NO750351L - - Google Patents

Abstract

Cephalosporins, the process for their preparation and their use as a drug.

Description

The invention relates to new cephalosporins, a process for their production and their use as medicine, especially as antimicrobial agents and agents for promoting growth and utilization in animals.

It is already known that certain acetamidocephalosporanic acids, such as cephaloglyein, which in the a-position of the acetamido group have an aryl residue and an amino group, are synthetically available and can be used as antibacterial agents (compare e.g. DOS 1,670,625, 1,795. 188 and I,795,292, US Patent Nos. 3,3,03,193, 3-352,858, 3-485.8l9 and 3-63^.^16, Japanese Patent Application No. 16,871/66 and British Patent No. 1,073-530) . However, they do not manage to fight infections, such as e.g. is caused by bacteria from the Pseudomonas group.

It was found that the new cephalosporins with the general

• formula I

in

in which

A means hydrogen, optionally substituted alkyl, aryl or the R-^-X group, in which X means the -CO group or the -SO2 group and R^ means hydrogen, optionally substituted alkyl, aryl, thienyl, furyl, amino, monoalkylamino, dialkylamino, pyrrolidyl or piperidyl and where R-^ can further be alkoxy, if X means the -CO group, B means phenyl, methylphenyl, chlorophenyl, hydroxyphenyl or the rest

E means hydrogen, hydroxy or acetoxy,

and those with regard to the chirality center C<*>can exist in the two possible R and S configurations and as mixtures of the resulting

terating diastereomers and their non-toxic, pharmaceutically acceptable salts have strong antimicrobial, especially antibacterial, properties.

Furthermore, it was found that for the cephalosporinia of the general formula I, when compounds of the general formula II

in which

*

B, E and C have the above meaning,

is reacted in the presence of a base with compounds of the general formula III

in which

A has the above meaning and

•W means halogen, azide, phenoxy, nitrophenoxy, dinitrophenoxy, mono- to pentahalophenoxy or benzylthio,

and the 8-lactam antibiotics formed are optionally transferred in the free acid or non-toxic, pharmaceutically acceptable salts.

■ Surprisingly, the compounds according to the invention show a considerably higher antibacterial effect; especially against bacteria from the families of Enterobacteriaceae and Pseudomonadaceae, such as e.g. the cephalosporins known from the prior art, cefaloglyein. and cephalothin. The substances according to the invention are thus an enrichment of the pharmacy.

If cephaloglycine and 1-chloro-carbonyl-2-oxo-imidazolidine are used as starting substances, the course of the reaction can be reproduced by the following formula:

in

In the general formulae, optionally substituted A and R-j- means straight or branched alkyl with preferably 1 to 4, especially 1 or 2 carbon atoms.

For example, optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl should be mentioned.

The alkyl radicals A and R- can preferably have one or more

1 to 5', especially 1 to 3 identical or different substituents.

As substituents, the following must be stated, for example: Halogen, preferably fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine, cyano and nitro. As substituted alkyl residues A and R-^ the following should be mentioned, for example: chloromethyl, fluoromethyl, trifluoromethyl, chlorodifluoromethyl, 8,8,8-trifluoroethyl, pentafluoroethyl, cyanomethyl, 8-cyanoethyl, y-cyanopropyl, nitromethyl, 8-nitroethyl, ynitropropyl The alkyl radical R-^ can further have an R2-SO group, R2 meaning straight or branched alkyl with 1 to 4, especially 1 or 2 carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl. Substituted alkyl A preferably means methyl, ethyl, cyanomethyl and 8-cyanoethyl and optionally substituted alkyl R means methyl, ethyl, cyanomethyl, cyanoethyl, trifluoromethyl, pentafluoroethyl and methylsulfonylmethyl.

The aryl radicals A and R-^ mean phenyl or naphthyl, preferably phenyl.

Monoalkyl and dialkylamino residues R-^ preferably contain 1 to 4, especially 1 or 2 carbon atoms per alkyl group. Examples should be mentioned: Methylamino, diethylamino, dimethylamino and methylethylamino. Methylamino, ethylamino and dimethylamino are preferred.

Pyrrolidyl and piperidyl R-^ are preferably bonded above

the nitrogen atom of X.

If X means the CO group can also mean alkoxy.

Alkoxy R-^ means straight or branched alkoxy with preferably 1 to 4, especially 1 or 2 carbon atoms. For example, it should

mention is made of methoxy, etboxy, n- and i-propoxy and n-, i- and t-butoxy.

Methoxy is preferred.

Thienyl and furyl. R-^ is preferably bonded in the 2-position.

In methylphenyl, chlorophenyl and hydroxyphenyl B, methyl, chlorine and hydroxy can be in the ortho, para or meta position to bond the phenyl ring. The para position is preferred. j

E means especially hydrogen.elier acetoxy, especially

acetoxy.

Halogen W is preferably fluorine, chlorine, bromine and

iodine,' especially chlorine and bromine, especially preferably chlorine.

In nitrophenoxy and dinitrophenoxy W, the nitro groups can be found in the ortho-, meta- and/or para-position to the bond

,of the phenyl ring to the oxygen atom.

'Mono- to pentahalophenoxy W contains 1 to 5, preferably 1 or 2 identical or different half-halogen atoms, the halogen atoms being preferably fluorine, chlorine and/or bromine atoms, especially chlorine and/or bromine atoms.

Particularly preferably, A means hydrogen, methyl, ethyl, methylsulfony1, 6-cyanoethylsulfony1, phenylsulfony1, 2-thienylsulfonyl, trifluoromethylsulfony 1, methylaminosylphony 1, formyl, methylcarbonyl1, trifluoromethylcarbonyl1, pentafluoroethylcarbonyl1, cyanomethylcarbonyl1, 6-cyanoethylcarbonyl, phenylcarbonyl, 2-thienylcarbonyl1, 2 -furylcarbony1 or methylsulfonylmethylsulfony1, B means phenyl, p-hydroxyphenyl1 and

especially .phenyl,„E means hydrogen or acetoxy and W means

*

chlorine and C preferably means the R configuration.

To the above non-toxic, pharmaceutically acceptable salts of the compound of formula. In belong the salts of the acidic carboxyl groups, e.g. sodium, potassium, magnesium, calcium, aluminum and ammonium salts and non-toxic substituted ammonium salts with amines, such as di- and tri-lower alkylamines (preferably C-^ to C^ per alkyl group), procaine, dibenzylamine, N,N' -dibenzylethylenediamine, N-benzy1-g-phenyl1-ethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine, dehydroabiethylamine, N,N'-bis-dehydroabiethylethylenediamine, N-lower-alkylpiperidine and others commonly used in pharmaceutical chemistry.

amines,' e.g. such as have also been used for the formation of

salts of penicillins.

i All crystal forms, salts and hydrate forms of the compound with the general formula I are similarly suitable as antibacterial agents within the scope of the invention. Thus is

for example the free acids and e.g. the sodium salts both in amorphous and crystalline form and both anhydrous and in various hydrate forms, for example as monohydrate, are similarly suitable as antibacterial agents within the scope of the invention.

The compounds with the general formula II can be used as starting materials for the present invention in the form of all crystal forms, hydrate forms, salts of the N-sily1 compounds and of easily cleavable derivatives of the acidic carboxyl groups, such as e.g.

the easily cleavable esters, amides or hydrazides.

The starting substances of the general formula II are already known. They are e.g. disclosed in DOS 1,670,625, 1,795-188 and 1,795-292, US Patent Nos. 3-303,193, 3-352,858; 3,485,819 and 3-634,416, Japanese Application No. 16,871/66 and British Patent No. 1,073,530. Examples include: 7-(a-amino-phenylacetamido)-3-methyl-cef-3-em-4-carboxylic acid, 7-(a-amino-phenylacetamido)-3-hydroxymethyl-cef-3-em-4 -carboxylic acid, 7-(α-amino-phenylacetamido)-3-acetoxymethyl-cef-3-em-yl carboxylic acid , 7-(α-amino-4-methylphenylacetamido)-3-acetoxymethyl-cef^3-em-4 -carboxylic acid, 7-(α-amino-4-methylphenyl lacetamido)-3-methyl-ceT-3-em-4-carboxylic acid , 7-(α-amino-4-methylphenyl lacetamido)-3-hydroxymethyl-cef -3-em-4-carboxylic acid, 7-(a-amino-4-chlorophenylacetamido)-3-methyl-cef-3-em-4-carboxylic acid, 7-(a-amino-4-chlorophenylacetamido)-3-hydroxymethyl -cef-3-em-4-carboxylic acid, 7-(α-amino-4-chlorophenylacetamido)-3-acetoxymethyl-cef-3-em-4-carboxylic acid, 7-(α-amino-4-hydroxyphenylacetamido) )-3-acetoxymethyl-cef-3-em-4-carboxylic acid, .7-(α-amino- 4-hydroxyphenylacetamido)-3-niethyl-cef-3-em-4-carboxylic acid , 7 -(α-amino-4-hydroxyphenylacetamido)-3-hydroxynrethyl-cef-3_em-4-carboxylic acid, 7-(α-amino-cyclohexa-1,4-dienyl(l)acetamido)-3-acetoxymethyl-cef-3-em -4-carb book syllic acid, 7-(α-amino-cyclohexa-1,4-dieny 1(1)acetamido)-3-methyl-cef-3-em-4-carboxylic acid, 7-(α-amino-cyclohexa-1,4- dieny1(1)acetamido)-3-hydroxymethyl-cef-3-em-4-carboxylic acid. The compounds used as starting materials and with the general formula III are known or are prepared by generally common methods from the known or by common methods readily available compounds with the general formula IV

in which

A has the above meaning,

and e.g. phosgene. The compounds of the general formula III in which W is azide are obtained from the corresponding compounds of the general formula III in which W is halogen, e.g. chlorine, by reaction, for example with alkali azides. The compounds of the general formula III, in which W is an unsubstituted or substituted phenyl radical or benzylthio radical, are prepared from the compounds of the general formula III, in which W is halogen and the corresponding phenols' or benzyl mercaptan or by reacting compounds of the general formula IV with the corresponding chlorocarboxylic acids or chlorothiocarboxylic acid esters.

As examples of compounds with formula III which can be used according to the invention, the following should be mentioned: 1-chlorocarbonyl-2-oxo-imidazolidine, 1-azidocarbonyl1-2-oxo-imidazolidine, 1-phenoxycarbonyl1-2-oxo-imidazolidine, 1-p-nitrophenoxycarbonyl1-2-oxo-imidazolidine, 1-o-chlorophenoxycarbonyl1-2-oxo-imidazolidine, 1-chlorophenoxycarbonyl1-2-oxo-imidazolidine oxo-3-methyl-imidazolidine, 1-azidocarbonyl-2-oxo-3-methyl-imidazolidine, 1-chlorocarbonyl-2-oxo-3-ethyl-imidazolidine,

1-azidocarbonyl-2-oxo-3-ethyl-imidazolidine,

1-Chlorocarbonyl-2-oxo-3-phenyl-1-imidazolidine,

1-azidocarbonyl-2-oxo-3-phenyl-imidazolidine,

1-chlorocarbony1-2-oxo-3-methylsulfony1-imidazolidine, 1-chlorocarbonyl1-2-oxo-3"cyanomethylsulfony1-imidazolidine, 1-chlorocarbony1-2-ox0-3-8-cyanoethylsulfony1-imidazolidine j 1-chlorocarbonyl1-2- oxo-3-trifluoromethylsulfony1-imidazolidine, 1-chlorocarbonyl1-2-ox0-3-methylaminosulfony1-imidazolidine, 1-chlorocarbonyl1-2-ox0-3-phenylsulfony1-imidazolidine, 1-chlorocarbonyl1-2-oxo-3-thienyl(2) sulfony1-imidazolidine,

1-chlorocarbonyl1-2-oxo-3-furyl(2)sulfony1-imidazolidine, 1-chlorocarbonyl1-2-oxo-3-formyl1-imidazolidine,

1-Chlorocarbonyl-2-oxo-3-methylcarbonyl-imidazolidine,

1-chlorocarbonyl-2-oxo-3-ethylcarbonyl-imidazolidine,

1-chlorocarbonyl1-2-oxo-3-trifluoromethylcarbonyl1-imidazolidine, 1-chlorocarbonyl1-2-ox0-3-pentafluoroethylcarbonyl1-imidazolidine, 1-chlorocarbonyl1-2-ox0-3-phenylcarbonyl1-imidazolidine,

1-Chlorocarbonyl-2-oxo-3-thienylcarbonyl-imidazolidine,

1-chlorocarbonyl-2-oxo-3-furylcarbonyl-imidazolidine, 1-chlorocarbonyl1-2-oxo-3-cyanomethylcarbonyl1-imidazolidinej1-chlorocarbonyl1-2-ox0-3-6-cyanoethylcarbonyl1-imidazolidine, .1-chlorocarbonyl1-2-ox0-3-methylsulfonyl1-methylsulfonyl1-imidazolidine.

Mixtures of water with such organic solvents as are miscible with water such as ketones, e.g. acetone and methyl ethyl ketone, ether, e.g. e.g. tetrahydrofuran and dioxane, lower alkylnitriles, e.g. acetonitrile, dimethylformamide, alkyl alcohols, e.g. isopropanol and/or dimethylsulfoxide, as well as these organic solvents (individually or as a mixture) without the addition of water. If, due to the presence of water, a pH measurement is possible during the reaction - according to the invention, the pH value of the reaction mixture is kept by adding bases or by using buffer mixtures, preferably between 6.5 and 7.5. However, the reaction according to the invention can also be carried out in other pH ranges, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. Furthermore, it is possible to carry out the reaction in water-immiscible solvents, such as halogenated hydrocarbons, e.g. chloroform or methylene chloride with the addition of organic amines, preferably triethylamine, diethylamine or N-ethylpiperidine. Furthermore, the reaction can be carried out in a mixture of water and a water-immiscible organic solvent, such as e.g. ether (diethyl ether), halogenated hydrocarbons, e.g. chloroform, further methylene chloride, carbon disulphur, ketones immiscible with water, e.g. isobutyl methyl ketone, esters, e.g. ethyl acetate, hydrocarbons, e.g. benzene, as it is appropriate to stir vigorously and to keep the pH value when adding base or using buffer solutions between approx. 4.5 and 9.0 or e.g. 2.0 and 3.0. However, the reaction can also be carried out in water alone - i.e. in the absence of organics

solvents, in the presence of an organic or inorganic base or with the addition of buffers.

As organic bases which are added in the reaction according to the invention, tertiary, aliphatic or aromatic amines are suitably used, e.g. pyridine or lower trialkylamines, e.g. triethylamine, or secondary, aliphatic or aromatic amines that are difficult to acylate due to steric hindrance, e.g. dicyclohexylamine. The number of usable bases is therefore hardly limited.

Inorganic bases include, above all, alkali and alkaline earth hydroxides, e.g. sodium hydroxide, potassium hydroxide and calcium hydroxide.

The amount of base used is e.g. determined by

the desired adherence to a specific pH (compare to what is stated above). Where there is no pH measurement or setting or it is not possible or not appropriate due to a lack of sufficient amounts of water in diluents, preferably approx. 1 to 5, especially approx. 2 molar equivalent base.

For example, phosphate buffers (sodium phosphate/phosphoric acid), acetate buffers (sodium acetate/acetic acid) and citrate buffers (sodium citrate/citric acid) can be used as buffer mixtures, as the quantity ratio for compliance with the desired pH value can be easily determined.

The reaction temperatures can be varied within a large area. Usually you work between approx. -20 and approx. +50°C, preferably between 0 and +20°C. As with most chemical reactions, higher or lower temperatures than indicated in the examples can be used. , .

The turnover can be carried out at normal pressure, but also at

reduced or increased pressure. Usually you work at normal pressure.

When carrying out the method according to the invention • the reaction participants can e.g. are reacted with each other in equimolar amounts. However, it may be appropriate to use one of the two reaction participants in excess, in order to facilitate the purification or purification of the desired cephalosporin and to increase the yield. The amount of reaction participants with formulas II and III can be varied to a large extent without adverse consequences. For example, one can use reaction participants with the general formula II with an excess of 0.1 to 0.3 mol equivalents and thereby achieve a smaller cleavage

of the reactant of the general formula III in an aqueous solvent mixture. The surplus of reaction participants with it

general formula II can be easily removed due to the good solubility in aqueous miriale acids when working up the reaction mixture. On the other hand, however, one can also advantageously use the reaction participant of the general formula III with an excess of, for example, 0.1 to 1.0 mol equivalents. Thereby, the reaction participant with the general formula 11' is used better and the subsequent cleavage of the reaction participant with the general formula III as a side reaction in aqueous solvents is compensated.

•When they added compounds with the general formula III in excess

in water quickly transforms into neutral nitrogen-containing heterocycles which can be easily removed; the purity of the penicillins is hardly affected by this.

The preparation of the reaction mixture for the preparation

of the cephalosporins according to the invention and their salts as well as the purification of the new compounds takes place throughout in the manner generally known from cephalosporin chemistry. The preparation of the free acids of formula I can e.g. take place by acidifying a-v a solution of the salts, e.g. the sodium salt of an inorganic or organic acid, e.g. with dilute hydrochloric or acetic acid. The free acids of the general formula I can be transferred in the usual way in the salts with non-toxic bases, e.g. by adding the relevant base to an ethereal solution of the acids with formula I.

As new active substances, for example, the following must be mentioned in detail:<1>

7- {D-α-/~ (2^oxb-imidazolidin-1-y 1 )-carbonyl lar.iino7-phenyl lacetamido } - 3-acetoxymethyl-cef-3-em-carboxylic acid

7-{D-a-/ (2-oxo-imidazolidin-1-y1)-carbon<y>1amino7<->phen<y>lacetamido}-3-methyl-cef-3-em-^-carboxylic acid t ■ j 7 - {D-a-/ (2-oxo,-3-methyl 1-imidazolidin-1-y 1)-carbonylamino7-phenyl-acetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a- / (2-ox0-3-ethyl-imidazolidin-1-yl)-carbonylamino7-phenylacet-amido }~3-aethoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a-/ (2-ox0-3- mesy 1-imidazolidin-1-y1)-carbonylamino7-phenyl-acetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a-/ (2-oxo-3-methyl amino sulf ony 1-imidazolidin-1-y 1)-carb ony 1--amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a-/ (2-oxo-3-phenylsulfony1- imidazolidin-1-y1)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7~{D-a-7 (2-oxo-3-phen<y>lsulfon<y>1-imidazolidin- 1-<y>1)-carbonyl-amino7--enylacetamido}'-3-methyl 1-ce f-3-em- 4-carb ok sy Isic acid 7-{D-a-_/ (2-oxo-3 -thienyl-(2)-sulfony 1-imidazolidin-1-y1)-carbony 1-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4 -carboxylic acid 7- { D- a -/_ (2-oxo-3-formy 1-imidazolidin- 1-y 1)-carbonylamino/- pheny 1-acetamido}-3-acetoxymethyl-cef-3- em-4-carboxylic acid 7- {D-α-_/ (2-oxo-3-acety 1-imidazolidin-1-y 1)-carbonylamino7-phenyl 1-acetamido}-3-acetoxymethyl-cef-3-em -4-carboxylic acid 7 -{D-α-/_ (2-oxo-3-benzoyl 1-imidazolidin-1-yl)-carbonylamino7-phenyl 1-acetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-α-/_ (2-oxo-3-furoyl(2)-imidazolidin-1-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-α-/ (2-oxo~3-thienyl (2 )-carbonyl 1-imidazolidin-1-y 1)-carbonyl 1-amino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a-/ (2-oxo-3-(mesy 1)-mesy 1-imidazolidin-1-y 1)-carbonyl 1-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a- /(2-oxo-3_cyanoacety1-imidazolidin-1-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid 7-{ D- a-/_ (2-oxo-3-B -cyanopropiony 1-imidazolidin-1-y 1)-carbonylamino7-phenylacetamido}-3 -acetoxymethyl-cef-3-em-4-carboxylic acid 7-{D-a-/_ (2-ox 0-3- cyanomethylsulfony 1-imidazolidin-1-y 1)-carbony 1-amino/-phenylacetamido} -3-acetoxymethyl-cef-3-em-4-carboxylic acid 7- {D-α/_ ( 2-oxo-3-trifluoroacety 1-imidazolidin-1-y 1)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef- 3-em-4-carboxylic acid 7~{D-α-/_ (2-oxo-3-pentafluoropropionyl-imidazolidin-1-yl)-carbonyl-amino/-phenyl lacetamido }-3-acetoxymethyl 1-ce f-3-em-4-carboxy I acid I and 7-{D-a-7 (2-oxo-3"trifluoromethylsulfonyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-eø -4-carboxylic acid

The active substances according to the invention have a strong antimicrobial effect with low toxicity and good tolerability. These

properties enable their use as active substances in medicine, as well as substances for the preservation of inorganic or organic materials, especially of organic materials of any type, e.g. polymers, lubricants, paints, fibres, leather, paper and wood, from foodstuffs and from water.

The active substances according to the invention are effective against a very broad spectrum of microorganisms. With their help, e.g. gram-negative and gram-positive bacteria and bacteria-like microorganisms are combated as well as those due to these agents. produced diseases are prevented, improved and/or cured.

The active substances according to the invention are particularly effective against bacteria and bacteria-like microorganisms.

They are therefore particularly well suited for prophylaxis and chemotherapy of

local and systemic infections in human and animal medicine, which are produced by these producers.

For example, local and/or systemic diseases can be treated and/or prevented, which are caused by the following agents. or by mixtures of the following organisms: Micrococcaceae, such as Staphylococcus, e.g. Staphylococcus aureus, Staph.epidermidis, Staph.aerogenes and Gaffkya tetra- gena (Sbaph. = Staphylococcus).

Lactobacteriaceae, such as Streptococcus, e.g. Streptococcus pyogenes, a- or g-haemolytic Streptococcus, not (y-)-haemolytic Streptococci, Str.viridans, Str. faecalis (Enterococcus), Str.agalactiae, Str. lactis, Str. equi, Str.anaero-

bis and Diplo.coccus pneumoniae (Pneumococcus) (Str. = Streptococcus) .

Neisseriaceae, such as Neisserien, e.g. Neisseria gonorrhoeae (Gonococcus), N.meningitidis (Meningococcus), 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.renal,• C.ovis, C.murisepticum, Listeria bacteria, e.g. Listeria monocytogenes, Erysipelothrix bacteria, e.g. Erysipelo-thrix insidiosa, Kurthia bacteria, e.g. Kurthia zopfii (C. = Coryhebacterium).

Mycobacteriaceae, which produce Mycobacteriosis, e.g. Mycobacterium tuberculosis, M.bovis, M.avium, so-called atypical mycobacteria of the Runyon group 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. ozaenae, Erwiniae, e.g. Érwinia spee, 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., Salmonellae, 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, as Vibrio bacteria, eg". Vibrio chole-rae, V.proteus, V.fetus (V. = Vibrio), Spirillum bacteria, eg 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, Br.melitensis, Br. suis (Br. = Brucella), Haemophilus bacteria, e.g. Haemophilus influenzae, H.ducreyi, H.suis, H.canis, Haegypitcus (H. = Haemophilus), Bordetella bacteria, e.g. Bordetella pertussis, B. bronchiseptica (B. = Bordetella), Moraxella bacteria, eg..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).

Achromobacteriaceae, such as Flavobacterium Alcaligensis■

faecalis, Achromobacter, e.g. Achromobacter anitratus.

Bacillaceae, as Aerobic Spore formers, e.g. Bacillus anthracis, B.subtilis, B.cereus (B. = Bacillus), Anaerobic Spore forming-Chlos tridien, e.g. Clostridium perfringens, Cl. specicium,

Cl. oedematiens, Cl. histolyticum, Cl. tetani, Cl. botulinum (Cl. = 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. = Leptospira).

The above-mentioned enumeration of the originator is only to enumerate

include, for example and in no way limiting.

As diseases, which are prevented, improved and/or can be cured by the active substances according to the invention, the following should be mentioned, for example:

Diseases of the respiratory tract and larynx.

Otitis, Pharyngitis, Pneumonia, Peritonitis, Pyelo-phritis, Cystitis, Endocarditis, systemic infections, Bronchitis, ' Arthritis.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more active substances according to the invention or which consist of one or more active substances according to the invention as well as methods for producing these preparations.

The present invention also includes pharmaceutical preparations in dosage units. These mean that the preparations are in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, whose active substance content corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. contain 1, 2, 3 or 4 single doses or 1/3, 1/3 or 1/4 of a single dose. A single dose contains

preferably the amount of active substance which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

With non-toxic, inert pharmaceutically suitable carriers

■is to understand solid, semi-solid or liquid diluents, fillers and other formulation aids of any type.

Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granulators, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragees, capsules, pills and granules can

contain the active substance(s) in addition to the usual carrier substances such as (a) fillers and thickeners, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) moisture retention agents, e.g. glycerol, (d) explosives, e.g. Agar-Agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. c. ethyl 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 points (a) to (i).

The tablets, dragees, capsules, pills and granules

can be equipped with the usual ones possibly containing opacifiers

r covers and sleeves and also be composed so that they release the active substance or substances only or preferably in a specific part of the digestive tract, possibly delayed, as the embedding mass e.g. polymer substances and wax can be used.

The active substance(s) may possibly be present

with one or more of the above-mentioned carriers also in micro-encapsulated form.

Suppositories can contain the usual water-soluble or water-insoluble substances in addition to the active substance(s).

carriers, e.g. polyethylene glycols, fats, e.g. cocoa butter and higher esters (e.g. C-^-alcohol with C-^g-f acetic acid) or mixtures of these substances. - Ointments, pastes, creams and gels can contain the usual carrier substances, e.g. animal or vegetable fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can contain the usual carrier substances in addition to the active substance(s), e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder.

or mixtures of these substances. Sprays can also contain the usual propellants, e.g. chlorine, fluorine, hydrocarbons.

Solutions and emulsions can next to it or those

active substances contain the usual 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, oil, especially cottonseed oil, peanut oil, corn germ oil, olive

oil, castor oil and sesame oil, glycerol, glycerblformal, tetrahydro-furfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral application, the solutions and emulsions can also be available in sterile and blood isotonic form.

In addition to the active substance(s), the suspensions may 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 of these substances.

t The aforementioned formulation forms can also contain coloring agents, preservatives such as odor and taste improving additives, e.g. peppermint oil and eucalyptus oil and sweetener, e.g. saccharin.

The therapeutically active compounds must be present

in the pharmaceutical preparations listed above, preferably in a concentration from approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the overall mixture.

In addition to the active substances according to the invention, the above-mentioned pharmaceutical preparations may also contain further pharmaceutical active substances.

The production of the above-mentioned pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance or substances with the carrier substance or

- the substances.

The present invention also includes the use of

the active substances according to the invention as well as pharmaceutical preparations, which contain one or more active substances according to the invention in human and veterinary medicine to prevent, improve and/or cure the above-mentioned diseases.

The active substances or the pharmaceutical preparations can be applied locally, orally, parenterally, intraperitoneally and/or rectally, preferably parenterally, especially intravenously and intramuscularly.

Generally, in both human and veterinary medicine, it has been shown to be advantageous to administer the active substance(s) according to the invention in total amounts from approx. 6 to approx. 800j preferably 10 to 300 mg/kg body weight per 24 hours, possibly in the form of several, e.g. three individual submissions to achieve the desired results. The single doses contain the active substance(s) according to the invention, preferably in amounts from approx. 2 to approx. 300, especially 5 to 100 mg/kg body weight. However, it may be necessary to deviate from the dosages mentioned, namely 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 application of the medicine as well as the time period or interval, before delivery follows. Thus, in some cases it may be sufficient to come out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. The determination of each. optimal dosage and type of application of the active substances required can easily be carried out by any professional due to his professional knowledge.

In the case of use as a lining additive, the new compounds can be given in the usual way together with the lining or with preparations or the drinking water. Thereby, an infection due to gram-negative or gram-positive bacteria can be prevented and a better utilization of the feed is also achieved.

The new cephalosporins are distinguished by strong antibacterial effects, which were investigated in vivo and in vitro and by oral resorbability.

The cephalosporins according to the invention can be expanded

of the yirknings.spectrum or to increase effectiveness is combined with amino-glycoside antibiotics such as gentamicin, kanamicin, amikacin or tobramycin.

The effect of the cephalosporins according to the invention can be demonstrated, for example, by the following in vitro and in vivo tests:

a) In vitro experiments.

The cephalosporins of Examples 3, 6 and 7, which may be considered

as typical representatives of the compounds according to the invention were diluted with Miiller-Hinton nutrient broth while adding. of 0.1% by weight glucose to a content of 100.ug/ml. In the nutrient solution, there were each time 1 x 10 to 2 x 10 bacteria per milliliters. The small tubes were cultured with this mixture each time for 24 hours and there-

after that, the degree of ambiguity was determined. Freedom from ambiguity indicates the impact. At a dosage of 100 µg/ml, the following bacterial cultures were clear

(sp . = species) : Klebsiella pneumoniae, Enterobacter aerogenes sp., Providencia, 'Serratia marcescens, Escherichia coli BE, Salmonella sp, Shigella sp., Proteus, indole-negative and indole-positive sp., Pasteurella pseudotuberculosis, Brucella sp., Haemophilus influenzae, Bordetella

bronchiseptica, 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 experiments.

The following table 1 shows the effect of one of the cephalosporins according to the invention which can be considered a typical representative of

in the compound according to the invention, against a number of bacteria in animal experiments with white mice. The white mice of strain CF-^ were infected intraperitoneally with the type of bacteria indicated in each case.

Therapy: 1 time: 30 minutes after infection.

ED^q is the dose at which 50% of the infected animals still

survives after 24 hours.

The preparation of the compound according to the invention with

formula I shall be explained in more detail by means of examples.

Explanation of the abbreviations used:

Acetic ester-r = acetic acid ethyl ester, ether = diethyl ether,

DMSO = dimethylsulfoxide, mesyl = methylsulfony1.

All yield statements in % refer to % of the theoretical. All temperatures are given in °C.

■

The 7-(cc-amino-phenyl.lacetamido)-3-methyl-cef-3-em-4-carboxylic acid used in the following examples contained approx. 5% water, Mon ;

however, anhydrous 7-(α-amino-phenyl-acetamido)-3-methyl-cef-3-em-4-carboxylic acid may also be used.

The 7-(α-amino-phenylacetamido)-3-acetoxymethyl-cef-3-em-4-carboxylic acid used in the examples contained 8% water, however, you can also use anhydrous 7-(α-amino- phenylacetamido)-3-acetoxymethyl-cef-3-em-4-carboxylic acid.

By "Cefalesin" is meant the 7-(a-amino-phenylacet-amido)-3-methyl-cef-3-em-4-carboxylic acid and by "Cephaloglycin" the , 7-(a-amino-phenylacetamido)-3- acetoxymethyl-cef-3-em-4-carboxylic acid with D = R configuration in the side chain.

The NMR spectra of the cephalosporins were, unless otherwise stated, taken in CD-^OD solution. Thereby the designation in brackets means:.

s = singlet m = multiplet

d = doublet AB = AB system

t = triplet AX = AX system

q = quartet A2B2A2^2-System'

The IR spectrum of the cephalosporins was recorded in nujolssuspension.

in Cephalosporins. γ-lactam content was determined by the extinction of the 8-lactam carbonyl band by the IR spectrum as well as by the NMR spectrum.

The suspension of 1.3 parts by weight of cephaloglycin dihydrate i

15 parts by volume of 80% aqueous tetrahydrofuran were adjusted to pH 7.5 with triethylamine and mixed in portions during 10 minutes at temperatures between 10 and 20°C with 0.51 parts by weight of 1-chlorocarbonyl-2-oxo-imidazolidine, -idet The pH was maintained with triethylamine at 7 - 8.

Stirring was continued until the addition of triethylamine was no longer necessary to maintain pH 7 - 8. Now it was mixed with 20 parts by volume of water, tetrahydrofuran removed at room temperature on a rotary evaporator, the aqueous solution extracted once with

vinegar and filtered. Pour over, with 20 parts by volume of vinegar

in ester and acidified under ice-cooling with 2N HC1 to pH 2, the cephalosporin's free acid, which is poorly soluble in water and in vinegar, fell out as a crystalline precipitate, namely suctioned off and washed with vinegar. The product was dried briefly on a rotary evaporator and then dissolved in 5 parts by volume of dimethylacetamide and mixed with 3 parts by volume of a one molar solution of sodium 2-ethyl hexanoate in ether, which contained some methanol. The mixture was now stirred into 30 parts by volume of ether-methanol mixture (volume ratio 10:1) under ice cooling. It was allowed to settle, decanted from the solvent, slurried with ether and suctioned to dryness. They were dried in a vacuum desiccator over P20 and paraffin cut for 24 hours.

Yield of sodium 7-{D-α-(2-oxo-imidazolidin-1-yl)-carbonylamino-7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylate: 80$.

IR band at 3250, 3060, 1765, 1723, 1652, 1607, 1540, 1274, 1235.

and .1032 cm

The NMR signal at t: = 2.55 (s, 5H), 4.27 + 4.95 (AX, 1H + 1H), .

4.5 (s, 1H), 5.2 (s, 2H), 6.05-6.8 (AX, 4H),

6.5+6.8 (AB, 2H) and 7.9 ppm (s, 3H) (in b20).

Electropherogram shows only one spot with antibiotic activity, against B. subtilis, Escherichia coli and Pseudomonas aeruginosa.

'B)

To a vigorously stirred solution of 3.5 parts by weight of imidazolidinone (2) (prepared according to Fischer and Koch, Ann. 232, page 224 (1886)) in 50 parts by volume of absolute tetrahydrofuran, 4 parts by weight of phosgene in 10 parts by volume of absolute tetrahydrofuran were added dropwise during

■ of 15 minutes. It was then stirred at 10°C for 3 hours and then a stream of dry air was passed through the reaction mixture to blow out formed hydrochloric acid and residues of phosgene. It was. now evaporated on a rotary evaporator in vacuum to dryness and the solid residue dried over concentrated sulfuric acid and at approx. 12 torr.

Yield: 93% 1-chlorocarbonyl-2-oxo-imidazolidinone.

Melting point 153°C after recrystallization from acetone-pentane.

Calculated: C 32.3 H 3.4 N 18.8 Cl 23.9

Found : C 32.3 H(4.5) N 18.7 Cl 23.9 in the NMR signal at t 5.7 to 6.1 (2H) and 6.3 to 6.7

(2H), (acetone-dg as solvent) symmetric A2B2 system.

IR band at 3230 ,. 1790., 1700, 1270 and 1150 cm"<1.>

Example 2.

7-{D-a-/-(2-oxo-imidazolidin-1-y1)-carbonylamino/-phenylacetamido}-3-methyl-cef-3-em-4-carboxylic acid was on the

method prepared from 1.83 parts by weight of cephalexin monohydrate and 0.82 parts by weight of 1-chlorocarbonyl-2-oxo-imidazolidine in the form of crystalline <>>free cephalosporin acid.

Yield: 86%.

IR bands at 3335, 3270 , 3.040 , 1782, 1724, 1663, 1530,

1310 and 1240 cm<-1>.

.The NMR signal at t = 0.6 (d,lH), 0.8 (d, 1H), 2.3 (s,lH),

J 2.6 (s,5H), 4.0-4.4 (m,2H), 5.0 (q,1H), 5.9-6.9 (m,6H) and 7.9 ppm ( 3H)

(in DMS0-d6)-.''

The electropherogram shows only one spot with antibiotic action.

Example 3.

2.2 parts by weight of cephaloglycin were dissolved in 30 parts by volume of 80% aqueous tetrahydrofuran using the precisely required amount of triethylamine. At 20°C it was then introduced

0.85 parts by weight of 1-chlorocarbonyl-2-oxo-3-methyl-imidazolidine with stirring. With the corresponding addition of triethylamine, this is maintained

and then pH of 7.0. It was then stirred until no more triethylamine had to be added to maintain pH 7.0

(approx. 1 hour). It was now diluted with the same volume of water, pH adjusted to 6.5, tetrahydrofuran removed in vacuo, remaining aqueous solution screened with a mixture of ether and acetic acid ethyl ester (1:1), with stirring and slight cooling acidified to pH

2, the organic phase separated, washed with water, dried over magnesium sulfate and precipitated using an approx. 1 molar sodium 2-ethyl hexanoate solution in methanolic ether the sodium salt of cephalosporin.

The sodium salt appeared as a gel-like, but absorbable precipitate. After washing with ether, it was dried in a desiccator.

Yield: 2.1 parts by weight of sodium 7~{D-a-/_~(3-methyl-2-oxo-imidazolidin-k-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3_em-4-carboxylic acid. "

6-lactam content: approx. 75%.

IR bands in the carbonyl region 1780, 1720, 1650, 1610 and 1540 cm"<1> (in Nujol).

The NMR signal at x = 2.4-2.8 (5H), 4.15-4.35 (1H),

4.9-5.2 (4H), 6.2-6.8 (6H), 7.2 (3H) and 7.95 ppm (3H).

The 1-chlorocarbonyl-2-oxo-3-methyl-imidazolidine used as starting compound was prepared from 1-methyl-2-oxo-imidazolidine and phosgene in tetrahydrofuran. Melting point 94 - 95°C.

Example 4.

This cephalosporin sodium salt was prepared in the manner indicated in Example 3 from 2.2 parts by weight of cephaloglycin and 0.8 parts by weight of 1-chlorocarbonyl-2-oxo-3-ethyl-imidazolidine.

Yield: 1.9 parts by weight of sodium .

3-lactam content: approx. 82%.

IR bands in the carbonyl region 1780, 1720, 1675, 1610 and 1540

-1

cm.

The cephalosporin sodium salt contained approx. 2 mol of water and was contaminated with approx. 0.5 mol sodium 2-ethylhexanoate. This was taken into account in the calculated analysis values.

Calculated: C 49.0. H 5.5 N 10.2 S 4.7

Found :Ci48.7H5.5N10.4s4.9.

The 1-chlorocarbonyl-2-oxo-3-ethyl-imidazolidine used as starting material, melting point (of the not fully analyzed substance) 54°C, was formed from 1-ethyl-2-oxo-imidazolidine by reaction with phosgene in tetrahydrofuran. 1-Ethy1-2-oxo-imidazolidine was formed from 2-oxo-imidazolidine by reaction with ethyl iodide in tert-butanol/Na-tert-butanol.

It has a boiling point of 70 - -960C at 0.7-1.0 mm Hg.

Example 5-

This cephalosporin sodium salt was prepared in the manner indicated in Example 3 from 2.1 parts by weight of cephalexin and 1.0 parts by weight of 1-chlorocarbonyl-2-oxo-3-ethyl-1-imidazolidine and isolated as free acid. The cephalosporin acid was precipitated on acidification as a mucilaginous ether-acetic ester phase insoluble precipitate.

Yield: 3.1 parts by weight of 7-{D-ot-[(3-ethyl-2-oxo-imidazolidin-1-y1)-carbonylamino]-phenylacetamido}-3-methyl-1-c.ef-3- em-4-carboxylic acid.

3-lactam content: approx. 8l%.

The NMR signal at t =' 2.4-2.8 (5H9, 4.1-4.4 (2H), 4.9-5.1

(1H), 6.1-6.9 (8H), 7.8-8.0 (3H) and 8.7-9.0 ppm (3H).

IR bands in the carbonyl region: 1770, 1710, 1650 and 1530- cm"1.

Example 6.

t

Sodium 7-{D-α-(2-oxo-3-mesyl-imidazolidin-1-yl)-carbonyl-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylate was prepared on the method mentioned in example 1 of 1.3 parts by weight of cephaloglycin dihydrate and 0.77 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine in 71% yield.

IR bands at 3230, 1760, 1727, 1654, 159.8, 1518, 1250, 1230, 1157, 1120 and 973 cm"1.

The NMR signal at t = 2.3-2.7 (m,5H), 4.25+4.95 (AX, 1H+1H), 4.4 (s,1H), 5.1 (d,2H ), 6.05 (s,4H),'6.6 (m,5H) and 7.9 ppm (3H).

In the electropherogram, only one spot appeared with an antibiotic effect.

b) 1-chlorocarbonyl-3-methylsulfonyl-imidazolidinone(2):

16.4 parts by weight of 1-methylsulfony-1-imidazolidinone (2) were

boiled in dioxane for 3 days with 27 parts by weight of trimethylchlorosilane and 20

parts by weight of triethylamine. Precipitated triethylamine hydrochloride, mixed with 11 parts by weight of phosgene, was filtered off and left to stand overnight at room temperature. It was then evaporated to dryness and recrystallized from boiling acetone.

i Yield: 70%, melting point 178°C.

Calculated: C 26.5 H 3.1 Cl 15.7 N 12.4 S.l4.l

Found : C 27.2 H 3.4 Cl 15.3 N 12.0 S 14.1.

The NMR signal at t = 5.6-6.2 (4H) and 6.6 ppm (3H). IR bands at 3010, 1807, 1721, 1360,-1165, 984 and 742 cm"<1.>

■ The same product can also be prepared well from 1-methyl-sulfonylimidazolidinone (2) and excess phosgene in methylene chloride.

C) N-methylsulfonyl-imidazolidinone-2:-

Regulation 1. i

To the suspension of 43 parts by weight of imidazolidinone-2 in 400 parts by volume of dry tetrahydrofuran, 63 parts by weight of methanesulfochloride were added dropwise at room temperature, stirred for 1 hour at 30-40°C and then heated for 1 hour under reflux. The solvent was then distilled off in a vacuum and kept for 1 hour at 60°C below the oil point. The residue was recrystallized from hot acetone.

Yield: 25%, melting point 193°C.

Calculated: C 29.3 H 4.9 N 17.1 S 19.5 ;

Found, : C'29.0 H 5.0 N 17.2 S 19.6.

IR bands at 3250, 3115, 1715, 1350 and ll60cm<_1.>The NMR signal at t = 2.4 (1H), 6.2 (2H), 6.5 (2H) and

6'.8 ppm (3H).

Regulation 2.

To the suspension of 43 parts by weight of imidazolidinone-2 in 300 parts by volume of dry tetrahydrofuran, 80 parts by weight of methanesulfochloride and then 56 parts by weight of triethylamine were dripped over the course of 30 minutes with stirring so that the internal temperature was at 35-40°C. Mon.;''then stirred for 2 hours at 45°C, then removed the solvent in vacuo, extracted it. the remaining residue twice with each time -150 parts by volume of chloroform and recrystallized the remaining crystals from methanol.

Yield: 49%.

The product was determined by melting point and IR spectrum. and it is consistent with the above-mentioned N-methylsulfonylimidazolidinone-2.

Example 7.

Sodium-7- { D- a-/_ (2-ox 0-3-pheny lsulf ony 1-imidaz ol idin-1- y 1 ).^carb ony lamino7-pheny lacetamido }-acetoxymethyl 1-cef- 3-em-4-carboxylate was prepared in the manner described in example 1, from 1.3 parts by weight of cephaloglycin dihydrate and 1.0 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenylsulfonyl-imidazolidine in a 64% yield.

IR band at 3250, 1760, 1728, I670, l604, 1515, 1240,

1170 and 1118 cm<-1>.

The NMR signal at t = 0.5 (d,lH), 1.25 (d,lH), 1.7-2.0

(m,2H), 2.0-2.3 (m,3H), 2.3-2.8

(m,5H), 4.1-4.5 (m,2H), 4.8-5.1 (m,3H9, 6.05 (broad s,4H), 6.6 (m,2H) and 7.9 ppm (s,3H) (in DMSO-dg).

■3-lactam content according to NMR and IR spectrum 80-90%.

• B)

A mixture of 80 parts by weight of 1-phenylsulfonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of methylene chloride, which had been prepared at 0°C, was stirred. overnight at room temperature and then evaporated to dry-

hot. It was then slurried in 500 parts by volume of ice water and the residue was sucked off, taken up in 500 parts by volume of methylene chloride, dried over MgSO 4 , filtered off and again evaporated to dryness. It was recrystallized from acetone/petroleum ether. Melting point l6l°C. Yield 64% of 1-chlorocarbonyl-2-oxo-3.-phenylsulfony 1-imidazolidine.

Calculated: C 4l.6 H 3.5 Cl 12.3 N 9.7 S 11.1

Found : C 4l.6 H 3.0 Cl 12.2 N 9.7 S 10.7 '

IR bands at 1802, 1732 and 1200 cm"<1> (in Nujol).

The NMR signal at x = 1.8-2.1 (2H), 2.1-2.5 (3H) and

5.7-6.1 ppm (4H).

The mixture of 86 parts by weight of 2-oxo-imidazolidine, 194 parts by weight of benzenesulfonyl chloride, 800 parts by volume of tetrahydrofuran, 500 parts by volume of chloroform and 101 parts by weight of triethylamine• was stirred overnight at 50°C and then evaporated to dryness in vacuo. The residue was eventually stirred completely in 1,000 parts by volume of ice water, then filtered off and recrystallized from ethanol. Melting point 155°C.

Yield of 1-phenylsulfonyl-2-oxo-imidazolidine: 35%.

Calculated: C 47.7 H 4.4 N 12.4 S 14.2

Found : C 47.8 H 4.5 N 12.2 S 14.3

IR bands at 3280, 1740, 1700, 1280, 1178, 1095 and.

1060 cm'<1> (in Nujol).-

The NMR signal at x = 1.8-2.6 (6H), 6.1 (2H) and 6.7 ppm (2H) (in DMSO-dg).

Example 8.

A)

This cephalosporin was prepared in the manner described in example 1 from 1.5 parts by weight of cephaloglycin dihydrate and 0.95 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylaminosulfonylimidazolidine.

Yield of sodium 7-{D-ct-_/(2-oxo-3_methylaminosulfophyl-imidazolidin-1-y1)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3~em-4-carboxylate: 52%.

IR band at 3220 , 1760, 1718, 1665, 1600,.1518, 1252,

1230 and 1175 cm"<1..>

The NMR signal at x = 2.4-2.9 (m,5H), 4.35+5.05 (AX,

1H+1H), 4.45 (s,1H), 5.1 (d,2H), 6.15 (s,4H), 6.6 (AB,2H) and 8.0

ppm (3H).

3-lactam content according to IR and NMR spectrum: 85~90%.

The suspension of 17.9 parts by weight of 1-methylaminosulphonyl-2-oxo-imidazolidine in 100 parts by volume of methylene chloride was mixed dropwise at 10 C with the solution of 7.1 parts by volume of Tusgen in 30 parts by volume of tetrahydrofuran. 7.9 parts by volume of pyridine were then added dropwise to 30 parts by volume of tetrahydrofuran at 10°C, stirred for 30 minutes at

10°C and 3 hours at room temperature, evaporated in vacuo to dryness, taken up in 100 parts by volume of methylene chloride, shaken with 25 parts by volume of water and dried the methylene chloride solution over MgSO||. After evaporation of the solution in vacuo, the residue was recrystallized from benzene. Melting point 79 - 80°C.

Yield: 80% of 1-chlorocarbonyl-2-oxo-3-methylamino-sulfony1-imidazolidine.

IR bands at 3250, 1795, 1720, 1285, 1232, 1175, ll40 and

l 955 cm 1 (in Nujol).

8.6 parts by weight of 2-oxo-imidazolidine were mixed in 70 parts by volume of acetonitrile at 15°C dropwise with 13.0 parts by weight of N-chlorosulfonylmethylamine in 20 parts by volume of acetonitrile, then 10.0 parts by weight of triethylamine were added dropwise, stirred for 1 hour at room temperature and 1 hour at 50°C. After cooling to room temperature, it was suctioned off, washed out with acetonitrile and the combined acetonitrile phases

was evaporated in vacuo to dryness, the residue was recrystallized from acetone.

Yield: 50%, melting point 182°C.

By repeated recrystallization from isopropanol, 1-methylaminosulfonyl-2-oxo-imidazolidine with melting point 184°C was obtained in 44% yield.

Calculated: C 26.8 H 5.0 N 23.2 S 17.9

Found : C 27.0 H 5.1 N 23.3. S 17,6

IR bands at 3240, 1704, 1260, 1170, 1130 and' 1080 cm<-1> (in Nujol). Example 9-

2.2 parts by weight of cephaloglycin dihydrate were suspended in

30 parts by volume of methylene chloride, mixed with 1.3 parts by weight of triethylamine, cooled to -20°C and added to a solution of 1.0 parts by weight of 1-chlorocarbony 1-3-c<y>anomet<y>lcarbon<y>1<- >imidazolidinone (2) in 6 parts by volume of methylene chloride. After 30 minutes of stirring at -10°C and 30 minutes at 20°C, the methylene chloride was removed. Processing to sodium-'7-{D-a-l_ (2-oxo-3~cyanacety 1-imidazolidin-1-y 1)-carbonylamino7-phenyl-acetamido}-3-acetoxymethyl-cef-3-em-4- carboxylate proceeded as in example 3-

3-lactam content: 70 - 75%.

Characteristic IR bands: 2210, 1760, 1670, l6l0 cm'<1.>

B) 1-chlorocarbonyl-3-cyanomethylcarbonyl-imidazolidinone(2):

10 parts by weight of 1-cyanomethylcarbonyl-irnidazolidinone (2)

was suspended in 100 parts by volume of methylene chloride, cooled to -10°C and mixed with 9.2 parts by weight of phosgene and stirred for 30 minutes at 0°C. 7.7 parts by weight of pyridine were added dropwise and stirred overnight. The precipitated pyridine hydrochloride was sucked off, the filtrate evaporated and the residue recrystallized from acetone.

C) 1-Cyanomethylcarbonylimidazolidinone(2) :

8.6 parts by weight of imidazolidinone (2) were suspended in 30 parts by volume of tetrahydrofuran and a solution of 10.4 parts by weight of cyano-cetyl chloride in 20 parts by weight of tetrahydrofuran was added dropwise while cooling, the temperature being kept between 25 and 30°C. Hydrogen chloride was subsequently formed with the help of a stream of nitrogen (approx. 1 hour) and the reaction product was sucked off. After recrystallization from acetonitrile, 6.3 parts by weight (52%) of 1-cyanomethylcarbonyl-imidazolidinone (2) of melting point 214-217°C were obtained.

Calculated: C 47.06 H 4.6l N 27.44

Found: C 47.2. H 4.8 N 27.5

Characteristic IR bands: 2260, 1750, 1670 cm"<1>.

NMR signals in 6 (DMSO): 7.80 (s.1H), 4.35 (s.2H),

m centered at 3.84 (2H),

m centered at 3.35 (2H).

Example 10.

A)

2.2 parts by weight of cephaloglycin dihydrate were reacted with 1.1 parts by weight of 1-chlorocarbonyl-3-8-cyanopropionyl-imidazolidinone (2) in the manner indicated in example 9. 332 parts by weight reaction product (71%) of melting point 203°C with an 8-lactam content of 90%: Sodium-7-{D-a-_/ (2-oxo-3-8-cyanopropiony 1-imidazolidin-1- y 1)-Carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylate.

Calculated: C 50.32 H 4.06 N 13.54 S 5.17

Found : C 49.6 H 4.2 N 13.6 S 5.2

Characteristic IR bands: 2250, 1765 , 1735, 1675, l6l0 cm 1 .

B) 1-chlorocarbonyl-3-6-cyanopropionyl-imidazolidinone(2):

8.5 parts by weight of 1-8-cyanopropionyl-imidazolidinone (2) were reacted with 9.9 parts by weight of phosgene as in Example 9B.' The product was extracted with a little cold water, sucked off and dried. 5.1 parts by weight (44%)■of decomposition point 127-130°C. •

Calculated: C 4l.85 H 3.51 N 18.30 Cl 15.44 Found : C 42.2 H 3.4 N 17.9 Cl 15.8

Characteristic IR bands: 2250, 1795 , 1715, l685 cm_1..

C) 1-8-cyanopropionyl-imidazolidinone(2):

5.3 parts by weight of 8-cyanopropionic acid chloride were reacted with 3.9 parts by weight of imidazolidinone (2) as in example 9C. Recrystallization from acetone, 3.6 parts by weight (48%) of melting point 130-132°C.

Calculated: C 50.30 H 5.43 N 25.15

Found : C 50.2 H 5.5 N 25.1

Characteristic IR bands: 2250, 1750, 1670 cm<-1.>

NMR signals in 6 (DMSO): 7.62 (s,1H), 3.80 ..(t,2H),

m centered at 3.3 (4'H)3 2.67 (t,2H).

Example 11.

A)

2.2 parts by weight of cephaloglycin dihydrate were reacted with 1.3 parts by weight of 1-chlorocarbonyl-3-cyanornetylsulfony-1-imidazolidinone (2) in the manner indicated in Example 9A to sodium-7-{D-a-[<_>(2-oxo-3~ cyan — methylsulfony1-imidazolidin-1-y1)carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-carboxylate (B-lactam content from IR spectrum 70-75%).

Characteristic IR bands: 2210, 1760, 1735, 1675, 1610 cm'<1>.

B)

1-Chlorocarbonyl1-3-cyanomethylsulfonyl1-imidazolidinone (2). \

9.5 parts by weight 1-cyanomethylsulfonyl-imidazolidinone(2)

was reacted with 9.9 parts by weight of phosgene as in the example. 9B.

C)

1-cyanomethylsulfony1-imidazolidinone (2).

13.4 parts by weight of cyanomethylsulfonyl chloride were reacted with

8.6 parts by weight of imidazolidinone (2) as in example 9C. Recrystallize-

ing of methyl ethyl ketone, 4.1 parts by weight (21.6%) of decomposition point 168-172°C.

Calculated: C 31.75 H 3.73 N 22.21 S 16.95

'.Found : C 31.8 H 3.8 N 22.2 S 16.9 r Characteristic IR bands: 2260, 1730 cm"<1.>

NMR signals in 6 (acetone): 4.90 (s,2H), 4.12 (t,2H), 3.64 (t,2H).

Example 12.

A)

in

Sodium 7-{D-a-[(2-oxo^3-methoxycarbonyl-1-imidazolidin-1-yl)-carbonylamino]-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylate was prepared on the example 1 specified method of 1.55 parts by weight of 1-chlorocarbonyl-2-oxo-3-methoxycarbonyl-imidazolidine and 3.0 parts by weight of cephaloglycin in a 23% yield.

IR bands at 3270, 1760 , 1750, 167.0, 1610 and 1525 cm"<1> (in Nujol). NMR signals at x = 2.3-2.9 (5H), 4.25 (1H) , 4.43 (1H), 4.95 (1H),

5.3 (2H), 5.9-6.4 (7H), 6.6 (2H) and 7.8 ppm (3H) (in D2O).

B) 1-chlorocarbonyl-2-oxo-3-methoxycarbonyl-imidazolidine.

This carbamic acid chloride was prepared in the manner described in example 14 B from 8 parts by weight of N-methoxycarbonylimidazolidone-2, 9.7 parts by weight of triniethylchlorosilane, 9 parts by weight of triethylamine and 6.2 parts by weight of phosgene.

Yield 72%, melting point 129°C.

Calculated: C 34.8 H 3.4 Cl 17.2 N 13.6

Found : C 34.8 H 3.4 Cl 17.1 N 13.6.

IR bands at 1820, 1737, 1690 and 1260 cm"<1>.-

NMR signals at x = 5.7-6.3 (4H) and 6.1 ppm (3H).-

C) N-Methoxycarbonyl-imidazolidone-2.

14.9 parts by weight of N-chlorocarbonyl-imidazolidone-2 were introduced into 70 parts by volume of ice-cold methanol and stirred for 1 hour at room temperature, then 1 hour at 40-50°C. After removal of excess methanol, it was recrystallized from acetone:

Yield: 55%, melting point 185°C.

Calculated: C 41.6 H 5.5 N 19.4

Found :C41,8h4,8N19,2-

IR bands at 3320, 1745 and 1670 cm"<1.>

Example 13-

Sodium 7-{D-a-/_~j(2-oxo-3-benzoyl-imidazolidin-1-yl)-carbonylamino-7-phenylacetamido}-3'-acetoxymethyl-cef-3-em-4-carboxylate was prepared on the method described in example 1 of 1.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-benzoyl-imidazolidine and 3.0 parts by weight of cephaloglyein.

Yield: 67.5%.

IR bands at 3300, 1750, 1730, 1665, 1615 and 1505 cm"<1> (in Nujol). NMR signals at x =£.2-2.9 (-10H.) , 4.25 (IH) , 4.4 (1H), 5.0 (1H), 5.3 (2H), 5.8-6.3 (4H), 6.5 (1H), 6.9 (1H) and 7.8 ppm (3H)' (in D2O). B) 1-chlorocarbonyl-2-oxo-5-benzoyl-imidazolidine.

This carbamic acid chloride was prepared in the manner described in example 14 B from 4.8 parts by weight of N-benzoyl-imidazolidone-2,

4.4 parts by weight of trimethylchlorosilane and 2.8 parts by weight of phosgene.

Yield: - 100%, melting point 153-154°C.

Calculated: C 52.2 H 3.6 Cl 14.0 N 11.1

Found: C 51.2 H 4.4- Cl 13.2 N 11.1 IR bands at 3060, 1768, 1725 and 1672 cm<-1.>NMR signals at t = 2.5- (5H) and . 6.0 ppm (UH).

C) N-benzoyl-imidazolidone-2.

8.6 parts by weight of imidazolidone-2 in 100 parts by volume of dry tetrahydrofuran were mixed during 15 minutes at 5-10°C with 15.5 parts by weight of benzoyl chloride in 30 parts by volume of tetrahydrofuran and then stirred for 3 hours at 10°C. The solvent was removed, the residue shaken with a mixture of chloroform and aqueous NaHCO-^ solution for 15 minutes, the chloroform removed, the water still extra-

hardened once with chloroform, the combined organic phases washed with water, dried over MgSO4 and evaporated. The residue was recrystallized from acetic acid/ether.

Yield: 30%, melting point l69-170°C.

Calculated: C 63.2 H 5.3 N 14.8

Found: C .63 , 0 H 5 , 3 N 14 , 8

IR bands at 3190, 3110, 1742, 1718 and 1655 cm"<1.>

NMR signals at x = 2.2-2.9 (5H), 3.9 (1H), 6.0 (2H). and 6.6 ppm (2H). Example 14.

Sodium 7-{D-α-/_ (2-oxo-3-acety 1-imidazolidin-1-y 1)-carbonylaminoZ-phenylacetamido}-3-acetoxymethylcef-3-em-4-carboxylate was prepared in the manner described in example 1 of 1.43 parts by weight of 1-chlorocarbonyl-2-oxo-3-acetyl-imidazolidine and 3.0 parts by weight of cephaloglycin. Yield 65%.

IR bands at 3260, 1750, 1735, l680, 1615, 1520,, 1315, 1260, 1240-1215 and 750 cm<-1>(ii Nujol).

NMR signals at x ^0.35 (1H), 0.9 (1H), 2.3-2.8 (5H), 4.1-4.55 (2H), 5.03 (3H), 6 .2 (4H), 6.65 (2H), 7.5 (3H) and 7.9 ppm (3H),

(in dimethylformamide).

Calculated: C 49.5 H 4.1 N 12.0 S 5.5

Found : C 48.7 H 5.3 N 11.4 S 5.6.

B) 1-chlorocarbonyl-2-oxo-3~acety1-imidazolidine.

20 parts by weight of N-acetyl-imidazolidone-2 were mixed with 24 parts by weight of triethylamine and 150 parts by volume of dry benzene and mixed

dropwise during 30 minutes while stirring at room temperature with 27 parts by weight of trimethylchlorosilane in 40 parts by volume of benzene'.

Under moisture exclusion, it is then moistened for 18 hours under reflux, filtered after cooling from precipitated triethylamine hydrochloride

IN

(22 parts by weight = 100%), which was carefully washed out with dry benzene. The benzene solution thus formed was mixed at 5°C with the solution of 17 parts by weight of phosgene in 50 parts by volume of benzene and left overnight at 5°C. The solvent was then removed under vacuum and the residue dried under an oil pump. It was recrystallized from an acetone/pentane mixture.

Yield: 8l%, melting point 104°C.

Calculated: C 37.7 H-3.7' Cl 18.6 N 14.7

Found : C 39.3 H 4.3 Cl 17.7 N 14.7.

IR bands at 1798, 1740, 1690 and 1660 cm"<1.>

NMR signals at x = 5.65-6.3 (4H) and 7.45 ppm (3H).

According to the NMR spectrum, the product also contained 5~10% N-acetyl-imidazolidone, which, however, does not interfere with reaction with cephaloglycin.

C) N-acetyl- imidazolidone-2.

To the suspension of 25.8 parts by weight of imidazolidone-2 in 350 parts by volume of dry tetrahydrofuran, 23.6 parts by weight of acetyl chloride in 100 parts by volume of tetrahydrofuran were dripped over the course of 60 minutes at 0°C.

It was stirred for 3 hours at room temperature, then dry air was blown through the solution for a while, then the residue is recrystallized from boiling nitromethane.

Yield: 52%, melting point 188°C.

Calculated: C 46.9 H 6.9 N 21.9

Found : C 47.0 H 6.2 N 22.5

IR bands at 3230, 1730 and l640.cm<_1.>

NMR signals at x = 6.2 (2H), 6.5 (2H) and 7.6 ppm (3H). Example 15-

i Sodium-7-{D-α-/~(2-oxo-3-furoyl-(2)-imi<d>azolidin-1-yl)-carbonylamino/-phenylacetamido}-3_acetoxynretyl-cef-3-em-4- carboxylate was prepared in the manner described in example 1 from 1.82 parts by weight of 1-chlorocarbonyl-2-oxo-3-furoyl-(2)-imidazolidine and 3.0 parts by weight of cephaloglycine. Yield: 78.6%.

IR band at. 3310 , 3250 , 1775, 1750, 1730,. 1660, 1520, 1325, 1260-1220 and 753-738 cm<_1> (in Nujol).

NMR signals at x = 0.55 (1H), 1.0 (1H), 1.93 (1H), 2.4-2.75 (6H), 3.2 (1H), 4.1-4 ;6 (2H, 5.05 (3H), 6.1 (4H), 6.7 (2H) and 7.98 ppm (3H) (in dimethylformamide).

B) 1-chlorocarbonyl-2-oxo-3-furoyl-(2)-imidazolidine.

This carbamic acid chloride was prepared in the manner described in example 14 B from 9 parts by weight of N-furoyl(2)-imidazolidone-2, 8.7 parts by weight of trimethylchlorosilane and 6.0 parts by weight of phosgene.

Recrystallization from benzene.

Yield: 55%, melting point 119°C.

Calculated: C 44.5 .H 2.9 Cl 14.6 N 11.5

Found : C 45.0 H 3.6 Cl 13.4 N 11.5-

IR bands at 3150, 3100, l800, 1745, 1715, 1650, 1620 and 1255 cm"<1.>

NMR signals at x = 2.3 (1H), 2.5 (1H), 3.4 (1H)<p>g 5.9 ppm (4H). C), N-furoyl-(2)-imidazolidone-2.

This substance was prepared in the manner described in example 13 C from imidazolidone-2 and furan-α-carboxylic acid chloride. Instead of at 10°C, it was stirred for 3 hours at 30-40°C. Recrystallization from nitromethane.

Yield: 53%, melting point l44-l46°C.

Calculated: C 53.2 H 4.5 N 15.6

Found' : C 51.2 H 4.5 N 15.3.

IR bands at 3245, 3120, 1740, 1622, 156b, 1257 and 1240 cm"<1.>NMR signals at x = 2.25 (1H), 2.6 (1H), 3.35 (1H), 6.0 (2H) and 6.4 ppm (2H).

Example 16.

Sodium 7-{D-α-/_-(2-oxo-3-benzoyl-1-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-methyl-cef-3-em-4-carboxylate was prepared in the manner described in example 1 of 2.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-benzoyl-imidazolidine and 3.0 parts by weight of cephalexin. Yield 79%.

IR bands at 3300, 1740, l660,'l600, 1500, 1320, 1250 and 1230 cm"<1>(in Nujol). NMR signals at x ■ = 0 ,.6 (1H), 1.0 (IB ') , 2.1-2.8 (10H), 4.05-4.6 (2H), 5.07 (1H), 6.0 (4H), 6.85 (2H) and 7.95 ppm (3H).

Example 1J.

A)

Sodium 7-{D-α-/_-(2-oxo-3-sulfamy 1-imidazolidin-1-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3~em-4-carboxylate was prepared on the method indicated in example 3 of 2.2 parts by weight of cephaloglycin dihydrate and 2.2 parts by weight of 1-chlorocarbonyl-2-oxo-3-sulfamyl-imidazolidine (added as a solution in 5 parts by volume of acetonitrile) in a yield of 0.5 parts by weight. At the same time, the free acid of the same cephalosporin was formed in a yield of 2.4 parts by weight. If you dissolve this free acid in 7 parts by volume of dimethylformamide and add this solution dropwise to the mixture of 4.8 parts by volume of 1 molar sodium 2-ethylhexanoate solution in (containing methanol)

■ether, 120 parts by volume of ether and 12 parts by volume of ethanol, a further 1.8 parts by weight of the sodium salt of cephalosporin are obtained. IR bands (in the carbon range) at 1755, 1-720, 1655, 1600 and 1520 cm"<1>, (in Nujol).

NMR signals at x = 2.3-2.75 (5H), 4.1-4.45 (2H), 4.9-5.2 (3H), 5.9-6.2 (J»H ), 6.5-6.65 (2H) and 7.9 ppm (3H) (CD30D).

i From the NMR spectrum it can be deduced that the substance contains approx. 3.7 mol B^O and 0.7 mol dimethylformamide.. This was taken into account in the following calculated analysis data.:

Calculated: C 39.5 H.4.2 N 12.8 S 8.7.

Found :' C 40.0 H 4.2 N 12.3 S 8.2.

B) 1-chlorocarbonyl-2-oxo-3-sulfamy1-imidazolidine.

The solution of 17.8 parts by volume of triethylamine in 30 parts by volume of dichloromethane and then allowed to stand for 17 hours. The precipitate formed was removed by filtration, the filtrate evaporated in vacuo and the residue extracted several times with acetic acid ethyl ester at 20°C. The acetate extracts were combined. They left a hard varnish after evaporation. The IR spectrum showed a strong acid chloride band at 1805 cm 1 (Nujol). Furthermore, it can be deduced from the IR spectrum that the substance also contained considerable ■mender starting product._

C) 1-sulfamy1-2-oxo-imidazolidine.

To the suspension of 25.8 parts by weight of 2-oxo-imidazolidine

in 180 parts by volume of acetonitrile, the solution of 36.3 parts by weight of amidosulfochloride in 90 parts by volume of acetonitrile was added at 10°C. The mixture was then stirred for 15 minutes without further cooling and then heated for 1 hour at 50°C. After cooling, the precipitate present was suctioned off, stirred for a few minutes in 500 parts by volume of water, suctioned off, the filtrate evaporated completely in vacuo, the residue boiled with 400 parts by volume of isopropanol, then suctioned off, suspended in 30 parts by volume water, suctioned off again, washed twice each time with 10 water and dried by volume.

Yield: 15 parts by weight, melting point 188°C (slowly decreasing).

^Calculated: C 21.8 H 4.2 N 25.5 S 19.4

Found : C 21.8 H 4.3 N 25.4- S 19.6.

Example 18.

A)

Sodium 7-{D-α-[(2-oxo-3-phenyl-imidazolidin-1-yl)-carbonylamino]-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylate was prepared on the 3 described method of 2.2 parts by weight of cephaloglycin dihydrate and 1.0 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenyl-imidazolidine and was formed by acidification to pH 2 primarily in the form of a sparingly soluble precipitate as free acid (3.5 parts by weight). This was dissolved in 3.5 parts by volume of dimethylacetamide, from undissolved it was clearly filtered through some A120-^, to the filtrate as well as the calculated amount of 1 molar sodium 2-ethyl hexanoate solution in methanol-containing ether - and this mixture stirred into 100 parts by volume of ether. The precipitated sodium salt was sucked off, washed with the mixture of 50 parts by volume of ether and 10 parts by volume of methanol and dried.

Yield: 1.6 parts by weight.

The substance crystallized with 1.5 mol H^O. This was taken into account in the calculated analysis data:

Calculated: C 52.4 H 4.5 N 10.9 S 5.0

Found : c'52.4 H 5.5 N 10.9 S 5.0/

IR bands (in the carbonyl region): 1760, 1715, 1655, 1600 and 1525 cm"<1> (in Nujol).

NMR signals at t = 2.1-2.9' (10H9, 4.1-4.5 (2H), 4.9-5.15 (3H), 5.9-6.1'(4H) , 6.5-6.7 (2H) and 7.95 ppm (3H) (in dimethylformamide-dy/

CD^OD)..

B) 1-chlorocarbonyl-2-oxo-3-phenyl-imidazolidine.

16.2 parts by weight of 1-phenyl-2-oxo-imidazolidine were suspended in 160 parts by volume of tetrahydrofuran and added dropwise at 10°C,

12.0 parts by weight of phosgene, dissolved in 30 parts by volume of tetrahydrofuran. It was then stirred for 4 hours at 10°C and left overnight at 20°C, then a precipitate formed with suction, washed with tetrahydrofuran and dried.

Yield: 20.3 parts by weight, melting point 208°C.

NMR signals at t = 2.25, 3.0 (5H) and 5.9-6.7 ppm (4H) (dimethylsulfoxide-dg).

Calculated: C 53.5 H 4.0 Cl 15.8 N 12.5

Found: : C 53.6 H 4.3 Cl 16.1 N 11.8.

Example 19.

Sodium 7-{D-ct-/_(2-oxo-3-phenyl 1-imidazolidin-1-y 1)-carbonylamino7-phenylacetamido}-3-methyl-cef-3-em-4-carboxylate was prepared on the in the above-mentioned example method of 2.5 parts by weight of cephalexin hydrate and 1.54 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenyl-imidazolidine, first as free acid and then as sodium salt in a yield of 3.5 parts by weight.

IR bands (in the carbonyl region) at: 1755, 1720, 1670, 1595 and 1530 cm"<1>(Nujol).

The substance is crystalline and exists as a dihydrate.

This was taken into account in the calculated analysis values:

Calculated: C 52.6 H 4.7 N 11.8 S 5.4

Found : C -52.6 H 4.7 N 12.0 S 5.4.

Claims (16)

1. Cephalosporins of formula I in which A means hydrogen, optionally substituted alkyl, aryl or the R-^ -X group, in which X means the -CO group or the -SC^ group and R-^ means hydrogen, optionally substituted alkyl, aryl, thienyl, furyl, amino, monoalkylamino, dialkylamino, pyrrolidyl or piperidyl and where R-^ can further mean alkoxy, if X means the -CO group, B means phenyl, methylphenyl, chlorophenyl, hydroxyphenyl or the rest E means hydrogen, hydroxy or acetoxy, and those with regard to the chirality center C can exist in the two possible R and S configurations and as mixtures of resulting diastereomers and their non-toxic, pharmaceutically acceptable salts. 2. Compounds according to claim 1, wherein A means hydrogen. 3. Compounds according to claim 1, wherein A means methyl. 4. Compounds according to claim 1, wherein A means CH-^S02-. 5. Compounds according to claim 1, wherein A means CI-UNH-SO2-. 6. Compounds according to claim 1, wherein A means 7. Compounds according to claim 1, wherein A means CH^CO-. 8. Compounds according to claim 1, wherein A means 9. Compounds according to claim 1, wherein A means 10 . Compounds according to claim 1, wherein A means CH-^NHCO-. 11. Compounds according to claim 1, wherein A means CH^OCO-. 12. Compounds according to claim 1, wherein B means phenyl. 13. Compounds according to claim 1, wherein B means 14. Compounds according to claim 1, in which C exists in the D-=R configuration. 15. Compounds according to claim 1, wherein E means CH^COO-. . 16. Compounds according to claim 1, wherein A means hydrogen, methyl, CH,S02<!> , or CH~3NH-SO2, B means phenyl or C exists in D- = R-configuration and E stands for CH^COO-. 17 . 7- {D-ot-_/— (2 - ox o-imidazolidin-1-y 1)-carb ony lamino7- phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. l8. 7-{D-α-/ <-> (2-oxo-imidazolidin-1-yl)-carbonylamino7- phenylacetamido}-3-methyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts..19. 7-{D-aW(2-oxo-3-methyl-imidazolidin-1-yl)-carbonyl-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 20. 7-{D-α-[(2-oxo-3-ethyl-imidazolidin-1-yl)-carbonyl-amino]-phenyllacetamido'-}-3-acetoxymethyl-1-cef-3-em-4 -carboxylic acid with formula and their pharmaceutically acceptable salts.. 21. 7-{D-α-_/(2-oxo-3-mesyl-imidazolidin-1-yl)-carbonyl-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid with formula and their pharmaceutically acceptable salts. 22. 7-{D-ot-/_ (2-oxo-3-methylaminosulfonyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxyl- acid with formula and their pharmaceutically acceptable salts. carboxylic acid with and their pharmaceutically acceptable salts. 24. 7~{D-α-/_(2-oxo-3~phenylsulfony 1-imidazolidin-1-y 1)-carbonylamino/-phenylacetamido}-3-methyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 25. 7-{D-α-/_(2-oxo-3-thienyl-(2)-sulfonyl-imidazolidin-1-yl)carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxyl - acid with formula' and their pharmaceutically acceptable salts.26. 7_{D-a-(2-ox'o-3-formyl-imidazolidin-1-yl)-carbonyl-amino-7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 27. 7-{D-a-(2-oxo-3-acetyl-imidazolidin-1-yl)-carbonyl-amino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid with formula and their pharmaceutically acceptable salts. 28. 7-{D-a-(2-oxo-3-benzoyl-imidazolidin-1-yl)-carbonyl-amino-7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 29. 7-{D-α-[(2-oxo-3-furoyl(2)-imidazolidin-1-yl)-carbonyl-amino]-phenylacetamido}-3-acetoxymethyl-cef-3-em-4- carboxylic acid with formula and their pharmaceutically acceptable salts. 30. 7-{D-ct-/_ (2-oxo-3~thieny 1 (2 )-carbonyl 1-imidazolidin-1-y 1)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4 -carboxy1- <v> acid with formula and their pharmaceutically acceptable salts. 31. 7~{ D- a -/_ (2-oxo-3-(mesyl)-mesyl-imidazoldin-1-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxyl- acid with formula and their pharmaceutically acceptable salts. 32. 7-{D-α-/_ (2-oxo-3-cyanoacetyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 33- 7-{D-α-/ <_> (2-oxo-3-8-cyanopropionyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxinretyl-cef-3_em-4-carboxyl- acid with formula and their pharmaceutically acceptable salts. 34. 7-{D-α-/_ (■2-oxo-3-cyanomethylsulfonyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxyl- acid with formula and their pharmaceutically acceptable salts. 35- 7~{D-α-/_ (2-oxo-3~trifluoroacetyl-imidazolidin-1-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxyl- acid with formula and their pharmaceutically acceptable salts. 36. 7-{D-α-_/(2-oxo-3-pentafluoropropionyl-imidazolidin-1-yl)-carbonylamino/-phenylacetamido}-3-acetoxymethyl-cef-3-em-4-carboxylic acid of formula and their pharmaceutically acceptable salts. 37» 7~{D-α-/_ (2-oxo-3-trifluoromethylsulfony1-imidazolidin-1-y 1)-carboxylamino7-phenyl lacetamido }-^3-acetoxymethy 1-ce f-3-em -4- carboxylic acid with formula.- and their pharmaceutically acceptable salts.. 38. Sodium salts of the compounds according to claims 1 to 37. 39- Process for the production of cephalosporins with formula I in in which A means hydrogen, optionally substituted alkyl, aryl or the R^ -X group, in which S means the -CO group or the -SO2 group and R-^ means hydrogen, optionally substituted alkyl, aryl, thienyl, furyl, amino, monoalkylamino, dialkylamino, pyrrolidyl or piperidyl and where R 2 further can mean alkoxy, if X means the CO group. B means phenyl, methylphenyl, chlorophenyl, hydroxyphenyl or the rest E means hydrogen, hydroxy or acetoxy, and may exist with respect to the chirality center•C in the two possible R and S configurations and as mixtures of the resulting diastereomers and of their non-toxic, pharmaceutically acceptable salts, characterized in that, in the presence of a base, compounds of formula II are reacted in which i B, E and C have the above meaning, with compounds of the general formula III in which A has the above meaning and W means halogen, azide, phenoxy, nitrophenoxy, dinitrophenoxy, mono- to pentahalophenoxy or benzylthio, and transfers the formed 8-lactam antibiotics optionally in the free acids or in non-toxic, pharmaceutically acceptable salts. 40. Medicinal product, characterized by a content of at least one cephalosporin according to claims 1 to 38. 41. Process for the production of antibacterial agents, characterized in that cephalosporins according to claims 1 to 38 are mixed with inert, non-toxic, pharmaceutically suitable carriers. 42. Method for the treatment of bacterial diseases, characterized in that one applies cephalosporins according to claims 1 - 38 to humans or animals, which are ill from bacterial diseases.