AU676218B2 - New cephalosporins containing a substituted oxyimino radicalin position 7, their preparation process and intermediates and their use as medicaments - Google Patents

Description

P'/00(/011

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

00 TOB CWETDBYAPLCN ITORMDBES OPLTD BYEI APPLIANTEIAMNS Th)ie floin Aplianet ROUSE a u lectioAisivninicuigEh e, ehdo pef. mn itkon om: 1la New cephalosporins containing a substituted oxyimino radical in position 7, their preparation porcess and intermediates and their use as medicaments.

The present inventioin relates to new cephalosporins containinj a substituted oxyimino radical on the side chain in position 7, their preparation process, their use as medicaments, the compositions containing them and the new intermediates obtained.

A subject of the invention is the products of general formula

NH

Hi ^cS% (I) 0 N C 1- II I II As. C% o 0 N H 0 11 c

A

20 0 0 syn isomer, in the or form or in the form of an (R,S) mixture, in the form of an internal salt or their salts with organic or mineral acids, in which formula:

R

1 represents a group of formula 99« o ff0 /0f[

(K)

C.

30 .R' in which R' 1 i represents an alkyl radical containing 1 to 4 carbon atoms, a cyano, carboxy or alkoxy-carbonyl radical, in which the alkyl radical contains 1 to 4 carbon atoms, or R 1 represents a group of formula

(L)

2 A and identical or different, represent a hydrogen atom, an equivalent of an alkali metal, alkaline--earth metal, magnesium, ammonium or an organic amino base, or one only or each of the CO2A or CO 2 A' groups represents

CO

2 the wavy line indicates that the CH 2

R

2 group can be found in E or Z position and R 2 represents in the quaternary ammonium form, one of the following radicals: R- R R (C 2 R Y T Z R T R' T

R'

R

J, i hb *e 0 R .R R R' SR' V z VY .0R aI i r- a h r T T T

R'

in which X represents CH 2 NH, 0 or S; a Q, J, Y, T, U, V, W and Z, identical or different, represent independently of each other CH r C or N, it being understood that each of these cyclic radicals contains 1 to 5 heteroatows, that at least one of these heteroatoms is the nitrogen atom 15 and that these cyclic radicals are substituted by one or more R or R' radicals; R and identical or different, represent a hydrogen atom, a halogen 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, a C0 2

-Q

1

CO-NQI(Q

2

NQI(Q

2

SC

2

-NQ

1

(Q

2

CS-NH

2 NH-CO-QI, CH=N-OH, CH=N-O-Q1, CH 2

-CN,

CH

2 -S-Qj/radical in which Q, and Q 2 identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 3 4 carbon atoms, P1, 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 having the definitions indicated above for R and the dotted line indicates that P 1 and P 2 can optionally form with the nitrogen atom to which they are linked, a heterocycle with or 6 members.

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

By alkyloxy radical containing 1 to 4 carbon atoms is meant one of the following radicals: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy .r tert-butoxy.

By halogen atom is meant the 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 be a pyrrolidine, morpholine or piperidine radical.

*o 20 The products of formula can exist in the form of salts. Among the values of A and an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium can be mentioned. Among the organic bases the following can be mentioned: methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris[(hydroxymethyl) amino] methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyiglucamine.

The products of formula can also be presented in the 30 form of a pure internal salt, in salified form or in combined form with the acids of the solution. Among the acids with which the product or products of formula can be salified, the following acids can be mentioned among others: acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, para-toluenesulphonic, phophoric, sulphuric, hydrochloric, hydrobromic, hydroiodic.

In a preferred embodiment of the invention, A' represents a hydrogen atom and CO 2 A represents C02 4 Tha expression in quaternary ammonium form indicates that the R2 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 2 represents one of the following radicals: N CO o

N

S

N N~A~J~

Y

N I

N

E

N C X -OCY He.

4 x.7 ,oc'- 1 X3 o

S

a* so eoo* 4 o *a 5 Et O M 6O e 5~ie a z If- N NY aII*'rr

I

or also one of the following radicals: a a a a ~II1IhI 011L11 N H

N

.4 0 N *2 CN1

C)N

~N.

C>

N

C

.1e C N Ne e N o *a

S

S

S

S S

S..

*SSS

S S S 14X 2N-N n a-CHC.

0 0e ile

S.

S S A more particular subject of the invention is the 25 products of general formula as defined above in which R.

represents one of the following radicals: quinolinium, isoaruinolinium, 4-(rnethvlthio) pyridinium, thierio[2,3-b]-pyridinium, imidazo(l,2-a)pyridinium or 6,7-dihydro-5H- pyrindinium, those in which R, represents a radical of formula in which R1 1 represents a cyano, carboxy or alkoxycarbony. radical.

A quite particular subject of the invention is product the name of which follows: the internal salt of Galpha, 7beta-(Z)]] l-rJ-[7-I:[(2-amino 4-thiazolyl) l[carboxy 3,4-dihydroxy 2-thienyl) methoxy] imino] acetyl] ;:tmino] 2-carboxy 8-oxo 5-thia I-azabicycloC4,2, Oloct-2-en-3-YlI 2-propenyl] quinolinium.

A

6 Also a subject of the invention is a preparation process for the products of formula as defined above, characterized in that an ester of formula (II):

II

/13\ i(II) 0 3

R

1 in which X repreqents a -oai \group or a radical capable of generating a -ste a ng\group in situ, R 1 p represents an R 1 group as defined above, in which the hydroxy or amino radicals are protected and R 3 represents the remainder of an easily cleavable ester, is treated with N-hydroxy phthalimide, if appropriate in the presence of an activating agent, in order to produce a derivative of formula (III): e 0 S0(III) S. 0 CH OR 3 RiP

S

which derivative of formula (III) is hydrolyzed into the O-substituted hydroxylamine of formula (IV): 0 H II

(IV)

R

3 R. p le I" which product of formula (IV) is condensed with a derivative of (2-amino thiazol-4-yl) 2-oxoacetic acid of formula

S(V)

C ,OH 0 C I I 0 in which R 4 represents a hydrogen atom or a protective group of the amine function, in order to form the derivative of the alpha-alkoxy imino acetic acid of formula (VI): .N HR d S

N

(VI)

0 C o II r !r 0 30 a functonal derivative of which is prepared, if appropriate, which product of formula (VI) or functional derivative is amidified with an ester of the hydrochloride of 7-amino 3-(3-halogeno 1-propenyl) 8-oxo l-azabicyclo[4,2,0]oct-2- en-2-carboxylic acid of formula

(VII):

NC1 S 0 CNCH~CH 2 Fta 1 xR 0

(VIIL)

or its salts, in which Hal represents a halogen atom and R represents the remainder of an easily cleavable ester, in order to produce a 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 (VIII): N H R

SS

0I N R 3 C% ~0 0 20 0 C H 0 C H CH "AC H 2 Ra 1

(VIII)

R IP 0 0 a. a 0 which product of fLormula (VIII) is converted, if appropriate, into the analogous 3-(3-iodo propenylated) product of formula (IX)

I

P 0. 0 0N which product of formula (IX) is treated with a base of

(IX)

9 formula R 2 in order to obtain the product of formula 11 H

R

H

0 N 0 C H 0 C H=CH 'CH 2 R 2 101 RiP C dA- 0 0 from which product of formula if desired, the or (Z) isomers are isolated or the isomers are converted into the isomer and which product of formula is subjected to one or more of the following reactions, in any order: a) cutting by hydrolysis or by the action of thiourea of all or part of the ester groups or protective groups of the amino 6. radical or radicals or the hydroxyl radicals, b) esterification or salification by a base of the carboxylic radical or radicals, c) salification by an acid of the amino radical or radicals, d) separation of the products in the form of an R,S mixture into R or S.

.Also a subject of the invention is a variant of the process described above, characterized in that the O-substituted hydroxylamine of formula (IV) is condensed with a product of formula (XI):

N

2D C, R I q 0 R, p0 in order to produce a product of formula as defined previously.

The protected hydroxy functions which can be carried by the Rlp group are chosen from the following groups: acyloxy such as for example formyloxy, acetoxy, propionyloxy, chioroacetoxy, bromoacetoxy, dichioroacetoxy, trichloro-acetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy, benzoylformoxy, p-nitro benzoyloxy. The following groups can also be mentioned: ethoxycarbonyloxy, methoxycarbonyloxy propoxycarbonyloxy, 2,2,2-trichloro ethoxycarbonyloxy, benzyloxycarbonyloxy, tert-butoxy-carbonyloxy, 1-cyclopropyl ethoxycarbonyloxy, phthaloyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy and pivaloyloxy, phenylacetoxy, phenyipropionyloxy, mesyloxy, chlorobenzoyloxy, para-nitrobenzoyloxy, para-tert-butyl benzoyloxy, caprylyloxy, acryloyoxy, methylcarbamoyloxy, phenylcarbamoyloxy, naphthylcarbamoy loxy.

The following radicals can also be mentioned: phenoxy, 4-chloro phenoxy, tolyloxy or tert-butyl phenoxy, tetra-hydropyrannyloxy, tetrahydrothiopyrannyloxy, methoxytetra-hydropyrannyloxy, trityloxy, benzyloxy, 4-methoxy benzyloxy, benzhydryloxy, trichioroethoxy, 1-methyl l-methoxyethoxy, or the alkoxy alkoxy-methyl radicals such as methoxy ethoxy methyl.

The two hydroxy radicals can also be protected by forming one of the following radicals: methylenedioxy, isopropylenedioxy, 1,1-cyclohexyl bis(oxy), diphenyl-methylenedioxy, carbonate or hydroxy borannylbis(oxy).

The protected hydroxy functions which can be carried by the Rlp group are preferably chosen from the following groups: methoxyethoxymetnoxy, propionyloxymethoxy, acetoxy-methoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy, butyryl-oxymethoxy, valeryloxymethoxy, pivaloyloxymethoxy, 2-acetoxy ethoxy, 2-propionyloxy ethoxy, 2-butyryloxy ethoxy, 2-iodo-ethoxy, 2,2,2-trichloro ethoxy, vinyloxy, allyloxy, ethynyloxy, propynyloxy, benzyloxy, I 4-methoxy benzyloxy, 4-nitro benzyloxy, phenylethoxy, trityloxy, diphenylmethyloxy or 3 ,4-dimethoxyphenoxy.

The 2-methoxy ethoxymethoxy (MEI4-O) group is particularly preferred.

The remainders of easily cleavable ester groups which can be represented by R 3 and R 5 are chosen from the following groups: butyl, isobutyl, tert-butyl, pentyl, hexyl, m&athoxymethyl, ethoxymethyl, isopropyloxymethyl, aipha-methoxy ethyl, alpha-ethoxy ethyl, methyithiomethyl, ethyithiomethyl, isopropyithiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxym~ethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, tert-butyl-carbonyloxymethyl, hexadecanoyloxymethyl, pivaloyloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetoxy ethyl, 2-acetoxy ethyl, 1-propionyloxy ethyl, 2-propionyloxy ethy'l, 1-butyryloxy ethyl, 2-butyryloxy ethyl, l-(tert-butylcar- :0,00, onyloxy) ethyl, 1-acetoxy propyl, 1-hexadecanoyloxy ethyl, 1-propionyloxy propyl, 1-methoxycarbonyloxy ethyl, 20 methoxy-carbonyloxymethyl, 1-acetoxy butyl, 1-acetoxy hexyl, 1-acetoxy heptyl, phthalidyl, 5,6-dimethoxy phthalidyl, tert-butylcarbonylmethyl, vinyl, allyl, 2-chloro, allyl, ethynyl, propynyl, methoxycarbonylmethyl, benzyl, 4-methoxy :benzyl, 4-nitro, benzyl, phenethyl, trityl, diphenyl methyl, phenyl, 4-chloro phenyl, tolyl, tert-butyl phenyl, 3,4-dimethoxy phenyl, methoxyethoxymethyl, dimethylamino-ethyl, cyanomethyl, tert-butoxycarbonylmethyl, 2, 2-ethylenedioXy ethyl, cyanoethyl, 2, 2-dixnethoxy ethyl; 2-chioro ethoxymethyl, (2-hydroxy ethoxy) ethyl, 2,3-epoxy *:de 30 propyl, 3-dimethylamilo 2-hydroxy propyl, 2-hydroxy ethyl, 2-methylaminoethoxymethyl, (2-amino ethoxy) mathyl, 3-methoxy 2, 4-thiadiazol-5-yl, tetrahydropyrann-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-brcmo 1-acetoxy ethyl, 2-f luoro 1-acetoxy ethyl, 2-methoxy 1-acetoxy ethyl, 2-methyl 1-acetoxy propyl, 0 1-methyl 1-acetoxy ethyl, 1-(methoxyacetoxy) ethyl, l-acety.

carbonyloxyethyl, 1-hydroxy acetoxyethyl, 1-(2-thienyl) carbonyloxyethyl, 1-(2-furyl) carbonyloxyethyl, 2-furyl) carbonyloxyethyl, 1-(2-pyrrolyl) carboryloxyethyl, 1-(propionyloxycarbonyloxy) ethyl, 1-(propoxycarbonyloxy) ethyl, 1-(isopropoxycarbonyloxy) ethyl, 1-(methonyethoxycarbonyloxy) ethyl, 1-(allyloxycarbonyloxy) ethyl, isopropoxycarbonyl methyl, l-((2,3-epoxy propyl) oxycarbonyloxy] ethyl, l-[(2-furyl) methoxycarbonyloxy] ethyl, 1.-[(2-fluoro ethoxy) carbonyloxy] ethyl, 1-(methoxy-carbonyloxy) propyl, 1-(methoxycarbonyloxy) 1-methyl ethyl, (methoxycarbonyloxy) chloromethyl, 1-(methoxycarbonyloxy) 2-chloro ethyl, 1-(methoxy carbonyloxy) 2-methoxy ethyl, l-(methoxycarbonyloxy) allyl or a 5-methyl 2-oxo 1,3-dioxol-4-yl remainder.

The diphenylmethyl radical is preferred for R3 and 4-methoxy benzyl or diphenylmethyl for R 5 The protective group of the amino radical that can be represented by R 4 or that can be carried by the Rlp group can be, for example, one of the following groups: carbamoyl, methyl carbamoyl, phenyl carbamoyl, naphthylcarbamoyl. as well as the corresponding thiocarbamoyls, a substituted or non-substituted alkyl radical with 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, 30 dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl benzoyl, toluolyl, naphthoyl, chlorobenzoyl, para-nitro benzoyl, para-tert-butyl benzoyl, phenoxyacetyl, caprylyl, decanoyl 1 acryloyl, phthaloyl, mesyl, phenylacetyl, phenyl-propionyl, oxalyl, succinyl, pivaloyl, a lower alkoxy-carbonyl or a cycloalcoxycarbonyl such as for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, lcyclopropylethoxycarbony1, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, 4 hexyloxycarbonyl, trichloroethoxy carbonyl, an aralkoxycarbonyl group, such as benzyloxycarbonyle.

The trityl group is preferred for R4 and benzyloxy-carbonyl for R 1 p.

The above list is not limitative, it is obvious that other amine protective groups, groups known especially from the chemistry of the peptides, can also be used.

The X group can be a hydroxy radical, an alkylsulphonylox-y radical such as methylsulphonyloxy, an aryl-sulphonyloxy radical such as phenyl or tolylsulphonyloxy, or a halogen atom such as chlorine, bromine or iodine. The hydroxy and chloro values are more particularly preferred.

The hydrolysis of the derivative of formula (III) is carried out by methods known to an average man skilled in the art.

The functional derivative of the acid of formula (VI) can be for example a halide, a symmetrical or mixed anhydride, the amide, the azide or an activated ester.

20 As an example of a mixed anhydride that formed with isobutyl chloroformate and that formed with pivaloyl chloride and the carboxylic-sulphonic mixed anhydrides formed for example with para-toluene sulphonyl chloride can for example be mentioned.

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

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

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

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

When an acid halide is used and in a general manner when a hydrohalic acid molecule is released during the reaction, the reaction preferably takes place in the presence of a base such as soda, potash, sodium or potassium carbonates and acid carbonates, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

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

A product of formula (VI) can also be reacted directly with a product of formula (VII) in the presence of a carbodiimide such as diisopropylcarbodiimide or l-(3-dimethylamino propyl) 3-ethyl carbodiimide (EDC). An example of such a preparation is given further on in the experimental part.

The action of the reagents capable of introducing the R 2 radical and producing the product of formula 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 can be .carried out in situ or separately in the presence of sodium iodide then ,.he desired reagent is added, in the presence or 20 not of an organic solvent such as dichloromethane, acetonitrile or tetrahydrofuran.

The desired reagent of formula R2 can also be reacted directly on the product of formula (VIII) or in the Spresence of silver tetrafluoroborate.

The isomerism of the products of formula can be different to that of the products of formula (VIII) or (IX) used at the start. In the case where the Z isomer is isolated, this isomer can be converted into the E isomer according to the usual methods, notably by the action of 30 iodine.

According to the values of R 3

R

4

R

5 and R 1 p, the action on the product of formula of one or more hydrolysis, hydrogenolysis agents or of thiourea has the aim of eliminating the R4 radical when the latter represents a protective radical of the amino radical, of converting the

R

1 p group into an R 1 group, when the latter carries a hydroxyl radical protective group and/or of eliminating the

R

3 and R 5 radicals when these represent, among the easily cleavable ester groups, one of those that it is desired to eliminate.

However, it is of course possible to eliminate R 4 and to convert the R 1 p group into an R 1 group, when the latter carries a hydroxyl radical protective group without affecting the R 3 and R 5 substituents when these have to be preserved.

The nature of the reagents employed in such a case is well known to an average man skilled in the art. For example, a description of the different elimination methods for the different protective groups will be found in the French Patent B.F. 2,499,995. An example of such reactions is given further on in the experimental part.

Given the nature of the preferred protective groups that are used: trityl for R 4 2-methoxy ethoxy methyl to protect the hydroxy functions, and benzyloxycarbonyl to protect the amino function of R 1 diphenylmethyl for R 3 and 4-methoxy benzyl or diphenylmethyl for R 5 trifluoroacetic acid is preferably used without a solvent or in a solvent such as 2 anisole or a mixture of solvents such as anisole/methylene chloride. Then a salt is obtained with trifluoroacetic acid.

One can return to the free base by the action of a base such as triethylamine carbonate.

The salification of the products can be carried out according to the usual methods; for example it can be 4.

obtained by the action, on a product in acid form or on a :solvate, for example an 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.

Salts of mineral acids can also be used such as trisodium 30 phosphate. Salts of organic acids can also be used such as 4 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 16 lower carboxylic or alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, by one or more aryloxy radicals, preferably phenoxy.

In addition, sufficiently soluble aromatic acids can be used as organic acids such as, for example, benzoic acids substituted, preferably 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, (4-ethyl 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 is preferably used as the sodium salt.

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

It can also be obtained by the action of arginine, 25 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 used.

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

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. In general, the operation is carried out by reacting the acid of formula or a functional derivative with a derivative of formula: Z-Re 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, of which group a non-exhaustive list is shown above. In some cases, it can be advantageous to carry out an esterification on a product the amine and/or reaction groups of which present on the oxyimino are blocked before removing the protective group of the amine and 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 also contains an asymmetrical carbon which can be in the 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 an average man skilled in the art, for example by 20 chromatography.

The derivatives of formula (II) are new. As such, and in particular as intermediate products necessary for the preparation of the products of formula they constitute one of the subjects of the invention. These derivatives can be obtained starting from a derivative of formula (XII): RI-CHO

(XI)

of which, if necessary, the reactive functions are protected, 30 in order to obtain a derivative of formula (XIII):

R

1 p-CHO

(XIIT)

which derivative of formula (XII) or (XIII) is converted into the alpha-hydroxy acid derivative of formula (XIV):

I,

18 0

II

HOq

/C

CH OH

R

1

P

which can be, if desired, converted into a corresponding halogenated or alkyl- or arylsulphonylated derivative, which is then esterified.

The derivatives of formula (II) in which X represents a halogen atom can in a preferential manner be obtained by a process according to which an aldehyde of formula (XII) or (XIII) is treated with the malononitrile, in order to obtain the derivative of formula (XV):

*."CN

0 0

R

1 P-CH=C

(XV)

20

CN

which is subjected to the action of an oxidizing agent in order to oLtain the epoxide of formula (XVI): 0* R p CH C

CN

':06 30 which is treated with a hydrohalic acid to obtain the acid of formula (XVII): 0 11

(XVII)

CH OH

RIP

L

which is esterified.

The derivatives of formulae (III), fV), (VIII), (IX) and as well as the derivatives of formulae (XIV), (XVI) and (XVII) are also new. As such and in particular as intermediate products necessary for the preparation of the products of formula they constituteone of the subjects of the invention.

iqote derivatives of formula (II) in which X represents a hydroxy radical can also be prepared by a process according to which a compound of formula (XVIII):

R

1 p-CH 2

-COOR

3

(XVIII)

is subjected to the action of an oxidizing agent, in order to 15 obtain a ketonic derivative of formula (XIX): @0 *eo

R

1 p-C-COOR 3

(XIX)

0* e f 3 20 which is reduced to the corresponding secondary alcohol of formula An example is shown hereafter in the experimental part.

The compounds of formula (XII) are known, for example, from the references CA 111P194772, 108P150482, 101P38342, 25 97P215983, 95P203734 or also J. Am. Chem. Soc. 73 2956 (1951), or can be prepared by methods known to an average man skilled in the art, starting with the compounds described in these references.

o As for the compounds of formula (XVIII) and the corresponding acid, they are described in the European Patent Application 136721, as well as in J. of Antibiotics Vol. 36 No. 8 p. 1020 (1983). In a general manner, the compounds of formula (XVIII) can be prepared from the acid, by methods known to an average man skilled in the art.

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

These properties make the said products as well as their pharmaceutically acceptable acid salts suitable for use as medicaments in the treatment of infections caused by sensitive germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, anthrax,.phlegmons, erysipelas, acute primary or post-influenzal staphylococcia, bronchopneumonia, pulmonary suppurations.

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

Therefore a subject of the present invention is also as medicaments and notably antibiotic medicaments, the products of formula as defined above as well as their salts with .i pharmaceutically acceptable acids.

20 A more particular subject of the invention is as medicaments, the products of formula as described above in which R 2 is chosen from the following radicals: quinolinium, isoquinolinium, 4-(methylthio) pyridinium thieno[2,3-b]pyridinium, imidazo pyridinium and 6,7-dihydro 5H-pyrindinium and those in which R 1 represents a radical of formula in which R' 1 represents a cyano, carboxy or alkoxycarbonyl radical.

A special subject of the invention is, as medicaments and in particular antibiotic medicaments, the product the 30 name of which follows: the internal salt of 6alpha, 7beta-(Z)]] 1-[3-[7-[[(2-amino 4-thiazolyl) [[carboxy 3,4-dihydroxy 2-thienyl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicyclo[4,2,0]oct-2-en-3-yl] 2-propenyl] quinolinium as well as their pharmaceutically acceptable salts.

The invention extends to the pharmaceutical compositions containing at least one of the medicaments defined above as P1 ~31 active ingredient.

These compositions can b. administered by buccal, rectal, parenteral route, in particular 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 be presented in the pharmaceutical forms currently used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, lotions, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients 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.

These 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 25 water.

The administered dose is variable according to the illness 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 in man, 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.

The products of formulae and (VII) are known from the literature, in particular from Belgian Patent Application BE864828 and the European Patent Application EP 0,333,154.

The following examples illustrate the invention without p M however limiting it.

PREPARATION: diphenylmethyl [5-cyano 3,4-bis [(2-methoxy ethoxy) methoxy] thienyl chloro acetate STAGE A: 3,4-bis((2-methoxy ethoxy) methoxy] 5-cyano 2ethoxycarbonyl thiophene 92 g of 3,4-dihydroxy 5-cyano 2-ethoxycarbonyl thiophene (described in the Japanese Application No. J57116064)and 860 cm 3 of methylene chloride are mixed together under an inert gas atmosphere at 0 C, 153 cm 3 of diisopropylethylamine, then 102 cm 3 of methoxyethoxymethyl chloride are added slowly.

After 45 minutes, the reaction mixture is washed with a 0.

solution of hydrochloric acid then with a 1M solution of sodium bicarbonate and finally with water saturated with sodium chloride. After drying and evaporating the solvent, 15 161 g of expected product is obtained which is used as is in the following stage: i' NMR spectrum (CDC13, 300 MHz, ppm): i 1.36 4.34 CO 2 Et; 3.36 3.38 2-OCH 3 3.50 to 3.63 3.94 (4H) O-(CH 2 2 -0; 5.36 5.42 2 =C-0-CH2-0; IR Spectrum (CHC1 3 Absorptions at 2225 cm-1 (conjugated 1720 cm 25 1554, 1490 cm 1 (conjugated system).

Stage B: 3,4-bis[(2-methoxy ethoxy) methoxy] 5-cyano 2-hydroxymethyl thiophene A mixture of 161 g of the product obtained in Stage A and 1 litre of tetrahydrofuran is agitated under an inert gas atmosphere and 262 g of lithium triterbutoxy alumino hydride is added at 50C over 5 hours. The temperature is allowed to rise and the reaction mixture is maintained under agitation for 36 hours. The suspension is concentrated and poured into a mixture of 1.2 litres of a saturated aqueous solution of ammonium chloride, 1.5 litres of water and 0.5 litre of ethyl acetate. Agitation is carried out for 18 hours, followed by filtering, the filtrate is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is

I

evaporated off. 108 g of expected product is obtained which is used as is for the following stage.

Stage C: 3,4-bis[(2-methoxy ethoxy) methoxy] 5-cyano 2-formyl thiophene 450 cm 3 of methylene chloride is added to the 108 g of the alcohol obtained in .tage B. The reaction mixture is cooled down to 5 0 C then 497 g of manganese dioxide is added slowly. After total disappearance of the starting product, filtration is carried out and the filter is rinsed with ethyl acetate. The filtrate is concentrated to dryness and the residue is chromatographed on silica eluting with methylene chloride ethyl acetate mixtures 98/2, 97/3 then 96/4. 67 g cf expected product is obtained.

NMR spectrum (CDC1 3 300 MHz, ppm): 3.35 3.38 (3H) the 0-CH3's; 3.58 3.93 (4H) the O-(CH 2 2 -O's; 5.37 5.44 (2H) the O-CH 2 -O's; 10.04 (1H) CHO IRSpectrum (CHCL 3 Absorptions at 2220 cm 1 1670 cm-1 conjugated aldehyde); 1582, 1550, 1485 cm 1 (heterocycle).

Stage D: diphenylmethyl [5-cyano 3,4-bis[(2-methoxy ethoxy') methoxy] thienyl chloro acetate 63.6 g of the product obtained in Stage C, 1 litre of 25 toluene, 15.8 g of malodinitrile and a 4 A molecular sieve are mixed together. The mixture is cooled down to 5 0 C, and 1.8 cm 3 of piperidine is added, then agitation is carried out for 40 minutes.

74 cm 3 of terbutylhydroperoxide in a 3M solution in toluene is added to the reaction mixture, over 5 mn and without exceeding 11 0 C. After 20 minutes, the mixture is filtered, the filter is rinsed with ethyl acetate and the solvent is evaporated off. 82 g of an oil constituted by a dicyanoepoxide is collected.

The product is taken up in 1.8 litres of tetrahydrofuran, then 240 cm 3 of 1N hydrochloric acid is added to the solution over about 7 minutes followed by agitation at ambient temperature for 1 hour.

cc I I I I I I 24 870 cm 3 of a solution at 0.38 mol/l of diphenyldiazomethane in ethyl ether is added to the reaction mix~ ire, over about 12 minutes. Agitation takes place for 2 hours at ambient temperature, then extraction with ethyl ether followed by washing with iN soda then with water saturated with sodium chloride. The organic phase is dried and the solvent is evaporated off, then the residue is chromatographed on silica eluting with cyclohexane ethyl acetate mixtures- then 68 g of expected product is obtained.

NI4R spectrum (CDC1 3 250 MHz, ppm): 3.31 3.36 (3H) the 0-CH 3 's; 3.48 3.58 3.82 (in), 3.92 (in) (8H) the 0-(CH 2 2 -0's; 5.17 (syst. AB), 5.41 (2H1) the 0-CH 2 -0 t s; 5.98 (1H)

C

7.34 (in) (1OH) the phenyls.

IR Spectrum (CHC1) Absorptions at 2221 cmn 1 1746 cm- 1 1603, 15989, 251496 cm 1 (aromatic-heteroatom) 2EXAMPLEI 1: Internal salt of 6alpha, 7beta-(Z)]J 1-(3-[7-EE(2-amino 4-thiazolyl) (carboxy *.3,4-dihydroxy 2-thienyl) methoxy] iminoj acetyl] amnino] 2-carboxy 8-oxo 5-thia I-azabicyclo[4,2, O]oct-2-en-3-yl] 2-propenyl] quinoliniuu StAge A: diphenylmethyl (5-cyano 3,4bis[(2-methoxy ethoxy) methoxy] thienyl] phthalimidoxy acetate 13.1 g of N-hydroxy phthalimide, 6.55 g of sodium bicazbonate and 400 cm 3 of water are mixed together, the mixture is agitated for 2 hours then 25 g of diphenylniethyl [5-cyano 3,4-bis[(2-methoxy ethoxy) methoxy] thienyl chloroacetate in 400 cm 3 of dichlorethane is added, then 0.89 g de triethyl benzylaminonium chloride is added. Agitation is carried out for 13 hours at ambient temperatur e, followed by extraction with dichlorethane. The organic phase is washed with water with sodium chloride added to it, dried and the solvent is evaporated off. The residue is purified by chromatography on silica eluting with a cyclohexane ethyl acetate mixture then and 15.4 g of expected product is obtained.

NMR spectrum (CDC13, 300 MHz, ppm): 3.28 3.36 (3H) -O-CH3; 3.46 3.58 (2H), 3.78 to 3.95 (4H) -0-(CH 2 )2-O; 5.21 (AB) 5.37 (AB) (2H) O-CH 2

-O;

0- 6.26 (1H) C-C-- 15

S

6.96 (1H) -C02-CH-2; 7.2 to 7.4 (10H), 7.75 (4H) phthalimide H.

S.

.IR Spectrum (CHC1 3 Absorptions at 2222 cm- 1 1796 and 1740 cm-1 C=O, 1610-1580 cm-1 and 1496 cm- 1 conjugated system aromatic.

Stage B: diphenylmethyl aminoxy [5-cyano 3,4bis[(2-methoxy ethoxy) methoxy] thienyl] acetate.

5.06 g of the product prepared in the preceding stage is 25 dissolved under a nitrogen atmosphere in 72 cm 3 of methanol, the mixture is cooled down to -11°C then 0.35 cm 3 of hydrazine hydrate is added, the same temperature is maintained for 15 minutes, another 0.02 cm 3 of hydrazine hydrate is added, then after 30 minutes, another 0.04 cm 3 The reaction mixture is maintained under agitation for minutes. In this way the expected product is obtained in solution, which is used as it is for the following stage.

Stage C: [[[2-[5-cyano 3,4-bis[(2-methoxy ethoxy) methoxy] thienyl] 2-oxo 2-(diphenylmethoxy) ethyl] oxy] imino] [2-[(triphenylmethyl) amino] thiazol-4-yl] acetic acid 3 g of oxo [2-((triphenylmethyl) amino] thiazol-4-yl] acetic acid (described in the Belgian Patent Application No.

864828) is added to the solution obtained in the preceding 1 stage and the temperature is allowed to rise.

cm 3 of methylene chloride is added then the crystals formed are separated. The filtrate is concentrated to dryness and the residue is chromatographed on silica eluting with a methylene chloride methanol mixture (95-5) and the product is again recovered. In total 5.5 g of the crude expected product is obtained.

Stage D 4-methoxy benzyl 7beta-[[[[[2-[5-cyano 3,4bis[(2-methoxy ethoxy) methoxy] thienyl] 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 l-azabicyclo[4,2,0]oct-2-en-2-carboxylate 2.44 g of 4-methoxy benzyl 7beta-amino 3-[(Z)-3-chloro l-propenyl] 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-2-car- 15 boxylate hydrochloride (described in the European Patent Application No. 0,333,154), 5.5 g of the product prepared in the preceding stage, 60 cm3 of methylene chloride are mixed together at 0 C then 1.75 g of l-(3-dimethylamino propyl) 3-athyl carbodiimide (EDC) is added, and agitation is carried out for 45 minutes while allowing the temperature to rise.

The reaction medium is treated with 100 cm 3 of 0.5 M potassium hydrogenophosphate, then washed with a sodium chloride solution. After drying, the solvent is evaporated off. 8.5 g of expected product is collected. (Rf 0.42 25 [eluant: methylene chloride ethyl acetate which can be purified by chromatography on silica eluting with a cyclohexane ethyl acetate mixture NMR spectrum (CDCl 3 300 MHz, ppm): 3.20 3.34 -O-CH 3

S-CH

2 3.43 3.59 3.92 3.45 3.90, 4.14 (1H) -O-CH 2

-CH

2

-O,-CH-CH

2

-X

5.02 H 6 5.86 H 7 5.40 to 5.50 o-CH-OCO, O-CH 2

-O;

5.78

CH

2

-CH=CH-(AZ);

6.20 to 6.35

CH

2 6.77

H

5 thiazole; I I 27 6.91 (4H) Aromatics, -C02-CH-

NH-CO-

IR Spectrum (CHCl 3 Absorptions at 3404 cm-1: 2221 cm-1: 1791, 1730 and 1684 cm-1: B-lactame; 1613, 1587, 1526, 1517 and 1496 cm-1: aromatic C=C, heteroatom and amide II.

Stage E: 4-methoxy benzyl 7beta-[[[[[2-[5-cyano 3,4-bis[(2-methoxy ethoxy) methoxy] thienyl] 2-oxo 2-(diphenylmethoxy) ethyl] oxy] imino] [2-[(triphenylmethyl) amino] thiazol-4-ylj acetyl] amino] -3-iodo 1-propenyl] 8-oxo 5-thia l-azabicyclo[4,2,0]oct-2-en-2-carboxylate g of the product obtained after chromatography in the preceding stage, 20 cm 3 of acetone and 0.5 g of sodium 15 iodide are agitated for 1 hour 10 minutes at ambient temperature in the presence 30 mg of iodine. After elimination of the solvent, the residue is taken up in methylene chloride, the organic phase is washed with a sodium thiosulphate solution then with a sodium chloride solution, dried, the solvent is eliminated and the residue is chromatographed on silica eluting with a cyclohexane ethyl acetate mixture 0.9 g of expected iodated product is collected.

Stage F: 1-[3-[7beta-([[[2-[5-cyano 3,4-bis[(2-methoxy ethoxy) methoxy] thienyl] 2-oxo 2-(diphenylmethoxy) ethyl] oxy] imino] [2-[(triphenylmethyl) amino] thiazol-4-yl] acetyl] amino] 2-[(4-methoxy benzyloxy) carbonyl] 8-oxo l-azabicyclo[4,2,0][oct-2-en-3-yl] 2-propenyl] quinolinium iodide 0.450 g of the product obtained in the preceding stage is dissolved in 5 cm 3 of methylene chloride and 185 ul of quinoline is added. Agitation is carried out, the solvent is evaporated off and agitation is maintained for 1 hour ?0 minutes, followed by taking up in ether, crystallizing, separating and chromatographing on silica eluting with a methylene chloride methanol mixture In this way 0.260 g of expected product is collected. Rf 0,37 [eluant: methylene chloride methanol (90-10)].

's~ I I v 28 Stacqe G: Internal salt of C 6R- C3 Ealpha, 7beta l-[3-C7-([(2-amino 4-thiazolyl) [[carboxy 3,4-dihydroxy 2-thienyl) methoxyl imino] acetyl] amino] 2-carboxy 8-oxo 5-thia l-azabicycloC4,2,0]oct-2-en-3-yl] 2-prot'zayl] quinolinium A mixture containing 0.255 g of the product prepared in the preceding stage and 3 cm 3 of trifluoroacetic acid containing 10% anisole is agitated at ambient temperature for 2 hours and 45 minutes. After adding isopropyl ether, filtering, washing and drying for 16 hours under reduced pressure at ambient temperature, 0.118 g of the desired internal salt is isolated.

NI4R analysis of the *Proton (DMSO 300 MHz in ppm) R/S structure; 63 syn; 6E/AdZ mixture 70/30.

11*0015 5.18 (in) and 5.30 (in) H 6 5.65/5.90 H 7 0H- =CH-CH 2 N anWC-C 2 6.39 (in) C=CH-CH 2

E);

6.61 J=11) C=CH-CH 2 6.70 and 6.74 H 5 thiazole; 6.95 J=15.5): =C-CH-CH (4E); 8.07 (mn) (1H) 8.29 (mn) (2H) 8.51 (in) 9.34 (in) (1H) 25 and 9.57 (mn) H of the quinoliniun; 11.6 =C-NH-CH.

IR Spectrum (nujol) General absorption OH/NH, 2215 cm- 1 Conjugated C=N, 1778 cm- 1 3-lactame, 1672 cin 1 other C=O.

PREPARATION 2: diphenylmethyl aipha-bromo CS-(terbutoxycarbonyl) amino] 3-(1,2,4-thiadiazole acetate Stag~e A: diphenylinethyl (5-(terbutoxycarbonyl) amino] 3- 4-thiadiazole) acetate.

7.25 g of (5-(terbutoxycarbonyl) amino] 3-(1,2,4-thiadiazole) acetic acid is mixed at ambient temperature with cm 3 of inethylene chloride and 49 cm 3 of methanol. The solution is cooled down to 0 0 C and 93.3 cm 3 of diphenyldiazoinethane in a 0.3M solution in ether is added dropwise.

The reaction medium is allowed to return to ambient temperature over 2 hours 30 minutes, the solvents are evaporated off under reduced pressure, 13.66 g of crude product is obtained which is chromatographed on silica (eluant: methylene chloride-acetonitrile 98-2). 8.38 g of expected product is recovered.

NMR Spectrum (CDC1 3 300 MHz in ppm) 1,52 terbutyl 4,06 CH 2

-CO

2 6,92 (m C0 2

-CH-$

2 7,26 phenyls 10,20 (sl) NH Stage B: diphenylmethyl alpha-bromo amino] 3-(1,2,4-thiadiazole) acetate.

15 146 mg of bromine (47 p1) is added to 390 mg of the ester prepared in Stage A in solution in 6 cm 3 of acetic acid. Agitation is carried out for 2 hours 30 minutes at ambient temperature, the solvent is evaporated off, the residue is taken up in methylene chloride, washed with an aqueous solution of sodium bicarbonate at 10%, dried and the solvents are evaporated off. 390 mg of crude product is recovered which is chromatographed on silica (eluant: methylene chloride). 190 mg of expected product is obtained.

NMR Spectrum (CDC13 250 MHz in ppm) 25 1,55 terbutyl 6,95 phenyls 7,2 a 7,4 -CH-Br 9,23 NH EXAMPLE 2 internal salt of 6alpha, 7b4ta-(Z)]] 1-[3-(7-[[(2-amino 4-thiazolyl) [[carboxy (5-amino 1,2,4thiadiazol-3-yl) m6thoxy] imino] acetyl] amino] 2-carboxy 8oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl] 2-propenyl] quinolinium Stage A diphenylmethyl a-phtalimidoxy amino] 3-(1,2,4-thiadiazole) acetate.

130 mg of sodium bicarbonate and 252 mg of hydroxyphtalimide in 3 cm 3 of water are agitated for one hour under an inert atmosphere then 390 mg of the bromo ester prepared as indicated in Preparation 2 then 17.6 mg of triethylbenzylammonium chloride are added dropwise. Vigorous agitation is carried our for 20 hours, 10 to 20 cm 3 of methylene chloride is added, followed by decanting, extracting with methylene chloride, drying and evaporating the solvent. 426 mg of crude product is obtained which is purified by chromatography on silica (eluant: methylene chloride -ethyl acetate 98-2), and 169 mg of expected product is obtained.

NMR Spectrum (CDC13 300 MHz in ppm) 1,56 terbutyl 5,98 -CH-COO 7,07

CH-

2 7,15 7,35 phenyl 7,72 (m)-7,76 phthalimide 15 8,53 (sl) -NH- Stage B diphenylmdthyl a-aminoxy amino] 3-(1,2,4-thiadiazole) acetate.

s 58 mg of the phthalimido ester prepared in the preceding stage in 1 cm 3 of methylene chloride is cooled down to 0 C under an inert atmosphere, then 5.5 gl of hydrazine hydrate is added, agitation is carried our for 30 minutes, followed by filtration, the precipitate is rinsed with methylene chloride, the solvent is evaporated off under reduced pressure at ambient temperature and 58 mg of crude product is 25 recovered which is chromatographed on silica (eluant: cyclohexane ethyl acetate 26 mg of expected product is obtained.

NMR Spectrum (CDC13 300 MHz in ppm) 1,55 (sl) terbutyl 6,22 -CH-COO 6,90 7,30 ph6nyls 6,56 ou 7,10 O-CH-t 3,10 mobile H's Stade C l-[3-[7-((2-(triphenyl) amino] 4-thiazolyl] (2diphenylmethoxy) carbonyl] [5-(terbutoxycarbonyl) amino] (l,2,4-thiadiazol-3-yl) methoxy] imino] acetyl] amino] methoxy) benzyloxycarbonyl] 8-oxo 5-thia 1-azabicyclo- [4,2,0]oct-2-en-3-yl] 2-propenyl] quinolinium iodide.

-c, hr r- 65.4 mg of l-[3-[7beta-[[oxo [2-(triphenylmethyl) amino] 4-thiazolyl] acetylj amino] 2-[(4-methoxy) benzyloxycarbonyl] 8-oxo 5-thia 1-azabicyclo oct-2-en-3-yl] 2-propenyl] quinolinium iodide, 1 cm of methanol and 0.3 cm 3 of methylene chloride are mixed together under an inert atmosphere at ambient temperature. 36 mg of the aminoxy derivative prepared as in the preceding stage in 0.5 cm 3 of methylene chloride is added, then 12.5 mg of paratoluene sulphonic acid is added. Agitation is carried our for hours at ambient temperature, the solvent is evaporated off under reduced pressure at ambient temperature then the residue is taken up in ether. After agitation for 15 minutes, the precipitate is filtered off, dried under reduced pressure for one hour and 83 mg of crude is collected which is used as S 15 it is for rest of the synthesis.

S. Stage D internal salt of 6alpha, 7beta-(Z)]] 1- [3-[7-[[(2-amino 4-thiazolyl) [[carboxy (5-amino 1,2,4-thiadiazol-3-yl) methoxy] imino] acetyl] amino] 2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl] 2-propenyl] quinolinium 83 mg of the above crude product in 0.8 cm 3 of a solution of trifluoroacetic acid with 10% anisole is agitated for 3 hours at ambient temperature. Filtration is carried out, followed by rinsing with trifluoroacetic acid, then .o 25 ethyl ether (about 2 cm 3 is added and agitation is carried out for 30 minutes. After ,iltering and rinsing with ether, the precipitate is dried under reduced pressure for 16 hoirs at ambient temperature. 34 mg of expected crude product is obtained.

NMR Spectrum (CDC13 300 MHz in ppm) 5,26

H

6 5,48 after exchange 6,53 H 7 6,09 (dt) AE

CH=CH-CH

2 6,53 CH=CH-CH 2 6,75 H 5 of the thiazole 9,73 mobile) -NH- In addition to the product described above in the Example, the following products constitute products which can s I 0 1- g be obtained according to the methods of the invention: o 0 a. a a.

a a a a. a.

a a a a 0* 0 a a.

a o 0 0* 0 ~0

EXAMPLE 3: Preparations were prepared for injections of formula: Product of Example 1 500 mg- Sterile aqueous excipient sufficient quantity for 5 cm 3 PHARMACOLOGICAL STUDY Activity in vitro, method of dilutions in solid medium.

A series of dishes are prepared in which an equal quantity of sterile nutritive medium is distributed, containing increasing quantities of the product to be 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 minimum inhibitirg concentrations (MIC) expressed in micrograms/cm 3 to be determined.

20 The resvits are expressed in MIC 50 and MIC 90 which is the minimum concentration of antibiotic inhibiting the growth of the strains studied by 50 and 90%. The following results were obtained: Ist 1, 1111 Strains Penicillinsensitive Staphylococcus aureus (14 strains) Penicillin- resistant Staphylococcus aureus 21 strains' Streptococci group D strains) 0. 04-0. 15 0.08-1.2 2.5-20 0. 0. 0. 2.

Enterobacteria produ(. ing B.-lactamases MIC 50

MIC

90 Chromosomnal 0.15-5 1.2 Plasmidic SHV-2 (13 strains) 0.08-1.2 0.3 1.2 SHV-4 (29 strains) 0.6-20 2.5 TEM-3 (35 strains) 0.15-20 1.2

Claims (3)

1-L3-(7-[C(2-amino 4-thiazolyl) [jcarboxy 3,4-dihydroxy 2-thienyl) methoxy] imino] acetyl] amino]

2-carboxy 8-oxo 5-thia l-azabicyclo(4,2,0]oct-2-en-3-yl] 2-propenyl] quinolinium. 6) Preparation process for the products ot formula as I I 41 defined in claim 1, characterized in that an ester of formula (II): 0 II X. /C CH 0 (II) R 1 P in which X represents. a ~e \group or a radical capable of generating a agroup in situ, RLp represents an R 1 group as defined above, in which the hydroxy or amino radicals are protected and R 3 represents the remainder of an easily cleavable ester, is treated with N-hydroxy phthalimide, if appropriate in the presence of an activating agent, in order to produce a derivative of formula (III): 0 o (III) II OiP 25 iP which derivative of formula (III) is hydrolyzed into the O-substituted hydroxylamine of formula (IV): a" 0* o 0* a. a H, I I C H R P (IV) OR 3 3 which product of formula (IV) is condensed with a derivative of the (2-amino thiazol-yl) 2-oxoacetic acid of formula I N H R A (V) 0 H 0 C 0 in which R 4 represents a hydrogen atom or a protective group of the amine function, in order to form the derivative of the aipha-alkoxy imino acetic acid of formula (VI): NHR 4 N 20 (VI) C .0 0C% 0H *0 N C C 0 R 3 0 CH R I P a functional derivative of which is prepared, if appropriate, which product of formula (VI) or functional derivative is amidified with an ester of the hydrochloride of 7-amino 30 3-(3-halogeno 1-propenyl) 8-oxo 5-thial-azabicyclo oct-2-en-2-carboxylic acid of formula (VII) C vICH Ha1(VII) 0 o R 5 H~a 0 43 or its salts, in which Hal represents a halogen atom and R represents the remainder of an easily cleavable ester, in order to produce the derivative of 7- (N-substituted amido)

3-(3-halo I-propenyl) 8-oxo 5-thia l-azabicyclo[4,2,0] oct-2- en-2-carboxylic acid of formula (VIII): N H Y I (VIII) 0 it R C. ~0 0 N 0 CH0 C HC C H 2 Ha 1 R IP 0 C 0 R which product of formula (VIII) is converted, if appropriate, into the analogous 3-(3-iodo propenylated) product of formula (Ix): H 0 Y C (IX) 30 R 3 C~ A 0 0 CH0 C H=CH C" HH-I R~~p 0 0C% R which product of formula (IX) is treated with a base of formula R 2 in order to obtain the product of formula 44 NHR r (x) ii I II R 3 ,C 0 0 N 0 CH 0 CH=CH^'CH RI C R 0 0 from which product of formula if desired, the or (Z) isomers are isolated or the isomers are converted into the isomer and which product of formula is subjected to one or more of the following reactions, in any order: a) cutting by hydrolysis or by the action of thiourea of all or part of the ester groups or protective groups of the amino radical or radicals or of the hydroxyl radicals, b) esterification or salification by a base of the carboxylic radical or radicals, 20 c) salification by an acid of the amino radical or radicals, d) separation of the products in the form of an R,S mixture into R or S. 7) Variant of the process according to claim 6, characterized in that the O-substituted hydroxylamine of formula (IV) is condensed into the product of formula (XI): 0H 30 1 (XI) o c 0-,C R 0 0 I to produce the product of formula as defined in claim 6. 8) Process according to claim 6 or 7, characterized in that L *IB~*ll~ ;I-I~ the compound of formula (II) is prepared by a process according to which the reactive functions of a derivative of formula (XII): R 1 -CHO (XII) in which R 1 is defined as in claim 1, are, if necessary, protected in order to obtain a derivative of formula (XIII): R 1 p-CHO (XIII) in which R 1 p is defined as in claim 6, which derivative of formula (XII) or (XIII) is homologated into the alpha-hydroxy acid derivative of formula (XIV): 0 jI (XIV) 20 HO /C C H OH R P which, if desired, is converted into the corresponding halogenated or alkyl- or arylsulphonylated derivative, then esterified. 9) Process according to claim 6 or 7, characterized in that the compound of formula (II) in which X represents a halogen 30 atom is prepared by a process according to which an aldehyde of formula (XII) or (XIII), as defined in claim 8, is treated with malononitrile, in order to obtain the derivative of formula (XV): CN R 1 p-CH=C (XV) SCN It. 46 which is subjected to the action of an oxidizing agent in order to obtain the epoxide of formula (XVI): 0 5 CN R/ (XVI) R p-C H--C CN which is treated with hydrohalic acid in order to obtain the acid of formula (XVII): 0 II Ha l. C C.cH OH (XVII) I R P Pharmaceutical compositions containing at least one product according to any one of claims I'to 5 as active ingredient together with a pharmaceutically acceptable diluent, carrier or adjuvant. 11) A method of treatment of infections caused by gram(+) bacteria or gram bacteria in a human or animal patent comprising administering to said patient a product according to any one of claims 1 to 5 or a composition according to claim 12) The products of formulae (VIII), and as defined in claim 6. 13) All products according to claim 1, salts thereof, processes of manufacture, medicaments, or compositions comprising the same substantially 9/1197VSAP7465.SP ,46 ail r r i*r 1 ehdofteteto netin asdb rm()bcei rga 25 (-)bcei nahmno nmlptetcmrsn diitrn osi I I 47 as herein described with reference to any one of the examples. DATED this 9th day of Wiif1 997. ROUSSEL UCLAF By their Patent Attorneys: CALLINAN LAWRIE ~vc, 9/11,9VSAP7465.SME47 ABSTRACT A subject of the invention is the products of general formula N H2 S i N ~CN N S 0 N C AC 0 0N 0 C H 0 CHC H ~C H 2 R2 p-i 0 A S. ~2 Q. S S 4 4 s,,y isomer, in the or form or in the form of an mixture, in the form of the internal salt or their salts with organic or mineral acids, in which formula: R 1 represents a group of formula HO0 S in which R' 1 is alkyl (1 to 4 carbons), cyano, carboxy or alkoxycarbonyl, (alkyl 1 to 4 carbons), or R, repres3ents a group of formula H 2 N A and A' represent a hydrogen, an equivalent of an alkali metal, an alkaline-earth metal, magnesium, amamonium or an amino organic base, or one only or each of the C0 2 A or CO 2 A' groups represents C0 2 and R 2 a quaternary ammonium. These D.roducts have useful pharmacological properties which justify their use as medicaments. .0.0 0:66.: