DE2548663A1 - Alpha-(imidazolidinone carbonylamino) penicillins - and cephalosporins, antibacterials useful e.g. as feed additives - Google Patents

Abstract

Beta-lactams of formula (I) and their pharmaceutically acceptable salts are new: A=H or CH3O, B=phenyl (opt. substd. by >=1 OH, halo, CH3O, CN and CH3SO2), thienyl, cyclohexenyl or 1,4-cyclohexadien-1-yl. E=O or S. Y is one of the groups -S-C(CH3)2. CH(COOH)- or -U-CH2. C(CH2T)=C(COOH)-, T=H, alkanoyloxy, OH, pyridinium, aminopyridinium, carbamoyloxy, azido, CN, thiocarbamoylthio, or opt. substd. phenylthio or 5-6 membered heterocyclylthio. U = O, S or CH2. Z = opt. substd. cycloalkyl, cycloalkenyl or cycloalkadienyl, the CH2 gps. opt. replaced by one O, S, SO, SO2 or by one or two CO, and a benzene ring can be fused on; or Z is an opt. substd. 5-6 membered pseudoaromatic heterocycle. (I) can have either configuration about the asterisked C atom or may be mixtures of the diastereoisomers). They are prepd. from corresp. alpha-aminoacetamido penicillins, etc. by reaction with 1-(CEW)-3-(Z)-imidazolidin-2-one (W=halo, azido or other nucleophilically-displaceable gp.). (I) are antibacterials. They may be used for therapeutic or prophylactic control of disease; to preserve polymers, foods etc. against spoilage and as feed additives to improve feed utilisation and growth rate. Specified cpd., D-alpha-((3-cyclopropylimidazolidin-2-one-1lyl) carbonylamino)benzylpenicillin was prepd. by reacting ampicillin trihydrate with 1-chlorocarbonyl-2-oxo-3-cyclopropylimidazolidine.

Description

β-lactam compounds, process for their preparation

as well as their use as medicaments The present invention relates to new P-Lac tamY connections, a process for their production and their use as medicaments, in particular as antibacterial agents and as agents for promotion the growth and improvement of feed conversion in animals.

Ss-lactam compounds substituted in a certain way, as in certain Wise substituted - (imidazolidin-2-oxo-l-ylcarbonylamino) -denzylpenicillins and Corresponding cephalosporins with an imidazolidin-2-oxo-l-yl-carbonylamino side chain are from German Offenlegungsschrift 2.104.580, 2,152,967, 2,258,973, 2,402,465 and 2,428,139 are known.

The new β-lactam compounds of the formula I have now been found in which A is hydrogen or methoxy; B for phenyl; phenyl substituted by hydroxy, halogen, methoxy-, -CN and / or CH3 -So 2 -substituted; for thienyl; Cyclohexenyl or 1,4-cyclohexadien-1-yl; E represents oxygen or sulfur; Y for the groups stands in which the carbon atom carrying the carboxyl group is bonded to the nitrogen atom of the ß-lactam ring and T stands for hydrogen! Alkvl-CO-O-, HydroxV-, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, thiocarbamoylthio, the group -S-phenyl, which can be substituted, or the group -S-Het, in which Het is optionally substituted heterocyclic 5- or 6-membered ring, U represents oxygen, sulfur or the -CH2 group; and Z represents optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl, where -CH2 groups of the cycloalkyl radicals can also be replaced by an oxygen or sulfur atom or an -SO- or -SO2 group or by one or two -CO groups and where a benzene ring can be fused onto these rings; or represents an optionally substituted pseudoaromatic heterocyclic 5- or 6-membered ring; and where the β-lactam compounds of the formula I can exist in the two possible configurations R and S with respect to the chiral center C and as mixtures of the resulting diastereomers and the non-toxic, pharmaceutically acceptable salts of these compounds.

The novel β-lactam compounds according to the invention differ of the known compounds of the prior art in that the N3 of the imidazolidinone radical with a carbon atom of a cyclic radical, directly, i.e. without an intermediate member, e.g. a carbonyl or sulfonyl group.

The compounds according to the invention have strong antibacterial properties and have the property, growth and feed conversion in animals to improve.

It has also been found that the β-lactam compounds of the formula I are obtained when compounds of the formula II: in which * A, B, C and Y have the meaning given above, or their derivatives obtained by silylation on the carboxyl group or on the carboxyl and primary amino group, with compounds of the general formula III: where Z and E have the meaning given above and w stands for halogen, azide or another nucleofugal leaving group, in the presence of a solvent and optionally an acid binder at temperatures of about -200C to about + 50 ° C and the resulting ß-lactam Compounds, if appropriate after cleavage of the silyl group (s), if desired, converted into their non-toxic, pharmaceutically acceptable salts or, if desired, prepares the free acids from the salts or silyl esters obtained, if desired.

Surprisingly, the new β-lactam compounds are well tolerated very effective against a wide range of pathogens. the Substances according to the invention thus represent an enrichment for pharmacy.

If the amino-benzylpenicillin and l-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine are used as starting materials, the course of the reaction can be represented by the following equation: Tetrahydrofuran / H20 / (D) SUCH3 5 pH = 6.5-7.5 Q - CO-NH o ° C-2s ° c pH = 6.5-7, s W ~ T -SO-> 4 to CH3 NH | COOH COOH :1 N In the formulas, optionally substituted cycloalkyl, cycloalkenyl and cycloacadienyl Z denote those with 3 to 7, preferably 3 to 6, ring carbon atoms. Examples include: Cyclopropyl, 1-Cyclopropen-1-yl, 2-Cyclopropen-1-yl, Cyclobutyl, 1-Cyclobuten-1 -yl, 2-Cyclobuten-1-yl, Cyclopentyl, 1-Cyclopenten-1-yl, 2-cyclopenten-1-yl-, 3-cyclopenten-1-yl-, cyclohexyl, 1-, 2- or 3-cyclohexen-1-yl, 1,4-cyclohexadien-1-yl and the radicals Examples of optionally substituted pseudoaromatic heterocyclic 5- or 6-membered rings Z include: furyl (preferably furyl-2); Pyrryl (preferably 2-pyrryl); 1-methylpyrryl-2 or -3; Thienyl (preferably 2-thienyl); Oxazolyl (attached in the 2-, 4- or 5-position); Thiazolyl (attached in the 2-, 4- or 5-position); Isoxazolyl (attached in the 3-, 4-, or 5-position); Isothiazolyl (attached in the 3-, 4- or 5-position) 1,2,5-oxadiazolyl-3-; 1,2,5-thiadiazolyl-3-; 1,3,4-oxadiazolyl-2-; 1,3,4-thiadiazolyl-2-; 1,2,4-oxadiazoylyl (attached in the 3- or 5-position); 1,2,4-thiadiazolyl (attached in the 3 or 5 position); Pyrazolyl (attached in the 3-, 4-, or 5-position); 1,2,4-triazolyl (attached in the 3- or 5-position); Tetrazolyl; Pyridyl (attached in the 2-, 3- or 4-position); Pyridazinyl (attached in 3- or 4-position); Pyrimidinyl (attached in the 2-, 4-, or 5-position); eC-Pyronyl (bonded in the 3-, 4-, 5- or 6-position); Y'-Pyronyi (bound in the 2- or 3-position) and benzthiazolyl-2-, thiazolyi (bound in the 2-, 4- or 5-position).

Cycloalkyl, cycloalkenyl and cycloalkadienyl Z and the heterocyclic 5- or 6-membered rings Z can be mono-, di- or tri-, preferably mono- or di-substituted, in particular monosubstituted. Examples of substituents include: lower alkyl, in particular methyl, ethyl, propyl, isopropyl, t-butyl, preferably methyl; Lower alkylidene, especially methylene, ethylidene and isopropylidene; Vinyl, propenyl, allyl, isopropenyl; Lower alkoxymethyl, especially methoxymethyl; Lower alkylthiomethyl, especially methylthiomethyl; Trifluoromethyl; Hydroxymethyl; Formyl; Lower alkanoyl, especially acetyl; Lower alkanoyloxymethyl, especially acetoxymethyl; Benzyl; Aryl, especially phenyl; Cyanomethyl; the groups CH3-NH-CO-CH2- and (CH3) 2N-CO-CH2-; Lower alkoxycarbonyl, especially methoxycarbonyl and ethoxycarbonyl; Carboxy; Cyano; Hydroxy; Lower alkanoyloxy, especially acetoxy; Lower alkoxy, especially methoxy and ethoxy; Benzyloxy; Halogen, in particular fluorine, chlorine, bromine, preferably chlorine; Mercapto; Lower alkylthio, especially methylthio and ethylthio; Lower alkylsulfinyl, especially methylsulfinyl and ethylsulfinyl; Lower alkylsulfonyl, especially methylsulfonyl and ethylsulfonyl; the groups CH3-CO-NH-, CH3-CO-N (CH3) -, CH3-S02-NH- and The cycloalkyl, cycloalkenyl and cycloalkadienyl radicals Z are preferably unsubstituted, the unsubstituted cyclopropyl radical being emphasized in particular.

The heterocyclic 5- or 6-membered rings Z are very special preferably unsubstituted or mono-substituted, with preferred substituents Lower alkyl, trifluoromethyl, lower alkylsulfonyl, lower alkylthio and trifluoromethyl should be mentioned. Particularly preferred heterocyclic rings Z are: Pyridyl-2, -3 or -4; Furyl; 5-methylthio- (1,3,4-hiadiazol) -2-yl, 5-i-propylthio- (1,3,4-thiadiazol) -2-yl; 5-methylsulfonyl- (1,3,4-thiadiazol) -2-yl; 5-trifluoromethyl- (1,3,4-thiadiazole) -2-yl; 5-sec-butyl- (1,3,4-thiadiazol) -2-yl and benzthiazolyl-2-.

A particularly preferably represents hydrogen and E particularly preferably for oxygen. U particularly preferably denotes sulfur.

In the definition of T, alkyl in alkyl means -CO-O- preferably Alkyl having 1 to 4, in particular 1 or 2, carbon atoms. Examples are methyl and called ethyl, preferably methyl. T is particularly preferably hydrogen, OH or methyl-CO-O-; The thiocarbamoylthio radical (definition of T) can be found on the N atom be substituted by one or two lower alkyl radicals. Furthermore, this N atom Part of a pyrrolidine, piperidine, morpholine and N4 lower alkylpiperazine ring be.

The heterocyclic ring Het consists of -S-Het (definition of T) of 5 or 6 ring members and contains 1 to 4, preferably 2 to 4, very particularly preferably 3 or 4 identical or different heteroatoms, the heteroatoms being Oxygen, sulfur and nitrogen are available.

The heterocyclic ring is preferably unsaturated and particularly contains preferably 2 double bonds. The heterocyclic ring can be one or more, preferably 1 or 2, in particular contain a substituent.

Examples of substituents include: halogen, such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine; Amino, lower alkylamino; Di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl part), lower alkyloxy (meaning of "lower alkyl" see below), trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5, especially 2 or 3 carbon atoms. As -S-Het are listed as particularly preferred: R1 = H, CH3 or C2H5; X = O, S CH3, CF3, NHCH3, NHCHO, N (CH3) 2 or NHCOCH3; x = 0.5 The -S-phenyl radical in the definition of T can carry one or more, preferably 1 to 3, in particular 1 or 2, identical or different substituents, those substituents being preferred which are listed above as possible substituents of the radical -S-Het .

Under nucleofugal leaving groups in the definition of W are all nucleofugal groups commonly used in organic chemistry and before to understand especially those which are described in Angewandte Chemie, 81 (1969), page 543 are.

The phenyl radical B can be one or more, identical or different preferably 1 to 3, in particular 1 or 2 and very preferably 1 of the above Carry substituents. In the case of monosubstitution, the substituent is preferably in 4-position (based on the bond of the phenyl radical to the asymmetric carbon atom).

Halogen as a substituent in the phenyl radical B means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, especially fluorine and chlorine.

B particularly preferably represents phenyl, 4-hydroxyphenyl and 1,4-cyclohexadien-1-yl.

Non-toxic, pharmaceutically acceptable salts of the compounds of the formula I are salts of these compounds with inorganic and organic bases on the acidic carboxyl group or the acidic carboxyl and sulfonic acid groups. Bases that can be used for this purpose are all in pharmaceutical chemistry, in particular in Chemistry of antibiotics, commonly used bases are used.

Examples of inorganic bases are: alkali and alkaline earth metal hydroxides, Alkali and alkaline earth carbonates and alkali hydrogen carbonates, such as sodium and potassium hydroxide, Calcium and magnesium hydroxide, sodium and potassium carbonate, calcium carbonate, sodium and potassium hydrogen carbonate; Aluminum hydroxide and ammonium hydroxide. As organic Bases can be primary, secondary and tertiary aliphatic amines as well as heterocyclic Amines are used.

The following may be mentioned as examples: Diur; Tri-lower alkylamines, e.g. diethylamine, Triethylamine, tri-ß-hydroxyethylamine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-3enzylß-phenyl-ethylamine, N-methyl- and N-ethylmorpholine 1-ephenamine, deühydroabiethylamine, N, N'-bis-dehydroabiethylethylenediamine, N-lower alkylpiperidine. Also so-called Basic amino acids such as lysine or arginine can advantageously be used as bases Find. Particularly preferred salts are the sodium salts With the The expression "lower alkyl" is in each case both straight-chain and branched Alkyl groups with 1 to 5, preferably 1 to 3, in particular 1 or 2 carbon atoms Understood. In connection with other groups as in "di-lower alkylamino" relates the term f-lower alkyl- "refers only to the alkyl portion of the group in question.

Particularly preferred compounds of the general formula I are those in which A stands for hydrogen; B represents phenyl, hydroxyphenyl (particularly preferably p-hydroxyphenyl) or 1,4-cyclohexadien-1-yl; E is oxygen; Y for the groups where T -O-CO-CH3OH, 1-methyl-tetrazol-5-yl-thio, 2-methyl-1,3,4-thiadiazol-5-yl-thio, 3-methyl-1,2,4 -thiadiazol-5-yl-thio, or 2-trifluoromethyl-1,3,4-thiadiazol-5-ylthio and means; Z for cyclopropyl, furyl (preferably furyl-2-) pyridyl; Benzthiazolyl-2- or 1,3,4-thiadiazol-2-, which can be substituted in the 5 position by sec-butyl, trifluoromethyl, methylthio, i-propylthio or methylsulfonyl, is in the D = R configuration , as well as the sodium salts of these compounds.

All crystal forms and hydrate forms of the compounds according to the invention of the general formula I and their salts have an antibacterial effect in the same way.

The compounds of the general formula which can be used according to the invention II are already known or can be obtained by known methods (cf. e.g. E.H. Flynn, Cephalosporins and Penicillins, Academic Press, New York and London, 1972).

Examples are: O-aminobenzylpenicillin (short name: Ampicillin), a6 -amino-p-hydroxybenzylpenicillin (short name: amoxicillin) α-amino-p-methylbenzylpenicillin, α-amino-p-chlorobenzylpenicilin, 6- (2-amino-2- (1,4-cyclohexadien-1-yl) acetammido) penicillanic acid (Short name: Epicillin), 7- (-Aminophenylacetamido) -3-methyl-ceph-3-em-4-carboxylic acid, 7- (0C-aminophenylacetamido) -3-acetoxy-methyl-ceph-3-em-4-carboxylic acid (short name: Cephaloglycine), 7- (oC-Amino-phenylacetamido) -3 - ((1-methyltetrazol-5-yl) -thiomethil) -ceph-3-em-4-carboxylic acid, 7- (od-Aminophenylacetamido) -3 - ((2-methyl-134-thiadiazol-5-yl) -thiomethyl) -ceph-3-em-4-carboxylic acid as well as the sodium salts and the mono- and di- (trimethylsilyl) derivatives of these compounds.

All crystal forms, hydrate forms and salts of the compounds of the general Formula II are suitable as starting materials for the process according to the invention.

The compounds of the general formula used as starting materials III are known or can be obtained by known methods.

You can, for example, in the usual way by reacting the heterocyclic compounds of the general formula IV: with, for example, molar amounts of the compounds of the general formula W-CE-W, such as phosgene or thiophosgene, in inert organic solvents such as tetrahydrofuran or in mixtures of water and inert organic solvents such as chloroform at temperatures from 0 to 25 0C in the absence or be prepared in the presence of the molar amount of a base such as triethylamine and customary work-up and purification.

The preparation of the compounds of the general formulas IV and III is in each case, as far as they are not described in the literature, in the examples specified. All other output connections are easily accessible in the same way.

Examples are: zu WI ZI Cyclopropyl Cl furyl-1- cl II Br furyl-2- Br II N3 pyrrolyl-2- Cl 2-methylcyclopropyl Cl pyrrolyl-3- Cl 2,2-dimethylcyclopropyl Cl pyridyl-2- Cl 1-methylcyclopropyl Cl pyridyl- 3- cl 2-chlorocyclopropyl Cl pyridyl-4- Cl 2-methoxycyclopropyl Cl isoxazolyl-5- Cl 2-methylcarbonylcyclopro- isoxazolyl-4- Cl pyl Cl 2-furylcyclopropyl Cl 1,2 pyronyl-6- Cl 1-cyclopropenyl Cl 2- Methylsulfonyl-2-cyclopropenyl Cl (1,3,4-thiadiazol) -5-yl Cl cyclobutyl Cl benzthiazolyl-2-Cl 3-methoxycyclobutyl Cl pyrimidinyl-2-Cl cyclopentyl Cl The diluents used in the inventive reaction of the compounds of the formulas II and III water and practically all customary inert organic solvents, optionally mixed with water.

One uses for the implementation with the connections of the general Formula III the nonsilylated compounds of the general formula II, so can this reaction, for example, in any mixtures of water with such organic solvents that are miscible with water, e.g. ketones such as acetone, Ringäthenlz.B. Tetrahydrofuran and dioxane, nitriles, e.g.

Acetonitrile, formamides, e.g., dimethylformamide, dimethyl sulfoxide or Alcohols, e.g. isopropanol. The pH of the reaction mixture is maintained during this by adding bases or using buffer solutions (e.g. phosphate or citrate buffers) for example between about 6.5 and about 8.0. The inventive method leaves but also in a different pH range, between pH 1.5 and pH 9.5, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. It is also possible the reaction in water-immiscible solvents, e.g. halogenated hydrocarbons, such as chloroform or methylene chloride with the addition of a base, preferably triethylamine, To carry out diethylamine or N-ethylpiperidine. Furthermore, the reaction in a mixture of water and a water-immiscible solvent, such as ethers, e.g. diethyl ether, halogenated hydrocarbons, e.g. chloroform and methylene chloride, carbon disulfide, ketones, e.g. isobutyl methyl ketone, esters, e.g. ethyl acetate, aromatic solvents e.g. benzene etc. it is advisable to stir vigorously, and the pH value by adding a base or Use of buffer solutions between 1.5 and 9.5, preferably between 4.5 and To hold 9.0 or e.g. 2.0 and 3.0. The reaction can also be carried out in water alone in the absence of organic solvents in the presence of an organic or inorganic base or with the addition of buffer substances.

Suitable as silyl radicals for the compounds of general formula II all silyl groups described in the literature and used for similar purposes. Of some of these silyl groups, for example the trimethylsilyl group, it is known that they are quickly split off by solvents containing water or HO groups will. Of other silyl groups, for example the dimethoxymethyl or the Dimethyl-tert-butyl-silyl groups, on the other hand, are known to be significantly more resistant to hydrolysis are. Depending on the type of silyl radicals used, you may therefore need to work in completely anhydrous and hydroxyl-free solvents. Used one monosilylated for the reaction with the compounds of general formula III Compounds of the general formula II can be used with or without, preferably work with the addition of a base.

If disilylated compounds of the general formula II are used, so you can work with or without, preferably without, the addition of base.

Any of the bases commonly used in organic chemistry can be used as the base inorganic and organic bases are used, such as alkali and alkaline earth hydroxides, Alkaline earth oxides, alkali and alkaline earth carbonates and hydrogen carbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines as well as heterocyclic Bases. Examples are sodium, potassium and calcium hydroxide, calcium oxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, ethylamine, methyl ethylamine, Triethylamine, Hydroxiäthylamin, aniline, pyridine and piperidine called.

As buffer mixtures, all are usually suitable in organic chemistry buffer mixtures used, such as phosphate buffer, citrate buffer and tris (hydroxymethyl) aminomethane buffer.

The reaction temperatures can be used in the implementation of the compounds II and III can be varied within a larger range.

In general, between about -2OOC and about + 500C is preferred between 0 and + 250C. As with most chemical reactions, higher or temperatures lower than those specified are used. But if you go considerably beyond the stated values, there are increasing levels of side reactions take place that reduce the yield or detrimental to the purity of the products influence.

On the other hand, excessively lowered reaction temperatures decrease the rate of reaction is so great that reductions in yield can occur.

The reaction can take place at normal pressure, but also at reduced or increased pressure. In general, normal pressure is used.

When carrying out the process according to the invention, the reactants can are reacted with one another in equimolecular amounts. However, it can it may be expedient to use one of the two reactants in excess to be used to purify or purify the desired ß-lactam antibiotic to facilitate and increase the yield.

For example, one can use the reactants of the general formula II use with an excess of 0.1 to 0.3 molar equivalents and thereby a less decomposition of the reactants of the general formula III ih a water-containing one Reach solvent mixture. The excess of the reactants of the general Because of its good solubility in aqueous mineral acids, formula II can be used when working up Easily remove the reaction mixture.

On the other hand, you can also use the reactants of the general formula III with an excess of, for example, 0.1 to 1.0 molar equivalents insert. This improves the reactants of the general formula II exploited and the side reaction occurring in aqueous solvents Compensation for the decomposition of the reactants of the general formula III. Since the Compounds of the general formula added in excess are dissolved in water rapidly convert to neutral nitrogen-containing heterocycles that are easily removed leave, the purity of the p-lactam compounds is hardly affected.

Bases can be used in equimolar amounts, but also in excess the reactants of the formulas II and III are added. The amount of base is of course dependent on compliance with the selected pH value range.

The work-up of the reaction batches for the preparation of the inventive ß-lactam compounds and their salts and the purification of these compounds takes place consistently in the manner commonly used with penicillins or cephalosporins and way, e.g. B. by removing the solvent, taking up in organic solvents, Precipitation and recrystallization.

The sodium salts are particularly advantageous by precipitation obtained with sodium 2-ethylhexanoate from an ethereal solution of the free acids.

If you use the mono- or in the reactions according to the invention disilylated compounds of the general formula II, the hydrolytic one takes place Cleavage of the silyl radical or radicals in the course of the warm work-up of the reaction batches, optionally at acidic pH.

As new active ingredients are mentioned in detail (formula V, VI, VII and VIII) E.g. Phenyl 4-hydroxyphenyl r cyclohexa-1,4-dien-l-yl 1? Thienyl (2) C "4-methylsulfonyl-phenyl "t-phenyl 4-hydroxyphenyl Cyclohexa-1,4-dien-1-yl (1 thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dienyl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-l-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydr oxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4- Hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-1-yl Thienyl- (2) 4-Methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-1-yl Thienyl- (2) 4-Methyl-sulfonyl -phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dienyl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl Cyclohexa-1,4-dienyl-1-yl thienyl- (2) 4-methylsulfonyl-phenyl-phenyl-4-hydroxyphenyl Cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-1-yl Thienyl- (2) 4-Methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-1-yl Thienyl- (2j 4-Methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) -4-methyl sulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-l-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-l-yl thienyl- (2) 4- Methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-l-yl thienyl- (2) 4-methoxysulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-l-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-l-yl Thienyl- (2) 4-Methylsulfonyl-phenyl Phenyl 4-Hydroxyphenyl Cyclohexa-1,4-dien-1-yl Thienyl- (2) 4-Methylsulfonyl- phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl thienyl- (2) 4-methyl sulfonyl-phenyl phenyl phenyl phenyl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl Phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl phenyl 4-hydroxyphenyl cyclohexa-1,4-dien-1-yl phenyl 4-hydroxyphenyl Cyclohexa-1,4-dien-1-yl phenyl 4-hydroxyphenyl Cyclohexa-1,4-dien-1-yl thienyl- (2) -4-methylsulfonyl-phenyl ZBT > Phenyl -O-CO-CH3 1, ll -OH NN tu f -SII NN N CH3 rc tr S'-CH, "-S -ts -CH3 ~ o-Co-NH2 5jäCH3 lt lt Rome -S-CS-N N-CH, lt 4-hydroxyphenyl -O-CO-CH3 II II -OH NN n 11 -SJk N, N CH3 according to II NN -s-¼ V,? 1-CH, according to n -O-CO-NH2 tu II CH3 4-hydroxyphenyl -S-CS-N N-CH3 Cyclohexa-1,4-dien-yl. -O-CO-CH3 do -OH N -N -S- N'N CH3 NNN "sIr, CH3 ,., -O-CO-NH2 ß <CH3 tu Fu CH3 tt -S-CS - CH3 lt thienyl- (2) -O-CO-CH3 do tr -OH N - N Fu X Fu CH3 NN "tu -S 5» CH3 tu tu -O-CO-NH2 do do CH3 "4-methylsulfonyl-phenyl -O-CO-CH3 tu lt -OH NN do do 1 (ii WELL CH3 tu tu - N -S <S> CH3 4-methylsulfonyl-phenyl -O-CO-NH2 N TCH uu "-StsoN H3O Phenyl -O-CO-CH3 > Phenyl -O-CO-CH3 n tu -OH N -N do H3 NN uu uu 4 ut tu OH3 H3C H3C $ "-O-CO-CH3 do uu -OH NN tt n ut CH3 do a -S-II S CH3 1 OH3 vrr3 tu -O-CO-CH3 uu uu -OH NN tu 11 -stp3N cH3 do CH3 Q> CH3 Cl phenyl -0-00-OH3 W "-OH M {N uu -S (N, N CH3 N - N (1 tr sl! {HOLE3 do ut -H H30-O-> -O-CO-CH3 L. do ut -OH NN . -S t, N CH3 NN uu uu t S) -CH3 n uu -H H3 0-CO- r "-O-CO-CH3 do do -OH do uu CH3 N- N uu tu -S t s-CH3 do uu -H Phenyl -O-CO-CH3 n tu -OH tu uu tN, N CH3 1? u? t S jL CH3 uu ut -H bS uu "-O-CO-CH3 ut -OH NN uu CH3 NN uu l4S YLCH3 0t -O-CO-CH3 NN uu uu -St NN CH3 NN do do -S S3-CH3 uu uu "-O-CO-NH2 N 1I CH3 uu ut ra uu uu -S-CS-N N-CHw My 3 tu -0-CO-NH2 uu C tu H2C-O ut - n \ -O-CO-CH3 do H3O ul tu a-phenyl 0 0tr 0 09 CH3 (¼, CH, H3C J uu L II II ul 11 0aS uu tu ut do ut § -O-CO-CH3 do do -OH NN do do -ut j Nt CH3 Phenyl -S-NN uu ut -H tu cyclohexa-1,4-dien-l-yl -H t7 phenyl -O-CO-CH3 "" -OH N- N It "-St CH3 NN 1, 6I, Bc3 do uu -H t1 uu "-O-CO-CH3 H do -OH NN do do -S 1! CH3 NN -S <S; CH3 uu -H rl iT N 11 -O-CO-CH3 H n -0-00-OH3 N>o> n -O-CO-CH3 W t phenyl -O-CO-CHs 01 00- CH3ffO2- kN, 5 # \ N ut ut CHjO, - S, I (CH3) 2CH-S 4 S 1 N - N C2H5s 1 / \\ ut uu OH3 For? IC-1! ut uu F3C 4 S>" aSy ut uu t O-CO-CH 3 NN iu -SA NN CH3 NN -S - S'-CH3 uu ut -O-OO-NH2 5} öTOH3 do uu E.g. Phenyl lg lot each " NI, ZBT Phenyl -O-CO-CH3 Po. "I. FoF 'ul ~ It 11 lt tl It If one or more asymmetric centers or cis and trans forms occur in the radicals Z of the general formulas I and III, all possible R, S, cis and trans forms and all possible combinations of these forms apply.

The compounds according to the invention have low toxicity and good tolerance and strong antimicrobial activity. These properties enable their use as active ingredients in medicine as well as substances for Preservation of inorganic and organic materials, especially organic Materials of all kinds, e.g. polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The compounds according to the invention are against a very broad spectrum effective against microorganisms. With their help, e.g. gram-negative and gram-positive Fights bacteria and bacteria-like microorganisms as well as those caused by these pathogens caused diseases can be prevented, improved and / or cured.

The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine suitable that are caused by these pathogens.

For example, local and / or systemic diseases can be treated and / or prevented by the following pathogens or by mixtures the following pathogens: Micrococcaceae, such as staphylococci, e.g. Staphylococcus aureus, Staph. epidermidis, staph. aerogenes and Gaffkya tetzta (Staph. = Staphylococcus); Lactobacteriaceae such as streptococci, e.g., Streptococcus pyogenic, aC- or ß-hemolytic streptococci, not (y -) - hemolytic streptococci, St.viridans, st.

faecalis (enterococci), Str agalactiae, Str lactis, Str equi, Str. anaerobis and Diplococcus pneumoniae (pneumococci) (Str. = Streptococcus); Nesseriaceae, such as Neisseria, e.g. Neisseria gonorrhoeae (gonococci), N.meningitidis (meningococci), N. catarrhalis and N. flava (N. = Neisseria); Corynebacteriaceae, such as Corynebacteria, e.g. Corynebacterium diphtheriae, C.pyogenes, C.diphtheroides, C. acnes, C.parvum, C.bovis, C.renale, C.ovis, C.murisepticum, Listeria bacteria, e.g. Listeria monocytogenes, Erysipelothrix, bacteria, e.g.

Erysipelothrix insidiosa, Kurthia bacteria, e.g. Kurthia zopfii (C. = Corynebacterium); Enterobacteriaceae, such as Escherichiae bacteria of the Coli group, Escherichia bacteria, e.g. Escherichia coli, Enterobacter bacteria, e.g. E. aerogenes, E.cloacae, Klebsiella bacteria, e.g., K.pneumoniae, K.ozaenae, Erwiniae, e.g., Erwinia spec., Serratia, e.g. Serratia marcescens (E. = Enterobacter) (K. = Klebsiella), Proteae bacteria of the Proteus group, Proteus, e.g. Proteus vulgaris, Pr.morganii, Pr.rettgeri, Pr.mirabilis (Pr. = Proteus), Providencia e.g. Providencia sp., Salmonelleae, Salmonella bacteria, e.g. salmonella paratyphi A and B, S.

typhi, S.enteritidis, S.cholerae suis, S.typhimurium (S. = Salmonella), Shigella bacteria, e.g. Shigella dysenteriae, Sh.ambigua, Sh.flexneri, Sh.boydii, Sh.sonnei (Sh. = Shigella); Pseudomonadaceae, such as Pseudomonas bacteria, e.g., Pseudomonas aeruginosa, Ps.pseudomallei (Ps. = Pseudomonas), Aeromonas bacteria, e.g. Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas); Spirillaceae, like Vibrio bacteria, e.g. Vibrio cholerae, V.

proteus, V. fetus (V. = Vibrio), Spirillum bacteria, e.g.

Spirillum minus; Parvobacteriaseae or Brucellaceae, such as Pasteurelle bacteria, e.g. Pasteurella multocida, Past.pestis (Yersinia), Past. pseudotuberculosis, Past.tularensis (Past. = Pasteurella), Brucella bacteria, e.g. Brucella abortus, Br.melitensis, Br.suis (Br. = Brucella), Haemophilus bacteria, e.g. Haemophilus influenzae, H.ducreyi, H.suis, H.canis, H.aegypitcus (H. = Haemophilus), Bordetella bacteria, e.g. Bordetella pertussis, B.bronchiseptica (B. = Bordetella), Moraxella bacteria, e.g. Moraxella lacunata; Bacterioidacea, such as Bacteroides bacteria, e.g. Bacteroides fragilis, B. serpens (B. = Bacteroides), fusiform bacteria, e.g.

Fusobacterium fusiforme, Sphaerophorus bacteria, e.g. sphaerophorus necrophorus, Sph. necroticus, Sph.pyrogenes (Sph. = Sphaerophorus); Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis, B.subtilis, B.cereus (B. = Bacillus), Anaerobic spore-forming chlostridia, e.g. Clostridium perfringens, Cl.septicium, Cl.

oedematiens, Cl.histolyticum, Cl.tetani, Cl.botulinum (C1. = Clostridium); Spirochaetaceae, such as Borrelia bacteria, e.g. Borrelia recurrentia, B. vincentii (B. = Borrelia), Treponema bacteria, e.g.

Treponema pallidum, Tr.pertinue, Tr.carateum (Tr. = Treponema), Leptospira bacteria, Leptospira interrogans, e.g. Leptospira icterohaemorrhagiae, L. canicola, L.grippotyphosa, L. pomona, L.

mitis, L. bovis (L. 8 Leptospira); The obligatory list of pathogens is only to be understood as an example and in no way restrictive.

As diseases that are prevented by the compounds according to the invention, can be improved and / or cured, for example: Diseases the respiratory tract and the pharynx; Otitis; Pharyngitis; Pneumonia; Peritonitis; Pyelonephritis; Cystitis; Endocarditis; System infections; Bronchitis; Arthritis.

the present invention includes pharmaceutical preparations, the one in addition to non-toxic, inert pharmaceutically suitable carriers or contain more than one compound according to the invention or the one or more Compounds according to the invention exist as well as processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can e.g.

1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose contain. A single dose preferably contains the amount of active ingredient in a Application is administered and usually a full, half or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or contain the active ingredients in addition to the usual carriers, such as (a) fillers and extenders, e.g. starches, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binding agents, e.g.

Carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) Humectants, e.g., glycerin, (d) disintegrants, e.g.

Agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarder, e.g. paraffin and (f) absorption accelerator, e.g.

B. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, Glycerine monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed using e.g. polymer substances and waxes as embedding compounds can be.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) and mixtures of these Fabrics.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. animal and vegetable fats, waxes, Paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used the usual propellants e.g. contain chlorofluorocarbons.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular Cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient or ingredients, suspensions can contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures or contain substances.

The formulation forms mentioned can also contain colorants and preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners e.g.

Contain saccharin.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture be.

The pharmaceutical preparations listed above can also the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above is carried out in the usual way by known methods, e.g.

by mixing the active ingredient (s) with the carrier (s).

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more of the invention Contains active ingredients in human and veterinary medicine for prevention and improvement and / or cure the diseases listed above.

The active ingredients or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular administered intravenously and intramuscularly.

In general, it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) according to the invention in total amounts from about 6 to about 800, preferably 15 to 300 mg / kg of body weight per 24 hours, possibly in the form of several, e.g. 3, individual doses to achieve the desired Deliver results. A single dose contains the one or more according to the invention Active ingredients, preferably in amounts of about 2 to about 300, in particular 10 to 150 mg / kg body weight. However, it may be necessary from the The dosages mentioned vary depending on the type and body weight the object to be treated, the nature and severity of the disease, the nature of the Preparation and application of the drug as well as the period or

Interval within which the administration takes place. So it can in some cases it may be sufficient with less than the above amount of active ingredient get along, while in other cases the above-mentioned amount of active ingredient exceeded must become. Determining the optimal dosage and type of application required in each case the active ingredients can easily be made by any person skilled in the art on the basis of his specialist knowledge.

In the case of application as a feed additive, the new compounds in the usual way together with the feed or with feed preparations or with be given to the drinking water. This can cause infection by gram-negative or gram-positive bacteria and also a better utilization of the feed can be achieved.

The new ß-lactam compounds are characterized by strong antibacterial Effects that have been tested in vivo and in vitro, and by oral absorbability the end.

The ß-lactam compounds according to the invention can for the purpose of Expansion of the spectrum of activity or to increase the effectiveness e.g. also with aminoglycoside antibiotics such as gentamicin, sisomicin, kanamicin, amikacin or tobramicin can be combined.

The effectiveness of the β-lactam compounds according to the invention can be exemplified can be demonstrated by the following in vitro and in vivo tests: a) In vitro test The compounds of Examples 1, 6, 16 and 29, which are typical representatives of the Compounds of the invention that can be viewed were made with Muller-Hinton nutrient broth diluted with the addition of 0.1% by weight glucose to a content of 100 / ug / ml. In the nutrient solution contained 1 x 105 to 2 x 105 bacteria per milliliter. The tubes with this approach were each incubated for 24 hours and then the degree of turbidity was determined. Freedom from haze indicates effect. When it comes to the dosage of 100 / ug / ml the following bacterial cultures were turbid (sp. = species): Klebsiella pneumoniae; Enterobacter Aerogenes sp .; Serratia marcescens; Escherichia coli BE; Salmonella sp .; Shigella sp .; Proteus, indole negative and indole positive sp .; Pasteurella pseudotuberculosis; Brucella sp .; Haemophilus influenzae; Bordetella bronchisptica; Staphylococcus aureaus 133; Neisseria catarrhalis sp .; Diplococcus pneumoniae sp .; Streptococcus pyogenes W .; Enterococcus sp .; Lactobacillus sp .; Corynebacterium diphteriae gravis; Corynebacterium pyogenes M; Clostridium botulinium; Clostridium tetani; Borrelia sp .; b) In vivo experiment From the following table 1 goes the action of one of the new ß-lactam compounds, which are considered typical of the Compounds of the invention can be considered against some from Bacteria emerged in animal experiments with the white mouse.

The CF1 strain white mice were injected intraperitoneally with each specified type of bacteria infected.

Table 1 Animal experiment with the white mouse: Determination of the ED50 according to 2.4 hour germ dose in mg of the compound from Example 1 per kg / body weight (subcutaneous) Escherichia coli C 165 1 x 200 Klebsiella 2 x 100 Therapy: once: 30 Minutes after infection twice: a) 30 minutes after infection b) 90 minutes after infection The ED50 is the dose at which 50% of the infected animals remain after 24 hours survive.

The compounds according to the invention can be prepared by the following Examples explained (The melting points were, unless otherwise stated, on the Definitely a Kofler heating bank. You are corrected).

example 1 For the suspension of 2.0 parts by weight. Ampicillin trihydrate in 50 parts by volume. 80% aqueous tetrahydrofuran is added while stirring so much triethylamine that the ampicillin is just dissolved at about pH 8.0. Then 0.94 parts by weight are carried while cooling with ice / water. 1-chlorocarbonyl-2-oxo-3-cyclopropylimidazolidine while keeping the pH of the mixture at 7.0-7.5 by adding triethylamine accordingly.

Stirring is continued until this pH is not maintained Triethylamine must be added more. Then with 60 vol. Tln. Water diluted, the pH optionally brought to 7.0, the tetrahydrofuran largely on a rotary evaporator removed, the remaining solution washed once with ethyl acetate, then with fresh Layered ethyl acetate, while stirring and cooling with dilute hydrochloric acid up to acidified to pH 2.0, the organic phase separated, the warmer phase again extracted with ethyl acetate and then the combined ethyl acetate extracts Washing with saturated sodium chloride solution over MgSO, dried.

After removing the desiccant, the same volume of ether is added diluted and then by adding an approximately 1 molar solution of sodium 2-ethylhexanoate in ether (which contains approx. 10% methanol) the D - D (3-cyclopropylimidazolidine -2-on-1-yl) carbonylamino7-benzylpenicillin sodium pleases.

Yield: 2.7 parts by weight.

Mp .: 21000 decomposition P-lactam content: 89%. (That contains penicillin 4% ß-lactam ring open substance.) IR bands (carbonyl area) at: 1755,1710,1650,1585 and (i.Nujol) 1520 cm 1.

NMR signals at # = 2.4-2.8 (5H), 4.4 (1H), 4.4-4.7 (AB, 2H), (i.CD3OD) 5.8 (1H), 6.1-6.8 (4H), 7.25-7.7 (1H), 8.4 (3H), 8.5 (3H) and 9.15-9.4 ppm (4H).

According to the NMR spectrum, the substance contains about 1 molar equivalent of water, 0.1 molar equivalent of ethyl acetate and 0.05 molar equivalent of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis data: Calc. : C 51.2 H 5.4 N 12.5 S 5.7 Found: C 50.5 H 5.2 N 12.4 S 5.9 This substance is obtained from 1-cyclopropyl-2-oxo-imidazolidine and phosgene (1.0-1.3 molar equivalents) in tetrahydrofuran at 5-10 ° C. in 4-5 hours. It crystallizes after the solvent has been stripped off and triturated with ether.

Yield: 75% of theory

M.p .: 50-52 ° C NMR signals at # = 5.7-6.65 (4H), 7.1-7.5 (1H) and 9.0-9.3 (i.CDCl3) ppm (4H).

Calc .: C 44.5 H 4.8 N 14.9 Cl 18.8 Found: C 43.9 H 5.0 N 14.8 Cl 18.9 This substance is obtained from N-cyclopropyl-ethylenediamine (boiling point 4 = 54-580; obtained by reacting cyclopropylamine with 2-chloroethylamine) and diphenyl carbonate (4 hours 1800).

Bp 0.1 5 = 92-99 ° Calc .: C 57.1 H 7.9 N 22.2 Found: C 57.1 H 7.9 N 20.4 Example 2 This penicillin is obtained if you add 1.5 parts by weight.

Amoxicillin trihydrate with 0.68 parts by weight. 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine brings together in the manner described in Example 1 to implement.

Yield: 1.6 parts by weight of D-α - [(3-Cyclopropyl-imidazolidin-2-on-1-yl) -carbonylamino7-p-hydroxybenzylpenicillin.

ß-lactam content: 77% (The penicillin contains about 12% ß-lactam ring-open Substance.) IR bands (carbonyl range): 1750, 1695, 1650, 1590 and (i.Nujol) 1530-1500 cml.

NMR signals at T = 2.5-2.9 (2H), 3.05-3.40 (2H), 4.35-4.7 (3H), (i.CD3OD) 5.83 (1H), 6.1-6.8 (4H), 7.25-7.7 (1H), 8.4 (3H), 8.5 (3H) and 9.05-9.4 ppm (4H).

According to the NMR spectrum, the penicillin contains about 1.5 molar equivalents of water, 0.16 molar equivalents of ethyl acetate and 0.16 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures: Calc .: C 49.3 H 5.3 N 11.5 S 5.3 Found: C 48.8 H 5.3 N 11.5 S 5.5 Example 3 This penicillin is in the manner described in Example 1 from 1.0 parts by weight. Epicillin and 0.54 parts by weight.

Obtained l-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine.

Yield: 1.2 parts by weight. D 3-Cyclopropyl-imidazolidin-2-on-1-yl) -carbonylamino] -α- (1,4-cyclohexadienl-yl) -methylpenicillin-sodium.

ß-lactam content: 89. (The penicillin contains about 2% P-lactam ring-open Substance.) IR spectrum (carbonyl range): 1760, 1705, 1650, 1590 and (i.Nujol) 1520 cm 1 NMR signals at # = 4.1 (1H), 4.3 (2H), 5.05 (1H), 5.8 (1H), 6.0-6.75 (4H), 7.0-7.6 (5H), 8.3 (3H), 8.4 (3H) and 9.1-9.3 ppm (4H).

According to the NMR spectrum, the substance contains about 1.6 molar equivalents Water, 0.13 molar equivalents of ethyl acetate and 0.07 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures.

Calc .: C 50.1 H 5.7 N 12.1 S 5.6 Found: C 49.8 H 5.5 N 12.2 S 5.8 Example 4 This cephalosporin is obtained when 1.5 parts by weight.

Cephaloglycine dihydrate and 0.6 parts by weight. 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine reacted with one another in the procedure described in Example 1 for penicillins.

Yield: 1.6 parts by weight. Sodium 7- {D-α - [(3-cyclopropylimidazolidin-2-on-1-yl) carbonylamino7-pheynacetamido ~ | -3-acetoxymethyl-ceph-3-em-4-carboxylate.

$ ß-lactam content: 89%.

IR spectrum (carbonyl range): 1790, 1735 (shoulder), (i.Nujol) 1715, 1680 (shoulder), 1615 and 1550-1530 cm 1 NMR signals at r = 2.35-2.75 (5H), 4.2-4.5 (2H), 4.95-5.2 (i.CD3OD) (3H), 6.1-6.7 (6H), 7.3-7.7 (1H), 7.95 (3H) and 9.15-9 , 35 rpm (4H).

The substance contains about 2 molar equivalents of water and 0.35 molar equivalents of ethyl acetate. This was taken into account in the calculated analysis values: Calc .: C 48.0 H 5.1 N 10.8 S 5.0 Found: C 48.1 H 5.0 N 11.5 S 5.1 Example 5 This penicillin is made in the manner described in Example 1 from 2.0 parts by weight. Ampicillin trihydrate and 1.1 parts by weight.

1-chlorocarbonyl-2-oxo-3- (2-pyridil) -imidazolidine was obtained.

Yield: 1.6 parts by weight. D-oc- # [3- (2-pyridil) -imidazolidin-2-on-1-yl] -carbonylamino} -benyzlpenicillin-sodium.

ß-lactam content: 79%. (The penicillin contains about 6% of the substance which is created by opening the ß-lactam ring of penicillin.) IR spectrum (carbonyl range): 1780, 1715, 1685 (shoulder), (i.Nujol) 1655, 1595 and 1515 cm 1.

NMR signals at = 1.5-3.1 (9H), 4.35 (1H), 4.35-4.6 (2H), (i.OD3oD) 5.8 (1H), 5.8-6.3 (4H), 8.4 (3H) and 8.5 ppm (3H).

According to the NMR spectrum, the penicillin contains about 1.2 molar equivalents Water, 0.27 molar equivalents of ethyl acetate and 0.3 molar equivalents of sodium 3-ethylhexanoate. This was taken into account in the calculated analysis values.

Calc .: C 52.1 H 5.2 N 12.8 S 4.9 Found: C 51.8 H 5.4 N 12.9 S 5.3 For the suspension of 6.0 parts by weight. 1- (2-pyridyl) -2-oxoimidazolidine in 60 parts by volume. Tetrahydrofuran is added dropwise at 1000, the solution of 3.4 Vol.Tln. Phosgene in 10 parts by volume.

Tetrahydrofuran, left to stand overnight at 0 ° C, then added dropwise at 0 ° up to 5 ° C the mixture of 5.6 parts by volume. Triethylamine and 10 vol. Tetrahydrofuran admitted, then left to stand for 24 hours at 20 ° C., then removed the precipitate present and the filtrate is concentrated somewhat in vacuo.

2.4 parts by weight separate. of the acid chloride.

M.p .: 176-180 ° (crude product).

Calc .: C 41.2 H 3.4 C1 27.1 N 16.0 Found: C 42.0 H 4.4 C1 25.2 N 16.2 The substance used as the starting product: 1- (Pyridil) -2-oxo-imidazolidine is from N-ß-chloroethyl-N '- (pyridin-2-yl) urea (melting point: 116 ° C; prepared from 2-aminopyridine and P-chloroethyl isocyanate) obtained by reaction with KOH in aqueous ethanol.

M.p .: 164 ° C.

Example 6 This penicillin is obtained when 4.0 parts by weight.

Ampicillin trihydrate and 2.6 parts by weight. 1-chlorocarbonyl-2-oxo-3- (3-pyridyl) imidazolidine hydrochloride reacted with one another in the manner described in Example 1 and during the isolation Removal of undissolved matter, the aqueous phase at pH 3.0 with 5 times the amount of ethyl acetate off shakes.

Yield: 2.1 parts by weight. crystalline D 23- (3-pyridyl) imidazolidin-2-on-1-yl] carbonylamino } -benzylpenicillin sodium.

0-lactam content: 86%. (The penicillin contains about 9% ß-lactam ring-open Proportion.) IR spectrum (carbonyl range): 1760, 1720, 1600 and 1530 cm 1 (i Nujol) NMR signals at # = 1.15 (d, 1H), 1.6-2.1 (2H), 2.3-2.8 (6H), (i.CD3OD) 4.4 (1H), 4th , 4-4.65 (2H), 5.8 (1H), 6.07 (4H), 8.43 (3H) and 8.50 ppm (3H).

The penicillin contains about 2 molar equivalents of water and 0.05 molar equivalents Sodium 2-ethylhexanoate. This was taken into account in the calculated analysis data.

Calc .: C 50.6 H 5.0 N 13.9 S 5.3 Found: C 48.8 H 5.2 N 13.4 S 5.8 In the suspension of 4.0 parts by weight. l- (3-pyridyl) -2-oxo-imidazolidine in 40 parts by volume. Benzonitrile is introduced into phosgene at 800 ° C. for 6 hours, then stirring is continued for 20 hours.

at 800C, sucks off the precipitate after cooling and washes with it Ether.

Yield: 6.1 parts by weight.

Mp .: 204-2060C (crude product) Calc .: C 41.2 H 3.4 C1 27.1 N 16.0 found: C 42.0 H 3.5 C1 26.8 N 16.0 The substance used as a starting material: 1- (3-pyridyl ) -2-oxo-imidazolidine is produced from N- (pyridin-3-yl) ethylenediamine (boiling point = 132-40 ° C;) from N- (pyridin-3-yl) -aminoacetonitrile by hydrogenation) and carbonic acid diethyl ester manufactured.

M.p .: 158.5-160.5 ° C.

Example 7 2.0 parts by weight Ampicillin trihydrate are 40 Vol.Tln.

Suspended water, adjusted the pH to 7.5-8.0 with sodium hydroxide solution, 2.25 parts by weight l-chlorocarbonyl-2-oxo-3- (4-pyridyl) -imidazolidine hydrochloride under Stirring and cooling with ice / water added while the pH by means of the ln sodium hydroxide solution held at 7.5. It is stirred for 30 minutes, covered with ethyl acetate, with dilute HCl acidified to pH 2.0 with stirring, one in water and ethyl acetate insoluble oil separated (: is free penicillic acid; when rubbed with Water solid), then the ethyl acetate phase separated off with saturated sodium chloride solution washed and the sodium salt precipitated therefrom using sodium 2-ethylhexanoate solution.

Yield: 0.45 parts by weight. D-a-C 9- (4-pyridyl) -imidazolidin-2-on-1-yl2-carbonylamino 3 benzylpenicillin sodium and 0.8 parts by weight. the corresponding free acid.

IR spectrum (carbonyl range): 1750, 1705, 1660, 1580 and (i.Nujol) 1515 cm 1.

NMR signals at; = 1.4-1.65 (2H), 2.15-2.4 (2H), 2.4-2.8 (5H), (i.OD3OD) 4.3-4.65 (3H), 5.8 (1H), 6.05 (4H), 8.4 (3H) and 8.5 ppm (3H).

B-lactam content: 57%.

The penicillin still contained water, ethyl acetate, sodium 2-ethylhexanoate and about 12% of the corresponding β-lactam ring-open product.

For the suspension of 8.0 parts by weight. 1- (4-pyridyl) -2-oxoimidazolidine in 80 vol. Benzonitrile are 4.6 parts by volume.

Given phosgene and stirring at 80-90 ° for a further 2 hours.

Phosgene initiated. The mixture is then stirred at 200 for 36 hours, again 8 hours. Heated to 800, cooled, filtered off with suction, washed with tetrahydrofuran and dried over NaOH in a desiccator.

Yield: 11.7 parts by weight.

Fp .: 2450 (when pushing up quickly) Ber .: C 41.2 H 3.4 C1 27.1 N 16.0 found: C 41.3 H 3.6 C1 26.1 N 16.2 IR spectrum (carbonyl range): 1805, 1730, 1635 and 1585 cm 1.

(i Nujol) The substance used as the starting material: 1- (4-pyridil) -2-oxo-iminidazolidine is made from N-ß-chloroethyl-N '- (4-pyridyl) urea (melting point: 122 ° C; prepared from 4-aminopyridine and ß-chloroethyl isocyanate) and KOH obtained in ethanol.

M.p .: 2040C.

Example 8 This penicillin is obtained if you add 1.0 parts by weight.

Ampicillin trihydrate and 0.77 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-methylsulfonyl-1,3,4-thiodiazol-2-yl) imidazolidine reacted with one another in the manner described in Example 1.

Yield: 1.0 part by weight. D-or- rC3- (5-methylsulfonyl-1,3,4- 'thiodiazol-2-yl) -iminidazolidin2-one-1-yl] -carbonylamino} -benzylpenicillin-sodium.

ß-lactam content: 77%. (The penicillin also contains 10% of the corresponding ß-lactam ring-open compound.) IR spectrum (carbonyl range): 1750, 1720, 1655, 1590 and (i.Nujol) 1520 cm 1.

NMR signals at 2.25-2.8 (5H), 4.3 (1H), 4.3-4.65 (2H), (i.CDβOD) 5.55-6.1 (4H), 4.55 (3H), 8.43 (3H) and 8.50 ppm (3H).

According to the NMR spectrum, the substance contains about 4 molar equivalents of H2O and 0.13 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis values: Calc .: C 38.9 H 4.6 N 13.2 S 13.0 Found: C 38.6 H 4.4 N 13.2 S 13.1 In the suspension of 7.4 parts by weight. 1- (5-methylsulfonyl-1, 3,4-thiadiazol-2-yl) -2-oxo-imidazolidine in 80 parts by volume.

Benzonitrile is passed in phosgene at 80 ° C. for 7 hours.

The starting product goes into solution. Then ether is added, suctioned off and recrystallized from acetonitrile.

Yield: 3.1 parts by weight.

M.p .: 204-2050.

This substance is made from N-ß-chloroethyl-N '- (5-methylsulfonyl-1,3,4-thiadiazol-2-yl) urea obtained in a manner known per se by the action of KOH in aqueous ethanol.

Fp .: 2090.

The urea used as the starting substance is made from 2-amino-5-methylsulfonyl-1,3,4-thiadiazole obtained by reaction with ß-chloroethyl isocyanate.

Fp .: 163640.

Example 9 This cephalosporin is obtained when 1.0 parts by weight.

Cephaloglycine dihydrate and 0.67 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-methylsulfonyl-1,3,4-thiqdiazol-2-yl) imidazolidine reacted with one another in the manner described in Example 1.

Some of the free cephalosporic acid separates out as in Water with a pH of 1.5 and ethyl acetate from undissolved precipitate (: 0.15 parts by weight, IR spectrum: 1765, 1720 and 1650 cm 1). Most of the acid, however, goes into the organic Phase and can be precipitated from it as the sodium salt. That initially as sticky The sodium salt which appears to be precipitated is deposited on trituration with ethanol and ether loose white powder.

Yield: 1.3 parts by weight. Sodium 7- ß D-oc-i (3- / 5-methylsulfonyl 1,3,4-thiqdiazol-2-yl / -imidazolidin-2-on-1-yl) -carbonylamino] -phenylacetamido} -3-acetoxymethylceph -3-em-4-carboxylate.

ß-lactam content: 66%. (The cephalosporin also contains 11% β-lactam ring open product.) IR spectrum (carbonyl range): 1755.1715.1650.1590 and 1520cm-1 (i.Nujol) NMR signals at 15 = 2.3-2.75 (5H), 4.05-4.4 (2H), 4.9-5.1 (3H), (i.DMF-d7) 6.35 (3H), 6; 5-6.85 (2H) and 8.0 ppm (3H) The substance contains according to the NMR spectrum, 8.5 molar equivalents of H2O and 0.07 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis data.

Ber. : C 34.6 H 4.9 N 11.3 S 11.1 Found: C 34.4 H 3.4 N 11.1 S 11.1 Example 10 This penicillin is in the manner described in Example 1 from 1.0 parts by weight. Amoxicillin trihydrate and 0.74 parts by weight.

1-chlorocarbonyl-2-oxo-3- (5-methylsulfonyl-1,3,4-thiodiazol-2-yl) imidazolidine obtain.

Yield: 1.5 parts by weight. D-oc- {[3- (5-Metylsulfonyl-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-1-yl) -carbonylamino -4-hydroxybenzylpenicillin sodium.

P-lactam content: 84%.

IR spectrum (carbonyl range): 1755, 1715, 1660, 1595 and (i.Nujol) 1500 cm1 NMR signals at g = 2.5-2.85 (2H), 3.05-3.35 (2H), 4.3-4.65 (3H), (i.OD3OD) 5.8 (broad, 5H), 6.55 (3H), 8.4 (3H) and 8.48 ppm (3H).

Example 11 This penicillin is obtained when 1.0 parts by weight.

Epicillin in the manner described in Example 1 with 1-chlorocarbonyl-2-oxo-3- (5-methylsulfonyl-1,3,4-thiadiazol-2-yl) imidazolidine implements.

Yield: D-or- t- (5-Metylsulfonyl-1,3,4-thiodiazol-2-yl) -iminidazolidin-2-on-1-yl] -carbonylamino} -alpha ;-( 1,4-cyclohexadiene- 1-yl) methyl pelicillin sodium.

ß-lactam content: 78%. (The penicillin also contains 10% of the ß-lactam ring open Product.) IR spectrum (carbonyl range): 1750, 1710, 1660, 1585 and (i.Nujol) 1515 cm 1.

NMR signals at g = 4.03 (1H), 4.28 (2H), 4.48 (2H), 4.96 (1H), (i.CD3OD) 5.55-6.0 (5H), 4.53 (3H), 7.1-7.4 (4H), 8.36 (3H) and 8.43 ppm (3H).

According to the NMR spectrum, the penicillin contains about 4.1 molar equivalents Water and 0.07 molar equivalents of sodium 2-ethylhexanoate. This was calculated for the Analysis data taken into account.

Calc .: C 38.6 H 4.8 N 13.4 S 13.1 Found: C 38.6 H 4.4 N 13.5 S 13.3 Example 12 This penicillin is obtained when 1.0 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 0.76 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-isopropylthio-1,3,4-thiadiazol-2-yl) imidazolidine implements.

Yield: 1.5 parts by weight. D-oc-L3- (5-Isopropylthio-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -benzylpenycillin-sodium.

ß-lactam content: 75%. (The penicillin contains 11% of the ß-lactam ring-open Product.) IR spectrum (carbonyl range): 1765, 1735, 1710, 1670 and (i.Nujol) 1585 cm 1.

NMR signals at t = 2.35-2.77 (5H), 4.35 (1H), 4.35-4.65 (2H), (i.CD30D) 5.83 (1H), 5.90 (broad, 4H), 6.15 (Sept, 1H), 8.43 (3H), 8.50 (3H), 8.55 (3H) and 8.64 ppm (3H).

According to the NMR spectrum, the penicillin contains about 3.7 molar equivalents Water and 0.04 molar equivalents of sodium 2-ethylhexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 42.5 H 5.0 N 13.7 S 13.4 Found: C 42.0 H 5.1 N 13.5 S 13.7 The mixture of 5.5 parts by weight. 1- (5-Isopropylthio-1,3,4-thiadiazol-2-yl) -2-oxo-imidazolidine, 70 parts by volume. Tetrahydrofuran and 2.1 vol. Phosgene is stirred for 48 hours at 40 ° C., then the solution of 3.1 parts by volume is cooled.

Triethylamine and 15 vol. Tetrahydrofuran added dropwise and more Stirred at 20.degree. C. for 72 hours. It is filtered off with suction, with tetrahydrofuran and acetonitrile washed. The combined filtrates are evaporated in vacuo and the residue recrystallized from ethyl acetate.

Yield: 2.5 parts by weight.

M.p .: 154-56 ° C.

Calc .: C 35.3 H 3.6 C1 11.6 N 18.3 0 10.4 s 20.9 Found: C 35.5 H 4.0 C1 11.6 N 17.9 0 10.3 S 20.9 This substance is obtained in a known manner from N-ß-chloroethyl-N '- (5-isopropylthio-1,3,4-thiadiazol-2-yl) urea (melting point 141-42 °, prepared from 2-amino- 5-isopropylthio-1,3,4-thiadiazole and ß-chloroethyl isocyanate) and KOH in aqueous ethanol.

M.p .: 151-520C.

Example 13 This cephalosporin is obtained when 1.0 parts by weight.

Cephaloglycine dihydrate in the manner described in Example 1 with o, 66 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-isopropylthio-1,3,4-thiodiazol-2-yl) imidazolidine implements.

Yield: 1.5 parts by weight. Sodium 7 {D-α - [(3- / 5-isopropylthio-1,3,4-thiodiazol-2-yl / -imidazolidin-2-on-1-yl) -carbonylamino5-phenylacetamido -3-acetoxymethylceph-3-em-4-carboxylate.

p-lactam content: 80%. (The cephalosphorine contains about 10% of the ß-lactam ring-open product.) IR spectrum (carbonyl range): 1755 (shoulder), 1740, 1715, (i.Nujol) 1655, 1595 and 1525 cm C27H28N7NaO8S3. 4H2O Calc .: C 42.1 H 4.2 N 12.7 S 12.5 Found: C 42.1 H 4.1 N 12.6 S 12.4 Example 14 This penicillin is obtained when 1.0 parts by weight.

Amoxicillin trihydrate in the manner described in Example 1 with 0.77 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-isopropylthio-1,3,4-thiqdiazol-2-yl) imidazolidine implements.

Yield: 11.4 parts by weight. D-α - {[3- (5-Isopropylthio-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamine -4-hydroxybenzylpenicillin sodium.

ß-lactam content: 89%.

IR spectrum (carbonyl range): 1755, 1715, 1650 and 1585 cm -1.

(i.Nujol) NMR signals at # = 2.57-2.83 (2H), 3.08-3.34 (2H), 4.38-4.7 (3H), (i.CD3OD) 5.83 (1H), 5.9 (broad, 4H), 6.22 (Sept, 1H), 8.4 (3H), 8.5 (3H), 8.55 (3H ) and 8.65 ppm (3H).

According to the NMR spectrum, this penicillin contains about 3.6 molar equivalents Water and 0.09 molar equivalents of sodium 2-ethylhexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 41.9 H 4.9 N 13.3 S 13.0 Found: C 42.2 H 4.7 N 12.7 S 12.8 Example 15 This penicillin is obtained when 1.0 parts by weight.

Epicillin in the manner described in Example 1 with 0.88 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-isopropylthio 1,3,4-thiodiazol-2-yl) imidazolidine.

Yield: 1.5 parts by weight. D-oc- {[3- (Isopropylthio-1,3,4-thiudiazol-2-yl ) -imidazo lidin-2-on-1-yl7-carbonyl amino} -α- (1,4-cyclohexadien-1-yl) -methylphenycillin sodium.

p-lactam content: 71 *.

IR spectrum (carbonyl range): 1750, 1710, 1660 and 1585 cm-1.

(i.Nujol) NMR signals at # = 4.05 (1H), 4.28 (2H), 4.43 (2H), 4.95 (1H), (i.CD3OD) 5.8 (1H), 5.88 (broad, 4H), 6.2 (Sept, 1H), 7.28 (broad, 4H), 8.33 (3H), 8.4 (3H), 8.5 (3H) and 8.62 ppm (3H).

Example 16 This penicillin is obtained when 1.0 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 0.75 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-trifluoromethyl-1,3,4-thiodiazol-2-yl) imidazolidine implements.

Yield: 1.5 parts by weight. D-α- {[3- (5-Trifluoromethyl-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -benzylpenicillin sodium.

p-lactam content: 84%. (The penicillin also contains 5% of the corresponding ß-lactam ring open product.) IR spectrum (carbonyl range): 1793, 1775, 1725, 1700, 1675, (i.Nujol) 1605 and 1530 cm 1.

NMR signals at # = 2.37-2.83 (5H), 4.38 (1H), 4.4-4.63 (2H), (i.CD3OD) 5.85 (broad, 5H), 8.45 (3H) and 8.52 ppm (3H).

According to the NMR spectrum, the penicillin contains about 2.5 molar equivalents Water and 0.13 molar equivalents of sodium 2-ethylhexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 41.1 H 4.0 N 13.9 S 9.1 Found: C 41.3 H 4.9 N 13.8 S 9.0 This substance is obtained if phosgene is added to 1- (5-trifluoromethyl-1,3,4-thiodiazol-2-yl) -2-oxo-imidazolidine in tetrahydrofuran, triethylamine is added after 24 hours and after a further 24 hours Standing at 20 ° C worked up.

Mp (crude product): 170-79 °.

Calc .: C 28.0 H 1.3 C1 11.8 N 18.6 S 10.7 Found: C 28.8 H 1.4 Cl 11.0 N 19.2 S 11.1 IR spectrum (CO.Cl): 1770 cm -1.

(1. Njoi) This substance is produced in a manner known per se from N-ß-chloroethyl-N '- (5-trifluoromethyl-1,3,4-thiodiazol-2-yl) urea (mp: 190C, prepared from 2-amino-5 -trifluoromethyl-1,3,4, -thiadiazole and ß-chloroethyl isocyanate) and KOH obtained in aqueous ethanol.

Fp .: 19900.

Example 17 This cephalosporin is obtained when 1.0 parts by weight.

Cephaloglycine dihydrate in the manner described in Example 1 with 0.65 parts by weight of 1-chlorocarbonyl-2-oxo-3- (5-trifluoromethyl-1,3,4-thiodiazol-2-yl) -imidazolidine implements.

Yield: 1.3 parts by weight. Sodium 7- {D-alpha; - [(3- / 5-Trifluoromethyl-1,3,4, -thiodiazol-2-yl / -imidazolidin-2-onl-yl) -carbonylamino] -phenylacetamido} -3- acetoxymethylceph-3-em4-carboxylate.

ß-lactam content: 81. (The cephalosporin contains 7% of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1783, 1730, 1685, 1610 and (i.Nujol) 1540 cm 1.

C25H21F3NaO8S2. 2.8 H2O Calc .: C 40.5 H 3.6 N 13.2 S 8.6 Found: C 40.5 H 4.4 N 13.0 S 8.4 Example 18 This penicillin is obtained when 1.0 parts by weight.

Amoxicillin trihydrate in the manner described in Example 1 with 0.72 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-trifluoromethyl-1,3,4-thiodiazol-2-yl) -imidazolidine brings to implementation.

Yield: 1.3 parts by weight. D-oc- {[3- (5-Trifluoromethyl-1,3,4-thiadiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -4-hydroxybenzylpelicillin sodium.

ß-lactam content: 175%.

IR spectrum (carbonyl range): 1765, 1725, 1670, 1610 and (i.Nujol) 1510 cm 1.

NMR signals at 1 = = 2.65-2.9 (2H), 3.1-3.4 (2H), 6.4-6.65 (3H), (i. CD3OD) 5.75 (1H), 5.9 (broad, 4H), 8.45 (3H) and 8.50 ppm (3H).

According to the NMR spectrum, the substance contains 0.98 molar equivalents of sodium 2-ethylhexanoate and 3.2 molar equivalents of water.

This was taken into account in the calculated analysis data.

Calc .: C 42.4 H 4.9 N 11.2 S 7.3 Found: C 42.4 H 5.6 N 11.2 S 7.3 Example 19 This penicillin is obtained when 1.0 parts by weight.

Epicillin in the manner described in Example 1 with 0.86 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-trifluoromethyl-1,3,4, -thiodiazol-2-yl) -imidazolidine.

Yield: 1.5 parts by weight. D-α - {[3- (5-Trifluoromethyl-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -α- (1,4-cyclohexadiene-1 -yl) -methylpelicillin sodium.

ß-lactam content: 87%. (The penicillin also contains about 5% of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1770, 1730, 1675, 1610 and (i.Nujol) 1530 cm-l NMR signals at t = 4.08 (1H), 4.32 (2H), 4.50 (2H), 4.95 (1H), (i.CD3OD) 5.80 (broad, 5H), 7.28 (broad, 4H), 8.35 (3H) and 8.44 ppm (3H).

According to the NMR spectrum, this penicillin contains about 1.9 molar equivalents Water and 0.1 molar equivalent of sodium 2-ethylhexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 41.4 H 4.2 N 14.3 S 9.3 Found: C 41.4 H 5.0 N 14.4 S 9.4 Example 20 This penicillin is obtained when 1.0 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 0.7 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-methylthio-1,3,4-thiqdiazol-2-yl) imidazolidine implements.

Yield: 1.1 parts by weight. D-α - {[3- (5-Methylthio-1,3,4-thiodiazol-2-yl) -imidazolidin-2-on-yl] -carbonylaomino} -benzylpenicillin sodium.

0-lactam content: 85 *. (The penicillin contains about 5% of the corresponding ß-lactam ring open products.) IR spectrum (carbonyl range): 1765, 1725, 1670, 1610 and (i.Nujol) 1535 cm-1.

NMR signals at L = 2.35-2.80 (SH), 4.37 (1H), 4.4-4.64 (2H), (i.CD3OD) 5.85 (1H), 5.95 (broad, 4H), 7.3 (3H), 8.44 (3H) and 8.52 ppm (3H).

C23H24N7NaO6S3. 2.9 H2O Calc .: C 41.4 H 4.5 N 14.7 S 14.4 Found: C 41.1 H 4.4 N 14.9 S 14.3 9.2 parts by weight 1- (5-Methylthio-1,3,4-thiodiazol-2-yl) -2-oxoimidazolidine are in 100 parts by volume. Suspended tetrahydrofuran, then the solution of 3.9 Vol.Tln. Phosgene in 15 parts by volume. Tetrahydrofuran is added, the mixture is then stirred for 6 days at 200 ° C., then the solution of 5.9 parts by volume is added dropwise. Triethylamine in 20 parts by volume. Tetrahydrofuran is added and the mixture is stirred for a further 6 days at 200.degree. The triethylamine hydrochloride formed is then filtered off with suction and the residue of the filtrate evaporated in vacuo is recrystallized from ethyl acetate.

Yield: 0.8 part by weight.

M.p .: 1830C.

Calc .: C 30.2 H 2.5 C1 12.7 N 20.1 S 23.0 Found: C 30.7 H 2.4 C1 12.7 N 19.5 S 23.1 This substance is obtained in a known manner from N-ß-chloroethyl-N '- (5-methylthio-1,3,4-thiodiazol-2-yl) urea (melting point: 487-880C, prepared from 2-amino- 5-methylthio-1,3,4-thiadiazole and ß-chloroethyl isocyanate) by the action of KOH in aqueous ethanol.

M.p .: 185-86 ° C.

Example 21 This penicillin is obtained when 1.0 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 0.72 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-butan-2-yl -1,3,4-thiadiazol-2-yl) imidazolidine implements.

Yield: 1.6 parts by weight. crystalline D-α - {[3- (5-butan-2-yl-1,3,4-thiadiazol-2-yl) -imidazolidin-2-one-1-yocarbonylamino} -benzylpenicillin-sodium.

p-lactam content: 80%. (The penicillin contains about 5% of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1793, 1767, 1720, 1670, 1605, (i.Nujol) 1540 and 1500 cml NMR signals at # = 2.33-2.82 (5H), 4.35 (1H), 4.35-4.6 (2H), (i.CD3OD) 5.85 (1H), 5.92 (broad, 4H), 6.4-7.28 (m, 1H) and 7.7-9 , 3 ppm (14 Hj.

The penicillin contains about 2.7 molar equivalents of water and 0.25 molar equivalents Sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures.

Calc .: C 47.0 H 5.5 N 13.7 S 9-.0 Found: C 46.9 H 5.3 N 13.7 S 9.1 For the solution of 6.5 parts by weight. 1- (5-Butan-2-yl-1,3,4-thiadiazol-2-yl) -2-oxo-imidazolidine in 70 parts by volume. Tetrahydrofuran is added to the solution of 2.6 parts by volume while cooling with ice / water.

Phosgene in 10 parts by volume. Tetrahydrofuran, stir overnight at 200, then gives the solution of 4.0 Vol.Tln again with cooling.

Triethylamine in 20 parts by volume. Tetrahydrofuran to, stir for 24 hours.

at 200C and left to stand for about 10 days at the same temperature. It is then filtered off with suction and the filtrate is evaporated in vacuo. The residue will be off Recrystallized ethyl acetate.

Yield: 1.6 parts by weight.

M.p .: 132-330C.

This substance is obtained in a manner known per se from N-ß-chloroethyl-N '- (5-butan-2-yl-1,3,4-thiodiazol-2-yl) urea (Mp .: 99-100 ° C, made from 2-amino-5-butan-2-yl-1,3,4-thiadiazole and ß-chloroethyl isocyanate) by the action of KOH in aqueous ethanol.

M.p .: 105-060C.

Example 22 This cephalosporin is obtained when 1.0 parts by weight.

Cephaloglycine in the manner described in Example 1 with 0.63 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-butan-2-yl-1,3,4-thiadiazol-2-yl) imidazolidine.

Yield: 1.2 parts by weight. Sodium 7- (D-α - [(3- / 5-butan-2-yl-1,3,4-thiqdiazol-2-yl / -imidazolidin-2-on-1-yl) carbonylamino] phenylacetamido } -3-acetoxymethyl-ceph-3-em-4-carboxylate.

P-lactam content: 90%.

IR spectrum (carbonyl range): 1767, 1730, 1675, 1610, 1540 (i.Nujol) and 1500 cm 1.

NMR signals at t = 2.35-2.83 (5H), 4.23-4.47 (2H), 5.0-5.25 (3H), (i.d. CD3OD) 5.9 (broad, 4H), about 6.4-7.3 (3H), 8.0 (3H), and 8.0-9.25 ppm (8H).

C28H30N7Na08S2 .3 3 H20 Calc .: C 45.8 H 4.9 N 13.4 S 8.7 Found: C 45.9 H 4.5 N 13.3 S 8.7 Example 23 This penicillin is obtained when 1.0 parts by weight.

Amoxicillin trihydrate in the manner described in Example 1 with 0.7 parts by weight 1-chlorocarbonyl-2-oxo-3- (5-butan 2-yl-1,3,4-thiadiazol-2-yl) imidazolidine implements.

Yield: 0.9 parts by weight. D-α- {3- (5-Butan-2-yl-1,3,4-thiadiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -4-hydroxybenzylpenic illin sodium.

ß-lactam content: 93%.

IR spectrum (carbonyl range): 1785, 1770, 1730, 1675, 1612, (i.Nujol) 1540 (shoulder) and 1500 cm 1.

NMR signals at # = 2.5-2.9 (2H), 3.05-3.4 (2H), 4.38-4.67 (3H), (i. CD3OD) 5.87 (1H), 5.94 (broad, 4H), 6.4-7.25 (1H) and 7.95-9.3 ppm (14H).

According to the NMR spectrum, the penicillin contains about 2.6 molar equivalents Water and 0.1 molar equivalent of sodium 2-ethyihexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 45.8 H 5.2 N 14.0 5 9.1 Found: C 46.0 H 5.3 N 14.0 S 8.9 Example 24 This penicillin is obtained when 1.0 parts by weight.

Epicillin in the manner described in Example 1 with 0.83 parts by weight. 1-chlorocarbonyl-2-oxo-3- (5-butan-2-yl-1,3,4-thiadiazol-2-yl) imidazolidine.

Yield: 1.2 parts by weight. D-α - {[3- (5-Butan-2-yl-1,3,4-thiadiazol-2-yl) -imidazolidin-2-on-1-yl] -carbonylamino} -α- (1,4 -cyclohexadien-1-yl) methylpencillin sodium ß-lactam content: 86% (The penicillin also contains 4% of the corresponding ß-lactam ring open Product., IR spectrum (carbonyl range): 1773, 1730, 1682, 1615, (i.Nujol) 1540 (shoulder) and 1508 cm NMR signals at t = 4.03 (1H), 4.3 (2H), 4.48 (2H), 4.98 (1H), (i.CD3OD) 5.8 (1H), 5.9 (broad, 4H), 6.3-7.3 (m, 1H), 7.3 (broad, 4H) and 7.9-9.3 ppm (14H).

The penicillin contains 2.3 molar equivalents of water and about 0.125 molar equivalents Sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures.

Calc .: C 47.2 H 5.6 N 14.3 S 9.3 Found: C 47.2 H 5.5 N 14.3 S 9.4 Example 25 This penicillin is obtained if you add 2.0 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 1.4 parts by weight 1-chlorocarbonyl-2-oxo-3-benzthiazol-2-yl-imidazolidine converts.

Yield: 3.1 parts by weight. D-α - [(3-Benzthiazol-2-imidazolidin-2-on-1-yl) carbonylamine J-benzylpenicillin sodium.

ß-lactam content: 72%. (The penicillin also contains 7 ffi of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1790, 1712, 1675-1663, 1612 (i.Nujol) and 1525 cm 1.

NMR signals at # = 2.5-2.85 (9H), 4.38 (1H), 4.4-4.65 (2H), (i.CD3OD) 5.85 (1H), 6.0 (broad, 4H), 8.45 (3H) and 8.52 ppm (3H).

According to the NMR spectrum, the penicillin contains about 3.5 molar equivalents Water and 0.5 molar equivalents of sodium 2-ethylhexanoate. This was calculated for the Analysis figures taken into account.

Calc .: C 48.8 H 5.2 N 11.0 S 8.4 Found: C 48.8 H 5.0 N 11.0 S 8.4 For the suspension of 8.0 parts by weight. 1- (Benzthiazol-2-yl) -2-oxo-imidazolidine in 50 parts by volume. Benzonitrile are 3.4 parts by volume. Given phosgene. It is then heated for 20 hours.

to 800 and then conducts 4 hours at the same temperature. long phosgene. This is repeated three more times. Then after cooling down Sucked off, washed with ether and dried over NaOH in a desiccator.

Yield: 5.9 parts by weight.

Fp .: 2580 (sublimation) Calc .: C 46.8 H 2.8 C1 12.6 N 14-, 9 S 11-, 4 found: C 47.0 H 2.9 C1 12.7 N 14, 8 S 11.4 This substance is obtained in a manner known per se from N-ß-chloroethyl-N'-benzthiazol-2-ylurea (melting point: 1840, solidifying again, then: melting point: 2580; prepared from 2-aminobenzothiazole and p-chloroethyl isocyanate) and KOH in aqueous ethanol.

M.p .: 2580C.

Calc .: N 19.2 S 14.6 Found: N 19.1 S 14.2 Example 26 This cephalosporin is obtained when 1.0 parts by weight.

Cephaloglycine dihydrate in the manner described in Example 1 with 0.61 parts by weight 1-chlorocarbonyl-2-oxo-3- (benzthiazol-2-yl) imidazolidine. At the Acidification of the aqueous sodium salt solution, however, separates the free acid of cephalosporin as a precipitate that is sparingly soluble in water and ethyl acetate the end. This is filtered off with suction, then dissolved in a little dimethylformamide, the calculated Amount of a molar sodium 2-ethylhexanoate solution in methanol-containing ether was added and then stirred this solution into a lot of ether. The sodium salt sought falls in the process the end.

Yield: 1.3 parts by weight of sodium 7- {D-α - [(3-Benzthiazol-2-ylimidazolidin-2-one-1-yl) carbonylamino] -phenylacetamido} -3-acetoxymethyl-ceph-3-en- 4-carboxylate.

p-lactam content: 87%. (The cephalosporin also contains 4% of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1770, 1730, 1670, 1612 (i. Nujol) and 1518 cm1 C29H25N6NaO8S2. 2.6 H2O Calc .: C 48.4 H 4.2 N 11.7 S 8.9 Found: C 48.4 H 4.0 N 11.8 S 8.9 Example 27 This penicillin will behave if you add 1.0 parts by weight.

Amoxicillin trihydrate in the manner described in Example 1 with 0.68 parts by weight 1-chlorocarbonyl-2-oxo-3- (benzthiazol-2-yl) imidazolidine.

Yield: 1.4 parts by weight. D-α - {[(3-Benzthiazol-2-ylimidazolidin-2-on-1-yl] carbonylamino} -4-hydroxybenzylpenicilin sodium.

ß-lactam content: 75%.

IR spectrum (carbonyl range): 1783, 1762, 1725, 1660, (i.Nujol) 1610-1595 and 1510 cm-l.

NMR signals at 7 = 2.15-2.5 (2H), 2.5-2.9 (4H), 3.08-3.32 (2H), (i.OD3OD) 4.38-4.65 (3H), 5.85 (1H), 6.05 (broad, 4H), 8.42 (3H) and 8.49 ppm (3H).

According to the NMR spectrum, the penicillin contains 4.7 molar equivalents of water and 0.75 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures; Calc .: C 47.1 H 5.5 N 10.0 S 7.6 Found: C 47.1 H 6.1 N 10.0 S 7.5 Example 28 This penicillin is obtained when 1.0 parts by weight.

Epicillin in the manner described in Example 1 with 0.8 parts by weight. 1-chlorocarbonyl-2-oxo-3-benzthiazol-2-ylimidazolidine converts.

Yield: 1.5 parts by weight. D-α - [(3-Benzthiazol-2-yl-imidazolidin-2-on-1-yl) -carbonylamino] -α- (1,4-cyclohexadienl-yl) -methylpenicillin sodium.

ß-lactam content: 62%. (The penicillin also contains 14% of the corresponding ß-lactam ring-open product.) IR spectrum (carbonyl range): 1790, 1769, 1728, 1675-1663, (i.Nujol) 1610 and 1518 cm NMR signals at 12 = 2.13-2.9 (4H), 4.08 (1H), 4.33 (2H), 4.5 (2H), (i.CD3OD) 5.0 (1H), 5.83 (1H), 6.07 (broad, 4H), 7.28 (broad, 4H) , 8.35 (3H) and 8.45 ppm (3H).

According to the NMR spectrum, the penicillin contains 4.8 molar equivalents of water and 0.82 molar equivalents of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures: Calc .: C 48.0 H 6.0 N 10.0 S 7.6 Found: C 48.0 H 6.8 N 10.0 S 7.7 Example 29 This penicillin is obtained when 0.7 parts by weight.

Ampicillin trihydrate in the manner described in Example 1 with 1.1 parts by weight (Excess, since the substance was not pure) 1-chlorocarbonyl-2-oxo-3-furan-2-yl-imidazolidine implements.

Yield: 0.6 part by weight. D- (x-L- (3-furan-2-yl-imidazolidin-2-on-1-yl) carbonylamino7-benzylpenicillin sodium.

ß-lactam content: 88%.

IR spectrum (carbonyl range): 1773 (shoulder), 1755, 1724, (i.Nujol) 1665, 1605, 1550 (shoulder) and 1520 cm C2 * H2 * N5Na07S .3 3 H20 Calc .: C 47.7 H 5 , 0 N 11.6 S 5.3 Found: C 47.6 H 5.7 N 11.6 S 5.3 To the solution of 2.0 parts by weight cooled to -150C. l-furan-2-yl-2-oxo-imidazolidine (crude product) in 30 parts by volume. Tetrahydrofuran are 0.9 parts by volume. Given phosgene. The mixture is stirred for 15 minutes at -150 ° C. and then 3 3/4 hours at 200 ° C. and then filtered off with suction. The precipitate is washed with ether and the combined filtrates are evaporated in vacuo. The oily residue is rubbed with ether and the precipitate that forms is then filtered off with suction. The product is washed with ether and then dried over P, O, in a desiccator.

Yield: 1.5 parts by weight. (The product is not pure. However, the impurities do not interfere with the further conversion.) Mp .: about 9000, decomposition.

For the solution of 16.0 parts by weight. N-ß-chloroethyl-N'-furan-2-ylurea in 180 vol. Tetrahydrofuran are 43.2 parts by volume at -50 ° C under nitrogen. a 13% butyl lithium solution in hexane was added dropwise. Then one leaves under Stand nitrogen at 200C for 3 days. The precipitate is filtered off and treated with tetrahydrofuran washed. The combined filtrates are then evaporated in vacuo. The oily one The residue is converted into a powder by treatment with ether.

This is suctioned off and dried (14.4 parts by weight.). The substance still contains about 1 molar equivalent of LiCl. It was purified by sublimation.

Yield: 8.85 parts by weight.

M.p .: 118-121 ° C.

IR spectrum (carbonyl range): 1730, 1710, 1600 and 1530 cm-1.

(i.Nujol) NMR signals at I = 2.7-2.9 (1H), 3.5-3.7 (1H), 3.85-4.05 (1H) (i.CD3oD) and 5 , 85-6.7 ppm (4H).

This substance is obtained by using a solution of furoylazide in Toluene heated to 75-950C and after the rearrangement and elimination of nitrogen with ß-chloroethylamine added.

Fp .: 1080 decomposition, Calc .: C 44.6 H 4.8 N 14.9 0 17.0 found: C 44.8 H 5.1 N 14.8 0 17.0 NMR signals at @ = 2.75-2.95 (1H), 3.55-3.75 (1H) , (i.CD3OD) 3.9-4.1 (1H) and 6.2-6.7 ppm (4H).

Example 30 Sodium 7- {D-α - [(2-Oxo-3-cyclopropyl-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3 - [(1-methyl-tetrazol-5-yl) -thiomethyl] - ceph-3-em-4-carboxylate.

This cephalosporin was in the implementation of 4.6 parts by weight.

7- (D-α-Amino-phenylacetamido) -3 - [(1-methyl-tetrazol-5-yl) -tiomethyl] -ceph-3-em-4-carboxylic acid and 1.9 parts by weight. 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine in 60% yield obtain.

ß-lactam content according to the IR and NMR spectrum: 80%.

IR bands at 3400, 3250, 1763, 1710, 1655, 1610, 1535 and 1284 cm 1 (in Nujol).

NMR signals at 2.3-2.8 (5H), 4.25 (1H), 4.4 (1H), 5.0 (1H), 5.6 (2H), 5.9 (3H), 6.0-6.8 (6H "7.35 (1H) and 9.1 ppm (4H)).

(in CD3OD).

Example 31 Sodium 7- {D-α - [(2-Oxo-3-cyclopropyl-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3 - [(2-methyl-1,3,4-thaizol-5- yl) thiomethyl] ceph-3-em-4-carboxylate.

This cephalosporin was in the manner described in Example 1 from 4.4 parts by weight. 7- (D-α-Aminophenylacetamido-3 - [(2-methyl-1,3,4-thiadiazol-5-yt) -thiomethyl7-ceph-3-em-4-carboxylic acid and 1.9 parts by weight. 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine in 70% yield obtain.

Lactam content according to the IR and NMR spectrum: 75%.

IR bands at 3250, 1761, 1714, 1659, 1605, 1536 and 1283 cm 1 (in Nujol).

NMR signals at # = 2.4-2.8 (5H), 4.3 (1H), 4.4 (1H), 5.05 (1H), 5.4 (1H), 5.8 (1H), 6.0-6.8 (6H), 7.3 (3H), 7.4 (1H) and 9.2 ppm (4H) (in CD3od).

Example 32 Sodium 7- £ D-oc-W (2-oxo-3-cyclopropyl-imidazolidin-1-yl) carbonylamino] phenylacetamido} -3 - [(3-methyl-1,2,4-thiadiazole-5- yl) thiomethyl] ceph-3-em-4-carboxylate.

This cephalosporin was in the manner described in Example 1 from 4.4 parts by weight. 7- (D-α-Amino-phenylacetamido-3 - [(3-metyl -1,2,4-thiadiazol-5-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid and 1.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-cyclopropylimidazolidine in 62% yield obtain.

ß-lactam content According to IR and NMR spectrum approx. 85-90%.

IR bands at 3250, 1762, 1715, 1658, 1618, 1540 and 1288 cm 1 (in Nujol).

NMR signals at # = 2.4-3.0 (5H), 4.25-4.6 (2H), 5.1 (1H), 5.6 (2H), 6.0-7.0 ( 6H), 7.5 (3H), 7.6 (1II) and 9.3 ppm (in CD3OD).

Example 33 This cephalosporin is obtained if you add 10 parts by weight. 7- (D - α-Amino-phenylacetamido-3 - [(3 - [(2-trifluoromethyl-1,3,4-thodazol-5-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid in is reacted with 0.39 parts by weight of 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine in the manner described in Example 1. When the reaction mixture, freed from tetrahydrofuran, is acidified to pH 1.0, the free cephalosporic acid precipitates To convert it into the sodium salt, it is dissolved in a little dimethylformamide, the calculated amount of sodium 2-ethylhexanoate (dissolved in methanol-containing ether) is added and this mixture is stirred into 150 parts by volume of OOC ether Ether and then treated with isopropanol The product is then filtered off with suction and dried over P.01 in a desiccator.

Yield: 0.9 parts by weight. Sodium 7- {D-α - [(2-Oxo-3-cyclopropylimidazolidin-1-yl) carbonylamino] phenylacetamido} -3 - [(2-trifluoromethyl-1,3,4-thiodiazol-5-yl) thiomethyl S-ceph-3-em-4-carboxylate.

ß-lactam content: 60% (determined iodometrically).

Fp .: from about 19500 decomposition ..

IR bands at 3400, 3230, 1770, 1760, 1715, 1660, 1600 and 1525-35 cm 1 (in Nujol).

Example 34 This cephalosporin is obtained when 1.0 parts by weight.

7- (D-Amino-pheny1acetamido) -3-hydroxymethyl-ceph-3-em-4-carboxylic acid in the manner described in Example 1 with 0.49 parts by weight. 1-chlorocarbonyl-2-oxo-3-cyclopropyl-imidazolidine implements.

Yield: 1.1 parts by weight. Sodium 7- {D - α - [(2-Oxo-3-cyclopropylimidazolidin-1-yl) carbonylamino] phenylacetamido} -3-hydroxymethyl-ceph-3-em-4-carboxylic acid.

ß-lactam content: 85% (determined iodometrically) mp: from about 220 ° C decomposition.

NMR signals at # = 2.55 (5H), 4.0-4.3 (1H), 4.5 (1H), 4.8-5.1 (1H), 6.0-6.9 ( 6H), 7.2-7.7 (1H) and 9.1-9.4 ppm (4H).

IR bands at: 3400, 3250, 1780, 1760, 1720, 1655 cm 1 (in Nujol).

Example 35 This cephalosporin is in the manner described in Example 1 from 2.0 parts by weight. Cephaloglycine and 1.13 parts by weight. 1-Chlorocarbonyl-2-oxo-3-pyrimid-2-ylimidazolidine was obtained in 33 ffi yield.

Sodium 7-D-α - [(2-oxo-3-pyrimid-2-yl-imidazolidine content 1-carboxamido] -phenylacetamido} -3-acetoxymethyl-ceph-3-em-4-carboxylate according to the NMR spectrum: 60%.

IR bands at 3460-3140, 1770, 1755, 1717, 1654, 1598, 1565-1520, 1252, 1228, 1068, 1024, 748, 720 and 620 cm 1 (in Nujol).

NMR signals at t = 1.25 (2H), 2.3-3.0 (6H), 4.25 (1H), 4.45 (1H), 5.1 (3H), 5.8-6.4 (4H), 6.5 (1H), 6.85 (1H) and 7.9 ppm (3H) (in D2O).

The suspension of 5.4 parts by weight. l-pyrimid-2-yl-2-oxo-imidazolidine in 50 parts by volume Benzonitrile is 24 hours.

Phosgene slowly passed through for a long time at 1000C with stirring.

After cooling to room temperature, it is filtered off with suction and washed out with ether. Yield of 1-chlorocarbonyl-2-oxo-3-pyrimid-2-yl-imidazolidine hydrochloride: 5.9 Parts by weight

The combined mother liquors are evaporated and on the oil pump dried. Yield of 1-chlorocarbonyl-2-oxo-3-pyrimid-2-yl-imidazolidine: 2 parts by weight.

IR bands at 1800, 1714, 1556, 1276, 1162, 729 cm -1 (in Nujol).

Calculated: C 42.3 H 3.1 C1 15.7 N 24.7 Found: C 42.5 H 4.1 C1 16.2 N 22.7 Production as in Example 29 C from 20 parts by weight. 1-pyrimid-2-yl-3- 8-chloroethylurea (from 2-aminopyrimidine and β-chloroethyl isocyanate in 50% yield after recrystallization from methanol. Mp = 163 ° C.) and the equivalent amount of n-butyllithium in tetrahydrofuran. Recrystallization with aqueous acetone. M.p.> 2600C. Yield of 1-pyrimid-2-yl-2-oxoimidazolidine: 81%.

Calculated for 80% product + 10% LiCl + 10% H20 C 41.0 H 5.0 N 27.2 0 16.7 Found: C 40.5 H 4.9 N 27.4 0 16.2 IR bands at 3450-3050, 1718, 1678, 1640, 1570 and 1264 cml (in Nujol).

Example 36 This penicillin is made in the manner described in Example 1 from 6.7 parts by weight. Ampicillin and 3.7 parts by weight. L-chlorocarbonyl-2-oxo-3-pyrimid-2-yl-imidazolidine was produced in 33% yield.

D-α - [(2-Oxo-3-pyrimid-2-yl) -imidazolidine) -1-carboxamido] -benzylpenicillin sodium content according to the IR and NMR spectrum: 87%.

IR bands at 3420-3180, 1768, 1755, 1716, 1659, 1598, 1526, 1423, 1398, 1255 cml (in Nujol).

NMR signals at 57 = 1.2 (2H), 2.3-2.9 (6H), 4.3 (1H), 4.5 (2H), (in CDsOD) 5.8 (1H), 5.6-6.3 (4H), 8.4 (3H) and 8.46 ppm (3H) Example 37 This penicillin is in the manner described in Example 1 from 1.0 parts by weight. Epicillin and 0.6 parts by weight. 1-Chlorocarbonyl-2-oxo-3-pyrimid-2-yl-imidazolidine produced in 40% yield.

D-α - [(2-oxo-3-pyrimid-2-yl-imidazolidine) -1-carboxamidov-a- (cyclohexa-1,4-dien-1-yl) methylpenicillin sodium content according to IR and NMR spectrum: 73? IR bands at 1770, 1755, 1716, 1650, 1590-1520 and 1253 cm (in Nujol).

NMR signal at # = 1.5 (2H), 2.75 (1H), 4.05 (1H), 4.3 (2H), (in D20) 4.5 (2H), 5.05 (1H), 5.7 (1H), 6.05 (4H), 7.3 (4H), 8.4 (3H) and 8.45 ppm (3H). Example 38 H. 0 t sF NA N-CONH MH-CONH X $ CH3 COONa This penicillin is made in the manner described in Example 1 from 2.0 parts by weight of amoxicillin and 1.25 parts by weight.

1-Chlorocarbonyl-2-oxo-3-pyrimid-2-yl-imidazolidine in 41% yield manufactured.

Content of D-α - [(2-Oxo-3-pyrimid-2ylimidazolidine) -1-carboxamido] -p-hydroxybenzylpenicillin sodium: 75% according to the IR and NMR spectrum.

IR bands at 3320, 1770, 1757, 1716, 1654, 1595-1505, 1255 cm 1 (in Nujol).

NMR signals at Z = 1.35 (2H), 2.7 (3H), 3.1 (2H), 4.476 (1H), (in D20) 4.53 (2H), 5.8 (1H), 6.05 (4H) and 8.spm (6H).

Example 39 This cephalosporin is obtained if you add 4.5 parts by weight.

Cephaloglycine dihydrate and 3.3 parts by weight. of the hydrochloride of 1-chlorocarbonyl-2-oxo-3- (3-pyridyl) imidazolidine reacted with one another in the procedure described in Example 1 for penicillins and during isolation, after removing undissolved material at pH 7, the free acid of the cephalosporin precipitates at pH 1.5, washed with water and ethyl acetate and dried.

Yield: 4.6 parts by weight, melting point: from about 2300 decomposition, melt under Decomposes around 2580.

IR spectrum (carbonyl range): 1780, 1725 and 1670-75 cm -1 (in Nujol).

The cephalosporic acid can be converted into the sodium salt as follows: Dissolve in DMF; gives the calculated amount of an approximately 1 molar sodium 2-ethylhexanoate solution in ether / methanol (approx. 10/1) and the salt precipitates with ether (400 parts by volume).

Yield: 4.7 parts by weight. Sodium 7- # D-oc- £ (3- / 3-pyridyl / imidazolidin-2-on-1-yl ) -carbonylamino7-phenylacetamido -3-acetoxymethyl-ceph-3-em-4-carboxylate.

Fp .: decomposition from around 1980; not clearly melted until 2600.

ß-lactam content: 75%.

IR spectrum (carbonyl range): 1770 (shoulder), 1750, 1715, 1670, 1620, 1530 cm-1 (Nujol).

Example 40 The mixture of 5.4 parts by weight. Cephaloglycine dihydrate, 90 vol. Dichloromethane, 5.7 parts by volume. Triethylamine and 10 parts by weight. anhydrous MgSO is stirred for 1.5 hours at 200C and the desiccant is suctioned off. 4.6 parts by weight are added to the filtrate. l-chlorocarbonyl-2-oxo-3- (4-pyridyl) -imidazolidine and the mixture for 3 hours at 200C.

touched. Then the reaction mixture is completely evaporated, the residue rubbed with water and washed with water after suction.

Yield: 4.5 parts by weight. 7- {D-α - [(3- / 4-pyridyl / imidazolidin-2-on-1-yl) -carbonylamino7-phenylacetamido ~ l -3-acetoxymethylceph-3-em-4-carboxylic acid.

M.p .: decomposes at around 250-2600.

ß-lactam content: 74%.

The electropherogram shows only one effective against bacterial subtilis Spot.

IR spectrum (carbonyl range): 1770, 1720-25, 1655 and 1595 cm -1 (Nujol).

Example 41 This cephalosporin is obtained when 1.5 parts by weight.

Cephaloglycine dihydrate in the manner described in Example 1 with 0.7 parts by weight L-chlorocarbonyl-2-oxo-3- (3-furyl) imidazolidine converts. The at pH 1.5 precipitated cephalosporic acid is filtered off with suction, washed with water and dried.

Yield: 1.1 parts by weight.

IR spectrum (carbonyl range): 1775, 1720, 1655 and 1535 cm -1 (Nujol).

This free acid is in the manner described in Example 39 in converted to the sodium salt.

Yield: 1.3 parts by weight. Sodium-7- fD-a- £ (3- / 3-furyl / -imidazolidin-2-on-l-yl) -carbony1aminoJ-phenylacetamido -3-acetoxymethyl-ceph-3-em-4-carboxylate.

Fp .: slow decomposition from 2150C.

ß-lactam content: 87%.

IR spectrum (carbonyl range): 1760 (shoulder), 1740 (shoulder), 1710, 1660, 1600 and 1520 cm 1 (Nujol).

The substance contained 3.9 molar equivalents of water. This was taken into account in the calculated analytical data: calculated: C 46.2 H 4.7 N 10.4 S 4.7 found: C 45.9 H 4.7 N 10.7 S 4.7 This substance is made from 2-oxo-3- (3-furyl) -imidazolidine and phosgene in tetrahydrofuran in the presence of triethylamine at -150C to + 200C in the course of 15-20 hours.

obtain.

Yield: 51% of theory

Fp .: 94-980 (crude product; still contains some starting product).

This substance is made from N- (3-furyl) -N '- (ß-chloroethyl) urea and Butyl lithium in tetrahydrofuran at -600C.

preserved and purified by sublimation.

M.p .: 105-1170.

This substance is made from furan-3-isocyanate (from furan-3-carboxylic acid azide obtained by Curtius degradation in toluene) and ß-chloroethylamine in dichloromethane.

M.p .: 85 ° (dec.) Calculated: C 44.4 H 4.8 N 14.8 Found: C 44.8 H 4.7 N 14.6 Example 42 This penicillin is in the manner described in Example 1 from 1.1 parts by weight. Ampicillin trihydrate and 0.6 parts by weight.

Obtained l-chlorocarbonyl-2-oxo-3- (3-furyl) -imidazolidine.

Yield: 1.0 part by weight. D-α - {[3- (3-Furyl) imidazolidin-2-on-1-yl] carbonylamino} benzylpenicillin sodium (crystalline).

Fp .: from about 2200C decomposition.

ß-lactam content: 91%.

IR spectrum (carbonyl range): 1780, 1700, 1680, 1640, 1590 and 1510 cm 1 (Nujol).

The substance contains 2.4 molar equivalents of water. This was at the calculated analysis data taken into account: calculated: C 48.6 H 4.5 N 11.8 S 5.4 found: C 48.6 H 4.7 N 12.0 S 5.5 Explanation of some of the abbreviations used: i. = in melting point = melting point parts by weight = parts by weight parts by weight = parts by weight Vol. Parts = parts by volume Parts by volume = parts by volume hours = hours ether = diethyl ether Ethyl acetate = ethyl acetate Nujol = paraffin oil All temperatures are 0C and all yield data in 'relate to% of theory.

Claims (25)

Claims: 1 ß-lactam compounds of the formula I in which A is hydrogen or methoxy; B for phenyl; phenyl substituted by hydroxy, halogen, methoxy, - CN and / or CH3-SO2; for thienyl; Cyclohexenyl or 1,4-cyclohexadien-1-yl; E represents oxygen or sulfur; Y for the groups in which the carbon atom bearing the carboxyl group is bonded to the nitrogen atom of the ß-lactam ring and T stands for hydrogen, alkyl-CO-O-, hydroxy-, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, thiocarbamoylthio, the group -S-phenyl, which may be substituted, or the group -S-Het, in which Het is an optionally substituted heterocyclic 5- or 6-membered ring; U represents oxygen, sulfur or the -CH2 group; and Z represents optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl, where -CH2 groups of the cycloalkyl radicals can also be replaced by an oxygen or sulfur atom or an -SO- or -SO2 group or by one or two -CO groups and where a Benol ring can be fused onto these rings; or represents an optionally substituted pseudoaromatic heterocyclic 5- or 6-membered ring; where the β-lactam antibiotics of the formula I can be present in the two possible configurations R and S with respect to the chiral center C * and as mixtures of the resulting diastereomers and the non-toxic, pharmaceutically acceptable salts of these compounds. 2. Compounds according to claim 1, in which A is hydrogen; B represents phenyl, hydroxyphenyl or 1,4-cyclohexadien-l-yl; E is oxygen; Y for the groups stands, where T -O-CO-CH3 OH, 1-methyl-tetrazol-5-yl-thio, 2-methyl-1,3,4-thiadiazol-5-yl-thio and 3-methyl-1,2, Means 4-thiadiazol-5-yl-thio; Z for cyclopropyl, furyl; Pyridyl; Benzthiazolyl-2- or 1,3,4-thiadiazolyl-2-, which can be substituted in the 5 position by sec-butyl, trifluoromethyl, methylthio, i-propylthio or methylsulfonyl, in the D = R configuration is present, as well as the sodium salts of these compounds. 3. Compound of formula and their pharmaceutically acceptable salts. 4. Compound of Formula and their pharmaceutically acceptable salts. 5. Compound of formula and their pharmaceutically acceptable salts. 6. Compound of Formula and their pharmaceutically acceptable salts. 7. Compound of Formula and their pharmaceutically acceptable salts. 8. Compound of Formula and their pharmaceutically acceptable salts. 9. Compound of Formula and inre pharmaceutically acceptable salts. 10. Compound of Formula and their pharmaceutically acceptable salts. 11 compound of formula and their pharmaceutically acceptable salts. 12. Compound of formula and their pharmaceutically acceptable salts. 13. Compound of Formula and their pharmaceutically acceptable salts. 14. Compound of Formula and their pharmaceutically acceptable salts. 15. Compound of formula and their pharmaceutically acceptable salts. 16. Compound of Formula and their pharmaceutically acceptable salts. 17. Compound of formula and their pharmaceutically acceptable salts. 18. Compound of Formula and their pharmaceutically acceptable salts. 19. Compound of Formula and their pharmaceutically acceptable salts. 20. The sodium salts of the compounds according to claims 1 to 19. 21. Process for the preparation of ß-lactam compounds of Formula OK I! A. Z - N - N-CE-NH-CH-CO-NH-C-CH 7 flY CHl / Bt B 2 2 0 in which A is hydrogen or methoxy; B for phenyl; phenyl substituted by hydroxy, halogen, methoxy-, -CN and / or CH3-SO2-; represents thienyl, cyclohexenyl or Ir4-cyclohexadien-1-yl; E represents oxygen or sulfur; Y for the groups in which the carbon atom bearing the carboxyl group is bonded to the nitrogen atom of the β-lactam ring and T stands for hydrogen, Alkvl-CO-O-, Hvdroxv-, PYridinium, aminopyridinium, carbamoyloxy, azido, cyano, thiocarbamoylthio, the group -S-phenyl, which can be substituted, or the group -S-Het, in which Het stands for an optionally substituted heterocyclic 5- or 6-membered ring, U stands for oxygen, sulfur or the -CH2 group; and z represents optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl, where -CH2 groups of the cycloalkyl radicals can also be replaced by an oxygen or sulfur atom or an -SO- or -SO2 group or by one or two -CO groups and where a benzene ring can be fused onto these rings; or represents an optionally substituted pseudoaromatic heterocyclic 5- or 6-membered ring; where the ß-lactam antibiotics of the formula I can be in the two possible configurations R and S with respect to the chiral center C and as mixtures of the resulting diastereomers and the non-toxic, pharmaceutically acceptable salts of these compounds, characterized in that compounds of the formula II: in which A, B, C and Y have the meaning given above, or their derivatives obtained by silylation on the carboxyl group or on the carboxyl and primary amino group, with a compound of the general formula III: where Z and E have the meanings given above and W stands for halogen, azide or another nucleofugal leaving group, in the presence of a solvent and optionally an acid binder at temperatures of about -2O0C to about + 50C, and optionally the β-lactam antibiotics obtained after cleavage of the silyl group (s), if desired, converted into their nontoxic, pharmaceutically acceptable salts or, if desired, prepared the free acids from the salts or sityl esters obtained, if desired. 22. Medicines, characterized by a content of at least a ß-lactam compound according to claims 1 to 19. 23. A method of making antimicrobial agents, thereby characterized in that one ß-lactam compounds according to claims 1 to 19 with inert, non-toxic, pharmaceutically suitable carriers mixed. 24. Use of ß-lactam compounds according to claims 1 to 19 to promote growth and improve feed conversion in animals. 25. Methods of preventing, ameliorating and / or curing bacterial Diseases, characterized in that ß-lactam compounds according to the claims Applied from 1 to 19 people or animals if necessary.