NO843802L - 7BETA-ACYLAMIDO-3-CEFEM-4-CARBOXYLIC ACID ESTIMATE, PROCEDURE FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THEIR USE - Google Patents

Description

The invention relates to a method for production

of physiologically cleavable 7g-acylamido-3-cephem-4-carboxylic acid esters. The esters have therapeutic activity, and are used in pharmaceutical preparations containing these esters, and the esters are used as medicines and for the production of pharmaceutical preparations.

The invention relates to the production of 7g-acylamido-3-cephem-4-carboxylic acid esters with the formula:

hcoei X means nitrogen or the group -C-H, Y means oxygen, sulfur or the group or

averealkyl, A means

methylene or with amino substituted amino, hydroxy, car-. 1-boxy, hydroxyimino or etherified or esterified hydroxyimino substituted methylene, R, means hydrogen, halogen, lower alkyl or lower alkoxy, means hydrogen, lower alkyl, phenyl or substituted phenyl and R^ means unsubstituted or substituted, aromatic five- or six-membered heterocyclyl, phenyl or substituted phenyl, as well as stereoisomeric mixtures of these stereoisomeric salts. The preceding and the following mean that in connection with groups or residues, e.g. lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc, used terms "lower",

that the groups or residues thus designated, if nothing else is expressly stated, contain up to 7 and preferably up to 4 C atoms.

When A means amino substituted amino, hydroxy or carboxy substituted methylene, the C atom of the substituted methylene group A (2-C atoms of the 7B side chain) has R or S configuration. The invention includes the pure R-

and S compounds with respect to this C atom, as well as R, S mixtures of compounds of formula I.

When A means hydroxyimino or etherified or esterified hydroxyimino substituted methylene, the free, etherified or esterified hydroxy group at the doubly basic nitrogen can be in the syn- (or Z-) or anti- (or E-) position, as syn- ( or the Z-) position is preferred. In the syn position, the free, etherified or esterified hydroxy group is directed to the cephem structure, where the anti position is directed in the opposite direction.

R 2 means lower alkyl, phenyl or substituted phenyl, the C atom substituted by R_ has the R or S configuration. The invention includes the pure R and S compound with respect to this C atom, and R, S mixtures of compounds of formula I.

The invention includes all tautomeric forms which correspond to the compounds of formula I, even if only certain tautomeric forms should be mentioned in the description.

The general expressions used here have the following meanings:

Y with the meaning methyl, further

Substituted amino is e.g. lower alkylamino, preferably methylamino, further ethyl-, n-propyl or tert-butylamino, dilower alkylamino, e.g. dimethylamino, lower alkanoylamino, preferably formylamino, further acetylamino, N-lower alkyl-N-lower alkanoylamino, e.g. N-methyl-N-formylamino or N-methyl-N-acetylamino, lower alkylsulfonylamino, preferably methylsulfonylamino (mesylamino), further ethylsulfonylamino, N-1averalkyl-N-lower alkylsulfonylamino, e.g. N-methyl-N-methylsulfonylamino, amino lower alkylsulfonylamino, e.g. 2-aminoethylsulfonylamino (taurylamino), or N-lower alkyl-N-aminolower alkylsulfonylamino, e.g. N-methyl-N-2-aminoethylsulfonylamino.

Ethered hydroxyimino is e.g. lower alkoxyimino, preferably methoxyimino, further ethoxy-, n-propoxy or tert-butoxyimino, cycloalkoxyimino, preferably cyclopropoxyimino, further cyclobutoxy-, cyclopentyloxy- or cyclohexyloxyimino, lower alkenyloxyimino, e.g.

vinyl or allyloxyimino, or carboxylaverealoxyimino, e.g. 1- or 2-carboxyporop-2-yloxyimino, further carboxymethoxyimino.

Esterified hydroxyimino is e.g. carbamoyloxyimino, lower alkylcarbamoyloxyimino, e.g. methylcarbamoyloxyimino or dilavealkylcarbamoyloxyimino, e.g. dimethylcarbamoyloxyimino.

Halogen is preferably chlorine, further fluorine or bromine.

Lower alkyl R has 1-4 C atoms, and is preferably methyl, further ethyl, n-propyl or n-butyl.

Lower oxyR^ has 1-4 C atoms and is preferably methoxy, further ethoxy, n-propoxy or n-butoxy.

Lower alkyl R2 is preferably methyl, further ethyl.

The phenyl residue R ? or R^ can be substituted with 1-3 substituents from the lower alkyl group, e.g. methyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkanoyl, e.g. formyl or acetyl, lower alkanoyloxy, e.g. acetoxy, halogen, e.g. fluorine, chlorine or bromine, nitro, cyan, amino, lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino, lower alkanoylamino, e.g. acetylamino, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, dilower alkylcarbamoyl, e.g. dimethylcarbamoyl, lower alkylsulfonylamino, e.g. methyl- or ethylsulphonylamino, sulphamoyl, lower alkyl sulphamoyl, e.g. methylsulfamoyl, dilavealkylsulfamoyl, e.g. dimethylsulfamoyl or di-n-propylsulfamoyl, halolower alkyl, e.g. chloromethyl or trifluoromethyl, hydroxylaveralky1, e.g. hydroxymethyl, and amino lower alkyl, e.g. aminomethyl or 2-amino-ethyl.

Substituted phenyl or R 1 is preferably lower alkyl, di lower alkyl or tri lower alkyl phenyl, e.g. 4-methyl-, 4-tert.-butyl, 3,4-dimethyl-, 2,3-dimethyl-, 2,4-dimethyl- or 2,4,6-trimethylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, f .ex. 4-hydroxy-, 2,4-dihydroxy-, 2,3,4-trihydroxy-, 2,4,6-trihydroxy- or 3,4,5-trihydroxyphenyl, hydroxy-lower alkylphenyl, e.g. 2-hydroxy-3-methylphenyl, lower alkoxy, dilavereal oxy or trilavereal oxyphenyl, e.g. 4-methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, hydroxy-lower oxyphenyl, e.g. 4-Hydroxy-3-Methoxy-phenyl, Hydroxy-dilaverealoxyphenyl, e.g. 3-hydroxy-2,4-dimethoxyphenyl, lower alkanoylphenyl, e.g. 2-, 3-

or 4-acetylphenyl, lower alkanoyloxyphenyl, e.g. 2-,

3-, 4- or 5-acetoxyphenyl, or 3,4- or 3,5-diacetoxyphenyl, halophenyl, e.g. 2-, 3- or 4-fluoro-or 2-, 3- or 4-chlorophenyl, nitrophenyl, e.g. 2-,

3- or 4-nitrophenyl, cyanophenyl, e.g. 2-, 3- or 4-cyanophenyl, amino- or diaminophenyl, e.g. 2-, 3- or 4-aminophenyl or 3,5-diaminophenyl, amino-hydroxyphenyl, e.g. 3-amino-4-hydroxy- or 4-amino-2-hydroxyphenyl, lower alkylaminophenyl, e.g. 2- or 4-methylaminophenyl, dilaverealkylaminophenyl, e.g. 2-, 3- or 4-dimethylaminophenyl, lower alkanoylaminophenyl, e.g. 2-, 3- or 4-acetylaminophenyl, sulfamoylphenyl, e.g. 2-, 3- or 4-sulfamoylphenyl, halolower alkylphenyl, e.g. 2-, 3-

4- trifluoromethylphenyl, or amino lower alkylphenyl, e.g.

2-, 3- or 4-aminomethylphenyl.

An aromatic five- or six-membered, monocyclic heterocycle R has at least 1 C atom and is one of its C atoms connected to the carbonyl group and contains 1-4 nitrogen atoms or an oxygen or sulfur atom, and optionally 1-3 nitrogen atoms.

Substituents of this heterocycle R^ are, for example, lower alkyl, e.g. methyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkanoyloxy, e.g. acetoxy, halogen,

e.g. chlorine, amino, monolower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino, lower alkanoylamino, e.g. acetylamino, oxo or oxido.

Unsubstituted or unsubstituted aromatic, five-membered heterocyclyl R is, for example, unsubstituted or substituted by the aforementioned substituents aza-, diaza-, triaza-, tetraaza-, thia-, thiaza-, thiadiaza- or oxacyclyl, preferably pyrrolyl, e.g. pyrrol-2-yl, lower alkylpyrrolyl, e.g. 1-methylpyrrol-2-yl, imidazolyl, e.g. imidazol-2-yl, lower alkylimidazolyl, e.g. l-methylimidazol-2-y1, triazole,

e.g. 1H-1,2,3-triazol-5-yl, lower alkyltriazolyl, e.g. 1-methyl-1H-1,2,3-triazol-5-yl, tetrazolyl, e.g. 1H-tetrazol-5-yl, lower alkyltetrazolyl, e.g. 1-methyl-1H-tetrazol-5-yl, thienyl, e.g. thien-3- or -2-yl, thiazolyl, e.g. thiazol-2-yl, thiadiazolyl, e.g. 1,2,3-thiadiazol-5-yl or furyl, e.g. fur-2-elyl-3-yl.

Unsubstituted or substituted, aromatic, six-membered heterocyclyl R 1 is, for example, unsubstituted or with said substituents substituted aza-, diaza- or oxacyclyl, preferably pyridyl, e.g. pyrid-2-, -3- or -4-yl, hydroxypyridyl, e.g. 2-hydroxypyrid-5-yl, dihydroxypyridyl, e.g. 2,6-dihydroxypyrid-4-yl, aminopyridyl, e.g. 2-aminopyrid-3-yl, dihydroxypyrimidinyl, e.g.

2,4-dihydroxypyrimidin-6-yl, pyrazinyl, e.g. pyrazin-2-yl, aminopyrazin-2-yl, e.g. 3-aminopyrazin-2-yl or pyranyl, e.g. pyr-2-on-5-yl.

In connection with formula I functional groups present, especially the carboxy, amino or hydroxy group are possibly protected with suitable protecting groups (conventional protecting groups), which are commonly used in the production of penicillin, cephalosporin and peptide compounds. These protective groups must protect the relevant functional groups against unwanted side reactions such as acylations, etherifications, esterifications, oxidations, volvolysis, etc., and be easily cleavable under gentle reaction conditions, e.g. solvolytic, reductive, photolytic or also enzymatic.

The protection of functional groups with such protective groups, the protective groups themselves as well as their cleavage reactions, is for example discussed in "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Greene, Th, W., "Protective Groups in Organic Synthesis" ., Wiley, New York 1981, in "The Peptides"., vol. 1, Schrøder and Lubke, Academic press, London and New York 1965, as well as in "Methoden der organischen Chemie"., Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Suttgart 1974.

A carboxy group is usually protected in esterified form, the ester group being selectively cleavable under gentle conditions. One in the esterified for protected carboxy group is primarily esterified with a lower alkyl1 group,

which in the 1-position of the lower alkyl group is branched or in the 1- or 2-position of the lower alkyl group is substituted with suitable substituents.

A protected carboxy group which is esterified with a lower alkyl group, which is branched in the 1-position of the lower alkyl group, is, for example, tert.-lower alkylcarbonyl, arylmethoxycarbonyl with one or two aryl residues, where aryl preferably means unsubstituted or e.g. with 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, e.g. benzyloxycarbonyl, by the said substituents substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or the aforementioned substituents substituted diphenylmethoxycarbonyl, e.g. di-(4-methoxyphenyl)-methoxycarbonyl.

A protected carboxy group which is an ester with a lower alkyl group, which is substituted in the 1- or 2-position of the lower alkyl group with suitable substituents, is, for example, 1-lower alkyl lower oxycarbonyl, e.g. methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthiolower oxycarbonyl, e.g. 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, as well as 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl, or 2-iodoethoxycarbonyl.

A carboxy group can also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a lower alkylsilyloxycarbonyl group, e.g. trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can also be substituted with two lower alkyl groups, e.g. methyl groups, and the amino group, or the hydroxy group belonging to the carboxy group of another molecule with formula I. Connection with such protective groups has e.g. prepared using dimethyldichlorosilane as silylating agent.

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

A protected carboxy group is also under physiological conditions, e.g. enzymatically cleavable, esterified carboxy, primarily acyloxylavereal oxycarbonyl, wherein acyl, e.g. means the acyl group of a carboxylic acid of a carboxylic acid monoester or an amino acid, or in which acyloxylavereal oxy e.g. acyloxymethoxy forms the residue of a lactone.

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

Under physiological conditions, e.g. enzymatically cleavable esterified carboxy is preferably lower alkanoyloxy-lower oxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl, or loweralkanoyloxyethoxycarbonyl, e.g. acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, lower alkoxycarbonyloxy-lower oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert.-butoxycarbonyloxymethoxycarbonyl, aminolower alkanoyloxymethoxycarbonyl, especially α-aminoloweralkanoyloxymethoxycarbonyl, e.g. glycyloxymethoxycarbonyl, 1-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, further phthalidyloxycarbonyl, e.g. 2-phthalidyloxycarbonyl, or indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl.

An amino can e.g. be protected in the form of an acylamino, etherified mercaptoamino or silylamino group selectively cleavable under gentle conditions or as an acid group.

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

with halogen or aryl substituted lower alkane carboxylic acid

or the unsubstituted or e.g. with halogen lower alkoxy or nitro substituted benzoic acid, or a carbonic acid half-ester. Such an acyl group is, for example, halo-gen laveralkanoyl, 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. chloro, lower alkoxy or nitro substituted benzoyl, e.g. benzoyl, 4-chloro-benzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl radical branched or in the 1- or 2-position by suitable substituents substituted lower alkoxycarbonyl.

In the 1-position of the lower alkyl ether, branched lower alkoxycarbonyl is, for example, tert.-lower alkylcarbonyl, e.g. tert.-butoxycarbonyl (BOC), arylmethoxycarbonyl with one or two aryl residues, wherein aryl preferably means 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)methoxycarbonyl.

In the 1- or 2-position with suitable substituents substituted lower alkoxycarbonyl, for example aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, where the silyl group is substituted with an organic ester, 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-triphenylsilylethoxycarbonyl.

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

A silylamino group is, for example, a lower alkylsilylamino group, e.g. trimethylsilylamino. The silicon atom of the silylamino group can also only be substituted with two lower alkyl groups, e.g. methyl groups and the amino group or carboxyl group of another molecule of formula I.

Compounds with such protecting groups allow e.g. prepared using dimethyldichlorosilane as silylating agent.

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

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

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

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

an organic silyl radical with the further above-mentioned substituents, e.g. trimethylsilyl or dimethyl-n-butylsilyl, further an easily cleavable, ether group such as tert.-lower alkyl, e.g. tert.-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic hydrocarbon residue, for example 1-lower alkoxy lower alkyl or 1-lower alkylthio lower alkyl, e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl with 5-7 ring atoms, e.g. 2-tetrahydrofuryl or tetrahydrofuranyl, or a corresponding thia analogue, as well as 1-phenyl lower alkyl, e.g. benzyl

or diphenylmethyl, as the phenyl radicals can for example be substituted with halogen, e.g. chlorine, lower alkoxy. e.g.

methoxy and/or nitro.

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

IN.

Such salts are formed, for example, by acidic groups present in connection with formula I, e.g. a carboxy group, 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 with ammonia under suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines as tetracyclic bases suitable for salt formation. Such bases are, for example, lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic residues of carboxylic acid, e.g. 4-amino-benzoic acid-2-diethyldiaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. dicyclohexylamine or benzylamines, e.g. N,N'-dibenzylethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline.

The basic groups present in the compound with formula I, e.g. amino groups, can form acid addition salts, e.g. inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. in unsaturated carboxylic acids, e.g. fumaric or maleic acid, hydroxy acid, e.g. lactic acid, tartaric acid or citric acid, or an aromatic acid, e.g. salicylic acid, as well as with amino acids, such as arginine and lysine.

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

The compounds of formula I and their pharmaceutically acceptable non-toxic salts of valuable antibiotic active substances, which can be used in particular as antibacterial antibiotics. For example, compounds of formula I are effective in vivo by oral application to mice against systemic infections due to Gram-positive germs, e.g. Streptococcus pyogenes, in a dose range of approx. 0.5 more

3.0 mg/kg (ED^q) or against systemic infections due to Gram-negative germs, e.g. enterobacteria, e.g. Escherichia coli, in a range from 0.2 to 3.0 mg/kg (ED^q).

The new compounds of formula I can therefore be used as oral anti-bacterial antibiotics, e.g. in the form of orally administrable pharmaceutical preparations, e.g. capsules,

tablets, syrups etc., to combat infections.

The compounds of formula I are distinguished by a surprisingly good absorption or oral administration, which is demonstrated by high renal excretion (RE). Thus, peroral administration of the hydrochloride of 7B-/T2-(2-amino-thiazol-4-yl)-2-Z-methoxyiminoacetamido7-3-cephem-4-carboxylic acid-2-acetoxybenzoyloxymethyl esters according to the invention is measured in mice, a renal excretion of 23.2%, and in rats a renal excretion of 32.5% of the administered amount of the active substance.

The invention preferably relates to compounds of formula

it

In which X means nitrogen or the group -C-H, Y means oxygen or sulphur, A means amino substituted amino, e.g. lower alkanoylamino, e.g. formylamino, lower alkylsulfonylamino, e.g. methylsulfonylamino, N-lower alkyl-N-lower alkylsulfonylamino, e.g. N-methyl-N-methylsulfonylamino, or N-aminolower alkylsulfonyl-N-lower alkylamino, e.g. N-2-aminoethylsulfonyl-N-methylamino, hydroxyamino or esterified hydroxyimino, e.g. lower alkoxyimino, e.g. methoxyimino, or carboxylavereal oxyimino, e.g. 2-carboxy-2-propoxyimino, substituted methylene, R means hydrogen, halogen, e.g. chlorine, lower alkyl, e.g. methyl, or lower alkoxy, e.g. methoxy, R2 means hydrogen, lower alkyl, e.g. methyl, phenyl or substituted phenyl, e.g. lower alkyl, dilower alkyl, or trilower alkylphenyl, e.g. 2-, 3- or 4-methyl, 2-, 3- or 4-tert.-butyl, 3,4-dimethyl-, 2,3-dimethyl-, 2,4-dimethyl- or 2,4,6- trimethylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, e.g. 4-hydroxy-, 2,4-dihydroxy-, 2,3,4-trihydroxy-, 2,4,6-trihydroxy- or 3,4,5-trihydroxyphenyl, hydroxy-lower alkylphenyl, e.g. 2-hydroxy-3-methylphenyl, lower alkoxy, dilavereal oxy or trilavereal oxyphenyl, e.g. 4-methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, hydroxy-lower oxyphenyl, e.g. 4-Hydroxy-3-methoxyphenyl, hydroxy-dilaveresalkoxyphenyl, e.g. 3-hydroxy-2,4-dimethoxyphenyl, lower alkanoylphenyl, e.g. 2-, 3- or 4-acetylphenyl, lower alkanoyloxyphenyl, e.g. 2-, 3-, 4- or 5-acetoxyphenyl or 3,4- or 3,5-diacetoxyphenyl, halophenyl, e.g. 2-, 3- or 4-fluoro- or 2-, 3- or 4-chlorophenyl, nitrophenyl, e.g. 2-, 3- or 4-nitrophenyl, cyanophenyl, e.g. 2-, 3- or 4-cyanophenyl, amino- or diaminophenyl, e.g. 2-, 3- or 4-aminophenyl or 3,5-diaminophenyl, amino-hydroxyphenyl, e.g. 3-amino-4-hydroxy- or 4-amino-2-hydroxyphenyl, lower alkylaminophenyl, e.g. 2-or 4-methylaminophenyl, diloverealkylaminophenyl, e.g. 2-, 3- or 4-dimethylaminophenyl, lower alkanoylaminophenyl, e.g. 2-, 3- or 4-acetylaminophenyl, sulfamoylphenyl, e.g. 2-, 3- or 4-sulfamoylphenyl, halolower alkylphenyl, e.g. 2-, 3- or 4-trifluoromethylphenyl, or amino lower alkylphenyl, e.g. 2-, 3- or 4-aminomethylphenyl and R^ means pyrrolyl, e.g. pyrrolyl-2-yl, lower alkylpyrrolyl, e.g. 1-methylpyrrol-2-yl, imidazolyl, e.g. imidazol-2-yl, lower alkylimidazolyl, e.g. 1-methylimizol-2-yl, triazolyl, e.g. 1H-1,2,3-triazol-5-yl, lower alkyltriazolyl, e.g. 1-methyl-1H-1,2,3-triazol-5-yl, tetrazole, e.g. 1H-tetrazol-5-yl, lower alkyltetrazolyl, e.g. 1-methyl-1H-tetrazol-5-yl, thienyl, e.g. ten-3- or

-2-yl, thiazolyl, e.g. thiazol-2-yl, thiadiazolyl, e.g. 1,2,3-thiadiazol-5-yl, or furyl e.g. fur-2- or -3-yl, pyrid-2-, -3- or -4-yl, hydroxypyridyl, e.g. 2-hydroxypyrid-5-yl, dihydroxypyridyl, e.g. 2,6-dihydro-roxypyrid-4-yl, aminopyridyl, e.g. 2-aminopyrid-3-yl, dihydroxypyrimidinyl, e.g. 2,4-dihydroxypyrimidine-6-

yl, pyrazinyl, e.g. pyrazin-2-yl, aminopyrazin-2-yl, e.g. 3-aminopyrazin-2-yl or pyronyl, e.g. pyr-2-on-5-yl, phenyl or substituted phenyl with the below-mentioned substituents, as well as their pharmaceutically acceptable salts, e.g. the hydrochlorides.

The invention relates in particular to compounds of formula

In which X means nitrogen or the group -C-H, Y means oxygen or sulphur, A means hydroxyimino, etherified hydroxyimino, e.g. lower alkoxyimino, e.g. methoxyimino, or carboxylavereal oxyimino, e.g. 2-carboxy-2-propoxyimino, substituted methylene, R means hydrogen, halogen, e.g. chlorine or lower alkoxy, e.g. methoxy,

R 2 means hydrogen, lower alkyl, e.g. methyl, phenyl or substituted phenyl, e.g. lower alkylphenyl, e.g. 2-,

3- or 4-methylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, e.g. 4-Hydroxy-, 2,4-dihydroxy-, 2,3,4-trihydroxy-, 1,4,6-trihydroxy- or 3,4,5-trihydroxyphenyl, lower alkoxy, dilavereal oxy or trilower-I. Alkoxyphenyl, . e.g. 4-methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, hydroxy-lower oxyphenyl, e.g. 4-hydroxy-3-methoxy-phenyl, lower alkanoylphenyl, e.g. 2-, 3- or 4-acetylphenyl, lower alkanoyloxyphenyl, e.g. 2-, 3-, 4- or 5-acetoxyphenyl, or 3,4- or 3,5-diacetoxyphenyl, halophenyl, e.g. 2-, 3- or 4-fluoro- or 2-, 3- or

4-chlorophenyl, nitrophenyl, e.g. 2-, 3- or 4-nitrophenyl, lower alkanoylaminophenyl1, e.g. 2-, 3- or 4-acetylaminophenyl, haloalylphenyl, e.g. 2-, 3- or 4-trifluoromethylphenyl, or amino lower alkylphenyl, e.g. 2-,

3- or 4-aminomethylphenyl, and means pyrrolyl, e.g. pyrrol-2-yl, lower alkylpyrrolyl, e.g.

1-methylpyrrol-2-yl, imidazolyl, e.g. imidazol-2-yl, lower-alkylimidazoly1, e.g. 1-methylimidazol-2-yl, triazolyl, e.g. 1H-1,2,3-triazol-5-yl, lower alkyltriazolyl, e.g. 1-methyl-1H-1,2,3-triazol-5-yl, tetrazolyl, e.g. 1H-tetrazol-5-yl, lower alkyltetrazolyl, e.g. 1-methyl-1H-tetrazol-5-yl, thienyl, e.g. thien-3- or -2-yl, thiazolyl, e.g. thiazol-2-yl, thiadiazolyl, e.g. 1,2,3-thiadiazol-5-yl,

or furyl, e.g. fur-2- or -3-yl, pyrid-2-, -3- or

-4-yl, hydroxypyridyl, e.g. 2-hydroxypyrid-5-y1, dihydroxypyridyl, e.g. 2,6-dihydroxypyrid-4-yl, aminopyridyl, e.g. 2-aminopyrid-3-yl, dihydroxypyrimidinyl, e.g. 2,4-dihydroxypyrimidin-6-y1, pyrazinyl, e.g. pyrazin-2-yl, aminopyrazinyl, e.g. 3-aminopyrazin-2-yl or pyronyl, e.g. pyr-2-on-5-yl, phenyl or substituted phenyl, e.g. lower alkyl, dilower alkyl or trilower alkylphenyl, e.g. 2-, 3- or 4-methyl-, 2-, 3-

or 4-tert-butyl-, 3,4-dimethyl-, 2,3-dimethyl-, 2,4-dimethyl- or 2,4,6-trimethylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, e.g. 4-hydroxy-, 2,4-dihydroxy-, 2,3,4--. trihydroxy-, 2, 4, 6-trihydroxy- or 3,4,5-trihydroxyphenyl, hydroxy-lower alkylphenyl, e.g. 2-hydroxy-3-methylphenyl, lower alkoxy, dilavereal oxy or trilavereal oxyphenyl, e.g. 4-Methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, hydroxy-laveralkoxyphenyl, e.g. 4-Hydroxy-3-Methoxy-phenyl, Hydroxy-dilaverealoxyphenyl, e.g. 3-hydroxy-2,4-dimethoxyphenyl, lower alkanoylphenyl, e.g. 2-, 3-

or 4-acetylphenyl, lower alkanoyloxyphenyl, e.g. 2-,

3-, 4- or 5-acetoxyphenyl, or 3,4- or 3,5-diacetoxyphenyl, halophenyl, e.g. 2-, 3- or 4-fluoro- or 2-, 3- or 4-chlorophenyl, nitrophenyl, e.g. 2-, 3- or

4-nitrophenyl, cyanophenyl, e.g. 2-, 3- or 4-cyanophenyl,

amino- or diaminophenyl, e.g. 2-, 3- or 4-aminophenyl, or 3,5-diaminophenyl, amino-hydroxyphenyl, e.g. 3-amino-4-hydroxy- or 4-amino-2-hydroxyphenyl, lower alkylaminophenyl, e.g. 2- or 4-methylaminophenyl, dilaverealkylaminophenyl, e.g. 2-, 3- or 4-dimethylaminophenyl, lower alkanoylaminophenyl, e.g. 2-, 3- or 4-acetylaminophenyl, sulfamoylphenyl, e.g. 2-, 3- or 4-sulfamoylphenyl, halolower alkylphenyl, e.g. 2-, 3- or 4-trifluoromethylphenyl, or amino lower alkylphenyl, e.g. 2-, 3- or 4-aminomethylphenyl, as well as their pharmaceutically acceptable salts, e.g. the hydrochlorides.

Primarily, the invention comprises compounds of formula I, in which X means the group -C-H, Y means sulphur, A means with etherified hydroxyimino, e.g. lower alkoxyimino, e.g. methoxyimino, substituted methylene, R 1 means hydrogen, R 2 means hydrogen or lower alkyl, e.g. methyl,

and R^ means furyl, e.g. fur-2- or -3-yl, phenyl or substituted phenyl, e.g. lower alkyl, dilower alkyl or trilower alkylphenyl, e.g. 2-, 3- or 4-methyl-,

2-, 3- or 4-tert-butyl-, 3,4-dimethyl-, 2,3-dimethyl-, 2,4-dimethyl- or 2,4,6-trimethylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl , e.g. 4-hydroxy-, 2,4-dihydroxy-, 2,3,4-trihydroxy-, 2,4,6-trihydroxy- or 3,4,5-trihydroxyphenyl, hydroxy-lower alkylphenyl, e.g. 2- hydroxy-3-methylphenyl, lower alkoxy, dilavereal oxy or trilavereal oxyphenyl, e.g. 4-methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy-, or 3,4,5-trimethoxyphenyl, hydroxy-lower-alkoxyphenyl, e.g. 4-Hydroxy-3-Methoxyphenyl, Hydroxy-dilaverealoxyphenyl, e.g. 3-hydroxy-2,4-dimethoxyphenyl, lower alkanoylphenyl, e.g.

2-, 3- or 4-acetylphenyl, lower alkanoyloxyphenyl, e.g. 2-, 3-, 4- or 5-acetoxyphenyl, or 3,4- or 3,5-diacetoxyphenyl, halophenyl, e.g. 2-, 3- or 4-fluoro-or 2-, 3- or 4-chlorophenyl, nitrophenyl, e.g. 2-,

3- or 4-nitrophenyl, cyanophenyl, e.g. 2-, 3- or 4-

amino- or diaminophenyl, e.g. 2-, 3- or 4-aminophenyl or 3,5-diaminophenyl, aminohydroxyphenyl, e.g. 3-amino-4-hydroxy- or 4-amino-2-hydroxyphenyl, lower alkylaminophenyl, e.g. 2- or 4-methylaminophenyl, diloweralkylaminophenyl, e.g. 2-, 3- or 4-dimethylaminophenyl, lower-alkanoy laminophenyl, e.g. 2-, 3- or 4-dimethylaminophenyl, lower alkanoylaminophenyl, e.g. 2-, 3- or 4-acetylaminophenyl, sulfamoylphenyl, e.g. 2-, 3- or 4-sulfamoylphenyl, halolower alkylphenyl, e.g. 2-, 3- or 4-trifluoromethylphenyl, or amino lower alkylphenyl, e.g. 2-,

3- or 4-aminomethylphenyl, as well as their pharmaceutically acceptable salts, e.g. the hydrochlorides.

The invention includes above all the compounds of formula I mentioned in the examples and their pharmaceutically acceptable salts.

The compounds of formula I are prepared, for example, by

a) in a connection with formula

in which R^, R£ and R^ have the meaning mentioned under formula I, the 76-amino group is optionally protected with a group which enables the acylation reaction, and a functional group present in R2 or R^ is protected, the 76-amino group is acylated by reaction with a acylating agent which introduces the acyl residue of a carboxylic acid of formula

in which A, X and Y have the meaning given under formula I, and the amino group is optionally protected or

b) a compound of formula

in which A, X, Y and R have the meaning mentioned under formula I, the amino group is optionally protected and a functional group present in A is protected, or a salt thereof, or a reactive, functional derivative of this compound, is optionally reacted stepwise with an esterifying agent which introduces the group or, c) for the preparation of a compound of formula I, in which X, Y, A, R2 and R^ have the meaning mentioned under formula I and R^ means hydrogen, R^ is split off in a compound of formula

in which X, Y, A, Rp and R have the meaning mentioned under formula I, amino group is optionally protected, and a functional group present in A, R2 or R^ is protected, Rq means a cleavable group, or

d) a 1-oxide of formula

in which X, Y, A, R^, R2 and R^ has the formula I indicated

meaning, the amino group and a functional group present in A, R2 or R^ is possibly protected, is transferred with a suitable reducing agent to the 1-sulphide, or

e) for the preparation of compounds of formula I, in which X means the group =C-H and Y means oxygen or sulphur, A

If R1, R2 and R2 have the above-mentioned meaning under formula, a compound with formula VII is condensed,

where Hal means halogen, A, R-^, R2 and R^ have the meaning mentioned under formula I, the amino group and a functional group present in A, R2 or R^, possibly protected with urea or thiourea respectively or f) for the preparation of compounds with formula I, in which X means nitrogen and Y means sulphur, A, R^, R 2 and R^ have the meaning mentioned under formula I, a compound of formula

in which X.^ means hydrogen, halogen or hydroxy, A, R.^, R^ and R^ have the meaning mentioned under formula I, the amino group and any A, R 2 or R^ present functional group is optionally protected with a salt of rhodanohydrogen acid or if X^means hydrogen, with dirhodan,

and in a formed compound, the amino protecting group(s) and other protecting groups present are cleaved off and, if desired, a formed compound is transferred to a salt or a formed salt to the free compound or to another salt.

Method a) (acylation).

7 The amino group in a starting material of formula II is optionally protected with a group which enables the acylation reaction. Such a group is, for example, an organic silyl group, further a ylidene group, which together with the amino group forms a Schiff base. An organic silyl group of e.g. such a group which also with a carboxy group in R., can form a protected carboxy group primarily trilower alkylsilyl, especially trimethylsilyl. In the silylation reaction to protect the 4-carboxy group in a starting material with formula II, by using an excess of the silylating agent 7, the ε-amino group can also be silylated. A ylidene group is primarily a 1-aryl lower alkylidene, especially a 1-arylmethylene group, in which aryl in particular means a carboxylic, primarily monocyclic, aryl residue, e.g. optionally with lower alkyl, hydroxy, lower alkoxy and/or nitro substituted phenyl.

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

An acylating agent that introduces the acyl residue of a carboxylic acid of formula III is the carboxylic acid of formula III together with a condensing agent or a reactive, functional derivative or salt of this carboxylic acid. In a starting material with formula III, the amino group at the heterocycle is optionally protected with a further, above-mentioned usual protecting group, e.g. tert.-butoxycarbonyl.

In a starting material of formula III, this amino group can also be protected in ionic 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 III is used for acylation, the reaction is carried out in the presence of suitable condensing agents, such as carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-dicyclohexy1- or N-ethyl -N<1->3-dimethyl-aminopropyl-carbodiimide, suitable heterocyclic 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 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, or a suitable acylamino 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. an aprotic solvent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, optionally for cooling or heating, e.g. in a temperature range of approx. -40°C to approx. +100°C, preferably at approx. -20°C to approx. +50°C, and possibly under inert gas, e.g. nitrogen atmosphere.

A reactive functional derivative of a carboxylic acid of formula III is capable of forming the carboxamide function -CONH- and is primarily an anhydride, preferably a mixed anhydride of the carboxylic acid of formula III. A mixed anhydride is formed, for example, by condensation

of carboxylic acid of formula III with another acid, e.g. an inorganic acid, e.g. halohydrogen acid, and is, for example, the corresponding carboxylic acid halide, e.g. the carboxylic acid chloride or bromide. A reactive functional derivative of a carboxylic acid of formula III is also formed by condensation with an organic carboxylic acid, e.g. with an unsubstituted or with 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, e.g. ethyl or isobutyl half-ester of carbonic acid, or with an organic, e.g.

aliphatic or aromatic suTfbnic acid, ■ f-, eg . methanesulfonic acid or p-toluenesulfonic acid.

A reactive, functional derivative of a carboxylic acid of formula III is likewise an activated ester of the carboxylic acid of formula III, which is, for example, formed by condensation with a substituted vinyl alcohol, i.e. with an enol, e.g. a lower alkenol, an iminomethyl ester halide, e.g. dimethyliminomethyl ester chloride, prepared from the carboxylic acid of formula III and e.g. Dimethyl-(1-chloroethylidene)-iminium chloride with formula /(CH3)2N =C(Cl)CH3_/C1 , which

his side can get 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. N-benztriazole esters, 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 III, e.g. with equivalent

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 an N,N-dilaverealkylaniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine, e.g. an N-lower alkyl substituted morpholine, e.g. N-methylmorpholine, or is, for example, a nitrogenous, aromatic base, e.g. pyridine. A suitable base is furthermore an inorganic base, and for example an alkali metal, e.g. sodium-, -hydroxide-,

carbonate or hydrogen carbonate, or an oxirane, for example a 1,2-lower alkylene oxide, such as ethylene oxide or propylene oxide, further a silylamide, e.g. trimethylsilyl-acetamide, 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 III is preferably carried out in an inert, preferably anhydrous, aprotic 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, cyclic ether, e.g. tetrahydrofuran, an ester, e.g. acetic acid ethyl ester, or a nitrile, e.g. acetonitrile, further in a solvent which is miscible with water, e.g. an alcohol, e.g. methanol or ethanol, or acetone, optionally in the presence of water, optionally at a temperature range of approx. -40°C to approx. +100°C, preferably at approx. -10°C to approx. +50°C, and possibly under intertgas-, e.g. nitrogen atmosphere.

Method b) (the esterification)

In a starting material of formula IV, a functional group present in A, e.g. a hydroxy or carboxy group, with one of the above-mentioned protecting groups. The salt of a carboxylic acid of formula IV is an alkali metal, e.g. sodium or potassium salt, or a salt with an organic base, e.g. an organic amine, e.g. a tertiary amine, such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyldiisopropylamine, an N,N-diaverealkylaniline, e.g. N,N-dimethylaniline, a cyclic tertiary amine, e.g. an N-lower alkylated morpholine, e.g. N-methylmorpholine, a base of the pyridine type, e.g. pyridine or collidine, or a bicyclic amidine, e.g. 1,5-diazabicyclo/5.4.0/undec-5-ene (DBU).

Esterifying agent that introduces the group

0

-CH-O-C-R3

is, for example, a compound with formula I,

in which Y means a reactive, esterified hydroxy group and R and R have the meaning mentioned under formula I.

A reactive, esterified hydroxy group Y^ in a compound of formula IX is a hydroxy group esterified with a strong inorganic or organic acid. Corresponding groups Y^ are especially halogen, e.g. chlorine, bromine or preferably iodine, further sulfonyloxy groups such as lower alkane or arylsulfonyloxy groups, e.g. methane, ethane, benzene

or toluenesulfonyloxy groups, or halogensulfonyloxy groups, e.g. the chlorosulfonyloxy group, etc.

The esterification of 4-carboxy groups in a starting material with formula IV is carried out in a manner known per se,

e.g. in the presence of one of the condensing agents mentioned under method a), e.g. dicyclohexylcarbodiimide, or a base, e.g. a bicyclic amidine, e.g. diazabicyclo/5.4.0/undec-5-ene, or a quaternary ammonium base, e.g. a tetraalkylammonium hydroxide, carbonate or bicarbonate, e.g. wherein alkyl is methyl, ethyl, propyl, isopropyl, butyl etc., or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

A compound of formula IV, wherein the 4-carboxy group

which is to be esterified, exists 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) (acylation), by condensation of the carboxylic acid of formula IV with an inorganic acid,

a carboxylic acid with a carboxylic acid half-ester, or a sulphonic acid or by condensation with a vinylogenic alcohol.

The esterification can also take place stepwise, with a compound of formula IV being reacted with a dihalide of formula:

in which one of the radicals Hal^ and Hal2 means chlorine, bromine or iodine and the other bromine or iodine, or a reactive, functional derivative of a compound of formula IV, e.g. the acid chloride, with an aldehyde of formula: or a compound of formula IV with a reactive derivative of aldehyde, of formula XI, e.g. an acetal, and the formed compound of formula in which Z^means hydroxy or a reactive, esterified hydroxy group, is reacted in situ or after isolation with a carboxylic acid of formula:

or a salt of this carboxylic acid, e.g. an alkali

numerical, e.g. the sodium salt or if Z^ is hydroxy,

with a reactive>functional derivative of this carboxylic acid, e.g. the acid chloride.

The reaction of compounds of formula IV with the dihalide of formula X takes place in the presence of one of the following methods

a)' mentioned bases or condensation agents.

The turnover of the reactive, functional derivative

of the compound of formula IV with an aldehyde of formula XI, may proceed in the presence of zinc chloride following that of Ulrich, C.H. and Adams, R., in JACS 43, page 660 (1921) stated method.

The compounds of formula XII and their pharmaceutically acceptable non-toxic salts are valuable antibiotic active substances which can be particularly useful as anti-bacterial antibiotics. Thus, compounds of formula XII in vivo by oral application to mice are effective against systemic infections by gram-positive germs, e.g. Streptococcus pyogenes, or gram-negative germs, e.g. enterobacteria. The compounds of formula XII can therefore be used as oral antibacterial antibiotics, e.g. in the form of orally administrable pharmaceutical preparations, e.g. capsules, tablets, syrups etc. to fight infections. Moreover, the compound of formula XII exhibits surprisingly good absorption after oral administration, which can be demonstrated by high renal excretion.

The reaction of compounds of formula XII, wherein Z^ is hydroxy, with a reactive, functional derivative of a carboxylic acid, of formula XIII or a compound of formula XII, wherein Z^ is a reactive, esterified hydroxy group with a carboxylic acid of formula XIII, or a salt of this carboxylic acid, takes place with the condensing agents or bases mentioned under method a).

The esterification reaction is carried out in a suitable solvent or solvent mixture, for example in a carboxylic acid amide such as a formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride,

or chlorobenzene, a ketone, e.g. acetone, an ester, e.g. acetic acid ethyl ester or a nitrile, e.g. acetonitrile, or in a mixture of immiscible solvents, e.g. methylene chloride/water, or diethyl ether/water (phase transfer). The turnovers are carried out at room temperature, if necessary at a reduced or increased temperature, e.g.

at -40°C until the boiling temperature of the reaction mixture, preferably at -10°C to +40°C, and if necessary, in an inert gas, e.g. nitrogen atmosphere.

Procedure c) (Rp cleavage)

In a starting material of formula V, one is A, R, or

R^functional group present, with e.g. an amino, hydroxy or carboxy group protected with one of the above-mentioned protecting groups. The leaving group Rq is in hydroxy or amino, preferably esterified hydroxy, or substituted amino. An esterified hydroxy group Rq can be esterified with an inorganic or organic one

acid, such as a strong mineral acid, e.g. a halohydrogen acid such as hydrochloric, hydrobromic or hydroiodic acid, or an organic carboxylic or sulphonic acid, including formic acid, e.g. an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acid, further with a carboxylic acid half-derivative. Thus, Rq means e.g. halogen, such as chlorine, bromine or iodine, lower alkylsulfonyloxy, e.g. methylsulfonyloxy or ethylsulfonyloxy, arylsulfonyloxy, e.g. benzenesulfonyloxy or p-toluenesulfonyloxy, lower alkanoyloxy, e.g. acetoxy or propionyloxy, arylcarbonyloxy, e.g. benzoyloxy or lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy or ethoxycarbonyloxy. A substituted amino group R is a secondary or

12° 1 tertiary amino group -N(R )(R ) , in which one of the residues R

o o o

and R represents hydrogen and the other residue or both

° 1 2

residues R and R mean an optionally substituted aliphatic,

OE OE

cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic residue, or if Rq and Rq are connected, means optionally substituted, optionally with heteroatoms such as oxygen, sulfur or nitrogen, interrupted alkylene group. Such substituted, secondary and tertiary amino groups are, for example, mono- or dilower alkylamino such as methyl-, ethyl-, propyl-, dimethyl-, diethyl-, dipropyl-, methylethyl- or methylpropylamino,

mono- or dicyclohexylamino, diphenylamino, benzyl-, dibenzyl- or phenylethyl- or diphenyl-ethylamino, aziridino, pyrrolidino, piperidino, morpholino, thiamorpholino or 4-lower alkylpiperazino.

The cleavage of a compound of formula R -H, i.e. of water, with an acid or amine, is preferably carried out in the presence of an acid, e.g. a strong organic carboxylic or sulfonic acid, such as a halogen lower alkane carboxylic acid, e.g. trifluoroacetic acid, or an arylsulfonic acid, e.g. p-toluenesulfonic acid, a reactive acid derivative, e.g.

an anhydride or especially an acid halide, e.g. acid chloride, an inorganic, e.g. phosphoroxygenic or sulphuroxygenic acid, e.g. phosphorus oxychloride or thionyl chloride. When splitting off water, a base is used, e.g. a tertiary organic base, e.g. pyridine, or a suitable acidic ion exchanger, e.g. on a sulphonic acid basis, e.g. a sulfonated polystyrene ion exchanger. Condensing agents such as carbodiimide compounds, e.g. dicyclohexyl carbodiimide. The cleavage takes place in the presence of a solvent such as an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. benzene or toluene, or a solvent mixture, since one can use liquid acids such as trifluoroacetic acid, at the same time also as a solvent. If necessary, one also uses a water absorbent or a water separator, and works under cooling or heating and/or in an inert gas, e.g. nitrogen atmosphere.

Preferably, Rq in a starting material of formula V means an esterified hydroxy group. Generally, proton acceptors, e.g. bases, e.g. inorganic bases, e.g. dilute aqueous alkali metal hydroxides, e.g. sodium or potassium hydroxide, in which, in addition to water, organic solvents such as suitable ketones are also used, e.g. acetone, or ethers, e.g. dioxane or aqueous mixtures thereof, and can work at a pH value of a maximum of approx. 9, if necessary during cooling or heating and/or in an inert gas, e.g. nitrogen atmosphere.

Tert-amines are preferably used as proton acceptors, especially proton acceptors, which do not attack the lactam ring,

primarily tert.-aliphatic or tert.-cycloaliphatic mono- and diamines such as tri-lower alkylamines, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine, or bicyclic amidines, e.g. 1,5-diazabicyclo/4.3.0/non-5-one or 1,5-diazabicyclo/5.4.0/undec-5-ene. You can also use basic ion exchangers, e.g. on an ammonium hydroxy basis, as proton acceptors. Certain esterified hydroxy groups R , especially sulfonyloxy, e.g. the methanesulfonyloxy group can be cleaved from compounds of formula V in the form of an acid of formula RQ-H also by absorption, e.g. on silica gel, aluminum oxide, etc., and elution (chromatography).

Method d) (reduction of 1-oxide)

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

The reduction of the 1-oxide of the 3-cephem compound of formula VI 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-acting metal cations, e.g. tin, iron, copper or methane cations>which are used in the form of their salts, e.g. as tin II chloride, acetate or formate, iron II chloride, 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 nitrileacetic acid, reducing dithionite, iodine or iron II cyanide salts, e.g. alkali metals, e.g. sodium or potassium dithionite, sodium or potassium iodide or potassium iron-II cyanide, hydroiodic acid, reducing trivalent, inorganic or organic phosphorus compounds, such as phosphines, further esters, amides and halides of phosphonium, phosphine, or phosphoric acid, as well as to these phosphorus -oxygen compounds corresponding to phosphorus-sulfur compounds, in which in these compounds organic residues primarily mean 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, benzenephosphonic acid dimethyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, forfor trichloride, phosphorus tribromide, further forforic acid triphenyl ester halogen adducts, e.g. chlorine and bromine adducts, in which 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-acting halosilane compounds which have at least one hydrogen atom bound to the silicon atom, which, in addition to halogen such as chlorine, bromine or iodine, can also have organic residues such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl, for example diphenylchlorosilane or dimethylchlorosilane, as well as halosilane compounds, in which all hydrogen substances are replaced by organic residues, such as trilower alkylhalosilane, e.g. trimethylchlorosilane or trimethyliodosilane etc., reducing quaternary chloromethyleneiminium salts, especially -chlorides or -bromides, in which the iminium group is substituted by a bivalent or

two monovalent organic residues as optionally substituted lower allyl, respectively lower alkyl, such as N-chloromethylene-N,N-dimethyliminium chloride or N-chloromethylenepyrrolidinium chloride, or complex metal hydrides such as sodium borohydride in the presence of suitable activating agents, such as cobalt II chloride.

Activating agents are used together with such 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 especially 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 materials 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 derivatives, such as lower alkane carboxylic acid esters, or nitriles, e.g. acetic acid ethyl esters or acetonitrile, or amides of inorganic or organic acids, e.g. dimethylformamide or hexamethylphosphoramide, ethers, e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone or sulphones, especially aliphatic sulphones, e.g. dimethyl sulfone or tetramethylene sulfone etc., together with the chemical reducing agents, these solvents preferably not containing water.

Thereby, you usually work at temperatures of approx. - 20°C to approx. 100°C, when using highly reactive reducing agents or activating agents, the reaction is also carried out at lower temperatures, and possibly under a zero-gas atmosphere, e.g. nitrogen

atmosphere.

The above-mentioned acid separations can, if the reaction participants are liquid, be carried out without a solvent, but usually in the presence of a solvent,

as an optional halogenated hydrocarbon, e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as methylene chloride, cyclohexane or toluene, a lower alkanol, e.g. acetone or ether, e.g. tetrahydrofuran or dioxane, or a solvent mixture, including an aqueous mixture, if necessary while cooling or heating at -30°C to 150°C, preferably at about -10°C to 60°C, and/or in an inert gas, e.g. nitrogen atmosphere.

Procedure e) (loop closure)

In a starting material of formula VII, a functional group present in A, R^, R2 and R^ is, e.g. an amino, hydroxy or carboxy group, possibly protected with one of the above-mentioned protecting groups. Hal means halogen, preferably chlorine, further bromine, iodine or fluorine. When in the product of formula I Y is to mean oxygen, urea is used when Y means sulphur, thiourea, in an equivalent amount or in excess.

Cyclization is usually carried out in a solvent such as water or an organic inert solvent or a mixture thereof. Suitable organic solvents are alcohols such as methanol, ethanol or iropropanol, 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 methyl acetate or amides such as dimethylformamide or dimethylacetamide etc. The reaction can be carried out in the presence of a base mentioned under method a). The reaction temperature is between room temperature and the boiling temperature of the reaction mixture, preferably between 60°C and the boiling temperature of the reaction mixture.

The cyclization can also take place step by step, with an open intermediate first occurring, e.g. with partial formula NH2-C(=NH)-0-CH2-CO-A respectively NH2~C(=NH)-S-CH2-CO-A- which is then dehydrated in the second step by heating.

Procedure f) (loop closure)

In a starting material of formula VIII, one in A, , R 2

and R^ functional group present, e.g. an amino, hydroxy or carboxy group, possibly protected with one of the above-mentioned protecting groups. X meaning halogen is preferably bromine, further fluorine, chlorine or iodine. Suitable salts are rhodanhydrogen acid, for example alkali, alkaline earth or heavy metal rhodanides, e.g. sodium, potassium, magnesium or lead rhodanide, or also ammonium rhodanides, in which the ammonium group is derived from ammonia or from organic nitrogen bases, e.g. ammonium or mono-, di-, tri- or tetralower alkyl ammonium rhodanide, in which lower alkyl, e.g. is methyl, ethyl or iso-propyl.

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 in mixtures thereof, and if necessary , during cooling or heating, i.e. at temperatures between approx. -8°C until the boiling temperature of the reaction mixture, preferably between approx. 20°C and the boiling temperature of the reaction mixture, and/or in an inert gas atmosphere.

The starting material of formula VIII, in which X^ is halogen, can be prepared in situ, possibly in the presence of the salt of rhodanohydrogen acid, for example by treating a compound of formula VIII, in which X^ is hydrogen, in one of the aforementioned solvents, with a hypohalide , e.g. sodium or potassium hypobromide, or with a halogen or alkali metal base, such as a hydroxide carbonate or lower alkanolate, e.g. with bromine and sodium methylate or potassium carbonate. The halogenation preferably takes place during cooling, e.g. at a temperature of approx. -15°C to approx. 0°C.

The starting material of formula VIII, wherein X is hydroxy,

can also be produced in situ, for example by treating a compound of formula VIII, in which X is hydrogen, with an oxidizing agent such as hydrogen peroxide.

The reaction of the starting material with formula VIII, wherein

X means hydrogen, with dirodane is preferably also carried out in one of the aforementioned inert solvents and under corresponding reaction conditions. Optionally, an acid addition salt of a compound of formula VIII can also be used, which is transferred in situ in the free compound or can be formed in situ in the radical, e.g. from a rhodanide, e.g. lead rhodanide, and a halogen, e.g. bromine.

After operations.

Substitution of the hydroxyimino group

In an obtained compound of formula I in which X, Y, R^, R^ and R^ have the meanings mentioned under formula I and A means a methylene group substituted with hydroxyimino, one can substitute the hydroxyimino group and thus arrive at compounds of formula I, in which A means with etherified or esterified hydroxyimino substituted methylene. All functional groups except the hydroxyimino group are protected.

Diazolarealkanes are suitable for substitution of the hydroxyimino group, e.g. diazomethane, esterified lower alkanols or cycloalkanols, e.g. esters with strong inorganic acids, e.g. lower alkyl-, e.g. methyl-, or cycloalkyl-, e.g. cyclopropyl, -halides, e.g. -chlorides, -bromides or -iodides, dilave alkyl sulfates, e.g. dimethyl sulfate, fluorosulfonic acid lower alkyl ester, e.g. -methyl ester, halogen-substituted methanesulfonic acids-lower alkyl esters, e.g. trifluoromethanesulfonic acid methyl esters, suitable acetates, e.g. geminal dilavereal oxylower alkanes, e.g. 2,2-dimethoxypropane, trilower alkyl oxonium salts (so-called Meerwein salts), e.g. trimethyloxonium hexafluoroantimonate, dilave alkyloxycarbenzium salts, e.g. dimethoxycarbenium hexafluorophosphate, dilave alkylhalonium salts, e.g. dimethylbromonium hexafluoroatominate, 1-lower alkyl-3-alkyltriazen compounds, e.g. 1-methyl-3-(4-methylphenyl)-triazene. These reagents are used in a manner known per se as alkylating agents, usually in a suitable, anhydrous solvent, e.g. in benzene, carbon tetrachloride or tetrahydrofuran, if necessary in the presence of a condensing agent, e.g. a base, e.g. 1,S-diazabicyclo/5.4.0/undec-5-ene, while cooling until

-50°C or heating, the boiling temperature of the reaction mixture and possibly under a protective gas atmosphere, e.g. nitrogen atmosphere.

The esterification of the hydroxyimino group takes place in a manner known per se, e.g. by carbamoylation. Thereby, a compound of formula I in which A means hydroxyimino substituted methylene, and in which functional groups are present in protected form, is treated with a carbamoylating agent. Suitable carbamoylating agents are reactive derivatives of carbamic acids, especially isocyanates or mixed anhydrides, e.g. carbamic acid chlorides which can be prepared in situ from phosgene and an amine.

The reaction with isocyanates takes place in an anhydrous, inert solvent, for example an optionally halogenated hydrocarbon, e.g. benzene, xylene or methylene chloride,

an ether, e.g. diethyl ether, dioxane or tetrahydrofuran or an ester, e.g. acetic acid ethyl ester, optionally in the presence of a basic catalyst, for example a tertiary amine, e.g. triethylamine or pyridine, at room temperature

trip or slightly reduced or elevated temperature, e.g. between -20°C and +50°C.

For the reaction with a mixed anhydride of the carbamic acid, the hydroxyimino group is preferably metallized beforehand, for example with an alkali metal hydride, e.g. sodium or lithium hydride. The compound of formula I metallized at the hydroxy group can also be treated in the first instance with phosgene and then with the amine R-Nf^ and in this way be carbamoylated step by step. These reactions likewise take place in an inert solvent and at the temperatures indicated above.

Cleavage of the protecting group.

In a formed compound of formula I, in which one or more functional groups are protected, these protecting groups, e.g. a protected carboxy, amino or hydroxy group is released in a manner known per se, e.g. by solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by reduction, especially hydrogenolysis, simultaneously or selectively.

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

Thus, one can transfer tert.-lower oxycarbonyl 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 diphenylmethoxycarbonyl, e.g. by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylene thioglycol, to free carboxy. Suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can be converted to free carboxyl by chemical reduction, e.g. by treatment with an alkali metal, e.g. sodium dithionite or with a reducing metal, e.g. zinc, or metal salt, such as a chromium II salt, e.g. chromium-II chloride, usually in the presence of a hydrogen ion releasing agent, which, together with the metal or metal salts, manages to produce nascent hydrogen as an acid, primarily a suitable carboxylic acid, which in a possibly e.g. with hydroxy substituted lower alkane carboxylic acid, e.g. acetic acid, formic acid, glycol, 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, 2-halo-lavereal oxycarbonyl can, as mentioned above, also be converted, possibly after conversion of a 2-bromo-lavereal oxycarbonyl group into the corresponding 2-iodo-lavereal oxycarbonyl group or aroylmethoxycarbonyl1, into free carboxyl, since aroylmethoxycarbonyl can optionally is cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also be converted to free carboxyl by treatment with a fluoride anion-donating salt of hydrofluoric acid such as an alkali metal fluoride, e.g. sodium, or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as 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. With an organic silyl group such as trilower alkylsilyl, e.g. trimethylsilyl, esterified carboxy, 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 protecting group, preferably by means of solvolysis or reduction. 2-halolower oxycarbonylamino can be cleaved, optionally after conversion of a 2-bromolower oxycarbonylamino group, into 2-iodolower oxycarbonylamino, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino, by treatment with a suitable 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, and removed by treatment with an alkali metal, e.g. sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.-lower oxycarbonylamino, e.g. tert.-butoxycarbonylamino (BOC), 2-trisubstituted silylethoxycarbonylamino or 4-nitrogenylthio, can be cleaved by treatment with a suitable acid, e.g. formic acid or trifluoroacetic acid, and an amino group protected with an organic silyl group, e.g. by means of hydrolysis or alcoholysis. One with 2-haloacetyl, e.g. 2-chloroacetyl protected amino group, can be cleaved by treatment with thiourea in the presence of a base followed by solvolysis, such as alcoholysis or hydrolysis of the formed condensation product. An amino group protected with 2-substituted silylethoxycarbonyl can also be transferred to a free amino group by treatment with a fluoride anion-yielding salt of hydrofluoric acid, as above in connection with the release of a correspondingly protected carboxy group.

In the form of an acid group protected amino, e.g. by reduction to free amino, e.g. by treatment with zinc in the presence of an acid such as acetic acid. 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. 20-25°C or when cooling or heating.

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

Selective cleavage reactions are preferably carried out, i.e. those where the ester grouping and the methoxyimino group are not attacked at all or only slightly. Such a preferred method is the acidolytic cleavage of a tert.-lower oxycarbonyl group, especially the tert.-butoxycarbonyl group, by means of a suitable acid, especially trifluoroacetic acid, optionally in an inert solvent, such as an optionally halogenated hydrocarbon, e.g. methylene chloride, at temperatures of approx. -20°C to approx. 50°C, preferably at 0°C to room temperature.

Salt formation

Salts of compounds of formula I can be prepared on

in and of itself known manner. Thus, salts of compounds of formula I can be formed, e.g. by reaction of the acidic groups with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of ot-ethyl-caproic acid, with an alkali metal, e.g. 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 I are obtained in the usual way, e.g. by treatment with one or more equivalents of an acid, e.g. lactic acid, citric acid or tartaric acid, or a suitable anion exchange reagent.

Inner salts of compounds of formula I can e.g. formed by neutralization of salts such as acid addition salts, at the isoelectric point, e.g. with weak bases or by treatment with liquid ion exchangers.

Salts can be transferred in the usual way to 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.

Mixtures of isomers can be divided into the individual isomers in a manner known per se, e.g. by fractional crystallisation, chromatography etc.

The method also includes the embodiments according to which compounds formed as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at

one step or another, further starting materials can be used in the form of derivatives or formed during the reaction.

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

Pharmaceutical preparations.

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

Pharmaceutical preparations contain an effective amount of the pure active substance of formula I itself, or an effective amount of the active substance of formula I in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for oral administration.

For oral administration, tablets or gelatin capsules are used which contain the active substance together with additives, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, and if desired, swelling and blowing agents, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or fizzy mixes, or adsorbents, colourants, flavorings and sweeteners. Suppositories are primarily fat emulsions or suspensions.

Present pharmaceutical preparations as if desired

may contain further pharmacologically valuable additives, are produced in a manner known per se, e.g. by means of usual mixing, dissolving or lyophilisation methods, and contains approx. 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100%

of the active substance. Depending on the type of infection,

the condition of the infected organism, daily doses of approx. 0.25 - approx. 2.0 g p.o. for the treatment of warm-blooded animals (humans or animals) of approx. 70 kg weight.

Starting materials.

The compounds of formula II are valuable intermediates and are also covered by the invention. These are produced, for example, as a compound with formula

in which the 7B-amino group is optionally protected and R^ has the meaning mentioned under formula I, or a reactive, functional derivative of this compound, the step sieve is optionally reacted with an esterification agent which introduces the group The production of the starting material with formula II takes place analogously to the esterification method b), in compound of formula XIV is reacted with a compound of formula IX or stepwise, whereby a compound of formula XIV is reacted with a dihalide of formula X or a reactive, functional derivative of a compound of formula XIV with a reactive derivative of the aldehyde of formula XI. Intermediate products with formula

which is also covered by the invention, is then reacted in situ or after isolation with a carboxylic acid with

mel XIII or a salt of this carboxylic acid, or when Z^ is hydroxy, with a reactive ionic functional derivative of this carboxylic acid.

Compounds of formula III are known or can, if they

are new, are produced in a manner known per se. When a compound of formula III the group A means with substituted amino substituted methylene, one can prepare a lower alkanoylamino, lower alkylsulfonylamino or amino lower alkyl sulfonylamino derivative by acylation of the a-amino compound of formula III (A=methylene substituted by amino) with a lower alkane carboxylic acid, lower alkanesulfonic acid or amino lower alkanesulfonic acid, or a reactive, functional derivative thereof, e.g. an acid chloride. By subsequent reaction with an alkylating agent, e.g. methyl iodide or ethyl iodide, compounds of formula III are obtained, in which A means with N-lower alkyl-N-lower alkanoylamino, N-lower alkyl-N-lower alkylsulfonylamino or N-lower alkyl-N-aminolower alkanesulfonylamino substituted methylene.

The compounds of formula IV are known or can, if they

are new, are prepared in a manner known per se, for example by acylation of a compound of formula XIV with a compound of formula III analogous to method a).

Compounds of formula V are valuable intermediates

and these are produced, for example, in a connection with formula

in which the 7B-amino group and the 4-carboxy group are optionally protected, with a group which enables the acylation reaction, acylate the 7B-amino group by reaction with an acylating agent which introduces the acyl residues of a carboxylic acid of formula III, in which A, X and Y have the formula I mentioned significance, and the amino groups are optionally protected, and reacts a formed acylated compound of formula evneutless in situ with an esterifying agent which introduces the group

and optionally transfers the 3-hydroxy group to another cleavable group.R .

The acylation of a compound of formula XVI with the carboxylic acid of formula III or a reactive, functional derivative of this carboxylic acid, e.g. the acid chloride, takes place in the manner described under method a). The subsequent esterification takes place analogously to method b), in that the acylated compound of formula I XVII is reacted with a compound of formula IX or stepwise in that the compound of formula XVII is reacted with a dihalide of formula X or a reactive derivative of the aldehyde of formula XI. The transfer of the 3-hydroxy group to another cleavable group Rq is described in German Offenlegungsschrift 2 332 078 and takes place e.g. by 3-acylation, e.g. with the acetyl residue, e.g. by reaction with acetic anhydride.

Intermediate products with formula

is then reacted in situ or after isolation with a carboxylic acid of formula XIII or a salt of this carboxylic acid, or if means hydroxide, with a reactive, functional derivative of this carboxylic acid.

Compounds of formula We are valuable intermediates

and is produced, for example, as a compound of formula

in which X, Y, A and R-^ have the meaning mentioned under formula I or a reactive, functional derivative of this compound, possibly reacted stepwise with an esterification agent which introduces the group The production of the starting material with formula VI takes place analogously to esterification method b), in that a compound of formula XIX is reacted with a compound of formula IX, or stepwise, whereby a compound of formula XIX is reacted with an aldehyde of formula XI, or a compound of formula XIX is reacted with a reactive derivative of the aldehyde of formula XI. The intermediate with formula

is then reacted in situ or after isolation with a

carboxylic acid of formula XIII or a salt of this carboxylic acid, or if Z represents hydroxy, with a reactive, functional derivative of this carboxylic acid.

Compounds with formula VII are valuable intermediates and are produced, for example, in a manner known per se,

whereas in a compound of formula II, in which the 7B-amino group and the 4-carboxyl group are optionally protected with a group that enables the acylation reaction, the 76-amino group is acylated by reaction with an acylating agent which introduces the acyl residues of the carboxylic acid with formula

in which Hal means halogen and A the meaning mentioned under formula I, and a functional group present in A is protected.

The acylation of a compound of formula II with the carboxylic acid of formula XXI or a reactive, functional derivative of this carboxylic acid, e.g. the acid chloride, takes place analogously to procedure a).

Compounds of formula VIII are valuable intermediates and are prepared, for example, in a manner known per se, whereby in a compound of formula II, in which the 76-amino group and the 4-carboxy group are possibly protected with a group that enables the acylation reaction, the 7B-amino groups are acylated by reaction with an acylating agent which introduces the acyl residues of a carboxylic acid of formula

in which X^ means hydrogen, halogen or hydroxy, and A has the meaning mentioned under formula I, and the amino group and a functional group present in A are protected.

The acylation of compounds of formula II with the carboxylic acid of formula XXII or a reactive, functional derivative of this carboxylic acid, e.g. acid chloride, takes place analogously to procedure a).

Compounds of formula IX are known, and allow, if they

are new, prepared by reacting a dihalide of formula X with a carboxylic acid of formula XIII or a salt of this carboxylic acid by reacting an aldehyde of formula XI with a reactive, functional derivative of a carboxylic acid of formula XIII, e.g. . the acid chloride or by reacting a reactive derivative of the aldehyde with formula XI, e.g. an acetate with a carboxylic acid of formula XIII analogous method b).

The compounds of formula XIV and XVI are known, and partly commercially available.

Compounds of formula XV are known.

Compounds of formula XVII are known and, if they are new, can be prepared in a manner known per se. When in a compound of formula XVI the group A means substituted amino substituted methylene, the lower alkanoylamino, lower alkylsulfonylamino or amino lower alkylsulfonylamino derivatives can be prepared by acylation of the a-amino compound of formula XVII (A = methylene substituted with amino)

with a lower alkane carboxylic acid, lower alkanesulfonic acid or amino lower alkanesulfonic acid, or a reactive, functional derivative thereof, e.g. an acid chloride. By subsequent reaction with an alkylating agent, e.g. methyl iodide or ethyl iodide, compounds of formula XVII are obtained, in which A means with N-lower alkyl-N-lower alkanoylamino, N-lower alkyl-N-lower alkylsulfonylamino or N-lower alkyl-N-aminolower alkanesulfonylamino substituted methylene.

Compounds of formula XIX are known or can, if they

are new, are produced in a manner known per se, e.g. by acylation of a 1-oxide compound of formula:

with a carboxylic acid of formula III analogous method

a) .

The compounds of formula XXI, XXII and XXIII are known.

The invention will be explained with the help of some examples, where the temperatures are indicated in °C. DC = thin layer chromatography.

Example 1. 7B-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-2-acetoxybenzoyloxynethyl ester.

A suspension of 3.83 g (10 mmol) of 7B-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid in 25 ml of dry N,N-dimethylformamide, brought into solution by mixing with 1.34 ml (0.9 mmol) 1,5-diazabicyclo /5.4.0/undec-5-eri at <1Q°C. ... A solution of 4.57 g (20 mmol) of 2-acetoxybenzoyloxymethyl chloride in 5 ml of N,N-dimethylformamide is added and stirred for 18 hours at 22°C.

The dark red, clear solution formed is added to 130 ml of 0.3 molar aqueous dipotassium hydrogen phosphate solution at 0°C with stirring, the mixture is saturated with sodium chloride and extracted 3 times with 250 ml of cold ethyl acetate each time. The organic extracts dried over sodium sulphate and purified with activated charcoal are evaporated until an oily residue is obtained. After the residue's digestion in diethyl ether, the undissolved part is dissolved in acetic acid ethyl ester and mixed with 0.8 ml of 12N aqueous hydrogen chloride solution. The title compound is obtained as the hydrochloride. DC: Rf approx. 0.36 (acetone-toluene 6:4; Merck DC-finished plate silica gel 60 F254 ^'" NMR spectrum see the table.

Example 2.

7p-/ 2-( 2- aminothiazol-4- yl)- 2- Z- methoxyiminoacetamido/- 3- cephem- 4- carboxylic acid- 2- acetoxybenzoyloxynethyl ester.

A suspension of 7.7 g (20 mmol) of 73-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid in 30 ml of absolute dimethylformamide is mixed at 0-5 °C with 3.0 ml (20 mmol) 1,5-diazabicyclo/5.4.0/undec-5-ene and stir for a long time at this temperature (approx. 50 min.) until a clear solution is obtained. After adding 1.8 ml (24 mmol) of chloroiodomethane, the mixture is stirred for 17 hours at 22°C. The solution containing 7-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid chloromethyl ester is evaporated somewhat to remove excess chloroiodomethane in vacuo and then mixed with a solution of 5.4 g (30 mmol) of 2-acetoxybenzoic acid and 4.5 ml of 1,5-diazabicyclo/5.4.0/-undec-5-ene in 25 ml of dimethylformamide. It is allowed to stand for 18 hours at 22°C and worked up analogously to example 1. A crude product is obtained which is purified by column chromatography

on silica gel. From the fractions eluted with a methylene chloride-methanol 9:1 mixture, the pure title compound is obtained which is identical to the product obtained according to example 1.

Example 3.

Analogous to example 1 or 2, the following esters or their hydrochlorides can be prepared (Rf value applies to system acetone-toluene 6:4, Merck DC-finished plates kieselgel 60 F254' NMR values see the table).

)7 O-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-

cephem-4-carboxylic acid-4-methoxybenzoyloxynethyl ester, Rf approx. 0.31;

b) 76-/2-(2-aminothiazol-4-yl)"-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-methylbenzoyloxymethyl ester, Rf

about. 0.40;

c) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-4-tert-butylbenzoyloxymethyl ester, Rf, ca. 0.39; d) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-benzoyloxymethyl ester, Rf approx. 0.41; e) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-cyanobenzoyloxymethyl ester, Rf approx. 0.36; f) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-3-chlorobenzoyloxymethyl ester, Rf approx. 0.42;, g) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-nitrobenzoyloxymethyl ester, Rf approx. 0.34; h) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-2-furoyloxymethyl ester, Rf approx. 0.34; i) 76-[2-(2-aminothiazol-4-yl)-2-Z-met ok sy iminoacetamido/-3-cephem-4-carboxylic acid-3,4,5-trimethoxybenzoyloxymethyl-ester, Rf ca. 0.36; k) 7B-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-1-benzoyloxyethyl ester, Rf approx. 0.39; 1) 76-/2-(2-aminothiazol-4-yl)-2-Z-met oksy iminoacetamido/-3-cephem-4-carboxylic acid-4-aminobenzoyloxynethyl ester, Rf approx. 0.25;

m) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/- 3-cephem-4-carboxylic acid-2-acetylbenzoyloxynethyl ester,

Rf approx. 0.35;

n) 7 6-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/- 3-cephem-4-carboxylic acid-3-trifluoromethylbenzoyloxymethyl-

ester, Rf approx. 0.45;

o) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-sulfamoylbenzoyloxymethyl ester;

p) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-cephem-4-carboxylic acid 4-hydroxybenzoyloxymethyl ester;

q) 7 6 ~/ 2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/- 3-cephem-4-carboxylic acid- -benzoyloxybenzyl ester, Rf approx. 0.57;

r) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido7-3-cephem-4-carboxylic acid 4-di-n-propylsulfamoylbenzoyloxymethyl ester, Rf approx. 0.50;

s)7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-2-chlorobenzoyloxymethyl ester, Rf approx. 0.43;

t) 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-chlorobenzoyloxymethyl ester, Rf. about. 0.40; ,

u) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-3,4-diacetoxybenzoyloxymethyl ester, Rf approx. 0.37;

v) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-4-acetoxybenzoyloxymethyl ester,

Rf approx. 0.39;

w) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-3,5-diacetoxybenzoyloxymethyl ester, Rf approx. 0.41;

x) 7 6-(2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-3-acetoxybenzoyloxymethyl ester,

Rf approx. 0.34.

Table

Chemical supplies (in ppm in relation to tetramethylsilane) of the proton in the NMR spectra of the compounds formed according to examples 1-3:

Bands of the other H in the following areas:

H-2: 3.65-3.71 m, H-3: 6.62-6.72 m, H-6: 5.15-5.20 d (J=5)

H-7: 5.87-5.90 dd (J=5 and 8), NH-7: 9.59-9.83 d (J=8), H(y): 6.76-6.95 s H(z): 3.85-3.99 s.

Example 4.

Tablets containing 250 mg of 76-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido7~3-cephem-4-carboxylic acid-2-acetoxybenzoyl methyl ester hydrochloride as active substance are prepared as follows:

The active substance is mixed homogeneously with the additives and pressed into tablets. For the production of film dragees, the tablets are each coated with 1 mg of aqueous varnish. Instead of sodium carboxymethyl starch, sodium carboxymethyl cellulose can also be used.

Example 5.

Capsules containing 0.250 mg of 76-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-2-acet-oxybenzoyloxymethyl ester hydrochloride as active ingredient are prepared as follows:

The active substance, wheat starch and magnesium stearate are mixed well together and filled in capsules No. 1.

Example 6.

Capsules containing 0.5 g of 7B-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxylic acid-2-acetoxy-benzoyloxymethyl ester hydrochloride as active ingredient are prepared as follows:

The active substance is mixed with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol, the mixture is passed through a sieve with a mesh size of 3 mm and the granules are dried under reduced pressure at 40-50°C. The granulate is sieved through a sieve with a mesh size of 0.8 mm, the corn starch and magnesium stearate are added, the mixture is mixed and filled into capsules (size 0).

Claims (9)

1. Process for the preparation of compounds of formula ten where X means nitrogen or the group -C-H, Y means oxygen, sulfur or the groups or A .means methylene or with amino substituted amino, hydroxy, carboxy, hydroxyimino or etherified or esterified hydroxyimino, substituted methylene, means hydrogen, halogen, lower alkyl or lower alkoxy, R2 means hydrogen, lower alkyl, phenyl or substituted phenyl, and R^ means unsubstituted or substituted, aromatic, five- or six-membered heterocyclyl, phenyl or substituted phenyl, as well as stereoisomeric mixtures of these stereoisomers and salts of these compounds, characterized by ata) in a compound with formula in which R^ , R 2 and R^ have the meanings given above, The 7-amino group is optionally protected with a group which enables the acylation reaction and a functional group present in R2 or R^ is protected, the 7-amino group is acylated by reaction with an acylating agent which introduces the acyl residue of a carboxylic acid of formula in which A, X and Y have the above meaning, and the amino groups are optionally protected, orb) a compound of formula in which A, X, Y and R^ have the above meaning, the amino group is optionally and a functional group present in A is protected, or a salt thereof, or a reactive, functional derivative of this compound, is optionally reacted stepwise with an esterification agent who introduces the group orc) for the preparation of a compound of formula I, in which X, Y, A, R 2 and R 2 have the meaning indicated above and means hydrogen, becomes in a compound of formula in which X, Y, A, R2 and R^ have the above-mentioned meaning, the amino group is optionally protected, and a functional group present in A, R2 or R^ is protected, Rq means a cleavable group, RQ is cleavable, ord) a 1 -oxide with formula in which X, Y, A, R-^, R2 and R^ have the above meaning, the amino group and a functional group present in A, R2 or R^ is optionally protected, transferred with a suitable reducing agent to the 1-sulphide, or e) for the preparation of compounds of formula I, in which X means the group =Ci-H and Y means oxygen or sulphur, A, R , R 2 and R 2 have the meaning given above, gives a compound of formula in which Hal means halogen, A, R^, R2 and R^ have the meaning mentioned under formula I, the amino group and a functional group present in A, R-, or R^ is optionally protected, condensed with urea, respectively thiourea, or f) for the preparation of a compound of formula I in which X means nitrogen and Y means sulphur, A, R-^ , R 2 and R^ have the meaning indicated above, a compound is reacted with formula in which X^ means hydrogen, halogen or hydroxy, A, R^ , R 2 and R 2 have the above meaning, the amino group and a functional group present in A, R 2 or R 2 is optionally protected with a salt of rhodanese hydrogen acid or, if X-^ means hydrogen, with dirodane, and a formed compound, the amino protecting group or groups and other protecting groups present are cleaved off, and if desired, a formed compound is transferred in a salt or a formed salt in the free compound or in another salt. 2. Process for the preparation of compounds according to claim 1 with formula I in which X means nitrogen or it the group - C- E, Y means oxygen or sulphur, A means with amino, lower alkylsulfonylamino, N,N-dilower alkylsulfonyl-amino, N-aminolower alkylsulfonyl-N-lower alkylamino, hydroxyimino, lower alkoxyimino or carboxylavereal oxyimino substituted methylene, means hydrogen, halogen, lower alkyl or lower alkoxy, R^ means hydrogen, lower alkyl, phenyl, lower alkyl-, di-lower alkyl- or tri-lower alkyl phenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, hydroxy lower alkyl phenyl, lower alkoxy-, di lave real oxy or tri lave real oxy phenyl, hydroxy lave real oxy phenyl, hydroxy di lave real oxy phenyl, lower alkanoyl phenyl, lower alkanoyloxyphenyl, halogenophenyl1 . . the features mentioned in claim 1. 3. Process for preparing compounds according to claim 2 with formula I, in which X means nitrogen or ii the group -C-H, Y means oxygen or sulphur, A means methylene substituted with hydroxyimino, lower alkoxyimino or carboxyllower oxyimino, R^ means hydrogen, halogen or lower alkoxy, R^ means hydrogen, lower alkyl, phenyl, lower alkylphenyl, hydroxy-, dihydroxy or trihydroxy phenyl, lower alkoxy, dilavereal oxy or trilavereal oxyphenyl, hydroxyl lavereal oxyphenyl, loweralkanoylphenyl, loweralkanoyloxyphenyl, halophenyl, nitrophenyl, loweralkanoylaminophenyl, halogenoloweralkylphenyl or aminoloweralkylphenyl, and means pyrrolyl, loweralkylpyrrolyl, imidazolyl, loweralkylimidazolyl, triazolyl, loweralkyltriazoly1, tetrazolyl, loweralkyltetrazoly1, tieriyl, thiazolyl, thiadiazolyl, furyl, pyridyl, hydroxypyridyl, dihydroxypyridyl, aminopyridyl, dihydroxypyrimidinyl, pyrazinyl, aminopyrazin-2-y1, pyronyl, phenyl, loweralkyl-, dilaverealkyl- or trilaverealkylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, hydroxylaverealkylphenyl, loweralkoxy-, dilavere Alkoxy- or trilavereal oxyphenyl, 4-methoxy-, 3,4-dimethoxy-, 2,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, hydroxy-lower-alkoxyphenyl, hydroxydilavereal oxyphenyl, loweralkanoylphenyl, loweralkanoyloxyphenyl, halophenyl, nitrophenyl, cyanophenyl, amino- or diaminophenyl1, amino-hydroxyphenyl1, lower alkylaminophenyl, diloweralkylaminophenyl1, lower-alkanoylaminophenyl, sulfamoylphenyl, halogenloweralkylphenyl or aminoloweralkylphenyl, and their pharmaceutically acceptable salts, characterized in that they carry out the features mentioned in claim 1. 4. Process for preparing compounds according to claim 3 with formula I, in which X means the group -C-H, Y means sulphur, A means lower alkoxyimino substituted methylene, R^ means hydrogen, R^ means hydrogen or lower alkyl and R^ means furyl, phenyl, lower alkyl-, dilower alkyl- or trilower alkylphenyl, hydroxy-, dihydroxy- or trihydroxyphenyl, hydroxylower alkylphenyl, lower alkoxy- , dilavereal oxy- or trilavereal oxyphenyl1, hydroxy lavereal oxyphenyl , hydroxydilavereal oxyphenyl, loweralkanoylphenyl, loweralkanoyloxyphenyl, halogenophenyl, nitrophenyl, cyanophenyl, amino- or diaminophenyl, aminohydroxyphenyl, loweralkylaminophenyl, dilaverealaminophenyl, loweralkanoylaminophenyl, halogenoloweralkylphenyl or aminoloweralkylphenyl, and their pharmaceutically acceptable salts, characterized in that implement the features mentioned in claim 1. 5. Process for making compounds ten according to claim 4 with formula I, in which X means the group -C-H, Y means sulphur, A means methoxyimino substituted methylene, means hydrogen, R^ means hydrogen or methyl and R^ means fur-2- or -3-yl, phenyl, 2-, 3- or 4-methyl-, 2-, 3- or 4-tert-butyl-, 3,4-dimethyl-, 2,3-dimethyl, 2,4-dimethyl- or 2,4,6-trimethylphenyl, 4-hydroxy-, 2,4- dihydroxy-, 2,3,4-trihydroxy-, 2,4,6-trihydroxy- or 3,4,5-trihydroxyphenyl, 2-hydroxy-3-methylphenyl, 4-methoxy-, 3,4-dimethoxy-, 2 ,3-dimethoxy-, 2,4-dimethoxy- or 3,4,5-trimethoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-2,4-dimethoxyphenyl, 2-, 3- or 4-acetylphenyl, 2 -, 3-or 4-acetoxyphenyl, 2-, 3- or 4-flour- or 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-aminophenyl or 3,5-diaminophenyl, 3-amino-4-hydroxy- or 4-amino-2-hydroxyphenyl, 2- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-sulfamoylphenyl, 2-, 3- or 4-trifluoromethylphenyl or 2-, 3- or 4-aminomethylphenyl and their pharmaceutically acceptable salts, characterized in that the methods mentioned in claim 1 are carried out traits. 6. Process for the production of 7B-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido/-3-cephem-4-carboxyl-acid-2-acetoxybenzoyloxymethyl ester according to claim 5, characterized in that it is carried out the features mentioned in claim 1. 7. Process for the production of 7B-/2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido7-3-cephem-4-carboxyl-acid-4-methylbenzoyloxymethyl ester according to claim 5, characterized in that the in claim 1 said move. 8. Process for the production of 73-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-cephem-4-carboxylic acid 4-tert-butylbenzoyloxymethyl ester according to claim 5, characterized in that the steps mentioned in requirement 1 are carried out. 9. Method for producing pharmaceutical preparations containing compounds according to claim 1 with formula I, characterized in that compounds with formula I or salts thereof are prepared according to the method according to claim 1, and these are mixed with a pharmaceutical carrier material.