HU184969B - Process for preparing acyl derivatives - Google Patents

Abstract

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Description

The present invention relates to the preparation of novel cephem carboxylic acid derivatives.

More particularly process (I), a new cephalosporin derivatives of the formula (wherein R ^l is methyl, acetoxymethyl group, a lower alkyl, hydroxy and / or oxo-substituted triazinyl alkylthiomethyl group, a lower alkyl group a substituted thiadiazolylthiomethyl group, a lower alkyl substituted tetrazolylthiomethyl group or a pyridinium methyl group;

R ² is hydrogen, lower alkyl or R ^{3 is} OCO- (lower alkyl) where R ^{3 is} hydrogen or an alkali metal cation and

X is sulfur or -SO) and their (lower alkyl) -COO- (lower alkyl) esters, salts thereof, and hydrates of the compounds of formula (I), esters and salts thereof. The term "lower alkyl" contains up to 4 carbon atoms.

R ¹ pl. may be a group of the formula -CH ₂ SR ⁵ wherein R ⁵ is e.g. 1-methyltetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo- triazin-3-yl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-aza-triazin-3-yl, or 1,2,5,6-tetrahydro-2-methyl-5, 6-dioxo-triazin-2-yl and the like. may.

In addition to hydrogen, R ^{2 is} lower alkyl (e.g., C 1-4 alkyl such as methyl, ethyl, η-propyl, isopropyl, n-butyl) or R ^{3 is} OCO- (lower alkyl). may also be represented by the group where R ³ is hydrogen or an alkali metal cation. The above reports are discussed in more detail below.

R ³ OCO (lower) alkyl group at the carboxyl groups are bonded to any site of the alkyl chain. This group is e.g. 1-carboxyethyl, 2-carboxyethyl, 1-carboxy-1-methylethyl, 2-carboxy-1-methylethyl, 1-carboxy-1-methyl-n-propyl, carboxy methyl group, etc. Preferably 1-carboxy-1-methylethyl.

The lower alkanoyloxy-lower alkyl esters of the compounds of formula I, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters and the like. They are.

Salts of the compounds of formula I, e.g. alkali metal salts (e.g. sodium or potassium salts), ammonium salts, alkaline earth metal salts (e.g. calcium salts), organic bases (e.g. amines such as N-ethylpiperidine, procaine, dibenzylamine, Ν, Ν salts with '-dibenzylethylenediamine, alkylanilines or dialkylamines, etc.) or amino acids (e.g., arginine or lysine, etc.). The salts may be mono- or di-salts. Additional salt formation of the hydroxyl group in R ⁵ is a heterocylic group substituted by a hydroxyl group, and R ² is R ³ OCO- (lower alkyl) carboxyl groups in participating.

The compounds of formula I further form salts with addition salts with organic or inorganic acids. Of these salts, e.g. hydrogen halides, e.g. hydrochlorides, hydrobromides or hydroiodides), salts with other mineral acids (e.g. sulfates, nitrates, phosphates, etc.), alkyl and mono-aryl sulfonates (e.g. and salts with other organic acids (e.g., acetates, tartrates, maleates, cephrates, benzoates, salicylates, ascorbates, etc.).

The compounds of formula I, including their salts, also readily hydrolyzable esters thereof, may be hydrated. Hydration may occur during the manufacturing process or may be due to the hygroscopic properties of the initially anhydrous product.

The compounds of the present invention may be in the form of the isomers represented by the general formula (A) or the anti-isomers represented by the general formula (B) or a mixture of the two isomeric forms. Preferably, the isomeric forms and mixtures containing predominantly the isomeric forms.

Particularly preferred compounds of formula I are the following derivatives: (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3- {[(2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-triazin-3-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct. -2-ene-2-carboxylic acid;

(6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3 - {[(2,5-dihydro-6-hydroxy) -2-Methyl-5-oxo-aza-triazin-3-yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; 5-oxide; (6R, 7R) -7- [2- (2-amino-4-szelenazoIil) -2 - ((Z) -methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-l- azabicyclo [4.2 to] oct-2-ene-2-carboxylic acid; (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-l- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, pivaloyloxymethyl ester; (6B, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxy-amino) -acetamido] -3 - {[(5-methyl-1,3, 4-thiadiazol-2-yl) -io] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene-2-carboxylic acid;

(6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3 - {[(l-methyl-lH-tetrazol-5 yl) thio] -: N-ethyl} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

(6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -8-oxo-3 - {[(1,4, 5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -5-thia-l-azabicyclo [4.2.0] oct-2-ene 2-carboxylic acid;

(6R, 7R) -3- (acetoxymethyl) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

(6R, 7R) -3- (acetoxymethyl) -7 - {(Z) -2- (2-amino-4-szeIenazoIil) -2 - [(l-carboxy-l-methylethoxy) imino] acetamido} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

l - {[i6R, 7R) -7- (Z) -2- (2-Amino-4-selenazolyl) -2 - [(l-carboxy-l-methylethoxy) imino] acetamido] -2- carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl} pyridinium hydroxide (inner salt) and salts thereof, and hydrates of these compounds or salts thereof.

The process of the present invention is characterized in that

a) reacting a compound of formula II (wherein R ¹ , R ² and X are as defined above; Hal is halogen and the carboxyl group may be in protected form) or a salt thereof with a selenium urea and optionally protecting group on the carboxyl group; with the exception of (lower alkyl) -COO- (lower alkyl); obsession

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b) a compound of formula III (wherein R ¹ , R ² and X are as defined above; R is a cleavable protecting group and the carboxyl group may be in protected form) or a salt thereof, and a protecting group optionally present on the carboxyl group; except for (lower alkyl) -COO- (lower alkyl); obsession

c) for the preparation of compounds of formula I wherein R ¹ is -CH ₂ -SR ⁵ (wherein R ⁵ is lower alkyl, hydroxy and / or oxo-substituted triazinyl, lower alkyl-substituted thiadiazolyl, or lower carbon); alkyl-substituted tetrazolyl and R ² and X are as defined above) a compound of Formula IV (wherein R ² and X are as defined above; Z is halogen, lower alkanoyloxy, lower alkyl or aryl); sulfonyl oxivagy azido group and the carboxyl group may be protected formed with an inorganic or tertiary organic base salt) or its salt in presence of water (V), thiol of the formula (R ⁵ is as defined above) and, optionally, wherein optionally the carboxyl group optionally present in protect cleaving the group;

and optionally subjecting a compound of formula (I) thus obtained to one or more of the following conversions: In the preparation of compounds of formula (I) wherein X is -SO- (wherein R ¹ and R ² are as defined above), Oxidizing a compound of formula (I) wherein X is sulfur (wherein R ¹ and R ² are as defined above) or a salt thereof; and / or in the preparation of (lower alkyl) -COO- (lower alkyl) esters of the compounds of formula (I), a carboxylic acid of formula (I) is esterified; and / or in the preparation of salts or hydrates of the compounds of formula (I) or hydrates of the salts, the resulting compound of formula (I) is converted to a salt or hydrate or a salt to a hydrate.

The carboxyl group in the 3-position of the starting materials of formula (II) and (III) may be optionally protected e.g. readily cleavable esters, e.g. in the form of silyl esters (e.g. trimethylsilyl esters).

Other readily hydrolyzable esters discussed above may also be formed to protect the carboxyl group. The carboxyl group may also be protected by salt formation with inorganic or tertiary organic bases (e.g. triethylamine).

In process (a) of the present invention, a halide of formula II or a salt thereof is reacted with selenium urea, preferably in an inert solvent (e.g., a lower alkanol, such as ethanol, or a lower ketone, such as acetone, or ether, such as tetrahydrofuran or dioxane; dimethylformamide, dimethylacetamide, water or a mixture of the above solvents). The reaction was allowed to proceed for approx. It can be carried out at a temperature of 0 to 60 ° C, preferably at room temperature. The halide of formula (II) may be used as the corresponding chloride, bromide, fluoride or iodide, preferably chloride or bromide. The compound of formula (II) may be used in the form of the free carboxylic acid or its salt; the salt of the compound of formula (II) may be one of the salts of the compound of formula (I).

After process (aa), the protecting group which may be present in the reaction product may be cleaved, if desired. The silyl protecting group (silyl ester) is particularly easily cleaved by aqueous treatment. The lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably enzymatically utilized by the appropriate esterase. preferably approx. It can be cleaved at 20-40 ° C. The carboxylic acid may be liberated from the protected carboxyl group (e.g., triethylamine salts) by acid treatment. This acidic treatment is e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

In the compounds of formula (III) used as starting material in process (b) of the present invention, R, e.g. it may be a protecting group which can be cleaved by acid hydrolysis (e.g. tertiary butoxycarbonyl or trityl group) or a basic group which can be cleaved by basic hydrolysis (eg trifluoroacetyl group, etc.). Preferably R is chloro, bromo or iodoacetyl, especially chloroacetyl. The latter protecting groups can be easily cleaved by treatment with thiourea.

The starting materials of the formula (III) are e.g. by acylation of the corresponding 7-amino compound by reacting a compound of formula (VI) (wherein X and R ¹ are as defined above and the carboxyl and / or amino group may be present in a protected form) with a compound of formula (VII). carboxylic acid of formula (where R and R ² are as defined above), or reacted with a reactive functional derivative thereof, and if desired, splitting off optionally at the carboxy group optionally present protecting group.

The carboxyl group in the 7-amino compound of formula (VI) may be optionally protected as described for compounds of formula (II), (III) and (IV). The amino group in the compounds of formula III is e.g. silyl protecting group (e.g., trimethylsilyl).

As a reactive functional derivative of the carboxylic acids of formula VII, e.g. an acid halide (e.g. acid chloride, acid bromide or acid fluoride), an azide, an anhydride (especially mixed anhydride with a stronger acid), a reactive ester (e.g. N-hydroxysuccinimide ester) or an amide (e.g. imidazolid) can be used.

The reaction of the 7-amino compound of formula VI with the carboxylic acid or reactive functional derivative of formula VII can be carried out in a manner known per se. so e.g. by reacting a free carboxylic acid (VII) with an ester (VI) in the presence of a carbodiimide (e.g., dicyclohexylcarbodiimide) in an inert solvent (e.g., ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene). or dimethylformamide) and then the ester group is cleaved. Cxazolium salts (e.g. N-ethyl-5-phenylisoxazolium-3'-sulfate) can be used as condensing agents instead of carbodiimides.

Alternatively, a salt of a carboxylic acid of formula (VI) (e.g., a trialkylammonium salt such as a triethylammonium salt) may be reacted with a derivative of a carboxylic acid of formula (VII) as described above. e.g. in a solvent as listed above).

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Alternatively, an acid halide (e.g., an acid chloride) of a carboxylic acid of formula VII can be reacted with an amine of formula VI.

The reaction is preferably carried out in the presence of an acid acceptor. As an acid binder, e.g. an aqueous alkali metal hydroxide solution (e.g. sodium hydroxide), an alkali metal carbonate (e.g. potassium carbonate) or lower alkyl amines (e.g. triethylamine) may be used. Preferably, the solvent is water or a mixture of water and an inert organic solvent such as tetrahydrofuran or dioxane. Aprotic organic solvents (e.g. dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, etc.) may also be used as the reaction medium. When using silylated starting materials of formula (VI), anhydrous media are employed.

The 7-amino compounds of formula (VI) are also conveniently reacted with the compounds of formula (VII) or their reactive functional derivatives. -40 ° C to room temperature, preferably approx. It can be carried out at 0-10 ° C.

Compounds of formula (III) wherein R ¹ is a group -CH ₂ SR ⁵ and R is a non-monohalogenated group (e.g., chloro, bromo or iodoacetyl) can be prepared by thiolation such that A compound of Formula VIII (wherein X and R ² are as defined above, R 0 is R, but may not represent a monohalogenated group; Z is a leaving group and the carboxyl group may be protected in the form of an inorganic or organic tertiary organic salt) the presence of water (V) thiol of formula (wherein R ⁵ is as defined above) and, if desired, splitting off optionally at the carboxy group optionally present protecting group.

The leaving group at Z is e.g. halogen (e.g. chloro, bromo or iodo), acyloxy (e.g. lower alkanoyloxy such as acetoxy; lower alkyl or arylsulfonyloxy such as mesyloxy or tosyloxy) or azido .

The reaction of a compound of formula VIII with a thiol of formula V is known in the art, e.g. at about 40-80 ° C, preferably about 40 ° C. 60 ° C in water or approx. 6-7, preferably ca. This may be done in pH 6.5 buffer. The carboxyl group in the resulting compound of formula (III) may be optionally protected, e.g. by salt formation or esterification.

R ¹ is a compound of formula ₂ SR ^L group of formula (VI) may be prepared by reaction of a -CH the formula (IX) with a compound of formula (wherein X is as defined above and Z is a leaving group and the carboxyl group of inorganic or in the form of a salt with a tertiary organic base may be reacted with a thiol (V) in the presence of water. The reaction may be carried out under the conditions described for the reaction of compounds of formula VIII and V. The compounds of formula (VIII) may also be prepared by reacting a compound of formula (IX) with a carboxylic acid of formula (VII) or a reactive functional derivative thereof under the conditions described for the reaction of compounds of formula (VI) and (VII).

The carboxyl and / or amino group in the compounds of formula (VI) may be protected, if desired, e.g. esterification or salification or silylation of the carboxyl group.

The carboxylic acids of formula (VII) are pi. by reacting a compound of Formula X (wherein R ² and Hal are as defined above and R ⁶ is lower alkyl, preferably methyl or ethyl) with selenium urea; the reaction may be carried out under the conditions described for the reaction of compounds of formula II with selenium urea. The amino group of the compound of formula XI thus obtained (wherein R ² and R ⁶ are as defined above) is preferably protected by reaction with the corresponding halide of formula R-Hal followed by the resulting compound of formula XII (wherein R , R ² and R ⁶ are as defined above), the ester group of R ^{6 is} saponified by treatment with acid or base. The carboxylic acid (VII) thus obtained can be converted into its reactive derivatives by methods known per se.

The thiols of formula (V) are in tautomeric equilibrium with the corresponding thions. The ether group of the thiols (hon) etherified at the 6-position can generally be introduced by reacting an S-protected thiol (e.g., a benzhydride protected thiol) with a suitable ether-containing halide, preferably iodide, in an inert organic solvent, such as potassium carbonate. ) in the presence of ca. 10-50 ° C, and then deprotecting; the benzhydryl group can be removed with anisole and trifluoroacetic acid at room temperature.

Process b) of the present invention involves the removal of a protecting group R in a compound of formula III. The protecting groups which can be cleaved by acid hydrolysis are preferably removed by treatment with lower alkanecarboxylic acids or halogenated lower alkanecarboxylic acids. Formic acid or trifluoroacetic acid is particularly preferably used for this purpose. The reaction is usually carried out at room temperature, but may be carried out at slightly lower or higher temperatures, e.g. approx. 0-40 ° C. Generally, the deprotected protecting groups may be removed by treatment with dilute aqueous alkali metal hydroxide at 0-30 ° C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups are treated with thiourea in an acidic, neutral or alkaline medium for ca. It can be removed at 0-30 ° C. The protecting group cannot be removed by hydrogenolysis (e.g. in the case of a benzyl group) because during hydrogenolysis the oxime group would be reduced to an amino group.

The optional carboxyl protecting group may be cleaved in a manner analogous to that described in process a). The protecting group on the carboxyl group may be removed before the R protecting group is cleaved.

The compounds of formula (IV) used in process (c) of the present invention may be prepared by cleavage of the protecting group R on an amino group in a compound of formula (VIII). The reaction may be carried out in the manner detailed for the cleavage of the amino protecting group R in the compounds of formula (III).

In the compounds of formula (IV), the leaving group at Z is e.g. a halogen atom (e.g. chlorine, bromine or iodine), an acyloxy group (e.g. lower al-4184969 cananyloxy group such as an acetoxy group; a lower alkyl or arylsulfonyloxy group such as mesyloxy or tosyloxy) or an azido group.

The reaction of a compound of formula (IV) with a thiol of formula (V) is carried out in a manner known per se, e.g. at about 40-80 ° C, preferably about 60 ° C, in water or about 5 ° C. 6 — Ί, preferably

This may be done in a powder of pH 6.5. The optional carboxyl protecting group may be cleaved as described in process a). 10

A compound of formula (I) wherein X is a sulfur atom obtained by process a), b) or c) or a salt thereof can be oxidized to the corresponding derivative X where it is -SO- by organic or inorganic oxidants. Oxidizing agents include compounds capable of delivering oxygen easily, e.g. organic peroxides, e.g. monosubstituted organic peroxides, e.g. C1-4 alkyl or alkanoyl hydroperoxides, such as, e.g. t-butyl hydroperoxides, peracetic acid, peracetic acid; and phenyl-substituted derivatives of the aforementioned hydroperoxides, such as, e.g. cumene hydroxy peroxide, perbenzoic acid and the like.

The phenyl substituent may optionally carry further lower groups (eg, C 1-4 alkyl or alkoxy), halogen or carboxyl groups, such as, e.g. 4-methyl-perbenzoic acid, 4-methoxy-perbenzoic acid, 3-chloro-perbenzoic acid, mono-perphthalic acid. In addition, various inorganic oxidizing agents, e.g. hydrogen peroxide, ozone; permanganates, e.g. sodium or potassium permanganate; hypochlorites such as sodium, potassium or ammonium hypochlorite; peroxymmonic and peroxydic sulfuric acids. The oxidation is particularly preferably carried out with 3-chloroperbenzoic acid. The oxidation is preferably carried out in an inert solvent. As reaction medium, e.g. aprotic inert solvents (e.g. tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate or acetone) or protic solvents (e.g., water, lower alkanols such as methanol, ethanol, or optionally halogenated lower alkanecarboxylic acids, such as formic acid, acetic acid or trifluoroacetic acid). The reaction is usually carried out for approx. -20 ° C and approx. It can be carried out at temperatures of + 50 ° C.

When the oxidizing agent is used in an equimolar amount or a small excess of the compound of formula I wherein X is sulfur 45, the corresponding sulfoxide of formula I wherein X is -SO- is obtained. 50

The (lower alkyl) -COO- (lower alkyl) esters of the carboxylic acids of formula (I) may be prepared by reacting a carboxylic acid of formula (I) preferably with a halide containing the appropriate ester group, in particular iodide. The reaction can be accelerated by addition of a base (e.g., alkali metal hydroxides or carbonates or organic amines, e.g. triethylamine). The corresponding halide is preferably used in excess. The esterification is preferably carried out in an inert organic solvent (e.g. dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide, or preferably dimethylformamide). The reaction temperature is ca. 0-40 ° C.

Salts and hydrates of the compounds of formula (I), 65 and 65, respectively. the hydrates of the salts may be prepared by reacting a carboxylic acid of formula (I) with an equivalent amount of a suitable base, conveniently in a suitable solvent (e.g. water or organic solvent such as ethanol, methanol, acetone, etc.). Two, respectively. using three equivalents of base on the hydroxy group in the 3-position optionally substituted hydroxy group of the hydroxy group; the carboxy (lower) alkyl group at the R ² site also has salt formation and di- or tri-salt is obtained. The temperature at which the salt is formed is not critical and is usually carried out at room temperature or at slightly lower or higher temperatures, about 0-50 ° C.

The formation of hydrates during the production process is generally automatically spontaneous due to the hygroscopic properties of the initially anhydrous compounds. Targeted preparation of the hydrates may be accomplished by the step of completely or partially anhydrous the product (carboxylic acid of formula (I)). ester or salt] ca. It is exposed to a humid atmosphere at a temperature of 10-40 ° C.

The resulting mixture of color and anti-forms of the compounds of formula (I) may be separated into the corresponding color and anti-forms by conventional means. The separation can be done e.g. by recrystallization or chromatography, suitable solvents; solvent mixtures.

The compounds of formula (I) and (III), their easily hydrolyzable esters and their salts, respectively. the hydrates of these compounds have antibiotic activity, especially bactericidal activity. These compounds are active against Gram-positive and Gram-negative microorganisms, including β-lactamase-forming Staphylococci, Streptococci and various β-lactamase-forming Gram-negative bacteria, e.g. Pseudomonas aeruginosa, Escherichia coli,

Strains of the species Serratia marcescens, Proteus and Klebsiella are effective in a broad spectrum of activity.

The compounds of formula (I) and (III) and their corresponding lower alkyl-COO-lower alkyl esters, their salts and their corresponding salts. hydrates of these products can be used in medicine to treat and prevent infectious diseases. The daily dose of the active ingredient in adults is about 0.1-2 g. The pharmaceutical compositions prepared from the novel compounds of the present invention are particularly preferably administered parenterally.

The antimicrobial activity of the novel compounds of the present invention is demonstrated by assays with the following test compounds:

Compound A = (6R, 7R) -7- [2-2-amino-4-selenazolyl) -2- (Z) -methoxyimino) -acetamido] -3 - {[(1-methyl-1H-tetrazole) 5-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt;

Compound B = (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3 - {[(5-methyl-1, 3,4-thiadiazol-2-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt;

Compound C = (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3 - {[(2,5-dihydro-) 6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene-2 carboxylic acid, disodium salt;

Compound D = (6R, 7R) -3- (acetoxymethyl) -7- [2- (2-amino-4-5184969)

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Intravenous activity test compound was administered twice, 1 and 3 hours after infection. The test compound is subcutaneously glazed in various doses of alkaline saline and 50% of the test animals are assayed by groups of 5 pathogens, provided that no other dose is given in the table ( _CDS0 , mg). / kg) is infused intraperitoneally with suspensions of the probit method. It's ours. The number of surviving animals is determined on day 4.

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The toxicity of some representatives of the new chemical compounds of the present invention is given in the following table:

Method of administration

s. c. p. 0th The final product of Example 6 > 4000 > 5000 10 B (final product of Example 5) > 4000 > 5000 C (final product of Example 1) > 4000 > 5000 D (final product of Example 8) > 4000 > 5000 E (final product of Example 2) > 4000 > 5000 F (final product of Example 3) > 4000 > 5000 15 G (final product of Example 7) > 4000 > 5000 H (final product of Example 4) > 5000

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The novel compounds of the present invention may be formulated in pharmaceutical compositions containing the active ingredient and carriers suitable for enteral or parenteral administration, in organic or inorganic inhalers. As a carrier, e.g. water, gelatin, gum arabic, lactose, gum opener, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and the like. It can be used. The active ingredient may be formulated in solid (e.g., tablet, dragee, suppository, capsule) or liquid (e.g., solution, suspension or emulsion) form. The compositions may optionally be sterilized or reconstituted. excipients (e.g., preservatives, i.e., stabilizers, wetting or emulsifying agents, salts for altering the osmotic pressure, local anesthetics or buffers) and / or other pharmaceutically acceptable substances. The compounds of the formula I, their salts and the like can be used. their hydrates may preferably be used in the form of parenteral formulations and may be prepared in the form of lyophilisates or dry ampoules, which may be diluted with conventional agents (e.g. water or isotonic sodium chloride solution) before use. The compounds of formula (I) are readily hydrolyzable esters, respectively. ethers, salts of these chemicals or hydrates thereof may also be used in the form of enteral (e. g., oral) formulations.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - [(Z) -methoxyimino) acetamido] -3 - {[(2,5-dihydro-) 6-Hydroxy-2-methyl-5-oxo-aza-triazin-3-yl) -thio] -methyl} -8-oxo-555-thia-1-axabicyclo [4.2.0] oct-2-ene-2 Preparation of disodium salt of carboxylic acid

11.55 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6-hydroxy) -2-methyl-560-oxo-aza-triazin-3-yl) thio] methyl} -8-oxo-5-thiaazabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 160 ml ethanol and 25 g of selenium urea were added at 25 ° C. The reaction mixture was stirred for 1.5 hours at 25 ° C under nitrogen with the exclusion of light; initially, a tan-like substance is precipitated which subsequently crystallizes.

-8184969

The crystalline hydrobromide was filtered, washed with ethanol and low-boiling petroleum ether and dried under vacuum at 40 C ^r. The red hydrobromide of the title compound is obtained which is dissolved in a mixture of 4.5 g of sodium acetate trihydrate in 35 ml of water and 35 ml of acetone to convert it to the disodium salt. To the resulting solution was added acetone (35 mL) until it became cloudy. Filter the small amount of insoluble reddish selenium through a pleated filter. Acetone (15 mL) was added to the orange filtrate. The excellent oil-resin material is filtered through a pleated filter and discarded. Crystallization of the disodium salt from the yellow filtrate is started by rubbing with a glass rod. The mixture was allowed to crystallize for one hour and then the crystallized mixture was allowed to crystallize for about 1 hour until the crystallization was complete. Acetone (50 mL) was added dropwise over 1 hour. The precipitated crystals are filtered off, washed with 50 ml of 85:15 acetone-water and low boiling petroleum ether and dried overnight in vacuo at 25 ° C. The title compound is obtained in the form of a pale beige color, Md = ~ 139 ° (c = 0.5, water). The nuclear resonance spectrum and the microanalysis correspond to the given structure. The product contains 3.5 moles of crystalline water.

The starting material used is (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-aza-triazin-3-yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid can be prepared as follows:

Acetic acid tert-butyl ester (592.1 g) was dissolved in glacial acetic acid (560 ml). The solution is heated to 9-10 ° C for 2.5 hours

A solution of 290.6 g of sodium nitrite in 635 ml of water is added dropwise. The resulting yellow slurry was stirred for 30 minutes at 20 ° C, then mixed with 940 ml of water and stirred for a further 2 hours. The mixture was mixed with water (900 mL) and ice (900 g) and extracted with ethyl acetate (3 x 1 L) in a stirrer. The combined ethyl acetate extracts were washed with water (3 x 1 L), mixed with water (5 L), and adjusted to pH 6.8 with sodium bicarbonate. The separated aqueous phase was washed once with water and the ethyl acetate solution was dried over sodium sulfate and concentrated in vacuo at 40 ° C. The (Z) -2-hydroxyimino-3-oxo-butyric acid tert-butyl ester is obtained in the form of a yellow oil which is dried under high vacuum at 40 ° C for 9 hours.

626.65 g of (Z) -2-hydroxyimino-3-oxo-butyric acid tert-butyl ester are dissolved in 2.86 L of acetone. The solution was cooled to 5 ° C and 703.5 g of potassium carbonate was added portionwise. To the yellow slurry, 322 ml of dimethyl sulfate was added dropwise over 1 hour without cooling, so that the temperature of the mixture did not rise above 25 ° C. The light beige suspension is stored at 20-25 ° C for approx. Stir for 4 hours until starting material is no longer detectable by thin layer chromatography. The mixture was poured into water (7 L) and extracted with ethyl acetate (3 x 1 L). The combined ethyl acetate extracts were washed with water (3 x 1 L), dried over sodium sulfate and concentrated in vacuo at 40 ° C. The residual yellow oil was dried under gentle vacuum at 40 ° C for 5 hours and then evaporated. The (Z) -2- (methoxyimino) -3-oxo-butyric acid tert-butyl ester was obtained as a yellow oil, b.p. 57 ° C / 0.02 mmHg.

g of (Z) -2- (methoxyimino) -3-oxo-butyric acid tert-butyl ester is dissolved in 400 ml of trifluoroacetic acid. The solution was allowed to stand at 25 ° C for 1 hour and then concentrated in vacuo at 35 ° C. The oily residue was crystallized from ether / petroleum ether. Yield: (Z) -2- (methoxyimino) -3-oxo-butyric acid as a yellowish, water-soluble melting point at 80 ° C.

145 g of (Z) -2- (methoxyimino) -3-oxo-butyric acid are dissolved in 1000 ml of alcohol and anhydrous dichloromethane. To the solution was added 10 ml of 30% glacial acetic acid hydrobromic acid. Then, after approx. A solution of bromine (37.5 ml) and dichloromethane (112.5 ml) was added dropwise over 2 hours while the temperature of the reaction mixture was gently cooled to 20-25 ° C. The reaction mixture is then purged with a stream of nitrogen to remove hydrogen bromide. Then, 250 g of ice, 250 ml of water and 2 liters of ether were successively added. The aqueous phase was separated and discarded. The organic layer was washed with water (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated in vacuo. The residual brown oil was crystallized from carbon tetrachloride. Almost colorless (Z) -4-bromo-2- (methoxyimino) -3-oxo-butyric acid is obtained.

(7R) -7-Amino-3-deacetoxy-3- [2,5-dibydro-6-hydroxy-2-methyl-5-oxo-triazin-3-yl] thio] -ephephalosporanic acid (37.1 g) It is suspended in 800 ml of ethyl acetate and 100 ml of N, O-bis (trimethylsilyl) acetamide are added. The mixture was stirred for 30 minutes at 25 ° C with the exclusion of moisture until a light yellow solution was formed. To the solution thus obtained cooled to -10 ° C, 22.4 g of (Z) -4-bromo-2- (methoxyimino) -3-oxobutyric acid and 20.8 g of phosphorus pentachloride in 300 ml of alcohol are added. and a solution of (Z) -4-bromo-2- (methoxyimino) -3-oxobutyric acid chloride prepared by reacting it in anhydrous dichloromethane at -10 ° C to 0 ° C. The reaction mixture was stirred for 30 minutes at 0-5 ° C and for 1 hour at 25 ° C. Then 1 liter of ethyl acetate and 500 ml of water were added with stirring. The aqueous phase and the resinous intermediate layer were discarded. The organic layer was washed with water (6 x 500 mL), dried over sodium sulfate and concentrated to 200 mL under vacuum at 40 ° C. The resulting orange concentrate was added dropwise to 1.8 L of ether while stirring. The precipitated amorphous reaction product was filtered, washed successively with 1 liter of ether and 1 liter of low-boiling petroleum ether and dried overnight in vacuo at 35 ° C. As a beige colored amorphous substance, (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene-2-carboxylic acid \ at gives [a] | f = -223, Γ (C = 1, methanol).

Example 2 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3 - {[(2,5-dihydro-) 6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene-2 -Carboxylic acid 5-oxide disodium salt

5.93 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 5-Oxide was suspended in a mixture of 30 ml of water and 30 ml of acetone, and 4.5 g of sodium acetate trihydrate was added, followed by 1.35 g of selenium urea. The reaction mixture was stirred for 30 minutes at 25 ° C. The small amount of insoluble reddish material is filtered through a pleated filter. Acetone (15 mL) was added to the orange filtrate until turbid, whereupon the reaction product crystallized immediately. The mixture was stirred for an additional 15 minutes

The crystalline solid -9184969 was filtered off, washed with 50 ml of 85:15 acetone-water, acetone and low-boiling petroleum ether and dried under vacuum at 25 ° C. The resulting beige crude title compound was dissolved in water (30 mL) for recrystallization. Filter the small amount of insoluble selenium on a pleated filter. Acetone was added to the filtrate until turbid, whereupon the disodium salt crystallized immediately. The mixture was stirred for an additional 15 minutes, the disodium salt was filtered off, washed with 50 ml of 85:15 acetone-water, acetone and low-boiling petroleum ether and dried overnight under a gentle vacuum at 40-45 ° C. The product was left in the air for 1 hour to maintain a constant water content. The title compound is obtained as a beige crystalline solid, [z] q -117.5 ° (c = 0.8 in water). The nuclear resonance spectrum and the microanalysis correspond to the given formula. The product contains 6 moles of water.

The starting material used is (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 5-oxide can be prepared as follows:

17.31 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-aza-triazin-3-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.] oct-2-ene-2-carboxylic acid in 170 ml of ethanol and dissolved in 6.1 g of 85% 3-chloroperbenzoic acid in portions over 45 minutes. The reaction product precipitates. The reaction is slightly exothermic and the temperature rises from 25 ° C to 30 ° C. After the addition of an additional amount of oxidizing agent, the reaction mixture was stirred for about 15 minutes. Stir at 25 ° C. The excellent product is filtered off, washed with a little ethanol, ether and low-boiling petroleum ether, and vacuum dried to ca. Dry at 40 'C. Fraction I of the desired product is obtained. The mother liquor was vigorously concentrated in vacuo at 40 ° C. The crystallization material is filtered off, washed with a little ethanol, ether and low boiling petroleum ether and dried in vacuo at 40 ° C. Part II containing the desired product. fraction. The combined Annexes I and II. fraction was dissolved in methanol (100 mL) for purification. The solution was diluted with 900 mL of ethanol. A small amount of insoluble material was filtered off and the yellow filtrate was concentrated in vacuo at 40 ° C. The precipitated material is filtered off, washed with a little ethanol, ether and low-boiling petroleum ether. The title compound is obtained in the form of a beige solid, [α] D = -244 ° (c = 0.9, methanol). To obtain recrystallization and high purity, 10 g of the product thus obtained are dissolved in 50 ml of acetone. The product crystallizes immediately from solution. The precipitated crystals are filtered off, washed with acetone and low-boiling petroleum ether and dried overnight in a gentle vacuum at 40-45 ° C. The resulting beige-colored pure had a rotation of λmax-249.2 ° (c = 1, methanol). The product has a nuclear resonance spectrum and microanalysis as shown.

Example 3 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3-methyl-8-oxo-5-thia Preparation of -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt

8.4 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3-methyl-8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is suspended in 160 ml of ethanol and mixed with 2.7 g of selenium urea. The reaction mixture was stirred at 25 ° C for 1 hour under nitrogen and without light. The resulting solution is filtered through a pleated filter to remove boiling insoluble selenium. The resulting yellow filtrate was combined with 22 ml of 2N ethyl acetate-2-ethyl caproic acid sodium salt solution; a pink cephalosporin sodium salt is precipitated. Methanol (160 mL) was added and an orange solution was again formed which was filtered through a pleated filter to remove the finely divided red selenium. The yellow filtrate was mixed with 160 mL of ethanol and vacuum dried at 40 ° C for ca. Concentrate to 100 ml. The crystalline material is filtered off, washed with ethanol and low boiling petroleum ether. Fraction I containing the title compound was obtained. The mother liquor and the ethanol used for the washing were evaporated again, and a new material crystallized out which was filtered and washed with ethanol and low-boiling petroleum ether. The title compound containing II. fraction. For cleaning purposes the combined

I and II. The fractions were dissolved in methanol (100 mL), diluted with ethanol (400 mL), filtered through a pleated filter with a small amount of finely divided red selenium and the filtrate was concentrated in vacuo at 40 ° C. The crystallization material is filtered off, washed with ethanol and low-boiling petroleum ether and dried overnight under high vacuum at 40-45 ° C. The resulting beige pure material had a Mn = +87 (c = 1, water). The nuclear resonance spectrum and the microanalysis correspond to the given structure.

The starting material used is (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3-methyl-8-oxo-5-thia-1-. Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid can be prepared as follows:

a) Silylation of 7-amino-deacetoxycephalosporanic acid

6.7 g of 7-amino-deacetoxycephalosporanic acid are suspended in 400 ml of ethyl acetate and mixed with 50 ml of N, O-bis (trimethylsilyl) acetamide. With the moisture excluded, the mixture is heated to about 35-40 ° C for approx. Stir for 45 minutes The resulting light yellow solution is cooled to -10 ° C to -15 ° C and stored under humidity until use in the acylation reaction.

b) Preparation of (Z) -4-bromo-2- (methoxyimino) -3-oxo-butyric acid chloride

11.2 g of (Z) -4-bromo-2- (methoxyimino) -3-oxo-butyric acid

In 150 ml of methylene chloride, 10.4 g of phosphorus pentachloride are added at 0-5 ° C. The resulting solution was stirred at 0-5 ° C for 15 minutes and then without cooling for 45 minutes.

(c) Acylation and processing

The acid chloride solution prepared in (b) is ca. It is added dropwise over 30 minutes at -10 ° C to the silylated 7-aminodeacetoxycephalosporanic acid solution prepared in (a). The reaction mixture was stirred at -10 ° C to 0 ° C for 30 minutes, then for about 30 minutes. Stir for 1.5 hours at 25 ° C. The reaction mixture was poured into 500 ml of water and 1000 ml of ethyl acetate. The organic phase

Wash with 4 x 500 mL water, dry over sodium sulfate 11

-10184969 and concentrated in vacuo at 40 ° C. The crystallization reaction product is filtered off, washed with ethyl acetate, ether and low-boiling petroleum ether and dried in vacuo at 40 ° C overnight. White pure crystalline material, statically charged, [α] D = + 86.8 ° (c = 1, dimethylformamide). The nuclear resonance spectrum and microanalysis correspond to the structure given.

Example 4 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3-methyl-8-oxo-5-thia Preparation of -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester

2.33 g of (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3-methyl-8-oxo-5 Dissolve the sodium salt of thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 25 ml of dimethylformamide.

The solution is cooled to 0-5 ° C and mixed with 2.24 g of pivaloyloxymethyl iodide under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at 0-5 ° C and then poured into 500 ml of water. The aqueous solution was extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (2 x 100 mL), 5% sodium bicarbonate (2 x 200 mL), water (1 x 100 mL), dried over sodium sulfate and concentrated in vacuo at 40 ° C. To the residue is added low boiling petroleum, the excellent amorphous reaction product is filtered off and washed with low boiling petroleum. The resulting yellowish amorphous reaction product is purified by chromatography on silica gel, eluting with ethyl acetate. Fractions containing the title compound were combined and concentrated in vacuo at 40 ° C. After purification from a mixture of ethyl acetate and low-boiling petroleum ether, the title compound was obtained as a light beige colored solid, mp = +64.8 ° (c = 1.07, ethyl acetate). The nuclear resonance spectrum and microanalysis correspond to the structure given.

Example 5 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3 - {[(5-methyl-1, Preparation of 3,4-Thiadiazol-2-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt

5.5 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(5-methyl-1,3,4) -thiadiazol-2-yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 80 ml of ethanol and 1.35 g of selenium are added. urea. The reaction mixture was stirred at 25 ° C for 1.5 hours under nitrogen and without light. A resinous substance is precipitated. Methanol (300 mL) was added and the resulting solution was treated with 2N ethyl acetate-2-ethyl caproic acid sodium salt solution. Filter off a small amount of brown sludge. The yellow-brown filtrate was stirred for 30 minutes at 25 ° C with charcoal and then filtered. The light yellow filtrate was diluted with 500 mL of ethanol and vigorously concentrated in vacuo at 40 ° C. The crystallization material is filtered off, washed with ethanol and low-boiling petroleum ether and dried under high vacuum at 40 ° C overnight. The title compound is obtained in the form of a beige pure substance, [α] D = -53.4 ° (c = 1, water). The nuclear resonance spectrum and microanalysis correspond to the structure given.

The starting material used is (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3- {η 5 -methyl-1,3,4 -thiadiazol-2-yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is prepared in a manner analogous to that described in Example 1. color in the form of an amorphous material having a nuclear resonance spectrum consistent with the structure shown.

Example 6 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) acetamido] -3 - {[(1-methyl-1 H- Preparation of tetrazol-5-yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt

10.7 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(1-methyl-1H-tetrazole-5) -yl) thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 160 ml of ethanol and 2.7 g of selenium at 25 ° C. urea. The reaction mixture was stirred for 1 hour at 25 ° C under nitrogen and with the exclusion of light, with the formation of a resinous substance. Methanol (200 mL) was added and the resulting solution was treated with 2N ethyl acetate-2-sodium caproic acid (22 mL). The desired compound is partially precipitated. An additional 200 mL of methanol was added and the little insoluble reddish selenium was filtered off. Ethanol (200 mL) was added to the filtrate until cloudiness began and concentrated under vacuum at 40 ° C. After 200 ml of distillate had passed, the precipitate was filtered off, washed with ethanol and low-boiling petroleum ether. The resulting fraction I was discarded. The mother liquor was concentrated in vacuo at 40 ° C and then evaporated. After collecting 250 ml of distillate, the precipitate was filtered off, washed with ethanol and low-boiling petroleum ether and dried under high vacuum at 45 ° C overnight. The obtained beige colored II. Fraction 1 is the title compound, [.alpha.] D = -22.1 DEG (c = 1, water). The nuclear resonance spectrum and microanalysis correspond to the structure given.

The starting material used is (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -3 - {[(1-methyl-1H-tetrazole-5) -yl) -thio] -methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is prepared in the form of a beige amorphous material in a manner analogous to that described in Example 1, [?] D ⁵ = -27.3 ° (c = l, methanol). The product has a nuclear resonance spectrum as defined.

Example 7 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -8-oxo-3 - {[(1,4, 5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -5-thia-l-azabicyclo [4.2 to] oct-2-ene-2-carboxylic acid - Preparation of the sodium salt

8.66 g of (6R, 7R) -7 - ([4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -8-oxo-3 - {[(1,4, 5,6-Tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl) thio] methyl} -5-thia-1-azabicyclo-11184969 [4.2.0] oct-2-ene The 2-carboxylic acid is suspended in 120 ml of ethanol and mixed with 2.03 g of selenium urea, and the reaction mixture is stirred for about 10 minutes to give a thick slurry, to which 120 ml of methanol is added, which results in a partial solution. The mixture was concentrated in vacuo at 40 DEG C. The reddish residue was dissolved in methanol (300 mL) and the small amount of insoluble selenium was filtered off, the filtrate was combined with 2N sodium acetate 2N ethyl acetate, and the cephalosporin sodium precipitated. The mixture was diluted with 1 liter of water and the insoluble material was filtered off, the yellow filtrate was mixed with 250 ml of ethanol and concentrated in vacuo at 40 DEG C. The excellent material was filtered off with ethanol and a low boiling pet. washed with rolether and dried in vacuo at 40 [deg.] C. The resulting beige crude product was purified by dissolution in 500 mL of methanol and 250 mL of ethanol. The cloudy solution was filtered through a pleated filter and the light yellow filtrate was concentrated in vacuo at 40 ° C. The precipitated material was filtered off and dried overnight under high vacuum at 40 ° C. The title compound is obtained in the form of a beige colored pure, m.p. = 37.6 ° (c = 1, water). The product has a nuclear resonance spectrum and microanalysis as shown.

The (6R, 7R) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido] -8-oxo-3 - {[(1, 4,5,6-Tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl) thio] methyl} -5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid is described in Example 1. in an analogous manner beige crystals prepared, [α] θ ⁵ = -141.7 ° (c = 0.9% in dimethylformamide).

Example 8 (6R, 7R) -3-Acetoxymethyl-7- [2- (2-amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -8-oxo Preparation of sodium salt of -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

4.8 g of (6R, 7R) -3- (acetoxymethyl) -7- [4-bromo-4 - ((Z) -methoxyimino) -3-oxobutyramido] -8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 25 ml of methanol and mixed with 1.35 g of selenium urea. The reaction mixture was stirred at 25 ° C for 1 hour under nitrogen and without light. 10 ml of 2N ethyl acetate-2-ethyl caproic acid sodium salt solution are then added. Filter the small amount of insoluble red selenium through a pleated filter. Approx. 150 ml of ethanol are added. The mixture was filtered through a pleated filter and the yellow filtrate was concentrated in vacuo at 40 DEG C., whereupon the cephalosporin sodium crystallized. The crystalline material is filtered off, washed with ethanol and low boiling petroleum ether and dried overnight under high vacuum at 40 ° C. The title compound was obtained as a beige colored pure, [α] D 20 = + 53.4 ° (c = 1, water). The nuclear resonance spectrum and the microanalysis correspond to the given structure.

The starting material used is (6R, 7R) -3- (acetoxymethyl) -7- [4-bromo-2 - ((Z) -methoxyimino) -3-oxobutyramido) -8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid was prepared in the same manner as in Example 1 as a beige crystalline solid, [α] D = + 59.1 ° (c = 1, methanol).

Example 9 (6R, 7R) -3-Acetoxymethyl-7 - {(Z) -2- (2-amino-4-selenazolyl) -2 - [(1-carboxy-1-methyl-ethoxy) - Preparation of disodium salt of imino] -acetamido} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid g (6R, 7R) -3- (acetoxymethyl) -7 - {2 - [(Z) - [1- (tert-Butoxycarbonyl) -1-methyl-ethoxy] -imino] -2- (2-tritylamino) -4-selenazolyl) -acetamido} -8-oxo The tert-butyl ester of -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is stirred with 400 ml of trifluoroacetic acid for 30 minutes at 25 ° C. The solution was concentrated in vacuo at 40 ° C. The remaining resin was treated with low boiling petroleum ether. The precipitated solid was filtered, washed with low boiling petroleum ether and dried overnight in vacuo at 40 ° C. An amorphous yellowish mixture is obtained which does not yet contain a complete decomposed material. For complete deprotection, the resulting isolated material was dissolved in a mixture of 160 mL of trifluoroacetic acid and 160 mL of 100% formic acid and stirred for 1.5 hours at 40 ° C. The residue was stirred with 500 ml of ether, filtered, washed with ether and low-boiling petroleum ether and dried in vacuo at 40 ° C. The title compound was obtained as yellowish trifluoroacetate. This product was dissolved in methanol (500 mL) to convert it to the disodium salt, and the resulting solution was mixed with 2N ethyl acetate-2-ethyl caproic acid sodium salt solution (70 mL) and ethanol (500 mL). The small precipitate was filtered off and the orange filtrate was concentrated in vacuo at 40 ° C. The crystalline material is filtered off, washed with ethanol and low-boiling petroleum ether and dried under high vacuum for 2 days at 40 ° C. The title compound was obtained as a yellowish substance, [a] £ ⁵ = + 35.6 ° (c = l, water). The product has a nuclear resonance spectrum and microanalysis as shown.

The starting material used is (6R, 7R) -3- (acetoxymethyl) -7- {2 - [(Z) - [1- (tert-butoxycarbonyl) -methylethoxy] imino] -2- [2 - (Tritylamino) -4-selenazolyl] -acetamido} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid tert-butyl ester may be prepared as follows:

a) Preparation of 2-amino-4-selenazole-acetic acid ethyl ester (Z) -oxime

46.13 g of selenium urea are dissolved in a mixture of 726 ml of ethanol and 363 ml of water. The resulting solution was stirred in a nitrogen atmosphere at 20-25 ° C in portions for about 10 minutes. 72.6 g of ethyl 4-chloro-2- (Z) -hydroxyimino-2-oxobutyrate are added over 15 minutes. The reaction solution is stirred for one and a half hours at 20-25 ° C under a nitrogen atmosphere, and then the small amount of red selenium is filtered off. The light yellow filtrate was stirred at 25 ° C with a solution of 68 g of sodium acetate trihydrate in 726 ml of water while raising the pH from 2.8 to 5.3 and the reaction product crystallized out. After stirring for a further 1.5 hours at 25 ° C, the precipitated product is filtered off, washed with 250 ml of ethanol and low-boiling petroleum ether and dried in vacuo at 45 ° C overnight. The title compound is obtained as a pure substance (m.p. 193-195 ° C). The product has a nuclear resonance spectrum and microanalysis as shown.

-12184969

b) Preparation of 2-tritylamino-4-selenazole-pyruvic acid ethyl ester (Z) -oxime hydrochloride

72.1 g of ethyl 2-amino-4-selenazole acetic acid (Z) oxime are dissolved in 150 ml of dimethylformamide. The solution was filtered to remove traces of selenium. The yellow filtrate was mixed with triethylamine (38.25 mL), cooled to -30 ° C, and stirred with ca. and 1.56 g of trityl chloride at -30 ° C. The reaction mixture was stirred for ca. Allow to warm to 20-25 ° C over 1 hour and stir at 25 ° C for 3 hours. The mixture was poured into 1 L of ethyl acetate and washed with 2 L of water. The resulting brownish organic layer was mixed with 1 L of 1 N aqueous hydrochloric acid and shaken well. The precipitated hydrochloride was filtered, washed successively with 400 ml of ether and 600 ml of ethyl acetate, 2 liters of ether and 1 liter of low-boiling petroleum ether and dried under vacuum at 45 ° C overnight. White pure crystals, m.p. 193-195 ° C dec. The product has a nuclear resonance spectrum and microanalysis as shown.

c) Preparation of 2-tritylamino-4-selenazole-pyrroloic acid ethyl ester O- [1- (tert-butoxycarbonyl) -1-methylethyl] oxime

Dissolve 108.2 g of 2-tritylamino-4-selenazole-pyruvic acid ethyl ester (Z) -oxime hydrochloride in 400 ml of dimethyl sulfoxide, then 400 ml of acetone, 138.5 g of particulate potassium carbonate and 49 g of α-bromo isobutyric acid tert-butyl ester is added. After stirring for 2 hours, an additional 70 g of powdered potassium carbonate was added. The mixture was stirred for a further 2 hours at 25 ° C under nitrogen. The resulting dark suspension was removed in vacuo at 45 ° C under vacuum and then poured into a mixture of water (2 L) and ethyl acetate (2 L). The aqueous phase was extracted with additional 1 L of ethyl acetate and discarded. The combined dark organic layers were washed with water (2 x 1 L), dried over sodium sulfate and concentrated in vacuo at 40 ° C. The brownish-black resin obtained as an evaporation residue was recrystallized from high boiling petroleum ether. The title compound is obtained in the form of beige crystals, m.p. 123 ° C. According to the product's nuclear resonance spectrum, the color and anti-isomeric forms exhibit an approx. It consists of a mixture of 70: 30. Microanalysis corresponds to the structure given.

d) Preparation of 2-tritylamino-4-selenazole-pyruvic acid (Z) -O- [1- (tert-butoxycarbonyl) -1-methylethyl] oxime

90.5 g of ethyl 2-tritylamino-4-selenazole-pyruvic acid-O- [1- (tert-butoxycarbonyl) -1-methylethyl] oxime in a mixture of 850 ml of methanol and 140 ml of 2N sodium hydroxide solution reflux. The dark solution was concentrated in vacuo at 40 ° C. The solid evaporation residue was partitioned between 1 L of water and 1 L of ethyl acetate with 500 mL of methylene chloride and acidified with 140 mL of 3N aqueous hydrochloric acid. The green organic phase is separated off, the small amount of selenium is filtered off, the filtrate is washed with water, dried over sodium sulfate and concentrated in vacuo at 40 ° C. The crystallization material is filtered off, washed with ethyl acetate and low boiling petroleum ether and dried in vacuo at 14 ° C overnight. The pure title compound (pure Z form) was obtained as a melting point at 167-168 ° C with decomposition. The product has a nuclear resonance spectrum and microanalysis as shown.

e) (6R, 7R) -3- (Acetoxymethyl) -7- {2 - [(Z) - ((1-tert-butoxycarbonyl) -1-methylethoxy) imino] -2- [2- ( Preparation of tritylamino) -4-selenazolyl] -acetamido} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid tert-butyl ester

37.1 g of 2-tritylamino-4-selenazole-pyruvic acid (Z) -O- [1- (tert-butoxycarbonyl) -1-methylethyl] oxime and 19.7 g of 7-aminocephalosporanic acid tert-butyl ester 5 ml of pyridine in 600 ml of methylene chloride. To the resulting solution was added 13.62 g of dicyclohexylcarbodiimide and the mixture was stirred for 2 hours at 25 ° C. The crystallized dicyclohexylurea was filtered off and the yellow filtrate was concentrated in vacuo at 40 ° C. The residue was dissolved in 1 L of ethyl acetate and washed successively with 500 ml of 1N hydrochloric acid, 500 ml of dilute sodium chloride solution and 500 ml of 5% aqueous sodium bicarbonate solution and concentrated in vacuo at 40 ° C. . The residue was evaporated to an orange-brown foam which was dissolved in 200 ml of ether for crystallization and filtered off with a small amount of insoluble material. The filtrate was stirred for 30 minutes at which time the material partially crystallized. Isopropyl ether (300 mL) was added and stirred for a further 30 minutes to complete crystallization. The precipitated product was filtered off, washed with isopropyl ether and low boiling petroleum ether and dried overnight in vacuo at 40 ° C. The title compound obtained, which was practically colorless, had a [α] π = + 5 ° (c = 2.2, dimethylsulfoxide). The product has a nuclear resonance spectrum and microanalysis as shown.

Example 10 1 - {[(6R, 7R) -7 - [(Z) -2- (2-Amino-4-selenazolyl) -2 - [(1-carboxy-1-methylethoxy) imino] - Acetamido] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl) methyl} pyridinium hydroxide, sodium salt (inner salt)

8.44 g of (6R, 7R) -3-acetoxymethyl-7 - {(Z) -2- (2-amino-4-selenazolyl) -2 - [(1-carboxy-1-methylethoxy) ) -imino] -acetamido} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, disodium salt, 28.48 g of sodium iodide in 8.8 ml of water and 8 ml solution of pyridine at 80 ° C. The reaction mixture was stirred for 1 hour at 80 ° C. The dark solution was poured into water (400 mL) and concentrated in vacuo at 45 ° C. The residue was dissolved in 450 ml of water and acidified to pH 1 with 3N aqueous hydrochloric acid. The excellent decomposition product is filtered off, washed with 100 ml of water and discarded. The light yellow filtrate was washed twice with ethyl acetate and adjusted to pH 6 with 3N aqueous sodium hydroxide solution. The mixture was vigorously concentrated in vacuo at 40C and lyophilized overnight. The lyophilisate was dissolved in 100 mL of water to remove the inorganic salts and applied to a 1 kg Amberlite XAD-2 column. The inorganic salts are washed with 3 L of water and the product is eluted with 2 L of 8: 2 water-ethanol. Contains the title compound

Fractions -13184969 were concentrated in vacuo at 40 ° C and lyophilized overnight. The title pure compound was obtained as a beige-colored, high-volume lyophilisate, [α] D = + 3 ° (c = 0.8 in water). The product has a nuclear resonance spectrum and microanalysis as shown.

Example 11 (6R, 7R) -3- (Acetoxymethyl) -7- [2- (2-amino-4-selenazolyl) -2 - ((Z) -hydroxyimino) -acetamido] -8- Preparation of oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt

9.28 g of (6R, 7R) -3- (acetoxymethyl) -7- [4-bromo-2 - ((Z) -hydroxyimino) -acetoacetamido] -8-oxo-5-thia- 1-Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 200 ml of methanol and mixed with 2.7 g of selenium urea. After stirring for 1 hour at 25 ° C, 22 ml of 2N ethyl acetate-2-ethyl caproic acid sodium salt solution and 100 ml of water were added. A small amount of selenium from the solution is removed by filtration. The yellow filtrate was made up to 1000 ml with ethanol; slight turbidity occurs. The mixture was stirred for 30 minutes, the crystallized sodium salt was filtered off, washed with ethanol and low-boiling petroleum ether and dried overnight under high vacuum at 40 ° C. The pure title compound was obtained as a yellowish solid, [α] D 20 = + 70.8 ° (c = 1, in water). The product has a nuclear resonance spectrum as defined.

Example 12 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - ((Z) -hydroxyimino) -acetamido] -3-methyl-8-oxo-5-thia Preparation of -1-azabicyclo [4.2.O] oct-2-ene-2-carboxylic acid sodium salt

12.2 g of (6R, 7R) -7- [4-bromo-2 - ((Z) -hydroxyimino) -acetacetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [ 4.2.0] A mixture of oct-2-ene-2-carboxylic acid and 4.06 g of selenium urea in 250 ml of ethanol was stirred at 25 ° C for 2 hours. A small amount of selenium was filtered off from the solution. The yellow filtrate was mixed with 35 ml of 2N ethyl acetate-2-ethyl caproic acid sodium salt and stirred for 30 minutes. The excellent sodium salt is filtered off, washed with ethanol and low-boiling petroleum ether and dried overnight under high vacuum at 40 ° C. The title pure compound was obtained as a beige colored amorphous material, [α] D = 1106 ° (c = 1, water). The product has a nuclear resonance spectrum as defined.

Example 13 (6R, 7R) -7- [2- (2-Amino-4-selenazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3 - {[(2,5-dihydro- 6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2 -Carboxylic acid 5-oxide disodium salt

1.92 g of (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3 - {[) 2,5-dihydro -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene 2-Carboxylic acid disodium salt was dissolved in a mixture of 13 ml water and 4 ml acetone. The resulting solution was stirred at room temperature for approx. A solution of 3-chloroperbenzoic acid (0.58 g, 90%) in acetone (5 ml) was added dropwise over 30 minutes. Additional acetone was added dropwise to the solution starting to cloud and the solution was filtered. The crystallization is started by scraping with a glass rod and the solution is stirred for 1.5 hours. The precipitated crystals are filtered off, washed with 10 ml of 85% aqueous acetone, 10 ml of acetone-petroleum ether (low boiling point) and dried in vacuo at 40 ° C. The title compound is obtained as a slightly beige crystalline solid, -116 ° (c = 1, water). The nuclear resonance spectrum and microanalysis correspond to the structure given. The product contains 6 moles of water and is identical to the compound prepared in Example 2.

Example 14

Preparation of dry ampoules for intramuscular administration

0.6 g of (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - ((Z) -methoxyimino) -acetamido] -3 - {[(2,5-dihydro) -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8-oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene The disodium salt of 2-carboxylic acid is prepared in a conventional manner by lyophilisate which is filled into ampoules. Before use, the lyophilisate

Mix with 1.7-2.5 ml of a 1% aqueous lidocaine hydrochloride solution.

Example 15

Gelatin capsules of the following pharmaceutical formulations are known per se and are known in the art:

component Quantity, kapszulán- Kent (6R, 7R) -7- [2- (2-amino-4-szelenazoIil) -2 - ((Z) - -metcxi) acetamido] -3-methyl-8-oxo- -5-thia-azabicyclo [4.2 to] oct-2-ene-2- carboxylic acid pivaloyloxymethyl ester 500 mg Luviskcl (water soluble polyvinylpyrrolidone) 20 mg mannitol 20 mg talc 15 mg Magnesium stearate 2 mg Total weight: 557 mg

Patent claims

Claims (19)

A process for the preparation of cephalosporin derivatives of formula (I) wherein: R ¹ is methyl; acetoxymethyl group; triazinylthiomethyl substituted with lower alkyl, hydroxy and / or oxo; lower alkyl substituted thiadiazolylthiomethyl, lower alkyl15 -14184969 dish substituted tetrazolylthiomethyl or pyridinium methyl; R ² is hydrogen, lower alkyl or R ^{3 is} OCO- (lower alkyl) where R ^{3 is} hydrogen or an alkali metal cation and X is a sulfur atom or a -SO group) and a (lower alkyl) -COO) lower alkyl ester and its salts as well as the hydrals of the compounds of the formula I, their esters and their salts. a) reacting a compound of formula II (wherein R ¹ , R ² and X are as defined above; Hal is a halogen atom and the carboxyl group may be in protected form) or a salt thereof with a selenium urea and optionally protecting group on the carboxyl group; except for (lower alkyl) -COO- (lower alkyl); obsession b) a compound of formula III (wherein R ¹ , R ² and X are as defined above; R is a cleavable protecting group and the carboxyl group may be in protected form) or a salt of R and a protecting group optionally present on a carboxyl group; except for (lower alkyl) -COO- (lower alkyl); obsession c) for the preparation of compounds of formula I wherein R ¹ is -CH ₂ -SR ⁵ (wherein R ⁵ is lower alkyl, hydroxy and / or oxo-substituted triazinyl, lower alkyl-substituted thiadiazolyl, or lower carbon); alkyl-substituted tetrazolyl and R ² and X are as defined above) a compound of Formula IV (wherein R ² and X are as defined above; Z is halogen, lower alkanoyloxy, lower alkyl or aryl); may be protected formed sulfonyl group or an azido group and the carboxyl group of an inorganic or tertiary organic base salt) or a salt thereof with Compound (V) with a thiol compound of formula (wherein R ⁵ is as defined above) and optionally where the carboxyl group in presence of water case v cleavage of the yeast group; and then optionally converting a compound of formula (I) thus obtained into one or more of the following transformations: in the preparation of compounds of formula (I) wherein X is -SO- (wherein R ¹ and R ² are as defined above), oxidizing the resulting compound of formula (I) wherein X is sulfur, wherein R ¹ and R ² are as defined above, or a salt thereof; and or In the preparation of (lower alkyl) -COO- (lower alkyl) esters of compounds of formula (I), a carboxylic acid of formula (I) is esterified; and / or in the preparation of salts or hydrates of the compounds of formula (I) or hydrates of the salts, the resulting compound of formula (I) is converted to a salt or hydrate or a salt to a hydrate. (Priority: 10.10.1980) Process for the preparation of a), b) or c) according to Claim 1, in the form of the isomeric mixtures or predominantly syn isomeric forms of the compounds of the formula I, characterized in that the starting material is a isomeric or predominantly isomeric form. a compound of formula (II), (III) and (IV) in the form of a mixture of isomers of the isomer (wherein R ¹ , R ² , X, Hal, R and Z are as defined in claim 1). (Priority: 10/8/1980) 3 according to claim 1), b) or c) or the method of claim 2 for preparing a compound of formula (I) ^R2 is methyl (wherein ^R1 and X are as defined in claim 1); characterized in that the compounds of the general formulas (II), (III) and (IV) in which R ² is a methyl group (wherein R ¹ , X, Hal, R and Z are as defined in claim 1) are used as starting materials. (Priority: 10/8/1980) The process of a), b) or c) of claim 1 or the process of claim ^{2 for the} preparation of compounds of formula I wherein R ² is hydrogen (wherein R ¹ and X are as defined in claim 1), characterized in that the compounds of formula (II), (III) and (IV) wherein R ² is hydrogen are the starting materials (wherein R ¹ , X, Hal, R and Z are as defined in claim 1). (Priority: 10/8/1980) Method a), b) or c) according to claim 1, or A process according to claim ^{2 for the} preparation of compounds of formula I wherein R ² is a carboxymethyl group (wherein R ¹ and X are as defined in claim 1), wherein the starting material is a carboxymethyl group protected by R ² . (II), (III) and (IV) are used compounds of formula (which ^R1, X, Hal, R and Z are as defined in claim 1 wherein), followed by deprotecting the protective group of a carboxyl group. (Priority: 10/8/1980) According to the sixth to claim 1, a), b) or c) or the method of claim 2 for preparing a compound of formula (I), R ² represents 1-carboxy-l-methyl-ethyl group (wherein R ¹ and X is as defined in claim 1, wherein the starting materials are the compounds of formulas (II), (III) and (IV) containing 1-carboxy-1-methylethyl protected by R ^2. R ¹ , X, Hal, R and Z are as defined in claim 1) and the protecting group on the carboxyl group is cleaved. (Priority: March 18, 1981) A process according to claim 1, a), b) or c) or a process according to claims 2-6. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein X is S (wherein R ¹ and R ² are as defined in any one of claims 1 to 6), characterized in that ) and compounds of formula IV (wherein R ¹ and R ² are as defined in any one of claims 1 to 6 and Hal, R and Z are as defined in claim 1). (Priority: 10/8/1980) The process of claim 7, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3 - {[(2) , 5-Dihydro-6-hydroxy-2-methyl-5-oxo-triazin-3-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct. -2-ene-2-carboxylic acid, its salts and its salts and salts of hydrates thereof, characterized in that on starting syn form, R ¹ is [(2,5-dihydro-6-hydroxy-2-methyl -5-oxo-aza-triazin-3-yl) -thio] -methyl, R ² is methyl, R ⁵ is 2,5-dihydro-15184969 Compounds of formula (II), (III), (IV) and (V) containing -6-hydroxy-2-methyl-5-oxo-triazin-3-yl and X are sulfur (wherein Hal , R and Z are as defined in claim 1). (Priority: 10/8/1980) Method a), b) or c) according to claim 1 or steps 2-6. A process according to any one of claims 1 to 8 and (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -3 - {[(2) 5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-l-azabicyclo [4.2 to] oct 2-ene-2-carboxylic acid-5-oxide, its salts and its salts and salts of hydrates thereof, characterized in that on starting syn form, R ¹ is [(2,5-dihydro-6-hydroxy- 2-methyl-5-oxo-triazin-3-ylthio] -methyl, R ² is methyl, R ⁵ is 2,5-dihydro-6-hydroxy-2-methyl-5-oxo; a compound of the general formulas (ID, (III), (IV) and (V)) containing a triazin-3-yl group and an X -SO group (wherein Hal, R and Z are as defined in claim 1) or oxidizing the compound of claim 8. (Priority: 10.10.1980) The process of claim 7, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -3-methyl-8 oxo-5-thia-l-azabicyclo [4.2 to] oct-2-ene-2-carboxylic acid, its salts and its salts and salts of hydrates thereof, characterized in that on starting syn form, R ¹ and (T 1) cs (III) wherein R ² is methyl and X is sulfur (wherein Hal and R are as defined in claim 1). (Priority: 10/8/1980) The process of claim 7, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -3 - {[( 5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, e. its salts and its salts with salts and hydrates thereof, characterized in that starting from syn iormában, ^R1 is [(5-methyl-3,4-tiadiazo1-2-yl) thio] methyl group R ² is methyl, R ⁵ is 5-methyl-1,3,4-thiadiazol-2-yl, and X is sulfur, compounds II, III, IV and V (wherein Hal, R and Z are as defined in claim 1). (Priority: 10/8/1980) The process of claim 7, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -3 - {[( 1-Methyl-1H-tetrazol-5-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, its salts and these compounds and salts of hydrates thereof, characterized in that in the syn-isomer as a starting material, R ¹ is [(l-methyl-lH-tetrazol-5-yl) thio-methyl group, ^R2 is methyl, ^R5 the compounds of formula (II), (III), (IV) and (V) containing 1-methyl-1H-tetrazol-5-yl and X being sulfur (wherein Hal, R and Z are as defined in claim 1) given), (Priority: 10.10.1980) 13. The process of claim 7, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -8-oxo-3 - {[(1,4,5,6-Tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl) thio] methyl} -5-thia-1-azabicyclo [4.2.0] ] for the preparation of oct-2-ene-2-carboxylic acid, salts of this compound and hydrates of this compound and its salts, characterized in that the starting material is sin (R *) [(1,4,5,6-tetrahydro-O)] -4-methyl-5,6-dioxo-triazin-3-yl) thio] methyl, R ^{2 is} methyl, R ⁵ is 1,4,5,6-tetrahydro-4-methyl-5 6-dioxo-triazin-3-yl and X are sulfur atoms of the formulas II, III, IV and V (wherein Hal, R and Z are as defined in claim 1). (as defined in claim 1). (Priority: 10/8/1980) 14. The process of claim 7, (6R, 7R) -3- (acetoxymethyl) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) - acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, salts thereof, and hydrates of this compound and its salts, characterized in that Compounds of formula (II) and (III) wherein R ¹ is acetoxymethyl, R ² is methyl and X is sulfur (wherein Hal and R are as defined in claim 1). (Priority: 10/8/1980) 15. The process of claim 7, wherein (6R, 7R) -3- (acetoxymethyl) -7 - {(Z) -2- (2-amino-4-selenazolyl) -2 - [(1-carboxylic acid) -1-methyl-ethoxy) -imino] -acetamido} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, salts thereof, and hydrates of this compound and its salts characterized in that the starting materials used are the compounds of the general formula (II) and (III) containing in the information: R ¹ is an acetoxymethyl group, R ² is a protected 1-carboxy-1-methylethyl group and X is a sulfur atom. (wherein Hal and R are as defined in claim 1) and the protecting group on R ^{2 is} cleaved. (Priority: 1981. VIII. 18.) A process according to claim 7 for the preparation of 1 - {(6R, 7R) -7 - [(Z) -2- (2-amino-4-selenazolyl) -2 - [(1-carboxy-1-methylethoxy) ) -imino] -acetamido] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl} pyridinium hydroxide, salts thereof, and hydrates of this compound and its salts, characterized in that (6R, 7R) - (3-acetoxymethyl) -7 - [(Z) -2- (2-amino-4-selenazolyl) -2 - [(1) -carboxy-1-methyl-ethoxy) -imino] -acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid or its alkali metal salt is reacted with pyridine. (Priority: VHI, 18, 1981) 17. A method according to any preceding claim of a compound of formula pivaloyloxymethyl esters (I), this ester salts and the esters and salts of hydrates thereof, characterized in that a carboxylic acid of formula (I) (where R ^1, R ² and X are as (1) with a pivaloyloxymethyl halide. (Priority: 10/8/1980) 18. The process of claim 10, (6R, 7R) -7- [2- (2-amino-4-selenazolyl) -2 - [((Z) -methoxyimino) acetamido] -3-retryl-8 The pivaloyloxymethyl ester of -oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid for the preparation of salts thereof and the hydrates of this compound or salts, characterized in that is reacted with a pivaloyloxymethyl halide. (Priority: 10/8/1980) 19. A process for the preparation of a pharmaceutical composition according to claim 1 A cephem carboxylic acid derivative of the Formula I (wherein R ¹ , R ² and X are as defined in claim 1) or a (lower alkyl) -COO- (lower alkyl) ester, salt or the hydrate of a compound of formula (I), ester or salt thereof as an active ingredient is admixed with pharmaceutically acceptable, non-toxic, inert solid or liquid carriers and / or excipients for use in such formulations and formulated into pharmaceutical compositions. (Priority: 10/8/1980)