NO834775L - CEPHALOSPORINE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. Cephem derivatives of the general formula see diagramm : EP0111935,P10,F1 and physiologically acceptable acid addition salts thereof in which R**1 denotes hydrogen, R**2 denotes hydrogen, R**3 denotes C1 -C4 -alkyl optionally substituted by fluorine, A denotes a quinolinium or an isoquinolinium radical, each of which can also be substituted once or twice by C1 -C4 -alkyl and in which the R**3O group is in the syn position. For the Contracting State : AT A process for the preparation of cephem derivatives of the general formula I see diagramm : EP0111935,P11,F1 and physiologically acceptable acid addition salts thereof in which R**1 denotes hydrogen, R**2 denotes hydrogen, R**3 denotes C1 -C4 -alkyl optionally substituted by fluorine, A denotes a quinolinium or an isoquinolinium radical, each of which can also be substituted once or twice by C1 -C4 -alkyl and in which the R**3O group is in the syn position, which comprises a) reacting a compound of the general formula II see diagramm : EP0111935,P11,F2 or salts thereof or a reactive derivative of the compound II in which R**1, R**2 and R**3 have the abovementioned meaning and R**8 denotes an amino group or a protected amino group and R**9 denotes a group which can be replaced by quinoline, isoquinoline or substituted quinolines or isoquinolines corresponding to the radicals A of the formula I, with quinoline, isoquinoline or one of their derivatives, and alpha) splitting off a protective group which is present where appropriate and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephen compound of the general formula III see diagramm : EP0111935,P12,F3 or acid addition salts thereof in which R**2 and A have the abovementioned meaning, it also being possible for the amino group to be present in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yl)-2-syn-oximinoacetic acid of the general formula IV see diagramm : EP0111935,P12,F4 in which R**1, R**3 and R**8 have the above meaning, or with an activated derivative of this compound, and alpha) splitting off a protective group which is present where appropriate and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt

Description

The invention relates to new cephalosporin derivatives and methods for their production, in particular polar cephem derivatives, which are substituted in the 3-position of the cephem ring with specific quinolinium and isoquinolinium methyl residues, and which have a very good antimicrobial effect against gram-positive and gram-negative bacteria and are therefore suitable as drug for the treatment of microbial infections.

The object of the invention is thus cephem derivatives with

the general formula I

and their physiologically compatible acid addition salts, wherein

R"'" is hydrogen or halogen,

R 2 is hydrogen or methoxy,

R 3 is hydrogen, optionally substituted C 1 -C 8 -alkyl,

optionally substituted C 1 -C 8 -alkenyl, C 1 -C 4 -alkynyl C 3 -C 7 -cycloalkyl, C 1 -C 4 -cycloalkyl-C 1 -C 1 -alkyl,

C. -C<_,>-c<y>cloalkene<y>l<,> the group -(CH2)

where m or n are each 0 or 1, 4 5 in R , and R can be the same or different _ _ 2 and is hydrogen, aryl, a C^-C4 alkyl group, or together with the carbon atom ^q to which they are attached form a methylene or a C^-C^ cycloalkylidene group, wherein alkyl and cycloalkyl may be further substituted one or repeatedly? 6 7 7

R is a group -CO 2 R , where R is hydrogen, C 1 -C 2 -alkyl,

-CH2OC1-C4-alkyl, -Cr^OOC-C^-C^-alkyl, or means an equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base, a nitrile group

or a carbamoyl group -CONI^, which may be substituted once or twice on the nitrogen atom,

A is a quinolinium or an isoquinolinium residue, which

each can also be equally or differently substituted one or more times with C₁-C₂-alkyl, which in turn may be substituted with C₁-C₂- alkoxy, halogen, trifluoromethyl or hydroxy,

and where the R 3O group is in the syn position.

The present invention is particularly directed to compounds

1 2

where R , R and A have the above-mentioned meanings and

R 3 is hydrogen, C 1 -C 3 -alkyl, which may be substituted one

or several times with halogen, C 1 -C 8 -alkylthio, C 1 -C 8 -alkyloxy, aryl or heteroaryl, C 1 -C 2 -alkenyl, which may be substituted one or more times with halogen, C 1 -C 2 -C -alkynyl, C^-C^-cycloalkyl, C3-C7-cycloalkyl-C-L-C6-alkyl, C^-C^-cycloalkenyl,

and where the group

has the meaning mentioned above, as the R 3 O group is also in the syn position in these preferred compounds.

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

R"*": hydrogen, fluorine, chlorine, bromine, especially fluorine and chlorine. R2: hydrogen, methoxy. ;3 ;R: hydrogen,;C₁-C₁-alkyl, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, especially methyl, ethyl; alkyl substituted with halogen, e.g. chlorine, bromine, iodine or fluorine, especially trifluoroethyl, 2,2,3,3-tetrafluoropropyl; alkyl which is substituted with C 1 -C 8 alkylthiosufex. methylthio, ethylthio, propylthio; alkyl which is substituted by C 1 -C 8 alkyloxy, e.g. methyloxy, ethyloxy; alkyl substituted with aryl, e.g. phenyl, tolyl, chlorophenyl, especially benzyl; alkyl substituted with heteroaryl, e.g. 1,3-thiazol-4-yl, especially 1,3-thiazol-4-yl-methyl; C 2 - C 1 -alkenyl, such as e.g. vinyl, allyl, isopropenyl, methylallyl, especially allyl, methylallyl; C2-C4-alkenyl substituted with halogen, such as e.g. chlorine or bromine, especially 3-chloro-propen-2-yl, 2-bromo-propen-2-yl, ;2-chloro-propen-2-yl; C 1 -C 4 -alkynyl, especially propargyl; ;C₁-C₁-cycloalkyl, especially cyclopropyl j. cyclobutyl, cyclopentyl, cyclohexyl, especially cyclopentyl; ;C 1 -C 4 -cycloalkylmethyl, especially cyclopropylmethyl; ;C 1 -C 4 -cycloalkenyl, especially cyclopentenyl, cyclohexenyl, the group ; 4 5 ;where R and R can be the same or different and are hydrogen, aryl, preferably phenyl, C^-C4~alkyl, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, preferably methyl, ethyl, especially methyl, , or ; where R 4 and R 5 form a methylene group or a C3~C7 cycloalkylidene group together with the carbon atom to which they are attached, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and where the cycloalkylidene group can be substituted, e.g. with C-3-C4-alkyl, preferably methyl, with halogen, preferably fluorine and chlorine, or may also be substituted with the alkylene with ;3-6 C atoms; ;m = 0 or 1;n= 0 or 1, the sum of m and n being 1 or 2. ;Preferred examples the group ; ; are the following:; For the case that n = 0 and m = 1: ; For the case that m = 0 and n = 1: -CH2~°9"^or ^a case that n and m = 1: ; 6 7 7 ;R is the group -CC^R , where R is hydrogen, C^ -C4~alkyl, ;such as methyl, ethyl, propyl, isopropyl, butyl sec.butyl, tert.butyl, preferably methyl, ethyl, especially methyl, or an equivalent of an alkali metal, such as sodium, potassium, lithium, preferably sodium and potassium, one equivalent of an alkaline earth metal, preferably calcium or magnesium, ammonium, and one equivalent of an organic amine base, such as trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine , tris(hydroxymethyl)aminomethane, arginine, lysine; a nitrile group, a carbamoyl group; which may be substituted once on the nitrogen atom by C^-Cg-alkyl, hydroxy-C^-Cg-alkyl, C^-C^-alkoxycarbonyl, C-^-Cg-alkylcarbonyl, carboxymethyl, C^-Cg-alkyloxycarbonylmethyl, aminocarbonylmethyl, C^-Cg-alkylaminocarbonyl, carbamoyl, hydroxy, C^-C^-alkyloxy, or may be substituted twice on the nitrogen atom with C^- C ^-alkyl, ;A: a quinolinium residue; which may be substituted 1 or more times, preferably 1 to 3 times, especially 1 to 2 times, with the same or different substituents, for example with C₁-C₁ alkyl, especially with methyl, ethyl, propyl, isopropyl, butyl, hydroxy -C 1 -C 4 -alkyl, especially hydroxymethyl, C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl, especially methoxymethyl; with C₁-C₁-alkoxy, for example ethoxy, methoxy; with halogen, such as fluorine, chlorine, bromine, iodine; with trifluoromethyl or hydroxy; or an isoquinolinium residue which may be substituted in the same manner as the quinolinium residue above. Preferred examples of A are e.g. the following: quinolinium, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylquinolinium, 3-, 5-, 56-, 7- or 8-hydroxyquinolinium, 3-, 4- , 5-, 6-, 7- or 8-methoxyquinolinium, 3-bromo-, 3-chloro-, 5-chloro-, 5,7-dichloro-, 7-trifluoromethyl-, 5-chloro-8-hydroxy -, 5-chloro-7-iodo-8-hydroxyquinolinium; isoquinolinium, 1-, 3-, 4-, 5-, 6-, 7- or 8-methylisoquinolinium, 4-chloro-, 4-bromo-, 4-hydroxy-, 5-hydroxyisoquinolinium. The object of the invention is further a method for the preparation of compounds of formula I and their physiologically compatible acid addition salts which are characterized by a) reacting a compound of the general formula II or its salts or a reactive derivative of 12 3 compound II where R, R and R have the above-mentioned meanings and R g means an amino or a protected amino group and R 9 means one with quinoline, isoquinoline or substituted quinoline or isoquinoline, which corresponds to the residue A in formula I, replaceable group, with quinoline, isoquinoline or a derivative thereof and a) cleaves off any protective group present and 3) if necessary, transfers the product obtained in a physiologically compatible acid addition salt, ; or; b) reacts a 7-amino-cephem compound with the general formula III; ; or an acid addition salt thereof, in which R 2 and A have the meanings mentioned above, the amino group can also, in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yl)-2-syn-oximinoacetic acid with the general formula IV, ; 13 8 ;where R , R and R have the above-mentioned meaning,;or with an activated derivative of this compound and;a) cleaves off a possibly present protecting group and, if necessary, transfers the product obtained in a physiologically compatible acid addition salt. If the preparation of the compounds of the general formula I takes place by nucleophilic substitution of R in the compounds of the general formula II with quinoline, isoquinoline or one of their specified derivatives, then as residue R 9 especially acyloxy acid residues of lower aliphatic carboxylic acids come into consideration , preferably with 1 to 4 C atoms, such as e.g. acetoxy or propionyloxy, especially acetoxy, which may optionally be substituted, such as e.g. chloroacetoxy or acetylacetoxy. As R 9, other groups also come into consideration such as, for example, halogen, especially chlorine, bromine or iodine, or carbamoyloxy. According to the invention, the nucleophilic substitution reaction uses starting compounds with the general formula II, where R 9 stands for acetoxy, or salts thereof, such as e.g. a sodium or potassium salt. The reaction is carried out in a solvent, preferably in water or in a mixture of water and an organic solvent that is easily miscible with water, such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide or ethanol. The reaction temperature is usually in the range from approx. 10 to approx. 100°C, preferably between 20 and 80°C. The base components are added in amounts that lie between approximately equimolar amounts and an excess of up to approx. 15 times. The substitution of the residue R is facilitated by the presence of neutral salt ions, preferably iodide or thiocyanate ions in the reaction medium. In particular, approx. 10 to approx. 80 equivalents of potassium iodide, sodium iodide, potassium thiocyanate or sodium thiocyanate. The reaction is advantageously carried out near the neutral point, preferably at a pH value in the range from approx. 5 to approx. 8. If the group R g is present as a protected amino group, then e.g. optionally substituted alkyl, such as, for example, 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 trichloroethoxycarbonyl, benzyloxycarbonyl or tert-butyloxycarbonyl, preferably tert-butyloxycarbonyl and benzyloxycarbonyl; or dimethylaminomethylene, themselves as amino-protecting groups. ;The protecting group can be removed in a manner known per se after the substitution reaction, e.g. the trityl group by means of a carboxylic acid, such as acetic acid, trifluoroacetic acid, formic acid, or the benzyloxycarbyl group. hydrogenolytic. The reaction product of formula I can be isolated from the reaction mixture in the usual way, e.g. by freeze-drying the aqueous phase, chromatography or also by precipitation as a sparingly soluble salt, for example as a hydroiodide or hydrothiocyanate salt. The nucleophilic substitution reaction on compounds of the general formula II can also be carried out so that the reaction is carried out in the presence of a base corresponding to the residue A, which e.g. quinoline or isoquinoline, and with trimethyliodosilane. This variant of the substitution reaction is preferably carried out by adding trimethyliodosilane to a mixture of compound II and the base in a suitable solvent. However, it can also be carried out so that the compound II is first reacted with trimethyliodosilane according to the reaction conditions mentioned below and then the base is added. Suitable solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, trichloroethane, tetrachloromethane, or lower alkylnitriles, such as acetonitrile or propionitrile. The base is added at least in stoichiometric amounts and up to a 20-fold excess, preferably working with a 5- to 15-fold excess. Trimethyliodosilane is likewise added in at least stoichiometric amounts and up to a 20-fold excess, preferably in a 5- to 15-fold excess. ;The reaction is carried out at a temperature between -5°C and +100°C, preferably between 10° and 80°C. The reaction product of formula I can be isolated in the usual way after hydrolysis of the reaction mixture by the addition of water or aqueous mineral acids, e.g. dilute HC1, HBr, HJ or H2SO4, ;from the aqueous phase in the usual way, e.g. by freeze-drying the water phase, chromatography and the like. Preferably, the polar reaction product is precipitated from the aqueous solution in the form of a sparingly soluble salt, for example after the addition of KSCN or KJ as a hydrothiocyanate or hydroiodide salt. In the case that R 9 stands for a carbamoyloxy group, the substitution reaction is carried out analogously. When R 9 stands for halogen, especially bromine or iodine, the substitution is carried out in a manner known from the literature. If the compound II is simultaneously present in the form of a reactive derivative, for example silyl derivatives which are formed by the reaction of the compound with the general formula II with a silyl compound, come into consideration, such as e.g. trimethylchlorosilane, bis-(trimethylsilyl)acetamide or bis(trimethylsilyl)trifluoroacetamide. In this case, the reaction is conveniently carried out in the presence of an inert solvent, such as methylene chloride or acetonitrile. The acylation of the compounds of the general formula III or of their addition salts, for example with hydrochloric acid, bromic acid, nitric acid, sulfuric acid, phosphoric acid or an organic acid, such as e.g. methanesulfonic acid, p-toluenesulfonic acid or maleic acid, is carried out with carboxylic acids of the general formula IV or with a reactive derivative of such an acid. In many cases, it is also an advantage to protect the 2-amino group in the compound with the general formula IV before the reaction. As amino protecting groups, the above-described protecting groups for Rg are suitable. After the acylation, the protecting group can be cleaved off in a manner known per se, e.g. the trityl group by means of a carboxylic acid, such as formic acid or trifluoroacetic acid, or the chloroacetyl group by means of thiourea. If the carboxylic acid with the general formula IV as well as its derivative protected in the amino group is itself added as an acylating agent, then it is suitably carried out in the presence of a condensing agent, for example a carbodiimide, such as N,N'-diecyclohexylcarbodiimide. ;The activation of the carboxylic acid with the general formula IV can occur 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, as described in BRD patent document 28 04 040. ;As an activated derivative of the carboxylic acid with the general formula IV, halides, preferably chloride, which are obtained in a manner known per se by treatment with halogenating agents, such as e.g. phosphorus pentachloride, phosgene or thionyl chloride, under gentle reaction conditions known from the literature for cephalosporin chemistry. As activated derivatives of the carboxylic acid with the general formula IV, anhydrides and mixed anhydrides, azides, activated esters and thioesters are also suitable, preferably with p-nitrophenol, 2,4-dinitrophenol, methylene cyanohydride, N-hydroxysuccinimide and N-hydroxyphthalimide, in particular those same with 1-hydroxybenzotriazole and 6-chloro-1-hydroxybenzotriazole and 2-mercaptobenzitazole. As mixed anhydrides, those with lower alkanoic acids, such as e.g. acetic acid, and especially preferred those with substituted acetic acids, such as e.g. trichloroacetic acid, pivalic acid or cyanoacetic acid. Particularly suitable, however, are also the mixed anhydrides with carbonic acid half-esters, which are obtained, for example, by reacting the carboxylic acid with formula IV, where the amino group is protected with chloroformate benzyl ester, -p-nitrobenzyl ester, ;-iso-butyl ester, -ethyl ester or -allyl ester. The activated derivatives can be reacted as isolated substances, or also in situ. Usually, the reaction of the cephem derivative of the general formula III with a carboxylic acid of the general formula IV or an activated derivative thereof occurs in the presence of an inert solvent. Chlorinated hydrocarbon, such as preferably methylene chloride and chloroform} ether, such as e.g. diethyl ether, preferably tetrahydrofuran and dioxane; ketone, such as preferably acetone and butanone; amide, such as preferably dimethylformamide and dimethylacetamide, or pyridine, is particularly suitable. It may also prove advantageous to use a mixture of the mentioned solvents. This is thus often the case when the cephem compound of the general formula III is reacted with an in situ produced activated derivative of a carboxylic acid of the formula IV. ;The reaction of cephem compounds of formula III with carboxylic acids of formula IV or their activated derivatives can enter a temperature range from approx. -80 to approx. +80°C, preferably between -30 and +50°C, however especially between approx. -20°C and room temperature. ;The reaction duration depends on the reactants, the temperature and the solvent, resp. the solvent mixture and is usually between approx. 1/4 and approx. 72 hours. The reaction with acid halides can optionally be carried out in the presence of an acid-binding agent for binding the liberated hydrogen halide. Tertiary amines are particularly suitable as such, such as e.g. triethylamine, dimethylaniline or pyridine; inorganic bases, such as potassium carbonate or sodium carbonate; alkylene oxides, such as propylene oxide. There may also be an advantage with the presence of a catalyst, such as e.g. dimethylaminopyridine. If the amino group in the compounds of the general formula III is present in the form of a reactive derivative, it may be a derivative known from the literature for amidations. For example, silyl derivatives which are formed by the reaction of compounds of the general formula III with a silyl compound, such as e.g. trimethylchlorosilane or bis-(trimethylsilyl)-acetamide. If the reaction is carried out with a compound that is activated in the amino group, then it is appropriate to carry out the reaction in an inert solvent, such as e.g. methylene chloride, tetrahydrofuran or dimethylformamide. As physiologically compatible acid addition salts of the compounds with the general formula I, mention should be made, for example, of those with hydrochloric acid, bromic acid, nitric acid, phosphoric acid, sulfuric acid or organic acids, such as e.g. methanesulfonic acid, p-toluenesulfonic acid or maleic acid. The compounds of the general formula III can be obtained in a manner known per se, for example from 7-aminocephalosporanic acid or from 7-aminocephalosporanic acid where the amino group is protected, in the same way as has previously been described for the nucleophilic substitution of R 9 . The compounds with the general formula IV as well as the quinoline and isoquinoline derivatives corresponding to the residue A are known from the literature, or can be prepared by methods known from the literature. The compounds of the general formula I and their physiologically compatible acid addition salts obtained according to the invention exhibit remarkably good antibacterial activity, both against gram-positive and also against gram-negative bacterial germs. Also against penicillinase- and cephalosporinase-producing bacteria, the compounds of formula I are unexpectedly very effective. As they also exhibit favorable toxicological and pharmacological properties, they constitute valuable chemotherapeutic agents. The invention therefore also relates to pharmaceutical preparations for the treatment of microbial infections, which are characterized by a content of one or more of the compounds according to the invention. The products according to the invention can also be used in combination with other active substances, for example from the range of penicillins, cephalosporins or aminoglycosides. The compounds of general formula I and their physiologically compatible acid addition salts can be administered orally, intramuscularly or intravenously. Pharmaceutical preparations containing one or more of the compounds of the general formula I as active compound can be prepared by mixing the compounds of formula I with one or more pharmacologically compatible carriers or diluents, such as e.g. fillers, emulsifiers, lubricants, flavourings, dyes or buffer substances, and is transferred into a suitable galenic preparation form, such as tablets, dragees, capsules, or into a suspension or solution suitable for parenteral use. Examples of carriers or diluents include tragacanth, milk sugar, talc, Agar-Agar, polyglycol, ethanol and water. Buffer substances are, for example, organic compounds such as N,N<1->dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzyl-phenethylamine, 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 use the active compounds as such without a carrier or diluent in a suitable form, for example in capsules. Suitable doses of the compounds of the general formula I or their physiologically compatible acid addition salts range from approx. 0.4 to 20 g/day, preferably from 0.5 to 4 g/day, for an adult with approx. 60 kg body weight. It can be given as a single dose or usually as several doses, as the single doses contain the active compound in an amount of approx. 50 to 1000 mg, preferably fracca.100 to 500 mg. Cepheme compounds which in the 3-position of the cephem ring have a methyl group substituted with a nucleophilic residue have already been claimed in DE-OS 27 16 707. However, it was not expected that the compounds obtained according to the invention would excel compared to the in DE-OS 27 16 707 obtained compounds with an unexpected superiority with regard to their antibacterial properties. The following production examples for syn compounds which can be produced according to the invention serve to further explain the invention, but do not limit it thereby. ;Example 1 ;3-[(2-isoquinolinium)methyl)-7-[2-syn-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;a) A mixture of 4.55 g (0.01 mol) 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid, 66.4 g; (0.4 mol) potassium iodide, 0.3 g of ascorbic acid, 12.9 g (0.1 mol) of isoquinoline, 75 ml of water and 25 ml of acetone were heated to 66-68°C for 4 hours with stirring. After cooling, the precipitate was diluted with 600 ml of acetone and chromatographed over 400 g of silica gel (Merck 0.063 - 0.2 mm). It was eluted with 1 L of acetone:water (8:1), 500 ml of acetone:water (5:1), then with acetone:water (2:1). The title compound was eluted with acetone:water (2:1). After freeze-drying the product fraction, 2.36 g (45% of the theoretical) of a colorless, amorphous solid was obtained. ;IR(KBr): 1765 cm<-1>(lactam-CO). ;1H-NMR(CF3CO2D);(£ = 3.45 and 3.93 (AB,J = 18HZ, 2H, SCH2); ;4.21 (s,3H,OCH3); 5.25 - 6.50 ( m,4H, 3-CH2and 2 laetam-H); 7.41 (s, 1H, thiazole); ;7.95 - 8.80 (m,6H, isoquinoline-H); 9.79 ppm (bs, 1H , isoquinoline-H).3) To a mixture of 4.55 g (0.01 mol) 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid and 11 g (0.085 mol) of isoquinoline in 100 ml of methylene chloride, 14 g (0.07 mol) of trimethyliodosilane were added at 5°C and the mixture was heated for 2 hours under reflux. After cooling, 80 ml of 2N HCl was added. From the precipitated resinous precipitate it was decanted off. The precipitate was dissolved in aqueous sodium bicarbonate solution and the solution chromatographed as above. After the freeze-drying of the product fraction, 1.95 g (37% of the theoretical) of a colorless solid was obtained, which with regard to all properties is identical to that described above. ;Example 2 ;3-[(1-quinolinium)methyl]-7-[2-syn-methoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; a) ;a) Analogously to example 1), 4.55 g (0.01 mol) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid was reacted with 12.9 g (0.1 mol) quinoline. After chromatography, 1.42 g (27% of the theoretical) of a colorless solid was obtained. ;IR(KBr): 1765 cm"<1>(lactam-CO);<1>H-NMR(CF3CO2D): = 3.40 and 3.80 (AB,J = 19Hz, 2H, SCH2)! ;4 .21 (s,3H, 0CH3); 5.30 - 6.50 (m, 4H, 3-CH2and 2 lactam-H for each 1 d at 5.41 and 6.10, J = 5Hz, Cg-respectively C7~ H); 7.42 (s, 1H, thiazole); 7.95 - 8.65 (m, ;5H, quinoline-H); 8.95 - 9.40 ppm (m, ;2H, quinoline-H). ;3) The reaction was carried out as described in example 13) with 11 g of quinoline. ;Yield: 2.15 g (41% of the theoretical) colorless solid. The compounds are identical in all properties to the one described above. ;b) ; 0.4 g (2 mmol) of 2-(2-amino-1,3-thiazol-4-yl)2-syn-methoxyiminoacetic acid was dissolved in 6 ml of N,N'-dimethylformamide. After addition of 0.28 g (2.1 mmol) of 1-hydroxybenz-triazole hydrate and 0.41 g (2 mmol) of N,N'-dicyclohexylcarbodiimide were stirred for 2 hours at room temperature, dicyclohexylurea was filtered off and to the filtrate was added a solution of 0, 83 g (2 mmol) 7-amino-3-[(1-quinolinium)methyl]cef-3-em-4-carboxylate dihydrochloride in 8 ml N,N<1->dimethylformamide and 1 m l water. The mixture was stirred for 3 hours at room temperature, evaporated under vacuum and the residue was dissolved in 10 ml of water. A little undissolved was filtered off and the solution chromatographed on silicon dioxide gel (Merck, "Lobar" column C, Pressure approx. 1 bar) with acetone : water 2: 1. The product fraction was evaporated under vacuum and freeze-dried. 0.74 g (70.8%) of the title compound was obtained in the form of a colorless solid. It is identical in all characteristics to the one described above. ;The compounds described in examples 3-37 were obtained;as amorphous solids using the corresponding starting compounds in an analogous manner as described in examples 1 and 2. ;Example 3 ;3-[(2-isoquinolinium)methyl]-7- [2-syn-methoxyimino-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; 1H-NMR(CF3CO2D): λ = 3.44 and 3, 91 (AB,J = 18Hz, 2H, SCH2; ;4.21 (s, 3H, 0CH3) ; 5.20-6.48 (m,4H, 3-CH2and 2 lactam-H); 7.92 -8 .80 ;(m, 6H, isoquinoline-H); 9.78 ppm (bs, 1H, isoquinoline-H'?. ;Example 4; ;3-[(1-quinolinium)methyl]-7-[2-syn -methoxyimino-2-(2-amino-5-chloro-thiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR (CF3CO2D):§ = 3.39 and 3 .80 (AB,J = 19Hz, SCH2, 2H); ;4.21 (s, 3H, 0CH3); 5.25-6.55 (m,4H, 3-CH2and 2 lactam-H); 7.90-8 .60 ;(m, 5H, quinoline-H); 9.00-9.45 ppm; (m, 2H, quinoline-H); Example 5 ;3-[(2-isoquinolinium)methyl]-7-[2 -syn-methoxyimino-2-(2-amino-5-bromothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR (CF3CO2D):£= 3.45 and 3 ,9 0 (AB, J= 19Hz, 2H, SCH2); ;4.22 (s, 3H, 0CH3); 5.22-6.50 (m, 4H, 3-CH 2 -and 2 lactam-H); 7.90-8.80 (m, 6H, isoquinoline-H); 9.76 ppm (bs, 1H, isoquinoline-H) ;Example 6 ;3-[(1-quinolinium)methyl]-7-[2-syn-methoxyimino-2-(2-amino-5-bromothiazol-4- yl)acetamido]-cef-3-em-4-carboxylate ;<1>H-NMR (CF3CO2D):c\=3.40 and 3.82 (AB, J=19Hz, 2H,SCH2):;4, 21 (s, 3H, 0CH3); 5.21-6.57 (m, 4H, 3-CH 2 and 2 lactam-H); 7.85-8.65 (m, 5H, quinoline-H); 9.05-9.50 ppm (m, 2H, quinoline-H). ;Example 7 ;3-[(2-isoquinolinium)methyl-7-[2-syn-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;<1> H-NMR(CF 3 CO 2 D): = 1.40 (t, J= 7Hz, 3H, CH 2 CH 3 ); 3.46 and 3.85 (AB, J=18Hz, 2H, SCH^); 4.50 ;(q, J= 7 Hz, 2H, CH2CH3); 5.20-6.45 ;(m,4H,3-CH2 and 2 lactam-H); 7.42; (s, 1H, thiazole-H); 8.0-8.75 (m, 6H, isoquinoline-H); 9.80 ppm (bs, 1H, isoquinoline-H). ;Example 8; ;3-[(1-quinolinium)methyl]-7-[2-syn-ethoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;<1> H-NMR(CF3CO2D): = 1.42 (t, J= 7Hz, 3H, CH2CH3; 3.43 and 3.72 (AB, J = 19Hz, 2H, SCH2); 4.51 ;(q, J= 7Hz, 2H, CH2CH3)! 5.25-6.50 ;(m, 4H, 3-CH2 and<->2 lactam-H); 7.45 (s, 1H, thiazole-H); 8.00-8 .70 (m, 5H, quinoline-H; 8.97-9.45 ppm (m, 2H, quinoline-H). ;Example 9 ;3- [ T,2-isoquinolinium) methyl] -7- [ 2- synpropyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR(CF3CO2D): = 1.05 (t, J= 6Hz, 3H, CH3 ); 1.55-2.15 ;(m, 2H, CH2); 3.45-3.88 (AB, J = 18Hz, 2H, SCH2); 4.48 (t, J= 7Hz, NOCH2); ;5.28-6.30 (m, 4H, 3-CH2 and 2 lactam-H); ;7.42 (s, 1H, thiazole); 7.90-8.80 (m, 6H, isoquinoline-H) ; 9.80 ppm (bs, 1H, isoquinoline-H) ; Example 10 ; 3-[(1-quinolinium)methyl]-7-[2-syn-propyloxyimino-2-(2-amino-thiazol-4- yl)acetamido]-cef-3-em-4-carboxylate ;"""H-NMR (CF 3 CO 2 D) : S= 1.02 (t, J = 6Hz, 3H, CH 3 ); 1.5-2.2; (m, 2H, CH2); 3.40 and 3.70 (AB, J =;18 Hz, 2H, SCH 2); 4.45 (t, J - 6 Hz, NOCH 2 ); 5.30-6.50 (m, 4H, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); ;7.95-8.70 (m, 5H, quinoline-H); 8.93-9.42 ppm (m, 2H, quinoline-H). ;Example . 11 . ;3-[(2-isoquinolinium)methyl]-7-[2-syn-isopropyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;<1>H- NMR (CF 3 CO 2 D): δ = 1.40 and 1.50 (d, J=6Hz, 6H, 2CH 3 ); ;3.45 and 3.88 (AB, J = 18Hz, 2H, SCH2); ; 4.75 (m, 1H, CH); 5.20-6.40 (m, 4H, 3-CH 2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 8.01-8.85 (m, 6H, isoquinoline-H); ;9.80 ppm (bs, 1H, isoquinoline-H). ;Example 12 ;3-[(1-quinolinium)methyl]-7-[2-syn-isopropyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;1HHNMR( CF3C02D) : (5 = 1.45 and 1.55 (d, J=6Hz, 6H, 2CH3); ;3.43 and 3.80 (AB, J = 19Hz, 2H, SCH2); ;4.72 ( m, 1H, CH); 5.15-6.35 (m, 4H, 3-CH2 and 2 lactam-H); 7.41 (S, 1H, thiazole); 7.95-8.62 (m, 5H , quinoline-H); ;8.96- 9.45 ppm (m, 2H, quinoline-H). ;Example 13 ;3- [.'('2-isoquinolinium)methyl] -7- [2-syn-allyloxyimino- 2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>HNMR (CF3CO2D): δ = 3.47 and 3.86 (AB, J = 18Hz, 2H, SCH2) ;4.85-6.45 (m, 9H, 5Allyl-H, 3-GH2 and 2 laetam-H); 7.41 (s, 1H, thiazole); ;8.00-8.85 (m , 6H, isoquinoline-H); 9.80 ppm (bs, 1H, Isoquinoline-H). ;Example 14 ;3-[(1-quinolinium)methyl]-7-[2-syn-allyloxyimino-2-(2 -amino-thiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR (CF3CO2D): & = 3.40 and 3.78 (AB, J=18Hz, 2H, SCH2); ;4.80-6.50 (m, 9H, 5 allyl-H, 3-CH2and 2 lactam-H) 7.41 (s, 1H, thiazole); ;7.98-8.65 (m , 5H, quinoline -H); 9.00 9.45 ppm (m, 2H, quinoline-H). ;Example 15 ;3-[(2-isoquinolinium)methyl]-7-[2-syn-methylthiomethoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; <1>H-NMR (CF 3 CO 2 D): S = 2.28 (s, 3H, SGH 3 ); 3.47 and 3.88 (AB, ;J= 18Hz, 2H, SCH2); 5.15-6.30 ; (m, 6H, CH2S, 3-CH2 and 2 lactam-H); ;7.42 (s, 1H, thiazole); 7.90-8.82 (m, 6H, isoquinoline-H); 9.75 ppm (bs, 1H, isoquinoline-H). ;Example 16 ;3-[(1-quinolinium)methyl]-7-[2-syn-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;1H- NMR (CF 3 CO 2 D): η = 2.25 (s, 3H, SCH 3 ); 3.45 and 3.85 (AB, ;J= 18Hz, 2H, SCH2); 5.10-6.35 (m, 6H, ;CH 2 S, 3-CH 2 and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.95-8.66 (m, 5H, quinoline-H); 8.92-9.41 ppm (m, 2H quinoline-H). ;Example 17 ;3-[(2-isoquinolinium)methyl]-7-[2-syn-ethyloxyethoxyimino-2-( 2-( 2- aminothiazol-4- yl) acetamido]- cef- 3- em- 4- carboxylate ;<1>H-NMR(CF3CO2D): & = 1.33 (t, J=7Hz, 3H, CH2CH3); 3.42 and 3.83 (AB, J =18Hz, 2H, SCH2); 4.35 - 6.32 (m, 10H, OCH2CH2OCH2, 3-CH2 and 2 lactam-H); 741 (s, 1H, thiazole); 7.90-8.85 (m, 6H, isoquinoline-H); 9.80 ppm (bs, 1H, isoquinolin-H). ;Example 18 ;3-[(1-quinolinium)methyl]-7-[2-syn-ethyloxyethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef - 3- em- 4- carboxylate ;<1>H-NMR(CF3CO2D): & = 1.35 (t, J = 7Hz, 3H, CH2CH3); 3.45 and 3.80 (AB, J=18Hz, 2H, SCH^T 4.30-6.35 ;(m, 10H, OCH CH2OCH2, 3-CH2 and 2 lactam-H); 7.41 (S,<2>1H, thiazole); 7.95-8 .65 ;(m, 5H, quinoline-H); 8.95-9.42 ppm (m, 2H, quinoline-H). ;Example 19 ;3-[(2-isoquinolinium)methyl]-7-[2 -syn-cyclopropylmethoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR (CF3CO2D):§ = 1.05-1.7 (m, 5H, cyclopropyl); 3.40 and 3.85 (AB, J = 18 Hz, 2H, SCH2); 4.25; (d, j = 7Hz, 2H, NOCH2); 5.25-6.35 (m, 4H, 3-CH 2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.90-8.80 (m, 6H, isoquinoline-H; ;9.79 ppm (bs, 1H, isoquinoline-H). ;Example 20 ;3-[(1-quinolinium)methyl]-7-[ 2 -syn-cyclopropylmethoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; 1H-NMR(CF3CO2D) : £ = 1.)l -1.7 (m , 5H, cyclopropyl); 3.42; and 3.78 (AB, J = 18 Hz, 2H, SCH2); ; 4.26 (d, J=7 Hz, 2H, NOCH 2 ); 5.23-6.32 ; (m, 4H, 3-CH 2 and 2 lactam-H); 7.41; (s, 1H, thiazole); 7.95-8.65 (m, 5H, quinoline-H); 8.95-9.40 ppm (m, 2H, quinoline-H). ;Example 21 ;3-[(2-isoquinolinium)methyl]-7-[2-syn-cyclopentyl-oxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; <1>H-NMR (CF 3 CO 2 D): 6 = 1.4-2.2 (m, 8 cyclopentyl-H); 3.42 and 3.88 (AB, J = 18Hz, 2H, SCH2); 4.9-6.3 ; (m, 5H, cyclopentyl-H, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.95-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (bs, 1H, isoquinoline-H). ;Example 22 ;3-[(1-quinolinium)methyl]-7-[2-syn-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;<1 >H-NMR (CF 3 CO 2 D): δ = 1.4-2.2 (m, 8 cyclopentyl-H); 3.40 and 3.75 (AB, J= 18 Hz, 2H, SCH2); 5.1 (m, 1 cyclopentyl-H); 5.30-6.38 (m, 4H, 3-CH 2 ; and 2 lactam-H); 7.42 (s, 1H, thiazole); ;7.95-8.65 (m, 5H, quinoline-H); 8.95-9.40 ppm (m, 2H, quinoline-H). ;Example 23 ;3-[(2-isoquinolinium)methyl]-7-[2-syn-(1,3-thiazol-4-yl)methyl-oxyimino-2-(2-aminothiazol-4-yl)acetamido] -cef-3-em-4-carboxylate; 1H-NMR(CF 3 CO 2 D): δ = 3.45 and 3.88 (AB, J=18 Hz, 2H, SCH 2 ); ;5.25-6.20 (m, 6H, NOCH2, 3-CH2 and 2 lactam-H); 7.35 (s, 1H, thiazole); 7.90-8.80 (m, 7H, 6 isoquinoline-H and 1 thiazole-H); 9.70-9.85 (m, 2H, each 1 isoquinoline and 1 thiazole-H) ; Example 24 ; 3-[(2-isoquinolinium)methyl]-7-[2-syn-carboxymethyl-oxyimino-2-( 2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ;<1>H-NMR (CF3CO2D):& = 3.43 and 3.90 (AB, J = 19Hz, 2H,; SCH2); 5.10 (s, 2H, 0CH2)| 7.42 (s, 1H, thiazole); 7.95-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (m, 1H, isoquinoline-H). ;Example 25 ;3-[(1-quinolinium)methyl]-7-[2-syn-(2-carboxy-2-propen-1-yl-oxyimino)-2-(2-aminothiazol-4-yl)acetamido ]-cef-3-em-4-carboxylate ;<1>H-NMR (CF 3 CO 2 D): η = 3.43 and 3.88 (AB, J = 18Hz, 2H, SCH 2 ); ;5.1-6.45 (m, 6H, NOCH2, 3-CH2 and 2 lactam-H); 6.55-6.92 (m, 2H, C=CH 2 ); 7.42 (s, 1H, thiazole); 7.93-8.64 (m, 5H, quinoline-H); ;8.92-9.40 ppm (m, 2H, quinoline-H). ;Example 26 ;3-[(1-quinolinium)methyl]-7-[2-syn-(2-carboxy-2-propyl-oxy-imino)- 2-(2-aminothiazol-4-yl)acetamido]- cef- 3- em- 4- carboxylate """H-NMR (CF3CO2D): å = 1.80 (s, 6H, 2xCH3) ; 3.43 and 3.88 (AB, J= 18 Hz, 2H, SCH2 ); 5.25-6.30 (m, 4H, 3-CH2; and 2 lactam-H); 7.40 (s, 1H, thiazole); 7.95-8.60 (m, 5H, quinoline- H); 8.90-9.35 ppm ; (m, 2H, quinoline-H); Example 27 ; 3-[(2-isoquinolinium)methyl]-7-[2-syn(1-carboxy-ethyl-oxy -imino)- 2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;"""H-NMR (CF3CO2D) : 6 = 1.71 (d, J=7Hz, 3H, CH3); 3.45 and 3.90 ;8AB, J=18Hz, 2H, SCH2); 4.92-6.40 (m, ;5H, CH-CH3, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.96-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (bs, 1H, isoquinoline-H) ; Example 28 ; 3-[(2-isoquinolinium)methyl]-7-[2-syn-(1-carboxy-cyclopropyl-oxyimino)-2-(2- aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate ; <1>H-NMR (CF 3 CO 2 D): δ = 1.52-1.95 (m, 4 cyclopropyl-H); 3.46 and 3.90 (AB, J = 18 Hz, 2H, SCH2); 5.15-6.30 (m, 4H, 3-CH 2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.95-8.80 (m, 6H, isoquinoline-H); 9.80 ppm (bs, 1H, isoquinoline-H). ;Example 29 ;3-[(1-quinolinium)methyl]-7-[2-syn-(1-carboxy-cyclobutyloxy-imino)-2-(2-aminothiazol-4-yl)acetamido]-cef-3- em-4-carboxylate ;<1>H-NMR (CF 3 CO 2 D): δ = 2.0-3.2 (m, 6 cyclobutyl-H); 3.45 and 3.92 ;(AB, J = 18 Hz, 2H, SCH2); 5.25-6.38 ; (m, 4H, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.95-8.60 (m, 5H, quinoline-H); ;8.93-9.42 ppm (m, 2H, quinoline-H). ;Example 30 ;3-[(1-quinolinium)methyl]-7-[2-syn-(1-carboxy-cyclopentyloxy-imino) 2-[(2-aminothiazol-4-yl)acetamido]-cef- 3- em- 4-carboxylate ;<1>H-NMR (CF 3 CO 2 D):£ = 1.4-2.4 (m, 8 cyclopentyl-H); 3.45 and 3.90 (AB, J=18 Hz, 2H, SCH2); 5.15-6.34 ; (m, 4H, 3-CH2 and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.90-8.62 (m, 5H, quinoline-H} 8.93-9.40 ppm (m, 2H, quinoline-H). ;Example 31 ;3-[2-isoquinolinium)methyl]-7- [2-syn-methoxycarbonyl-methyloxy-imino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate; " H-NMR (CF3CO2D) : δ = 3.43 and 3.90 (AB, J=19Hz, 2H, SCH2); 3.94 (s, 3H, CH3); 5.03 (s, 2H, NOCH2) ; ;5.20-6.45 (m, 4H, 3-CH2 and 2 lactam-H); ;7.42 (S, 1H, thiazole); 7.90-8.75 (m, 6H, isoquinoline-H ); 9.80 ppm (bs, 1H, isoquinoline-H). ;Example 32 ;3-[1-quinolinium)methyl]-7-[2-syn-cyanomethyloxyimino-2-(2-amino-thiazol-4- yl)acetamido]-cef-3-em-4-carboxylate ;<1>H-NMR (CF 3 CO 2 D): δ = 3.42 and 3.78 (AB, J = 19Hz, 2H, SCH 2 ); ; 5.12 (s, 2H, N 0CH 2 ); 5.25-6.38 (m, 4H, 3-CH 2 and 2 lactam-H); 7.43 (s, 1H, thiazole); 7.95-8.65 (m , 5H, quinoline-H); 8.93-9.38 ppm (m, 2H, quinoline-H). ;Example 33 ;3-[(2-isoquinolinium)methyl]-7-[2-syn-carbamoylmethyl- oxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate <1>H-NMR (CF3CO2D):& = 3.42 and 3.92 (AB, J = 19Hz , 2H, SCH2); ;4.95-6.35 (m, 6H, NOCH2, 3-CH2and 2 lactam-H); 7.44 (s, 1H, thiazole), 7.90-8.75 (m , 6H, isoquinoline-H); 9.78 ppm (bs, 1H, isoquinoline-H). ;Example 34 ;3-[(1-quinolinium)methyl]-7-[2-syn-carbamoylmethyloxy-imino-2- ( 2-aminothiazole - 4-yl)acetamido]-ceph-3-em-4-carboxylate; <1>H-NMR (GF 3 CO 2 D): S = 3.42 and 3.85 (AB, J = 19Hz, 2H, SCH 2 ); ;4.92-6.40 (m, 6H, NOCH2, 3-CH2 and 2 lactam-H); 7.44 (s, 1H, thiazole); ;7.95-8.65 (m, 5H, quinoline-H); 8.95-9.40 ppm (m, 2H, quinoline-H). ;Example 35 ;3-[(4-methyl-1-quinolinium)methyl]-7-[2-syn-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em-4- carboxylate ;<1>H-NMR (CF 3 CO 2 D) : é> = 3.15 (s, 3H, CH 3 ); 3.40 and 3.80 (AB, J= ;18Hz, 2H, SCH2); 4.23 (s, 3H, 0CH3); ;5.30-6.40 (m, 4H, 3-CH2 and 21actam-H; for each ld at 5.42 and 6.11; J= 5Hz,; C-6 resp. C-7-H); 7.42 (s, 1H, thiazole); ;7.80-8.75 (m, 5H, quinoline-H); 9.06 ppm (d, J=6Hz, 1 quinoline-H). ;Example 36 ;3-[(5-hydroxy-2-isoquinolinium)methyl]-7-[2-syn-methoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-cef-3-em- 4- carboxylate ;<1>H-NMR (CF3CO2D):: &<=>3.45 and 3.91 (AB, J =18Hz, 2H, SCH2) ; ;4.21 (s, 3H, 0CH3) 5.25-6.35 (m, 4H, 3-CH2 and 2 lactam-H); 7.41 (s, 1H, thiazole); ;7.95-8.80 (m, 5H, isoquinoline-H); 9.78 ppm (bs, 1H, isoquinoline-H).;Example 37 ;3-[(1-quinolinium)methyl]-7-α-methoxy-7-[2-syn-methoxy-imino-2-( 2 - aminothiazol-4-yl)acetamido]-cef-3-em-4-carboxylate;<1>H-NMR (CF3CO2D): δ = 3.30-3.95 (m, 5H, 0CH3 and SCH~2) ; 4.23 ;(s, 3H, 0CH3); 5.25-6.45 (m, 4H, 3-CH 2 ; and 2 lactam-H); 7.43 (s, 1H, thiazole); ;7.90-8.63 (m, 5H, quinoline-H)* 8.90-9.35

ppm (m, 2H, quinoline-H).

Example 38

7-[2-(2-aminothiazol-4-yl)-2-syn-difluoromethoxyimino-acetamido]-3- isoquinolinium methyl- cef- 3- em- 4- carboxylate

Method 2, variant b

Solution A:

0.53 g of 2-(2-aminothiazol-4-yl)-2-syn-difluoromethoxyiminoacetic acid, 0.30 g of 1-hydroxybenzotriazole hydrate and 0.41 g of dicyclohexylcarbodiimide were suspended in 25 ml of N,N-dimethylformamide (DMF) , stirred for 2 hours at room temperature and the dicyclohexylurea was filtered off.

Solution B:

0.68 g of 7-amino-3-iodomethyl-cef-3-em-4-carboxylic acid was suspended in 40 ml of DMF and after addition of Ov65 g of isoquinoline, it was stirred for 4 hours at room temperature. Solution A was dropped into solution B under ice-cooling and it was stirred overnight at room temperature. The solution was evaporated under vacuum, dissolved in a little water with the addition of sodium bicarbonate until pH = 6 and chromatographed on silica gel ("Lobar-B" column, manufactured by Merck) with acetone/water (3:1). - By freeze-drying the product fraction, 0.09 g of colourless, amorphous solid was obtained.

1H-NMR (CF 3 CO 2 D): h =3.40 and 3.90 (AB , J=18Hz, 2H, SCH 2 );

5.30-6.42 (m, 4H, CH2N® and 2 lactam-H), 6.70 (t, J = 72Hz, 1H, CHF2), 7.45

(s, 1 thiazole-H), 8.0-8.8 (m, 6-isoquinoline-H), 9.80 ppm (bs, 1 isoquinoline-H).

In an analogous manner as described in examples 1, 2 and 38, the compounds listed below were obtained which correspond to the general formula I with R 2 = hydrogen and which bear those in table

1 3

Il indicated substituents as the residues R, R and A.

Claims (9)

1. Cephem derivatives of the general formula I and their physiologically compatible acid addition salts, wherein R"*" is hydrogen or halogen, R 2 is hydrogen or methoxy, R 3 is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C -C 1 -cycloalkyl, C 3 -C 1 -cycloalkyl-C -C 8 -alkyl, C. -C.sub.1 -cycloalkenyl, the group (CH2 )n where m or n are each 0 or 1, 4 5 R and R can be the same or different and are hydrogen, aryl, a C 1 -C 3 -alkyl group, or form together with the carbon atom to which they are attached, a methylene or a C 3 -C 4 -cycloalkylidene group, wherein alkyl and cycloalkyl may be further substituted one or more times; g 7 7 R is a group -CO 2 R , where R is hydrogen, Cl~ C4~ alky1' -CH2 0~ Ci~ C4~ alkY 1' -CH-OOC-C1 -C4 -alkyl, or means an equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base; a nitrile group or a carbamoyl group -CONH2, which may be substituted once or twice on the nitrogen atom, A is a quinolinium or an isoquinolinium residue, as each may be substituted one or more times, equal or different, by C₁ -C₂ alkyl, which may also be substituted, C₁ -C₂ -alkyl, halogen, trifluoromethyl or hydroxy, and where the R O group is in syn- score. 2. Process for the preparation of compounds of formula I and their physiologically compatible acid addition salts, characterized in that mana) reacts a compound of the general formula II or salts thereof or a reactive derivative of 12 3 compound II, where R , R and R have the above-mentioned meanings and R g means an amino or a protected amino group and R 9 means one with quinoline, isoquinoline or substituted quinoline or isoquinoline, which corresponds to the residue A in formula I, replaceable group, with quinoline, isoquinoline or a derivative thereof, and a) cleaves off a possibly present protecting group and 3) if necessary, transfer the obtained product into a physiologically compatible acid addition salt, orb) react a 7-amino-cephem compound with the general formula III or an acid addition salt thereof, where R 2 and A have the meanings mentioned above, the amino group can also be present in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yl)-2-syn- oximinoacetic acid of the general formula IV, 13 8 where R , R and R have the meanings given above, or with an activated derivative of this compound, and a) cleaves off a possibly present protecting group, and if necessary, transfer the obtained product in a physiologically compatible acid addition salt. 3. Method according to claim 2, characterized in that the nucleophilic substitution of the substituent R 9 takes place in the presence of neutral salt ions, especially of iodide or thiocyanate ions. 4. Method according to claim 2, characterized in that the nucleophilic substitution of the substituent R 9 takes place in the presence of the base which forms the basis for the residue A, and trimethyliodosilane. 5. Pharmaceutical preparation which is effective against bacterial infections, characterized in that they contain a cephem derivative of the general formula I. 6. Procedure for the production of pharmaceutical preparations that are effective against bacterial infections, characterized in that a cephem derivative of the general formula I is brought into a pharmaceutically suitable administration form, possibly together with usual pharmaceutical carriers, diluents or buffer substances. 7. Use of cephem derivatives of the general formula I, for combating bacterial infections. 8. Cepheme derivative according to claim 1, characterized in that in the general formula I R 1 stands for hydrogen and halogen, R 2 for hydrogen, R 1 for C 1 -C 1 -alkyl and A for quinoline or isoquinoline. 9. Cepheme derivative according to claim 8, characterized in that halogen stands for chlorine and the C 1 -C 3 -alkyl group stands for methyl or ethyl.