DE2456307A1 - Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives - Google Patents

Abstract

Antibiotics are of formula (I) and non-toxic salts and hydrates (where R = H or CH3O; Z = R1R2CN- or R1R2C(OH).NH-; R1 and R2 = H; opt. substd. alkyl or alkenyl; opt. substd. cycloalkyl, cycloalkenyl, cycloalkedienyl, aralkyl, aryl, or heterocyclyl; COOH; COOCH3; COOC2H5; CN; NO2; lower alkylcarbonyl; CONH2 or SO2NH2 (both opt. mono- or di-CH3 substd.); R1 and R2 can together complete and opt. unsatd. 3-7 membered, opt. substd. carbocyclic or heterocyclic ring; A = CH2CH2, CH2CH2CH2 or 1,2-phenylene; B = opt. substd. phenyl, cyclohexynl or cyclohexadienyl; X = S,O% SO; SO2 or CH2; Y = -C(CH3)2.CH(COOH)- or -CH2.C-(CH2T)=C(COOH)-; T = H, alkylcarbonyloxy, pyridinium, aminopyridinium, carbamoyloxy, N2, CN, OH, phenylthio (opt. substd.) or 5-6 membered heterocycylthio (opt. substd.). The cpds. exist as individual stereoisomers about C or mixts., and where Z = R1R2CN- as syn or anti isomers). (I) are antibacterials more active, and with a broader spectrum of activity against Gram negative species (esp. those which elaborate beta-lactamase), than known penicillins and cephalosporins. They can be used therapeutically, to preserve polymers, lubricants etc. and as feed additives to increase growth rate and improve feed utilisation.

Description

ß-lactam antibiotics, process for their production and their use as a medicament The present invention relates to novel B-lactam antibiotics Process for their production and their use as pharmaceuticals, in particular as antibacterial agents and agents for promoting growth and improvement feed conversion in animals.

It has already become known that certain α- (imidazolidin-2-oxo-1-yl-carbonylamino) -benzylpenicillins have an antibacterial effect (cf. Belgian patents 767 647 and 767 648 as well as Dutch patent 7 114 254 and German Offenlegungsschrift 2 152 968).

The new B-lactam antibiotics according to the invention differ chemically different from the known compounds of the prior art mainly by that the N3 of the imidazolidinone radical is connected to the N atom of an imide group.

It has been found that: the new ß-lactam antibiotics of the formula I. in which R represents hydrogen or methoxy; Z for the groups where R1 and R2 are identical or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl or optionally substituted heterocyclyl and R1 and R2 together with the carbon atom to which they are bonded, can form a 3 to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring which can be substituted; A for -C112-CH2-, - CH2 -CH2-CH2- or stands; B represents optionally substituted phenyl, cyclohexenyl or cyclohexadienyl; and Y for the groups CH3 ii C \ and 6 C-CH-T stands, -CH / CH3 2 3 y COOH in which the carbon atom bearing the carboxyl group is bonded to the nitrogen atom of the B-lactam ring and T is hydrogen, alkyl-CO-O-, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, the group -S-phenyl, which are substituted can, or denotes the group -S-Het, in which Het denotes an optionally substituted heterocyclic 5- or 6-membered ring; where these compounds of the formula I can exist in the two possible R and S configurations with respect to the * chiral center C and as mixtures of the diastereomers resulting therefrom, and where the compounds of the formula I, if Z is for the group and R1 and R2 are different, with respect to the imino group, can be both in the syn form and in the anti form, and these compounds of the formula 1 can also be in the various hydrate forms, and the non-toxic, pharmaceutically acceptable salts of these compounds of formula I have strong antibacterial properties and - have the property of improving growth and feed conversion - in animals.

It has also been found that the new β-lactam antibiotics of the formula I are obtained when compounds of the formula II in which R, 3, C and Y have the meaning given above, or their salts, with compounds of the formula III in which Z and A 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 from about -200C to about + 50 ° C and the β-lactam obtained -Antibiotics optionally converted into their non-toxic, pharmaceutically acceptable salts or, if desired, produces the free acids from the salts obtained.

Surprisingly, the compounds according to the invention show a significantly higher and above all broader antibacterial effect, d. H. Effect against several Bacterial families in the gram-negative range, as z. B. those from the prior art known ß-lactam antibiotics. The substances according to the invention thus represent a Enrichment of pharmacy.

If, for example, D-oC-aminobenzylpenicillin and 1-chlorocarbonyl-3-benzylidenimino-imidazolidin-2-one are used as starting materials, the course of the reaction can be represented by the following equation: \ / C-CONi) yN CH3 + X CH = NN N-CO-CI COOH COOH Tetrahydrofuran / H2 0 0-200C pH = 6.5-7.5 Tt (R) CH = NN Co> H33 b COOH y COOH In the general formulas, optionally substituted alkyl R1 and R2 are straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl may be mentioned as examples.

As optionally substituted alkenyl R¹ and R² are straight-chain or branched alkenyl having preferably 2 to 6, in particular 2 to 4 carbon atoms. Examples are optionally substituted ethenyl, propenyl (1), propenyl (2) and butenyl- (3) called.

Optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl R1 and R2 are mono-, bi- and tricyclic and preferably contain 3 to -10, in particular 3, 5 or 6 carbon atoms. Examples are optionally substituted cyclopropyl, Cyclobutyl Cyclopentyl, Cyclopentenyl, Cyclohexyl, Cyclohexenyl, Cyclohexadienyl, Cycloheptyl, bicyclo- [2.2.1] -heptyl, bicyclo- [2.2.2] -octyl and adamantyl are mentioned.

Optionally substituted aryl R1 and R2 are preferably aryl 6 to 10 carbon atoms in the aryl part.

Optionally substituted phenyl or naphthyl are exemplary called. Substituents in the phenyl ring are in the o, m or p position.

Optionally substituted aralkyl R1 and R2 are Aralkyl substituted in the aryl part and / or alkyl part with preferably 6 or 10, in particular 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part, the alkyl part being straight-chain or branched can be. Optionally substituted benzyl and phenylethyl are exemplary called.

As optionally substituted heterocyclyl R1 and R2 are heteroparaffinic, heteroaromatic and heteroolefinic 5- to 7-membered, preferably 5- or 6-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms. The heteroatoms are oxygen, sulfur or nitrogen. Examples are optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, Triazolyl, oxtriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, Tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl.

Alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl and Aralkyl R1 and R2 can be one or more, preferably 1 to 3, in particular 1 or 2 identical or different radicals R³ carry. Are very particularly preferred the said radicals R¹ and R² are unsubstituted or contain a substituent R3.

Heterocyclyl R and R2 can be one or more, preferably 1 to 3 in particular 1 or 2 identical or different 4.

Wear leftovers R. Heterocyclyl R1 and R2 are very particularly preferably unsubstituted or contains a substituent R4.

In the following statements, the term "lower alkyl" means everywhere, also in connection with other atoms or groups (e.g. 3. lower alkoxy, HCON- (lower alkyl), etc.) straight or branched chain alkyl with preferably 1 to 6, especially 1 to 4 carbon atoms. Examples may be substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl called. "Lower alkyl" can by 1 to 5, in particular 1 to 3 identical or different halogen atoms, where the halogen atoms are preferably fluorine, chlorine and bromine, in particular fluorine and Stand chlorine, be substituted. Examples are trifluoromethyl, chloro-di-fluoromethyl, Bromomethyl, 2,2,2-tri-fluoroethyl and pentafluoroethyl called.

R3 preferably denotes halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine; Amino; Mono-lower alkylamino, preferably methylamino, ethylamino, especially methylamino; Di-lower alkylamino, preferably dimethylamino, diethylamino, especially dimethylamino; Pyrrolidyl; Piperidyl; HCO-NH-; Lower alkyl-CO-NH-, preferably CH3-CO-NH-; H-CO-N (lower alkyl) -, preferably H-CO-N (CH3) -, H-CO-N (C2H5) -; Lower alkyl-CO-N (lower alkyl) -, preferably CH3-CO-N (CH3) -; (Lower alkyl) 2C = N-; Lower alkyl-SO2-NH-, preferably CH3-SO2-NH-, C2H5-SO2-NH-, in particular CH3-SO2-NH-; Lower alkyl-SO2-N (lower alkyl) -, preferably CH3-SO2-N (CH3) 2-; HO-SO2-NH-; HO-SO2-N (lower alkyl) -, preferably HO-SO2-N (CH3) -, HO-SO2-N (C2H5) -; Amidino; (Lower alkyl) 2-N-CH = N-, especially (CH3) 2N-CH-N-; Guanido, nitro, azido, hydroxy, lower alkyl-oxy-, preferably CH3-O-, C2H5-O-, especially CH3o-; H-CO-O-, lower alkyl-CO-O-, preferably CH3-CO-O, C2H5-CO-O-, (CH3) 3C-CO-O-; Lower alkyl-O-CO-O-, preferably CH3-O-CO-O-, C2H5-O-CO-O-, (CH3) 3C-O-CO-O-; H2N-CO-O-; Lower alkyl-NH-CO-O, preferably CH2-NH-CO-O-, C2H5-NH-CO-O-; (Lower alkyl) 2 N-CO-O-. preferably (CH3) N-CO-O-, (C2H5) 2N-CO-O-, H2N-SO2-O-; Lower alkyl-NH-SO2-O-, preferably CH3-NH-SO2-O-, C2H5-NH-SO2-O-; (Lower alkyl) 2 N-SO2-O-, preferably (CH3) 2 N-SO2-O-, (C2H5) 2 N-SO2-O-; HOOC-, H2N-CO-; (Lower alkyl) 2N-CO-, especially (CH3) 2N-CO- and (C2H5) 2N-CO-; OHC-; HO-SO2-O-, HS-; Lower alkyl-S-, preferably CH3-S-, CF3-S-, C2H5-S-, (CH3) 2CH-S-; Lower alkyl-S-, preferably HO3S-; Lower alkyl-SO2-, preferably CH3-SO2-, CF3SO2-, C2H5-SO2-; the group H2N-SO2-, lower alkyl-NH-SO2-, preferably CH3-NH-SO2-, C2H5-NH-SO2-; (Lower alkyl) 2N-SO2-, preferably (CH3) 2 N-SO2-, (C2H5) 2 N-SO2-; the group HO-SO2-S-; straight-chain or branched alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, preferably methyl; and phenyl or phenoxy.

In the event that R4 is on one or more carbon atoms in the heterocyclyl R1 and R2, R4 is preferably lower alkyl, preferably methyl, ethyl, Isopropyl, especially methyl; the group trifluoromethyl; Halogen, preferably Fluorine, chlorine, bromine; Amino; Lower alkylamino, preferably CH3-NH-, C2H5-NH-; Di-lower alkylamino, preferably (CH3) 2N-, (C2H5) 2N-; Formylamino; Acetylamino; CH3-O-CO-NH-, C2H50-CO-NH-; CH3-SO2-NH-; Hydroxy; Methoxy, ethoxy; Methylthio, ethylthio; CH3-SO2-; CH3-SO-; the Groups HOOC-; HO3S-; HCO-; Lower alkyl-CO-, preferably CM3-CO-; Lower alkyl-O-CO-, preferably CH3-O-CO-, C2H5 O-CO-; and -CN.

In the event that R4 is in a nitrogen-containing heterocyclyl R1 and R2 R4 is preferably a substituent on one or more nitrogen atoms Lower alkyl, preferably methyl, ethyl, propyl, isopropyl, especially methyl and ethyl; the group -CN; -CHO; -C-0O-lower alkyl, preferably -COO-CH3, -COOC2H5, -CoOCH (CH3) 2, -COO-C (CH3) 3; -CO-NH2; -CO-NH-lower alkyl, preferably -CO-NH-CH3, -CO-NH-C2H5, -CO-NH-CH (CH3) 2; and -CO-lower alkyl, preferably -CO-CM3, -CO-C2H5-, -CO-CH (CH3) 2.

The rings which may be formed by R¹ and R² together with the carbon atom to which they are attached are saturated or unsaturated. Unsaturated rings preferably contain 1 or 2 double bonds. The rings can contain 1 or more, preferably 1 or 2, in particular 1, heteroatom or hetero group. Oxygen, sulfur and / or nitrogen may be mentioned as heteroatoms. Examples of hetero groups are the SO2 group and the lower alkyl-N group, in the case of 6-membered rings a heteroatom or a hetero group is preferably in the 4-position (based on the carbon atom to which R1 and R2 are bonded) . The following are particularly preferred rings: Niederaikyi- and Lower alkyl-N t The rings which are formed by R1 and R2 together with the carbon atom to which they are attached can contain one or more, preferably 1 to 3, in particular 1 or 2, identical or different substituents R.

R5 preferably denotes halogen, preferably fluorine, chlorine, bromine; Hydroxy; Lower alkoxy, preferably methoxy and ethoxy; Lower alkylthio, preferably Methyltho, ethylthio; Amino; Lower alkylamino, preferably CH3-NH-, C2H5-NH-; Di-lower alkylamino, preferably dimethylamino and diethylamino; the groups -CN; -COOH; -COOCH3, -COOC2H5; and straight or branched chain lower alkyl, preferably methyl and ethyl.

At least one of the radicals R1 and R2 is particularly preferably Hydrogen.

Z particularly preferably represents the group Connections that do the rest contain arise if this radical is already contained in the compounds of formula III or can arise if work is carried out in aqueous solvents.

Phenyl B can be one or more, preferably 1 to 3, in particular Carry 1 or 2 identical or different substituents. The substituents can are in o-, m- and / or p-position. Preferably there is one substituent in p or m position. Examples of substituents are halogen, such as fluorine, Chlorine, bromine and iodine, preferably fluorine, chlorine and bromine; Alkyl of 1 to 6, preferably 1 to 4, in particular 1 or 2, carbon atoms; Cyano and methylsulfonyl listed. Substituted phenyl radicals B in particular are the hydroxyphenyl radical (preferably p-Mydroxyphenyl), the methylphenyl radical (preferably p-methylphenyl), the cyanophenyl radical (preferably m- and p-cyanophenyl), the methylsulfonyl radical (preferably p-methylsulfonylphenyl) and the fluorophenyl radical (preferably o-fluorophenyl and m-fluorophenyl) mentioned.

In the definition of T, alkyl in alkyl preferably means -CO-O- Alkyl having 1 to 4, in particular 1 or 2, carbon atoms. Examples are methyl and called ethyl, methyl being particularly preferred.

The heterocyclic ring Het consists of -S-Het (definition of T) from 5 or 6 ring members and contains 1 to 4, preferably 1 to 3 identical or different heteroatoms, the heteroatoms being oxygen, sulfur and nitrogen stand.

The heterocyclic ring is preferably unsaturated and particularly preferably contains 2 double bonds. The heterocyclic ring can contain one or more, preferably 1 or 2, in particular one, substituent. Examples of substituents include: halogen, such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, amino, iJiederalkylamino, 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 above), trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5, in particular 2 or 3 carbon atoms. As -S-Het are listed as particularly preferred: 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, the preferred substituents being those which are mentioned above as possible substituents of the radical. -S-Het to be performed.

Compounds according to the invention in which C is in the D- = R configuration.

All crystal forms and hydrate forms of the compounds according to the invention of the general formula 1 and their salts have an antibacterial effect in the same way.

Halogen W represents fluorine, chlorine and bromine, preferably bromine or chlorine, especially for chlorine.

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.

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 the chemistry of antibiotics, bases commonly used are used. Examples of inorganic bases are: alkali and alkaline earth 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 Amines can be primary, secondary, and tertiary aliphatic amines as well heterocyclic Amines are used. Examples include: di- and tri-lower alkylamines, z. B. diethylamine, triethylamine, tri-B-hydroxyithylamine, procaine, dibenzylamine, , '- Dibenzylethylenediamine, N-benzyl-ß-phenylethylamine, N-methyl- and W-ethylmorpholine, 1-ephenamine, dehydroabietylamine,, '- bis-dehydroabietylethylenediamine, N-lower alkylpiperidine.

So-called basic amino acids such as lysine or arginine can also be used find advantageous use as bases. Particularly preferred salts are the sodium salts.

Very particularly preferred compounds of the formula I are those in which the definition of the radicals is as follows: R stands for hydrogen; Z stands for the groups R1 is hydrogen; and R2 is phenyl optionally substituted by halogen (especially chlorine), alkoxy with 1 to 4 carbon atoms (especially methoxy), itro, cyano or alkylsulfonyl with 1 to 4 carbon atoms (especially methylsulfonyl), preferably in the p-position, or optionally by halogen (in particular chlorine or bromine) is preferably furyl or thienyl substituted in the 4- or 5-position, the furyl and thienyl ring preferably being bonded in the 2-position; and A is -CH2-CH2-; and B is phenyl, hydroxyphenyl (preferably p-hydroxyphenyl) or cyclohexadienyl (preferably cyclohexa-1,4-dien-1-yl); and Y stands for the groups where T is -O-CO-CH3; and C is in the D = R configuration; as well as the sodium salts of these compounds.

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

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.

Examples include: α-aminobenzylpenicillin, α-amino-p-hydroxybenzylpenicillin, α-amine-p-methylbenzylpenicillin, α-amino-p-chlorobenzylpenicillin, 6- 2-Amino-2- (1,4-cyclohexadien-1-yl) -acetamido7 ~ penicillanic acid, 7- (α-Amino-phenylacetamido) -3-methyl-ceph-3-em-4-carboxylic acid, 7- (α-Amino-phenylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid.

As salts of the compounds of the formula II, salts can preferably be used with bases are used, which as for the salt formation with compounds of Formula I can be listed appropriately. The sodium salts are particularly preferred.

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

You can e.g. B. can be obtained in the following way (cf.

also JACS 78 (1956) 5349): Examples of starting compounds of the general formula III according to the invention are: 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine 1-azidocarbonyl-2-oxo-3-benzalimino-imidazolidine 1-chlorocarbonyl-2-oxo-3- (4 -chlor) -benzalimino-imidazolidine 1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzalimino-imidazolidine 1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalimino-imidazolidine 1-chlorocarbonyl-2 -oxo-3- (4-cyano) -benzalimino-imidazolidine 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzaliminoimidazolidine 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine 1-azidocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine 1-chlorocarbonyl-2-oxo-3- (furan-2-aldimino) -imidazolidine 1-azidocarbonyl-2-oxo-3- (furan -2-aldimino) -imidazolidine Those compounds of the general formula III in which W is azide are used in a conventional manner, for. B. from the corresponding compounds III, in which W is halogen, obtained by reaction, for example, with alkali azides.

The diluent used in the process of the invention is water and all inert organic solvents, preferably those with water are miscible, in question. These include, in particular, lower dialkyl ketones, e.g. B. acetone, Methyl ethyl ketone, cyclic ethers, e.g. tetrahydrofuran and dioxane; Nitriles, e.g. Acetonitrile; lower dialkylformamides, e.g., dimethylformamide; lower alkyl alcohols, e.g. ethanol and isopropanol as well as dimethyl sulfoxide.

These solvents can also be mixed with one another as well in any mixtures of one or more of these solvents with water be used. The inventive method can thus be carried out in Presence of: (a) only water, (b) only one or more organic solvents or (c) water and one or more average organic solution. Is a pH measurement because of the presence of water possible during the reaction of the present invention, the pH of the reaction mixture becomes by adding bases or by using buffer mixtures, preferably between 6.5 to 7.5 held. However, the process according to the invention can also be carried out very well in a different pH range, for example between 4.5 and 9, o or at pH 2, o up to 4.5. It is also possible to make the reaction immiscible with water Solvents, e.g. B. halogenated hydrocarbons, such as chloroform or methylene chloride, with the addition of organic bases, preferably lower alkylamines, e.g. B. triethylamine, Diethylamine or cyclic bases, e.g. B. to carry out N-ethylpiperidine. Farther the reaction can be in a mixture of water and one immiscible with water Solvents such as B. lower alkyl ethers, such as diethyl ether, halogenated hydrocarbons, such as chloroform and methylene chloride; Carbon disulfide; Isobutyl methyl ketone; Esters such as ethyl acetate; aromatic hydrocarbons such as benzene, it is advisable to stir vigorously and adjust the pH by adding a base or Use of conventional buffer solutions, e.g. B.

Phosphate, acetate or citrate buffer, between 4.5 and 9.0 or e.g. B. 2, o and 4.5 to hold. However, the reaction can also be carried out in the absence of water alone of organic solvents in the presence of an organic or inorganic one Carry out base or with the addition of customary buffer substances.

Acid binders can all be used in the chemistry of antibiotics commonly acid binders used can be used. These include inorganic bases and organic bases which are difficult to acylate due to steric hindrance. Sodium and potassium hydroxide may be mentioned as examples of inorganic bases Organic bases are practically all open-chain which cannot be acylated or are difficult to acylate or cyclic Amines and also heteroaromatic bases are possible. Examples of bases are tertiary amines, preferably lower alkylamines, e.g. B. Triethylamine and / or cyclic bases, e.g. B.

Pyridine and, as a secondary amine that is difficult to acylate, dicyclohexylamine called.

In the process according to the invention, the addition of a base is only possible required if acidic compounds are formed during the reaction, e.g. B. in the case that W stands for halogen or azide.

The reaction temperatures can be varied within a relatively wide range will. In general, work is carried out between about -20 ° C. and + 50 ° C., preferably between 0 and + 20 ° C.

As with most chemical reactions, however, in principle higher or lower temperatures can also be used.

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 proportions can the counterpart of formulas II and III can be varied within wide limits without that the result is adversely affected. The starting materials can, for. Am equimolecular amounts are reacted with one another. However, it can be appropriate to use one of the two reactants in excess to To facilitate the cleaning or purification of the desired penicillin and to 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 in a water-containing one Reach solvent mixture.

The excess of the reactants of the general formula II can because of the good solubility in aqueous mineral acids when working up the Easily remove the reaction mixture.

On the other hand, it is also possible to 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 III added in excess are dissolved in water rapidly convert to neutral nitrogen-containing heterocycles that are easily removed the purity of the antibiotics is hardly affected.

The amount of the optionally used bases is e.g. B. by the desired adherence to a certain pH value. Where a pH measurement and cessation does not occur or because of lack of sufficient amounts of water in the diluent is not possible or does not make sense, are preferred 2 molar equivalents of base added.

The work-up of the reaction batches for the preparation of the inventive Compounds and their salts occurs consistently in the case of these bodies in general known way. Also the isolation and purification of the invention Compounds as well as the release of free acids from salts or the conversion of the free acids into salts is carried out by generally customary methods organic chemistry, which is familiar to every person skilled in the art.

The compounds of general formula I are in the form of the free ones Acid both crystalline and amorphous and both anhydrous and in various hydrate forms in the same way antibacterially effective. The connections are also general Formula T in the form of its salts, e.g. B. sodium salts, both crystalline and amorphous and both anhydrous and anhydrous, for example as a hydrate, in the same way antibacterial effect.

As new active ingredients are mentioned (formulas IV and V): R1 R2 BH C6H5 C6H5 H C6H5 4-HO-C6H4 H C6H5 Cyclohexa-1,4-dien-1-yl H 4-Cl-C6H4 C6H5 H 4-Cl-C6H4 Cyclohexa-1,4-dien-1-yl H. 4-CH3O-C6H4 C6H5 H 4-CH3O-C6H4 Cyclohexa-1,4-dien-1-yl R1 R2 BH 4-NO2-C6H4 C6H5 H 4-CN-C6H4 C6H5 H 4-CH3SO2-C6H4 C6H5 H 4-CH3SO2 -C6H4 4-HO-C6H4 H 4-CH3SO2-C6H4 Cyclohexa-1,4-dien-1-yl H 2-thienyl Cyclohexa-1,4-dien-1-yl H 2-thienyl C6H5 H 4-Br-thienyl C6H5 H 5-Cl-Thienyl C6H5 H 2-Furyl C6H5 H CH3 C6H5 CH3 CH3 C6H5 CF3 C2H5 C6H5 n-C4H9 CH3 C6H5 C6H5 C6H5 C6H5 Cyclohexyl H C6H5 C6H4-CH2- H C6H5 C6H5 C6H5 C6H5 C6H5 R1 R2 B C6H5 C6H5 R1 R2 BTH C6H5 C6H5 OCOCH3 H 4-Cl-C6H4 C6H5 OCOCH3 H 4-CH3O-C6H4 C6H5 OCOCH3 H 4-CH3SO2-C6H4 C6H4 OCOCH3 H 2-thienyl C6H4 OCOCH3 H CH3 C6H4 C6H4 C2 C6H4 OCOCH3 C6H4 H C6H4 H R1 R2 BT C6H4 OCOCH3 C6H4 OCOCH3 The active ingredients according to the invention have a strong and broad antimicrobial activity with low toxicity. These properties enable them to be used as chemotherapeutic agents in medicine and as substances for the preservation of inorganic and organic materials, in particular organic materials of all kinds, e.g. polymers, lubricants, paints, fibers, leather, paper and wood Food and water The active ingredients according to the invention are effective against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, ameliorated and / or cured.

The active ingredients 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, which 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 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); Neisseriaceae, such as Neisseria, e.g. Neisseria genrrohoeae (gonococci), N. menigitidis (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.murispecticum, Listeria bacteria, e.g. Listeria monocytogenes, Erysipelothrix bacteria, e.g. Erysipelothrix insidiosa, Kurthia bacteria, e.g. Kurthia zopfii (C. = Corynebacterium); Mycobacteriaceae, such as pathogens causing mycobacteriosis, e.g.

Mycobacterium tuberculosis, M.bovis, M-avium, so-called atypical Nykobacteria of Runyon groups I, II, III and IV, M.leprae (M. = Mycobacterium); 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.pneumoniae, K.ozaenae, Erwiniae, e.g. Erwinia spec., Serratia, e.g.

Serratia marcescens (E. = Enterobacter) (K. = Klebsi-ella), Proteae bacteria the Proteus group: Proteus, e.g.

Proteus vulgaris, Pr.morganii, Pr.rettgeri, Pr.mirabilis, Providencia, e.g. Providencia sp. (Pr. = Proteus), Salmonellae: Salmonella bacteria, e.g. Salmonella paratyphi A and B, S.typhi, S.enteritidis, S.cholerae suis, S.typhimurim (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, such as Vibrio bacteria, e.g. Vibrio cholerae, V. proteus, V. fetus (V. = Vibrio), Spirillum bacteria, e.g. Spirillum minus; Parvobacteriaceae or Brucellaceae, such as Pasteurella bacteria, e.g. Pasteurella multocida, Past.pestis (Yersinia), Past.pseudotuberculosis, Past.tularensis (Past. = Pasteurella), Brucella bacteria, e.g. Brucella abortus, Brqmelitensis, Br.suis (Er. = 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; Bacterioidaceae, 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.oedematien, Cl.histolyticum, Cl.tetani, Cl.botulinum (Cl. = Clostridium); Spirochaetaceae, such as Borelia bacteria, e.g. Borrelia recurrentia, B.vincentii (B. = Borrelia), Treponema-Bakteriemn, e.g. Treponema pallidium, Tr.perinue, Tr.

carateum (Tr.- Treponema), Leptospica bacteria, Leptospira interrogans, e.g. Leptospira icterohaemorrhagiae, L.canicola, L.grippotyphosa, L. pomona, L. mitis, L. bovis (L. = Leptospira); The above list of pathogens is only to be understood as an example and in no way restrictive.

As diseases that are prevented by the active ingredients 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 ; local infections.

The present invention includes pharmaceutical preparations, the one in addition to non-toxic, inert pharmaceutically suitable carriers or contain several active ingredients according to the invention or those of one or more There are active ingredients according to the invention and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules whose Active Strff content correspond to a fraction or a multiple of a single dose. The dosage units can be, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amount Active ingredient that is administered in one application and that usually corresponds to a whole, hold one 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 neither kind of understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, uppositories, 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, gelatine, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retarders, e.g.

Paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g., cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. Kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and sheaths, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably delayed in a certain part of the intestinal tract using e.g. polymer substances and waxes as embedding materials 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) or 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. Hilch sugar, 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 application are in sterile and blood isotonic form.

In addition to the active substance or substances, suspensions can contain the usual carrier substances 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 of these substances contain.

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 such as 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 except the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients 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 orally or parenterally how to be administered intravenously or 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 5 to about 1000, preferably 20 to 200 mg / kg of body weight per 24 hours, possibly in the form of several individual doses to achieve the desired results to administer. A single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to about 250, in particular 10 to 100 mg / kg of body weight.

However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and the application of the newspaper as well as the period or interval within to which the administration takes place. So in some cases it may be sufficient get by with less than the above amount of active ingredient, while in others Cases the amount of active ingredient listed above must be exceeded. The definition the required optimal dosage and type of application of the active ingredients can easily be done by any skilled person on the basis of their specialist knowledge.

In the case of application as a feed additive, the new compounds in the usual concentrations and preparations together with the feed or with Feed preparations or be given with the drinking water. This can cause infection prevented, ameliorated and / or cured by gram-ative or gram-positive bacteria as well as promoting growth and improving recovery of the feed can be achieved.

The new penicillins and cephalosporins are characterized by strong antibacterial effects tested in vivo and in vitro, and by oral Absorbability.

The penicillins and cephalosporins according to the invention can be used for the purpose the expansion of the spectrum of effects and an increase in effectiveness ß-lactamase-producing bacteria can be achieved with other anti-bacterial agents E.g. with penicillins, which are particularly resistant to penicillinase, can be combined. Such a combination would be e.g. that with oxacillin or dicloxacillin.

The penicillins and cepnalosporins according to the invention can be used for the purpose the expansion of the spectrum of effects and to achieve an increase in effectiveness also with aminoglycoside antibiotics, such as. B. gentamicin, kanamicin, amikacin or Tobramicin.

The effectiveness of the ß-lactam antibiotics according to the invention can by the following in vitro and in vivo experiments are demonstrated by way of example: 1. In vitro experiments Examples 1.3., 2.3. and 2.4., which are typical representatives The compounds of the invention that can be viewed were made with Mueller-Hinton nutrient broth diluted with the addition of 0.1% glucose to a content of 100 mg / ml. In the nutrient solution there were 1 x 105 to 2 x 105 bacteria per milliliter. The tubes with this approach were incubated for 24 hours and then the Degree of turbidity determined. Freedom from haze indicates effect. With a dosage of 100 pg / ml the following bacterial cultures were free of turbidity (sp. = species) Klebsiella pneumoniae; Enterobacter aerogenes sp .; Providencia; Serratia marcescens; E. coli BE; Salmonella sp .; Shigella sp .; Proteus, indole negative and indole positive; Pasteurella pseudotuberculosis; Brucella sp .; Haemophilus influenzae; Bordetella bronchiseptica; Staphylococcus aureus 133; Neisseria catarrhalis sp .; Diplococcus pneumoniae sp .; Streptococcus pyogenes W .; Enterococcus sp .; Lactobacillus sp .; Corynebacterium diphteriae gravis; Corynebacterium pyogenes M; - Clostridium tetani; Pseudomonas aeruginosa sp.

2. In vivo experiments The following table 1 shows the effect of a of the compounds according to the invention against a number of bacteria 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 experiments with the white mouse Determination of the ED100 after 24 hours Germ dose in mg of the ß-lactamanti- biotics of example 1.3., 2.3., 2.4 per kg / body weight (subcutaneous) Escherichia coli C 16 2 x 150 Klebsiella 63 2 x 150 Therapy: twice: 30 and 90 minutes after infection. The ED100 is the dose at which 100% of the infected animals still survive after 24 hours.

The method according to the invention is illustrated by the following examples: The oc-aminobenzylpenicillin used in the following examples contained about 14 water, but you can just as well use anhydrous oc-aminobenzylpenicillin [cf.

Use U.S. Patent 3,144,457.

The oc-amino-p-hydroxybenzylpenicillin used in the examples contained about 13 water, but anhydrous a-amino-p-hydroxybenzylpenicillin can just as well be used use.

The 6- [2-amino-2- (1,4-cyclohexadien-1-yl) acetamido] penicillanic acid used in the examples was largely anhydrous.

The 7- (a-aminophenylacetamido) 3-methyl-ceph-3-em-4-carboxylic acid used in the examples contained about 5% water, but anhydrous 7 - (- Amino-phenylacetamido) -3-methyl-ceph-3-em-4-carboxylic acid can just as well be used use.

The 7 - (- Smino-phenylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid used in the examples contained 8% water, but anhydrous 7- (α-amino-phenylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid can just as well be used use.

The water content of the starting compounds is essential for the implementation of the method according to the invention is irrelevant.

With "Ampicillin" that is a-aminobenzylpenicillin, with "Amoxicillin" that α-amino-p-hydroxy-benzyipenicillin and with 2'Epicillin "that α-amino-α- (1,4-cyclohexadien-1-yl) -methylpenicillin meant by the D = R configuration in the side chain.

With "Cefalexin" that is 7- (å-amino-phenylacetamido) -3-methyl-ceph-3-em-4-carboxylic acid and with "cephaloglycine" that 7- (α-amino-phenylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid Meant by the D = R configuration in the side chain.

The NMR spectra of the compounds according to the invention were when nic.ht otherwise stated, included in CD3OD solution.

The terms in brackets mean: s = singlet m = Multiplet d- = doublet AB = AB system t = triplet q = quartet The IR spectra of the compounds according to the invention were, unless otherwise stated, in paraffin oil suspensions recorded.

Explanation of the abbreviations used in the examples: Vol. = Volume DMF = Dimethylformamide Part by weight. = Parts by weight ether = diethyl ether parts by volume. = Parts by volume of ethyl acetate = acetic acid hour. = Hours ethyl ester hours = hour room temperature = approx. 20 ° C THF = tetrahydrofuran abs. = absolute decomposition p = decomposition point The yield data in "mean yields in" the theory of example 1 2-Oxo-imidazolidine (31.5 parts by weight) is dissolved in 2N sulfuric acid (1000 parts by volume), the solution is cooled to 3-60 ° C., and the sodium nitrite solution (25.25% by weight) is dissolved within 13 minutes .Tle.) In water (50 vol. Parts) are added dropwise with stirring and further cooling, then another 1.5 hours.

stirred in an ice bath and then cleaned zinc dust (55 parts by weight) entered in the course of an hour. It is 0.5 hours with ice cooling-and then 1 hour left.

stirred at room temperature. The unreacted zinc is then suctioned off, washed with a little water, benzaldehyde to the combined filtrates (35 parts by weight) and vigorously stirred for 0.5 hours. The precipitated l-benzalimno-2-oxo-imidazolidine is then filtered off with suction and after drying (49.2 parts by weight; melting point = 194-2000C) from ethanol recrystallized.

Yield 41.4 parts by weight, m.p. = 2020C.

IR spectrum: 1720 cm -1 (C = O).

Calculated: C 63.5 H 5.9 N 2-2.2 Found: C 64.1 H 5.7 N 22.7 The mixture of 1-benzalimino-2-oxo-imidazolidine (11.7 parts by weight) (see 1.1.), Benzene (120 parts by volume) and triethylamine (13.8 parts by volume) is heated to the boil and then the solution of trimethylchlorosilane (10 parts by weight) in benzene (50 parts by volume) was added dropwise with stirring over the course of 1 hour.

It is then kept boiling for 5.5 hours, the precipitated Triethylammonium hydrochloride filtered off with suction while hot and washed with hot benzene. to The solution of phosgene becomes the cooled, combined benzene filtrates (6.2 parts by weight) in benzene (30 sv-ol. Parts). It is left tightly closed overnight stand at room temperature.

A stream of dry air then removes excess Most of the phosgene removed. The l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine is sucked off and dried.

Yield 8.9 parts by weight, melting point = 250-252 ° C decomp.

IR spectrum: 1800 cm 1 (-CO-C1) calculated: C 52.5 H 4.0 C1 14.1 N 16.7 found: C 51.8 H 5.6 C1 14.6 N 16.8 Ampicillin (14 parts by weight) is suspended in 80% aqueous tetrahydrofuran (140 parts by volume), and the solution is brought into solution using the amount of triethylamine required (then pH 8.0), 1-chlorocarbonyl-2-oxo-3 -benzalimino-imidazolidine (7.8 parts by weight.) (see 1.2.) slowly added with stirring and the pH was kept at 7.0-7.5 by adding triethylamine accordingly. Stirring is then continued for as long as triethylamine has to be added to maintain the specified pH range (approx. 1-2 hours). It is diluted with water (200 mol. Parts), the pH is adjusted to 6.5, the tetrahydrofuran is largely evaporated in vacuo, the remaining aqueous solution is washed once with ether in a separating funnel, then covered with ethyl acetate and acidified using diluents HC1 with stirring up to pH 2. The organic phase is then separated off, washed with saturated NaCl solution, dried over MgSO4 and, after dilution with the same volume of ether, an approximately 1 molar sodium 2-ethylhexanoate solution in methanol-containing ether is added until precipitation has ceased. The sodium 6- CD-cx-lr (2-oxo-3-benzaliminoimidazolidin-1-yl) carbonylamino] phenylacetamido} penicillanate is filtered off with suction, with ether and then with a mixture of ether and methanol (5-10% ) and isopropanol and dried.

Yield 6.2 parts by weight, ß-lactam content 91%.

According to the NMR spectrum, the substance still contains 2.5 mol of H 2 O, 0.1 mol Isopropanol and 0.04 mol of N-atrium-2-ethyl-hexanoate.

This was taken into account in the calculated analysis values.

Calculated: C 51.5 H 5.3 N 13.0 S 590 found: C 50.9 H 5.2 N 12.9 S 5.1 NMR signals at # = 2.1-2.8 (IIIH); 4.3-4.65 (3H); (i.CD3OD) 5.8 (1H); 6.1 - 6.35 (4H) and 8.3 - 8.6 ppm (6H).

IR spectrum (carbonyl range): 1770, 1730, 1665, 1610 and (in paraffin oil) 1540 cm -1 This penicillin is listed under 1.3. described manner from amoxicillin trihydrate (6.0 parts by weight.) and l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine (3.6 parts by weight.) (see 1.2.). When the aqueous reaction solution is acidified with dilute hydrochloric acid (about 20% by weight) to pH 1.5, some of the penicillic acid released is not absorbed by the ethyl acetate. This part is filtered off with suction, washed with water and dried (yield: 5.2 parts by weight). Penicillin sodium salt can then also be precipitated from the ethyl acetate phase with sodium 2-ethylhexanoate (yield: 1.4 parts by weight).

6- {D-α - [(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino] -4-hydroxyphenylacetamino} -penicillanic acid Yield: 5.2 parts by weight.

β-lactam content (iodometric): 81% (from NMR spectrum): 89 ff According to the NMR spectrum, the substance contains 3.4 mol of H2O and 0.5 mol of ether per mol of substance. If one takes this into account in the calculated analysis values, one finds: calculated: C 51.2 H 5.9 N 12.4 S 4.7 found: C 50.7 H 5.5 N 12.8 S 4.8 NMR signals at # = 2.2-3.3 (IOH); 4.3-4.65 (3H); (i.CD3OD) 5.7 (1H); 6.15-6.4 (4H) and 8.35 - 8.6 ppm (6H).

IR spectrum (carbonyl range): 1780, 1740 (shoulder), (in paraffin oil) 1725, 1645, 1520 cm-1.

Sodium 6- {D-α - [(2-oxo-3-benzalimino-imidazolidin-1-yl) -carbonylamino7-4-hydroxyphenylacetamido} penicillanate yield: 1.4 parts by weight.

0-lactam content (iodometric): 96% (from NMR spectrum): 87% According to the NMR spectrum, the substance contains 2.5 mol of H2O and 0.25 mol of sodium 2-ethylhexanoate per mole of substance (also an unknown, derived from the Amoxil used Contamination of unknown amount). If one takes into account the identified admixtures the calculated analytical values give: Calculated: C 50.6 H 5.2 N 12.2 S 4.6 found: C 51.2 H 6.0 N 11.7 S 4.5 NMR signals at # = 2.1-3.3 (IOH); 4.4-4.7 (3H); 5.8 (1H); (i.CD5OD) 6.1-6.4 (4H) and 8.3-8.6 ppm (6H).

IR spectrum (carbonyl range): 1770, 1735, 1670, 1600 (in paraffin oil) and 1560-1520 cml, This penicillin is listed under 1.3. described manner from epicillin (1.5 parts by weight.) and l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine (1.1 parts by weight.)

Yield: 1.7 parts by weight. Sodium 6- {D-α - [(2-oxo-3-benzalimino-imidazol-l-yl) -carbonylamino7-cyclohex-1,4-diyl (1) -acetamido} penicillanate with a P-lactam content (iodometric) of 90%, (from the NMR spectrum derived: 91).

According to the NMR spectrum, the substance contains 2.5 mol of H2O and 0.072 mol Sodium 2-ethylhexanoate. This was taken into account in the following analysis values: Calculated: C 51.2 H 5.4 N 13.0 S 4.9 found: C 50.9 H 5.7 N 13.6 S 4.6 NMR signals at # = 2.0-2.65 (5H); 4.0 (1H); 4.25 (2H); (i.CD3OD) 4.45 (2H); 4.95 (1H); 5.75 (1H); 6.0-6.3 (4H); 7.1-7.4 (4H) and 8.25-8.5 ppm (6H).

IR spectrum (carbonyl range); 1765, 1730, 1660, 1600 (in paraffin oil) and 1530 cm 1.

Q = H, Na 2.25 parts by weight. Cephaloglycine dihydrate in 50 ml 8o percent. suspended in aqueous THF and as in Example 1.3 with 12.6 parts by weight. 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine implemented and processed.

When acidifying with dilute hydrochloric acid (e.g.

2N HC1) precipitates 7- {D-α - [(2-oxo-3-benzalimino-imidazolidin 1-yl) -carbonylamino] -phenylacetamido} -3-acetoxymethylceph-3-em-4-carboxylic acid from (1.9 parts by weight, corresponding to 61.4%). It is tn 5 vol. Dissolved dimethylacetamide, with 3 vol. a methanolic 1 M sodium 2-ethyl-hexanoate solution: ag added and with stirring to 30 vol.

Part of a 10: 1 mixture of ether / methanol, with 1.7 Part by weight of sodium 7- {D-α - [(2-oxo-3-benzaliminoimidazolidin-1-yl) carbonylamino-phenylacetamido 3-acetoxymethyl-ceph-3-em-4-carboxylate from Zer -p. 180-1850C fail.

The ethyl acetate phase is worked up as in Example 1.3, with another 0.9 vol. (corresponding to 28.0%) of the sodium salt can be obtained.

C29H27N6NaO8S. H2O calc .: C 52.72 H 4.42 N 12.71 S 4.85 found: 52.5 4.9 12.2 4.6 IR (KBr): 1760, 1725, 1670, 1605, 1520 cm -1.

NMR (CD3OD / D20): 7.75 and 7.40 (m, IIH), 5.75 (d, IH), 5.57 (s, IH), 5, GO (d, lH), 4.87 (superimposed by the signal of the exchangeable protons), 3.82 (m, 4H), 2.08 (s, 3H) #.

The signals of the C-2 protons are overlaid by the CD3OD solvent peak.

The ß-lactam content is between 80-85.

Example 2 2.1.

15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight. Sodium nitrite and 27.5 parts by weight Zinc dust is as in Example 1.1. processed and with 23.2 parts by weight. Stirred 4-chlorobenzaldehyde overnight.

20.5 parts by weight of 1- (4-chloro) -benzalimino-2-oxo-imidazolidine of melting point 233-2350C.

C10H10ClN3O calc .: C 53.70 H 4.51 N 18.79 Cl 15.85 found: 53.9 4.5 18.7 16.0 IR (KBr): 3250, 3130, 1735, 1705, 1595 cm -1.

NMR (d6-DMSO): 7.66 and 7.45 (AB, 4H), 7.60 (s, 1H), 7.15 (s, broad, 1H), m, centered at 3.6 (4H) &.

2.2.

To a boiling solution of 21.4 parts by weight. 1- (4-chloro) -benzalimino-2-oxo-imidazolidine and 31.0 parts by weight of triethylamine in 240 parts by volume. absolute dioxane is used within 1 hour with stirring a solution of 31.0 wt.

Tln. Trimethylchlorosilane in 100 vol. Tin. Section. Dioxane dripped.

The mixture is then refluxed overnight, hot from the precipitated Triethylammonium hydrochloride sucked off, washed with hot dioxane and after cooling with a solution of 9.9 parts by weight of phosgene in 60 parts by volume.

Section. Dioxane added. After 12 hours Standing at room temperature will Blow out excess phosgene with dry air. The precipitation will suctioned off, the filtrate concentrated and the residue from abs. Recrystallized acetonitrile. 8.9 parts by weight of 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzalimino-imidazolidine from decomp. -p. 188-1920C.

IR (paraffin oil): 1800, 1700 cm-1 2.3.

7.9 parts by weight Ampicillin trihydrate in 80 parts by volume. 80% by volume.

aqueous THF with 2.8 parts by weight. l-chlorocarbonyl-2-oxo-3- (4-chloro) -benzalimo-imidazolidine as in example 1.3. implemented. 1.4 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {4-chloro} -benzalimino-imidazolidin-1-yl) -carbonylamine H7-phenylacetamidopenicillanate from Zerp. -p.

210-5 ° C with a ß-lactam content of 87%.

IR (KBr): 1760, 1725, 1665, 1595 cm -1.

NMR (CD3OD): 7.6-7.2 (m, IOH), 5.60 (s, 1H), 5.45 (q, 2H), 4.15 (s, 1H), 3.80 (broad s, 4H), 1.57 (s, 3H), 1.48 (s, 3H) a.

2.0 parts by weight Epicillin sodium in 40 vol. 80% by volume of THF with 3.5 parts by weight l-chlorocarbonyl-2-oxo-3- (4-chloro) -benzalimino-imidazolidine such as in example 1.5.

implemented. 0.4 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {4-chloro} -benzalimino-imidazolidin-1-yl) -carbonylamino] -cyclohex-1,4-dienyl (1) -acetamido} -penicillanate with a ß-lactam content of 92%.

IR (KBr): 1770, 1730, 1670, 1605 cm-1.

NMR (CD3OD): 7.78 (s, 1H), to 7.76 and 7.36 (AB, 4H), 5.95 (m, 1H), 5.72 (s, 2H), 5.50 (s , 2H), to 5.00 (s, 1H), 4.20 (s, 1H), 3.95 (s, broad, 4H), 2.75 (s, broad, 4H), 1.65 (s , 3H), 1.58 (s, 3H) #.

2.25 parts by weight Cephaloglycine dihydrate in 40 vol. 8o vol% THF are with 3.5 parts by weight. 1-chlorocarbonyl-2-oxo-3- (4-chloro) -benzalimino-imidazolidine as in example 1.6. implemented. It contains 0.6 parts by weight. Sodium 7- {D-α [(2-oxo-3- {4-chloro} -benzalimino-imidazolidin-1-yl) -carbonylamino-7-phenylacetamidoi 3-acetoxy-methyl-ceph-3-em-4-carboxylate with a ß-lactam content of 80-85%.

IR (KBr): 1760, 1720, 1660, 1595 cm-1.

NMR (CD3OD): 7.7 and 7.4 (m, IOH), 5.65 (d, 1H), 5.60 (s, 1H), 5.0-4.8 m (superimposed by the signal of the exchangeable protons) 3.88 and 3.70 (superimposed Multiplets), 2.03 (s, 3H) #.

C29H26ClN6NaO8S. 1 1/2 H20. 1/4 dimethylacetamide calc .: C 50.25 H 4.22 N 11.72 '5 4.48 found: 50.1 4.5 11.1 5.4 Example 3 15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight sodium nitrite and 27.5 parts by weight. Zinc dust is produced as in Example 2.1. processed and with 22.4 parts by weight. 4-methoxybenzaldehyde implemented. 15.8 parts by weight are obtained. 1- (4-Methoxy) -benzalimino-2-oxo-imidazolidine, m.p. 179-181 ° C.

IR (KBr): 3250, 3130, 1725, 1700, 1605 cm-1.

NMR (d6-DMSO): 7.56 and 6.92 (AB, 4H), 7.52 (s, 1H), 7.04 (s, 1H), 3.72 (s, 3H), m centered at 3.52 (4H) g.

C11H13N3O2 calc .: C 60.27 H 5.97 -N 19.17 found: 60.3 5.9 18.9 To a boiling solution of 13.6 parts by weight. 1- (4-methoxy) -benzalimino-2-oxo-imidazolidine and 27.6 parts by volume. Triethylamine in 120 parts by volume. Section. Benzene is a solution of 20.0 parts by weight. Trimethylchlorosilane in 50 parts by volume abs.

Benzene was added dropwise and as in Example 1.2. implemented and worked up. 6.2 parts by weight are obtained. 1-chlorocarbonyl 2-oxo-3- (4-methoxy) -benzalimino-imidazolidine from fp.

204-2080C.

IR (paraffin oil): 1800 cm-1.

6.9 parts by weight Ampicillin trihydrate in 70 parts by volume. 80% by volume of THF and 2.4 parts by weight l-chlorocarbonyl-2-oxo-3 (4-methoxy) -benzalimino-imidazolidine implemented as in Example 1.3. 4.5 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {4-methoxyi-benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} - penicillanate vom Zers.-p. 213-2230C with a P-lactam content of 87%.

IR (KBr): 1770, 1730, 1675, 1605 cm 1 NMR (CD3OD): 7.60 and 6.85 (AB, 4H), 7.4 (m, 5 + 1H), 5.60 (s, 1H ), 5.45 (q, 2H), 4.15 (s, 1H), 3.72 (s, 3H), 3.63 (broad s, 4H), 1.55 (s, 3H), 1, 50 (s, 3H) #.

2.0 parts by weight Epicillin sodium in 40 vol. Parts 80 vol.% THF are mixed with 2.1 parts by weight of 1-chlorocarbonyl-2-oxo-3- (4-methoxy) -benzalimino-imidazolidine as in Example 1.5.

implemented. 3.5 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {4-methoxy} -benzalimino-imidazolidin-1-yl) -carbonylamino-cyclohex-1,4-dienyl (1) -acetamidoi penicillanate with a ß-lactam content of 68%.

IR (KBr): 1760, 1720, 1655, 1600 cm -1.

NMR (CD3OD): 7.60 and 6.85 (AB, 4H), 7.40 (s, overlying AB system, 1H), 5.90 (broad s, 1H), 5.67 (s, 2H ), 5.50 (s, 2H), 5.00 (s, 1H), 4.20 (s, 1H), 3.77 (broad s, 4H), 2.72 (broad s, 4H), 1.65 (s, 3H), 1.57 (s, 3H) #.

Q = H, Na 2.25 parts by weight. Cephaloglycine dihydrate in 40 parts by volume, 80% by volume THF are suspended with 1.41 parts by weight. 1-chlorocarbonyloxo-3- (4-methoxy) -benzalimino-imidazolidine as in example 1.6. implemented and processed.

Acid falls 7- {D-α - [(2-oxo-3- {4-methoxy} -benzalimino-imidazolidin-1-yl) -carbonylamino-phenylacetamido -3-acetoxymethyl-ceph-3-em-4-carboxylic acid from (1.2 parts by weight.) As in Example 1.4. with 1.9 vol. a lm sodium 2-ethyl-hexanoate solution to sodium 7- {D-α - [(2-oxo-3-j4 methoxy) -benzalimino-imidazolidin-1-yl) -carbonylaminol-phenylacetamido 3-acetoxymethyl-ceph-3-em-4-carboxylate is implemented (0.7 parts by weight).

The ethyl acetate phase is as in Example 1.3. worked up, whereby another 1.6. Parts by weight of the sodium salt of the decomposition p.

220-2300 with a ß-lactam content of 80% can be obtained IR (KBr): 1770, 1? 0, i660, lG10 cm-1.

NMR (CD3OD / D20): 7.55 and 6.85 (AB, 4H), 7.40 (s, superimposed on the AB system, 1H), 5.67 (d, lH), 5.47 (s, lH), 5.15-4.85 (m, overlaid by the signal of the exchangeable Protons), 3.76 (broad s, 4H), 2.05 (s, 3H) &.

C30H29N6NaO9S. H2O 690.6 calc .: C 52.18 H 4.52 N 12.17 S 4.65 found: 51.9 4.4 11.8 5.1 Example 4 15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight. Sodium nitrite and 27.5 parts by weight. Zinc dust and 24.9 parts by weight.

4-Nitrobenzaldehyde are as in Example 2.1. implemented.

The resulting 1- (4-nitro) -benzalimino-2-oxo-imidazolidine is through Cooking with ethanol freed from impurities; 37.6 parts by weight of m.p. 265-2670C.

IR (KBr): 3430, 3260, 1720, 1595, 1570 cm "" '1.

NMR (d6-DMSO): 8.20 and 7.88 (AB, 4H), 7.68 (s, 1H), 7.37 (broad s, 1H), m, centered at 3.65 (4H) #.

calc .: C 51.28 H 4.31 N 23.92 wt .: 51.2 4.3 23.9 8.8 parts by weight 1- (4-nitro) -benzalimino-2-oxo-imidazolidine, 12.1 parts by weight. Triethylamine, 12.0 parts by weight. Trimethylchlorosilane and 3.9 parts by weight. Phosgene are as in Example 2.2. implemented. The 1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalimino-imidazolidine is-from ats. Recrystallized acetonitrile; 2.6 parts by weight result. vom Zers.-p '.

188-1920C, IR (paraffin oil): 1800, 1760, 1700 cm-1.

6.8 parts by weight Ampicillin trihydrate in 70 parts by volume. 80% by volume of aqueous TMF are 2.5 parts by weight. 1-chlorocarbonyl-2-oxo-3- (4-nitro) -benzalimino-imidazolidine as in example 1.3. implemented. 3.0 parts by weight are obtained. Sodium 6 4 [(2-oxo-3- {4-nitro} -benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicillanate vom Zers.-p.

220-50C with a lactam content of 98%.

IR (KBr): 1765, 1730, 1670, 1600 cm-1.

NMR (CD3OD): 8.30 and 7.96 (AB system, 4H), centered at 7.81 (s, 1H), m at 7.45 (5H), 5.64 (s *, 1H), 5.57 (q, 2H), 4.20 (s, 1H), 3.88 (broad s, -4H), 1.58 (s, 3H), 1.50 (s, 3H) #.

C27H26NqNaO8S s 2.5 H2O calc .: C 47.93 H 4.62 N 14.50 S 4.74 found: 47.7 4.3 14.4 4.8 Example 5 12.6 parts by weight 2-oxo-imidazolidine, 10.1 parts by weight. Sodium nitrite and 21.8 parts by weight. Zinc dust is produced as in Example 2.1. processed and with 17.3 parts by weight. 4-cyanobenzaldehyde implemented. 26.2 parts by weight are obtained. l- (4-cyano) -benzalimino-2-oxo-imidazolidine, which is freed from impurities by successive washing with water, ethanol and ether. M.p. 265-2670C.

(IR (KBr): 3210, 3120, 2220, 1720, 1590 cm -1.

NMR (d6-DMSO): 7.88 (s, 4H), 7.66 (s, 1H), 7.30 (broad s, 1H), m centered at 3.7 (4Hg calc .: C61.68H 4.71 N 26.15 found 59.8 4.6 25.9 7.5 parts by weight 1- (4-cyano) -benzalimino-2-oxo-imidazolidine and 12.1 parts by weight. Triethylamine in 60 parts by volume. Section. Dioxane and 12.0 parts by weight. Trimethylchlorosilane in 25 parts by volume. Section.

Dioxane and 3.9 parts by weight. Phosgene are as in Example 2.2. implemented. The 1-chlorocarbonyl-2-oxo-3- (4-cyano) -benzalimino-imidazolidine is obtained from abs. Acetonitrile recrystallized; 4.7 parts by weight result. from m.p. 260-264 ° C.

IR (paraffin oil): 1800 cm 1.

calc .: C 52.09 H 3.28 N 20.25 C1 12.82 found: 52.0 3.3 20.3 12.5 7.9 parts by weight Ampicillin trihydrate in 80 Vol.Tln.So Vol .-% aqueous THF with 2.7 wt.Tln. 1-chlorocarbonyl-2-oxo-3- (4-cyano) -benzalimino-imidazolidine as in Example 1.3. implemented. 2.3 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {4-cyano} -benzalimino-imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicillanate from Zers.-p. 225-230 ° C with a ß-lactam content of 88.

IR (KBr): 2220, 1770, 1730, 1665, 1600 cm -1.

NMR (CD3OD): 7.95-7.20 (10H), 5.56 (s, 1H), 5.42 (q, 2H), 4.12 (s, 1H), 3.87 (broad s, 4H), 1.57 (5, 3H), 1.48 (s, 3H) S.

C28H26N7Na6S. 2.5 H2O calc .: C 51.21 H 4.76 N 14.93 found: 51.6 4.9 14.4 Example 6 This substance is used in the example 1.1. described manner - but in a 1: 1 (vol.) Water-dichloromethane mixture - from 15.8 parts by weight. Imidazolidone and 31.0 parts by weight.

4-methylsulfonylbenzaldehyde produced. The crude product is made from nitromethane recrystallized.

Yield: 9.2 parts by weight. 1- (4-methylsulfonyl) -benzalimino-2-oxo-imidazolidine, M.p. = 2640C.

NMR signals at # = 2.0 (4H), 2.2 (1H), 5.9-6.65 (4H) and 6.7 ppm (3H).

calc .: C 49.4 H 4.9 N 15.7 0 18.0 S 12.0 found: 48.6 5.0 15.7 18.3 12.1 This substance is in the example 1.2. described manner from 9.2 parts by weight. l- (4-methylsulfonyl) -benzalimino-2-oxo-imidazolidine. The crude product is recrystallized from nitromethane and acetonitrile. Yield 5.4 parts by weight. 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) -benzalimino-imidazolidine.

Mp = 208-2130C.

calc .: C 43.7 H 3.6 Cl 10.8 N 12.8 S 9.7 found: 43.8 4.9 10.2 12.5 9.5 This penicillin is used in the example 1.3. described manner from ampicillin trihydrate (2.0 parts by weight) and 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) benzalimino-imidazolidine (1.6 parts by weight). The penicillic acid precipitates out as a crystalline precipitate which is insoluble in water and ethyl acetate (1.6 parts by weight). This penicillic acid is dissolved in a little dimethylformamide, the calculated amount of sodium 2-ethylhexanoate solution (in methanol-containing ether) is added and the sodium salt of penicillin is precipitated by pouring it into a large amount of ether.

Yield: 0.85 parts by weight. D-α - {[2-oxo-3- (4-methylsulfonyl) -benzalimino-imidazolidin-1-yl; 7-carbonylaminoy benzylpenicillin sodium.

ß-lactam content: 90%.

According to the NMR spectrum, the penicillin contains about 1.5 mol of water, 0.2 mol of ethyl acetate, 0.25 mol of dimethylformamide and 0.15 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated analytical values: C 49.1 H 5.1 N 11.6 S 8.5 found: 48.5 4.8 11.8 8.4 NMR signals at 2.05 (4H ), 2.2 (1H), - 2.2-2.8 (5H), 4.3-4.65 (3H), 5.8. (1H), 5.9-6.4 (4M) , 6.85 (3H) and 8.2-8.7 ppm (6H).

This penicillin is used in the example 1.3. and 6.3.

described manner from amoxicillin (1.5 parts by weight.) and 1-chlorocarbonyl-2-oxo-3- (4-methylsulSonyl) benzaliminoimidazolidine (1.18 parts by weight), first as crystalline penicillic acid (1.8 parts by weight) and then obtained as the sodium salt. Yield: 2.0 parts by weight. D-α - {[2-oxo-3- (4-methylsulfonyl) benzalimino-imidazolidin-1-yl -carvbonylaminoi p-hydroxybenzylpenicillin sodium.

ß-lactam content: 85%.

According to the NMR spectrum, this penicillin contains about 2.0 mol of water, 0.25 mol of ethyl acetate, 0.7 mol of dimethylformamide and 0.08 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis data.

Calcd .: C 47.4 H 5.1 N 11.7 S 8.0 found: 47.2 5.0 11.1 7.9 NMR signals at t = 2.1 (4H), 2.2 (1H), 2.5-3.3 (4H), 4.35-4.65 (3H), 5.8 (1H), 5.9-6.4 (4H), 6.85 (3H) and 8.2-8.7 ppm (6H).

This penicillin is used in the example 1.3. and 6.3.

described manner from epicillin (1.0 part by weight.) and l-chlorocarbonyl-2-oxo-3- (4-methylsulSonyl) benzaliminoimidazolidine (0.94 parts by weight), first as crystalline penicillic acid (1.8 parts by weight) and then obtained as the sodium salt. Yield: 1.6 parts by weight.

D-α - {[2-oxo-3- (4-methylsulfonyl) benzalimino-imidazolidin-1-yl] -carbonylamino} -α- (1,4-cyclohexadien-1-yl) -methylpenicillin sodium.

0-lactam content: 81%.

According to the NMR spectrum, this penicillin contains about 3.0 mol of water, 0.3 mol of ethyl acetate, 0.4 mol of dimethylformamide and 0.12 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated analytical values: calc .: C 47.3 H 5.5 N 11.3 S 8.1 found: 46.9 5.5 11.3 8.1 NMR signals at # = 2, 0 (4H), 2.15 (1H), 4.0 (1H), 4.25 (2H), 4.45 (2H), 5.0 (1H), 5.8 (1H), 5.8 -6.3 (4H), 6.8 (3H), 7.0-7.4 (4H) and t ', 2-8.7 ppm (CM).

This cephalosporin is in the example 1.3. and 6.3. described manner from cephaloglycine (1.5 parts by weight.) and 1-chlorocarbonyl-2-oxo-3- (4-methylsulfonyl) benzalimino-imidazolidine (1.0 part by weight) partly initially as a crystalline acid (in ethyl acetate and water undissolved part) (1.0 part by weight) and partly as the sodium salt (in ethyl acetate dissolved part and precipitated therefrom as the sodium salt) (0.75 parts by weight.). From the Penicillic acid is then, as in Example 6.3. described, yet another sodium salt manufactured. Total yield: 1.85 parts by weight. 7-D-α - {[2-oxo-3- (4-methylsulfonyl) -benzaliminoimidazolidin-1-yl7-carbonylamino; phenylacetamido / -3-acetoxymethyl-ceph-3-em-4-carboxylic acid sodium.

p-lactam content: 84%.

According to the NMR spectrum, this cephalosporin contains about] ,, 7 mol of water, 0.4 mol of dimethylformamide, 0.4 mol of ethyl acetate and 0.16 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated analysis figures: calc .: C 47.4 H 4.6 N 10.5 S 7.5 found: 47.3 4.2 10.8 8.1 NMR signals at # = 2.1 (4H), 2.25 (1H), 2.5-2.9 (5H), 4.3-4.6 (2H), 5.05-5.3 (3H), 6.0-6.3 (4H), 6.7 (2H), 6.9 (3H) and 8.0 ppm (3H) ,.

Example 7 7.1.

15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight. Sodium nitrite and 27.5 parts by weight Zinc dust and 18.5 parts by weight.

Thiophene-2-aldehyde are as in Example 1.1. implemented.

The resulting 1- (thiophene-2-aldimino) -2-oxo-imidazolidine is through Boiling with ethanol freed of impurities or recrystallized from dimethylformamide. 22.4 wt.

Parts of m.p. 263-2650C.

IR (KBr): 3240, 1705 (wide) cm-1.

NMR (d6-DMSO): 7.88 (s, 1H), 7.3-7.0 (heteroaromatic protons, as well as NH, 4H), m, centered at 3.6 (4H).

calc .: C 49.22 H 4.65 N 21.52 S 16.42 found: 49.4 4.6 21.4 16.1 9.8 parts by weight 1- (Thiophene-2-aldimino) -2-oxo-imidazolidine, 16.2 parts by weight. Triethylamine, 16.1 parts by weight. Trimethylchlorosilane and 5.1 parts by weight. Phosgene are as in Example 1.2. implemented. 7.7 parts by weight are obtained. l-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine from Zersp.

184-1880C.

IR (paraffin oil): 1830, 1720 cm the chlorocarbonyl compound still contains the starting material that? as it does not interfere with subsequent reactions, it was not removed.

2.6 parts by weight 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) imidazolidine and 4.1 parts by weight. Ampicillin trihydrate in 40 vol.

Tln. 80 vol .-% aqueous THF are as in Example 1.3.

implemented. 0.4 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {thiophene-2-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicillanate vom Zers.-p. 210-2200C with a ß-lactam content of 89.

IR (KBr) t 1760, 1720, 1660, 1600 cm -1.

NMR (CD3OD): 7.90 (s, 1H), 7.5-8.8 (aromatic and heteroaromatic.

Protons, 8H), 5.51 (s, with overlapping m around 5.4 from 3H together), 4.12 (s, 1H), 3.79 (ready s, 4H), 1.57 (s, 3H), 1.48 (s, 3H) #.

C25H25N6Na6O6S2. 2.5 H 2 O 0.25 ether; 656.1 calc .: C 47.60 H5.0O N 12.81 S 9.79 found: 47.6 5.5 12.4 10.0 2.6 parts by weight l-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) -imidazolidine and 2.0 parts by weight. Epicillin sodium in 40 vol.

So% by volume of aqueous THF are reacted as in Example 1.5. You get 0.8 part by weight Sodium 6- {D-α - [(2-oxo-3- {thiophene-2-aldimino} -imidazolidin-1-yl) -carbonylamino] -cyclohex-1,4-dienyl (1) -acetamidoi penicillanat vom Zersp.

205-2150C with a ß-lactam content of 89%.

IR (KBr): 1770, 1730, 1665, 1605 cm -1.

NMR (CD3OD): 8.00 (s, 1H), 7.5-7.0 (heteroaromatic protons, 3H), 5.95 (broad s, 1H), 5.70 (s, 2H), 5.50 (s, 2H), 5.00 (s, 1H), 4.20 (s, 1H), 3.86 (broad s, 4H), 2.73 (broad s, 4H), 1.64 (s, 3H), 1.57 (s, 3H) #.

C25H27NaO6S2. 2 H2O, 530.6 calc .: C 47.61 H 4, -95 N 13.32 S 10.16 found: 47.6 5.1 13.0 10.2 Q = H, Na 1.50 parts by weight. 1-chlorocarbonyl-2-oxo-3- (thiophene-2-aldimino) imidazolidine and 2.25 parts by weight. Cephaloglycine dihydrate in 40 VolqTln.8o Vol .-% THF are as in Example 1.6. converted When acidifying falls 7- {D-α - [(2-oxo-3- {thiophene-2-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -3-acetoxymethyl-ceph-3-em- 4-carboxylic acid from (0.6 parts by weight.) As in Example 1.4. with 3 vol. a 1 M sodium 2-ethyl-hexanoate solution to sodium 7- {D-α - [(2-oxo-3-Whiophen-2-aldimino} -imidazolidin-1-yl) -carbonylaminoJ-phenylacetamido} -3 -acetoxymethyl-ceph-3-em-4-carboxylate is implemented. The ß-lactam content is 75-80%.

IR (KBr): 1755, 1720, 1660, 1600 cm-1.

NMR (CD3OD): 7.95 (s, 1H), 7.5-6.8 (aromatic and heteroaromatic.

Protons, 8H), 5.75-5.00 (m, 3H), 4.8 (overlaid by the signal of the exchangeable Protons), 3.82 (broad s, 4H), 2.00 (s, 3H).

Example 8 15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight sodium nitrite and 27.5 parts by weight. Zinc dust and 15.8 parts by weight.

Furan-2-aldehyde are as in Example 1.1. implemented.

17.5 parts by weight are obtained. l- (Furan-2aldimino) 2-oxo imidazolidine from M.p. 218-2200C.

IR (KBr); 3200, 3110, 1715, 1585 cm-1.

NMR (d6-DMSO): 7.70 (m, 1H) 7.50 (s, 1H), 7.15 (broad s, 1H), 6.50-6.75 (m, 2H), m, centered at 3.55 (4H).

calc .: C 53.63 H-5.06 N 23.45 found: 53.7 5.0 23.2 11.5 parts by weight 1- (Furan-2-aldimino) -2-oxo-imidazolidine, 10.0 parts by weight. Triethylamine, 13.2 parts by weight. Trimethylchlorosilane and 6.2 parts by weight. Phosgene are as in Example 1.2. implemented. 3.8 parts by weight are obtained. l-chlorocarbonyl-2-oxo-3- (furan-2-aldimino) -imidazolidine from Zersp. 1300C.

IR (paraffin oil): 1800, 1700 cm-1.

The chlorocarbonyl compound still contains starting material which, since it does not interfere with the subsequent reactions, has not been removed.

6.1 parts by weight 1-chlorocarbonyl-2-oxo-3- (furan-2-aldimino) imidazolidine and 20.4 parts by weight. Ampicillin trihydrate in 200 parts by volume. 80% by volume of aqueous THF will be as in example 1.3. implemented. 2.3 parts by weight are obtained. Sodium 6 D-o-g 2-oxo-3- (furan-2-aldimino-imidazolidin-1-yl) carbonylamino] phenylacetamido} penicillanate from Zersp.

? 00-2070C with a P-lactam content of 81%.

IR (KBr): 1760, 1715, 1660, 1600 cm -1.

NMR (CD3OD): 7.60 (s, 1H), 7.50-6.35 (aromatic and heteroaromatic.

Protons, 8H), 5.55 (s, 1H), 5.40 (q, 2H), 4.12 (s, 2H), m, center at 3.75 (4H), 1.55 (s, 3H), 1.48 (s, 3H).

C24H25N6NaO7S. 1.5 H2O. 0.25 ether calc .: C 49.22 H 5.04 N 13.76 S 5.2O found: 49.5 4.8 13.5 5.2.

Example 9 18.9 parts by weight 2-oxo-imidazolidine, 15.2 parts by weight sodium nitrite and 33.2 parts by weight. Zinc dust is produced as in Example 2.1. processed and with 29.1 parts by weight. 2-chlorothiophene-5-aldehyde implemented. 36.0 parts by weight are obtained. 1- (2-chlorothiophene-5-aldimino) -2-oxo-imidazolidine, which was purified by successive washing with water, ethanol and ether. M.p. 194-1970C.

IR (KBr): 3260, 1700 (broad), 1580, cm -1, NMR (d6-DMSO): 7.92 and 7.78 (s, together lH, syn and anti form), 7.16 and 7.10 (AB with superimposed NH, 3H), m, centered at 3.6 (4H) #.

calc .: C 41.84 H 3.51 N 18.28 S 13.96 found: 41.9 3.8 18.0 14.3.

8.6 parts by weight of 1- (2-chlorothiophene-5-aldimino) -2-oxo-imidazolidine and 12.1 parts by weight Triethylamine in 60 parts by volume. abs. dioxane and 12, o parts by weight. Trimethylchlorosilane in 25 vol. parts abs.

Dioxane and 3.9 G, ew.Tle. Phosgene is produced as in Example 2.2.

implemented. The precipitated after driving off the excess phosgene Precipitate is filtered off with suction and dried. 5.1 parts by weight are obtained. 1-chlorocarbonyl-2-oxo-3- (2-chloro-thiophene-2-aldimino) imidazolidine vom Zers.p.

215-220 ° C.

IR (paraffin oil): 1800 cm-1.

13.9 parts by weight Ampicillin trihydrate in 140 parts by volume, 80% by volume aqueous THF with 5.0 parts by weight. 1-chlorocarbonyl-2-oxo-3 (2-chlorothiophene-2-aldimino) imidazolidine as in example 1.3. implemented. 7.5 parts by weight are obtained.

Sodium 6- {D-α - [(2-Oxo-3- {2-chlorothiophene-2-aldimino} -imidazolidin-1-yl) -carbonylamino / -phenylacetamido? -Penicillanate vom Zers.-p. 215-225 ° C with a p-lactam content of 90%.

IR (KBr): 1765, 1730, 1670, 1605 cm -1.

NMR (CD30D): 7.77 (s, 1H), m, centered at 7.32 (5H), 7.06 and 6.83 (AB, 2H), 5.55 (s, 1H), 5.42 (q, 2H), 4.13 (s, 1H), 3.77 (broad s, 4H), 1.56 (s, 3H ), - 1.48 (s, 3H).

C25H24ClN6NaO6S2. 1 H2O. 1/4 ether calc .: C 47.10 H 4.33 N 12.68 S 9.68 C1 5.35 found: 47.0 4.2 12.5 9.5 4.9.

Example lo 15.8 parts by weight 2-oxo-imidazolidine, 12.6 parts by weight sodium nitrite and 27.5 parts by weight. Zinc dust is produced as in Example 2.1. processed and with 31.5 parts by weight. 3-bromothiophene-5-aldehyde implemented. 41.2 parts by weight are obtained.

1- (3-bromothiophene-5-aldimino) -2-oxo-imidazolidine, which is obtained by successive Washing with water, ethanol and ether is purified and recrystallized from DMF.

Mp 253-255 ° C.

IR (KBr): 3230, 1710 cm -1.

NMR (d6-DMSO): 7.77 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), m, centered at 3.6 (4H).

calc .: C 35.04 H 2.93 N 15.33 S 11.70 Br 29.15 found: 34.7 2.9 15.5 11.8 29.1.

12.2 parts by weight of 1- (3-bromothiophene-5-aldimino) -2-oxoimidazolidine and 14.1 parts by weight Triethylamine in 120 parts by volume. Section. Dioxane and 14.0 parts by weight. Trimethylchlorosilane in 50 parts by volume Section. Dioxane and 4.6 parts by weight.

Phosgene are as in Example 2.2. implemented. The one after the expulsion the excess phosgene precipitated is filtered off with suction and the filtrate concentrated, the residue with abs. Aether rubbed and sucked off. 7.5 is obtained Parts by weight 1-chlorocarbonyl-2-oxo-3- (3-bromothiophene-5-aldimino) -imidazolidine of m.p. 165-170, which still contains part of the starting material.

IR (paraffinol): 178c, 169o cm 1, 6.5 parts by weight Ampicillin trihydrate in 70 parts by volume. 80% by volume of aqueous THF and 2.7 parts by weight. 1-Chlorocarbonyl-2-oxo-3- (3-bromothiophene-5-aldimino) -imidazolidine are as in Example 1.3. implemented. 2.2 parts by weight are obtained. Sodium 6- {D-α - [(2-oxo-3- {3-bromothiophene-5-aldimino} -imidazolidin-1-yl) -carbonylamino] -phenylacetamido} -penicillanate from decomp. 210-220 ° C with a ß-lactam content of 85%.

IR (KBr): 1765, 1730, 1675, 1610 cm 1 NMR (CD5OD): 7.83-7.20 (8H), 5.53 (s, 1H), 5.42 (q, 2H), 4.12 (s, 1H), 3.78 (broad s, 4H), 1.55 (s, 3H), 1.48 (s, 3H ) #.

Claims (30)

Claims 1. β-lactam antibiotics of the formula I. in which R represents hydrogen or methoxy; Z for the groups where R1 and R2 are identical or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl or optionally substituted heterocyclyl and R1 and R2 together with the carbon atom to which they are bonded, can form a 3 to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring which can be substituted; A for -CH2-CH2-, -CH2-CH2-CH2- or stands; B represents optionally substituted phenyl, cyclohexenyl or cyclohexadienyl; and Y for the groups in which the carbon atom which carries the carboxyl group is bonded to the nitrogen atom of the ß-lactam ring and T is hydrogen, alkyl-CO-O-, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, the group -S-phenyl, which may be substituted, or denotes the group -S-Het, in which Het denotes an optionally substituted heterocyclic 5- or 6-membered ring; where these compounds of the formula I, with respect to the chiral center C, can exist in the two possible R and S configurations and as mixtures of the diastereomers resulting therefrom, and where the compounds of the formula I, if Z for the group and R1 and R2 are different, with respect to the imino group can be both in the syn formais and in the anti form, and these compounds of the formula I can also be in the various mydrate formins, and the non-toxic, pharmaceutically acceptable salts of these compounds of Formula I. 2. Compounds according to claim 1, in which R represents hydrogen; Z for the groups where R1 is hydrogen and R2 is phenyl which is optionally substituted by halogen, alkoxy having 1 to 4 carbon atoms, nitro, cyano or alkylsulfonyl having 1 to 4 carbon atoms or is optionally furyl or thienyl which is substituted by halogen; and A is -CM2-CH2-; and B is thienyl, hydroxyphenyl or cyclohexadienyl; and Y for the groups CM, CH3 H2 g C \ and C "C-CH2-T -cfK CM C ' 3 COOH COOH where T is -C-CO-CH3; and C is in the D = R configuration. 3. Compound of formula 4th Compound of formula 5. Compound of formula 6th Compound of formula 7th Compound of formula 8th. Compound of formula 9. Compound of formula 7o. Compound of formula 11. Compound of Formula 12. Compound of formula 13, compound of formula 14. Compound of Formula 15. Compound of formula 16. Compound of Formula 17. Compound of formula 18. Compound of Formula 19. Compound of Formula 20. Compound of Formula 21. Compound of Formula 22, compound of formula 23. Compound of Formula 24. The non-toxic pharmaceutically acceptable salts of Compounds of claims 2 to 23. 25. The sodium salts of the compounds of claims 2 to 23. 26. Process for the preparation of β-lactam antibiotics of the formula I. in which R represents hydrogen or methoxy; Z for the groups where R1 and R2 are identical or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl or optionally substituted heterocyclyl and R1 and R2 together with the carbon atom to which they are bonded, can form a 3 to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring which can be substituted; A for -CH2-CH2-, -CH2-CH2-CH2- or stands; B represents optionally substituted phenyl, cyclohexenyl or cyclohexadienyl; and Y for the groups stands in which the carbon atom, which carries the carboxyl group, is bound to the nitrogen atom of the ß-lactam ring and T is hydrogen, alkyl-CO-O-, pyridinium, aminon pyridinium, carbamoyloxy, azido, cyano, the group -S-phenyl, which may be substituted or denotes the group -S-Het, in which Het denotes an optionally substituted heterocyclic 5- or 6-membered ring; where these compounds of the formula I can exist in the two possible R and S configurations with respect to the * chiral center C and as mixtures of the diastereomers resulting therefrom, and where the compounds of the formula I, if Z is for the group and R1 and R2 are different, with respect to the imino group, can be both in the syn form and in the anti form, and these compounds of the formula I can also be in the various hydrate forms, and the non-toxic, pharmaceutically acceptable salts of these compounds , characterized in that compounds of the formula II in which * R, B, C and Y have the meaning given above or their salts, with compounds of the formula III in which Z and A have the meaning given above and W stands for halogen, azide or another nucleated leaving group, in the presence of a solvent and optionally an acid binder at temperatures of about -20 ° C to about + 50 ° C and the resulting If necessary, ß-lactam antibiotics are converted into their non-toxic, pharmaceutically acceptable salts or the free acids are produced from the salts obtained. 27. Medicines, characterized by a content of at least a ß-lactam antibiotic according to claims 1 to 25. 28. Process for the production of pharmaceuticals, characterized in that that ß-lactam antibiotics according to claims 1 to 25 with inert, non-toxic, pharmaceutically suitable carriers mixed. 29. Use of the compounds according to claims 1 to 25 for Accelerating growth and promoting feed utilization in animals. 30. Animal feed and premix containing at least one compound according to claims 1 to 25.