NO802028L - AMINO-THIADIAZOLYL COMPOUNDS, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING SUCH COMPOUNDS AND APPLICATION OF THE LATER - Google Patents

Description

The invention relates to new 73-aminothiadiazolyl-acetamido-3-cephem-4-carboxylic acid compounds, process for their preparation, pharmaceutical preparations containing such compounds and their use as antibiotics.

In DT-OS 2 745 246 certain 73-thia-diazolylacetamido-3-cephem-4-carboxylic acid compounds with antibiotic action were described. Compared to these compounds, the compounds according to the present invention represent an improvement to some extent, as they are surprisingly distinguished by a particularly outstanding antibiotic effect. This outstanding effect is somewhat surprising, as the compounds according to the present invention do not fall under the preferred embodiments in DT-OS

2 745 246. The invention relates in particular to 73-aminothiadiazolyl- acetamido-3-cephem-4-carboxylic acid compounds of the formula

in which Am denotes an optionally protected amino group, R., stands for hydrogen, optionally substituted lower alkyl or cycloalkyl or optionally N-substituted carbamoyl, R 2

means hydrogen or lower alkoxy, stands for hydrogen, acyloxy or heterocyclylthio, and R denotes an optionally protected carboxyl group, and salts of such compounds which exhibit a salt-forming group, methods for the preparation of these compounds, pharmaceutical agents containing such compounds and their use.

In the present description of the invention

means in the context of definitions of groups and compounds used expressions "lower", e.g. in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl or lower alkylamino, or in compounds such as lower

alcohols and such, that the corresponding groups or compounds, unless otherwise expressly defined, contain up to 6, preferably up to 4 C atoms.

An optionally protected amino group Am is a primary, secondary or tertiary amino group such as amino, lower alkylamino or dilower alkylamino, whereby the primary or secondary amino groups may be protected as indicated below. In a lower alkyl or dilower alkylamino group, lower alkyl contains 1-4 C atoms and is, for example, methyl, ethyl, propyl or butyl. Am is preferably optionally protected amino or methylamino.

A lower alkyl group 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 joints, and is e.g. cyclobutyl, cyclopentyl or cyclohexyl and especially cyclopropyl.

Substituents of substituted lower alkyl or cycloalkyl R^ are e.g. optionally etherified hydroxy, e.g. lower alkoxy, primary, secondary or tertiary amino Am, e.g. amino or dilower alkylamino, optionally functionally converted, including esterified, amidated or protected carboxyl or sulfo, as well as optionally with lower alkyl N-substituted ureidocarbonyl. Preferred are the substituted lower alkyl and cycloalkyl groups substituted with a carboxyl or sulfo group, whereby these preferably stand for the carbon atom which is connected to the oxygen atom of the oxyimino group. Such substituted lower alkyl and cycloalkyl groups R^ are, for example, 2-aminoethyl, 2-dimethylaminoethyl, carboxymethyl, 1- or 2-carboxyethyl, 1-, 2- or 3-carboxyprop-1-yl- 1-, 2- or 3-carboxyprop- 2-yl, 1-carboxybut-1-yl, 1-carboxycycloprop-1-yl and 1-carboxycyclobut-1-yl, as well as corresponding sulfo-substituted lower alkyl and cycloalkyl groups.

The carboxy and sulfo groups in the residue R^ can, for example, be esterified with lower alkyl such as methyl or ethyl, or one of the physiologically cleavable groups, e.g. pivaloyloxymethyl, or be amidated with an amine such as NH^ or a primary or secondary amine such as a mono- or di-lower alkylamine, such as methyl- or ethylamine, or with dimethyl- or diethylamine, or be protected as approximately indicated for R^. In a ureidocarbonyl group in the residue R^, both nitrogen atoms can be substituted independently of each other with lower alkyl such as methyl or ethyl. Such groups are, for example, ureidocarbonyl or 1,3-dimethylureidocarbonyl.

Optionally N-substituted carbamoyl as the residue R 1 is a group -C(=O)-NHR, in which R means hydrogen, lower alkyl, e.g. methyl, ethyl or 1- or 2-propyl, optionally protected carboxyl lower alkyl, e.g. carboxymethyl, 1- or 2-carboxyethyl or 1-, 2- or 3-carboxypropyl, in which carboxy may be protected with one of the usual carboxyl protecting groups, for example it may be esterified with lower alkyl, e.g. methyl, ethyl, n- or iso-propyl, or m- or tert.butyl, optionally protected sulpholower alkyl, e.g. sulfomethyl, 1- or 2-sulfoethyl or 1-, 2- or 3-sulfopropyl, in which sulfo can be protected with one of the usual sulfo-protecting groups, for example can be esterified with lower alkyl, e.g.

methyl or ethyl, optionally protected hydroxyl lower alkyl, e.g. hydroxymethyl, 2-hydroxyethyl or 2- or 3-hydroxypropyl, in which hydroxy may be protected with one of the usual hydroxy protecting groups, e.g. can be acylated as acetylated, optionally protected amino lower alkyl, e.g. 2-aminoethyl, 2- or 3-aminopropyl or 2-, 3- or 4-aminobutyl, in which amino may be protected with one of the usual amino protecting groups, e.g. acylated such as acetylated, aryl lower alkyl, for example phenyl lower alkyl, e.g. benzyl or 1- or 2-phenylethyl, halogen lower alkyl, for example fluoro-, chloro- or bromo-lower alkyl, e.g. 2-chloroethyl, 3-chloropropyl or 4-chlorobutyl, or wherein R is aryl, e.g. phenyl or with lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine or nitro, single to triple substituted phenyl.

A lower alkoxy group R2 preferably contains 1-4 C atoms and is, for example, ethoxy, propoxy, butoxy or especially methoxy.

In an acyloxy group R., acyl is for example the acyl residue of an optionally substituted lower aliphatic carboxylic acid, a lower alkoxycarboxylic acid, a lower alkanesulfonic acid, an aromatic sulfonic acid, an aromatic carboxylic acid, an aryl-substituted lower alkanecarboxylic acid or an optionally N-substituted carbamic acid.

Such acyloxy groups R^ are for example lower alkanoyloxy, especially acetyloxy, further formyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, pivaloyloxy, acetoacetoxy, oxalyloxy, succinyloxy and the like, lower alkoxycarbonyloxy, such as methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy . , aroyl, such as benzoyl, toluoyl, naphthoyl, phthaloyl, indanecarbonyl and the like, aryl lower alkanoyl such as phenylacetyl and the like, whereby the above-mentioned acyl residue may contain one or two suitable substituents such as halogen, e.g. chlorine, bromine, iodine or fluorine, hydroxy, cyano, nitro, cavereal oxy, e.g. methoxy, ethoxy, propoxy, isopropoxy and the like, lower alkyl. e.g. methyl, ethyl, propyl, iso-propyl, butyl and the like, lower alkenyl, e.g. vinyl, allyl etc. or e.g. f eny.l > . tolyl etc. Suitable examples for acyloxy with one or more of these substituents are preferably halogen, lower alkanoyloxy, e.g. chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy or trifluoroacetyloxy.

In the acyl residue of an optionally N-substituted carbamic acid, N-substituents are optionally with halogen, e.g. chlorine, or with lower alkanoyl, e.g. acetyl or propionyl, substituted lower alkyl radicals, e.g. methyl, ethyl, 2-chloroethyl or 2-acetoxyethyl. Such acyloxy groups R_ are e.g. carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-(2-chloroethyl)carbamoyloxy or N-(2-acetoxyethyl)carbamoyloxy.

In a heterocyclylthio group R^, heterocyclyl is in particular an optionally substituted, over one ring carbon atom bonded to the thio group, heterocyclic residue with 1 to 4 ring nitrogen atoms and optionally a further ring heteroatom from the group of oxygen and sulphur.

Such heterocyclyl residues are primarily optionally substituted, e.g. the below-mentioned substituents containing monocyclic, five- or six-membered diaza-, triaza-, tetraza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- or oxadiazacyclic residues of an aromatic or partially saturated character.

Substituents for such heterocyclyl residues are i.a. lower alkyl, especially methyl, as well as ethyl, n-propyl, isopropyl or straight-chain or branched butyl, or with a hydroxy esterified hydroxy such as lower alkanoyloxy, halogen such as chlorine, carboxy, esterified carboxy such as lower alkoxycarbonyl, sulfo, amidated sulfo, amino, mono- or dilower alkylamino , acylamino such as lower alkanoylamino, or with a substituted, such as a carboxy or halogen substituted lower alkanoylamino substituted lower alkyl, for example 2-hydroxyethyl, 2-acetoxyethyl, 2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, sulfomethyl, 2-sulfoethyl , sulfamylmethyl, 2-sulfamylethyl, 2-aminoethyl, 2-dimethylaminoethyl or 2-acetylaminoethyl. Further substituents of the heterocyclic radical are cycloalkyl, e.g. cyclopentyl or cyclohexyl, aryl, as optionally with halogen, e.g. chlorine, or nitro substituted phenyl, aryl, lower alkyl, e.g. benzyl, or heterocyclyl such as furyl, e.g. 2-furyl, thienyl, e.g. 2-thienyl, or oxazolyl, e.g. 2- or 5-oxazolyl, or functional groups such as halogen, e.g. fluorine, chlorine or bromine, optionally substituted amino, as optionally with lower alkyl mono- or di-substituted amino. e.g. amino, methyl-

amino or dimethylamino, acylamino such as lower alkanoylamino or with a halogen or carboxy substituted lower alkanoylamino such as acetylamino, 3-chloropropionylamino or 3-carboxypropionylamino, nitro, hydroxy, lower alkoxy, e.g. methoxy, ethoxy, n-butyloxy or 2-ethylhexyloxy or optionally functionally converted carboxy, such as carboxy, esterified carboxy such as lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, optionally substituted as N-mono- or N,N-dileveralkylated carbamoyl, e.g. N-methylcarbamoyl or N,N-dimethylcarbamoyl or cyan,

as well as oxo or oxido, whereby one or more such substituents which are primarily connected with ring carbon atoms but also, especially lower alkyl and oxido, with ring nitrogen atoms can be present.

Preferred heterocyclylthio groups R^, in which the heterocyclic residue produces a corresponding monocyclic, five-membered residue, are, among other things, imidazolylthio, e.g. 2-imidazolylthio, optionally with lower alkyl and/or phenyl substituted triazolylthio, e.g. 1H-1,2,3-triazol-4-ylthio, 1-methyl-1H-1,2,3-triazol-4-ylthio, 1H-1,2,4-triazol-3-ylthio, 5-methyl- 1H-1,2,4-triazol-3-ylthio, 3-methyl-1-phenyl-1H-1,2,4-triazol-5-ylthio, 4,5-dimethyl-4H-1,2,4- triazol-3-ylthio or 4-carboxymethyl- or 4-phenyl-4H-1,2,4-triazol-3-ylthio, especially optionally as indicated substituted tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, 1-methyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1 -(2-carboxyethyl)-1H-tetrazol-5-ylthio, 1- sulfomethyl-1H-tetrazol-5-ylthio, 1-(2-sulfoethyl)-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-phenyl-1H-tetrazol- 5-ylthio or

1 - (4-chlorophenyl)-1H-tetrazol-5-ylthio, optionally with lower alkyl or thienyl substituted thiazolylthio or isothiazolylthio, e.g. 2-thiazolylthio, 4-(2-thienyl)-2-thiazolylthio, 4,5-dimethyl-2-thiazolylthio, 3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, especially also optionally as indicated substituted thiadiazolylthio, e.g. 1,2,3-thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4-thiadiazol-5- ylthio, 2-(3-carboxypropionylamino)-1,3,4-diazol-5-ylthio, 1,2,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thiatriazolylthio, e.g. 1,2,3,4-thiatriazolyl-5-ylthio, optionally as indicated substituted oxazolylthio or isoxazolylthio, e.g. 5-oxazolylthio, 4-methyl-5-oxazolylthio, 2-oxazolylthio, 4,5-diphenyl-2-oxazolylthio or 3-methyl-5-isoxazolylthio or optionally as indicated substituted oxadiazolylthio, e.g. 1,2,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, 2-phenyl-1,3,4-oxadiazol-5-ylthio, 5-(4-nitrophenyl )-1,3,4-oxadiazol-2-ylthio or 2-(2-thienyl)-1,3,4-oxadiazol-5-ylthio.

Preferred heterocyclylthio groups / in which the heterocyclic radical produces a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical are, among others optionally with halogen substituted 1-oxido-pyridyl-thio, e.g. 1-oxido-2-pyridylthio or 4-chloro-1-oxido-2-pyridylthio, optionally with a hydroxy substituted pyridazinylthio, e.g. 3-hydroxy-6-pyridazinylthio, optionally with a lower alkyl, lower alkoxy or halogen substituted N-oxido-pyridazinylthio, e.g. 2-oxido-6-pyridazinylthio, 3-chloro-1-oxido-6-pyridazinylthio, 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio, 3-ethoxy-1- oxido-6-pyridazinylthio, 3-n-butyloxy-1-oxido-6-oyridazinylthio or 3-(2-ethylhexyloxy)-1-oxido-6-pyridazinylthio or optionally with lower alkyl, amino,, dilower alkylamino or carboxy substituted 2-oxo -1,2-dihydro-pyrimidinylthio, e.g. 2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-amino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-dimethylamino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-carboxy-2-oxo-1,2-dihydro- 4- pyrimidinylthio or 6-carboxy-2-oxo-1,2-dihydro-4-pyrimidinylthio or optionally similarly substituted 4-oxo-3,4-dihydro-2-pyrimidinylthio as especially with substituted 4-oxo-3, 4-dihydro-2-pyrimidinylthio or optionally with lower alkyl, such as methyl or ethyl, and up to two oxo substituted triazinylthio, especially N-lower alkyl-5,6-dioxo-1,2,4-triazin-3-ylthio, e.g. . 1-, 2- or 4-methyl-5,6-dioxo-1,2,4-triazin-3-ylthio, or the tautomeric aromatic hydroxy compounds corresponding to the oxo compounds.

The functional groups present in compounds of formula (I), especially carboxyl and amino, further hydroxy and sulfo groups, are optionally protected with protective groups used in penicillin, cephalosporin and peptide chemistry.

Such protecting groups are easily cleavable, i.e. without unwanted side reactions taking place, for example solvolytic, reductive, photolytic or also under physiological conditions.

Protective groups of this kind and their cleavage are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, further in "The Peptides", vol. In, Schrøder and Liibke,

Academic Press, London, New York, 1965, as well as in "The Method

der organischen Chemie", Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart, 1974.

Then carboxyl groups such as the carboxyl groups R4, e.g. in the usual way protected in esterified form, whereby such ester groupings are easily cleavable under mild conditions.

Suitable protected carboxyl groups are, for example, lower alkoxycarbonyl, e.g. methoxy- or ethyloxy-carbonyl, or especially tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkyloxycarbonyl, e.g. adamantyloxycarbonyl, arylmethoxycarbonyl, in which aryl preferably produces one or two, optionally e.g. with lower alkyl, especially tert.-lower alkyl, e.g. tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono- or polysubstituted phenyl residues,

which possibly, e.g. as mentioned above substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, or optionally, e.g. as above-

for indicated substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl or di-(4-methoxy-phenyl)-methoxycarbonyl or 2-halogeno-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(S^) ) (S^)-silyl-ethoxycarbonyl in which the substituents , S2 and mean independently of each other each optionally substituted, e.g. e.g. with lower alkyl, lower alkoxy, aryl, halogen or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue with e.g. up to 15 C atoms,

as a corresponding optionally substituted lower alkyl, aryl lower alkyl, cycloalkyl or aryl residue, e.g. 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(dibutyl-methyl-silyl)-ethoxycarbonyl or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl or 1-lower oxylower oxycarbonyl such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, or 1-lower alkylthiolower oxycarbonyl such as 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl or arylmethoxycarbonyl, in which the aroyl groups preferably optionally prepare, e.g. with a halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, or polyhaloaryloxycarbonyl such as pentachloro-phenyloxycarbonyl. Esterified carboxyl groups are optionally corresponding silyloxycarbonyl, especially organic silyloxycarbonyl groups or corresponding stannyloxycarbonyl groups. These contain silicon or the tin atom is preferably lower alkyl, especially methyl, further lower alkoxy, e.g. methoxy, and/or halogen, e.g. chlorine,

as substituents. Suitable silyl resp. stannyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, lower-alkyl-lower-alkyl-halo-silyl, e.g. methoxy-methyl-chloro-silyl or dilave alkyl-halo-silyl, e.g. dimethylchlorosilyl, or similarly substituted stannyl compounds, e.g. tri-n-butyl-stannyl.

Preferred protected carboxyl groups are tert-butyloxycarbonyl, optionally, e.g. as indicated substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.

A cleavable, esterified carboxyl group under physiological conditions is primarily an acyloxy-methoxycarbonyl group, in which acyl means e.g. the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or in which acyloxymethyl forms the residue of a lactone. Such groups are lower alkanoyl-oxymethoxycarbonyl, e.g. acetyloxymethyloxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxy-methoxycarbonyl, especially α-amino-lower alkanoyloxy-methoxycarbonyl, e.g. glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, further phthalidyloxycarbonyl, e.g. 2-phthalidyloxycarbonyl, or indanyloxycarbonyl, e.g. 5-indaninyloxycarbonyl.

A protected amino group such as the group Am, can e.g. present in the form of an easily cleavable acylamino, mono-, di- or triarylmethylamino-, etherified mercaptoamino-, 1-acyl-2-lower alkylideneamino-, silyl- or stannylamino group or as an azido group.

In a corresponding acylamino group, acyl is, for example, the acyl residue of an organic carboxylic acid with e.g. up to 18 C atoms, especially one optionally, e.g. with halogen or aryl, substituted aliphatic carboxylic acid or optionally, e.g. with halogen, lower alkoxy or nitro, substituted aromatic carboxylic acid or a carboxylic acid half-ester. Such acyl groups are, for example, lower alkanoyl such as formyl, acetyl, propionyl, halo? trichloroacetyl, phenylacetyl, phenoxyacetyl, thienylacetyl, benzoyl, 4-chloro-, 4-methoxy- or 4-nitro-benzoyl, lower alkoxycarbonyl, especially tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. adamantyloxycarbonyl, arylmethoxycarbonyl, wherein aryl preferably denotes one or two, optionally e.g. with lower alkyl, especially tert.-lower alkyl, e.g. tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono- or polysubstituted phenyl residues, such as optionally substituted benzoyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl or substituted diphenylmethoxycarbonyl, e.g. benzhydryloxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl, or 2-halo-lower oxycarbonyl, e.g. 2,2, 2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(S^)(S2)(S^)-silylethoxycarbonyl, wherein the substituents S^, S2 and independently of one another each mean a optionally substituted, e.g. with lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue with e.g. up to 15 C atoms,

as a corresponding optionally substituted lower alkyl, aryl lower alkyl, cycloalkyl or aryl residue, e.g. 2-tri-lower alkylsilylethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2-(dibutylmethylsilyl)ethoxycarbonyl or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl or aroylmethoxycarbonyl, wherein the aroyl group preferably denotes optionally, e.g. with a halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl.

Additional acyl groups in the acylamino groups are residues of organic phosphoric, phosphonic or phosphinic acids with

12 12

formula (R )(R )P(=0)-, in which R and R independently of each other mean a hydroxy group etherified with a hydrocarbon residue or a hydrocarbon residue, whereby the hydrocarbon residues preferably contain up to 15 C atoms, are for example aliphatic, araliphatic, cycloaliphatic or aromatic nature, is possibly e.g. with lower alkyl, lower alkoxy, aryl, halogen or nitro substituted, and means, for example, alkyl, especially lower alkyl such as methyl, ethyl, propyl, isopropyl or butyl, phenyl lower alkyl such as benzyl, p-nitro- or p-chloro-benzyl, cycloalkyl such as cyclopropyl, cyclopentyl , cyclohexyl or cycloheptyl or homoaryl such as phenyl, o-, m- or p-tolyl, p-methoxyphenyl, p-biphenylyl, p-chlorophenyl or p-nitrophenyl. Such residues are, for example, dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibenzylphosphoryl, di-p-nitrobenzylphosphoryl,

dicyclohexylphosphoryl, diphenylphosphoryl, phenoxy-phenyl-phosphonyl, diethylphosphinyl and diphenylphosphinyl.

In a mono-, di- or triarylmethylamino group, the aryl residue is especially optionally substituted phenyl residues.

Such groups are, for example, benzyl, diphenylmethyl or tritylamino.

An etherified mercapto group in an amino group protected by such a residue is primarily arylthio or aryl-lower alkylthio, in which aryl is particularly optional, e.g.

with a lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine and/or nitro substituted phenyl. A corresponding amino protecting group is e.g. 4-nitrophenylthio.

In a 1-acyl-2-lower alkylidene residue that can be used as an amino protecting group, acyl is preferably the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. with lower alkyl, such as methyl or tert.-butyl, lower alkoxy,

as methoxy, halogen, as chlorine, and/or nitro substituted benzoic acid or of a carboxylic acid half-ester such as a carboxylic acid-lower alkyl half-ester. Corresponding protecting groups are primarily 1-lower alkanoyl-2-propylidene, e.g. 1-acetyl-2-propylidene or 1-lower alkyloxycarbonyl-2-propylidene, e.g. 1-ethoxycarbonyl-2-propylidene.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which silicon-resp. the tin atom preferably contains lower alkyl, especially methyl, further lower alkoxy, e.g. methoxy and/or halogen, e.g. chlorine, as substituents. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, lower-alkyl-lower-alkyl-halo-silyl, e.g. methoxy-methyl-chloro-silyl or di-averealkyl-halo-silyl, e.g. dimethyl-chloro-silyl or similarly substituted stannyl, e.g. tri-n-butylstannyl.

An amino group can also be protected in protonated form; as anions, those of strong, inorganic acids, such as halogen hydrogen acids, e.g. the chlorine or bromine anion, or of sulphonic acid which

p-toluenesulfonic acid.

Preferred amino protecting groups are the acyl residue of carboxylic acid half-esters, especially tert-butyloxycarbonyl, optionally, e.g. as indicated substituted benzyloxycarbonyl or diphenylmethoxycarbonyl or 2-halo-lower oxycarbonyl such as 2,2,2-trichloroethoxycarbonyl.

Hydroxy protecting groups are e.g. acyl residues such as 2,2-dichloroacetyl or especially the acyl residues of carboxylic acid residues indicated in connection with a protected amino group, especially 2,2,2-trichloroethoxycarbonyl or organic silyl or stannyl residues, further easily cleavable 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residues, primarily 1-lower oxy-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl or 2-oxa- or 2-thiacyclolower alkyl with 5-7 ring atoms, e.g. 2-tetrahydro-furyl or 2-tetrahydropyranyl or corresponding thia analogues, as well as easily cleavable, optionally substituted α-phenyl lower alkyl residues, such as optionally substituted benzyl or diphenylmethyl, whereby as substituents the phenyl residue comes into consideration e.g. halogen such as chlorine, lower alkoxy such as methoxy and/or nitro.

A protected sulfo group is primarily one with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, such as a lower alkanol, or with a silyl or stannyl residue, such as trilower alkylsilyl, esterified sulfo group. In a sulfo group, the hydroxy group can be etherified, for example like the hydroxy group in an esterified carboxy group.

Salts are especially those of compounds of formula I with acidic groups, e.g. with free carboxyl and sulfo-v groups. Such salts are primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines are taken into account, as well as heterocyclic bases for salt formation, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-amino-benzoic acid-2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N,N'-debenzyl-ethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of formula I with a basic group can form acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbonic 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 with a free carboxyl group and free amino groups can also exist in the form of internal salts, i.e. in zwitterionic form, or part of the molecule can exist as an internal salt and the other part as a normal salt.

Pharmaceutical unsuitable salts can also be used for isolation and purification. For therapeutic use, only pharmaceutical harmless salts are used, which are therefore preferred.

The group =N-O-R^ can exist in syn- (Z-) or anti (E-) form, whereby the syn form is preferred.

The aminothiadiazolyl group with the subformula

can also exist in their tautomeric form as the iminothia-diazolinyl group with the partial formula

or as a mixture of both forms. The equilibrium between the two tautomers depends on the nature of the substituents and external factors such as temperature, solvent or pH value. In the context of the present invention, this group is referred to in the description and in the claims only as "aminothiadiazolyl", although the iminothiadiazolinyl form is also to be included.

The compounds of formula I, in which protective groups have been removed, but in which carboxyl groups are possibly esterified in a physiologically cleavable form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotic active substances which can be particularly used as antibacterial antibiotics. For example, they are effective in vitro against gram-positive and gram-negative microorganisms such as cocci, e.g. staphylococci, such as Staphylococcus aureus, streptococci, such as Streptococcus pyogenes and Streptococcus pneumoniae, enterococci and micrococci, including Neisseria species, e.g. Neisseria gonorrhoeae, in minimal concentrations from <0.005 mcg/ml to approx. 32 mcg/ml, and effective against Enterobacteriaceae, e.g. against Escherichia coli, Klebsiella, Serratia, Enterobacter or Proteus spp, as well as against Pseudomonas aeruginosa, Haemophilus influenzae and other gram-negative and gram-positive rod bacteria, in minimum concentration from <0.005 to approx. 16 mcg/ml. In vivo, by subcutaneous application to mice, they are equally effective against gram-positive and gram-negative bacteria, e.g. Staphylococci, Escherichia coli, Proteus and Pseudomonas aeruginosa, in minimal doses from <0.15 to approx. 100 mg/kg.

Certain preferred compounds are distinguished by

a particularly long residence time in the body. In the mouse, for example, the half-life is up to 60 minutes.

The new compounds can therefore correspondingly, e.g.

in the form of antibiotic: effective preparations find applications

for the treatment of infections caused by gram-positive or gram-negative bacteria and cocci, especially in infections caused by enterobacteria, such as Escherichia coli.

Groups that are to be emphasized are compounds of formula I, in which Am produces an optionally protected secondary or tertiary amino group and , R2 r R^0<3 R^ have the meanings given under formula I or in which R^ stands for hydrogen, substituted lower alkyl or cycloalkyl or optionally N-substituted carbamoyl and Am, R2,

R^ and R^ have the meanings indicated under formula I, or in which R2 means lower alkoxy and Am, R^, R^ and R^ have the meanings indicated under formula I, and the salts of such compounds with salt-forming groups.

Compounds of formula I, in which the functional groups are protected, are used as starting materials for the preparation of compounds of formula I. The present invention primarily relates to such compounds of formula I, in which Am means amino or methylamino, R^ means hydrogen, lower alkyl , especially methyl, with carboxy substituted lower alkyl or cycloalkyl, especially 2-carboxy-2-propyl or 1-carboxy-1-cyclopropyl, or a group -C(=0)-NHR, in which R means hydrogen or lower alkyl, especially methyl, R2 indicates hydrogen or methoxy,

R^indicates lower alkanoyloxy such as acetoxy, carbamoyloxy, N-lower alkylcarbamoyloxy or optionally substituted, with a ring carbon atom attached to the thio group heterocyclylthio, such as triazolylthio, tetrazolylthio, thiazolylthio, thiatriazolylthio, thiadiazolylthio, oxazolylthio, oxadiazolylthio, pyridazinylthio, pyrimidinylthio or triazinylthio, in which the heterocyclic rings may be partially hydrogenated and optionally substituted, for example, with lower alkyl, such as methyl, N,N-dilower alkylamino lower alkyl, such as 2-N,N-dimethylaminoethyl, carboxy lower alkyl, such as carboxymethyl or 2-carboxyethyl, sulfo lower alkyl, such as sulfomethyl or 2-sulfoethyl, amino, carboxy lower alkyl amino, carbamoyl, oxo or hydroxy, and R denotes carboxyl or in physiologically cleavable form esterified carboxyl, e.g. acyloxy-methoxycarbonyl, pharmaceutically usable salts of such compounds as well as the starting materials and intermediates usable for their preparation.

Compounds that are particularly preferred are compounds of formula I, wherein Am is amino or methylamino, R 2 is hydrogen, methyl, 2-carboxy-2-propyl, 1-carboxy-1-cyclopropyl, carbamoyl or N-methylcarbamoyl, R 2 is hydrogen or methoxy, R 2 means acetoxy, carbamoyloxy, optionally with lower alkyl, carboxy lower alkyl, sulpho lower alkyl or di lower alkyl amino lower alkyl substituted tetrazolylthio, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-sulfomethyl-1H-tetrazol-5-ylthio, 1(2-sulfoethyl)-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio , 1 -(2-dimethylamirioethyl)-1H-tetrazol-5-ylthio, optionally with lower alkyl substituted thiadiazolylthio, such as 2-methyl-1,3,4-thiadiazol-5-ylthio or 3-methyl-1,2,4- thiadiazol-5-ylthio, optionally with hydroxy substituted pyridazinylthio, e.g. 3-hydroxy-pyridazin-6-ylthio, optionally with hydroxy substituted pyrimidinylthio, e.g. 4-hydroxy-2-pyrimidinyl-resp. to that tautomer 4-oxo-3,4-dihydro-2-pyrimidinylthio, or with lower alkyl and two hydroxy substituted triazinylthio, such as 2-lower alkyl-5,6-dihydroxy-1,2,4-triazin-3-ylthio, resp. in addition tautomeric 1,2,5,6-tetrahydro-2-lower alkyl-5,6-dioxo-1,2,4-triazin-3-ylthio, e.g. 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazinyl-3-ylthio, and R4 means carboxyl or in physiologically cleavable form esterified carboxyl, e.g. pivaloylmethoxycarbonyl or phthalidyloxycarbonyl, pharmaceutically usable salts of such compounds as well as the starting materials and intermediates usable for their production.

The invention relates in particular to the compounds of formula I described in the examples, their pharmaceutically acceptable salts as well as the new starting materials and intermediates described therein.

The compounds according to the present invention are obtained according to methods known per se.

Compounds of formula I and salts of such compounds containing a salt-forming group are prepared, for example, by

a) acylates in a> compound of formula

in which , R^ and have the meanings given above, and in which the 7B-amino group is optionally substituted with a group permitting the acylation, the 73-amino group by treatment with an acyl residue of the carboxylic acid of formula

introducing agent, in which Am and R^ have the indicated meanings, or

b) reacts a compound of formula

in which Am, R2, R^ and R^ have the meanings given above, with a hydroxylamine of formula r^N-O-R^(V), in which R^ has the meaning given above, or c) isomerizes a 2-cephem compound of formula in which Am , , R2, R^ and R^ have the meanings given above, or d) for the preparation of a compound of formula (I), in which Am means a primary or secondary amino group,

processes a compound with formula

in which X means halogen or hydroxy and R^, R2 in R3 and R^ have the meanings given above, with a salt of the Rhodan hydrogen acid, respectively. with an isorhodan hydrogen ester, or treats a compound of formula (VII), wherein X is hydrogen, with rhodane, or e) to produce a compound of formula (I), wherein R^ is hydrogen and wherein Am, R2, R and R4 have the meanings given above, treating a compound of formula in which Am, R2, °9 R4^are ^e meanings given above, with a nitrosating agent, or f) for the preparation of a compound of formula (I), in which R^ means optionally substituted lower alkyl or cycloalkyl or optionally N-substituted carbamoyl and in which Am, R2, R3 and R^ have the meanings given above, treats in a compound of formula in which Am, R2, R3 and R^ have the meanings given above, the hydroxyimino group with an agent introducing the residue R^, or g) for the preparation of a compound of formula (I), in which R2 means lower alkoxy and in which Am, R^, R^ and R^ have the meanings given above, introduces into a compound of formula

in which Am, R^, R^ and R^ have the meanings given above, whereby functional groups are present in protected form,

a lower alkoxy group in the 7a position,

h) for the preparation of a compound of formula (I), in which R^ stands for heterocyclothio and in which Am, R^, R 2 and R^

has the meanings given above, treats a compound with formula

in which Am, R^, R2 and R^ have the above meanings and Rg° means a residue exchangeable with a heterocyclylthio radical R3, with a mercaptan H-R^, or i) for the preparation of a compound of formula (I), in which R^ stands for acyloxy and wherein Am, R^, R 2 and R^ have the meanings given above, treating a compound of formula wherein Am, R^, R 2 and R^ have the meanings given above, with an acylating agent, or j) for the preparation of a compound of formula (I), in which R^ denotes free carboxyl and in which Am, R^, R 2 and R^ have the meanings given above, removes in a compound of formula in which Am, , and R^ have the meanings given above and R^ denotes a protected carboxyl group, the carboxyl-protecting group and replaces with hydrogen, or k) for the preparation of a compound of formula (I), in which R^ denotes an esterified carboxyl group and in which Am, R.j , R.sub.2 and R^ have the above meanings, esters in a compound of formula wherein Am, R^, R^ and R^ have the meanings indicated above , the 4-carboxyl group, or 1) for the preparation of compounds of formula (I), in which Am is a primary, secondary or tertiary amino group, reacts a compound of formula

wherein y is halogen and , R2, R^ and R^ have the meanings given above, with ammonia or a primary or secondary amine Am-H or a metal amide thereof, and, if necessary, cleaves off in a resulting compound undesired protecting groups, and /or, if desired, transfers an obtained compound with a salt-forming group in a salt, or transfers an obtained salt in a free compound or in another salt.

Progress<ang>small<e>_<a>)__^<Ac>Y<ler>in2]_j_ Optionally present, the amino group substituting and their acylation permitting residue in a starting material with formula II are for example organic silyl or stannyl groups, further also ylidene groups which together with the amino group form a Schiff's base. The mentioned organic silyl or stannyl groups are e.g. the same?, which also with the 4-carboxyl group on the cef ent ring are able to form a protected carboxyl group, by the silylation or stannylation of a carboxyl group in a starting material of formula II, can, by using an excess of silylation or the stannylating agent, the amino group is optionally silylated or stannylated.

The mentioned ylidene groups are primarily aryl-methylene groups, in which aryl stands in particular for a carbocyclic, primarily monocyclic aryl residue, e.g. for optionally, as with nitro or hydroxy, substituted phenyl.

The other functional groups present in the starting substances of formula II can be protected by the protective groups already mentioned under the compounds of formula I. Preferably, all reactive functional groups not participating in the acylation reaction, but in particular any acylatable amino, hydroxy and mercapto groups present, are protected.

The for the acyl residue of a carboxylic acid of formula

III introducing acylating agent is, for example, carbonic acid itself or reactive, functional derivatives thereof.

If a free acid of formula III, in which all functional groups apart from the reactive carboxyl group can be protected, is used for the acylation, suitable condensing agents such as carbodiimides are usually used, for example N,N<1->diethyl-, N,N'-dipropyl -, N,N<1->dicyclohexyl-or N-ethyl-N<1->3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, e.g. carbonyldiimidazole or isoxazolinium-3<1->sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate or an acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out

in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, under cooling or heating and/or in an inert gas atmosphere.

A reactive, i.e. amide-forming functional derivative of an acid of formula III, in which all functional groups except the reacting acid group can be protected, is primarily an anhydride of such an acid, including and preferably a mixed anhydride. Mixed anhydrides are e.g. those with inorganic acids such as halogen hydrogen-i acids, i.e. corresponding acid halides, e.g. -chlorides or -bromides, further with nitrogen hydrogen acids, i.e.

the corresponding acid acids, with a phosphorous acid, e.g. phosphoric acid, diethylphosphoric acid or phosphoric acid or with a sulphurous acid, e.g. sulfuric acid, or with hydrocyanic acid. Further mixed anhydrides are e.g. those with organic carboxylic acids, such as with optionally, flex, with halogen, such as fluorine or chlorine, substituted lower alkane carboxylic acids, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of the carboxylic acid such as the ethyl or isobutyl half-ester of the carboxylic acid, or with organic, especially aliphatic or aromatic sulphonic acids, e.g. p-toluenesulfonic acid.

Further acid derivatives suitable for reaction with the amino group in an acid of formula III, in which all functional groups except the reacting carboxyl group can be protected, are activated esters such as esters with vinylogenic alcohols (i.e. enols such as vinylogenic lower alkenols or iminomethyl ester halides such as dimethyliminomethyl ester chloride (prepared from the carbonic acid and dimethyl-chloromethylidene-iminium chloride of the formula {(CH3)2N=CHC1} ® Cl ® ), or aryl esters such as 4-nitrophenyl- or 2,3-dinitrophenyl esters, heteroaromatic esters such as benztyrazole-, e.g. 1-benztriazole esters or diacylimino esters such as succinyl imino or phthalyl imino esters.

The acylation with an acid derivative such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid binding agent, for example an organic base such as an organic amine, e.g. a tertiary amine such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine or N,N-dilaverealkylaniline, e.g. N,N-dimethylaniline or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as N-methylmorpholine or a pyridine-type base, e.g. pyridine, an organic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate or an oxirane, for example a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above-mentioned acylations are preferably carried out

in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide such as a formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. acetone, an ester, e.g. acetic acid ethyl ester or a nitrile, e.g. acetonitrile, or mixtures thereof, at room temperature, if necessary - at low or elevated temperature, approx. at -40° to approx. 100°, preferably at -10° to +40°, and/or in an inert gas, e.g. nitrogen atmosphere.

The acylation can also take place in the presence of an acylase which produces the desired amide compound. Such acylases are known and are formed by a number of microorganisms, e.g. of acetobacters such as Acetobacter aurantium, achromobacters such as Achromobacter aeris, aeromonas such as Aeromonas hydrophila or Bacillus megaterium, e.g. 400. In the enzymatic acylation, amides, esters and thioesters are used in particular as corresponding lower alkyls, e.g. methyl or ethyl ester,

to the carboxylic acid of formula III. An enzymatic acylation is carried out in a nutrient medium containing the micro-organism, in a filtrate of the culture slurry or optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous, optionally a buffer-containing medium at approx. 30-40°, preferably at approx. 37°.

In an acid of formula III to be acylated, or

in an acid derivative thereof, a protected amino group can also be present in ionic form, i.e. the starting material of formula III can be used in the form of an acid addition salt, preferably with a strong inorganic acid such as a hydrohalic acid, e.g. hydrochloric or sulfuric acid.

Furthermore, an acid derivative can, if desired, be formed

in situ. Then you get e.g. a mixed anhydride by treatment with an acid of formula III, with correspondingly protected, functional groups or by treatment with a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine,

such as pyridine or 4-methylmorpholine, or when treating a metal, e.g. alkali metal salt, with a suitable acid derivative such as a corresponding acid halide or optionally substituted lower alkane carboxylic acid, e.g. trichloroacetyl chloride, with a half-ester of a carboxylic acid half-halide, e.g. chloroformic acid ethyl ester or isobutyl ester, or with a halide of a dilave alkyl phosphoric acid, e.g. diethyl phosphorous bromide, and uses the thus obtainable mixed anhydride without isolation.

?E§m2§G2§mÉ£§_^i_iQm§§É2i22_§Y_2lS§2?5§£Yi§S2EliEE§?}_?B§^ l2Y^E2]S5Yi<am:>'-ner!: I a compound of formula IV, in which functional groups are possibly protected, the oxo group in the 7B-acylamido group is transferred by treatment with hydroxylamine or a substituted hydroxylamine of formula H2N-0-R1(V) in a

hydroxyiminomethylene- or -substituted hydroxyimino-methylene group.

The reaction of the oxo group with the hydroxylamine compound is carried out in the usual way, e.g. allowing both reaction partners to react in a solvent, such as water or an organic solvent such as an alcohol, e.g. methanol, at a slightly elevated or lowered temperature, such as between approx. -20° to approx. +100°, preferred at approx. 0° to approx. 30°, possibly in an inert gas, such as nitrogen atmosphere. The hydroxylamine compound can, also in situ, be set free from one of their salts, e.g. a hydrohalide such as hydrochloride, by treatment with an inorganic base such as an alkali metal hydroxide, e.g. sodium hydroxide, or by treatment with an organic base such as a tertiary amine, eg a trilower alkylamine, such as a trilower alkylamine such as triethylamine or ethyl diisopropylamine, or by treatment with a heterocyclic tertiary base such as pyridine.

EE§<m>2§S2§<m>åt§_2i_iI§2<m>§Ei§§Ei22i<:>

In a 2-cephem compound of formula VI, the optionally protected carboxyl group in the 4-position preferably exhibits the α-configuration.

2-cephem compounds of formula VI are isomerized by treating them with a weakly basic agent and isolating the corresponding 3-cephem compound. Suitable isomerizing agents are e.g. organic, nitrogen-containing bases, especially tertiary, heterocyclic bases of an aromatic character, i

first series of pyridine-type bases such as pyridine itself as well as collidines or lutidines, further quinoline, tertiary aromatic bases, e.g. those of the aniline type, such as N,N-dilower alkylanilines, e.g. N,N-dimethylaniline or N,N-diethylaniline or tertiary aliphatic, azacycloaliphatic or araliphatic bases such as N,N,N-trilower alkylamines, e.g. N,N,N-trimethylamine, N,N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes, e.g. N-methyl-piperidine or N-phenyl-lower alkyl-N,N-dilower alkylamines, e.g. N-benzyl-N,N-dimethylamine, as well as mixtures thereof, such as

the mixture of a pyridine-type base and an N,N,N-trilower alkylamine, e.g. pyridine and triethylamine. Furthermore, inorganic or organic salts of bases can also be used, especially of medium to strong bases with weak acids such as alkali metal or ammonium salts of lower alkane carboxylic acids, e.g. sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate as well as other analogous bases or mixtures of such basic agents.

When isomerizing with basic agents, one preferably works in an anhydrous medium in the presence or absence of: a solvent such as a possibly halogenated one, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon or a solvent mixture, whereby liquid bases used as reactant, under reaction conditions, can also simultaneously serve as solvent, during cooling, at room temperature or during heating, preferably in a temperature range from approx. -30°C to approx. +100°C, in an inert gas, e.g. nitrogen atmosphere, and/or in a closed vessel.

The 3-cephem compounds thus obtainable can be prepared in a manner known per se, e.g. by adsorption and/or crystallization, separate from any 2-cephem compounds still present.

The isomerization of 2-cephem compounds of formula VI is preferably carried out by oxidizing this in the 1-position, if desired, separating 1-oxides from the obtainable isomer mixture, and reducing the thus obtainable 1-oxides of corresponding 3-cephem compounds.

Suitable oxidizing agents for oxidation in the 1-position of 2-cephem compounds 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, especially organic carboxylic acids with a dissociation constant

-5

of at least 10 . Suitable inorganic peracids are periodic and persulphuric acid. Organic peracids are equivalent to percarbon-

and persulfonic acids which as such can be added or can

is formed in situ using at least one equivalent of hydrogen peroxide and a carbonic acid. Thereby, it is appropriate to use a large excess of the carbonic acid when e.g. acetic acid is used as a solvent. Suitable peracids are e.g. permauric acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

The oxidation can optionally be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation ion constant of at least 10 ~*, whereby low concentrations can be used, e.g. 1-2% and less, but also larger amounts of acid. Thereby, the effect of the mixture depends primarily on the strength of the acid. Suitable mixtures are e.g. such as hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid. The above-mentioned oxidation can be carried out in the presence of suitable catalysts. So can e.g. the oxidation with percarboxylic acids is catalyzed by the presence of an acid with a dissociation ion constant of at least 10 ~*, whereby their action depends on their strength. Acids suitable as catalysts are e.g. acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a small excess of approx. 10% to approx. 20%, whereby a larger excess can also be used, i.e. up to a 10-fold amount of the oxidizing agent or more. The oxidation is carried out under mild conditions, e.g. at temperatures of approx. -50°C to approx. +100°C, preferably from approx. -10°C to approx. +40°C.

The reduction of 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. Examples of reducing agents that come into consideration are: Catalytically activated hydrogen, whereby noble metal catalysts are used, which contain palladium, platinum or rhodium, and which are optionally used together with a suitable carrier material such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations, which are used in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. such as stannous chloride, fluoride, acetate or formate, ferric chloride, sulphate, oxalate or succinate, copper chloride, benzoate or oxide or manganese chloride, sulphate , -acetate or -oxide or as complexes, e.g. with ethylenediaminetetraacetic acid or nitroltriacetic acid; reducing dithionite, iodine or iron II cyanide anions, which are used in the form of corresponding inorganic or organic salts such as alkali metal, e.g. sodium or potassium dithionite, sodium or potassium iodide or iron II cyanide, or in the form of corresponding acids such as hydroiodic acid; reducing trivalent inorganic or organic phosphorus compounds such as phosphines, further esters, amides and halides of phosphinic acid, phosphonic acid or phosphoric acid, as well as these phosphoroxygen compounds corresponding to phosphorus-sulfur compounds, in which organic residues primarily produce aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups, such as e.g. triphenylphosphine, tri-n-butylphosphine, diphenylphosphinic acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acid methyl ester, phosphonic acid triphenylester, phosphonic acid trimethylester, phosphorus trichloride, phosphorus tribromide etc.; reducing halosilane compounds which contain at least one hydrogen atom bound to the silicon atom, and which, in addition to halogen, such as chlorine, bromine or iodine, may also contain organic residues such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tri-bromosilane, diphenylchlorosilane, dimethylchlorosilane, dimethyliodosilane or also halosilane compounds, in which all hydrogen atoms are replaced with organic residues such as tri-lower alkylhalosilane, e.g. . trimethyliodosilane or cyclic sulphur-containing silanes, such as 1,3-dithia-2,4-disila-cyclobutane or 1,3,5-trithia-2,4,6-trisila-cyclohexane, which silicon atoms are substituted with hydrogen carbon^ - residues as especially lower alkyl residues, e.g. 2,2,4,4- tetramethyl-1,3-dithia-2,4-disilacyclobutane or 2,2,4,4,6,6-hexamethyl-1,3,5-trithia-2,4,6- trisilacyclohexane etc.; reducing quaternary chloromethylene iminium salts, esp

-chlorides or bromides, in which the iminium group is substituted with a bivalent or two monovalent organic residues as optionally substituted lower alkylene -> or lower alkyl groups, such as N-chloromethylene-N,N-diethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; and complex metal hydrides such as sodium borohydride, in the presence of suitable activating agents such as cobalt II chloride and borane dichloride.

As an activating agent that is used together with them

of the above-mentioned reducing agents, which themselves do not exhibit Lewis acid properties, i.e. they are primarily used together with the dithionite, iodine or iron II cyanide and the non-halogen-containing trivalent phosphorus reducing agents or by catalytic reduction, are especially organic carbon and sulphonic acid halides, further sulphur, phosphorus or silicon halides with the same or greater hydrolysis constant of a different order than benzoyl chloride, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; pivalic acid 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, benzenephosphonic acid dichloride, dimethylchlorosilane or trichlorosilane, further suitable acid anhydrides such as trifluoroacetic anhydride or cyclic sultones such as ethanesultone, 1,3 -propane sultone, 1,4-butane sultone or 1,3-hexane sultone.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, their selection is primarily determined by the solubility of the starting material and the choice of the reducing agent, so e.g. lower alkane carboxylic acids or esters thereof such as acetic acid and acetic acid ethyl ester, by 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 carboxylic 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, e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone or sulphones, especially aliphatic sulphones, e.g. dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, whereby these solvents preferably do not contain water. In this way, you usually work at temperatures from approx. -20°C to approx. 100°C, whereby by using highly reactive activators, the reaction can be carried out at lower temperatures.

In a compound of formula VII, X as halogen is, for example, chlorine, iodine or preferably bromine. Suitable salts for rhodanhydrogen acid (thiocyanic acid) are, for example, alkali, alkaline earth or heavy metal salts, e.g. the sodium, potassium, magnesium or lead salt or also ammonium salts which are derived from ammonia or organic nitrogen bases, e.g. the ammonium salt, or mono-, di-, tri- or tetralower alkyl ammonium salts, wherein lower alkyl means methyl, ethyl, isopropyl or the like.

Suitable isorhodan hydrogen esters are, for example, isorhodan hydrogen lower alkyl esters, which are also referred to as lower alkyl isothiocyanates, such as methyl, ethyl, propyl or butyl isothiocyanate.

The condensation of compounds of formula VII with

a salt of the rhodane hydrogen acid or with rhodane gives compounds of formula (I), in which Am is a free, primary amino group, while the condensation with an isorhodan hydrogen acid ester gives a compound of formula (I), in which Am is a free secondary amino group, for example a lower alkylamino -group.

The reaction is preferably carried out in an inert solvent such as a lower alcohol, e.g. 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 and the like, or also in mixtures thereof, possibly under cooling or heating, i.e. at temperatures between approx. -80° to approx. +100°, preferably between approx. -20° to approx. +20°, possibly in an inert gas atmosphere.

A compound of formula VII, in which X is halogen, can also be prepared in situ, possibly in the presence of the rhodan hydrogen salt, for example by treating a compound of formula VII, in which X is hydrogen, in one of the aforementioned solvents with a hypohalogenite, e.g. sodium or potassium hypobromite, or with a halogen and an alkali metal base such as a hydroxide, carbonate or alcoholate, e.g. with bromine and sodium methylate or potassium carbonate. This halogenation preferably takes place during cooling, e.g.

at approx. -15° to approx. 0°.

A compound of formula VII, in which X is hydroxy, can likewise be prepared in situ, for example by treating a compound of formula VII, in which X is hydrogen, with an oxidizing agent such as hydrogen peroxide.

The reaction of a compound of formula VII, in which X is hydrogen, with the rhodan also takes place in one of the aforementioned inert solvents and under similar reaction conditions. Optionally, an acid addition salt to a compound of formula VII can also be used, which is transferred into the free compound in situ, or the rhodanate can be formed in situ, e.g. of a rhodanide, e.g. lead rhodanide, and a halogen, e.g. bromine.

Procedure_e)__^Nitroserine2_ :

In a compound of formula VIII, the functional groups are preferably protected.

Suitable nitrosating agents are nitric acid and derivatives derived from it such as nitrosyl halides, e.g. nitrosyl chloride or nitrosyl bromide, the salt of nitric acid as alkali metal salts, e.g. sodium or potassium nitrite or especially esters of nitric acid such as lower alkyl esters, e.g. butyl, pentyl or especially iso-amyl nitrite.

When a salt is used as a nitrosating agent for the nitric acidification, the reaction is preferably carried out in the presence of a strong inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid or acetic acid. When using an ester for the nitric acidification, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkylate.

The nitrosation is carried out in a suitable solvent such as water, a carbonic acid, e.g. acetic acid, a lower alcohol, e.g. methanol or ethanol, an ether, e.g. dioxane or tetrahydrofuran, or a hydrocarbon, e.g. hexane or benzene, or in mixtures thereof, during cooling or heating, especially at approx. -15° to room temperature.

Procedure_f i_iAlkYl§Ei22_22_lS§E2am2Yi2EiS2_§Y_^Y§E2lS§Yl i<m>i222EHEE22l<:>In a starting material of formula If are alkylable respectively. carbamoylatable groups, besides the reactive hydroxyimino group, preferably protected.

The etherification of the free hydroxy group is carried out with one of the desired conventional etherification agents introducing optionally substituted lower alkyl or cycloalkyl residues.

Suitable etherification agents are, for example, diazo compounds such as diazolaveralkanes or -cycloalkanes, e.g. diazomethane, diazoethane or diazo-n-butane, which may optionally be substituted in the alkane part. These reagents are brought into the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. methylene chloride, or an ether, such as a dilower alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent under cooling, at room temperature or under slight heating, further, if necessary, in a closed vessel and/or under an inert gas, e.g. nitrogen atmosphere, for use.

Further suitable etherification agents are esters of corresponding alcohols, primarily those of strong inorganic or organic acids such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, further sulfuric acid or halo-sulfuric acid, e.g. fluorosulphuric acid or strong organic sulphonic acids, which possibly, e.g. with halogen as fluorine substituted lower alkanesulphonic acids or aromatic sulphonic acids, such as e.g. possibly, e.g. with lower alkyl such as methyl, halogen, such as bromine or nitro substituted benzenesulfonic acids, e.g. methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid, e.g. dilower alkyl sulfates, such as dimethyl sulfate, further fluorosulfonic acid lower alkyl esters, e.g. fluorosulfonic acid methyl ester or optionally halogen-substituted methanesulfonic acid lower alkyl ester, e.g. trifluoromethanesulfonic acid methyl ester. They are usually used in the presence of an inert solvent such as an optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. methylene chloride, an ether such as dioxane or tetrahydrofuran or a mixture. Thereby, suitable condensation agents such as alkali metal carbonates or hydrogenates are preferably used, e.g. sodium or potassium carbonate or hydrogen carbonate (usually together with a sulphate), or organic bases, such as usually steric, blocked, tri-lower alkylamines, e.g. N,N-diisopropyl-N-ethylamine (preferably together with lower alkyl halogen sulfates or optionally halogen-substituted methanesulfonic acid lower alkyl esters), whereby work is carried out under cooling, at room temperature or during heating, e.g. at temperatures from approx. -20°C

to approx. 50°C and, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

Further etherifying agents are corresponding acetals, e.g. gem-lower alkyl lower alkanes such as 2,2-dimethoxy-propane, which find use in the presence of a strong organic sulphonic acid such as p-toluenesulphonic acid, and a suitable solvent such as a di lower alkyl or lower alkylene sulphoxide, e.g. dimethylsulfoxide, or orthoester, e.g. orthoformic acid trilower alkyl ester, e.g. orthoformic acid triethyl ester which is used in the presence of a strong mineral acid, e.g. sulfuric acid, or in the presence of a strong organic sulphonic acid, such as p-toluenesulphonic acid, and a suitable solvent, such as an ether, e.g. dioxane.

Further etherification agents are corresponding tri-R^-oxonium salts (so-called Meerwein salts), di-R^-O-carbenium salts or di-R^-halonium salts, in which R^ denotes the residue to be introduced, for example trilower alkyl oxonium salts and dilavereal oxycarbenium or dilave alkylhalonium salts, especially corresponding salts with complex, fluorine-containing acids, such as corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloroantimonates. Such reagents are e.g. trimethyloxonium or triethyloxonium hexafluoroantimonate, -hexachloroantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. These etherification agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran or methylene chloride or in a mixture thereof, if necessary, in the presence of a base such as an organic base, e.g. a, preferably sterically blocked, tri-lower alkylamine, e.g. N,N-diisopropyl-N-ethylamine, and under cooling, at room temperature or under slight heating, e.g. at approx. -20°C to approx. 50°C, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

Further etherifying agents are finally corresponding to 1-R,j-3-aryltriazene compounds, in which R^ denotes the residue which

must be introduced, and aryl preferably means an optionally substituted phenyl residue, e.g. lower alkylphenyl such as 4-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyl triazenes, e.g. 3-(4-methylphenyl)-1-methyl-triazene. These reagents are usually used in the presence of inert solvents such as optionally halogenated hydrocarbons or ethers, e.g.

benzene, or solvent mixtures, and under cooling, at room temperature and preferably at elevated temperature, e.g. at approx. 20°C to approx. 10 0°C, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

The introduction of a carbonyl group -C(=0)-NHR instead of the hydrogen atom takes place in a manner known per se by carbamoylation. For this purpose, a compound of formula (If), in which all reactive groups, which are not to be carbamoylated or which will consume and destroy the reagents, are present in a protected form, is optionally treated in stages with a carbamoylating agent. Suitable carbamoylating agents are reactive derivatives of the carbamic acid R-NH-C(=0)OH, especially the isocyanates R-N=C=0 or the mixed anhydrides, e.g. the carbamic acid chlorides R-NH-C(=0)Cl, which can also be prepared in situ from phosgene and an amine R-NH2.

The reaction with the isocyanates takes place in one of the usual inert solvents, for example a possibly halogenated hydrocarbon, e.g. benzene, xylol or methylene chloride, an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, or an ester, e.g. acetic acid ethyl ester, optionally in the presence of a basic catalyst, for example a tertiary amine, e.g. triethylamine or pyridine, at room temperature or slightly reduced or elevated temperature, approximately between -20° and +50°.

For reaction with a mixed anhydride to the carbamic acid, the alcohol group is advantageously first metallized, for example with an alkali metal hydride, e.g. sodium or lithium hydride. The compounds of formula (If) metallized to the hydroxy group can first be treated with phosgene and then with the amine R-NH2 and in this way stepwise carbamoylated. This reaction also takes place in an inert solvent and at the temperatures indicated above.

In a compound of formula If, in which all functional groups are present in protected form, the 7a-lower alkoxy group R_ can be introduced in a manner known per se, for example by treating the aforementioned intermediate one after another with an anion forming agent, an N-halogen -ring agent and a lower alkanol.

A suitable anion forming agent is primarily an organometallic base, especially an alkali metal base, primarily a lithium organic base. Such compounds are particularly corresponding alcoholates, such as suitable lithium lower alkanolates, primarily lithium methylate, or corresponding metal hydrocarbon bases, such as lithium lower alkanes and lithium phenyl. The reaction with the anion-forming organometallic base is usually carried out under cooling, e.g. from approx. 0°C to approx. -80°C, and in the presence of a suitable solvent or diluent, e.g. an ether such as tetrahydrofuran, using lithium methylate also in the presence of methanol, and, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

It is usually used as an N-halogenating agent

a sterically hindered, organic hypohalogenite, especially -chlorite, and primarily a corresponding aliphatic hypohalogenite, e.g. -chlorite, as a tert-lower alkyl hypohalite, e.g. -chlorite. First of all, tert,-butyl hypochlorite is used, which is reacted with the non-isolated product of the anionization reaction.

The N-halogenated intermediate is converted in the presence of an excess of anion-forming base, especially of lithium methylate, under reaction conditions and without being isolated into a 7-acylimino-cephem compound, and this is transferred by addition of lower alkanol into a 7a-lower oxy-cephem compound . If necessary, the elements of halogen hydrogen, especially hydrochloric acid, must be split off from the N-halogenated intermediate; this occurs with the addition of a halogen-hydrogen-releasing base such as a suitable alkali metal low-alkanolate, e.g. lithium tert.-butylate, whereby this reaction usually takes place under conditions of the anion- and N-halogen compound-forming reaction, whereby one works in the presence of methanol and instead of the acylimino compound the 7a-lower oxy-cephem compound can be obtained directly. One usually starts from a compound of formula If, in which functional groups are present in protected form, this is reacted with an excess of the anion-forming agent, e.g. lithium methylate or phenyllithium, in the presence of methanol, is then treated with the N-halogenating agent, e.g. tert.butyl hypochlorite, and then directly obtains the desired compound of formula I, in which functional groups are protected. You can also add the lower alkanol afterwards, whereby you can carry out the dehydrohalogenation and the addition of the lower alkanol at slightly higher temperatures than the anion- and N-halogen compound-forming reactions, e.g. at approx. 0°C to approx. -20°C, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

In the above-mentioned reactions which can be carried out under basic conditions, 3-cephem compounds can, possibly partially, isomerize to 2-cephem compounds. A formed 2-cephem compound or a mixture of a 2- and a 3-cephem compound can be isomerized in a manner known per se to the desired 3-cephem compound.

Method_h)__4Thioliserin2i<:>

In a starting material of formula Ih, a suitable residue R^<0> exchangeable with a heterocyclylthio group is, for example, one of the aforementioned acyloxy groups, such as a hydroxy group esterified with an optionally substituted lower aliphatic carboxylic acid, or one of the aforementioned sulfonyloxy groups R^. Such esterified hydroxy groups R^<0> are especially acetyloxy, further formyloxy and acetoacetyl; as well as mesyloxy or tosyloxy.

The reaction of such a compound with a heterocyclic mercaptan compound H—R^ can be carried out under neutral or slightly basic conditions in the presence of water and optionally a water-miscible organic solvent. The basic conditions can, for example, be set by adding an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. of sodium, potassium or calcium hydroxide, carbonate or bicarbonate. Organic solvents can be used, e.g. water-miscible alcohols, e.g. lower alkanols such as methanol or ethanol, ketones, e.g. lower lacanones such as acetone, amides, e.g. lower alkanecarboxylic acid amides such as dimethylformamide, or nitriles, e.g. lower alkanoic nitriles such as acetonitrile,

and such. The reaction is carried out at room temperature or, depending on reactivity, under cooling or slight heating. Optionally, the thiolation can take place in the presence of water-soluble salts of hydroiodic acid and/or thiocyanic acid such as corresponding alkali, alkaline earth, ammonium or quaternary ammonium salts, including phase-transferring salts. Suitable salts are, for example, lithium, potassium, magnesium, calcium and especially sodium and tetra-n-butylammonium iodide. The reaction is then preferably carried out in concentrated aqueous solutions of these salts.

In a starting material of formula If, all acylatable groups, apart from the 3-hydroxymethyl group to be acylated, are preferably present in protected form.

The acylation takes place according to methods known per se by treatment with an acylating agent which introduces the desired acyl residue. Suitable acylating agents are the free acid itself or a reactive functional derivative thereof,

as an anhydride, including a mixed anhydride or an internal anhydride or an activated ester.

If a free acid H-R^ is used for acylation, suitable condensation agents such as carbodiimides are used, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-dicyclohexyl- or N-ethyl-N'-3 -dimethyl-aminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole or isoxazolinium-3'-sulfonate and N-tert.-butyl-5-methyl-isoxazolinium perchlorate or an acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out

in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, under cooling or heating and/or in an inert gas atmosphere.

A reactive, i.e. ester-forming functional derivative of an acid is primarily an anhydride of such an acid, including and preferably a mixed anhydride, but also an internal anhydride, i.e. a corresponding ketene or a corresponding isocyanate. Mixed anhydrides are e.g. those with inorganic acids, such as halogen hydrogen acids, i.e. the corresponding acid halides, e.g. -chlorides or -bromides, further with nitric acid, i.e. the corresponding acid acids, with a phosphorous acid, e.g. phosphoric acid or phosphoric acid, or with a sulphurous acid, e.g. sulfuric acid, or with hydrocyanic acid. Further mixed anhydrides are e.g. those with organic carboxylic acids, as with possibly, e.g. with halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acid, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of the carboxylic acid, such as the ethyl or isobutyl half-ester of the carboxylic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, e.g. p-toluenesulfonic acid.

For reaction with the hydroxy group suitable activated esters are e.g. esters with vinylogenic alcohols (ie enols), such as vinylogenic lower alkenols or iminomethyl ester halides such as dimethyliminomethyl ester chloride (prepared from the carbonic acid and dimethyl-chloro-methylidene-iminium chloride of the formula {(CH3)2N=CHC1}<©>Cl © ), or aryl esters such as 4-nitrophenyl or 2,3-dinitrophenyl ester, heteroaromatic ester such as benztriazole, e.g. 1-benztriazole ester or diacylimino ester such as succinylimino or phthalylimino ester.

The acylation with an acid derivative such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid binding agent, for example an organic base such as an organic amine, e.g. a tertiary amine, such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine, or N,N-dilaverealkyl-aniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as N-methylmorpholine or a pyridine-type base, e.g. pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above-mentioned acylation is preferably carried out

in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide such as a formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. acetone, an ester, e.g. acetic acid ethyl ester, or a nitrile, e.g. acetonitrile, or mixtures thereof, at room temperature, if necessary, at a reduced or elevated temperature, at approx. -40° to approx. +100°, preferably at -10° to +40°, and/or in an inert gas, e.g. nitrogen atmosphere.

Furthermore, an acid derivative can, if desired, be formed

in situ. Then you get e.g. a mixed anhydride by treatment of an acid H-R^ with correspondingly protected functional groups, or a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine such as pyridine or 4-methylmorpholine, or a metal, e.g. alkali metal salt, with a suitable acid derivative such as a corresponding acid halide or optionally substituted lower alkane carboxylic acid, e.g. trichloroacetyl chloride, with a half-ester of a carboxylic acid half-halide, e.g. chloroformic acid ethyl ester or isobutyl ester, or with a halide of a dilave alkyl phosphoric acid, e.g. diethyl phosphorous bromide, and use the mixture thus obtainable

ede anhydride without insulation.

To introduce a carbamoyl group, the compound of formula If is reacted with a suitable carboxylic acid derivative, in particular with an isocyanate or carbamic acid compound such as a silyl isocyanate, e.g. silyl tetraisocyanate, a sulphonyl isocyanate, e.g. chlorosulfonyl isocyanate, with a carbamic acid halide, e.g. -chloride (which leads to N-unsubstituted 3-aminocarbonyloxymethyl compounds), or then with an N-substituted isocyanate or with an N-mono- or N,N-disubstituted carbamic acid compound as a corresponding carbamic acid halide, e.g. e.g. -chloride, whereby one usually works in the presence of a solvent or diluent and, if necessary, during cooling or heating, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

lS§E22lS§Yl2£liEE§_<R>4i<:>

In a starting compound of formula Ij is released

the protected carboxyl group R. in a manner known per se such as by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction, optionally stepwise and optionally simultaneously with other protected functional groups.

Then you can e.g. an optionally in the 2-position with a silyl group or in the 1-position with a lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl group, a polycycloalkoxycarbonyl or a diphenylmethoxycarbonyl group is transferred into the free carboxyl group by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally by adding a nucleophilic compound such as phenol or anisole. An optionally substituted benzyl-oxycarbonyl group can be released, e.g. by hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst. Furthermore, one can use certain substituted benzyloxycarbonyl groups such as 4-nitro-benzyloxycarbonyl, also with chemical reduction, e.g. by treatment with an alkali metal, e.g. sodium dithionite, or with a reducing metal, e.g. zinc, or metal salt such as a chromium II salt, e.g. chromium-II chloride, usually in the presence of a hydrogen-releasing agent which, together with the metal, is capable of producing nascent hydrogen, as an acid, primarily a carboxylic acid or α-hydroxycarboxylic acid such as especially acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid , mandelic acid, p-chloromandelic acid, tartaric acid and the like, or by treatment with an alcohol or thiol, whereby water is preferably added, transfer into the free carboxyl group. By treatment with a reducing metal or metal salt, as described above, one can also convert a 2-halogen-lower oxycarbonyl group (possibly after conversion of a 2-bromo-lower oxycarbonyl group into a 2-iodolower oxycarbonyl group) or an aroylmethoxycarbonyl group in the free carboxyl group, whereby a aroylmethoxycarbonyl group can likewise be cleaved by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide. A substituted silylethoxycarbonyl group can also be transferred by treatment with a salt of the hydrofluoric acid, which gives the fluoride anion, such as an alkali metal fluoride, e.g. sodium or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base such as tetraalkylammonium fluoride or trialkylarylammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or N,N-dimethylacetamide, in the free carboxyl group. A polyhalo-aryloxycarbonyl group such as the pentachlorophenyloxycarbonyl group is saponified under mild basic conditions such as dilute caustic soda or organic bases in the presence of water to the free carboxyl group.

An e.g. by silylation or stannylation, the protected carboxyl group can be released in the usual way, e.g. by treatment with water or an alcohol.

The transfer of the free carboxyl group in a compound of formula Ik into an esterified carboxyl group, especially one that is cleavable under physiological conditions, takes place according to esterification methods known per se, for example by esterifying a compound of formula Ik, in which other functional groups such as amino, hydroxy or sulfo groups, optionally present in protected form, or with respect to the carboxyl group to be esterified, a reactive functional derivative thereof, or a salt thereof, with a corresponding alcohol or a reactive functional derivative thereof.

Suitable reactive functional derivatives of the carboxyl group to be esterified are anhydrides, especially mixed anhydrides, and activated ester.

The esterification of the free carboxyl group with the desired alcohol is carried out in the presence of a condensation agent.

Common condensing agents are carbodiimides, e.g. N,N'-diethyl, N,N'-dipropyl-, N,N<1->dicyclohexyl- or N-ethyl-N<1->3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, e.g. carbonyldiimidazole or isoxazolinium-3'-sulfonate and N-tert-butyl-5-methylisoxazolinium perchlorate or an acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out

in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, under cooling or heating and/or in an inert gas atmosphere.

Mixed anhydrides are e.g. those with inorganic acids such as halogen hydrogen acids, i.e. the corresponding acid halides, e.g. -chlorides or -bromides, further with nitric acid, i.e. the corresponding acid acids, with a phosphorous acid, e.g. phosphoric acid, diethylphosphoric acid or phosphoric acid, or with a sulphurous acid, e.g. sulfuric acid, or with hydrocyanic acid. Further mixed anhydrides are e.g. those with organic carboxylic acids, as with possibly, e.g. with halogen such as fluorine or chlorine, substituted lower alkane carboxylic acids, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of carboxylic acid, such as with the ethyl or isobutyl half-ester of the carboxylic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, e.g. p-toluenesulfonic acid.

Activated esters suitable for reaction with the alcohol are e.g. esters with vinylogenic alcohols (ie enols),

such as vinylogenic lower alkenols, or iminomethyl ester halides such as dimethyliminomethyl ester chloride (prepared from the carbonic acid and dimethyl-chloromethylidene-iminium chloride of the formula {(CH3)2N=CHC1} © Cl © ), or aryl esters such as 4-nitrophenyl- or 2,3-dinitrophenyl ester, heteroaromatic ester such as benztriazole-, e.g. 1-benztriazole esters, or diacylimino esters such as succinylimino or phthalylimino esters.

The acylation with an acid derivative such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid binding agent, for example an organic base, such as an organic amine, e.g. a tertiary amine, such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine or N,N-dilaverealkylaniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g. pyridine, an organic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above-mentioned acylations are preferably carried out

in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide such as a formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or

chlorobenzene, a ketene, e.g. acetone, an ester, e.g. acetic acid ethyl ester or a nitrile, e.g. acetonitrile, or mixtures thereof, at room temperature, if necessary, at a reduced or elevated temperature, approx. at -40° to approx. +100°, preferably at -10° to +40°, and/or in an inert gas, e.g. nitrogen atmosphere.

Furthermore, the acid derivative can, if desired, be formed in situ. Then you get e.g. one mixed anhydride by treating the carbonic acid with correspondingly protected functional groups, or a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine such as pyrioline or 4-methylmorpholine or a metal, e.g. alkali metal salt, with a suitable acid derivative, such as a corresponding acid halide or optionally protected lower alkane carboxylic acid, e.g. trichloroacetyl chloride, with a half-ester of a carboxylic acid half-halide, e.g. chloroformic acid ethyl ester or isobutyl ester, or with a halide of a dilave alkyl phosphoric acid, e.g. diethyl phosphorous bromide, and uses the thus obtainable mixed anhydride without isolation.<1>

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

The amines Am-H are used in free form, i.e. as ammonia, lower alkylamine, as methyl-, ethyl-, propyl- or butylamine or diloweralkylamine as dimethyl-, diethyl-, di-propyl-, dibutyl-, methyl-ethyl-, ethyl -propyl-, methylbutyl-, propyl-butylamine, or the like, or in the form of metal amides thereof, for example as alkali metal amide, such as lithium, sodium or potassium amide.

The exchange reaction preferably takes place in an inert organic solvent such as benzene, toluene, dimethylformamide, tetrahydrofuran or the like, or, when exchanging Y for NH2, also in liquid ammonia, whereby possibly bases that bind the acid H-Y as tertiary amines, e.g. ethyl diisopropylamine, pyridine or the like can be added.

The turnover takes place, depending on responsiveness,

at room temperature or during cooling or heating, between approx. -70° and approx. +100°, preferably between approx.

-70° and approx. +50°.

^YSE§lt5i22_§Y_S§§IPerformance<g>ru<p>_ger:

In a prepared compound of formula I, in which one or more functional groups are protected, these can, e.g. protected carboxyl, amino, hydroxy, mercapto and/or sulfo groups, in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis or by means of reduction, especially hydrogenolysis or chemical reduction, optionally stepwise or at the same time is released.

The transfer of a protected into a free carboxyl group can take place according to method j).

A protected amino group, e.g. Am, relax on

known per se and according to the nature of the protecting groups in different ways, e.g. by means of solvolysis or reduction. A 2-halo-lower oxycarbonylamino group (optionally after conversion of a 2-bromo-lower oxycarbonyl group into a 2-iodo-lower oxycarbonyl group), an acylmethoxycarbonylamino group or a 4-nitrobenzyloxycarbonylamino group can be released, e.g. by treatment with a suitable chemical reducing agent, such as zinc in the presence of a carbonic or α-hydroxycarboxylic acid such as aqueous acetic acid, an aroylmethoxycarbonyl group can also be released by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate, and a 4-nitro-benzyloxycarbonylamino group can also be released by treatment with an alkali metal, e.g. sodium dithionite, a diphenylmethoxycarbonylamino-, tert.-lower oxycarbonylamino-, 2-(S1) (S,,) (S3)-silyl-ethoxycarbonylamino- or polycycloalkoxycarbonylamino group can be released by treatment e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxy-carbonylamino group is released, e.g. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydration

catalyst such as a palladium catalyst, a triarylmethyl group is released, e.g. by treatment with aqueous mineral acid and an amino group protected with an organic silyl or stannyl group, e.g. by means of hydrolysis or alcoholysis. One of the 2-haloacetyl, such as 2-chloro-acetyl, protected amino group of the formed condensation product can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt such as an alkali metal thiolate of the thiourea and the following solvolysis, such as alcoholysis or hydrolysis. An amino group protected by a substituted-silylethoxycarbonyl group can also be transferred by treatment with a salt of hydrofluoric acid which gives fluoride anions, as indicated above by the liberation of a corresponding protected carboxyl group, in the free amino group. A phosphorus, phosphonic or phosphinamido group can be transferred by treatment with a phosphorus-containing acid such as a phosphoric, phosphonic or phosphinic acid, e.g. orthophosphoric acid or polyphosphoric acid, an acid ester thereof, e.g. monomethyl, monoethyl, dimethyl or diethyl phosphate or monomethylphosphonic acid or an anhydride thereof, such as phosphorus pentoxide and the like, in the free amino group.

An amino group protected in the form of an acid group is transferred in a manner known per se by reduction in the free amino group, for example by catalytic hydrogenation with hydrogen and a hydrogenation catalyst such as platinum oxide, palladium or also Raney nickel, or also by zinc and acid, which acetic acid.

The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or also in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at approx. 20 to 25°, or also at lowered or raised temperature.

A hydroxy group protected by an acyl group, a silyl or stannyl group or by an optionally substituted α-phenyl lower alkyl residue is released as a correspondingly protected amino group. One hydroxy group protected by 2,2-dichloroacetyl is released by basic hydrolysis and one hydroxy group protected by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue is released by acidolysis.

A protected sulfo group is released analogously to a protected carboxyl group.

Preferably, the protecting group is chosen so that they can all be cleaved at the same time, for example acidolytically as in treatment with trifluoroacetic acid or formic acid, or reductively, as in treatment with zinc and glacial acetic acid or with hydrogen and a hydrogenation catalyst such as a palladium/carbon catalyst.

The described cleavage reactions are carried out according to conditions known per se, if necessary during cooling or heating, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

Salt formation:

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Then one can form salts of compounds of formula I with acid groups, e.g. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of α-ethylcaproic acid or sodium bicarbonate, or with ammonia or a suitable amine, whereby stoichiometric amounts or only a small excess of the salt-forming agent are preferably used. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I which contain a free carboxyl group, can e.g. formed by neutralization of salts such as acid addition salts, at the isoelectric point, e.g. with weak bases or by treatment with liquid ion exchangers.

Salts can be transferred in the usual way in the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. during treatment

with a suitable basic agent.

The method also includes such embodiments after which compounds formed as intermediates are used and remaining method steps are carried out with these, or the method is interrupted at any step; furthermore, starting substances can be used in the form of derivatives and formed during the reaction.

Such starting materials are preferably used, and the reaction conditions are chosen so that the compounds indicated above as particularly preferred are obtained.

Starting compounds of formula II as well as corresponding compounds with protected functional groups are known or can be prepared in a manner known per se.

Starting compounds of formula III and methods for their preparation have not been known to date. These compounds can be prepared according to the following reaction core:

Step_1_i

Compounds of formula IX are known or can be prepared in a manner known per se.

In the known compounds of formula IX is transferred

a primary or secondary amino group according to one of the usual methods, e.g. acylation or silylation and the like or alkylation, in a protected or tertiary amino group Am<1>. A protected amino group Am' is one of the protected amino groups indicated under Am, in particular one of the aforementioned acylamino groups such as in particular tert.-butoxycarbonylamino or N-methyl-tert.-butoxycarbonylamino. A tertiary amino-

group Am<1> is e.g. one of the aforementioned dilaverealkylamino groups..During the alkylation, the alkyl group may optionally first go to the ring nitrogen atom in the 4-position, after which by heating to approx. 100° a realkylation occurs in the exo-amino group. Such alkylation and rearrangement takes place, for example, also in the methylation of 5-amino-3-methyl-1,2,4-thiadiazole.

Tr in nn _ 2 2.

A compound of formula XI, optionally in esterified form, is obtained by carboxylating a compound of formula X. The carboxylation takes place in a manner known per se, by metallizing a compound of formula X and treating with carbon dioxide. Organolithium compounds such as lower alkyllithium, e.g. methyl, ethyl or butyllithium, aryllithium, e.g. phenyllithium, or lithium amides such as lithium dilaverealkylamides, e.g. lithium diisopropylamide, and the like. The metallization is carried out in an inert solvent such as an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, or a hydrocarbon, e.g. hexane, benzene or a tertiary amine or diamine, e.g. tetramethylethylenediamine, and the like, at low temperatures, approx. at 0° to -80°. Carbon dioxide is then introduced at the same temperature or the metallization mixture is poured onto dry ice. If instead of carbon dioxide a haloformic acid ester is used, an ester of an acid with formula XI is obtained.

An ester can also be obtained, possibly only as a by-product, when compounds of formula X are carboxylated, in which Am<1> is a secondary amino group protected by an esterified carboxyl. Thereby, the acyl protecting group can migrate from the amino group on the methyl carbanion in the 3-position, so that after working up a compound of formula XI results, in which Am<1> is a free secondary amino group and in which the carboxyl group is present in esterified form. For example, 5-(N-methyl-N-tert.-butoxy-carbonylamino)-3-methyl-1,2,4-thiadiazole when treated with lithium diisopropylamide gives 2-(5-methylamino--1,2,4-thiadiazole- The 2-yl)acetic acid tert-butyl ester. The reaction mixture is worked up by treatment with water and acid or base and extraction in the usual way.

Trirm_3 £

An α-keto compound of formula XII or an ester thereof is obtained by treating the compound of formula XI or an ester thereof with a suitable oxidizing agent. Numerous such oxidizing agents are known. Selenium dioxide is preferably used. The reaction is carried out in an inert solvent such as an ether, e.g. dioxane or tetrahydrofuran, an amide, e.g. dimethylformamide, or a tertiary amine, e.g. pyridine, or the like, at a lowered or elevated temperature, approx. at 0° to approx. 100°, preferably at room temperature up to approx. 80°C.

Step_4a£

A compound of formula III or an ester thereof, in which Am means a protected or tertiary amino group Am<1>, is obtained by treating a compound of formula XII or an ester thereof with a hydroxylamine of formula f^N-O-R-i (V) . The reaction can be carried out as described under method b).

Step_4b)_£

A compound of formula III or an ester thereof, in which Am represents a protected or tertiary amino group Am<1>, can also be obtained by nitrosating a compound of formula XI or an ester thereof and, if desired, transferring a compound of formula III obtained, in which R^ means hydrogen, in a compound of formula III, in which R^ stands for optionally substituted lower alkyl. The nitrosation can be carried out as described under method e) and the alkylation can be carried out as described under method f).

Step_4c)_£

A compound of formula III or an ester thereof, in which Am represents a free primary or secondary amino group, can also be obtained by treating a compound of formula XIII or an ester thereof, in which X represents halogen or hydroxy and has the meaning indicated above, with a salt of rhodanhydrogen acid, resp. an isorhodane hydrogen ester or treating the compound of formula XIII, wherein X is hydrogen, with rhodane. The cyclization reaction with the salt of the rhodan hydrogen acid or with rhodan is carried out as described under method d).

A compound of formula III or an ester thereof, in which Am means a primary, secondary or tertiary amino group, can also be obtained by reacting a compound of formula XIX or an ester thereof, in which Y is halogen and R^ has the above meaning, with ammonia or a primary or secondary amine Am-H, or a metal amide thereof. The yield of halogen Y, e.g. of chlorine, against the amino group Am occurs as described under procedure 1).

In a compound of formula III, a protected amino group Am<1> can be transferred into a free amino group or into another protected amino group, or if R^ is hydrogen, the group =N-OH can be etherified or carbamoylated analogously to method f). Few esters of compounds of formula III are transferred in a manner known per se into the free carboxylic acids.

Reactive derivatives of compounds of formula III which are suitable for acylation are prepared in a manner known per se, possibly in situ.

Compounds of formula XIII are obtained starting from compounds of formula XIV over compounds of formula XV

according to steps 6 and 7.

Step_5_£

Compounds of formula XV, in which R° is lower alkyl, and R^ has the meaning indicated above, and in which the carboxyl group is optionally protected, can be obtained by forming a compound of formula XIV, in which it has the meaning indicated above and where the functional groups optionally is protected, the alcohol deposits HOR°. The addition of the alcohol to the nitrile takes place in a manner known per se in the presence of an acid, e.g. a halogen hydrogen acid such as hydrochloric acid, at a lowered or elevated temperature, preferably between approx. -30° to +40°, especially around approx. 0°. The reaction is carried out in any inert solvent, preferably in the alcohol H0R° itself. The acid addition salt of the iminoester with formula XV or a protected derivative thereof is obtained.

Step_6^

A compound of formula XV, in which R° means lower alkyl and R.J has the meaning given above, a derivative thereof, in which functional groups are protected or an acid addition salt thereof, is transferred by treatment with ammonia into a compound of formula XIII, in which X is hydrogen and in which functional groups are possibly protected. Instead of ammonia, ammonium hydroxide or ammonium chloride can also be used. The reaction with ammonia in an aqueous or non-aqueous solvent at temperatures between approx. -30° to approx. +40°. In a compound of formula XIII, in which X is hydrogen, this can be substituted with halogen, as described under method d).

Step_7 j_

Compounds of formula XIX, in which Y denotes halogen and R.J has the above meaning, esters or salts thereof are obtained by reacting a compound of formula XIII, in which X is hydrogen, or an ester or salt thereof,

with a perhalomethyl mercaptan of the formula Y^C-S-Y, in which Y has the meaning given above.

In the starting material and in the product of formula XIX

Y is preferably chlorine. The reaction is carried out in the presence of one of the H-Y bases which neutralizes the halogen hydrogen> formed in an organic or organic-aqueous solvent or

solvent mixture. Organic bases such as tertiary amines can be used as bases, e.g. trilower alkylamines such as trimethylamine, ethyldiisopropylamine, or aromatic amines such as pyridine or inorganic bases, e.g. alkali metal hydroxides such as lithium, sodium or potassium hydroxide, or the like, preferably in stoichiometric amounts. Water, organic solvents such as alcohol, e.g. methanol or ethanol, halohydrocarbons such as methylene chloride or chloroform, amides such as dimethylformamide, sulfoxides such as dimethyl sulfoxide, ethers such as dioxane, tetrahydrofuran, or the like, or optionally mixtures or aqueous emulsions thereof, which improves emulsification, optionally an emulsifier such as sodium dodecyl sulfate may be added. The reaction is carried out at room temperature, with cooling or slight heating, depending on reactivity, i.e. at approx. -15° to approx. +50°, preferred at approx. -10° to approx. +20°.

Compounds of formula IV are obtained by acylation of compounds of formula II with compounds of formula XII or a reactive functional derivative thereof.

Compounds of formula VI can be obtained as by-products in the preparation of compounds of formula I under basic conditions. They must not be present in pure form, they can also be used in a mixture with compounds of formula I.

Compounds of formula VII are obtained by acylation of compounds of formula II with compounds of formula XIII, or a reactive functional derivative thereof, or analogously to steps 6 and 7, starting from compounds of formula above compounds of formula

which in turn can also be obtained by acylation of compounds of formula II with compounds of formula XIV or XV, or reactive functional derivatives thereof.

Compounds of formula VIII can be obtained from compounds of formula II by acylation with compounds of formula XI, or reactive functional derivatives thereof, according to method a), optionally the groups Am, R2, R3 and R3 can be transferred into other groups Am, R2 . active compounds of formula I. These compounds and the methods for their preparation are also the subject of the present invention.

Connections with the formulas (If) to (Ik) fall

under the general formula I and can be obtained according to one of the methods a) to e). Also with these compounds, groups Am, R1, R2, R3 or R4 present can be transferred into other groups Am, R1, R2, R3 or R4, whereby methods such as those indicated for corresponding reactions for the preparation of compounds of formula I can be suitably used.

Compounds with formula XVIII can be prepared in different ways, for example analogously to method a),

c), f), i), j).or k) or step 7, especially when analogous to method a), acylate in a compound with

formula II, wherein R2, R3 and R4 have the indicated meanings,

and in which the 78-amino group is optionally substituted with a group that allows acylation, acylate the 73-amino group by treatment with an acylating agent which introduces the acyl residue of a carboxylic acid of formula XIX, or by reacting, analogously to step 9, a compound of formula VII, in which X means hydrogen and , R2, R-j°9R4^are ^e stated meanings, or a salt thereof, with a perhalogenmethylmercaptan of formula Y^C-S-Y, and if desired, they carry out the subsequent operations mentioned in the preparation of the compounds of formula I.

The new intermediate products and starting compounds and the process for their production are likewise the subject of the present invention.

The pharmacologically usable compounds according to the present invention can e.g. is used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together or in a mixture with an inorganic or organic, solid or liquid, pharmaceutically usable carrier, which is suitable for external, rectal, oral or preferably for parenteral administration. Suitable forms of such preparations are ointments, suppositories, tablets, dragées, capsules or ampoules.

Preferably, the pharmacologically inactive compounds according to the present invention are used in the form of injectables, e.g. intramuscular or intravenous, administrable preparations or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions whereby these can be prepared before use, e.g. of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannite. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservative, stabiliser, wetting and/or emulsifying agent, solubility enhancer, salts for regulating the osmotic pressure and/or buffer. The present pharmaceutical preparations, which, if desired, may contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g. using conventional dissolution or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance. Depending on the nature of the infection and the condition of the infected organism, daily doses of approx.

0.5 g to approx. 5 g s.c. for the treatment of warm-blooded beings from approx. 70 kg weight.

The following examples serve to illustrate the invention; temperatures are given in degrees Celsius.

In the examples, the following abbreviations are used:

BOC: tert-butyloxycarbonyl

F.: Melting point

Thin-layer chromatography: Opti-UPC^2~plates from the company Antec are glass plates coated with silica gel, whereby the silica gel was treated with dodecyltrichlorosilane (for reverse-phase chromatography).

Example_el_a )_£ 5-tert^butoxyCarbonylamino-3 thia^ia52l.L

A suspension of 20.0 g (0.174 mol) of 5-amino-3-methyl-1,2,4-thiadiazole (DBP 955 684) in 100 ml of BOC anhydride is stirred at 100° (bath temperature) for 12 hours. The reaction mixture is cooled, the volatile components are removed in vacuo and the partially crystalline residue is purified by recrystallization from isopropyl alcohol. 18.2 g of the title compound are then obtained with an Rf value of 0.65 (silica gel, acetic acid). UV spectrum (ethanol): X max (e) 222 (4000); 245 (8250) nm. IR spectrum (Nujol): Characteristic absorption bands at 5.90; 6.45; 8.75 y;

F.: 136-7°.

Example_el_b )_£ Zzi^ Z%^% i.^] i% 2} S^ Y^^^ 2^ Y.^^ i^ 2zl±ZLåz%^^^ 2^ :Z 3-y_l joint Y£2 .in

A freshly prepared solution of lithium diisopropylamide in 100 ml abs. tetrahydrofuran (from 26 ml (0.184 mol) of diisopropylamine and 104 ml (0.208 mol) of an approximately 2 N solution of butyllithium in hexane) is added at -78° under nitrogen with 10.0 g (0.046 mol) of 5-tert .butoxycarbonylamino-3-methyl-1,2,4-thiadiazole in 50 ml abs. tetrahydrofuran and stirred for 30 min. at this temperature. After heating the reaction mixture to -30°, CO2 is introduced for 30 min. The solution is added with 100 ml of water and diluted with

50 ml of diethyl ether. The organic phase is separated, the aqueous

phase is adjusted to pH 2.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is separated, washed with aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is precipitated by diethyl ether. The title compound is obtained with an Rf value of 0.40 (silica gel; chloroform:

methanol:glacial vinegar 85:12:3); F.: 16 3-5°; UV spectrum (methanol): X max (e) 215(5250); 245(8250) nm; IR spectrum (nujol): characteristic absorption bands at 2.85; 2.90; 3.15; 6.45 y.

Example_c )_j_ 2-^5-tert ^butoxycarbonylamine^ ^iå£2il5lYi!l2-oxoacetic acid^

A suspension of 5.0 g (19.25 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid and 4.2 g of selenium dioxide in 100 ml of abs. dioxane is stirred for 3 hours at 80°. After filtering the reaction mixture, the filtrate is evaporated in vacuo. The residue is diluted with 150 ml of ethyl acetate and extracted with aqueous sodium bicarbonate solution. The ethyl acetate phase is separated, washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. Uniform 5-tert.butoxycarbonylamino-3-formyl-1,2,4-thiadiazole is obtained with an Rf value of 0.65 (silica gel, chloroform:methanol:glacial acetic acid 85:12:3) IR spectrum (CH2C12): characteristic absorption bands at 2.90; 5.80; 6.15; 6.50; 8.70 y. The aqueous sodium bicarbonate phase is adjusted with 2 N hydrochloric acid to pH 1.0 and extracted with ethyl acetate. The organic phase is separated, washed with aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The uniform title compound is then obtained in the form of a foam with an Rf value of 0.30 (silica gel, chloroform: methanol: glacial acetic acid 85:12:3); UV spectrum (methanol: X max (e) 219(7150); 243(7900) nm; IR spectrum (nujol): characteristic absorption bands 3.10; 5.80; 6.15; 6.45; 8.60 y.

Example_el_d)_£ 2-|5-tert^butoxYk§r^onYlamino diazol-3-Yli~2^Z )_-methoxyYimino

A suspension of 3.4 g (12.4 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid, 1.11 g (13.35 m mol) methoxyamine hydrochloride and 1.1 ml of pyridine in 70 ml of 95% ethanol are stirred for 3 hours at room temperature. The reaction mixture is evaporated in vacuo. The residue is diluted with 100 ml of ethyl acetate and 100 ml of water, the aqueous phase is adjusted to pH 2 with 2 N HCl and then extracted with ethyl acetate. The organic phase is separated, washed with aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue consists of an approx. 9:1 Z/E isomer mixture. The title compound is obtained as a uniform product by fractional crystallization from methylene chloride. Rf value: 0.30 (silica gel, s-butanol/glacial acetic acid/water 67:10:23); F.: 137-39° (Decomposition); IR spectrum: characteristic absorption bands at 2.75; 2.90; 5.85; 6.18; 6.45; 9.60 y; UV spectrum (methanol): X max (e): 234(22250) nm.

Example )_£ 5-^N-metYylN-tert^butocSYcarb m§tYilli2iilthiadiazole

A suspension of 15 g (116.3 m mol) of 5-N-methylamino-3-methyl-1,2,4-thiadiazole in 55 ml of BOC anhydride is stirred at 100° (bath temperature) for 4 hours. The reaction mixture is cooled, the volatile parts are removed in vacuo and the residue is chromatographed (silica gel, toluene/increasing proportions of ethyl acetate). This gives 22.3 g of the title compound with an Rf value of 0.65 (silica gel, toluene/ethyl acetate 1:1). F.: 47-48°. IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 5.90; 6.55; 8.80 y.

Example_el_f )_£ Zzi^ Z^ Z^^ Y. l.^ ii^ 2zli. Zzz. lz% i^^^ 2] :Z2zlllz

A freshly prepared solution of lithium diisopropyl amide in 30 ml abs. tetrahydrofuran {of 7.8 ml (55.2 m mol) of diisopropylamine and 30 ml of an approx. 2 N solution of butyllithium in hexane} is added at -78° under nitrogen with 3.15 g (13.8 m mol) 5-(N-methyl-N-tert.butoxycarbonylamino)-3-methyl-1,2,4 -thiadiazole in 15 ml abs. tetrahydrofuran and stirred for 50 min. at this temperature. The reaction mixture or while stirring on solid CC^and is stirred for 30 min. The solution is added with 60 ml of water and extracted with diethyl ether. The aqueous phase is adjusted to pH 2.0 with 2 N hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over magnesium sulphate and evaporated.

After chromatography of the residue on silica gel with toluene/equal portions of ethyl acetate, the uniform title compound is obtained with an Rf value of 0.50 (silica gel, ethyl acetate) mp: 91-92°. IR spectrum (Cl₂C₂): characteristic absorption bands at 2.90; 5.80; 8.65 y.

Example_2ii 2-^5-N-methylamino-2i2i4-thiadia

A suspension of 2.3 g (10.0 m mol) of 2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-acetic acid tert-butyl ester and 3.0 g of selenium dioxide in 50 ml abs. dioxane is stirred for 3 hours at 90°. After filtering the reaction mixture, the filtrate is evaporated in vacuo. The residue is triturated with diethyl ether. You then get the residual compound with an Rf value of 0.55 (silica gel, chloroform/methanol 9:1). IR spectrum (CH 2 Cl 1 ): characteristic absorption bands at 2.90; 3.10; 5.80; 5.90; 6.25; 9.35; 9.70 y.

Example _K)_£ 2-^5-N-methylamino-2i2i4-thiadiazo m2É2lSEYimi22l2^^ilS§Y£§z£§£tibutYi2ster

A suspension of 2.0 g (8.0 m mol) 2-(5-methylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid tert-butyl ester, 0.736 g (8.64 m mol ) methoxyamine hydrochloride and 0.72 ml of pyridine in 50 ml of 95% ethanol are stirred for 3 hours at room temperature, then evaporated in vacuo. The residue, which consists of both Z- and E-isomers of the title compound, is fractionally crystallized from a mixture of methylene chloride/ethyl acetate. The uniform Z-isomer with an Rf value of 0.75 is obtained (silica gel, chloroform/methanol 9:1). F.: 153-155°. IR spectrum ( CR^ Cl^ ): characteristic absorption bands at 2.90; 3.10; 5.80; 6.25; 9.50 y. Preparative layer chromatography of the mother liquor (silica gel, chloroform/methanol 95:5) gives the E-isomer with an Rf value of 0.70 (silica gel, chloroform/methanol 9:1).

Exemgel_2!i_2-^5-N-metYlamin^

A mixture of 1.5 g (6.24 m mol) 2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetic acid tert-butyl ester in 15 ml of methylene chloride is added at room temperature with 15 ml of trifluoroacetic acid and stirred for 40 min., then stirred in 200 ml of diethyl ether/hexane 1:2. The precipitate is isolated by filtration, dissolved in water and the aqueous phase is adjusted with aqueous sodium bicarbonate solution to pH 5.3. The aqueous solution is partially evaporated and subsequently added with abs. ethanol. The precipitate is isolated by filtration and washed with diethyl ether. The title compound is obtained with an Rf value of 0.35 (silica gel, s-butanol/glacial acetic acid/water 67:10:23). IR spectrum (nujol): characteristic absorption bands at 2.80; 3.05; 5.85; 6.20; 6.40;

9.50 y.

The compound from example i) can also be prepared according to the following examples j) to m): Example_el_ j )_£ 2-^5-N-metYl-N-tert^butocSYk ./.4-thiadiazol-3-yl-acetic acid- t 215-N-methylamino-1_1214-thiadiazo butyl ester

A freshly prepared solution of lithium diisopropylamide in 200 ml abs. tetrahydrofuran {of 26 ml (0.184 mol) of diisopropylamine and 110 ml of an approx. 2 M solution of butyllithium in hexane} is added at -78° under nitrogen with 21.0 g (92.0 m mol) 5-(N-methyl-N-tert.butoxycarbonylamino)-3-methyl-1,2,4 -thiadiazole in 100 ml abs. tetrahydrofuran and stirred for 1 hour at this temperature. Then heat to -20° and add 200 ml of water. The mixture is diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica gel, toluene/increasing proportions of ethyl acetate).

The uniform 2-(5-N-methyl-N-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetic acid tert-butyl ester with an Rf value of 0.80 is obtained (silica gel, ethyl acetate ). IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 5.78; 5.85; 6.60 y, as well as uniform 2-(5-N-methylamino-1,2,4-riadiazol-3-yl)-acetic acid tert-butyl ester with Rf value 0.50 (silica gel, ethyl acetate).

Example_el_k)_ j___2-^5-N-metYl-N-t /.izthiadiazol-S-yll-g-oxo-

From 5.0 g (15.2 m mol) 2-(5-N-methyl-N-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)'-acetic acid tert.butyl ester and 4.2 g of selenium dioxide in 75 ml of dioxane is obtained analogously to example g) of the title compound with an Rf value of 0.70 (silica gel, chloroform/methanol 95:5). F.: 96-98°. IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 5.80; 5.90; 6.60 y.

Example _l)_j___2-j,5-N-methyl-N^ter , ^i^^^-thiadiazole-^-Yli-^-Z-metocSYimino^aceticYre^tert^ 2ii£Yi§§£2E

Of 6.3 g (18.3 m mol) 2-(5-N-methyl-N-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxo-acetic acid tert-butyl ester , 1.65 g of methoxyamine hydrochloride and 1.6 ml of pyridine in 40 ml of 95% ethanol gives analogously to example h) the title compound with an Rf value of 0.80 (silica gel-chloroform/methanol 99:1). F.: 125-127°; IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 5.78; 5.90; 6.62; 8.90 y.

Example _m)_£ 2-^S-N-methylamino-K^^-thiadia<m>2£2?S§Yi<m>iD22^^i?S§Y^§

The title compound can be obtained analogously to example i) from 0.5 g (1.34 m mol) -2-(5-N-methyl-N-tert.butoxycarbonylamino^1,2,4-thiadiazol-3-yl)-2- Z-Methoxyiminoacetic acid tert-butyl ester and 5 ml of trifluoroacetic acid.

Example_n)_:_ 2-^5-N-methyl^N-tert^butoxYka li^i^-thiadiazole^S-Ylii2-Z-methoxyYimino-aceticYr§

A solution of 500 mg (2.30 m mol) of 2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetic acid in 7.5 ml of water is added to 0.48 ml triethylamine in 7.5 ml dioxane and stirred for 10 min. at room temperature, then 615.5 mg of 2-(tert.butoxycarbonyloxyimino)-2-phenylacetonitrile are added and stirred for 4 hours at 40°. After adding a further 300 mg of 2-(tert.butoxycarbonyl-oxyimino)-2-phenylacetonitrile, the mixture is stirred for a further 16 hours at 40°, then diluted with diethyl ether and extracted with water. The aqueous phase is adjusted to pH 3.0 with 20% citric acid and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated in vacuo. The title compound is obtained with an Rf value of 0.60 (silica gel, s-butanol/glacial vinegar/water 67:10:23).

Example _o]_^__2-^5-tert ^butoxy diazol-3-yl acetic acid ethyl ester

A mixture of 30.0 g (0.115 mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid in 350 ml of methylene chloride is added successively with 26.16 g of N,N-dicyclohexylcarbodiimide , 5.13 ml abs. methanol and 1.71 g of 4-pyrrolidinopyridine and stirred for 3 hours at room temperature. After adding a further 0.5 ml of abs. methanol and 2.6 g of N,N-dicyclohexylcarbodiimide are stirred for a further 60 min. The precipitate is filtered off, the filtrate is washed successively with aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is triturated with diethyl ether. The uniform title compound is obtained with an Rf value of 0.50 (silica gel, toluene:ethyl acetate 1:1). IR spectrum (Cl₂C₂): characteristic absorption ion bands at 2.90; 5.75; 5.85; 6.50; 8.70 y.

Example_2ii 2-^5-tert^butoxyCarbonYla^ 5lYill2-oxoacetic acid metYi§§§ter

A suspension of 20.0 g (73.18 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-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 evaporated 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 evaporated. The title compound is obtained in the form of a foam with an Rf value of 0.35 (silica gel, toluene:ethyl acetate 1:1). IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 2.95; 5.75; 5.85; 6.50 y.

Example_g)_£ Zzi^ Z^ Eti^^ Q^ Y^^^^ Yl^ k^ zlLZL^ Z^ i^ Z ^i522il^lYi!l2-hYdroksYiminoeddik

A suspension of 21.8 g (75.88 m mol) 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid methyl ester, 7.48 g hydroxylamine hydrochloride and 9 .8 ml of pyridine in 300 ml of 95% ethanol is stirred for 3 hours at room temperature. The reaction mixture is evaporated in vacuo. The residue is dissolved in ethyl acetate and the solution is successively extracted with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is crystallized from diethyl ether. The title compound is obtained with an Rf value of 0.30 (silica gel, chloroform: methanol 95:5). F.: 131-132°. IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 2.85; 5.75; 5.85; 6.50; 8.70; 8.90 y.

Example _r)_j_ 2-[5-tert ^butoxycarbonylami 3-yl)_; 2-hydroxy iminoacetic acid

A solution of 8.0 g (26.46 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyimino-acetic acid methyl ester in 175 ml of 95% ethanol 8.6 g of potassium hydroxide and 70 ml of water are added and stirred for 5 hours at 40°. The reaction mixture is evaporated in vacuo, 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, adjusted with 2 N HCl to pH 2.0 and extracted with ethyl acetate. The organic phase is separated, washed with sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is crystallized from diethyl ether. The uniform title compound with an Rf value of 0.60 is obtained (silica gel, s-butanol/glacial acetic acid/water 67:10:23). F. 158-160°

(fission); IR spectrum (nujol): characteristic absorption bands at 3.10; 5.85; 8.65 y.

Example _s)_j___2-^5-tert ^butok

A solution of 2.85 g (8.95 m mol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyimino-acetic 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. n-hexane is added to the reaction mixture and the precipitate formed is filtered off. After recrystallization of the precipitate from methylene chloride, the uniform title compound is obtained with an Rf value of 0.25 (UPCj 2 plates, water/acetonitrile 6:1).

F. 124-127°. IR spectrum (nujol): characteristic absorption bands at 5.75; 5.85; 6.40y.

Example_t ]_^__2-^5-tertibuto ^i§52ll3-yl ]_-2-Z-^2-tert^butox 2^^ilS§YE§m2tYl2ster

A solution of 1.4 g (6.27 m mol) 2-bromoisobutyric acid tert-butyl ester and 1.94 g (14.03 m mol) finely powdered potassium carbonate in 12.50 ml of dimethyl sulphoxide is added at room temperature under nitrogen with a solution of 1.70 g (5.62 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetic acid methyl ester in 7.5 ml of dimethylsulfoxide and stirred for 14 hours at this temperature. The reaction mixture is evaporated to dryness at 30° in high vacuum. The residue is taken up in 200 ml ethyl acetate and washed successively with water, dilute hydrochloric acid (1 N), water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo to dryness. The residue is crystallized by approx. 5 ml of ether and gives the title compound with melting point 142-144°.

Example_u)_ j_ 2-^5-tert ^butoxycarbonylami^ zol-3-yl )_-2-Z-^2-tert^butoxacetic acid

A solution of 11 g (22.55 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert-butoxycarbonylprop-2-yloxyimino )acetic acid methyl ester in 290 ml of methanol and 96 ml of 2 N caustic soda is allowed to stir at a temperature of 50° C. for one hour. The reaction mixture is evaporated to dryness at 35° under high vacuum. The residue is taken up in 200 ml of water (distilled) and extracted once with 200 ml of ethyl acetate. The aqueous phase is overlaid with 200 ml of acetic acid ethyl ester and acidified with concentrated hydrochloric acid. The acetic acid ethyl ester phase is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo, whereby the title compound is obtained in crystalline form. DC-Rf value 0.2 (silica gel, chloroform/methanol 4:1); IR spectrum (dioxane): characteristic absorption bands at 5.81; 5.74; 3.3 y. F.: 180-183°.

<E>E§m§<tiiiiD>2_<§Y>_<£2E2i2>^<§I§§E>_<m§>^_<f2£m§I>_<I>_

Example_1_j_ Z g-{ 2-^5-tert^butoxycarbonyl la^ ^i552ll2lYlil2-Z-methoxyiminoacetamide 22f 22llllS§E22!l§Y£2åif §2Ylm§£Yl§§t2£i

a) A solution of 1.5 g (4.96 m mol) of 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyimino-acetic acid in 20 ml of methylene chloride and 0 .44 ml of pyridine is added at -15° under nitrogen with 0.88 ml (6.0 m mol) of diethyl phosphorous bromide and stirred for 30 min. at this temperature. After addition of 2.1 g (4.70 m mol) 7B-amino-3-acetoxy-

methyl 3-cephem-4-carboxylic acid diphenyl methyl ester at -15°

the reaction mixture is stirred at room temperature for 25 hours, then diluted with 250 ml of methylene chloride, washed successively with dilute sulfuric acid, water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by preparative layer chromatography on silica gel with chloroform. The uniform title compound is obtained with an Rf value of 0.40 (silica gel, toluene/ethyl acetate 1:1); IR spectrum (Cr 2 C 2 ): characteristic absorption ion bands at 3.10; 5.65; 5.80; 5.95; 6.40; 8.20 u; UV spectrum (methanol): X max (e) 232(26280) nm.

The same compound can also be prepared as follows.

b) A solution of 200 mg (0.28 m mol) 7B-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyimino-acetamido}-3-acetoxymethyl -3-cephem-4-carboxylic acid diphenyl methyl ester in 15 ml of methanol is added dropwise with a 0°-

cold solution of diazomethane in diethyl ether, until the reaction is complete and stirred at 0-5° for 30 min. The reaction mixture is evaporated in vacuo and the residue is purified

by preparative layer chromatography on silica gel with chloroform. The title compound is obtained with an Rf value of 0.40 (silica gel, toluene/ethyl acetate 1:1).

Example_2£ Z§li2ii5-amino=li2i4=thiadiazole=3-ylX methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carbon-<acid>e__(sodium salt)_

A solution of 3.8 g (5.23 m mol) of 7g-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-acetoxymethyl-3 -cephem-4-carboxylic acid diphenyl methyl ester in 8.5 ml methylene chloride and 2.8 ml anisole is added at room temperature with 3 9 ml trifluoroacetic acid and stirred for 25 min., then stirred in 900 ml diethyl ether/hexane 1:2. The precipitate consisting of the trifluoroacetate of the 7$-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyimino-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid is isolated by filtration, dissolve in methanol-containing water (10 ml methanol/500 ml water), and the aqueous phase is adjusted with aqueous sodium bicarbonate solution to pH 6.8. The solution is lyophilized, and the sodium salts obtained are purified by means of chromatography on silica gel "Opti UPCj2" (company Antec) with water/acetonitrile 6:1. The uniform title compound is obtained with an Rf value of 0.30 (UPC12 plates, water/acetonitrile 6:1); F. from 150°

(fission); UV spectrum (methanol): AMax (e): 234 (12240) nm; IR spectrum (nujol): characteristic absorption bands at 3.00; 5.65; 5.95; 6.20; 6.52; 8,10; 9.60 y.

Example_3 j_ Z§li 2ii5-tert^butoxycarbonylamine diazol-3-yl).-2-Z-methoxyimine 5-ylthiomethyl).-3-cef em-4-carboxylic acid-diphenylmethyl ester^

a) From 575 mg (1.90 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid, 880 mg (1.80 m mol) of 78-amino -3-(1-Methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester and 0.33 ml (2.30 m mol) diethyl phosphorous bromide in 10 ml methylene chloride and 0.17 ml pyridine is obtained analogously example 1 the uniform title compound with Rf value 0.30 (silica gel, toluene/ethyl acetate 1:1); IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 2>90; 5.65; 5.85; 5.95; 6.10; 6.45; 8.60 y. ai) Preparative layer chromatography on silica gel with toluene/ethyl acetate 1:1 also gives 78-{2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido} 3-(1-Methyltetrazol-5-yl-thiomethyl)-2-cephem-4-carboxylic acid diphenyl methyl ester with Rf value 0.35 (silica gel, toluene/ethyl acetate 1:1). The 3-cephem title compound can also be obtained as follows: b) A suspension of 0.50 g (1.65 m mol) 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)- 2-Methoxyimino-acetic acid and 0.152 g (0.825 m mol) of cyanuric chloride in 30 ml of acetone are heated for 30 min. at 40°, whereby a solution occurs. After adding 0.166 g (1.65 m mol) of triethylamine, the solution is stirred for 3 hours at room temperature. After adding 0.815 g (1.65 m mol) of 78-amino-3-(1-methyl-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester, the mixture is stirred for a further 2 hours at room temperature, then evaporated in vacuo, dilute with 50 ml of water and extract with methylene chloride. The organic phase is washed successively with phosphate buffer pH 8.0 and aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue contains the title compound with Rf 0.30 (silica gel, toluene/ethyl acetate 1:1). c) 0.50 g (1.65 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid and 7 ml of ethyl acetate are added at -5° to a stirred suspension of a Vilsmeier reagent (prepared from 0.25 g (1.98 m mol) oxalyl chloride and 0.15 ml of N,N-dimethylformamide in 1 ml of dry ethyl acetate. The mixture is stirred for 45 min. at 0° and then cooled at -10°. After the addition of 0.81 g (1.65 m mol) 73-amino-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester, the mixture is stirred for 2 hours at 0°, then diluted with 50 ml of ethyl acetate and washed successively with water, phosphate buffer pH 8.0 and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The crude product is further purified by refining acetone-hexane. The title compound is obtained with Rf 0, 30 (silica gel, toluene/ethyl acetate 1:1). d) A suspension of 629 mg (0.84 m mol) 7S-{2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl )-2-oxo-acetamido-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid-diphenylmethyl ester, 0.75 g (0.90 m mol) of methoxyamine hydrochloride and 0.7 ml of pyridine in 40 ml of 95% ethanol are stirred for 3 hours at room temperature. The reaction mixture is evaporated in vacuo. The residue is diluted with 25 ml of ethyl acetate and washed successively with water, dilute sulfuric acid and aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is purified by preparative layer chromatography on silica gel with toluene/ethyl acetate 3:2. The title compound is obtained with an Rf value of 0.30 (silica gel, toluene/ethyl acetate 1:1). e) From 185 mg (0.26 m mol) 76-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetamido}-3-(1-methyltetrazol- 5-yl-thiomethyl)-3-cephem-carboxylic acid diphenyl methyl ester in 15 ml of methanol and a solution of diazomethane in diethyl ether gives analogously to example 1b) the title compound with an Rf value of 0.30 (silica gel, toluene/ethyl acetate 1:1). f) A solution of 187 mg (0.25 m mol) 76-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyaminoacetamido}-3 -(1-methyltetrazol-5-yl-thiomethyl)-2-cephem-4-carboxylic acid diphenyl methyl ester in 4 ml of methylene chloride is cooled to 0°, at this temperature 50 mg of m-chloroperbenzoic acid (approx. 90%) is added and stirred for 30 min. Then excess peracid is decomposed after addition of sodium thiosulfonate. The reaction solution is successively extracted with aqueous sodium bicarbonate and aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is precipitated by acetone/diethyl ether. One obtains 7f3-{2-(5-tert.butoxycarbonylamino-'.1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido-3-(1-methyl-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide with Rf value 0.35 (silica gel, acetic ester). g) A solution of 115 mg (0.15 m mol) of the 1-oxide in 3 ml N,N-dimethylformamide is cooled to -10°, added with 0.04 ml (0.30 m mol) phosphorus trichloride and stirred for 35 min .. The reaction solution is poured onto ice and diluted with 20 ml of ethyl acetate. The cooled organic phase is extracted successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. After preparative layer chromatography on silica gel with toluene/ethyl acetate 1:1, the uniform title compound with Rf 0.30 is obtained (silica gel, toluene/ethyl acetate 1:1). Example_4j_ l§. zilzi^ Z^ i^ l2zlL2. i. izt:i^ i^ 2lz^. ZY. liz2. Z^ Z m§£ok^yiminoacetamide^}-3-^2lm^ a) From 650 mg (0.87 m mol) 73-{2-(5-tert.butoxycarbonylamino-1 , 2 , 4-thiadiazole-3 -yl)-2-Z-methoxyiminoacetamido}.-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester in 1.4 ml methylene chloride, 0.47 ml anisole

and 6.5 ml of trifluoroacetic acid, the title compound is obtained analogously to example 2 with an Rf value of 0.25 (UPCj2 plates, water/acetonitrile 6:1); UV spectrum (methanol): X max (e) 232

(25200) nm; IR spectrum (nujol): characteristic absorption bands at 3.00; 5.70; 6.25; 6.55; 9.62 y.

The same compound can also be prepared as follows: b) A suspension of 0.478 g (1.0 m mol) 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z- methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt, 0.207 g (1.5 mmol) 1-methyltetrazol-5-yl-thiol, 0.369 g (1.0 mmol) tetrabutylammonium iodide and 2.0 g potassium iodide in 2 ml of water, stirred at 70° for 22 hours, then diluted with water and extracted with ethyl acetate. The aqueous phase is evaporated and chromatographed (UPCj2 plates, water:acetonitrile 6:1). The uniform title compound with an Rf value of 0.35 is obtained (UPCj 2 plates, water/acetonitrile 6:1).

Example _5 j_ Z§-{ ^-^S^tert^butoxycarbonylam diazol-3-yl )_-2-Z-methoxy iminoac m2tY:Ll3-cef §2llllS§£E22§YE§§i£2I}¥im2tYi§ §t2E.L

From 575 mg (1.9 m mol) 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid, 1.10 g (1.8 m mol) 7Bammonium-3 -carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenyl methyl ester tosylate and 0.4 ml of diethyl phosphorous bromide in 15 ml of methylene chloride and 0.3 ml of pyridine gives, analogously to example 1, the title compound with an Rf value of 0.60 (silica gel, ethyl acetate); UV spectrum: X max (e) 230 (sh) nm; IR spectrum (nujol)': characteristic absorption ion bands at 2.90; 3.10; 5.60; 5.80; 6.25; 6.45 y.

Example _6j_ Z^ zL^ zi^ Z^ i^ zlLZL^ Ztih^^^ lzlzYllzZz^ Z 5§t2lS§Yi^i22<a>2§t<a>Si§2ll2lh<a>E2§22Yl23S§Y<m >§tYil2l2§^2<m>lll]S5E22G§YE2_l2§tEiH5!§aitii

Of 700 mg (0.95 m mol) 76-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-carbamoyloxymethyl-3-cephem-4- carboxylic acid diphenylmethyl ester in 1.5 ml of methylene chloride, 0.5 ml of anisole and 7.1 ml of trifluoroacetic acid gives, analogously to example 2, the title compound with an Rf value of 0.50 (UPC^2 plates, water/acetonitrile 6:1);

F.: approx. 215 (fission); UV spectrum (methanol): X max

230 shs; IR spectrum (nujol): characteristic absorption bands at 2.85; 3.05; 5.60; 5.80; 6.25; 6.45 y.

Example<_>7^ Z§liili5lt§Eti2<y>t2]S§Y]S5E222YiamiS2lli2/.li ti§di§zol-3-yl )_-2-Z-met^ t§trahydro-2-methyl1- 5^6-dioxo-22£l2l§ml!l]S§£222s.YE2

A solution of 0.74 g (2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazole -3-yl)-2-Z-methoxyiminoacetic acid in 5 ml of ethyl acetate and stir the now clear solution for 45 min at 0° After the addition of a with 1 ml of 2 N caustic soda at pH

7.5 adjusted solution of 0.74 g of 76-amino-3-(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1;,2,4-triazin-3-yl- thiomethyl) - 3-cephem-4-carboxylic acid in 5 ml of water, the reaction mixture is stirred for 3 hours at 0° and kept at pH 7.5 by the dropwise addition of 2 N caustic soda. After adding 100 ml of ethyl acetate, the aqueous phase is adjusted to pH 1.5 with 2 N hydrochloric acid and extracted 3 times with 100 ml of ethyl acetate each. The combined extracts are washed with sodium chloride solution, dried with magnesium sulfate and crystallized after evaporation while showering with ethyl acetate. The title compound is obtained, which splits over 180°. IR spectrum (nujol): characteristic absorption bands at 3.12; 5.63; 5.78; 6.11; 6.46 y; UV spectrum (ethanol): X max (e): 238 (35800)nm.

Example _8|_ Zalll^yl^amino^zii^thiadiazole^ m2t2lS§YimiS2a22t5mi^2ll5lili2i5i6-tetra ^i23S§2lli2i4-triazin-3-yl-thiome

0.52 g 76-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1,2,5,6-

Tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl-thiomethyl)-3-cephem-4-carboxylic acid is dissolved in 5 ml of trifluoroacetic acid and stirred for 5 minutes. at room temperature. One isolates as in example 2 and obtains the title compound with an Rf value of 0.2 (UPCj 2 plates, water/acetonitrile 4:1); B. approx. 210° (cleavage) ; IR spectrum (nujol): characteristic absorption bands at 2.29; 5.67; 5.99; 6.29; 6.53 y.

Example_el_9:_ l^ ziizi^ Z^ i^ 2zl^. Zh. izt:i^ <li^ 2lzl' zYV- Zi'. zZ. Z m§t2lSSYiminoacetoami^

A suspension of 1.43 g (30 m mol) of 73~{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acetoxymethyl-3-cephem- 4-carboxylic acid sodium salt and 0.44 g (3.6 m mol) of 3-methyl-1,2,4-thiadiazol-5-yl-thiol in 10 ml of aqueous sodium bicarbonate solution are stirred at 70° and at a pH of 6.0- 6.5 for 2 hours, then brought to pH 7.0 with solid sodium bicarbonate and extracted with ethyl acetate. The aqueous phase is evaporated in vacuo. After chromatography on silica gel "Opti UPC^2" with acetonitrile:water 1:9, the uniform title compound with Rf 0.40 is obtained (UPCj 2 plates, water-acetonitrile 4:1). F. from 185° (cleavage). UV spectrum (methanol): X max (e): 230 (25050); 272 (17700) nm; IR spectrum (nujol): characteristic absorption bands at 3.0;

5.65; 6.0; 6.55; 9.60 y.

Example_1_0£ Zåriili^ramino^z2. / 4zthiadiazole = 3-yl )_-2 = Z=_ m§tok^yiminoacetamide^}-3-^ thio<m>et<y>l-3-cef§m-4-carbonic acid_sodium salt

a) A suspension of 0.478 g (1.0 m mol) 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acetoxymethyl-3- cephem-4-carboxylic acid sodium salt, 0.240 g (1.5 m mol) 1-carboxymethyltetrazol-5-yl-thiol, 0.370 g tetrabutylammonium iodide and 2.0 g potassium iodide in 2 ml water are stirred at 70° for 2 hours, then diluted with water and extracted with ethyl acetate. The ethyl acetate extracts are washed with aqueous sodium bicarbonate solution. The combined aqueous phases are adjusted cold with 4N hydrochloric acid solution to pH 1.5 and extracted with ethyl acetate. The ethyl acetate extracts are washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is triturated with ethyl acetate, the solid product is filtered off and washed with ethyl acetate-ether 1:1. The residue is dissolved in water containing methanol and adjusted with solid sodium carbonate to pH 7. After lyophilization of this solution and chromatography of the residue on silica gel "Opti UPC^2" with <3 acetonitrile: water 1:6

the uniform title compound with an Rf value of 0.65 is obtained (UPCj 2 plates, water-acetonitrile 6:1). B. approx. 210° (cleavage) . IR spectrum (nujol) characteristic absorption bands at 3.00; 5.68; 6.20; 6.55; 9.62 u; UV spectrum (methanol):

X max (e) 232 (24450) nm.

The same compound can also be prepared as follows: b)-- A suspension of 0.570 g (1 m mol) 78~{2-(5-ammonium-1,2,4-thiadiazol-3-yl)-2-Z- Methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate and 0.160 g (1 m mol) 1-carboxymethyl-tetrazol-5-yl-thiol in 5 ml of aqueous sodium bicarbonate solution are stirred at a pH of 6.0-6 .5 during 2 hours at 70°, then it is brought to solid form with sodium bicarbonate at pH 7.0 and extracted with ethyl acetate. The aqueous phase is evaporated in vacuo. After chromatography on silica gel "Opti UPCj2" (company Antec) with acetonitrile:water 1:6, the uniform title compound is obtained with an Rf value of 0.65 (UPCj 2 plates, water:acetonitrile 6:1).

Example_1_li ZaliliziS-tert^butoxycarbonylam ((ia2ol-3-yl)_22-methoxyiminoaceta^ammonium)_ethyl}-2H-tetrazol§YI§ltetrafluoroborate

0.298 g (0.99 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid is added at -5° to a stirred suspension of a Vilsmeier reagent (prepared of 0.1 ml (1.2 m mol) oxalyl chloride and 0.09 ml of N,N-dimethylformamide in 4 ml of dry ethyl acetate) and the mixture is stirred at

this temperature for less than 30 min. (resolution 1). On the other hand, a mixture of 0.473 g (1.0 mmol) of 73-amino-3-{1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl-thiomethyl}-3 is stirred -cephem-4-carboxylic acid tetrafluoroborate, 1.1 ml of N,0-bis(trimethylsilyl)acetamide and 5 ml of dry ethyl acetate for 30 min. at room temperature and then cooled to -15° (solution 2). Solution 1 is added to the -15° cold solution 2 and the mixture is stirred at this temperature for 3 hours, then diluted with 40 ml of ethyl acetate and extracted with water. The aqueous extracts are evaporated and lyophilized. Part of the lyophilisate is chromatographed (UPCj 2-plates), water: acetonitrile 1:1). The uniform title compound with Rf 0.30 is obtained (UPC^2 plates, water-acetonitrile 1:1). IR spectrum (KBr): characteristic absorption bands at 2.95; 5.62; 5.85; 6.00; 6.45 y; UV spectrum (methanol): X max (e) 235 (17400) nm.

Example_1_2 j_ Z§.-{ zZzilz^ i^ 2zlLZjLlzt:i^ i^ 2lzIzY. liZzå' Z m§É2lS§Yi™il}2§22tamid^2-3 i<X>zL 2-N^N-dimet<y>l<amin>oet<y>l}-1<_>H< -__>t§ÉE<a>52iz5lYlilti2m§£Yil<3->cef§m-4-carbonic acid_sodium salt

A solution of 2.1 g (2.77 m mol) 73-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-{1- {2-(N,N-dimethylammoniumethyl}-1H-tetrazol-5-yl}-thiomethyl-3-cephem-4-carboxylic acid tetrafluoroborate in 4.7 ml of methylene chloride is added at room temperature with 21 ml of trifluoroacetic acid and stirred for 30 minutes. , then stir in 1.0 ml of diethyl ether/hexane 1:2. The precipitate is isolated by filtration, dissolved in 50 ml of methanol and quenched with a methanolic approximately 3N sodium 2-ethylhexanoate solution at pH 7.0. After addition of 100 ml of ether the formed precipitate is filtered off and chromatographed (silica gel "Opti UPC^2", water/acetonitrile 9:1). The uniform title compound is obtained with Rf 0.35 (UPC^2 plates, water/acetonitrile 4:1). F. 190° (decomposition). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 5.95; 6.20; 6.45 y; UV spectrum (methanol) X maK , s= 231 nm (e =27800).Example<_>el<_>1<_>3£Zål<l>2ii5-tert_ :<_>butoxYk§Ebo<n>Ylamino-1_ i2i4 = ^^^ i^ 2lz2zYliz^ 22 ^^ i^ 2lz^ Z^ 22^ 2] S^ Y^ 2t:Ylz2z22Z2^ ziz ]SaE22!}§Y£2Z2-if 22Yim2tYl2§ter

A solution of 500 mg (1.90 m mol) 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid and 830 mg (1.90 m mol) 73-amino-3 -acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester in 10 ml dry tetrahydrofuran is added at 0° with 210 mg 1-hydroxybenzotriazole and 475 mg (2.30 m mol) N,N'-dicyclohexylcarbodiimide in 6 ml dry tetrahydrofuran, stirred under 3i hours at 0° and then heated to room temperature. After filtering the reaction mixture, the filtrate is diluted with 50 ml of ethyl acetate and washed successively with aqueous sodium bicarbonate and aqueous sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by preparative layer chromatography on silica gel with chloroform/methanol 95:5. The uniform title compound with an Rf value of 0.65 is formed (silica gel, chloroform/methanol 95:5). UV spectrum (methano<l>)<:>X max. s(<e>) 248 (14500) nm; IR

IUcLK S

spectrum (methylene chloride): characteristic absorption bands at 3.0; 5.57; 5.80; 6.45; 8.15 a.m.

Example _1_4£ Z§li2.li5l£§Eti2y£23S§YlS§£2°DYl§I!}i22lli2jLil thiadiazol-3-y 1 )_-2-hydroxyim 2l22l§Sl^zlS§£222§Y£2l§ i^§SYim2tYi§§£§E

A solution of 340 mg (0.5 m mol) 7S-{2-(5-tert-butoxycarbonylamino^-1,2,4-thiadiazol-3-yl)-acetamido}-3-acetoxymethyl-3-cephem- 4-carboxylic acid diphenylmethyl ester in 3 ml of glacial acetic acid is added at 10-15° with 38 mg (0.55 m mol) of sodium nitrite and stirred for 30 min. at this temperature. The reaction mixture is diluted with 20 ml of ethyl acetate and washed successively with water, aqueous sodium bicarbonate and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by preparative layer chromatography on silica gel with ethyl acetate. The title compound is obtained with Rf 0.30 (silica gel, ethyl acetate). IR spectrum (nujol): characteristic absorption bands at 3.05;

5.65; 5.85; 5.90; 6.45; 9.05 y.

Example _1_5_£ Z§li2limited^b^toxic vessel^

5}2£Yiil5l22^25}lll]Sa£222§YE§I^i^2SYi2}§tYi§§£§E

From 518 mg (2.0 m mol) 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid, 940 mg (1.90 m mol) 73-amino-3-(1 -methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, 210 mg of 1-hydroxybenzotriazole and 475 mg (2.30 m mol) of N,N'-dicyclohexylcarbodiimide in 30 ml of tetrahydrofuran is obtained analogously to example 13 the uniform title compound with Rf value 0.60 (silica gel, chloroform/methanol/glacial acetic acid 85:12:3). IR spectrum (methylene chloride) characteristic absorption bands at 3.0; 5.65; 5.90; 6.45 y.

Example _1_6j_ 7 $-{ 2-^5-tert^butoxycarbonylam ^ia22ll2lYiil2-hydroxyiminoacetamide 5-y 1-thiomethyl )_-3-cef em-4-carb

From 258 mg (0.38 mmol) 73-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetamido}-3-(1-methyltetra-zol-5-yl) -thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester and 29 mg (0.42 m mol) of sodium nitrite in 2.5 ml of glacial acetic acid gives, analogously to example 14, the title compound with an Rf value of 0.30 (silica gel, toluene/ethyl acetate 1 :1). IR spectrum (nujol) characteristic absorption bands at 2.90; 5.60; 5.85; 5.95; 6.20; 6.45; 9.10 y.

Example_1_7:_ Zåli^llS-tert^butoxycarbonylami thia§ia52ll2lYlil2-oxo-acetamido}-3-£i23!2£Yiil3-cef 2mlll^aE222§YE2l^i^22Ylm§£Yl§§É2E

0.683 g (2.50 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid and 12 ml of ethyl acetate are added at -5° to a stirred suspension of a Vilsmeier reagent (prepared from 0.38 g (3.0 m mol) oxalyl chloride, 0.20 ml of N,N-dimethylformamide in 1.5 ml of dry ethyl acetate). The mixture is stirred for 35 min. at 0°. After addition

of 1.235 g (2.50 m mol) of 7B-amino-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester is stirred for 3 hours at 0°, then diluted with 50 ml ethyl acetate and washed successively with water, phosphate buffer solution pH 8.0 and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by preparative layer chromatography on silica gel with chloroform/ethyl acetate/glacial vinegar 100/100/0.5. The uniform title compound with Rf 0.60 is obtained (silica gel, chloroform/ethyl acetate/glacial acetic acid 100:100:0.5). IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 2.75; 5.60; 5.85; 6.10; 6.45; 8.50 y.

Example_1_8£ 7B-{2-jS-amino-l^^-t^ ^Y^£2?S§Yi5i52§S§tamido }- 3-21-methyltet 2z22£ §5?ziz]SaE222SYre_n^tr^um salt

Of 355 mg (0.5 m mol) 73-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetamido}-3-'

(1-Methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 0.80 ml methylene chloride, 0.27 ml anisole and 3.75 ml trifluoroacetic acid gives analogously to example 2 the uniform title compound with Rf- value 0.15 (UPCj 2 plates, water/acetonitrile 9:1). F.: from 185° (cleavage). IR spectrum (nujol): characteristic absorption bands at 3.00; 5.65; 5.95; 6.25; 6.55; 9.10 y.

Example _1_9^ Z 9il22t2lS§Yl2§li2 li 5-tert ^butoxy carbonyl 2^2 L4-thiadiazol-3-yl )_-2-Z-methoc m§£Yiz2l22^2ml4l]SSE222§Y£§I§if § DYlm2tYl§§t§E

A solution of 2.18 g (3.0 m mol) 7B-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acet oxymethyl -3-cef em- 4 -carbonic acid -di - phenyl methyl ester in 200 ml abs. tetrahydrofuran is cooled to -75° (dry ice-acetone bath) and a pre-cooled solution of lithium methoxide in methanol (83 mg of lithium dissolved in 9 ml of methanol) is added dropwise over the course of 2 min., whereby the temperature rises to -70° and an orange colored solution is formed. The reaction mixture is stirred for a further 2 min. at -75°, then 0.25 ml of tert-butyl hypochlorite is added and further stirred at -75°. After 8 min. a further 0.2 ml of tert-butyl hypochlorite is added to the solution. After 30 min. 3.3 ml of glacial acetic acid and a solution of 1.5 g of sodium thiosulphate in 1.9 ml of water are added dropwise to the reaction mixture. The cooling bath is removed and the solution is heated to room temperature. The mixture is evaporated in vacuo and diluted with ethyl acetate. The ethyl acetate solution is washed successively with water, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by chromatography on silica gel with methylene chloride and increasing proportions of ethyl acetate. The title compound is obtained with Rf 0.30 (silica gel, toluene/ethyl acetate 3:2). IR spectrum (methylene chloride): characteristic absorption bands at 2.95; 5.60; 5.85; 5.95; 6.45; 9.50 y.

Example_20£ l^ Z^^^ YzlåziZzi^ Z^ h^ zlLZj- lzti^^ i^^ lzlz yl)_-2-Z-me took sy iminoacetamido ]S§E^22§Y£§_I}§trium salt

Of 0.44 g (1.01 m mol) 7α-methoxy-7|3-{2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido} -3-acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester in 3 ml of methylene chloride, 1 ml of anisole and 14.2 ml of trifluoroacetic acid gives, analogously to example 2, the title compound with an Rf value of 0.45 (UPC^2~plates, water/ acetonitrile 9:1). F. from 190° (cleavage). IR spectrum (nujol): characteristic absorption bands at .3.0; 5.60; 5.95; 6.20; 6.55; 9.55 y.

Example_21_2. 2§zi2li§I§mi!12lli.2.i.llthiadiazole = 3=yl )_ = 2 = Z =<m>§£2lS§Yi<m>i22<a>2§£<a>5i^2ll2l <a>22t2lS§Y5!2£Yll2l2§£2<m>llllS§£22?}§YE2lEiY<a>l2Yl2^§Y5l§tYi§§t§E

A mixture of 1.91 g (4.0 m mol) 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acetoxymethyl- 3-cephem-4-carboxylic acid sodium salt in 22 ml of N,N-dimethylformamide is added at 0° with 0.9 ml (3.85 m mol) of iodomethyl pivalate and stirred for 60 min. at this temperature, after which it is poured into 120 ml of phosphate buffer solution pH 7.0 and extracted with ethyl acetate/acetone 4:1. The organic extracts are washed with aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is triturated with diethyl ether, the solid is filtered off and washed with diethyl ether/hexane 1:1. The title compound is obtained with an Rf value of 0.80 (silica gel, s-butanol/glacial vinegar/water 67:10:23). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.60; 5.70; 5.90; 6.15; 6.45 y.

Example_22£ låziZzi^ Z^ i^ zlj- ZLåz^ i^ i^^ lzlzY- llz^ Z^ Z m§tok§Yi5i52a2§tamido}-3-carba^

Of 2.39 g (5.0 m mol) 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-carbamoyloxy-methyl-3- cephem-4-carboxylic acid sodium salt and 1.13 ml (4.81

m mol) of iodomethylpivalate in 25 ml of N,N-dimethylformamide gives, analogously to example 21, the title compound with an Rf value of 0.70 (silica gel, s-butanol/glacial acetic acid/water 67:10:23). IR spectrum (nujol): characteristic absorption bands at 3.05; 5.60; 5.72; 5.95; 6.25; 6.45 y.

Example_23j_ lQziZzi^ Z§Eill2zlj. ZLizt:i^ i^ ?L2lzIzY. llz^ zå' z m2t2lS§Yimi22a22ta™i^2ll2zlll52£Yi£2££a52lz5lYil£iomethyl )_-5l22^§mlillSaE^2S§YE§lEiYal2Yi2lSSYm§tYi§ster

From 4.27 g (8.0 m mol) 76-{2-(5-amino-1,2,4-thiadiazol-3-yl}-2-Z-methoxyiminoacetamido-3-(1-methyl-tetrazol- 5-yl)-thiomethyl)-3-cephem-4-carboxylic acid sodium salt and 1.8 ml (7.70 m mol) iodomethylpivalate in 45 ml of N,N-dimethylformamide gives, analogously to example 21, the title compound with Rf value o.80 (silica gel, acetone/glacial vinegar/water/ammonia 20:8:5:1). IR spectrum (nujol): characteristic absorption bands at 2.95; 5.65; 5.80; 5.95; 6.45 y. Eczema_2 4 j_ l& zLZzilz^ i^ 2zlj. 2. j. iz^ i^ i^ 2lzlzY. liZz^. Z !22l:2k§Yi!I!i22§2§}=§roi^ t§t£§52il5lYlz£i2m§£YiIl3-cef em-4 ik^r^on^yr^-pivaloyloksy-<m2t>Yl §§t§EltiY^£2]Si2<£i>^

From 3.5 g (5.91 m mol) 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-{1-{2- (N,N-dimethylamino)-ethyl}-1H-tetrazol-5-y1-thiomethyl}-3-cephem-4-carboxylic acid sodium salt and 1.35 ml (5.78 m mol) iodomethylpivalate in 30 ml of N,N- dimethylformamide gives analogously to example 21 the title compound which is isolated as hydrochloride. Rf value 0.60 (acetone/glacial vinegar/water/ammonia 20:8:5:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.60; 5.85; 6.05; 6.45 y.

Example_25 j_ Z§li2ii5-amino=li2i4=thiadiazol-3=yl 2§£2l£§Yi<m>i22§2§l:§<m>iå2l^ m§£Yit§tE§52i~5-yl- thiomethyl-3-cephem-4-carboxylic acid pivaloyl-oxymethyl ester

From 4.8 g (8.28 m mol) 76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-carboxymethyl-tetrazole -5-yl-thiomethyl)-3-cephem-4-carboxylic acid sodium salt and 3.6 ml (15.44 m mol) of iodomethylpivalate in 60 ml of N,N-dimethylformamide gives analogously to example 21 a crude product which gives after chromatography on silica gel the title compound with Rf value 0.55 (silica gel, acetone/glacial acetic acid/water/ammonia 20:8:5:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.20; 6.50 y.

Small amounts of 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-carboxymethyl-tetrazol-5-y1-thiomethyl) are also obtained )-3-cephem-4-carboxylic acid pivaloyloxymethyl ester with an Rf value of 0.40 (silica gel, acetone/glacial acetic acid/water/ammonia 20:8:5:1).as well as of 7B-{2-(5-amino-1 ,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1 - pivaloyloxymethoxycarbonylmethyl-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid with an Rf value of 0.30 ( silica gel, acetone/glacial acetic acid/water/ammonia 20:8:5:1). Eksemgel_2 6£ ZSli^zlS-ter^b^tok^ykar^onyla^ thiadiazol-3-Ylii2-Z-metoxYin} m§£Ylltetrazol-5-YlithiometYlil3-cef

295 mg (0.98 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid is added at -5° to a stirred suspension of a Vilsmeier reagent (prepared of 0.1 ml (1.2 m mol) oxalyl chloride and 0.09 ml of N,N-dimethylformamide in 4 ml of dry ethyl acetate) and the mixture is stirred at this temperature for 30 min. (solution 1). On the other hand, 408 mg (1.0 m mol) of 73-amino-3-(1-sulfomethyl-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, 0.69 ml of triethylamine and 3 ml of N,0-bis(trimethylsilyl)acetamide under 30 min. at room temperature and then cooled to -15°

(solution 2). Solution 1 is added to the -15° cold solution 2 and the mixture is stirred at this temperature for 1 hour. The insoluble components are filtered off and the filtrate is added to diethyl ether/petroleum ether 1:1. The separated solid is filtered off and washed with petroleum ether. After preparative layer chromatography on silica gel UPC^ with water/acetonitrile 4:1, the uniform title compound with an Rf value of 0.40 is obtained (UPC12 plates, water/acetonitrile 4:1). IR spectrum (nujol): characteristic absorption bands at 3.10; 5.65; 5.85; 6.05; 6.20; 6.45 y.

Example_2 7_2_ 7 3 = { 2-_(5=amino=1 i2i4=thiadiazol=3=yl )_=2-Z = m§£2lS§YimiS2a2iɧmi^2lz2lillsulf omethyl-tetrazol-5-Yl-thio-< m>§ÉYlil5l2§^2?!l<4>l]S§E22D§Y£2_S§t£i<ym>§§It

A solution of 400 mg (0.58 mmol) 7$-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1 -sulfomethyl-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid in 0.95 ml of methylene chloride is added at room temperature with 4 ml of trifluoroacetic acid and stirred for 30 min. at room temperature, then stir in 300 ml of diethyl ether/hexane 1:2. The precipitate is isolated by filtration, dissolved in 8 ml of methanol and adjusted with a methanolic 3N sodium-2-ethylhexanoate solution to pH 7.0. After adding 70 ml of ether, the precipitate formed is filtered off and chromatographed (UPCj 2 plates, water/acetonitrile 9:1). The uniform title compound with an Rf value of 0.40 is obtained (UPCj 2 plates, water/acetonitrile 9:1). F.: from 175° (cleavage). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.20; 6.50; 9.65 u; UV spectrum (methanol): X max (e) 233 (21950) nm.

Example_28^ ZSliiilS-amino-lj,^, 4=thiadiazole = 3=Yill2-Z = m§tgksYiminoacetamido}-3-^4-ok YllÉi2 m§tYlil2l9§f§?Bliz]S§E^22§YE§_2 §t£iy5}§§lÉ

A suspension of 478 mg (1.0 m mol) of 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acet-oxymethyl-3- cephem-4-carboxylic acid sodium salt and 154 mg

(1.2 m mol) 4-oxo-3,4-dihydro-pyrimidin-2-yl-thiol in 5 ml of water is adjusted with sodium bicarbonate in solid form to pH

6.5 and stirred at this pH value for 4 hours at 70°. The solution is brought to pH 7.0 with sodium bicarbonate in solid form and lyophilized. The residue is purified by preparative layer chromatography on UPC^ plates with water/dioxane 98:2. The uniform title compound is obtained with an Rf value of 0.25 (UPC12 plates, water/dioxane 98:2). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.15; 9.60 y.

Example_2 9£ Z§li2zi5-N=methylamino=li2i4=thiadiaz 2z5z<m>2£2lS§Yi5!iB2§£2£§mi^2lz2z§22£23S§Y<m>2tYiz2z2§£§?JzlzISaE222§Y £§Z^if §nYlm§£ylester

1.84 g (10.0 m mol) of 2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid and 5 ml of ethyl acetate are added at -5° to a stirred suspension of a Vilsmeier reagent (prepared from 1 ml (1.20 m mol) oxalyl chloride and 0.9 ml of N,N-dimethylformamide in 30 ml of dry ethyl acetate). The mixture is stirred at 0° for 1 hour and then cooled to -10°. After adding 2.75 g (11.0 m mol) of 76-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenyl methyl ester, the mixture is stirred at 0° for 3 hours, then diluted with 100 ml of ethyl acetate and washed successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The organ-

ice phase is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with chloroform. The title compound is obtained with an Rf value of 0.35 (silica gel, ethyl acetate). IR spectrum (methylene chloride): characteristic absorption bands at 3.0; 5.65; 5.80; 5.90; 6.40 y.

Example _30j_ Zåli ^zlS-N^methyl lamino-2i2£4-thiadia 2l5-methoxyiminoacetamido}i3-acetoxymethyl-3-cephem-4-kar^ §YE2_12<a>£EiH3!§al<t>

From 1.0 g (1.57 m mol) 76-{2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-acetoxymethyl-3-cephem- 4-carboxylic acid diphenylmethyl ester in 1.3 ml of methylene chloride, 2.5 ml of anisole and 10 ml of trifluoroacetic acid gives analogously to example 4 the title compound with an Rf value of 0.20 (UPC1^) — plates, water/acetonitrile 6:1). F. from 180° (cleavage). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 5.95; 6.25; 6.50; 8.15 y.

Example_31_l Z§li ^ilS-tert^butoxycarbonyl lam ^i§52ll2zYlil2-Z-methylcarbamoyloc §2§£°lS§Y?B§iYil2l22£25}lizlS5£222§YE2l§i£§2Yi<m>§tYi§ §tea

1.05 g (3.70 m mol) of 2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetic acid and 0.4 ml of N-methylmorpholine are given at -5 ° to a stirred suspension of a Vilsmeier reagent (prepared from 0.031 ml of oxalyl chloride and 0.29 ml of N,N-dimethylformamide in 10 ml of ethyl acetate). The mixture is stirred for 30 min. at 0° and then cooled to -10°. After adding 1.357 g (3.1 m mol) of 73-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenyl methyl ester, the mixture is stirred for 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 evaporated in vacuo. Part of the crude product is purified by preparative layer chromatography with ethyl acetate. The uniform title compound is obtained with an Rf value of 0.60 (silica gel, ethyl acetate). IR spectrum (CH 2 Cl 2 ): characteristic absorption bands at 2.95; 3.10; 5.65; 5.80;

5.95; 8.20 y.

Example_32^ Z§li2ii5-amino=1, 2 , i-thiadiaz^l^^ylX-g-Z;; m2ÉYikar^amoylok^Yiminoa^ lzlSaE22I}SYEe_natr^umsalt

From 519 g (0.68 m mol) 76-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyimino-acetamido}-3-acetoxymethyl-3- cephem-4-carboxylic acid diphenyl methyl ester in 1.1 ml methylene chloride, 0.37 ml anisole and 5 ml trifluoroacetic acid gives, analogously to example 2, the title compound with Rf value 0.40 (UPCj 2~Plater / water/acetonitrile 6:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.67; 6.22; 8.10 y.

Example_33£_7 8-{2-i5-amino-m§tYllSaE2a™2Yi2^§Yi™i22a22Éami§2ll2zillm2tYit2££a52il5l Yllti2m2tYlil3-cephem-4zcarbonic acid_sodium salt

From 530 mg (1.02 m mol) 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-acetoxymethyl-3-cephem-4- carbonic acid sodium salt and 150 mg (1.09 m mol) 1-methyltetrazol-5-ylthio in 5.1 ml of aqueous sodium bicarbonate solution one obtains analogously to example 10b) the uniform title compound with an Rf value of 0.35 (UPC^ plates, water/ acetonitrile 6:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.20 y.

Example_34 j_ Z 3^ { 2=j5=amino=2i2i4=thiadiazol-3=y m§thylcarbamoyloxyiminoacetam 52il5lYil£i25§iYi!l3-cef§m-4-carboxylic acid_sodium salt (1) and Zåli^ilS-amino-^i^i ^-thiadiazole-S-y a22ta5i^2ll2lilllSa£22h§Ym§tYyltetrazol-5-yl-2§£§SZ^zlSa£222SYEe_sodium salt (2)

A suspension of 0.260 g (0.5 m mol) 7B~{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyimino-acetamido}-3-acetoxymethyl-3- cephem-4-carboxylic acid sodium salt and 0.08 g of 1-carboxymethyl-tetrazol-5-yl-thiol in 2.5 ml of aqueous sodium bicarbonate solution are stirred at a pH of 6.5 for 3 hours at 70°, then a further 0.02 g 1-carboxymethyl-tetrazol-5-ylthiol and after setting the pH value to 6.5 with sodium bicarbonate in solid form, stir for a further 1 hour at 70°, then bring the pH to 7.0 with sodium bicarbonate in solid form and extract with ethyl acetate. The aqueous phase is evaporated in vacuo. After chromatography on silica gel "Opti UPC^2" (company Antec) with water, the uniform title compound (1) is obtained with an Rf value of 0.60 (UPCj 2 plates, water:acetonitrile 6:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.67; 6.17 y as well as the uniform title compound (2) with Rf value 0.85 (UPCj 2-plates, water:acetonitrile 6:1), IR spectrum (nujol): characteristic absorption bands at 3.05; 5.67; 6.15; 8.30 y.

Example_35j_ låziZzi^ Z^ hli2zijLlj. iz^^ i^ 2l. z2zYliz2. Z?iZ ™2tYll5aE2am2Yl2lS§Yimi!22a^5lYilti2m§tYlil<3-c>efem-4zkarbonsy<re>_<n>sodium salt__(]_!°9Z§li2zI5-amino=li2i4-thiadiazol-3-^ a2§£ §!2i^2ll3-_( 1^£mlf_ 2^2 ty l-tetrazol-5-y 1-thiomethyl )_-2§£§mzlllSa^22I}§Y£§_5§trium salt__( 2)_

A suspension of 0.306 g (0.5 m mol) 7B-{2-(5-ammonium-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxy-iminoacetamido}-3-acetoxymethyl-3- Cepheme-4-carboxylic acid trifluoroacetate, 0.164 g of sodium 1-sulfomethyl-tetrazol-5-yl-thiolate and 2.0 g of sodium iodide in 1.0 ml of aqueous sodium bicarbonate solution are stirred at a pH of 6.5 under 2 hours at 70°, then cooled and poured into 500 ml of ethanol. The precipitate is filtered and washed successively with ethanol and hexane. After chromatography on silica gel Opti UPC12, one obtains the uniform title compound (1) with an Rf value of 0.20 (UPC | 2 plates, water:acetonitrile 98:2) and the uniform title compound (2) with an Rf value of 0.65 (UPC12 plates, water:acetonitrile 98:2). Example_36 in l§. zilzi^ Z§^ i^ 2zlj. lj. izt:i^ i§i^ 2lzlzY. llzZz^ Z5§tYlcarbamoYloksYiminoacetam tiometYlil2lS§£§mllllS§E22S§YE§ZEiYai2Yl2]S§Ym§£Yi§§t§£

From 2.30 g (4.0 m mol) 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-(1-methyltetrazol-5 -γ1-thiomethyl)-3-cephem-4-carboxylic acid sodium salt, and 0.9 ml (3.85 m mol) iodomethylpivalate in 20 ml N,N-dimethylformamide gives analogously to example 21 the title compound with an Rf value of 0.85 ( silica gel, acetone/glacial vinegar/water/ammonia 20:8:5:1). IR spectrum (nujol): characteristic absorption bands at 2.95; 5.63; 5.93; 6.45 y.

Example_37£ l& zi^ zi^ Z^ Z^ 2t:Yl§^^ 2zlLZLlz% L^' åi^ 2^ zlzY. l:}. Z ^iZ-methoxyiminoacetamido}-3-^lik ti2?!§tYlil2l2§£2<m>lållS§£222§Y£2_2§tEi^™§§it

From 350 mg (0.71 mmol) 78-{2-(5-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4- carboxylic acid sodium salt and 136 mg of 1-carboxymethyl-tetrazol-5-ylthiol in 3 ml of aqueous sodium bicarbonate solution, the title compound is obtained analogously to example 10b) with an Rf value of 0.70 (UPCj 2 plates, water/acetonitrile 9:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.25; 6.45 y.

Example_38_2. ZāliiziS-N-methyl-tert^butox l2i4-thiadiazol-3-yl)_-2-methoxy £2t£a52il5lYll£i2?D2tYiil2l22f 2ml4-carboxylic acid diphenylmethyl ester

316 mg (1.0 m mol) of 2-(5-N-methyl-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid and 5 ml of ethyl acetate are added at -5° to a stirred suspension of the Vilsmeier reagent (prepared from 151.5 mg of oxalyl chloride and 0.09 ml of N,N-dimethylformamide in 1 ml of ethyl acetate). The mixture is stirred for 45 min. at 0° and then cooled to -10°. After adding 490 mg of 78-amino-3-(1-methyltetrazol-5-y1-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester, the mixture is stirred for 3 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 sulphate and evaporated in vacuo. The title compound is obtained with an Rf value of 0.25 (silica gel, toluene/ethyl acetate 1:1). IR spectrum (CH 2 C 2 ): characteristic absorption bands at 3.0; 5.65; 6.45 y.

Example_39 j_ l§. zi^ zi^ Z^ Z^ 2^ Yl^^ 2zlL^ Llzt:^^^^. 2^ zlzY.' L}. Z

-methoxyiminoacetamido}z3-i2lm§tyltetrazol-5-yl-thio-

From 460 mg (0.61 m mol) 73-{2-(5-N-methyl-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}^-(1-methyltetrazole -5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 1 ml of methylene chloride, 0.33 ml of anisole and 4.6 ml of trifluoroacetic acid gives, analogously to example 2, the title compound with an Rf value of 0.35 (UPC^2 ~Plates, water/acetonitrile 6:1). IR spectrum (nujol): characteristic absorption bands at 3.0; 5.65; 6.45 y.

Example_40j__7§-{ 2-^5-tert ^butoc ^ia52ll2lYiil2-Z-2-tertibutoxykar a22tami^2il5la22É2lS§Y5}§tYll3-cef §m-4-carboxylic acid

A suspension of 15 ml methylene chloride abs., 0.3 ml dimethylformamide and 0.33 ml (7.84 m mol) oxalic acid dichloride is stirred at -10° for 30 min. under nitrogen. Then 1.3 g (3.01 m mol) of 7B-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.butoxycarbonylprop-2 -yloxy-imino)acetic acid to the suspension. The formed clear solution is stirred for 30 min. at 0-5° under nitrogen. A freshly prepared solution of 0.87 g (3.19 m mol) 7 (3-aminocephalosporanic acid in 18 ml of methylene chloride abs. and 3 ml of N,O-bistrimethylsilylacetamide is added dropwise to this solution 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 under vacuum to dry foam. The title compound with an Rf value of 0.43 is obtained (silica gel, acetic ester/acetic acid 9:1) IR spectrum (nujol): characteristic absorption bands at 5.6, 5.82, 6.04 y.

Example_41_i 2§li2zI53amino=li2i4=thiadiazol-3-yl ISa£22iS§Y2E2El2-yloxyimino)_acetamide 22f §mlillSaE22D§Y£§_^iD§trium salt

A solution of 2.3 g (3.35 m mol) 7B-{2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.- butoxycarbonylprop-2-yloxyimino)acetamido}-3-acetoxy-methyl-3-cephem-4-carboxylic acid in 12.54 ml (16.38 m mol) trifluoroacetic acid and 2.10 ml (19.28 m mol) anisole are stirred at room temperature 1 hour. The reaction mixture is evaporated at 30° bath temperature under vacuum to dryness, the residue is stirred with ether and the product is filtered off". The product is then dissolved in 28 ml of methanol and sodium ethyl hexanoate is added. The solution is stirred into 50 ml of ethyl acetate. The precipitated product is filtered off and dried under high vacuum. The title compound is obtained with an Rf value of 0.78 (UPCj 2 plates, water/acetonitrile 4:1). IR spectrum (nujol): characteristic absorption bands at 3.04; 5.68; 6.24; 6.57 y.

Example_42 j_ 2§li 2ii5-tert^butoxycarbonylami^ thiadiazol-3-yl )_-2-Z-J[ 2-^ i<m>iS2il<a>22t§<m>i^2ll^lill5}§tYit§££ <a>52iz5zYi£i2S§tYiil2l 22£§5!zåzlS<a>£222§YE2Z^i^§2Yi<m>§tYi2§É2£

A solution of 15 ml of methylene chloride, 0.094 ml (0.854 mmol) of N-methylmorpholine and 0.35 g (0.814 mmol) of 7B-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazole-3- yl)-2-Z-(2-tert.butoxycarbonylprop-2-yloxyimino)acetic acid is cooled to -10°, added with 0.11 ml (0.854 m mol) of chloroformic acid butyl ester and stirred for 45 min. After adding 0.422 g (0.854 mmol) of 7B-amino-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester, the solution is stirred for 5 hours at room temperature. The reaction mixture is evaporated in vacuo at 35° bath temperature to dryness. The residue is taken up in ethyl acetate and washed successively with dilute sodium bicarbonate solution, water, 1N hydrochloric acid and saturated sodium chloride solution,

dried over magnesium sulfate and evaporated in vacuo. The residue is cleaned on thick-layer plates. The title compound is obtained with an Rf value of 0.49 (silica gel, toluene/ethyl acetate 1:1'). IR spectrum (nujol): characteristic absorption bands at 5.58; 5.82; 6.17; 6.44 y.

Example_43 j_ 7§={ 2 = i5=amino=li2i4=thiadiazgl-3 lS5£22lS§YEE2El2-yloxyimino)_acetami 5lYi£i2m2£Ylll3 igef em-4 -carboxylic acid I§i55£Ei!im§§it

A solution of 100 mg (0.11 m mol) 7$-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-K2-tert.butoxycarbonylprop-2- yloxyimino)acetamido}-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml (65.33 m mol) trifluoroacetic acid and 1 ml (3.18 m mol) anisole are stirred at room temperature 3 hours. The reaction mixture is evaporated in vacuo at 30° bath temperature to dryness, the residue is stirred with ether and the precipitate is filtered off. The product is dissolved in 2 ml of methanol and added

is added with sodium ethyl hexanoate. The solution is clarified with activated carbon. The clear solution is introduced into 10 ml of acetic acid ethyl ester and evaporated by water jet vacuum until crystallization occurs. The title compound is obtained with an Rf value of 0.38 (UPCj 2 plates, water/acetonitrile 9:1). IR spectrum (nujol): characteristic absorption bands at 2.95; 5.67; 5.97; 6.25 y.

Example_44^ Zåli2zi5-amino=1 i2i4=thiadiazole = 3=yl )_=2 = Z=_ I2icarboxyprop-2-yloxyimino)_ac ^i^2tYi5mi222tyl)_tetrazol-5-ylthi acid

A solution of 0.28 g (0.5 mmol) of 1-(2-N,N-dimethylaminoethyl)-5-mercapto-tetrazole and 1.64 g (10.94 mmol) of sodium iodide in 0.80 ml of water heated to 80°, added with 0.12 g (0.71 m mol) 78~{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop- 2-yloxyimino)acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid disodium salt and 0.05 ml concentrated hydrochloric acid and stirred at 70° for 1 hour. The reaction mixture cooled to room temperature is stirred in 15 ml of ice water, filtered clear and added with 0.1 N caustic soda until pH 6 is achieved. After evaporation of the solvent at 35° in a vacuum, the residue is dried in a high vacuum and purified chromatographically on UPC^2 plates. The title compound is obtained with an Rf value of 0.21 (UPC^2 plates' water/acetonitrile 9:1). IR spectrum (nujol): characteristic absorption band at 5.68; 5.94 and 9.24 y.

Example_45£- l^ ziZzi^ Z^ i.^ 2zlLZi. izt:h^^^ 2lz2zY. lLz a£2ta5i^2il2la£§t2lS§Y5§tYlz3l£§f §5lll^a£222§Y£§i2aÉEiH5}I salti

From 1.0 g (1.47 m mol) 78-{2-(5-tert.butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid -diphenyl methyl ester in 2.4 ml of methylene chloride, 0.8 ml of anisole and 11.2 ml of trifluoroacetic acid, the title compound is obtained analogously to example 2 with an Rf value of 0.35 (UPCj 2 plates, water/acetonitrile 6:1). UV spectrum (methanol): X max (e):246 (8100).

Example_4 6 j_ Zåzi2:Zi^ Z^^ 2zli. ?LL^ zt:i^^^ 2lzl' zY^}. Z^ :2. §. t:Z amido} z3-_( 1_Im§tYit§ÉE§52iz§lYll£i2m§£Yiil5z2§f §mzlz]SaE222Z §YE§_i2<a>££±H5!§<a>i£i

From 0.70 g (0.95 m mol) 76-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetamido}-3-(1-methyltetrazol-5-yl -thiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 1.5 ml of methylene chloride, 0.5 ml of anisole and 7.2 ml of trifluoroacetic acid gives, analogously to example 2, the title compound with an Rf value of 0.35 (UPCj 2-plates, water/acetonitrile 4:1). UV spectrum (methanol): X max (e): 244 (13240).

Example_47 j_

In an analogous manner to the above-mentioned examples, starting from corresponding starting materials, the following compounds are obtained: 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3 - (2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, 7 6-{2-(5-amino-1,2,4-thiadiazol-3- yl)-2-Z-methoxyiminoacetamido}-3-{1-(2-sulfoethyl)-1H-tetrazol-5-yl-thiomethyl}-3-cephem-4-carboxylic acid,

76-{2 - (5-amino-1,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacet-amido}-3-acetoxymethyl-3-cephem-4-carboxylic acid,

7g<->{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(3-hydroxypyridazin-6-yl-thiomethyl)-3-cephem- 4-carbonic acid,

78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxymethoxyimino)acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid,

76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-carbamoyloxy-iminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid,

7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(1-carboxycyclopropyloxyimino)acetamido}-3-(1-methyltetrazol-5-ylthio-methyl- 3-cephem-4-carboxylic acid,

73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-{1-(2-sulfoethyl)-tetrazol-5-ylthiomethyl}- 3-cephem-4-carboxylic acid,

78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxy-iminoacetamido}-3-{1 -(2-carboxyethyl)-tetrazol-5-ylthiomethyl}- 3-cephem-4-carboxylic acid,

73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxy-iminoacetamido}-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-

3- cephem-4-carboxylic acid pivaloyloxymethyl ester,

76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxy-iminoacetamido}-3-(1-dimethylaminomethyltetrazol-5-ylthio-methyl-3-cephem-4 -carbonic acid pivaloyloxymethyl ester,

76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxy-iminoacetamido}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid,

76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-{1-(2-dimethylaminoethyl)-tetrazol-5-ylthio-methyl }-3-cephem-4-carboxylic acid, 7 6-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-carbamoyloxyimino-acetamido}-3-(1-methyltetrazol- 5-ylthiomethyl-3-cephem-4-carboxylic acid,

7g<->{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-carbamoyloxyimino-acetamido}-3-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4- carboxylic acid ,

76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-carbamoyloxyimino-acetamido}-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4- carbonic acid,

73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-carbamoyloxyimino-acetamido}-3-(1-dimethylaminomethyltetrazol-5-ylthiomethyl)-3-cephem-4- carbonic acid,

7B-{2-(5-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid,

76-{2-(5-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-{ 1 -(2-dimethylaminoethyl)tetrazol-3-ylthiomethyl}-3-cephem -4-carbonic acid,

7B-{2-(5-methylaminc-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid pivaloyloxymethyl ester,

76-{2-(5-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid- pivaloyloxymethyl ester,

73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacet-amido}-3-{1 -(2-dimethylaminoethyl)tetrazol-5-yl-thiomethyl}-3 -cephem-4-carboxylic acid,

7 B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacet-amido}-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid -pivaloyloxymethyl ester, 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido}-3-(1 - carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 76-{2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-(1-sulfo-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 7 8- {2-(5-amino-1,2,4-thiadiazpl-3-yl)acetamido}-3-{1 -(2-dimethylaminoethyltetrazol-5-ylthiomethyl}-3-cephem-4-carboxylic acid,

the sodium salts and the disodium salts of such compounds which contain a resp. two acidic groups and the hydrochlorides of such compounds containing a basic group.

Example_48^

Dry ampoules or vials, containing 0.5 g of active substance, e.g. 7$-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4 -carbonic acid (sodium salt), is prepared as follows.

Composition (for 1 ampoule or vial)

A sterile, aqueous solution of the active substance and mannitol is closed under aseptic conditions in 5 ml ampoules or 5 ml vials and tested.

Example_£49

Dry ampoules or vials containing 0.25 g of active substance, e.g. 76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4- carbonic acid (sodium salt), is produced as follows:

Composition (for 1 ampoule or vial)

A sterile, aqueous solution of the active substance and mannitol is closed under aseptic conditions in 5 ml ampoules or 5 ml vials and tested.

Claims (23)

1. Process for the preparation of 7B-aminothiadiazol-yl-acetamido-3-cephem-4-carboxylic acid compounds of formula in which Am denotes an optionally protected amino group, R. stands for hydrogen, optionally substituted lower alkyl^ or cycloalkyl, or optionally N-substituted carbamoyl, R 2 means hydrogen or lower alkoxy, R^ stands for hydrogen, acyloxy or heterocyclothio and R^ denotes an optionally protected carboxyl group and salts of such compounds which exhibit a salt-forming grouping, characterized in that mana) acylates in a compound of formula in which R2 , R^ °<3 R 4 have the meanings indicated above, and in which the 7B-amino group is optionally substituted with a group that allows acylation, the 73-amino group by treatment with a for the acyl residue of a carboxylic acid of formula introducing acylating agent, in which Am and R^ have the meanings given above, orb) reacts a compound of formula in which Am, R2 , R^ and R^ have the meanings given above, with a hydroxylamine of formula H2 N-O-R1 (V), in which R^ has the meaning given above, orc) isomerizes a 2-cephem compound of formula in which Am, R^, R2, R^°9 R^ when the meanings given above, ord) for the preparation of compounds of formula (I), in which Am means a primary or secondary amino group, treat a compound of formula in which X means halogen or hydroxy and R^ , R 2 , R^ and R^ have the meanings given above, with a salt of the rhodanhydrogen acid, respectively. with an isorhodan hydrogen ester or treating a compound of formula (VII), in which X is hydrogen, with rhodane, or e) for the preparation of a compound of formula (I), in which R^ means hydrogen and in which Am, R 2 , R^ and R^ have the meaning indicated above, treat a compound with formula wherein Am, R 2 , R 4 and R 4 have the meanings given above, with a nitrosating agent, or f) for the preparation of a compound of formula I, in which R.j means optionally substituted lower alkyl or cycloalkyl or optionally N-substituted carbamoyl and in which Am, R2, R^ and R^ have the meaning indicated above, treats in a connection with formula in which Am, R2, R^ and R^ have the meanings given above, the hydroxyimino group with an agent introducing the residue R^, g) for the preparation of a compound of formula (I), in which R 2 means lower alkoxy and in which Am, R 1 , R 1 and R 4 have the meanings given above, are introduced into a compound with formula in which Am, , R., and R^ have the meanings indicated above, whereby functional groups are present in protected form, a lower alkoxy group in the a-position, or h) for the preparation of a compound of formula (I), in which R^ stands for heterocyclylLo and wherein Am, , R 2 and R 4 have the meanings given above, treats a compound of formula in which Am, R^, R2 and R^ have the meanings given above, and R3 means a residue exchangeable with a heterocyclylthio residue R^, with a markaptan H-R^, or i) for the preparation of a compound of formula (I), in which R^ stands for acyloxy and in which Am, R^ , R 2 and R 4 have the meanings indicated above, treat a compound of formula in which Am, , >R2 and R^ have the meanings given above, with an acylating agent, or j) for the preparation of a compound of formula (I), in which R^ denotes free carboxyl and in which Am, R^ , R 2 and R^ have the meanings given above, are removed in a compound with formula wherein Am, R^ , R 2 and R^ have the meanings given above, and R^ denotes a protected carboxyl group, the carboxyl protecting group and substituted with hydrogen, or k) for the preparation of a compound of formula (I), wherein R^ denotes an esterified carboxyl group and in which Am, R^, R2 and R^ have the meanings given above, esterifies in a compound of formula in which Am, , R 2 and R 3 have the meanings given above, the 4-carboxyl group, or 1) for the preparation of compounds of formula (I), in which Am is a primary, secondary or tertiary amino group, reacts a compound of formula wherein y is halogen and , R 2 , R 3 O 9 R 4 have the meanings given above, with ammonia or a primary or secondary amine Am-H, or a metal amide thereof, and, if necessary, cleaves off in a compound obtained unwanted protective group, and /or, if desired, transfers an obtained compound with a salt-forming group into a salt, or transfers an obtained salt into a free compound or into another salt. 2. Method according to patent claim 1 for the preparation of compounds of formula (I), in which Am means amino or methylamino, R^ means hydrogen, methyl, 2-carboxy-2-propyl or 1-carboxy-1-cyclopropyl, R2 means hydrogen or methoxy, R^ means acetoxy, carbamoyloxy, optionally with loweralkyl or carboxyloweralkyl substituted triazolylthio such as 4-carboxymethyl-1,2,4-triazolylthio, optionally with loweralkyl, carboxyloweralkyl, sulfolaloweralkyl or diloweralkylaminoloweralkyl substituted tetrazolylthio, such as 1-methyl-1H -tetrazol-5-ylthio, 1-sulfomethyl-1H-tetrazol-5-ylthio, 1-(2-sulfoethyl)-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-( 2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, optionally with lower alkyl substituted thiadiazolylthio, such as 2-methyl-1,3,4-thiadiazol-5-ylthio or 3-methyl-1,2,4-thiadiazol-5 -ylthio, optionally with hydroxy-substituted pyridazinylthio, such as 3-hydroxy-pyrida-zin-6-ylthio, optionally with hydroxy-substituted pyrimidinylthio, such as 4-hydroxy-2-pyrimi dinyl- or the addition tautomeric 4-oxo-3,4-dihydro-2-pyrimidinylthio, or with lower alkyl and two hydroxy substituted triazinylthio, such as 2-lower alkyl-5,6-dihydroxy-1,2,4-triazin-3-yl-thio , and R 4 means carboxyl or in physiologically cleavable form esterified carboxyl, e.g. pivaloyloxymethoxycarbonyl or phthalidyloxycarbonyl, as well as pharmaceutically usable salts of such compounds. 3. Process for the preparation of 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1,2,5,6-tetrahydro-2 -methyl-5,6-dioxo-1,2,4-triazin-3-yl-thiomethyl)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 4. Process for the preparation of 76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido}-3-(1-methyltetrazol-5-yl-thiomethyl)- 3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 5. Process for the preparation of 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acet-oxymethyl 1-3-cef em-4 - carboxylic acid pivaloyloxymethyl esters and pharmaceutically acceptable salts thereof according to patent claim 1. 6. Process for the preparation of 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-carba-moyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, and pharmaceutically acceptable salts thereof according to patent claim 1. 7. Process for the preparation of 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-methyl-tetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid pivaloyloxymethyl ester and pharmaceutically acceptable salts thereof according to patent claim 1. 8. Process for the preparation of 7B-{2^ (5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-{2-(N,N-dimethylamino)ethyl} -1H-tetrazol-5-y1-thiomethyl}-3-cephem-4-carboxylic acid pivaloyloxymethyl ester and pharmaceutically acceptable salts thereof according to patent claim 1. 9. Process for the preparation of 76-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1- pivaloyloxymethoxycarbonylmethyl-tetrazol-5-yl-thiomethyl -3-cephem-4-carboxylic acid pivaloyloxymethyl ester and pharmaceutically acceptable salts thereof according to patent claim 1. 10. Process for the preparation of 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(4-oxo-3,4-dihydro-pyrimidine -2-yl-thiomethyl)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 11. Process for the preparation of 78-{2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 12. Process for the production of 73-{-2-<5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid and pharmaceutical tolerable salts thereof according to patent claim 1. 13. Process for the preparation of 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}- -3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 14. Process for the production of 73-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-(1-carboxymethyl-tetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 15. Process for the production of 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido}-3-(1-carboxymethyl-tetrazol-5-y1-thiomethyl )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 16. Process for the preparation of 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-(1-sulfomethyl-tetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 17. Process for the production of 7B-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido}-3-(1-sulfomethyl-tetrazol-5-yl-thiomethyl )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 18. Process for the production of 7(3-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido}-3-(1-methyltetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid pivaloyloxymethyl ester and pharmaceutically acceptable salts thereof according to patent claim 1. 19. Process for the preparation of 73-{2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-carboxymethyltetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 20. Process for the preparation of 73-{2-(5-N-methylamino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido}-3-(1-methyltetrazol-5-yl-thiomethyl) )-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 21. Process for the preparation of 7B-{2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxy-prop-2-yloxyimino)-acetamido} -3-acetoxymethyl-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 22. Process for the preparation of 78~ {2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamido}-3-(1 -methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1. 23. Process for the preparation of 78-{2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop)-2-yloxyimino)-acetamido}-3-{ 2-N,N-dimethylaminoethyl)tetrazol-5-ylthiomethyl}-3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof according to patent claim 1.