NO864475L - CEPHALOSPORIN DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Abstract

Cephalosporin derivatives of the formula <IMAGE> pharmaceutical preparations active against bacterial infections and which contain such cephem derivatives, process for the production of the pharmaceutical preparations and use of the cephem derivatives for combating bacterial infections.

Description

The invention relates to new cephalosporin derivatives which are substituted in the 3' position of the cephem ring with the imidazole ring bound above the nitrogen thorn, and which have a very good antimicrobial effect against gram-positive and gram-negative bacteria, and there-

for a drug suitable for the treatment of microbial infection ^samt—eft-£j£©mg^n-g-små-tee-H^

The object of the invention is therefore cephalosporin derivatives of the general formula I

and their physiologically tolerable acid addition salts, wherein

R1 means hydrogen or halogen,

2

R means hydrogen,

C 1 -C 8 alkyl may be substituted one or more times

the same or different with halogen, aryl, heteroaryl, C-^-C4~alkylthio, C-^-C^-alkyl, nitrile or carbamoyl, the amino group may be substituted once or twice, the same or different with C^-Cg-alkyl , hydroxy-(C^-C^)-

alkyl, hydroxy or methoxy,

■ C2-C8-alkenyl, which may optionally be substituted by or

several times the same or different with halogen.

C2-C6-alkynyl, which may optionally be substituted with

halogen,

C₁-C₁-cycloalkyl which may optionally be substituted with

halogen,

C4-C7~cycloalkenyl,

C₁-C₁-cycloalkylmethyl,

important information

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the groups -CH2=CH-R<7>or _(CH2)n

where m and n resp. means 0 or 1,

and R 5 and R f can be the same or different and mean hydrogen, aryl or a C^-C^-alkyl group, or together with the carbon to which they are attached form a methylene or a C^-C^-cycloalkylidene group,

R 7 means a HOOC or C 1 -C 4 -alkylOOC group,

R 1 means an imidazol-1-yl residue

which may be substituted one or more times by C-^-Cg-alkyl which may be substituted one or more times-

is with hydroxy, acetoxy, carbamoyloxy, chlorine, carboxy, C-^-Cg-alkyloxycarbonyl, formyl, C-^-Cg-alkylcarbonyl,

cyano, carbamoyl, amino, C-^-Cg-alkyloxy, and since two neighboring alkyl groups can also be joined to an even

tually with C-^-C8-alkyl, halogen, hydroxy, oxo, carboxy, carbamoyl substituted di- to decamethylene ring, in which a C atom is replaced by an oxygen or sulfur atom, which

may contain one or two double bonds,

with C2~C8-alkenyl which may be substituted with hydroxy,

with C 1 -C 1 -alkynyl,

with C3-C8 cycloalkyl,

with C0-C1-cycloalkylmethyl,

with phenyl or benzyl, which may be substituted with C-L-C4-alkyl, halogen, hydroxy, C1-C4-alkyloxy, or

with C 1 -C 8 -alkylthio or with C 1 -C 8 -alkylthio,

with halogen, trifluoromethyl, cyano, hydroxy or more

capto,

with carboxy, C 1 -C 8 -alkoxycarbonyl or carbamoyl, which may be substituted once or twice at the nitrogen atom

is with C-1-C8-alkyl, hydroxy or methoxy, with carba-

zoyl, which at nitrogen may be substituted once or twice by C^-C^-alkyl, by nitro, amino or di-(C1~C2)-alkylamino,

with formyl, C 1 -C 4 -alkylcarbonyl or arylcarbonyl,

R 4 denotes hydrogen, C 1 -C 8 -alkyl, benzhydryl, allyl, propar-

gyl, raethoxymethyl, C-^-Cg-alkanoyloxy-C-j^-Cg-alkyl, C-^-Cg-alkoxycarbonyloxy-C1-Cg-alkyl, phthalidyl or 5-methyl-1,3-dioxolen-2-one-4 -y1-mety1, and in which the R<2>0 group is in the syn position.

As particularly preferred, for example the following substituents are taken into consideration:

R"*-: hydrogen, fluorine, chlorine, bromine,; R 2: a C-^-C^-alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, which may preferably be one or more times 1 to 4 times especially 1 to 2 times substituted for example with fluorine, such as in particular monofluromethyl, difluoromethyl, trifluoromethyl 1, 1,1, 2, 2-tetrafluoroethyl, 1,1,1-trifluoroethyl, 1,1 ,2,2-tetrafluoropropyl, with aryl, such as for example with phenyl, 2- or 3- or 4-tolyl, 2- or 3- or 4-chloro-phenyl, substituted alkyl, especially benzyl, ;with heteroaryl substituted alkyl such as for example 1,3-thiazol-4-yl-substituted alkyl especially 1,3-thiazol-4-ylmethyl or with imidazolyl substituted alkyl such as for example imidazol-1-yl-;ethyl,;with C ^-C^-alkylthio substituted alkyl, such as especially methyl-thiomethyl, with C^-C^-alkyloxy-substituted alkyl, such as especially methyloxymethyl, ethyloxymethyl, ethyloxyethyl, with nitrile or carbamoyl substituted alkyl, the amino group may also be substituted in addition one or two times, for example, with C^-C4~alkyl, such as sp especially N-methyl- or N-ethyl- or N-propyl-carbamoylmethyl, N,N-dimethyl-carbamoylmethyl, N-hydroxy- or N-methoxycarbamoyl-methyl, N-methyl-N-hydroxycarbamoylmethyl; or N-hydroxymethyl -carbamoy1-methyl1,;C2-C8-alkenyl radical such as in particular 2-propenyl, 2-butenyl, which may be substituted one or more times, preferably one to two times with halogen, such as in particular 3-chloro-2-propenyl1, 2- bromo-2-propenyl, ;C"2-C8-alkynyl, such as in particular propargyl,;<C>3-<C>7-cycloalkyl, such as in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, ;C3-C7-cycloalkylmethyl, such especially cyclopropyl- and cyclo-butylmethyl, ;C.-C7-cycloalkenyl, such as especially cyclopenten-1-yl,; the group ; ; 7 R where R means the group COOH, and R ; and R can be the same or different and mean hydrogen, aryl, preferably phenyl, C₁-C₂-alkyl, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, preferably methyl, ethyl, especially methyl, or where R 5 and R 6 together with the carbon atom to which they are attached can form a methyl group or a C3-C7 cycloalkylidene group which e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, ;m = 0 or 1,;n = 0 or 1, the sum of m and n meaning 1 or 2.;Preferred examples for the group ; ; is the following:; For the case that n = 0, and m = 1: CH(CH3), C(CH3)2, CH(C2H5) ; CHC2H5, CH(CH2)9CH3, ;for the case that m = 0 and n = 1: -CH2-, and if n and m = 1: -CH2-C(=CH2)-, ;R 3: an imidazole- 1-yI residue, may be substituted one or more times, preferably 1 to 3 times, especially 1 to 2 times, for example with optionally 1 to 2 times, preferably optionally once substituted C-^-C^-alkyl, such as especially methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, or also resp. 2 methyl or ethyl groups with 3 methyl groups, or also with methyl in combination with ethyl, propyl or isopropyl, ;hydroxy-C^-C^-alkyl, such as especially hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybuty1, hydroxy-sec .-buty1 or hydroxy-tert.-butyl and while e.g. also two hydroxyl groups can stand by the alkyl residue, ;acetoxy-C-^-C^-alkyl, such as acetoxymethyl, carbamoyloxy-Ci-C^-alkyl, such as carbamoyloxymethyl, chloro-C;|_-C4-alkyl, such as chloromethyl, ;carboxy-C-^-C^-alkyl, such as especially carboxymethyl 1 and carboxy-ethyl, C-^r-C4-alkoxy<y>carbon<y>l-C]_-C4-alkyl, such as especially methyloxycar- bonylmethyl, ethyloxycarbonylmethyl, methyloxycarbonylethyl, formyl-C-L-C^-alkyl, such as especially formylmethyl, ;Ci-C^-alkylcarbonyl-C^-C^-alkyl, such as especially methylcarbonyl-1-methyl, ethylcarbonylmethyl, methylcarbonylethyl and ethylcarbonyl-1-ethyl, ; cyano-C^-C-^-alkyl such as cyanomethyl and cyanoethyl, carbamoyl-C1-C4-alkyl, such as carbamoylmethyl, carbamoyl-ethyl, ;amino-C1-C4-alkyl, such as aminomethyl, aminoethyl, C1-C4 -alkyloxy-C1-C4-alkyl, such as in particular methyloxymethyl, ethyloxymethyl, propyloxymethyl, isopropyloxymethyl, methyloxyethyl, ethyloxyethyl, methyloxypropyl and methyloxyisopropyl, C3-C4~alkenyl, such as allyl, 2-methylallyl and buten-3-yl , which can also be substituted with hydroxy such as in particular hydroxyallyl and hydroxybutenyl, ;C₁-alkynyl, such as in particular propargyl,;C₁-Cg-cycloalkyl and C₁-Cg-cycloalkyl-methyl, the carbon number referring to the cycloalkyl part, which in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclopentylmethyl, preferably cyclopropyl and cyclohexyl, phenyl and benzyl, which can also be substituted, for example, with halogen, especially chlorine and fluorine, which e.g. 4-Chloro-benzyl, 4-fluorophenyl, ;C^-C^-Alkoxy, such as in particular methoxy, ethoxy, propoxy, iso-propoxy, butyoxy, isobutoxy and tert.-butoxy, preferably methoxy, ;C^-C^- alkylthio, such as especially methylthio, ethylthio, propylthio; and isopropylthio,; halogen, such as especially fluorine, chlorine, bromine, iodine, trifluoromethyl cyano, hydroxy, mercapto, carboxy, C-^-C^-alkoxycarbonyl, such as e.g. methoxycarbonyl 1, ethoxy-carbonyl, ;carbamoyl, which at the nitrogen atom may be substituted once or twice by C^-C^-alkyl, such as in particular N-methyl, N-ethyl-, N,N-dimethylcarbamoyl, by hydroxy or methoxy , like for example. N-hydroxy- or N-methoxycarbamoy1, ;nitro, amino, dimethylamino,;carbazoyl, which at the nitrogen atom may be substituted once or twice with C-,-C.-alkyl, preferably methyl as ;1 11 ;especially N - methyl-N,N-dimethylcarbazoy1,;formyl, C^-C4~alkylcarbonyl1, especially acetyl and propionyl, arylcarbonyl, such as especially benzoyl. ;Means R 3 an imidazol-1-yl residue, which is substituted with two adjacent to a di- to decamethylene ring, preferably a tri- to pentamethylene ring closed alkyl groups, since in these condensed rings a C atom can also be replaced by oxygen - or a sulfur atom, and one or two double bonds may be contained, so this includes, for example: ; R 4 means hydrogen, C^-C^-alkyl, such as methyl, ethyl, tert-butyl, benzhydryl, allyl, propargyl, methoxymethyl, C-L-C5-alkanoyloxy-C-^-C^-alkyl, such as acetoxy- ;methyl, propionyloxymethyl1, isopropionyloxymethyl1, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxy- ;methyl, isovaleryloxymethyl, 1-acetoxyethyl1, 1-n-propion-yloxyethyl, 1-acetoxypropyl, ;C^-Cg-Alkoxycarbonyloxy-C^-C "3-alkyl, such as in particular 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, methoxycarbonyloxymethyl, phthalidyl, 5-methy 1-1,3-dioxolen-2-|on-4-yl-methyl. ;The object of the invention is furthermore, a method for preparing compounds of formula I and their physiologically tolerable acid addition salts, the method being characterized by ;a) a compound of the general formula II j;i ; or its salts, in which R<1>, R<2> and R<4> has the meaning given under formula I, the amino group can also be protected and R g means one with imidazole or the imidazole ivat corresponding to the residue R 3 in formula I exchangeable group, is reacted with imidazole or its imidazole derivative, a) a possibly present protecting group is cleaved off, and B) if necessary, the formed product is transferred to a physiologically tolerable acid addition salt, or b) a compound with the general formula III in which R and R have the meaning given above with formula II and R<9> means hydrogen or an amino protecting group, is reacted with imidazole or the imidazole derivative which is the basis of the residue R 3 defined in formula I, forming the compound with the general formula IV; 3 4 9 ; in which R , R and R have the above-mentioned meaning, and; a) an optionally present amino protecting group is cleaved off, and ; 3) the compound IV in which R g means hydrogen, is reacted either as such or in the form of a reactive derivative with a 2 -syn-oxyiminoacetic acid of the general formula V; ; 12; in which R and R have the aforementioned meaning, and the amino group also; can be present in protected form or with a derivative of this compound activated by the carboxyl group, and a) any protective group present is cleaved off, 6) if necessary, the formed product with the general formula I to a physiologically tolerable acid addition salt, and ;Y) if esters are to be obtained, transferred according to method variants a) or b) formed compounds of formula I, in which R<4>means hydrogen, on i and for in a known manner to the ;4 ;esters specified under R.;Should the preparation of the compound with the general formula;I according to process variant a) take place by nucleophilic exchange of R g in the compounds with the general formula II with imidazole or one of the specified imidazole derivatives, then acyloxy residues with lower aliphatic carboxylic acids, preferably with 1 to 4 C atoms, such as e.g.: acetoxy or propionyloxy, especially acetoxy, come into consideration as residues R g which may optionally be substituted such as, for example: chloroacetoxy or acetylacetoxy. For Rg, other groups also come into consideration, such as, for example, carbamoyloxy or a halogen atom such as e.g. chlorine, bromine or iodine. ;The nucleophilic exchange reaction of compounds with the*. general formula II can take place such that the reaction is carried out in the presence of imidazole or imidazole derivatives corresponding to the residue R 3 , and of tri-C1-C4-alkyliodosilanes such as e.g. trimethyl or triethyl iodosilane. Thereby, it can be proceeded in such a way that compound II, where R Q means acetoxy, is first brought into reaction with trimethyliodosilane, after under the following reaction conditions, the formed compound II with R g = J is isolated and then reacted with imidazole or the imidazole derivative, or 3 -CH2J compounds are brought into reaction in situ by adding imidazole resp. imidazole deriv. Instead of trimethyliodosilane, reaction mixtures of iodine and hexamethyldisilane can, for example, also be used, which were previously brought into reaction at temperatures between approx. 60 and 120°C in a manner known from the literature, as dimethyliodosilane is formed. Instead of trimethyliodine-

silane, triethyliodosilane can also be used, which is prepared in a manner known from the literature, with the same good results.

The reaction is carried out at temperatures between approx. -5° and + 100°C, preferably between 10° and 80°C.

Suitable inert, aprotic solvents are e.g. chlorinated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride or lower alkylnitriles, such as acetonitrile or propionitrile or freegeners, especially with methylene chloride being an excellent solvent.

The residue R 3 corresponding to imidazole resp. imidazole derivative is added to at least a stoichiometric amount until a 20-fold excess is preferably used with such amounts that the released amount of iodohydrogen is bound, and also at least 1 mol, preferably 1.5-5 mol of imidazole resp. imidazole derivative is available for the substitution.

Then next to the group R g which is to be exchanged in the output compounds II also other functional groups such as e.g. amino groups or carboxyl groups react with dimethyl-iodosilah, the latter is added in at least double to 15-fold, preferably in 3- to 10-fold excess.

Such functional groups can also by adding a silylation agent such as e.g. bistrimethylsilylacetamide, N-methyl-N-trimethylsilyltrifluoroacetamide, bistrimethylsilyltrifluoroacetamide, trimethylchlorosilane, hexamethyldisilazane, bis-trimethylsilylur.instoff, are silylized either without or in the presence of a base, preferably of the desired to the group R<3> basic imidazole resp. imidazole derivative in the amounts mentioned above. Dimethyliodosilane is then added in at least a stoichiometric amount, or in excess, preferably in a double to a 10-fold excess.

If the amino groups in the formulas II and V are in protected form, they are suitable as amino protecting groups, e.g. optionally substituted alkyl, such as tert.-butyl, tert.-amyl, benzyl, p-methoxybenzyl, trityl, benzhydryl, preferably trityl, trialkylsilyl, such as trimethylsilyl, optionally substituted aliphatic acyl, such as e.g. formyl, chloroacetyl, bromoacetyl, trichloroacetyl, and trifluoroacetyl, preferably formyl, or optionally substituted alkoxycarbonyl, such as for example trichloroethoxycarbonyl, benzyloxycarbonyl or tert-butyloxycarbonyl, preferably tert-butyloxycarbonyl and benzyloxycarbonyl, or dimethylaminomethylene.

After the exchange reaction, the protecting group can be split off in a manner known per se hydrogenolytically, e.g. the tri-group by means of a carboxylic acid such as acetic acid, trifluoroacetic acid, formic acid, or benzyloxycarbonyl group,

The reaction product with formula I can, for example, after the addition of water or aqueous mineral acid, e.g. dilute HCl, HBr, HJ or H2S04, is isolated from the aqueous phase in the usual way, e.g. by freeze-drying from the aqueous phase, chromatography or precipitation by addition of an organic solvent. The reaction products are preferably isolated by precipitation from the reaction solution in the form of a poorly soluble salt, for example a hydroiodide salt.

In the event that R represents a carbamoyloxy group, the exchange reaction is carried out analogously. If R means bromine, the exchange takes place in a manner known from the literature.

According to method variant b), the compound with the general formula I is obtained by acylation of compounds with the general compound IV or their addition salts, for example with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or by an organic acid, such as e.g. methanesulfonic acid or toluenesulfonic acid, with carboxylic acids of the general formula V or with a reactive derivative of such an acid.

It is therefore not necessary to isolate the compound of the general formula IV. The reaction can also be carried out such that compounds with the general formula III, for example 7-aminocephalosporanic acid or 3-iodomethyl-7-amino-cef-3-em-4-carboxylic acid or their reactive derivatives in a suitable solvent, are reacted with to the residue R 3 with the general formula IV corresponding to imidazole resp. imidazole derivative, qg the formed compound of the general formula IV is acylated in situ to the compounds of the general formula I. According to the invention, starting compounds of the general formula III are used in this reaction, in which R p means iodine. The appropriate solvents are chlorinated hydrocarbons such as e.g. methylene chloride and chloroform. Ethers such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile and amides such as preferably dimethylformamide and dimethylacetamide. It may also prove advantageous to use mixtures of the mentioned solvents.

If the compounds of the general formula III are present in a reactive derivative, silyl derivatives in particular come into consideration, which are formed by the reaction of the compounds of the general formula III with the silyl compound such as e.g. trimethylchlorosilane, bis-(trimethylsilyl)-trifluoroacetamide, etc. The base corresponding to the residue R 3 is used in at least a stoichiometric amount to a 10-fold excess, preferably 1.5 to 5 equivalents. The reactions are carried out at temperatures between approx. -50 and +100°C, preferably between +20 and +50°C.

The compounds of the general formula IV can also be prepared from compounds of the general formula II, wherein R 8 means acetoxy, in an analogous manner as described above for the compounds of the general formula II.

If the carboxylic acids of the general formula V and their derivatives protected by the amino group are used as acylating agents themselves, then it is appropriate to work in the presence of a condensing agent, for example a carbodiimide, such as N,N<1->dicyclohexylcarbodiimide.

The activation of carboxylic acid with the general formula V

can take place in a particularly favorable way by treatment with certain carboxylic acid amides and, for example, phosgene, phosphorus pentachloride, tosyl chloride, thionyl chloride or oxalyl chloride, which e.g. mentioned in the German patent 28 04 040.

As activated derivatives of carboxylic acid with the general formula V, particularly suitable are also halides, preferably chlorides which are obtained in a manner known in and for Éeq by treatment with a halogenating agent, such as e.g. phosphorus pentachloride, phosgene or thionyl chloride under gentle reaction conditions known in the literature for cephalosporin chemistry.

As activated derivatives of the carboxylic acids of the general formula V, the anhydrides and mixed anhydrides, azides, activated esters and thioesters are also suitable. As with mixed anhydrides, those with lower alkanoic acids such as e.g. acetic acids, and especially preferably those with substituted acetic acids, such as e.g. trichloroacetic acid, pivalic acid, and cyanoacetic acid. Particularly suitable, however, are also the mixed anhydrides with carboxylic acid half-esters, which are obtained, for example, by reacting the carboxylic acids with formula V, in which the amino group is protected with chloroformate benzyl ester, -p-nitrobenzyl ester, -isobutyl ester, -ethyl ester or allyl ester.

Those with p-nitrophenol, 2,4-dinitrophenyl, methylcyanohydrin, N-hydroxysuccinimide and N-hydroxyphthalimide are preferably suitable as activated esters, especially those with 1-hydroxybenzotriazole and 6-chloro-1-hydroxybenzotriazole. Particularly preferred thioesters are, for example, those with 2-mercaptobenzothiazole and 2-mercaptopyridine. The activated derivatives can also be converted in situ as isolated substances.

In general, the reaction of the cephem derivatives with the general formula IV takes place with a carboxylic acid of the general formula

mel V, or an activated derivative thereof in the presence of an inert solvent. Particularly suitable are chlorinated hydrocarbons, such as preferably methylene chloride and chloroform, ethers such as diethyl ether, preferably tetrahydrofuran and dioxane, ketones, such as preferably acetone and butanone, amides such as preferably dimethylformamide and dimethylacetamide or pyridine. It may also prove advantageous to use mixtures of the mentioned solvents. This is often to-

delle when cephem compounds of the general formula IV are reacted with an in situ produced activated derivative of a carboxylic acid of formula V.

The reaction of the cephem compound of formula IV with carboxylic acid of formula V, resp. their activated derivatives, can pre-

go in a temperature range from c/éi. -80o to c-a'. +80°C, preferably between -20°C and room temperature.

The reaction duration depends on the reaction participants, the temperature and the solvent, resp. solvent mix-

is, is normally between 1/4 and ^approx. 72 hours.

The reaction with acid halides can optionally be carried out in the presence of an acid binding agent to bind the free

made halogen hydrogen. As such, tertiary amines such as e.g. triethylamine or dimethylaniline, inorganic bases such as potassium carbonate or sodium carbonate, alkylene oxides such as propylene oxide. Also

in the presence of a catalyst such as of dimethylaminopyri-

Yours may be of benefit. If the amino group is present in the compounds of the general formula IV in the form of a reactive derivative, it may be one known from the literature for amidations. Thus, for example, silyl derivatives which are formed by the reaction of compounds of the general formula IV with a silyl compound, such as e.g. trimethylchlorosilane or bis-(trimethylsilyl)acetamide. If the reaction is carried out in this way with the amino group activated compound, then it is appropriate to carry out the reaction in an inert solvent, such as e.g. methylene chloride, tetrahydrofuran, or dimethylformamide.

Should compounds of the general formula I be obtained, in which R 4 means C-^-Cg-alkanoyloxy-C^-Cg-alkyl, C-^-Cs-alkoxy-carbonyloxy-C-j^-Cg-alkyl, phthalidyl or 5- methyl-1, 3-dioxo-len-2-on-4-ylmethyl, then the compounds of the general formula I in which R 4 = hydrogen are reacted in a manner known per se with a compound of the general formula VI

in which R a = hydrogen or a C 1 -C 6 alkyl group, R 1 = a C 1 -C 8 alkyl group, Rfa means a C 1 -C 8 alkyl or a C 1 -C 6 -alkyl group, or VII or VIII

wherein as also in formula VI X means halogen, preferably chlorine, bromine or iodine. Methods are used as they are known for the esterification reaction. Means R4 C1,-Cb,-alkyl,

benzhydryl, allyl or propargyl, then the esterification methods known in the literature for these groups are used. Protecting groups can be removed in a known manner as mentioned above.

As physiologically tolerable acid addition salts of compounds with the general formula I, mention should be made, for example, of those with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, or organic acids, such as e.g. methanesulfonic acid, p-toluenesulfonic acid or maleic acid.

The imidazoles used according to the invention and other starting compounds are known in the literature, or can be obtained by methods known in the literature.

The compounds obtained according to the invention with the gene

real formula I and their physiologically tolerable acid addition

salts show remarkably good antibacterial action,

both against gram-positive and gram-negative bacterial germs.

Also against penicillinase- and cephalosporinase-producing bacteria

are the compounds of formula I unexpectedly well active. As they also show favorable toxicological and pharmacological properties, they are valuable chemotherapeutics.

The compounds produced according to the invention can thus be used in pharmaceutical preparations for the treatment of microbial

other infections which are characterized by the content of one or more of the compounds according to the invention.

The products according to the invention can also be used

in the combination of other active substances, for example from the range of penicillins, cephalosporins or aminoglycosides.

The compounds of the general formula I and their physiologically tolerable acid addition salts can be administered orally, intra-

intramuscularly or intravenously.

Medicinal preparations containing one or more compounds of the general formula I as active ingredient are prepared by mixing/compounds of formula I with several pharmacologically tolerable/carriers or diluents, such as e.g. fillers, emulsifiers, lubricants, flavor correctors, dyes or buffering substances, and bring in a suitable galenic preparation form such as tablets, dragees, capsules or a suspension/or solution suitable for parenteral application.

/

in

IN

As carriers or diluents, mention should be made, for example, of tragacanth, milk sugar, talc, agar-agar, polyglycols, ethanol and water. Buffer substances are, for example, organic compounds such as N,N<1->dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglutamine, N-benzylphenethylamine, diethylamine, tris-(hydroxymethyl)aminomethane, or inorganic compounds such as e.g. phosphate buffer, sodium bicarbonate, sodium carbonate. For the parenteral application, suspensions or solutions in water with or without buffer substances are preferably considered. It is also possible to apply the active substances as such without carriers or diluents in a suitable form, for example in capsules.

r

f

Suitable doses of the blinding with the general formula I or their physiologically tolerable acid addition salts are at approx. 0.4 to 20 g/day, preferably at 0.5 to 4 g/day, for an adult of approx. 60 kg body weight.

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Single or generally multiple doses can be administered, as the single doses can contain the active substance in an amount of approx. 50 to 1000 mg, preferably of approx. 100 to 500 mg.

The following exemplary embodiments of syn-compounds that can be produced according to the invention serve for further explanation

of the invention without thereby limiting it.

Example 1

7-/2-(f2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido7-3-/~(2-methylimidazol-1-yl)methyl/-cef-3-em-4-carboxylic acid Process a )

11.8 g (26 mmol) of !-/_ 2-(2-aminothiazol-4-yl)-2-syn-methoxy-imino-acetamido7-cephalosporin acid are suspended in 50 ml of chloroform, mixed with 16.25 ml (88 mmol ) N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) and stirred for 1 hour at room temperature. It cools at 18°C. 10 ml (79 mmol) of iodotrimethylsilane are added and stirred for a further 20 minutes at room temperature (23°C). It is evaporated in a vacuum, the oil active

The residue is dissolved in 50 ml of acetonitrile and 2.1 is added

ml of tetrahydrofuran. This solution is immediately added to a mixture of 2.63 g (32 mmol) of 2-methylimidazole and 11 ml (59

mmol) MSTFA in 26 ml of acetonitrile and the dark colored solution is allowed to stand for 1.5 hours at room temperature. During ice-cooling and shaking, 3:rl ml of water are then added.

The formed precipitate is filtered off after 10 minutes, washed twice with acetonitrile, then with ethanol and ether and dried. Yield of title compound from hydroiodide salt: 13.8

g (88% of the theoretical). The crude hydroiodide is dissolved in aqueous sodium bicarbonate solution and chromatographed over silica gel (5 x 55 cm column) with acetone:water (5:1). After lyophilization of fractions 8-14 (800 ml) 1.1 g (9%) of A 2 compound is obtained, fractions 15-24 (1.2 1) give 7.5 g (60%) of the title compound as yellowish colored amorphous solid.

<1>H-NMR(DMSO-d6): <5 = 2.33 (s, 3H), 1M-CHg), 3.02 and 3.26

AB,J=18 Hz, 2H, SCH2), 3.82 (s, 3H,

OCH3): 4.90 (AB, 2H, CH2N), 5.02 (d,

J = 5Hz, 6-H), 5.60 (dd, J = 5 and 9Hz, 7-H) , 6.70, (s, 1H, , thiazole-H) , 6.78 (d, J=2Hz , 1 imidazole-H), 7.20 (bs, 3H,

NH 2 and 1 imidazole-H), 9.52 ppm (d, J = 9Hz, 1H, CONH).

Procedure b, variant a

3.39 g (10 mmol) of 7-amino-3-iodomethyl-cef-3-em-4-carboxylic acid are suspended in 80 ml of tetrahydrofuran and stirred after the addition of 5 ml (20 mmol) of bis(trimethylsilyl)acetamide (BSA)

1.5 hours at room temperature. During cooling, 1.23 g (15 mmol) of 2-methylimidazole are then added and stirred for 1.5 hours at room temperature (23°C). During cooling, 1 ml of water is then added, the formed precipitate is suctioned off,

and washed with ethanol, acetone and ether. 4.5 g of mono-hydroiodide salt of 7-amino-3-[(2-methylimidazol-1-yl)methyl]-cef-3-em-4-carboxylic acid is obtained. The crude salt is introduced into a solution of 2.86 g (9 mmol) of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid-hydroxybenztriazole active ester in 60 ml of N,N-dimethylformamide and 2 ml of water. 8 hours at 5°C are recommended. The DMF solution is taken up in 1 liter of ether, the precipitate is dissolved in aqueous sodium bicarbonate solution and the dark colored solution is chromatographed over a "Lobar-C" silica gel column (company Merck-Darmstadt) with acetone/water (5:1). After freeze-drying the product fractions, 990 mg is obtained

(23% of the theoretical) of an amorphous solid. It is identical in all properties to the product formed according to method a).

Procedure b, variant

7-amino-3-[(2-methylimidazol-1-yl)methyl]-cef-3-em-4-carboxylic acid monohydro iodide

2.96 g (10.8 mmol) 7-aminocephalosporanic acid and 10 ml (9.7 g, 37.8 mmol) N,0-bis(trimethylsilyl)-trifluoroacetamide (BSTFA)

in 25 ml of methylene dichloride is maintained for 1 hour under reflux. The solution is cooled to 20°C, and 4 ml (28 mmol) of iodotrimethylsilane are added. It is kept for 20 minutes at room temperature, evaporated in a vacuum and the oily residue dissolved

in a mixture of 20 ml of acetonitrile and 0.8 ml of tetrahydrofuran. It is cooled to 15°C, a solution of 1.07 g (13 mmol) of 2-methylimidazole and 5.0 ml of BSTFA in 10 ml of acetonitrile is added. The dark colored mixture is allowed to stand for 1.5 hours at room temperature, and is then hydrolysed while cooling by adding 1 ml of water. The formed precipitate is filtered off after 1 hour, washed twice with acetonitrile, then with ethanol and ether and dried. 20.2 g (10 mmol 92% of the theoretical) of the title compound are obtained.

NMR (CF 3 CO 2 D): δ = 2.81 (s, 3H, CH 3 ), 3.60 (AB, 2H, SCH 2 ),

5.1 - 5.8 (m,.4H, 2-lactam-H and CH2N),

7.2 - 7.55 ppm (m, 2 imidazole-H).

By acylation with 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetic acid-hydroxybenztriazole active ester in DMF/H20, variant a 7-/ 2(2-aminothiazol-4-yl) is obtained as described above -2-syn-methoxyimino-acetamido/-3-_-(2-methylimidazol-1-yl)methyl 1/cef-3-em-4-carboxylic acid after chromatography as amorphous,

solid. The compound is identical in all properties to that according to method a).

Example 2

7-/ 2-(2-aminothiazol-4-yl)-2-syn-(2-carboxyprop-2-yl-oxyimino)acetamido7-3-/~ (2-methyl-imidazol-1-yl) methyl/- cef- 3- em- 4- carboxylic acid.

1.1 g (2 mmol) of 2-syn-(2-tert-butyloxycarbonyl-prop-2-yl-oximino)-2-(2-tritylaminothiazol-4-yl)-acetic acid is stirred together with 0.32 g of 1-hydroxy -1H-benzotriazole hydrate and 0.5

g of N,N'-dicyclohexylcarbodiimide in 9 ml of dimethylformamide for 3 hours at room temperature. Precipitated di-cyclohexylurins are filtered off and added to the solution of the active ester 760 mg (1.8 mmol) 7-amino-3-[(2-methylimidazol-1-yl)methyl]-cef-3-em-4 -carboxylic acid monohydroiodide (example 1. method b, variant 3). After 17 hours at room temperature, the precipitated product is stirred into 800 ml of ether

aspirated and dried in a vacuum. The crude product is dissolved in 20 ml of 90% trifluoroacetic acid. After 20 minutes, the oily residue is evaporated in vacuo, evaporated twice with toluene. The residue is dissolved in aqueous sodium bicarbonate solution and chromatographed over a "Lobar G" silica gel column (company Merck, Darmstadt) with ethyl acetate/isopropanol/water (20:15:10). After freeze-drying the product fractions, 306 mg (28% of the theoretical) of the title compound is obtained as a pale yellow amorphous solid.

<1>H-NMR (DMSO-d6): δ = 1.42, (s, 3H, CH3): 1.47 (s, 3H, CH3),

3.00 and 3.18 (AB, J = 18Hz, 2H, 5CH2), 4.75 and 4.95 (AB, 2H, CH2W), 4.99

(d, J = 5Hz, 6-H), 5.58 (dd, J = 5 and 8Hz, 7-H), 6.70 (s, 1H, thiazole-H), 6.82 (s, 1 imidazole -H), 7.15 (bs, 3H, NH2 and 1 imidazole-H), 10.55 ppm (d,

J = 8 Hz, 1H, CONH).

Analogous to example 1 method a), the examples listed below are obtained as amorphous solids that correspond to it

4 12 3 general formula I with R = hydrogen, and in which R , R and R have the meanings given in table 1.

Example 13

!-(_ 2-(2-aminothiazol-4-yl)-2-syn-hydroxyimino-acetamido7-3-/~( 2- methyl- imidazol-1-yl) methyl7-cef-3-em-4- carboxylic acid .

From 671 mg (1 mmol) of 2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid, 160 mg of 1-hydroxy-1H-benzotriazole hydrate and 250 mg of N,N1 -dicyclohexylcarbodiimide in 4.5 ml DMF is prepared analogously to example 2, a solution of the active ester. After addition of 380 mg (0.9 mmol) 7-amino-3-(2-methylimidazol-1-yl)methyl-cef-3-em-4-carboxylic acid monohydro-iodide, stand for 4 hours at room temperature and 17 hours at 5°C. Precipitated dicyclohexylurea is filtered off, the solution is evaporated in vacuo. The oily residue is dissolved in 20 ml of 90% trifluoroacetic acid. Leave for 30 minutes at room temperature, evaporate in vacuo and evaporate the residue twice with toluene. The residue is then suspended in ether, filtered off with suction and washed with ether. Yield: 0.35 g. This crude product is dissolved in aqueous sodium bicarbonate solution and chromatographed over a "Lobar B" silica gel column with ethyl acetate/isopropanol/water (20:15:10). After freeze-drying the product fractions, 80 mg of the title compound is obtained as a yellowish colored amorphous solid.

<1>H-NMR (CF3CO2D) : 2.80 (s, 3H, CH3), 3.40 and 3.65 (AB, J =

18Hz, 2H, SCH2): 5.05 - 5.72 (m, 3H, AB of CH 2N and 6-H), 6.29 (d, J = 5Hz, 7-H), 7.3-7, 6 (m, 3H, 2 imidazole-H, 1 thiazole-H),

Analogous to example 1, method b) variant 3, the examples listed below of 7-amino-3-[(2-methylimidazol-1-yl)methyl-7-cef-3-em-4-carboxylic acid monohydroiodide and the corresponding HOBT are obtained -active esters as amorphous solids corresponding to the general formula I with Rx in oa R 4= hvdroaen

2 and in which R has the meaning given in table 2.

Example 21

Pivaloylmethyl-7-/ 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido7-3-/~(2-methyl-imidazol-1-yl)methyl/-cef-3-em-4 -kar-boxylate.

A mixture of 954 mg (2 mmol) !-/_ 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido7-3-_^ (2-methyl limidazol-1-yl)-methyl l7- cef-3-em-4-carboxylic acid (Example 1) and 200 mg (2 mmol) of potassium hydrogen carbonate in 10 ml of water are lyophilized, the residue is evaporated twice with toluene, and dissolved in 10 ml of dry N,N-dimethylformamide (DMF). While stirring, add wood

5°C a solution of 2 mmol iodomethyl pivalate in 0.5 ml DMF, stirred for 2 hours, again 0.5 ml iodomethyl pivalate solution is added and stirred for a further hour. After adding 20 ml of water, extract three times with 50 ml of acetic acid ethyl ester each time, the organic phase is dried with sodium sulphate, the solvent is removed in vacuo. The oily residue is chromatographed over a "Lobar C" silica gel column with ethyl acetate:isopropanol:water (50:2:5). The product fractions are evaporated, the residue is expelled with ether, the title compound being obtained as an amorphous solid. (140mg).

<1>H-NMR (DMS0-d_): δ = 1.16 (s, 9H, (CH0)n), 2.25 (s, 3H, CH_),

3.22 and 3.38 (AB, J=18Hz, 2H, SCH2),

3.83 (s, 3H, 0CH3), 4.48 (bs. AB, CH2

N), 5.19 (d, J=5Hz, 6-H), 5.56 (dd, J=

5 and 9Hz, 7-H), 5.88 and 5.96 (AB, J=7Hz,

2H, CH2OCO), 6.80 (s, 1 thiazole-H), 6,

95 and 7.06 (as well as a d, J = 2Hz, 2 imidazole-H), 7.22 (bs, 2H, NH2), 9.66 ppm (d, J=9Hz, 1H, CONH). Analogous to example 1, method b, variant 3, as well as examples 14-20 and table 2, the below listed examples 1 4 are obtained which correspond to the general formula I with R and R = hydrogen ? 3 and in which R and R have the meaning given in Table 3. Analogously to example 1, method a) the compounds of the examples listed below are obtained as amorphous solids, corresponding to the general formula I with R<1> and R<4>= hydrogen, 2 3 and in which R and R have the meaning given in Table 4. Example 76 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido7-3-(2-methylimidazol-1-yl)methyl]-cef-3-em-4-carboxylic acid Method b), variant 3 1. Tert.-butyl 1-7-amino-3-/(2-methylimidazol-1-yl)methyl 7-cef-3-em-4-carboxylate. 1.77 g (5.4 mmol) of 7-aminocephalosporanic acid tert-butyl ester and 5 ml (18.7 mmol) of BSTFA in 12 ml of methylene dichloride are heated to boiling for 1 hour. After cooling, 2 ml (15 mmol) of trimethyiodosilane are added and allowed to stand for 20 minutes at room temperature. It is evaporated, the oily residue is dissolved in 10 ml of acetonitrile and a solution of 524 mg (6.4 mmol) of 2-methylimidazole in 5.2 ml of acetonitrile and 2.6 ml of BSTFA is added. It is allowed to stand for 3 hours at room temperature. After addition of 0.6 ml of water, a small amount of a dark precipitate forms which is suctioned off (140 mg) and discarded. The mother liquor is evaporated, the residue is chromatographed over a silica gel column with methylene dichloride/methanol/aqueous ammonia (90:10:1). Fractions 3-5 ( 130 ml) is evaporated and it gives gives 310 mg of the title compound as an amorphous, brownish solid. <1>H-NMR (DMSO-d6): δ = 1.50 (s, 9H, (CHgJj), 2.29 (s, 3H, lm-CH3), 3.18 and 3.27 (AB, J = 18Hz, 2H, SCH2), 5.78 and 5.88 (AB, J = 15Hz, CH2N), 4.80 and 5.01 (resp. Id, J = 5Hz, 2 lactam-H), 6.90 and 7.12 ppm (2 s resp. 1 imidazole-H), 2. Tert.butyl-7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido/-3-_ ] ( 2-me ty 1 amida z ol-1-yl) me ty lf-cef -3-em-4-carboxylate.

To dissolve 0.5 mmol of 2-(2-aminothiazol-4-yl)-2-syn-methoxy-iminoacetic acid-hydroxybenztriazole active ester, prepare from 100 mg (0.5 mmol) acid, 90 mg of hydroxybenztriazole and 110 mg of dicyclohexylcarbodiimide in 2.5 ml N,N-dimethylformamide (DMF). A solution of 190 mg (0.54 mmol) of product from example 76/1 in 2 ml of DMF is added. After 4 hours at room temperature, cyclohexylurea is sucked off, the solution is diluted with 150 ml of ethyl acetate and washed twice with aqueous sodium bicarbonate solution and twice with water. After drying with MgSO4, the solvent is removed in vacuo, the partially solid residue is digested with ether. The undissolved solid is filtered off, washed with ether and dried. Yield: 150 mg.

<1>H-NMR (DMSO-d6): 6 = 1.48 (s, 9H, (CH3)3)f2.28 (s, 3H, CH3) ,

3.28 and 3.39 (AB, J = 18Hz, 2H, SCH2), 3.84 (s, 3H, OCH3), 4.82 and 4.93 (AB,

J = 15Hz, 2H, CH2N), 5.28 (d, J = 5Hz, 6-H), 5.60 (dd, J = 5 and 8Hz, 7-H), 6.74, (s, thiazole- H), 6.86 (s, imidazole-H), 7.21 (bs, 3H, NH 2 and 1 imidazole-H), 9.60 ppm (d, J = 8Hz, CONH).

3. Preparation of the title compound.

30 mg of the compound from example 76/2 are dissolved in 3 ml of trifluoroacetic acid. After 30 minutes, evaporate in vacuo, the residue is expelled several times with ether. 25 mg of a colorless solid is obtained, which in all properties (Rf value, NMR spectrum) is identical to the compound from example 1.

Claims (5)

1. Cephalosporin derivatives of the general formula I —and—their—f y-s4.ol-ogi-.s-k—tå-l-ba-r-e—s-y-r-e add-i-s j-ons-s-a 1 ter , h vor i R means hydrogen or halogen 2 R means hydrogen, C-.-C,-alkyl, which may be one or more times identically or differently substituted with halogen, (ar-yJJ, h.e.te-^ o=i— Va-ry-l-i! Je^€^--a-l-k -yl-t-i-e7—Gy-G-j- a-l-k-y-l-ok-s-y-,—n-i-t-r-i-1 jeller car--bamoyl, in which the amino group may be singly or twice identically or differently substituted with C,-C_.-alkyl, h-yd-ro-k-s-y--G-j _—Gy)—a-l-k-y-l-7 —h-y-drek-s-y—e-lie-r—-me-tok-s-y-r C^ -C^ -alkenyl, s-em—e -ve-n-true-l-^fc—ka-n—be—a—e-l-ler— f -l-er e— -ga-nge-r—-1-i-k-t^ e-l-l-e-r—fo-rs-k-j-eil-ig—s-u-bs-ti-feue-r-t—med—h-ai-oge-n^ C 2 -C ^ - at 1 new 1, as—eve-rttu-e-l-tr—k-a-n—væ-r-e—s-ub-s-tifeue-r-tr-med -h-a-l-eg^ n-,- C^ -C^ -cycloalkyl, s-om—evefttrue-l-t—k-a-n—v-ær-e—s-ubs-t-i-tuated—with— the group m and n |pespi means 0 or 1, R 5 and R 6 can be the same or different and mean hydrogen,\ a^<y> -l| or a C^C -^ alkyl group or, together with the carbon to which they are attached, jen—iBe^efyrbeft—ollorf forms a C3 -C7 -cycloalkylidene group^ R<7> means ^fe^HOOC^^ R 3 means an imidazole-1-yI residue which may be one or more times the same or different, substituted with C-^ -Cg-alkyl, which may be one or more times substituted with hydroxy, acctoxy-7 —carba— -me-yloxy, chlorine, carboxy, C -C ^ - a 1 ky l-©k s y ka-r-feen-y-l-,—f-e^-— -my-l-v —G-p-G-g-a4-ky-l-ka-r-bon-y-l-, cyano, carbamoy-1-,—am-i-no-,—C^ -Cg- —a-l-k-y-l-© k-sy, and since 2 neighboring alkyl groups can also be closed to e«— even tue lt mod—€y-€-g—a-l-k-y-l-7 —-h-a-l-ogen-r~ hyd--r-ok -s-y-,—ok-so-,—ka-r-bokvs-y-,—k-a-r-bamoy-l—s-u-b-s-tituated di- to decamethylene ring, since the C atom can be o- o-rsta-i^efe -t—me-d—e^fe <r> oksygcB-—eiie-r—s-ve^ vei-a-lre-m-T —© g—© g-s-å—en—ei-l-e-r—to—dobbe- tte —^j-R ^j-R gQ -r can in°h^ldt, - with C^-Cg-alkonyl /—s-em ka-n—væ^e—s-i^b-s^fei-t-u-e-r-tr-med—h-yå-r-ek-s-y-med C^ -Cg-alkynyl/ / with C 1 -C 8 cycloalkyl, -with—Cy=C^~G y-k4,oal4cyime-fey-l., me d f e ny 1 .©AAe*—fe-e-n-zy-1—&©m—k-a-n—væ-ee—s-ute s-ti-feue-:^1^me d~Gy--—«- -C 1 -alkyl, . h-a-l-ege-n-v—h-yd-search-sy-,—Gy-G^-arL-k-y-l-ek-sy-, with C-^ -Cg-Alkoxy -eii& r—with—G^ G^ -=aik-y-l-f ei-© -,— with halogen, fe*^^-«-© -r-me-fe-y-l-, —cy-a-n© -,—hy-d-r-© k-sy—e-l-l-e-r—me-E^ k-a-p^ te© -, with carboxy, C-^ -Cg-alkoxycarbonyl or carbamoyl, which with the nitrogen atom may be substituted one or twice with C1-C8-alkyl, hydroxy o-ller me^-ek-sy-,- with carbazoyl, which at the nitrogen atom may be substituted once or twice by C 1 -C 1 -alkyl, with nine faiths, -amino or-d-i—(^j -Gy)—-a-l-k-y-l-am-i-n© -, R <4> means hydrogen, c~c5^-1-k-y-l-,—ben-z-hyd-r-y-l-?—a-l-l-y-1-,—p-repa-r-gy-l-y- -me^-ksyme^y-l-T—GY-G^-a4-k-a-n-©y4-©k-sy^ kc4tsy-k^ xt>anyJ.--ok-sy-^-1 -^-g^ a-lky -l-,—f-t-ai^-dyi—el-le-r—5-me-fey-l---l-,-3--2 ^d-x-okso.l e n=-2—o n=4.=me-ty-l-,—o g_ h v.o ri—R_=o=g- r- up p e-n—s-tø-r—,i— sew-n-=— C , pOLU| L - 2. method for the production of (c e f a Ib s porxnd-e-r±va-t~- ^ ~ex—-med—d-en—gen-e^e-l-l-e—fo-r-mel^I_o^_jie^e.S- Jy.s.i.ologi-sk-—tåiba-re_ ) sy-r-eadd-i-s-j-on-s^airterTl characterized by ata) a compound of the general formula II 12 4 or its salts, in which R , R and R have the meaning given under formula I, the amino group can also be protected and R g means one with imidazole or the imidazole derivative corresponding to the residue R 3 of formula I, exchangeable group, is reacted with imidazole or its imidazole derivative, a) a possibly present protecting group is split off, |ag| C&-) hvTs necessary~transfer the formed product with a -physiolx>gi-sk-4:ålb^ or'b) compound of the general formula III 4 8 in which R and R have the meaning given above for formula II, and R 9 means hydrogen or an amino protecting group, is reacted with imidazole or the imidazole derivative which is the basis of the residue R 3 defined in formula 1 to form a compound of the general formula IV 3 4 9 in which R , R and R have the above meaning, and a) a possibly present amino protecting group is cleaved off, and "B) compound IV, in which R q means hydrogen, as such or in the form of a reactive derivative reacting the 2-syn- oxyiminoacetic acid as the general formula V 1 2 in which R and R have the aforementioned meanings and the amino group can also be present in protected form, or with a derivative of this compound activated at the carboxyl group, and , a) a possibly present protecting group is split off, and Y ) if esters are to be obtained, the compounds of formula I obtained according to method variant a) or b) in which R 4 is hydrogen, are transferred in a manner known per se to the esters indicated under R <4>. 3. Against bacterial infections/active pharmaceutical preparations, characterized by a content of cephalosporin derivatives with/the general formula I. 4. Process for the production of pharmaceutical preparations effective against bacterial infections, characterized in that a cephalosporin derivative of the general formula I is prepared in a pharmaceutically suitable administration form, possibly with pharmaceutically common carriers or excipients. 5. Use of/cephalosporin derivatives of the general formula I for combating bacterial infections.