NO841268L - 7-BETA-ACYLAMIDO-3-CEFEM-4-CARBOXYLIC ACID COMPOUNDS, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THEIR USE - Google Patents

Description

The present invention relates to new 78-acylamido-3-cephem-4-carboxylic acid compounds, methods for their preparation, pharmaceutical preparations containing these compounds, the use of these compounds as medicine and for the preparation of pharmaceutical preparations,

as well as new intermediates and methods for their preparation.

The present invention relates to 73-acylamido-3-cephem-4-carboxylic acid compounds of formula

where m is zero, 1 or 2,

is hydrogen, lower alkyl, lower alkenyl, lower alkoxy,

em group with formula -CF^-I^ where R ? is a free, esterified or etherified hydroxy or mercapto group, an azido or an ammonium group, or a group of formula

-CH=CHR2, where R2 is a preferred mercapto group,

R 1 is carboxy or protected carboxy, and

R4 is heterocyclyl, which is bonded to the 2-C atom of the 76-side chain, with one of its C atoms,

as well as stereoisomers, mixtures of these stereoisomers, hydrates and salts thereof, methods for their preparation, pharmaceutical preparations containing these compounds, and the use of these compounds as medicine or for the preparation of pharmaceutical preparations.

In the description of the present invention, the term "lower", used in connection with groups or residues, e.g. lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc, that the group or residue designated in this way contains up to 7 and preferably up to .4 C atoms if they are not expressly defined otherwise.

In connection with formula I, m is primarily 0. If

m is 1, the 1-oxido group can be in the a or B position.

There may also be a mixture of compounds of formula I with the 1-oxido group in both positions.

The 2-carbon atom in the 7B side chain with the substituted amino group -NHCHO and the residue R4; has R or S configuration. The 2R, 2S and 2R,S compounds are covered by formula I, the 2S compounds being preferred.

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

Lower alkenyl R contains 1 - 4 C atoms and is, for example, vinyl or allyl.

Lower oxy R^ contains 1 - 4 C atoms and is, for example, ethoxy, propoxy, butoxy or especially methoxy.

Halogen R is fluorine, bromine, iodine or preferably chlorine.

Esterified hydroxy or mercapto R^ is a hydroxy or mercapto group that is esterified, e.g. with an aliphatic carboxylic acid, one with acyl, e.g. lower alkanoyl, e.g. acetyl, substituted, aliphatic carboxylic acid, carbamic acid or a substituted carbamic acid, and is, for example, lower alkanoyloxy, e.g. formyloxy or acetoxy, lower alkanoyllower alkanoyloxy, e.g. acetacetoxy, carbamoyloxy or substituted carbamoyloxy or lower alkanoylthio, e.g. acetylthio, carbamoylthio or substituted carbamoylthio.

Carbamoyloxy or carbamoylthio R can for example be substituted with lower alkyl, e.g. methyl or ethyl, or with halogen, fkes. chlorine, or lower alkanoy1-

oxy, e.g. acetoxy, substituted lower alkyl, e.g. 2-chloroethyl or 2-acetoxyethyl, and is, for example, methyl-

or dimethylcarbamoyloxy, ethyl or dimethylcarbamoyloxy, ethyl or diethylcarbamoyloxy, 2-chloroethylcarbamoyloxy, 2-acetoxyethylcarbamoyloxy, respectively methyl or dimethylcarbamoylthio.

Etherated hydroxy or mercapto R2 is etherified e.g.

with an aliphatic hydrocarbon residue, and is, for example, lower alkoxy with 1-4 C atoms, e.g. methoxy or ethoxy, or lower alkylthio with 1-4 C atoms, e.g. methylthio.

Etherated mercapto R 2 is preferably unsubstituted or substituted, monocyclic, aromatic or bicyclic, aromatic or partially saturated heterocyclylthio, which contains at least one C atom and is connected to the sulfur by one of its C atoms, e.g. monocyclic, aromatic, heterocyclylthio with 1-4 nitrogen atoms or with one oxygen or sulfur atom and optionally 1-3 nitrogen atoms, containing 5 or 6 ring atoms, containing an aromatic heterocyclylthio with 1-5 nitrogen atoms and optionally one oxygen or sulfur atom, containing 5 or 6 atoms per ring.

The heterocyclic radical in the heterocyclylthio group R2 is particularly unsubstituted or substituted, monocyclic, aromatic, 5- or 6-membered diaza-, triaza-, tetraza-, thiaza-, thiadiaza-, thia-, oxaza- or oxadiazacyclyl or unsubstituted or substituted bicyclic , aromatic, aza-, diaza-, triaza-, tetraza-, pentaza-, thiaza- or oxazabicyclyl containing 5 or 6 ring atoms per ring.

Substituents on these heterocyclic residues are, for example, lower alkyl, e.g. ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl, especially methyl, which may be substituted for example with hydroxy, esterified hydroxy, e.g. lower alkanoyloxy, e.g. acetoxy, or halogen, e.g. fluorine or chlorine, lower alkylphosphonyl, e.g. methyl-

or ethylphosphonyl, diaverealkylphosphonyl, e.g. dimethyl or diethylphosphonyl, carboxy, sulfo, esterified carboxy, e.g. lower alkoxycarbonyl, e.g. ethoxycarbonyl, sulfoamino, sulfamoyl, amino, lower alkylamino, e.g.

methyl- or ethylamino, dilaverealkylamino, e.g. dimethylamino or diethylamino, acylamino, e.g. lower alkanoylamino, e.g. acetylamino, or with carboxy or halogen, e.g. chlorine, substituted lower alkanoylamino, e.g. carboxy-acetylamino or chloroacetylamino, cyan, as well as tetrazolyl, e.g. 1H-tetrazol-5-yl.

Such substituted lower alkyl residues are, for example, hydroxyl lower alkyl, e.g. hydroxymethyl (bonded to a C atom) or 2-hydroxyethyl, acetoxy lower alkyl, e.g. acetoxymethyl or 2-acetoxyethyl, halolower alkyl,

e.g. chloromethyl, 2-chloroethyl, 2,2,2-trichloroethyl or trifluoromethyl, lower alkylphosphonolower alkyl, e.g. ethylphosphonomethyl, dilaverealkylphosphonolaverealkyl, e.g. diethylphosphonomethyl, carboxy-lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, lower alkoxycarbonyllower alkyl, e.g. ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, sulfamoyl-lower alkyl, e.g. sulfamoylmethyl or 2-sulfamoylethyl, amino lower alkyl, e.g. aminomethyl (bonded to a C atom), or 2-aminoethyl, lower alkylaminolower alkyl, e.g. 2-methylaminoethyl, diloweralkylaminoloweralkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, lower alkanoyl-aminolower alkyl, e.g. 2-acetylaminoethyl, carboxyl lower-alkanoylamino lower alkyl, e.g. 3-carboxypropionylaminoethyl or 2-carboxyacetylaminoethyl, or halolower alkanoyl-aminolower alkyl, e.g. 3-chloropropionylaminoethyl or 2-chloroacetylaminoethyl, as well as tetrazolyl lower alkyl, e.g. 1H-tetrazol-5-ylmethyl or 2-(1H-tetrazol-5-yl)-ethyl.

Further substituents on the heterocyclic moiety are lower alkenyl, e.g. vinyl or allyl, aryl, e.g. phenyl, or halogen, e.g. fluorine, chlorine or bromine, as well as amino bonded to a C atom of the heterocyclic residue, substituted amino, e.g. amino which is mono- or disubstituted with lower alkyl, e.g. methyl or ethyl,

e.g. methylamino or dimethylamino, acylamino, e.g., lower alkanoylamino, e.g. acetylamino, or lower alkylsulfonylamino, e.g. mesylamino, or lower alkanoylamino substituted with halogen, e.g. chlorine, or carboxy, e.g. 3-chloropropionylamino or 3-carboxypropionylamino, nitro, hydroxy, lower alkoxy, e.g. methoxy or ethoxy, carboxy, esterified carboxy-, e.g. lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, amidated carbonyl, e.g. carbamoyl, mono- or di-lower alkylcarbamoyl, e.g. methylcarbamoyl or dicarbamoyl, or cyan, as well as oxo or oxido.

Unsubstituted or substituted monocyclic aromatic five-membered heterocyclylthio is preferably -imidazo lylthio, e.g. imidazol-2-ylthio, triazolylthio, e.g. 1H-1,2,3-triazol-4-ylthio or 1H-1,2,4-triazol-3-ylthio, triazolylthio which is substituted with lower alkyl, e.g. methyl, and/or phenyl, e.g. 1-methyl-1H-1,2,3-triazol-4-ylthio, 5-methyl-1H-1,2,4-triazol-3-ylthio or 4,5-dimethyl-1,2,4-triazol- 3-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl or ethyl, or substituted lower alkyl, e.g. ethyl or diethylphosphonomethyl, carboxymethyl, 2-carboxyethyl, sulfomethyl, 2-sulfoethyl, 2-dimethylaminoethyl, cyanomethyl, or tetrazolylmethyl, e.g. 1-methyl-1H-tetrazol-5-yl-thio, 1-ethyl- or 1-diethylphosphonyImethyl-1-1H-tetrazol-5-yl-thio, 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-cyanomethyl-1H-tetrazol-5-ylthio or 1-(1H-tetrazol-5-ylmethyl)-1H-tetrazol-5-ylthio, thiazolylthio, e.g. thiazol-2-ylthio, or thiazolylthio which is substituted with carboxyl lower alkyl, e.g. carboxymethyl, and/or lower alkyl, e.g. methyl, e.g. 4-methyl-5-carboxymethyl-thiazol-2-ylthio or 4,5-dimethylthiazol-2-ylthio, isothiazolylthio, e.g. isothiazole-3-, -4- or

-5-ylthio, thiadiazolylthio, e.g. 1,2,3-thiadiazole-4-

or -5-ylthio or 1,3,4-thiadiazol-2-ylthio, 1,2,4-thiadiazol-3- or -5-ylthio, or 1,2,5-thiadiazol-3-ylthio, thiadiazoly lthio as is substituted with eth-lower alkyl, e.g. methyl, e.g. 2-methyl-1,3,4-thiadiazol-5-ylthio, thiatriazolylthio, e.g. 1,2,3,4-thiatriazol-5-ylthio, oxazolylthio, e.g. oxazol-2-, -4- or -5-ylthio, oxazolylthio which is substituted with a lower alkyl,

e.g. methyl, e.g. 4-methyloxazol-5-ylthio, isoxazolylthio substituted with a lower alkyl, e.g. methyl, e.g. 3-methyl-5-isoxazolyl-thio, oxadiazolylthio e.g. 1,2,4-oxadiazolylthio, or oxadiazolylthio substituted with lower alkyl, e.g. methyl, e.g. 2-methyl-1,3,4-oxadiazol-5-ylthio.

Unsubstituted or substituted, monocyclic, aromatic, six-membered heterocyclylthio is preferably 5,6-dioxo-tetrahydro-as-triazinylthio which may be substituted with a lower alkyl, e.g. methyl, carboxyl lower alkyl, e.g. carboxymethyl, or with sulpholower alkyl, e.g. sulfomethyl, e.g. 1- or 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro -as-triazin-3-ylthio, 1- or 2-carboxymethyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-carboxymethyl-5,6-dioxo- 1,4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-sulfomethyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4 -sulfomethyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio and tautomeric compounds thereof.

Unsubstituted or substituted, bicyclic, aromatic heterocyclylthio containing five or six ring atoms per ring is preferably indolylthio, with a lower alkyl,

eg methyl, substituted indolylthio, eg indole-2-

ylthio or N-methylindol-2-ylthio, isoindolylthio, e.g. isoindol-2-ylthio, quinolylthio, e.g. quinol-2-, -4-

or -8-ylthio, benzimidazolylthio, with lower alkyl,

e.g. methyl, or carboxy-lower alkyl, e.g. carboxymethyl, substituted benzimidazolylthio, e.g. 1-methyl-, 1-carboxymethyl- or 1-(2-carboxyethyl)-benzimidazol-2-ylthio, benztriazolylthio, with lower alkyl, e.g.

methyl, or carboxy-lower alkyl, e.g. carboxymethyl, substituted benztriazolylthio, e.g. 1-methyl- or 1-carboxymethyl-1H-benzo(d)-triazol-5-ylthio, tetrazolo-pyridazinylthio or with lower alkyl, e.g. methyl or ethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, dilower alkylcarbamoyl, e.g. dimethylcarbamoyl, amino, lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino or diethylamino, substituted tetrazolo-pyridazinylthio, e.g. 8-methyl-, 8-ethyl-, 8-carboxy-, 8-carboxymethyl-, 8-(2-carboxyethyl)-, 8-carbamoyl-, 8-methylcarbamoyl-, 8-dimethylcarbamoyl-, 8-amino-, 8 -dimethylamino-or 8-diethylaminotetrazolo-(1,5-b)pyridazin-6-ylthio.

An ammonium group R2 is derived from a tertiary, aliphatic or an aromatic nitrogen base, the respective base being bound with its nitrogen atom to the methylene group which is in the 3-position in the cephem skeleton.

An ammonium group R2 derived from a tertiary, aliphatic nitrogen base is e.g. trilower alkylammonio, e.g. trimethyl or triethylammonio.

An ammonium group R2 derived from an aromatic nitrogen base is formed, e.g. of an unsubstituted or substituted, aromatic heteroring with 1-3 nitrogen atoms and a total of 5 or 6 ring atoms and is, for example, 1-pyrazolio, with a lower alkyl, e.g. methyl or ethyl, lower alkenyl, e.g.

vinyl or allyl, carboxy lower alkyl, e.g. carboxymethyl, lower alkoxycarbonyl lower alkyl, e.g. methoxycarbonylmethyl, sulpholower alkyl, e.g. sulfomethyl, amino lower alkyl, e.g. 2-aminoethyl, or diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, in the 2-position substituted 1-pyrazolio, e.g. 2-methyl- or 2-ethyl-1-pyrazolium, 2-allyl- or 2-vinyl-1-pyrazolium, 2-sulfomethyl-1-pyrazolium, 2-(2-aminoethyl)-1-pyrazolium or 2-(2 -dimethylaminoethyl)-1-pyrazolio, 1-triazolio, with lower alkyl, e.g. methyl or ethyl, carboxyl lower alkyl, e.g. carboxymethyl or diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, in the 3-position substituted 1-triazolium, e.g. 3-methyl-1-triazolium, 3-carboxymethyl-1-triazolium or

3-(2-dimethylaminoethyl)-1-triazolio, pyrazinio, pyrimidino, pyridazinio or with lower alkyl, e.g. methyl, halogen, e.g. chlorine, amino, lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino, hydroxyl-lower alkylamino, e.g. 2-hydroxyethylamino, or dihydroxy-lower alkylamino, e.g. di-(2-hydroxyethyl)-amino, substituted pyrazinio, pyrimidinio, or pyridazinio, e.g. 2- or 3-methyl-, 2- or 3-chloro-, 2- or 3-amino- or 2- or 3-di-(2-hydroxyethyl)-aminopyrazinium, 2-methyl-pyrimidinio, 3-methylpyridazinio or 3 -chlorpyridazinio.

That of an aromatic heteroring with 1-3. nitrogen atoms and

the combined 5 or 6 ring atoms derived the ammonium group R ? is preferably pyridinium or with a lower alkyl, e.g. methyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, hydroxyl lower alkyl, e.g. hydroxymethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, cyano-lower alkyl, e.g. cyanomethyl, carboxyl lower alkyl, e.g. carboxymethyl, sulpholower alkyl, e.g. 2-sulfoethyl, carboxyl alkenyl, e.g. 2-carboxyvinyl, carboxy-lower alkylthio, e.g. carboxymethylthio, thiocarbamoy1, halogen, e.g. bromine or chlorine, carboxy, sulfo or cyano mono- or disubstituted pyridinio, e.g. lower alkylpyridinio, e.g. 2-, 3- or 4-methylpyridinium or 2-, 3- or 4-ethylpyridinium, carbamoylpyridinium, e.g. 3- or 4-carbamoylpyridinio, lower alkylcarbamoyl-

pyridinium, e.g. 3- or 4-dimethylcarbamoylpyridinio, diaverealkylcarbamoylpyridinio, e.g. 3- or 4-dimethylcarbamoylpyridinium, hydroxyl lower alkylpyridinium, e.g.

3- or 4-Hydroxymethylpyridinio, lower alkoxy lower alkylpyridinio, e.g. 4-methoxymethylpyridinio, cyano-lower alkylpyridinio, e.g. 3-cyanomethylpyridinio, carboxyl lower alkylpyridinio, e.g. 3-carboxymethylpyridinio, sulfo-lower alkylpyridinio, e.g. 4-(2-sulfoethylpyridinio), carboxyl alkenylpyridinio, e.g. 3-(2-carboxyvinyl)-pyridinio, carboxyl lower alkylthiopyridinio, e.g. 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, e.g. 4-thiocarbamoylpyridinium, halopyridinium, e.g. 3-bromo- or 4-bromopyridinio, carboxypyridinio, e.g. 3- or 4-carboxypyridinio, sulphopyridinio, e.g. 3- or 4-sulfopyridinium, cyanopyridinium, e.g. 3-cyanopyridinio, carboxyl lower alkylcarbamoylpyridinio, e.g. 3-carboxymethyl-4-carbamoylpyridinio, aminocarbamoylpyridinio, e.g. 2-amino-5-carbamoylpyridinium, carboxycarbamoylpyridinium, e.g. 3-carboxy-4-carbamoylpyridinium, cyanohalomethylpyridinium, e.g. 3-cyano-4-trifluoromethylpyridinio, amino-carboxypyridinio, e.g. 2-amino-3-carboxypyridinio, or with lower alkoxy-imino lower alkyl, e.g. methoxyiminomethyl or 1-methoxyiminoethyl, monosubstituted pyridinio, e.g. 3- or 4-methoxyiminoethylpyridinio or 3- or 4-(1-methoxyiminoethyl)-pyridinio.

The ammonio group R2 derived from an aromatic nitrogen base, e.g. pyridinium, can also be disubstituted with the lower alkylene, e.g. ethylene, 1,3-propylene or 1,4-butylene, or lower alkenylene, e.g. 1,3-propylene or 1,4-but-1- or but-2-enylene. These substituents can in turn be substituted with hydroxy, lower alkoxy, e.g. methoxy, or halogen, e.g. chlorine. Such an ammonium group is, for example, 3,4- or preferably 2,3-cyclobuteno-, -cyclopenteno- or -cyclohexenopyridinium.

The ammonio group R2 derived from an aromatic nitrogen base, e.g. pyridinium, can also be condensed with a 5- or 6-membered, saturated or unsaturated, e.g. partially saturated or aromatic heteroring, e.g. with tetrahydro-pyran or -furan, dihydropyran or -furan, pyran,

furan or thiophene, as well as with benzene.

Pyridinium condensed with benzene is e.g. quinolium

or isoquinolinium, which may be substituted with amino,. lower alkylamino, e.g. methylamino, diaverealkyl-

amino, e.g. dimethylamino, hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, lower alkyl, e.g. methyl, cyan, trifluoromethyl, sulfo, sulfamoyl, carboxy, lower alkoxycarbonyl, e.g. ethoxycarbonyl, hydroxy lower alkyl, e.g. hydroxymethyl, lower alkanoyl, e.g. formyl or acetyl, thiocarbamoyl, carbamoyl, or lower alkoxyiminolower alkyl, e.g. methoxyiminomethyl or 1-methoxyiminoethyl, such as e.g. 3-, 4-, 5-, or 7-aminoquinolinium or -isoquinolinium, 3-, 4-, 5- or 7-hydroxyquinolinium or -isoquinolinium, 3-, 4- or 5-methylquinolinium or -isoquinolinium, 3-, 4 - or 5-carbamoylquinolinium or -isoquinolinium, 3-, 4-

or 5-methoxyiminoquinolinium or -isoquinolinium or 3-, 4- or 5-(1-methoxyiminoethyl)-quinolinium or

-isoquinolinium.

An ammonium group R2 is primarily pyridinium or with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, carbamoyl or lower alkylene substituted as well as benzene-condensed pyridinium, e.g. 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio,

3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, 2,3-cyclopentenopyridinium or quinolium.

In a group of formula -CH=CH-R2, the preferred mercapto group R2ce has previously mentioned meanings, e.g. heterocyclylthio, and means preferably with lower alkoxy, e.g. methoxy, substituted 5,6-dioxotetrahydro-as-triazinylthio, e.g. 4-Methoxy-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio.

Protected carboxy R^ is carboxy esterified with

one of the carboxy protecting groups described below, particularly under physiological conditions cleavable, esterified carboxy.

A cleavable under physiological conditions, esterified carboxy group R is primarily an acyloxylave-alkylcarbonyl group, where acyl, e.g. the acyl group in an organic carboxylic acid means a carboxylic acid monoester or an amino acid, or where acyloxylavereal oxy, e.g. acyloxymethoxy, forms a lactone residue.

Acyl is preferably the acyl group of an optionally branched lower alkane carboxylic acid, the acyl group of the optionally branched lower alkyl monoesterified carboxylic acid or the acyl group of an optionally branched α-amino lower alkane carboxylic acid.

Under physiological conditions, cleavable, esterified carboxy R 1 is preferably lower alkanoyloxylavereal oxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethoxycarbanoy 1 , e.g. acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, lower alkoxycarbonyloxylavereal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert-butoxycarbonyloxymethoxycarbonyl, aminolower alkanoylmethoxycarbonyl, especially α-aminolower alkanoyloxymethoxycarbonyl, e.g. glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl1, further

phthaLidy oxycarbonyl, e.g. 2-phthalidyloxycarbonyl,

or indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl.

Heterocyclyl R 4 is bound to the 2-C atom in the 7g side chain with one of its C atoms and is, for example, unsubstituted or substituted, aromatic, monocyclic oxaza-,

thiaza-, diaza-, thiadiaza-, triaza- or tetrazacyclyl, e.g. oxazolyl, e.g. oxazol-4-yl, thiazolyl, e.g. thiazol-4-yl, isothiazolyl, e.g. isothiazole-3- or

-4-yl, imidazolyl, e.g. imidazol-4-yl, thiadiazolyl,

e.g. 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, or 1,3,4-thiadiazol-2-yl, triazolyl, e.g. 1,2,4-triazol-3-yl, or tetrazolyl, e.g. tetrazol-5-y1.

Substituents on the heterocyclyl radical R 2 are the same substituents as mentioned above for the heterocyclylthio group R 2 .

Heterocyclyl R 1 is preferably aminooxazolyl, e.g. 2-aminooxazol-4-yl, aminothiazolyl, e.g. 2-aminothiazol-4-yl, aminoimidazoly1, e.g. 2-aminoimidazol-4-y1, aminothiazolyl, e.g. 5-amino-1,2,4-thiadiazol-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl,

or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-y1.

The functional groups present in the compound

with formula I, in particular the carboxy, amino, hydroxy and sulfo group, is optionally protected with such protective groups (conventional protective groups) as are usually used in penicillin, cephalosporin and peptide chemistry, and which on cleavage give the 2-formamido group. These protective groups must protect the relevant functional groups against unwanted side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis, etc., and be easily desolvable under gentle reaction conditions, i.e. under avoidance of cleavage, e.g. solvolytic, reductive, photolytic or also enzymatic cleavage, as well as other side reactions.

The protection of functional groups with such

protective groups, the protective groups themselves, as well as their cleavage reactions are written, for example, in "Protective Groups in Organic Chemistry", Plenum Press,

London und New York 1973, in Greene, Th.W. "Protective

Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Vol. I, Schroder and Lubke, Academic Press,

London und New York 1965, as well as in "Methoden der organischen Chemie", Houben.Weyl, 4th Auflage, Bd. 15/1 Georg Thieme Verlag, Stuttgart 1974.

A carboxy group, e.g. the carboxy group R^, moreover

a carboxy group present in R2 is usually protected in esterified form, the ester group being selectively cleavable under gentle conditions. A carboxy group protected in esterified form is primarily esterified with a lower alkyl group, which is branched in the lower alkyl group's 1-position or is substituted in the lower alkyl group's 1- or 2-position with suitable substituents.

A protected carboxy group which is esterified with a branched lower alkyl group in the 1-position is, for example, tert-lower carboxycarbonyl, e.g. tert-butoxycarbonyl, arylmethoxycarbonyl,

with one or two aryl residues, where aryl means preferably unsubstituted or e.g. with a lower alkyl, e.g. tert-lower alkyl, e.g. tert-butyl, lower alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono-, di- or tri-substituted phenyl, for example benzyloxycarbonyl, with the aforementioned substituents substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted with the aforementioned substituents, fke.s de-(4-methoxy-phenyl)-methoxycarbonyl.

A protected carboxy group, which is esterified with a lower alkyl group substituted in 1- or 2-side addition with suitable substituents, is for example 1-lower alkyllower alkylcarbonyl, e.g. methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthiolaverealkboxycarbonyl, e.g. 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, such as 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl.

A carboxy group can also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, trilower alkylsilyloxycarbonyl, e.g. trimethylsilyloxycarbonyl. The silicon atom in the silyloxy-carbonyl group can also be substituted with two lower alkyl groups, e.g. methyl groups, and the carboxy group elides the amino group to another molecule with formula I. Compounds with such protective groups can be prepared, e.g.

using dimethyldichlorosilane as silylating agent.

A protected carboxy group is preferably tert-lower carboxycarbonyl, e.g. tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl1.

An amino group, e.g. in R2 and R. amino groups present, can e.g. be protected in the form of an acylamino, etherified mercaptoamino or silylamino group that can be selectively cleavable under mild conditions, or as an azido group.

In an easily cleavable acylamino group, acyl is, for example, the acyl group from an organic carboxylic acid with up to 10 carbon atoms, especially an unsubstituted one or one, e.g.

with halogen or aryl, substituted lower alkanecarboxylic acid or the unsubstituted or, e.g. with a halogen, lower alkoxy or nitro, substituted benzoic acid, or a carboxylic acid half-ester.

Such an acyl group is, for example, halogen-lower alkanoyl, e.g. 2-Haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl or e.g. with halogen,

e.g. chlorine, lower alkoxy, e.g. methoxy, or nitro-substituted benzoyl, e.g. benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, or 4-nitrobenzoyl, or in the 1-position of the lower alkyl radical branched or in the 1- or 2-position with suitable substituents substituted lower alkoxycarbonyl.

In the 1-position of the lower alkyl radical, branched lower alkoxycarbonyl is, for example, tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl (BOC), arylmethoxycarbonyl with one or two aryl residues, where aryl means preferably unsubstituted or e.g. with lower alkyl, especially tert-lower alkyl, e.g. tert-butyl, lower alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono-, di- or tri-substituted phenyl, for example diphenylmethoxycarbonyl or di(4-methoxyphenyl)-methoxycarbonyl1.

Lower oxycarbonyl which is substituted in 1- or 2-

position with suitable substituents is, for example, aroylmethoxycarbony1, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-ethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, where the silyl group is substituted with organic residues, e.g. lower alkyl, phenyl lower alkyl or phenyl, for example 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)-ethoxycarbonyl, or 2-triphenylsilylethoxycarbonyl1.

In an etherified mercaptoamino group, the etherified mercapto group is primarily arylthio, e.g. 4-nitrophenylthio.

A silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. trimethylsilylamino. The silicon atom in the silylamino group can also be substituted with bare

2-lower alkyl groups, e.g. methyl groups, and amino-

group or the carboxyl group in a second molecule of formula I. Compounds with such protective groups can be prepared, e.g. using dimethyldichlorosilane as silylating agent.

An amino group can also be protected in protonated form. As anions, the anions are primarily of strong inorganic side, such as hydrohalic acids, e.g. the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acids, suitable.

A protected amino group is preferably tert-butoxycarbonylamino (BOC), 4-nitrobenzyloxycarbonylamino, diphenylmethoxycarbonylamino, or 2-halolower oxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino.

A hydroxy group, e.g. an R2 present hydroxy group can, for example, be protected with an acyl group, e.g. with halogen, substituted lower alkanoyl, e.g. 2,2-dichloroacetyl, or in particular with an acyl residue of a carboxylic acid half-ester mentioned for protected amino groups.

A preferred hydroxy protecting group is, for example, 2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl,

an organic silyl radical with the previously mentioned substituents, e.g. trimethylsilyl or dimethyl-n-butylsilyl, furthermore an easily cleavable, etherified group, such as tert-lower alkyl, e.g. tert-butyl, an oxa- or a thialiphatic or

-cycloaliphatic hydrocarbon residue, for example 1-lower alkyl lower alkyl or 1-lower alkyl thiol lower alkyl, e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthiethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl with 5-7 ring atoms, e.g. 2-tetrahydro-furyl or 2-tetrahydropyranyl, or a corresponding thia analogue, as well as 1-phenyl lower alkyl, e.g. benzyl or diphenyl-methyl, the phenyl residue may be substituted, for example

with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro.

A sulfo group, e.g. one in present sulfo group,

is preferably protected with a tert-lower alkyl group,

e.g. tert-butyl, or with a silyl group, e.g. with trilower alkylsilyl. A sulfo group can be protected e.g. with the same protecting groups as the carboxy group.

Salts are primarily the pharmaceutically acceptable or usable non-toxic salts of compounds of formula I.

Such salts are formed, for example, by those in connection with

formula I present acidic groups, e.g. carboxy or sulfo groups, and are primarily metal or ammonium salts, for example alkali metal and alkaline earth metal,

e.g. sodium, potassium, magnesium or calcium salts,

as well as ammonium salts which are formed from ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases for salt formation. Such bases are, for example, lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamine, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethyl-aminoethyl ester, lower alkyl amines, e.g. 1-ethylpiperidine, cycloalkylamine,

e.g. dicyclohexylamine, or benzylamines, e.g. N,N1 - di-benzylethylenediamine, also pyridine-type bases, e.g. pyridine, collidine or quinoline.

Basic groups present in connection with formula I, e.g. amino groups, can form acid addition salts, e.g.

with inorganic acids, e.g. mineral acids, such as hydrochloric acid,

sulfuric acid or phosphoric acid, or with suitable organic carboxylic acids or sulphonic acids, e.g. unsaturated carboxylic acids, e.g. fumaric or maleic acids, hydroxy acids, e.g., lactic, tartaric or citric acids, or aromatic acids, e.g. salicylic acid, as well as with amino acids, such as arginine and lysine, used.

If in connection with formula I there are several

acidic groups, e.g. two carboxy groups, or several basic groups, e.g. two amino groups, mono- or poly-salts can be formed. When the compound of formula I has at least one acidic group, e.g. the free carboxy group, and at least one basic group, e.g. an amino group in , these can exist in the form of internal salts, i.e. in zwitterionic form. In connection with formula I, an acidic and a basic group can be present in the form of an internal salt and further acidic and/or basic groups, for example as acid addition and/or base addition salts.

Pharmaceutically unsuitable salts can also be used for isolation or purification. For therapeutic use, only pharmaceutically usable, non-toxic salts are used, which are therefore preferred.

The compounds of formula I, where the functional groups are present in free form and the carboxyl groups are possibly present in physiologically cleavable esterified form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotically active compounds, which can particularly be used as anti-bacterial antibiotics.

For example, they are effective in vitro against gram-positive and

gram negative microorganisms, including 8-lactamase-producing strains, e.g. against cocci such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Neisseria gonorrhoeae in minimal concentrations from approx. 0.001 to approx. 16 ug/ml, against enterobacteria, e.g. against

Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Proteus spp., Enterobacter cloacae,

Serratia marcescens, Haemophilus influenzae, and Pseudomonas aeruginosa, and against anaerobic gram-positive and gram-negative bacteria, e.g. Bacteroides fragilis or Clostridium perfringens, in minimal concentrations from approx. 0.001 to approx.

8 ug/ml.

In the test report below, the effect of compounds of formula I is shown using selected compounds.

Trial report

I. Test Compounds:

1. The sodium salt of 3-acetoxymethyl 1-7 6- (2R,S)-2-(2-aminothiazol-4-yl)-2-formamido-acetamido)-3-cephem-4-carboxylic acid. 2. The sodium salt of 3-carbamoyloxymethyl 1-73-[(2S)-2-(2-aminothiazol-4-yl)-2-formamido-acetamido-3-cephem-4-carboxylic acid]. 3. The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7$-£(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido - 3-ce f em-4-carboxy ls yre). 4. The sodium salt of 3-(1,2,3-thiadiazol-5-ylthiomethyl)-73-[(2S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido-3-cef em-4- carboxylic acid

II. Experimentally:

A. The antibiotic activity of the test compound in vitro was examined by the agar dilution method of Ericsson, H.M., and Sherris, S.C., 1971, Acta Path. Microb. Scand. Section B, Suppl. No. 217, Vol. 1 - 90, in DST agar. The minimum inhibitory concentration (MIC = minimum inhibitory concentration) found/for the growth of the test organisms is stated in micrograms per ml (ug/ml) for the investigated compounds in Table 1.

III Test results:

Compounds of formula I, where the functional groups are protected, are used as starting materials for the production of compounds of formula I where functional groups are present in free form or in physiologically cleavable form.

The present invention preferably relates to such compounds of formula I where the functional groups are present in free form or in physiologically cleavable protected form, and their pharmaceutically acceptable salts, according to which these compounds mainly have the indicated effect, and can be used for the indicated purposes.

The invention preferably relates to compounds of formula I where m is zero, R., is hydrogen, lower alkyl, lower alkoxy, halogen or a group of formula -CH2-R2/where R2 is lower alkanoyloxy, carbamoyloxy, unsubstituted or substituted, monocyclic, aromatic or bicyclic, aromatic or partially saturated heterocyclylthio, containing at least one C atom and connected by one of its C atoms to the sulphur, azido or ammonio derived from a tertiary,

aliphatic or of an aromatic nitrogen base, R-, is carboxy or under physiological conditions cleavable, esterified carboxyl and R^ is unsubstituted or substituted, monocyclic, .aromatic oxaza-, thiaza-, diaza-, thidiaza-, triaza- or tetrazacyclyl, as well pharmaceutically acceptable salts of such compounds with salt-forming groups.

The invention relates in particular to compounds of formula I

where m is zero and R^ is hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, or a group of formula -Cf^-F^where R2 means lower alkanoyloxy,

e.g. acetoxy, carbamoyloxy, unsubstituted or substituted, monocyclic, aromatic, five or six ring atoms containing heterocyclylthio with 1 - 4 nitrogen atoms or with an oxygen or sulfur atom and optionally 1 - 3 nitrogen atoms or bicyclic, aromatic, five or six atoms per ring containing heterocyclylthio with 1 - 5 nitrogen atoms and optionally one oxygen or sulfur atom, azido or an ammonio group which is formed from an unsubstituted or substituted aromatic heteroring with 1 - 3 nitrogen atoms and a total of 5 or 6 ring atoms, R^ is carboxy or acyloxyvarealoxycarbonyl and R ^is unsubstituted or substituted oxazolyl, thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, triazolyl or tetrazolyl, as well as pharmaceutically acceptable salts of such compounds with salt-forming groups.

Emphasis should be placed on compounds with formula I where m is zero and

R^ is hydrogen or a group of formula -Cr^-F^/where

R2 means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, diaza-, triaza-, tetraza-, thiaza-, thiadiaza-, oxaza- or oxadiazacyclylthio, which may be substituted with lower alkyl, e.g. methyl, dilower alkylaminolower alkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, sulfolavera-

alkyl, e.g. sulfomethyl or 2-sulfoethyl, carboxyl lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, carbamoyl, cyano-lower alkyl, e.g. cyanomethyl, tetrazoyl lower alkyl, e.g. 1H-tetrazol-5-ylmethyl, or with oxo, azido, pyridinio, with lower alkyl, e.g. methyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, hydroxy lower alkyl, e.g. hydroxymethyl, lower alkyl lower alkyl, e.g. methoxymethyl, cyano-lower alkyl, e.g. cyanomethyl, carboxy lower alkyl, e.g. carboxymethyl, sulpholower alkyl, e.g. 2-sulfoethyl, carboxylave alkeny1, e.g. 2-carboxyvinyl, carboxyl lower alkylthio, e.g. carboxymethylthio, thiocarbamoyl, halogen, e.g. bromo or chloro, carboxyl, sulfo or cyano mono- or disubstituted pyridinium, with lower alkoxyimino lower alkyl, e.g. methoxyiminomethyl or 1-methoxyiminoethyl, or lower alkylene, e.g. ethylene, 1,3-propylene or 1,4-butylene, monosubstituted pyridinio or benzene-condensed pyridinio, R3 denotes carboxy, lower alkanoyloxylavereal oxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl, or loweralkanoyloxyethoxycarbonyl, e.g. acetoxymethoxycarbonyl, pivaloylmethoxycarbonyl or 1-propionyloxyethoxycarbonyl, lower alkyloxycarbonyl, e.g. 1-ethoxycarbonyl-1-oxyethoxycarbonyl or tert-butoxycarbonyloxymethoxycarbonyl, R 4 means aminooxasolyl, e.g. 2-aminooxyazol-4-yl, aminothiazolyl, e.g. 2-aminothiazol-4-y1, aminothiadiazolyl,

e.g. 5-amino-1,2,4-thiadiazol-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-yl, and pharmaceutically acceptable salts of such compounds.

The present invention mainly relates to compounds of formula I where m is zero and R^ means hydrogen or a group of formula -CH 2 -R 2 , where R 2 means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, imidazolylthio, e.g. imidazol-2-ylthio, triazolylthio, e.g. 1H-1,2,3-triazole-4-

ylthio, or 1H-1,2,4-triazol-3-ylthio, with lower alkyl,

e.g. methyl, substituted triazolylthio, e.g. 1-methyl-1H-1,2,3-triazol-4-ylthio, 5-methyl-1H-1,2,4-triazol-3-

ylthio or 4,5-dimethyl-1,2,4,triazol-3-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, carboxyl alkyl, e.g. carboxymethyl or 2-carboxyethyl, carbamoyl, cyano lower alkyl or with tetrazoly lower alkyl, e.g. 1H-tetrazol-5-ylmethyl, substituted tetrazolylthio, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-(2-carboxyethyl)-1H-tetrazo1-5-ylthio, 1-sulfomethyl-1H-tetrazo1-5- ylthio, 1-(2-sulfoethyl)-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-cyanomethyl-1H-tetrazol-5-ylthio, or 1-( 1H-tetrazol-5-ylmethyl)-1H-tetrazol-5-ylthio, thiazolylthio, e.g. thiazol-2-ylthio, or with carboxyl lower alkyl, e.g. carboxymethyl, and/or lower alkyl, e.g. methyl, substituted thiazolylthio, e.g. 4-methyl-5-carboxymethylthiazol-2-ylthio or 4,5-dimethylthiazol-2-ylthio, isothiazolylthio, e.g. isothiazol-3-, -4- or -5-ylthio thiadiazolylthio, e.g. 1.2.3- thiadiazol-3- or -5-ylthio, 1,3,4-thiadiazol-2-ylthio, 1.2.4- thiadiazol-3- or -5-ylthio or 1,2,5-thiadiazol-3- ylthio, with lower alkyl, e.g. methyl, substituted thiadiazolylthio, e.g. 2-methyl-1,3,4-thiadiazol-5-ylthio, thiatriazolylthio, e.g. 1,2,3,4-thiatriazol-5-ylthio, oxazolylthio, e.g. oxazol-2-, -4- or -5-ylthio, with lower alkyl, e.g. methyl, substituted oxazolylthio, e.g. 4-methyloxazol-5-ylthio,

with lower alkyl, e.g. methyl, substituted isoxazolylthio, e.g. 3-methylisoxazol-5-ylthio, oxadiazolylthio, e.g. 1,2,4-oxadiazol-5-ylthio, or with lower alkyl, e.g. methyl, substituted oxadiazolylthio, e.g. 2-methyl-1,3,4-oxadiazol-5-ylthio, with lower alkyl, e.g. methyl, substituted 5,6-dioxo-tetrahydro-as-triazin-3-ylthio, e.g. 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio, or 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as -triazin-3-ylthio, azido, pyridinio or med

hydroxy lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g.

chlorine or bromine, carbamoyl or lower alkylene, e.g. 1,3-propylene, substituted or with benzene, condensed pyridinium, e.g. 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio,

3- or 4-chloropyridinio, 3- or 4-bromo-pyridinio, 3-

or 4-carbamoylpyridinio, 2,3-cyclopentenopyridinio or quinolinio, R₂carboxy, lower alkanoyloxylaverealoxy-r carbonyl, e.g. lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethoxycarbanyl, e.g. acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert-butoxycarbonyloxymethoxycarbonyl, and means aminooxazol-4-yl, aminothiazoly1, e.g. 2-aminothiazole-4-

yl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazol-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-y1, stereoisomers, mixtures of these stereoisomers and pharmaceutically acceptable salts of such compounds.

The present invention primarily relates to compounds of formula I where m is zero and R 1 means hydrogen or a group of formula -CH-R 2 , where R 2 means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, triazolylthio, e.g. 1H-1,2,3-triazol-4(5)-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl or carboxy-lower alkyl, e.g. carboxymethyl, substituted tetrazolylthio, e.g. 1-methyl-1H-tetrazo1-5-ylthio,1-(2-dimethylaminoethyl)-1H-tetrazo1-5-ylthio, 1-sulfomethyl-1H-tetrazol-5-ylthio or 1-carboxymethyl-1H-tetrazol-5 -ylthio, thiadiazolylthio, e.g. 1,2,3-thiadiazol-4-or -5-ylthio, 1,3,4-thiadiazol-2-ylthio, 1,2,4-thiadiazol-3-or -5-ylthio, or 1,2,5 -thiadiazol-3-ylthio, with lower alkyl, e.g. methyl, substituted 5,6-dioxo-tetrahydro-as-triazinylthio, e.g. 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as- triazin-3-ylthio, azido, pyridinio or with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine,

carbamoyl or lower alkylene, e.g. 1,3-propylene,

substituted or with benzene condensed pyridinio, e.g.

3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio,

3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio,

3- or 4-bromopyridinio, 3- or 4-carbamoylpyridinio, 2,3-cyclopentenopyridinio or quinolinio means carboxy, lower alkanoyloxylavereal oxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonylethoxycarbonyl or tert-butoxycarbonyloxymethoxycarbonyl, and R^aminoaxazolyl,

e.g. 2-aminooxazol-4-yl, aminothiazolyl, e.g. 2-aminothiazol-4-yl, or aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazol-3-yl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically acceptable salts of such compounds.

The invention relates in particular to the compounds of formula 1 described in the examples, their pharmaceutically usable salts, as well as the starting compounds and intermediates described there.

Manufacturing Procedures:

Compound with formula 1, where the carboxy group is present

in free form is esterified in a physiologically cleavable form,

hydrates and salts of such compounds are prepared, for example, by

a) in a connection with formula

where ra and R^ have the meanings mentioned under formula 1, R^ means protected carboxy, in an R. present functional group is protected, and the 7 8-amino group is optionally protected with a group permissible in the acylation reaction, acylate the 7 8-amino group by reaction with an acylating agent which introduces the acyl residue from a carboxylic acid of formula

where R^ has the meaning mentioned under formula 1, and a functional group present in R^ is possibly present in protected form, or

b) in a connection with formula

where m, R.. R^ and R^ have the meanings mentioned under formula 1, and a functional group present in R^ and/or R^ is optionally protected, and the 2-amino group is optionally protected with a formyl formation reaction permissible group, converts The 2-amino group by reaction with a formylating agent in the 2-formamido group, or

c) isomerizes a 2-cephem compound of formula

where R^, R^ and R^ have the meanings mentioned under formula 1 and one in R.| and/or R^ present functional group is optionally present in protected form, to the corresponding 3-cephem compound of formula 1, or d) for the preparation of a compound of formula 1, where R 4 means 2-amino-oxazol-4-yl or 2 -aminothiazol-4-yl,

condenses a compound of formula

where Hal means halogen, R- and R^ have the meanings mentioned under formula 1 and a functional group present in R^ is possibly protected, with urea or thiourea, or

e) for the preparation of compound of formula 1 where R 1 means 5-amino-1,2,4-thiadiazol-3-yl, reacts a compound

with formula

where X 1 means hydrogen, halogen or hydroxy, R 1 and R 2

has the meanings mentioned under formula 1 and a functional group present in R^, optionally protected, with a salt of rhodanehydrogen acid or, if X 1 is hydrogen, with dirhodane, or

f) for the preparation of a compound of formula 1, where R. is a group of formula -CH2-R2oq R2 means etherified mercapto, reacts a compound of formula 2, where m and R^ have the meanings mentioned under formula 1, and R^ is the group of formula -CH2-R2, where R2 means a nucleophilic leaving group, with a compound of formula

where R^ has the meanings mentioned under formula 1, and R2<1>

means lower alkylthio or heterocyclylthio, and, if desired, converts a compound of formula 1 obtained according to the invention, into another compound of formula 1 according to the definition, and/or transfers a compound of formula 1 obtained according to the invention, where m means 0, a compound of formula 1, where m means 1 or 2, and/or a compound of formula 1, where m means 1 or 2, in a compound of formula 1, where m means 0, and/or in a compound of formula 1, transfers functional groups present in protected form into free functional groups, and/or transfer an obtained salt into the free compound or into another salt, and/or transfer an obtained free compound with a salt-forming group into a salt and/or separate an obtained mixture of isomeric compounds with formula 1 in the individual isomers.

Procedure a) (acylation):

In a starting material with formula 2, a functional group present in R, e.g. a carboxy, amino or hydroxy group, protected with one of the above-mentioned protecting groups.

The 78-amino group in a starting material with formula 2 is optionally protected with a group leaving during the acylation reaction. Such a group is, for example, an organic silyl group, further a ylidene group, which together with the amino groups forms a Schiff base. An organic silyl group is e.g. such a group which can also form a protected carboxy group with the carboxy group R 1 , primarily trilower alkylsilyl, especially trimethylsilyl. In the silylation reaction for the protection of a 4-carboxy group in a starting material of formula 2, the amino group can also be silylated by using an excess of the silylation agent. A ylidene group is primarily a 1-aryl lower alkylidene group, in particular a 1-arylmethylene group, where aryl in particular stands for a carbocyclic, primarily monocyclic, aryl residue, e.g. for optionally with a lower alkyl, hydroxy, lower alkoxy and/or nitro substituted phenyl.

An acylating agent which introduces the acyl residue of a carboxylic acid of formula 3 is the carboxylic acid of formula 3 in the presence of a condensing agent, or a reactive, functional derivative or salt of this carboxylic acid.

Carboxylic acid of formula 3 with 2R or 2S configuration can be used, or reactive, functional derivatives thereof or 2R,S compounds in the acylation. The acylation is preferably carried out with the 2S compound.

In a starting material with formula 3, a functional group present in R^, e.g. an amino group on the heterocyclic ring, protected with one of the above-mentioned protecting groups, e.g. amino protecting groups, BOC.

In a starting material with formula 3, this amino group can also be protected in ionized form, e.g. in the form of an acid addition salt, which is for example formed with a strong inorganic acid, e.g. a hydrohalic acid, e.g. hydrochloric acid, or sulfuric acid, or with an organic acid, e.g. p-toluenesulfonic acid.

If a free acid of formula 3 is used for acylation, the reaction is usually carried out in the presence of suitable condensation agents such as carbodiimides, for example diethyl, dipropyl, dicyclohexyl or N-ethyl-N'-3-dimethylamino-propylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, or a suitable acylamine compound , e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in the liquid phase, preferably in the presence of a solvent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, possibly during cooling or heating, e.g.

in a temperature range from approx. -40 C to approx. +100°C, preferably from approx. -20°C to approx. +50°C, and possibly under inert gas, e.g. nitrogen atmosphere.

A reactive, functional derivative of a carboxylic acid with formula 3 is suitable for forming the carboxamide residue -CONH- and is primarily an anhydride of the carboxylic acid with formula 3, preferably with a mixed anhydride. A mixed anhydride is formed, for example, by condensation of the carboxylic acid with formula 3 with another acid such as e.g.

an inorganic acid, e.g. a hydrohalic acid, and is, for example, the corresponding carboxylic acid halide, e.g. the carboxylic acid chloride or bromide. A mixed anhydride is further formed by condensation with hydrogen nitric acid and is, for example, the carboxylic acid. Further inorganic acids suitable for the formation of mixed anhydrides are phosphorus-containing acids, e.g. phosphoric acid, diethyl phosphoric acid and

phosphoric acid, sulphurous acids, e.g. sulfuric acid,

or hydrocyanic acid. A reactive functional derivative of a carboxylic acid with formula 3 is also formed by condensation

tion with an organic carboxylic acid, e.g. with an unsubstituted or with a halogen, e.g. fluorine or chlorine, substituted lower alkanecarboxylic acid, e.g. pivalic acid or trifluoroacetic acid, with a lower alkyl half-ester of carboxylic acid with,

e.g. the ethyl or isobutyl half-ester of carboxylic acid, or with an organic, e.g. aliphatic or aromatic, sulphonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid.

A reactive functional derivative of a carboxylic acid with formula 3 is likewise an activated ester of the carboxylic acid with formula 3, which is, for example, formed by condensation with a vinylogenic alcohol, i.e. with an enol, e.g. a vinylogenic lower alkenol, an iminomethyl ester halide, e.g. dimethylimino. methyl ester chloride, prepared from carboxylic acid of formula 3 and e.g. Dimethyl-(1-chloroethylidene)-iminium chloride with the formula £(CH3)2N<+>= C(Cl)CH^jci , which in turn can be obtained e.g. of N,N-dimethylacetamide and phosgene or oxalyl chloride, an aryl ester, e.g. one with halogen, e.g. chlorine, and/or nitro substituted phenyl ester, e.g. pentachloro-, 4-nitrophenyl- or 2,3-dinitrophenyl ester, an N-heteroaromatic ester, e.g. the N-benztriazole ester, or an N-diacylimino ester, e.g. N-succinylimino or N-phthalylimino ester.

The acylation with a reactive functional derivative of the carboxylic acid of formula 3, e.g. with a corresponding anhydride, especially an acid halide, is preferably carried out in the presence of a suitable base. A suitable base is, for example, an amine, e.g.

a tertiary amine, e.g. trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-di-isopropylamine, or N,N-di-lower alkylaniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine, e.g. N,N-lower alkylated morpholine, e.g. N-methyl-morpholine, or is, for example, a base of the pyridine type,

e.g. pyridine or quinoline. A suitable base is furthermore a

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 is an oxirane, for example a 1,2-lower alkylene oxide, such as ethylene oxide or propylene

oxide, further a silylamide, e.g. trimethylsilylacetamide,

a carboxylic acid amide, e.g. dimethylformamide, urea or a nitrile, e.g. acetonitrile.

The acylation with a reactive, functional derivative,

of the carboxylic acid with formula 3, is preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, e.g. formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. acetone, a cyclic ether, e.g. tetrahydrofuran, an ester, e.g. acetic acid ethyl ester, or a nitrile, e.g. acetonitrile, or in mixtures thereof, possibly in the presence of an alcohol, e.g. methanol or ethanol, or water, possibly at reduced or elevated temperature, e.g.

in a temperature range from approx. -40°C to approx. +100°C, preferably from approx. -10°C to approx. +50°C, and possibly under inert gas, e.g. nitrogen atmosphere.

The acylation of a compound of formula 2 can also take place by using a suitable reactive, functional derivative of the acid of formula 3 in the presence of a suitable acylase. Such acylases are known and can be formed with the help of a number of microorganisms, e.g. by means of acetobacter, such as Acetobacter aurantium, achromobacter, such as Achromobacter

aeris, aeromonas, such as Aeromonas hydrophilia or bacillus, such as Bacillus megaterium 400 . In such enzymatic acylation, an amide, an ester or thioester is used in particular, as a lower alkyl, e.g. methyl or ethyl ester, of the carboxylic acid with formula 3, as a reactive, functional derivative. Such acylation is usually carried out in a nutrient medium that contains

the appropriate microorganism, in a filtrate of the culture liquid or, optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous medium which optionally contains a buffer, e.g. in a temperature range from approx. +20°C to approx. +40°C, preferably at approx. +37°C.

A reactive functional derivative of an acid of formula 3 used in the acylation reaction can, if desired, be formed in situ. Thus, one can e.g. prepare a mixed anhydride in situ, by reacting an acid with formula 3 where functional groups are optionally protected, or a suitable salt thereof, e.g. an ammonium salt, which-

e.g. is formed with an organic base, such as pyridine or 4-methyl-morpholine, or a metal salt, e.g. an alkali metal salt, e.g. sodium salt, with a suitable derivative of another acid, for example an acid halide, an unsubstituted or with halogen, e.g. chlorine, substituted lower alkanecarboxylic acid, e.g. trichloroacetyl chloride, 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 phosphor bromide, which can be formed by reacting triethyl phosphite with bromine. The mixed anhydride thus obtained can be used in the acylation reaction without isolation.

Method b) (formylation):

In a starting material with formula 4, a functional group present in R- and/or R^, e.g. a carboxy, amino or hydroxy group, be protected with one of the aforementioned protecting groups.

The 2-amino group in a starting material of formula 4 is optionally protected with a group compatible with the formylation reaction. Such a group is, for example, an organic silyl group, e.g. a tri-lower alkylsilyl group,

e.g. trimethylsilyl, or a ylidene group, which together with the amino group forms a Schiff base, and is the same group with which the 78-amino group in a starting material with formula 2 is optionally substituted, and which is compatible with the acylation reaction according to method a).

A functional group present in R., e.g. amino groups in the 2-aminothiazol-4-yl, 2-aminooxazol-4-yl or 5-amino-1,2,4-thiadiazol-3-yl group are protected with common protecting groups, e.g. common amino protecting groups, e.g. tert-butoxycarbonyl (BOC), the formamido group being obtained by their cleavage.

Suitable formylating agents are formic acid or its esters, e.g. a lower alkyl ester, e.g. methyl or ethyl ester,

an aryl ester, e.g. one with halogen, e.g. chlorine, and/or nitro substituted phenyl ester, e.g. pentachloro-, 4-nitrophenyl- or 2,3-dinitrophenyl ester, or an N-heteroaromatic ester, e.g. N-benztriazole ester, mixed anhydrides of formic acid with other carboxylic acids or derivatives thereof,

e.g. acid chlorides, e.g. acetic acid, trichloro- or trifluoroacetic acid or propionic acid or acid chlorides, e.g. acetyl chloride, mixed anhydrides with sulphonic acids or sulphochlorides, e.g. methanesulfonic acids or mesyl chloride, formamide, formyl fluoride, chloral or carbon monoxide in the presence of a catalyst.

If the free formic acid is used in formylation n, the formylation is usually carried out in the presence of the same condensing agent that was used in the acylation of the 78-amino group in a compound of formula 2, with a free carboxylic acid of formula 3 according to method a),:f. e.g.

in the presence of a carbodiimide, e.g. N,N'-dicyclohexy1-carbodiimide.

In the formylation with formic acid, the same solvent is used and the same reaction conditions are maintained as in the acylation with a carboxylic acid of formula 3 according to method a).

In the formylation with formic acid esters and mixed anhydrides of formic acid, the same solvent is used, e.g. acetic acid or acetic anhydride, and the same reaction conditions are maintained as in the acylation with a reactive, functional derivative of a carboxylic acid with formula 3 according to method a).

The formylation with formamide takes place at an elevated temperature, e.g. about. 70° - 100°C, e.g. in an excess formamide. For formylation with chloral, the chloral is usually added during cooling, e.g. below 0°C', and then heats up slowly, e.g. up to the boiling point temperature of the reaction mixture. The formylation with formamide or chloral usually takes place analogously to the reaction conditions mentioned in "Houben-Weyl, Methoden der Organischen Chemie", volume 11/2, on pp. 27 - 30.

In the formylation with carbon monoxide, metals are used as catalysts, e.g. cobalt and nickel, or metal salts, e.g. copper (I) - or copper (II) chloride. Work is carried out at excessively high pressure, e.g. over 150 atm.

Method c) (isomerization):

In a 2-cephem starting material of formula 5 it has

the optionally protected 4-carboxy group is preferably in the α-configuration.

The isomerization of a 2-cephem compound with formula 5 corresponding to a 3-cephem compound with formula 1 takes place by oxidizing in the 1-position with a suitable oxidizing agent and,

if desired, separates a possibly obtained isomer mixture of the 1-oxide and reduces a thus obtained 1-oxide of

The 3-cephem compound of formula 1, where m means 1, to 3-cephem compound, where m means 0.

Suitable oxidizing agents for the oxidation of the sulfur atom in the 1-position of a 2-cephem compound of formula 5 are organic peracids or mixtures of hydrogen peroxide

and acids, especially organic carboxylic acids with a dissociation constant of at least 10 ^. Organic peracids are, for example, percarboxylic and persulfonic acids, which can be added as a peracid or can be formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid.

When the peracid is formed in situ, a large excess of the carboxylic acid is conveniently added, e.g. acetic acid, as a solvent. Suitable organic peracids are preferably permauric acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

The oxidation can likewise be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation ion constant of at least 10 ~*, as low concentrations can be used, e.g. 1-2% and less, but also larger quantities of the relevant acids. Moreover, the oxidative effect of the mixture depends primarily on the acid strength.

Suitable mixtures are e.g. hydrogen peroxide with acetic acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable acid catalysts. Thus, e.g. the oxidation is catalyzed by a percarboxylic acid in the presence of an acid with a dissociation constant of at least 10, its catalytic effect depending on its acid 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 smaller excess of approx. 10% to approx. 20%, as one can also use a larger excess, i.e. up to 10 times the 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 a 1-oxide of the 3-cephem compound, i.e.

a 3-cephem compound of formula 1, where m means 0,

can be carried out in a manner known per se by treatment with a suitable reducing agent, if necessary in the presence of an activating agent. Suitable reducing agents are, for example: reducing tin, iron, copper or manganese cations, which can be used in the form of their salts, e.g. such as tin (II) chloride, acetate or formate, iron (II) chlorides, sulphate, oxalate or ammonium iron sulphate, copper (I) chloride or oxide or manganese (II) chloride, sulphate, -acetate or

-oxide, or as organic or inorganic complexes,

e.g. with ethylenediaminetetraacetic acid or nitrolotriacetic acid; reducing dithionite, iodine or iron (II) cyanide anions, which are used in the form of their inorganic or organic salts, e.g. such as alkali metal, e.g. sodium or potassium dithionite, sodium or potassium iodide or sodium or potassium ferric cyanide; hydrogen iodide, reducing-acting trivalent, inorganic or organic phosphorus compounds, such as phosphine, further esters, amides and halides of phosphonic, phosphinic or phosphoric acids, as well as phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, where organic residues in these compounds primarily aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or phenyl lower alkyl, e.g. triphenylphosphine, diphenylphosphonic acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzene-phosphonic acid dimethyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, further phosphoric acid triphenyl ester halogen adducts, e.g. chlorine or bromine derivatives, where the phenyl radical is optionally substituted with lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or with halogen, e.g. chlorine, etc.; reducing effect. halosilane compounds, which have at least one hydrogen atom attached

to a silicon atom, and which further contains halogen, such as chlorine, bromine or iodine, also organic residues, such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl, for example diphenylchlorosilane or trimethyliodosilane, as well as halosilane compounds, where all hydrogen atoms are replaced by organic residues, such as trilower alkylhalosilane, "e.g. trimethylchlorosilane or trimethyliodosilane, etc.; reducing quaternary chloro-methylene-iminium salts, especially -chlorides or bromides,

where the iminium group is substituted with a bivalent or two monovalent organic residues, such as optionally substituted lower alkylene, respectively lower alkyl, such as N-chloromethylene-N,N-dimethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; or complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt (II) chloride, as well as borane dichloride.

Activating agents are used together with reducing agents that have no or only weak Lewis acid properties. These are primarily used together with dithionite, iodine or iron (II) cyanide salts and non-halogen-containing trivalent phosphorus reducing agents and are particularly organic carboxylic and sulphonic acid halides, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide, or chloroacetic acid chloride.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting compound and the choice of reducing agent, e.g. optionally substituted, e.g. halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. benzene, methylene chloride, chloroform or nitromethane, suitable acid agents, such as lower alkane carboxylic acid esters, or -nitrile, e.g. acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, e.g. dimethylformamide or hexamethylphosphoramide, ketones, e.g. acetone,

or sulfones, especially aliphatic sulfones, e.g.

dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agent, as these dissolve

means do not contain any water.

Thereby, you usually work at temperatures from approx. -20°C

to approx. 100°C, when using highly reactive reducing agents or activating agents, the reaction is also carried out through lower temperatures and possibly under an inert gas atmosphere, e.g. nitrogen atmosphere.

Procedure d) (loop closure):

In a starting material of formula VI, a functional group present in R.j, e.g. an amino or carboxy group, optionally protected with one of the protective groups mentioned further on. Hal means halogen, preferably chlorine, further bromine, iodine or fluorine. When in the product of formula 1,

should mean 2-aminooxazpl-4-yl, urea is used, and when R4 means 2-aminothiazol-4-yl, thiourea is used in equivalent amounts or in excess.

The cyclization is usually carried out in a solvent, such as water or an organic, inert solvent, or a mixture thereof. As an organic solvent are alcohols, such as methanol, ethanol or isopropanol, ketones, such as acetone, ethers, such as dioxane or tetrahydrofuran. nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, esters, such as ethyl acetate, or amides, such as dimethylformamides or dimethylacetamide, and the like are suitable. The turnover can be carried out in the presence of a under procedure of the said base. The reaction temperature will lie between room temperature and the boiling point of the reaction mixture, preferably between 60°C and the boiling point of the reaction mixture.

The cyclization can also take place in stages, as it first occurs

an open intermediate, e.g. with the partial formula NH2-C(=NH)-0-C<H>2-CO-CH-NHCO respectively NH^-C(=NH)-S-CH - CO-CH-NHCO, which is then dehydrated in the second step during heating.

Procedure e) (loop closure):

In a starting material of formula 7, one of the functional groups present, e.g. an amino or carboxy group, possibly protected with a protective group mentioned further above. X^ meaning halogen is preferably bromine, further fluorine, chlorine or iodine. Suitable salts of the hydrogen aurodanide acid are, for example, alkali, alkaline earth or heavy metal rhodanides, e.g. sodium, potassium, magnesium or lead rhodanide, or also ammonium rhodanide, where the ammonium group is derived from ammonia or from organic nitrogen bases, e.g. ammonium or mono-, di-, tri-

or tetralower alkylammonium rhodanide, where lower alkyl, e.g. methyl, ethyl or isopropyl.

r

The reaction is preferably carried out in an inert solvent, such as a lower alkanol, 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, or also of in mixtures thereof, and, if necessary, while cooling or heating, i.e. at temperatures between approx. -80°C and approx. +100°C, preferably between approx. -20°C and room temperature, and/or in an inert gas atmosphere.

The starting material of formula 7, where X^ is halogen, can be prepared in situ in the presence of rhodan hydrogen salts, for example by treating a compound of formula 7, where 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 low-alkanolate, e.g. with bromine or sodium methylate or potassium carbonate. The halogenation preferably takes place during cooling, e.g. at a temperature from approx. -15°C to approx. 0°C.

The starting material of formula 7, where X is hydroxy, can optionally be set in situ, for example by treating a compound of formula 7, where X is hydrogen, with an oxidizing agent, such as hydrogen peroxide.

The reaction of the starting material with formula 7, where X is hydrogen, with dirhodane is preferably similarly carried out in one of the aforementioned inert solvents and under similar reaction conditions. Optionally, an acid addition salt of compounds of formula 7 can also be used which is transferred into the free compound in situ, or the dirhodan can be formed in situ, e.g. from a rhodanide, e.g. lead rhodanide, and a halogen, e.g. bromine.

Method f) (reaction of thiocarboxylic acid esters):

In a starting material with formula 2, the 7 8-amino group is optionally protected with one of the groups mentioned under method a), which are compatible with the acylation reaction, e.g. trimethylsilyl, and 4-carboxy group R 3 with one of the usual carboxy protecting groups mentioned, e.g. diphenylmethyl1.

The nucleophilic leaving group R^ is e.g. halogen, e.g. chlorine, azido, benzimidazol-2-ylthio or preferably acetoxy.

In a compound of formula 8, R2' is lower alkylthio,

e.g. methylthio, or, preferably, heterocyclylthio,

e.g. 1H-1,2,3-triazol-4(5)-ylthio, 1H-1,2,4-triazol-3-ylthio, 1-ethyl- or 1-diethylphosphonylmethyl-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-cyanomethyl-1H-tetrazol-5-ylthio, 1-(1H -tetrazol-5-ylmethyl)-1H-tetrazol-5-ylthio, thiazol-2-ylthio, isothiazol-3-, -4- or -5-ylthio, 1,2,3-thiadiazol-4- or -5- ylthio, 1,3,4-thiadiazol-2-ylthio, 1,2,4-thiadiazol-3- or -5-ylthio, 1,2,5-thiadiazol-3-ylthio, 2-methyl-1,3, 4-thiadiazol-5-ylthio, 1,2,3,4-thiatriazol-5-ylthio, oxazol-2-, -4- or -5-ylthio,

1- or 2-methyl-5,6-dioxo1,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as -triazin-3-ylthio, 1- or 2-carboxymethyl-5,6-dioxo1,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-carboxymethyl-5,6-dioxo-1, 4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-sulfomethyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-sulfomethyl -5,6-dioxo-1,4,5,6-tetrahydro-as-triazine-3-

ylthio and tautomers thereof.

The reaction of the thiocarboxylic acid ester of formula 8 with

a compound of formula 2, where the nucleophilic leaving group R 2 means halogen, e.g. chlorine, azido or acetoxy, takes place under neutral or slightly alkaline conditions, preferably at a pH value of approx. 7 to 8, adding e.g. an aqueous sodium or potassium bicarbonate solution to the reaction mixture. The reaction with a compound of formula 2, where the nucleophilic leaving group is the benzimidazolylthio group, takes place preferably under acidic conditions, putting e.g. 0.05 to 1 equivalent of an aqueous mindralic acid, e.g. diluted hydrogen chloride or sulfuric acid, sulphonic acid, e.g. methane- or p-toluenesulfonic acid, or carboxylic acid, e.g. acetic acid.

One preferably allows 1 to 2 equivalents of the compound of formula 2 to react per mol.used thiocarboxylic acid residue with formula 8.

The reaction takes place analogously to those mentioned earlier under method a) - reaction of a carboxylic acid of the formula 3 with a 7B-amino compound of the formula 2 - mentioned reaction conditions and in one of the solvents mentioned there.

Finishing treatments:

In an obtained compound with formula 1 can in the usual way, i

and in a manner known per se, functional groups not yet protected are protected or present protecting groups are exchanged with other protecting groups, e.g. by splitting off the present protecting group and introducing this desired, second protecting group.

- transformations:

In an obtained compound of formula 1, where functional groups are possibly protected, one can in a manner known per se replace a group R^ with another residue R^, or convert a group R^ into another residue R^. Thus, one can, for example, in connection with formula 1 where R^ means a group of formula -CH2-R20<3 R2f-ex. is a residue replaceable with nucleophilic substituents, or in a salt thereof by treatment with a markaptan compound, e.g. a heterocyclyl mercaptan compound, or with a thiocarboxylic acid compound replace such a residue R2 with an etherified mercapto group, e.g. heterocyclyl mercapto group, respectively an esterified mercapto group R2.

A suitable, with nucleophilic substituents, e.g. an etherified mercapto group, replaceable residue is, for example, a hydroxy group esterified with a lower aliphatic carboxylic acid. Such an esterified hydroxy group is particularly acetyloxy and acetoacetoxy.

The setup of such a compound of formula 1 with a suitable mercaptar compound, e.g. heterocyclyl mercaptan compound, can be carried out under acidic, neutral or slightly basic conditions. In acidic conditions, you work in the presence of concentrated sulfuric acid, which is optionally diluted with an inorganic solvent, e.g. polyphosphoric acid. In neutral or slightly basic conditions, the reaction is carried out in the presence of water and possibly a water-miscible organic solvent. Buffer solutions can also be used as reaction medium.

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. by adding sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As an organic solvent, e.g. alcohols that are miscible with water, e.g. lower alkanols, such as methanol or ethanol, ketones, e.g. lower alkane, such as acetone, amides, e.g. lower alkanecarboxylic acid amides, e.g. dimethylformamide, or nitriles, e.g. lower alkanoic acid nitriles, e.g. acetonitrile.

In a compound of formula 1, where a group of formula - CE^ means R2, where R2 means a free hydroxy, the free hydroxy group can be esterified with the acyl residue to an optionally N-substituted carbamic acid. The esterification of the free hydroxy group with an isocyanate compound, e.g. halosulfonyl isocyanate, e.g. chlorosulfonyl isocyanate, or with a carbamic acid halide, e.g. carbamic acid chloride, leads to Nm-substituted 3-carbaroyloxymethyl-1-cephalosporins of formula 1. The esterification of the free hydroxy group with an N-substituted isocyanate compound with an N-mono-or N,N-disubstituted carbamic acid compound, e.g.

a correspondingly substituted carbamic acid halide, e.g.

an N-mono- or N,N-disubstituted carbamic acid chloride, leads to N-mono- or N,N-disubstituted 3-carbamoyloxymethyl cephalosporins of formula 1. One usually works in the presence

of a solvent or diluent and, if necessary, during cooling or heating, in a closed container and possibly under inert gas, e.g. nitrogen atmosphere. Compounds of formula 1, where R- means a group with

formula -CH2-R2, where R2 means free hydroxy, can be prepared from a compound of formula 4 by splitting off the acetyl residue from an acetoxy group R2, e.g. by hydrolysis in a weakly basic medium, e.g. in an aqueous sodium hydroxide solution at pH 9 - 10, or by treatment with a suitable esterase,

such as a suitable enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, e.g. from orange peel, and then the following formylation according to method b).

Furthermore, one can react a compound with formula 1, where R 2 means a group -CH -R 2 / where R 2 e.g. is the residue defined above, cleavable with nucleophilic substituents,

e.g. acetoxy or acetacetoxy, with an organic base, in particular a tertiary, nitrogen-containing base, for example a tertiary, aliphatic amine, or preferably a tertiary, heterocyclic, aromatic nitrogen base, e.g. pyridine or pyrimidine, with the substituents mentioned further above under neutral or slightly acidic conditions, preferably at a pH value from approx. 6.5, in the presence of water and possibly in a water-miscible organic solvent. One thus obtains a compound of formula 1 where Rr is the residue of formula -CH2-R2 and R2 is an ammonium group defined earlier. Weakly acidic conditions can be set by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or sulfuric acid. As an organic solvent, for example, the water-miscible solvents mentioned above can be used. To increase the yield, salts, for example alkali metal salts, such as sodium and especially potassium salts, of inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid and especially hydrogen iodide, as well as thiocyanic acids, or of organic acids, such as lower alkane

carboxylic acids, e.g. acetic acid. Suitable salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate.

Also salts of certain anion exchangers, e.g. liquid ion exchangers in salt form, such as "Amberlite LA-1" (liquid secondary amine with a molecular weight of 351-393; oil-soluble and water-insoluble; mekg/g = 2.5 - 2.7, e.g. in acetate form), with acids , e.g. acetic acid, can be used for this purpose.

Conversion to the 1-oxide, 1-dioxide and 1-sulfide:

A compound of formula 1 where the symbol m means 0 can be converted with the oxidizing agent described under method c) into the corresponding 1-oxide, where the symbol m has the value 1.

The 1-oxide of formula 1, which exists in a or B configuration, can be prepared in a manner known per se according to that from DE off. document, no. 30 13 996 known method, namely by oxidation of a compound of formula 2, where m is 0 and the 7B-amino group, for example, is protected with the ylidene group, which together with the amino group forms a Schiff base, with a percarboxylic acid, e.g. e.g. m-chloroperbenzoic acid, chromatographic separation of obtained a- and B-1-oxides with formula 2 and subsequent acylation with a carboxylic acid with formula 3.

A compound of formula 1, where the symbol m means 0 or

1 can be transferred into the corresponding 1-dioxide, where m has the value 2, by reaction with oxidizing agents which transfer sulfide or sulfoxide groups into sulfone groups.

Such oxidizing agents are in particular hydrogen peroxide or organic peracids, in particular aliphatic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, chloroperbenzoic acids, e.g. m-chloroperbenzoic acids, or monoperphthalic acid. The oxidation is carried out preferably in a suitable non-aqueous, inert

solvent, for example a halohydrocarbon,

e.g. methylene chloride, chloroform or carbon tetrachloride,

an alcohol, e.g. methanol or ethanol, a ketone, e.g. acetone, an amide, e.g. dimethylformamide, or a liquid organic carboxylic acid, e.g. acetic acid, or a mixture of these solvents at room temperature, with cooling or slight heating, i.e. at approx. -50°C to approx. +40°C, preferably approx. -20°C to approx. 0°C. The oxidation can also be carried out in stages, as it is oxidized to the sulphoxide stage (m = 1) at a lower temperature, i.e.

at approx. -20°C to approx. -10°C, which is optionally isolated, where after the sulfoxide is oxidized to the sulfone (m = 2) in another step, preferably at a higher temperature, e.g.

-10°C to 0°C.

For processing, any excess oxidizing agent still present can be destroyed by reaction with a reducing agent, e.g. a thiosulphate, e.g. sodium thiosulfate. A 1-oxide with formula 1, where the symbol m has the value 1, as well as a 1-dioxide, where the symbol m has the value 2, can be converted with the reducing agent described under method c) into the corresponding 1-sulphide, where the symbol m has the value 0.

Cleavage of protecting groups:

In an obtained compound with formula 1, where one or more functional groups are protected, these protective groups, e.g. protected carboxy, amino, hydroxy and/or sulfo groups are selectively released in a manner known per se, by means of volvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis. During the cleavage of the protecting group, reaction conditions which lead to cleavage of the formamido group must be avoided. The reaction conditions that must be observed are written in overview

the article of Lakshmi P.U. and Ramachandran L.K., J.Sci.

Ind. REs. 30 (12) 680-688 (1971).

A protected carboxyl group is released in a manner known per se and depending on the type of protecting group in a different manner, preferably by means of solvolysis or reduction.

Thus one can transfer tert-lower oxycarbony1 or

in the 2-position with an organic silyl group or in the 1-position with lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl or optionally substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl, e.g. with treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of the nucleophilic compound, such as phenol, anisole or ethylene thioglycol,

in free carboxy. Appropriately substituted benzyloxycarbonyl,

as 4-nitrobenzyloxycarbonyl, can be transferred into free carboxy by 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 ion-releasing agent, which together with the metal or the metal salt can give nascent hydrogen, as an acid, primarily a suitable carboxylic acid, as an optional, e.g. with hydroxy substituted lower alkane carboxylic acid, e.g. acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water. By treatment with a reducing metal or metal salt, as described above, 2-halogen-lower oxycarbonyl can also be converted, possibly after conversion of a 2-bromo-lower alkoxycarbonyl group into the corresponding 2-iodo-lower oxycarbonyl group, or aroylmethoxycarbonyl in free carboxyl, since aroylmethoxycarbonyl can be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, which

sodium thiophenolate or.sodium iodide. Substituted 2-silyl-ethoxycarbonyl can also be transferred into free carboxyl by treatment with a salt of hydrogen fluoride which releases 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, tetra-lower alkyl ammonium fluoride or tri-lower alkyl aryl ammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethylsulfoxide or N,N-dimethylacetamide Carboxy which is etherified with an organic silyl group, such as trilower alkylsilyl, e.g. trimethylsilyl,

can usually be released solvolytically, e.g. by treatment with water, an alcohol or an acid.

A protected amino group is released in a manner known per se and depending on the type of protective group in a different manner, preferably by means of solvolysis or reduction. 2-halolower oxycarbonylamino, possibly after conversion of 2-bromolower oxycarbonylamino group into 2-iodolower oxycarbonylamino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, e.g. by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. sodium dithionite.

Optionally substituted diphenylmethoxycarbonylamino, tert-lower oxycarbonylamino, e.g. BOC, or 2-trisubstituted silylethoxycarbonylamino or 4-nitrophenylthio can be cleaved by treatment with a suitable acid, e.g. ant-

or trifluoroacetic acid, and an amino group protected by an organic silyl group can be cleaved, e.g. by means of hydrolysis or alcoholysis. One with 2-halogenacety1, e.g. 2-chloroacetyl, protected amino group can be cleaved by

treatment with thiourea in the presence of a base and subsequent solvolysis, such as alcoholysis, or hydrolysis, of the resulting condensation product. A 2-substituted silylethoxycarbonyl protected amino group can also be transferred into the free amino group by treatment with a salt of hydrofluoric acid which releases the fluoride anion, as indicated above in connection with the release of a corresponding protected carboxy group.

Amino, protected in the form of an azido group is transferred e.g. through reduction in free amino by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, 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°C to 25°C, or also during cooling or heating.

A hydroxy group protected with a suitable acyl group, an organic silyl group or optionally substituted 1-phenyllower alkyl group is released as a corresponding protected amino group.

A hydroxy group protected with 2,2-dichloroacetyl is released, e.g. by basic hydrolysis, while a hydroxy group etherified by tert-lower alkyl or with a 2-oxa- or 2-thialiphatic or -cycloaliphatic hydrocarbon residue is released by acidolysis, e.g. by treatment with a halogenated carboxylic acid, e.g. trifluoroacetic acid.

A protected, especially esterified, sulfo group is released analogously to a protected carboxyl group.

The described cleavage reactions are carried out under conditions known per se, if necessary during cooling or heating, and optionally in an inert gas, e.g. nitrogen atmosphere.

In the presence of several protected functional groups, e.g. a protected amino and a protected carboxy group, the protection group is preferably chosen so that they can be cleaved off at the same time without the formamido group being cleaved, for example acidolytically, such as when treated with trifluoroacetic acid or formic acid, or reductively, such as when treated with zinc and acetic acid.

Esterification of a free carboxy group:

The conversion of a free carboxy group, e.g. the free carboxy group R^, to an esterified carboxy group,

particularly in a carboxy group which is cleavable under physiological conditions, takes place according to esterification procedures known per se. For example, a compound of formula 1 is reacted, where the carboxyl group to be esterified is present in free form, and other functional groups, e.g. amino or hydroxy groups, are present in protected form, or a compound of formula 1, where the carboxyl group to be esterified is present in the form of a reactive, functional derivative, or a salt of a compound of formula 1, with the appropriate alcohol or a reactive, functional derivative of this alcohol.

In the esterification of a compound of formula 1, where the carboxyl group to be esterified is present in free form, with the desired alcohol, the same condensation agent is used, e.g. carbodiimide, the same solvent and the same reaction conditions are maintained as in the acylation according to method a).

A compound of formula 1, where the carboxyl group to be esterified is in the form of a reactive, functional derivative, is for example a mixed anhydride or an activated ester, which can be obtained in the manner described under method a) fecylation) by condensation of the carboxylic acid with formula 1, with an inorganic acid, a carboxylic acid, with a carboxylic acid half-ester, a sulphonic acid or by condensation with a vinylogenic alcohol.

A reactive, functional derivative of the alcohol to be used for the esterification is primarily the ester, which is formed by condensation with a strong inorganic or organic acid, for example the corresponding halide, e.g. chloride, bromide or iodide, or the corresponding lower alkane-, e.g. the methanesulfonyloxy compound.

In the esterification of the compound of formula 1, where the carboxyl group to be esterified is in the form of a reactive functional derivative, with the appropriate alcohol or in the esterification of a compound of formula 1, where the carboxyl group to be esterified is in free form, with a reactive functional derivative of the appropriate alcohol, the same solvent is used and the same reaction conditions are maintained as in the acylation with a reactive, functional derivative of a carboxylic acid with formula 3 according to method a).

A compound of formula 1, where the carboxyl group to be esterified is in the form of a reactive, functional derivative, can also be prepared in situ analogously to the method described in method a) (acylation) and reacted with the appropriate alcohol without isolation.

Salt formation:

Salts of compounds of formula 1 can be prepared on

in and of itself known manner. Thus, salts of compounds with formula 1 can be formed according to the method described in the examples or e.g. by reacting the acid groups with metal compounds, such as alkali metal salts

of suitable carboxylic acids, e.g. the sodium salt of α-ethylcaproic acid or sodium carbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of formula 1 are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchanger

reagent. Inner salts of compounds with formula 1 can be formed, e.g. by neutralizing salts, such as acid addition salts, at the isoelectric point, e.g. with weak bases, or when treated with liquid ion exchangers.

Salts can normally be transferred in the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. by treatment with a suitable basic agent.

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

Mixtures of diastereomers, e.g. 2R,S compounds, with formula 1, can be separated in a manner known per se, e.g.

by fractional crystallization of an intermediate product, chromatography, etc. in the individual isomers.

The method also includes the embodiments whereby

compounds defined as intermediates are used as starting compounds and the remaining process steps are carried out with these, or the process is interrupted at

a very different step; Furthermore, output connections can be used in the form of derivatives or formed in the course of turnover.

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

Pharmaceutical preparations:

The pharmacologically usable compounds of formula 1, their hydrates or salts can be used for the preparation of pharmaceutical preparations.

Pharmaceutical preparations contain an effective amount of

the pure active compound of formula 1 alone or an effective amount of the active compound of formula 1 in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers suitable for parenteral or oral administration.

For example, the active compound, with formula 1, is used

according to the present invention in the form of injectable, e.g. intravenously administrable, preparations or of the infusion solution. Such solutions are preferably isotonic aqueous solutions or suspensions, such as e.g. can be prepared from lyophilized preparations containing the pure active compound or the active compound together with a carrier material, e.g. mannitol,

before use. Pharmaceutical preparations for oral use are sterilized and may contain excipients, e.g. preservative, stabiliser, wetting and/or emulsifying agent, solubility mediator, salts for regulating the osmotic pressure and/or buffer. The present pharmaceutical preparations which, if desired, can contain further pharmacologically valuable compounds, e.g. other active compounds, contains approx. o.1% to 100%, especially approx. 1% up to 100% of the active compound.

The pharmaceutical preparations are manufactured in and of themselves

known way, e.g. using conventional dissolution or lyophilization methods.

Application:

Compounds of formula 1, their hydrates or pharmaceutically usable salts can be used as antibiotic active agent in the form of pharmaceutical preparations in a method for the therapeutic treatment of humans or animals, e.g. for the treatment of infections caused by gram-positive bacteria, e.g. Staphylococcus aureus, or gram-negative bacteria and cocci, e.g. of enterobacteria, e.g. Escherichia coli, Klebsiella pneumoniae or Proteus spp.

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., i.v., i.m. or p.o. for the treatment of people or warm-blooded animals weighing approx. 70 kg.

Output connections:

The starting materials of formulas 2 and 4 used in the methods for producing the compounds according to the present invention are known or, if they are new, can be produced in a manner known per se.

Compounds of formula 3, which have been developed for the preparation of formula 1, are new and likewise the subject of the present invention. These are produced, for example, in an amino acid group with the formula where R^ has the meaning mentioned under formula 1 and RQ is an ester-forming group and a functional group present in R4 is optionally present in protected form, and the 2-amino group is optionally protected with a group that is compatible with the formylation reaction, converts the 2-amino group to the 2-formamido group by reaction with a formylating agent and cleaves the ester-forming group Rq and, if desired, separates a racemic mixture obtained of 2R and 2S compounds and isolates the 2R or 2S compounds and /or transfers the obtained carboxylic acid in the reactive, functional derivatives mentioned under method a).

In an amino acid derivative, an ester-forming group Rq is, for example, lower alkoxy, e.g. methoxy, ethoxy, N-propoxy, branched lower alkoxy, e.g. tert-butoxy, substituted lower alkoxy, e.g. benzyloxy, 4-nitrobenzyloxy, 4-methoxybenzyloxy or diphenylmethoxy, or sulphonyloxy, e.g. lower alkylsulfonyloxy, e.g. mesyloxy, or arylsulfonyloxy, e.g. tosyloxy.

A functional group present in R^, e.g. the amino group in the 2-aminothiazol-4-yl, 2-aminooxazol-4-yl or 5-amino-1,2,4-thiadiazol-3-yl group is protected with common protecting groups, e.g. common amino protecting groups, e.g. tert-butoxycarbony1 (BOC).

A protective barrier for the 2-amino group that is compatible

with the formylation reaction, is described above under method b) and is e.g. trilower alkylsilyl, e.g. trimethylsilyl.

The conversion of the 2-amino group into the 2-formamido group takes place

with the formylating agents mentioned under method b), e.g. a mixed anhydride of formic acid with mesyl chloride, under the reaction conditions mentioned there.

The splitting off of the group RQ takes place in a manner known per se, e.g. by saponification with a basic agent, e.g. sodium or potassium hydroxide.

For the formylation, amino acid derivatives of formula 9 can be used, with 2R or 2S configuration or 2R,S compounds.

The separation of an obtained mixture of 2R and 2S compounds and the isolation of the optically pure 2R or 2S compounds of formula 3 can take place according to one of the numerous methods for splitting racemic mixtures described in the literature.

For example, carboxylic acids with formula 3 can be obtained, where the 2-C atom has the S configuration, enzymatically analogous to that of Roper J.M. and Bauer D.P. in Synthesis, S.

1041 - 1043 (1983) stated method by reacting the isomer mixture of the lower alkyl ester with formula 3, e.g. the ethyl ester, with a non-specific serine proteinase,

e.g. "Subtilisin Carlsberg", as only S-carboxylic acids of formula 3 are formed, and separation of the S-carboxylic acid of formula 3 from the R-ester.

Preferably, a racemic mixture obtained of the 2R" compound of formula 3 is reacted in methanol solution with

(S)-1-Phenylethylamine. Thereby, the salt of the 2S-compound (III) crystallizes out with (S)-1-phenylethylamine. This salt is purified and after reaction with an acid, e.g. dilute aqueous mineral acid, e.g. aqueous HCL solution, the 2S-carboxylic acid with formula 3 is obtained. The 2R-carboxylic acid salt remaining in the methanol-containing mother liquor can be isolated if necessary by precipitation with ether. After reacting this salt with a mineral acid, R-carboxylic acid with formula 3 is obtained.

The transfer of the reactive, functional derivatives mentioned under method a) takes place with derivatization methods that are known for carboxylic acids.

Compounds of formula 4 and their preparation are known

and described e.g. in US patent document no. 4,098,888, or if they are new, can be produced by reacting a compound of formula 2 with an amino acid of formula 9

(Rq = H) or a reactive, functional derivative thereof, e.g. the acid chloride analogously to method a).

2-Cefem compounds of formula 5 are new. They can be prepared analogously to the acylation method a) or analogously to the formylation method b) starting from a known or in a known manner that can be prepared in a known way 2-cephem compound of formula

In addition, 2-cephem compound of formula 5 can be formed as a by-product with method a), especially when working under basic conditions.

Compounds with formula 6 are new and can be prepared, for example, in a manner known per se by acylating 7 The 6-amino group by reaction with an acylating agent which introduces the acyl residue from a carboxylic acid of formula

where Hal means halogen.

The acylation of a compound of formula 2 with the carboxylic acid of formula 11 or a reactive, functional derivative of these carboxylic acids, e.g. the acid chloride, takes place analogously to method a).

Compounds of formula 7 are new and can be prepared in a manner known per se by acylating the 7B-amino group in a compound of formula 2 where the 76-amino group and the 46-carboxy group are optionally protected with a group that is compatible with the acylation reaction, by reaction with an acylating agent which introduces the acyl residue from a carboxylic acid of formula

where X means hydrogen, halogen or hydroxy.

The acylation of a compound of formula 2 with carboxyl-

the acid with formula 12 or a reactive, functional derivative of this carboxylic acid, e.g. the acid chloride,

takes place analogously to procedure a).

Compounds of formula 8 are new and can be prepared on

in and of itself known manner according to the one in ET patent application no.

47014 specified method with reaction of a compound of formula 3 or a reactive, functional derivative thereof with a mercaptan of formula R2'-H.

Compounds of formula 9 and 10 are known.

Compounds with formulas 11 and 12 can, for example, be prepared by formylation of the corresponding amino acid analogously to method b).

The following examples serve to illustrate the invention; temperatures are given in degrees Celsius, wavelengths in the UV spectra in nanometers (nm), e-value in parentheses and for IR--1

spectrum, the wavenumber (cm) is indicated.

In the examples, the following abbreviations are used:

BOC: tert-butoxycarbonyl1

mp: melting point

(a) (a)D .

Example 1:

a) The sodium salt of 3-acetoxymethyl 1-78-C (2R,S)-2-(2-aminooxazol-4-yl)-2-formamido-acetamido! ? - 3-cephem-4-carboxylic acid.

A solution of 4.4 g of 3-acetoxymethyl-78-(2R,S)-2-(2-BOC-amino oxazol-4-yl)-2-formamidoacetamido -3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of methylene chloride is stirred for 1 hour with 19.7 ml of trifluoroacetic acid and 3.3 ml of anisole, 250 ml of ice-cooled toluene are added and evaporated. After digestion of the residue with ether, suction and drying, the trifluoroacetic acid salt of the title compound is obtained as a beige powder. This suspension

their in 20 ml of water and the solution is adjusted at 0°C with 1 N sodium hydroxide solution to pH 7.2 and chromatographed over an adsorption resin, e.g. Amberlite ER-180, (manufacturer: Rohm + Haas, Milan). The title compound is obtained with an Rf value of 0.9 (silica gel 60; acetonitrile/

water 1:1); UV (water): 218 (1 1500) and 265 (10100); [aj = +77-1° (0.969% in H 2 O). b) 3-acetoxymethyl-78-[(2R,S)-2-(2-BOC-aminooxazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

In a solution of 2.8 g of 2-(2-BOC-aminooxazol-4-yl)-2-formamidoacetic acid, 4.4 g of 3-acetoxymethyl-78-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 1.8 g 1-Hydroxybenztriazole in 30 ml of tetrahydrofuran is added dropwise at -5°C into a solution of 2.5 g of N,N<1->dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran. It is stirred for 1 hour at 0° and for 2 hours at approx.

25°C. For processing, the precipitate is filtered off, the reaction mixture is evaporated, the residue is taken up in acetic acid ethyl ester and successively shaken with cold, saturated sodium hydrogen carbonate solution, approx. 2N citric acid and once again with saturated sodium bicarbonate and saturated sodium bicarbonate solution. After drying the organic phase over sodium sulfate and evaporation, the title compound b) is obtained as crude product, which is purified by column chromatography (silica gel M + N; toluene/ethyl acetate); Rf value 0.85 (silica gel 60; methylene chloride/ethanol 9:1).

The starting material is produced in the following way:

c) 2-(2-BOC-aminooxazol-4-yl)-2-formamidoacetic acid

To 2.8 g of 2-(2-di-BOC-aminooxazol-4-yl)-2-formamidoacetic acid methyl ester in 50 ml of ethanol is added a solution of 2.2 g of potassium hydroxide in 20 ml of water and stirred for 30 minutes at room temperature. The reaction mixture is then evaporated under vacuum, diluted with acetic acid ethyl ester and acidified with 4N hydrochloric acid to pH 1.5. The organic phase is separated, shaken with saturated sodium chloride solution, dried over sodium sulphate and evaporated. After digestion of the residue with ether, the title compound c) is obtained with a melting point of 107 - 10 9°C.

d) 2-(2-di-BOC-aminooxazol-4-yl)-2-formamidoacetic acid ester

To a solution of 5.5 g of the formate salt of the 2-(di-BOC-aminooxazol-4-yl)-2-aminoacetic acid methyl ester, in 15 ml of methylene chloride, at -5°C to 0°C, 4 ml of triethylamine and then a solution of 1.6 g of methanesulfochloride in 7 ml of methylene chloride. It is stirred for a further 90 minutes. For work-up, the reaction mixture is evaporated, the residue is dissolved in 1 acetic acid ethyl ester and shaken in sequence with saturated sodium bicarbonate solution, water, 1N hydrochloric acid and saturated sodium bicarbonate solution. After drying the organic phase over sodium sulfate and evaporation, the title compound d) is obtained as crude product, which is used without purification.

e) 2-(2-di-BOC-aminooxazol-4-yl)-2-aroinoacetic acid methyl ester formate

2 g of 2-(2-di-BOC-aminooxazol-4-yl)-2-Z-methoxyiminoacetic acid methyl ester are dissolved in 12.5 ml of formic acid, 12.5 ml of methanol and 1.25 ml of water. At approx. 0 - 10°C, 15.9 g of zinc dust are added in portions over 30 minutes. After 30 minutes of stirring at this temperature, the solid is filtered off under suction and the filtrate is evaporated. The residue is dissolved in water and shaken out with ether. After lyophilization of the aqueous phase, the title compound e) is obtained as a formate salt.

f) 2-(2-di-BOC-aminooxazol-4-yl)-2-Z- methoxyiminoacetic acid methyl ester

9.9 g of 2-(2-aminooxazol-4-yl)-2-Z-methoxyiminoacetic acid methyl ester are suspended in 32.7 g of di-tert-butyl dicarbonate. After adding 0.5 g of 4-dimethylaminopyridine, it is stirred for 30 minutes at room temperature, whereby dissolution occurs little by little. The solution is diluted with acetic acid ethyl ester and shaken successively with saturated sodium chloride solution, Q,\ N hydrochloric acid and again with saturated sodium chloride solution„. The organic phase is dried over sodium sulfate and evaporated under vacuum. The residue is crystallized from hexane. The title compound f) melts at 85 - 87°C.

g) 2-(2-aminooxazol-4-yl)-2-Z- methoxyiminoacetic acid methyl ester

47.6 g of 4-bromo-2-methoxyiminoacetic acid methyl ester and

120 g of urea are heated in 480 ml of dimethylformamide for 1 hour at 100°C, add a further 30 g of urea and allow the reaction to take place for a further 1 hour at 100°C. The dark reaction mixture is poured into ice water, extracted thoroughly with acetic acid ethyl ester, the organic phase is shaken three times with water and twice with saturated sodium chloride solution and dried over sodium sulfate. After evaporation under vacuum, the title compound g) is crystallized from an acetic acid ethyl ester-diethyl ether mixture. Melting point 142 - 147°C.

Example 2:

3- acetoxymethyl- 7g-( 2R, S )- 2-( 2- aminooxazol- 4- yl)- 2- formamidoacetamido)- 3- cephem- 4- carboxylic acid pivaloyloxy methyl ester

To a solution of 2.4 g of 3-acetoxymethyl-76-{j2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid sodium salt in 15 ml of dimethylformamide 1.8 ml of iodomethylpivalate are added dropwise at 0° over the course of 5 minutes and the mixture is stirred for a further 1 hour at room temperature. The reaction mixture is diluted with acetic acid to ester, the solution is shaken with saturated sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica gel 60 with methylene chloride-ethyl acetate 1:1 and ethyl acetate,

and provides the title compound.

Example 3:

a) The sodium salt of 3- acetoxymethyl- 7£- [( 2R, S)- 2-( 2- B0C-aminothiazol-4- yl) - 2- formamidoacetamido] - 3- cephem- 4-carboxylic acid

The crude 3b) acetoxymethyl-78-Q2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester which can be obtained according to example 3b), is suspended in 2 ml of anisole. After adding 10 ml of trifluoroacetic acid, the reaction mixture is stirred for one hour at room temperature and evaporated under vacuum at a temperature just under 40°C. The oily residue is added to 100 ml of ether with stirring. The resulting crystalline precipitate is filtered off, washed with ether, dissolved in a mixture of 5 ml of water and 25 ml of methanol and the solution is adjusted to a pH value of 7.2 with 1 N sodium hydroxide solution. The solution is evaporated under vacuum and the concentrate is chromatographed on an adsorption resin, e.g. Amberlite ER-180 (r). The product-containing fractions eluted with water are combined, evaporated under vacuum and then lyophilized in high vacuum. The obtained title compound contains 5.3% water and exists as a mixture of diastereomers where the S-diastereomer predominates over the R-diastereomer in the ratio approx. 3.5:1; IR (Nujol): 3310, 3200, 1765, 1670, 1610, 1520, 1235.

b) 3- acetoxymethyl- 7B- [( 2R, S) - 2- ( 2- BOC- aminothiazol-4- yl) - 2- formamidoacetamido] - 3- cephem- 4- carboxylic acid redi f phenyl methyl ester

To a solution of 1.5 g (0.005 Mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid, 2.19 g (0.005 Mol) 3-acetoxymethyl-76- amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 0.90 g (0.006 Mol) 1-hydrobenztriazole)

(water content approx. 10%) in 30 ml tetrahydrofuran which has been cooled to -5°C, a solution of 1.13 g

(0.0055 Mol) of dicyclohexylcarbodiimide in 15 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour at 0°C and 12 hours

at room temperature, then filtered and the filtrate evaporated under vacuum. Ethyl acetate was added to the residue, so that the title compound b) precipitated out.

c) (2R.S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid

To a 0°C cooled suspension of 10 g (0.0366 Mol) (2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid in a mixture of 100 ml of tetrahydrofuran and 100 ml of glacial acetic acid, 80 ml of formic acetic anhydride is added while stirring over the course of 5 minutes. The reaction mixture, which little by little dissolves, is stirred for a further 1 hour at 0°C and then evaporated under vacuum at just under 40°C. Dissolve the contents of the flask in 100 ml of toluene, evaporate again under vacuum and dissolve the residue in 100 ml of ethyl acetate. On cooling to 0°C, the title compound c) crystallizes out, which after washing with ethyl acetate and ether at 127°C melts during decomposition.

d) ( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2- formamidoacetic acid ethyl ester and ( 2R, S)- 2-( 2- BOC- aminothiazol- 4- yl)- 2- formamidoacetic acid 33 ml of formic acetic anhydride is added over 10 minutes at 5-10°C to a well-stirred solution of 10 g (0.0332 Mol) (2R,S)-2-amino-2-(2-BOC-aminothiazol-4 -yl)-acetic acid ethyl ester in 30 ml of acetic acid. After 20 minutes, the cooling bath is removed, the reaction mixture is stirred for a further 3 hours and then evaporated under vacuum at less than 40°C. The residue is distributed between ethyl acetate and ice-cold aqueous sodium bicarbonate solution, the organic phase is washed successively with 2N citric acid, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then it is dried over sodium sulfate and evaporated. The crude product is purified by chromatography over silica gel with a particle size of 0.063 - 0.200 mm using methylene chloride and methylene chloride/methanol (30:1) as eluent. The product-containing fractions are evaporated and recrystallized from ether/hexane. The obtained (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid ethyl ester, which melts at 110 - 114°C, is dissolved in a mixture of 10 ml of methanol and 30 ml of 1N caustic soda. It is stirred for 20 minutes at room temperature, then 30 ml of 1N hydrochloric acid is added and the reaction mixture is extracted with ethyl acetate. The organic phase washed with a little water is dried over sodium sulphate and evaporated. Thereby, the (2R,S)-2-(2-BOC-aminothiazol-4-y1)-2-formamidoacetic acid crystallizes out, which after washing with ether at 125°C melts during decomposition.

Example 4:

a) The sodium salt of 3- acetoxymethyl- 73~ Q2R, S)- 2-( 2-aminothiazol-4- yl)- 2- formamido- acetamido]- 3- cephem-4- carboxylic acid 3.4 g (0.0047 Mol ) 3-acetoxymethyl-73-(2R)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido -3-cephem-4-carboxylic acid diphenylmethyl ester is suspended in 3 ml of anisole. After adding 15 ml of trifluoroacetic acid dropwise over the course of 5 minutes, the reaction mixture is stirred for a further hour at room temperature, evaporated at less than 40°C under vacuum and 100 ml of ether is added to the oily residue while stirring. The resulting precipitate is filtered off, split with ether, dissolved in a mixture of 40 ml of methanol and 10 ml of water and the solution is adjusted with 1N sodium hydroxide solution at a pH value of 7.2. The solution is evaporated under vacuum to a volume of approx. 10 ml and the concentrate is chromatographed on an absorption charoix, e.g. Amberlite ER-180. The product-containing fractions eluted with water and a water/isopropanol mixture (92.5:7.5) are combined, evaporated under vacuum and lyophilized under high vacuum.

The obtained title compound contains 4.8% water; £oQ =

+36^ 1° (0.517% in H 2 O); IR (Nujol): 3310, 3200, 1765, 1670, 1610, 1520, 1235.

b) 3- acetoxymethyl- 7B-[( 2S) - 2- ( 2- aminothiazol- 4- y 1) - 2- formamidoacetamido) - 3- cephem- 4- carboxylic acid

Analogous to example 4a), starting from 3.3 g of 3-acetoxymethyl-73-[(2S)-2-(2-BOC-aminothiazol-4-y1)-2-formamidoacetamidoj-3-cephem- 4-carboxylic acid diphenyl methyl ester after addition of 3 ml of anisole and 15 ml of trifluoroacetic acid the title compound b) with a water content of 4.8%;

a = +102 - 1° (0.366% in H 2 O); IR (Nujo): 3310, 3200, 1765, 1670, 1610, 1520, 1235.

c) 3- acetoxymethyl- 7B- [( 2R) - 2- ( 2- BOC- aminothiazol- 4- yl) - 2- formamido- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester and 3- acetoxymethyl- 7B- £( 2S)- 2-( 2- BOC-aminothiazol-4-yl)- 2- formamidoacetamido^ - 3- cephem- 4- carboxylic acid di f enyl methyl ester

To -5°C cooled solution of 3.01 g (0.01 Mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid, 4.38 g (0.01 Mol) 3-acetoxymethyl-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 1.8 g (0.012 Mol) 1-hydroxybenztriazole (water content approx. 10%) in 70 ml of tetrahydrofuran, a solution of 2.26 g ( 0.011 Mol) of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 1 hour at 0°C and 2 hours at room temperature, filtered after standing overnight and the filtrate evaporated under vacuum. Dissolve the residue in 100 ml of tetrahydrofuran, add to the solution 50 g of silicon dioxide gel with a particle size of 0.063-0.200 mm and evaporate the slurry in a rotary evaporator at less than 40°C. The mixture is added to 100 ml of hexane, evaporated, suspended in 100 ml of hexane and transferred to a rapid column equipped with 600 g of silicon dioxide gel with a particle size of 0.04-0.063 mm. The mixture is separated with an ethyl acetate/hexane mixture (4:1) at a pressure of 0.4 bar. The R-title compound, melting point 128-132°C, and the S-title compound, melting point 163-167°C are obtained.

Example 5:

The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-L(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4 - carboxylic acid

Analogous to example 3b), reacting a solution of 2.26 g (0.0075 Mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid, 3.71 g (0.0075 Mol), 3-(1-methyl-1H-tetrazol-5-ylthio-methyl)-78-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 1.24 g (0.0083 Mol) 1-hydroxybenztriazole in 60 ml tetrahydrofuran, as well as a solution of 1.63 g (0.0079 Mol) dicyclohexylcarbodiimide in 20 ml tetrahydrofuran, 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B- [(2R,S)- 2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamidoJ-3-cephem-4-carboxylic acid diphenyl methyl ester; melting point 182°C (during decomposition).

This is treated analogously to example 3a) with a mixture

of 15 ml of trifluoroacetic acid and 3 ml of anisole. The isolation of the product takes place chromatographically on an absorption resin,

e.g. Amberlite ER-180, whereby water and a water/isopropanol mixture (19:1) are used as eluent. The title compound obtained after lyophilization contains 4.1% water; [cf] = -19- 1° (0.516% in H20) ; IR (Nujol): 3315, 3200, 1768, 1670, 1610, 1520).

Example 6:

a) The sodium salt of 3- carbomoyloxymethyl- 7B- C( 2R)- 2- (2-aminothiazol-4-yl)-2-formamido-acetamido]-3-cephem-4- carboxylic acid

Analogously to example 4a), starting from 3.3 g of 3-carbamoyloxymethyl-7B-2-|T2-BOC-aminothiazol-4-yl)-2-formamidoacetamido]}-3-cephem-4-carboxylic acid diphenyl methyl ester after addition of 3 ml of anisole and 15 ml of trifluoroacetic acid, the title compound a) with a water content of 6.6%;

£a] = +29 - 1° (0.552% in H20) ; IR (Nujo) ; 3318, 3200,

1765, 1668, 1610, 1518).

b) 3- carbamoyloxymethyl- 7$- C( 2S)- 2-( 2- aminothiazol-4- yl)-2- formamido- acetamido]- 3- cephem- 4- carboxylic acid

Analogous to example 4a), starting from 3.3 g of 3-carbamoyloxymethyl-7B-£(2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamide 5j -3-cephem-4 -carboxylic acid diphenylmethyl-

ester after the addition of 3 ml of anisole and 15 ml of trifluoroacetic acid, the title compound b) with a water content of

6.5%; [aj= +92 - 1°; IR (Nujol) : 331 8, 3200 , 1 765 , 1668, 161 0, 1518.

c) 3- carbamoyloxymethyl- 7B- [( 2R)- 2-( 2- BOC- aminothiazol- 4- yl)- 2- formamidoacetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester

and 3- carbamoyloxymethyl- 7B- C( 2S)- 2-( 2- BOC- aminothiazol- 4- y1)-2- formamido- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester

To a solution cooled to -5°C of 1.13 g (0.00375 Mol) (2R,S)-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid, 1.65 g (0.00375 Mc 3-carbamoyloxymethyl-7'B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 0.62 g (0.00413 mol) 1-hydroxybenztriazole (water content approx. 10%) in 30 ml tetrahydrofuran, a solution of 0.81 g (0.00393 Mol) dicyclohexylcarbodiimide in 10 ml tetrahydrofuran is added dropwise. The reaction mixture is stirred for 1 hour at 0°C and for 12 hours at room temperature, filtered and the filtrate is evaporated under vacuum. The residue is distributed between ethyl acetate and ice-cooled aqueous sodium bicarbonate solution, wash the organic phase sequentially with 2N citric acid, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry over sodium sulfate and evaporate under vacuum. - 0.06 mm At a pressure of 0.25 bar, elute with an ethyl acetate/hexane mixture (2:1) the R-title compound and with ethyl acetate the S-title compound.

Example 7:

a) The sodium salt of 7B-C(2R)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid

2.5 g (0.00385 Mol) 7B-(j2R)-2-(2-BOC-aminothiazol-4-yl)-2-

formamidoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is suspended in 3 ml of anisole. After adding 15 ml of trifluoroacetic acid, the reaction mixture is stirred for 15 minutes at room temperature, evaporated at less than 40°C under vacuum and 100 ml of ether is added with stirring to the oily residue. The resulting precipitate (trifluoroacetic acid salt of the title compound) is filtered off, washed with ether and a mixture of 30 ml of water and 30 ml of methanol is added. It is then evaporated with 1N sodium hydroxide

solution to a pH value of 7.2 set solution under vacuum and chromatograph the concentrate on an absorption resin, e.g. Amberlite ER-180^. The product-containing fractions eluted with water are combined, evaporated under vacuum and then lyophilized under high vacuum. The title compound obtained a) contains 6.3% water; £ofJ = +95 - 1°

(0.559% in H 2 O>; IR (Nujol) : 3290, 3185, 1755, 1680, 1645, 1595, 1515.

b) 73- £( 2S)- 2-( 2- aminothiazol-4-yl)- 2- formamidoacetamido)-3-cephem- 4- carboxylic acid

Analogous to example 7a), starting from 2.1 g (0.00323 Mol) 73- [(2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido]-3- cephem-4-carboxylic acid diphenyl methyl ester the title compound b) with a water content of 5.4%;

[αj =<+>160 - 1° (c = 0.584 in% in H20) ; IR (Nujol): 3270 ,

3190, 1755, 1650, 1600, 1520.

c) 73-£(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido). - 3- cephem- 4- carboxy lsy re

7.14 g (0.011 mol) of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamido-acetamidoj-3-cephem-4-carboxylic acid diphenyl methyl ester are suspended in 6 ml of anisole and 30 ml of trifluoroacetic acid are added at room temperature while stirring over the course of 5 minutes.

Stir for a further 20 minutes and then evaporate the reaction mixture at approx. 30°C under vacuum. After adding 150 ml of ether to the oily residue, the precipitate formed (trifluoroacetic acid salt of the title compound) is filtered off, washed with ether and dissolved in a mixture of 30 ml of methanol and 7.5 ml of water. It is then evaporated with 1N caustic soda to a pH value of 7.2, the solution adjusted under vacuum and the concentrate chromatographed on an absorption resin, e.g. Amberlite ER-180®,

whereby one elutes first with water, then with a water/isopropanol mixture (19:1). The product-containing fractions are combined, evaporated under vacuum and lyophilized under high vacuum. The obtained title compound c) contains 7.1% water and exists as a mixture of diastereomers,

where the R component dominates over the S component in the ratio approx. 4:3; JV] = + 107<1>1° (0.487% in H2O); IR (Nujol): 3300, 3195, 1760, 1665, 1600, 1515.

d) 73- C( 2R) - 2- ( 2- BQC- aminothiazol-4- yl)- 2- formamidoacetamidcj - 3- cephem- 4- carboxylic acid diphenyl methyl ester and 7 3- £( 2S)- 2-( 2- BOC- aminothiazol-4- yl)- 2- formamidoacetamido] - 3- cephem-4- carboxylic acid diphenyl methyl ester

Analogous to example 4c), 10 g (0.0332 Mol) are reacted

(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid with 12.6 g (0.0332 Mol) 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. The separation of the formed diastereomer mixture takes place by means of flash chromatography on 1,000 g of silica gel with a particle size of 0.04-0.063 mm, whereby by elution with ethyl acetate and hexane (3:1) the (R)-title compound and with ethyl acetate/hexane (4:1) The (S) title compound is obtained as crude products.

e) 76- f( 2R, S) - 2- ( 2- BOC- aminothiazol- 4- yl) - 2- formamido-acetamido) - 3- cephem- 4- carboxylic acid diphenyl methyl ester

Analogous to example 4c), 5 g (0.0166 Mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid and 6.08 g (0.0166 Mol) 76 -amino-3-cephem-4-carboxylic acid diphenyl methyl ester. The product is purified by flash chromatography on 600 g of silicon dioxide gel with a particle size of 0.04 - 0.063 mm, whereby the title compound e) is obtained as a crude product by elution with a mixture of methylene chloride/methanol (25:1).

Example 8:

a) The sodium salt of 76~ C( 2R)- 2-( 2- aminothiazol- 4- yl)- 2-formamidoacetamidoj - 3- cephem- 4- carboxylic acid pivaloy 1-oxymethyl ester

To a suspension of 0.746 g (0.00172 Mol) of the sodium salt of 76-[(2R)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid (water content 6, 3%) in 7 ml of dimethylformamide, 0.52 g (0.00215 Mol) of iodomethylpivalate is placed at 5°C. The reaction mixture is stirred for 1 hour at 10°C and then distributed between 50 ml of ethyl acetate and 20 ml of water. The organic phase is washed successively with ice-cooled saturated sodium bicarbonate solution, water and saturated sodium bicarbonate solution, evaporated under vacuum and 30 ml of ether is added to the residue while stirring. Thereby, the desired compound precipitates out in crystalline form. The further purification takes place by means of rapid chromatography and silicon dioxide gel with a particle size of 0.04 - 0.063 mm. A methylene chloride/methanol mixture (15:1) is used for elution. The obtained R-title compound melts at 175-180°C;

[aj = + 52 - 1° (0.465% in H 2 O) .

b) 73- C( 2S)- 2- ( 2- aminothiazol-4- yl)- 2- formamidoacetamido) - 3-cephem- 4- carboxylic acid pivaloyloxymethyl ester

Analogously to example 8a), starting from the sodium salt of 73~£(2S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid and iodomethylpivalate S-title compound is obtained , melting point 173 - 175°C;

[a] = + 105<*>1° (0.464% in H20) .

Example 9:

The sodium salt of 3-(1,2,3-thiadiazol-5-ylthiomethyl)-73-{! t2R, S)- 2-( 2- aminothiazo1- 4- yl)- 2- formamidoacetamidoj- 3- cephem- 4- carboxylic acid

A solution of 1.6 g (0.00319 Mol) adjusted to pH 7

of the sodium salt of 3-acetoxymethyl-73-£(2R)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid and 0.64 g of sodium 1,2,3 -thiadiazole-5-thiolate dihydrate (0.00363 Mol)

in 20 ml of water is stirred for 5 hours at 75°C. By successive addition (at intervals of 45 minutes) of 0.1N caustic soda to the reaction mixture, neutral reaction conditions are maintained. The reaction mixture is then evaporated to a volume of approx. 5 ml and chromatographed on an absorption resin,

e.g. Amberlite ÉR-180<®>, eluting first with water,

then with water/isopropanol mixture (19:1). The product-containing fractions are combined, evaporated under vacuum and then lyophilized under high vacuum. The obtained title compound contains 8% water and exists as a mixture of diastereomers, where the R component dominates over the S component in the ratio of approx. 2:1; |cQ = -30 - 1° (0.582% in H20) ;

IR (Nujol); 3300, 3190, 1760, 1660, 1600, 1515.

Example 10:

a) The sodium salt of 3-(1,2,3-thiadiazol-5-ylthiomethyl)-73~ [(2R)-2-(2- aminothiazol-4-yl)-2-formamidoacetamido^-3-cephem-4- carboxylic acid

A solution of 5.4 g (0.00692 Mol) 3-(1,2,3-thiadiazol-5-ylthiomethyl)-7 3-[( 2R )-2-(2-BOC-aminothiazol-4-yl) -2-formamidoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 7.5 ml anisole and 37.5 ml trifluoroacetic acid is stirred for 2 hours at room temperature and then evaporated under vacuum at a maximum of 40°C. After adding 160 ml of ether to the oily residue, a precipitate is formed by stirring, which is filtered off, washed with ether, dried and suspended in a mixture of 40 ml of methanol and 20 ml of water. The suspension is adjusted with 2N sodium hydroxide solution to a pH value of 7.2, the resulting solution is evaporated under vacuum at a maximum of 40°C and the resulting concentrate is chromatographed on an absorption resin, e.g. Amberlite ER-180<®>, (column diameter 3 cm; column height 30 cm). Elute first with water, then with a water/isopropanol mixture (19:1). The still slightly contaminated product-containing fractions are combined, evaporated under vacuum at a maximum of 40°C and lyophilized under high vacuum. For further purification, the lyophilisate (2.1 g) is dissolved in 8 ml of water and chromatographed on 150 g of silylated silica gel, e.g. OPTI-UP C12 ' with particle size 0.04 - 0.063 mm. Elute first with water (500 ml) and then with a mixture (200 ml) of water and acetonitrile (97:3). The product-containing fractions are combined, evaporated under vacuum at 40°C and lyophilized under high vacuum. The obtained title compound b) contains 5.9% water; [aj = -55 - 1° (0.491% in H20) ; IR (Nujol): 3305, 3190, 1765, 1668, 1605, 1505.

b) 3-(1,2,3-thiadiazol-5-ylthiomethyl-7B-C(2S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid

A solution of 3.1 g (0.00397 Hol) 3-(1,2,3-thiadiazol-5-ylthiomethyl)-73-(j2S)-2-(2-BOC-aminothiazol-4-yl)-2 -formamidlo-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of anisole and 15 ml of trifluoroacetic acid is stirred for one hour at room temperature and then evaporated under vacuum at a maximum of 40°C. After adding approx. 50 ml of ether to the oily residue, a precipitate forms with stirring, which is filtered off, washed with ether, dried and suspended in a mixture of 30 ml of methanol and 10 ml of water. The suspension is adjusted with 2N sodium hydroxide solution at a pH value of 7.2. This gives an almost clear solution which is filtered and evaporated under vacuum at a maximum of 40°C to a volume of approx. 10 ml. The concentrate is chromatographed on an absorption resin, e.g.

(s)

Amberlite ER-180^ (column diameter 3 cm; column height 30 cm), whereby one elutes first with water, then with a mixture of water and isopropanol (97:3). The product-containing fractions are combined, evaporated under vacuum at a maximum of 40°C and lyophilized under high vacuum. To remove traces of impurities, the lyophilisate is dissolved in 15 ml of water and purified by means of rapid chromatography on 90 g of silylated silica gel, e.g. OPTI-UP C12 with particle size 0.04 - 0.063 mm, whereby one elutes first with water (500 ml) and then with a mixture (1000 ml) of water/acetonitrile (98:2). The product-containing fractions are combined, evaporated under vacuum at a maximum of 40°C and lyophilized under high vacuum. The obtained title compound c) contains 6.4% water; yes] = +2 - 1°

(0.421% in H 2 O); IR (Nujol): 3305, 3200, 1762, 1668, 1605, 1515.

c) 3-( 1, 2, 3- thiadiazol-5- ylthiomethyl)- 73- £( 2R)- 2-( 2- BOC-aminothiazol-4- yl)- 2- formamidoacetamidol - 3- cephem- 4-carboxylic acid diphenyl methyl ester and 3-(1,2,3-thiadiazol-5-ylthiomethyl)-73-C(2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester

To a solution cooled to -5°C of 9.0 g (0.0181 Mol) 3-(1,2,3-thiadiazol-5-ylthiomethyl)-7 8-amino-3-cephem-4-carboxylic acid diphenyl methyl ester [Preparation see J. Med.

Chem. 22, 121 4 (1979)], 5.46 g (0.0181 Mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid and 3.26 g (0 .0217 Mol) 1-hydroxybenztriazole (water content approx. 10%)

a solution of 4.12 g (0.02 mol) dicyclohexylcarbodiimide in 40 ml of tetrahydrofuran is dripped into 100 ml of tetrahydrofuran over the course of 15 minutes. React the ion mixture. stirred for 1 hour at 0°C and 14 hours at room temperature, then filtered and the filter contents washed with tetrahydrofuran. After adding to the filtrate 60 g of silica gel with a particle size of 0.06 - 0.2 mm, the slurry is evaporated on a rotary evaporator at a maximum of 40°C until dryness and the silica gel charged with the substance mixture is transferred to a rapid column equipped with 1 kg of silica gel with particle size 0.04 - 0.06 mm (in ethyl acetate/hexane 2:1). By elution with an ethyl acetate/hexane mixture (mixing ratio ethyl acetate/hexane during the course of chromatography increasing from 2:1 to 9:1), the crude (R) title compound with an Rf value of 0.18 (DC -finished plates, mark, silicon dioxide gel 60 F254'etYl~acetate/hexane 4:1) and a melting point (within foaming) of

about. 120°C, a mixture of R and S title compound as well as the crude S title compound with an Rf value of 0.11.

After recrystallization of the mixture fraction from methanol/ethyl acetate, the S-title compound is obtained again.

Both fractions with S-title compound obtained by flash chromatography and by recrystallization are combined and suspended for approx. 40 ml of methanol. One stirs for 3 hours

at room temperature, filters and washes filter in-

the mixture with a little methanol and ether. The title compound S thus obtained melts at 164° - 166°C

(during foaming).

d) 3-( 1, 2, 3" thiadiazol-5- ylthiomethyl)- 7g- C( 2S)- 2-( 2- BOC- aminothiazol- 4- yl)- 2- formamidoacetaminol - 4-cephem- 4- carboxylic acid diphenyl methyl ester

can also be obtained in the following way:

To a solution cooled to -5°C, .of 4.96 g (0.01 Mol) 3-(1,2,3-thiadiazol-5-ylthiomethyl)-7|3-amino-3-cephem-4- carboxylic acid diphenyl methyl ester, 3.01 g (0.01 Mol) (2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid and 1.80 g (0.012 Mol) 1-hydroxybenztriazole (water content approx. 10 %)

in 75 ml of tetrahydrofuran, a solution of 2.27 g (0.011 mol) of dicyclohexylcarbodiimide in 25 ml of tetrahydrofuran is dripped over the course of 10 minutes. The reaction mixture is stirred for 1 hour at 0°C and 5 hours at room temperature, then filtered and the filtrate evaporated under vacuum. The residue is partitioned between ethyl acetate and ice-cooled aqueous sodium bicarbonate solution, the organic phase is washed with saturated ordinary sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. After recrystallization of the residue from methanol/ecphyl acetate, the title compound is obtained, melting

point 164° - 166°C (while foaming). It is identical to the (S)-title compound obtained according to example 10d).

Example 11: (2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid To a solution of 21.09 g (0.07 Mol) (2R,S)-2-(2-BOC -aminothiazol-4-yl)-2-formamidoacetic acid in 250 ml of methanol, a solution of 8.48 g (0.07 Mol) S(-)-1-phenylethylamine in 50 ml of methanol is placed under stirring at room temperature. Already after approx. After 2 minutes, crystallization begins, after which the crystal mass is still stirred for another hour at room temperature. After suctioning off and washing the filter residue twice each time with 50 ml of methanol, the crude S(-)-1-phenyl-ethylammonium salt of (2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid is suspended in

400 ml of ethanol and the suspension is boiled for 45 minutes under reflux. Cool to room temperature, filter and wash with 100 ml of cold ethanol. The residue is suspended once more in 400 ml of ethanol, boiled for 15 minutes under reflux, filtered after cooling to room temperature and washed with 100 ml of cold ethanol. The S(-)-1-phenyl-ethylammonium (2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetate dried at 60°C in high vacuum melts with decomposition at 201° to 202°C .

11.5 g (0.027 Mol) of this salt are distributed with vigorous stirring between a mixture of 186 ml of water plus 37 ml of 1N hydrochloric acid and 310 ml of a mixture of ethyl acetate/methanol (9:1). The organic phase is separated and the aqueous phase is washed three times with 50 ml of ethyl acetate each time.

The combined organic phases are washed with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. The residue is crystallized twice each time from 200 ml of acetonitrile. After drying at 260°C in high vacuum, the title compound melts with decomposition at 115°-120°C; (aj = +169.9<->1.8° (0.562%

in methanol).

Example 12:

a) The sodium salt of 3-(1H-1,2,3-triazol-4(5)-ylthiomethyl)-73-p2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3 -cephem- 4- carboxylic acid

0.53 g (0.695 mmol) 3-(1H-1,2,3-triazol-4(5)-ylthiomethyl-

76- £(2R,S) -2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamidoj-3-cephem-4-carboxylic acid diphenyl methyl ester is stirred in a mixture of 2 ml of anisole and 10 ml of trifluoroacetic acid in | hour at room temperature. The reaction mixture is then evaporated at a maximum of 30°C under vacuum. After adding approx. 30 ml of ether to the oily residue, a precipitate forms on stirring which is filtered off, washed with ether, dried and suspended in a mixture of 4 ml of methanol and 2 ml of water. The suspension is adjusted with a 1N sodium hydroxide solution at a pH value of 7.2, the resulting solution is evaporated under vacuum and the concentrate is chromatographed on an adsorption resin, e.g. Amberlite water, ER-180, whereby one elutes first with water, then with a water/isopropanol mixture (97.5:2.5). The product-containing fractions are combined, evaporated under vacuum and lyophilized under high vacuum. The title compound obtained a) contains 6.2% water; [a] = -27° 1° (0.537% in H20) ; IR (Nujol): 3305, 3192, 1760, 1670, 1600, 1518.

b) 3-(1H-1,2,3-triazol-4(5)-ylthiomethyl)-7 6-[(2R,S)-2-(2-BOC-amino-thiazol-4-yl)-2 - f ormamidoacetamidectl - 3-cephem- 4- carboxylic acid diphenyl methyl ester

To a solution cooled to -5°C of 0.301 g (0.001 Mol)

(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid,

0.48 g (0.001 Mol) 3-(1H-1,2,3-triazol-4(5)-ylthiomethyl)-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 0.18 g (0.0012 Mol ) 1-hydroxybenztriazole (water content approx. 10%) in 7.5 ml of tetrahydrofuran, a solution of 0.226 g (0.0011 mol) of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran is dripped. The reaction mixture is stirred for T hours at 0°C and 5 hours at room temperature, then filtered and the filtrate evaporated under vacuum. The residue is taken up in ethyl acetate, the organic phase is washed with aqueous

sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry over sodium sulfate and concentrate under vacuum. The residue is purified by flash chromatography on silicon dioxide gel with a particle size of 0.04 - 0.063 mm, whereby the title compound b) is obtained as a crude product by elution with ethyl acetate.

Example 13:

a) The sodium salt of 3- azidomety 1- 7 B- C( 2R, S)- 2-( 2- aminothiazol- 4- y1)- 2- formamido- acetamido) - 3- cephem- 4- carboxylic acid

Analogously to example 12a), starting from 0.4 g of 3-azidomethyl-7B- [(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido] -3- cephem-4-carboxylic acid diphenyl methyl ester the title compound a) with a water content of 6.2%;

[aj = +76 - 1° (0.415% in H20) ; IR (Nujol): 3310,

3195, 2112, 1765, 1672, 1610, 1520.

b) 3-azidomethyl-7B-C(2R)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid

Analogous to example 12a), starting from 0.8 g of 3-azidomethyl-7B-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-formamido-acetamidoj-3-cephem -4-carboxylic acid diphenyl methyl ester, the title compound b) with a water content of 3.8%;

[a] = + 34-1° (0.494% in H20) ; IR (Nujol): 3305, 31 92 ,

2110, 1763, 1670, 1605, 1518.

c) 3-azidomethyl-7B-C(2S)-2-(2-aminothiazol-4-yl)-2-formamido-acetamidoj-3-cephem-4-carboxylic acid

Analogously to example 12a), starting from 0.8 g of 3-azidomethyl-7B~[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester the title compound c) with a water content of 7.3%;

[<_>a]= + 100 - 1° (0.517% in H20) ; IR (Nujol): 3305, 3190, 21 10, 1762, .1668, 1606, 1516.

d) 3- azidomethyl- 7B- C( 2R)- 2-( 2- BOC- aminothiazol- 4- yl)- 2- formamido- acetamidoj - 3- cephem- 4- carboxylic acid diphenyl ester and 3- azidomethyl- 7B-^ ( 2S)- 2-( 2- BOC- aminothiazol-- 4- yl)- 2- formamidoacetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester

Analogous to example 12b), 2.14 g (0.0071 Mol) are reacted

(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid

with 3 g (0.0071 Mol) of 3-azido-methyl-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. The separation of the formed diastereomer mixture takes place by means of rapid chromatography on silicon dioxide gel with a particle size of 0.0 4 - 0.06 3 mm, whereby by elution with a hexane/ethyl acetate mixture (mixing ratio hexane/ethyl acetate during the chromatography process decreasing from 2 :1 to 1:4) the (R)-title compound, melting point 151°-160°C (decomp.) and the (S)-title compound, melting point 161°-166°C (decomp.) are obtained successively as crude product.

e) 3- azidomethyl- 7B- [( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2- formamido- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester

Analogous to example 12b), 0.461 g (0.00153 Mol), T2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-formamidoacetic acid is reacted with 0.645 g (0.00153 Mol) 3-azidomethyl -7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. The purification of the product takes place by means of flash chromatography on silicon dioxide gel with a particle size of 0.04 - 0.063 mm, whereby the title compound e) is obtained as a crude product by elution with ethyl acetate/hexane (2:1).

Example 14: 3-(2,3-cyclopentenopyridiniomethyl)-73-C(2R)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylate To a solution of 0.477 g (0.001 Mol) sodium salt of 3-acetoxymethyl-73-[( 2R )-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid and 2.25 g (0.015 Mol) sodium iodide in 2 ml of water, 0.238 g (0.002 Mol) of 2,3-cyclopentenopyridine is added. The reaction mixture is stirred for 2.5 hours at 75°C and then chromatographed on an adsorption resin, e.g. Amberlite ER-180<®>, whereby water and a mixture of water and isopropanol (19:1) are used as eluent. The product-containing fractions are combined, evaporated under vacuum and lyophilized under high vacuum. The title compound obtained contains 10.0% water; IR (Nujol)® : 3305, 3200, 1769, 1666, 1615, 1515.

Example 15:

Analogous to example 1-14, the following compounds are obtained: 12.01. Sodium salt of 73-[(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid, IR (Nujol): 3300, 3195, 1.760, 1658, 1602 , 1520. 12.02. Sodium salt of 3-(1H-1,2,3-triazol-4(5)-ylthiomethyl)-73- [(2R,S)-2-(2-amino-oxazol-4-yl)-2-formamidoacetamido] -3-cephem-4-carboxylic acid, IR (Nujol): 3310, 3195, 1760, 1662, 1600, 1515.

o

12.03. Sodium salt of 3-(1,2,3-thiazol-5-ylthiomethyl)-73-Q(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido]-3-cephem-4- carboxylic acid, IR (Nujol): 3305, 3190,

1762, 1660, 1605, 1517.

12.04. Sodium salt of 3-(2-methyl-1,3,4-thiazol-5-ylthiomethyl)-73- [(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido) - 3- cephem-4-carboxylic acid, IR (Nujol): 3315, 3200, 1765, 1668, 1610, 1522.

12.05. Sodium salt of 3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-73- [( 2R, S )- 2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3- cephem-4-carboxylic acid, IR (Nujol): 3310, 3197, 1760, 1665, 1602, 1515.

12.06. Disodium salt of 3-(1-carboxymethyl)1H-tetrazol-5-ylthiomethyl)-7 8- [(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidaacetamido]-3-cephem-4 -carboxylic acid, IR

(Nujol): 3320, 3202, 1768, 1610, 1522.

12.07. Disodium salt of 3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-78- [_(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido)-3-cephem-4 -carboxylic acid, IR

(Nujol): 3315, 3198, 1766, 1665, 1608, 1520.

12.08. Disodium salt of 3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-78- [(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido)-3-cephem-4- carboxylic acid,

IR (Nujol): 3315, 3200, 1765, 1668, 1605, 1520.

12.09. Disodium salt of 2-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-78- [(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4- carboxylic acid,

IR (Nujol): 3312, 3200, 1765, 1670, 1608, 1522.

12.10. 3-(3-Bromopyridiniomethyl)-7 6 [(2R, S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido)-3-cephem-4-carboxylate, IR (Nujol): 3310, 3195 , 1765, 1665, 1608, 1515.

12.11. 3-(3-Bromopyridiniomethyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylate, IR (Nujol): 3315, 3198 , 1769,

1664, 1610, 1515.

12.12. 3-(4-carbamoylpyridiniomethyl)-76-[(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamide^-3-cephem-4-carboxylate, IR (Nujol): 3320, 3200 ,

1765, 1665, 1605, 1518.

12.13. 3-(4-Carbamoylpyridiniomethyl)-76-£(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylate, IR (Nujol): 3315, 3198 ,

1765, 1667, 1610, 1515.

12.14. Sodium salt of 78-[(2R,S)-2-(5-amino-1,2,4-thiazol-3-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid, IR (Nujol): 3308 , 3202, 1755, 1663, 1595, 1517.

12.15. 3-(2,3-cyclopentenopyridiniomethyl)-76-[(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamidoj-3-cephem-4-carboxylate, IR (Nujol): 3310, 3200, 1768, 1660, 1612, 1518.

12.16. Sodium salt of 3-(1,2,4-thiadiazol-5-ylthiomethyl)-78- jj2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid, IR (Nujol): 3312, 3195, 1760, 1655, 1600, 1520.

12.17. Sodium salt of 3-azidomethyl-76- [(2R,S)-2-(2-aminooxazol-4-yl)-2-formamidoacetamidoj -3-cephem-4-

carboxylic acid, IR (Nujol): 3310, 3200, 2113, 1765, 1670, 1608, 1520,

their R and S derivatives, the carboxylic acids and physiologically cleavable esters, e.g. pivaloyloxymethyl ester or 1-ethoxycarbonyloxyethyl ester.

Example 16:

Dry ampoules or containers containing 0.5 g, e.g. sodium salt of 3-acetoxymethyl 1-78 - [(2R, S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamidoj-3-cephem-4-carboxylic acid, can be prepared in the following way:

Composition: (for 1 ampoule or container)

Active compound 0.5 g

Mannitol 0.05 g

A sterile aqueous solution consisting of active compound and mannitol is filled under aseptic conditions into ampoules holding 5 ml or containers holding 5 ml, after which these are closed and tested.

Claims (11)

1. Process for the preparation of 76-acylamido-3-cephem-4-carboxylic acid compounds of formula 0 where m is zero, one or two, R.j is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, halogen, a group of the formula -CH2 -R2 , where R-, is a free, esterified or etherified hydroxy or mercapto group, an azido or an ammonium group, or a group of the formula - CH=CHR2 , where R2 is a preferred mercapto group, Rn is carboxy or protected carboxy, and Stf R 1 is heterocyclyl, which is bonded with one of its C atoms to the 2-C atom in the 7B side chain, and salts of these compounds, characterized in that a) a compound of formula where m and have the meanings mentioned under formula 1, R3 means protected carboxy, a functional group present in R^ is protected and the 76-amino group is optionally protected with a group that is compatible with the acylation reaction, the 76-amino group is acylated by reaction with an acylating agent which introduces the acyl residue in a carboxylic acid of formula where R^ has the meaning mentioned under formula 1, and a functional group present in R^ is possibly present in protected form, orb) a compound of formula where m, R^, R^ and R^ have the meanings mentioned under formula 1, and a functional group present in R^ and/or R^ is optionally protected, and the 2-amino group is optionally protected with a group that is compatible with the formylation reaction, converts the 2-amino group into the 2-formamido group by a reaction with a formylating agent, or c) isomerizes a 2-cephem compound of formula where R^ , R^ and R^ have the meanings mentioned under formula 1 and the functional group present in R.j and/or R^, possibly present in protected form, to the corresponding 3-cephem compound with formula 1, or d) for the preparation of a compound of formula 1, where R 1 means 2-aminooxazol-4-yl, or 2-aminothiazol-4-yl, condenses a compound of formula where Hal means halogen, R^ and R^ have the meanings mentioned under formula 1 and a functional group present in R^ is possibly protected, with urea, respectively thiourea, or) for the preparation of a compound of formula 1, where R4 means 5 -amino-1,2,4-thiadiazol-3-y1. reacts a compound with formula where X1 means hydrogen, halogen or hydroxy, R- and R3 have the meanings mentioned under formula 1 and a functional group present in R^ is optionally protected, with a salt of hydrogenrhodanide or, if hydrogen, with dirhodane or f) for the preparation of a compound of formula 1, where R^ is a group of formula -CH2-R2 and R2 means etherified mercapto, reacts a compound of formula 2, where m and R^ have the meanings mentioned under formula 1, and R-| is the group of formula -CH2 -R2, where R2 means a nucleophilic leaving group, with a compound of formula where R^ has the meanings mentioned under formula 1 and R2<1> means lower alkylthio or heterocyclylthio, and, if desired, converts an obtained compound of formula 1 according to the invention into another compound of formula 1 according to the definition, and/or transfers an obtained compound of formula 1 according to the invention, where m means 0, to a compound of formula 1, where m means 1 or 2, and/or transfers a compound of formula 1, where m means 1 or 2, to a compound of formula 1, where m means 0, and/or transfers one in a compound of formula 1 in protected form in the present functional group to a free functional group, and/or transfers an obtained salt to the free compound or to another salt, and/or transfers an obtained free compound with a salt-forming group into a salt, and/or separates an obtained mixture of isomeric compounds with formula 1 into the individual isomers. 2. Compounds according to claim 1 with formula 1, where m is 0, R.j means hydrogen, lower alkyl, lower alkoxy, halogen or a group of formula -CH2~ R2 , where R2 is lower alkanoyloxy, carbamoyloxy, unsubstituted or substituted, monocyclic,. aromatic or bicyclic, aromatic or partially saturated heterocyclylthio, which contains at least one C atom and is connected by a of its C atoms with sulfur, azido or ammonium derived from a tertiary, aliphatic or from an aromatic nitrogen base, R^ is carboxy or under physiological conditions cleavable, esterified carboxy, and R^ is unsubstituted or substituted, monocyclic, aromatic oxaza -, thiaza-, diaza-, thiadiaza-, triaza-, or tetrazacyclyl, as well as pharmaceutically acceptable salts of such compounds with salt-forming groups, characterized by carrying out the process steps mentioned in claim 1. 3. Process for the preparation of compounds according to claim 2 with formula 1, where m is zero and R^ is hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, or a group of the formula -CH2 -R2, where R2 means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, unsubstituted or substituted, monocyclic, aromatic, heterocyclylthio with 1 to 4 nitrogen atoms or with an oxygen or sulfur atom and optionally 1 to 3 nitrogen atoms containing 5 or 6 ring atoms, or bicyclic, aromatic heterocyclylthio with 1 to 3 nitrogen atoms and optionally an oxygen or sulfur atom, containing 5 or 6 atoms per ring, acido or an ammonio group which is formed from an unsubstituted or substituted aromatic heteroring with 1 - 3 nitrogen atoms and a total of 5 or 6 ring atoms, R^ is carboxy or acyloxylavereal oxycarbonyl and R^ is unsubstituted or substituted oxazolyl, thiazolyl, isothiazolyl, imidazolyl, thiadiazoly 1; triazolyl or tetrazolyl, as well as pharmaceutically acceptable salts of such compounds with salt-forming groups, characterized in that the process features mentioned in claim 1 are carried out. 4. Method for producing compounds according to claim 3 with formula 1, where m is zero and R-] is hydrogen or a group of formula -CF^ -I^/ where R2 means lower alkanoyloxy, carbamoyloxy, diaza-, triaza-, tetraza -, thiaza-, thiadiaza-, oxaza- or oxadiazacyclylthio, which may be substituted with loweralkyl, dilaverealkylaminoloweralkyl, sulfolaverealkyl, carboxylaverealkyl, carbamoyl, cyanlaverealkyl, tetrazplylaverealkyl or with oxo, azido, pyridinio, pyridinio which is mono- or disubstituted with loweralkyl, carbamoyl , lower alkylcarbamoyl, hydroxyl lower alkyl, lower hydroxy lower alkyl, cyano lower alkyl, carboxy lower alkyl, sulfola lower alkyl, carboxy lower alkenyl, carboxy lower alkyl thio, thiocarbamoyl, bromine, chlorine, carboxy, sulfo or cyan, pyridinio, which is monosubstituted with lower alkoxyimino lower alkyl or lower alkylene, or pyridinio which is fused with benzene, R ^ is carboxy,. lower real kano <y> 1-oxylavereal oxycarbonyl or lower alkoxycarbonyloxylavereal oxycarbonyl, R^ is aminooxazolyl, aminothiazolyl, aminothiadiazolyl, hydroxythiadiazolyl or aminotriazolyl, and pharmaceutically usable salts of such compounds, characterized by carrying out the method features mentioned in claim 1. 5. Method for producing compounds according to claim 4 with formula 1, where m is zero and R^ is hydrogen or a group of formula -CH2 -R2 , where R^ means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, imidazolylthio, triazolylthio, triazolylthio substituted with lower alkyl, tetrazolylthio, tetrazolylthio substituted with lower alkyl, diloweralkylaminoloweralkyl, sulfoloweralkyl, carboxyloweralkyl, carbamoyl or with tetrazolyloweralkyl, thiazolylthio, thiazolylthio substituted with carboxyloweralkyl and/or loweralkyl, isothiazolylthio , thiadiazolylthio, thiadiazolylthio substituted with a lower alkyl, thiatriazolylthio, oxazolylthio, oxazolylthio substituted with a lower alkyl, isoxazolylthio substituted with a lower alkyl, oxadiazolylthio, oxadiazolylthio substituted with a lower alkyl, 5,6-dioxotetrahydro-as-triazine-3 -ylthio, which is substituted with lower alkyl, azido, pyridinio, pyridinio which is substituted with hydroxy lower alkyl, carboxy, carboxy lower alkyl, halogen, carbamoyl or lower alkylene or condensed with benzene, 2,3-cyclopentenopyridinium or quinolium, R-, is carboxy , lower alkane oyloxyvareal oxycarbonyl or lower alkoxycarbonyloxyvareal oxycarbonyl, and R^ is aminooxazolyl, aminothiazolyl, aminothiadiazolyl or aminotriazolyl, stereoisomers and mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds, characterized by carrying out the method features mentioned in claim 1. 6. Process for the preparation of compounds according to claim 5 with formula 1, where m is zero and R-j means hydrogen or a group of formula -CH2 -R2, where R2 means acetoxy, carbamoyloxy, 1H-1,2,3-triazole-4 (5)-ylthio, 1H-tetrazol-5-ylthio, 1-methyl-1H-tetrazol-5-ylthio, 1(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5 -ylthio, 1,2,3-thiadiazol-4- or -5-ylthio, 1,3,4-thiadiazol-2-ylthio, 1,2,4-thiadiazol-3- or -5-ylthio, 1,2 ,5-thiadiazol-3-ylthio, 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio, azido, pyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromo-pyridinio, 3- or 4-carbamoylpyridinio, 2,3-cyclopentenopyridinio or quinolinio, R means carboxy, pivaloyloxymethoxycarbonyl, 1-propionyloxyethoxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl or tert-butoxycarbonyloxy methoxycarbonyl, and R4 means 2-arainooxazol-4-yl, 2-aminothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, stereoisomers, mixtures of d ice stereoisomers, hydrates and pharmaceutically usable salts of such compounds, characterized in that the process features mentioned in claim 1 are carried out. 7. Process for the preparation of the sodium salt of 3-acetoxymethyl-76-[(2R,S)-2-(2-amino-4-oxazolyl)-2-formamidoacetamido]-3-cephem-4-carboxylic acid, according to claim 6, characterized by carrying out the procedural features mentioned in claim 1. 8. Process for the preparation of the sodium salt of 3-acetoxymethyl-7B-[(2R,S)-2-(aminothiazol-3-y1)-2-formamidoacetamido]-3-cephem-4-carboxylic acid, according to claim 6, characterized by that one carries out the procedural features mentioned in claim 1. 9. Process for the preparation of the sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-73- [(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido] - 3-cephem-4-carboxylic acid, according to claim 6, characterized in that the process features mentioned in claim 1 are carried out. 10. Process for the preparation of the sodium salt of 3-(1,2,3-thiadiazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-formamidoacetamido]- 3-cephem-4-carboxylic acid, according to claim 6, characterized in that the process features mentioned in claim 1 are carried out. 11. Method for producing pharmaceutical preparations containing compounds according to claim 1, with formula 1, characterized in that compounds with formula 1 or salts thereof are prepared according to the method according to claim 1, and mixing these with a pharmaceutical carrier material.