AU708973B2 - New cephalosporins containing in position 7 a substituted benzyloxyimino radical, their preparation process and intermediates, their use as medicaments - Google Patents

Abstract

Syn isomer of cpds. of formula (I), and their salts, are new. In (I), R1-R3, R5 = H, halo, OH, 1-4C alkyl (opt. substd. by halo, 1-4C alkyloxy, SH etc.); R4 = OH or 1-8C acyloxy; R7 = H or (1-3C alkyloxy)carbonyl; A = e.g. H, an equivalent of alkali(ne earth) metal, Mg, ammonium or aminated organic base etc.; or CO2A = CO2-; wavy line shows that CH2R6 can be in E- or Z-position; R6 = e.g. quat. ammonium or gp. of formula (i); X = CH2, NH, O or S; and Y, T, U, V, W and Z = CH or N; with the provisos.

Description

/Rx 502 N in which Rx and Ry, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon' atoms,

R

4 represents a hydroxy radical or an acyloxy radical containing 1 to 8 carbon atoms,

R

7 represents a hydrogen atom, A represents a hydrogen atom, an equivalent of an alkali metal, an alkaline-earth metal, magnesium, ammonium or an amino organic base, or A represents the remainder of an easily-cleavable ester group, or CO 2 A represents

C

02 e, the wavy line signifies that the CH 2

R

6 group can be found in the E or Z position and R 6 represents, in quaternary ammonium form, one of the following radicals: 0**9 S a 9 a.

S

S a

S

**45 S S a.

*5SS 5* a a S S a

S

S..

S

S.

S

V t -4- /P3 p 2 V 1 T Z I NU N n~^Z RN^ C:T 2 R N N V x V X

RR

RR

R R N X CH 3 C 2

R

R R

R'

VZz y

U-

4

Y

1 iI R in which m is equal 1, 2 or 3, X represents CH2, NH, 0 or S; Q, J, Y, T, U, V, W and Z, identical or different, represent independently of each other CH or N, it being understood that each of these cyclic radicals contains 1 to 5 heteroatoms, that at least one of these heteroatoms is the nitrogen atom and that these cyclic radicals can be substituted by one or m-,,more R or R' radicals; I I i R and identical or different, represent a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 4 carbon atoms, a halogen atom, a cyano radical, one of the following radicals: C0 2

-Q

1

CO-

NQ1(Q 2

NQ

1

(Q

2 S0 2

-NQ

1

(Q

2

CS-NH

2

NH-CO-Q

1

CH=N-OH,

CH=N-O-Q

1

CH

2 -CN, CH 2

-S-Q

1

S-Q

1 in which Q 1 and Q2, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms,

P

1

P

2 and P 3 identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by one of the substituents indicated above for R and the dotted line indicates that P 1 and P 2 can also form with the nitrogen atom to which they are linked, a heterocycle with 5 or 6 members.

By alkyl radical containing 1 to 4 carbon atoms is meant the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- "butyl or tert-butyl radical.

By alkyloxy radical containing 1 to 3 and 1 to 4 carbon atoms is meant the methoxy, ethoxy, propoxy, isopropoxy as well as butoxy, isobutoxy, sec-butoxy or tert-butoxy radical.

20 By alkylthio radical containing 1 to 4 carbon atoms is meant the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio or tert-butylthio radical.

By alkylamino radical containing 1 to 4 carbon atoms is 25 meant the methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino or tertbutylamino radical.

S.

By dialkylamino radical containing 2 to 8 carbon atoms is meant in particular the dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ethyl methylamino, propyl methylamino, butyl methylamino or propyl ethylamino radical.

By (alkylamino) carbonyl radical containing 2 to carbon atoms is meant in particular the (methylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl, (isopropylamino) carbonyl or (butylamino) carbonyl radical.

By (dialkylamino) carbonyl radical containing 3 to 9 carbon atoms is meant in particular the (dimethylamino) carbonyl, (diethylamino) carbonyl or (dipropylamino) carbonyl radical.

By acyloxy radical containing 1 to 8 carbon atoms is meant in particular the acetoxy, propionyloxy or benzoyloxy radical.

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

When P 1 and P 2 form a heterocycle with the nitrogen atom to which they are linked, it can in particular be a pyrrolidino, morpholino or piperidino ring.

When R 4 represents an acyloxy radical, it is in particular the acetoxy, propionyloxy or benzoyloxy radical.

Among the values of A there can be mentioned an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. There can also be mentioned an equivalent of an organic base, for example methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris[(hydroxymethyl) amino] methane, ethanol- ."amine, pyridine, picoline, dicyclohexylamine, morpholine, 20 benzylamine, procaine, lysine, arginine, histidine, Nmethylglucamine.

a The products of formula can also be in the form of a :pure internal salt, in salified form or in a form combined with acids of the solution.

25 Among the acids with which the products of formula (I) can be salified, there can be mentioned amongst others, the following acids: acetic, trifluoroacetic, fumaric, maleic, tartaric, methanesulphonic, benzenesulphonic, paratoluenesulphonic, phosphoric, sulphuric, hydrochloric, hydrobromic, 30 hydroiodic.

Among the bases with which the products of formula (I) can be salified, there can be mentioned, amongst others, the bases corresponding to the salts mentioned above. Examples of salification by bases are given further on.

3 In a preferred method of the invention CO 2 A represents

CO

2 e The expression "in the form of quaternary anmonium" indicates that the R 6 radical is linked by the or one of the nitrogen atoms that it contains.

A particular subject of the invention is the products of general formula as defined above, in which R 6 represents one of the following radicals: 9

S.

9 9*9 9 9 {H e Y li

{OQ

:2>I

+OCH

le le 0 6 il

NH

C)

Cli, li~ N Nil 2 me N

I

NH

2 i 0 cxN N H o 'c

N

EQ

101

K,-

N

N-H

j ""CON F-(7

R

N Na N le

C/

jN 1 e oi Me re 11 lie

KHH

0 e l he CH2Z nie ie O li C N A more particular subject of the invention is the products of general formula as defined above in which R 6 represents the quiirolinium, isoquinoliniumn, 4-(methylthio) pyridinium, thieno pyridinium, 1-methyl pyrrolidinium, N-methyl N-ethyl N-(2-axnino 2-oxoethyl) aminium, imidazo(l,2a)pyridinium or the 6,7-dihydro-5H--pyrindinium radical, those in which R 3 and R 4 each represent a hydroxy radical, those in which R 2 and R 5 each represent a chlorine or fluorine atom, those in which R 2 represents a fluorine atom and those in which R 2 represents a methoxy radical and one of Ror R 5 represents a chlorine atom.

A quite particular subject of the invention is the products of which the names follow: the internal salt of 6alpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 1-azabicyclo[4,2,0)oct-2-en3.yl) 2-propenyl) quinolinium, the internal salt of Ealpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxy- 20 phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicycloII4,2,0]oct-2-en-3-yl) 2-propenyl) quinolinium, -the internal salt of (ER- 6alpha, 7beta- 1- (3- (7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 1-azabicyclo4,2,]oct2en3.yl) 2-propenyl) imidazo(1,2-a) pyridiniun, -the internal salt of 6alpha, 7beta-(Z))) 1-(3- (((2-amino 4-thiazolyl) (((2,5-dichloro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) imidazo(1,2-a) a: pyridinium, the internal salt of 6alpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,o]oct-2-en-3..yl) 2-propenyl) 6,7-dihydro SH- 1 -pyrindinium, the internal salt of 6alpha, 7beta(Z))) N(2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphenyl) 8 methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia Iazabicyclo[4,2,0]oct-2-en-3.yl) 2-propenyl) 6,7-dihydro pyrindiniui, the internal salt of 6alpha, 7beta(Z))) (((2-amino 4-thiazolyl) ((5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1azabicyclo[4,2,0loct-2-en3y1) 2-propenyl) quinolinium, the internal salt of Galpha, 7beta(Z))) (((2-amino 4-thiazolyl) ((nethoxycarbonyl) 4-dihydroxy fluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0loct-2.en3yl) 2-propenyl) quinolinium.

A subject of the invention is also a preparation process for the products of formula as defined above, characterized in that the aromatic aldehyde of formula (II): Hi, C Z::

R

2 P 4 *.in which R 1

R

2

R

3

R

4 and R 5 are as defined above, has, if necessary, its reactive functions protected and is thus converted into an aromatic aldehyde of formula (lIIp) H 0 9.

9.R 2~ P 4 p R, a inwihR9 SR~rRpadRPrprsn h auso ipb,,,,,si alehd offomII(I s ihr raedb ,reducin agni-re ootinteachlo oml

S

(III) HOK 1.

P.

RE

(III)

R 2 p TR P or homologated into the aipha-hydroxy acid of formula li) .I C

CCH

a a

B.

Baa.

S *5 U

U

B a B a Ba U a.

U

R

R2 p

R

Rp

P

(III,)

which acid is esterified into an alpha-hydroxy ester of formula (1112): H 0 0QA 1c

P

2ir R 5P (1112) in which Alk represents an alkyl radical containing 1 to 4 carbon atoms, which ester or alcohol of formula (1112) or (III) is treated with N-hydroxv phthalimide, if appropriate in the presence of an activating agent, in order to obtain the derivative of formula (IV):

(IV)

R

which is hydrolyzed into an 0-substituted hydroxylainine of formula (V: H2N S S

S

S

*55*

S.

S

S.

S S

SS*

S

*5 S

SS

S

S*

S

S.

S a 4S*i** Rp

P

which is condensed with a derivative of 2-12-amino thiazol-4yl) 2-oxo acetic acid of formula (VI): N H 8

(VI)

o It 0 in which R.

8 represents a hydrogen atom or a protective group of the amine function, in order to form the derivative of "syn" alpha-alkoxyimino acetic acid of formula (VII): 0

YN

C 0

(VII)

E

ip .5

P

S.

S S

S.

S S. S

S

*5 5

S.

.5 S C *5 S S *5 S S 5

S

a functional derivative of which, if appropriate, is prepared, which product of formula (VII) or functional derivative is amidified with an ester of 7-amino 3- (3-halo Ipropenyl) 8-oxo 5-thia 1-azabicyclo[4,2,O]oct-2en-2.

carboxylic acid hydrochloride of formula (VIII): 25 HdCl, H 2 N S

N

0 CH =CHVvC H H a1 0 0.CN 9

(VIII)

in which Rg represents the remainder of an easily cleavable ester, to produce the derivative of 7- (N-substituted arnido) 3- (3-halo 1--propenyl) 8-oxo 5-thia l-azabicyclo[4,2,0joct-2en-2-carboxylic acid of formula

(IX):

N H R

N

H

N C I I I 7 0N

(IX)

C h=C H\AC H 2 Ha 1 R IP 'R 2 P 0 ,'C-,0,R9

R

R3pF a a a a.

.a a a a.

a. a a a.

which is converted, if appropriate, into the 3- (3-iodo propenyl) analogue of formula

N

0 C

N

0 aa

OH

A

a 1 V C H C H VA C H 2- 0 a-U 11

A

which is treated with a base of formula R 6 in order to obtain the product of formula (XI): 13

NHPR

N

N C'I "C N S(XI) 1 11 F7N ,0 c N P. /p o C-o CH 0 CH CH CH 2

R

C

R P C 0 2p P 4 3p :'from which product of formula (XI) if appropriate, the or isomers are isolated or the isomers are converted into isomers, which product of formula (XI) is subjected, S 20 if appropriate, to one or more of the following reactions in an appropriate order: a) cutting by hydrolysis or by the action of thiourea of all or part of the ester protective groups and of the groups protecting the amino radical or the hydroxyl radicals, b) esterification or salification by a base of the carboxylic radical, c) salification by an acid of the amino radical, d) separation of the products in the form of an R,S mixture Sinto R and S.

Also a subject of the invention is a variant of the process described above, characterized in that the 0substituted hydroxylamine of formula is condensed with the product of formula (XII): 14 NH R

N

H

C C 0 0NCH 0 C 0 9 in order to produce the product of formula (XI) as defined ::*previously.

*4.':The protected hydroxy functions which can be represented by R 1 p 1

R

2 pI R 3 p 1

R

4 p and R5p are chosen from the acyloxy groups such as for example formyloxy, acetoxy, propionyloxy, 20 chloroacetoxy, bromoacetoxy, dichioroacetoxy, trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy, benzoylformoxy, p-nitro benzoyloxy. The following groups can also be mentioned: ethoxycarbonyloxy, methoxycarbonyloxy, propoxycarbonyloxy, 2,2,2 -trichloro 25 ethoxycarbonyloxy, alJlyloxycarbonyloxy, trimethylsilylethoxycarbonyloxy, benzyloxycarbonyloxy, tert -butoxycarbonyloxy, 1cyci opropyl ethoxycarbonyl oxy, phthal oyl oxy, butyryl oxy, **isobutyryloxy, valeryloxy, isovaleryloxy, oayoy 4 succinyloxy and pivaloyloxy, phenylacetoxy, phenylpropionyl oxy, mesyloxy, chlorobenzoyloxy, para-nitrobenzoyloxy, paratert-butyl benzoyloxy, caprylyloxy, acryloyloxy, methylcarbamoyl oxy, phenyl carbamoyl oxy, naphthyl carbamoyl oxy.

They can also be chosen from the following radicals: phenoxy, 4-chloro phenoxy, tolyloxy or tert-butyl phenoxy, tolylsulphonyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, methoxytetrahydropyranyloxy, trityloxy, benzyloxy, 4-methoxy benzyloxy, benzhydryloxy, trichloroethoxy, 1-methyl 1-methoxyethoxy, the alkoxy alkoxy-methoxy radicals such as methoxy ethoxy methoxy or also the triznethylsilylethoxym.ethoxy or trimethylsilylethoxcy radicals.

Two adjacent hydroxy radicals can also be protected by forming a methylenedioxy, isopropylenedioxy, 1,1- cyclohexyl bis (oxy), diphenylmethylenedioxy, carbonate or hydroxy boranylbis (oxy) radical.

The protected hydroxy functions which can be represented by RIP, R 2 p. R 3 p' R 4 p and R 5

P

1 are preferably chosen from the following groups: methoxyethoxymethoxy, propionyloxymethoxy, acetoxymethoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy, butyryloxyrnethoxy, valeryloxymethoxv, pivaloyloxyinethoxy, 2-acetoxy ethoxy, 2 -propionyloxy ethoxy, 2-butyryloxy ethoxy, 2-iodoethoxy, 2 2 ,2-trichloro ethoxy, vinyloxy, allyloxy, ethynyloxy, propynyloxy, benzyloxy, 4- methoxy benzyloxy, 4-nitro benzyloxy, phenylethoxy, trityloxy, diphenylmethyloxy or 3, 4-dimethoxyphenoxy.

The 2-methoxy ethoxymethoxy (MEM-O) group is particularly preferred.

The remainder of an easily-cleavable ester group which 20 is represented by R 9 is chosen notably from the following groups: butyl, isobutyl, tert-butyl, pentyl, hexy., inethoxymethyl, ethoxyrnethyl, isopropyloxymethyl, alpha -methoxy ethyl, alpha-ethoxy ethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, B. **25 propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadecanoylox-ymethyl, pivaloyloxymethyl, .propionyloxyethyl, isovaleryloxyethyl, 1-acetoxy ethyl, 2acetoxy ethyl, l-propionyloxy ethyl, 2 -propionyloxy ethyl, 1butyryloxy ethyl, 2-butyryloxy ethyl, l-(tert-butylcarbonyloxy) ethyl, 1-acetoxy propyl, I-hexadecanoyloxy ethyl, 1propionyloxy propyl, 1- methoxycarbonyloxy ethyl, methoxycarbonyloxynethyl, 1-acetoxy butyl, 1-acetoxy hexyl, 1acetoxy heptyl, phthalidyl, 5,6-dimethoxy phthalidyl, tertbutylcarbonylmethyl, vinyl, allyl, 2-chloro allyl, ethynyl, propynyl, methoxycarbonylmethyl, benzyl, 4-methoxy benzyl, 4nitro benzyl, phenethyl, trityl, diphenyl methyl, phenyl, 4-chloro phenyl, tolyl, tert-butyl phenyl, 3,4-dimethoxy phenyl, methoxyethoxymethyl, dimethyl-aminoethyl, cyanomethyl, tert-butoxycarbonylmethyl, 2,2-ethylenedioxy ethyl, cyanoethyl, 2,2-dimethoxy ethyl, 2-chioro ethoxymethyl, (2-hydroxy ethoxy) ethyl, 2,3-epoxy propyl, 3 -dimethylamino 2-hydroxy propyl, 2-hydroxy ethyl, 2methylaminoethoxymethyl, (2-amino ethoxy) methyl, 3-methoxy 2,4-thiadiazol-s-yl, tetrahydropyran-2-yl, 1-methoxy 1-methyl ethyl, 2-hydroxy 1-methyl ethyl, isopropyl, carbamoylmethyl, chloromethyl, 2-chloro ethyl, 2,2,2-trichloro ethyl, 2-iodo ethyl, acetyl, methyl, 2-methylthio ethyl, thiocyanatomethyl, 2-chloro 1-acetoxy ethyl, 2-methoxy I-acetoxy ethyl, 2-methyl 1-acetoxy propyl, 1-methyl 1-acetoxy ethyl, 1-(methoxyacetoxy) ethyl, 1-acetyl carbonyloxyethyl, 1-hydroxy acetoxyethyl, 1-(2-thienyl) carbonyloxyethyl, 1-(2-furyl) carbonyloxyethyl, 1-(5-nitro 2-furyl) carbonyloxyethyl, 1-(2pyrrolyl) carbonyloxyethyl, 1-(propionyloxycarbonyloxy) ethyl, 1-(propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1-(methoxyethoxycarbonyloxy) ethyl, 1-(allyloxycarbonyloxy) ethyl, isopropoxycarbonyl methyl, 2 ,3-epoxy propyl) oxycarbonyloxy] ethyl, 1-[(2-furyl) methoxycarbonyloxy] ethyl, l-[(2-fluoroethoxy) carbonyloxy] ethyl, 1- (methoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) -methyl ethyl, (methoxycarbonyloxy) chloromethyl, 1- (methoxycarbonyloxy) 1-methyl ethyl, (methoxycarbonyloxy) chloromethyl, 1- (methoxycarbonyloxy) 2-chloro ethyl, 1-(methoxycarbonyloxy) 2-methoxy ethyl, 1-(methoxycarbonyloxy) 2-methoxy ethyl, 1- (methoxycarbonyloxy) allyl or 5-methyl 2-oxo 1,3-dioxol-4-yl.

The diphenylmethyl radical is more particularly preferred.

The protective group of the amino radical which can be represented by R 8 can be for example a carbamoyl, methyl carbamoyl, phenylcarbamoyl, naphthylcarbamoyl group, as well as the corresponding thiocarbamoyls, a substituted or nonsubstituted alkyl radical having 1 to 6 carbon atoms such as, preferably, trichloroethyl, tert-butyl or tert-amyl, an aralkyl radical such as benzyl, 4-methoxy benzyl, phenethyl, trityl, 3,4-dimethoxy benzyl or benzhydryl, a substituted or non-substituted aliphatic, aromatic or heterocyclic acyl radical, such as for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl benzoyl, toluolyl, naphthoyl, chlorobenzoyl, para-nitro benzoyl, para-tert-butyl benzoyl, phenoxyacetyl, caprylyl, decanoyl, acryloyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl, oxalyl, succinyl, pivaloyl, a lower alkoxycarbonyl or cycloalkoxycarbonyl radical such as for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, trichloroethoxy carbonyl, an aralkoxycarbonyl, such as benzyloxycarbonyl.

The trityl group is preferred.

The above list is not limiting, it is evident that others amine protective groups, known to a man skilled in the art, groups known in particular in the chemistry of the peptides, can also be used.

The reducing agent which is reacted on the aldehyde of 20 formula (IIp) is notably a hydride such as sodium borohydride or lithium-aluminium hydride or also diisobutylaluminium hydride.

The esterification of the alpha hydroxy acid of formula (III1) can be carried out by means known to a man skilled in the art, in particular by the action of diazomethane in solution in methylene chloride or tetrahydrofuran.

The activating agent in the presence of which Nhydroxyphthalimide is reacted can be a phase transfer agent.

S uch agents are known to a man skilled in the art.

30 The hydrolysis of the phthalimide of formula (IV) is carried out by the action of hydrazine, preferably in hydrate form.

The functional derivative of the acid of formula

(VII)

can be for example a halide, a symmetrical or mixed anhydride, the amide, the azide or an activated ester.

As an example of a mixed anhydride there can be mentioned for example that formed with isobutyl chloroformate and that formed with pivaloyl chloride and the carboxylicsulphonic mixed anhydrides formed for example with paratoluene sulphonyl chloride.

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

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

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

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

When an acid halide is used and in a general manner when an acid molecule is released during the reaction, the reaction is preferably carried out in the presence of a base such as sodium or potassium carbonates and acid carbonates, sodium acetate, triethylamine, N,N-diisopropyl ethyl amine, 20 pyridine, morpholine or N-methylmorpholine.

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

A product of formula (VII) can also be made to act directly with a product of formula (VIII) in the presence of a carbodiimide such as diisopropylcarbodiimide or 1-(3dimethylamino propyl) 3-ethyl carbodiimide (EDC). An example of such a preparation is given further on in the experimental p. art.

The action of the reagents capable of introducing the R S 30 radical and of producing the product of formula (XI) is carried out under the following conditions: When Hal represents for example a chlorine atom, a substitution of the chlorine atom by an iodine atom in the presence of sodium iodide can be carried out in situ or separately, then the desired reagent is added, in the presence or not of an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, acetone or methylethylketone.

The appropriate reagent of formula R 6 can also be made to act directly on the product of formula (IX) or in the presence of silver tetrafluoroborate.

The isomerism of the products of formula (XI) can be different from that of the products of formula (IX) or In the case where the Z isomer is isolated, this isomer can be converted into the E isomer according to the usual methods, notably by the action of iodine.

According to the values of Rg, Rg, Rip, R 2 p, R3p, R4 p and R 5 p, the action on the product of formula (XI) of one or more hydrolysis, hydrogenolysis agents or of thiourea aims to eliminate the Rg radical when this represents a protective group of the amino radical, to convert the Rlp, R2p R3p, R4 p and R5p radicals respectively into R 1

R

2

R

3

R

4 and R radicals when these carry a protective group of the hydroxyl radicals and/or to eliminate the R 9 radical when this represents, among the easily-cleavable ester groups, one of those which it is desired to eliminate.

However, it is of course possible to eliminate R 8 and to S: 20 convert the Rlp, R2p R 3 p, R4 p and R5p radicals respectively into R 1

R

2

R

3

R

4 and R 5 radicals when these carry a protective group of the hydroxyl radicals without affecting the R 9 substituent when this must be preserved. The nature of the reagents to be used in such a case is well known to a man skilled in the art. A description of the different methods for eliminating the different protector groups will be found for example in the French Patent B.F. 2,499,995.

SExamples of such reactions are given further on in the experimental part.

30 Given the nature of the preferred protective groups which are used: trityl for Rg, 2-methoxy ethoxy methyl to protect the hydroxy functions and 4-methoxy benzyl for R 9 a trifluoroacetic acid/anisole mixture is preferably used without solvent or in a solvent such as methylene chloride.

Then a salt is obtained with trifluoroacetic acid. If desired the free base can be returned to by the action of a base such as a carbonate or triethylamine.

The salification of the products can be carried out according to the usual methods; it can for example be obtained by the action on a product in acid form or on a solvate, for example the ethanolic solvate, or a hydrate of this acid, of a mineral base such as sodium or potassium hydroxide, sodium or potassium carbonate or acid carbonate.

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

In addition, there can be used as organic acids, 20 sufficiently soluble aromatic acids such as, for example, benzoic acids preferably substituted by lower alkyl radicals.

As examples of such organic acids, the following acids can be mentioned: formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic, chloropropionic, crotonic, phenyl acetic, (2-thienyl) acetic, (3-thienyl) acetic, (4ethyl phenyl) acetic, glutaric, the monoethyl ester of adipic acid, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxy propionic, 3-methoxy propionic, 3-methyl thiobutyric, 4-chloro butyric, 4-phenyl butyric, 3-phenoxy butyric, 4-ethyl benzoic, 1-propyl benzoic.

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

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

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

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

The salts are obtained in amorphous or crystallized form according to the reaction conditions employed.

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

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

The optional esterification of the products is carried out under standard conditions. The operation is generally carried out by reacting the acid of formula or a functional derivative with a derivative of formula: Z-Re 20 in which Z represents a hydroxyl radical or a halogen atom such as chlorine, bromine, iodine and Re designates the ester group to be introduced, a non-exhaustive list of which group is given above. In certain cases, it may be advantageous to carry out an esterification on a product whose amine and/or reaction groups present on the oxyimino are blocked before removing the protective group of the amine and of the reaction group present on the oxyimino.

The products of formula contain several asymmetrical carbons. In the cepheme nucleus, which contains two asymmetrical carbons, the two carbons are in R configuration.

Furthermore, the radical present on the oxyimino function may also contain an asymmetrical carbon which can be in R or S form or in the form of an R S mixture. The separation of the two diastereoisomers can be carried out by means known to a man skilled in the art, for example by chromatography.

The products of general formula possess a very good antibiotic activity on gram e bacteria such as staphylococci, streptococci and in particular on penicillin-resistant staphylococci. Their effectiveness on enterobacteria which produce chromosomal or plasmidic P-lactamases is particularly remarkable.

These properties make the said products as well as their pharmaceutically acceptable acid salts suitable to be used as medicaments in the treatment of infections caused by susceptible germs and in particular in that of staphylococcal infections, such as staphylococcal septicemias, malignant staphylococcal infections of the face or skin, pyodermatitis, septic or suppurating sores, anthrax, phlegmons, erysipelas, acute primary or post influenzal staphylococcal infections, broncho-pneumonia, pulmonary suppurations, meningitis, as well as in the treatment of infections in people with suppressed immune systems.

These products can also be used as medicaments in the treatment of colibacilloses and associated infections, in infections caused by proteus, klebsiella and salmonella and in others illnesses caused by gram e bacteria.

Therefore a subject of the present invention is also, as 20 medicaments and notably antibiotic medicaments, the products of formula as defined above, wherein R 1

R

2

R

3

R

4

R

and A are defined above and R 7 represents a hydrogen atom as well as their pharmaceutically acceptable acid salts, except tert-butyl.

A particular subject of the invention is as medicaments the preferred products of formula as described above and in particular in which R 6 is chosen from the following radicals: quinnlinium, isnnquin linium, 4- (methyIthio) 0pyridinium, thieno[2,3-b]pyridinium, 1-methyl pyrrolidinium, 30 j: N-methyl N-ethyl N-(2-amino 2-oxoethyl) aminium, imidazo i: pyridinium and 6,7-dihydro A more particular subject of the invention is, as medicaments and notably antibiotic mnedicaments, the products of which the names follow: the internal salt of 6alpha, 7beta-(Z))) l-(3- (7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphenyl) inethoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) quinolinium, the internal salt of 6alpha, 7beta-(Z))) l-(3- (7-(((2-arnino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0loct-2-en-3-yl) 2-propenyl) quinolinium, -the internal salt of 6alpha, 7beta-(Z))) l-(3- (((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0)oct-2-en-3-yl) 2-propenyl) imidazo(l,2-a) pyridinium, the internal salt of Ealpha, 7beta-(Z))) l-(3- (7-(((2-amino 4-thiazolyl) (((2,5-dichioro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,Olloct-2-en-3-yl) 2-propenyl) imidazo(l,2-a) pyridinium, the internal salt of 6alpha, 7beta-(Z))) 1-(3- (((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxy- 9: phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 1-pyrindinium, -the internal salt of 6alpha, 7beta(Z))) (((2-amino 4-thiazolyl) ((2,5-dichloro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia. 1azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H-1pyrindinium, the internal salt of 6alpha, 7beta(Z))) X (((2-amino 4-thiazolyl) ((5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia. 1azabicyclo[4,2,ojoct-2-en-3-yl) 2-propenyl) quinolinium, the internal salt of 6alpha, 7beta(Z))) (((2-amino 4-thiazolyl) ((methoxycarbonyl) 4-dihydroxy Sfluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo ~/&thia l-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 0 24 quinoleinium, as well as their pharmaceutically acceptable salts.

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

These compositions can be administered by buccal, rectal or parenteral route, notably by intramuscular route or by local route as a topical application on the skin and mucous membranes.

The products of formula and in particular those in which A represents a cleavable ester can be administered by oral route.

The compositions according to the invention can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients 20 usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

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

30 The dose administered is variable according to the illness being treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 0.250 g and 4 g per day, by oral route for an adult, with the product described in Example 1 or also comprised between 0.500 g and 1 g three times per day by intramuscular route.

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

Finally a subject of the invention is, as new industrial products and notably as intermediate products necessary for the preparation of the products of formula the products of formulae (VII), and (XI) as defined previously.

The products of formula (II) are known in a general manner and for the most part commercially available; others can be prepared from commercially-available products, according to the methods described in the European Application 0551034. For the preparation of the products of formula the methods described in the literature can also be used, in particular the so-called Rosemund reduction, the reduction of benzoic acids, or the formylation of aromatic rings such as for example the Vilsmeier-Haack reaction, the Gatterman-Koch reaction, the Reimer-Tiemann reaction or the reaction with formyl fluoride Am. Chem.

Soc. 82, 2380 (1960)).

The products of formulae (VI) and (VIII) are also known in the literature, notably in the Belgian Patent Application 20 BE 864828 and the European Patent Application EP 0,333,154.

The preparation of the products of formula (XII) is o described in the European Application 0,551,034.

The following examples illustrate the invention without however limiting it.

EXAMPLE 1: Internal salt of (6R(3(E),6 ,7 amino-thiazolyl) (((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.

Stage A: 2,5-dichloro 3,4-bis(2-methoxyethoxy)methoxy benzyl alcohol.

1.59 g of sodium borohydride is added, in portions at 0°C, to a solution of 16.1 g of 2,5-dichloro-3,4-bis-(2methoxyethoxy) methoxy benzaldehyde in 200 ml of methanol, Agitation is carried out for 30 minutes at 0°C then 2.4 ml of acetic acid is added while allowing the temperature to return to ambient temperature. The reaction medium is evaporated to dryness under reduced pressure and the residue is taken up in zlo- 1 MZ 80 ml of ethyl acetate, followed by washing with a salt water 0

S

26 solution, drying, filtering and evaporating to dryness under reduced pressure and in this way 13.6 g of desired product is collected, used as it is for the following stage.

I.R. Spectrum CHCl 3 OH 3610 cm- 1 Aromatic: 1555 cm 1 N.M.R. Spectrum CDC1 3 3.38

CH

3 of OMEM; 3.58 4.00 5.24 5.25 the CH2's of OMEM; 4.78

CH

2 of the alcohol; 7.35 aromatic H.

Stage B: (2,5 dichloro-3,4-bis(2-methoxyethoxy)methoxy)phenyl) ((1,3-dihydro 1,3 dioxo-2H-isoindol-2-yl)oxy)methyl.

11.09 ml of diethyl azodicarboxylate is added dropwise, without exceeding +5 0 C, to a solution, cooled down to to 0OC, of 18.39 g of triphenyl phosphine in 150 ml of tetrahydrofuran, agitation is carried out for 15 minutes and 11.43 g of N-hydroxyphthalimide is added in fractions. The reaction medium is cooled down to 0 0 C and a solution of 13.6 g of the product obtained in Stage A above in 40 ml of tetrahydrofuran 20 is added dropwise, and after agitation for one hour at 0 C the reaction medium is brought to dryness under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, followed by washing with water, drying, filtering and evaporating to dryness under reduced pressure. 50 g of product is obtained which is chromatographed on silica, eluting with a methylene chloride ethyl acetate 80-20 mixture. 17.9 g of desired product is collected.

I.R. Spectrum: 1790 cm 30 1750 cm-1

C=O

1736 cm-1 1610 cm- 1 aromatic 1560 cm-1 N.M.R. Spectrum CDCl 3 3.38

CH

3 of OMEM; 3.57-3.98-5.25-5.27: the CH 2 's of OMEM: 7.52 (s)-7.75 to 7.84 the aromatics.

StaQe C: 2 ,5-dichloro-3,4-bis(2-methoxyethoxy)methoxy oxyaminobenzyl.

3.24 ml of hydrazine hydrate is added to a solution, cooled down to 0°C, of 17.7 g of the product obtained in Stage B above, in 120 ml of dichloromethane, then agitation is carried out for one hour at 0°C. The insoluble part is filtered off and concentrated to dryness under reduced pressure, the residue is taken up in 50 ml of ethyl ether, followed by washing with water, drying and evaporating to dryness under reduced pressure. The product obtained is chromatographed on silica, eluting with a methylene chlorideethyl acetate 80-20 mixture. 9.6 g of product is collected which is taken up in 80 ml of ethyl ether, washed with water, dried and evaporated to dryness under reduced pressure.

9.15 g of expected product is obtained.

I.R. Spectrum CHC1 3 3324 cm- 1

CH

2

-ONH

2 1583 cm-1: aromatic 1558 cm1: NH 2 N.M.R. Spectrum CDC1 3 3.38 CH 3 3.58 (m)-4.00 (m)-5.25 the CH 's of OMEM; 20 4.74 CH 2

-ONH

2 5.55 NH2; 7.28: aromatic.

Stage D: (2,5-dichloro-3,4 bis((2-methoxyethoxy)methoxy) phenyl methoxy imino) (2-((triphenylmethyl) amino) 4thiazole-acetic acid.

t9.5 g of oxo-[2-[(triphenylmethyl) amino]-thiazol-4-yl] acetic acid (described in the Belgian Patent Application No.

.864828) is added in portions at ambient temperature to a suspension of 8.34 g of the product obtained in Stage C with ml of methanol. Agitation is carried out for one hour followed by evaporation to dryness. The residue is taken up in methylene chloride, washed with 0.1N hydrochloric acid, dried, filtered then concentrated to dryness. 20 g of product is collected which is chromatographed on silica, eluting with a methylene chloride methanol mixture.

Chromatography is carried out a second time under the same conditions in order to obtain 13.51 g of desired product.

I.R. Spectrum CHC1 3 3404 cm-1: =C-NH 1620 cm- 1 COO- C=N 28 1592 cm- 1 1577 cm- 1 heterocycle 1529 cm- 1493 cm 1: aromatic N.M.R. Spectrum CDC1.

3 3.35 CH 3 of OMEM; 3.55 -3.95 -5.17 -5.20

CH

2 's of OMEM; 5.13 (bs) CH 2 6.54 H thiazole; 7.20 to 7.28: aromatic.

Stag~e E: (4-methoxyPhenyl)methyl 6 ,6 3-(3chioro 1-propenyl) 7- ((2,5-dichloro-3,4 bis( (2-methoxyethoxy) methoxy) phenyl methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclooct-2-ene-2-carboxylate.

4.37 g of (4-methoxyphenyl)methyl 7 -amino 3- [3-chloro 1-propenyl) 8-oxo 5-thia 1-azabicyclo(4.2.0)oct-2-ene-2 carboxylate hydrochloride (described in the European Patent Application No. 0,333,154) is added to a solution of 8.1 g of the product obtained in Stage D in 40 ml of methylene ::-:*chloride, the reaction medium is cooled down to -5 0 C and 2.33 g of dimethylamino propyl-ethyl-carbodiimide is :::.introduced, agitation is carried out for 2 hours 30 minutes at 0 0 C. The solution is then washed with 2 times 10 ml of :y phosphate buffer solution at pH 7, then with salt water, followed by drying, filtering and evaporating to dryness under reduced pressure in order to obtain 10.54 g of product 5* which is chroinatographed on silica, eluting with a methylene chloride ethyl ether 90-10 mixture. 6.52 g of desired product is collected.

Spectrum CDC1 3 3.27 j=18) -3.45 j=18): CH 2 S; 3.36-3.37

CH

3 of OMEM; 3.57-3.98 (in) and 5.15 to 5.35: the CH 2 's of OMEM and

CH

2 3.81: methoxy benzyl; 5.01-5.05

N-CH-CH-S;

5.91-5.93 (dd) N-CI{-CH-S; 3.72 and 3.92 (dd, j=12 8):

CH

2 Cl; 5.73 (dt, j 11 8) and 6.24 j 11) -CH=CH-

CH

2 Cl (delta Z) 6. 02 (dt) and 7.04 j 15) -CH=Cki-CH 2 Cl (delta E) 7.30 trityl; 6. 88 to 7.30: the aromnatics; 5.15 to 5.37: O-CH 2 Stacre F: (4-methoxyphenyl)inethyl 6a,7p 3-(3iodo 1-propenyl) dichloro-3,4 bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) (2-((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia l-azabicyclo(4.2.0)oct-2-ene-2-carboxylate.

1.59 g of sodium iodide and an iodine crystal are added to a solution of 3.1 g of the product obtained in Stage E, above, in 12.5 ml of acetone. Agitation is carried out for minutes at ambient temperature, the reaction medium is evaporated to dryness under reduced pressure and the residue is taken up in 10 ml of methylene chloride, followed by washing with an aqueous solution of 10% sodium thiosulphate then with salt water, drying, filtering and concentrating to dryness under reduced pressure. 3.79 g of desired product is obtained which is used as it is for the following stage.

Stage G: 6o0, 7P iodide of dichloro-3,4-bis-((2-methoxyethoxy) methoxy) phenyl) methoxy) imino) (2-((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2-(((4-methoxyphenyl) methoxy) carbonyl) S-azabicyclo(4.2.0)oct-2-en-3-yl) -2-propenyl) -quinolinium.

20 1.57 ml of redistilled quinoline is added to a solution of the compound, obtained in Stage F, in 3 to 4 ml of methylene chloride. The solvent is evaporated off under reduced pressure then agitation is carried out for one hour at ordinary pressure. Ethyl ether is added, the reaction medium is agitated for 30 minutes, followed by separation, washing with ether and drying under reduced pressure. 4 g of product is collected which is chromatographed on silica, eluting with a methylene chloride methanol 95-05 mixture.

2.18 g of desired product is collected.

I.R. Spectrum 3404 cm-1: =C-NH o 1788 cmf: C-O

-I

1721 cm 1 1689 cm-1 1628 cm-1: C=C 1613 cm'l: C=N 1595 cm- 1 /A 529 cm-1: aromatic 1517 cm 1 1493 cm-1: amide II N.M.R. Spectrum CDC1 3 3.34 CH 3 of OMEM; 3.55 (m)-3.96 and 5.13 to 5.31: the CH 2 's of OMEM and CH 2 6.86 mobile): CO-NH; 6.70 H thiazole; 7.27 trityl; 4.97

N-CH-CH-S;

5.88 (dd, d ap. exch.): N-CH-CH-S; 6.90 to 7.27: aromatic 4 H's; 3.78 OCH 3 of the benzyl; 5.13 to 5.31: CH 2 3.47 (d)-3.64 S-CH2; 6.51 (dt, j=15.5 CH propenyl; 6.06 and 6.21 (bdd, j=15 CH 2 propenyl; 7.98 to 10.45: 7H quinoline.

Stage H: Internal salt of 6a, 70 amino-4-thiazolyl) (((2,5-dichloro-3,4-dihydroxyphenyl)methoxy)imino)acetyl)amino)- 2 -carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0.)oct-2-en-3-yl) -2-propenyl) -quinolinium.

A solution of 2.1 g of the product obtained in Stage G in 20 ml of a solution cooled down to 0°C of trifluoroacetic acid with 10% anisole is agitated for 10 minutes at 0°C, then the temperature is left to rise and agitation is carried out 20 for 2 hours 30 minutes at ambient temperature. Filtration is carried out, followed by washing with a few millilitres of trifluoroacetic acid, cooling down to 0°C and the addition of 70 ml of ethyl ether. Agitation is carried out for minutes at 0 C then for 90 minutes at ambient temperature.

25 After filtration and washing three times with 10 ml of ethyl ether, the product obtained is agitated again for one hour with 30 ml of ethyl ether. Filtration is carried out as previously followed by drying under reduced pressure, and 1.076 g of desired product is collected.

30 I.R. Spectrum Nujol Absorption OH/NH 1778 cm' 1 C=O (beta lactame) 1666 cm-1 1594 cm- 1 heterocycle 1544 cm-1: aromatic 1532 cm- 1 amide II COO" N. M.R. Spectrum Dimethylsulphoxide 9 6 aromatic 1H, 5.08 -CH 2 9.74 mob.): i'; i> t 31 NH; 6.76 thiazole H; 5.17 N-CH-CH-S; 5.80 (dd, d ap. exch.): N-CH-CH-S; 3.51-3.72 S-CHj 2 6.38 (dt, j=:15.5 propenyl CH; 7.00: the other propenyl CH; 5.89 propenyl CH 2 8.25 to 9.59: 7H quinoline.

EXAMPLE 2: Internal salt of 6cy, 7P 1-3-(7- (((2-amino-4-thiazolyl) 2 ,5-dichloro-3,4-dihydroxyphnyl) methoxy) imino) acetyl)auino) 2 -carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-3-yl) -2-propenyl) -imidazo pyridinium.

Stage A: (4-methoxyphenyl)methy. 6ar, 7P3 3-(3chioro 1-propenyl) 7- dichloro-3,4-bis( (2-methoxyethoxy) methoxy) phenyl methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclooct-2-ene-2-carboxylate.

By operating as in Stage F of Example 1 starting from 3.2 g of the product obtained in Stage E of Example 1, 3.55 g of desired product is obtained, used as it is for the following stage.

.Stacre B: 6a7 iodide of 20 dichloro-3,4-bis((2-methoxyethox)methoxy) phenyl) methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2- (((4-methoxyphenyl) methoxy) carbonyl) 1-azabicyclo(4.2.0)oct-2-en3yly2propenyl)-imidazo(12 a) pyridiniun.

By operating as in Stage G of Example 1 starting from 3.55 g of the product obtained in Stage A above and using too 0.69 ml of imidazo (1,2 a) pyridine, 4.05 g of the crude product was obtained and after chromatography on silica (eluant: methylene chloride methanol 96-4) 2.05 g of 30 desired product ias obtained.

I.R. Spectrum *3404 cnf 1

-C-NH

1787 cnf 1 C=a 1720 cmf 1 1689 cm- 1 1648 cm 2 1 C-C 1613 cm& 1

C-N

1600 cm- 1 1587 cm- 1 1528 cnf 1 aromatic 1517 cnf 1 1493 cm-1: amide II N.M.R. Spectrum CDC1.

3 3.33-3.34 CH 3 of OMEM; 3.56 (m)-3.95 Cm) and 5.10 to 5.50: the CH 2 's of OMEM and CH 2 6.86 mobile): CO- NH; 6.70 Cs): thiazole H; 7.25 to 7.33 Cm): trityl; 4.99 (d, N-CH-CH-S; 5.88 (dd, d ap. exch.): N-CH-CH-S; 6.89 to 7.33: aromatic 5 H's; 3.78 OCH 3 of the benzyl; 5.10 to 5.50: CH 2 3.47 (d)-3.60 Cd, j=18): S-CIH 2 6.27 j=16 6.3) and 7.15 Cd, j=16): the propenyl CH's; 5.10 to 5.50: propenyl CE 2 7.44 to 9.21: 7H imidazo pyridine.

Stage C: Internal salt of C6R(3(E), 6a7 axnino-4-thiazolyl) (((2,5-dichloro-3,4-dihydroxyphenyl) rethoxy)imino)acetyl)amino) -2-carboxy-8-oxo-5-thia-l-azabicycloC4.2.0)oct-2-en-3-yl)-2-propeny.)-imidazoC12.a)pyridiniun.

By operating as in Stage H of Example 1 starting from 1.45 g of the product obtained in Stage B above, and using 14 ml of a trifluoroacetic acid solution with 10k anisole, 0.678 4 :4g of desired product is obtained.

Spectrum Nujol Absorption OH/NH 25 1774 cmf 1 C=O (beta lactame) 1674 cm-1 1620 cnf 1 aromatic 1528 crn-1: amide 11 COO- N.M.R. Spectrum Dimethylsulphoxide 6.96 aromatic 1H, 5.08 -CH 2 9.72 Cd, mob.): NH; 6.77 Cs): thiazole H; 5.17 Cd, N-CH-CE-S; 5.79 Cdd, d ap. exch.): N-CH-CH-S; 3.53-3.72 Cd, S-CE 2 6.25 Cdt, j=15.5 6)-6.88 Cd, j=16): the propenyl CH's; 5.89 Cm): propenyl CE 2 7.57 to 8.96: 6H imidazo pyridine.

EXAMPLE 3: Internal salt of 6a, 7P 1-3-(7- ((2-amino-4-thiazoly.) (((2,5-dichloro-3,4-dihydroxyphenyl) methoxy) imino)acetyl) amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo(4.2.O)oct-2-en-3-yl)-2-propenyl)-6,7 dihydro 5H-1pyrindinium.

Stage A: (4-methoxyphenyl)methy. 6ca,7p 3-(3chioro, 1-propenyl) 7- dichloro-3,4-bis- ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclooct-2-ene-2-carboxylate.

By operating as in Stage F of Example 1 starting from 3.2 g of the product obtained in Stage E of Example 1, 3.33 g of desired product is obtained, used as it is for the following stage.

Stage B: 6ty,7f3 iodide of dichloro-3 ,4-bis- ((2-methoxyethoxy) methoxy) phenyl) methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2- (((4-methoxypheny.) methoxy) carbonyl) 1-azabicyclo(4.2.0)oct-2-en-3-yl)-2-propenyl)j6,7 dihydro SHl-pyrindiniun.

By operating as in Stage G of Example 1 starting from 3.33 g of the product obtained in Stage A above and using 1.60 ml of (2,3)cyclo penteno pyridine, 3.55 g of the crude product was obtained and after chromatography on silica (eluant: methylene chloride -methanol 2.20 g of a.:desired product was obtained.

I.R. Spectrum 3404 cm< 2

-C-NH

1788 cnf1 C=O 1720 cnf' 1689 cm- 1 *1614 cm- 1

C-N/C=C

1600 cm 1 1587 cm- 1 *1527 cm 1: aromatic a1517 cm- 1492 cm- 1 amide II N.M.R. Spectrum CDC1 3 3.34-3.35 CH 3 of OMEM; 3.56 (m)-3.96 (in) and 5.13 5.33 (bs) the CH 2 1 s of OMEM and CH 2 6.89: CO-NHj; 6.70 thiazole H; 7.28 trityl; 4.99: N-CH-CI-S; 5.89 (dd, d ap. exch.): N-CH-C-H-S; 6.89 to 7.28: aromatic 5 H's; 3.78

OCH

3 of the benzyl; 5.13 to 5.33: CH 2 3.55-3.68 (d, j=18): S-CkH 2 6.37 j=16 6.5) and 7.02 j=16): the propenyl CH's; 5.49 to 5.60: propenyl CH 2 2.41 to 9.14: 9H pyrindiniun.

Stage C: Internal salt of 6oz,7p amino-thiazolyl) 2 ,5-dichloro-3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2 bicyclo(4.2.0)oct-2-en3yl)2.propeny)..,7 dihydro pyrindinium.

By operating as in Stage H of Example 1 starting from 2.18 g of the product obtained in Stage B above, and using ml of a trifluoroacetic acid solution with 10k anisole, 1.094 g of desired product is obtained.

I. R. Spectrum Nuj ol Absorption OH/NE 1780 cnf 1 .C-O (beta lactame) 1674 cm<I1 N.M.R. Spectrum Dimethylsulphoxide 6.78 (s)-6.97 aromatic 1H, 5.08 -CH 2 9.75 (d, 20 mob.): NE; 6.78 (s)-6.97 thiazole H; 5.19

N-

CH-CH-S; 5.82 (dd, d ap. exch.): N-CH-CH-S; 3.54-3.77 (d, j=18): S-CH 6.25 (dt)-6.88 j=16): the propenyl CH's; -2 5.33 propenyl CH 2 2.23 to 8.76: 9H pyrindinium.

EXAMPLE 4: Internal salt of (6R(3(E, 6(x,7f 1-3-(7- 25 (((-amino-4-thiazolyl) (((2,5-difluoro-3,4-dihydroxyphenyl) methoxy) imino)acetyl)amino) 2 -carboxy-8-oxo-5-thia-1-azab icycl1o 2. 0) oc t -2 en -3 yl) 2 propenyl -q u inol n iu m.

Stagre A:2,5 difluoro 3 ,4-bis(2-methoxyethoxy)methoxy benzyl alcohol.

30 By operating as in Stage A of Example 1, starting from 21 g of 2,5 difluoro 3 4 -bis(2-methoxyethoxy)methoxy benzaldehyde and using 2.26 g of sodium borohydride, 20.53 g of desired product was obtained.

N.M.R. Spectrum CDC1 3 3.36 OH 3 Of OIMEM; 3.56 (in) 3.94 (mn) 5.22 5.24 the CH 2 's of OMEM; 4.67 CH 2 of the alcohol; 5.96 aromatic H6.

p ta e B: (2,5 difluoro-3,4 bis(2-methoxyethoxy)methoxy)phenyl) ((1,3-dihydro 1,3-dioxo-2H-isoindol-2-yl)oxy)methyl.

By operating as in Stage B of Example 1, starting from 2 g of the alcohol obtained in Stage A above and using 2.98 g of triphenyl phosphine, 1.79 ml of diethyl azodicarboxylate and 1.38 g of N-hydroxyphthalimide, 890 mg of desired product was obtained.

N.M.R. Spectrum CDC13 3.30 CH 3 of OMEM; 3.35-3.91-5.22-5.25: the CH2's of OMEM; 5.20 N-O-CH 2 7.14 H6; 7.78: the aromatics.

Stage C: 2,5 difluoro-3,4 bis(2-methoxyethoxy)methoxy oxyaminobenzyl.

By operating as in Stage C of Example 1, starting from 14.8 g of the product obtained in Stage B above and 2.12 ml of hydrazine hydrate, 7.2 g of expected product is obtained after chromatography on silica (eluant: methylene chloride ethyl acetate 60-40 mixture).

I.R. Spectrum CHC1 3 3335 and 1585 cm-1: CH 2

-O-NH

2 20 1630 and 1495 cm-l: aromatic N.M.R. Spectrum CDC13 S".i 3.37: O-CH 3 3.57 (m)-3.95 (m)-5.24 the CH 2 's of OMEM; 4.68 CH2-O-NH 2 5.49 NH2; 7.28: aromatic H6.

Stage D: (2,5-difluoro-3,4-bis((2-methoxyethoxy)methoxy) phenyl methoxy imino) (2-((triphenylmethyl)amino) 4-thiazoleacetic acid.

By operating as in Stage D of Example 1, starting from 4 g of the product obtained in Stage C above and using 4.92 g of oxo-[2-[(triphenylmethyl)amino]thiazol-4-yl]acetic acid (described in the Belgian Patent Application No. 864828), 7.53 g of desired product is obtained, after chromatography S• on silica (eluant: methylene chloride methanol 90-10 mixture).

I.R. Spectrum CHC13 3404 cm-l: =C-NH 1607 cm- 1 COO-/heterocycle/aromatic: -i 1597 cm 1 1529 cm-1 1529 cm 1495 cm- 1 N.M.R. Spectrum CDC1 3 3.28 O-CH 3 of OMEM; 3.50 (m)-3.87 (m)-5.15 the CH Is of OMEM; 4.93 CH 2 ;64 b) haoeH 7.10 to 7.25: trity.; 6.88 aromatic H6.

Stage E: (4-methoxyphenyl)methy. 6a7 3-(3chioro 1-propenyl) 7- difluoro-3,4-bis( (2-inethoxyethoxy)methoxy) phenyl methoxy) imino) 2 -((triphenylmethyl)amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclooct-2-ene-2-carboxylate.

By operating as in Stage E of Example 1, starting from 1.78 g of the product obtained in Stage D, and 780 mg of (4methoxyphenyl)methyl 7f3-axnino 3- [3 -chioro 1-propenyl) 8 -oxo l-azabicyclo(4.2.0)oct2-ene-2carboxylate hydrochloride (described in the European Patent Application No.

0,333,154), 1 g of desired product is obtained after chromatography on silica (eluant: mnethylene chloride ethyl acetate 80-20 mixture).

N.M.R. Spectrum CDC1 3 .303.4 C2S 3.33-3.35

CH

3 of OMEM; 3.55-3.92 (in) and 3.74 the CH 2 1 s of ONEM, CH=CH-CH 2 5.15-5.21 (AB)-5.32. O-C11 2 -0Oof OMEM, CH1 2

O-CH

2 .0 9 methoxy benzyl; 7.30 trityl; 6.88: the aromiatics; 5.91 H7; 6.75: thizole 115; 6.71 CO-NH-CH; 6.98 NH; for AZ: 5.09 H16; 5.72

-CH=CH-CH

2 6.74 CH=CH-

CH

2 for AE: 4.99: H6; 6.85: -CH=CH-CH 2 Stage F: (4-methoxyphenyl)methyl 6ca,7p 3-(3iodo 1-propenyl) 7- difluoro-3,4-bis( (2-iethoxyethoxy) methoxy) phenyl methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo(4.2.0)oct-2-ene-2 -carboxylate.

By operating as in Stage F of Example 1 starting from 6 g of the product obtained as in Stage E above, and using 3.15 g of sodium iodide, 6.45 g of desired product is obtained which is used as it is for the following stage.

Stagre G: 6oe,7p iodide of difluoro-3,4-bis 2 -methoxyethoxy)methoxy) phenyl) methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 2- (((4-methoxyphenyl) methoxy) carbonyl) -1-azabicyclo(4.2.0)oct-2-en-3-yl) -2-propenyl) -quinolinium.

By operating as in Stage G of Example 1 starting from 2 g of the compound obtained in Stage F, using 0.954 ml of quinoline, 684 mg of desired product is obtained after chromatography on silica (eluant: methylene chloride methanol 92-08).

Stag~e H:Internal salt of 6a,7p amino-4-thiazolyl) (((2,5-difluoro-3,4-dihydroxypheny.) methoxy)imino)acetyl)amino) -2-carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-3-yl) -2-propenyl) -quinolinium.

By operating as in Stage H of Example 1 starting from 663 mg of the product obtained in Stage G, using 6 ml of trifluoroacetic acid with 10t~ anisole, 321 mg of desired product is collected.

N.M.R. Spectrum Dimethylsulphoxide 3.53-3.72 j=17.5): CH 2 S; 5.04 4 -CH 2 5.16 (d, j=5) HE; 5.78 (dd, j=5 H7; 5.88 (AB) =CH-Cii 2 6.38 (dt, j=16 =CH-CH2-N+;66 dj= 1:H1 (difluoro ring); 6.75 thiazole HI 6.98 j=16): =C-CH=CH-; 8.06 to 9.58: quinoline 7H'; 9.69 (d j=8, mobile): CO-NH-CE; 7.30-9.60: mobile H's.

EXAMPLE 5: Internal salt of (6R(3 61x,7p 1-3- (2amino-4-thiazolyl) (((2,5-difluoro-3,4-dihydroxyphenyl) methoxy)imino)acetyl)amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo(4.2.O)oct-2-en-3-yl) -2-propenyl) -imidazo(1,2-a) Stacge A:(6R(3(E),6az,7p iodide of S. 30 difluoro-3,4-bis((2-methoxyethoxy)methoxy) phenyl) methoxy) i-mino) 2 -((triphenylmethyl)amino) 4-thiazolyl) acetyl) amino) 2- (((4-methoxyphenyl) methoxy) carbonyl) 1-azabicyclo(4.2.)oct2en3yl) -2-propenyl) -imidazo (1,2a) pyridinium By operating as in Stage G of Example 1 starting from 2 g of the product obtained in Stage F of Example 4 and using 0.492 ml of imidazo pyridine, 950 mg of 'the desired ftV~~1\'roduct was obtained after chromatography on silica (eluant: methylene chloride methanol Stacre B: Internal salt of amino-4-thiazolyl) 1 5-difluoro-3,4-dihydroxyphenyl) methoxy)imino)acetyl)amino) 2 pyridiniun.

By operating as in Stage H of Example I starting Ifrom 940 mg of the product obtained in Stage A above, and using 9 ml of a trifluoroacetic acid solution with l0%k anisole, 0.351 g of desired product is obtained.

N.M.R. Spectrum Dimethylsulphoxide 3.53-3.72

CH

2 S; 5.05 c-CH 2 5.17 H6; 5.78 H7; 5.28 =CH-CH 6.25 (dt, j=16 6): =CH-CH2-N"' 6.70 (dd, j=6 11): H6'' (difluoro ring); 6.76 thiazole H; 6.98 j=16): =C-CH=CH-; 7.57 to 8.44: 6H' guinoline; 9.48 and 9.70 CO-NH-CH; 7.30-9.65: mobile H's.

EXAMPLE 6: Internal salt of (6R(3(E),6ca,7P(Z))) amino-thiazolyl) (((2,5-difluoro-3,4-dihydroxyphenyl) methoxy)imino)acetyljamino) -2-carboxy-8-oxo-5-thia-l-azabicyclo(4.2.O)oct-2-en-3-yl)-2-propenyl)..67.dihydro 5H-1pyrindinium.

Stag~e: (6R(3(E),6a,7P iodide of difluoro-3 ,4-bis ((2-methoxyethoxy)methoxy) phenyl) methoxy) imino) ((triphenylmethyl)amino) 4-thiazolyl) acetyl) amino) 2- (((4-methoxyphenyl) methoxy) carbonyl) I-azabicyclo(4.2.0)oct2en3yly2.propenyly67-dihydro 1-pyrindinium.

By operating as in Stage G of Example 1 starting from 30 2 g of the product obtained in Stage F of Example 4 and using 0.595 ml of (2,3)cyclo penteno pyridine, 899 mg of desired product was obtained after chromatography on silica (eluant: methylene chloride methanol Stage B: Internal salt of amino-4-thiazolyl) (((2,5-difluoro-3,4-dihydroxyphenyl) methoxy)imino)acetyl)amino) -2-carboxy-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-en3yl)-2.propenyl-6,7 dihydro pyrindinium.

By operating as in Stage H of Example 1 starting from 899 mg of the product obtained in Stage A above, and using 8 ml of a trifluoroacetic acid solution with 10k7 anisole, 420 mg of desired product is obtained.

N.M.R. Spectrum Dimethylsuiphoxide 2. 24 14 37 pyrindiniun; 3.5 5 78 CH 2

S;

5.06 4'-CH 2 5.19 H6; 5.81 H7; 5.34 (in):

=CH-CH

2 -Ne; 6.29 (dt)-6.87 j=16): CH=CH 6.72 (dd, j=6.9 18): H6'' (difluoro ring); 6.78 thiazole H; 7.92 (dd) 42 77 H 5 H'14 and H 16; 9. 74 CO-NH- CH.

EXAMPLE 7: Internal salt of (6R(3(E),6cx,7P(Z))) amino- 4 -thiazolyl) 4-dihydroxy-5-fluorophenyl) methoxy) imino) acetyl) amino) -2-carboxy-8-oxo-5-thia-1-azabicyclooct-2-en-3-yl) -2-propenyl) -quinolinium.

Stage A: 5-f luoro 3,4 bis(2-methoxyethoxy) methoxy benzyl alcohol.

The operation is carried out as in Stage A of Example 1 starting from 9.2 g of 5-fluoro-3,4-dihydroxyphenyl) methoxy benzaldehyde using 1. 02 g of sodium borohydride. In this way 7.7 g of desired product is collected, used as it is for the following stage.

Stage B: (5-f luoro-3,4 bis(2-methoxyethoxy) methoxy) phenyl) a ((1,3-dihydro 1,3-dioxo-2H-isoindol-2-yl) oxy) methyl.

The operation is carried out as in Stage B of Example 1 25 using 2.98 g of triphenyl phosphine and 1.79 ml of diethyl azodicarboxylate, 138 g of N-hydroxyphthalimide, starting .9 from 1.9 g of the product obtained in Stage A above. 1.87 g of desired product is collected.

I.R. Spectrum: 30 1794 cnf 1 1737 cm- 1

C=O

1620 cm- 1 1601 cmf 1 aromatic 1510 cm- 1 N.M.R. Spectrum CDC1 3 3.36 (s)-3.38 CH 3 of OMEM; 3.56-3.89-3.96-5.12: the

CH

2 's of OMEM: 7.01 to 7.75:' the aromnatics.

luoro 3,4-bis(2-methoxyethoxy) methoxy oxyam~inobenzyl The operation is carried out as in Stage C of Example

I

starting from 1.3 g of product obtained in Stage B above, using 0.2 ml of hydrazine hydrate. After chromatography on silica (eluting with a methylene chloride ethyl acetate mixture 60-40), 710 mg of expected product is collected.

I.R. Spectrum CHiC1 3 3 3 3 0 c nf 1 C H 2 O N H 2 a o a i e

N

1618, 1594, 1583 and 1509 cm 1 aoti+de.H 2 N.M.R. Spectrum CDC1 3 3.37 and 3.38

CH

3 3.57 (m)-3.84 (m)-3.98 (m)-5.21 (s)-5.30 the CH 2 's of OMEM; 4.59 Cs): CH 2 -0NH 2 5.45 Cbs): NH 2 6.81 (dd)-6.98 Cm): aromatic.

Stagqe D: (Z ca- 5-fluoro-3,4-bis(C 2-methoxyethoxy) methoxy) phenyl methoxy imino) 2 -((triphenylmethyl)amjno) 4-thiazoleacetic acid.

The operation is carried out as in Stage D of Example 1 starting from 745 mg of the product obtained in Stage C and 9 9using 650 mg of oxo-[ 2 -[(triphenylmethyl) amino] thiazol-4- 9* 20 yl] acetic acid (described in the Belgian Patent Application No. 864828) in order to obtain 1.18 g of desired product.

I.R. Spectrum CHCl 3 3404 cnf 1

-C-NH

1593, 1577, 1530 and 1510: conjugated system aromatic N.M.R. Spectrum CDC1 3 3.36 (s)-3.38

CH

3 of OMEM; 3.58 (m)-3.80 (m)-3.95 the CH 2 's of OMEM; 5.18 (s)-5.19 (s)-5.25

CH

2 -o-N and 0-

CH

2 O; 6.62 Cs): thiazole H; 6.78 to 7.31: aromatic; 10.35 mobile H: CO 2

H.

Stage E: 4 -methoxyphenyl)methyl 16R(3(E), 6a, 6P3 3-(3chloro 1-propenyl) 7-CC (5-fluoro 3,4-bis ((2-methoxyethoxy) methoxy) phenyl methoxy) imino) ((triphenylmethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo(4.2.0y.

oct-2-ene-2 -carboxylate.

The operation is carried out as in Stage E of Example 1 starting from 1.1 g of the product obtained in Stage D and using 699 mg of (4-methoxy phenyl) methyl 713-amino 3- [3chloro 1-propenyl) 8-oxo 5-thia l-azabicyclo4.2.)oct.2ene.

2-carboxylate hydrochloride (described in the European Patent Application No. 0,333,154), and 336 mg of dimethylamino propyl ethyl carbodiimide, and after chromatography on silica (eluant: methylene chloride ethyl ether 85-15), 860 mg of desired product is collected, used as it is for the following stage.

Stage F: 4 -methoxyphenyl)methyl 6a, 7 3-(3iodo 1-propenyl) 7-(((5-fluoro 3,4-bis((2-methoxyethoxy) methoxy) phenyl methoxy) imino) 2 -((triphenylmethyl)amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia 1-azabicyclo- (4.2.0)oct-2-ene-2-carboxylate.

The operation is carried out as in Stage F of Example 1 starting from 720 mg of the product obtained in Stage E above, using 286 mg of sodium iodide and an iodine crystal.

770 mg of desired product is obtained which is used as it is for the following stage.

Stage G: 6a, 7P iodide of fluoro 3 4 -bis((2-methoxyethoxy) methoxy) phenyl) methoxy) imino) (2-((triphenylmethyl)amino) 4-thiazolyl) acetyl) 20 amino) 2 -(((4-methoxyphenyl) methoxy) carbonyl) 1 -azabicyclo(4.2.0)oct-2-en-3-yl)-2-propenyl) -quinolinium.

770 mg of the product obtained in Stage F above is agitated for one hour at ambient temperature with 0.43 ml of redistilled quinoline. Precipitation is carried out by the 25 addition of ethyl ether, the precipitate is separated off, washed with ether and dried under reduced pressure. 820 mg of product is collected which is chromatographed on silica, eluting with a methylene chloride methanol mixture 96-04.

231 mg of desired product is collected.

30 N.M.R. Spectrum CDC1 3 3.78-3.93

CH

3 of OMEM; 3.42 (m)-3.54 and 3.72 to 5.22: the CH 2 's of OMEM and CH 2 6.86 mobile): CO- NH; 6.48 thiazole H; 7.28: trityl; 4.98 N-CH-CH-S; 5.84 N-CH-CH-S; 6.70 to 6.97: aromatic H's; 5.28: CH2-4; 3.52 (d)-3.61

S-CH

2 6.42 propenyl CH; 6.03 (dd) and 6.17 propenyl CH 2 8.14 to 10.4 7H quinoline.

Stage H: Internal salt of ON C amino-4-thiazolyl) (((-3,4-dihydroxy-5-fluorophenyl) methoxy) Nv 'l imino) acetyl) amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo- (4.2.0)oct-2-en-3-yl)-2-propenyl)-quinolinium.

The operation is carried out as in Stage H of Example 1 starting from 120 mg of the product obtained in Stage G, using 1.2 ml of trifluoroacetic acid with 10% anisole, in this way 31 mg of desired product is collected.

N.M.R. Spectrum Dimethylsulphoxide 6.59 aromatic H, 4,92 -CH 2 9.66 mob.): NH; 6.72 thiazole H; 5.17 N-CH-CH-S; 5.78 N-CH-CH-S; 3.52-3.74 S-CH 2 6.98 j=15.5): propenyl CH; 6.38: the other propenyl CH; 5.90 propenyl CH 2 8.27 to 9.57: 7H quinoline.

EXAMPLE 8: Internal salt of 6a, 1-3-(7- (((2-amino-4-thiazolyl) (((methoxycarbonyl)-3,4-dihydroxy-5fluorophenyl) methoxy) imino) acetyl) amino)-2-carboxy-8-oxo- 5-thia-1-azabicyclo(4.2.O0)oct-2-en-3-yl)-2-propenyl) -quinolinium.

Stage A: methyl [3-fluoro 4,5-bis[(2-methoxyethoxy) methoxy] phenyl] hydroxy acetate .20 5.3 g of [3-fluoro 4,5bis[(2-methoxyethoxy) methoxy phenyl] hydroxyacetic acid (described in the European Patent Application No. 551,034) is dissolved at 20 0 C and under an inert gas atmosphere in 66 cm 3 of tetrahydrofuran then 78 cm 3 S of a solution of diazomethane in ether at 15 g/l (2 25 equivalents of diazomethane) is added at 150C and the whole is maintained under agitation for 16 hours. Water is added and acidification is carried out by the addition of acetic acid. The organic phase is washed with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. 30 g of crude expected product is obtained, used as it is for the following stage.

Stage B: methyl [3-fluoro 4,5-bisU(2-methoxy ethoxy) methoxy] phenyl] phthalimidoxy acetate 2.25 g of N-hydroxy phthalimide and 7 g of triphenyl phosphine are added to a solution of 5.5 g of the product obtained in Stage A in 60 cm 3 of tetrahydrofuran. The reaction mixture is cooled down to -10 0 C and 4.1 cm 3 of diethyl azodicarboxylate is added then the whole is

'A,

(Qf cii maintained under agitation at 0°C for 2 hours. After concentration to dryness, the crude product is washed with isopropyl ether then dried. 6.5 g of expected product is obtained.

IR Spectrum (CHC1 3 Absorptions at 1745, 1759, 1739 cm 1 C=0, 1615, 1597, 1509, 1490 cm- 1 aromatic C=C's.

Stage C: methyl oxyamino [3-fluoro 4,5-bis[(2-methoxyethoxy) methoxy] phenyl] acetate 2 g of the product obtained in Stage B, 40 ml of ethanol and 4 ml of a 1M solution of hydrazine hydrate in ethanol are agitated for 2 hours at 20 0 C. The insoluble product formed is filtered off, followed by rinsing with methylene chloride, ml of phosphate buffer is added to the filtrate, followed by agitation for 5 minutes and extraction with methylene chloride, washing with water, drying and evaporating to dryness under reduced pressure. The residue is taken up in ml of methylene chloride, agitation is carried out for minutes at 0°C, followed by filtration and rinsing with 20 methylene chloride and the filtrate is concentrated to dryness under reduced pressure. 1.6 g of the desired product s 0 is collected.

I.R. Spectrum (Nujol) Absorption OH/NH 25 C=O 1751, 1722 cm- 1 Aromatics 1615, 1590,1507 cm- 1 StaQe D: e-((methoxycarbonyl)-5 fluoro 3,4-bis methoxyethoxy) methoxy) phenylmethoxy) carboxymethyl) imino) (2-((triphenylmethyl) amino) 4-thiazoleacetic acid.

The operation is carried out as in Stage D of Example 1 starting from 710 mg of the product obtained in Stage C and using 747 mg of oxo-[2-[(triphenylmethyl) amino] thiazol-4yl] acetic acid (described in the Belgian Patent Application No. 864828) in order to obtain 1.14 g of the desired product.

N.M.R. Spectrum CDCl 3 3.36 (s)-3.42 CH 3 of OMEM; 3.56 (m)-3.64 (m)-3.82 3.965 the CH 2 's of OMEM; 3.79 CO 2

CH

3 5.21 5.20 to 5.28 O-CH 2 5.80 CH-O-N; 6.78 thiazole H; 9 9 9 4 9 4* 4 9 *9 9 a 9 9 9 a 9 S 9e S 9 4 9 9**4 a. a 4S a 6.88 to 7.32: aromatic.

Saga-e E: (4-inethoxyphenyl)n.ethyl 6cr,6p 3-(3chloro 1-propenyl) 7- ((methoxycarbonyl) 5-f luoro 3 ,4-bis xnethoxyethoxy) methoxy) phenyl methoxy) imino) (2- ((triphenylinethyl) amino) 4-thiazoly.) acetyl) amino) 8-oxo l-azabicyclo(4.2.o)oct-2.ene2carboxylate.

The operation is carried out as in Stage E of Example 1 starting from 1.14 mng of the product obtained in Stage D and using 786 mng of (4-methoxyphenyl) methyl 7-amino 3- [3-chloro 1-propenyl) 8-oxo 5-thia 1-azabicyclo(4.2.0)oct.2...

carboxylate hydrochloride (described in the European Patent Application No. 0,333,154), and 378 mng of dimethylamino propyl ethyl carbodiimide, and after chromatography on silica (eluant: methylene chloride ethyl ether 85-15), 1.01 g of desired product is collected, used as it is for the following stage.

StAge F: 4 -rethoxyphenyl)methyl 6ar, 7P3 3-(3iodo 1-propenyl) 7- (((methoxycarbonyl) 5-fluoro 3,4-bis methoxyethoxy) methoxy) phenyl methoxy) imino) (2- 20 ((triphenylinethyl) amino) 4-thiazolyl) acetyl) amino) 8-oxo 5-thia l-azabicyclo(4.2.0)oct.22carboxylate.

The operation is carried out as in Stage F of Example 1 starting from 1 g of the product obtained in Stage E, above, using 380 mg of sodium iodide and an iodine crystal. 1.05 g 25 of desired product is obtained which is used as it is for the following stage.

Stage G: 6a,73 iodide of (((((methoxycarbonyl) 5-fluoro 3 ,4-bis ((2-methoxyethoxy) methoxy) phenyl) methoxy) imino) ((triphenylmethyl) amino) 30 4-thiazolyl) acetyl) amino) 2f(((4-methoxyphenyl) methoxy) carbonyl) 8-x--halaaiylo420ot2e- l-2propenyl) quinoijnium: (delta Z) isomer and (delta E) isomer.

The operation is carried out as in Stage G of Example 7 starting from 1 g of the product obtained in Stage F above using 0.5 ml of redistilled quinoline. 0.99 g of expected product is collected.

N.M.R. Spectrum CDC1 3 (delta Z isomer) >3.32-3.35-3.36

CH

3 of OMEM; 3.30 (mn) to 4.05 and

~)I~J

A

5.24 to 5.35: the CH 2 's of OME4; 5.86 5.87 CH-O-N-; 8.48 NH; 6.76 to 7.35 thiazole and trityl H; 5.42- 5.47 N-CH-CH-S; 5.97 Cdd): N-CH-CH-S; 6.76 to 7.35: aromatic H's; 5.24 to 5.35: CH 2 3.-30 -4.05 S-CR 2 6.51 (bd, j=11) propenyl CH; 5.90 the other propenyl

CH;

5.69 (dmn, j=16)-6.07 Cbdd, j=.16 and propenyl CH 2 7.87 8.01 to 8.22 8.99 10.30 80/20 R/s mixture with delta Z and syn oxixne.

N.M.1R. Spectrum CDC1.

3 (delta E isomer) 3.28-3.34-3.35

CE

3 of OAEM; 3.42 (in) to 4.00 and 5.10 to 5.32: the CH 2 's Of OMEM; 5.81 5.84 CH-O-N=; 8.55 NH{; 6.78 to 6.80 thiazole H; 6.85 to 7.40 trityl; 4.97-5.04 N-CHj-CH-S; 5.88-5.94

N-CH-CH-S;

6.85 to 7.40 aromatic H's; 3.69-3.73-3.80-3,82:

-OCH

3 and CO 2

CH

3 3.40 (m)-4.00

S-CR

2 6.38 to 6.63 (in): propenyl CE; 6.00-6.15 propenyl

CE

2 7.94 8.15 8.26 8.43 9.00 10.36 quinoline. (35/65 *q R/S mixture with delta E and syn oxime.

Staae H: Internal salt of (6R(3 6a, 7P 1-3-C(7-C(2- 20 amino- thiazolyl) C C(methoxycarbonyl) phenyl) methoxy) imino) acetyl) axnino)-2-carboxy-8-oxo-5.

thia-1-azabicyclo(4.2.0)oct-2.en3yl)-2-propenyl)quinolinium.

The operation is carried out as in Stage H of Example 1 starting from 300 mg of the product obtained in Stage G, using 3 ml of trifluoroacetic acid and 0.3 ml of anisole.

112 mng of the desired product is obtained.

I.R. Spectrum (Nujol) General absorption

OH/NH

C=O 1770, 1742 and'01670 cmf Conjugated system, COO- and secondary amnide 1627, 1590 and 1525 cm- 1 N.M.R. Spectrum Dimethylsuiphoxide 3 .64-3. 65 Cs) CO 2

CH

3 6.69 Cm) to 6.78 Cm): aromatic H and thiazole H; 5.46 Cs): 5.12-5.16

N-CH-CH-S;

5.82 Cm): N-CH-CH-S; 3.52-3.70:

S-CR

2 6.96 Cdd ed.): Spropenyl CH; 5.88 Cm): propenyl CE 2 8.07 to 9.58: 7H ~'~uinoline.

In addition to the products described above in the examples, the products corresponding to the formula below and resulting from the combinations of the different values of the substituents represented in the following tables, constitute products which can be obtained according to the invention.

NH2

N

H

-N N C I I* I *Ph

A

200 0 a N H

-CO

2

CH

3 C I 0OH c I c 1 o il

NN

0

N

S.

S S

S.

5555

S

S

S S 5* S S

N

0 49 FPhR6R 0 N NH 2 1 0 1 C H 3 COCH3 0 OH OH0

OH

C Hf N 0 Nl

GNH

CH C 0 0 IF N X EXAMPLE 9: Preparations for injections were prepared of formula: Product of Example 1 500 mg Sterile aqueous excipient s.q. for 5 cm 3 PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION In vitro activity, method of dilutions in solid medium.

A series of dishes is prepared into which an equal quantity of sterile nutritive medium is divided, containing increasing quantities of the product being studied then each dish is seeded with several bacterial strains.

After incubation for 24 hours in a heating chamber at 37 0 C, the growth inhibition is evaluated by the absence of any bacterial development which allows the minimal inhibitory concentrations (MIC) to be determined, expressed as micrograms/cm 3 The results are expressed in the form of geometric means of all the MIC's obtained, for a specific group of strains.

20 The following results were obtained (table): 4.

Penicillin- Product of resistant Example Staphylococci (:22 strains) 1 0,78 2 0,91 3 1,37 4 0,37 0,55 6 0,63 7 0,3 8 0,3 Cefotaxime resistant Enterobacteria (36 strains) 0,11 0,19 0,13 0,38 0,26 0,36 0,2 Pseudomonas ae rug ino sa (23 strains) 0,086 0,42 0,26 0,14 1,12 0,47 0 ,49 51a Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

2* a The claims defining the invention are as follows: 1) The products of general formula

NH

9

H

N C 0e N R 2

R

1 s0 C 0 r R 2 4 syn isomer, in the form of internal salts or salts with 20 mineral or organic acids or with bases, in which formula:

R

1

R

2

R

3 and R 5 identical or different, represent a hydrogen atom, a halogen atom or a radical chosen from the group constituted by the following radicals: hydroxy, alkyl containing 1 to 4 carbon atoms optionally substituted by one 25 or more halogen atoms, alkyloxy containing 1 to 4 carbon atoms, mercapto, alkylthio containing 1 to 4 carbon atoms, nitro, cyano, amino, alkylamino containing 1 to 4 carbon atoms, dialkylamino containing 2 to 8 carbon atoms, carbamoyl, (alkylamino) carbonyl containing 2 to 5 carbon 30 atoms, (dialkylamino) carbonyl containing 3 to 9 carbon atoms, acyloxy containing 1 to 8 carbon atoms and /Rx SO2N which Rx and Ry, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms,

R

4 represents a hydroxy radical or an acyloxy radical containing 1 to 8 carbon atoms,

R

7 represents a hydrogen atom, A represents a hydrogen atom, an equivalent of an alkali metal, an alkaline-earth metal, magnesium, ammonium or an amino organic base, or A represents the remainder of an easily-cleavable ester group, or C02A represents C0 2 6 the wavy line signifies that the CH 2

R

6 group can be found in the E or Z position and R 6 represents, in quaternary ammonium form, one of the following radicals: 4* *epO S S S 4*

S

S. .5 A S

S.

S S 0 S S S 555.

S S S

S.

5

SSS*

5 5 S S S. S S .5

S

O

0 Kv

'C

V

C

20 25 v. w U R-- U T T

R'

\/3

P

1 2 R

W

T Y v^\ R-4-

U

N T N Z R' N N

V--

V

X

R 4 ^CH2) R /\y R-K XRC41 T R'

R'

R fR N N X

CH

3 C 2)M R R R vl z v ,x T R 4- 1^ 11 R TR

T

in which m is equal 1, 2 or 3, X represents CH 2 NH, 0 or S; Q, J, Y, T, U, V, W and Z, identical or different, represent independently of each other CH or N, it being understood that 30 each of these cyclic radicals contains 1 to 5 heteroatoms, that at least one of these heteroatoms is the nitrogen atom and that these cyclic radicals can be substituted by one or more R or R' radicals; R and identical or different, represent a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 4 carbon atoms, a halogen atom, a cyano radical, one of the following radicals: C0 2

-Q

1

CO-

SNQ(Q

2

NQI(Q

2 S0 2

-NQI(Q

2

CS-NH

2 NH-CO-QI, CH=N-OH,

Claims (2)

1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) quinolinium, the internal salt of 6alpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) ((2,5-difluoro 3,4-dihydroxy- phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) imidazo(1,2-a) pyridinium, the internal salt of 6alpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) (((2,5-dichloro 3,4-dihydroxy- phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) imidazo(1,2-a) pyridinium, the internal salt of 6alpha, 7beta-(Z))) 1-(3- (7-(((2-amino 4-thiazolyl) (((2,5-difluoro 3,4-dihydroxy- phenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 1-azabicycloll4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 1-pyrindinium, the internal salt of 6alpha, 7beta(Z))) (((2-amino 4-thiazolyl) ((2,5-dichioro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1- azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 6,7-dihydro 5H-1- pyrindinium, the internal salt of 6alpha, 7beta(Z))) ((2-amino 4-thiazolyl) ((5-fluoro 3,4-dihydroxyphenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo 5-thia 1- azabicycloll4,2,0]oct-2-en-3-yl) 2-propenyl) quinolinium, 15 the internal salt of 6alpha, 7beta(Z))) ((2-amino 4-thiazolyl) ((methoxycarbonyl) (3,4-dihydroxy **fluorophenyl) methoxy) imino) acetyl) amino) 2-carboxy 8-oxo l-azabicycloil4,2,0]oct-2-en-3-yl) 2-propenyl) quinolinium, 20 9) Preparation process for the products of formula as defined in claim 1, characterized in that the aromatic aldehyde of formula (III): C *(II) R 3 in which R 1 R 2 1 R 3 R 4 and R 5 are as defined in claim 1, has, if necessary, its reactive functions protected and is thus converted into an aromatic aldehyde of formula (II p) 33 R R. (II p) in which Rlpi R 2 pI R 3 pf R4p and R5P represent the values of R 1 R 2 1 R 3 1 R 4 and R 5 respectively as defined previously or a protected reactive function, said aldehyde of formula (II p) is-either treated by a reducing agent, in order to obtain the alcohol of formula (III): a a. a a a. a *aa. a. a a a a. a a a a. a 'P R,2 (III) P P or homologated into the alpha-hydroxy acid of formula (III,): H C H (TTT.. I-, a a a *aa a.. a R 2 P P,4 R P which acid is esterified into an alpha-hydroxy ester of formula (1112): 0 C H 0 A 1o (1112) RI RK T R in which Alk represents an alkyl radical containing 1 to 4 carbon atoms, which ester or alcohol of formula (1112) or (III) is treated with N-hydroxy phthalimide, if appropriate in the presence of an activating agent, in order to obtain the derivative of formula (IV): *a*q b* (IV) 01- "R 7 P R'P R which is hydrolyzed into an 0-substituted hydroxylamile of formula MV: H 2N 1-1 /R 7 R R 5 P R3 p which is condensed with a derivative of 2- (2-amino thiazol-4- yl) 2-oxo acetic acid of formula (VI): N H II N 1-1 (VI) in which R 8 represents a hydrogen atom or a protective group of the amine function, in order to form the derivative of "'syn" aipha-alkoxyimino acetic acid of formula (VII): S. 0S 0**O S S S. S S 55 9 I S S. 5 S. S S *55) .5.5 S. 55 S S NH R N N I IFI R 700 C H (VII) R I -P IR2

9. S S S 455555 S R 3 p a functional derivative of which, if appropriate, is prepared, which product of formula (VII) or functional derivative is amidified with an ester of 7-amino 3-(3-halo 1- propenyl) 8-oxo 5-thia l-azabicyclo[4,2,0]oct- 2 -en- 2 carboxylic acid hydrochloride of formula (VIII): H C1 H 2 NS (VIII) C H -C H 'IC H 2-Hal1 in which R 9 represents the remainder of an easily cleavable ester, to produce the derivative of 7- (N-substituted amido) 3- (3-halo 1-propenyl) 8-oxo 5-thia l-azabicyclo[4,2,0]oct- 2 en-2-carboxylic acid of formula (IX): ITH R N 0 7 0 N CIH 0 C H=C H 'vICH 2 Ha 1 (IX) R R 0 C'0 RP which is converted, if appropriate, into the 3- (3-iodo propenyl) analogue of formula 0 P. R N H N C. H 0 C H C C 2 5P0 C 0 R9 RP RP. which is treated with a base of formula R 6 in order to oti the product of formula (XI): N HR N H NN C H 0 2 0 0R (XI) R 2 p R4 P 63 from which product of formula (XI) if appropriate, the or isomers are isolated or the isomers are converted into isomers, which product of formula (XI) is subjected, if appropriate, to one or more of the following reactions in an appropriate order: a) cutting by hydrolysis or by the action of thiourea of all or part of the ester protective groups and of the groups protecting the amino radical or the hydroxyl radicals, b) esterification or salification by a base of the carboxylic radical, c) salification by an acid of the amino radical, d) separation of the products in the form of an R,S mixture into R and S. 10) Variant of the process according to claim 9, 15 characterized in that the O-substituted hydroxylamine of formula is condensed with the product of formula (XII): H *2 0 C H =C Hv C H 2 R 6 O 0 in order to produce the product of formula (XI) as defined in claim 9. 11) As medicaments, the products corresponding to formula as defined in claim 1, wherein R 1 R 2 R 3 R 4 R 5 and A are defined in claim 1 and R 7 represents a hydrogen atom as well as their pharmaceutically acceptable acid salts, except tert-butyl. 64 12) As medicaments, the products as defined in any one of claims 2 to 8, as well as their pharmaceutically acceptable acid salts. 13) Pharmaceutical compositions containing, as active ingredient, at least one medicament according to one of claims 11 or 12. 14) As new industrial products, the products of formulae (VII), and (XI) as defined in claim 9. 15) The products general formula according to Claims 1 to 9 substantially as hereinbefore described with reference to any one of the accompanying Examples. 16) Use of the products of general formula according to Claims 1 to 9 as cephalosporins substantially as hereinbefore described. DATED this 24th day of June, 1999 HOECHST MARION ROUSSEL By their Patent Attorneys: CALLINAN LAWRIE X. ^O^JjJ-'w j 1 ABSTRACT The subject of the invention is the products of formula NH N H NC R 7 0 0 N CH 0 CH=ClH "CH 2 -R P50' C 0 A r r r r r r r syn isomer, in the form of internal salts or salts of acids or bases, in which: R 1 R 2 R 3 and R 5 represent a hydrogen or halogen atom or one of the following radicals: hydroxy, alkyl optionally substituted by halogen, alkyloxy, mercapto, alkylthio, nitro, cyano, amino, alkylamino, dialkylamino, carbamoyl, (alkylamino) carbonyl, (dialkylamino) carbonyl, carboxy, alkoxycarbonyl, acyloxy and S Rx 0 2 N in which Rx and Ry represent hydrogen or alkyl, R 4 represents hydroxy or acyloxy, R 7 represents hydrogen or alkyloxycarbonyl, A represents hydrogen, an alkali or alkaline-earth metal, magnesium, ammonium or an amino organic base, or the remainder of an ester group, or C02A represents CO2, CH 2 R 6 is in E or Z position and R 6 represents a cyclic or non- cyclic quaternary ammonium. These products possess useful pharmacological properties which justify their use as medicaments. o* r« f* .e. o e C °e Ca S S wCS. oo