CH642662A5 - CEPHALOSPORINE AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to a cephalosporin derivative of the formula (I '):

3rd

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xciu-c-c-conh.

0

II m

S

or /

N ^ 3

coor ^

(r)

h2n-

O'

-n-

T

coor,

(v)

r.

in which X 'represents a hydrogen atom or a halogen atom, Rs represents a halogen atom, an alkoxyl group, a thiol group, methylthio, an amino group or the radical n-n

-v-z in which the symbols have the meanings defined above, or reacted with a salt thereof, or by io a new compound of the formula (VII):

means, where Z is hydrogen or an optionally substituted hydroxyl, amino, thiol or hydrocarbon group or is -CH2R5, where Rs is a hydrogen atom or a radical derived from a nucleophilic group, -COOR4 is an optionally esterified carboxyl group and Ro is an alkyl group, and salts thereof. The invention further relates to a process for the preparation of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -alkoxyiminoacetamido] cephalo-sporin derivatives of the formula (II):

cjj-c-c-conh

3 11 11

0 n ór / -

0

S

-n y ~ e3

COORjj

(vii)

20 in which the symbols have the meanings defined above, or a salt thereof halogenated, the compound (VII) or a salt thereof being obtained by using the new 3-oxo-2-alkoxyiminobutyric acid of the formula (VI):

iun / s

2 y

n c-conh -

II n

~ 0r

0

(ii)

n-

* R.

25 ch, -c-c-c00h

3 II II 0 N

s

OR.

(vi)

coor,

in which the symbols have the meanings defined above, in which the above compound (I) is reacted with thio-urea.

It has been found according to the invention that the new 7- (4-halo-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivatives or their salts, which are represented by the above formula (I), can be prepared by using a 7th - (4-Halogen-3-oxo-2-hydroxyiminobutyrylamino) cephalosporin derivative of the formula (III):

in which Re has the meaning defined above, or a reactive derivative thereof with a compound (V) or with a salt thereof. It was further found 35 that the derivative (II) has excellent antibacterial activity and can be produced in good yield by reacting the compound (I) thus prepared or a salt thereof with thiourea.

The invention provides a cephalosporin derivative of the formula (I '):

XCH-c-c-conh ■ 2, i 11

45

0 n oh

0

(iii)

coor x'cho-c-c-c0nh-

2 II II

0 n

<i or.

D

0 "

(I »)

"r.

coor,

in which the symbols have the meanings defined above, or alkylate a salt thereof, or by preparing a new 4-halo-3-oxo-2-alkoxyiminobutyric acid of the formula (IV):

xch-c-c-c00h sn 11

0 n s

OR.

(iv)

in which X 'represents a hydrogen atom or a halogen atom, and the other symbols have the meanings defined above, or a salt thereof and a process for the preparation of a 7- [2- (2-aminothiazol-4-yl) -2- ( syn) -alkoxyiminoacetamido] -cephalosporin derivative or a salt thereof, in which the compound (I) or a salt thereof is reacted with thiourea.

In formulas (I), (III) and (IV), X represents a halogen atom, for example chlorine, bromine, fluorine or iodine. They usually use chlorine or bromine frequently. The symbol R3 on the cephem ring in the formulas (I), (II), 60 (III), (IV), (V) and (VII) means a halogen atom, an alkoxyl group, a thiol group, an amino group or the rest

-n j'-z

65

in which the symbols have the meanings defined above, or a reactive derivative thereof with a 7-amino-cephalosporin derivative of the formula (V):

(wherein Z is hydrogen or an optionally substituted hydroxyl, amino, thiol or hydrocarbon group) or -CH2R5, where Rs is a hydrogen atom or one of

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a residue derived from a nucleophilic group. The symbol Rs used here means a hydrogen atom or a residue derived from a nucleophilic group. The residue of a nucleophilic group represented by Rs is, for example, a hydroxyl group, a mercapto group, a lower aliphatic acyloxy group with 2 to 4 carbon atoms, which can be substituted, for example acetyl -oxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyl-oxy, 3-ethoxycarbamoylpropionyloxy, 4-carboxybutyryl-oxy, etc .; an optionally substituted aromatic acyloxy group such as mandelyloxy, 2-carboxybenzoyloxy, 2- (car-bethoxycarbamoyl) benzoyloxy, 2- (carbethoxysulfamoyl) benzoyloxy, etc .; a carbamoyloxy group, cyano, azide, amino, Carbamoylthio, Thiocarbamoyloxy, a carbamoyloxy group whose amino group is protected (such as an N-mono-, di- and Trihalogenacetylcarbamoylgruppe, for example N-Chloracetylcarbamoyloxy, N-dichloroacetyl-carbamoyloxy, etc .; a N-Chlorsulfonylcarbamoyloxy group, an N-trimethylsilylcarbamoyloxy group) and a phenylglycyloxy group. These residues of the nucleophilic compounds can also be substituted by generally 1 or 2 substituents, for example alkyl groups (for example lower alkyl groups with 1 to 3 carbon atoms, for example methyl, ethyl or propyl) or acyl groups (for example lower aliphatic acyl groups with 2 to 4 carbon atoms) , for example acetyl, propionyl or butyryl; aromatic acyl groups, for example benzoyl, p-chlorobenzoyl, p-methylbenzoyl, mandeloyl etc.). On the other hand, the radical Rs derived from a nucleophilic group can be a quaternary ammonium group or a heterocyclic ring which is bonded to the methyl group in the 3-position via sulfur outside the ring. The heterocyclic ring mentioned here is a 5- or 6-membered ring with 1 to 4 heteroatoms from the group consisting of oxygen, sulfur or nitrogen, where the nitrogen can be in the form of an oxide. Commonly used heterocyclic rings are as follows; Pyridyl, N-oxide-pyridyl, pyrimidyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, diazolyl, thia-zolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadia-zolyl, 1, 2,5-thiadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1H-tetrazolyl or 2H-tetrazolyl. These heterocyclic rings can have substituents on the ring. Such substituents include lower alkyl groups with 1 to 3 carbon atoms, for example methyl, ethyl or propyl, lower alkoxy groups with 1 to 3 carbon atoms, for example methoxy, ethoxy or propoxy, halogen atoms, for example chlorine or bromine, trihalo-substituted lower alkyl groups, for example trifluoromethyl or trichloroethyl, hydroxyl, mercapto, amino, carboxyl, carbamoyl, a disubstituted lower alkylamino lower alkyl group having 1 to 3 carbon atoms, for example dimethylaminoethyl or dimethylaminomethyl and carboxymethyl. When these substituents are present on the heterocyclic ring, the number of these substituents is generally 1 or 2. Examples of the quaternary ammonium group represented by Rs are pyridinium, 3-methylpyridinium, 4-methylpyridinium, 3-chloropyridinium, 3-bromopyridinium, 3 -Iodopyridinium, 4-carbamoylpyridinium, 4- (N-hydroxymethylcarbamoyl) pyridinium, 4- (N-carbomethoxycarbamoyl) pyridinium, 4- (N-cyancarbamoyl) pyridinium, 4- (carboxymethyl) -pyridinium, 4- (hydroxymethyl) -pyridinium, 4- (trifluoromethyl) -pyridinium, quinolinium, picolinium or lutidinium. When R3 is halogen, alkoxyl, thiol or amino, the above-mentioned chlorine or bromine can be used as the halogen atom. Typical alkoxyl groups are methoxy and ethoxy. If R3 has the remainder n-n

-y ~ z means the substituents on the hydroxyl group, the amino group, the thio group or the hydrocarbon group (for example an alkyl group; preferably having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isobutyl or tert-butyl, an aralkyl group, for example benzyl, an aryl group, for example phenyl or naphthyl), which is each represented by Z, lower alkyl groups, acyl groups, aralkyl groups or aryl groups, as mentioned above. These substituents may also be substituted by a carboxyl group, a sulfo group, a hydroxyl group or another group. If Z is an amino group, those groups may also be included in which a pyrolidino, morpholino or thiomorpholino group is formed together with the nitrogen atom. Typical examples for the remainder n-n

-yz are the following: 5-acetylamino-l, 3,4-thiadiazol-2-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-5-dimethylamino-1,3,4- thiadiazol-2-yl, 5-methyl-l, 3,4-thiadiazol-2-yl and 1,3,4-thiadiazol-2-yl.

The carboxyl group represented by -COOR4, which may be esterified, means a carboxyl group, an inorganic salt thereof, such as an alkali or alkaline earth metal salt, e.g. the sodium or potassium salt, or an organic salt, e.g. the triethylamine salt and further an esterified carboxyl group. Examples of such esters are methyl, ethyl, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, alkanoyloxymethyl (e.g. acetoxymethyl, etc.), di- or trialkylsilyl (e.g. trimethylsilyl -, etc.), alkoxysilyl, benzhydryl, 1-indanyl, phthalidyl, 5-indanyl, phenacyl, phenyl, p-nitrophenyl, alkoxy-alkyl, (e.g. methoxymethyl, ethoxymethyl), alkenyl -, Trichlorethyl, methylsulfonylethyl, benzoylmethyl, benzyloxymethyl, t-butyl, methoxybenzyl, trityl, methylthio-methyl, pivaloyloxymethyl, cc-acetoxybutyl or a-acy-loxy-a-substituted methyl esters, for example an a-eth-oxycarbonyloxy-a-methyl-methyl ester. These esters can preferably be those which can react to the free acid under mild conditions without opening the β-lactam ring. The groups R4 which are convertible to hydrogen under mild acidic or alkaline conditions include, for example, the following diphenylmethyl, substituted phenyl, lower alkylsulfonylethyl or pivaloyloxymethyl or groups which can be eliminated by an oxidation or reduction reaction, for example trichloroethyl or benzyl. The compound (II) can be in the form of a salt with an inorganic acid, for example in the form of a hydrochloric acid salt or hydrobromic acid salt.

As the alkyl group represented by Rs in the formulas (I), (II), (IV), (VI) and (VII), lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, etc. can be used.

The wavy line in formulas (I), (III), (IV), (VI) and (VII) indicates that the groups OH or OR <s in either one or the other of the two possible configurations, namely syn and anti can exist, or that the respective group can exist in both configurations.

The reactions according to the process of the invention, namely the preparation of the compound (I) by alkylation of the compound (III), are explained below. The alkylation reaction generally takes place in

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a solvent under ice cooling or at about room temperature, and in most cases it will be accomplished within a few minutes to a few hours. Any solvent which is inert in the reaction can be used, for example tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, water or a mixture from that. An alkyl halide, for example methyl iodide, methyl bromide, ethyl iodide, ethyl bromide etc., dimethyl sulfate, diethyl sulfate, diazomethane, diazo-ethane or methyl p-toluenesulfonate can be used as the alkylating agent. Except when diazomethane or diazoethane is used, the compound (III) with the aforementioned alkylating agent in the presence of an alkali metal carbonate, for example sodium carbonate, potassium carbonate, etc., an alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide, etc. or an organic base, for example triethylamine, pyridine, dimethylaniline etc. implemented. The compound (I) thus prepared can be purified by isolation according to conventional procedures, and can also be used as the starting material in the subsequent reaction without isolation.

The reaction for producing the compound (II) by reacting the compound (I) with thiourea is generally carried out in a solvent. Any solvent that is inert in the present reaction can be used. Examples of such solvents are water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpiperidone and mixtures thereof. The reaction takes place under ice cooling, at room temperature or with heating. Usually, the thiourea is used in an amount of 1 to several equivalents of the compound (I). The reaction time is I to 48 h, preferably 1 to 10 h. The compound (II) thus prepared can be purified by isolation according to the customary procedures, for example by concentration, concentration under reduced pressure, crystallization, recrystallization, solvent extraction, salting out, fractional distillation, distillation or chromatography.

The compound (IV) or the compound (VI) is reacted with the 7-aminocephalosporin derivative (V) to give the compound (I) or the compound (VII). The compound (IV) or the compound (VI) is used as an acrylating agent of the amino group in the 7-position of the compound (V) in free form or in the form of a reactive derivative thereof. I.e. the compound (IV) or (VI) is intended for the acrylation reaction either in free form or in the form of a reactive derivative thereof, for example as an alkali or alkaline earth metal salt of the carboxyl group (for example sodium, potassium or calcium salt), as a salt with an organic Amine, for example trimethyl-amine, pyridine, etc., as the acid halide thereof (for example, acid chloride, acid bromide, etc.) as the acid anhydride, as the mixed acid anhydride, as the active amide or as the activated ester. A p-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester can be used as the activated ester. A mixed acid anhydride with a carboxylic acid monoester, for example mono-methyl carbonate, mono-isobutyl carbonate etc. or a mixed acid anhydride with a lower alkane carboxylic acid which can be substituted by a halogen atom or by halogen atoms, for example pivalic acid or trichloroacetic acid, can be used as the mixed acid anhydride. be used. If the compound (IV) or (VI) is used in the form of the free acid or in the form of the salt, a

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suitable condensing agent can be used. N, N'-disubstituted carbodiimides, for example N, N'-dicyclohexylcarbodiimide, azolide compounds, for example N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, for example N-ethoxycarbonyl, can be used as condensing agents -2-ethoxy-l, 2-dihydroquinoline, phosphorus oxychloride or alkoxyacetylene, 2-halopyridinium salts (about 2-chloropyridiniumethyl iodide, 2-fluoropyridinium methyl iodide) etc. If a condensing agent is used, it is believed that the reaction will be via a reactive derivative the compound (IV) or (VI) takes place. The reaction is generally carried out in a suitable solvent. Halogenated hydrocarbons, for example chloroform, methylene dichloride, etc., an ether, for example, tetrahydrofuran, dioxane, etc., are often used as solvents. Dimethylformamide, dimethylacetamide, acetone, water or a mixture thereof. The compound (IV) or (VI) is generally used in an amount of about 1 to a few moles per mole of the compound (V). The reaction generally takes place in the range from -50 to 40 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 10 hours. The compound (I) thus produced is isolated by the conventional procedures described above. Compound (VII) can be isolated in the same way by conventional procedures, but it can also be used as a starting material in the subsequent step.

The reaction usually used for the halogenation of active hydrogen in organic chemistry can also be used in the reaction in which the compound (VI) or (VII) is halogenated to give the compound (IV) or (I). For example, chlorine, bromine, sulfuryl chloride, etc. can be used as the halogenating agent. Sometimes the reaction can proceed smoothly in a solvent. Usable solvents are chloroform, methylene chloride, dichloroethane, dichlorethylene, carbon tetrachloride, acetic acid, benzene, toluene, etc. The reaction can be carried out with ice cooling or with heating, but usually at a temperature in the range from 0 to 60 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 10 hours. The resulting compound (IV) or (I) can be purified by isolation using conventional procedures. The compound (IV) can be used as starting material for the reaction with the compound (V) in the form of the reaction mixture without isolation as such.

The starting compounds used according to the invention, for example the esters of 3-oxo-2-alkoxyiminobutyric acid, which are represented by the formula (VI), are described, for example, in the following literature references: J. Indian Chem. Soc., 42,677 (1965); J. Am. Chem. Soc., 60, 1328 (1938). The compound (VI) can be prepared by eliminating the ester groups from the corresponding esters under customary conditions for the ester hydrolysis. Usually, the compound (VI) is used as a raw material without purification for the preparation of the compound (IV) or (VII). The other compound (III) can be prepared according to the procedure in Chem. Pharm. Bull., 25.3117 (1977) or a similar method. The 7-aminocephalosporin derivative of the formula (V) can be prepared according to the following references: DE-OS 4 614 78, DE-OS 2 607 064, DE-OS 2 619 242, Japanese Patent Application No. 520 83/1975, ( corresponding to GB-PS 14 530 49 and DE-OS 2 439 880), DE-OS 2 460 331 u. DE-OS 2 460 332, Japanese Patent Application No. 138 696/1976 (corresponding to DE-OS 2 620 094), Japanese Patent Application No. 129 590/1975 (corresponding to GB-PS 15 035 81 and DE-OS 2 506 330 ), Japanese Patent5

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Application No. 954 85/1975 (corresponding to US-PS 40 136 51 and DE-OS 2 620 308) and Japanese Patent Application No. 108 087/1976 (corresponding to DE-OS 2 606 192), J. Am. Chem. Soc., 96, 4986 (1974), Helv. Chim. Acta, 57, 1919 (1974), ibid. 57, 544 (1974), ibid. 55, 423 (1972), ibid. 58, 2437 (1975), J. Am. Chem. Soc., 98, 2342 (1976), Helv. Chim. Acta, 55.408 (1972), GB-PS 13 77 61 and DE-OS 2151 567. Methods analogous to this can also be used.

The compounds (IV) and (VI) prepared in this way are

c-conh -

-s-.

n

0 ^ '

OFL

1, -j

"r" •

coor ,,

compounds for the synthesis of the new compounds of formula I '. As such, the compounds of the formula V are new cephalosporin derivatives with antibacterial activity, of which the halogen derivatives are intermediate compounds for the synthesis of the compound (II).

It is believed that the cephalosporin derivative represented by formula (II) can be described by the structure of the tautomeric isomers, namely the 2-aminothiazo isomer and the 2-iminothiazoline isomer:

h n -

1

N

H

\

c-conh, -

II

Nx or 6

"H J

, R, COOR ^

For convenience, compound (II) is shown in the form of the thiazole type.

Typical examples of the compound (I) according to the invention are listed below:

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (l-

methyl-lH-tetrazol-4-yl) thiomethyl-3-cephem-4-carbon

acid;

7- (4-Bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid rebenzhydric ester;

7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalospo-ranoic acid;

7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalospo-ranoic acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) cephalo-sporanoic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) cephalo-sporanoic acid;

7- (4-Chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid;

7- (4-Chloro-3-oxo-2-methoxyiminobutyrylamino) -3- [1- (2-N, N-dimethylaminoethyl) -1 H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3-carba-

moyloxymethyl-3-cephem-4-carboxylic acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3-carba-

moyloxymethyl-3-cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) desacetoxy-

cephalosphoric acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-aceta-

mido-l, 3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3- (5-

methyl-1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (l, 3,4-

thiadiazol-2-yl) -3-cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-dime-

thylamino-1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (5-N-

methylacetamido-1,3,4-thiadiazol-2-yl) -3-cephem-4-carbon-

acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3-chloro-3-

cephem-4-carboxylic acid;

7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3-methoxy-2s 3-cephem-4-carboxylic acid;

7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) -3-methoxy-

3-cephem-4-carboxylic acid;

7- (4-Bromo-3-oxo-2-methoxyiminobutyrylamino) -3-methylthio-3-cephem-4-carboxylic acid.

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Typical examples of the compound (VII) according to the invention are listed below: 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid;

35 sodium 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (l-methyl-1 H-tetrazol-4-yl) thiomethyl-3-cephem-4-carboxylate; 7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-te-trazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester;

40 7- (3-oxo-2-ethoxyiminobutyrylamino) cephalosporanic acid; 7- (3-Oxo-2-ethoxyiminobutyrylamino) t-butyl cephalosporanoate;

7- (3-oxo-2-methoxyiminobutyrylamino) cephalosporanic acid; Sodium 7- (3-oxo-2-methoxyiminobutyrylamino) cephalo-45 sporanate;

7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (2-methyl-l, 3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid; 7- (3-Oxo-2-methoxyiminobutyrylamino) -3- [1- (2-N, N-dimethylaminoethyl) -IH-tetrazol-5-yl] thiomethyl-3-cephem-4-50 carboxylic acid; 7- (3-Oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid:

Sodium 7- (3-oxo-2-methoxyiminobutyrylamino) -3-carbamoyloxymethyl-3-cephem-4-carboxylate; ss 7- (3-oxo-2-methoxyiminobutyrylamino) desacetoxycepha losporanoic acid;

7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (5-acetamido-l, 3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid; 7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (5-methyl-1,3,4-60 thiadiazol-2-yl) -3-cephem-4-carboxylic acid; 7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid;

7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (5-dimethylamino-l, 3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid; 65 7- (3-Oxo-2-methoxyiminobutyrylamino) -3- (5-N-methyllace-tamido-1,3,4-thiadiazol-2-yl) -3-cephem-4-carboxylic acid; 7- (3-oxo-2-methoxyiminobutyrylamino) -3-chloro-3-cephem-

4-carboxylic acid;

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7- (3-Oxo-2-methoxyiminobutyrylamino) -3-methoxy-3-cephem-4-carboxylic acid;

7- (3-Oxo-2-methoxyiminobutyrylamino) -3-methoxy-3-cephem-4-carboxylic acid;

7- (3-Oxo-2-methoxyiminobutyrylamino) -3-methylthio-3-cephem-4-carboxylic acid.

Typical examples of the compound (IV) are as follows:

4-bromo-3-oxo-2-methoxyiminobutyric acid; 4-chloro-3-oxo-2-methoxyiminobutyric acid; 4-bromo-3-oxo-2-ethoxyiminobutyric acid; 4-chloro-3-oxo-2-ethoxyiminobutyric acid.

The invention is explained in more detail below by the examples:

Preparation 1

20.3 g of methyl 3-oxo-2-methoxyiminobutyrate are dissolved in 100 ml of methanol, and 200 ml of an aqueous sodium hydroxide solution are added dropwise to this solution over the course of about 30 minutes with stirring. A slight warming is observed in the course of the addition. After the dropwise addition, the mixture is stirred at room temperature for a further hour. The methanol was then evaporated under reduced pressure and the residue was washed with ethyl acetate. The aqueous layer is adjusted to pH 2.0 using 3N hydrochloric acid while cooling with ice, mixed with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and then concentrated to 3-oxo-2-meth-oxyiminobutyric acid in the form of a viscous, oily product which is further recrystallized from chloroform-n-hexane to form colorless crystals. Yield: 16.0 g, melting point: 81 to 82 ° C

NMR (CDCb): 2.40 ppm (3H, s, CHsCO), 4.10 ppm (3H, s, OCH.?), 10.87 ppm (lH, s, COOH)

Elemental analysis for C5H7NO4:

Calc .: C 41.38; H 4.86; N 9.65 Found: C 41.71; H 4.87; N 9.49

Preparation 2

40 ml of an aqueous 1N sodium hydroxide solution are added dropwise to a solution of 1.87 g of ethyl 3-oxo-2-ethoxyiminobutyrate in 80 ml of methanol. After the dropwise addition has ended, the mixture is stirred at room temperature for 1 hour and the mixture is worked up in the same manner as in preparation 1, a crude product of 3-oxo-2-ethoxyiminobutyric acid being obtained in the form of colorless crystals. Yield: 1.3 g.

NMR (CDCh): 1.35 ppm (3H, t, CH2CH3), 2.42 ppm (3H, s, CHsCO), 4.40 ppm (2H, q, CH2CH3), 7.82 ppm (l H, s ,

COOH).

example 1

A solution of 640 mg of bromine in 5 ml of methylene chloride is added dropwise to a solution of 590 mg of 3-oxo-2-ethoxyiminobutyric acid in 10 ml of methylene chloride. The resulting mixture is stirred at 40 ° C for 30 minutes. The reaction mixture is washed with ice water and then concentrated under reduced pressure to give a crude product of 4-bromo-3-oxo-2-ethoxyiminobutyric acid. Yield: 750 mg.

NMR (CDCb): 1.40 ppm (3H, t, CH2CH3), 4.37 ppm (2H, s, BrCH :), 4.45 ppm (2H, q, CH2CH3).

Example 2

A small amount of a solution of 7.71 g of bromine in 10 ml of methylene chloride is added dropwise to a solution of 7.0 g of 3-oxo-2-methoxyiminobutyric acid in 50 ml of methylene chloride. The mixture is heated in a water bath at 50 ° C. When the color of the bromine begins to disappear, the water bath is removed and the remaining bromine solution is added dropwise to the mixture at room temperature at a rate such that the color of the bromine disappears. When the color of the bromine has disappeared after the dropwise addition, stirring is stopped and the resulting mixture is concentrated under reduced pressure to an oily crude product of 4-bromo-3-oxo-2-methoxyiminobutyric acid. Yield: 11.1g

NMR (CDCls): 4.17 ppm (3H, s, OCH3), 4.37 ppm (2H, s, BrCHi).

Example 3

A solution of 400 mg of bromine in 3 ml of methylene chloride is added dropwise to a solution of 320 mg of 3-oxo-2-ethoxyiminobutyric acid in 10 ml of methylene chloride and the resulting mixture is stirred at room temperature for 2 hours. Thereafter, 500 mg of phosphorus pentachloride is added to the reaction mixture, and stirring is continued for 1 hour at room temperature, whereby a solution of 4-bromo-3-oxo-2-ethoxyiminobutyric acid chloride in methylene chloride is obtained. On the other hand, a solution of 660 mg of t-butyl 7-aminocephalosporanate and 500 mg of pyridine in 10 ml of methylene chloride is cooled to -30 ° C and, while stirring, the acid chloride solution obtained above is added dropwise to the solution at the indicated temperature in the course of about 15 minutes . After the dropwise addition is complete, the mixture is warmed to room temperature and stirring of the mixture is continued for 2 hours. The mixture is then concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and the ethyl acetate layer is washed with 3N hydrochloric acid, then with water, then with an aqueous 5% sodium hydrogen carbonate solution and again with water and then dried. The semi-solid residue obtained after evaporation of the ethyl acetate is purified by chromatography using silica gel.

whereby t-butyl 7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate is obtained as a fluffy solid. Yield: 620 mg.

NMR (CDCb): 1.36ppm (3H, t, CH2 CHs), 1.50ppm (9H, s, -C (CH3) 3), 2.05 ppm (3H, s, CH3CO), 3.44 ppm ( 2H, q, 2-CH2), 4.37 ppm (2H, q, CH2CH3), 4.55 ppm (2H, s, BrCH2), 4.90 ppm (2H, q, 3-CH2), 4.99 ppm (1H, d, 6-H), 5.83 ppm (1H, dd, 7-H), 7.12 ppm (1H, d, CONH).

Example 4

100 mg of thiourea are added to a solution of 200 mg of t-butyl 7- (4-bromo-3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate in 5 ml of ethanol and the mixture is stirred at room temperature for 2 h. After the ethanol has evaporated under reduced pressure, ethyl acetate and water are added to the residue and the mixture is shaken. The ethyl acetate layer is washed with water and dried. The oily product obtained after evaporation of the ethyl acetate is purified by chromatography using silica gel, giving t-butyl 7- [2- (2-aminothiazol-4-yl) -2- (syn) ethoxyiminoacetamido] cephalosporanate as a fluffy solid becomes. Yield: 152 mg.

s

10th

15

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642662

NMR (CDCb): 1.22 ppm (3H, t, CH2CH3), 1.43 ppm (9H, s, C (CHj) 3), 1.97 ppm (3H, s, CHsCOO), 3.36 ppm ( 2H, q, 2-CH2), 4.19 ppm (2H, q, CH2CH3), 4.82 ppm (2H, q, 3-CH2), 4.93 ppm (1H, d, 6-H), 5 , 55 ppm (2H, bs, NHz), 5.86 ppm (lH, dd, 7-H), 6.74 ppm (lH, s, thiazole 5-H), 7.32 ppm (lH, d, CONH ).

Example 5

290 mg of 3-oxo-2-methoxyiminobutyric acid are dissolved in 10 ml of methylene chloride. To the resulting solution, a solution of 220 mg of bromine in 1 ml of methylene chloride is added, and the mixture is stirred at room temperature for 1 hour. Then 500 mg of dicyclohexylcarbodimide and 495 mg of benzhydril 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate are added to the reaction mixture and the mixture becomes 3 stirred for h at room temperature. After evaporating the methylene chloride under reduced pressure, ethyl acetate is added to the residue. The insoluble constituents are filtered off, and the filtrate is washed with an aqueous 5% sodium hydrogen carbonate solution and then with water and then dried. The oil product obtained after evaporation of the ethyl acetate is purified chromatographically with the aid of silica gel, 480 mg of benzhydryl 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1 H-tetrazol-5-yl ) -thiomethyl-3-cephem-4-carboxylate can be obtained.

NMR (CDCb): 3.70 ppm (2H, s, 2-CH2), 3.80 ppm (3H, s, N-CH3), 4.11 ppm (3H, s, OCH3), 429 ppm (2H, q, 3-CH2), 4.53 ppm (2H, s, BrCH2), 4.99 ppm (1H, d, 6-H), 5.85

ppm (lH, dd, 7-H), 6.88 ppm (lH, s, CH - ^^ 2) 7.31 ppm (10H, s, 2 ^ "

Example 6

After dissolving 610 mg of benzhydryl 7- (4-bromo-3-oxo-2-methoxyiminobutyrylamino) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate in a mixture of 20 ml of ethanol and 10 ml of tetrahydrofuran, 304 mg of thiourea are added to the solution, and the resulting mixture is stirred at room temperature for 2 hours. Then the solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate, washed with water and then dried. The residue obtained after the evaporation of the ethyl acetate is purified chromatographically with the aid of silica gel, 540 mg of benzhydryl 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy iminoacetamido] -3- (1 - methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate can be obtained.

NMR (CDCb): 3.70 ppm (2H, s, 2-CH2), 3.78 ppm (3H, s, N-CH3), 3.97 ppm (3H, s, OCH3), 4.28 ppm ( 2H, q, 3-CH2), 5.02 ppm (1H, d, 6-H), 5.97 ppm (1H, dd, 7-H), 6.77 ppm (1H,

s, thiazole 5-H), 6.90 ppm (lH, s, O »

7.31 ppm (10H, s -o *>, 7.77 ppm (1H, d, CONH).

50 mg of this product are added to a mixture of 0.5 ml anisole and 2.5 ml trifluoroacetic acid. The mixture is stirred at room temperature for 30 minutes and then anhydrous ether is added. The resulting precipitates are collected by filtration. The

Precipitates are dissolved in a small amount of an aqueous 5% sodium hydrogen carbonate solution and the solution is passed through a column filled with Sephadex LH-20 (Sephadex LH-20 is a trademark of Pharmacia Fine Chemicals Co., Sweden), 35 mg of purified sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylate can be obtained.

NMR (D20): 3.59 ppm (2H, q, 2-CH2), 3.93 ppm (3H, s, OCHs), 3.98 ppm (3H, s, N-CH3), 4.08 ppm ( 2H, q, 3-CH2), 5.12ppm (1H, d, 6-H), 5.72ppm (1H, d, 7-H), 6.93 ppm (1H, s, thiazole 5-H).

Example 7

A mixture of 250 mg of phosphorus pentachloride with a solution of 145 mg of 3-oxo-3-methoxyiminobutyric acid is stirred in methylene chloride at room temperature for 1 hour to obtain a solution of 3-oxo-2-methoxyimino-butyric acid chloride. On the other hand, a solution of 495 mg of benzhydryl 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate and 240 mg of pyridine in 10 ml of methylene chloride is heated to -30 ° C to which the acid chloride solution prepared above is added dropwise over a period of about 20 minutes. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours and then mixed with 100 ml of ethyl acetate. The mixture is washed with water, 1N hydrochloric acid, water, an aqueous 5% sodium hydrogen carbonate solution and then with water, and then dried. The residue obtained after evaporation of the solvent is purified chromatographically with the aid of silica gel, 440 mg of benzhydryl 7- (3-oxo-2-methoxyiminobutyrylamino) -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl 3-cephem-4-carboxylate can be obtained.

NMR (CDCb): 2.38 ppm (3H, s, CHsCO), 3.72 ppm (2H, s, 2-CH2), 3.80 ppm (3H, s, N-CHa), 4.10 ppm ( 3H, s, OCHs), 4.28 ppm (2H, q, 3-CH2), 5.00 ppm (1H, d, 6-H), 5.88

ppm (lH, dd, 7-H), 6.88 ppm (lH, s, CH - ^^ 2), 6.92 ppm (lH, d, CONH), 7.31 ppm (IOH, s, 2 * *

Example 8

A solution of 160 mg of 3-oxo-2-ethoxyiminobutyric acid in 5 ml of methylene chloride is mixed with 250 mg of phosphorus pentachloride and stirred at room temperature for 1 hour to obtain a solution of the acid chloride. On the other hand, a solution of 330 mg of t-butyl 7-amino-cephalosporanate and 240 mg of pyridine in 5 ml of methylene chloride is cooled to -50 ° C, to which the acid chloride solution prepared above is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 h. The reaction mixture is then mixed with 100 ml of ethyl acetate and washed with water, 3N hydrochloric acid, water, an aqueous 5% hydrogen carbonate solution and then with water, and then dried. The residue obtained after evaporation of the solvent is purified chromatographically with the aid of silica gel, 340 mg of t-butyl 7- (3-oxo-2-ethoxyiminobutyrylamino) cephalosporanate being obtained.

NMR (CDCb): l, 34ppm (3H, t, CH2CH3), l, 50ppm (9H, s, C (CH3 », 2.04 ppm (3H, s, CHsCOO), 2.37 ppm (3H, s,

8th

5

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642 662

CHìCO), 3.42 ppm (2H, q, 2-CH2), 4.33 ppm (2H, q, CH2CH3), 4.89 ppm (2H, q, 3-CH2), 4.97 ppm (lH, d, 6-H), 5.83 ppm (1H, dd, 7-H), 6.84ppm (1H, d, CONH).

Example 9

A solution of 235 mg of t-butyl 7- (3-oxo-2-ethoxyimino-butyrylamino) cephalosporanate in 10 ml of methylene chloride is heated to 35 ° C., and a solution of 88 mg of bromine in 3 ml of methylene chloride is added. When the color of the bromine begins to disappear, heating is stopped and stirring is continued at room temperature until the mixture is essentially decolorized.

After shaking the reaction mixture with ice water, the methylene chloride layer is separated, washed with water and dried. The residue obtained after the evaporation of the methylene chloride is purified chromatographically with the aid of silica gel, 190 mg of t-butyl 7- (4-bromo-3-oxo-2-ethoxybutyrylamino) cephalosporanate being obtained. This product was found to be identical to the product of Example 5 in terms of NMR.

Example 10

419 mg of 7- (4-chloro-3-oxo-2-hydroxyiminobutyrylamino) cephalosporanic acid are added to a mixture of 7 ml of water and 7 ml of acetone.

300 mg of sodium carbonate are dissolved in the entire mixture with stirring and with ice cooling, and then 600 mg of dimethyl sulfate are added dropwise to the resulting solution. After 30 minutes, a further 300 mg of sodium carbonate and a further 300 mg of dimethyl sulfate are added to the mixture, and stirring is continued for a further 30 minutes. 20 ml of ice water are then added to the reaction mixture and the pH is adjusted to 2.0 with 10% hydrochloric acid. The mixture is then extracted with ethyl acetate, and the extracted layer is washed with water, dried and concentrated, a crude powdery product being obtained from 280 mg of 7- (4-chloro-3-oxo-2-methoxyiminobutyrylamino) cephalosporanic acid.

NMR (Ô6-DMSO): 2.00 ppm (3H, s, CHsCOO), 3.50 ppm (2H, bs, 2-CH2), 4.01 ppm (3H, s, OCHa), 4.76 ppm ( 2H, s, CICH2CO), 4.81 ppm (2H, q, 3-CH2), 5.11 ppm (1H, d, 6-H), 5.73 ppm (1H, dd, 7-H), 9 , 53 ppm (1H, d, CONH).

s

Example 11

A solution of 210 mg of 7- (4-chloro-3-oxo-2-methoxyimi-nobutyrylamino) cephalosporanic acid in 4 ml of N, N-dimethyl-acetamide is mixed with 100 mg of thiourea and the resulting mixture is stirred at room temperature for 4 hours long stirred. 30 ml of ether are added to the reaction mixture, and the oily product separated off is separated off by decantation. The oily product is dissolved in an aqueous 5% sodium hydrogen carbonate solution and purified by column chromatography using Amberlite XAD-2 (Amberlite XAD-2 is a trademark of Rohm & Hass Co., USA). 141 mg of sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido] cephalosporanate are obtained as a white powder.

20th

NMR (D20): 2.07 ppm (3H, s, COCH3), 3.53 ppm (2H, q, 2-CH2), 3.98 ppm (3H, s, OCHs), 4.75 ppm (2H, q, 3-CH2), 5.21 ppm (1H, d, 6-H), 5.81 ppm (1H, d, 7-H), 7.01 ppm (1H, s, thiazole 5-H).

25th

Example 12

The following table shows examples of the compounds which were prepared according to the procedures using a combination of Examples 10 and 11, a combination of Examples 5 and 6 and a combination of Examples 8,9 and 4.

H0N A

2 y

; N ~

'C-CONH -

40

N \

0 "

^ L

N-

OCH.

-p-

COORjj -

No. Rj

R4

NMR (solvent, ppm)

-CH2OCONH2 -CH3

N N

, -UU

-C! I2S- ^ s- ^ 0H3

~ ch2s n

N N

ü 11

I xCH3

ch5ch0n j d ch3

Oh well

N / A

N / A

D2O; 3.47 (2H, q, 2-Cm), 3.92 (3H, s, OCH3), 4.68 (2H, q, 3-CH2), 5.27 (1 H, d, 6-H) , 5.72 (1 H, d, 7-H), 6.95 (1 H, s, thiazole 5-H) D2O; 1.94 (3H, s, 3-CH3), 3.46 (2H, q, 2-CH2), 4.00 (3H, s, OCH3), 5.17 (lH, d, 6-H), 5.76 (1 H, d, 7-H), 6.99 (1 H, s, thiazole 5-H)

D2O; 2.57 (3 H, s, thiadiazole 2-CH3), 3.52 (2H, q, 2-CH2), 3.95 (3H, s, OCH3), 5.18 (1H, d, 6-H) ), 5.73 (lH, d, 7-H), 6.95 (lH, s, thiazole 5-H)

.CHa

D2O; 2.20 (6H, s, NC

),

-CH3

3.88 (3H, s, 0CH3), 5.10 (1H, d, 6-H), 5.66 (1H, d, 7-H), 6.90 (1H, s, thiazole 5-H)

-CH0S

2 S '

CHoCOONa

D2O; 3.56 (2H, q, 2-CH2), 3.96 (3H, s, OCH3), Na 4.18 (2H, s, -CH2COONa), 5.20 (lH, d, 6-H), 5.74 (1H, d, 7-H),

6.97 (1 H, s, thiazole 5-H)

642 662

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R4

NMR (solvent, ppm)

-CH0S-6 2

N "

N

ii

'N

CH2COONa

DzO; 3.55 (2H, q, 2-CH2), 3.96 (3H, s, OCH3), Na 4.72 (2H, s, -CH2COONa), 5.18 (lH, d, 6-H), 5.72 (1H, d, 7-H),

6.95 (1 H, s, thiazole 5-H)

-CH "S

-O-

• CH.

2 "^" "3

N-N +

0

D2O; 2.60 (3H, s, pyridazine 6-CH3), 3.52 (2H, q, 2-CH2), Na 3.98 (3H, s, OCH3), 5.21 (1 H, d, 6- H), 5.76 (1 H, d, 7-H),

6.95 (1 H, s, thiazole 5-H)

N N

; i "iL,

-CH2S- ^ 0 ^ -CH3

D2O; 2.48 (3H, s, oxadiazole 2-CHs), 3.55 (2H, q, 2-CH2), Na 4.02 (3H, s, OCH3), 5.13 (1H, d, 6-H) ), 5.73 (1 H, d, 7-H),

6.97 (1 H, s, thiazole 5-H)

—N

ii

-ch2s-vn

H

D2O; 3.57 (2H, q, 2-CH2), 3.94 (3H, s, OCH3), 5.21 (lH, d, 6-H), 5.72 (1 H, d, 7-H) , 6.94 (1 H, s, thiazole 5-H), 7.95 (1H, s, thiazole 4-H)

10th

N-

-4

NHCCH,

N / A

D2O; 2.26 (3H, s, COCH3), 4.02 (5H, bs, 2-CH2 and OCH3), 5.37 (1H, d, 6-H), 5.92 (1H, d, 7-H) ), 7.01 (1 H, s, thiazole 5-H)

0

11 cl

12 OCH3

13 SCH3

Na Na Na

D2O; 3.60 (2H, q, 2-CH2), 3.90 (3H, s, OCH3), 5.20 (1 H, d, 6-H), 5.71 (lH, d, 7-H) , 7.04 (1 H, s, thiazole 5-H)

D2O; 3.60 (2H, q, 2-C H2), 3.76 (3H, s, 3-OCH3),

4.01 (3H, s, ^ r = N-OCH3), 5.24 (1 H, d, 6-H), 5.66 (1 H, d, 7-H), 7.06 (1 H , s, thiazole 5-H)

D2O; 2.10 (3H, s, SCH3), 3.62 (2H, q, 2-CH2), 3.95 (3H, s, OCH3), 5.10 (1H, d, 6-H), 5, 71 (1H, d, 7-H), 7.10 (1H, s, thiazole 5-H)

s: singlet, D: doublet, t: triplet bs: broad singlet, q: quartet, m: multiplet,

dd: double doublet

B

Claims (13)

642 662 2nd PATENT CLAIMS 1. Cephalosporin derivative of the formula: X1CHn-C-C-CONH- 2 il ii 0 n <; 0Rr 0 N r. (! ') XCH - C-C-CONH 2 left 0 n S OH (X a cooR.r (III) COOR, in which X 'represents a hydrogen atom or a halogen atom, R3 represents a halogen atom, an alkoxyl group, a thiol group, methylthio, an amino group or the radical n-n -V-z in which X represents a halogen atom and R3 and -CQOR4 have the meaning defined in claim 1, or alkylates a salt thereof. 5. Process for the preparation of a 7- [2- (2-aminothiazol-4-yl) -2- (syn) -alkoxyiminoacetamido] cephalosporin derivative of the formula: 15 where Z is hydrogen or an optionally substituted hydroxyl, amino, thiol or hydrocarbon group, or -CH2R5, where Rs is a hydrogen atom or a radical derived from a nucleophilic group, -COOR4 is an optionally esterified carboxyl group and Râ is a Means alkyl group, or a salt thereof. Process for the preparation of the 7- (4-halo-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof according to Claim 1, characterized in that a 4-halo-3-oxo-2-alkoxyimino butyric acid of the formula: H2N- | f 20th C-CONH « \ or, (II) COOR. XCHo-C-C-C00H 2 I! II 0 N / OR. 2s in R3 is a halogen atom, an alkoxyl group, a thiol group, methylthio, an amino group or the rest n-n -v-z 30th (iv) in which X represents a halogen atom and Rs has the meaning defined in claim 1, or a reactive derivative thereof with a 7-aminocephalosporin derivative of the formula: where Z is a hydrogen atom or an optionally substituted hydroxyl, amino, thiol or hydrocarbon group, or is -CH2R5, where Rs is a hydrogen atom or a radical 35 derived from a nucleophilic group, -COOR4 is an optionally esterified carboxyl group, and Rs is an alkyl group, or a salt thereof, characterized in that the 7- (4-halo-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative of the formula: H2N - / SN ! » A os R. (v) COOR. XCH-C-C-CONH 2li II 0 N s OR. (I) or a salt thereof, wherein R3 and -COOR4 have the meanings defined in claim 1. 3. A process for the preparation of the 7- (4-halo-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof according to claim 1, characterized in that a 7- (3-oxo-2-alkoxyiminobutyryl- amino) cephalosporin derivative of the formula: CHT-C-C-CONH- 3 il il 0 N ( ORc 0 * rÛ "R. (vii) COOR, in which R3, -COOR4 and R «have the meanings defined in claim 1, or a salt thereof halogenated. Process for the preparation of the 7- (4-halo-3-oxo-2-alkoxyiminobutyrylamino) cephalosporin derivative or a salt thereof according to Claim 1, characterized in that a 7- (4-halo-3-oxo-2 -hydroxyimino-butyrylamino) -cephalosporin derivative of the formula: in which X represents a halogen atom, and R3, -COOR4 and Rs have the definition given above, or a salt 50 thereof prepared by the process of claim 2 and then reacted with thiourea. 6. The method according to claim 5 for the preparation of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 - [(l-methyl-1 H-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carbon- 55 acid. 7. The method according to claim 5 for the preparation of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3-car-bamoyloxymethyl-3-cephem-4-carboxylic acid. 8. The method according to claim 5 for the preparation of 7- [2- (2-69 aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -cepha- losporanic acid. 65