy (2,5-dichloro-3)] 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-Propenyl] 4- (methylthio-pyridinium inner salt, (R) or (S) isomer or a mixture thereof

_Rf value = 0.6, developed in acetone-water 8: 2 as the eluant.

Example 15 1 (±) (cis) (Z)] 7- [3- [7 - [[(2-Amino-4-thiazolyl)] - [[carboxy (3-bromo-4,5-dihydroxyphenyl) ) methoxy] imino] acetyl] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl] -2 (E ) -propenyl] -thieno [2,3b] pyridinium inner salt, (R) or (S) isomer or a mixture thereof

Example 16 (6R- (3- (E) 6alpha, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy-4) -fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl -2-propenyl) quinolinium

Step A: Diphenylmethyl 4-fluoro (2,3bis-hydroxy) phenyl] hydroxyacetate

47.7g to a solution of the compound prepared in Reference Example 11 in 500 ml of diethyl ether and cooled to 10 ° C was added 480 ml of a 0.3 M solution of diphenyl diazomethane over 2 hours. then the temperature of the reaction mixture was adjusted to -5 ° C and acetic acid (10 ml) was added. The resulting solution was used in the next step without further treatment.

Step B: Diphenylmethyl [4-fluoro-2,3bis-1- (2-methoxyethoxylmethoxy) phenyl] hydroxyacetals

To the solution obtained in the previous step was added diisopropylethylamine (238 ml) and diethyl ether was replaced with methylene chloride (500 ml). The reaction mixture is then cooled to a temperature between 6 'C and 10' C. and methoxyethoxymethyl chloride (53 mL) was added over 75 minutes. The resulting mixture was stirred for 75 minutes and water (500 mL) was added. After decantation, the organic phase is washed with normal hydrochloric acid solution, then with normal sodium carbonate solution and finally with water, dried and evaporated to dryness. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1: 1). The resulting crude product (26.1 g) was subjected to repeated chromatography on silica gel eluting with a 97: 3 mixture of methylene chloride and acetone. 14.58 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum: CDCl3, 300, p.p.m.

3.34-3.36: C-O-Me groups; 3,52-3,80-3,91:

O-CH ₂ -CH ₂ -O; 4.06 (d J = 6.5): mobile hydrogen; 5.17-5.27 0 ₂ -0-CH groups; 5.49 (d J = 7.5): C ₆ H ₅ -CH-O; 6.84 (dd J = 9 and 10): _H6; 6.96 (dd J = 9 and 6): 7.20-7.40 and 6.94 (sl): aromatics

Step C: Diphenylmethyl [4-fluoro-2,3bis [(2-methoxyethoxy) methoxy] phenyl] phthalimidoxyoxyacetate

The procedure of Example 4, Step C was followed, starting from Step B above

14.42 g of compound. The product is finally purified by chromatography on silica gel, eluting with a 99: 1 mixture of methylene chloride and methanol. 11.89 g of the title compound are obtained.

IR skeptrum: CHC1 ₃

1792-1756-1734 cm ^-1 : C = O, 1600-1492 cm ^-1 : aromatic.

Nuclear Magnetic Resonance Spectrum: CDCl ₃ , 250 MHz, 2 OMEM: 3.30 (s), 3.34 (s): OCH ₃ ; 3.47 (m) -3.84 (m): O-CH ₂ -O; 5.10-5.27: O-CH ₂ O; then 6.30 (s): ArCH (ON =) - CO ₂ -; 6.95 (s): CO ₂ CH (C ₆ H ₅ ) ₂ ; 6.84 (t): H ₅ ; 7.15 (2H> -7.19-7.32 (9H) -7.74 (4H): aromatic hydrogens.

Step D: Diphenylmethylamino-oxy [4-fluoro-2,3bis [(2-methoxy-ethoxy / methoxy] -phenyl] -acetate

At -10 ° C, to a solution of 11.27 g of the compound prepared in Step C above in 112.7 ml of tetrahydrofuran is added 0.88 ml of hydrazine hydrate over 1 hour, and the reaction mixture is stirred at the same temperature for 1.5 hours. stirred. The insoluble material is filtered off and the filtrate is evaporated to dryness. The residue was purified by chromatography on silica gel using a 80:20 by volume mixture of methylene chloride and ethyl acetate as eluent. 4.72 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum: CDCl ,,, 250 MHz:

3.35 (s) - 3.36 (s): OHCH ₃ ; 3.54 (m) (4H) -3.93 (m) (4H): O-CH ₂ -CH ₂ -O; 5.20 (s) -5.27 (s): O-CH ₂ O;

6.78 (dd J = 9.5 and 9): H ₅ ; 6.89 (m): H ₆ ; 573 (s):

Ar-Ctf (ONH ₂ ) -CO ₂ ; 6.94 (s): CO ₂ -Ctf- (C ₆ H ₅ ) ₃ ;

7.10 (m) (2H) - 7.21 (m) (5H): 10 for aromatic H (C ₆ H ₅ ) ₂ groups.

Step E: [[[1- [4-Fluoro-2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino]] -2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid

In the same manner as in Example 1, Step E, 4.65 g of the compound prepared in Step D above and 3.45 g of the oxo-2- (triphenylmethyl) compound described in Belgian Patent Application 864 828 are obtained. amino] -thiazol-4-yl] -acetic acid. Finally, the product was purified by chromatography on silica gel, eluting with a 96: 4 mixture of methylene chloride and methanol. This gave 6.5 of the title compound.

IR spectrum: CHCl

3410 cm @ ^-1 : = C-NH-; 1781 cm ^-1 : C = O; 1618,

1607, 1528. 1496 cm ^-1 : CO ₂ , aromatic and heteroaromatic.

Nuclear Magnetic Resonance Spectrum: DMSO, 300 MHz:

3.18 (s) - 3.21 (s): OCH ₃ ; 3.43 (s) 4H-3.81 (m) 4H:

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O-CH ₂ -CH ₂ -O; 5.17 (s) 2H-5.21 (s) 2H _O-CH2 O; 5.87 (s) 3 / 4H: AlCl ₂ (O-NH ₂ ) -CO ₂ ; 6.68 (s)

3/4 H: H _and thiazole; 6.84 (s) 3 / 3H: CO ₂ CH (C ₆ H ₅ ) ₂ ; about 6.95-7.10: H ₅ , H ₆ ; near 7.18-7.50: other aromas; 8.65 (s, 1): = C-HN.

Step E: 4-Methoxybenzyl 7beta - [[1- [4-fluoro-2,3bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro-1 propenyl] - 8-oxo-5-thia -] - aza-bicyclo [4,2,0] oct-2-ene-2-carboxylate

Following the procedure described in Example 1, Step E but operating at -10 ° C and starting from

6.44 g of the compound prepared as described in Step E above are used. Finally, the product was purified by chromatography on silica gel using a 90:10 by volume mixture of methylene chloride and ethyl acetate as eluent. 5.35 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum: CDCl ₃ , 400 MHz:

3.05 (d, 1H) -3.2 (d IH): _CH2 S; [3.24 (s), 3.26 (s)]

3H-3.35 (s 3H): OCH ₃ ; 3.35 (m, 2H) -3.55 (m,

2H) -3,70-4,15: OCH ₂ CH ₂ O and CH ₂ Cl-CTF, 3.81 (s): // _C? OAr; 4.96 (d) -4.97 (d): H ₆ cephalo; 5,125.31 (6-7H): OCH ₂ O, CO ₂ CH ₂ At, ArCl ₂ (ONH ₂ ) CO ₂ -; 5.81 (m): H ₇ Cephalo; 5.75 (m): CH ₂ = C // CH C1 (Z); 6.26 (d, J = 11) -6.29 (d J = 11):

-C // = CH-CH ₂ -C1 (Z); about 6.77: H ₅ thiazole; close

6.85-7.45: aromatic hydrogens + CO ₂ C H (C ₆ H ₅ ) ₂ ;

7.85-8.20: NH.

Step G: 4-Methoxybenzyl 7beta - [[[1- [4-fluoro-2,3bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) -amino] -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo-propenyl] -8 oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-2-carboxylate

Following the procedure of Example 1, Step G, starting from 1.2 g of the compound prepared in Step E above, 1.05 g of the title compound is obtained.

NMR Spectrum:

3.23 (s) -3.26 (s) -3.35 (s): _CH3 O; near 3.50-3.95:

O-CH ₂ -CH ₂ -O, of which 3.81: CH ₃ OAr; close

4.0: = CH-CH ₂ -I; 4.92 (m): H ₆ cephalo; 5.16 to 5.30:

OCH ₂ O, CO ₂ C // ₂ Ar; 5.50 (m): H ₇ Cephalo; 6.12 (m):

= C // - CH ₂ I (E); 6.42 (s) -6.44 (s): Ar-C H (ONH ₂ ) CO ₂ -; 6.66 (t, J = 9, nearly = 0.5H): aromatic hydrogen at the ortho position of F; 6.76 (s): H ₅ thiazole; 6.77 to 7.45 aromatic hydrogens; 7.95 (d) -8.25 (d): NH.

Step H: 1- [3- [7beta - [[[[[1- [4-Fluoro-2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl)) -methoxy) ethyl] oxy] -imino [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxybenzyloxy) ) carbonyl] -8-oxo-5-thia -] - aza-bicikloj4,2,0] - [oct-2-ene-3-yl] -2-propenyl-quinolinium iodide

The procedure of Example 1, Step H was followed using 1.02 g of the compound prepared in Step G above and 0.46 g of quinoline. The product was finally purified by chromatography on silica gel, eluting with a 97: 3 mixture of methylene chloride and methanol. This gives 347 mg of the title compound as a 50-50% mixture of (R) and (S). Nuclear Magnetic Resonance Spectrum: CDCl ₃ , 400 MHz:

3.20 (s) -3.26 (s) -3.34 (s) -3.35 (s): _CH3 O; 3.79 (s) -3.80 (s): _CH3 Ar; 3.42 (m) -3.54 (m) -3.90 (m):

OCH ₂ CH ₂ O; 4.89 (d): H ₆ cephalo; 5.12-5.28:

OCH ₂ O, CO ₂ C « ₂ Ar; 5.77 (separate dd) H ₇ Cephalo; 6.00 (dd) -6.13 (dd): = CH-C H 2 -N ⁺ =; 6.38 (s> 6.44 (s): Ar-C H - (O-) CO ₂ -; 6.51 (m): = CH-CH ₂ (E); 6.72 (s): H ₅ thiazole; 6.70-7.15: H ₅ H ₆ fluorophenyl; C tf = CH-CH ₂ ; CO ₂ CW (C ₆ H ₅ ) ₂ ; near 7.30: aromatic hydrogens (C ₆ H ₅ ) ₃ -C.

Step 1: (6R- (3- (E) 6alpha, 7beta (Z))) - 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy) 4-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl) quinolinium inner salt

The procedure of Example 1, Step I, was followed using 339 mg of the compound prepared in Step H above and 5 ml of 10% anisole in trifluoroacetic acid to give 180 mg of the step and one example. of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

5.15 (d separated): H ₆ Cephalo; 5.75 (dd) close

5.81 to 5.95; H ₇ cephalo, = CH-C // ₂ N ⁺ =,

Ar-C // (- O-) CO ₂ ; 6.38 (m): CH-C // - _CH2 (E);

6.99 (d, resolved, J = 16): CTF = CH-CH ₂ (E); 6.59 (d, resolved, J = 10): H _s fluorophenyl; 6.75-6.81: H ₆ and H ₅ thiazole; 7.35 (broad): NH ₂ and / or C ₆ H ₅ ; 8.07 (t, 1H), 8.26 (m, 2H), 8.52 (d, 1H), 8.56 (dd, 1H) 9.30 (d, 1H) 9.58 (sl, 1H) ): quinoline; near 10.50: OH; 9.46 (d): CON //.

Example 17 (6R (3- (E) 6alpha, 7beta (Z))) 7- (3- (7- (3- (7 - (((2-Amino-4-thiazolyl))) ((Carboxy- , 3-dihydroxy-4-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2 -en-3-yl) -2-propenyl) -thieno- (2,3-b) -pyridinium Internal salt Step A: 1- [3- [beta] - [[[1-4-fluoro-2 , 3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy} imino] - [2- (triphenylmethyl) amino] -thiazol4-yl] -acetylamino] -2- [4-methoxybenzyloxycarbonyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] - [oct-2 -en-3-yl] -2-propenyl-thieno (2,3-b) -pyridinium iodide In the same manner as in Example 16, Step H, 944 mg of the compound prepared in Example 16, Step G was used. and 0.45 g of thieno- [2,3-b] pyridine to give 339 g of the title compound after chromatography on silica gel, eluting with a 95: 5 mixture of methylene chloride and methanol.

HU 211 871 A9

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

3.20 (s) -3.27 (s) -3.34 (s) -3.35 (s): _OCH3; 3,403,60 and 3.77 to 4.00: _{OCH2 CH2} O, _CH2 S; 3.79 (s) 3.80 (s): ArOCH ₃ ; 4.92 (d, J = 5) -4.99 (d, J = 5): H ₆ cephalo; nearly 5.18 to 5.30; OCH ₂ O, CO ₂ CH ₂ Ar; near 5.77 (m): H ₇ cefalo; 5.68 (m) -5.96 (m): = CH-CH ₂ N ⁺ =; 6.39 (s) -6.45 (s): Ar-C / Y (-O-) CO ₂ ; 6.73 (s) -6.74 (s): H ₅ thiazole; about 6.77 (s): H ₅ fluorophenyl; 6.90-7.40: benzene hydrogens, CO ₂ C H (C ₆ H ₅ ) ₂ , C H = CH-CH ₂ (E); 6.92 (m): CH ₂ = CH-CH (E); 7.54 (d) -7.66 (d): H ₃ and 7.837.87: H ₂ , and 8.06 (m): H ₅ and 8.80 (d): H ₄ , and 10.05 ( m): H ₆ and 8.23 (d) -8.34 (d): CONH group of thieno [2,3-b] pyridine.

Step B: (6R (3 (E) 6alpha, 7beta (Z))) 7- (3- (7- (3- (7 (((2-amino-4-thiazolyl)) - ((carboxy- , 3-dihydroxy-4-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2 Internal salt of -en-3-yl) 2-propenyl) -thieno- (2,3-b) -pyridinium The procedure of Example 16, Step I, was prepared using 332 mg of starting material prepared as described in Step A above. 164 mg of the title compound of this step are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz):

5.18 (d) separated: H ₆ cephalo; 5.67 (d):

= CHC // ₂ N ⁺ =; 5.77-5.90: _H7 cephalo; Ar-CTF (O) CO -; 6.31 (m): CH-CW = _CH2 (E); 7.14 (d, J = 15) C / 7 = CH-CH ₂ (E); about 6.80 (m) H ₅ thiazole, H ₅ fluorophenyl; 7.36 (br): NH ₂ : 6.59 (J = 9); H ₆ ; 7.89 (d. J = 6) -8.15 (dd) -8.28 (d J = 6) -9.08 (d) -9.23 (d): thieno [2.3-b] pyridine H ₃ '- H ₅ '- H ->' H ₄ - H ₆ '/ Example 8 <6R (3- (E) 6alpha, 7beta (Z)) - 1- (3- (7- (3- ( ((2-amino-4-thiazolyl) ((carboxy- (2,3-dihydroxy-4-fluoro-phenyl) -ethoxy) -imino / acetyl / amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo - Internal salt of [4,2,0] oct-2-en-3-yl / 2-propenyl / 4-methylthiopyridinium

Step A:} - [3- [7beta- [1 '] - [4-fluoro-2,3-bis (2-methoxy-ethoxy / methoxy] -phenyl] -2-oxo-2- (diphenylmethoxy) -ethyl ] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl-acetylamino] -2 - [(4-methoxybenzyl-oxycarbonyl] -8-oxo-5-thia -l-azabicyclo [4,2,0] - [oct-2-ene-3-yl] -2-propenyl 4- (methylthio) pyridinium iodide

Example 16 was carried out as in Step H using 1.052 g of the compound prepared in Example 16, Step G and 462 mg of 4-methylthio-pyridine. Purification by chromatography on silica gel using methylene chloride / methanol (95: 5, v / v) gave 536 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz):

6.21 (s): CH ₃ S; 3.21 (s) -3.26 (s) -3.34 (s) -3.35 (s): OCH ₃ ; 3.79 (s) -3.88 (s): _CH3 OAr; 3.43 (m) -3.54 (m) -3,80-4,00 CH ₂ S, _{OCH2 CH2} O; 4.92 (d): H ₆ cephalo; 5.70 (dd) - + 5.77 (dd): H ₇ cephalo; 5.33 (m) 5.54 (m); CH ₂ N =; 5.17 to 5.30: _OCH2 O; CH ₂ CH ₂ Ar;

6.33 (m): _CH2-CH = CTF (E); 6.35 (s): AiCW (-O-) CO ₂ -; 6.74 (s) -6.75 (s): H ₅ thiazole; 6.72-7.16: H ₅ , H ₆ fluorophenyl, CO ₂ C ₆ C ₆ H ₅ , 4H aromatic, CH = CHCH ₂ (E); 7.20-7.38: aromatic hydrogen C 1 -C ₆ H ₅ ) ₃ , (C ₆ H ₅ ) ₂ -CH ₂ -CO ₂ ; 7.61 (d 2H) -8.8 (m, 2H); H ₃ ', H ₅ ' and H ₂ ', H ₆ ' of pyridinium; 7.83 (d), 8.15 (d): -CONH.

Step B (6R (3- (E) 6alpha, 7beta (Z)) / 1- (3- (7- (3 - (((2 amino-4-thiazolyl)) ((carboxy (2,3-dihydroxy) 4-fluorophenyl (methoxy) -imino / acetyl / amino / 2-carboxy-8-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl / 2-propenyl) -4-Methylthiopyridinium Internal salt The procedure described in Example 16, Step I, was carried out using 500 mg of the compound prepared in Step A above to give 251 mg of the title compound and the title compound. of the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz):

3.50-3.70: CH ₂ S; 2.72 (s): CH ₃ S; 5.18 (m): H ₆ cephalo; near = 5.77 (m): H ₇ cephalo; 5.24 (m): _CH-CH2-N ^+; 5.83 (s), 5.87 (s): _OCH2 O, ArCO ₂ CH _2; 6.28 (m): CH-CW = _CH2 (E); 6.98 (d, J = 16): C H -CH-CH ₂ ; 6.61 (t, separate): H ₆ fluorophenyl; 6.77-6.82: H ₅ and H ₆ thiazole; 7.32: NH ₂ ; 7.96 (d) -8.71 (d): H ₃ '-H ₅ ' and H ₂ '-H ₆ ' of pyridinium.

Example 19 (6R (3- (E) 6alpha, 7beta (Z)) / 2- (3- (7 - (((2-amino-4-thiazolyl) ((carboxy- (2,3-dihydroxy-4) inner salt of -fluorophenyl) methoxy / iminoZacetyl / amino Z 2 -carboxy-8-oxo-5-thialaabicyclo [1,4,2,0] oct-2-en-3-yl / 2-propenyl) isoquinolinium

Step A: 1- (3- [7beta - [[[([1- [4-Fluoro-2,3bis [(2-methoxyethoxy) methoxy] phenyl) -2-oxo-2- (diphenylmethoxy) ) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl] acetylamino] -2- (4-methoxybenzyl-oxycarbonyl] -8-oxo -5-Thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] -isoquinolinium iodide

Example 16, Step H using 917 mg and 416 mg of isoquinoline from the compound prepared in Example 16, Step G as starting material. Purification by chromatography on silica gel (eluent: methylene chloride: methanol = 96: 4) gave the title compound (473 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

3.20 (s) -3.26 (s) -3.34 (s) -3.35 (s): _CH3 O; 3.76 (s) -3.78 (s). ArOCH ₃ ; 3.40-4.00: OCH ₂ -CH ₂ ) O, CH ₂ S; H ₆ cephalo; 5.80 (m); H ₇ cephalo; near 5,185.30: OCH ₂ O, ArCO ₂ CH ₂ ; about 6.48 (m): CH ₂ CH = (E); 6.38 (s) -6.44 (s): Ar-C 7 (-O-) CO ₂ -;

6.73 (s) -6.75 (s): H ₅ thiazole; near = 6.76 - 7.40: aromatic hydrogens (phenyl groups),

CO ₂ C / 7 (C ₆ H ₅ ) ₂ ; 7.96 (m, 1H) -8.10 (m, 2H) -8.26 (m, 2H) -8.49 (m, 1H) -8.69 (m, 1H) -10.90 ( separated s, 1H): isoquinoline.

HU 211 871 A9

Step B: (6R (3- (E) octyl, 7beta (Z))) - 2- (3- (7 - (((2 amino-4-thiazolyl)) - ((carboxy (2,3-dihydroxy) 4-fluorophenyl) -methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl) isoquinolinium inner salt

The procedure of Example 16, Step I, was followed using 460 mg of the compound prepared in Step A, above, to give 176 mg of the title compound and 176 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz):

3.72: CH ₂ X; 5.18 (separated d): H ₆ cephalo; 5.77 (dd, d exchange) - H ₇ Cephalo; CH ₂ -N ⁺ =;

5.83 (s), 5.87 (s): Ar ₂ // C (O) CO ₂ -; CH = C77CH ₂ (ΔΕ); 7.10 (d, J = 10), C77-CH = CH ₂ (E), 6.59 (m), 6.80 (m): _{H6, H5} fluorophenyl; 6.77-6.80: H ₅ -azole; 8.09 (0-8.28 (t) and 8.37 (d) -8.53 (d) -8.61 (d) -8.74 (m) -10.06 (s): isoquinoline H ₆ '-H ₇ ' and H _? '-H ₄ ' and H ₅ and H _g and H 1.

Example 20 (6R (3- (E) octyl, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) - ((carboxy- (2,3-dihydroxy) -4-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia] azabicyclo [4,2,0] oct-2-ene 3-yl) -2-propenyl) imidazo [1,2-a] pyridinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [4-Fluoro-2,3bis [(2-meroxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl] acetyl] -2 - [(4-methoxy-benzyl-8-oxo-oxikarbonilJ 5-thia -] - aza-bicyclo [4,2,0] - [oct-2-ene-3-yl] -2-propenyl] imidazo (l, 2-a) pyridinium iodide

Example 16, Step H using 955 mg and 401 mg of imidazo [1,2-a] pyridine from the compound prepared in Example 16, Step G as starting material. Purification by chromatography on silica gel (eluent: methylene chloride: methanol = 95: 5) gave the title compound (486 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

3.20 (s) -3.26 (s) -3.34 (s) -3.35 (s): _CH3 O; 3,403.95: OCH ₂ CH ₂ O, CH ₂ S; 4.89 (d): H ₆ cephalo; 5.74 (m): H ₇ Cephalo;

5.20 to 5.42 (9H, excess) ArCO ₂ C // ₂ OCH ₂ O, CH-C _7/2 ⁺ -N =; 6.28 (m): = C ₁ --CH ₂ (E); 6.38 (s) -6.44 (s): Ar-C 7 / (- O-) CO ₂ -; 6.88 (s) -6.90 (s):

CO ₂ C 7 / (C ₆ H ₅ ) ₂ ; nearly 6.75 to 7.35: aromatic hydrogens (phenyl groups) and hydrogens of a nitrogen-containing bicyclic ring; 7.85 (m, 1H) -8, O3 (d, 1H) -8.36 (d, 1H) 9.09 m, 1H); additional hydrogen atoms of the nitrogen-containing bicyclic ring; 7.94 (d), 8.25 (d): CONH.

Step B: (6R (3- (E) octyl, 7beta (Z))) - 1- (3- (7 - (((2 amino-4-thiazolyl)) - ((carboxy (2,3-dihydroxy) 4-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) Internal salt of -2-propenyl) imidazo (1,2-a) pyridinium

The procedure of Example 16, Step I, was followed using 476 mg of the compound prepared in Step A above to give 215 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz):

3.70 (m): _CH2 S; 5.15 (separated d): H ₆ cephalo; 5.74 (dd, d exchange) -5.82 (dd, d exchange): H ₇ cephalo; 5.28 (m): CH ₂ -N ⁺ =; 5.83 (s), 5.86 (s): Al-CH (-O-) CO ₂ -; 5.25 (m): CH-C // - _CH2 (E); 6.89 (d, resolved, J = 15.5): C // ~ CH = _CH2 (E); 6.60 (m), 6.78 (m): H ₅ , H ₆ fluorophenyl; 6.76 (s) -6.80 (s): H ₅ azole; 7.57 (m) -9.05 (m) -8.19 (m) and 8.28 (separated d, J = 2.5) -8.44 (separated d, J = 2.5) -8 , 96 (d, J = 6.5): H ₅ '-H ₆ ' -H ₇ '-H ₄ ' and H ₂ ', H ₃ ' of imidazo (1,2-a) pyridinium, 944 ( d) -9.56 (d): COHN-C; 7.32 (m) -9.40 (m): mobile hydrogens.

Example 27 (6R (3- (E) 6alpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) - ((carboxy- (2,3-dihydroxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl Internal salt of -2-propenyl) -4- (methylthio) pyridinium

Step A: Ethyl [(2,3-dihydroxy) phenyl] -hydroxyacetate

To a solution of 1.1 g of pyrocatechin in 20 ml of methylene chloride cooled to -20 ° C is added 10 ml of a 1M solution of titanium chloride in methylene chloride and the resulting mixture is stirred at the same temperature for 30 minutes. A solution of 1.02 g of ethyl glyoxylate in 10 ml of methylene chloride is then added over 5 minutes. After the addition was complete, the reaction mixture was stirred at -20 ° C for a further 2 hours and then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and the resulting aqueous mixture was extracted several times with methylene chloride. The combined extracts were washed, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: methylene chloride / ethyl acetate = 7: 3). This gave 860 mg of the title compound, mp 86 'C.

IR spectrum: CHCl ₃

3595 cm- ¹ , 3040 cm- ¹ , complex and associate, 1730 cm- ¹ = C = O, 1602-1402 cm- ¹ : aromatic.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz):

5.33 (s): C-C77 (OH) COOEt ·, 1.26 (0-4.27 (m):

COOEt; 3.75-5.86-7.45: mobile hydrogens; 6,76,95: aromatic hydrogens.

Step B: Methyl [2,3-bis - [(2-methoxyethoxy) phenyl] hydroxyacetate

To a solution of 8.1 g of the compound prepared in Step A above in 750 ml of acetonitrile is added 15.69 g of methoxyethoxymethyl chloride and

N-ethyldiisopropylamine (16.35 g) was added and the resulting mixture was stirred at 0 ° C for 16 h and then poured into water (100 mL). The acetonitrile is then distilled off and the residue is taken up in methylene chloride

HU 211 871 A9. The resulting solution was washed with 1 N hydrochloric acid, water and finally 10% aqueous sodium carbonate solution, dried and evaporated to dryness under reduced pressure. The crude product (12.3 g) was purified by chromatography on silica gel (eluent: cyclohexane: ethyl acetate = 5: 5). 6.7 g of the title compound are obtained.

IR spectrum: CHCl 3

3315-3440 cm ^-1 , OH complex; 1735 cm ^-1 : C = O;

1601-1590 cm ^-1 : aromatic.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz):

1.21 and 4.22: CO ₂ Et; 3.37: OCH ₃ ; 3,57-3,83-3,93:

CH ₂ -CH ₂ -O; 5.25-5.28: O-CH ₂ -O; 4.07: OH;

5.39: C-CH (OH) -CO ₂ Et.

Step C: Diphenylmethyl [2,3-bis-1- (2-methoxyethoxy-methoxy] -phenyl] -hydroxyacetate

a) Saponification

To a solution of the compound prepared as described in Step B above, in acetone (8.54 g, 4000 mL) was added 2N aqueous sodium carbonate (22 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH 2 with N hydrochloric acid, the volume was reduced to half under reduced pressure, the concentrate was diluted with water (200 mL) and the aqueous mixture was extracted with methylene chloride and ethyl acetate. The combined extracts were dried and evaporated to dryness under reduced pressure. 8.2 g of [2,3bis - [(2-methoxyethoxy) methoxy] phenyl] hydroxyacetic acid are thus obtained.

b) Esterification

To a solution of 9.2 g of the acid prepared in step a) above in 300 ml of methylene chloride, cooled to 0 ° C, is added 109 ml of a 0.3 M solution of diphenyl diazomethane in diethyl ether and the resulting mixture is stirred at room temperature. and stirred at room temperature for 16 hours. The reaction mixture is then cooled to 0 'C. followed by the addition of acetic acid. The reaction mixture is evaporated to dryness under reduced pressure and the crude product is purified by chromatography on silica gel using a 6: 4 by volume mixture of cyclohexane and ethyl acetate as eluent. 10.2 g of the title compound are obtained.

IR spectrum: CHCl ₃

3350-3520 cm ^-1 : OH complex; 1742 cm ^-1 : C = O;

1600-1585-1495 cm ' ¹ : aromatic.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

3.34-3.37: CH ₃ ; 3.54-3.83: O-CH ₂ -CH ₂ ; 4.08:

OH; 5.18-5.28: _OCH2 O; 5.53: C-CH (OH) C (C ₆ H ₅ ) ₂ .

Step D: Diphenylmethyl [2,3-bis-1- (2-methoxyethoxy-methoxy-1-phenyl-phthalimidoxy-acetate)

To a solution of 227 mg of the compound prepared in Step C above in 25 ml of tetrahydrofuran was added 226 mg of triphenylphosphine and 77 mg of N-hydroxyphthalimide at room temperature, the reaction mixture was cooled to -5 ° C and added over 2 hours. 136 μΐ (150 mg) of diethyl azodicarboxylate. The reaction mixture was then stirred for 2 hours and then allowed to warm to room temperature. The reaction mixture was poured into ice-cold water (25 mL) and the aqueous mixture was extracted with methylene chloride first, then ethyl acetate. The combined extracts were dried and evaporated to dryness under reduced pressure. The crude product (760 mg) was purified by chromatography on silica gel (eluent: methylene chloride: acetone = 97: 3, v / v). This gave 230 mg of the title compound.

IR spectrum: CHCl ₃

1794-1738 cm ^-1 : C = O; 1602-1588-1488 cm ' ¹ : aromatic.

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz):

3.31-3.36: CH ₃ ; 3.46-3.52-3.79-3.89: CH ₂ -CH ₂ O; 5.24: O-CH ₂ -O; 6.43: C-Ctf (ON =) CO ₂ C-;

6.95: CH- (C ₆ H ₅ ) ₂ ; 7.72: Ατ-Η phthalimido; 7.0-7.35: aromatic Ar-H.

Step E: Diphenylmethylamine oxy [2,3-bis - [(2-methoxyethoxymethoxy) phenyl] acetate

To a solution of the compound prepared as described above in Step D in a mixture of 6.2 g of 400 ml of ethanol in 20 ml of methylene chloride is added 1.42 ml (1.47 g) of hydrazine hydrate and the resulting mixture is stirred at room temperature for 3 hours. . The reaction mixture was evaporated to dryness under reduced pressure and the residue was taken up in methylene chloride. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. 5.0 g of the title compound are obtained.

IR spectrum: CHCl ₃

3335 cm ^-1 : ONH ₂ ; 1745 cm ^-1 : C = O; aromatics

1602, 1589, 1577, 1495 cm ^-1 : aromatic.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz):

3.35-3.37: OCH ₃ ; 3.54-3.83-3.95: O-CH ₂ -CH ₂ O; 5.26-5.29: O-CH ₂ -O; 5.75: -CCH (ONH ₂ ) CO ₂ C- (C ₆ H 5) ₂ ; 5.86: O-NH ₂ ; 6.95:

COO-C // (C ₆ H ₅ ) ₂ .

F. [[[N- [2,3-bis - [(methoxyethoxy-methoxy-phenyl) -2-oxo-2- (diphenylmethoxy) -ethyl] -oxy] -imino] - [2- (triphenylmethyl) -amino] thiazol-4-yl] acetic acid

From the compound prepared as described in Step E above, 5.0 g and 4.016 g of compound 864 828 are obtained. A mixture of [2 - [(triphenylmethyl) amino] thiazo-4-yl] acetic acid, prepared as described in Belgian Patent Application, was stirred in methanol (60 mL) for 6 hours and then evaporated to dryness. The residue was purified by chromatography on silica gel using a 7: 3 by volume mixture of ethyl acetate and ethanol as eluent. 5.55 g of the title compound are obtained.

IR: CHC1 ₃ = NH-C: 3405 ^cm-1; C = 1735 cm <^-1>; C = N, aromatic and CO ₂ : 1619-1602-1529-1494 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz):

3.13-3.31: CH ₃ ; 3.34-3.49-3.76: O-CH ₂ -CH ₂ -O;

HU 211 871 A9

5.14 to 5.18: O-CH ₂ -O; 6.11: -C-CH (ON =) CO ₂ C-;

6.46: -CO ₂ -CH (C ₆ H ₅ ) ₂ ; 6.81: CH thiazole; 6.72-7.3 aromatic hydrogens.

Step G: 4-Methoxybenzyl 7beta - [[[[[]] - [2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro] pmpenyl] -8-oxo -5-thia -} - azabicyclo [4,2,0] oct-2-ene-2-carboxylate

To a cooled solution of 6.18 g of the compound prepared in Step F above in 150 ml of methylene chloride at 0 ° C is added 3.55 g of 4-methoxybenzyl 7-beta-amino, prepared as described in EP 333 154. 3 - [(Z) -3-chloro-1-propenyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylate hydrochloride and 1.6 g of N-ethyl- dimethylaminopropylcarbodiimide (abbreviated as EDAC) and the resulting reaction mixture was stirred at the same temperature for 10 minutes and then allowed to warm to 20 ° C over 2 hours. The reaction mixture was poured into a 1M aqueous potassium hydrogen phosphate solution, and the resulting mixture was extracted first with methylene chloride and then with ethyl acetate. The combined extracts were dried and evaporated to dryness. The residue was purified by chromatography on silica gel using a 9: 1 by volume mixture of methylene chloride and ethyl acetate as eluent. 5.1 g of the title compound are obtained.

IR spectrum: CHCl ₃

3404 cm ^-1 : = C-NH; 1790-1731-1684 cm -1: C = O; aromatics, heteroatom, amide II: 1613-1587-15261517-1496 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz):

3.24-3.37: CH ₂ -O-CH ₃ and CS-CH ₂ ; 3.44-4.0: CH 2 Cl 2 and C ₆ H ₅ OCH ₃ ; 3.44-4.0: O-CH ₂ -CH ₂ -; 5,155,28: _-O-CH2 -O; From 5.67 to 5.88, 6.29 _C-CH-CH2 C1; CH thiazole; 6.7-7.4: aromatic; 8.01-8.37: NH.

Step H: 4-Methoxybenzyl 7beta - [[[[[1- [2,3bis [(2-methoxyethoxymethoxy) phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] -] oxy] imino] - [2 - [(triphenylmethyl) aminolthiazol-4-yl]

0.57 g of sodium iodide and a single iodine crystal are added and the resulting reaction mixture is stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was taken up in methylene chloride. The resulting solution was washed with 10% aqueous sodium thiosulfate solution, then water, dried and evaporated under reduced pressure. 1.28 g of the title compound are obtained, which product is used in the next step without further purification.

Step I: 1- [3- [7beta - [[[[[1-14,4-2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy)] -ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] -thiazol-4-yljacetyl] amino] -2- [4-methoxybenzyloxycarbonyl] -8-oxo-5- thia - / - azabicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] -4-methylthio-pyridinium iodide

1.28 g of the compound prepared as described above in Step H are mixed with 1.15 g of thiomethylpyridine and 3 ml of methylene chloride, and the resulting mixture is evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (eluent: methylene chloride: methanol = 97: 3, then 96: 4 and finally 95: 5). 415 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz):

2.6: _S-CH3; 3.21-3.25-3.35-3.36-3.37: -O-CH ₃ ;

3.4-3.9: O-CH ₂ -CH ₂ -O; 3.77-3.79: C ₆ H ₅ OCH ₃ .

Step J: (6R (3- (E) 6alpha, 7beta (Z))) -1- (3- (7 - (((2 amino-4-thiazolyl)) - ((carboxy (2,3-dihydroxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2- pmpenyl) 4- (methylthio) pyridinium inner salt

A mixture of the compound prepared in Step I above, 400 mg, 4.5 ml trifluoroacetic acid and 0.5 ml anisole was stirred at room temperature for 2 hours, then water (0.5 ml) was added and stirring was continued at room temperature for 2 hours. The reaction mixture is filtered, rinsed twice with 3 ml of trifluoroacetic acid and finally 15 ml of diethyl ether are added. After stirring for 15 minutes, the precipitate formed is filtered off and dried under reduced pressure. This gave 22 mg of the title compound of the step and of the example.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz) ppm

2.71: SCH ₃ ; 3.72 _CS-CH2-C; 5,19-5.76-5,83:

_S-C // - (- N =) - C // - NH ~; 5.22: -C = C-CH ₂ N ⁺ ;

5.91-5.95: H iminocarboxybenzyl; 6.28:

-CH = C 1 - -CH ₂ -N- ⁺ ; 6.98: -Cr 1 = CH-CH ₂ -N-r ₁

6.59-6.79: aromatic hydrogens; 6.79-6.83: H thiazole;

9.49: NH.

Example 22 (6R- (3- (E), heptal, 7beta (Z))) 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxyphenyl) ) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia -] - azabicyclo [4,2,0] oct-2-en-3-yl) -2-pnopenil ) -thieneo (2,3bj-pyridinium inner salt;

Step A: J- [3- [7beta - [[[[[1- [2,3bis [(2-methoxyethoxymethoxy) phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino] - [2- (triphenylmethyl-amino) - [2 - [(triphenylmethyl) -amino] -thiazol-4-yl] -acetylamino] -2 - [(4-methoxybenzyloxycarbonyl) - 8-Oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] -thieno- (2,3b) pyridinium iodide

In the same manner as in Example 21, Step I, starting from 1.24 g of the compound prepared in Example 21, Step H and

Using 1.28 g of thieno [2,3-b] pyridine. Purification by silica gel chromatography (eluent: methylene chloride: methanol = 97: 3, 96: 4, and finally 95: 5) gave 450 mg of the title compound.

IR: CHC1 ₃ = NH-C: 3404 ^cm-1; C = O: 1790-1731-1684 cm -1;

C = C: aromatics, heteroatoms, and amide Π: 1613—

HU 211 871 A9

1587-1526-1517-1496 cm- ¹ : thieno-pyridine: 1599 cm- ¹ .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.21-3.26-3.34-3.37: CH ₂ -O-CH ₃ ; 3.43-3.533.82: O-CH ₂ -OC / 7 ₂ -CH ₂ ; 3.80: C ₆ H ₅ O-CH ₃ ;

5.2-5.3: O-CH ₂ -O-CH ₂ -, CO ₂ -C ₂ C ₆ H ₅ -O-;

5.90: _CH2-CH-N ^+; 6.45-6.6: C-CW = CH-CH2N ⁺ ; 6.51-6.56: CO2-C H (C ₆ H ₅ ) ₂ ; 6.73: H thiazole;

6.85-8.78: aromatic hydrogens.

Step B: (6R- (3- (E), halpha, 7beta (Z))) 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0} oct-2-en-3-yl) -2- propenyl) thieno (2,3-b) pyridinium inner salt;

The procedure of Example 21, Step J was followed using 430 mg of the compound prepared in Step A above. This gives 206 mg of the title compound of the step and of the title compound.

IR spectrum: nujol

C = O: 1775 cm- ¹ (beta-lactam) 1670 cm- ¹ (complex); conjugated system, aromatic. NH ₂ , amide: 1599-1580-1520 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3.69: -SC / AC-: 5.18-5.78-5.86: -NH-CH-CHS-; 5.67: = CH-CH _; -N ⁺ ; 5.91 to 5.95:

-C-CH (ON =) CO ₂ H-; 6.31 and 7.15: hydrogens of propylene; 6.59 and 6.79: aromatic hydrogens; 6.78 and 6.82: thiazole hydrogen; 7.89-9.22: thienopyridine: 9.49 and 9.61: amide.

Example 23 (6R- (3- (E) -alpha, 7beta (Z))) 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxyphenyl) ) -methoxy) imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia -) - azabicyclo-14.2.0 oct-2-en-3-yl) -2-propenyl) -imidazo (f) , 2-a) pyridinium inner salt;

Step A: 1- (3- [7beta - [[[[[1- [2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl)] oxyimino] - [2- (triphenylmethyl) amino] -thiazol-4-yl] -ethylamino] -2 - [(4-methoxybenzyloxycarbonyl] -8-oxo-5-thia] - azabicyclo [4.2.0] - [oct-2-ene-3-yl-2-propenyl] imidazole (1,2-a) pyridinium iodide

In the same manner as in Example 21, Step I, starting from 1.24 g of the compound prepared in Example 21, Step H and

1.28 g imidazopyridine. 270 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3.25-3.20-3.35-3.37: CH ₂ OCH ₃ ; 3.30-3.90:

OCH ₂ -C ₂ -OCH ₃ ; 3.30-3.90: -S-Ctf ₂ -C-; 3,783.79: -C ₆ H ₁ -OCH ₃ ; 4.88 and 5.72 NH-Ctf-Ctf-S;

5.10 - 5.50: C-O-CH ₂ -OCH ₂ -, = C-Ctf ₂ -N ⁺ ; 6.28:

C-CH = CW-CH ₂ -; 6.51-6.56: 1H-C-CH (O = N) CO ₂ CH; 6.7-7.4: aromatic hydrogen, thiazole hydrogen, propylene hydrogen; 7.93-8.20: NH.

Step B: (6R- (3- (E), halpha, 7beta (Z))) 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2- propenyl) imidazofo 1,2-a) -pyridinium inner salt The procedure described in Example 21, Step J was carried out using 280 mg of the compound prepared in Step A above as the starting material, giving 140 mg of the compound the title compound of the example is obtained.

IR: CHC1 ₃ = CO: 1775-1670 ^cm-1; conjugated system, aromatic amide II: 1598-1530-1510 cm- ¹ .

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.45 to 4.20: _-S-CH2 -; 5.16-5.76-5.82: -NH-CWCH-S; 5.29: _CH2-N ⁺ ~; 5.91-5.94: C-CH (-ON =) CO ₂ H: 6.26: 1H propylene; 6.58-6.70-6.95: H thiazole, aromatic, 1H propylene; 9.47-9.58: NH; 7,488.06-8.20-9.86-8.29-8.44: bicycle.

Example 24 (6R- (3- (E), heptal, 7beta (Z))) 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxyphenyl) ) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo-14,2,0] oct-2-en-3-yl) -2-propenyl) inner salt of -imidazo (J, 2-a) quinolinium;

Step A:} -1,3- [7beta - [[[[[]] - [2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy -imino] -1- (triphenylmethyl) amino] -thiazol-4-yl] acetylaminol-2 - [(4-methoxybenzyloxycarbonyl) -8-oxo-5-thia-J-aza bicyclo [4,2,0] - [oct-2-en-3-yl 2propenilj-quinolinium iodide

Example 21 was carried out as described in Step I, starting with 1.33 g and 1.2 g of quinoline from the compound prepared in Example 21, Step H. Purification by chromatography on silica gel, eluting with methylene chloride / methanol (97: 3 then 95: 5) gave the title compound.

NMR spectrum

3.42-3.95: OCH ₂ -CH ₂ -OCH ₃ ; 3.78-3.79: -C ₆ H ₄ OCH _3; 5.13-5.28: -OCtf ₂ -O-CH ₂ ; CH = C (= ON); 5.96 to 6.11: _CH2-N ^+; 6,49'-6.55: CW ₂ CO _2, (C _{6 H?)} 6.85-8.93: aromas.

Step B (6R- (3- (E), halpha. 7beta (Z))) 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy (2,3-dihydroxyphenyl) ) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia -] - aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl ) imidazof J, 2-a) inner salt of quinolinium

Example 21 was carried out as described in Step J, starting from 465 mg of the compound prepared in Step A above, to give 225 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO 300 MHz)

3.3-3.8: -SCH ₂ -; 5.15 and 5.78: -NH-CW-CW-S-;

5.91: -C-CW (ON =) CO ₂ H and CH ₂ -N ⁺ -; 6.39: = CCH = CW-; 6.99: = CC - CH -; 6.7-6.9: aromatic hydrogens; 8.07-9.58: bicyclic hydrogen.

HU 211 871 A9

Example 25 (6R- (3- (E), 6alpha, 7beta (Z))) 7- (3- (7 - (((2-Amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3) , dihidmxi 4-chlorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- il) -2-propenyl) inner salt of N, N-dimethyl] -benzolaminium;

Step A: [{[1- [2,5-Dichloro-3,4-bis -] (2-methoxy-ethoxy) -methoxy] -phenyl] -2-oxo-2- (diphenylmethoxy) -ethyl] oxy] imino] - [2 - [(triphenylmethylamino) -thiazol-4-yl] acetic acid

The procedure of Example 1, Step E was followed. Starting with 3.5 g of [2,6-dichloro-3,4-bis [(2-methoxyethoxy) phenyl] acetate, which was prepared as described in Example 9, Step E, and 2.37 g of compound 864 828. can be prepared using oxo [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid as described in Belgian Patent Application. Purification by chromatography on silica gel (ethyl acetate: ethanol = 9: 1) gave 5.14 g of the title compound.

Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl ₃ )

3.30 (s): OCH ₃ ; 3.51-3.92 (m): -O-CH ₂ -CH ₂ OCH ₃ ; 5.16 (s, 5.18 (s): O-CH ₂ O, 6.25. C H CO-CH-gh _H6; 7.20-7.30: aromatic hydrocarbons.

fi. Step 4: 4-Methoxybenzyl 7beta [[[[[] - [2,5-dichloro-3,4-bis [(2-methoxy-ethoxy] -methoxy] -phenyl] -2-oxo-2 (diphenylmethoxy) ) ethyl] oxy] imino] - [2 - [(triphenylmethyl) -amino] -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro-l-propenyl] -8-oxo-5-thia -] - aza-bicyclo [4,2,0] oct-2-ene-2-carboxylate

In the same manner as in Example 1, Step F, 4.8 g of the compound prepared in Step A above and 2.26 g of the 4-methoxybenzyl 7beta obtainable are described in EP 333154. using amino - [(Z) -3-chloro-1-propenyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct2-ene-2-carboxylate hydrochloride. Purification by silica gel chromatography (eluent: methylene chloride: diethyl ether = 9: 1) gave 4.6 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.05 (m) -3.45 (m): -CH ₂ -Cl; 3.36-3.37 (s): -OCH ₃ ; 3.57 (m) -3.97 (m): O-Ctf ₂ -C ₂ -O-; 3.81 (s,

d) -O-OC / 7; 4.99-5.02 (d): NH-CH-CH-S; 5.86-5.90: NH-C / Y-CH-S; 5.15-5.26: OC // ₂ -O-; -5.75 (m): propylene H ₂ ; 6.26 (J = 11.5) (d) -6.35 (H = 11.5) (d): H, propylene; 6.47-6.50 (s): CO ₂ CHO _2; 6.85-7.40: aromatic hydrogens.

Step C: 4-Methoxy-benzyl-7-beta [[[{[1- [2,5-dichloro-3,4-bis [(2-methoxy-ethoxy) -methoxy] -phenyl] -2-oxo-2 (diphenyl) -methoxypethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo] propenyl] -8 oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-2-carboxylate

The procedure of Example 1, Step G, was followed using 150 mg of the compound prepared in Step A above.

160 mg of the title compound are obtained.

Step D:] - [3-7beta [[[[[N- [2,5-dichloro-3,4-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxybenzyl) oxy) carbonyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-3-yl] -2-propenyl] -N, N-dimethylbenzolaminium iodide

The procedure of Example 1, Step H was followed using 15 mg of the compound prepared in Step C above and 64 mg of N, N-dimethylaniline as starting material. Purification by chromatography on silica gel using methylene chloride / methanol (96: 4, v / v) as the eluent gave 55 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

CHi /

2.95 (s): N ⁺ ;

\

CW ₃

3.30-3.45: _CH2-S ~; 3.35-3.36-3.37 (s): O-CH ₃ ;

3.82 (s, d): O-OCH ₃ ; 3.90-4.05: -O-CH ₂ -CH ₂ -O-:

= CC / 7 ₂ -N (CH ₃ ) ₂ O; 4.49 (d) -4.98 (d): NH-CtfCH-S; 5.87 (m): NH-CH-CW-S; 5.18 - 5.30 (m):

O-CH ₂ -O and O-CW ₃ -O; 6.14 (m) (E): C-CH = C / CH ₂ -; 6.70-7.40 (m) C-CTF-CH-CH ₂ -, H thiazole, aromatic hydrocarbons; 8.17-8.25 (d): NH.

Step E: (6R- (3- (E), 6alpha, 7beta (Z))) 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,5-dichloro) 3,4-dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2- Internal salt of en-3-yl) -2-propenyl) -N, N-dimethyl] -benzolaminium The procedure of Example 1, Step I was followed. starting from 50 mg of the compound prepared as described in Step D above. This gave 22 mg of the title compound of the step and of the example.

Example 26 (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3) , 4-dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-J-azabicyclo [4,2,0] oct-2-en-3-yl) -2-pmpenyl) imidazo (1,2-a) -pyridinium inner salt

Step A: 1- [3- [7beta - [[[[[]] - [2,5-dichloro-3,4-bis - [(2-methoxyethoxy-pmethoxy) -phenyl] -2-oxo-2- (diphenyl) methoxy) ethylhydroxyimino] - [2- (triphenylmethyl) amino] -thiazol-4-yl] acetylamino] -2 - {(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia- l-azabicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl-imidazo (l, 2-a) pyridinium iodide

Example 1, Step H was prepared using 1.24 g and 0.497 g of imidazo [1,2-a] pyridine from the compound prepared in Example 25, Step C as starting material. After purification by chromatography on silica gel, eluting with a 95: 5 by volume mixture of methylene chloride and methanol.

Using 629 mg of the title compound, the title compound was obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3.34-3.36: -CH ₂ -OC ₃ ; 3.50 to 5.87: O-CTF ₂ CTF ₂ OMe; 3.80 (s): -φ-OCH ,; 4.94 (d, d): -NHCH-CH-S-; 5.20-5.24: O-CH ₂ -O, CO ₂ -CW ₂ -OH-; 5.86: NH-CH-CH-S; 6.15-6.35: H propylene; 6,476,51: = N-O-CH-; 6.77: H thiazole; 6.90-7.40: aromatic hydrogens; 7.88-8.04: hydrogen atom of imidazole; 7.88: -NH-CO.

Step B: (6R- (3- (E), heptane, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,5-dichloro) 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene Internal salt of 3-yl) -2-propenyl) imidazo (1,2-a) -pyridinium The procedure of Example 1, Step I was followed, starting from the compound prepared in Step A above. 327 g of the title compound of this step are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz)

3.50-3.75: -S-CW ₂ -C =; 5.16: -NH-CH-CH-S-;

5.79 (m): -NH-CH-CH-S-; 6.24 (m): = -CCH = CH-C-; 6.91 (dd): = C-CH-CH-C-; 6.83 (dd): H thiazole: 7.58-8.06 (t) and 8.21-8.96 (d): H pyridine; 8.29-8.45: H imidazole; 9.62: NH: 9.96: HN, COiH:

Example 27 (6R-) 3-E), 6alpha, 7beta (Z)) 1- (3- (7 - (((2-Amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl) 6,7-dihydro-5-H-pyridinium inner salt

Step A: 1- [3- [7beta - [[[[[l-1,2,5-dichloro-3,4-bis (2-methoxyethoxy) methoxy) phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxyimino) - {2- (triphenylmethyl) -aminojtiazol-4-yl] acetyl] -2 - [(4-methoxy-benzyloxy) carbonyl] -8- oxo-5-thia-l-aza-biciklol4,2,0] - [oct-2-ene-3-yl] -2-propenyl-6,7-dihydro-5H-pyridinium iodide

The procedure of Example 1, Step H was followed using 1.13 g of the compound prepared in Example 25, Step C and 457 mg of cyclopentano [2,3] pyridine. After purification by silica gel chromatography (eluent: methylene chloride / methanol = 9: 1), the title compound was obtained (460 mg).

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz)

2,41-3,23-3,45 -S-CH and _CH2 je cyclopentanone; 3.34-3.37: O-CH2; 3.57 to 3.98: _{O-CH2 -CH2} 0- _t 3.81: OO-CH ,; 4.97-5.88: NH-CH-CH-S-;

5.12 to 5.25: _O-CH2 -O-; 6.22 and 6.45 (ΔΕ) = CH-CH = CCH ₂ -; 6.85-7.35: CTF = C = CH-CH ₂ -;

6.46-6.50 (s): = NO-CH-CO ₂ -; 6.72: H thiazole; 6.85-7.35: aromatic hydrogens; 7.97-8.23 (d): NH;

7.79-9.20: H pyridine.

Step B: (6R- (3- (E), heptane, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,5-dichloro) 3,4-Dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene- 3-yl) -2-propenyl) -6,7-dihydro-5-H-pyridinium Internal salt The procedure described in Example 1, Step I was carried out using 447 mg of the compound prepared in Step A above. 194 mg of the title compound of this step and of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

2.23 (M): central CH ₂ ; 3.19 (t): = CCH ₂ groups; 5.17 (d): H, _N; 5.33 (m): _CH-CH2 N ^+; 5.78 (m) (2H): H ₇ and -O-CH-φ; 6.23 (m):

CH ₂ -CH = E; 6.82 (s): (s) (d): H _s , thiazole; 6.89 (dd):

= C-CH = CH (E); 7.01 (s, d): aromatic hydrogen; 7.91 (t): Hj '; 8.42 (d): H ₄ '; 8.76 (d): H ₆ '; 7.35 (1): NH ₂ ;

9.56-10.0: mobile hydrogens.

Example 28 (6R- (3- (E) -Halfa, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3) , 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-t-azabicyclo [4,2,0] oct-2-ene-3- il) -2-propenyl) 1-methylpyrrolidinium inner salt

Step A: 1- [3- [7beta-1 [1 - [[1- (2,5-Dichloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo] 2- (diphenylmethoxy) ethyl) oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] -acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl) - 8-oxo-5-thia-l-azabicyclo [4,2,0] - (oct-2-ene-3-yl) -2-propenyl-l-methyl-pyrrolidinium iodide

Example 1, Step H, using 605 mg and 174 mg of N-methylpyrrolidine from the compound prepared in Example 25, Step C, as starting material. Purification by silica gel chromatography (eluent: methylene chloride: methanol = 9: 1) gave 210 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl3, 400 MHz)

3.49-3.72 and 3.97: central and N ⁺ CH3; 3.20-3.333.34: OCH ,; 2.6: pyrrolidine; 4.01 to 4.28 ^ 1.52:

N ⁺ CH ₂ ; 5.25: 0Ο ₂ -ΟΗ ₂ -φ and O-CW ₂ -O; 6.09 and

6.17. = C-CH = CH-CH ₂ -; 6.85-7.42: = CCH = CH ₂ - and CO ₂ -CH-O ₂ .

Step B: (6R- (3- (E), heptane, 7bla (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,5-dichloro) 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene 3-yl) -2-propenyl] -1-methylpyrrolidinium inner salt

The procedure of Example 1, Step I was followed using 200 mg of the compound prepared in Step A above to give 93 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

2.09 (sl): 3 '4'-CH _2; close to 3.45 (sl):

CH _{2 at} 2 ', 5'; 2.99 (s): N ⁺ CH 3; 3.61 (d, d) and 3.80 (d), 3.86 (d): _CH2 S; 4.10 (d): = C-CH-O;

HU 211 871 A9

6.16 (m): CH-C // - _CH2 (E); 7.03 (d, J = 15): Ct = CH-CH ₂ , 7.01 (s) -7.06 (s) -6.83 (s) -6.48 (s): thiazole H ₅ and aromatic IH; 9.06 (d) -9.66 (d): CON 1 - CH; 9.95 (m) -7.40 (m): mobile hydrogens.

Example 29 (6R- (3- (E) -Halfa, 7beta (Z))) - (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-3) , dihidmxi 4-chlorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia -] - aza-bicyclo [4,2,0Jokt-2-en-3-yl) -2-propenyl) -1-methylthieno (2,3-c) pyridinium inner salt

Step A: 1- [3- [7beta - [[[[[]] - [2,5-dichloro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo] 2- (diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl ] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl-thieno (2,3-c) pyridinium iodide Example 1 The procedure described in Step H, Example 1, was prepared using 1 g of the compound prepared in Example 25, Step C and 458 mg of thieno [2,3-c] pyridine. Purification by chromatography on silica gel (eluent: methylene chloride: methanol = 9: 1) gave the title compound (520 mg).

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz)

3.56 (s) -3.98 (s): central CH ₂ 'and S-CH ₂ ; 3.79 (s): -OCH; 5.20 - 5.30: O-CH ₂ -O and CO ₂ -CH ₂ ->; 4.95-5.26 (m): MH-CH-CH-S, 6.33-6.48 (m) (E): C-CH = CW-; 6.80-7.40: = CC // = CH-; 5.59 (m) 5.80 (m): = C-CH ₂ -N =; 6.80-7.40: aromatic hydrogen; 6.77 (shoulder): H thiazole; 11.50 (sl, d): NH. -N = Ctfb. Step (6R- (3- (E), 6 alpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) <(carboxy- (2,5-dichloro-3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-I-azabicyclo [4,2,01okt-2-en-3-yl} -2-Propenyl) -1-methyl-thieno (2,3-c) pyridinium Internal salt of Example 1, Step I, starting from the compound prepared in Step A above. This gives 114 mg of the title compound of the step and of the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.19 (d): H ₆ ; 5.46 (d): N ⁺ CH ₂ -CH =; 5.79 (m): -O-Ctf-4, H ₇ ; 6.35 (m): (CH-CH ₂ (E); 6.81 (s) d: H ₅ thiazole; 7.00 (s): phenyl hydrogen; 7.07 (d, J = 16): = C-CH = CH (E); 7.34 (1): NH ₂ ; 7.94 (D, J = 5.5): H, 8.86 (d, J = 5.5): H ₂ '; 8.53 (d, J = 6.5) -8.73 (d, J = 6.5): H ₄ ' and H ₅ '; 9.91 (s, 1): H ₆ '. 9.59 (d, d): C-NH-CH; 9.88: mobile hydrogen.

Example 30 (6R- (3- (E) .alpha., 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (4-cyano-2,3 -dihidmxi) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl Internal salt of -2-propenyl) -thiene (2,3-b) pyridinium

Step A: [4-Cyano-2,3-bis -] - (2-methoxyethoxy) methoxy] phenyl] bromoacetic acid

At -5 ° C, to a mixture of 4.26 mg of lithium bromide, 598 mg of potassium carbonate and 5 ml of water is added 440 μΐ of bromoform, followed by dropwise addition of 825 mg of 4-cyanobis [(2-methoxyethoxy) prepared as described below. methoxy] benzaldehyde in 5 ml dioxane. After the addition was complete, the resulting reaction mixture was stirred at 0 ° C to -5 ° C for 72 hours and then poured into a mixture of 15 ml of ethyl acetate and 11 ml of hydrochloric acid at the same temperature with stirring. The mixture was extracted several times with ethyl acetate, and the combined extracts were washed and evaporated to dryness under reduced pressure. The resulting oil was used in the next step without further purification.

Step B: Diphenylmethyl [4-cyano-2,3-bis - [(2-methoxyethoxy) methoxy] phenyl] bromoacetate

The compound prepared as described in Step A above was dissolved in 10 mL of methylene chloride and 470 mg of diphenylmethane was added to the resulting solution. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel using a 2: 1 by volume mixture of cyclohexane and ethyl acetate as eluent. 450 mg of the title compound are obtained.

NMR spectrum

3.31 (s), 3.37 (s): OCH, '; 3.43 (m) -3.61 (m) -3.77 (m) -4, O5 (m): the central _CH2 '; 5.18 (d> -5.25 (d), 5.29 (AB) OCH ₂ O; 6.02 (s): = CH-X.

Step C: Diphenylmethyl 4-cyano [2,3-bis-1- (2-methoxyethoxy) methoxy] phenyl] phthalimidoxyoxyacetate

To a solution of 820 mg of the compound prepared in Step B above in 13 ml of dimethylformamide was added 326 mg of N-hydroxyphthalimide and 196 mg of potassium acetate, and the resulting mixture was stirred at room temperature for 3 hours, evaporated to dryness on silica gel. The residue was purified by chromatography on a 1: 1 by volume mixture of cyclohexane and ethyl acetate. This gave 640 mg of the title compound which was used in the next step without further purification.

Step D: Diphenylmethyl 4-cyano [2,3-bis - [(2-methoxyethoxy) methoxy] phenyl] amine oxyacetate

The procedure of Example 1, Step D was followed using 640 mg of the compound prepared in Step C above and 50 μ 50 of hydrazine hydrate as starting material. This gave 320 mg of the title compound.

Step E: [[[1- [4-Cyano-2,3-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxyimino] - [ 2 - [(triphenylmethylamino) thiazol-4-ylacetic acid

The procedure of Example 1, Step E was followed. starting material as described in Step D above

Of the compound prepared in A9 using 320 mg and 234 mg of triphenylaminothiazol-4-yl-acetic acid. This gave 550 mg of the title compound. NMR (CDC1 ₃ ppm)

3.32 (s), 3.37 (s): _OCH3 groups; 3.48 (t) -3.60 (t) -3.75 (m) -4.03 (m): the central _CH2 groups;

5.13 (AB) -5.24 (B): O-CH ₂ -O group;

CO ₂ /

6.27 (s): O-CH-;

\

Φ

6.74 (s): H, uazole; 6.92 (s) -CO-CH ₂ 0 _2; 7,097.32: aromatic hydrogens; 2.60 mobile hydrogen: NH.

Step F: 4-Methoxybenzyl 7beta - [[[[[1- [4-cyano-2,3bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl) oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro] propenyl] -8-oxo-5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

The procedure of Example 1, Step F was followed using 550 mg of the compound prepared in Step E above. Purification by silica gel chromatography (eluent: methylene chloride / ethyl acetate = 8: 2) gave the title compound (580 mg).

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

Step G: 4-Methoxybenzyl 7beta - [[[[[1- [4-cyano-2,3-bis [f2-methoxyethoxy] methoxy] phenyl] -2-oxo-2 (diphenylmethoxy) ethyl) oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3-l (Z) -3-chloro-1-propenyl] -8- oxo-5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

The procedure of Example 1, Step G was followed. using 580 mg of the compound prepared as described in Step F above as starting material. This gave 615 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ )

3.25 (s) -3.27 (s) -3.37 (s> 3.2-3.6 (m) OCH ₃ and

CH ₂ S groups; 3.44 (m) -3.60 (m) -3.8 (m): central HC ₂ groups; 4.01 (m) C // ₂ -I; 4.93 (d): H ₆ ; 5.17-5.38 (m), 0-CH ₂ -0 group; 5.78 (dd) -5.86 (dd): H ₇ ; 6.12 (m): CH ₂ = CW-CH; 6,436.46 (s): OC / ί-φ; 6.75 (s) -6.76 (s): H ₅ thiazole; 6.83-7.45 (m): aromatic hydrogens, HC ₂ ] H ₂₆ O ₆ =, CO ₂ -C / 60 ₂ ; 7.82-8.15 (d): mobile hydrogen: CONW.

Step H: 1- [3- [7beta - [[[[II- [4-cyano-2,3-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl-acetyl] amino] -2 - [(4-methoxy-benzyloxy) karbonilj- 8-Oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] -thieno- (2,3-b) pyridinium iodide Example 6 The procedure described in Step H, starting with 615 mg of the compound prepared in Step G above and 290 μΐ of thieno [2,3b] pyridine was used as starting material. Purification by chromatography on silica gel (eluent: methylene chloride: methanol = 9: 1) gave 300 mg of the title compound.

NMR (CDC1 ₃ ppm)

3.20 (s) -3.26 (s) -3.35 (s) -3.37 (s): _CH3 O; 3.43 (m), -3.5 (m) -4.02 (m): the central _CH2 groups; 3.80-3.81 (s): 0-OC / ₃ ; 4.93 (d, d): H ₆ ; 5.76 to 5.84 (m): _H7; 5.71-5.96 (m): C-CW ₂ -N ⁺ ; 6.40-6.45 (s): O-CH-CO ₂ -CH- <t>₂; 6.91 (m): = CH-CH ₂ (ΔΕ); 6.73-6.784 (s): H ₅ thiazole; 6.94 (m): aromatic H, -O-CW-φ ₂ , CA / = CH- (ΔΕ); 7,057,45: aromatic hydrogens.

/. Step: (6R- (3- (E), heptane, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (4-cyano-2,3- dihydroxyphenyl (methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl ) -thieneo (2,3-b) pyridinium inner salt The procedure described in Example 1, Step I, was carried out using 292 g of the compound prepared in the same manner as in Step H above to give 176 mg of the title compound and The title compound of Example 1b is obtained.

Nuclear Magnetic Resonance Spectrum (DMSO)

5.18 (d, d): H ₆ ; 5.82 (m): _H7; 5.68 (d): = C-CH ₂ N ⁺ ; 5.93 (s, d): OC / 7-φ; 6.29 (m): _CH2-CH = CH (ΔΕ); 6.79 (s, d): H ₅ thiazole; 6.94 (d, d), 7.03 (d): aromatic hydrogens; 7.89 (d) H ₃ ', 8.28 H ₂ ', 8.15 H ₅ ', 9.22 H ₄ ': thienopyridine; 9.54-9.69: CO-N / YCH; 10.33: Mobile hydrogens.

30. Reference Example

4-cyano-2,3-biszll2-methoxyethoxy) methoxy-benzaldehyde

Step A: 1,4-Dicyano-2,3-dihydroxyphenyl

To a mixture of 400 ml of tetrahydrofuran, 50 g of dicyanoethyl sulfide and 52 g of diethyl oxalate is added 46 g of sodium ethylate, and the resulting mixture is stirred for 1 hour and then concentrated under reduced pressure. The residue is taken up in 600 ml of water and 250 ml of ethyl acetate, and the resulting solution is washed with ethyl acetate and the aqueous phase is then acidified with concentrated hydrochloric acid. The mixture was extracted several times with ethyl acetate and the combined extracts were evaporated to dryness under reduced pressure. The residue was taken up in 400 ml of nitromethane, and the precipitate was collected and washed with water. to give the title compound 12.45 g, whose R value _r using 0.31, eluent methylene chloride: methanol 95:15 as the eluant.

Step B: 1,4-Dicyano-2,3-dimethoxyphenyl

From the compound prepared in Step A above, 1 g, 60 ml of acetone, 3.15 g of potassium acetate and

The mixture (1.5 ml) was stirred at reflux for 16 hours, then cooled, filtered and evaporated to dryness under reduced pressure. The resulting residue was chromatographed on silica gel

A9 was purified by chromatography using a 9: 1 by volume mixture of methylene chloride and hexane as eluent. This gave 820 mg of the title compound.

IR (CHCl ₃ ) conjugated CN 2240 cm ^-1 aromatic 1595-1555 cm ^-1

Step C: 4-Cyano-2,3-dimethoxybenzaldehyde

To a solution of 15.70 g of the compound prepared in Step B above is added 900 ml of toluene, followed by 61 ml of 1.5 M diisobutylaluminum hydride in toluene over 15 minutes at -74 ° C. The resulting reaction mixture was stirred at -70 'C to -74' C for 30 minutes and then acetone (20 mL) was added slowly. Stirring is continued for 10 minutes and the reaction mixture is poured into a mixture of 700 ml of N hydrochloric acid and 200 ml of ethyl acetate. The mixture was stirred at room temperature for 30 minutes, then decanted and extracted several times with ethyl acetate. The combined extracts were dried and evaporated to dryness. 15.5 g of the title compound are obtained. To this crude product was added 4.9 g of product from a previous experiment and the crude product (20.4 g) was subjected to silica gel chromatography (95: 5, toluene / ethanol) three times. 7.5 g of the title compound are obtained in pure form.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ )

4.06 to 4.10: _0-CH3; 7.38 (d) -7.60 (d): aromatic 2H, ortho coupling; 10.42 (s): CHO.

Step D: 4-Cyano-2,3-bis - [(2-methoxyethoxy) methoxy] -benzaldehyde

To a solution of 5.9 g of methylene chloride in 150 ml of methylene chloride at -70 ° C was added 124 ml of a 1 M solution of boron tribromide. and the resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was cooled to -30 ° C, and methanol (30 mL) was added slowly. After stirring for 30 minutes, the reaction mixture is concentrated to dryness under reduced pressure and the residue is taken up in 200 ml of ethyl acetate. The resulting solution was washed with water, dried and evaporated to dryness under reduced pressure. The residue (6.4 g) was added to methylene chloride (190 mL), cooled to 0 C and diisopropylethylamine (21 mL) was added followed by methoxyethoxymethyl chloride (141 mL). After stirring at room temperature for 3 hours, the reaction mixture was washed with normal hydrochloric acid, normal aqueous sodium carbonate solution and water, dried and evaporated to dryness. The residue was purified by chromatography on silica gel using a 9: 1 by volume mixture of methyl chloride and ethyl acetate as eluent. so

4.93 g of the title compound are obtained in the same manner as in the title.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ )

3.35 to 3.38 (s): O-CH ₃ groups; 3,53-3,62-3,88-

4.08 (m): the central _CH2 groups; 5.33-5.39 (s);

O-CH ₂ -O; 7.45 (DD = 05 and J = 8 Hz): _H6; 7.67 <d,

J = 9 Hz): H ₅ ; 10.39 (d, j = 0.5 Hz): CHO.

Example 31 (6R- (3- (E), heptane, 7beta (Z))) 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (4-cyano-2,3 -dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl) -quinolinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [4-Cyano-2,3-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl] 8-Oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl-quinolinium iodide

The procedure of Example 1, Step H was followed using 615 mg of the compound prepared in Example 30, Step G and 200 μΐ quinoline. Purification by chromatography on silica gel using methylene chloride / methanol (91: 9, v / v) gave 145 mg of the title compound.

Step B: (6R- (3- (E), heptane, 7beta (Z))) 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (4-cyano-2, 3-dihydroxyphenyl) -methoxy) -imino) -acetyl (-amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl) quinolinium inner salt

In the same manner as in Example 1, Step I, starting from 320 mg of the compound prepared in Step A above, 137 mg of the title compound of this step are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO)

3.30-3.80 (m): _CH2 S; 5.15 (d): H ₆ ; 5.60 (dd): H ₇ ;

5.91-5.93 (s): OC / Ζ-φ; 5.90 (m): CH ₂ -N ⁺ ; 6.37 (m): HC = C 1 - CH ₂ ; 6.93 (d, J = 16) // C = CH-CH ₂ ;

6.78-6.94 (d): H ₅ ', H ₆ '; 7.01 (s): H thiazole; 8,078.28 (t): H ₆ ", H ₇ "; 8.23 (dd) (J = 6 & 8 Hz): H ₃ ';

8:51 (d) -8.55 (dd): _H5 'and H _4' or H ₈ "; 9.34 (d,

J = 8 Hz) H ₄ ”or H ₈ ”; 9.59 (d, J = 6Hz): CH ₂ '.

9.52 (d) -9.68 (d): NC-NH-CO.

Example 32 (6R- (3- (E), heptane, 7beta (Z))) - 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (5-cyano-3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-ene-3- il) -2-propenyl) -thiene (2,3-b) -pyridinium inner salt (R, S isomer)

Step A: 1- [3- [7beta - [[[[[1- [5-Cyano-3,4-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl ] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] -thieno- (2,3b) pyridinium iodide (R , S isomer)

In the same manner as in Example 2, Step H, 1.5 g and 1.35 g of the compound prepared in Example 2, Step G were used as starting material.

A9 using thieno [2,3-b] pyridine. 1.22 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.27 (s) - 3.29 (s) - 3.35 (s) -3.36 (s): C = OMe groups; 3.80 (s) -3.81 (s): = C-O Me groups; 3,304,10: central CH ₂ and CH ₂ S groups; near 5,005.11: H _e ; about 5.20 to 5.40: O-CH ₂ -O groups;

6.76 (s) and 6.77 (s): H ₅ thiazoles; about 6.90 to 7.50: COOCHO ₂ and C ₆ H ₅ ; 9.58 (d) separated: H ₆ '; 7.52-8.90 other hydrogen atoms of quinoline;

8.22 and 8.34 (d): = C-NH-CH.

Step B: (6R- (3- (E), heptane, 7beta (Z))) - 7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (5-cyano-3) , 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia -] - aza-bicyclo [4,2,0] oct-2-en-3-yl ) -2-Propenyl) -thiene (2,3-b) -pyridinium Internal salt (R, S isomer)

The procedure of Example 1, Step I was followed using 1.2 g of the compound prepared in Step A above. This gives 730 mg of the title compound of the step and of the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.17 (d) separated: H ₆ ; 5.41 (s): O-CH-, 5.68 (d):

CH _; -N ⁺ ; 5.79 (m): H ₇ ; 6.87 (m): = C-CH = _CH2-CTF (E); 6.77 (s) and 6.79 (s): H ₅ thiazole; 7.12 and 7.17: aromatic and = C-CW = CH-; 7.89 (d): H, '; 8.28 (d): H ₂ '; 8.15 (dd): H, '; 9.09 (d): H ₄ '; 9.23 (d): separated H ₆ ; 10.38: mobile hydrogen; 739 (m): NH ₂ .

Example 33 (6R- (3- (E) .alpha., 7beta (Z))) - 7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (5-cyano-3, 4-Dihydroxy-phenyl) -methoxy-imino / acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-3 il) -2-propenyl) -thiene (2,3-b) -pyridinium inner salt (S isomer)

240 mg of the compound prepared in Example 32 were subjected to a Microbondapack column chromatography using 82:18 v / v water / acetonitrile (pH 2.7) as eluent. This gave 45 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.15 (d, J = 5): H ₆ ; 5.40 (s): O-Ctf-φ; 5.67 (d):

= CH-CH ₂ -N ⁺ ; 5.80 (dd, J = 5 and 8): _H7; 6.25 (m):

CW = CH₂; 6.79 (s): H₅ thiazole; 7.13 (m): aromatic and = CW-CH * (AE); 7.89 (d, J = 6) -8.28 (d, J = 6): K, and H₂'; 8.15 (m): H_s'; 9.09 (d, J = 8): H₄ '; 9.22 (d. J = 6): H₆'; 9.62 (d, J = 8): = C-NH-CH, 10.3410.43: OH; 7.33: NH₂ groups.

Example 34 (6R- (3- (E) -Halfa, 7beta (Z))) -7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3-chloro-4, 5-dihydroxy-phenyl / methoxy / imino / acetyl / amino / 2-carboxy-8-oxo-5-tiaJ azabicyclic l4,2,0] oct-2-en-3-yl) -2- propenyl) imidazo - (), 2-a) pyridinium inner salt

Step A: ([() - [3-Chloro-4,5-bis - [(2-methoxyethoxy / methoxy / phenyl] -2-oxo-2- (difemylmethoxy) ethyl] oxyimino) [2- (triphenylphosphine / methyl / amino / thiazo / yl-4 / acetic acid

In the same manner as in Example 1, Step A, starting from 2.56 g of the compound prepared in Example 4, Step D and 1.84 g of oxo [864 828]. Using 2 - [(triphenylmethyl) amino] thiazol-4-yl] acetic acid. After chromatography on silica gel using methylene chloride: methanol 97: to afford the title compound 3 by volume mixture of 3.34 g of the intended value of _Rf 0.54, eluent methylene chloride: methanol 9: 1 as eluent.

Step B: 4-Methoxybenzyl 7beta - [[[[[] - [3-chloro-4,5-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro -] - propenyl 8-oxo-5-thia-1-aza-bicyclooct-2-ene-2-carboxylate

In the same manner as in Example 1, Step E, 1.42 g of 4-methoxybenzyl 7-beta-amino [(Z) -3-chloro-1-propenyl] can be prepared as described in EP 330154. Using -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-2-carboxylate hydrochloride and 3.34 g of the compound prepared as described in Step A above. 2.88 g of the title compound are obtained, Rf = 0.44, using a 8: 2 by volume mixture of methylene chloride and ethyl acetate as the eluent.

Step C: 4-Methoxybenzyl 7beta - [[[[[1- [3-chloro-4,5-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) -amino} -thiazol-4-yl] acetyl] -3 - [(Z) -3-iodo-l-propenyl ] -8-oxo-5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

The procedure of Example 1, Step G was followed using 1.88 g of the compound prepared in Step B above. so

The title compound was 1.75 g having a _Rf value of 0.52, using methylene chloride: ethyl acetate 8: 2 by volume as eluent.

Step D: 1- [3-17 Beta - [[[[[1- [3-Chloro-4,5-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) -methoxy) ethyl j-oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxybenzyloxy) carbonyl ] -8-oxo-5-thia -] - azabicyclo [4,2,0] - [- oct-2-en-3-yl] -2-propenyl] -imidazo (1,2-a) pyridinium iodide

The procedure of Example 1, Step H was followed using 876 mg of the compound prepared in Step C above and 0.308 ml of imidazo [1,2-a] pyridine. After purification by chromatography on silica gel, eluting with a 97: 3 mixture of methylene chloride and methanol34

450 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz)

3.25-3.29 (s) -3,35-3,36 (s): _OCH3 groups;

3.43-3.55-3.72-4.01 (m): the central H ₂ and CH ₂ S groups; 3.78 (s, d): φ-Ο-Me; 4.94 (s, s) and 5.83 (m): _H6 and _H7; 5.17-5.35 and 5.43 (dt): OCH ₂ O, CO ₂ CH ₂ O, NCH ₂ =; 5.94 (s): O-CH-φ; 6.25 (m): -CH ₂ -C (ΔΕ); 6.76 (s): H ₅ thiazole; 6.89: O-C / H>₂; 685-7.40: φ-C, aromatic, CH = CH-C = (ΔΕ); 7.85 (d, d): H ₅ ', H ₆ '; 8.05 (d, d): H 4 '; 8.38 (d,): H ₃ '; 8.64 (d, d): H1 '; 8.38 (d, d): H ₃ '; 8.64 (d, d): H1 '; 9.11 (d, d): H ₇ '; 7.97-8.19 (d): NH groups.

Step E: (6R- (3- (E) -Halfa, 7beta (Z))) -7- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (3-chloro-4) , 5-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0Jokt-2-en-3-yl) - Internal salt of 2-propenyl) imidazo- (1,2-a) -pyridinium The procedure described in Example 1, Step I, was prepared using 489 mg of the compound prepared in Step D above, to give 187 mg. in an amount of the title compound of the step and of the example.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.62: _CH2 S; 5.29 (m): N ⁺ -CH ₂ -CH =; 5.35 (s, d): O-CH-φ; 6.22 (m): CH ₂ = CH (E); 6.77 (s): H ₅ thiazole; 6.85 (s) -6.90: -ΟΗ-φ ₂ , aromatic and CH = CHCH ₂ (E); 7.33: NH ₂ and φ-C; 5.13 and 5.75: H ₆ -H ₇ ; 7.58 (1) -8.06 (t): H ₅ '-H ₆ '; 8.28 (m) -8.44 (sl): H ₃ 'H ₂ '; 8.96 (d): H 4 '; 9.59 (d, d): H ₇ '; 9.29 (sl) 13.03-13.66: mobile hydrogen.

Example 35 (6R- (3- (E), heptane, 7beta (Z)) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3-chloro-4,5) -dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia]-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) -4 (methylthio-thiopyridinium inner salt)

Step A: 1- [3- [7-bis [[[[[1- [3-Dichloro-4,5-bis-1 (2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino} -thiazol-4-yl] acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] - oct-2-en-3-yl] -2-propenyl-4- (methylthio) -pyridinium iodide. The title compound was prepared using 875 mg and 385 mg of 4- (methylthio) pyridine from the compound prepared in Example 34, Step C. After purification by chromatography on silica gel, eluting with methylene Chloride / methanol (97: 3 then 90:10, v / v) gave the title compound (389 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

2.61 to 2.63: S-CH ₃ '; 3.25-3.28-3.36-3.37: OCH, groups; 3.78 (s) - 3.79 (s): oOME groups;

3.44-3.58-3.72-4.01: central CH ₂ and CH ₂ -S groups; 4.97 (d, d): H ₆ ; 5.50-5.35: _OCH2 O, _CO2 CTF -0 _2, CH ₂ ^N (1 H); 5.56 (m) -5.85: CH ² N ⁺ (1H); 6.24-6.39 (m): CH = CH-CH2 (ΔΕ); 6.78 (σλ): H ₅ τιαζολ; 6.89 (σλ): ΧΟ ₂ ΧΗ ₂ ™ φ; 7-7,40: φθ, aromatic and = C-CH = CH- (ΔΕ); 7.66 (δ, δ) 'σ 8.90 μ): τιο-πιριδινιυμ.

Β. Step: (6R- (3- (E), heptane, 7beta (Z))> 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (3-chloro-4,5- dihydroxyphenyl (j-methoxy) -imino (j-acetyl (j-amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2 Internal salt of -propenyl) -4-methylthio-pyridine The procedure described in Example 1, Step I was carried out using 389 mg of the compound prepared in Step A above as starting material, giving 174 mg of the title compound. and the title compound of the example.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

2.72: SCH ₃ ; 3.49 (s) -3.54 (d) -3.71 (d): _CH2 S; 5.13-5.17 (d): H ₆ (cis); 5.76 (m): H ₇ (cis); 5.23 (m): N ⁺ -CH ₂ ; 6.24: = Ctf-CH ₂ (ΔΕ); 6.77 'σ 6.78 (σ): H ₅ τιαζολ; 6.85 ™ 7.02: αρομΚσ 'σ = XH ™ XH =; 7.95 ™ 8.70 πιριδινιυμ; 9.30 (σλ) ™ 9.62 (δ, δ) ™ 9.96 (μλ): α μοβιλ ηιδρο / νεκ; 7.34: ΝΗ ₂ .

Example 36 (6R- (3- (E) -Halfa, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3-chloro-4,5) dihydroxy-phenyl) -methoxy-imino) acetyl) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl-2 -propenyl) -quinolinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [3-Dichloro-4,5-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- ( diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetylamino} -2 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl-quinolinium iodide

The procedure of Example 1, Step H was followed using 900 mg of the compound prepared in Example 34, Step C above and 0.366 mL of quinoline. Purification by chromatography on silica gel (eluent: methylene chloride: methanol = 97: 3) gave the title compound (384 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.24 (s) -3.29 (s) -3.36 (s, d): O-CH ₃ groups; 3.78 (s): φ-OMe; 3.40 (m) -3.58 (m) -3/71 (m) -4.00 (m): the central _CH2 groups; 5.07 and 5.26: CO ₂ CH ₂ and O-CH ₂ -O; 4.94 (s): H ₆ ; 5.04 (m): _H7; 6.00-6.20: = CH-CH ₂ -N ^+; 5.99 (s) found: φCH-O; 6.38 (m) -6.55: = CH-CH ₂ (ΔΕ); 6.75 (σ) ελκΥλχνϊλτ: H ₅ τιαζολ; 6.85 ™ 7.40: αρομΧσοκ 'σ = X ™ XH = XH ™ XH ₂ ; 7.91 (μ) ™ 8.08 ™ 8.26 (μ) ™ 8.42 (μ) ™ 8.95 (μ) ™ 10.49 (δ): κινολιν 'σ μοβιλ τιιδρο / ν.

Β. Step: (6R- (3- (E), heptane, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (3-chloro-4,5- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2 inner salt of -propenylj-quinolinium

The procedure of Example 1, Step I was followed, starting from Step A above

Using 384 mg of the compound prepared in A9 gives 192 mg of the title compound of this step and the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.35-3.70: _CH2 S; 5.11 (d, J = 5) -5.15 (d, J = 5):

h ₆ ;

SHE

II

5.32 (φ) -5.34 (s): φ-Ctf-CO; 5.74 (m): H ₇ ; 5.89 (m): = CH-C // _2- N; 6.36 (m): = C «-CH ₂ ; 6.75-7.00 (m): the remaining CH =, aromatic and H ₅ thiazole; 7.33: mobile hydrogens; 8.07-8.26-8.52-9.33: quinoline; 9.579.29-9.60-9.91 (m), 13.00 (eq) -1 13.70 (m): mobile hydrogens.

EXAMPLE 37 (6R- (3- (E), halpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy-2) -fluorophenyl) -methoxyfimino) -acetyl (amino) -2-carboxy-8-oxo-5-thialazabicyclo- (4,2,0] oct-2-en-3-yl) -2 -propenyl) -quinolinium inner salt

Step A:] alpha-hydroxy-2-fluoro (3,4-bis [2-methoxyethoxy) methoxy-J-phenyl] -acetic acid

The procedure described in Example 1, Step A, starting from 15.5 g of 2-fluoro-3,4-bis [(2-methoxyethoxy) methoxy] benzaldehyde, which was prepared as described below, was used. 20.7 g of the title compound are obtained, which product is used in the next step without further purification.

Step B: Diphenylmethyl [2-fluoro (3,4-bis [(2-methoxyethoxy) methoxy] J-phenyl] hydroxyacetate

The procedure of Example 1, Step B was followed, starting from 20.6 g and 9.08 g of diphenyldiazomethane from the compound prepared in Step A above. After purification by chromatography on silica gel. Elution with cyclohexane / ethyl acetate (7: 3) gave 3.2 g of the title compound. IR spectrum: CHCl ₃

OH 3600 cm- 'and 3530 cm'

C = O 1733 cm ^-1

Aromas 1620-1603-1588-1498 cm ' ¹

Step C: Diphenylmethyl [2-fluoro (3,4-bis (2-methoxyethoxy) methoxy] phenyl] phthalimidoxyacetate

The procedure of Example 1, Step C was followed using 3.2 g of the compound prepared in Step B above. Purification by chromatography on silica gel using methylene chloride / acetone (95: 5, v / v) gave the title compound (2.9 g).

IR spectrum: CHCl ₃

C = O 1794-1754-1737 cm ^-1

Aromas 1619-1597-1498 cm ' ¹

Step D: Diphenylmethylamine Oxy [2-Fluoro (3,4-bis (2-methoxyethoxy) methoxy-J-phenyl]-Steel

In the same manner as in Example 1, Step D

1.05 g of the title compound are obtained.

IR Spectrum: _CHCl3

O NHicl

C = O 1744 ^cm-1 _NH2 + aromatic starting 1620-1580-1498 cm ^-1

Step E: [[[] - [2-Fluoro (3,4-bis [(2-methoxy-ethoxy] -methoxy] -phenyl) -2-oxo-2- (diphenylmethoxy) -ethyl] -oxy] -imino] - [2 - [(triphenylmethyl) -amino) -thiazol-4-yl] acetic acid

In the same manner as in Example 1, Step E, 1.05 g of the compound prepared in Step D above and 0.777 g of oxo [2 - [( triphenylmethyl) amino] thiazol-4-yl acetic acid. 1.74 g of the title compound are obtained, which product is used in the next step without further purification.

Step E: 4-Methoxybenzyl 7beta - [[[[[1- [2-Fluoro-3,4-bis-1- (2-methoxyethoxy) methoxy] phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl J-oxyimino- [2- (triphenylmethyl) amino] thiazolyl] acetyl] amino] -3 - [(Z) -3-chloro] propenyl) -8 oxo-5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

In the same manner as in Example 1, Step F, 1.74 g and 0.784 g of the compound prepared in Step E above are used as starting material.

Using 4-methoxybenzyl-7-beta-amino-3 - [(Z) -3-chloro-1-propenyl] -8-oxo-5-thia-1-azabicyclooct-2-ene-2-carboxylate . Purification by chromatography on silica gel, eluting with methylene chloride / ethyl acetate (8: 2, v / v) gave the title compound (1.77 g) which was used in the next step without further purification.

Step G: 4-Methoxybenzyl 7beta - [[[[[1- [2-Fluoro-3,4-bis - [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2 (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] -thiazol-yl] -acetyl] -amino] -3 - [(Z) -3-iodo-1-propenyl] -8-oxo- 5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

Example 1 G. The procedure described was repeated, using 840 mg of the compound obtained as in Step F above as a starting material to afford the title compound 814 mg with _Rf = 0.45, eluent methylene chloride: ethyl acetate (8: 2).

Step H: 1- [3- [7beta - [[[[11- [2-Fluoro-3,4-bis - [(2-methoxyethoxymethoxymethoxy) phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo-l-propenilj8 -oxo-5-thia-1-azabicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] quinolinium iodide

In the same manner as in Example 1, Step H, 814 mg of the compound prepared in Step G above and 0.337 ml of starting material were obtained.

EN 211 871 A9 using quinoline. Purification by silica gel chromatography (98: 2 methylene chloride: methanol) gave the title compound (368 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.31 to 3.35: O-CH ₃ groups; 3.45 (d, J = 16):

CH ₂ S; 3,51-3,81-3,94: central _CH2 groups;

3.79 (s) -3.80 (s): Οφ-Ο-CH-); 4.91 (m): H ₆ ; 5.515 to 5.30: CO-CH ₂ - $, O-CH ₂ -O; 5.83:

H ₇ ; 6.05 (ml): = C-CH ₂ -N ⁺ ; 6.31 and 6.35 (m): az

OC / f-φ groups; 6.49 (ml): -CH ₂ -H-CH; 6,726.75: H ₅ thiazole; 6.87-7.40: aromatics, CO ₂ -Ci / -O ₂ ,

CW-CH = C; 7.90-8.20: quinoline, 8.40 (d, d): H ₄ ';

8.90 (d, d): H ₂ '.

Step I: (6R- (3- (E), halpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy) 2-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl) quinolinium inner salt

The procedure of Example 1, Step I was followed using 357 mg of the compound prepared in Step H above as starting material to give 176.9 g of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.14: H ₆ ; 5.41 (s) separated: O-CH-φ; 5.70-5.90:

CH ₂ N ⁺ and H ₇ ; 6.54 (d, J = 8.5) and 6.70-6.80: aromatics and _H5 thiazole; 6.37 (m): -CH = C H - CH ₂ (ΔΕ);

6.97 (δ, δ): ™ XH = XH ™ XH ₂ ; 7.34 (λ): NH ₂ ; 8.07 ™ 9.58: κινολιν; 9,16 ™ 9,49 ™ 9,69: μοβιλ ηιδρο / νεκ.

Example 37 Preparation of starting material

2-Fluoro-3,4-lbiszl (2-methoxyethoxy) methoxy] benzaldehyde

Step A: 2-Fluoro-3,4-bis-dihydroxybenzaldehyde

A mixture of 74.3 g of hexamethylenetetramine and 125 ml of trifluoroacetic acid was stirred at 80 ° C for 2 hours, then a solution of 34 g of 3-fluoropyrocatechin in 130 ml of trifluoroacetic acid was added. Stirring was continued at 80 ° C for 2 hours and then at room temperature for 16 hours. Subsequently, the trifluoroacetic acid was distilled off under reduced pressure and the residue was taken up in water and potassium carbonate was added until the pH reached 7. After filtration and repeated extraction with diethyl ether, the combined extracts were dried and evaporated to dryness under reduced pressure. This gave 39 g of the title compound which was used in the next step without further purification.

Step B: 2-Fluoro-3,4-bis [(2-methoxyethoxy) methoxybenzaldehyde

To a solution of 39 g of acetonitrile in 390 ml of the compound prepared in Step A above is added 261 ml of N-ethyldiisopropylamine, and the reaction mixture is cooled to -5 ° C and 113 ml of (2-methoxyethoxy) are added slowly. ) methyl chloride. The reaction mixture was stirred at the same temperature for 16 hours and then the acetonitrile was evaporated. The residue is taken up in 250 ml of methylene chloride and the resulting solution is washed with N hydrochloric acid, water, N sodium carbonate solution and finally water, dried, filtered and evaporated to dryness under reduced pressure. The product (49.5 g) was purified by chromatography on silica gel using a 96: 4 by volume mixture of methylene chloride and acetone as the eluent. 10.4 g of the title compound of this step and of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 200 MHz)

3.37-3.38 (s): _OCH3 groups; 5.24 (s) -5.37 (s): the 0-CH ₂ -O group; 3.56 (m) -3.83 (m) -4.00 (m): the central _CH2 groups; 10.26 (s): CHO; 7.09 (dd, J = 1.5-9): H ₄ ; 7.59 (dd, J = 7.5-9): H ₃ .

Example 38 (6R- (3- (E), heptal, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy-2) -fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia]-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) imidazo (1,2-a) pyridinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [2-Fluoro-3,4-bis - [(2-methoxyethoxy-methoxy) -phenyl] -2-oxo-2- (diphenyl) methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] -thiazol-4-yl] acetylamino] -2 - [(4-methoxybenzyloxy) carbonyl] - 8-Oxo-5-thia-1-azabicyclo [4.2.0] - [oct-2-en-3-yl] -2-propenylimidazo (1,2-a) pyridinium iodide Example 1 H. The residue was purified by chromatography on silica gel, eluting with methylene chloride (704.5 g) and using 0.25 ml of imidazo [1,2-a] pyridine as the starting material. Chloride: methanol (95: 5) gave the title compound (275 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3.32-3.33 (s): -OHCH ₃ ; 3.46-3.47 (d):

CH ₂ S; 3.78 (m): the <t + O-CH ₃ groups; 3.53

3.81 to 3.95: the central _CH2 groups; 4.82: H ₆ ; 5.78:

H ₇ ; 5.00-5.32: OCH ₂ O-, CO ₂ CH ₂ O, = CH-CH ₂ N ⁺ ;

5.40: another hydrogen atom of CH ₂ N ⁺ ; 6.32-6.37 (s): O-CH-φ; 6.28 (m): CH ₂ -CW = CH (ΔΕ); 6.74 (σ) ™ 6.76 (σ): H ₅ τναζολ; 6.8 ™ 7.40: oX,

ΧΟΧΗ ₂ ™ φ ₂ , aromatic, = CH-CH = CH (E); 7.84 (m) 9.13 (5H) imidazo pyridinium.

Step B: (6R- (3- (E), halpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy) 2-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0Jokt-2-en-3-yl) -2 -propenyl) -imidazo (1,2-a) pyridinium inner salt

The procedure of Example 1, Step I, was followed using 275 mg of the compound prepared in Step A above to give 116.2 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.60: _CH2 S; 5.11-5.14 (d): H ₆ ; 5.75 (dd) -5.79 (dd):

H ₇ 6; 5.30 (m): CH ₂ N ⁺ ; 5.64-5.65 (s): O-CH-φ;

6.25 (m): CH = CH-; 6.91-6.93 (d): CH = _CH-CH2;

HU 211 871 A9

6.57-6.74 (m): H ₅ 'and H 2'; 6.77 (s) -oh, 79 (s): H ₅ thiazole;

7.57-8.05 (dd): H ₅ 'and H 4'; 8.22 (d> -8.98 (d, d): H4 ',

H ₇ '; 8.30-8.46 (m): H ₂ ', H ₃ ; 9.48 (d) -9.55 (d): CHNH-C = O; 7.32-9.13-9.64 (m): mobile hydrogens.

Example 39 (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3) , 4-Dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-3 il) -2-propenyl) imidazophyl 1,2-a) inner salt of pyridinium

Step A: Diphenylmethyl [2,5-difluoro-3,4-bis-dihydroxy] phenyl-hydroxyacetate

In the same manner as in Example 1, Step B, 3.30 g of [2,5-difluoro-3,4-bis-dihydroxy] phenylhydroxyacetic acid and 2.77 g of diphenyl diazomethane were used. Purification by chromatography on silica gel (eluent: cyclohexane: acetone = 6: 4) gave the title compound (3.75 g).

IR spectrum is a complex absorption in the OH / NH region

OO 1752 cmaroma 1630-1535-1485 cm ¹ .

Step B: Methyl [2,5-Difluoro-3,4-bis (2-methoxyethoxy) methoxy) phenyl] hydroxyacetate

To a solution of 4.21 g of the compound prepared in Step A above in 45 ml of methylene chloride is added 2.96 g of diisopropylethylamine and 10 ml of methylene chloride, and the reaction mixture is cooled to -5 ° C. and then slowly add

2.71 g of methoxyethoxymethyl chloride and 5 ml of methylene chloride. The reaction mixture was stirred at the same temperature for 30 minutes and then poured into 30 ml of 0.1 N hydrochloric acid. After decantation, the residue is washed with saturated aqueous sodium carbonate solution at pH 8. dried, filtered and evaporated to dryness under reduced pressure. The crude product (6.9 g) was purified by chromatography on silica gel (eluent: methylene chloride / ethyl acetate = 85: 5). 3.577 g of the title compound are obtained.

IR:

near 3600 cm ^_1 (f) -3530 ^cm-1 complex OH.

1734 cm ^-1 : C = O

1624-1600-1589-1492 cm ^-1 : aromatic.

- 140.6 F ^2, _F _ _F4 J = 14, H = 6.5 ⁵ _F1H

- 135.2 F \ J _F4 _ _h ⁵ = 11

Step C: Diphenylmethyl 2,5-difluoro-3,4-bis (2-methoxyethoxy) methoxy) phenyl] phthalimidoxyoxyacetate

The procedure of Example 1, Step C was followed. starting from the compound prepared as described in Step B above, 4.419 g, 1.41 g of hydroxyphthalimide and 4.12 g of triphenylphosphine. Chromatography on silica gel, eluting with methylene chloride: acetone (97: 3) followed by cyclohexane: ethyl acetate (1: 1) gave the title compound (2.56 g).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.33 (s) -3.36 (s): _OCH3; 3.50 (m) -3.91 (m): _{OCH2 CH2} O; 5.20 (System B) -5.26 (A, System B): _OCH2 O;

SHE

II

6.26 (s): - C H - CO ₂ ; 6.94 (s): CO ₂ C // Ph ₂ -; 7.15-7.3 (m) -7.76 (m): aromatic hydrogens.

Step D: Diphenylmethylamine oxy [2,5-difluoro-3,4bis - [(2-methoxyethoxy) methoxy) phenyl] acetate

The procedure of Example 1, Step D was followed using 2.537 g of the compound prepared in Step C above and 0.21 ml of hydrazine hydrate as starting material. Purification by chromatography on silica gel, eluting with cyclohexane / ethyl acetate (1: 1, v / v), afforded 1.67 g of the title compound. Nuclear Magnetic Resonance Spectrum: 19 _F : CDCL

135.5 (dd) F ⁵

139.8 (dd) F ₂

JF5-F2 = 14

Ffs-month ⁼ ί θ'5

Ff2-H6 =

Step E: [[[1- [2,5-Difluoro-3,4-bis [2-methoxy-ethoxy] -methoxy] -phenyl] -2-oxo-2- (diphenylmethoxy) -ethyl] -oxy j-imino] -1- (triphenylmethyl) amino] -thiazol-4-yl acetic acid

In the same manner as in Example 1, Step E, 909 mg of the compound prepared as described in Step D above and 652 mg of oxo [2 - [(triphenyl-) - compound are prepared as described in Belgian Application 864 828. methyl) amino] thiazole] -4-ylacetic acid. After purification by chromatography on silica gel. Elution with a 96: 4 mixture of methylene chloride and methanol gave 1.138 g of the title compound. IR C = NH + absorptions near 3405 ^cm-1 of OH / NH region 1740-1727 ^cm-1 C = O

C = N aromatic + 1615-1597-1526-1495 cm ^-1 heteroaromatic

Step F: 4-Methoxybenzyl 7beta - [([[[[1- [2,5-Difluoro (3,4-bis - [(2-methoxyethoxy) methoxy] phenyl) -2-oxo-2] (diphenyl-methoxy) ethyl] oxyimino] - [2- (triphenylmethyl) -amino] -thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-chloro-propenyl ] -8-oxo-5-thia-1-aza-bicyclooct-2-ene-2-carboxylate

The procedure of Example 1, Step F was followed using 1.12 g of the compound prepared in Step E above. Purification by chromatography on silica gel (eluent: methylene chloride / ethyl acetate = 9: 1) gave 979 mg of the title compound of the title compound. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

HU 211 871 A9

3.08-3.20-3.40: CH ₂ S; 3.34 to 3.35 (s): CO-CH ₃ groups; 3.54 to 3.92 (m): the central _CH2 groups;

3.80-3.81 (s): Ar-O-CHCl ₂ Cl; 4.95-5.03: H ₆ cephalo; 5.16-5.25: OCH ₂ O, CO ₂ Ctf ₂ Ar; 5.75 (m): = C7 / ₂ -CH (Z); 5.85-6.00: _H7 cephalo, = _CH-CH2;

6.26 (d, J = 11) -6.35 (m): C-CH = CH-CH ₂ Cl, ArCHO: 6.70-6.78 (m): H ₅ thiazole; about 7.00 to 7.35: aromatic hydrogens; 7.80-8.30: N7 / -CH.

Step G: 4-Methoxybenzyl 7beta - [[[[[1- [2,5-difluoro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo-2 ( diphenylmethoxy) ethyl] oxyimino} - [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -3 - [(Z) -3-iodo-1 propenyl ] -8-oxo-5-thia-l-azabicyclo-oct-2-ene-2-carboxylate

Example 1 (G) was prepared using 969 mg of the compound prepared in Step G above as starting material. 725 mg of the title compound are obtained.

Step H: 1- [3- [7beta - [[[[[1- [2,5-Difluoro-3,4-bis [(2-methoxyethoxy) methoxy] phenyl] -2-oxo] 2- (diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxy-benzyloxy) -carbonyl ] -8-oxo-5-thia-J-azabicyclo [4,2,0] [oct-2-en-3-yl] -2-propenyl] imidazo (l, 2-a) pyridinium iodide

The procedure of Example 1, Step H was followed using 717 mg and 313 mg of imidazo [1,2-a] pyridine from the compound prepared in Step G above. Purification by silica gel chromatography (eluent: methylene chloride: methanol = 95: 5) gave the title compound (350 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3,32-3.33-3,34 (s): _CO-CH3; 3.53 to 3.92 (m): the central _CH2 groups; 3.30-3.80: _CH2 S; 3,793.80 (s): Ar-O-Ctf; 4.94 (dd): H _e cephalo; After 5,805,88 (d) exchange: H ₇ cefalo; (TD) -6.31

SHE

ΙΓ (td): = C H - CH ₂ N ⁺ ; 6.31 (s) -6.37 (s): Ar-CW-CO ₂ ;

7.84-8.18 (d): CO-N H -CH; 7.86-8.02 (m): heterocycle; 8.32-9.18: imidazopyridine; 6.75-7.45 (m): aromatic, H ₅ thiazole, C H = CH-CH ₂ , CO ₂ -C H - (? ₂ ; 5.18-5.30-5.43): CH ₂ -N ⁺ , OCH ₂ O,

SHE

II

Ar / O OC.

/. Step: (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3, 4-Dihydroxy-phenyl (1-methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-3 il) Internal salt of 2-propenyl) imidazo (1,2-a) pyridinium The procedure described in Example 1, Step I was carried out using 344 mg of the compound prepared as described in Step H above to give 170 mg. in an amount of the title compound of the step and of the example.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.16 (dd): H ₆ cephalo; 5.77 (m): H ₇ Cephalo; 5.29 (m):

CH ₂ -N ⁺ ;

SHE

II

5.64 (s, d): AlCH: 6.70 (dd): aromatic hydrogen coupled to 2F; 6.80 (s, d): H ₅ thiazole; 6.87 (d, d): CTF = CH-CH ₂ (E); 7.33 (sl): NH ₂ ; 8.28-8.44 (m): H ₂ 'and H ₃ '; 7.18-8.96 (4H): imidazopyridine; 9,039.63 (d): CN - CH; 9.84 is the other mobile hydrogen.

Preparation of Example 39 starting material:

[2,5-di-fluoro-3,4-dihydroxypropyl] phenyl-hydroxy acetic acid

Step A: 2,5-Difluorophenol

At -65 DEG C. to a solution of 62.19 g of 1,4-difluorobenzene in 500 ml of tetrahydrofuran was added 325 ml of a 1.6 molar solution of n-butyllithium in hexane and the resulting mixture was stirred for 2.5 hours. agitated. A solution of 53.8 g of trimethyl borate in 250 ml of diethyl ether is then added at the same temperature over a period of 30 minutes. The reaction mixture was stirred for 1.5 hours and then allowed to rise to -15 ° C. Stirring was continued for a further 15 minutes and then 350 ml of 10% hydrochloric acid was added. After decantation, the resulting residue is washed with water, dried and evaporated to dryness under reduced pressure. The resulting product (63.5 g) was taken up in toluene (400 mL) and the resulting solution was heated to 108 ° C and a 30% aqueous solution of hydrogen peroxide (180 mL) was added dropwise. Heating was continued at 90 ° C for 2 hours, then the reaction mixture was allowed to cool and filtered. The filtrate is decanted and the organic phase is washed with water, 10% ferric ammonium sulfate solution and water, and extracted twice with 300 ml each of 2N sodium carbonate solution. The combined extracts were acidified with concentrated hydrochloric acid and extracted several times with methylene chloride. The combined extracts were dried and evaporated to dryness under reduced pressure to give the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ )

5.21 (sl): OH: 6.55 (dddd): H ₄ ; J H ₄ -CH ₂ = 9, J H ₄ F ₂ = 2.5, J H ₄ -H ₆ = 3, J H ₄ F ₅ = 8; 6.74 (ddd): H ₆ ,

J H ₆ -H ₄ = 3, J H ₆ -F ₂ = 7; 7.01 (ddd): H ₃ , J H ₃ H ₄ = 9,

JH ₃ -F ₂ = 10, JH ₃ -F ₅ = 5.

Step B: 2,5-Difluoroanisole

Water (35.0 g, 350 mL of acetone, 44.6 g of potassium carbonate, 40.7 g of potassium bicarbonate, neutralized over potassium bicarbonate) was treated with water at room temperature and the aqueous mixture was stirred at room temperature. extraction with diethyl ether. The extract was washed, dried and evaporated to dryness under reduced pressure. 39.8 g of the title compound are obtained. NMR ^(I9 FCDC1 _3, 188 MHz)?

119.1 (dddd) F ₅

144.1 (dddd) F ₂ Jj ₂ -f5 - 15

= 5 Jf ₂ -h ³ = 1θ> 5 = 8 JF2 ^4-H = 3.5 = 10 3f ₂ -H 6 = 7

HU 211 871 A9

Step C: 3,6-Difluoro-guaiacol

Proceed as in Step A above, starting from 55.15 g of a 1.6 M solution of n-butyllithium in hexane, 220 mL of the compound prepared in Step B above, and trimethyl 36.4 g. borate and 200 ml of 30% hydrogen peroxide solution. 44.7 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 200 MHz)

4.02 (d, J = 2) OCH ₃

5.56 (sl) OH

6.57 (ddd) H ₄

6.75 (dt) H ₅ ^ Η5-Η4 ⁼ 9.5; H _{H5- F3} = 5; Jsf = 9.5; Jh4-fi = 1θ, 5;

Jh4-F6 = 5.

Step D: 3,6-Difluoro-catechin

The procedure of Reference Example 2, Step B, was followed using 21.15 g of the compound prepared in Step C, above, and 250 mL of a 1 M solution of boron tribromide. 17.62 g of the title compound are obtained.

Step E: 2,5-Difluoro-3,4-dihydroxyphenylhydroxyacetic acid

To a solution of 11.7 g and 7.37 g of monohydrated glyoxylic acid in 40 ml of water from the compound prepared in Step D above is added at + 10 ° C.

A solution of sodium carbonate (7.68 g) in water (80 ml) was added and the resulting mixture was stirred at 10 ° C for 30 minutes and then at room temperature for 3.5 hours. 0.74 g of monohydrated glyoxylic acid is then added and stirring is continued at room temperature for 1 hour. Then the pH of the reaction mixture was adjusted

To pH 1 is added concentrated hydrochloric acid. After extraction with ethyl acetate, the extract is dried, filtered and evaporated to dryness under reduced pressure. 17.0 g of the title compound of this step and of the title compound are obtained.

IR spectrum: Nujol complex absorption in the OH-NH region

C = O 1700 cm ^-1 aromatic 1640-1612-1526-1488 cm40. Example 6 (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-4,5-dihydroxy) -3-methoxyphenyl) -methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0-oct-2-en-3-yl) -2 -propenyl) -imidazo (1,2-a) pyridinium inner salt

Step A: [2-Chloro-4,5-bis [(2-methoxyethoxy) methoxy] 3-methoxy] benzaldehyde and 2-chloro-3,4-bis [(2-methoxyethoxy) - methoxy] -5-methoxybenzaldehyde

A mixture of 2.17 g of a solution of 3,4-bis [(2-methoxyethoxy) methoxy] -5-methoxybenzaldehyde, 21.7 g of methylene chloride and 1.76 g of 65% calcium hypochlorite in 10 ml of water was added. After stirring at 0 ° C to 5 ° C for 20 minutes, the mixture is extracted with methylene chloride. The extract was washed with water, dried and evaporated to dryness under reduced pressure. Thus 2.34 g

In the form of a 7: 3 mixture of isomers, the isomers mentioned in the title of the step are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

3.37: OCH ₃ groups; 3.7-4.1: central _CH2 groups; 5.29-5.33: OCH ₃ ; 3.91: OCH ₃ ; 7.54 and 7.30: ₆ H; 10.38 and 10.40: CHO.

Step B: [2-Chloro-4,5-bis [(2-methoxy-ethoxy) -methoxy] -3-methoxy-styrylcarboxylate and the corresponding 5-methoxy-isomer between + 5 ° C and + 10 ° C To a stirred solution of lithium bromide (2.162 g) in tetrahydrofuran (60 ml) and triphenylphosphoroacetate (4.03 ml) was added 2.97 ml of diethylamine and a solution of 6.72 g (60 ml) of tetrahydrofuran in the isomer mixture obtained in Step A above. . The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was taken up in methylene chloride and the resulting solution was washed with N hydrochloric acid, water, dried and evaporated to dryness under reduced pressure. 8.8 g (7: 3) of the two isomers mentioned in the title are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

1.35 (t, d) 4.28 (q ^ d): CO ₂ Et; 3.37-3.38: OCH ₃ groups; 3:57 (m) -3,84-4,04 (m): the central _CH2 groups; 3.88 (s) - 3.86 (s): OCH ₃ ; 5.24-5.28: OCH ₂ groups; 6.34 (d) -6.38 (d): CH = CH-CO ₂ ; 8.03-8.05 (d): -CH = CH-CO ₂ ; 6.93-7.30: aromatic hydrogen.

Step C: 12-Chloro-4,5-bis [(2-methoxyethoxy) methoxy] 3-methoxy) styrene and the corresponding 5-methoxy isomer

To a solution of 2.83 g of methylene chloride in 20 ml of methylene chloride at -70 ° C was added 11.7 ml of a 1M solution of diisobutylaluminum hydride in hexane and the same mixture was added to the same mixture. at room temperature for 20 minutes. After addition of 2 ml of water, stirring was continued at 20 ° C for 30 minutes, and the reaction mixture was dried, filtered and evaporated to dryness under reduced pressure. 1.95 g of a 7: 3 mixture of isomers are obtained in the same manner as in the step.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

3.37-3.38: OCH ₃ groups; 3,54-3,84-3,97 (m): the central _CH2 groups; 3.87 (s): OCH ₃ (3-position); 4.34 (d): -CH ₂ -OH; 5.29 (t): _CH2-CH = CH;

6.93 (d): -CW = CH-CH _2; 7.19 (s): aromatic hydrogen.

Step D: 2-Chloro-4,5-bis [(2-methoxyethoxy) methoxy] -3-methoxy] - {1,2-epoxy) styrene (Isomer A) and [2-Chloro-3,4 of bis-1- (2-methoxyethoxy) methoxy] -5-methoxy (1,2-epoxy) styrene (isomer B) at -5 ° C from a mixture of isomers prepared as described in Step C above, 4.78 g. To a solution of methylene chloride (ml) was added a solution of metachloroperbenzoic acid (2.79 g) in methylene chloride (50 ml).

The resulting reaction mixture was stirred at 20 ° C for 16 hours. The reaction mixture was then treated with 20 ml of saturated sodium bicarbonate solution and 50 ml of methylene chloride, followed by decantation, washing with water, drying and evaporation to dryness under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: methylene chloride: acetone = 85:15, v / v). 2.12 g of isomer A and 716 mg of isomer B are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

SHE / \

3.07 (t, d): CH CH-CH ₂ ; 3.37-3.38 8s): OCH ₃ groups; 3,57-3,83-3,97 (m): the central _CH2 groups; 3.88 (s): OCH ₃ (at position 3);

3.83 to 4.06 (ddd): -CH ₂ OH; 4.19 (d, J = 2):

SHE / \

-CH CH-CH ₂ ; 5.2 to 5.26 (s) OCH ₂ group; 1.94 (d, d J = 5.5-7.5): OH.

Step E: Diphenylmethyl [[2-chloro-4,5-bis ((2-methoxyethoxy) methoxy] -3-methoxy] phenyl] chloroacetate

a) Opening of the epoxy ring at 0 ° C A solution of 1.306 g of copper (II) chloride, 20 ml of tetrahydrofuran and 1 g of lithium chloride is stirred for 5 minutes and then added to this solution at 20 ° C as described in Step D above. produced. A solution of 2.055 g of epoxy type A isomer in 10 ml of tetrahydrofuran. The resulting reaction mixture was stirred at the same temperature for 5 hours and water (10 mL) was added. After decantation, washing, drying and evaporation to dryness under reduced pressure, 2.09 g of intermediate nuts are obtained.

b) Oxidation At a temperature of + 5 ° C to + 10 ° C, 9 ml of water, 3.79 g of sodium periodate are added to a solution of the nuts prepared in step a) above in a mixture of 2.035 g of carbon tetrachloride and 6 ml of acetonitrile. 50 mg of hydrated ruthenium chloride (containing 36-40% ruthenium) and the resulting reaction mixture was stirred at 20 ° C for 1 hour. Methylene chloride (20 ml) and water (10 ml) were added followed by decantation, washing, drying and evaporation to dryness under reduced pressure. 1.8 g of intermediate acid are obtained.

(c) Esterification

To a solution of the product obtained in step b) above in a solution of 1.8 g of methylene chloride in 20 ml is added 790 g of diphenyl diazol methane, which is stirred at 20 ° C for one hour and then concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride / methanol 9: 1 (v / v) as the eluent. 1.525 g of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

3.34-3.37: OCH, groups; 3,47-3,57-3,74-3,96 (m): the central _CH2 groups; 3.87 (s): 3-methoxy;

5.12-5.24: OCH ₂ groups;

cl

5.94: C-CW-CO ₂ -; 6.89 (s): CO ₂ -CH.

Step F: Diphenylmethylamine oxy [[2-chloro-4,5-bis [(2-methoxyethoxy) methoxy] -3-methoxy] acetate

a) Introduction of a phthalimidoxy group

A mixture of the compound prepared as described in Step E above, was stirred for 5 hours in a mixture of 1.48 g, 7.5 ml of dimethylformamide, 363 mg of potassium acetate and 604 mg of N-hydroxyphthalimide.

b) Hydrazinolysis

To the reaction mixture obtained in the previous step was added 180 μΐ of hydrazine hydrate at 20 ° C, followed by stirring at the same temperature for 20 minutes. The phthalyl hydrazide precipitates, is filtered off and washed with acetonitrile. Combine the filtrate and the washings and evaporate to dryness. The residue was purified by chromatography on silica gel using a 3: 1 by volume mixture of methylene chloride and ethyl acetate as eluent. 1.11 g of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz)

3.33-3.37 (s): _OCH3 groups; 3,44-3,57-3,713,97 (m): the central _CH2 groups; 3.88 (s): 3-methoxy; 5.09 and 5.23: OCH ₂ groups;

SHE

5.73 (s): -Ctf-CO ₂ -; 5.84: NH ₂ ; 6.91 (s) -6.94:

CO ₂ CH-O ₂ ; 7.07-7.35: aromas.

Step G: [[(] - [2-Chloro-4,5-bis (2-methoxyethoxy) methoxy] -3-methoxy] phenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxy] imino] - [2 - [(triphenylmethyl) amino] thiazol4-yl] acetic acid

In the same manner as in Example 1, Step E, 1.1 g of the compound prepared in Step E above and 835 mg of oxo [2 - [(triphenyl) oxide [8 - 828 mg] are obtained. -methyl) -amino] -thiazol-4-yl] -acetic acid. The product obtained is not isolated but used in the next step without further purification.

Step H: 4-Methoxybenzyl 7beta - [[[[[1- [2-chloro-4,5-bis - [(2-methoxyethoxy) methoxy] -3-methoxyphenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethylamino) -thiazol-4-yl] -acetyl] -amino] -3 - {(Z) -3-chloro-1-pmpenyl] -8- oxo-5-thia-l-azabicyclo [4,2,0Jokt-2-ene-2-carboxylate

The starting material was prepared as described in Step G of Example 1 and 4-methoxybenzyl 7-beta-amino-3- [4-methoxybenzyl] was prepared as described in Step G above and prepared as described in EP 333 154. (Z) -3-chloro-1-propenyl] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylate hydrochloride. Purification by chromatography on silica gel (eluent: methylene chloride: ethyl acetate = 9: 1) gave the title compound (36 g).

HU 211 871 A9

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3.25-3.29-3.36-3.37-3.81: OCH ₃ groups; 3,24,0: -SCH ₂ -, C-CH ₂ Cl, central CH ₂ ;

4.94 (d > -5.25: CO ₂ CW &_gt; ₂ , NH-CH-CH-S, OCH ₂ O groups; 5.75 (m): -CH = C H -CH ₂ (Z 5.9 (m): NH-C H -CH-S; 6.28 (d): -C H = CH-CH ₂ (Z); 6.87,15: aromatics + H ₅ thiazole; .

Step I: 4-Methoxybenzyl 7beta - [[[[[1- [2-chloro-4,5-bis - [(2-methoxyethoxy) methoxy] -3-methoxyphenyl] -2-oxo-2- (diphenylmethoxy) ethyl] oxyimino] - [2- (triphenylmethyl) amino] -thiazol-4-yl] acetyl] -amino] -3 - [(Z) -3-iodo-1-propenyl] -N- 8-oxo-5-thia-l-azabicyclo [4,2,0jokt-2-ene-2-carboxylate

The procedure of Example 1, Step G was followed, using 1.33 g of the compound prepared in Step H above. Purification by silica gel chromatography (9: 1 methylene chloride: ethyl acetate) gave the title compound (990 mg).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz)

3.24 (s) -3.26 (s) -3.35 (s) -3.36 (s): 2 OCH ₃ groups; 3.2-4.0 (m): -SC // _2- C and central CH ₂ ; 3.8 (s, d), 3.85-3.88 (s): 2 = C-OCH ₃ groups: 4.9-5.07 (m), 5.18-5.25 (m): 0-CW ₃ groups; 4.97-5.02 (d): CH-CH2 --S-; 5.87 (ddd): NH-CH-CH-S-; 6.51-6.53 (s): = NH-O-CH =; 6.79-6.80 (s): H ₅ thiazole; 6.84-7.37 (m): aromatic, the rest CH = C and

SHE

II

CO _; -CH-d) _; ; 7.78-8.3 (d): -CN // - CH.

Step J:] - [3- [7beta-1 [[[II- [2-chloro-4,5-bis-1- (2-methoxyethoxy) methoxy] -3-methoxyphenyl] -2-oxo-2 - (diphenylmethoxy) ethyl] oxyimino [2- (triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] -2 - [(4-methoxybenzyloxy) carbonyl ] -8-oxo-5-thia-N-azabicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl] imidazo (1,2a) pyridinium iodide

The procedure of Example 1, Step H was followed using 735 mg of imidazo [1,2-a] pyridine from the compound prepared in Step I above. This gave 750 mg of the title compound. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

3,145-3,38: -S-CH ₂ -C =, -CO-CH ₃ ;

3.78-3.79-3.85-3.87: = C-OCH ₃ ; 3.3-4.0: central

CH ₂ groups; 4.9-5.02: NH-CH-CH-S-; 5.8 (m): = NH-CH-CH-S; 6.27 (m): -CH = CH-CH ₂ (E); 6.53-6.54: = N-O-CH; 6.76-7.3: CO ₂ -O ₂ ,

-C 7 / = CH-CH ₂ and aromatics; 7.6-9.10: Imidazopyridine.

Step K: (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2-chloro-4, 5-dihydroxy-3-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene -3-yl) 2-pmpenyl) imidazo (1,2-a) pyridinium inner salt The procedure described in Example 1, Step I was carried out using 750 mg of the compound prepared in Step J above. 463 mg of the title compound of this step and of the title compound were obtained.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.12 (d, d): = NH-CH-Ctf-S-; 5.28 to 5.3: // CHC = N ⁺ _2; 5.74 (m): = NH-CH-CH-S; 5.75: = N-OCH-: 6.23 (m): = C-CH = Ctf-; 6.78 (s): H ₅ thiazole;

6.84 (d, J = 15): = C-Ctf = CH- (E); 7.36: NH ₂ ;

7.58-8.93: Imidazopyridine; 9.55: mobile hydrogens.

Example 41 (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-3,4) -dihydroxy-5-methoxyphenyl) -methoxy) -imino) -acetyl) -amino) -2-carboxy-8-chloro-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-3 yl) -2-propenyl) imidazo (1,2-a) pyridinium inner salt Example 40 EC. The title compound is prepared as described in Steps 1 to 6 or the isomer B obtained as described in Example 40, Step D to give the title compound.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.5-3.7 (m): _S-CH2-C =; 3.73 to 3.74 (s): _OCH3;

5.18: NH-CH-CH2 --S; 5.29: _CH2 N ^+; 5.79 (ddd):

NH-CH-CH-; 5.83-5.85 (s): = N-O-CH =; 6.25 (m): CH = CH-; 6.6 (s) -6.78 (s) -6.82 (s): aromatic,

H ₅ thiazole; 6.88 (d, d, J = 16): -Ctf = CH-CH ₂ (E);

7.58-8.96 (6H) Imidazopyridine.

Example 42 (6R- (3- (E) -alpha, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-4,5) dihydroxy-3-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0jokt-2-en-3-yl) -2-propenyl) quinolinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [2-Chloro (4,5-bis - [(2-methoxyethoxy) methoxy] -3-methoxyphenyl)} 2-oxo-2- (diphenylmethoxy) ethyl] oxyimino] -? - (triphenylmethyl) amino] thiazol-4-yl] acetylamino) -2 - [(4-methoxybenzyl) oxy) carbonyl] -8-oxo-5-thia-l-azabicyclo [4,2,0j- [oct-2-en-3-yl] -2-propenyl-quinolinium iodide

The procedure of Example 40, Step J was followed using 700 mg of the compound prepared in Example 40, Step I and 282 μΐ of quinoline. This gave 706 mg of the title compound.

Step B: (6R- (3- (E), 6alpha, 7beta (Z))) 1- (3- (7 - (((2 amino-4-thiazolyl)) - ((carboxy- (2-chloro-4) , 5-dihydroxy-3-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4,2,0) oct-2 inner salt of -en-3-yl) -2-propenyl) -quinolinium

The procedure of Example 40, Step K, was followed using 690 mg of the compound prepared in Step A above to give 434 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.4-3.8 (m): _S-CH2 -; 3.65-3.73 (s): = _C-OCH3;

HU 211 871 A9

5.1-5.14 (d): -NH-CH-CH-; 5.73: -NH-CH-CH-;

5.75 (s): = NO-CH =; 5.89 (m): CH = CH-C // _2;

6.75-6.76-6.78-6.79 (s): H ₅ thiazole, aromatic hydrogen; 6.35 (m): -CU = CH-C (E); 6.97 (dl, J = 16): -CH = CH-C (E); 8.07-9.58 (7H) quinoline; 9.53: -NH-C //-CH-; 7.35-9.24-13.0: mobile hydrogens.

Example 43 (6R- (3- (E), heptane, 7beta (Z))) 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-3,4) -dihidmxi-5-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- il) -2-propenyl) quinolinium inner salt

Step A: 1- [3- [7beta - [[[[[1- [2-Chloro (3,4-dihydroxy-5-methoxyphenyl) -2-oxo-2- (diphenylmethoxy) ethyl]]]] oxyimino] - [2- (triphenylmethyl] -amino] -thiazol-4-yl] acetyl] amino] -2 - [(4-methoxybenzyloxy) carbonyl] -8-oxo-5-thia- l-azabicyclo [4,2,0] - [oct-2-en-3-yl] -2-propenyl-quinolinium iodide

The procedure of Example 40, Step J was followed. using 450 mg of the compound prepared in Example 41, Step E as starting material. This gave 440 mg of the title compound.

Step B: (6R- (3- (E), 6alpha, 7beta (Z))) - 1- (3- (7 - (((2 amino-4-thiazolyl)) ((carboxy- (2-chloro-3, 4-dihydroxy-5-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene -3-yl) 2-propenyl) quinolinium inner salt

The procedure of Example 40, Step K, was followed using 440 mg of the compound prepared in Step A above to give 256 mg of the title compound of this step.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.48 to 3.84 (m): _S-CH2; 3.71-3.73 (s): C-OCG3;

5.17 d, d): -NH-CH-Ctf-C; 5.8 (m): -NH-CtfCH-, 5.82-5.84 (s): N-O-Ctf = 5.88 (m):

-CH = CH-C // ₂ -; 6.38 (d, m): CH ₂ = CH-CTF; 6.97 (d, d J = 16): -C7 / = CH- (E); 6.59 (s) -6.77 (s) -6.81 (s): H ₅ thiazole, aromatic; 8.06-9.58: quinoline (7H);

9.53-9.64 (d):

C-NH;

II

7.54 (m) -9.25 (m) -13.7 (m): mobile hydrogens.

Example 44

6R- (3- (E), heptane, 7beta (Z (S ') -)) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4,2,0) oct-2-ene -3-yl) -2-propenyl-quinolinium inner salt

10 mg of the compound prepared as described in Example 3 are subjected to chromatography on a MICROBONDAPACK C ₁₈ column eluting with water (adjusted to pH 2.7 with trifluoroacetic acid) and acetonitrile (containing 0.025% trifluoroacetic acid) in a ratio of 86:14 by volume. mixture. 1.5 mg of the desired (S) -isomer and 1.5 mg of the (R) -isomer are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz)

3.40-3.60 (m): _CH2 S; 5.13 (d, J = 5): H ₆ ; 5.77 (dd,

J = 5 and 8): H ₇ (d, after exchange); 5.32 (s): φ-CHO; 5.87 (m): CH ₂ N ⁺ ; 6.31 (m): CH = C H - CH ₂ ; 7.00 (d, J = 16): CW = CH-CH _2; 6.77 (s): 1 H thiazole; 6.72 (m): H '', H ₆ '; 7.25 (s): mobile 2H; 8.06 (dd, J = 7, 8), 8.28 (ddI, J = 7 and 9): _H6 ', _H7'; 8.22 (dd, J = 6 and 8): H ₃ '; 8.50 (d, J = 8) and 8.55 (d, J = 9): H4 _'s and H';

9.33 (d, J = 8): H _g '; 9.57 (d, J = 6): H ₂ ".

Example 45

6R- (3- (E), heptane, 7beta (Z (R *) -)) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4,2,0) oct-2-ene -3-yl) -2-propenyl] quinolinium inner salt

This compound was isolated as the (R) -isomer by chromatography as described in Example 44. Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz)

3.39 to 3.75 (m): _CH2 S; 5.16 (d, J = 5): H ₆ ; 5.32 (s): φ-CH-O; 5.74 (dd, J = 5 and 8): _H7; 5.88 (m): CH ₂ N ⁺ ; 6.36 (dt): CH = C H - CH ₂ ; 6.99 (d, J = 16): C H = CH-CH ₂ ; 6.73 (m) (3H); H _{5 is} thiazole and H ₂ 'and H ₆ '; 7.26 (s): mobile 2H; 8.07 (t, J = 8) and 8.28 (t, J = 8): H ₆ "and H ₇ "; 8.22 (dd, J = 6 and 8th): H ₃ '; 8.50 (d, J = 8) and 8.55 (c, J = 9): _H5 'and H _4'; 9.33 (d, J = 8): Hg '; 9.59 (d, J = 6): H ₂ "; 9.59 (d, m): CONH-CH; 014 (s): mobile hydrogen.

Example 46 [6R- [3- (E) -6alpha.7-Beta (Z) (S *)]] - 1- [3- [7 - [[(2-Amino-4-thiazolyl)] [carboxylic acid , 5-dichloro-4,5-dihydroxyphenyl) - [methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct- 2-en-3-yl) -2-propenyl] -4- (methylthio) quinolinium inner salt (R) or (S) or (R + S) mixture

This compound is the resolved isomer of the product prepared in Example 18.

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

2.71 (s): φ-SMe; about 3.57: = C-CH ₂ S; 5.15-5.25:

H ₆ and N ⁺ -CW ₂ -CH =; near 5.80 (sl): O-CH-φ and

H ₇ ; 6.25 (m): = C ₁ --CH ₂ ; about 6.98 (d): = CC = CH; 6.81 (s): H, thiazole; 7.00: ₆ H; 7.32 (1) 2H:

NH ₂ ; 7.96-8.70 (d): H pyridine; 9.58 (d): CN / 7CH; II

SHE

9.84 (s) -9.92 (s): OH; 13.28-13.78: other mobile hydrogen.

Example 47

6R- (3- (E), heptane, 7beta (Z (S *) -)) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- dichloro-3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4,2,0) oct-2-ene -3-yl) -2-pmpenyl) imidazo (1,2-a) pyridinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.15 (d, J = 5): H ₆ ; 5.29 δ (m): C ₁₂ -N ⁺ ; 5.79 (s):

OC / Ζ-φ; 5.79 (dd, d exchange): H ₇ ; 6.24

GB 211 871 A 9 (dt, J = 15.5 and 6.5): CTF = CH _2, close to 3.4 H; 6.81 (s) -6.99 (s): H ₅ thiazole, aromatic hydrogen; 6.86 (d, J = 15.5): = CC = CH; 7.58 (0-8.06 (t): H ₅ ', H ₆ ';

8.20 (d): H ₇ '; 8.96 (d): H 4 '; 8.28 (d> -8.44 (d): H ₂ ', H ₃ '; 9.56 (d): CH-N 1 - CO; 7.35 (m): close to 2H; 9.87 (sl): 1H, 9.96 (sl): 1H, mobile hydrogen.

Example 48

6R- (3- (E), 6alpha, 7beta (Z (R ') -) -1) - 3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2 5-dichloro-3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo (4,2,0) oct-2- inner salt of en-3-yl) -2-pmpenyl) imidazo (1,2-a) pyridinium

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

5.15 (d, J = 5): H ₆ ; 5.27 (m): Ctf ₂ -N ⁺ ; 5.78 (d, J = 5): H ₇ ; 5.81 (s): O-Ctf-φ, nearly 1.7 H; 6.24 (dt, J = 16 and 6): _CH2 = CW-close H, 0.85; 6.84 (s) -6.99 (s): nearly 1.7 H, H ₅ and aromatic 1H; 6.85 (d, J = 16): = CC // CH; 7.57 (dd, J = 6 and 7): H _s'; 8.05 (dd, J = 7 and 8.5): H ₆ '; 8.17 (d, J = 8.5): H ₇ '; 8.94 (d, J = 6): H ₄ '; 8.26 (d, J = 2 / -8.42 (d, J = 2): H ₂ ', H ₃ '. By following similar procedures to those described in the previous examples or starting from the appropriate intermediates, the following target compounds can be prepared:

Example 49

6R- (3- (E), 6alpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy-4-methoxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) -2- pmpenyl) quinolirtium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.52 (d) -3.70: CH ₂ S; 3.72-3.74: C-OMe; 5.15 (d, singlet): H ₆ ; 5.57 (dd) -5.8 (m): H ₇ ; 5.83 to 5.87:

SHE /

φ-CH; 5.70-6,0: _CH2-N ^+;

\

0 = 0

6.42 (d separated) -6.75 (d separated) aromatic hydrogen; 6.40 (m) -6.99 (d, singlet, J nearly 16): ethylene (E); 6.78-6.82: H ₅ thiazole; 8.07 (0-8.26: H ₃ ', H 1 ·, H ₇ '; 8.53 (d) -8.56 (d) -9.34 (d): H ₄ ', H ₅ ' 9.53 (d), _H8 '; 9.45 (dj 9.56 (d). NHC;

II

SHE

7.45 and 8.84: mobile hydrogen.

Example 50

6R- (3- (E), 6alpha, 7beta (Z)) -7- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-dihydroxy-4-methoxy) phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia -] - aza-bicyclo [4,2,0] oct-2-en-3-yl) -2- propenyl) thieno (2,3-b) pyridinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz)

3.54 (d) nearly 3.68 (d): = C-CH ₂ S; 5.18 (m): H ₆ ;

5.76 (m) -5.96 (m): H ₇ : 5.72 (s) -5.74 (s):? OM-OMe;

5.67 (m): C ₁₂ -CH =; 5.83 (s) -5.87 (s): CCl-O; nearly 6.80 (s) separated: hydrogen thiazoles; 6.42 (m) -o, 73 (m): H ₅ , H ₆ ; 6.30 (m) -7.15 (d) separated:

= C-CH = C 1 -CH (E); 7.88 (d): H ₃ '; 8.29 (d): H ₂ ';

8.15 (m): H ₅ '; 9.08 (d): H ₄ '; 9.22 (d): H ₆ '; 9.44 (d) -9.53 (d): = CN / 7-CH; 7.44 (m) -8.60-8.90:

mobile hydrogen.

Example 51

6R- (3- (E), 6alpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy-5-fluoro- phenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-en-3-yl) -2 -propenyl) -imidazo (1,2-a) pyridinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 400 MHz)

7.35 (m) -8.69 (m) -8.82 (m): mobile hydrogens;

3.52 (m) nearly 3.70 (m): CH ₂ S; 3.74 (s) -3.75 (s): C _1-3 O-O; 5.15 (d, singlet): H ₆ ; 5.74 (dd, d exchange) -5.81 (dd, d exchange): H ₇ ;

5.29 (m): Ctf ₂ -N ⁺ ; 5.83 (s) -5.86 (s): O-Ctf-φ;

6.25 (m) -6.90 (d, resolved): // C = CH - _CH2; 6.43 (d): H ₆ '; 6.72-6.80 (m): H ₅ 'and H ₅ thiazole; 7.58 (t): H ₆ '; 8.21 (d) -8.96 (d): H ₄ ", H ₇ "; 8.29 (sl): H ₃ ';

8.44 (sl): H ₂ '; 9.44 (d) -9.54 (d): CO-N H -CH.

Example 52

6R- (3- (E) .alpha., 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3,4-trihydroxyphenyl)) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-3-yl) -2-propenyl) -imidazo inner salt of (1,2-a) pyridinium

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.54 (m): CH ₂ S; 5.15 (d): H ₆ ; 5.82 (m): _H7 and CW-O-φ; 5.28 (m): = CH-CW ₂ -N ⁺ ; 6.26 (m): CH =,

6.5-7.4 (m): aromatic 6H; 7.58 (t): H ₅ '; 8.06 (t): H ₆ ';

8.20 (d), 8.96 (d): H ₄ ', H ₇ '; 8.29 (sI) -8.44 (sl): H ₂ ', H ₃ '; 9.41 (d) -9.53 (d): CO-Ntf-CH; 8.69 (mj-9.27 (m) -7.36 (m): mobile hydrogens.

Example 53

6R- (3- (E), 6alpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-difluoro-4,5- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-pmpenyl) imidazo (J, 2-a) pyridinium inner salt

NMR (DMSO, 300 MHz) close to 3.70: _CH2 S; 5.09 (d) -5.14 (d): H ₆ ; 5.29 (m): CH ₂ -N ⁺ ; 5.58 (s) -5.59 (s): O-CH-φ; 5.72 (m): H ₇ ;

6.22 (m): CH-C // - _CH2; 6.68 (m): H ₆ '; 6.77 (s) 6.77 (s) -6.78 (s): H ₅ thiazole; 6.85 (d, J = 16): = CC = CH-; 7.58 (1) -8.06 (l): _H5 ', _H6'; 8.19 (d) -8.96 (d): H ₄ , H ₇ '; 8.28 (m) -8.44 (sl): H ₂ ", H ₃ "; 7.32 (m), 9.5-9.9 (m): mobile hydrogens

Example 54

6R- (3- (E), 6alpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-difluoro-4,5- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-propenyl) quinolinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3:45 (m): _CH2 S; 5.09 (d) -5.14 (d): H ₆ ; 5.72 (m): H ₇ ; 5.58 (s) -5.59 (s): OC 1 - CO; 5.88 (m): CH ₂ 44

HU 211 871 A9

N ⁺ ; 6.34 (m): CH ₂ = CW-CH; 6.94 (d, J = 16) -6.97 (d, J = 16): C H = CH-CH ₂ ; 6.67 (m): H ₆ '; 6.75 (s) 6.77 (s): H ₅ thiazole; 8.07 (m) -8.26 (m) -8.53 (m) 9.34 (d) -9.57 (d): quinoline; 7.32 (m) -9.5-9.9 (m): mobile hydrogens.

Example 55

6R- (3- (E), halpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3,4- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-pmpenyl) pyridinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.58 (m): CH ₂ S; 5.18 (d, d): H ₆ ; 5.79 (m): H ₇ ; 5.41 (sl): CH ₂ N ⁺ ; 5.64 (s) -5.65 (s): OC 1 - C =; 6.30 (m): CH = _CH-CH2; 7.02 (dd, J = 16): CH = CHCH ₂ ; 6.70 (dd): H ₆ '; 6.78 (s> -6.80 (s): H ₅ thiazole;

8.18 (m). H ₃ +, H ₅ "; 6.83 (m): H ₄ '; 9.05 (d): H ₂ ', H ₆ ': 9.35 (d) -9.62 (d): CO-N / CH; 7.33 (m) -9.80 (m): mobile hydrogen.

Example 56

6R- (3- (E), halpha, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3,4- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-propenyl) 6,7-dihydro-5H-pyridinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

2.24 (m): _CH2 in the 6'-position; 3.14 (m) -3.37 (m): _CH2 in 5 'and 7 positions; 3.56 (m): CH ₂ S; 5.15 (d) -5.19 (d): H ₆ ; 5.79 (m): H ₇ ; 5.33 (d): = CHC / 7 N ₂ ^+; 5.63 (s) -5.65 (s): OC / 7-φ; 6.23 (m): CH = C 7 / -CH ₂ : 6.85 (d> -6.88 (d, J = 16): C 9 = CHCH ₂ ; 6.71 (dd, J = 10, 5 and 6): H ₆ "; 6.78 (s) -6.81 (s): H ₅ thiazole; 7.91 (m): H ₃ '; 8.43 (d, J = 8): H ₄ '; 8.76 (d. J = 6): H ₂ '; 9.54 (d) -9.63 (d): CH-NtfCO; 7.35 (m) -9.85 (m): mobile hydrogens.

Example 57

6R- (3- (E), halpha, 7beta (Z)) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3,4- dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-propenyl) quinolinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.4-3.7 (m): _CH2 S; 5.15 (dd): H 5 5.79 (m): H ₇ ; 5.62 (s) -5.64 (s): -O-Ctf-φ; 5.89 (m): _CH-CH2-N ^+;

6.37 (m): CH = C / Y-CH ₂ ; 6.97 (dd, J = 15.5): C H = CH-CH ₂ ; 6.76 (s) -6.80 (s): H ₅ thiazole; 6.70 (dd, J = 11 and 6): Hey '; 8.07 (m) -8.27 (m) -8.53 (m> -9.34 (d): quinoline; 9.58 (d): H ₂ ; 9.53 (d) -9.62 (d): CO-NtfCH; 7.30 (m) -9.83 (m): mobile hydrogen.

Example 58

6R- (3- (E), halpha, 17beta (Z)) -3- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3,4) -dihydroxy-phenyl) -methoxy-imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl) thiazolium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.50-3.75 (m): _CH2 S; 5.16-5.19 (d): H ₆ ; 5.81 (m):

H ₇ ; 5.33 (m): = CH-Ctf ₂ -N ⁺ ; 5.63 (s) -5.65 (s): OCW-φ; 6.26 (m): CH-C // - _CH2; 6.96 (dd, J = 16):

CH = CH-CH ₂ ; 6.71 (dd, J = 6 and 11): H ₆ '; 6.78 (s) -6.81 (s): H 1 thiazole; 8.37 (m) -8.51 (m): H ₄ ', H ₅ ';

10.20 (sl): H ₂ '; 7.30 (m), 9-5-9.9 (m) -13.25 (m) 13.75 (m): mobile hydrogens.

Example 59

6R- (3- (E), heptane, 7beta (Z)) -2- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3,4- dihidmxi-chlorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl) - 2-pmpenyl) isoquinolinium inner salt

Nuclear Magnetic Resonance Spectrum (DMSO, 300 MHz)

3.50-3.75 (m): _CH2 S; 5.18 (dd): H ₆ ; 5.80 (m): _H7;

5.53 (d): = CH-Ctf ₂ -N ⁺ ; 5.63 (s) -5.65 (s): O-Ctfφ; 6.37 (m): CH-C // - _CH2; 7.09 (dd, J = 15.5): CTF = CH-CH _2; 6.71 (dd, J = 11 and 6): H <"; 6.78 (s) -6.80 (s): H ₅ thiazole; 8.09 (t) -8.28 (t): H ₆ ', H ₇ ';

8.37 (d) -8.53 (d): H ₅ ', H _g '; 8.61 (d) -8.74 (d): H ₃ ', H ₄ '; 10.06 (s): H1 '; 7.35 (m) -9.84 (m): mobile hydrogens; 9.56 (d) -9.65 (d): CH-N H - CO.

Example 60

An injectable preparation was prepared using 500 mg of the product of Example 2 or 5 ml of sterile aqueous vehicle.

The following describes methods for assaying the pharmacological activity of the compounds of the invention.

In vitro activity as assayed by dilution in a liquid medium

Prepare a series of tubes by adding an equal volume of sterile medium to each tube. Subsequently, increasing volumes of test compound are added to each tube and each tube is inoculated with a bacterial strain. After incubation at 37 ° C for 24 hours in an oven, growth inhibition is evaluated by screening to determine minimum inhibitory concentrations expressed in g / cm ³ (English abbreviation: Μ IC). (Table I)

In vitro activity assay on solid media by dilution

A series of dishes is prepared by adding to each well an equal volume of sterile medium containing increasing amounts of the test compound and then inoculating each well with a variety of bacterial strains. After incubation in an oven at 37 ° C for 24 hours, growth inhibition was evaluated when no bacterial growth was observed. Thus, the minimum inhibitory concentrations expressed in g / cm ³ are determined. The results are expressed as MIC ₉₀ values, which are the minimum

A9 concentrations which inhibit the growth of the strain by 90% (Table II).

MIC, Table I

Example number of test compound Enterobacteries Clo- acae 1321 Staphylocoques aureus SG 5 11 Proteus A 235 Pseudomonas Aeruginosa 1771 9 0.04 0.08 0.04 0.3 3 0.08 0.15 0.04 0.6 1 0.08 0.15 0.04 0.06 2 0.15 0.30 0.02 0.3

MlC ^ j, II. spreadsheet

The test compound Oracillin- sensitive, penicillin- resistant Cephalosporinases produce Increased spectrum of β1 actamase pseudo- monas ae- Products Staphylo- shoot entero- producer ruginosa example number coccus au- bacterium- enterobak- strains today reus strains (20 strains) strains (20 strains) tertiary strains (16 strains) (39 strains) 39 2.5 0.3 2.5 0.08 43 0.3 2.5 1.2 1.2 27 5 0.3 10 0.08

PATENT CLAIMS

Claims (15)

PATENT CLAIMS Compounds of the formula I, in the form of a syn isomer thereof, in the form of the (R 1) or (S) or of the (R, S) mixture or of the salts or inner salts of mineral or organic acids of the formula I _{Rb R2, R3} and _R5 are independently hydrogen, halogénatomol, hydroxy, C1-4 alkoxy. mercapto, C1-4 alkylthio. nitro. cyano, amino, 1- C4-C4 alkylamino, C2-C8 dialkylamino, carbamoyl, C2-C5 (alkylamino) carbonyl, C3-C9 (dialkylamino) carbonyl, carboxy, They are C 5 -C 5 alkoxycarbonyl, C 1 -C 8 acyloxy, R ₄ is hydroxy or C 1 -C 8 alkoxy, provided that when R ₃ is hydroxy or C 1 -C 8 acyloxy, then R 1, R ₂ and R ₅ at the same time are other than hydrogen, A and A'independently represent hydrogen, 1 equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or organic amino base, or only one or both of -CO ₂ A or -CO ₂ A ' means the wavy line indicates that the -CH ₂ R ₆ group may be in the E or Z position and R ₆ is a quaternary ammonium group of the formula (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (ΧΧΠ) or (ΧΧΠΙ) X is oxygen or sulfur or methylene or imino, Q, J, Y, T, U, V, W and Z each independently represent a methyl group or a nitrogen atom, provided that each of these ring groups contains 1 to 5 heteroatoms and at least one of these heteroatoms is nitrogen and the ring groups may be substituted with one or more R or R 'groups; R and R 'independently of one another are halogen or C 14 alkyl, C 1 -C 4 alkoxy, cyano, -OC ₂ -C 7 -CONQ, (Q ₂ ), -NQ, (Q ₂ ), -SO ₂ NO 4 ( Q 2).-CS-NH ₂ , -nh-co-q, -ch = n-oh, -CH-N-O-Q], -CH ₂ -CN or -CH ₂ -S-Q | Q ₁ and Q ₂ are independently hydrogen or C 1 -C 4 alkyl, P 1, P ₂ and P ₃ independently represent an alkyl group containing up to 4 carbon atoms optionally substituted with one another in R and R 'and the dashed line between P ₁ and P ₂ indicates that P 1 and P _{2 are} optionally 5 - or form a 6-membered heterocyclic group with the nitrogen atom to which they are attached. Compounds of general formula (1) according to claim 1, wherein R ₆ represents one of the following groups: (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX). (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVIII), (XXXIX), (XXXXL), (XLI), (XLII), (XLIII) ), (XLIV), (XLV). (XLVI), (XLVII). (XLVIII) or (XLIX) or (L), (LI), (LII), (Lili), (LIV), (LV), (LVI), (LVII), (LVIII), (LIX) , (LX), (LXI), (LXII), (LXIII), (LXIV), (LXV), (LXV1), (LXVII) or (LXVIII). Compounds of formula I according to claim 1 or 2, wherein R 1 is quinolinium, isoquinolinium, 4- (methylthio) pyridinium, thieno [2,3-b] pyridinium, imidazo [1,2-a] pyridinium or 6,7-dihydro-5H-pyridinium. Compounds of formula (I) according to any one of claims 1, 2 or 3, wherein R ³ and R ⁴ are both hydroxy. Compounds of formula (I) according to any one of claims 1, 2 to 3 or 4, wherein R ² and R ⁵ are both chlorine. Compounds of formula (I) according to any one of claims 1, 2 to 3 or 4, wherein R ² and R ⁵ are each fluorine. Compounds of formula (I) according to any one of claims 1, 2, 3 or 4, wherein R ¹ and R ² are each fluorine. The serine of any one of claims 1, 2 to 3 or 4 A9 is a compound of formula I wherein R ² is methoxy and one of R ¹ and R ⁵ is chloro. Compounds of formula (I) according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8: (6R- (3- (E) octyl, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,3-difluoro-4, 5-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) imidazo (1,2a) inner salt of pyridinium; (6R- (3- (E) octyl, 7beta (Z))) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-difluoro-3, 4-dihydroxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl) imidazo (1,2a) pyridinium inner salt; (6R- (3- (E) 6alpha, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2-chloro-4,5- dihydroxy-3-methoxyphenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-azabicyclo [4,2,0] oct-2-ene-3 -yl) -2-propenyl) quinolinium inner salt; (6R- (3- (E) 6alpha, 7beta (Z))) -1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (2,5-dichloro-4, 5-Dihydroxy-3-methoxyphenyl) -methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- 3-yl) -2-propenyl) imidazo (1,2-a) pyridinium inner salt; 6R- (3- (E), 6alpha, 7beta (Z ( ^s ') -)) - 1- (3- (7 - (((2-amino-4-thiazolyl)) ((carboxy- (3,4-dihydroxy) -5-fluorophenyl) -methoxy) -imino) -acetyl) -amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo- (4,2,0) oct-2-en-3 -yl) -2-propenyl) quinolinium inner salt; [6R- [3- (E) 6alpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (2-chloro-3,4- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form; [6R- [3- (E) 6alpha. 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl) [[carboxy- (3-cyano-4,5-dihydroxyphenyl) methoxy] imino] acetyl ] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) -2-propenyl] -quinolinium, In the form of (R) - or (S) - or (R + S); [6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-fluoro-4,5- dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form; [6R- [3- (E) 6alpha, 7beta (Z)]] 2- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (2,5-dichloro-3,4) -dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-3-yl ) -2-propenyl] quinolinium inner salt in the (R) - or (S) - or (R + S) form; [6R- [3- (E) octyl, 7beta [Z (S *)]]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (3-cyano-4) 5-dihydroxyphenyl) methoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-ene-3- yl) -2-propenyl] -thieno [2,3-b] pyridinium inner salt; [6R- [3- (E) octyl, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy (2,5-dichloro-3,4- dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-en-3-yl) - 2-propenyl] isoquinolinium inner salt in (R) - or (S) - or (R + S) form; [6R- [3- (E) halpha, 7beta (Z)]] - 1- [3- [7 - [[(2-amino-4-thiazolyl)] [[carboxy- (2,5-dichloro-3, 4-Dihydroxy-phenyl) -methoxy] -imino] -acetyl] -amino] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene-3 -yl) -2-propenyl] -4- (methylthio) pyridinium inner salt in the (R) or (S) or (R + S) form. 10. A process for the preparation of a compound of formula I wherein an aromatic aldehyde of formula II wherein R 1, R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1 is functional. and an aromatic aldehyde of formula (II) _p where R _1p , R _2p , R _3p , R _4p and R _5p are the same R 1, R ₂ , R ₃ , R ₄ and R ₅ or protected, is homologated to an α-hydroxy acid of formula (III), and the resulting acid of formula (III) is esterified to an α-hydroxy ester of formula (IV) wherein R ₇ is a readily cleaved ester, reacting the compound (IV) thus obtained with N-hydroxyphthalimide, reducing the resulting compound (V) to an O-substituted hydroxylamine derivative (VI) , condensing the compound of formula (VI) with a (2-amino-thiazolol) -glyoxylic acid derivative of formula (VII) wherein R _g is hydrogen or amino-protecting group, and then forms a compound of formula (VIII). a hydroxyiminoacetic acid derivative of a 7-amino-3- (3-chloro-1-propenyl) -8-oxo-5-thiaazabicyclo [4,2,0] oct-2-ene-2 of formula IX carboxylic acid hydrochloride ester or a salt thereof, wherein R ₉ is a readily cleaved ester residue, then amidated with a compound of formula (X) 7- (N-substituted amido) -3- (3-chloro-1-propenyl) -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid derivative is converted to the 3- (3-iodopropenyl) derivative of the formula (II), treated with a base corresponding to the substituent R1 and, if desired, the (E) or (Z) isomer is isolated from the product (XII). The Z) isomer is converted to the (E) isomer, or a product of formula XII is subjected to one or more of the following steps in any order: (a) hydrolyzing the protecting groups on the amino and / or hydroxy moieties and all or part of the ester groups or subjecting them to thiourea; b) esterifying the carboxyl group or carboxyl groups or reacting it with a base to form a salt, c) forming an acid salt at the amino group, d) separating the products of the (R, S) mixture form into the products of the (R) and (S) forms. 11. A process according to claim 1, wherein a substituted hydroxylamine derivative of formula (VI) is condensed with a compound of formula (XIII) to form a compound of formula (XII). 12. A compound of formula I according to claim 1 A9 compounds and their pharmaceutically acceptable acid salts as therapeutic compounds. 13. Compounds of formula (I) and pharmaceutically acceptable acid salts thereof according to any one of claims 1 to 6 as therapeutic compounds. 5 A pharmaceutical composition comprising as active ingredient at least one therapeutic compound according to claim 12 or 13. 15. Compounds of formulas (III), (IV), (V), (VIII), (X), (XI) and (ΧΠ), wherein the substituents have the meaning given in claim 10, as novel industrial products.