DD201906A5 - PROCESS FOR THE PREPARATION OF 7 BETA-AMINOTHIADIAZOLYLACETYLAMINO-3 AMMONIOMETHYL-3-CEPHEM-4-CARBON ACID COMPOUNDS - Google Patents

Abstract

7 beta-aminothiadiazolylacetylamino-3-cephem-4-carboxylic acid compounds of the formula in which in particular Amino, T is a 1,2,4-thiadiazole radical, R 1 is an optionally substituted pyrazolio group, an optionally substituted triazolio group, a tri-lower alkylammonium group or a substituted pyridiniogroup and R 2 are hydrogen, lower alkyl, carboxy-lower alkyl, carbamoyl or N-substituted carbamoyl, have antibiotic properties and are active against Gram-positive and Gram-negative microorganisms. The novel compounds are prepared in a manner known per se. Also included are intermediates.

Description

Process for the preparation of ammoniomethyl compounds

Field of application of the invention

The present invention relates to a process for the preparation of novel 7β-aminothiadiazolylacetylamino-3-aminomethyl-3-cephem-4-carboxylic acid compounds, to pharmaceutical preparations containing such compounds, and to their use for the preparation of pharmaceutical preparations or as pharmacologically, in particular antibiotically active compounds.

Characteristic of the known technical solutions

German laid-open specification 27 45246 discloses processes for the preparation of 7β-thiadiazolylacetamido-3-cephem-4-carboxylic acid compounds having an antibiotic activity. These connections

4 are substituted in the 3-position of the cephem skeleton by the group -CH-R, wherein R is hydrogen, acyloxy or a heterocyclic thio group which may have one or more suitable substituents.

Object of the invention

The aim of the invention is to provide processes for the preparation of novel 7β-aminothiadiazolylacetylamino-3-cephem-4-carboxylic acid compounds of the formula I which, in contrast to the known compounds in the 3-position, are substituted by ammonium methyl groups.

Explanation of the essence of the invention

It is an object of the present invention to provide, starting from easily accessible starting materials, novel 7β-arainothiadiazolylacetylamino-3-cephem-4-carboxylic acid compounds.

which also have antibiotic activity, wherein the activity against certain pathogens even germs ict, and to provide methods for producing these compounds.

According to the invention, 7β-aminothiadiazolylacetylamino-3-ammoniomethyl-3-cephem-4-carboxylic acid compounds of the formula

(0)

Il / \

Am-T-C-C-N- · ·?

Π Ι ί i / ^

N ^H ^ \ S

I 1

COO

manufactured,

where η is 0 or 1, unsubstituted or substituted amino, T is a thiadiazole radical which is attached at one carbon atom with Am and at the other carbon atom with the group of the formula -C (= NOR) -, R is an unsubstituted or substituted pyrazolo group, an unsubstituted or substituted triazolio group, a tri-lower alkylammonium group or a pyridiniogroup of the formula a

Λ-Λ ^(A) '

R ^C R ^b

year - 2 -

wherein R ^a is cycloalkyl ,. Phenyl ,. Hydroxy ,. Lower alkoxy, halogen, cyano, carbamoyl, carboxyl or lower substituted lower alkyl, unsubstituted or carboxy substituted Ni alkylene or lower alkylthio, unsubstituted or lower alkyl, lower alkanoyl or aminobenzenesulfonyl monosubstituted amino, di-lower alkylamino, lower alkyl, hydroxy lower alkyl, lower alkoxy, hydroxy or Cyano monosubstituted carbamoyl, di-lower alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano ,. Nitro, or hydroxysulfoniaderalkyl, R is carbamoyl or hydrogen or has the meanings of R and R is hydrogen or has the meanings of R, and R is hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl or unsubstituted or substituted carbamoyl, and salts of such compounds that is a salt-forming. Group, process for the preparation of these compounds, pharmaceutical compositions containing these compounds, and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

In compounds of the formula I, the index η has in the first place the value 0. If η has the value 1, the corresponding 1-oxide is present in the α- or β-form.

In the present specification, the term "lower" used in the context of definitional, substituents or compounds means that the corresponding substituents or compounds, unless expressly defined otherwise, contain up to 7, preferably up to 4, carbon atoms.

Within the scope of the present description, the general definitions used above and below preferably have the following meanings:

Substituted amino Am is protected by, for example, the amino groups described below, i. easily cleavable and substituted in free amino substituted. Amino, in particular acylamino. However, it may also be protected secondary amino or tertiary amino, for example mono- or disubstituted by lower alkyl amino, in particular methylamines.

Lower alkyl is e.g. Methyl, ethyl, n -propyl, isopropyl, η-butyl, isobutyl ,. sec.butyl or tert.-butyl, furthermore n-pentyl, neopentyl, n-hexyl or n-eeptyl.

A Thiadiazolrest T is for example a 1,2,4-Thiadiazolrest, in the 3- or 5-position with Am ₅ .bzw. the group of the formula -CC = NOR ₇ ) -, wherein the group Am is preferably linked in the 5-position with the 1,2,4-Thiadiazolrest T. Further Thiadiazolreste T are 1,2,3-Thiadiazolreste, which are connected in the 4- and 5-position with the group Am or the group of the formal -CC = NOR), and the symmetrical 1,3,4- and 1 , 2,5-Thiadiazolreste, each of the two ring carbon atoms with the group Am or the group of the formula -CC = NOR ₉ ) - are connected. The thiadiazole group T substituted by an amino group may also be present in tautomeric form as a dihydrothiadiazole group substituted by an imino group or as a mixture of the two forms. The equilibrium between the two tautomers depends on the nature of the optionally substituted amino group Am and on external factors such as temperature, solvent or pH. In the context of the present invention, the thiadiazole group in the specification and in the claims is referred to as thiadiazole group only, although the dihydrothiadiazole form is also included.

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An unsubstituted. or 'substituted Eyrazoliogruppe' ¹ R ₁ is for example Pyrazoiio or by · lower alkyl, for example methyl, AethyI, propyl or tert-butyl, lower alkenyl, for example vinyl or allyl, carboxy lower alkyl, for example carboxymethyl or 2-carboxyethyl, Niederalkoxycarbonylniederalkyl, for example methoxycarbonylmethyl or ethoxycarbonylmethyl , Sulfonyl, for example sulfomethyl or 2-S-sulfoethyl, amino, eg, aminomethyl or 2-aminoethyl, Niederalkylaminoniederalkyl, for example methylaminomethyl, Diniederalkylaminoniederalkyl, eg dimethylaminomethyl or 2-Dimethylaminoäthyl, Carbamoylniederalkyl, eg Carbamoy !, methyl, Diniederalkylcarbamoylniederalkyl, eg Dimethylcarbamoylmethyl, Sulfamoylniederalkyl, eg SuIfamoy! Methyl, di-lower alkylsulfamoyl-n-alkyl, for example dimethylsulfamoylmethyl, hydroxy-lower alkyl, for example hydroxymethyl, or lower-alkoxy-lower alkyl, for example methoxymethyl, substituted pyrazolino.

Preferred substituted pyrazolo groups JL are, for example, 2-lower alkyl-1-pyrazolio, e.g. 2-methyl, 2-ethyl, 2-propyl or 2-tert-butyl-1-pyrazolio, 2-lower alkenyl-1-pyrazolio, e.g. 2-allyl or 2-vinyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, e.g. 2-carboxymethyl-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, e.g. 1-carboxymethyl-1-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-1-pyrazolio, e.g. 2-Methoxycarbonylmethyl-1- or 2-ethoxycarbonylmethyl-1-pyrazolio, 2-sulfo-lower alkyl-1-pyrazolio, e.g. 2-sulfomethyl-1-pyrazolio, 2-amino-lower alkyl-1-pyrazolio, e.g. 2- (2-aminoethyl) -1-pyrazolio, 2-di-lower alkylaminoloweralkyl-1-pyrazolio, e.g. 2- (2-dimethylaminoethyl) -1-pyrazolio, 2-carbamoyl-lower alkyl-1-pyrazolio, e.g. 2-carbamoylmethyl-lpyrazolio, 2-di-lower alkylcarbamoyl-lower alkyl-1-pyrazolio, e.g. 2-dimethylcarbamoylmethyl-1-pyrazolio, 2-sulfamoyl-lower alkyl-1-pyrazolio, e.g. 2-sulfamoylmethyl-1-pyrazolio, 2-hydroxy-lower alkyl-1-pyrazolio, e.g. 2-hydroxymethyl-l-pyrazolio, and 2-lower alkoxy-lower alkyl-1-pyrazolio, e.g. 2-methoxymethyl ^ -l-pyrazolio.

An unsubstituted or substituted triazolio group R is, for example, triazolio or lower alkyl, e.g. Methyl, ethyl, propyl or tert-butyl, lower alkenyl, e.g. Vinyl or allyl, carboxy-lower alkyl, e.g. Carboxymethyl or 2-carboxyethyl, sulfo-lower alkyl, e.g. Sulfomethyl or 2-sulfoethyl, amino-lower alkyl, e.g. Aminomethyl or 2-aminoethyl, di-lower alkylamino lower alkyl, e.g. Dimethylaminomethyl or 2-dimethylaminoethyl, carbamoyl-lower alkyl, e.g. Carbainoy! Methyl, sulfamoyl-lower alkyl, e.g. Sulfamoylmethyl, hydroxy-lower alkyl, e.g. Hydroxymethyl, or lower alkoxy lower alkyl, e.g. Methoxymethyl, substituted triazolio.

Preferred substituted triazolio groups R are, for example, 3-lower alkyl-1-triazolio, e.g. 3-methyl, 3-ethyl, 3-propyl or 3-tert-butyl-1-triazolio, 3-lower alkenyl-1-triazolio, for example 3-vinyl or 3-allyl-1-triazolio, 3 Carboxyniederalkyl-1-triazolio, for example, 3-carboxymethyl-l-triazolio, 3-sulfoloweralkyl-1-triazolio, for example, 3-sulfomethyl-l-triazolio, 3-amino-lower alkyl-1-triazolio, for example 3- (2-aminoethyl) -1 triazo.lio, 3-di-lower alkylaminoloweralkyl-1-triazolide, for example 3- (2-dimethylaminoethyl) -1-triazolide, 3-carbamoyl-lower alkyl-1-triazolio, for example 3-carbamoylmethyl-1-triazolio, 3-sulfamoyl-lower alkyl-1-triazolio for example 3-sulfamoylmethyl-1-triazolio, 3-hydroxy-lower alkyl-1-triazolio, eg 3-hydroxymethyl-1-triazolio, and 3-lower alkoxy-lower alkyl-1-triazolio, eg 3-methoxymethyl-1-triazolio.

A tri-lower alkylammonium group R is, for example, trimethylammonio, triethylammonio or dimethylethylammonio.

In a pyridiniogroup of the formula A, R is in the 2-, 3- or 4-position of the pyridine ring.

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In a pyridinio group of the formula A, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or Sul'fo-substituted lower alkyl R > denotes cyclopropyl, cyclopentyl, or cyclohexyl! Methyl, cyclopropyl, cyclopentyl or Cyclohexyl-1,1- or 1,2-ethyl, benzyl, 1- or 2-phenylethyl, diphenylmethyl or trityl, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, ethoxymethyl or methoxy-1,1- or 1,2 ethyl, chloromethyl, trifluoromethyl, 2-chloro, 2-bromo or 2-iodoethyl ,. 2., 2,2-trifluoro or 2,2,2-trichloroethyl, cyanomethyl, 1- or 2-cyanoethyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl or 2-carboxyethyl, sulfomethyl, 1-sulfo or 2-sulfoethyl.

Unsubstituted or carboxyl-substituted lower alkenyl or lower alkylthio R is, for example, vinyl, allyl, n-propenyl, 1-, 2- or 3-butenyl _v 2-carboxyvinyl or 3-carboxyallyl, methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio , 2-carboxyvinylthio or 3-carboxyallylthio.

Unsubstituted or monosubstituted by lower alkyl, lower alkanoyl or Aminobenzolsulfo'nyl amino R is, for example, amino, methylamino, Aethylamino or n-propylamino, formylamino, acetylamino or propionylamino or 3- or 4-Aminobenzolsulfonylamino.

Diniederalkylamino R is for example dimethylamino, diethylamino or di-n-propylamino.

By lower alkyl, hydroxy lower alkyl, lower alkoxy, hydroxy or cyano monosubstituted carbamoyl R is, for example, methylcarbamoyl or ethylcarbamoyl, hydroxymethylcarbamoyl or 1- or 2-hydroxyethylcarbamoyl, methoxycarbamoyl or ethoxycarbamoyl, N-hydroxycarbamoyl or N-cyanocarbamoyl.

Diniederalkylcarbamoyl R is, for example, dimethyl or carbamoyl Diethylcarbamoyl.

Cycloalkyl R is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. "Lower alkoxy R is, for example, methoxy," ethoxy or propoxy.

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Halogen R is, for example, fluorine, chlorine or bromine.

Lower alkoxycarbonyiyl R is, for example, methoxycarbonyl or ethoxycarbonyl.

Lower alkanoyloxy R is e.g. Formyloxy or acetoxy.

Lower alkanoyl R is e.g. Formyl, acetyl, propionyl, isobutyryl or n-butyryl.

Hydroxysulfone-lower alkyl R is, for example, hydroxysulfomethyl, 1-hydroxy-2-sulfoethyl ,. 2-hydroxy-1-sulfoethyl or 2-hydroxy-2-sulfoethyl.-

Pyridiniogruppen of formula A, wherein R has the abovementioned meanings, R has the meanings of R, carbamoyl or hydrogen and R is hydrogen, are preferred.

Preferred pyridiniogroups of formula A are, for example: hydroxy-lower alkylpyridinio, e.g. 3- or 4-hydroxymethylpyridinio, lower alkoxy-lower alkylpyridinio, e.g. 4-methoxymethylpyridinio, cyano-lower alkylpyridinio, e.g. 3-cyanomethylpyridinio, carboxy-lower alkylpyridinio, e.g. 3-carboxymethylpyridinio, sulfo-lower alkylpyridinio, e.g. 4- (2-sulfoethylpyridinio), carboxy-lower alkenylpyridinio, ζ.3. 3- (2-carboxyvinyl) -pyridinio, carboxy-lower alkylthiopyridinio, e.g. 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, e.g. 4-thiocarbamoylpyridinio, halopyridinio, e.g. 3-bromo or 4-bromopyridinio, carboxypyridinio, e.g. 4-carboxypyridinio, sulfopyridinio, e.g. 3-sulfopyridinio, cyanopyridinio, e.g. 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, e.g. S-carboxymethyl ^ -carbamoylpyridinio, aminocarbamoylpyridinio, e.g., 2-amino-5-carbamoylpyridinio, carboxycarb'amoyl. pyridinio, e.g. S-carboxy ^ -carbamoylpyridinio, cyanohalomethylpyridinio, e.g. 3-cyano-4-trifluoromethylpyridinio and aminocarboxypyridinio, e.g., 2-amino-3-carboxypyridinio.

The group of the formula = N-O-R is in the syn (or Z) -form or in the anti (or E) -form, with the syn (or Z) -form being preferred.

A lower alkyl group R preferably contains 1-4 C atoms and is, for example, ethyl, propyl, butyl or especially methyl.

A cycloalkyl group R preferably contains 3-8, primarily 3-6,. Ring members and is e.g. Cyclobutyl, cyclopentyl or cyclohexyl and especially cyclopropyl.

Substituents of substituted lower alkyl or cycloalkyl R are i.a. optionally etherified hydroxy, e.g. Lower alkoxy,. primary, secondary or tertiary amino Am, z "B. Amino or di-lower alkylamino, optionally functionally modified, eg esterified, amidated or protected, carboxyl or sulfo, and optionally lower alkyl N-substituted ureidocarbonyl The substituted lower alkyl and cycloalkyl groups are preferred substituted a carboxyl or sulfo group, which is preferably on the carbon atom, which is connected to the oxygen atom 'of the oxyimino group stand.

Such substituted lower alkyl or cycloalkyl groups R "are, for example. 2-aminoethyl ,. 2-Dimethylaminoethyl, carboxymethyl, 1- or 2-carboxyethyl, 1- ,. 2- or 3-carboxyprop-1-yl, 1- or 2-carboxyprop-2-yl, 1-carboxybut-1-yl, 1-carboxycycloprop-1-yl and 1-carboxycyclobut-1-yl, and the like by Sulo substituted lower alkyl and cycloalkyl groups.

The carboxy and sulfo groups in the group R- may be exemplified by lower alkyl, such as methyl or ethyl, or by a physiologically cleavable group, e.g. by pivaloyloxymethyl, esterified or by NH, a primary or secondary amine, e.g. a mono or di-lower alkylamine, e.g. Methyl or ethylamine or dimethyl or diethylamine, or be protected by the protective groups mentioned below.

Optionally-substituted carbamoyl as radical R is, for example, a group τ € C = O) -NHR, where R is hydrogen, lower alkyl, e.g. Methyl, ethyl or 1- or 2-propyl, optionally protected carboxy-lower alkyl, for example carboxy-methyl, 1- or 2-carboxyethyl or 1-, 2- or 3-carboxypropyl, wherein carboxy protected by one of the usual carboxyl protecting groups or for example by Lower alkyl, z.3, methyl, ethyl, n- or iso-propyl, or n- or tert-butyl may be esterified, optionally protected sulfo lower alkyl, for example Sulfomethyl, 1- or 2-5ulfoäthyl. or 1-, 2- or 3-sulfopropyl, wherein sulfo is protected by one of the usual sulfo-protecting groups, or for example by lower alkyl, e.g. Methyl or ethyl, optionally protected Eydroxyniederalkyl, e.g. Hydroxymethyl, 2-hydroxyethyl or 2- or 3-hydroxypropyl, wherein hydroxy is protected by one of the usual hydroxy protecting groups or, for example, acylated, e.g. acetylated, optionally protected amino-lower alkyl, e.g. 2-aminoethyl, 2- or 3-aminopropyl or 2-, 3- or 4-aminobutyl, wherein amino is protected by one of the usual amino-protecting groups or, for example, acylated, e.g. acetylated, may be aryl-lower alkyl, for example phenyl-lower alkyl, e.g. Benzyl or 1- or 2-ethylhexyl, lower haloalkyl, for example, fluoro, chloro or bromo-lower alkyl, e.g. 2-chloroethyl, 3-chloropropyl or 4-chlorobutyl, aryl, e.g. Phenyl, or lower alkyl, e.g. Methyl, lower alkoxy, e.g. Methoxy, halogen, e.g. Chloro or nitro, mono- to trisubstituted phenyl means.

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As mentioned above, functional groups present in compounds of the formula I, in particular the carboxyl, and amino groups, may furthermore be protected by the hydroxy or sulfo groups, where appropriate using the protective groups used in penicillin, cephalosporin and peptide chemistry come.

Such protecting groups are light, that is, without unwanted side reactions take place, for example, soIviIytisch, 'reductive, photolytic or even under physiological conditions, cleavable.

Protecting groups of this type, as well as their cleavage, are described for example in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, also in "The Peptides", Vol. I, Schröder and Lübke, Academic Press, London, New York, 1965, and in "Methods of Organic Chemistry", Houben-Weyl, 4-Edition, 3d.15 / 1, Georg Thieme Verlag, Stuttgart, 1974.

So are carboxyl groups z.3. protected in verestsrter form, such ester groups are easily cleavable under mild conditions. Carboxyl groups protected in this way contain lower-alkyl groups which are branched predominantly in the 1-position or suitably substituted in the 1- or 2-position as esterifying groups. Preferred esterified carboxylic groups include i.a. tertiary lower alkoxycarbonyl, e.g. tart.Butyioxycarbonyl, Arylmethaxycarbonyl, with one or two aryl radicals, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert -butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl radicals, as appropriate, z.3. As mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbyl or 4-methoxybenzyloxycarbonyl, or, as mentioned above, optionally substituted diphenylmethoxy

carbonyl, ζ.3. Diphenylmethoxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl, via methoxy-1-carbo-n-carbonyl, 1-kei-hexyl-1-thoxy-carbonyl or 1-ethoxymethoxycarbonyl, 1-niaderalkylthio-lower alkoxycarbonyl, such as 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmathoxycarbonyl, wherein the aroyl optionally, for example by halogen, such as bromine, substituted benzoyl, e.g., phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, ζ, B. 2,2,2-trichloroethoxycarboyl, 2-3-methoxycarbonyl or 2-iodoethoxycarbonyl, or 2- {trisubstituted silyl) -ethoxycarbanyl, in which the substituents independently of one another have an optionally substituted, z. by Niedaralkyl, Niederalkosy, aryl, halogen and / or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic Kohlenwassarstoffrest with eg «up to 15 carbon atoms, for example optionally substituted lower alkyl, Phenylniederalkyl, cycloalkyl or phenyl, eg 2-Triniederalkylsilyläthoxycarbonyl, such as Trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

Other protected carboxyl groups present in esterified form are silyloxycarbonyl, in particular organic silyloxycarbonyl groups, furthermore stannyloxycarbonyl groups. In these groups, the silicon or tin atom preferably contains lower alkyl, especially methyl, further lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Chlorine, as a substituent. Suitable silyl or stannyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, lower alkoxy-lower alkyl-halo-silyl, e.g., methoxymethylchlorosilyl, or diloweralkylhalosilyl, e.g., dimethylchlorosilyl, or appropriately substituted stannyl compounds, e.g., tri-n-butylstannyl.

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Preferred protected carboxyl groups are tertiary lower alkoxycarbonyl, such as tert-butyloxycarbony1, and especially optionally, 2.B. As mentioned above, substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.

A protected amino group, such as a corresponding group Am, may be present, for example, in the form of an easily cleavable acylamino, arylmethylamino, etherified mercaptoaniino, 2-acyl-lower alk-1-en-1-ylamino, silyl or stannylamino group or as azido group. -

In an easily cleavable acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or aryl, substituted alkanecarboxylic acid or an optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid diester. Such acyl groups are, for example, lower alkanoyl, such as forryl, acetyl, or propionyl, halo-lower alkanoyl, such as 2-haloacatyl, especially 2-chloro, 2-bromo, 2 Iodine, 2,2,2-trifluoro or 2,2, 2-trichloroacetyl, if appropriate, for example by halogen, lower alkoxy or nitro, substituted benzoyl, z.3. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of Niederalkylzestes branched or in the 1- or 2-position suitably substituted Niedalkalkoxycarbonyl, in particular tert-Niederalkoxycarbonyl, z.3. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, optionally substituted, e.g. by lower alkyl, especially tertiary-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or optionally substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) -methoxy-carbonyl, aroylmethoxycarbonyl, wherein the Aroy! Group is preferably

optionally, e.g. by halogen, such as 3rom, represents substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-3-methoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl wherein the substituents independently of one another each represents an optionally substituted, e.g. by lower alkyl, JTiederalkoxy, aryl, halogen or nitro, substituted, aliphatic, araliphatic, cycloaiiphatic or aromatic hydrocarbon radical with z.3. up to 15 carbon atoms, for example optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxycarbonyl, such as. 2-trimethylsilylethoxycarbonyl or. 2- (di-n-butylmethylsilyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as. 2-Triphenylsilyläthoxycarbonyl.

Weiters, as amino protecting groups in question Acy! Raste are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as Diniederalkylphosphoryl, z.3. Di-methylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally

substituted diphenylphosphoryl, e.g. Qiphenylphosphoryl, optionally, e.g. nitro-substituted diphenyl-lower alkylphosphoryl, e.g. Dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, optionally substituted phenyloxyphenylphosphonyl, e.g. Phenyloxy "-phenylphosphonyl, diloweralkylphosphinyl, e.g., diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g., diphenylphosphinyl.

In an arylmethylamino group which is a mono-, di- or in particular triarylmethylamino, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenyl methyl and in particular trityl amino.

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Sine etherified mercapto group in an amino group protected with such a H.sub.est is primarily arylthio or aryl-lower alkylthio, wherein aryl is especially optionally, e.g. substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro, phenyl. A corresponding amino protecting group is e.g. 4-nitrophenylthio.

In a 2-acyl-lower-alk-1-en-1-yl group useful as an amino-protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro, .substituted benzoic acid or, in particular, a carbonic monoester, such as a carbonic acid lower alkyl halide. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl, e.g. l-Aetnoxycarbonylprop-l-en-2-yl.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which the silicon or tin atom is preferably lower alkyl, in particular methyl, furthermore lower alkoxy, z.3. Methoxy, and / or halogen, e.g. Chlorine, as substituent ^ contains. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyltert-butylsilyl, lower alkoxy-lower alkylhalosilyl, e.g. Methoxymethylchlorosilyl, or di-lower alkylhalosilyl, e.g. Dimethylchlorosilyl, or appropriately substituted stannyl, e.g. Tri-n-butylstannyl.

An amino group can also be protected in protonated form; as corresponding anions are primarily those of strong inorganic acids, such as of hydrohalic acids, eg. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid, in question.

Preferred amino protecting groups are. Acyl radicals of carbonic ointment st: em, in particular tert-butyloxycarbonyl, optionally, z.3. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl, or .2-halo-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl. also Trityl or Fonnyl.

Hydroxy protecting groups are z..S. Acyl radicals, as appropriate, e.g. by halogen, substituted lower alkanoyl, such as 2,2-dichloroacetyl, or in particular the mentioned in connection with a protected aiaino acyl radicals of carbonic monoesters, in particular. 2,2,2-Trichloräthoxycarbonyl, or organic silyl or Stannylreste, furthermore easily wegungsbare -veräthemde groups, such as. tert-lower alkyl, z.3. tartaric, 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radical, primarily 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. Methosymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl having 5-7 ring atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thiol analogues, and optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenylmethyl, wherein as substituents of the phenyl radicals, e.g. Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro, come into question.

A protected sulfo group is primarily an esterified one such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, e.g. a lower alkanol, or with a SiIyI-. or stannyl, such as tri-lower alkylsilyl, esterified sulfo group. In a sulfo group, the hydroxy group, such as the hydroxy group in an esterified carboxy group, may be etherified. , "

233133 3

Salts of compounds of the invention are primarily pharmaceutically acceptable non-toxic salts, such as those of compounds of formula 1 having acidic groups, e.g. with a free carboxyl and sulfo group. Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, z.3. Sodium, Kaliunr-, magnesium or calcium salts, and ammonium salts, which are formed with ammonia or suitable organic amines, wherein primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for salt formation are suitable, such as lower alkylamines, eg Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. A-aminobenzoic acid Z-diethylaminoethylestar, tri-lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Μ, Ν'-Dibenzyläthylendiainin, further bases of. Pyridine type, e.g. Pyridine, collidine or quinoline. Compounds of formula I having a basic group may include acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine. In the presence of several acidic or basic groups, mono- or polysalts can be formed. Compounds of formula I having an acidic group, e.g. a free carboxyl group, and a basic group, e.g. an amino group, may also be in the form of internal salts, i. in zwitterionic form, or one part of the molecule may be present as an inner salt and another part as a normal salt.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

3133

The compounds of formula I in which the functional groups are in free, ie not in protected form, and their pharmaceutically acceptable non-toxic salts are valuable antibiotically active substances which can be used in particular as antibacterial antibiotics. For example, they are in vitro against Gram positive germs, for example against Gram positive cocci, eg Staphylococcus aureus , streptococci, eg Streptococcus pyogenes , Streptococcus pneumoniae and Streptococcus faecalis , against Gram positive anaerobic bacteria, eg Clostridium perfringens and Peptostreptococcus anaerobius in concentrations of about 0.05 μg / ml to about 64 μg / ml ,. against gram-negative bacteria, for example Ent er obacteriaceae , eg Escherichia coli , Proteus spp. , Klebsiella pneumoniae , Serrati a marcescans and Enterobacter cloacae , as well as Pseudomonas aeruginosa , Haemophilus influenzae and Neisseria spp . and against anaerobic Gram-negative bacteria, eg Bacteroides fragilis , in concentrations of about 0.005 to about 32 μg / ml, and also against other Gram-positive and Gram-negative bacteria. In vivo, when administered subcutaneously to the mouse, they are resistant to systemic infections caused by Gram-positive bacteria such as Staphylococcus aureus in a dose range of about 5 to about 100 mg / kg and against systemic infections caused by Gram-negative Germs such as Enterobacteriaceae , or Pseudomonas aeruginosa are effective in a dose range of about 0.9 mg / kg to about 100 mg / kg.

Test report _ «

I. For the following compounds the antibiotic activity was tested:

1. 7ß- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-carboxypyridiniomethyl) -3-cephem-4-carboxylate (Example 1 );

2. 7β- [2-_ (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamido] -3- (3-carboxymethylpyridiniome thy ) -3-cephem-4'-carboxy-lat (Example 2); -

233133

3. 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamido] -3- (2-meryl-1-pyrazolic-methyl) - 3-Cepha-4-carboxylate (Example 6);

4. 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-methyl-1-pyrazoliomethyl) -3-cephem-4 carboxylate (Example 8);

5.7β- [2- (5-Amino-1,2,4-thiadiazo1,3-yl) -2-Z-methoxy-imino'-acetamido] -3- (3-bromopyridiniomethyl) -3-cephem-4 carboxylate (Example 9);

6.7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate (Example 11 );

II. Methodology

A. The antibiotic activity of the test compounds in vitro was determined by the agar dilution method of Ericson HM and Sherris SC, 1971 , Acta Path. Microb. Scand. Section B, Suppl. 217, Vol. 1-90, determined in DST agar. The minimum concentrations MIC (= minimum inhibiting concentration) that are still found to inhibit the growth of the test organisms are given in micrograms per milliliter per μg / ml for the compounds tested in Table 1.

B. The chemotherapeutic efficacy in vivo against systemic. Infections in female SPF, MJF mice were determined by the method of Zak, 0., et al., 1979 , Drugs Exptl. Clin. Res. 5_, 45-59. The ED values found in milligrams of substance per kilogram of mouse (mg / kg) against a number of microorganisms are given for the subcutaneously (sc) applied test compounds in Table 2.

III. test results

Table 1: Antibiotic activity in vitro

microorganisms - 1 2 3 MIC (/ μg / ml) [5 6 Streptococcus pyogenes 0.1 1 0.5 (4 0.05 n. e.    Aronson 0.1 Clostridium perfringens 0.005 0.1 0.05 0.01 0.01 (Anaerobic) 0.005 Pseudomonas aeruginosa 1 0.5 2 0.5 0.1 ATCC 12055 0.5 Escherichia coli 205 0.05 1 0.5 0.1 0.05 0.1

Table 2: Chemotherapeutic activity in vivo in the mouse:

ED ₅₀ (mg / kg, sc) 1 2 3 4 5 6 [nfizierende microorganisms 0.9 6 2> 30 "5 10 2.4 30 0.9 10-30 n. e. 3-10 Escherichia coli 205 K 1075 Pseudomonas aeruginosa ATCC 12055

(n.e. = not checked)

233133 3

The novel compounds of formula I can therefore, for example in the form of antibiotically active preparations, for the treatment of infections caused by Gram-positive or Gram-negative bacteria and cocci, in particular by enterobacteria, such as Serratia marcescens or Escherichia coil , as well as by Pseudomonas. Find use. '...

Compounds of formula I in which the functional groups are protected are used as intermediates for the preparation of compounds of formula I wherein the functional groups are in free form.

The invention relates in particular to compounds of the formula I in which η is 0, amino, lower alkylamino, di-lower alkylamino or protected amino, T is a thiadiazole radical which has on one carbon atom with Am and on the other carbon atom with the group of the formula -C (= N -O-R ₇ ) -, R 2-lower alkyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio ,. 1-carboxy-lower alkyl-1-pyrazolio, 2-lower-alkoxycarbonyl-lower alkyl-1-pyrazolio, 3-lower-alkyl-1-triazolio or a pyridiniogroup of formula A, wherein R is substituted by cycloalkyl, phenyl, hydroxy, loweralkoxy, halogen, cyano, carbamoyl, carboxyl or sulfo Lower alkyl, unsubstituted or carboxy-substituted lower alkenyl or lower alkylthio, unsubstituted or lower alkyl, lower alkanoyl or amiobenzenesulfonyl monosubstituted amino, di-lower alkylamino, lower alkyl, hydroxyloweralkyl, loweralkoxy, hydroxy or cyano monosubstituted carbamoyl, di-lower alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, Lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, SuIfο, cyano, nitro or Hydroxysulfoniederalkyl, R is carbamoyl or hydrogen or has the meanings of R and R is hydrogen, and R is hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl o the unsubstituted or substituted carbamoyl, where the group of the formula

= N-O-R in particular, which has syn (or Z) form, and salts, in particular pharmaceutically acceptable salts of those compounds of formula I, the salt-forming groups have '.

The invention relates in the first place to compounds of the formula I in which η is 0, amino, lower alkylamino, for example methylamino, or protected amino, T is a thiadiazole radical which has at one carbon atom Am and at the other carbon atom the group of formula CC = NOR) -, IL 2-lower alkyl-1-pyrazolio, eg. 2-methyl-l-pyrazolio ,. 2-carboxy-lower alkyl-1-pyrazolio, eg 2-carboxymethyl-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, eg 1-carboxymethyl-1-pyrazolio ,. 2-lower alkoxycarbonyl-lower alkyl-1-pyrazolio, eg. 2-Methoxycarbonylmethyl-l-pyrazolio, 3-lower alkyl-ltriazolio, for example 3-methyl-l-triazolio or a pyridinio of the formula A, for example Hydroxyniederalkylpyridinio, eg 3- or 4-hydroxymethylpyridinio, Niederalkoxyniederalkylpyridinio, eg 4-Methoxymethylpyridinio, Cyanoniederalkylpyridinio, eg 3-cyanomethylpyridinio, carboxy-lower alkylpyridinio, eg 3-carboxymethylpyridinio, sulfo-lower alkylpyridinio, eg 4- (2-sulfoethylpyridinio), carboxy-lower alkenylpyridinio, eg 3- (2-carboxyvinyl) -pyridinio, carboxy-lower alkylthiopyridinio, eg 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, eg 4-thiocarbamoylpyridinio, halopyridinio for example 3-bromo or 4-bromopyridinio, carboxypyridinio, eg 4-carboxypyridinio, sulfopyridinio, eg 3-sulfopyridinio,. Cyanopyridinio, eg 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, eg. 3-carboxymethyl-4-carbamoylpyridinio, aminocarbamoylpyridinio, eg 2-amino-5-carbamoylpyridinio, carboxycarbamoyl-pyridinio, eg 3-carboxy-4-carbamoylpyridinio, cyanohalomethylpyridinio, eg 3-cyano-4-trifluoromethylpyridinio or aminocarboxypyridinio, eg. 2-amino-3-carboxypyridinio and R "is hydrogen, lower alkyl, eg methyl, carboxy-lower alkyl, eg 2-carboxy-2-propyl, carbamoyl, lower alkylcarbamoyl, eg methylcarbamoyl, or amino-lower alkyl, eg. 2-aminoethyl, wherein the group

233 133 3

of the formula = N-O-R has the syn (or Z) form, and salts, in particular pharmaceutically usable salts, of those compounds of the formula I which have salt-forming groups.

Particularly noteworthy are compounds of formula I, wherein η is 0 ,. Amino, T is a 1, 2,4-thiadiazole radical which is in the 5-position with Am and in 3-position with the group of the formula -C (= NOR ") -, R 2-lower alkyl-l-pyrazolio for example 2-methyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, for example 2-carboxymethyl-1-pyr-azolene, 2-lower-alkoxycarbonyl-lower alkyl-1-pyrazolio, eg 2-methoxycarbonylmethyl-1-pyrazolio, 3-lower alkyl-1-triazolio, e.g. 3-methyl-1-triazolio, or a pyridiniogroup of formula A, for example hydroxy-lower alkylpyridinio, e.g. 4-hydroxymethylpyridinio, carboxy-lower alkylpyridinio, e.g. 3-carboxymethylpyridinio, sulfo-lower alkylpyridinio, e.g. 4- (2-sulfoethylpyridinio), halopyridinio, e.g. 3-bromopyridinio, carboxypyridinio, e.g. 4-carboxypyridinio, sulfopyridinio, e.g. 3-sulfopyridinio or aminocarbamoylpyridinio, e.g., 2-amino-5-carbamoylpyridinio, and R is hydrogen, lower alkyl, e.g. Methyl, carboxy-lower alkyl, e.g., 2-carboxy-2-propyl, carbamoyl or lower alkylcarbamoyl, e.g. Methylcarbamoyl, where the group of the formula = N-O-R has the syn (or Z) -form, and salts, primarily pharmaceutically acceptable salts of compounds of the formula I.

Of particular note are compounds of the formula I in which η is 0, At the amino, T is a 1,2,4-thiadiazole-t-t which is in the 5-position with Am and in the 3-position with the group of the formula -C ( = NOR ₂ ) -, R 2-lower alkyl-l-pyrazolio, for example 2-methyl-l-pyrazolio or a pyridinio of the formula A, for example Hydroxyniederalkylpyridinio, eg 4-hydroxymethylpyridinio, Carboxyniederalkylpyridinio, eg 3-Carboxymethylpyridinio, Halogenpyridinio, eg 3-bromopyridinio, or carboxypyridinio, for example 4-carboxypyridinio, and R denotes lower alkyl, for example methyl or carboxy-lower alkyl, for example 2-carboxy-2-propyl or aminocarbamoylpyridinio,

eg. 2-amino-5-carbamoylpyridinio, where the group of the formula = NOR -'die syn (or Z) -form, as well as salts, in the first: line pharmaceutically acceptable salts of compounds of formula I.

Above all, the present invention relates to the compounds of formula I described in the examples, and their salts, in particular their pharmaceutically acceptable salts.

The following compounds of formula I alone should be emphasized:

7β- [2- (5-Amino-1,2,3-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (1-carboxy-pyridiniomethyl) -thyD-S-cephenr-1-carboxylate, 7β- [ 2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamido] -3- (3-carboxymethylpyridiniomethyl) -3-cephem-4-carbo-

xylate, '

7β- [2- (5-Amino-l * 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxy-iminoacetamido] -3- (2-methyl-1-pyrazoliomethyl) -3- cephem-4-carboxylate, 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyimino * acetamido] -3- (2-methyl-1-pyrazoliomethyl) - 3-Cephem-4-carboxylate, 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetanido] -3- (3-bromopyridiniomethyl) -3-cephem- 4-carboxylate, and 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate ,

Compounds of the formula I and salts of such compounds which have a salt-forming group are prepared, for example, by reacting

a) in a compound of the formula

233133 ό

(O)

H H · ί

cocr '

wherein the index η is O or 1, R are those mentioned under formula I.

Has meanings which 7β-amino group is optionally protected by a group permitting the acylation reaction and the 4-carboxy group is optionally protected, the 7β-amino group is reacted by reaction with an acyl radical of a carboxylic acid of the formula

Am-T-C-C-OH (III)

Il N

introducing acylating agent, wherein Am, T and R have the meanings mentioned under formula I and existing functional groups are optionally protected, acylated or

b) for the preparation of a compound of the formula I in which η is 0, a 2-cephem compound of the formula

^{H H}

o:: s

Am-TCB-NH - ♦ - ^ ^X , ·

I "π LJ ⁽¹ m ν N 0 - ^ - Ch ₂ R ₁

in which the 4-carboxyl group and further functional groups are optionally protected, isomerized to the corresponding 3-caphem compound or

c) a compound of the formula

cc)

a, a 0 HHT

Am-TCC-HN-ppj _{(v) j}

COCF

wherein η is 0 or 1, Am, T and R have the meanings given under formula I and wherein the ^ .- carboxyl group and further functional groups are optionally protected, with a hydroxylamine derivative of the formula HNOR (VI), wherein R is the same under formula I

* · & G L

and if appropriate, functional groups have been protected, reacted or

d) for the preparation of a compound of the formula I in which hydrogen is a compound of the formula

(0)

-A

₀ H

/ Vi

in which η is 0 or 1, Am, T and R have the meanings mentioned under formula I and in which the 4-carboxyl group and further

functional groups are optionally protected, treated with a nitrosating agent or

e) for preparing a compound of the formula I in which Am is a free or a secondary amino group, T is a 1,2,4-thiadiazole radical which is in the 5-position with Am and in the 3-position with the group of the formula -C ( = NOR ") - connected, a compound of the formula

133 3

(O)

H ΗΪ ^Π

: -Ά

0-R_I

² CO (T.

in which η is 0 or 1, X is hydrogen, halogen or hydroxy and R has the meanings mentioned under formula I and wherein the 4-carboxyl group, and further functional groups are given if protected, with a salt of Rhodanwasserstoffsäure, or with a Isorhodanwasserstofüsäureester or, if X _{1 is} hydrogen, treated with Dirhodan or

f). a compound of the formula '

0 H ΗΪ ^η

0-R ₇ I

COOH

wherein "η is 0 or 1, Am, T and R_ have the meanings given under formula I and X- represents a substitutable by nucleophilic substitution radical and wherein the 4-Carbgronsgrippe and other functional groups are optionally protected, with the rest R. corresponding organic tertiary base or

g) for the preparation of compounds of formula I, wherein Am is a primary, secondary or tertiary amino group, a compound of formula

• · p

Tf ^ Τ »__ rt Ά 1-Tir / \

O - R '

wherein η is O or 1, T, R and R "are as defined for formula I and Y is halogen, with ammonia or a primary or secondary amine Am-H or a metal amide reacts and, if desired, an available compound of formula I is converted into another compound of formula I and / or, if desired, an available compound of formula I in which η is 0, converted into a compound of formula I wherein η is 1, and / or a compound of formula I, in which η is 1, converted into a compound of formula I, wherein η is 0, and / or in an available compound of the formula I in the protected J form functional groups in the free functional groups

and / or converts an available salt into the free compound of the formula I or into another salt, and / or converts an available free compound of the formula I with a salt-forming group into a salt and / or an obtainable mixture of isomeric compounds into the salt separates individual isomers.

233133

Process a) (acylation) :

In a starting material of formula II, the 7β-amino group is optionally protected by an acylation-permitting group. Such groups are, for example, organic silyl or stannyl groups, and also ylidene groups which, together with the amino group, form a Schiff's see 3ase. The mentioned organic silyl or stannous groups are z.3. those groups which are able to form a protected carboxyl group even with a carboxyl group S.2. These are primarily tri-lower alkylsilyl, especially trimethylsilyl. In the silylation or stannylation. for the protection of a 4-carboxyl group in a starting material of the formula II, when using

an excess of the silylation or stannylation agent, the 7β-amino group also silylated or stannylated. The ylidene groups mentioned are in the first line 1-aryl-lower alkylidene, in particular 1-arylmethylene groups, wherein aryl is especially for a carbocyclic, primarily monocyclic aryl radical, z.3. optionally substituted by niaderalkyl, hydroxy, lower alkoxy and / or nitro phenyl.

Other functional groups present in a starting material of the formula II can z.3. protected by the above-mentioned protecting groups. Preferably, the non-participating in the acylation reaction functional groups, in particular optionally present acylatable amino, hydroxy and mercapto groups are protected accordingly.

In an acyl radical of the acid of formula III, an amino group present may also be protected in ionic form, i.e. the starting material of formula III having such an amino group may be disclosed in U.S. Pat

Form of an acid addition salt, preferably with a strong inorganic acid such as a hydrohalic acid, e.g. Hydrochloric acid or sulfuric acid ,, are used.

Acylienmgsmittel containing the. Acyl radical serein carboxylic acid of formula III are, for example, the carboxylic acid itself or their reactive, functional derivatives.

If a free carboxylic acid of formula III, in which existing functional groups may be protected except the participating in the reaction 4-Carb0x7! Group, is used for acylation, the reaction is usually in the presence of suitable KondensatxonsmxttaIn, _ such as carbodiimides, for example Ν, Ν 'Diethyl, Ν, Ν'-dipropyl, N, N'-bicyclohexyl or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl 5-pheny1-1,2-OXaZoIxUr-S ¹ -sulfonate or 2-tert-3-butyl-5-methyl-1,2-oxazolinium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethyl-carbycarbonyl dihydroquinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a dissolving or diluent, e.g. Methylene chloride, dimethylformamide, acetone

nitrile or tetrahydrofuran, in a mixture of these solvents with water or water, if desired or necessary, while cooling or heating, for example in a temperature range of about -40 ⁰ C to about + 100 ⁰ C, preferably from about -20 ° C to about + 5O ⁰ C and / or in an inert gas, z-.3. Nitrogen atmosphere, carried out.

233 133

A reactive branched derivative of a carboxylic acid of formula III wherein any functional groups other than the carboxy group involved in the reaction may be protected is primarily an anhydride of such an acid, inclusive, and preferably a mixed anhydride. Mixed anhydrides are e.g. those with inorganic acids such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, further with hydrazoic acid, i. the corresponding acid azides, with a phosphorus acid, e.g. Phosphoric acid, ethylhephoric acid or phosphorous acid, or with a sulfur-containing acid, e.g. Sulfuric acid or with hydrocyanic acid. Other mixed anhydrides are e.g. those with organic carboxylic acids, such as with optionally, e.g. halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. Pivalic acid or trichloroacetic acid, or with Halbestera, in particular Niederalkylhalbestem of carbonic acid, such as the ethyl or Isobutylhalbester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, z. p-toluene sulfonic acid.

Other suitable for the reaction with the amino acid derivatives of an acid of formula III, wherein existing functional groups may be protected except the participating in the reaction carboxyl group are activated esters, for example, esters with vinylogous alcohols, d.-h. with enols, such as vinylogous lower alkenols or iminomethyl ester halides, e.g. Dimethyliminomethylestarchlorid,

prepared from the carboxylic acid of formula III and e.g. Dimethyl (1-chloroethylidene) '- iminium chloride of the formula (CHjN ^ C (Cl) CH Cl, which in turn can be obtained, for example, from N, N-dimethylacetamide and phosgene, aryl esters, for example by halogen, wia chlorine, and / or nitro, substituted phenyl star, for example 4-nitrophenyl, 2,3-dinitrophenyl or pentachlorophenyl, N-hetaroaromatic esters, such as N-3enztriazol-, for example 1-benzotriazole, or N-Diacyliminoester, such as N- Succinylimino or N-phthalyliminoester.

The acylation with a reactive functional derivative of a carboxylic acid is Γοχϋβΐ III, ζ.Ξ. a * corresponding. Anhydride, in particular an acid halide, is preferably in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example trimethylamine, triethylamine or astyl-diisopropylamine, or N, N-Diniaderalky! -Aniline For example, N, N-dimethyl, aniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholines, such as N-methylmorpholine, or a pyridine-type base, eg, pyridine, an inorganic base, for example, an alkali metal or alkaline earth metal hydroxide , carbonate or hydrogen carbonate, for example, sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or a Qxirans, for example, a 1,2-Niederalkylenosids, such as ethylene oxide or propylene oxide.

The above acylations are preferably carried out in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxamide, such as a formamide, eg dimethylformamide, a halogenated hydrocarbon, eg methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, eg acetone, an ester, eg ethyl acetate , or a nitrile, for example acetonitrile, or a mixture thereof, if necessary or desired, at reduced or elevated temperature, for example in a temperature range of about -40 ⁰ C to about + 100 ⁰ C, preferably from about -1O ⁰ C to about +50 ⁰ C, and / or in an inert gas, .zB nitrogen atmosphere.

Acylation may also be accomplished by use of a suitable derivative of the Formula III acid in the presence of a suitable acylase. Such acylasans are known and can be formed by a number of microorganisms, for example by Acetobacter, such as Acetobacter aurantium , Achromobacter, such as Achromobacter aeris , Aeromonas, such as Aeromonas hydrophila, or Bacillus, such as Bacillus

megaterium 400 .In such an enzymatic acylation

in particular amides, esters or thioesters, such as lower alkyl, z.3. Usually, such acylation is carried out in a nutrient medium containing the corresponding microorganism, in a filtrate of the culture broth or, if appropriate after isolation of the acylase, after adsorption to a carrier, in a methyl ester or ethyl stearate aqueous, optionally containing a buffer medium, ζ.Έ>. in a temperature range of about + 2O ⁰ C to about -, preferably at about +37 "C performed.

A reactive functional derivative of an acid of formula III employed in the acylation reaction may be formed in situ , if desired. So you can z.3. make a mixed anhydride by reacting an acid of formula III, optionally with appropriately protected functional groups, or a suitable salt thereof, z.3. an ammonium salt, which z.3. with an organic base such as pyridine or 4-methylmorpholine. is formed, or a metal, z, 3. Alkali metal salt, with a suitable acid derivative, for example a corresponding acid halide, an optionally substituted lower alkanecarboxylic acid, eg trichloroacetyl chloride, a half ester of a Kohlensäurehalbhalogenids, eg ethyl chloroformate or -isobuty !, or with a halide of a Diniederalky! Phosphoric acid, z.3. Diäthylphosphorbromidat, which can be formed by reacting triethyl phosphite with bromine, is reacted. The mixed anhydride thus obtained can be used without isolation in the acylation reaction.

Process b) · (isomerization) :

 In a 2-cephem starting material of the formula IV, the optionally protected 4-carboxyl group preferably has the II configuration.

2-cephem compounds of formula Γ7 can be isomerized by treating them with a weakly basic agent and isolating the corresponding 3-caphem compound. Suitable isomerizing agents are e.g. organic, nitrogenous bases, especially tertiary heterocyclic bases of aromatic character, primarily pyridine-type bases such as pyridine itself, as well as picolines, collidines or lutidines, furthermore quinoline, tertiary aromatic bases, e.g. those of the aniline type, such as Ν, Ν-di-lower alkylanilines, e.g. N, N-dimethyl, aniline or Ν, Ν-diethylaniline, or tertiary aliphatic,, azacycloaliphatic or araliphatic bases, such as tri-lower alkylamines, e.g. Trimethylamine or Ν, Ν-diisopropylethylamine ,. N-lower alkyl azacycloalkanes, e.g. N-methylpiperidine, or N, N-di-lower alkylphenyl-lower alkylamines, e.g. Ν, Ν-dimethylbenzylamine, and mixtures of such basic agents as the mixture of a pyridine-type base, and a tri-lower alkylamine, e.g. Pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, especially of medium to strong bases with weak acids, such as alkali metal or ammonium salts of Nxederalkancarbonsäuren, e.g. Sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, as well as other analogous bases or mixtures of such basic agents.

In the isomerization of 2-cephem compounds of formula IV with basic agents, it is preferred to operate in anhydrous medium, in the presence or absence of a solvent such as an optionally halogenated, eg chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon or solvent mixed, wherein used as reactants under the reaction conditions liquid bases can simultaneously serve as a solvent, optionally with cooling or with heating, preferably in a temperature range from about -30 ⁰ C to about +100 ⁰ C, in an inert gas, eg nitrogen atmosphere , and / or in a closed vessel.

233

So available 3-cephem compounds of the formula I can be prepared in a manner known per se, e.g. separated by adsorption and / or crystallization, of any remaining 2-Caphem starting materials.

The isomerization of 2-csphem compounds of the formula IV to the corresponding 3-cephem compound is preferably carried out by wan these oxidized in 1-stallung, if desired, optionally separating isomer mixtures of the formed 1-oxides, and the thus obtainable 1-oxides reduced the corresponding 3-cephem compounds.

As suitable oxidizing agents for the oxidation in

Position of 2-caphem compounds of formula IV are inorganic peracids, which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids, with a Dissociation constant of at least 10 in question. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarbon and persulfonic acids, which may be added as such or formed in situ by use of at least one equivalent of hydrogen peroxide and a carboxylic acid. It is expedient to apply a large excess of the carboxylic acid, if, for example, acetic acid is used as Lösungsmittal. Suitable peracids are z.3, performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluenesulfonic acid.

The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid having a dissociation constant of at least 10, it being possible to use low concentrations, for example 1-2% and less, but also larger amounts of the acid. The effectiveness of the

Mixture primarily based on the strength of the acid. Suitable mixtures are e.g. those of hydrogen peroxide with acetic acid. Perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable catalysts. Thus, for example, oxidation with percarboxylic acids can be catalyzed by the presence of an acid having a dissociation constant of at least 10 ^: 1, the effectiveness of which depends on its strength. Acids suitable as catalysts are, for example, acetic acid. Perchloric acid and trifluoroacetic acid. Usually, at least equimolar amounts of the oxidizing agent are used, preferably a slight excess of from about 10% to about 20%, although larger excesses, ie up to 10 times the amount of oxidizing agent or more, can be used. The oxidation is carried out under mild conditions. for example, at temperatures of about -50 ⁰ C to about + 10O ⁰ C, preferably from about -10 ⁰ C to about -H0 ° C performed.

The reduction of the 1-oxides of 3-cephem compounds can be carried out in a manner known per se, by treatment with a reducing agent. if necessary, in the presence of an activating agent. Suitable reducing agents are, for example: catalytically activated hydrogen, using noble metal catalysts containing palladium, platinum or rhodium, which are optionally used together with a suitable support material, such as carbon or barium sulfate; reducing tin, iron, copper or manganese cations which are in the form of corresponding compounds or complexes of inorganic or organic type, e.g. as tin (II) chloride, fluoride, acetate or formate, ferrous chloride, sulphate, oxalate or succinate, cuprous chloride, benzoate or oxide, or manganese (II) chloride, sulfate, acetate or oxide, or as complexes, eg with ethylenediaminetetraacetic acid or nitrolotriacetic acid; reducing dithionite, iodine or iron II

'- 36 -

cyanide anions which are used in the form of corresponding inorganic or organic salts, such as alkali metal, eg sodium or potassium dithioxide, sodium or potassium iodide or iron 11-cyanide, or in the form of the corresponding acids, such as iodic acid ; reducing trivalent inorganic or organic phosphorus compounds such as phosphines, furthermore esters, amides and halides of the phosphonous, phosphine. or phosphorous acid, and these phosphorus oxygen compounds corresponding phosphorus-sulfur compounds, wherein organic radicals are primarily aliphatic, aromatic or araliphatic radicals, z.3. optionally substituted lower alkyl. Phenyl or phenyl-lower alkyl, e.g. Triphenyphine, tri-n-butylphosphine, diphenylphosphonoic acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenesphosphonous dimethylester, butanphosphonous acid methylstar, phosphoric acid triphenylestar, phosphorous acid dimethylester, phosphorus trichloride, .. phosphorus tribromide, etc .; reducing halosilane compounds which have at least one bound to the silicon atom · 'hydrogen atom, and which except halogen, such as chlorine, bromine or iodine, and organic radicals, such as aliphatic or aromatic groups, z.3. optionally substituted lower alkyl or phenyl, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, or dimethylchlorosilane, as well as halosilane compounds wherein all hydrogens are replaced by organic radicals such as tri-lower alkylhalosilane, e.g. Trimethylchlorosilane or trimethyliodosilane, or cyclic, sulfur-containing silanes, such as l, 3-dithia-2,4, -disilacyclobutane or 1,3,5-trithia-2,4, 6-trisilacyclohexane, their silicon atoms by hydrocarbon radicals, in particular lower alkyl are substituted, for example 2. 2,4,4-tetramethyl-1,3-dithia-2,4-disilacyclobutane or 2,2,4,4,6,6-hexamethyl-1,3,3,5-trithia-2,4,6 trisilacyclohexane, ete .; reducing quaternary chloromethyleniminium salts, in particular chlorides or bromides, in which the imino group is replaced by a bivalent or two monovalent organic radicals, such as, where appropriate,

substituted lower alkylene or lower alkyl, such as N-chloromethylene-N, N-diethyliminum chloride or N-chloromethylenepyrrolidinium chloride; or complex metal hydrides, such as sodium borohydrides. in the presence of suitable activating agents, such as cobalt-II-chloride, as well as borane dichloride "

As activating agents used together with those of those mentioned above for reducing agents which themselves do not have Lewis acid properties, i. are used in the first place together with the dithionite, iodine or iron-II cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in catalytic reduction, in particular organic carboxylic and sulfonic acid halides, furthermore sulfur, phosphorus or silicon halides with second order or higher second-order hydrolysis equivalent than 3-benzoyl chloride, eg, phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivaloyl chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenesulfonylacetic acid, dimethylchlorosilane or trichlorosilane, acid anhydrides such as trifluoroacetic anhydride, or cyclic sultones such as ethanesultone, propanesultone, 1, Mention of 3-butane sultone or 1,3-hexane sultone.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, in which selection is determined primarily by the solubility of the starting materials and the choice of the reducing agent, so z.3. Ni aderalkancarboxylic acid or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. Benzene, methylene

chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters or nitriles, e.g. Acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, e.g. Dimethylformamide or hexamethylphosphoramide, ether, ζ.3. Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. Acetone, or sulfones, especially aliphatic sulfones, e.g. Bimethylsulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably containing no water. It is usually carried out at temperatures of about -20 ° C to about 100 "C, wherein when using very reactive activating agents · the reaction can be carried out even at lower temperatures.

Process c) (formation of the optionally substituted hydroxyimino group) :

In a starting material of the formula V in which the 4-carboxyl groups and other functional groups are optionally protected, the oxo group in the 7β-acylamido group which does not belong to the amide group can be converted into an optionally O-substituted hydroxyimino group by treatment with a hydroxylamine derivative of the formula VI become. The reaction of a starting material of the formula V with a hydroxylamine derivative of the formula VI is carried out in a customary manner, for example by reacting the two reactants in a solvent such as water or an organic solvent such as an alcohol, for example methanol, at a slightly elevated or reduced temperature. For example, in a temperature range from about -20 ⁰ C to about + 100 ⁰ C, preferably from about 0 ⁰ C to about 30 ⁰ C, optionally in an inert gas such as nitrogen atmosphere, is reacted. The hydroxy-1-amine compound of formula VI may also be present in situ , for example from one of its salts, such as a hydrohalide such as hydrochloride, by treatment with an inorganic base such as an alkali metal hydroxide, eg sodium hydroxide, or an organic base such as a tertiary amine , for example a tri-lower alkylamine, such as triethylamine or ethyl

!. W w w _ 39 -

diisopropylamine, or a heterocyclic tertiary base such as pyridine.

Method d) (formation of the unsubituted hydroxyimino group):

In a starting material of the formula VXI, the functional groups are preferably protected. Suitable nitrosating agents are nitrous acid and derivatives derived therefrom, such as nitrosyl halides, e.g. Nitrosyl chloride or nitrosyl bromide, salts of nitrous acid, such as alkali metal salts, e.g. Sodium or potassium nitrite, or in particular esters of nitrous acid, such as corresponding lower alkyl esters, e.g. Butyl, pentyl or especially Isoamylnitrit. If one uses as Nitxqsierungsmittel. Salt of nitrous acid, then, the reaction is preferably in the presence of a strong inorganic or organic acid, z.3. Chloric acid, sulfuric acid, formic acid or acetic acid, carried out. When using a nitrous acid sstar, the reaction is preferably carried out in the presence of a strong 3ase, such as an alkali metal alkoxide.

The nitrosation is carried out in a suitable solvent, such as water, a carboxylic acid, for example acetic acid, a lower alkanol, for example methanol or ethanol, an ether, for example dioxane or tetrahydrofuran, or a hydrocarbon, for example hexane or benzene, or in mixtures thereof, if necessary Cooling or heating, in particular in a temperature range of about -15 ⁰ C to about room temperature, and / or carried out in an inert gas atmosphere.

Process e) (formation of the aminothiadiazolyl group) :

In a starting material of the formula VIII, X as halogen is, for example, chlorine or iodine, but preferably bromine. Suitable salts of Rhodanwasserstoffsäure are, for example, corresponding alkali, alkaline earth or heavy metal salts, such as the sodium, potassium,

Magnesium or 31eirh.odan.id, or ammonium thiocyanides, wherein the ammonium group is derived from ammonia or from organic nitrogen bases, 2.3. Ammonium or mono-, di-, tri- or Tetraniederalkylammoniumrhodanid, wherein lower alkyl z.3, methyl, ethyl or isopropyl. - - -

Suitable isorhodanhydrates are, for example, isorhodane hydrogen tris-lower alkyl esters, which are also called lower alkyl isothiocyanates, such as methyl, ethyl, propyl or butyl isothiocyanate.

The condensation of compounds of formula VIII with a salt of rhodanic acid or with dirhodane gives compounds of formula I, wherein Am is a primary amino group, while the condensation with. an isorhodanic acid ester gives a compound of the formula I in which Am is a free secondary amino group, for example a niaderalkylamino group.

The reaction is preferably carried out in an inert solvent such as a lower alkanol, eg methanol, ethanol, propanol or isopropanol, an ether such as diethyl ether, dioxane or tetrahydrofuran, an amide such as dimethylformamide, an aliphatic or aromatic hydrocarbon such as hexane, benzene or toluene , or even in a mixture thereof, and if necessary, with cooling or heating, ie at temperatures between about -80 ⁰ C to about + 100 ⁰ C, preferably between about -20 ⁰ C to about + 20 ⁰ C, and / or carried out in an inert gas atmosphere.

A starting material of formula VIII, wherein X is halogen, can also be prepared in situ , optionally in the presence of the rhodanhydride salt, for example by reacting a compound of formula VIII wherein X _{1 is} hydrogen in one of said solvents with a hypohalite , z.3. Sodium or potassium

hypobromite, or with a halogen and an alkali metal base, such as. a hydroxide, carbonate or lower alkoxide, for example with bromine, and sodium methylate or potassium carbonate treated. The halogenation takes place preferably with cooling, for example at a temperature of about -15 "C to about 0 ⁰ C instead.

A compound of formula VIHiworin S may also be prepared in situ , for example by treating a compound of formula VIII wherein X is hydrogen with an oxidizing agent such as hydrogen peroxide.

The reaction of a starting material of the formula. VIII, wherein X is hydrogen, with dirhodane is preferably also carried out in one of said inert solvent and under similar Reaktionsbedingtingen ♦ Optionally, an acid addition salt of a compound of formula VIII, which is converted in situ in the Fraie compound, or Dirhodan can be formed in situ , z.3. from a rhodanide, eg, lead rhodanide, and a halogen, eg, bromine.

Method f) (introduction of an .ATnmonio group) :

In a starting material of the formula IX in which the 4-carboxy group and also further functional groups are optionally protected, the group X "preferably represents an esterified hydroxy group, in particular an ether which is an organic acid, such as lower alkanecarboxylic acid, eg formic or acetic acid an inorganic acid such as hydrohalic acid, eg, hydrobromic or hydroiodic acid, esterified hydroxy group.

The reaction with a corresponding to the radical R tertiary organic base, in particular an optionally substituted pyridine is under neutral or weakly acidic conditions in a pH range of 3-8, preferably at about pH 6.5, in the presence of water and optionally in one with

Made of water-miscible organic solvent. The weakly acidic conditions can be adjusted by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or else sulfuric acid. As organic solvents, for example, water-miscible solvents such as lower alkanols, e.g. Methanol or ethanol, lower alkanone, e.g. Acetone, trichloroalkanecarboxamides, e.g. Dimethylformamide, or. Lower alkanecarboxylic acid nitriles, z.3. Acetonitrile, to be used. Furthermore, z.3. to increase the yields of the reaction mixture suitable salts, such as alkali metal, "eg sodium and especially potassium salts of acids, such as hydrogen halides, eg hydrogen chloride and in particular hydrogen iodide, and thiocyanic acid, or of organic acids, such as lower alkanecarboxylic acids, For example, acetic acid, in particular potassium iodide and potassium thiocyanate, also salts of suitable anion exchange ax acids, eg, acetic acid, z.3 liquid ion exchangers in salt form, z.3 Amberlite LA-I (liquid secondary amines with a molecular weight of 351-393; oil-soluble and water-insoluble; .mAeq / g = 2.5-2.7, z.3 in acatate form) can be used for this purpose.

Ammonio groups R 1, may advantageously be introduced using an intermediate of formula IX, wherein X - represents a substituted, especially an aromatic, substituted carbonylthio group and, in particular, the benzoylthio group. Such an intermediate can be 2.3. by reacting a starting material of formula IX, wherein X- is an esterified hydroxy group, especially lower alkanoylxy, eg acetyloxy, with a suitable salt, such as an alkali metal, eg sodium, salt of a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, eg thiobenzoic acid. The intermediate is then reacted with the tertiary amine base, especially a corresponding heterocyclic base such as an optionally substituted pyridine, using the

desired Anmoniumverb indung receives. The reaction is usually carried out in the presence of a suitable desulfurizing agent, in particular a mercury salt, e.g. Mercury II perchlorate, and a suitable solvent or diluent or mixture, if necessary, under cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere, performed.

Method g) (Exchange of 7 for Amine AmH) :

In a compound of the formula X, Y is bromine, iodine or preferably chlorine.

The amines Am ~ H are in free form, d.h.-. as ammonia, lower alkylamine, such as methyl, ethyl, propyl or butylamine, or di-lower alkylamine, such as dimethyl, diethyl, dipropyl, dibutyl, methylethyl, ethylpropyl, methylbutyl, propylbutylamine, or the like, or as metal azides thereof, for example, as alkali metal amides, such as lithium, sodium or potassium amides used.

The exchange reaction preferably takes place in an inert organic solvent such as 3-enol, toluene, dimethylformamide, tetrahydrofuran, or the like, or, in the exchange of Y for NK, also in liquid ammonia, the acid capturing H-Y. Bases, such as tertiary amines, z.3. Aethyldiisopropylamin, pyridine, or the like can be added.

The reaction takes place, depending on the reactivity, at room temperature or under cooling or heating from about -70 ⁰ C to about +100 ⁰ C, preferably between about -70 ⁰ C and about + 5O ⁰ C.

The compounds of the formula I obtainable according to the invention can be converted into other compounds of the formula I in a manner known per se.

233133 3

Subatization of a hydroxyimino group ; In a compound of formula I in which the 4-carboxy group and other functional groups, in particular those functional groups which can be substituted analogously to the hydroxyimino group, are preferably protected, the hydroxy group of the unsubstituted hydroxyimino may be known per se Way be etherified.

Suitable etherifying agents are, for example, diazonium halides, for example diazomethane, esters of alcohols of the formula R-OH, in which R represents optionally substituted lower alkyl or cycloalkyl, with strong inorganic or organic acids, such as lower alkyl or cycloalkyl halides, for example -chlorides, -bromides or iodides, or di-lower alkyl sulfates, furthermore fluorosulfonic acid lower alkyl esters, or optionally halogen-substituted methanesulfonic acid lower alkyl esters, as well as suitable acetals, z.3. P-lower alkoxy-lower alkanes , tri-R 1 -osonium salts (so-called corn-salt), di-R-O-carbenium salts or di-R-halium salts, where R "represents optionally substituted lower alkyl or cycloalkyl, such as tri-lower alkyloxonium salts, and di-lower alkoxycarbenium or di-lower alkyl halonium salts , in particular the corresponding salts with complex, fluorine-containing acids, or-1-R -3 ^ -Aryltriazenverbindungen, wherein R is optionally substituted lower alkyl or cycloalkyl and aryl is preferably an optionally substituted phenyl radical. These etherifying reagents are used in a manner known per se, for example as described above, usually in a suitable solvent or solvent mixture, if necessary in the presence of a condensing agent, such as a 3ase, under cooling or heating, in a closed vessel under pressure and in or an inert gas, eg nitrogen atmosphere.

The 'introduction of a carbamoyl group -CC = O) -NHR.- instead of the hydrogen atom is done in a conventional manner by carbamoylation. To this tick is a compound of the formula I in which

W * J% 0 - 45 -

R is hydrogen and any reactive groups which are not to be carbamoylated or which may consume or destroy the reagents are in protected form, optionally treated stepwise with a carbamoylating agent Suitable carbamoylating agents are reactive derivatives of carbamic acids R-NH- (= O) 0H , in particular isocyanates RN = C = O or mixed anhydrides, eg carbamic acid chlorides R-NH-C (= O) Cl, which can also be prepared in situ from phosgene and an amine R-NH ,,.

The conversion with isocyanates is carried out in one of the usual "inert solvents, for example an optionally halogenated hydrocarbon," for example. Benzene, benzene or methylene chloride, an ether, e.g. Diethyl ether, dioxane or tetrahydrofuran, or an ester, e.g. Ethyl acetate, optionally in the presence of a basic catalyst, for example a tertiary amine, e.g. Triethylamine or pyridine, at. Room temperature or slightly lower

i-r ·

elevated or elevated temperature, for example between -20 ^e C and + 5O ⁰ C.

For conversion with a mixed anhydride of carbamic acid, the alcohol group is preferably first metallized, for example with an alkali metal hydride, e.g. Sodium or lithium hydride. The compound of the formula I which has been metallated on the hydroxy group can also initially be treated with phosgene and subsequently with the amine R-NH and in this way be carbamoylated stepwise. These reactions also take place in an inert solvent and at the temperatures given above.

Substituting an amino group : An optionally monosubstituted amino group Am in a compound of the formula I which can be obtained according to the invention, in which the other functional groups present, in particular those which can be substituted analogously as an amino group, are preferably protected, can be in per se

known manner, e.g. by treating with a reactive ester of a lower alkanol, such as a lower alkyl halide, e.g. chloride, bromide or iodide, preferably in the presence of a solvent, or, with the introduction of methyl, with formaldehyde in the presence of. Be substituted formic acid. Furthermore, one, optionally monosubstituted amino group Am with a suitable derivative of a lower alkanecarboxylic acid, such as a corresponding halide, ζ, B-. Chloride, and in a thus obtainable lower alkanoylamino compound the carbonyl group, e.g. by reducing it to a methylene group by treatment with a suitable hydride reducing reagent, such as diborane. The substitution reaction is carried out in a manner known per se, preferably in the presence of a solvent, and if necessary under cooling or heating and / or in an inert gas atmosphere.

Formation of the 1-oxide : A compound of the formula I, in which η is, can be converted by oxidation, for example by one of the oxidation methods described under process b), into a compound of the formula I in which η is 1.

Reduction of the 1-oxide ; A compound of formula I, wherein η is, can be prepared by reduction, z.3. according to one of the reduction methods described under process b), into a compound of formula I, wherein η is 0, are converted.

Abspaltung von.Schutzgruppen : In an obtained compound of formula I, wherein one or more functional groups are protected, these, for example, protected carboxyl, amino, hydroxyl and / or sulfo groups, in a conventional manner, by solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or chemical reduction, optionally in stages. or released simultaneously.

Thus, one can tart.-Niedaralkoxycarbonyl or in 2 -step by an organic silyl group or in one-step by lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl or optionally substituted Diphanylmethoxycarbonyl eg by treatment with. a suitable acid, such as formic acid or trifluoroacetic acid, optionally without adding a nucleophilic compound, such as phenol or anisole, into free carboxyl. Optionally substituted benzyloxycarbonyl may be 2-3. be liberated by hydrogenolysis, ie by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can also be obtained by means of chemical reduction, for example by treatment with an alkali metal, eg. Sodium dithine, or with a reducing metal, for example zinc, or a metal salt, such as a chromium (II) salt , for example, chromium-II chloride _s usually in the presence of a hydrogen-donating Mittal, is capable of producing together with the metal nascent hydrogen, such as an acid, primarily a suitable carboxylic acid, such as an optionally substituted, for example hydroxy-substituted, Niederslkancarbonsäura, including Acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chloz-mandelic acid or tartaric acid, or anines alcohol or thiol, preferably adding water, convert into free carboxyl. By treating with a reducing metal or metal salt, as described above, one can also convert 2-halo-lower alkoxycarbonyl, optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group, or aroylmethoxycarbonyl into free carboxyl, wherein aroyl-methoxycarbonyl also can be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxy-carbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride,

2 3 3 13 3

e.g. Sodium or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether"), or with a flubrid of an organic quaternary 3asa, such as tetra-lower alkylammonium fluoride or tri-lower alkylarylanmonium fluoride, e.g. Tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or di-niyl-ethylac-stamide, are esterified with an organic silyl or stannyl group such as tri-lower alkylsilyl or -stannyl, 2.3.trimethylsilyl, the carboxyl can be solvolyzed in a conventional manner eg by treatment with water, an alcohol or acid. '

A protected amino group, e.g. Am, one sets in per se known and, depending on the nature of the protecting groups in various ways, preferably by solvolysis or reduction, free. Optionally, after conversion of a 2-bromo-lower alkoxycarbonyl-amino group into a 2-iodo-lower alkoxycarbonylamino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino may be used, for example, as follows: 2-HalogenniaderalkoxycarbotiylaTTn.no by treating with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonylamino may also be prepared by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4- nitrobenzyloxycarbonylann.no also by treatment with an alkali metal, e.g. Sodium dithionite, are split. Optionally substituted diphenylmethoxycarbonylamino, tertiary-lower alkoxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino may be prepared by treatment with a suitable acid, e.g. Formic or trifluoroacetic acid, optionally substituted benzyloxycarbanylamino e.g. by means of hydrogenolysis, .d.h. by treating with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst, optionally substituted triarylmethylamino, formylamino or 2-acyl-lower alk-1-en-yl-amino, e.g. by treating with an acid,

vis mineral acid, eg hydrochloric acid, or an organic. Acid, ses Ants- ₅ acetic or Trifluoressigsäura, optionally in the presence of water, and a protected with an organic SiIy1 or Sfcannyl group amino group are released, for example by hydrolysis or alcoholysis. Sine by 2-haloacetyl, z.3. 2-chloroacetyl, protected amino group can be liberated by treatment with thiourea in the presence of a 3ase, or with a thiolate salt such as an alkali metal thiolate, thiourea and subsequent solvolysis such as alcoholysis or hydrolysis of the resulting condensation product. A 2-substituted silyl-methoxycarbonyl-protected amino group may also be converted to the free amino group by treatment with a fluoride anion-providing salt of hydrofluoric acid as described above in connection with the release of a suitably protected carboxyl group. A phosphorus, phosphine or phosphine amido group can z.3. by treatment with a phosphorus-containing acid, such as a phosphoric, phosphonic or phosphinic acid, z.3. Orthophosphoric acid or polyphosphoric acid, an acidic ester, z.3. Mouomethyl, monoethyl, dimethyl or diethyl phosphate or monomethylphosphonic acid: or an anhydride thereof, such as phosphorus pentoxide, are converted into the free amino group.

An amino protected in the form of an azido group is z.3. converted by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, eg methylene chloride, or in water or a mixture of water and an organic solvent such as an alcohol or dioxane. at about 20 ⁰ C to 25 ° C, or under cooling or heating performed.

133

A protected by a suitable acyl group, an organic silyl or Stannylgnippe or by optionally substituted 1-Phenylniedcrslkyla Hydrcxygrupp * = was released as aiiie appropriately protected amino group. A 2,2-dichloroacatyl protected hydroxy group is e.g. by basic hydrolysis, while a hydroxy group etherified by tert-lower alkyl or by a 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radical is exemplified by acidolysis, e.g. by treatment with a "mineral acid or a strong carboxylic acid, e.g., trifluoroacetic acid.

A protected, in particular esterified, sulfo group is liberated analogously to a protected carboxyl group.

The described cleavage reactions are carried out under conditions known per se, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, z. Stickstoffafcnosphära.

Preferably, in the presence of multiple protected functional groups, the protecting groups are selected to simultaneously cleave more than one such group, for example acidolytically, such as by treatment with trifluoroacetic acid or formic acid, or reductive, such as by treatment with zinc and acetic acid, or with Hydrogen and a hydrogenation catalyst, such as a Pa lladium / coal / catalyst.

Salt formation : Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of the formula I with acidic groups, for example by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example "the sodium salt of a-ethyl-caproic acid, or with inorganic alkali metal or alkaline earth metal.

metal salts, .ζ.3. Sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of formula I are obtained in a conventional manner, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I which are e.g. contain a free carboxyl group, e.g. by neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.

Salts can be converted in the usual way in the free compounds, metal and ammonium salts ζ.3. by treatment with suitable acids, and acid addition salts e.g. by treating with a suitable basic Mittal.

G-amics of isomers can be prepared in a manner known per se, 2.3. fractionated crystallization, chromatography, etc. are separated into the individual isomers.

The method also includes those embodiments according to which compounds arising ils used as intermediates and starting materials, the latching handy method steps are carried out with these, or the process is discontinued at any stage; furthermore, starting materials may be used in the form of derivatives or formed during the reaction.

Preferably, such starting materials are used and the reaction conditions are selected so that one arrives at the compounds listed above as being particularly preferred.

Starting materials: those used in the process for preparing the compounds of

ν O I

'- 52 -

Starting materials used in the present invention are known or, if new, they can be prepared in a manner known per se.

The starting compounds of the formula II and III, and corresponding compounds having protected functional groups are known or can be prepared in a manner known per se.

The method of preparation of starting materials of the formula III is illustrated by the following reaction scheme for the preparation of a 2- (5-amino-1,2,2-thiadiazol-3-yl) -2-methoxyiminoacetic acid compound:

Level 2

(F)

(Am = protected amino group, R halogen)

lower alkyl; X = hydrogen or

Starting materials of formula IV may i.a. be obtained as a by-product in the preparation of compounds of the formula I. 2 B. when formed under basic conditions. They need not be in a pure form, but may be e.g. also be used in admixture with corresponding compounds of formula I.

Compounds of the formula V can be ζ ..3. by acylating compounds of formula II with compounds of formula D or a reactive functional derivative thereof, e.g. according to one of the methods described under method a).

Compounds of formula VTI may be prepared, for example, by acylating compounds of formula II with an acylating agent introducing the acyl of an acid of formula C, e.g. according to a method described under method a) can be obtained.

Compounds of formula VTII may be e.g. by acylating compounds of formula II with an acylating agent introducing the acyl of an acid of formula E, e.g. obtained by any of the methods described in Untar method a). Furthermore, it is possible, analogously to stages 6 and 7 in the scheme of the scheme for the preparation of starting materials of formula III, starting from compounds of formula

0 ^{H Ht}

^w · β ς

Il · V \

NsC-CC-HN - · ' T (H)

0-R, '

2 COOH

via compounds of the formula

(O)

0 H H ^

HN-C-C-C-HN = «OR N O =» '

COOH

zn reach the desired starting materials of the formula VIII. The compounds of the formulas H and J can in turn be obtained by acylation of compounds of the formula II with an acylating agent which introduces the acyl radical of an acid of the formula F or G, for example by one of the methods described under process a).

Starting materials of the formal ΙΣ can be 2.3. obtained, starting from the corresponding 7ß-amino-3- (S-CH -) - 3.-cephem-4-carbcnsäura compounds and the amino group 2.3. by treating with an acylating agent introducing the acyl radical of an acid of the formula III, 2.3. acylated according to one of the methods described under method a).

Compounds of the formula X can be prepared in various ways, for example analogously to the processes a) or b) or step 7, in particular by reacting, analogously to process a), in a compound of the formula II in which n, R- and R "denote and wherein the 7β-amino group is optionally substituted by an acylating group, acylating the 7β-amino group by treatment with an acylating agent introducing the acyl radical of a carboxylic acid of formula L, or by analogously to step 7, a compound of the formula VIII, wherein X _{1 is} hydrogen

and η, R and R have the meanings indicated, or a salt thereof, with a perhalomethyl mercaptan of the formula Ύ ... CSY , and if desired, carrying out the subsequent operations mentioned in the preparation of the compounds of the formula I.

New starting compounds, as well as intermediates and methods for their production are also the subject of the present invention.

The pharmacologically useful compounds of the present invention may e.g. are used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are preferably suitable for parenteral administration.

Preferably, the pharmacologically active compounds of the present invention are used parenterally, ζ.3. intramuscularly or intravenously, administrable to preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. from lyophilized preparations containing the active substance / alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and include adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by conventional solution or lyophilization processes, prepared and containing from about 0.1% to 100%, in particular from about '1% to about 50%, lyophilizates up to 100% of the active ingredient.

Compounds of the formula I can also be administered orally, ζ.B. i _n Verden form of capsules, administered. These contain the active ingredient, optionally together with suitable excipients, in the form of granules and in doses of about 0.2 to about 0.5 g per dosage unit.

Depending on the nature of the infection and condition of the infected organism, one uses daily doses of about 0.5 g to about 5 g s.c. for the treatment of warm-blooded animals weighing about 70 kg.

Particularly valuable pharmacologically are the following compounds according to the invention:

7β- [2- (5-Amino-1 ', 4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-carboxypyridiniomethyl) -3-cephem-4-carboxylate, 7β- [ 2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamido-SO-carboxy-methylpyridiniomethyl-S-cephem-4-carboxylate,

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamidoJ-S - ^ - methyl-l-pyrazoliomethyO - ^ - ^ cephem Carboxylate, 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-methyl-1-pyrazoliomethyl) -3-cephem-4 carboxylate, 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (3-bromopyridiniomethyl) -S-cephem ^ -carboxylate, and 7β - [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate.

embodiments

The following examples serve to illustrate the invention.

Temperatures are given in degrees centigrade.

- 56A -

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade.

The following abbreviations are used in the examples:

BOC: tert-butyloxycarbonyl F: melting point

Thin Layer Chromatography: Opti-UPC plates from Antec are silica gel coated glass plates treated with dodecyltrichlorosilane (for reverse phase chromatography). ·

Example 1:

^a ) 78- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyimino-acetamido] - S - ^ - carboxy-pyridiniomethyl ^ - cephem ^ -carboxylate

Sine solution of 0.478 g (1.0 mmol) of sodium 7ß- [2- _(5-am i _n o l, 2,4-thiadia2ol-3-yl) -2-Z-methoxyiminoacetamido] - 3-acetoxymethyl 3-cephem-4-carboxylate in 1 ml of water is added to a 80 ° C solution of 0.17 g (1.39 mmol) of isonicotinic acid and 1.71 g of sodium iodide in 0.4 ml of water and heated to 70 for 2 hours ° stirred. After cooling to room temperature, the reaction mixture is poured onto 100 ml of cold acetone, the precipitate formed is filtered and dried. After chromatographic purification of the crude product (silica gel "Opti UPC", water) gives the uniform title compound with an Rf value of 0.25 (UPC ,, - plates, water / acetonitrile 6: 1); IR spectrum (Nujol): characteristic absorption bands at 3.05; 5.70; 6 -25; 9.60 _; u.

The starting material can be prepared as follows:

b) Sodium-7ß - (- 2- (5-AmJnO-1,2,4-thiadiazol · -3-yl) -2-Z-methoxyiminoacetamido] -3-aeoxymethyl-3-cephem-4-carboscyl at

7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid is dissolved in methanol-containing water (10 ml methanol / 500 ml of water) and the aqueous phase was adjusted to pH 6.8 with aqueous sodium bicarbonate solution. The solution is lyophilized and the resulting sodium salts are purified by chromatography on Silica gel "Opti UPC" (Antec) with water / acetonitrile 6: 1 to give the uniform title compound of Rf 0.30 (UPC "plates , Water / acetonitrile 6: 1),

F. from 150 ° (decomp.); UV spectrum (methanol): A (J): 234 (12240) nm; IR spectrum (nujol): characteristic absorption bands at 3.00; 5.65; 5.95; 6.20; 6:52; 8.10; 9,60 ^ i. -.

Ι J Ö J - 58 -

Example 2 :

a) 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop-2-yloxyiminoacetamido] -3- (3-carboxymethylpyridiniomethyl) -1-cephem 4-carboxylate

To a pre-heated to 80 ⁰ C solution of 6.6 g (44 mmol) of sodium iodide and 0.58 g (4.22 mmol) of pyridyl-3-acetic acid in 1.6 ml of dist. Water is added to a solution of 2.28 g (3.84 mmol) of disodium 7-β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Z] prepared separately therefrom. 2-carboxyprop-2-yloxyiminoacetamido] -S-acetoxymethyl-S-cephem-4-carboxylate in 4 ml. Water. After addition of 0.23 ml of acetic acid (100%) is stirred at 70 ⁰ C for 3 hours. The reaction solution is added with cooling to -20 ° in 150 ml of acetone. The precipitate formed is filtered off, in 40 ml of dist. Dissolved water and lyophilized. After chromatographic purification of the crude product (silica gel "Opti UPC ₉ ", water) to obtain the uniform title compound with an Rf value of 0.19 (UPC plates, water). IR spectrum: 2.95; 5.64; 6.27 and 6.52 u.

The starting material can be prepared as follows:

b) 2- (5-tert-Butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) acetic acid methyl ester

A mixture of 30.0 g (115.0 mmol / l of 5-tert-butoxycarbonyl-n'-1,2,4-thiadiazol-3-yl) acetic acid in 350 ml of methylene chloride is added successively to 26.16 g of NjN '. -Dicyclohexylcarbodiimide, 5.13 ml of absolute methanol and 1.71 g of 4-pyrrolidinopyridine and stirred for 3 hours at room temperature, followed by the addition of another 0.5 ml of absolute methanol and 2.6 g of N, N'-dicyclohexylcarbodiimide The precipitate is filtered off with suction, the filtrate is washed successively with aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo.The residue is triturated with diethyl ether to give the same title compound "of Rf value 0, 50 (silica, toluene: ethyl acetate 1: 1); IR spectrum

- 59 -

(CH-Cl-): characteristic absorption bands at 2.90; 5.75; 5.85; 6:50; 8.70 u. - -

^c ) 2- (5 "tert-Butoxycarbcnylamino-l, 2,4-thiadiazol-3-yl) -2-oxoacetic acid methyl ester

A suspension of 20.0 g (73.18 mmol) of 2- (5-tert-butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) acetic acid methyl ester and 22.0 g of selenium dioxide in 330 ml of abs. Dioxane is stirred for 3 hours at 95 °. After filtering the reaction mixture, the filtrate is concentrated in vacuo. The residue is diluted with ethyl acetate, washed successively with water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The title compound is obtained in the form of a foam of Rf 0.35 (silica gel, toluene: ethyl acetate 1: 1); I?, - spectrum (CH-ClJ: characteristic absorption bands at 2.95, 5.75, 5.85, 6.50 u.

d) 2- (5-tert-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-hydroxy -iminoacetic acid methyl ester

A suspension of 21.8 g (75.88 mmol) of 2- (5-tert-3 -utoxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2-oxoacetic acid methyl ester, 7.48 g of hydroxylamine hydrochloride and 9.8 ml Pyridine in 300 ml of 95% ethanol is stirred for 3 hours at room temperature. The reaction mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is extracted successively with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in a vacuum. The residue is crystallized from diethyl ether. The title compound is obtained at Rf 0.30 (silica gel, chloroform: methanol 95: 5); F. 131-132 °; IR spectrum (CH-Cl): characteristic absorption bands at 2.85; 5.75; 5.85; 6:50; 8.70; '8.90 ^ t.

- 60 -

e) 2- (5-tert-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-Z- (2-tert.

A solution of 1.4 g (6.27 mmol) of 2-bromoisobutyric acid tert, -

butyl ester and 1.84 g (14.03 mmol) of finely pulverized potassium carbonate in 12.50 ml of dimethylsulfoxide under nitrogen at room temperature with a solution of 1.70 g (5.62 mmol) of 2- (5 tert.-Butoxycarbonylamino-1, 2, 4-thiadiazol-3-yl) -2-hydroxyimino-acetic acid methyl ester in 7.5 ml of dimethyl sulfoxide and stirred for 14 hours at this temperature. The reaction mixture is evaporated at 30 ° in a high vacuum to dryness. The residue is taken up in 200 ml of ethyl acetate and washed successively with water, dilute hydrochloric acid (1 N), water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is crystallized from about 5 ml of ether to give the title compound of melting point 142-144 °.

f) 2- (5-tert-3uto: cycarbonylamino-1, 2,4-thiadiazol-3-yl) -2-Z- ' (2-tert-butoxycarbonylprop-2-yloxyimino) acetic acid

A solution of 11 g (22.55 mmol) of 2- (5-tert-butoxycarbonylamino-L, 2,4-thiadiazol-3-yl) -2-Z- (2-tert-butoxycarbonylprop-2 -yloxyimino) -acetic acid methyl ester in 290 ml of methanol and 96 ml. 2N sodium hydroxide solution at a temperature of 50 ° for 6 1/2 hours. The reaction mixture is evaporated at 35 ° in a high vacuum to dryness. The residue is taken up in 200 ml of water (distilled) and extracted once with 200 ml of ethyl acetate. The aqueous phase is covered with 200 ml of ethyl acetate and acidified with conc. Hydrochloric acid acidified. The ethyl acetate phase is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give the title compound is crystalline; TLC Rf value: 0.2 (silica gel, chloroform / methanol 4: 1); IR spectrum (dioxane): characteristic bands at 5.81; 5.74; 3.3 ^; F: 180-183 °.

- 61 -

g) 7β-f2- (5-tert-butoxycarbonylamino-1, 2,4-thiadiazol-3-yl) -2-Z- (2-tert-butoxycarbonylprop-2-yloxyimino) -acetamido] -3-acatoxy - ' methyl-S-rephem - ^ - carboxylic acid

A suspension of 15 ml of methylene chloride abs., 0.3 ml of dimethylformamide and 0.33 ml (7.84 mmol) of oxalic acid dichloride is stirred at -10 ° for 30 minutes under nitrogen. Then, 1.3 g (3.01 mmol) of 2- (5-tert-butoxycarbonylamino-L, 2, A-thiadiazol-3-yl) -2-Z- (2-tert-butoxycarbonylprop-2-yloxyimino ) Acetic acid added to the suspension. The resulting clear solution is stirred for 30 minutes at 0-5 ° under nitrogen. To this solution is added dropwise a freshly prepared solution of 0.87 g (3.19 mmol) of 7β-aminocephalosporanic acid in 18 ml of methylene chloride abs. And 3 ml of N, O-bis (trimethylsilyl) -acetamide and stirred at a temperature of 0 -5 ° under nitrogen for 16 hours. The reaction solution is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to dry sludge. The title compound of Rf 0.43 (silica gel, ethyl acetate / acetic acid 9: 1) is obtained; IR spectrum (Nuj οI): characteristic absorption bands at 5.6; 5.82; 6.04 μ.

h) Disodium 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxy- prop-2-yloxyimino) -acetamido] -acetoxymethyl-S-cephem ^ -carboxy lat

A solution of 2.3 g (3.35 mmol) of 7β- [2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-Z- (2-tert-butoxycarbonylprop .-2-yloxyimino) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in .12.54 ml (16.38 mmol) trifluoroacetic acid and 2.10 ml "(19.28 mmol) anisole is added at room temperature The reaction mixture is evaporated to dryness at 30 ° C. in vacuo, the residue is stirred with ether and the product is filtered off, then the product is dissolved in 28 ml of methanol and sodium ethylhexanoate is added The precipitated product is filtered off and dried under high vacuum to give the title compound with an Rf value of 0.78

- 62 -

(UPC plates, water / acetonitrile 4: D; IR spectrum (Nuj oil): characteristic absorption bands at 3.04, 5.68, 6.24, 6.57 and ~ '' ''

Example 3 :

7ß- [2- (5-Amino-l, 2,4-thiadia2ol-3-yl) -2-methylcarbamoyloxyiminoacetamido ] -3- (4-carboxypyridiniomethyl) -3-cephem-4-carboxylate (A) and

7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-hydroxyimino-acetamido] -3- (4-carboxypyridiniomethyl) -3-cephem-4-carboxylate (3)

From 1.50 g (2.88 mmol) of sodium 7β- [2- (5-amino-1, 2, 4-thiadiazol-3-yl) -2-methylcarbamoyloxyiminoacetamido] -3-acetoxymethyl-3-cephem- 4-Carboxylate, 0.49 g (3.98 mmol) of isonicotinic acid and 4.90 g (32.7 mmol) of sodium iodide in 4.2 ml of water are obtained analogously to Example 1, the title compound A with an Rf value of 0.30 (UPC plates, water / acetonitrile 6: 1) and the title compound 3 with an Rf of 0.55 (UPC ₁ "plates, water / acetonitrile 6: 1).

The starting material can be prepared as follows:

b) 2- (5-tert-butoxycarbonylamine-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetic acid

Sine "solution of 8.0 g (26.46 mmol) of 2- (5-tert-butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2-hydroxyiminoessigsäuremethylester in 175 ml of ethanol with 8.6 g The reaction mixture is concentrated under reduced pressure, the residue is dissolved in water, the solution is adjusted to pH 8.5 with dilute hydrochloric acid and extracted with ethyl acetate, the aqueous phase is separated off , adjusted to pH 2.0 with 2N HCl and extracted with ethyl acetate, the organic phase is separated off, washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation.

^w -63-

ether crystallized. The unitary title compound of Rf 0.60 (silica gel, s-butanol / glacial acetic acid / water 67:10:23) is obtained; F. 158-16O ^S (Zers.); IR spectrum (Nujol): characteristic absorption bands at 3.10; 5.85; 8.65 u.

c) 2- (5-tert-Butoxycarbonylamino-1, 2,4-thiadiazol-3-yl) -2-Z-methyl-carbamoyliminoacetic acid

A solution of 2.85 g (8.95 mmol) of 2- (5-tert-butoxycarbonyl-1-amino-l, 2,4-thiadiazol-3-yl) -2-hydroxyiminoacetic acid in 20 ml of tetrahydrofuran is added at 0-5 ° with 10 ml of methyl isocyanate and stirred at this temperature for 2 hours. The reaction mixture is mixed with η-hexane and the resulting precipitate is filtered off with suction. After Umkristalisation of the precipitate of methylene chloride to obtain the uniform title compound of. Rf value 0.25 (UPC plates, water / acetonitrile 6: 1); Έ. 124-127 °; IR spectrum (Nujol): characteristic absorption bands at 5.75; 5.85; 6.40 ^ i.

d) 7β- [2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl ] -2-Z -methylcarbamoylo: 2-cyanoacetamido] -3-aceto-3-methyl-3-caphein. 4- carboxylic acid, diphenylmethyl ester

1.05 g (3.70 mmol) of 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-Z-methylcarbamoyloxyiminoacetic acid and 0.4 ml of N-methylmorpholine are added at - 5 ° to a stirred suspension of a Vilsmeier reagent (prepared from 0.031 ml Oxalylchlprid and 0.29 ml of Ν, Ν-dimethylformamide in 10 ml of ethyl acetate). The mixture is stirred for 30 minutes at 0 ° and then cooled to -10 °. After addition of 1.357 g (3.1 mmol) of 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester is stirred for 2 1/2 hours at 0 °, then diluted with ethyl acetate and washed successively with water, phosphate buffer pH 8 , 0 and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Part of the crude product is purified by preparative layer

33

- 64 -

Chromatography with ethyl acetate. Man. receives the unitary title compound of Rf 0.60 (silica gel, ethyl acetate); IR Spetrun (CH ₂ Cl ₂ ): characteristic absorption bands at 2.95; 3.10; 5.65; 5.80; 5.95; 8.2Ou.

e)

oxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylate;

From 0.519 g (0.68 mmol) of 7ß- [2- (5-tert-butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2-Z-methylcarbainoyloxyimino ⁱ acetamido] -3-acetoxymethyl-3- Cephem-4-carboxylic acid diphenylmethyl ester in 1.1 ml of methylene chloride, 0.37 ml of anisole and 5 ml of trifluoroacetic acid are obtained analogously to Example. 2h the title compound of Rf 0.40 (UPC plates, water / acetonitrile 6: 1); IS spectrum (Nujöl): characteristic absorption bands at 3.0; 5.67; 6.22; 8.10 μ.

Example 4: 7β- [2- (5-AnUnO-1: 4, 4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido } -3- (3-carboxymethylpyridininiomethyl) -3-cephem 4-carboxylate

Starting from 0.77 g (1.48 mmol) of sodium 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3 cephem-4-carboxylate, 2.63 g (1.93 mmol) of 3-pyridylacetic acid and 2.52 g of sodium iodide in 2.15 ml of water, the title compound of Rf value 0.20 (UPC.RTM. Plates, water / acetonitrile 6: 1); IR spectrum (Nujol): characteristic absorption bands at 3.0; 5.67; 6.22 and 9.62 ^ u.

Example 5: 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-2-carboxypropyl]

2-yloxyiminoacetamido] -3- (3-methyl-l-triazoliomethyl) -3-cephem-4- carboxylate

Starting from 0.573 g (1 mmol) of disodium 7β- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3 -acet-oxymethyl-3-ceρhem-4-carboxylate, 0.3 g (3.57 mmol) of l-methyl-1,2,3-triazole and 1.9 g of sodium iodide in 0.3 ml of water are obtained analogously to Example 2 the title connection.

- 65 -

Example 6: 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-2-carboxyprop • -

2 ~ yloxyiminoacetamido] -3 ~ (2 - methyl-l = pyrazolioinethyl) '- _3-C e _P HSM'A'-carbcxylat

Starting with 0.286 g (0.5 mmol) of disodium 7β- [2- (5-amino-1-1,2,4-thiadiazol-3 ^ 1) -2-Z-2-carboxyprop-2 = yloxyiminoacetamido ] -3- - acetosymethyl-S-cepheia-A-carboxylaC, 0.4 g (4.8 mmol) of N-methylpyrazole7 ~ and 1.0 g of sodium iodide in 0.3 ml of water are obtained analogously to Example 2, the titanium compound of Rf value 0.39 (UPC .- plates, Wassar / acetonitrile 9: 1).

Example 7: 7β- (2- (5-Amino) -1,2,4-thiadia2ol * -3-yl) -2-Z-methoxy-1-aminoacetamido ] -3- (3-methyl-1-triazoliomethyl) -3- cephem-4-carboxylate

Starting from 0.24 g (0.5 mmol) of sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Za: ethoxyimino-acetaldehyde 3,3-acetox-7methyl-3 -cephem ~ 4-carbosylate, 0.3 g of 1-methyl-l, 2,3-triazole and 1.9 g of sodium iodide in 0.3 ml of water are obtained analogously to Example 1, the Titalverbindung ·

Example 8: 7β- [2- (5-Amino-1,1,2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-γ-methyl-1-pyrazoliomethyl) -3- cephem-4-carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamidol-S-acetoxymethyl-S-cephem-4 -carboxylate, 0.115 g (1.4 mmol) of N-methylpyrazole and 7 g of sodium iodide in 1 ml of water are obtained analogously to Example Γ the title compound with an Rf value of 0.22 (UPC plates, water / acetonitrile 6: 1) ; IR spectrum (Nujol): characteristic absorption bands at 3.0; 5.75; 5.95; 6.20 and 9.62 / ·

233133 3

- 66 -

Example 9 : 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetate d] do] -3- (3-bromopyridiniomethyl ') - 3-cephem-4 carboxylate

Starting from 1.9 g (3.97 in mol) of sodium 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacatamido] -3-acetoxymethyl-3- cepheni-4-carboxylate, 0.54 ml (5.6 mmol) of 3-bromopyridine and 6.84 g of sodium iodide, in 4 ml of water, the title compound of Rf value 0.20 (UPC, plates , Water / acetonitrile 6: 1) IR spectrum (Nujol): characteristic absorption bands at 2.95, 5.75, 6.20, 6.70, 9.60 y ..

Example 10 : 7β- [2- (5-Amino-1 : 4, 4-thiadiazol-3-yl) ^ - Z -methoxyiminoacetamido] -3- (4-bromopyridiniomethyl) -3-cephem-4-carboxylate '

Starting from 1.44 g (3.0 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacatarrd.do] -3-acetoxymethyl-3 -caphem-4-carbo: cylate, 0.5319 g (3.3 mmol) of 4-3rompyridine, 5.2 g of sodium iodide and 3.15 ml of water are obtained analogously to Example 1, the Titalverbindung R value 0.22 (UPC Plates, water / acetonitrile 6: 1); ER spectrum (Nujol): characteristic absorption bands at 2.95; 5.70; 6.17; 9.65 y.

Example 11 : 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxyl at

2.87 g (6.0 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-.3-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4 Carboxylate are added to a pre-heated to 70 ° solution of 9.9 g of sodium iodide in 5.0 ml of water. After addition of 0.72 g (6.6 mmol) of 4-hydroxymethylpyridine and 0.36 ml of acetic acid is stirred for 5 hours at 70 °. The reaction solution is cooled to room temperature and added to 120 ml of 0 ° C cold ethanol. The precipitate formed is filtered off, washed with ethanol and dried. After chronicling

- 67 -

shear purification of the crude product on XÄD-2 resin (water / isopropyl alcohol 95: 5) and subsequent thick-layer chromatography on silica gel "Opti UPC ₁ -" cit water / acetonitrile 4: 1 gives the uniform title compound of Rf value 0.45 (UPC Plates, water / acetonitrile 6: 1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.70; 6.20; 9.80 μ.

Example 12 7-g- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxy-aminoacetamido] -3- [4- (2-sulfoethyl) -pyridiniomethyl ·] - 3-cβphem-4-carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7ß- [2- (5-amino-l, 2, 4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem- 4-carboxylate ,. 0.244 g (1.4 mmol) of sodium 4-pyridinethanesulfonate and 1.71 g of sodium iodide in 1 ml of water are obtained analogously to Example 1, the title compound of Rf 0.40 (UPC plates, water / acetonitrile 95: 5); IS spectrum (Nujol): characteristic absorption bands at "2.95, 5.65, 6.20, 9.80 ^ u.

Example 13 : Sodium 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-amino-3-carboxypyridiniomethyl) -3- cephem-4- " carboxylate

Starting from 1.90 g (4.0 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3- cephem-4-carboxylate, 0.83 g (6.0 mmol) of 2-aminonicotinic acid and 6.8 g of sodium iodide in 4 ml of water to give the title compound of Rf 0.35 (UPC plates, water / acetonitrile 95: 5).

Example 14 : 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-amino-5-carbamoylpyridiniomethyl) -3-cephem-4 carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-aminol, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4 carboxylate, 0.192 g (1.4 mmol) of 2-amino-5-carbamoylpyridine

--68'-

and 1.71 g of sodium iodide in 1 ml of water are obtained analogously to Example 1, the title compound of Rf value 0.28 (UPC plates, water / acetonitrile 6: 1): Ώ? -Spektrum (nuj oil): characteristic absorption bands at 3.10 ; 5.65; 7:40; 9.60 μ.

Example 15: Sodium 7.beta. - [2- _{(5-amino-l;, r} 2 4-thiadiazole-3-yl) -2-Z methoxyiminoacetamido] -3-C'3- (2-carboxyvinyl ·) -. pyridiniomethyl] -3-cephem-4-carboxylate -

Starting from 0.478 (1.0 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem- 4-carboxylate, 0.241 g (1.4 mmol) of sodium 3- (3-pyridyl) acrylate and 1.71 g of sodium iodide in 1 ml of water are obtained analogously to Example 1, the title compound of Rf 0.85 (UPC - Plates, water / acetonitrile 1: 1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.67; 6.15; 9.65; 10.20 u.

Example 16: Sodium 7ß- [2- (5-amino-l, _{2,4-thiadia2ol-3-yl?)} '- 2-Z-methoxyiminoacetamidol-3- (3-Ξul · fopyridiniomethyl) -3-cephem-4 -carboxyl stability

Starting from 1.9 g (4.0 mmol) of sodium 7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3- Cephem-4-carboxylate, 1.02 g (5.6 mmol) of sodium pyridine-3-sulfonate and 6.84 g of sodium iodide in 3 ml of water are obtained analogously to Example 1, the title compound: of Rf 0.35 (UPC Plates, water / acetonitrile 6: 1); IR spectrum (Nujol): characteristic absorption bands at 3.10; 5.82; 8.15; 9.10 jx.

Example 17 : 7β- [-2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-methoxymethylpyridiniomethyl) -3-cephem-4-carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-aminol, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4 carboxylate, 0.16 g (1.3 mmol) of 4-methoxymethylpyridine, and

1.70 g Natriumj οdid in 1.0 ml of water is obtained analogously to Example 1, the title compound of Rf 0.30 (UPC plates, water / acetonitrile 6: 1).

Example 18 : 7β- [2- (5-AmJnO-1,2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetainido] -3- (4-thiocarbamoylpyridiniomethyl) -3-cephem-4-carboxylate .

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem- 4-Carboxylate, 0.166 g (1.20 mmol) Thioisonicotinsäureamid and 1.65 g of sodium iodide in 0.8 ml of water are obtained analogously to Example 1, the title compound of Rf 0.37 (UPC plates, water / acetonitrile 4: 1 ).

Example 19 : 7β-C-2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamidoj-3- (3-cyanopyridiniomethyl) -3-cephem-4-carboxylate

Starting from 0.956 g (2.0 mmol) of sodium 7β- [2- (5-aminol, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4- carboxylate, 0.25 g (2.40 mmol) of 3-cyanopyridine and 3.4 g of sodium iodide in 3 ml of water are obtained analogously to Example 1, the title compound of Rf 0.30 (UPC plates, water acetonitrile 6: 1) ; IR spectrum (Nujol): characteristic absorption bands at 2.95; 4.65; 5.70; 6.20 μ ".

Example. 20 : 7β- [2 '- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (3-cyanomethylpyridiniomethyl) -3-cephem-4-carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem 4-Carboxylate, 0.156 g (1.5 mmol) of 3-cyanomethylpyridine and 1.70 g of sodium iodide in 1.2 ml of water are obtained analogously to Example 1, the title compound of Rf value 0.15 <UPC plates, water / acetonitrile :1); IR spectrum (Nujol): characteristic absorption bands at 3.0; 4.65; 5.67 μ. '

Example -21 : ^, - ^ - ^ - ^ - Amino-l, 2,4-thiadiazol-3-yl ·) - 2 ^ -methoxy-aminoacetamido] -3- (3-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-aminol, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem 4-Carboxylate, 0.164 g (1.5 mmol) of 3-hydroxymethylpyridine and 1.70 g of sodium iodide in 1 ml of water and 0.05 ml of acetic acid are obtained analogously to Example 11, the title compound, of Rf 0.40 (UPC plates , Water / acetonitrile 9: 1), IR spectrum (Nujol): characteristic absorption bands at 2.95, 5.67, 6.20 u.

Example 22: 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-methylcarbamoyl ] oxyiminoacetamido-3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4 carboxylate (A) and

7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate (B)

From 1.042 g (2.0 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methylcarbamoyloxyiminoacetamido] -3-acetoxymethyl-3-cephem-4 carboxylate, 0.24 g (2.2 mmol) of 4-hydroxymethylpyridine and 3.5 g of sodium iodide in 2.1 ml of water, analogously to Example 1, the title compound A of Rf value 0.40 (UPC plates, water / Acetonitrile 6: 1) and the title compound B of Rf 0.60 (UPC plates, water / acetonitrile 6: 1).

Example. 23 : sodium 7ß - [- 2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- methoxyiminoacetamido] -3- (3-carboxypyridiniomethyl) -3-cephem-4- carboxylate

Starting from 0.478 g (1.0 mmol) of sodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Z-methoxyimino-acetamido] -3-acetoxymethyl-3- Cephem-4-carboxylate, 0.20 g (1.64 mmol) of nicotinic acid and 1.70 g Natriumj odid in 1 ml of water obtained analogously to Example 1, the title compound of Rf value 0.20 (UPC plates, water / acetonitrile 9: 1);

- 71 -

IR spectrum. (Nujbl): characteristic. Absorption bands, at 3.0; 5.70; 6.20 u.

Example 24 : 7β- [· 2- (

acetamido] -3- (2-carboxymethyl-1-pyrazolo-methyl) -3-cephem-4-carboxylic acid (A) and

7β - [- 2 -. (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (1-carboxymethyl-1-pyrazoliomethyl) -3-cephem-4 -carboxylic acid (B)

From 1.44 g (3.0 mmol) of natium-7β- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem 4-carboxy-lat, 0.53 g (4.2 mmol) of pyrazolylacetic acid and 5.15 g of sodium iodide in 3 ml of water are obtained analogously to Example 1, a mixture of the title compound A with the Rf value 0.75 (UPC plates, water / Acetonitrile 6: 1) and B of Rf 0.70 (UPC plates, water / acetonitrile 6: 1).

Example 25: Disodium 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-Z-2- carboxyprop-2-yloxyiminoacetamido] -3- (2-carboxymethyl- 1-pyrazolio- methyl) -ceph-3-em-4-carboxylate

To a solution of 0.9 g (7.14 mmol) of pyrazolylacetic acid and 0.9 g of sodium iodide in 2.0 ml of water at 70 ° is added a solution of 2.8 g (6, OmMoI) of sodium 7β- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylate ~ in 4 ml of water. The reaction is carried out analogously to Example 1 and the title compound is obtained; IR spectrum (Nujol) 2.90; 5.65; 6.22 and 7.05 u.

233133

- 72 -

Example. 26: 7β- [2 - (5-amino-1, 2,4-thiadiazol-3-yl) -2-Z-me thoxyiminoacetamido] -3 -. (2-ethoxycarbonylmeth-1-yl-pyrazolymethyl) -3-cephem-4-carbczylat

From 1.0 g (2.1 mmol) of sodium 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem ~ 4 Carboxylate, 3.08 g (20 mmol) of ethyl pyrazolylacetate and 3.73 g (25 mmol) of sodium iodide are obtained analogously to Example 1, the title compound; IR spectrum (Nu j oil): 5.66; 5.77; 23.06 ^.

Example. 27 : In an analogous manner, the following compounds can be obtained using the appropriate starting materials:

7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-hydroxyiminoacetamido] -3- (2-methyl-1-pyrazoliomethyl) -3-cephem-4-carboxylate ; R f: 0.40 (water / acetonitrile 6: 1); IR: 3.0; 5.67; 6.20; 8.30 μ; 7ß- [2- (5-amino-I, 2,4-thiadiazol-3-yl) -2-Z-hydroxyimino-acetamido] -3- (3-methyl-l-triazoliomethyl) -3-cephem-4- carboxylate; Rf: 0.25 (water / acetonitrile 6: 1); IR: 5.65; 6,20 ^;

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3- (4-hydroxymethylpyridiniomethyl) -3- cephem-4-carboxylate; R f: 0.50 (water / acetonitrile 6: 1); IR: 5.67; 5.95; 9.20 μ; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-hydroxyimino-acetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) ^ 2-Z-hydroxyimino-acetamido] -3- (3-sulfopyridiniomethyl) -3-cephem-4-carboxylate; R f: 0.45 (water / acetonitrile 6: 1); IR: 3.0; 5.75; 9.15 u;

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3- (3-sulfopyridiniomethyl) -3- cephem-4-carboxylate; R f: 0.50 (water / acetonitrile 6: 1); IR: 3.05; 5.67; 5.95 u.

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-hydroxyimino-acetamido] -3- (3-carboxymethyl-4-carbamoylpyridiniomethyl) -3-cephem-4- carboxylate; R f: 0.35 (water / acetonitrile 4: 1); IR: 3.0; 5.67; 6.20 μ; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyimino-acetamido] -3- (3-carboxymethyl-4-carbamoylpyridiniomethyl) -3-cephem-4- carboxylate; R f: 0.30 (water / acetonitrile 4: 1); IR: 3.0; 5.65; 6.20; i;

- 73 -

7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z -. (2-carboxyprop-2-yloxy-imino) -acetamido] -3- (3-carboxymethyl-4- -carbamoylpyridiniomethyl) -3-cephem-4-carboxylate; Rf: C.37 (water / acetonitrile 4: i); IR: 3.0; 5.67; 6.2O ₁ U ;. 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-hydroxyimino-acetamido] -3- (3-carboxy-4-carbamoylpyridiniomethyl) -3-cephem-4 carboxylate; R f: 0.45 (water / acetonitrile 6: 1); IR: 3.0; 5.65; 6.17 y .; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (3-carboxy-4-carbamoylpyridiniomethy1) -3-cephem-4-carböxylat; R f: 0.35 (water / acetonitrile 6: 1); IR: 5.67; 6.20 ^ l; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3- (3-carboxy-4-carbamoylpyridiniomethyl ) -3-cephem-4-carboxylate; R f: 0.35 (water / acetonitrile 6: 1); IR: 5.67; 5.95; i; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-hydroxyiminoacetamido] -3- (3-brompyridiniomethyl) -3-cephem-4-carboxylate; R f: 0.35 (water / acetonitrile 6: 1); R f: 0.35 (water / acetonitrile 6: 1); IR: 3.0; 5.65; 6.2Ou; 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3- (3-brompyridiniomethyl) -3- cephem-4-carboxylate; Rf: 0.20 (water / acetonitrile 9: 1); IR: 3.0; 5.67 y .;

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-hydroxyiminoacetamido] -3- (4-brompyridiniomethyl) -3-cephem-4-carboxylate; Rf: 0.30 (water / acetonitrile 9: 1); IR :. 2.95; 5.65; 6.17; x;

7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z- (2-carboxyprop-2-yloxyimino) acetamido] -3- (4-brompyridiniomethyl) -3- cephem-4-carboxylate: R f: 0.20 (water / acetonitrile 9: 1); IR: 3.0; 5.70 / u;

7β- [2- (5-Amino-1,2,3,4-thiadiazol-3-yl) -2-Z-methoxy-iminoacetamido] -3- (4-carboxymethylthiopyridiniomethyl) -3-cephem-4-carboxylate IR :. 2.95; 5.65; and

7ß- [2- (5-amino-I, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (3-cyano-4-trifluoromethylpyridiniomethyl) -3-cephem-4-carboxylate; R f: 0.40 (water / acetonitrile 4: 1); IR: 5.67; 6..20 μ (Rf values on UPC plates and IR spectra in Nujol).

3.1 3 3

, - 74 -

Example 28: Dry ampoules or vials containing 0.5 g of active substance, e.g. Sodium salt of 78- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -

4-carboxylate, e.g. be prepared as follows:

Composition (for 1 vial or vial) Active substance 0.5 g Mannitol 0.05 g

A sterile aqueous solution of the active ingredient and mannitol is filled under aseptic conditions into 5 ml vials or 5 ml vials, and these are closed and tested.

Claims (12)

5 % Y% Y <yy - 75 - Invention claim: 1. A process for the preparation of Tβ-aminothiadiazolylacetylamino-S-aminomethyl-S-cephem-A-carboxylic acid compounds of the formula ⁰ Γ Il / \ Am-T-C-C-N- ··· (I) COO ^Θ where η is 0 or 1, unsubstituted or substituted amino, T is a thiadiazole radical which is attached at one carbon atom with Am and at the other carbon atom with the group of the formula -C (= NOR) -, R is an unsubstituted or substituted pyrazolo group, an unsubstituted or substituted triazolio group, a tri-lower alkylammonium group or a pyridiniogroup of the formula a (A), b wherein R is lower alkyl which is unsubstituted or carboxyl-substituted lower alkenyl or lower alkylthio, unsubstituted or lower alkyl, lower alkanoyl or aminobenzenesulfonyl monosubstituted amino, di-lower alkylamino, lower alkyl, hydroxy lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfo; Lower alkoxy, hydroxy or cyano monosubstituted carbamoyl, di-lower alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano, nitro, or hydroxysulfone lower alkyl, R means carbamoyl or hydrogen or the meanings 233133 - 76 - R is hydrogen and R is hydrogen or unsubstituted or substituted lower alkyl or cycloalkyl or unsubstituted or substituted carbamoyl, and salts of such compounds having a salt-forming group characterized in that a) in a compound of the formula (0) H H H ₂ N-. ! -CHR CoCp in which the index η is 0 or 1, R has the meanings given under formula I, the 7β-amino group is optionally protected by a group permitting the acylation reaction and the 4-carboxy group is optionally protected, the 7β-amino group is reacted by reacting with a Acyl radical of a carboxylic acid of the formula Aa-TCC-OH
Π N '
I introducing acylating agent, wherein Am, T and R have the meanings mentioned under formula I and existing functional groups are optionally protected, acylated or b) for the preparation of a compound of the formula I in which η is 0, a 2-cephem compound of the formula - 77 - IH
O · · S ! I in which ₅ T, R and R have the meanings mentioned under formula I and in which the 4-carboxyl group and further functional groups are optionally protected, isomerized to give the corresponding 3-ceprene compound or c) a compound of the formula (O) _n to-TCC-HH-p J _{(v) f} 0 O ' wherein η is 0 or 1, As, T and -R have the meanings given for Fortasl I and in which the 4-Ca.rbcxylgnippe and other functional groups are optionally protected, with a Eydroxylaminderivat of Forn ^ il H ~ i? -O -R_ (VT), wherein R- has the meanings mentioned under formula I and functional groups are optionally protected, or d) for the preparation & in compound of Fonasl I wherein R-hydrogen is bsdsutst, a compound of Forssl (O) OHE f ⁿ -Am-T-CH-C-NH- , '- CE, T - 78 - wherein η is O or 1, On ₉ T and R have the meanings mentioned under formula I and wherein the 4-Carboxylgmppe and other functional groups are optionally protected, treated with a nitrosating agent or e) for the preparation of a compound of the formula I in which Am represents a free or a secondary amino group, T is a 1,2,4-thiadiazole radical which is in the 5-position with Am and in the 3-position with the group of the formula -C (= NOR ") - connected, a compound of the formula HH ^ ¹ wherein η is O or .1, X is hydrogen, halogen or hydroxy and R has the meanings mentioned under formula I and wherein the ^ -Carboxylgruppe, and other functional groups are optionally protected, with a salt of Rhodanwasserstoffsäure, or with a Isorohodanwassersäureester or, if X. is hydrogen, treated with Dirhodan or f) a connection of the Forssl (0) 0 HH t ^Q Am-TCC-HK -5-J ^A. C-E, I ¹ COOH - 79 - wherein η is 0 or 1, Am, T and R have the meanings given under formula I and X _{n represents} a replaceable by nucleophilic substitution radical and wherein the 4-carboxyl group and other functional groups are optionally protected, with one 'the rest Reacting R ₁ corresponding organic tertiary base or g) for the preparation of compounds of formula I, wherein Am is a primary, secondary or tertiary amino group, a compound of formula (O) _n ^ 0 EH ^ η i I I - CS), N 0- H. · .1 v 0 - Ä ^z c » wherein η is 0 or 1, T, R and R ₂ 'are as defined for formula I and Y is halogen, with ammonia or a primary or secondary amine Am-H or a metal amide reacts and, if desired, a convertible compound of the formula I into another compound of the formula I and / or, if desired, an available compound of the formula I in which η is 0, converted into a compound of the formula I, wherein η 1, and / or a compound of the formula I in which η is 1, converted into a compound of formula I, wherein η is 0, and / or in an available compound of formula I in protected form functional groups in the free functional groups and / or converts an available salt into the free compound of the formula I or into another salt, and / or converts an available free compound of the formula I with a salt-forming group into a salt and / or an obtainable mixture of isomeric compounds into the salt separates individual isomers. 233133 - 80 - 2. A process according to item 1 for the preparation of compounds of the formula I characterized in that η is O, amines, lower alkylamino, di-lower alkylamino or protected amino, T is a thiadiazole radical which has on one carbon atom Am and at the other carbon atom with the Group of formula -C (= NOR) -, R 2-lower alkyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, 2-lower-alkoxycarbonyl-lower alkyl-1-pyrazolio, 3-lower-alkyl-1 triazolio or a pyridiniogroup of formula A, wherein R is lower alkyl substituted by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfo, unsubstituted or carboxyl substituted lower alkenyl or lower alkylthio, unsubstituted or monosubstituted by lower alkyl, lower alkanoyl or aminobenzenesulfonyl Lower alkyl, lower alkyl, hydroxy or cyano monosubstituted carbamoyl, di-lower alkylcarbamoyl, thiocarbainoyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano, nitro or hydroxysulfone lower alkyl, R represents carbamoyl or Is hydrogen or has the meanings of R and R was is hydrogen and R is hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl or unsubstituted or substituted carbamoyl, where the group of formula NORNOR "has in particular the syn (or -Z) form, and salts, especially pharmaceutically acceptable salts of such compounds of the formula I, which have salt-forming groups. 3. Process according to item 2 for the preparation of compounds of formula I, characterized in that η is 0, Amino, lower alkylamino, e.g. Methylamine, or protected amino, T is a Thiadiazolrest, which at one carbon atom with Am and at the other carbon atom with - 81 - the group of formula -C (= N-O-R ") -, R 2-lower alkyl-1-pyrazolio, e.g. 2-methyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, e.g. 2-carboxymethyl-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, e.g. 1-carboxymethyl-1-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-1-pyrazolio, e.g. 2-methoxycarbonylmethyl-1-pyrazolio, 3-lower alkyl-1-triazolio, e.g. 3-methyl-1-triazolio or a pyridiniogroup of formula A, for example hydroxy-lower alkylpyridinio, e.g. 3- or 4-hydroxytethylpyridinio, lower alkoxy-lower alkylpyridinio, e.g. 4-methoxymethylpyridinio, cyano-lower alkylpyridinio, e.g. 3-cyanomethylpyridinio, carboxy-lower alkylpyridinio, e.g. 3-carboxymethylpyridinio, sulfo-lower alkylpyridinio, e.g. 4- (2-sulfoethylpyridinio), carboxy-lower alkenylpyridinio, e.g. 3- (2-carboxyvinyl) -pyridinio, carboxy-lower alkylthiopyridinio, e.g. 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, e.g. 4-thiocarbamoylpyridinio, halopyridinio, e.g. 3-bromo or 4-bromo-pyridinio, carboxypyridinio, e.g. 4-carboxypyridinio, sulfopyridinio, e.g. 3-sulfopyridinio, cyanopyridinio, e.g. 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, e.g. 3-carboxy-t-ethyl-4-carbamoyl-pyridinio, aminocarbamoyl-pyridinio, e.g. 2-amino-5-carbaraoylpyridinio, carboxycarbarnoylpyridinio, e.g. 3-carboxy-4-carbamoylpyridinio, cyanohalomethylpyridinio, e.g. 3-cyano-4-trifluoromethylpyridinio or aminocarboxypyridinio, e.g. Z-amino-S-carboxypyridinio, and R is hydrogen, lower alkyl, e.g. Methyl, carboxy-lower alkyl, e.g. 2-carboxy-2-propyl, carbamoyl, lower alkylcarbamoyl, e.g. Methylcarbamoyl, or amino-lower alkyl, e.g. 2-aminoethyl, where the group of the formula = N-C-R- has the syn (or Z) -form, and salts, in particular pharmaceutically usable salts of those compounds of the formula I, which have salt-forming groups. 4. The method according to item 3 for the preparation of compounds of formula I, characterized in that η is 0, Am amino, T is a 1,2,4-Thiadiazolrest which in the 5-position with Am and in 3-position with the Group of the formula -C (= NO-.R) - is connected, R 2-lower alkyl-l-pyrazolio, for example ^ - 82 - 2-methyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, e.g. 2-carboxymethyl-1-pyrazolio, 2-lower alkoxycarbonyl, lower alkyl-1-pyrazolio, e.g. 2-methoxycarbonylmethyl-1-pyrazolio, 3-lower alkyl-1-triazolio, e.g. 3-methyl-1-triazolio, or a pyridinio group of formula A, for example hydroxy-lower alkylpyridinio, e.g. 4-hydroxymethylpyridinio, carboxy-lower alkylpyridinio, e.g. 3-carboxymethyl-pyridinio, sulfo-lower alkylpyridinio, e.g. 4- (2-sulfoethylpyridinio), halopyridinio, e.g. 3-bromopyridinio, carboxypyridinio, e.g. 4-carboxypyridinio, sulfopyridinio, e.g. 3-sulfopyridinio or aminocarbamoylpyridinio, e.g. 2-amino-5-carbamoylpyridinio, and R is hydrogen, lower alkyl, e.g. Methyl, carboxy-lower alkyl, e.g. 2-carboxy-2-propyl, carbainoyl or lower alkylcarbamoyl, e.g. Methylcarbamoyl, where the group of the formula = N-O-R has the syn (or Z) -form, and salts, especially pharmaceutically acceptable salts of compounds of the formula I. 5. The method according to item 4 for the preparation of compounds of formula I, characterized in that η is 0, Amino, T is a 1,2,4-Thiadiazolrest, which in the 5-position with Am and in 3-position with the group the Formula -C (N-O-R 1) -, R 2-lower alkyl-1-pyrazolio, e.g. 2-methyl-1-pyrazolio or a pyridiniogroup of formula A, for example hydroxy-lower alkylpyridinio, e.g. 4-hydroxymethylpyridinio, carboxy-lower alkylpyridinio, e.g. 3-carboxymethylpyridinio, halopyridinio, e.g. 3-bromopyridinio, or carboxypyridinio, e.g. 4-carboxypyridinio, and R "lower alkyl, e.g. Methyl or carboxy-lower alkyl, e.g. 2-carboxy-2-propyl or aminocarbamoylpyridinio, e.g. 2-amino-5-carbamoylpyridinio, where the group of the formula = N-O-R - has the syn (or Z) -form, and salts, primarily pharmaceutically acceptable salts of compounds of the formula I. QO OJ 6. The method according to item 5, characterized in that 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (4-carboxypyridiniomethyl) -3-cephem-4-carboxylate. 7. The method according to item 5, characterized in that 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-y 1) - ^ - Z ^ -carboxyprop - ^ - yloxyiminoacetamido] -3- ( 3-carboxyraethylpyridiniomethyl) -3-cephem-4-carboxylate. 8. The method according to item 5, characterized in that 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-methyl-1-pyrazolemethyl) -1-cephem-4-carboxylaf become. 9. The method according to item 5, characterized in that 7ß- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- [4- (2-sulfoethyl) -pyridiniomethyl] -3-cephem-4- caryboxylate be prepared. 10. The method according to item 5, characterized in that 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (2-amino-5-carbamoylpyridiniomethyl) -3-cephem-4-carboxylate become. 11. The method according to item 5, characterized in that 7β- [2- (5-Amino-1, 2,4-thiadiazol-3-yl) -2-Z-methoxyiminoacetamido] -3- (3-bromopyridiniomethyl) -3-cephem-4-carboxylate. 12. The method according to item 5, characterized in that 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-Z-thoxyiminoacetamido] -3- (4-hydroxymethylpyridiniomethyl) -3-cephem-4-carboxylate , 9 KM Π M Λ Π O A ... ί>i-> ο ν, ~>