DE2831332A1 - VINYLOXYIMINO DERIVATIVES OF 7-AMINOTHIAZOLYL ACETAMIDOCEPHALOSPORIC ACID, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

ROUSSEL-UCLAP, Paris, France

Vinyloxyimino derivatives of 7-aminothiazolylacetamido-cephalosporanic acid, their manufacture and pharmaceutical compositions

The invention relates to new vinyloxyimino derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid.

In the patent application P 2702501.0 (see. The FR additional application 77/22077) are new oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, their manufacture and pharmaceutical compositions are described;

The compounds have the general formula I.

(D,

CH ₀ -OC-CH. 2 y 3

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in the mean

R is a hydrogen atom or one by acid hydrolysis or hydrogenolysis easily cleavable group,

R ^{1 is} a hydrogen atom, a group which can easily be split off by acid hydrolysis or hydrogenolysis, or a saturated or unsaturated C 1 -C 4 -alkyl group

and ·

A is a hydrogen atom or an equivalent of an alkali metal, Alkaline earth metal, magnesium or an organic amine base,

where the group -OR ^1, as indicated by the wavy line, can be in one of the two possible positions, in syn or in anti position
and

R denotes a group which can be easily split off by acid hydrolysis or hydrogenolysis, if R 'is such a group Means group and, on the other hand, R represents a hydrogen atom when R 'is also hydrogen.

The compounds "d-er formula I can either in the by formula I or by the following formula I "described ·

Lx

structure exist:

CC-NiL I / H NO

R ¹ O

H ₂ -OC-CH ₃

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where the substituents R, R ¹ and A have the meaning defined above.

In four additional FR applications are further examples of compounds of general formula I and further developments of the manufacturing process concerned.

The invention relates to new vinyloxyimino derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid of the general formula I ₁ .

_{A 0}

in which:

R, a hydrogen atom or a trityl group and

A is a hydrogen atom or an equivalent of an alkali metal, alkaline earth metal, magnesium or an organic amine base,

the vinyloxy group being in the syn or anti position.

The invention relates in particular to the following compounds:

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3-Acetoxymethy 1-7-C ^2- (2-tritylamino- ⁱ J-thiazolyl) -2-vinyloxyimino-acetamide (^ - ceph-3-a-4-carboxylic acid ( syn -isomer), the sodium salt of 3-acetoxymethyl -7- [2- (2-tritylamino h- thiazolyl) -2-vinyloxyimino-acetamidq | -ceph-3-em- H -carboxylic acid ( syn -isomer)
and

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamidoT | -ceph-3-em-4-carboxylic acid ( syn -isomer) and its salts with alkali metals, alkaline earth metals, magnesium and organic amine bases .

The invention relates in particular to the following compounds:

3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido] -ceph-3-em-4-carboxylic acid ( syn isomer)

the sodium salt of 3-acetoxymethyl-7- [2- (2-amino-4-thiazoly]) -2-vinyloxyimino-acetamido] -ceph-3-em-4-carboxylic acid ( syn -Iso-

The invention also relates to a process for the preparation of the compounds of the formula Ι _κ

JH-R

in which:

Rj is a hydrogen atom or trityl

and
A is a hydrogen atom or an equivalent of an alkali

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metal, alkaline earth metal, magnesium or an organic amine base.

The process is characterized in that 7-aminocephalosporanic acid of the formula

with an acid of the formula H ₁ .

NH-C

O-CH = CII

or a functional derivative of this acid to a compound of the formula I ' _c

NII-C

(ΐ · ₅ )

NIL ^ 'O'-CHcrCIIp o

CO,

OC O

is implemented, if necessary by customary methods

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is reacted to the corresponding alkali metal salt, alkaline earth metal salt, magnesium salt or salt of an organic amine base, the acid of the formula i 'or its salt optionally with an acid to form a compound of the formula I ¹ V

■ HC-OC - CH ₀ (I ¹ V) 2 κ 3 5

is reacted, which may be converted, if necessary, by conventional methods in f Intsprechende salt of the acid I ¹ V.

As a functional derivative of the acid of the formula Ir- is

preferably the anhydride produced in situ by the action of cyclohexylcarbodiimide is used. The salt formation of the compounds of the formula IV or I ¹ V is preferably carried out by the action of an inorganic base, preferably sodium hydrogen carbonate, on the corresponding acids.

The preferred acid with which the acid of the formula I 'or one of its salts is treated is formic acid used.

. The invention also relates to a process which is characterized in that the compound of the formula 1I ₅ 'NHC (C ₆ H ₅ ) 3

. - "CO HI ²

O - CH = CIL

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by reacting a compound of the formula

X-CHp-CH.-X with X = Cl, Br or J
with a compound of the formula

NH-C (C ₆ H ₅ ) 3

in which alc denotes a C.- to C ₁ , -alkyl group,

in the presence of a base to a compound of the formula IV-

(IV,)

, NH-C (C. H_) 3 ο b

alc

is reacted with a strong base in a compound of formula V ^

NHC (C _c IL) 3 ο b

(V

N O -

CH = CH ₂

is converted, which then with a base and then with an acid in the desired "compound of

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Formula 1I ^ is converted.

Among the compounds of the formula

X-CH ₂ -CH ₂ -X

those compounds are preferred in whose formula X represents a Br atom.

Potassium carbonate in dimethylformamide is preferably used as the base in the presence of which the compound X-CH ₂ -CH ₂ - is reacted with the compound IHc.

However, potassium tert-butoxide can also be used in the same way can be used in dimethylformamide or tetrahydrofuran, and triethylamine can also be used.

The strong base with which the compound of the formula IV- is converted to the compound of the formula V_ is preferably potassium tert-butoxide in dimethyl sulfoxide is used at room temperature.

Potassium hydroxide in a dioxane-ethanol mixture is preferably used as the base in the presence of which the conversion of the compounds of the formula V _{1 into compounds of the formula H ^ is carried out.} However, other bases such as sodium hydroxide and barium hydroxide can also be used in the same way.

Dilute hydrochloric acid is preferably used as the acid for isolating the acid of the formula II, but Acetic acid and formic acid can also be used.

The invention also relates to the above processes for the preparation of the compounds of the formula II, - and I ^ , at

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which the group bonded to the oxime nitrogen above the oxygen is in the syn position.

For this purpose, connections of the. Formula III assumed, in which the corresponding OH group is in the syn position.

In the preparation of the compounds IVj-, V ₁ -, II and I, - it is possible in the course of the synthesis to retain the syn configuration of the compound III, -.

The compounds according to the invention have a very high antibiotic effect both against gram-positive ones Bacteria such as staphylococci, streptococci and especially penicillin-resistant staphylococci as well as against Gram-negative bacteria, in particular the koli-like bacteria, the Klebsiella and Proteus species and Salmonella on.

Because of these properties, the pharmaceutically suitable compounds according to the invention are suitable for treatment diseases caused by sensitive germs, especially staphylococcal infections such as staphylococcal septicemia, malignant staphylococcal facial or skin infections, pyoderma, septic or purulent Wounds, anthrax, phlegmon, erysipelas, acute primitive or post-flu staphylococcal infections, Bronchopneumonia or pulmonary suppurations as active ingredients in antibiotic drugs or as antibiotic drugs Medicinal applicable.

The products according to the invention can also be used as medicaments or as active ingredients in medicaments for treatment Colibacillosis and accompanying infections, infections by Proteus, Klebsiella and Salmonella as well as others

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Affections caused by gram-negative bacteria can be used to advantage.

The invention also relates to the compounds of the formula I mentioned by way of example as pharmaceutical Active ingredients, especially with antibiotic activity.

The compounds according to the invention include in particular:

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyih2-vinyloxyimino-acetamide] -ceph-3-em-4-carboxylic acid ( syn -isomer) and the sodium salt of ^ -acetoxymethyl-T - ^ - ^ -amino-Jl-thiazolyl) -2-vinyloxyimino-acetamido] -ceph-3-em- ⁱ l-carboxylic acid ( syn -isomer).

The invention also extends to pharmaceuticals Compositions which contain as active ingredient at least one compound according to the invention as defined above.

The compositions can be buccal, rectal, parenteral or topical with topical administration on the skin and administered to the mucous membranes.

The compositions can be solid or liquid and are those commonly used in human medicine pharmaceutical forms, for example as simple or sugar-coated tablets, gelatin capsules, granules, Suppositories, injectable compositions, pomades, creams and gels, in turn, following conventional procedures can be produced. The active ingredient (s) can usually be used in pharmaceutical compositions used excipients such as talc, gum arabic, lactose,

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Starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles or carriers, fatty substances of animal or animal origin of vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents or Preservatives are introduced.

The dose to be administered depends on the disease being treated, the person being treated, the particular Type of administration and the relevant compound.

In humans, for example, the dose varies between 0.500 g and 1 g given intramuscularly three times a day Administration of the compound of Example 3

The invention also relates to the following new compounds of the general formula IV ^

NII-C (C, H _c ) 3
ο 5

Civ.),

——C0_ ale ^ Il ²

"Ό -CH ₂ -CH ₂ X

in which X is a chlorine atom, bromine atom or iodine atom and

alc represent a C.- to C ^ -alkyl group,
as well as the compounds of the formula

NH-C

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in which R _{1 is} a hydrogen atom or a C ₁ to Cu alkyl group.

Those used according to the invention as starting materials Compounds of the formula IHc can be prepared as follows:

First, urea is compounded with the Formula A.

Gl-CH ₀ -CC-CO-alc

to a compound of the formula B

NlL

(B)

C0 "alc

OH

implemented, which then with 1 equivalent of trityl chloride to the desired Compound of the formula HL is implemented.

Compounds of the formulas B and HI, - in which the

-OH group

is in syn position, are obtained when the reaction of the thiourea with the compounds of formula A either in an aqueous solvent such as aqueous acetone or aqueous ethanol or at room temperature under the action of an approximately stochxometric amount of thiourea and for a fairly short reaction time of the order of magnitude

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from 1 to 3 hours or a combination of the two above process conditions is carried out.

The invention is explained in more detail below with the aid of examples, the details of which are not restrictive.

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example

jJ-Acetoxymethyl -? - [2- (2-tritylamino- ⁱ l-thiazolyl) -2-vinyl oxyiminoac et amidol -ceph-S-em-i-carboxylic acid ~

Stage A : 2- (2-Bromoethoxyimino) -2- (2-tritylamino-4-thiazolyl) -acetic acid ethyl ester (syn isomer)

A mixture of h ^ H g of 2-hydroxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid ethyl ester hydrochloride ( syn isomer) in 10 ml of dimethylformamide is presented, after which ¹ J, 1 * 1 g of potassium carbonate can be added. After stirring for 20 min at 20 ⁰ C. 8.65 ml of 1,2-dibromoethane are added. After stirring for a further 30 hours, the mixture is poured into a medium composed of 100 ml of distilled water and 20 ml of methylene chloride; it is then decanted, re-extracted with methylene chloride and, after washing again with distilled water, re-extracted again; after the organic solutions have dried, suction is performed. or centrifuged, washed and evaporated to dryness. The crude product obtained is chromatographed on silica using benzene with 5 % ether as the eluent. There is obtained a first fraction is recrystallized after dissolving at 50 to 60 ⁰ C from methanol to obtain and + 5 ⁰ C is filtered off or centrifuged at 0; in this way 1.16 g of a creamy white product are obtained; 117 ^° C

Thereafter, a homogeneous fraction is obtained in an amount of 1.258 g.

NMR spectrum (CDCl ₅ ):

Triplet at 3.55 ppm, J = 7 Hz (CH ₂ Br)

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Triplet at 1.51 ppm, J = 6 Hz (NO-CH ₂ ) singlet at 6.55 ppm (proton of the thiazole ring).

Level B; 2- (2-Tritylamino-4-thiazolyl) -2-vinyloxyiminoacetic acid ethyl ester ( syn isomer)

6.9 g of the 2- (bromoethoxyiniino) -2- (2-tritylamino - ^ - thiazolyl) -acetic acid ethyl ester ( syn -isomer) prepared in stage A are introduced into 35 ml of dimethylsulfoxide. Then 16 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran are added at 20 to 25 ° C. in the course of 5 minutes. After 30 minutes of stirring, 3 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran are also added at room temperature. The mixture is then stirred for a further 30 minutes, whereupon another 3 ml of the above potassium terb-butoxide solution and then, after a further 30 minutes, a further 3 ml of this solution are added.

After the last addition, the mixture is stirred for a further 30 minutes, whereupon it is poured into a mixture of 350 ml of water and ice and 90 ml of methylene chloride is poured.

It is then acidified to pH 2 with 28 ml of 1 N hydrochloric acid, decanted and re-extracted three times with 50 ml of methylene chloride. Then it is washed with distilled water, dried, sucked off or centrifuged, washed and dried to dryness evaporated. A black, resinous product is obtained, which by column chromatography on silica under ^ Using methylene chloride as the eluent is purified.

In this way 3.227 g of the desired product are obtained, which is in the present form

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is used for the following reaction stage.

NMR spectrum (CDCl ₃ ):

Massive at 4.16 to 4.83 ppm (CH ₂ ) Massive at 6.66 to 7.33 ppm (CH) singlet at 6.65 ppm (proton of the thiazole ring).

After recrystallization from absolute ethanol, a product with a ^{temperature of 114 °} C. is obtained.

Analysis results (CpoHpt-O-zN-sS):

calculated: found:

Level C: ^ - ^ -

acetic acid ( syn isomer)

% C. % H 8th N * S. 69 , 54 VJl , 21 8th , 69 6th , 36 69 , 2 5 , 2 , 3 6th , 6

3.227 g of the 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetic acid ethyl ester ( syn isomer) prepared in stage B are introduced into 3.2 ml of dioxane. At room temperature, 20 ml of a 0.5 M solution of KOH in absolute ethanol and 12 ml of absolute ethanol are added. ^{The mixture is then heated to 50 °} C. with stirring and in an argon atmosphere and kept at this temperature for 1 h, the potassium salt crystallizing out. After cooling to 20 ⁰ C is filtered off or centrifuged and washed with ethanol; the product is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of distilled water.

It is then acidified with 6 ml of 2N hydrochloric acid, with up to is stirred to achieve two homogeneous phases. At-

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then it is decanted off, washed three times with 20 ml of distilled water, re-extracted with ethyl acetate, dried, suction filtered or centrifuged and washed with ethyl acetate. It is then concentrated to 15 ml and cooled to 0 and +5 ⁰ C, whereupon suction filtered or centrifuged and washed with ethyl acetate. After drying, 2.53 g of the desired product are obtained, which is used in the present form for the subsequent reaction stage.

After recrystallization, a purified product is obtained; P. 150 ⁰ C.

Stage D: 3-acetoxymethyl-7- Q> - (2-tritylamino-H-thiazolyl) -2-vinyloxyimino-acetamido ^ -ceph-3-em-4-carboxylic acid ( syn- isomer)

2.53 g of the 2- (2-tritylamino-H-thiazolyl) -2-vinyloxyimino-acetic acid ( syn -isomer) prepared in stage C are introduced into 20 ml of methylene chloride. It is then cooled to +5 ° C. and 0.632 g of dicyclohexylcarbodiimxd are added all at once, whereupon the mixture is allowed to warm to room temperature. To obtain a suspension, the mixture is stirred under argon for 1 hour.

Separately from this, 0.718 g of 7-aminocephalosporanic acid are introduced into 10 ml of methylene chloride under argon. After cooling to +10 ⁰ C 1.1 ml of triethylamine is added (solution B).

The suspension A in 10 minutes at +5, +10 ⁰ C was added to solution B, then allowed to warm to room temperature min with stirring in about 35th Then 3 h at

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20 bx3 25 ⁰ C stirred.

After adding 0.6 ml of acetic acid, the mixture is stirred for 10 minutes, whereupon the dicyclohexylurea formed is suctioned off or is centrifuged off. The organic solution is washed with water, dried and distilled in vacuo. Through this a yellow, resinous product is obtained which is taken up in ethyl acetate, being a lighter, insoluble one The residue is filtered off. It is then evaporated to dryness, whereupon 3.475 g of the desired product can be obtained.

The used as starting material in example ± 2-hydroxyimino-2- (2-tritylamina-4-thiazolyl) -acetate hydrochloride (syn isomer) was prepared as follows:

2- (2-Amino-4-thiazolyl) -2-hydroxyimino-acetic acid ethyl ester (syn-isomer):

0.8 g of thiourea are dissolved in 2.4 ml of ethanol and 4.8 ml of water. A solution of 2 g of 4-chloro-2-hydroxyimino-acetyl acetic acid ethyl ester is then added over the course of 5 minutes and the mixture is stirred at room temperature for 1 hour. The main amount of ethanol is then drawn off in a slight vacuum, whereupon it is neutralized to pH 6 by adding solid sodium hydrogen carbonate. After cooling with ice water, suction filtration or centrifugation and washing with water, drying is carried out at 40 ° C. in a vacuum. In this way 1.32 g of the desired product are obtained; P. 232 ⁰ C.

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Analysis results (C ₁ -HgO, N, S):

. .._ ..% C HH KN % S calculated: 39.0β 4.21 19.52 14.9 found: 38.9 4.4 19.7 14.6

2- (2-Tritylamino-4-thiazolyl) -2-hydroxyimino-vinegar acid ethyl ester hydrochloride

43.2 g of the 2- (2-amino-4-thiazolyl) -2-hydroxyimino-acetic acid ethyl ester ( syn isomer) prepared as above are introduced into 120 ml of dry dimethylformamide.

After cooling to -35 ° C., 32 ml of triethylamine are added, after which 60 g of trityl chloride are added in portions over the course of 30 minutes. After rewarming, complete dissolution and then heating up to 30. ⁰ C found.

After 1 h, it is poured onto 1.2 l of ice water which contains 40 ml of hydrochloric acid (22 ° Be).

It is then stirred in an ice-water bath, suction filtered or centrifuged, washed with 1N hydrochloric acid and made into a paste with ether. 69.3 g of hydrochloride are obtained.

Example 2

Sodium salt of 3-acetoxymethyl-7- Q2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido] -ceph-3-em-4-carbon-

acid ( syn -isomer)

At room temperature, 2.628 g of the in Example 1 809886/0768

product obtained in resin form dissolved in 5.2 ml of acetone. Then 10.4 ml of a 1 M aqueous sodium hydrogen carbonate solution are added all at once. After 1 hour contact at 20 ⁰ C, the sodium salt is filtered off or centrifuged and washed twice with 2 ml of a water-acetone mixture (1: 1) and washed 2 ml of distilled water. After drying in vacuo at 40 C to be I ₃ 6L2 g of the desired crude product obtained.

Example 3

7- [2- (2-Amino-4-thiazoly1) -2-vinyloxyiminoacetamido] ceph-3-em-4-carboxylic acid ( syn isomer)

I, '6l2 g of the sodium salt of 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn isomer) obtained in Example 2 are dissolved in 4 ml of 98% formic acid. Immediately thereafter, 4 ml of distilled water are added, whereupon the mixture is stirred ^{at 40 ° C. for 15 min.} The heterogeneous suspension is triturated for 30 minutes at room temperature. Thereafter, it is filtered off with suction centrifuged at 20 ⁰ C or and washed twice with 1.6 ml of 50 iiger hydrochloric acid, whereupon evaporated to dryness and taken up again with 5 ml of distilled water. After removal or centrifugation at room temperature, it is washed with distilled water and then with diethyl ether. After drying, 300 mg of the desired product are obtained. The insoluble residue is separated off in the same way as above with 50% formic acid.

In this way, 0.214 g of additional acid is obtained.

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Analysis results ( C ₁₇ H. 3 7 ^N 5 ^S 2 % N % S. % C. 3 % H 14, 98 13th , 72 calculated: 43 , 68 , 66 15, 1 13th , 0 found: 44 , 2 , 9

NMR spectrum (DMSO):

6.91 ppm (proton of the thiazole ring) 7.28 ppm (free amino group NHp).

Example 4

Sodium salt of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido] -ceph-3 ~ em-4-carboxylic acid ( syn -isomer)

To 5.08 of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido] produced according to Example 3 g ceph-3-em-4-carboxylic acid (syn isomer), 5 ml of ethanol and then 10 ml of a 1 M aqueous sodium hydrogen carbonate solution added with stirring in an ice-water bath. After dissolving and adding 15 ml of ethanol, the mixture is ^{evaporated in vacuo at 30 °} C. and then taken up again with ethanol, whereupon it is dried to constant weight will. In this way, the aimed product is obtained.

Example 5

An injection composition of the following formulation was prepared:

3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-viny 1-oxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

500 mg of aqueous, sterile excipient to 5 ml

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Example 5

Gelatin capsules of the following formulation were produced:

-7- [2- (2-amino-4-thiazolyl) 2-vinyloxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn isomer) 250 mg

Excipient on 1 gelatin capsule ad 400 mg.

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Claims (12)

Expectations Vinyloxyimino derivatives of 7-aminothiazolyl-aeetamidocephalosporanic acid of the general formula I, - NH-R. in which: R * is a hydrogen atom or a trityl group and A is a hydrogen atom or an equivalent of one Alkali metal, alkaline earth metal, magnesium or an organic amine base, the vinyloxy group being in the syn or anti position. 2. J-acetoxymethyl -? - [2- (2-tritylamino-i »-thiazolyl) -2-vinyloxyimino-acetamido] -ceph-3-em - ^ - carboxylic acid ( syn -isomer) and its salts with alkali metals, alkaline earth metals , Magnesium and organic amine bases. 3. Sodium salt of 3-AcBtOXjTnIe ^ yI -? - [2- (2-tritylamino- ¹ ! - thiazolyl) -2-vinyloxyimino-acetamido3-ceph-3-em-4-carboxylic acid ( syn- isomer). 501-1720 / 5 / D-SP-Bk _809886/0768 ORfGiNAL INSPECTED 4. 3-Acetoxymethyl-7- C2- (2-amino-4-thiazolyl) -2-vinyloxyimino-acetamido] -ceph-3-em-ii-carboxylic acid ( syn -isomer) and its salts with alkali metals, alkaline earth metals, magnesium and organic amine bases. 5. A process for the preparation of the compounds of the formula I _r according to claim 1,. ■ characterized, that a compound of the formula X-CH ₂ -CH ₂ -X with X = Cl, Br or J with a thiazole derivative of the formula IH ₁ - NH - C (CH _r ) _ 6 5 3 C0 ₂ alc in the alc. represents a C ^ to C ^ alkyl group, in the presence of a base to a compound of the formula NH -C (C ₆ H ₅ ) ₃ CO ₂ a Ic is implemented, which by treatment with a strong base in a compound of the formula V 809886/0768 NII-C (CJI). 6 5 3 - ClI = CfL is converted, from which by treatment with a base and then with an acid a compound of the formula II, NH-C (C _r H _c ) 6 5 do - CH = CH ₂ is made, either directly or in the form of a functional derivative with 7-aminocephalosporanic acid the formula -CH. into an acid of the formula I ¹ , NH- C - (C ₆ H ₅ ) 0-CH = CH (V ₅ ) H_ OC CH 2 809886/0768 -n- is converted, which may be converted into the corresponding alkali metal salt, alkaline earth metal salt, magnesium salt by customary processes or salt of an organic amine base is transferred, where the acid of the formula I 'or its salts, if appropriate with an acid, to form a compound of the formula I " CH ₂ OC - CH ₃ COOH ° is implemented, which is optionally converted into the corresponding salt by customary processes. 6. The method according to claim 5, characterized in that the compounds 11 ^ to V ₁ - are used as syn isomers. 7. The method according to claim 5 or 6, characterized in that for converting the compound of formula IVp. into the compound of the formula V ₁ . the strong base used is potassium tert-butoxide in dimethyl sulfoxide at room temperature. 8. Compounds of the formula IV NH-C (C ,, H_), D 5 y CO ₂ aIc CH ₂ -CH ₂ X 809886/0768 in which: X-Cl, Br or J and ale a C ₁ to C 1 alkyl group 9. Compounds of the formula NH-C (C ₆ H ₅ ) ₃ S \ CO ₂ R Il N 0 -CH = CH ₂ in which R, - a hydrogen atom or a C ₁ - to C ^ -alkyl- group means. 10. Pharmaceutical compositions, characterized, that they contain at least one pharmaceutically suitable compound of the formula I ₁ according to claim 1 as active ingredient. 11. Pharmaceutical compositions, characterized in that that they contain at least one pharmaceutically suitable compound of the formula I as .Active substance - according to claim in the form of the syn -isomer. 12. Pharmaceutical compositions, characterized in that that they are 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-vinyloxyimino-acetamido] -ceph-3-emij-carboxylic acid ( syn -isomer) and / or their salts with alkali metals, Alkaline earth metals, magnesium or organic amine bases. 809886/0768