NO860483L - NEW CEPHALOSPORINES AND PROCEDURES FOR PRODUCING THEREOF. - Google Patents

Description

, ;The present invention relates to new cephalosporins, methods for their production, and the use of the compounds as pharmaceuticals, especially within antibacterial therapy.

Cephalosporins which, as acyl side chains, carry a .. 2-(2-aminothiazol-4-yl)-2- alkoxyiminoacetic acid residue and in the 3-position a pyridinium methyl residue are known from EP 64,740.

The present invention relates to new cephalosporins of general formula (I)

in which

R"<*>" stands for straight-chain or branched, saturated or unsaturated, possibly carboxy-substituted alkyl with up to 6 C atoms,

R 2 stands for straight-chain or branched alkyl with up to

6 C atoms, which are optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, The remainder

for the optionally substituted groups on the ring methylene group,

R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms which are optionally substituted

- with -OH, CHO, OCONH„, NHC0NH9

5 5 " 5

- with the groups COOR , NHCOR , COR in which

R 5 stands for hydrogen, alkyl with up to 8 C atoms, aryl

with 6-10 C atoms, or C7-C14 aralkyl,

- with halogen, cyano, SO-.H,

where

R 6 and R 7 independently of each other stand for hydrogen or together or individually for C-C-C-alkyl, C-C-C-alkenyl or phenyl, or where the substituents R^, R^ optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which

is optionally substituted with C 1 -C 4 -alkyl, or

- with the groups -SC^-Y or -O-Y, where

Y stands for C 1 -C 8 -alkyl, aryl with 6-10 C atoms or stands for C 7 -C 14 -aralkyl, and

R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted

- with OH, CHO, OCONH2, -NHCONH2,

- with the groups COOR5, NHCOR5, COR5,

where

R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C7~C14 aralkyl,

- with halogen, cyano, SO-.H,

- with the groups

where

R 6 : and R 7 independently of each other stand for hydrogen or together or individually stand for C 1 -C 6 -alkyl, C -C 1 -alkenyl or phenyl or where the substituents R 6 , R 7 optionally with the nitrogen atom form a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C1-C4 alkyl or

- with the group -S02~Y or -0-Y

where

Y stands for C 1 -C 8 alkyl, aryl with 6-10 C atoms

or

stands for C^-C^-aralkyl,

A

b) stands for CHO, SO3H,

c) r stands for COOR 5 , where R 5 has the above meaning or

d) stands for the group -Z-R 8

where

Z stands for

or -SO2- and R 8 stand for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, arylthio with in any case up to 6 C atoms, aryloxy, arylthio with up to 10 C-atoms, carboxy, C-^-C 8 -alkoxycarbonyl, -OCONH2, -NHCONH,,, SO3H or

where R^, R^ have the meanings indicated above,

- stands for aryl with 6-10 C atoms,

- stands for C7-C14~aralkyl,

- for heterocyclyl or

- for the group

where

6 7

R , R has the meaning given above.

When the remains

is substituted on the ring methylene group, this is with up to four, preferably up to two identical or different substituents such as: a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally further

substituted

- with -OH, CHO, -OCONHp, -NHCONH-

5 5 5

- with the groups COOR , NHCOR , COR , where

R 5 stands for hydrogen, alkyl with up to 8 C atoms,

aryl with 6-10 C atoms or C 1 -C 2 -aralkyl,

- with halogen, cyano, SO^H,

- with the groups

where

R 6 and R 7 independently of each other stand for hydrogen or together or separately for C₁-C₂-alkyl, C₁-C₂-alkenyl or phenyl or where the substituents R .■> R optionally with the nitrogen atom form a 5 - to a 7-membered ring, which, as an additional heteroatom, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms, and which is optionally substituted with C-^-C^-alkyl, or

- with the groups -S02~Y or -0-Y

where

Y stands for C-^-Cg-alkyl, aryl with 6-10 C atoms or for C^-C-^-aralkyl, or

g

b) the group -Z-R ,

where

Z stands for

or -SO.,- and

R 8 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio all with 6 C atoms, aryloxy, arylthio (6-10 C -atoms), carboxy, C 1 -C 8 -alkyloxycarbonyl,

-OCONH2-, -NHCONH2, -SC^H,

6 7

where R , R has the meaning stated above

- stands for aryl with 6-10 C atoms

- stands for Cy-C4-aralkyl

- for heterocyclyl or

- for the group - 6 7 where R , R again has the meaning stated above,

C) -OH, CHO, OCONH2, NHCONH-j,

d) the groups COOR<5>, NHCOR<5>, COR<5>,

where

in R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or G.,-C,.-aralkyl,

e) halogen, cyano, SO^H,

f) the group

where

6 7

R and R have the meaning given above,

g) the group -O-Y, where

Y stands for C^-C^-alkyl, aryl with 6-10 C atoms or

- for C 1 -C 2 -aralkyl.

Preferred compounds of the general formula I are compounds wherein

R"*" stands for straight-chain, branched, saturated or unsaturated, possibly carboxy-substituted alkyl with up to 4 C atoms,

R stands for straight chain or branched alkyl with up to

4 C atoms, which are optionally substituted with hydroxy, carboxy, methoxy, methoxycarbonyl, fluorine, chlorine or bromine, the rest

stands for those possibly substituted the remains

in which

R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is optionally substituted

- with OH, CHO, OCONH-, NHCONH-

5 5 5

- with the groups COOR, NHCOR, COR

in which

/'

R 5i stands for hydrogen, alkyl with up to v. 6 C atoms,

phenyl or benzyl,

- with fluorine, chlorine, bromine or SO^H,

- with the groups

in which

R 6 and R 7 independently of each other stand for hydrogen, for C 1 -C 1 -alkyl or phenyl or where the substituents R , R optionally with the nitrogen atom form a 5- or 6-membered ring, which, as further heteroatoms, may contain an oxygen , sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C₁-C₂_alkyl, or

- with the group -SC^-Y or -0-Y,

where

Y stands for C--C8-alkyl, phenyl or benzyl,

R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is at least singly substituted,

- with OH, CHO, OCONH-,, NHCONH-,

5 5 5

- with the groups COOR, NHCOR, COR

where

R<5> stands for hydrogen, alkyl with up to 6 C atoms,

phenyl or benzyl,

- with fluorine, chlorine, bromine or SO^H,

- with the groups or

6 7

where R and R have the above meaning,

-.with the groups -SO2-Y or -0-Y

where

Y stands for C 1 -C 8 alkyl, phenyl or benzyl, or

b) stands for CHO or SO3H,

c) stands for COOR<5>,

where

R<5> has the meaning indicated above, or

d) stand for the group -Z-R<8>,

where

Z stands for

or _SO2 and R 8 stand for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with fluorine, chlorine, bromine, hydroxy, carboxy, alkoxy or alkylthio with up to 3 C atoms, phenyloxy, phenylthio, alkoxycarbonyl with up to 3 C atoms, with OCONH2,

where R^ and R^ have the above meaning,

- for phenyl,

- for benzyl,

- for pyridyl, furyl, thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, oxazolyl, morpholinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl or piperazinyl, or - represents the group

where

6 7

R and R have the above meaning.

Particularly preferred compounds of formula I are compounds wherein

R"*", stands for methyl, ethyl, allyl or 1-carboxy-1-methylethyl,

R 2 stands for methyl, ethyl, 2-hydroxyethyl or carboxy-

methyl,

the rest

stands for the optionally substituted groups

in which

R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted

- with OH, CHO, OCONH-, NHCONH-,

5 5 5

- with the groups COOR , NHCOR or COR , in which

R stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl,

- with fluorine, chlorine or SO^H,

- with the groups

where R 6 , R 7 independently of each other stand for hydrogen, methyl, ethyl, phenyl or with the nitrogen atom form a ring such as pyrrolidine, piperazine, piperidine, morpholine or thiomorpholine, or

- stands for the group -S02~Y or -0-Y, in which

Y stands for alkyl (up to C4), phenyl or benzyl,

and

R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is at least singly substituted

- with OH, CHO, OCONH-,, NHCONH-,,

5 5 5

- with the groups COOR, NHCOR, COR

in which

5

R stands for hydrogen, alkyl (up to: C4), phenyl or benzyl,

■• - with fluorine, chlorine or SO^H,

- with the groups

or

in which

R^ and R^ have the meaning indicated above or

- with the groups -SC^-Y or -0-Y,

in which

Y stands for alkyl with up to 4 C atoms, phenyl or benzyl,

or

b) stands for CHO or SO^H,

c) stands for COOR

in which

5

R has the above meaning, or

d) stands for the group -Z-R 8

in which

Z stands for

or -SO2- and

R 8 stands for straight-chain or branched, saturated or unsaturated alkyl with up to 4 C atoms, which is optionally substituted with chlorine, fluorine, hydroxy, carboxy,

OCONH 2 , NHCONH 2 , SO-^H,

6 7

where R and R have the above meaning,

- stands for phenyl,

- stands for benzyl,

- for pyridyl, furyl, thienyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl or - for the group

where

R 6 , R 7 again have the meaning indicated above.

When the remains

is substituted, this can both in the preferred and also in the particularly preferred compounds of general formula I be substituted with a substituent such as: a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which in turn is further substituted

- with OH, CHO, OCONH-, NHCONH-,

5 5 5

- with the groups COOR, NHCOR, COR

in which

R 5 stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl,

- with fluorine, chlorine, SO^H,

- with the groups

in which R<6> and R<7> independently of each other stand for hydrogen, methyl, ethyl, phenyl or where R 6 , R 7 together with the nitrogen atom form a ring such as pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, or

- with the group -SO2-Y or -0-Y,

where

Y stands for alkyl with intl 4 C atoms, phenyl or benzyl,

g

b) the group -Z-R

in which

Z stands for

or -S02~, and R 8 stands for straight-chain, branched, saturated or unsaturated alkyl with up to 4 C atoms, which is optionally substituted with fluorine, chlorine, hydroxy, carboxy, OCONH2, NHCONH2, SO3H,

6 7

where R , R has the above meaning,

- stands for phenyl,

- stands for benzyl,

- for pyridyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, morpholinyl, piperidinyl or - for the group

where

R^, R7 again have the meaning indicated above,

c) OH, CHO, OCONH2, NHCONH2,

5 5 5

d) the groups COOR , NHCOR , COR ,

where

R 5 has the above meaning,

e) fluorine, chlorine, SO^H,

f) the groups

where R 6 , R 7 again have the meaning given above,

or

g) in the group -0-Y

in which

Y stands for alkyl with up to 4 C atoms, phenyl or benzyl.

From the compounds of formula I according to the invention, several isomers can arise, all of which are antibiotically active and, if necessary, can be separated by chromatography or crystallization.

The compounds of the general formula I can be prepared by reacting compounds of the general formula II

in which

R"*" has the above meaning,

in which the amino group can be protected or unprotected, after activation of the carboxyl group by transfer in a mixed anhydride, for example with chloroformate ethyl ester or methanesulfonic acid chloride by transfer in the acid halide or by transfer in an activated ester with for example N-hydroxybenztriazole or dicyclohexylcarbodiimide, with compounds of general formula III,

in which

has" the above meaning, where-

after, if necessary, the protecting group is removed and the desired salts or from the salts, the free acids, are produced.

For the coupling of the carboxylic acids (II) to B-lactams of the formula (III), a large number of the known methods from cephalosporins or penicillin chemistry is used. It has proven beneficial to activate the carboxylic acids

of general formula (II) without an amine protecting group and then coupling them with the 8-lactams of formula (III), which

is brought into solution with an amine.

Particularly advantageous is the activation with sulfonic acid derivatives of the formula V to anhydrides of the formula IV

in which

T stands for the residue R 9-SO^-O- or halogen, and

R stands for alkyl with up to 10 C atoms, which is optionally substituted with fluorine, chlorine, cyano, phenyl, alkoxycarbonyl, alkoxy or alkyl all with up to 4 C atoms, or - stands for phenyl, which is optionally substituted with fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio, alkoxycarbonyl all with up to 4 C atoms, nitro, trifluoromethyl or phenyl.

When R 9 is substituted, preferably 1-3 substituents are present, particularly preferred are those mentioned above.

Particularly preferably, R is a methyl or p-tolyl residue.

The mixed anhydrides of the formula (IV) are prepared by

that one dissolves the carboxylic acids of formula (II) and 1-1.4 equivalents of an amine in a solvent and allows the mixture to react with 1-1.2 equivalents of a sulphonic acid derivative of formula (V).

Any solvent is suitable as a solvent

which are stable under the reaction conditions, such as e.g. diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform or dimethylformamide.

As amines, tertiary amines such as e.g. triethylamine or tributylamine, but also sterically hindered secondary amines such as e.g. diisopropylamine, or mixtures of these amines.

The conversion can be carried out at temperatures between -80°C and room temperature. Preferably, the activation is carried out with C1-SO2CH3, in dimethylformamide at -40°C to -60°C in

during 0.2 to 24 hours, preferably 0.5 to 5 hours.

For dissolving the compounds of formula (III) they can

in the preparation of the compounds of formula (IV) the mentioned solvents or water and as bases the above-mentioned amines are used.

Activation of the carboxylic acids of general formula (II) by transfer into an activated ester with, for example, N-hydroxysuccinimide and dicyclohexylcarbodiimide or 1-hydroxybenztriazole and dicyclohexylcarbodiimide is also particularly advantageous.

Any solvent is suitable as a solvent

which is also suitable for the preparation of the anhydrides of formula

(IV).

The conversions can be carried out at temperatures between • -30°C and +100°C. Preferably activated with 1-hydroxybenztriazole and dicyclohexylcarbodiimide in dimethylformamide at room temperature for 2-6 hours, then filtered off from precipitated dicyclohexylurea and reacted with a compound of formula (III) in the form of a solution of the amine salt within 2-24 hours. To dissolve the compounds of formula (III), the solvents mentioned in the preparation of the compounds of formula (IV) can be used, as well as the amines mentioned in the same place as bases.

The compounds of the formula (III) are obtained by cleaving the amino protecting groups R"1"0 from the formula (VI).

Hereby, R"*"^ can either be an acid-labile protecting group such as the t-butyloxycarbonyl group or preferably an enzymatically cleavable protecting group. Preferred enzymatically cleavable protecting groups are phenylacetyl or 2-thienylacetyl.

The enzymatic cleavage takes place at room temperature

in water or a mixture of water and a polar organic solvent, such as e.g. acetonitrile or tetrahydrofuran, with immobilized penicillin G-acylase at pH 7-8, preferably at pH 7.5-7.8.

During the enzymatic cleavage, the pH value is kept constant by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or a tert.amine such as e.g. triethylamine, tripropylamine, tributylamine or pyridine.

The compounds of the formula (VI) can be prepared from esters of the formula (VII) via intermediate compounds of the formula (VIII).

In the esters of the formula (VII), X is a cleavable group such as mesylate, tosylate, brosylate, triflate, nonaflate, iodide, bromide, chloride and R is an acid protecting group common in cephalosporin chemistry, preferably an acidic cleavable protecting group, such as e.g. benzhydryl, 4-methoxydiphenylmethyl, t-butyl.

The compounds of the formula (VII) are transferred by cleavage of the acid protecting group R to the reactive free acids of the formula (VIII). In the case of the preferred acid-labile protecting groups R, the protecting group is split off in an organic solvent. The cleavage of the benzhydryl protecting group in methylene chloride with trifluoroacetic acid is preferred, possibly with the addition of an alkoxybenzene, preferably methoxybenzene. The cleavage takes place at -20°C to +30°C, preferably at 0°C within 5 minutes to an hour, preferably within 20 minutes.

The acid of formula (VIII) can be isolated after cleavage

of the protection group. However, it is not beneficial

- to isolate, but on the other hand directly and without purification to react - the compound of formula (VI). In this way, the ^solution of (VIII) that occurs during the reaction (VII) is gently evaporated —>

(VIII) in vacuum. The remaining crude acid is taken up

an organic solvent, preferably in tetrahydrofuran, and is reacted with 2-50 equivalents, preferably with 5-20 equivalents of a tert.amine of the formula

where

has the meaning stated above, in connection with

moieties of formula (VI).

The turnover is carried out at temperatures between -20°C

and 40°C, preferably at 25°C, within 10 minutes to 2 hours, preferably within 30 minutes. After the reaction has finished, the product can be precipitated by adding diethyl ether. The prepared crude product can be purified on a resin such as "Diaion HP 20" or "XAD 7". It is also advantageous and possible to convert the crude product directly further into compounds of the formula (III).

The compounds of formula (VI) can alternatively be prepared from acids of formula (IX), in which R has the above-mentioned

12

meaning and R is optionally substituted alkyl or aryl, such as methyl, ethyl, propyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, phenyl. Particularly preferably, R"*"^ constitutes a methyl group.

The starting compounds of the formula (IX) are suspended in a suitable organic solvent and brought into solution by silylation to silyl ester X. Particularly suitable organic solvents are chloroform, methylene chloride, dichloroethane. The silylation is carried out with a common silylation agent such as trimethylchlorosilane (TMCS), hexamethyldisilazane (HMDS), N,0-bis-(trimethylsilyl)acetamide (BSA), N,O-bis(trimethylsilyl)-trifluoroacetamide (BSTFA), N -methyl-N-trimethylsilylacetamide (MSA), N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), 1,3-bis-(trimethylsilyl)urea or trimethylsilyltrifluoromethanesulfonate.

In this way, several silylation agents can also be used in a mixture.

The silylation takes place at -30°C to +70°C, preferably

at -10°C to +10°C, within 5 minutes to 30 minutes. Preferably, a two to ten times excess of is used

■.silyléxihgsmidtel, f ortrnnnvi-s a two to five times excess.

The thus obtained solution of the trimethylsilyl ester of the formula (X) is reacted at -40°C to +30°C, <preferably with 3-4 equivalents of a trialkylsilyl iodide, particularly preferred trimethylsilyl iodide, during 15 minutes to 2 hours, preferably within 30 minutes to 1 hour, to compounds of formula (XI).

The compounds of the formula (XI) are advantageously not isolated, but reacted directly without purification with amines

to the compounds of formula (VI).

The compounds of general formula I can alternatively also be prepared by reacting compounds of the formula

(XII)

1 12 wherein R and R have the above meaning, as previously described for the reaction of the compounds of formula (VI) directly without isolation of the intermediate steps after silylation and transfer to iodide with amines

to compounds of formula (I).

The compounds according to the invention exhibit enr-strong and

broad antimicrobial activity, especially against gram-negatives

n and gram-positive bacteria. These properties enable use as chemotherapeutically active substances in medicine.

The compounds according to the invention are particularly effective

against bacteria and bacteria-like microorganisms. It is therefore particularly suitable for prophylaxis and chemotherapy in local and systemic infections in human and veterinary medicine, which are caused by these organisms.

For example, local and/or systemic disease states can be treated and/or prevented, which are caused by the following pathogens or mixtures of the following pathogens: Micrococcaceae, such as staphylococci, e.g. Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus aerogenes and Graffkya tetragena;

Lactobacteriaceae such as streptococci, e.g. Streptococcus pyogenes, a- or B-hemolytic streptococci, non-hemolytic streptococci, Streptococcus viridans, Streptococcus faecalis (enterococci) and Dipolococcus pneumoniae (pneumococci);

Enterobacteriaceae, such as Escherichie bacteria of the coli group: Escherichia bacteria, e.g. Escherichia coli, Enterobacter bacteria, e.g. Enterobacter-Aerogenes, Enterobacter-Cloacae, Klebsiella bacteria, e.g. Klebsiella pneumoniae, Serratia, e.g. Serratia marcescens, Proteae bacteria

of the Proteus group: e.g. Proteus vulgaris, Proteus morganii, • Proteus rettgeri, Proteus mitabilis;

Pseudomonadaceae, such as Pseudomonas bacteria, e.g. Pseudomonas aeruginosa;

Bacteroidaceae, such as Baeteroides bacteria, e.g. Bacteroides fragilis.

The above list of disease-causing agents is intended as examples and should not be restrictive.

Diseases that can be prevented, improved and/or cured by the compounds according to the invention can for example be mentioned: Disease states in the respiratory tract and larynx; ear infection, pharyngitis: pneumonia; peritonitis, pyelonephritis; cystitis, endocarditis, systemic infections, bronchitis, arthritis, local infections.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more compounds 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. This means that the preparations are available in the form of individual parts, e.g. tablets, dragées, capsules, pills, suppositories and ampoules, whose content of active substance constitutes a fraction or a multiple of a single dose. The dosage units can e.g. contain 1, 2, 3 or 4 single doses or h, 1/3 or 1/4 single dose. A single dose preferably contains the amount of active substance that is administered in one supply and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable carriers are understood to mean solid, semi-solid or liquid diluents, fillers and composition aids of any kind.

As preferred pharmaceutical preparations can be mentioned■tablets, dragées; capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragées, capsules, pills and granules may contain the active substance(s) in addition to the usual carriers such as (a) bulking and thickening agents, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid. (b) binders, e.g. carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) explosives, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retarders, e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents,

e.g. cetyl alcohol, glycerin monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants,

e.g. talc, calcium or magnesium stearate and solid polyethylene glycols or mixtures of the substances specified under (a) to (i).

The tablets, dragées, capsules, pills and granules may optionally be equipped with ordinary, possibly opacifying agent-containing covers or covers, and also

be composed in such a way that they release the active substance(s) only, or preferentially, in a specific part of the intestinal tract, possibly with delayed release, whereby as embedding masses e.g. polymer substances and waxes can be used.

The active substance(s) may also be present

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

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

carriers, e.g. polyethylene glycols, fats, e.g. cocoa

j fats and higher esters (e.g. C^^-alcohol with C-^g-f acetic acid) or mixtures of these substances.

For parenteral administration, the solutions may also be available

in sterile and blood isotonic form.

The therapeutically active compounds should preferably be present in the above-mentioned pharmaceutical preparations in a concentration of approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the total mixture.

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

The production of the above-mentioned pharmaceutical preparations takes place in the usual way by known methods, e.g.

by mixing the active substance or substances with the carrier fat or substances.

The active substance or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and/or rectally, preferably orally or parenterally as intravenously or intramuscularly.

In general, both within human and also within veterinary medicine, it has proven advantageous to use the active substance(s) according to the invention in total amounts of approx.

1 to approx. 1000, preferably 1 to 200 mg/kg body weight

per day, possibly in the form of several individual injections to achieve the desired result. A single supply contains the active substance(s) according to the invention preferably in amounts from 1 to 250, especially 1 to 60 mg/kg body weight. It may still be required to deviate from those mentioned

the dosages, depending on the type and body weight of

\the object of treatment, the type and severity' of the disease state, the type, and the preparation and the administration form of the medicine

as well as that time period or the interval within which the administration is to take place. Consequently, in some cases it may be sufficient to use less than the amount of active substance stated above, while the amount of active substance stated above must be exceeded in other cases. Determining

in any case, the optimal dosage required and the mode of delivery of the active substance can be easily determined by the person skilled in the art on the basis of his professional knowledge.

The compounds according to the invention can to achieve an expansion

of the spectrum of action is combined with another -lactam antibiotic or also with aminoglycoside antibiotics, such as e.g. gentamycin, sisomycin, kanamycin, amikacin or tobramycin.

The active substances according to the invention can be used

within all areas of animal husbandry as a means of

promote and accelerate growth and improve utilization in healthy and diseased animals.

The activity of the active substance is thereby great

degree regardless of the animal's type and strain. The active compounds have proven to be particularly valuable when breeding young and fattening animals. As animals for which the active substances can be used to promote and accelerate growth and improve utilization, the following useful and companion animals can be mentioned, for example:

Warm-blooded animals such as oxen, pigs, horses, sheep, goats,

cats, dogs, rabbits; fur animals e.g. mink and chinchilla; poultry, e.g. chickens, geese, ducks, turkeys, pigeons, parrots and canaries, and cold-blooded animals such as fish, e.g.

carp, and reptiles, e.g. snakes.

The amount of the active substances administered to

animals to achieve the desired effect, can because of the

the favorable properties of the active substance are varied within wide limits. It is preferably located at approx.

0.01 to 50, especially 0.1 to 10 mg/kg body weight per day. The duration of administration can range from a few hours

or days to several years. The amount of the active substance that is administered, as well as the duration of the administration, depends in particular on the type, the strain, the state of health and the type of housing and feeding for the animal and can be easily determined by the person skilled in the art.

The active substance is administered to the animals by usual procedures. The type of administration depends in particular on the type, conditions and state of health of the animal. Consequently, the administration can take place once or more times a day at regular or irregular intervals, orally

or parenterally. For reasons of expediency, oral administration is preferred in most cases, especially in the rhythm of the animal's food and/or fluid intake. Within the scope of the present invention, "food" means both solid and liquid food as well as drinks and water.

The active substances can be administered as pure substances or in compound form, i.e. in admixture with non-toxic, inert carriers of any type, e.g.

with carriers and in compositions that are common in nutritional preparations.

The active substances are optionally administered in compound form together with pharmaceutically active substances, mineral salts, trace elements, vitamins, egg whites, fats, dyes and/or flavorings in a suitable form.

Oral administration together with the feed and/or drinking water is recommended, where the active substance is added as needed in the total amount or only in parts

of the feed and/or drinking water.

The active substance is added by usual, methods by simple mixing as pure substance mixture, preferably in finely divided form or in compound form in a mixture with edible, non-toxic carriers, possibly in the form of

a premix or a preconcentrate for the feed and/or drinking water.

The feed and/or drinking water may possibly contain the active substance in a weight concentration of approx. 0.01 more

50, especially 0.1 to 10 ppm. The optimal size of the concentration of the active substance in the feed and/or drinking water is particularly dependent on the extent of feed and/or drinking water intake for the animal and can be easily determined by any person skilled in the art.

The type of lining and its composition are irrelevant here. All common or special pre-compositions can be used which preferably contain the usual equilibrium between energy and structural substances necessary for balanced nutrition. The lining can, for example, be composed of vegetable substances, e.g. hay, roots, grains, grain products, animal substances, e.g. meat, fat, bone meal, fish products, vitamins, e.g. vitamin A, D-complex and B-complex, proteins, amino acids, e.g. DL-methionine and inorganic substances, e.g. lime and table salt.

Pre-concentrates contain the active substances on the side

of edible substances, e.g. rye flour, maize flour, soya bean flour or lime, possibly with additional nutritional and structural substances such as proteins, mineral salts and vitamins. They can be prepared by the usual mixing methods.

Preferably in premixes and preconcentrates, the active substances can be protected from air, light and/or moisture, possibly with suitable means that cover the surface, e.g. with non-toxic waxes or gelatin. .Example of the composition of a chicken rearing feed which "contains an inactive substance according to the invention:

200 g wheat, .340 g .maize, 361 g soy waste, 60 g beef tallow,

15 g of dicalcium phosphate, 10 g of calcium carbonate, 4 g of iodized table salt, 7.5 g of vitamin-mineral mixture and 2.5 g of premix of active substance after careful mixing give 1 kg for.

1 kg of premix contains:

600 I.E. vitamin A, 100 I.E. vitamin , 10 mg vitamin E, 1 mg vitamin , 3 mg riboflavin, 2 mg pyridoxine, 20 ug vitamin B^2, 5 mg calcium pantothenate, 30 mg nicotinic acid,

200 mg choline chloride, 200 mg MnS04x H20, 140 mg ZnS04x 7H20, 100 mg FeS04x 7H20 and 20 mg CuS04x 5H20.

The premix of the active substance contains the active substance in the desired amount, e.g. 10 mg and in addition 1 g of DL-methionine as well as so much soybean meal that 2.5 g of premix is produced.

Example of the composition of pig breeding feed containing an active substance according to the invention: 630 g pre-grain waste (composed of 200 g maize, 150 g barley grain-150 g oat and 130 g wheat waste), 80 g fish meal, 60 g soy waste, 60 g tapioca flour, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs (composition e.g. as for chicken feed), 30 g sugar cane molasses and 2 g premix of active substance (composition e.g. as for chicken feed) gives, after careful mixing, 1 kg for .

The indicated premixes are preferably for breeding

and brooding of chickens respectively. pigs, they can still be used in the same or similar composition also for breeding and fattening other animals.

Production examples Example 1

a) - 3 - [ 1, 4- dimethyl- 3-oxo-plpe razinium] methyl- 7g" - phenyl-acetamido- 3- cephem- 4- carboxylate

Under nitrogen, 9.36 g (24 mmol) of 3-acetoxy-methyl-7e-phenylacetamido-3-cephem-4-carboxylic acid are suspended at room temperature in 100 ml of absolute methylene chloride and dissolved by the addition of 15.2 ml (72 mmol) N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA). After cooling to 0°C, 14 ml (96 mmol) of trimethylsilyl iodide are added and the reaction solution is then stirred for one hour at 0°C. 15.3 g (120 mmol) of 1,4-dimethyl-3-oxo-piperazine are then added and the solution is stirred for 30 minutes. 4.8 ml of water are then added and after a further 5 minutes the mixture is poured into 400 ml of ether. The ether is decanted from the oily residue, the residue is stirred out once more with ether and after renewed decantation it is taken up in water and chromatographed over absorbent resin "HP 20" (eluent: acetonitrile/water 5/95). Yield: 5.3 g of a mixture of 2 isomers.

<1>H-NMR (D--DMSO)

6

6(ppm) = 9.20 (l)bd, J = 7 Hz, 7.32 (5)m, 5.61 (l)dd,

J = 7 Hz, J = 5 Hz, 5.12 and 5.10 (l)d, J = 5 Hz,

5.02 (l)bd, J = 13 Hz, 4.33 and 4.18 (l)d, J =

13 Hz, 3.34-4.24 (10)m, 3.10 (3)s, 2.92 (3)s.

b) 7- amino- 3-( 1f4- dimethyl- 3- oxopiperazinium) methyl- 3- cephem-4- carboxylate

Dissolve 5.0 g of 3-(1,4-dimethyl-3-oxopiperazinium)methyl-7e-phenylacet--amido-3-cephem-4-carboxylate in 100 ml of water. It is adjusted to pH 7.8 with 4N triethylamine in ethanol. 6 g of penicillin-G-acylase are then added and the pH is kept constant by the addition of triethylamine. After completion of the enzymatic cleavage, the acylase is filtered off and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. From the precipitate that occurs, the liquid phase is suctioned off over silica gel and the filtrate is added to 2 liters of acetone. The desired

the product crystallizes out as ■hydrochloride and is filtered off with suction and dried. Yield: 3.3 g (x HC1 x H2O) as a mixture of two isomers.

^H-NMR (D20)

6 (ppm) = 5.40 and 5.39 (l)d, J = 5 Hz, 5.19 and 5.18 (l)d,

J = 5 Hz, 4.86 and 4.76 (l)d, J = 13 Hz, 4.24

and 4.21 (l)d, J = 13 Hz, 4.24 (l)d, J = 18 Hz, 4.06 (l)m, 3.62 - 4.00 (5)m, 3.56 and 3.54 (l)d,

J = 18 Hz, 3.17 and 3.15 (3)s, 2.98 (3)s.

c) 78 -[ ( Z )- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 1, 4- dimethyl- 3- oxopiperazinium) methyl- 3- cephem- 4- carboxylate

1.1 g (5.3 mmol) (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid is dissolved under nitrogen at room temperature for 8.1

ml of absolute dimethylformamide. After adding 339 µl of N-ethyl-diisopropylamine, 369 µl of tripropylamine and 456 µl of tributylamine, cool to -50°C. This solution is then quickly added to a solution of 1.6 g (4.0 mmol) 7-amino-3-(1,4-dimethyl-3-oxopiperazinium)methyl-3-cephem-4-carboxylate cooled to 0°C (x HC1 x H2O) in 2.55 mL of water and 2.1 mL of triethylamine. After 5 minutes, the reaction solution is poured on

500 ml of acetone. The resulting precipitate is suctioned off, dried and chromatographed over adsorber resin "HP 20" (eluent: acetonitrile/water 5/95). Yield: 700 mg of a mixture of two isomers.

<1>H-NMR (D,-DMSO)

b

5 (ppm) = 9.63 (l)bd, J = 7 Hz, 7.26 (2)bs, 6.76 (l)s,

5.71 (l)dd, y = 7 Hz, J = 5 Hz, 5.17/5.15 (l)d,

J = 5 Hz, 5.08/5.03 (l)d, J = 12 Hz, 4.32 (l)d,

J = 16 Hz, 4.13 (l)d, J = 16 Hz, 4.13/4.07 (l)d,

J = 12 Hz, 3.87 (3)s, 3.30 - 4.00 (6)m, 3.09 (3)bs, 2.92 (3)s.

Example 2

a) 7- amino- 3-( 4- methylsulfonyl- 1- methylpiperazinium)- methyl 3- cephem- 4- carboxylate

In an analogous example, 4,6,8 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 21 g of 4-methyl-sulfonyl-1-methylpiperazine. The product is precipitated from acetone and cleaved and worked up analogously to example 1b with penicillin G-acylase.

Yield: 1.05 g (x HC 1 x H 2 O).

<1>H-NMR (D20)

(ppm) = 5.39 (l)d, J = 5 Hz, 5.17 (l)d, J =5 Hz, 4.78 (l)d, J---= 13 Hz, 4.14 ( l)d, J = 13 Hz, 3.92 (l)d, J = 18 Hz, 3.40 - 3.80 (9)m, 3.10 (3)s, 3.06 (3)s.

b) 7B-[ Z- 2-( aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-( 4- methylsulfonyl- 1- methylpiperazinium) methyl 1- 3- cephem-4- carboxylate

Analogously to example 1c, 0.5 g of the product from example 2a is reacted with 0.34 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20": 0.56 g.

<1>H-NMR (D,-DMSO)

5(ppm) = 9.55 (l)d, J = 7 Hz, 7.25 (2)bs, 6.73 (l)s,

5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.13 (l)d,

J = 5 Hz, 5.14 (l)bd, J = 13 Hz, 4.06 (l)bd,

J = 13 Hz, 3.83 (3)s, 3.26 (3)s, 3.20 - 4.00 (10)m, 3.04 (3)s.

Example 3

a) 7- amino- 3-( 4-formyl-1- methylpiperazinium) methyl- 3- cephem-4- carboxylate

In an analogous example, 4.68 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 15 g of 4-formyl-1-methyl-piperazine. The product is precipitated from acetone and cleaved and worked up analogously to example 1b with penicillin G-acylase. Yield: 1.2 g (x HC1 x H2O).

<1>H-NMR (D20)

6 (ppm) = 8.02.(l)s, 5.38 (l)d, J = 5 Hz, 5.17 (l)d, J =

5 Hz,l 4.78 (Dd, J = 13 Hz, 4.14 (2)d, J = 13 Hz, 3.70 - 3.98 (3)m, 3.30 - 3.64 (6) m, 3.13 (3) p.

b) 76 -[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- formyl-1- methylpiperazinium) methyl- 3- cephem- 4- carboxylate

Analogously to example 1c, 0.6 g of the product from example 3a is reacted with 0.47 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after purification over adsorber resin "HP 20": 0.2 g.

<1>H-NMR (D,-DMSO)

6

<5(ppm) = 9.62 (l)d, J = 7 Hz, 8.12 (l)s, 7.26 (2)bs,

6.77 (l)s, 5.20 (l)dd, J = 7 Hz, J = 5 Hz,

5.17 (l)d, J = 5 Hz, 5.14 (l)bd, J = 13 Hz,

4.07 (l)bd, J = 13 Hz, 3.87 (3)s, 3.10 (3)s,

3.00 - 4.00 (8)m.

Example 4

a) 7- amino- 3-( 4- aminocarbonyl- 1- methylpiperazinium) methyl 3- cephem- 4- carboxylate

Analogously to the example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with a solution of 34 g of 1-aminocarbonyl-4-methylpiperazine in 150 ml of dimethylformamide. The product is precipitated from ether and cleaved and worked up analogously to example 1b with penicillin G-acylase. Yield 3.1 g (x HC1 x H2O).

<1>H-NMR (D20)

6(ppm) - 5.39 (l)d, J =5 Hz, 5.16 (l)d, J = 5 Hz, 4.80 (l)d, J = 13 Hz, 4.14 (l) d, J = 13 Hz, 3.85 - 4.02 (3)m, 3.35 - 3.72 (7)m, 3.22 (3)s.

b) 7;b'- [ Z- 2-( 2;- aminothiazol-4-yl) -- 2- methoxyimine. oace tamido] - 3-( 4- amino6carbonyl-1- methylpiperazinium) methyl- 3- cephem-4- carboxylate

Analogous to example 1c, 0.98 g of the product from example 4a is reacted with 0.68 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20": 0.9 g.

<1>H-NMR (Dg-DMSO)

(ppm) = 9.58 (l)d, J = 7 Hz, 7.53 (2)bs, 6.72 (l)s, 6.29 (2)bs, 5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.13 (l)d,

J = 5 Hz, 5.09 (l)bd, J = 13 Hz, 3.99 (l)bd,

J = 13 Hz, 3.82 (3)s, 3.18 - 3.92 (10)m, 3.00 (3)s.

Example 5

a) 7-amino- 3-( 4- dimethylaminosulfonyl- 1- methylpiperazinium)-methyl- 3- cephem- 4- carboxylate

Analogously to the example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 49 g of 1-dimethylaminosulfonyl-4-methyl-piperazine. The crude product is cleaved analogously to example 1b with penicillin G-acylase.

Yield 2.0 g (x HC1 x H2O).

<1>H-NMR (D20)

6(ppm) = 5.39 (l)d, J = 5 Hz, 5.96 (l)d, J = 5 Hz, 4.82 (l)d, J = 13 Hz, 4.18 (l) d, J = 13 Hz, 3.98 (l)d, J = 18 Hz, 3.48 - 3.80 (9)m, 3.13 (3)s, 2.89 (6)s.

b) 7 B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- dimethylaminosulfonyl- 1- methylpiperazinium) methyl-3- cephem- 4- carboxylate

Analogously to example 1c, 0.9 g of the product from example 5a is reacted with 0.55 g of Z-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.45 g.

1H-NMR (Dr-DMSO)

b

(ppm) = 9.59 (l)d, J =7 Hz, 7.24 (2)bs, 6.74 (l)s,

5-, 6 7 (l)dd, j ■= 7 Hz, J = 5 Hz, 5.13 (l)d, J =

5 Hz, 5.14 (l)bd, J - 13 Hz, 4.03 (l)bd, J =

13 Hz, 3.84 (3)s, 3.81 (l)d, J = 18 Hz, 3.20 - 3.60 (9)m, 3.04 (3)s, 2.82 (6 )p.

Example 6

a) 7- amino- 3-( 4- acetyl- 1- methylpiperazinium) methyl 1- 3- cephem-4- carboxylate

In an analogous example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylate were reacted with 34 g of 1-acetyl-4-methyl-piperazine. After chromatography of the crude product which is precipitated from ether on adsorber resin "HP 20", 7.5

g 3-(4-acetyl-1-methylpiperazinium)methyl-7-B-phenylacetmido-3-cephem-4-carboxylate, which is cleaved analogously to example 1b with penicillin G-acylase.

Yield 3.2 g (x HC1 x H2O).

<1>H-NMR (D20)

5 (ppm) = 5.31 (l)d, J = 5 Hz, 5.08 (l)d, J = 5 Hz, 4.80 (l)d, J = 13 Hz, 4.10 (l) d, J = 13 Hz, 3.20 - 4.00 (10)m, 3.05 (3)s, 2.03 (3)s.

b) 7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- acetyl- 1- methylpiperazinium) methyl- 3- cephem- 4- carboxylate

Analogously to example 1c, 1.59 g of the product from example 6a is reacted with 1.24 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.8 g.

1H-NMR (D,-DMSO)

D

(ppm) = 9.61 (l)d, J = 7 Hz, 7.26 (2)bs, 6.75 (l)s, 5.69 (l)dd, J = 7 Hz, J = 5 Hz , 5.16 (l)d, J = 5 Hz, 5.15 (l)bd, J = 13 Hz, 4.03 (l)bd, J = 13 Hz,

3.86 (3)s, 3.2 - 4.0 (10)m, 3.07 (3)s, 2.07 (3)s.

Example 7

a) 7-amino-3-(4-tert-butoxycarbonyl-1-methylpiperazinium)-_v . methyl- 3- cephem- 4- carboxylate

In an analogous example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylate were reacted with 48 g of 1-methyl-4-tert-butoxycarbonylpiperazine. The crude product is cleaved analogously to example 1b with penicillin G-acylase. Yield 1.9 g (x HC1

x H 2 O).

"""H-NMR (D20)

6 (ppm) = 5.29 (l)d, J = 5 Hz, 5.06 (l)d, J = 5 Hz,

4.64 (l)d, J = 13 Hz, 4.00 (l)d, J = 13 Hz, 3.75-4.00 (3)m, 3.20 - 3.55 (7)m, 2.98 (3)s, 1.32

(9)p.

b) 7- 8 -[ Z- 2-( 2- aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-( 4- tert- butoxycarbonyl- 1- methylpiperazinium) methyl-3- cephem- 4- carboxylate

Analogously to example 1c, 0.85 g of the product from example 7a is reacted with 0.52 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20" 0.2 g.

<1>H-NMR (Dg-DMSO)

(ppm) = 9.64 (l)d, J = 7 Hz, 7.30 (2)bs, 6.77 (l)s,

5.70 (l)dd, J = 7 Hz, J = 5 Hz, 5.17 (l)d, J

= 5 Hz, 5.14 (l)bd, J =. 13 Hz, 4.03 (l)bd, J =

13 Hz, 3.87 (3)s, 3.24 - 3.95 (10)m, 3.05 (3)s, 1.45 (9)s.

Example 8

a) 7-amino- 3-[ 4-( 3- hydroxypropyl)- 1- methylpiperazinium]-methyl- 3- cephem- 4- carboxylate

In an analogous example, 4.68 g of 3-acetoxymethyl-7B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 19 g of 4-(3-hydroxy-propyl)-1-methyl-piperazine. The product is precipitated from acetone and split and worked up analogously to example 1b with penicillin

G-acylase.

Yield: 2.3 g (x HCl x H 2 O).

<1>H-NMR (D20)

(ppm) = 5.47 (l)d, J = 5 Hz, 5.26 (l)d, J = 5 Hz,

4.97 (l)d, J - 15 Hz, 4.37 (l)d, J .= 15 Hz,

4.02 (l)d, J =18 Hz, 3.70-3.90 (10)m, 3.64 (1) d, J = 18 Hz, 3.45 (2)m, 3.33 ( 3)s, 2.04

(2) m.

b) 7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3- 4-( 3- hydroxypropyl)- 1- methyl piperazinium - methyl- 3- cephem- 4- carboxylate

Analogously to example 1c, 1.0 g of the product from example 8a is reacted with 0.66 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.68 g.

<1>H-NMR (D,-DMSO)

6

(ppm) = 9.60 (l)d, J = 7 Hz, 7.27 (2)bs, 6.74 (l)s,

5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.15 (l)d,

J = 5 Hz, 5.08 (l)d, J = 14 Ha, 4.02 (l)d,

J = 14 Hz, 3.83 (3)s, 3.81 (l)d, J = 18 Hz,

3.30 - 3.50 (7)m, 2.97 (3)s, 2.40 - 2.80 (6)m, 1.55 (2)m.

Example 9

7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyimnoacetamido]- 3-( 4- aminocarbonyl- 1- ethylpiperazinium) methyl- 3- cephem- 4-carboxylate

<1>H-NMR (D,-DMSO)

6

(ppm) = 9.64 (l)d, J = 7 Hz, 7.29 (2)bs, 6.77 (l)s,

6.33 (2)bs, 5.68 (l)dd, J = 7 Hz, J = 5 Hz,

5.10 (l)d, J = 13 Hz, 5.08 (l)d, J = 5 Hz,

3.96 (l)d, J = 13 Hz, 3.88 (3)s, 3.20 - 3.92 (12)m, 1.26 (3)m.

' Example 10

7B - [ Z-2 - ( 2- aminothiazol-4-yl ).- 2- methoxyiminoacetamido] - 3-[ 4-( 2-- hydroxyethyl) - 1- methylpiperazinium] methyl- 3- cephem-4- carboxylate

—H-NMR, (D-DMSO)

D

6 (ppm) = 9.64 (l)d, J = 7 Hz, 7.30 (2)bs, 6.78 (l)s,

5.70 (l)dd, J = 7 Hz, J = 5 Hz, 5.18 (l)d, J =

5 Hz, 5.12 (l)d, J = 13 Hz, 4.01 (l)d, J = 13

Hz, 3.88 (3)s, 3.85 (l)d, J = 18 Hz, 3.20 -

360, (7)m, 3.01 (3)s, 2.40 - 280 (6)m.

Example 11

76-[ Z- 2-( 2- aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-[ 1- methyl- 4-( 2- oxoimidazolidino) carbonylpiperazinium]- methyl-3- cephem- 4- carboxylate

<1>H-NMR (D.--DMSO)

(ppm) = 9.61 (l)d, J = 7 Hz, 7.50 (l)bs, 7.28 (2)bs,

6.76 (l)s, 5.69 (l)dd, J = 7 Hz, J = 5 Hz,

5.16 (l)d, J = 13 Hz, 5.15 (l)d, J = 5 Hz,

4.05 (l)d, J = 13 Hz, 3.88 (3)s, 3.20 - 3.96 (14)m, 3.08 (3)s.

Example 12

7g-[ Z- 2-( 2- aminothiazol- 4- yl)- 2- methoxyiminoacetamido]- 3-[ 1- methyl- 4-( 3- methylsulfonyl- 2- oxoimidazolidino) carbonyl-piperazinium] methyl- 3- cephem- 4- carboxylate

-H-NMR (Dg-DMSO)

(ppm) = 9.58 (l)d, J = 7 Hz, 7.24 (2)bs, 6.73 (l)s,

5)67 (l)dd, J = 7 Hz, J = 5 Hz, 5.15 (l)d,

J = 13 Hz, 5.12 (l)d, J = 5 Hz, 4.04 (l)d,

J = 13 Hz, 3.84 (3)s, 3.20 - 3.98 (14)m,

3.35 (3)s, 3.08 (3)s.

Claims (19)

1. Cephalosporins of general formula (I) kva'."r acted by at stands for straight chain or branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 6 C atoms, R stands for straight-chain or branched alkyl with 6 C atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl all with up to 3 C atoms, halogen or cyano, R"^ stands for straight-chain, branched or cyclic, saturated '•■. Or unsaturated alkyl with up to 10 C atoms which optionally is substituted by - OH, CHO, OCONH-, NHCONH- 5 5 5 - with the groups COOR , NHCOR , COR , in which R stands for hydrogen, alkyl with up to 8 C atoms, alkyl with 6-10 C atoms or C^-C-^-aralkyl, - with halogen, cyano, SO^H, - with the groups or in which R and R<7> independently of each other stand for hydrogen or together or separately for C-^-Cg-alkyl, C^-Cg-alkenyl or phenyl, or where the substituents R^, R optionally together with the nitrogen atom form a 5 - to a 7-membered ring, which, as an additional heteroatom, can contain an oxygen, sulfur and/or 1-2 nitrogen atoms, and which is optionally substituted with C₁-C₁-alkyl, or - with the groups -SO2~Y- or -O-Y, wherein Y stands for C-^-C8 alkyl, aryl with 6-10 C atoms or stands for C7-C14~aralkyl, and R4 a) stands for straight-chain, branched or cyclically saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted with OH, CHO, OCONH-, -NHCONH-, S 5 5 with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C 1 -C 4 -aralkyl, with halogen, cyano, SO,H, in which 6 7 R and R independently of each other stand for hydrogen or stand together or alone for C 1 -C 8 -alkyl, C 6 -C 7 -alkenyl or . phenyl■or, where the substituents R , R optionally with the nitrogen atom form a 5- -'.'" to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulphur, and/or 1-2 nitrogen atoms and which is optionally substituted with C 1 -C 4 alkyl, or with the group -SO2-Y or -O-Y in which Y stands for C₁-C₆ alkyl, aryl with 6-10 C atoms or stands for C7~C^4-aralkyl, b) stands for CHO, SO3H, c) stands for COOR 5 , in which R 5 has the above meaning, or d) stands for the group -Z-R 8, in which Z stands for or -SO.,- and R 8 stands for straight-chain, branched or cyclically saturated or unsaturated alkyl with up to Cg, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio all with up to 6 C atoms, aryloxy, arylthio with up to 10 C atoms, carboxy, C^-Cg- 6 7 where R , R has the above meaning, - stands for aryl with 6-10 C atoms, - for C7-C14~aralkyl - for heterocyclyl or - for the group 6 7 in which R , R has the meaning given above. 2. Cephalosporins according to claim 1, characterized in that the residues is substituted with up to four identical or different substituents from the group consisting of a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted again - with -OH, CHO, -OCONH2, -NHC0NH2, - with the groups COOR5, NHCOR5, COR<5>, in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, " aryl with 6-10 C atoms or C^-C-^-aralkyl, in which R^ and R<7> independently of each other stand for hydrogen or together or individually for C^-C^-alkyl, Cy-C^-alkenyl or phenyl or where the substituents R , R optionally together with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C^-C^-alkyl, or - with the group -SO-^Y or -O-Y in which Y stands for C-^-Cg-alkyl, aryl with 6-10 C atoms or - stands for Cy-C-^-aralkyl or o ,b) the group -Z-R^, wherein 1Z stands for or -SO.-,- and R 8 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio all with 6 C atoms, aryloxy, arylthio (6-10 C atoms), carboxy, C-^-Cg -Alkoxycarbo- in which R 6 , R 7 have the meaning given above, - stands for aryl with 6-10 C atoms, - for C7-C14 aralkyl, - for heterocyclyl or 6 7 in which R , R again have the meanings given above, c ) -OH, CHO, OCONH2, NHCONH2, - d) the groups COOR<5>, NHCOR<5>, COR<5>, in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or C7-C14 aralkyl, R and R have the above meaning, g) the group -0-Y, in which Y stands for C-1-C8-alkyl, aryl with -6-10 C-atoms or - ■ stands for- C-1-C4-aralkyl. 3. Cef alosporins according to claim 1, characterized in that R stands for a straight chain, branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 4 C atoms, R 2 stands for straight-chain or branched alkyl with up to 4 C atoms, which is optionally substituted with hydroxy, carboxy, methoxy, methoxycarbonyl, fluorine, chlorine or bromine, in which R<3> stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is optionally substituted - with OH, CHO, OCONH^, NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 6 C atoms, phenyl or benzyl, - with fluorine, chlorine, bromine or SO,H, wherein in R^ and R7 independently ■ of each other stand for. hydrogen, fo6 r C7,-C-.-alkyl or phenyl or where the substituents R , R optionally with the nitrogen atom form a 5- or 6-membered. ring, which, as further heteroatoms, may contain oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C^-C-^-alkyl, or - with the group -SC^-Y or - 0-Y, in which Y stands for C₁-C₁-alkyl, phenyl or benzyl, and R<4>a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is at least singly substituted - with OH, CHO, OCONH-, NHCONH-, - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 6 C atoms, phenyl or benzyl, 6 7 in which R and R have the meanings given above, - with the group -SO2-Y or -O-Y in which Y stands for C--C8-alkyl, phenyl or benzyl, or b) stands for CHO or SO3H, c) stands for COOR<5>, in which R5 has the meaning indicated above, or ■ * > d)..stands for the group -Z-R 8, in which Z stands for or -SC^- and R 8 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with fluorine, chlorine, bromine, hydroxy, carboxy, alkoxy or alkylthio with up to 3 C atoms, phenyloxy, phenylthio, alkoxy- in which R^ and R<7> have the meanings given above, - stands for phenyl, - for benzyl, - for pyridyl, furyl, thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, oxazolyl, morpholinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl or piperazinyl, or - stands for the group in which 6 7 R and R have the meanings given above. 4. Cephalosporins according to claim 1, characterized in that R"<*>" stands for methyl, ethyl, allyl or 1-carboxy-1-methylethyl, R 2 stands for methyl, ethyl, 2-hydroxyethyl or carboxymethyl, the rest groups stands for those possibly substituted in which R stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with; up to 6 C atoms, which are optionally substituted - with OH, CHO, OCONH_, NHCONH-, - with the groups COOR , NHCOR .or COR , in which R<5> stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl, in which R^,R<7> independently of each other stand for hydrogen, methyl, ethyl, phenyl or together with the nitrogen atom form a ring such as pyrrolidine, piperazine, piperidine, morpholine or thiomorpholine, or - with the group -SO2"Y or -O-Y , in which Y stands for alkyl with up to 4 C atoms, phenyl or benzyl, and 4 o R a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is at least singly substituted - with OH, CHO, OCONH-, NHCONH, 5 5 5 - with the groups COOR, NHCOR, COR, in which R 5 stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl, - with fluorine, chlorine or SO-,H, - with the groups or in which 6 7 R and R have the meanings given above, or - with the group -SO2-Y or -0-Y, in which Y stands for alkyl with up to 4 C atoms, phenyl or benzyl, or b) stands for CHO or SO3H, c) stands for COOR<5>, in which R5 has the meaning given above, or d) stands for the group -Z-R g in which Z stands for or -SO2- and R 8 stands for straight chain or branched, saturated or unsaturated alkyl with up to 4 C atoms, which is optionally substituted with chlorine, fluorine, hydroxy, carboxy, in which 6 7 R and R have the above meanings, - stands for phenyl, - for benzyl, - for pyridyl, furyl, thienyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, or - for the group wherein R<6><,>.R7<.>again have the meanings given above. 5. Cef allosporins according to claim 1, characterized are substituted with a substituent from the group consisting of: a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted again - with OH, CHO, OCONH-, NHCONH-, - with the group COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl, - with fluorine, chlorine, SO^H, - with the group in which R^ and R<7> independently of each other stand for hydrogen, methyl, ethyl, phenyl or where R 6 , R 7 together with the nitrogen atom form a ring such as pyrrolidine, piperidine, pierazine, morpholine or thiomorpholine, or - with the group -SO2 ~Y or 0-Y, in which Y stands for alkyl with up to 4 C atoms, phenyl or - benzyl, g b) the group -Z-R in which Z stands for or _SO2- and R 8 stand for straight-chain, branched, saturated or unsaturated .alkyl mecl up to'4'C atoms, which are optionally substituted tuated with fluorine, chlorine, hydroxy, carboxy, OCONH2, in which 6 7 R , R have the above meanings, - stands for phenyl, - for benzyl, - for pyridyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, morpholinyl, piperidinyl or - stands for the group in which 6 7 R , R again has the above meaning, c) OH, CHO, OCONH2, NHCONH2, d) the groups COOR5, NHCOR<5>, COR<5>, in which R<5> has the above meaning, e) fluorine, chlorine, SO,H, f) the group in which R 6 , R 7 again have the meaning indicated above, or g) the group -0-Y in which Y stands for alkyl with up to 4 C atoms, phenyl or benzyl. 6. Process for the preparation of cephalosporins of general formula (I), in which R stands for straight chain or branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 6 C atoms, R stands for straight-chain or branched alkyl with up to 6 C atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, R 3 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted - with -OH, CHO, OCONH-, NHCONH-,, 5 5 5 - the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or for C7-C14 aralkyl, - with halogen, cyano, SO^H, - with the groups in which R^ and R<7> independently of each other stand for hydrogen or together or separately for C-C-C-alkyl, C-C-C-Alkenyl or phenyl, or where the substituents R, R optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C^-C^-alkyl, - or with the group - SC^-Y or -0-Y, in which Y stands for C^-Cg-alkyl, aryl with 6-10 C atoms or - stands for C^-C^-aralkyl, and R 4 a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted - with OH, CHO, OCONH^, -NHCONH-, - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C-,-C14-aralkyl, - with halogen, cyano, SO..H, or in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C₁-C₂-alkyl, C₂-C₆-alkenyl or phenyl or in which the substituents 6 7 R ,'!R. optionally with the nitrogen atom forming a 5- to 7-membered ring; which, as additional heteroatoms, can contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which are optionally substituted - with C-L~C4-alkyl, or - with the group -SC^-Y or -0- Y in which Y stands for C3-C8-alkyl, aryl with 6-10 C atoms or - stands for C7-C14-aralkyl, b) stands for CHO, SO3H, c) stands for COOR in which 5 R has the meaning stated above, or d) stands for the group -Z-R<8>, in which Z stands for or -SO2- and R 8 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to Cg, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio with up to 6 C-atoms, aryloxy, arylthio with up to 10 C-atoms, carboxy, C,-C,-alkylthio in which 6 7 R , R has the above meaning, - stands for aryl with 6-10 C atoms, - for Cy-C^4~aralkyl, - for heterocyclyl or - for the group in which R6 ■ and R<7> have the meanings indicated above, characterized by reacting compounds of the general formula (II) wherein R"<*>" has the above meaning, in which the amino group may be protected or unprotected, after activation of the carboxyl group by transfer in a mixed anhydride, by transfer in the acid halide or by transfer in an activated ester, with compounds of general formula (III) in which has the above-mentioned meaning, then optionally the protecting group is removed and thereby the desired salts are produced or from the salts the free acids. 7. Process according to claim 6, characterized in that the carboxylic acids of general formula (II) are activated without an amine protecting group and then coupled with the B-lactams of formula (III), which are brought in the form of salts. in■solution:with an amine. 8. Method according to claim 6, characterized in that the carboxylic acids of general formula (II) are activated with sulfonic acid derivatives of formula (V) to anhydrides of formula (IV) according to the reaction scheme in which T stands for the residue R -S0--0- or halogen, and R 9 stands for alkyl with up to 10 C atoms, which is optionally substituted with fluorine, chlorine, cyano, phenyl, alkoxycarbonyl, alkoxy or alkyl with up to 4 C atoms, or - stands for phenyl which is optionally substituted with fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio, alkoxycarbonyl with up to 4 C atoms, nitro, trifluoromethyl or phenyl. 9 . Process according to claim 8, characterized in that the carboxylic acids of formula (II) and 1-1.4 equivalents of an amine dissolved in a solvent are allowed to react with 1-1.2 equivalents of a sulphonic acid derivative of formula (V). 10. Process according to claims 6-10, characterized in that diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform or dimethylformamide is used as solvent for the reaction. 11. Method according to claims 7-10, characterized in that triethylamine, tributylamine or diisopropylamine, or mixtures of these amines, are used as amines. 12 . Method according to claims 6-11, characterized in that the reactions are carried out at temperatures between -80°C and room temperature. 13 . Method according to claim 7, characterized in that the activation of the carboxylic acids of general formula (II) takes place by transfer in an activated ester with N-hydroxysuccinimide and dicyclohexylcarbodiimide or with 1-hydroxybenztriazole and dicyclohexylcarbodiimide. 14 . Method according to claim 13, characterized in that the reaction is carried out at temperatures between -30°C and +100°C. 15. Cephalosporins of general formula (I) in which R<1> stands for straight chain or branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 6 C atoms, R 2 stands for straight-chain or branched alkyl with up to 6 C-atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C-atoms, halogen or cyano, R^ stands for straight-chain, branched or cyclic , saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted - with -OH, CHO, OCONH-, NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which 5 R stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C7-C,.-aralkyl, - with halogen, - with the groups in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl or phenyl, or in which the substituents R , R optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C-^-C^-alkyl, or - with the group -SO2-Y or -0-Y, in which Y stands for C^Cg-alkyl, aryl with 6-10 C atoms or - stands for C-,-C^-aralkyl, and R 4 a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted, - with OH, CHO, OCONH.,, -NHC0NH2, -;with the groups COOR5, NHCOR<3>, COR5, in which R 5 stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or C^-C^^-aralkyl, in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C--C8-alkyl, C-1-C8-alkenyl or phenyl or where the substituents R, R optionally with the nitrogen atom form a 5- to 7- membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C^-C^alkyl, or - with the group -SO2~Y or -O-Y in which Y stands for C-^-C8-alkyl, aryl with 6-10 C atoms or - stands for C7-C14-aralkyl, b) stands for CHO, SO3H, c) stands for COOR<5>wherein R 5 has the above stated meaning, or d) stands for the group -Z-R, in which Z stands for or -SO2~and R 8 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with. until Cg, as appropriate is substituted with halogen, hydroxy, cyano, alkoxy, alkylthio with up to 6 C atoms, aryloxy, :■; , arylthio with up to 10 C atoms, carboxy, c±~ cq~ alkoxycarbonyl, -OCONH2, -NHCONH2, SO3H or in which 6 7 R , R have the meanings given above, - stands for aryl with 6-10 C atoms, - stands for C7-C14~aralkyl, - stands for heterocyclyl or - stands for the group in which R^ and R<7> have the above stated meanings, for use in the therapeutic treatment of human and animal bodies. 16. Medicinal product containing cephalosporins of general formula (I) in which R"*" stands for straight-chain or branched, saturated or unsaturated, possibly carboxy-substituted alkyl with up to 6 C atoms, R 2 stands for straight-chain or branched alkyl with up to 6 C atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, R 3 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted - with -OH, CHO, OCONH-, NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or for C^-C-^-aralkyl, - with halogen, cyano, SO-.H, in which R 6 and R 7 independently of each other stand for hydrogen or together or individually for C-C-C-alkyl, C-C-C-alkenyl or phenyl, or where the substituents R^, R optionally with the nitrogen atom form a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C-^-C^-alkyl, or - with the group -SO2-Y or -0-Y, in which Y stands for C-^Cg-alkyl, aryl with 6-10 C atoms, or - stands for C^-C^-aralkyl, and R<4>a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted - with OH, CHO, OCONH,, -NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or stands for c-j~ ci^~ aralkyl, wherein R^ and R<7> independently of each other stand for hydrogen or together or individually for C--C8-alkyl, C2-C8-alkenyl or phenyl and where the substituents R:, -.."R< 7> optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C-^-C4-alkyl, or - with the group -S02~Y or -0-Y in which Y stands for C-^-C8 alkyl, aryl with 6-10 C atoms, or - stands for Cy-C^-aralkyl, b) stands for CHO, SO3H, c) stands for COOR 5 , in which R 5 has the above meaning, or d) stands for the group -Z-R , in which Z stands for or -SC^- and „i R 8 stands for straight chain, branched or .cyclic, saturated or unsaturated alkyl with up to Cg, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio with up to 6 C atoms, aryloxy, arylthio with up to 10 C atoms, carboxy, C,-Cg-alkoxycarbonyl, -OCONH2 , -NHCONH-, SCUH in which 6 7 R , R has the meaning stated above, - stands for aryl with 6-10 C atoms, - stands for C^-C^-aralkyl, - stands for heterocyclyl or - stands for the group in which 6 7 R , R have the meanings indicated above. 17 . Use of cephalosporins of general formula (I) in which stands for straight chain or branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 6 C atoms, R 2 stands for straight-chain or branched alkyl with up to 6 C atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, R 3 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted - with -OH, CHO, OCONH-, NHCONH-, 5 5 - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or represents C7-C1-aralkyl, ■in which R 6 and R 7 independently of each other stand for hydrogen or together or individually stand for C-^-C8-alkyl, C2-C^-alkenyl or phenyl, or where the substituents R^, R optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C-^-C^-alkyl, or - .with the group -SG^-Y or -0-Y, in which Y stands for C^-Cg-alkyl, aryl with 6-10 C atoms or - stands for C^-C^-aralkyl, and R 4 a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted - with OH, CHO, OCONH-, -NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C7-C14~aralkyl, in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C 1 -C 8 -alkyl, C 1 -C 1 -alkenyl or phenyl or where the substituents 6 67 R-, R optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C^-<C> 4~alkyl, or with the group -SO2-Y or -0-Y, in which Y stands for C-^-Cg-alkyl, aryl with 6-10 C atoms or - stands for Cy-C-^-aralkyl, b) stands for CHO, SO3H, c) stands for COOR<5>, in which R5 has the above meaning, or d) stands for the group -Z-R 8, in which Z stands for C or -S0-- and ii 0 R 8 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to Cg, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio with up to 6 C atoms, aryloxy, arylthio with up to 10 C atoms, carboxy, c^_cg- in which 6 7 R , R has the above meaning, - stands for aryl with 6-10 C atoms, - stands for C^-C-^-aralkyl, - stands for heterocyclyl or - for the group in which R^, R7 have the above stated meanings, in the therapeutic treatment of human or animal bodies. 18. Use of cephalosporins of general formula (I) in which R stands for straight chain or <branched, saturated or unsaturated, optionally with carboxy-substituted alkyl with up to 6 C atoms, R stands for straight-chain or branched alkyl with up to 6 C atoms, which is optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, R 3 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally substituted - with -OH, CHO, OCONH-, NHCONH-, 5 5 5 - with the groups COOR , NHCOR , COR , in which R 5 stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or for C7-C4-aralkyl, in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C-^-Cg-alkyl, C2-Cg-alkenyl or phenyl, or in which the substituents R<6>, R<7> optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C-^-C^-alkyl, or with gr .up -SO.-,-Y .'or -0-Y, in which Y stands for C-^-C<g>--alkyl, • aryl with'6-10 C atoms or - for C 1 -C 2 -aralkyl, and R 4 a) stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted - with OH, CHO, OCONH^, -NHCONH-, - with the groups COOR , NHCOR , COR in which R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or stands for C^-C^-aralkyl, in which R 6 and R 7 independently of each other stand for hydrogen or together or separately for C-^-Cg-alkyl, C_6 -C,-alkenyl or phenyl or in which the substituents R , R optionally with the nitrogen atom form a 5- to 7- membered ring which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C1-C4-alkyl, or - with the group -SO2-Y or -O-Y in which Y stands for C-^-Cg-alkyl, aryl with 6-10 C atoms or - stands for C^-C-^-aralkyl, b) stands for CHO, SO3H, c) stands for COOR<5>, in which . R 5 has the above meaning, or d) stands for the group -Z-R<8>, in which Z stands for or -SO2- and R 8 stands for straight chain, branched or cyclic, saturated or unsaturated alkyl with up to Cg, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio with up to 6 C atoms, aryloxy, arylthio with up to 10 C atoms, carboxy, C 1 -C 6 -alkylthio in which R^, R7 have the above-mentioned meanings, - stands for aryl with 6-10 C_atoms, - stands for C^-C^-aralkyl, - stands for heterocyclyl or - stands for the group wherein R^ and R<7> have the meanings given above, for the manufacture of pharmaceuticals. 19 . Use of cephalosporins according to claims 1-5 in animal nutrition. 20. .. ' Animal remedy or ■ expensive pharmaceutical premix, characterized by the content of cephalosporins according to claims 1-5.