NO752202L - - Google Patents

Description

The invention relates to new acyl derivatives with the general formula

in which X constitutes a desacetoxy-cephalosporinyl residue and Y a 6-membered non-aromatic and not enolizable to an aromatic residue, optionally substituted "heterocyclic residue with 1 to 3 nitrogen atoms, of which at least one of these nitrogen atoms is substituted and at least one of the nitrogen atoms forms an amide group with a neighboring carbonyl group,

as well as salts and hydrated forms of these salts.

Examples of salts of compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as amines, e.g. N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethyl-ethylenediamine, alkyamines or dialkylamines, as well as salts with amino acids, such as e.g. arginine or lysine.

The compounds of formula I containing a free basic group, e.g. an amino group, forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkyl and mono-aryl sulphonates, such as ethane sulphonate, toluene sulphonate, benzene sulphonate and the like and also others organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The salts of the compounds of formula I may be hydrated. The hydration can take place during the course of the manufacturing process or in each case as a result of the hygroscopic properties of a first anhydrous salt of a compound of formula I.

Preferred compounds of formula I are those in which the radical X has the general formula

where means hydrogen or methoxy, R2cyan or pyridylthio or an aliphatic, alicyclic, aromatic or heteroaromatic residue, R^ hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, where a residue R2 different from cyan can be substituted by hydroxy, halogen , lower alkyl or lower alkoxy, and in case R 2 is a pyridylthio residue, R 2 is hydrogen.

In the context of the present invention, the term "halogen" means chlorine, fluorine or bromine, of which chlorine is preferred. In the context of the present invention, the term "aliphatic residue" means linear or branched alkyl or alkenyl residues with up to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl and the like, vinyl, propenyl, butenyl , pentenyl, hexenyl and the like whereby alkyl residues with 4 carbon atoms, particularly n-butyl and isobutyl are preferred. The term "alicyclic residue" refers to saturated or unsaturated, non-aromatic cyclic residues with 3-6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like, of which residues with 6 carbon atoms, especially cyclohexyl and cyclohexadienyl are preferred. The term "aromatic residue" refers in the context of the present invention to phenyl, phenyl-C 1-3 -alkyl-°9phenoxy-C 1-3~alkyl- and phenoxy-C 1-3 -alkyl residues, in which the phenyl and/or the alkyl residue may be substituted

with hydroxy, halogen, lower alkyl and/or lower alkoxy, (of which phenyl and para-hydroxyphenyl are preferred. The expression

"hetero-aromatic residue" refers in the context of the present [invention to 5- or 6-membered aromatic residues with 1-4 nitrogen atoms and/or an oxygen atom or a sulfur atom

such as, for example, sydnonyl, tetrazolyl, triazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and the like, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and the like, of which the 5-membered rings, especially thienyl, furyl, tetrazolyl, triazolyl, pyrazolyl and sydnonyl are preferred.

As particularly preferred compounds can be mentioned those in which R is 2-thienyl, 2-, furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyan, in which

when is 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydninyl or 4-pyridy.ltio is R_ hydrogen.

Preferred compounds of formula I are furthermore those in which the residue

Y is a non-aromatic, N-substituted and optionally an or

several carbon atoms substituted pyridonyl residue or a non-aromatic, at least one of the nitrogen atoms and optionally at one or more carbon atoms substituted pyrimidonyl-, pyra-

zonyl, pyridazonyl or triazonyl residue.

As examples of such compounds, those in which Y out-

<g>yr

a 2-oxopyridin-4-yl residue^

a 2-oxopyrimidin-4-yl residue, e.g. 1-amino, 1-ethyl-

or 1-butoxy-1,2-dihydro-2-oxopyrimidin-4-yl residue or 1-butoxy-1,2-dihydro-5-methyl-2-oxopyrimidin-4-yl residue

a 4-oxopyrimidin-2-yl residue, e.g. 1-ethyl-1,4-dihydro-6-methyl-4-oxopyrimidin-2-yl residue or 1,4-dimethyl-1,6-dihydro-6-oxopyrimidin-2-yl residue 5

a 2,6-dioxopyrimidin-4-yl residue^

a 2-oxopyrazin-3-yl residue\

a 2,3,5-trioxopyrazinyl-6-yl residue$ a 3-oxopyridazin-6-yl residue^

a 3-oxopyridazin-4-yl residue5

a 5,6r-dioxo-as-triazin-3-yl residue, e.g. 4-ethyl-, 4-methyl-, 4-allyl-, 4-butyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl- or |1,4-diethyl-1,4,5,6 -tetrahydro-5,6-dioxo-as-triazin-3-yristene

or 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-az-triazin-3-yl-jrestene^I

a 2-oxotriazin-4-yl residue5 or

a 2,4-dioxotriazin-6-yl residue.

As a substituent at a ring nitrogen atom comes into question

lower alkyl, alkenyl or alkynyl, cycloalkyl, hydroxy,

lower alkoxy, amino, mono- or di-lower alkylamino, formyl, lower alkanoyl or alkanoylamino, carbamoyl, mono-<1,>

or di-lower alkylaminocarbonyl,

and as a substituent at a ring carbon atom comes into question

lower ,alkyl or alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl,

cyan or halogen,

in which a lower alkyl group attached to a carbon or nitrogen atom can again be substituted by hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino, formyl,

lower alkanoyl or alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, cyan, halogen or epoxy.

The aforementioned lower alkyl-, alkenyl-,. the alkynyl and alkoxy residues contain up to 6 carbon atoms and the lower alkanoyl residues up to 7 carbon atoms. Examples of such alkyl residues are methyl, ethyl and the like. Examples of such alkenyl residues are vinyl, allyl and the like. Examples of such alkynyl residues are ethynyl, propynyl and the like. Examples of such alcohol residues are methoxy, ethoxy and the like. Examples of such alkanoyl residues are acetyl, propionyl and the like. The term "cycloalkyl" means cyclic hydrocarbon groups of 3-7 carbon atoms such as cyclopropyl, cyclohexyl and the like.

The following can be mentioned as particularly preferred compounds of formula I:

(7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-13-yl)-thio]methyl/-7-[2-(2 -thienyl)-acetamido]3-cephem-4-carboxylic acid, (7R)-3-/[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl )-thio]methyl/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/[ (1,4,5,6-tetrahydro-4- allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3- /[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-az-triazin-3-yl)-thio]methyl/-7-[2-(2-thienyl)-acetamido] -3-cephem-4-carboxylic acid, (7R)-3-/[(1,4,5,6-tetrahydro-4-(2-methoxyethyl)^5,6-dioxo-as-triazin-3-yl) -thio]methyl/-7 [2-(2-thienyl)-acetamido]-3-cephem-4- carboxylic acid, (7R)-3-/[(1,4,5,6-tetrahydro-1,4- dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid , (7R)-3- /[ (1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(2-thienyl)- acetamido]-3-cephem-4-carboxylic acid, (7R)-3-/[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio ]methyl/-7-[2-(2-thienyl)-ac ethamido]-3-cephem-4-carboxylic acid , (7S)-7-methoxy-3-/[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine-3- yl)-thio]methyl/-7-[2-(thienyl)-acetamido]-3-cephem-4- carboxylic acid, (7R)-3-/[ (1-ethyl-1,2-dihydro-2-oxo -4-pyrimidinyl)-thio]methyl/ -7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid,

(7R)-3-/[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/ |-7-[2-(2-thienyl)-acetamido]-3- cephem-4-carbonic acid, j

(7R)-3-[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[ 2-(2-thienyl)-3-acetamido ]-3-cephem-4-carboxylic acid,

(7R)-3-[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3 -cephem-4-carboxylic acid,

(7)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/- 7-[2-(2-thienyl)-acetamido]-3-cephem -4-carbonic acid, (7R)-3-[1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio] methyl/-7-[2-(2-thienyl)-acetamido]- 3-cephem-4-carboxylic acid, (7R)-7-(2-cyanacetamido)-3-[{1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -3-cephem-4-carboxylic acid, (7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[(R)- mandelamido]-3-cephem-4-carboxylic acid, (7R)-7-[ (R)-2-amino-2-phenylacetamido]-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3 -yl)-thio]methyl/-3-cephem-4-carboxylic acid, (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(5 -oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid, (7R)-3-[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/ -7-[2-(5-oxo-1,2,3- oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid,

(7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(1 -H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid,

(7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[(R)- 2-hydroxyhexanamido]-3-cephem-4-I carboxylic acid,

(7R)-3-[(1-aminc-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/

j-7-[2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylic acid,

(7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thiomethyl]-7-[ (R)-2- hydroxy-4-methylvaleramido]-3-cephem-4- carboxylic acid,

(7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[(R)- 2-hydroxy-2-(cyclohexylacetamido]-3-cephem-4-carboxylic acid,

(7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-(2 -furyl)-acetamido]-3-cephem-4-carboxylic acid,

(7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(1-tetrazolyl)-acetamido]-3- cephem-4-carbonic acid,

and their salts.

The compounds of formula I can exist as optically pure isomers and as mixtures of isomers.

The compounds of formula I and their salts can be prepared in a manner known per se by

a) reacts a compound with the general formula

in which X' produces a corresponding residue X

desacetoxy-cephalosporinyl residue, whose carboxyl residue is present in the 4-position in protected form, and a leaving group

with a compound of the general formula

wherein Y has the above meaning and

javsplits the protection group, or

b) reacts with a compound of the general formula i

in which Y has the above meaning and

X'' constitutes a desacetoxy-cephalosporanyl residue corresponding to the residue X, whose carbonyl residue i

4 position is available in protected form,

with an acid of formula

in which Z constitutes an acyl residue that comes into consideration as a substituent in the amino residue in the 7-position in

Cephalosprin,

or with a reactive functional derivative thereof, cleaves off the protecting group and, if desired, the reaction product in a salt.

The protection of the carboxyl residue in the residue X' or X<1>' in a compound of formula II or IV can e.g. happen by conversion to an easily cleavable ester, for example benzyl ester or silyl ester, e.g. the trimethylsilyl ester, or by salt formation. with an inorganic or tertiary organic base such as triethylamine.

As leaving group W, in a compound of formula II comes

e.g. in terms of halogens such as chlorine, bromine or iodine, acyloxy residues, for example* lower alkanoyloxy residues, such as acetoxy, lower alkyl or arylsulfonyloxy residues, such as mesyloxy or , tosyloxy or the azido residue. The reaction of a compound of formula II with a compound of formula III can be carried out in a manner known per se, e.g. at a temperature between 40 and 80°C, suitably at approx. 60°C, in a polar solvent, for example an alcohol such as a lower alkanol, such as ethanol", propanol and the like, dimethylformamide, dimethylsulfoxide, preferably in water or a buffer solution having a pH of about 6 to 7, preferably 6.5, over a period of time of about 3 to 8, for- ;stepwise 6 hours.;i As reactive functional derivatives of acids of formula V ;come into consideration, for example, halides, i.e. chlorides, bromides and fluorides 5 azides^anhydrides, especially mixed anhydrides with strong acids $ reactive esters, e.g. N-hydroxy-succinimid esters and amides, e.g. imidazolides. The reaction of a compound of formula IV with an acid of formula V or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula V is condensed with one of the aforementioned esters of formula IV using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent such as acetic acid, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and subsequently cleave off the ester group one. Instead of carbodiimides, it is also possible to use oxazolium salts as condensation agents, e.g. N-ethyl-5-phenyl-isoxazolium-3<1->sulfonate. In another embodiment, a salt of an acid with the formula IV is reacted, e.g. the trialkylammonium salt with a reactive functional derivative of an acid of formula V as mentioned above in an inert, e.g. one of the above-mentioned solvents. Reaction of a compound of formula IV with a compound of formula V or a reactive functional derivative thereof can conveniently take place at temperatures between about +5°C and -40°C, for example at about 0°C. After complete reaction of a compound of formula II or IV with a compound of formula III or V, the protective group is cleaved off. In the event that the protective group does not form a benzyl group (benzyl ester), this can be cleaved off by catalytic hydrogenation, e.g. by means of a noble metal catalyst, e.g. palladium-carbon. When the protecting group produces a silyl group (silyl ester), this group can be particularly easily cleaved off by treating the reaction product with water. The formation of this salt-forming protective group takes place by treatment with acid at a relatively low temperature, e.g. at approx. 0°C to 10°C. As an acid, e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid. The compounds of formula II are known and can be prepared in a manner known per se from corresponding cephalosporins, i.e. compounds with the general formula ; ; where X has the above meaning. Examples of compounds with formula II can be mentioned the alkali metal salts, e.g. the sodium salt, of cephalotin, 7-cc-methoxy-cephalotin, cephalotin, cephacetril, (7R)-mandelamido-cephalosporanic acid and 7-(3-sydnonacetamido)-cephalosporanic acid and the zwitterion cephaloglycine. The compounds of formula III are partly new, partly known. The new compounds of formula III can be prepared in an analogous manner to the preparation of known compounds. Thus, a 1-substituted 2-oxo-4-mercapto-pyridine can be prepared from correspondingly substituted 4-chloro-2-oxopyridine [Chem. Pray. 99, 255 (1966)] by nucleophilic yield, e.g. with an alkali hydrogen sulphide. In the same way, a 1,3-disubstituted 2,6-dioxo-1,2,3,6-tetrahydro-4-mercaptopyrimidine can be prepared from the corresponding 4-chloro-2,6-dioxo-1,2,3, 6-tetrahydropyrimidine. The 5,6-dioxo-3-mercapto-as-triazines can be prepared from the corresponding substituted thiosemicarbazides in analogy to the synthesis of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto -as-triazines, dissertation by K. H. Ongania (Innsbruck 1972). A thiol of formula III, which contains a double bond between the carbon atom substituted by the mercaptor residue and an adjacent nitrogen atom, can exist in the form of the tautomeric thioketone. A compound of formula IV can be prepared by reacting a compound of the general formula; ; wherein X'' and W. have the meanings given above, with a compound of formula III. The conversion can take place under the same conditions as for those of a compound of formula II; with a compound of formula III. The compounds of formula V and the reactive functional derivatives thereof are known or analogous to known compounds and can be prepared in a known manner. The compounds of formula V which exhibit an asymmetric carbon atom are normally found in the form of racemic mixtures. The splitting of such racemates into the optically active isomers can be carried out by known methods. Thus, for example, diastereomers can be formed from the racemic mixture with an optically active resolving agent such as e.g. an optically active base, e.g. α,α-(1-naphthyl)ethylamine or α-methylbenzylamine which can react with the carboxyl group. The formed diastereomers are separated by selective crystallization and then transferred to the corresponding optical isomers. A compound of formula I in the D form can be prepared by either cleaving a compound of formula I, which exists in the form of an isomer mixture in a known manner, for example by fractional crystallization of a salt, such as the potassium salt, and isolating the desired D-form or that one reacts a compound of formula III or IV with a compound of formula II or V present in the D-form or a reactive functional derivative of such a compound of formula V, whereby the latter method is preferred. The compounds of formula I, their salts and the hydrates of these salts are antibiotically, particularly bactericidally active. They have a broad spectrum of action against gram-positive and gram-negative microorganisms, in particular against penicillinase-positive staphylococci as well as various cephalosporinase-positive gram-negative bacteria such as escherichia coli, proteus, klebsiella, aeorbacter and serratia species. The compounds of formula I as well as the pharmaceutical the applicable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases, as well as as a disinfectant. For adults, a daily dose of approx. 1 g to approx. 4 g in consideration. The parenteral use of the compounds according to the invention is particularly preferred. The antimicrobial action of two of the compounds according to the invention, namely the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3- yl)-thio]methyl/-7-[2-(5-oxo-1,2,3-oxa-diazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid (compound A in subsequent table) and the sodium salt of (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[ 2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid (compound B in the following table) is evident from the following CD 0 values (mg/kg subcutaneously in mice ): ; ; The acute toxicity (LD,.^) of these substances when intravenously administered in mice amounts to 2000-4000 mg/kg for substance A and 1000-2000 mg/kg for substance B. Pharmaceutical preparations, preferably dry ampoules, may contain the compounds with formula I, their salts or hydrated forms of these salts, possibly in admixture with another therapeutically valuable substance. ;Example 1 ;(Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl /-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid.; 4.4 g cephalothin sodium salt a^°] = +130° (c = 1 in waterJJ;rSres in 100 ml of water with 2.25 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 1.05 g of sodium bicarbonate for 6 hours at 60°C and pH approx. 6.5 in a nitrogen atmosphere. The reaction mixture is then cooled to 10°C and adjusted to pH 2 with 2N hydrochloric acid. The thus precipitated substance is filtered off and washed with 25 ml of ice water. It is then dissolved in acetone and the ice is evaporated in vacuo. The remaining the residue is dissolved in dimethylformamide and the solution is mixed with 7.5 ml of a 2N solution of the sodium salt of 2-ethyl-caproic acid in acetic acid. By diluting with acetic acid, the desired substance crystallizes out. This is filtered off, subsequently washed with acetic acid, ether and petroleum ether and solidified in vacuo. Yield 4.5 g (80%). Melting point > 170°C (decomposition). ;[ oc]^° = +13.1° (c = 0.800 in water). The 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared as follows: 120 g of 4-ethylthiosemicarbazide is reacted in the presence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 g of oxalic acid dimethyl ester at the boiling point of the reaction mixture. The triazine is isolated in the form of the sodium salt from the reaction mixture and thereby obtained through acidification with an aqueous ice solution, melting point 189-;190°C. ;Example 2;Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[2-(2-thienyl)-'. acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 4.18 g of cephalothin sodium salt and 1.91 g of 1,4,5,6-tetrahydro-|4-methyl-5,6-dioxo-3-mercapto-as-triazine , yield 2.8 g (54.1%) j. ;Melting point 200-205°C (decomposition) [a]^° -2.7° (c = 0.592;|in water) . The triazine used in the above method is prepared analogously to example 1 from 176 g of 4-methylthiosemicarbazide and 198 g of oxalic acid dimethyl ester. Melting point 218-220°C (decomposition). ;Example 3;Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[2-(2-thiehyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 3.33 g of 1,4,5,6-tetrahydro-4-allyl-S,6-dioxo-3-mercapto-ase -triazine. Yield 3.0 g (36.8%). Melting point > 180°C (decomposition). [a]^0 = +19.7° (c = 0.376 in water). The triazine used in the above method is prepared analogously to example 1 from 26.2 g of 4-allylthiosemicarbazide and 23.6 g of oxalic acid dimethyl ester. Melting point 138-140°C. ;Example 4;Preparation of the sodium salt of (7R)-3-/[(1,4,5^-tetrahydro-^-butyl-S,6-dioxo-as-triazin-3-yl)-thio]methyl/- 7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 3.62 g of 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as-triazine. Yield 3.0 g (35.7%). Melting point > 160°C (decomposition). [a]^<0>= +17.6° (c = 0.640 ;in water). ;The triazine used in the above method is prepared analogously to example 1 from 14.7 g of 4-butylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 180-181°C. ;Example 5;Preparation of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-14-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)- thio]-methyl β-7-;[ 2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 3.65 g of 1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-3-mercapto- as-triazine. Yield 2.0 g ;(23.8/o).. [ot]p° = +10° (c = 0.280 in water). The triazine used in the above method is prepared analogously to example 1 from 14.9 g of 4-(2-methoxyethyl)-thiosemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 158-160°C. ;Example 6;Preparation of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl/-7-[2-(2-thienyl>-acetamido]-3-cephem-4-carboxylic acid. ;This compound is prepared analogously to example 1 from; 6.2 7 g of cephalothin sodium salt and 2.6 g of 1, 4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazine.Yield 4.6 g (58.0%). [ct]^° = -9.55 ° (c = 0.461 in water). ;The triazine used in the above method is prepared analogously to example 1 from 11.9 g of 1,4-dimethylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 231-233°C (decomposition). ;Example 7;Preparation of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid .. ;This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 2.01 g of 1,4, 5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto-az-triazine Yield 5.5 g (65.7%) Melting point > 175°C (dec) [cc] ^° = +10.2° (c =0.547 ;in water). The triazine used in the above method is prepared analogously to example 1 from 14.7 g of 1,4-diethylsemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 177-179°C. ;Example 8;(Preparation of the sodium salt of (7R)-3-[)1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl /-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 10.45 g of cephalothin sodium salt and 4.8 g of 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine. Yield 7.0 g (52.6%). Melting point 210-215°c (decomposition). [oc]^° = +8.85° (c =0.181 in water). The triazine used in the above process can be prepared as follows: 46.5 g of 1-ethylthiosemicarbazide is reacted in 700 ml of acetone at 40°C with 48 g of oxalic acid monomethyl ester chloride. 34.3 g of the product obtained is mixed with 9.2 g of sodium methylate in 300 ml of methanol. The triazine is isolated in the form of the sodium salt from the reaction mixture and thereby obtained through acidification with an aqueous solution, melting point 213-214°C (decomposition). ;Example 9;Preparation of the sodium salt Sv (7S)-7-methoxy-3-/[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)- thio]-methyl/-7-[2-(thienyl)-acetamido]-3-cephem-4-carboxylic acid. ;This compound was prepared analogously to example 1 from;5.16 g of 7-oc-methoxy-cephalothin sodium salt j~[ a] ^° =+194.5°;(c = 0.308 in water)/ and 1.82 g 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine. Yield 1.0 g (15.9%). ' [a]D<2o>= +54.6° (c = 0.308 in water). Example 10 Preparation of the sodium salt of (7R)-3-[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl) )-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 4.18 g of cephalothin sodium salt and 1.8 g of 1-ethyl-1,2-dihydro-4-mercapto-b-oxo-pyrimidine. Yield 3.2 g (65.3%). Melting point > 190°C (decomposition). [oc]D = -58° (c = 0.570 in water). ;Example 11;Preparation of the sodium salt of (7R)-3-[(1^butoxy-1;2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl) )-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 4.18 g of cephalothin sodium salt and 2.2 g of 1-butoxy-1,2-dihydro-4-mer-capto-2-oxo-pyrimidine. Yield 3.8 g (70%). [a]^° = -83^6° ;(c = 0.850 in water). The pyrimidine used in the above method is prepared from 2 g of 1-butoxyuracil and 4 g of phosphorus pentasulphide. Melting point 99-100°C; Example 12; Preparation of the sodium salt of (7R)-3-/[ (1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl/ -7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.0 g of cephalothin sodium salt and 3.36 g of 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine. Yield 0.8 g (9.7%). Melting point> 170°C (decomposition). The pyrimidine used above can be prepared analogously to example 11 by reacting 25 g of 1-butoxy-5-methyl-uracil with 50 g of phosphorus pentasulphide. 1-butoxy-5-methyl-uracil is prepared by reacting 110 g of butoxyurea with 184 g of (3, [3-diethoxy-α-methylpropionic acid ester.; Example 13; Preparation of the sodium salt a.v (7R)-3-/[ (1, 4-Dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. the compound is prepared analogously to example 1 from; 4.18 g of cephalothin sodium salt and 1.8 g of 1,4-dimethyl-1,6-dihydro-|2-mercapto-6-oxo-pyrimidine. Yield 1.35 g (26 .3%). Melting point 200-210°C (decomposition). [a]^° = +9.5° (c = 0.348 in water). ;Example 14;Preparation of the sodium salt of <. (7R)-3-[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido] -3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 2.98 g of 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine. Yield 3.2 g (40.4%). Melting point ;>170°C (decomposition). [α]^<0>= -14.4° (c = 0.333 in methanol). The pyrimidine used in the above procedure can be prepared as follows: 18 g of N-ethylthiourea is dissolved in 50 ml of acetic acid, boiled at reflux and mixed dropwise with 17.2 g of diketene. It is then boiled for 20 minutes at reflux and subsequently evaporated to 50 ml of water. 50 ml of water is added during dressing and stirring. The yellowish crystals fall out. - They are filtered off and recrystallized in tetrahydrofuran. Melting point 190°C. ;Example 15;Preparation of the sodium salt of (7R-)-7-(2-cyanacetamido),-^3-/[ ( 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as- triazin-3-yl)-thio] methyl/-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 9.5 g of cephacetril sodium salt and 5.46 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. Yield 3.3 g (26.8%). ;[ct]<2>°<_>+7;85° (c = 0.1785 in water). ;Example 16;Preparation of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[(R)-mandel-amido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 8.0 g of the sodium salt of (7R)-mandelamido-cephalosporanic acid and 3.72 g of l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3 -mercapto-as-triazine. ;Yield 1.7 g (16.8%). [a]£° = -19.6° (c = 0.500 in water). ;Example 17;Preparation of (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-/[( 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo -az-triazin-3-yl)-thio]-methyl/-3-cephem-4-carboxylic acid. ;This compound is prepared analogously to example 1 from 8.1 g of cephaloglycine and 3.78 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and is isolated as a zwitterion . Yield 4.19 g (40.5%). Melting point > 180°C (decomposition). [oc]^° = ;-86.3° (c = 0.2 76 in dimethylformamide). ExampleJ. 18; Preparation of the sodium salt of (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7 -[2-(5-oxo-1,2,3-oxazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid. ;This compound is prepared analogously to example 1 from 7.7 g of the sodium salt of 7-(3-sydnonacetamido)-cephalosporanic acid and ;3.46 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo -3-mercapto-as-triazine. Yield 3.3 g (31%). Melting point > 210°C (decomposition). ;[a]^° = +17.9° (c = 0.380 in water). ;Example 19;Preparation of the sodium salt of (7R)-3-[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(5- oxo-1,2,3-oxa-diazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 11.6 g of the sodium salt of 7-(3-sydnonacetamido)-cephalosporanic acid and 4.7 g of 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.6 g (23.2%). [<x]£° = -43.7° (c = 0.600 in water). ;Example 20;Preparation of the sodium salt of (7R)-3-/[(1;4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-methyl /-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid. 1.28 g of tetrazole-1-acetic acid is dissolved in a mixture of 50 ml of tetrahydrofuran and 5 ml of dimethylformamide. This solution is mixed at -20°C with successive 1.18 ml of N-methylmorpholine and 1.4 ml of chloroformic acid isobutyl ester and is then stirred for 20 minutes between -10°C and -20°C. An ice-cold solution of the salt obtained from 3.85 g of 7-amino-3-desacetoxy-3-[( 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3 -yl)-thio]-cephalosporanic acid and 1.4 ml of triethylamine in 50 ml of water. The reaction mixture is then stirred for 30 min. at 0°C and 1 hour at 20°C. It is then evaporated under vacuum, the aqueous phase is acidified with 5 ml of 2N hydrochloric acid, whereby the desired substance is precipitated as crude acid. This is filtered off, washed with plenty of acetic acid, then dissolved in dimethylformamide. This solution is mixed with a 2N solution of the sodium salt of 2-ethyl-caproic acid in acetic ester and then diluted with ethanol and ether whereby; the desired crude sodium salt (3.3 g) is precipitated. For purification, the substance thus obtained is dissolved in 20 ml of water and mixed with 60 ml of ethanol, whereby a dark resin is precipitated, which is discarded. The filtrate is evaporated in vacuo and the residue treated with ethanol and ether, which gives 2.3 g (44.5%) of pure substance as light beige powder with melting point 210°C (decomposition) and [ot]^<0>= + 23° ; (c = 0.824 in water). ;The 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]- used in the above method cephalosporanic acid is prepared as follows: 2.72 g of 7-amino-cephalosporanic acid are suspended together with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine in 100 ml of water. This suspension is mixed with 1.85 g of sodium bicarbonate, whereby a solution with a pH of 6.4 is produced. This is stirred for 3 hours under a nitrogen atmosphere at 60°C. It is then cooled to 20°C and stirred with the addition of 1 g of activated charcoal for another 1 hour under nitrogen. After filtration, the filtrate is adjusted to pH 3.8 with 2N hydrochloric acid, cooled to 0°C and stirred for 1 hour, whereby the substance crystallizes out. This is filtered off, subsequently washed with a little ice water, acetone, ether and petroleum ether and dried in high vacuum at 50°C. Yield 2.3 g (60%) beige powder with melting point 230-235°C (decomposition). ;The 7-amino-3-desacetoxy-|3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] used in the above method -i cephalosporanic acid can also be prepared according to another method and this as follows: 5.1 g of 7-amino-3-azido-3-desacetoxy-cephalosporanic acid is stirred with 5.16 g of 1,4,5,6-tetrahydro-4- ethyl-5,6-dioxo-3-mercapto-as-triazine and 4.2 g of sodium bicarbonate in 200 ml of a buffer of pH 7.0 for 6 hours at 60°C under a nitrogen atmosphere. The reaction solution is cooled to 25°C and adjusted to pH 3.5 with 2N hydrochloric acid. The desired substance is thereby crystallized out and is filtered off (2.2 g). By evaporation of the mother liquor, a further 1.7 g is obtained. Total yield 3.9 g (50%). ;Example 21;Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[(R)-2-hydroxy-hexanamido]-3-cephem-4-carboxylic acid. ; 4.4 g 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid is dissolved at 0°C in a mixture of 44 ml of water and 44 ml of acetone by adding 2.5 g of potassium bicarbonate while stirring. A solution of 3 g of (R)-2-dichloroacetoxy-n-caproic acid chloride (boiling point Q5 = 75-76°C) is then added drop by drop at 0°C with stirring in 30 ml of acetone to then stir for 2 hours at 0°C and 1 hour at 20°C. From the filtered solution, the acetone is distilled under reduced pressure at 30°C. The aqueous solution is stirred while adding potassium carbonate for 45 minutes at a pH of 9.5, then extracted twice with acetic acid and adjusted to a pH of 1.5-2.0 with 3N sulfuric acid at 0°C. It is extracted with ethyl acetate while adding dimethylformamide. The acetate solution is washed several times with a 10% sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure at 25°c. The residue is dissolved in 100 ml of isopropanol and mixed with 12 ml of a 2N solution of the sodium salt of 2-ethyl-caproic acid in isopropanol. The crude sodium salt is filtered off, precipitated from water-isopropanol and dried under reduced pressure. ;A beige powder is obtained, melting point 183°C cleavage,;|[a]^<5>= +8.2° (c = 1.00 inH20). Yield = 56%. ;Example 2 2;[Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl β-7-[(R)-2-hydroxy-4-methylvaleramido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 21 from 3.5 g of 7-amino-3-desacetoxy-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3 -yl)-thio]-cephalosporanic acid and 2.4 g of (R)-2-dichloroacetoxy-isocaproic acid chloride (boiling point Q2 = 63-64°C). Yield 51%, melting point from 180°C cleavage, [<xj^5 = +6.0° ;(c = 1.00 in H20) . ;Example 23;Preparation of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[(R)-2-hydroxy-2-(cyclohexyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 21 from 3.9 g of 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine -3-yl)-thio]-cephalosporanic acid and 2.9 g of (R)-2-dichloroacetoxy-2-(cyclohexyl)-acetyl chloride (boiling point 0 ^ ;= 105-107°C). Dividend 37%. Melting point from 190°C cleavage,;[a]£<5>= +2.8° (c 0.50 in H 2 O) . ;Example 24;Preparation of the sodium salt of (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/ -7-[2-(2-furyl)-acetamido]-3-cephem-4-carboxylic acid. ; 3.85 g 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid is dissolved with stirring at 0°C in a mixture of 40 ml of water and 40 ml of acetone by adding 2.4 g of potassium bicarbonate. A solution of 1.45 g of 2-(2-furyl)-acetyl chloride in 15 ml of acetone is added dropwise at -5°C, stirred for 3 hours at -5°C and 1.5 hours at 20°C. The reaction solution is extracted twice with ethyl acetate and the aqueous phase acidified at 0°C with 3N sulfuric acid to a pH of 2. Extracted with ethyl acetate while adding dimethylformamide, washed three times with 10% sodium chloride solution, dried over magnesium sulfate and evaporate the solution |under reduced pressure at 25°c. The residue is dissolved in methanol, mixed with 8 ml of a 2N solution of the sodium salt of 2-ethyl-caproic acid in isopropanol and the crude sodium salt is precipitated with diethyl ether, filtered off, washed with diethyl ether and then recrystallized from water with the addition of acetone. A beige powder is obtained, melting point from 180°C cleavage, [a]£<5>= +18.4° (c = 1.0 in H20), yield = 43%. Example 2 5 Preparation of the sodium salt of (7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(2- thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 8.36 g of cephalothin sodium salt and 3.0 g of 1-amino-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 4.1 g (40.2%). Melting point > 185°C (decomposition). [a]^<0>= -78.5° (c = 0.439 in water). The pyrimidine used in the above experiment is prepared from 8.6 g of 1-benzylideneamino-uracil [melting point 220-223°C} Lit.: Monatshefte fiirChemie 96, 1735 (1965)] and 12 g of phosphorus pentasulfide in pyridine, followed by hydrolysis with hydrochloric acid. Example 2 6 Preparation of the sodium salt of (7R)-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-methyl /-7-[2-(2-thienyl)-acetamido-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 8.36 g of cephalothin sodium salt and 3.34 g of 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine. Yield 5.8 g; (56%). Melting point 185°C (decomposition). [a]£° = -49.3 (c = 0.450 in water). The triazine used in the above method is prepared analogously to example 1 from 31.5 g of 2-methylthiosemicarbazide and 35.4 g of oxalic acid dimethyl ester. Melting point 260°C. ;Example 2 7;(Preparation of the sodium salt of (7R)-3-/[ (1, 2-dihydro-1-methyl-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-( 2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from; 8.36 g of cephalothin sodium salt and 2.98 g of 1,2-dihydro-4-mercapto-l- methyl-2-oxo-pyrimidine. Yield 6.3 g (62.4%). Melting point 180°C (decomposition). [a]^<0>= -67.7° (c = 0.604 in water). ; Example 2 8; Preparation of the sodium salt of (7R)-3-[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl)thio]-methyl]-7-[2-(2-thienyl) )-acetamido]-3-cephem-4-carboxylic acid.. ;This compound is prepared analogously to example 1 from; 8.36 cephalothin sodium salt and 3.32 g 1,2-dihydro-4-mercapto-1-methoxy-2 -oxo-pyrimidine. Yield 6.3 g (61.2%). Melting point 175-180°C (decomposition). [oc]^<0>= -90.6° (c = 0.338 in water). ;It The pyrimidine used in the above experiment is prepared analogously to example 11 from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulphide. Melting point 177° C. ;Example 2 9;Preparation of sodium salt from (7R)-3-[(1-ethoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(2-thienyl)-acetamido]- 3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 2.75 g of 1-ethoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.5 g (44%). Melting point > 180°C (decomposition). [oc]p° = -74.2° (c = 0.525 in water). The pyrimidine used in the above method is prepared analogously to example 11 from 6.4 g of 1-ethoxyuracil and 18 g of phosphorus pentasulphide. Melting point 119-120°C. ;Example 30;(Preparation of the sodium salt of (7R)-3-[(1,6-dihydro-1-j methyl-6-oxo-3-pyridazinyl)-thio]-methyl/-7-[2-( 2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. ;This compound is prepared analogously to example 1 from 1.25 g of cephalothin sodium salt and 0.470 g of 1,6-dihydro-3-mercapto-1-methyl-6 -oxo-pyridazine. Yield 1.0 g (66.7%). Melting point > 215° (dec.). [oc]<£>°=-49.7° (c = 0.332 in water). ;That in the above The pyridazine used is prepared from 2.88 g of 3-chloro-1,6-dihydro-1-methyl-6-oxo-pyridazine [melting point 91-92°C; Lit.: Monatshefte fur Chemie 99, 33 ( 1968)] and 5.88 g of sodium hydrogen sulphide in ethanol at 130°C and 5-7 atm.. Melting point 115° C.; Example 31; Preparation of the sodium salt of (7R)-3-/[ (1-amino-l, 2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl/-7-[2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylic acid. ;This compound is prepared analogously to example 20 from;9 .5 g of sydnon-3-acetic acid and 21.4 g of 7-amino-3-desacetoxy-3-[1-amino-1,2-dihydro-2-oxo-pyrimidin-4-yl-thio]-cephalo sporanic acid. Yield 9.7 g (32%). Melting point from 200°C decomposition, [oc]p° = -61.3° (c = 0.5 in water). ;Example 32;Preparation of (7R)-7-[(R)-2-amino-2-(para-hydroxyphenyl)-acetamido]-3-/[ (4-ethyl-1,4,5,6-tetrahydro -5,6-dioxo-az-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 by reacting 24.5 g of D-p-hydroxy-N-t-butyl-oxycarbonyl-cephaloglycine with 8.66 g of 1,4,5,6-tetrahydro-4-ethyl-5,6 -dioxo-3-mer-capto-as-triazine and subsequent removal of the t-butyloxycarbonyl protecting group with formic acid. Yield 5.7 g (23%). Melting point from 200°C decomposition, [α]^° = -79.8° (c = 0.3 in dimethylformamide). ;Example 33;(Preparation of the sodium salt of (7R)-3-/[ (4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl/ -7-[2-(4-pyridyl-thio)acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.0 g of cephapirin and 2.56 g of 1,4,5,6 -tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. Yield 1.9 g (26%). Melting point from 205°C cleavage, [oc]^° = +36.2 (c = 0.5 in water). ;Example 34;Preparation of the sodium salt of (7R)-3-[ethyl-1,4,5,6-tetrahydro-5,6-dioxo-az-triazin-3-yl) thio]methyl β-7-(2-pyrazol-1-yl-acetamido)-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6 g of (pyrazol-1-yl-methyl)-cephalosporin sodium salt and 3.12 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- 3-mercapto-as-triazine. Yield 4.0 g (51%). Melting point from 190°C (decomposition). ;Example 35;Preparation of the sodium salt of (7R)-3-/[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl)-thio]methyl/ -7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 8.36 g of cephalothin sodium salt and 3.34 g of 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine. Yield 5.5 g (53%). Melting point from 200°C decomposition, [oc]^° = -43° (c = 0.1 in water). The 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine used in the above process can be prepared as follows. A solution of 14.8 g of sodium in 1000 ml of methanol is mixed with 39.9 g of 5-methyl-2-thio-biurea and 72 g of diethyl carbonate and refluxed for 24 hours. The reaction solution is evaporated in vacuo to a volume of 200 ml. The thus crystallized substance is filtered off, then dissolved in 200 ml of water and acidified with 2N hydrochloric acid. The precipitated compound is filtered off and recrystallized from 350 ml of ethanol. Yield 11.2 g (23%) colorless substance with melting point 2 75°C. The 5-methyl-2-thio-biurea used in the above process can be prepared as follows: A solution of 76 g of thiourea in 1000 ml of dimethylformamide is mixed with 65.4 ml of methyl isocyanate and then stirred for 72 hours at 50-55°C. The reaction solution is evaporated in vacuo and the residue is recrystallized from water. Yield 79.4 g (60%) colorless substance with melting point 209-210°C. ;Example 36;Preparation of the sodium salt of (7R)-3-[1-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-( 2-thienyl)-acetamido]3-cephem-4-carboxylic acid. This compound is prepared analogously to example 1 from 6.27 g of cephalothin sodium salt and 3.04 g of 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine, yield 3, 5 g (42%). Melting point from 185°C decomposition, [oc]^° -95.2° (c =0.394 ;in water). The 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above method can be prepared as follows: 1.74 g of 1-ethyl-5-chloro-uracil is first mixed with 4.44 g of phosphorus pentasulphide and 0.1 ml of water, then with 30 ml of pyridine and refluxed for 3 3/4 hours. The reaction mixture is evaporated in vacuo at 40°C, the residue is suspended in 30 ml of water and mixed with 30 ml of 2N hydrochloric acid. The crystalline substance was filtered off, washed with water and recrystallized from ethanol. Yield 1.3 g (68%) yellow substance with melting point 217-2 20°C. The 1-ethyl-5-chloro-uracil used in the above procedure can be prepared as follows: In a solution of 9.9 g of 1-ethyl-uracil in 150 ml of glacial acetic acid, chlorine is introduced for as long (approx. 1/2 hour) to iodine-potassium starch paper j reacts positively and 1-ethyl-uracil is no longer detectable by thin-layer chromatography. The reaction mixture is evaporated in vacuo at 40°C and the crystalline residue recrystallized from 300 ml of ethanol. Yield 10.0 g (81%) colorless fine needles with melting point 244-247°C. ;The 1-ethyl-uracil used in the above method can be prepared as follows: ;To a solution of 15.0 g of sodium in 700 ml of ethanol, 44 g of N-ethyl urea and 105 g of (3, (3-diethoxypropionic acid ethyl ester) are added. the yellow reaction solution is stirred for 3 hours at ;25°C and then 15 hours under reflux. It is then evaporated in vacuo*, the above residue is dissolved in 300 ml of water, cooled to 0 oC

and acidified with 100 ml conc. hydrochloric acid, whereby a crystalline intermediate is precipitated (43 g). The latter is filtered off, washed with 100 ml of ice water and then heated in 250 ml to 80-100°C until the conversion to the desired water-soluble 1-ethyl-uracil is complete. The solution is evaporated in vacuo at 40°C and the remaining residue recrystallized of ethanol-ether. Yield 14.0 g (20%) colorless substance with melting point 150°C.

Example 37

Preparation of the sodium salt of (7R)-3-/[ (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-7-[2 -(1H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 20 based on

2.95 g of tetrazole-1-acetic acid and 8.55 g of 7-amino-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) -thio]-cephalosporanic acid. Yield 4.65 g (40%). Melting point 220-230°C (decomposition), [oc]^° = 53.6° (c = 0.321 in water).

Example 38

Preparation of the sodium salt of (7R)-7-(R)-mandelamido-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio ]jinethyl/-3-cephem-4-carboxylic acid. This compound is prepared analogously to example 21 from |9.25 g of D-O-dichloroacetyl-mandelic acid chloride and 11.1 g of 7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl -5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid. Yield 4.3 g (2 7%). Melting point 200-210°C (decomposition), [cc]^0 = 66.8° (c = 0.296

in water).

Example 39

Preparation of the sodium salt of (7R)-7-[2-(3-sydnonyl)-acetamido]-3-/[ (1,2,5,6-tetrahydro-2-methyl-5, 6-dioxo-as-triazine -3-yl)thio]methyl/-3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 20 from 5.76 g of sydnon-3-acetic acid and 14.95 g of 7-amino-3-desacetoxy-3-[(1,2',5,6-tetrahydro-2-methyl-5 ,6-dioxo-as-triazin-^3-yl)-thio]-cephalosporanic acid. Yield 7.0 g (33%). Melting point from 200°C cleavage, [a]^° = -25.5° (c = 0.227%).

Example 40

Preparation of the sodium salt of (7R)-3-//~[ 1-(dimethylamino)-1,2-dihydro-2-oxo-4-pyrimidinyl]thiojmethyl/-7-[2-(2-thienyl)

acetamido]-3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 1 on the basis of

3.34 g of cephalothin sodium salt and 1.42 g of 1,2-dihydro-1-dimethylamino-4-mercapto-2-oxo-pyrimidine. Yield 2.4 g (57%). Melting point from 165°C cleavage, [oc]^° = -65.2° (c = 0.55 7

in water).

Example 41

Preparation of the sodium salt of (7R)-3-/[(3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl)thio]methyl/-7-[(2-thienyl)-acetamido ] -3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 1 from 8.36 g of cephalothin sodium salt and 3.7 g of 3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine. Yield 4.7 g (44%). Melting point 225-230°c (decomposition), [<x]£° = +5.35° (c = 0.522 in water). The 3-chloro-1,6-dihydro-14-mercaptol-1-methyl-6-oxo-pyridazine used in the above process can be prepared as follows: A solution of 17.9 g of 3,4-dichloro-1,6- dihydro-1-methyl-6-oxo-pyridazine in 200 ml of methanol is mixed with a solution of 14.8 g of sodium hydrogen sulphide monohydrate in 200 ml of methanol. The reaction mixture is then stirred for 1 1/2 hours at 25°C in a nitrogen atmosphere. It is then filtered from little undissolved material and the filtrate is evaporated in a vacuum. The residue is suspended in 150 ml of water, acidified with 1N hydrochloric acid and extracted three times with ethyl acetate.

The combined ethyl acetate extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The thus resulting residue is recrystallized from ethanol. Yield: 9 g of yellowish needles with a melting point of 163°C.

The 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine used in the above method can be prepared as follows: 67.75 g of 3,4-dichloro-6-hydroxy-pyridazine is dissolved in 205 ml of 2N caustic soda and mix drop by drop with 36 ml of dimethylsulphate. The reaction mixture is then heated for 1/2 hour at 70°C, then cooled and extracted twice with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The remainder is recrystallized from high-boiling petroleum ether. Yield 54 g (73%). Melting point 97°c.

Example 42

Preparation of the sodium salt of (7R)-3-[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl)thio]methyl]-7-[2-(2-thienyl)-acetamido ]-3- cephem-4-carbonic acid.

This compound is prepared analogously to example 1 on the basis of

7.55 g of cephalothin sodium salt and 2.95 g of 1,2-dihydro-1,6-dimethyl-4-mercapto-2-oxo-pyridine. Yield 3.0 g (31%). Melting point 178-185°C (decomposition), [cc]£° +46.2° (c = 0.353 in water).

Example 43

|Preparation of the sodium salt of (7R)-3-[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl/-7-( 2-phenylacetamido)-3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 1 on the basis of

8.24 g of cephaloram sodium salt and 3.63 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. Yield 2.2 g (21%). Melting point 190-200°C (decomposition), [a]^° = +19.8 (c = 0.339

in water).

Example 44

Preparation of the disodium salt of (7R)-7-[(RS)-2-sulfo-2-phenylacetamido]-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-ase -triazin-3-yl)-thio]-methyl/-3-cephem-4-carboxylic acid.

9.07 g (7R)-7-[ (RS)-2-bromo-2-phenylacetamido]-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as -triazin-3-yl)-thio]-methyl/-3-cephem-4-carboxylic acid sodium salt is dissolved in 100 ml of water and mixed with 2.8 g of sodium sulphite. The reaction solution becomes

stirred 4 1/2 hours at 25°C, then acidified to pH 2 with 2N hydrochloric acid. The thus precipitated substance is filtered off and discarded. The filtrate is then extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts are likewise discarded. The aqueous phase containing the desired substance is then vacuum evaporated at 40°C to a volume of approx. 30 ml and chromatographed over a column of 400 g Amberlite XAD-2 (grain size: 300-1000 µm). Yield 1.0 g (10.6%). Melting point from 230°C cleavage, [cc]^° = -5.0°

(c = 0.1 in water) .

The (7R)-7-[(RS)-2-bromo-2-phenylacetamido]-3-/((1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- as-triazin-3-yl)-thio]-methyl/-3-cephem-4-carboxylic acid sodium salt is prepared analogously to example 21 from 23.1 g of 7-amino-3-desacetoxy-3-/(1,4, 5,6-tetrahydro-4-ethyl-5,6-dioxo-az-triazin-3-yl)-thio/-cephalosporanic acid and 14.0 g of DL-oc-bromophenylacetic acid Yield 10 g (28%) .Melting point from 190°C decomposition.

Example 45

(Preparation of the sodium salt of (7R)-3-[(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl)-thio]-methyl/-7-[2-(2-thienyl)- acetamido]-3-cephem-4-carboxylic acid.

This compound is prepared analogously to example 1 on the basis of

6.27 g of cephalothin sodium salt and 2.50 g of 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine. Yield 5.0 g (65%). Melting point from 175°C decomposition, [a]^° = +12.2° (c =0.5 in water).

The 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used in the above method can be prepared as follows:

To a solution of 22.2 g of sodium hydrogen sulphide monohydrate i

23.7 g of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine are added to 1000 ml of methanol and the mixture is stirred for 3 hours at 25°C. The precipitated sodium chloride and the yellow filtrate are then filtered in

pes in vacuum at 40°C. The evaporation residue is recrystallized

cert from ethanol. Yield 8.0 g (34%) yellow crude substance. For purification, 5.0 g is suspended in 50 ml of 0.5N hydrochloric acid, then strongly acidified with the addition of 10 ml of 2N hydrochloric acid, the mixture is stirred for 10 minutes at 25°C and then stored overnight in a refrigerator. The resulting orange-yellow crystalline seed

(3.65 g), is filtered off, washed with a little ice water and dried

in vacuum at 50°C. Melting point 204-206° (decomposition).

Example 46

Preparation of the sodium salt of (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[ 2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid (variant of the method in example 1).

4.0 g (7R)-3-(azidomethyl)-7-[2-(-thienyl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (melting point from 170°C decomposition $

[a]^° = +134.4 (c =0.5 in water)j is stirred in 100 ml of buffer with pH 7.0 with 2.07 g of 1,4,5,6-tetrahydro-4-ethyl-5 ,6-dioxo-3-mercapto-as-triazine and 1.01 g of sodium bicarbonate for 24 hours at 50-55°C under a nitrogen atmosphere. The reaction mixture is then cooled to 25°C and adjusted to pH 2 with 2N hydrochloric acid.

The thus precipitated crude acid is filtered off, washed with water for purification and then stirred for 10 minutes in 100 ml of vinegar. The thus purified acid is filtered off (1.3 g), suspended in 25 ml of methanol and mixed with 2.5 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate, whereby a solution is formed. Dilution with 100 ml of ethyl acetate precipitates the desired sodium salt. Yield 1.25 g (24%). The substance thus obtained is identical in all properties to the substance prepared in example 1.

Example 4 7

Preparation of the sodium salt of (7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(-tetrazolyl)-acetamido] -3- cephem-4-carboxylic acid.

This compound is prepared analogously to example 20 based on

6.4 g of tetrazole-1-acetic acid and 17.75 g of 7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-oxopyrimidin-4-yl)-thio]-cephalosporanic acid. Yield: 8.0 g (33%) melting point from 190°C, cleavage.

Example 48

Preparation of dry ampoules for intramuscular use:

A lyophilisate of 1 g of the sodium salt of (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3- yl)-thio]methyl/-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid and fill into an ampoule. For use, the latter is mixed with 2.5 ml of a 2% lidocaine hydrochloride solution.

Example 49

Preparation of tdrrampoules for intramuscular use:

A lyophilisate of 1 g of the sodium salt of (7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared analogously to example 4 7 )-thio]methyl/-7-[2-(5-oxo-1,2,3-oxa-diazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid and fill into an ampoule.

Claims (79)

1. Process for the preparation of acyl derivatives of the general formula in which X produces a desactoxy-cephalosporinyl residue and Y a 6-membered non-aromatic and not enolizable to an aromatic residue, optionally substituted heterocyclic residue with 1-3 nitrogen atoms, of which at least one of these nitrogen atoms is substituted and at least one of these nitrogen atoms forms an amide group with the carbonyl group in the neighboring position, as well as salts of these compounds and hydrates of these salts, characterized in that mana) reacts with a compound with the general formula in which X' produces a desacetoxy-cephalosproinyl residue corresponding to the residue X, whose carboxyl residue in the 4-position is in protected form and a leaving group, with a compound of the general formula wherein Y has the above-mentioned meaning and cleaves off the protecting group orb) reacts with a compound of the general formula wherein Y has the above meaning and X'' produces a desacetoxy-cephalosporanyl residue I corresponding to the residue X, whose carboxyl residue in the 4-position J available in protected form, jwith an acid of formula where Z produces an acyl residue, which comes into consideration as a substituent of the amino residue in the 7-position in cephalosporin, or with a reactive functional derivative thereof, cleaves off the protecting group and, if desired, converts the reaction product into a salt. 2. Method according to claim 1, characterized in that a compound with formula II is used as starting material, in which the residue X' has the general formula wherein R means a protected carboxy group, R^ hydrogen or methoxy, R^ cyano or pyridylthio or an aliphatic, alicyclic, aromatic or heteroaromatic residue, R^ hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, whereby residue R^ other than cyan may be substituted by hydroxy, halogen, lower alkyl or lower alkoxy, and R^ is hydrogen if R2 is a pyridylthio residue, or that one reacts a compound of formula IV, in which the residue X'' has the general formula wherein R and R^ have the above meaning, with a compound of the formula V, wherein the residue Z has the general formula in which R« and R^ have the above meaning. 3. Process according to claims 1 or 2, characterized in that a compound of formula II or V is used as starting material, in which the residues X' and Z respectively have the formulas X^ and R2 respectively, in which R2 is 2-thienyl, 2-furyl, 1-tetrazolyl , 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyan and R3 has the meaning stated in claim 2, whereby, if R2 is 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3 -sydnonyl or 4-pyridylthio, R 1 is hydrogen. 4. Method according to one of claims 1-3, characterized in that a compound of formula III or IV is used as starting material, in which Y produces a non-aromatic N-substituted and optionally substituted on one or more carbon atoms pyridonyl residue or a non-aromatic at least one of the nitrogen atoms and optionally on one or more carbon atoms substituted pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl residue. 5. Process according to one of claims 1-4, characterized in that a compound of formula III or IV is used as starting material, in which Y produces a non-aromatic, N-substituted and optionally substituted on one or more carbon atoms 2-oxopyridine-4 -yl residue or a non-aromatic, on at least one nitrogen atom and optionally on one or more carbon atoms substituted 2-oxopyrimidin-4-yl-, 4-oxo-pyrimidin-2-yl-, 2,6-dioxopyrimidin-4-yl-, 2-oxopyrazin-3-yl-, 2,3,5-trioxopyrazin-6-yl-, 3-oxopyridazin-6-yl-, 3-oxo-pyridazin-4-yl-, 5,6-dioxo-as- triazin-3-yl-, 2-oxotriazin-4-yl- or 2,4-dioxo-triazin-6-yl residue, where lower alkyl, alkenyl or alkynyl, cycloalkyl, hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino, formyl, lower alkanoyl or alkanoylamino, carbamoyl, mono- or di-lower alkylaminocarbonyl and as a substituent on a ring carbon atom lower alkyl or alkoxyj amino, mono- r di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, cyan or halogen, whereby a lower alkyl group bound to a ring nitrogen or ring carbon atom can again be substituted by hydroxy, lower alkoxy, amino , mono- or di-lower alkylamino, formyl, lower alkanoyl or alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, cyan, halogen or epoxy. 6. Process according to one of claims 1-5, characterized in that a compound of formula II derived from cephalotin, 7-oc-methoxy-cephalotin, cephacetril, (7R)-mandelamido-cephalosporanic acid, cephaloglycine, 7-( 3-sydnonacetamido)-cephalosporanic acid. 7. Method according to one of claims 1-5, characterized in that 4-ethyl-, 4-methyl-, 4-allyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl is used as starting material of formula III - or 1,4-diethyl-1,4,5,6-tetrahydro-5,6-dioxo-3-mercapto-as-triazine. 8. Method according to one of the claims 1-6, c a r a k - (terized by using as starting material with formula III 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as- triazine. 9. Procedure according to et. of claims 1-6, characterized in that 1-amino, 1-ethyl- or 1-butoxy-1,2-dihydro-4-mercapto-2-oxopyrimidine is used as starting material. 10. Process according to one of claims 1-6, characterized in that 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidine is used as starting material of formula III. 11. Method according to one of claims 1-6, characterized in that 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxopyrimidine is used as starting material of formula III. 12. Process according to one of claims 1-6, characterized in that 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine is used as starting material of formula III. 13. Method according to one of claims 1-5, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[ (1,4,5,6-tetrahydro-4- ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid.. 14. Method according to one of claims 1-5, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-oxo -pyrimidin-4-yl)-thio]-cephalosporanic acid. 15. Method according to one of claims 1-5, 13 and 14, (characterized in that tetrazole-l-acetic acid, α-hydroxycaproic acid, α-hydroxyisocaproic acid, cyclohexyl-oc-hydroxyacetic acid, sydnon- 3-acetic acid or fuiryl-2-acetic acid or a reactive functional derivative thereof. 16. Process according to one_ of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto- as-triazine. 17. Procedure according to et. of claims 1-7, characterized in that a compound of formula €1 derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4- methyl-5,6-dioxo-3-mercapto-as-triazine. 18. Method according to -et, of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto -as-triazine. 19. Method according to one of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercaptoase -triazine. 20. Process according to one of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-4-(2-methoxy-ethyl)-5,6-dioxo -3-mercapto-as-triazine. 21. Process according to one of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto -as-triazine. 22. Process according to one of claims 1-7, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto -as-triazine. 23. Method according to one of claims 1-6 and 8, characterized in that a compound is reacted with formula II derived from cephalothin with 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine. 24. Process according to one of the claims 1-7, characterized in that a compound of formula II derived from 7-a-methoxy-cephalin is reacted with 1,4,5,6-tetrahydro-4-methyl-5,6- dioxo-3-mercapto-as-triazine. 25. Process according to one of claims 1-6 and 9, characterized in that a compound of formula II derived from cephalothin is reacted with 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. 26. Process according to one of claims 1-6 and 9, characterized in that a compound of formula II derived from cephalothin is reacted with 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. 27. Method according to one of claims 1-6 and 10, characterized in that a compound of formula II derived from cephalothin is reacted with 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidine. 28. Method according to one of claims 1-6 and 11, characterized in that a compound of formula II derived from cephalothin is reacted with 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxopyrimidine. 29. Method according to one of claims 1-6 and 12, characterized in that. a compound of formula II derived from cephalothin is reacted with 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine. 30. Process according to one of claims 1-6 and 9, characterized in that a compound of formula II derived from cephalothin is reacted with 1-amino-1,2-dihydro-4-mercapto-2-oxopyrimidine. 31. Process according to one of claims 1-7, characterized in that a compound of formula II derived from cephacetril is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercaptoase -triazine. 32. Process according to one of claims 1-7, characterized in that a compound of formula II derived from (7R)-mandelamido-cephalosporanic acid is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo -3-mercapto-as-triazine. 33. Method according to one of claims 1-7, characterized in that a compound of formula II derived from cephaloglycine is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto- as-triazine. 34. Process according to one of claims 1-7, characterized in that a compound of formula II derived from 7-(3-sydnonacetamido)-cephalosporanic acid is reacted with 1,4,5,6-tetrahydro-4-ethyl-5,6 -dioxo-3-mercapto-as-triazine. 35. Method according to one of the claims 1-6 and 9-, k a r a k - .terized by reacting a compound of formula II derived from 7-(3-sydnonacetamido)-cephalosporanic acid with 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. 36. Process according to one of claims 1-5, 13 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[ (1,4,5,6-tetrahydro- 4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid with tetrazole-1-acetic acid or a reactive functional derivative thereof. 37. Method according to one of the claims 1-5, 13 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[ (1,4,5,6 -tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid with oc-hydroxycaproic acid or a reactive functional derivative thereof. 38. Method according to one of claims 1-5, 13 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro- 4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid with α-hydroxyisocaproic acid or a reactive functional derivative thereof. 39. Process according to one of claims 1-5, 13 and 15, characterized in that one reacts a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro- 4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid with cyclohexyl-oc-hydroxyacetic acid or a reactive functional derivative thereof. 40. Process according to one of claims 1-5, 13 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3[(1,4,5,6-tetrahydro-4- ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid with furyl-2-acetic acid or a reactive functional derivative thereof. 41. Process according to one of claims 1-5, 14 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2 -oxopyrimidin-4-yl)-thio]-cephalose poric acid with sydnon-3-acetic acid or a reactive functional derivative thereof. 42. Method according to one of claims 1-5, 14 and 15, characterized in that a compound of formula IV derived from 7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2 -oxopyrimidin-4-yl)-thio]-cephalos-Jporanic acid with tetrazole-1-acetic acid or a reactive functional derivative thereof. Ii 43. Process for the production of pharmaceutical preparations, characterized by mixing a compound with the general formula in which X produces a desacetoxy-cephalosporinyl residue and Y a 6-membered, non-aromatic and not enolizable to an aromatic <!>> residue, optionally substituted heterocyclic residue with 1-3 nitrogen atoms, of which at least one of these nitrogen atoms is substituted and at least one of these nitrogen atoms forms an amide group with a carbonyl group in a neighboring position, or a pharmaceutically usable salt thereof as active ingredient with a pharmaceutically tolerable carrier material. 44. Pharmaceutical preparations, characterized in that they contain a compound with the general formula in which X produces a desacetoxy-cephalosporinyl residue and Y a 6-membered, non-aromatic and not enolizable to an aromatic residue, optionally substituted heterocyclic residue with 1-3 nitrogen atoms, of which at least one of these nitrogen atoms is substituted and at least one of the nitrogen atoms forms an amide group with a carbonyl group in the neighboring position, or a pharmaceutically acceptable salt thereof. 45. Acyl derivatives characterized by the general formula in which X produces a desacetoxy-cephalosporinyl residue and Y a 6-membered, non-aromatic and not enolizable to an aromatic residue, optionally substituted heterocyclic residue with 1-3 nitrogen atoms, of which at least one of these nitrogen atoms is substituted and at least one of these the nitrogen atoms form an amide group with a neighboring carbonyl group, as well as salts of these compounds and hydrates of these salts. 46. Compounds according to claim 45, characterized in that the residue X has the general formula wherein hydrogen or methoxy, R 2 is cyano or paridylthio or an aliphatic, alicyclic, aromatic or heteroaromatic residue, R^ hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, whereby a residue R^ different from cyan can be substituted with hydroxy, halogen, lower alkyl or lower alkoxy, and R 1 is hydrogen if R 2 is a pyridylthio residue. 47. Compounds according to claim 45 or 46, characterized in that the residue X has the formula X^ , where R 2 is 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyan and R3 has the meaning stated in claim 4 2, in which R3 is hydrogen if R2 is a tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl or pyridylthio. 48. Compounds according to one of claims 45-4 7, characterized in that Y produces a non-aromatic, N-substituted and optionally substituted by one or more carbon atoms pyridonyl residue or one non-aromatic, on at least one nitrogen atom and optionally on one or more carbon atoms jsubstituted pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl residue. 49. Compounds according to one of claims 45-48, characterized in that Y produces a non-aromatic, N-substituted and optionally substituted on one or more carbon atoms 2-oxo-pyridin-4-yl residue or a non-aromatic, at least a nitrogen atom and optionally on one or more carbon atoms substituted 2-oxopyrimidin-,4-yl^ , 4-oxo-pyrimidin-2-yl- , 2,6-dioxopyrimidin-4-yl-, 2-oxopyrazin-3-yl- , 2,3,5-trioxopyrazin-6-yl-, 3-oxopyridazin-6-yl-, 3-oxopyridazin-4-yl-, 5,6-dioxo-as-triazin-3-yl-, 2-oxotriazine -4-yl or 2,4-dioxo-triazin-6-yl residue, whereby lower alkyl, alkenyl or alkynyl, cycloalkyl., hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino, formyl, lower alkanoyl or alkanoylamino, carbamoyl, mono- or di-lower alkylaminocarbonyl pg as substituent on ring carbon atom lower alkyl or alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, cyan or halogen, one of which to a ring nitrogen or ring carbon atom bonded lower alkyl group can again be substituted by hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino, formyl, lower alkanoyl or alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylaminocarbonyl, cyan, halogen or epoxy. 50. Compounds according to one of claims 45-49, characterized in that the residue X has the formula X^ , in which R2 is 2-thienyl, cyano, phenyl, cyclohexyl, 3-sydnonyl, 1-tetrazolyl, 2-furyl, n-butyl or isobutyl, R., hydrogen and, if R 2 is 2-thienyl, hydrogen or methoxy and R^ hydrogen or, if R 2 is phenyl, hydroxy or amino, or, if R 2 is cyclohexyl, n-butyl or isobutyl, produces hydroxy. 51. Compounds according to one of claims 45-50, characterized in that Y produces 4-ethyl-, 4-methyl-, 4-allyl-, 4-butyl-, 4-(2-methoxy-ethyl)-, 1 ,4-dimethyl- or 1,4-diethyl-1,4,5,6-tetrahydro-5,6-dioxo-3-mercapto-as-tria-zinyl or 1,2,5,6-tetrahydro-1- the ethyl-5,6-dioxo-3-mercapto-as-triazinyl residue. 52. Compounds according to one of claims 45-50, characterized in that Y produces the 1-amino-, 1-ethyl- or 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidinyl residue, 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidinyl residue, 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxopyrimidinyl residue or 1-ethyl-1, 4-dihydro-2-mercapto-6-methyl-4-oxopyrimidinyl residue. 53. (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2- (2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 54. (7R)-3-[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2- (2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 55. (7R)-3-[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2- (2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 56. (7R)-3-[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2- (2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 57. (7r)_3-/[(1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7- [2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 58. (7R)-3-[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[ 2-(2-thienyl)-acetamido]-3-'cephem-3-carboxylic acid and its salts. 59. (7R)-3-[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[ 2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 60. (7R)_3-/[ (1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2-( 2-thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 61. (7S)-7-Methoxy-3-[(1,4,5,6-tetrahydro-4-methyl-5,6-|dioxo-as-triazin-3-yl)-thio]methyl/- 7-[2-(thienyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 62. (7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(2-thienyl)-acetamido]- 3-cephem-4-carboxylic acid and its salts. 63. (7R)-3-/[ (1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-thienyl)-acetamido]-3-cephem- 4-carbonic acid and its salts. 64. (7R)-3-/[ (1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl)-acetamido]-3 -cephem-4-carboxylic acid and its salts-. - 65. (7R)-3-[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl)- acetamido]-3-cephem-4-carboxylic acid and its salts. 66. (7R)-3-[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl)-acetamido] -3-cephem-4-carboxylic acid and its salts. 67. (7R)-3-[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl/-7-[2-(2-thienyl)- acetamido]-3-cephem-4-carboxylic acid and its salts. 68. (7R)-7-(2-cyanacetamido)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl/-3-cephem-4-carboxylic acid and its salts. 69. (7R )-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[(R )-mandelamido]-3-cephem-4-carboxylic acid and its salts. 70. (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine -3-yl)-thio]-methyl/-3-cephem-4-carboxylic acid and its salts. 71. (7R )-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-|3-yl)-thio]methyl/-7-[2 -(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 72. (7R)-3-[(1-ethyl-1,2-dihydro-2,-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(5-oxo-1,2, 3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 73. (7R)-3-/[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[ 2- (1-H-triazol-1-yl)-acetamido]-3-cephem-4-carboxylic acid and its salts 74. (7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[(R )-2-hydroxyhexanamido]-3-cephem-4-carboxylic acid and its salts. 75. (7R)_3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7r-[(R) -2-hydroxy-4-methylvaleramido] - 3-cephem-4-carboxylic acid and its salts. 76. (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-tria- .zin-3-yl)-thio]methyl/-7-[(R)-7-hydroxy-2-(cyclohexyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 77. (7R)-3-/[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl/-7-[2( 2-Furyl)-acetamido]-3-cephem-4-carboxylic acid and its salts. 78. (7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(3-sydnonyl)-acetamido]- 3-cephem-4-carboxylic acid and its salts. 79. (7R)-3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-7-[2-(1-tetrazolyl)-acetamido]- 3-cephem-4-carboxylic acid and its salts.