NO834774L - CEPHALOSPORINE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LU, LI, NL, SE) A cephem derivative of the formula I see diagramm : EP0111934,P10,F3 and physiologically acceptable acid addition salts thereof in which R**1 denotes C1 -C2 -alkyl, R**2 denotes a pyridinium radical see diagramm : EP0111934,P10,F4 which is substituted by 2 alkyl groups in the ortho-position which are linked to form a trimethylene to pentamethylene ring in which one carbon atom can be replaced by an oxygen atom, or denotes a 1-quinolinium radical or a 2-isoquinolinium radical and in which the R**1 O group is in the syn-position. 1. Claims (for the Contracting State AT) A process for the preparation of a cephem derivative of the formula I see diagramm : EP0111934,P11,F4 and physiologically acceptable acid addition salts thereof in which R**1 denotes C1 -C2 -alkyl, R**2 denotes a pyridinium radical see diagramm : EP0111934,P12,F1 which is substituted by 2 alkyl groups in the ortho-position which are linked to form a trimethylene to pentamethylene ring in which one carbon atom can be replaced by an oxygen atom, or denotes a 1-quinolinium radical or a 2-isoquinolinium radical in which the R**1 O group is in the syn-position which comprises a) reacting a compound of the general formula II see diagramm : EP0111934,P12,F2 or salts thereof or a reactive derivative of the compound II in which R**1 has the meaning mentioned above and R**7 denotes an amino group or a protected amino group and R**8 denotes a group which can be replaced by the pyridine, quinoline or isoquinoline derivatives corresponding to the radicals R**2 of the formula I, with these pyridine, quinoline or isoquinoline derivatives, and alpha) splitting off a protective group which may be present and beta) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephem compound of the general formula III see diagramm : EP0111934,P12,F3 or acid addition salts thereof in which R**2 has the abovementioned meaning and in which the amino group can also be present in the form of a reactive derivative, with a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-synoximinoacetic acid of the general formula IV see diagramm : EP0111934,P12,F4 in which R**1 and R**7 have the meaning mentioned above, or with an activated derivative of this compound, and alpha) splitting off a protective group which may be present, 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 preparation, especially polar .cef.emderivates which are substituted in the 3' position of the cephem ring with specific pyridinium, quinolinium and isoquinolinium residues,

and which has a very good antimicrobial effect, against gram-positive and gram-negative bacteria, and is therefore suitable as a medicine for the treatment of microbial infections. The subject of the invention is therefore cephem derivatives of the general formula I

and their physiologically tolerable acid addition salts, wherein

R<1> denotes hydrogen, optionally substituted C 1 -C 8 -alkyl, optionally substituted C 1 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 3 -C 7 ~ cycloalkyl, C -j -C y -cycloalkyl-C -j 3 -C 8 -alkyl , C4-C7-cycloalkenyl, the group

3 4 in which m or n each means 0 or 1, R and R may be the same or different and mean hydrogen, aryl, a C 1 -C 4 -alkyl group, or together with the carbon the thorn in which a methylene is bound or a C^-Cy-cycloalkylidene group, wherein alkyl and cycloalkyl can furthermore be substituted one or more times, R means a group -C^R, in which R means hydrogen, C1-C4-alkyl, -Cr ^OC^-C^-alkyl, -Cr^OOC-C^-C^-alkyl or an equivalent, an alkali metal, alkaline earth metal, ammonium or an organic amine base, R"<*>" further means a nitrile group, a carbamoyl group - CONH^, which may be substituted once or twice by nitrogen R 2 means a pyridinium residue; which is substituted ;with 2 ortho-placed alkyl groups, ;which is closed to an optionally substituted di- to decamethylene ring, in which a ring C atom can be replaced by a heteroatom, and furthermore can also contain one or two double bonds, or means a 1-quinolinium or a 2-isoquinolinium residue which may also be substituted one or more times in the same or different manner with optionally substituted C]-~Cg~ alkyl, C-^-Cg- alkoxy, halogen, trifluoromethyl, or hydroxy , and in which the R<1>0 group is in the syn position. The invention relates in particular to compounds in which R<1> means hydrogen, C1-C8-alkyl, which may be substituted one or more times by halogen, C-, -C1-alkylthio, C1-C1-alkyloxy, ; lb -L b;aryl or heteroaryl, C Å „ -Cb,-alkenyl, which may be several times substituted with halogen, C^-C^-alkenyl, C^-Cy-cycloalkyl, C3~C7-cycloalkyl-C, -C 1 -alkyl, C 1 -C 1 -cycloalkenyl in which the group ; ; has the above meaning,;2 ;R means a pyridinium residue; ; which is substituted with 2 ortho-placed alkyl groups which are closed to an optionally substituted di- to decamethylene ring, in which a ring atom may be replaced by a heteroatom, and furthermore may also contain one or two double bonds. As possibly possible substituents of this di- to decamethylene ring, the following substituents in particular come into consideration which may appear one or more times, preferably once: , hydroxy, oxo, hydroxyimino, exomethylene, carboxy, C1 -C6 -alkyloxycarbonyl, cyano or carbamoyl. These substituents can appear on the aforementioned rings fused to pyridinium residues, regardless of whether the possible ring is saturated, unsaturated or also interrupted by a heteroatom. According to the invention, however, it preferably occurs on condensed saturated rings that do not contain a heteroatom. The ring fused to the pyridinium residue may contain two to ten ring members (di- to decamethylene), preferably however 3 to 5 ring members, and thus means, for example, a cyclopenteno, cyclohexeno or cyclohepteno ring. If such a condensed ring contains a double bond, a dehydrocyclopentadieno, dehydrocyclohexadieno or dehydrocycloheptadieno ring should be mentioned as examples. If in such rings a C atom is replaced by a heteroatom, oxygen or sulfur come into consideration as heteroatoms in particular. As an oxygen-containing condensed ring containing two or one double bond, the following should be mentioned, for example: Furo, pyrano, dihydrofuro and dihydropyrano, as condensed rings with a sulfur atom containing two or one double bond, thieno, thiopyrano, dihydrothieno and dihydrothiopyrano. Of the fused rings which contain a heteroatom, there is a substitution in particular for the above-mentioned substituents, especially in consideration of the rings which only contain a double bond, ; R 2 can in particular also mean a 1-quinolinium or a 2-isoquinolinium residue, each of which also may be substituted one or more times, identically or differently, by C 1 -C 8 -alkyl, which may be substituted by hydroxy, or C 1 -C 8 -alkoxy, C 1 -C 8 -alkyl, halogen, trifluoromethyl or hydroxy, and since also in the preferred compounds the RO group is in the syn position. As particularly preferred, the following substituents are for example taken into consideration: R"*": hydrogen, C-^-C^-alkyl such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, especially methyl, ethyl,

with halogen, e.g. chlorine, bromine, iodine or fluorine, substituted alkyl, especially trifluoroethyl, 2,2,3,3-tetrafluoropropyl, with C 1 -C 8 -alkylthio-substituted alkyl, e.g. methylthio, ethylthio,

with C 1 -C 8 -alkyloxy-substituted alkyl, e.g. methyloxy, ethyloxy, with aryl, e.g. phenyl, tolyl, chlorophenyl, substituted alkyl, especially benzyl with heteroaryl, e.g. 1,3-thiazol-4-yl, substituted alkyl, especially 1,3-thiazol-4-yl-methyl,

C₁-C₂-alkenyl such as e.g. vinyl, allyl, isopropenyl, methyl-

allyl, especially allyl, methylallyl, with halogen, such as e.g. chlorine.

bromine, substituted C 1 -C 4 -alkenyl, especially 3-chloro-propen-2-yl, 2-bromo-propen-2-yl, 2-chloro-propen-2-yl,

C₁-C₁-alkenyl such as especially propargyl,

C₁-C₁-cycloalkyl, such as especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, especially cyclopentyl,

C3-C7-cycloalkylmethyl, such as cyclopropylmethyl, C1-C7-cycloalkenyl, such as cyclopentyl, cyclohexyl

the group

3 4

wherein R and R can be the same or different and mean hydrogen, aryl, preferably phenyl, C-1-C4-alkyl, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, preferably methyl,

3 4

ethyl, especially methyl, or as R and R together with the carbon atom to which they are attached can form a methylene group or a C3-C7 cycloalkylidene group such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the cycloalkylidene group can be substituted, e.g. with C^-C^-alkyl, preferably methyl, with halogen, preferably fluorine and chlorine or may also be substituted with the alkylene with 3-6 C atoms,

m means 0 or 1,

n means 0 or 1, as the sum of m and n means 1 or 2.

For the case that m = 0 and n = 1:

for the case that m = 0 and n = 1: - CE^- and if n and m = 1:

R means the group -CO-pR / in which R means hydrogen, C-^-C^-alkyl son e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert-butyl, preferably methyl, ethyl, 'especially methyl or an equivalent of an alkali metal,' such as e.g. sodium, potassium, lithium, preferably sodium and potassium, an equivalent of an alkaline earth metal, preferably calcium or magnesium, ammonium, and an equivalent of an organic amine base, such as e.g. tri-methylamine, diethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine, tris (hydroxymethyl)aminomethane, arginine, lysine, a nitrile group, a carbamoyl group which at the nitrogen atom may be substituted once by C-^-Cg-alkyl, hydroxy-C-^-Cg-alkyl C-^-Cg-alkylcarbonyl, C-^-Cg-alkylcarbonyl, carboxy-methyl C-^-Cg-alkoxycarbonylmethyl, aminocarbonylmethyl, C]_-Cg~alkylaminocarbonyl, carbamoyl, hydroxy, C₁-Cg-alkyloxy, or which may be substituted twice by C₁-Cg-alkyl at the nitrogen atom,

R 2: a pyridinium residue, which is substituted by two to one di-

to decamethylene ring closed alkyl groups, which can again be substituted one or more times, preferably once, and which contain one or two double bonds, preferably the following condensed ring systems: Cyclopenteno, hydroxycyclopenteno, oxocyclopenteno, hydroxymethylcyclopenteno, exomethylene cyclopenteno, carboxycyclopenteno, C 1 -C 4 -Alkoxycarbonylcyclopenteno, especially methoxycarbonylcyclopenteno and carbamoylcyclopenteno,

cyclohexeno, hydroxycyclohexeno, oxocyclohexeno, hydroxymethyl-cyclohexeno, exomethylene-cyclohexeno, carboxycyclohexeno, C-^-C^-alkoxycarbonyl-cyclohexeno, especially methoxycarbonyl-cyclohexeno, and carbamoylcyclohexeno, cyclohepteno, hydroxy-, chloro-, oxo-, hydroxymethyl- , exomethylene-, or carboxy-cyclohepteno, C-^-C^-alkoxycarbonyl-cyclohepteno, especially methoxycarbonyl-cyclohepteno and carbamoylcyclohepteno

dehydro-cyclopenteno,

dehydro-cyclohexeno and dehydro-cyclohepteno.

If in the above-mentioned condensed ring systems a C atom is replaced by a heteroatom, especially oxygen or sulphur, then this comes into particular consideration:

2,3- and 3,4-furo, 2,3- and 3,4-pyrano,

2,3- and 3,4-dihydrofuro, 2,3- and 3,4-dihydropyrano,

methyl-dihydrofuro, methoxydihydropyrano and hydroxydihydropyrano,

a quinolinium or an isoquinolinium residue, which each time can also be substituted one or more times equally or differently with C 1 -C 8 alkyl such as e.g. methyl, ethyl, propyl, preferably methyl, hydroxy-C 1 -C 8 -alkyl, such as e.g. hydroxymethyl, with C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, such as e.g. methoxymethyl, ethoxymethyl, such as C 1 -C 8 -alkoxy, such as e.g. methoxy, ethoxy,

with halogen, trifluoromethyl or hydroxy.

The object of the invention is further a method for the preparation of compounds of formula I and their physiologically tolerable acid addition salts, the method being characterized in that

a) a compound of the general formula II

or their salts or a reactive derivative of the compound II, in which R"'" has the above meaning and R^ means an amino or protected amino group, and R 7 means one with pyridine, quinoline or isoquinoline derivatives, corresponding to the residue R 2 with formula I, exchangeable group, is reacted with these pyridine, quinoline or isoquinoline derivatives, and a) a possibly present protecting group is cleaved off, and 8) if necessary, the formed product is transferred to a physiologically tolerable acid addition salt,

or

b) a 7-amino-cephem compound' of the general formula III

or their acid addition salts, in which R z has the above meaning and since the amino group can also be present in the form of a reactive derivative, react with a 2-(5-amino-1,2,4-thia-diazol-3-yl)-2- syn-oximinoacetic acid of the general formula

IV,

in which

1 7

R and R have the above meaning, or with an activated derivative of this compound and

a) a normally present protective group is split off,

and

6) if necessary, the formed product is transferred in a physiologically tolerable acid addition salt.

Shall the preparation of the compound with the general formula

In the case of • nucleophilic exchange of R 8 in the compounds of the general formula II with the aforementioned pyridine, quinoline or isoquinoline derivatives, the residues R o in particular, taking into account acyloxy residues of lower aliphatic carboxylic acids, preferably with 1 to 4 C -atoms, such as acetoxy or propionyloxy, especially acetoxy, which may optionally be

substituted as e.g. chloroacetoxy, or acetylacetoxy,

for R Q other groups such as halogen, especially chlorine, bromine or iodine, or carbamoyloxy are also taken into account.

According to the invention, the starting compound with the general formula II is used in the nucleophilic exchange reaction

in which R o means acetoxy or their salts, 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 easily miscible with water, such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylsulphoxide or ethane. 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 quantities between approx. equimolar amounts, and an up to approx. 15 times profit. The exchange of the residue R o is facilitated by the presence of neutral 1-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 preferably carried out near the neutral point, preferably at a pH value in the range from approx. 5 to approx. 8.

If the group R is present as a protected amino function, then it is suitable as an amino protecting group, 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.

The protecting group can be cleaved off after the exchange reaction

in and of itself known way, e.g. the trityl group by means of a carboxylic acid, such as acetic acid, trichloroacetic acid, formic

acid or the benzyloxycarbonyl group hydrogenolytically.

The reaction products 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 exchange reaction on a compound of the general formula II can also take place in such a way that the reaction is carried out in the presence of the base component corresponding to the residue R 2 and of trimethyliodosilane. This variant of the exchange reaction is preferably carried out so that trimethyl iodosilane is added to a mixture of the compound II and the base in a suitable solvent. However, it is also possible to proceed in such a way that the compound 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, carbon tetrachloride or lower alkyl nitriles, some acetonitrile or propionitrile.

The base is added in at least a stoichiometric amount, up to a 2-fold excess, preferably working with a 5- to 15-fold excess. Dimethyliodosilane is likewise added in at least a stoichiometric amount up to a 20-fold excess, preferably in a 5- to 15-fold excess.

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

The reaction product with formula I can, after the hydrolysis of the reaction mixture by adding water or aqueous mineral acids, e.g. dilute HC1, HBr, HJ or H2SO4 is isolated from the aqueous phase in the usual way, e.g. by freeze-drying the water phase, chromatography, etc. Preferably, the polar reaction products are precipitated from the aqueous solution in the form of a poorly soluble salt, for example after the addition of KSCN or KJ, as a hydrothiocyanate or hydroiodide salt.

In the case that R o means a carbamoyloxy group, the exchange reaction is carried out analogously.

If R Q means halogen, especially bromine or iodine, then the exchange takes place in a manner known from the literature. If the compound II then exists in the form of a reactive derivative, then silyl derivatives, which are formed by the reaction of a compound of the general formula II with a silyl compound such as e.g. trimethylchlorosilane or bis-(trimethylsilyl)acetamide. In this case, the reaction is conveniently carried out in the presence of a solvent, such as methylene chloride or acetonitrile.

The acylation of the compounds with the general formula III or their addition salts, for example with hydrochloric acid, hydrobromic 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 a carboxylic acid of the general formula IV or with a reactive derivative of such an acid.

In many cases, it is therefore advantageous to protect 5-amino groups in connection with the general formula IV, before the conversion. The protective groups mentioned above for R 7 are suitable as amino protecting groups. After the acylation, the protecting group can be cleaved off in a manner known per se, e.g. the trityl group at a carboxylic acid such as formic acid or trifluoroacetic acid, or chloroacetyl acid using thiourea.

If the carboxylic acids with the general formula IV and their derivatives protected in the -amino groups are used as acylating agent, then work is appropriate in the presence of a condensing agent, for example a carbodiimide, such as for example N,N<1->dicyclohexylcarbodiimide.

The activation of the carboxylic acids with the general formula IV can take place in a particularly favorable way by treatment with specific carboxylic acid amides, for example phosgene, phosphorus pentachloride, tosyl

Chloride, thionyl chloride or oxalyl chloride such as e.g. about-

spoken in German patent 28.04. 040.

As activated derivatives of the carboxylic acid with the general

formula IV is also particularly suitable for halides, preferably chlorides 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 mild reaction conditions known in the literature for cephalosporin chemistry.

As activated derivatives, the carboxylic acid with the general

formula IV, there are further the anhydrides and mixed anhydrides, azides, activated esters and thioesters, preferably with p-nitrophenol, 2,4-dinitrophenol, methylene cyanohydrin, N-hydroxy-succinimide and N-hydroxyphthalimide, especially those with 1-hydroxybenzotriazole, 6 -chloro-1-hydroxybenzotriazole and 2-mercaptobenzthiazole. As mixed anhydrides, those with lower alkanoic acids such as e.g. acetic acid and particularly 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 carboxylic acid half-esters, which are obtained, for example, by reacting the carboxylic acids with formula IV, in which the amino group is protected with chloroformate benzyl ester, -p-nitrobenzyl ester, -isobutyl ester, -ethyl ester or -allyl ester.

The activated derivatives can be reacted with isolated substances, however also in situ.

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

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 e.g. diethyl ethers, 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 then the case for the cephem compound with the general one

formula III, an in situ produced activated derivative of a carboxylic acid with formula IV is reacted.

The reaction of the cephem compounds of formula III with carboxylic acid of formula IV resp. their activated derivatives can take place in a temperature range from approx. -80 to approx. +80°C, preferably between -30 and + 50°C, especially however between approx. -20°C and room temperature.

The reaction duration depends on the reaction participants, the temperature and the solvent, resp. the solvent mixture, and is normally between approx. 1/4 and approx. 72 hours.

The reaction with the acid halides can optionally be carried out in the presence of an acid binding agent as binding of the liberated halogen hydrogen. As such, tertiary amines such as e.g. triethylamine, dimethylaniline or pyridine, inorganic bases such as potassium carbonate, or sodium carbonate, alkylene oxides such as propylene oxide. Also the presence of a catalyst such as dimethylaminopyridine may possibly be of advantage. If in the compound with the general formula III the amino group is present in the form of a reactive derivative, it may be such as are known from the literature for the amidation. Thus, for example, we are talking about silyl derivatives which are formed by the reaction of compounds with the general formula III with a silver compound such as, for example trimethylchlorosilane or bis-(trimethylsilyl)acetamide. If the reaction is carried out with such an activated compound at the amino group, it is appropriate to carry out the reaction in an inert solvent such as e.g. methylene chloride, tetrahydrofuran or dimethylformamide.

As physiologically tolerable acid addition salts of the 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 acids, p-toluenesulfonic acid or maleic acid.

The compounds with the general formula III can be obtained in a manner known per se, for example from 7-aminocephalosporanic acids or 7-aminocephalosporanic acid protected by the amino group in the same way as was described above for the nucleophilic derivative

pp

sling off R .

Compounds with the general formula IV salt those corresponding to the radical R<2> pyridine-r, quinoline and i-soquinoline bases are known in the literature or can be prepared according to methods known in the literature.

The compounds of the general formula I obtained according to the invention and their physiologically tolerable acid addition salts show remarkably good antibacterial effects, both against gram-positive and gram-negative bacterial germs.

The compounds of formula I are also unexpectedly effective against penicillinase- and cephalosporinase-producing bacteria. As they also show favorable toxicological and pharmacological properties, they are valuable chemotherapeutics.

The invention thus 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 the general formula I and their physiologically tolerable acid addition salts can be administered orally, intramuscularly or intravenously. Medicinal preparations containing one or more of the compounds of the general formula I as active ingredient must be prepared by mixing the compounds of formula I with several pharmacologically compatible carriers or diluents such as e.g. fillers, emulsifiers, lubricants, flavor correctors, dyes or buffering substances, and brings a suitable galenic preparation form such as tablets, dragees, capsules, or one for parenteral application

no suspension or dissolution.

Examples of carriers and diluents include tragacanth, lactic acid, talc, agar-agar, polyglycol, ethanol and water. Buffer substances are, for example, organic compounds such as N,W'-dimethylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, tris(hydroxymethyl)aminomethane, or inorganic compounds such as e.g. phosphate buffers, sodium bicarbonate, sodium carbonate. For the parenteral application, suspensions or solutions in water with or without buffer substances are preferably taken into consideration. It is also possible to apply the active substances as such,

without carriers or diluents in a suitable form, for example in capsules.

Suitable doses of the compounds of 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.

Single or usually multiple doses can be administered, as the single doses can contain active substances in amounts from approx. 50 to 1000 mg, preferably from approx. 100 to 500 mg.

The following examples of embodiments of syn-compounds that can be produced according to the invention serve to explain the invention in more detail.

Example 1

3-(2,3-Cyclopenteno-1-pyridinium)methyl-7-(2-syn-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido7-ceph - 3- em- 4- carboxylate

a)

a) A mixture of 0.57 g (1 mmol) 1-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-methoxyimino-acetamido7-cephalosporinic acid-trifluoro- acetate, 30 mg ascorbic acid, 6.65 g (40 mmol) potassium iodide,_1.3 ml (15 mmol) 2,3-cyclopentenopyridine, 7 ml water and 3 ml acetone are heated for 4 hours at 65-67°C with stirring.

After cooling, the milky solution is chromatographed

on silica gel ("Lobar-C" column-Merck) with acetone water (2:1).

The product fractions are evaporated and freeze-dried. You get 0.14 g

(27% of theoretical) of a colorless amorphous solid.

IR (KBr): 177 0 cm"<1> (Lactam-CO)

<1>H-NMR (CF3C02D) : 6 = 2.20-2.80 "(m 2fcl, cyclopentene-H) :

3.10-4.05 (m, 6H, 4 cyclopentene-H

and SCH 2 ): 4.30 (s, 3H, 0CH 3 );

5.20-6.25 (m, 4H, 2-CK2 and 2 lactam-

H), 7.66-8.70 ppm (m, 3H, Py).

B) To a mixture of 0.57 g (1 mmol) 7-^~2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-methoxyimino-acetamido7-cephalosporin acid trifluoroacetate and 1.07 g (9 mmol) of 2,3-cyclopenteno-pyridine in 10 ml of methylene chloride are added at 5°C with 1.4 g (7 mmol) of trimethyliodosilane, and heated for 2 hours at reflux. After cooling, add 7 ml of 2n HC1, stir for 10 minutes at approx. 15°C and adjusted by adding solid potassium bicarbonate to pH 6.5. The aqueous phase is separated, chromatographed over a "Lobar-C" column with acetone:water (2:1). After freeze-drying the product fractions, 0.29 g (56% of the theoretical) is obtained of a colorless solid which is identical in all properties to the one mentioned above.

b) 404 mg (2 mmol) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-methoxyimino-acetic acid are dissolved in 6 ml of N,N-dimethylformamide. After

addition of 280 mg (2.1 mmol) 1-hydroxybenztriazole hydrate and 410 mg (2 mmol) N,N<1->dicyclohexylcarbodiimide is stirred for 2 hours at room temperature. Dicyclohexylurea is filtered off, and to the filtrate is added a solution of 808 mg (2 mmol) 7-amino-3-(2,3-cyclopenteno-1-pyridinium)methyl 7-ceph-3-em-4-carboxylate dihydrochloride in 10 ml of W,N-dimethylformamide and 1 ml of water. The mixture is stirred for 3 hours at room temperature, evaporated in vacuo and the residue dissolved in 10 ml of water. Undissolved is filtered off and the solution is chromatographed over a "Lobar-C" column with acetone:

water (2:1) .

The product fractions are freeze-dried and 580 mg (56% of the theoretical) of the title compound are obtained as an amorphous solid.

It is identical in all properties to the compound mentioned above.

Analogous to example 1, the compounds listed below are obtained as amorphous solids which correspond to a general formula I with R 1 = methyl and as residue R 2 are the substituents indicated in the second column of table 1.

Analogously to example 1, the compounds listed below are obtained as amorphous solids which correspond to the general formula I' 2 1 (R = 2,3 cyclopenteno-1-pyridinium) and as residue R they have the substituents indicated in the second column of table 2.

Analogous to example 1, the compounds listed below are obtained as amorphous solids which correspond to the general formula I with R 1 = methyl, and as residue R 2 they have the substituents indicated in the second column of table 3.

Claims (7)

1. Cephem derivatives of the general formula I and their physiologically tolerable acid addition salts, in which R <1> means hydrogen, optionally substituted C₁ -C₆ alkyl, optionally substituted C₆C₆ alkenyl, C₆C₆ alkynyl, C3 -C7 -cycloalkyl, C3 -C7 -cycloalkyl-C1 -Cg-alkyl, C4-C7-cycloalkyl, the group 3 4 wherein m or n each means 0 or 1, R and R can be the same or different and mean hydrogen, aryl, a C-^-C^ alkyl group, or the combination with the carbon atom to which they are attached to form a methylene- or a C3 - C7 -cycloalkylidene group, wherein alkyl and cycloalkyl can also be substituted one or more times, R<5> means a group -CO2R6, in which R6 means hydrogen, C-^-C^ alkyl, -CI^OC.^-C4 -alkyl, -CH2 OOC-C1 -C4 -alkyl, or an equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base, or means a nitrile group or a carbamoyl group -CONH2 which may be one or two times substituted by nitrogen, R 2 means a pyridinium residue which is substituted with two ortho-placed alkyl groups, which is joined to an optionally substituted di- to decamethylene ring, in which a C atom may be replaced by a heteroatom, and further may also contain one or two double bonds, or means a 1-quinolinium or a 2-isoquinolinium residue, each of which can also be substituted one or more times in the same or different way, with optionally substituted C-C-C-alkyl, C-C-C-Alkoxy, halogen, trifluoromethyl or hydroxy, and in which the R O group is in vision position. 2. Process for the preparation of compounds of formula I according to claim 1, and their physiologically tolerable acid addition salts, characterized by ata) a compound of the general formula II or their salts, or a reactive derivative of the compound of formula II, in which R" <*> " has the above meaning, 7 8 and R means an amino or protected amino group, and R means an exchangeable group with the pyridine, quinoline or isoquinoline derivatives corresponding to the residue R 2 of formed I is reacted with these pyridine, quinoline or isoquinoline derivatives, and a) a possibly present protection group is split off and 8) if necessary, the formed product is transferred to a physiologically tolerable acid addition salt, orb) a 7-amino-cephem compound of the general formula III or its acid addition salts, in which R 2 has the above meaning, and since the amino group can also be present in the form of a reactive derivative, is reacted with a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn- oximinoacetic acid of the general formula IV wherein R <1> and R <7> have the above meaning, or with an activated derivative of this compound, and a) a possibly present protection group is split off, and B) if necessary, the product formed is transferred to a physiologically tolerable acid addition salt. 3. Method according to claim 2, characterized in that the nucleophilic exchange of the substituent R takes place in the presence of neutral salt ions, especially iodide or thiocyanate ions. 4. Method according to claim 2, characterized in that the nucleophilic exchange of the substituent R o takes place in the presence of the base underlying the residue R 2 , and of trimethyliodosilane. 5. Pharmaceutical preparations effective against bacterial infections, characterized by a content of cephem derivatives with the general formula I. 6. Process for the production of pharmaceutical preparations effective against bacterial infections", characterized in that a cephem derivative of the general formula I, optionally together with pharmaceutically common carriers, diluents or buffer substances, is brought into a pharmaceutically suitable administration form. 7. Use of cephem derivatives of the general formula I for combating bacterial infections.