DE2808643A1 - 7 BETA SQUARE CLIP ON (2-AMINO 1,2-DIOXOETHYL) AMINO SQUARE BRACKET FOR ACYLCEPHALOSPORINE - Google Patents

Description

uZ:?: Case: '-'.- JJz- 400-Η

. CHuICj: ΐ · ϊ £ FABRIK YON ΗΕΥΒ ^ Γ-ί, G. ~ .bH b Munich 19, Volkartstrasse δ3 10

"73-if (" 2-Anirio-1,2-aioxoethyl) -aninoV-acylcephalosporine "

The Ξ-rfindur.g relates to the claims and the Description of marked items.

The r.est R- is in the CX configuration. 20th

"if the radical X is a pyridinium group or one through a Carbanioyl is substituted pyridinium group have the compounds of the invention have the general formula Ia

• HO R

ι Il ■

NU

1 '- ¹ - ClI. -N

T, ² V

(COO

C = O

R ₈ -NR ₃

in which Z represents a hydrogen atom or a carbamoyl group. The star on the carbon atom in the (X-position of the Oaite chain acid indicates a center of asymmetry.

809837/0673 ^{ßAD G} ^ 3ü ^. '

The lower alkyl radicals can be unbranched or branched radicals nit i bi3 7 »preferably 1 to 4 and in particular 1 or 2 xlohlsnc toff atoms be. Special examples of these leftovers are II = ethyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals. The lower alkoxy and alkylthio radicals correspond to lower ones. Alkvir residues. Special examples are those Met.'ioxy, ethoxy, propoxy, methylthic, ethylthio and propylthio groups. Specific examples of lie phenyl-lower alkyireate and Diphenyl-niecer-allcylreste are the 3enzyl-, Phenetayl- and diisocyanylmethylx group.

As saturated and unsaturated cycloalkyl radicals there are radicals irr with up to 7 carbon atoms and up to two double bonds irr. Pi: i ~ in Fra.-e. Specific examples are the cyclonropyl, ^ ⁵ cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, and also the cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, ^ - cycloriexadienyl and cycloheOtenj'l groups. The 1,4-cyclohexadienyl group is particularly preferred.

Specific examples of the substituents on the benzene ring are chlorine or tronatony, alkyl radicals with 1 to H carbon atoms, especially the methyl or ethyl group, alkoxy radicals with 1 to 4 carbon atoms, especially the methoxy or thoxy group, and hydroxyl groups. Specific examples of substituted phenyl groups are 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-hydroxyphenyl, 3,5-dichlorophenyl, 2-, 3- or 4-methylphenyl and 2-, 3- or h- ethoxyphenyl groups.

The salt-forming ions R are metal cations, v: ie the aluminum ion, Alkali metal ions, such as sodium or potassium ions, alkaline earth metal ions, such as calcium or magnesium ions, or ammonium ions, which are, for example, from phenyl-lower-alkylamines, such as dibenzylamine, Ν, Ν-dibenzylethylenediamine, lower Alky! Amines, such as methylamine or triethylamine, or N-lower-alkylpiparidines, such as N-ethylpiperidine. Sodium and

809837/0673 _Bm ","

Potash ions are the preferred salt-forming ions.

Fluorine, chlorine, chromium and iodine atoms come into play as halogen atoms Trage, chlorine and bromine atoms are preferred. In the case of the TriiialogenstlaylgruyDe R is the 2,2,2-trichloroethyl group preferred.

The trimethylsilyl group is the preferred tri- (lower-alkyl) -silyl group.
10

The lower alkanoyloxy groups have the general formula

! I

-O-C-lower-alkyl,

the alkyl group preferably representing a methyl group. The lower alkanoyloxy radicals can contain up to 7 carbon atoms. The radicals with up to H carbon atoms are preferred. The acetyloxy group is particularly preferred.

L-ar Suostituent R, - is a VJasserstoffatom or alkyl nit preferably 1 to ¹ I, especially 1 or 2 carbon atoms. R- is preferential one hydrogen atom.

The compounds of general formula I are acylic run " a cephem compound of the general formula II

HN ^ "^ ^(II)

³⁰ COOR

or its reactive derivative with a carboxylic acid of the al I. ~: e mean η formula III

R ₁ -CH-COOH 35

? ^H (in)

C = OC = OR ₈ -NR ₃

809837/0673 BAD ORIGINAL

or their action3 more capable. Derivative, for example an acid halide, an activated ester, such as your nitrophenyl ester or Dinitrooher.ylester, or a mixed anhydride, and / or in the presence of a coupling agent, such as dicyclohexylcarbodilraid, manufactured.

The compounds of the general formula II are preferred Used in the form of an ester. In this case, R denotes an easily cleavable radical, such as, preferably, a diphenyl-thyl group or a tert-butyl or trimethylsilyl group.

A preferred method for preparing the compounds of the invention is by reacting the carboxylic acid of the general type Formula III with an alkyl chloroformate in the present a 3ase, such as triethylamine, and then with the diphenylmethyl ester of the compound of the general formula II, The ester obtained is then treated with trifluoroacetic acid and anisole hydrolyzed. Ss becomes the link with the free carboxyl group received in the 4-3 position. The corresponding salt can be prepared from the carboxylic acid by reaction with a 3ase will.

This process can be carried out, for example, by dissolving or suspending the carboxylic acid in an inert organic solvent such as chloroform, tetrahydrofuran, methylene chloride, dioxane or benzene, and adding at temperatures from about 0 to 5 ° C an approximately equimolar amount of the compound of the general formula II can be carried out. The reaction product is after Usual methods isolated, for example by evaporating the Lüiungsmittel, According to a further method is a Compound of the general formula IV

R ₁ -CH-CO-NH-!

(IV)

_NH / j- _Nn ^ CH ^ -X

COOR

2 ^{7 /} '2

L -J

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preferably in the form of a salt, '- / ie of the trifluoroacetate, in an "organic solvent, such as acetonitrile, methylene chloride, Chloroform, dimetrolformamide, tetrahydrofuran, dioxane or 3er.sol, dissolved or suspended and converted into an ester, oeisoislweise by reaction with bis-itrimethylsilyl) -. acatanid, in den Trlmethylsilvlestsr, The compound obtained •; ied then with a compound of the general formula V

'N-C- C-hai (V)

R ₈ OO

in ä? r hai a halogen atom, preferably a chlorine atom, represents · 3ΐ-3; 1ΐ5, in an organic solvent, for example a c-? r above-mentioned solvent, at reduced Ie "o 3 r a D ure η, for example about 0 C, and in the presence of a H-i.iccenws.oserötoffacceptors, such as propylene oxide or butylene oxide,

LLe / compounds of the general formula I, in which X represents a pyridinium compound substituted by a carbamoyl group, are known by reaction of a compound of the all:.; j -. one η Formula I, in which X represents an acetoxy group, with ·? Ιώ3τπ. "If appropriate, carbamoyl-substituted pyridine in a ^ m polar solvent, such as water, and in the presence of a catalyst, such as an Allcalinistallthiocyanat, according to the in of 5JS-IS 3 792 047 and DE-OS 2 23 ¹ J 280 described processes.

Veroindungen of the general formula I ₁ in which X represents a Heterothio ~ ruope, can also be prepared in such a way that one first prepares a compound of the general formula I in which X represents an acetoxy group and then this varo-indu. ".!?; with a mercaptan of the general formula VI

809837/0673

oaar entsprachenden the alkali metal salt, preferably the Natriumsal ^ of formula VII = specified in the US? Sen 3 c55 213, 3 ~ -9 ~ J-described methods 309 ~ na 3,392,737 un-

Ji ^ "compounds of the general formula III, in which R, a oxygenator. represents, from a C <amino acid ester of general formula VI

R-CH-cooY nm

₁ -C

¹⁰ NH

in which H _{1 has} the above meaning and X is an easily cleavable group, vrie a diphenylmethyl, nitrophenyl, dinitroohenyl, tert-butyl or triisethylsilyl group VII -

hal-C-C-OZ

«Ij

i ^ ώΓ hai a halo-jenatom, preference v / ei se a chlorator, and Z means a lower alkyl radical, in ^ e ^ presence of a base, v. ^T he triethylamine, prepared In this reaction forms an intermediate of the general formula VIII

R-CH-COOY

NH (VIII)

I C = O

i oz

The implementation of this intermediate product with an acid, vrie Trifluoroacetic acid and anisole, provide the free carboxylic acid of the general formula IX

R-CH-COOH J- f

NH

35 9 ^{= O}

C = O

I!

OZ
L _J

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The treatment of the compound of the general formula IX with ammonia or an amine of the general formula NHR, and then Acidification gives the acylating agent the general Formula III, activated derivatives of this compound; become ciurcr. Implementation with, for example, thione chloride, a Ver-33t3run ~ 3: rjLt; tel or an anhydride, prepared by conventional methods.

As an alternative, a Z < -amino acid ester of the general formula VI, preferably the diohenylmethyl ester, nitrocellulose ester or dinitrophenyl ester, with an oxalyl halide, v? Ie oxalyl chloride, becomes a compound of the general formula X.

R -CH-COOY_ ¹ I.

NH _(x)

C = O I

C = O I

shark

ur .- '23 3t.; t, in which a halogenated, preferably a chlorine atom and Y represents one of the ester groups mentioned in the foregoing, vfie a dipnenylmethyl, p-nitrophenyl or 2,4-dinitrophenyl ester group means »The implementation of this compound with Ansnoniali or an Ämin of the general formula HN-R-, gives

a compound of the general formula XI

R ₁ -CH-COOY ¹ I NH

C = O (X ₁ )

30 ^C i ^{= 0}

NH-R ₃

When the radical Y is a nitroohenyl or dinitrophenyl group represents, the intermediate of the general formula XI can be reacted with the compound of the general formula II, If the radical Y is a diphenylmethyl group, this will be

809837/0873

Zwischer.produz- preferably with an acid such as hydrochloric acid in Glacial acetic acid, to a compound of the general formula ZII

R ₁ -CH-COOH ¹ I.

NH

I (XII)

C = O I
C = O

I.
NH-R ₃

implemented subsequently with the connection of the general Formula II, preferably in the form of the diphenylmethyl ester, sur Reaction is brought. Sodanr is the ester group on the above described // split off.

The salts of the carboxylic acids of the compounds of the general
Forr..el I are produced by reacting the carboxyl group with salsbildendsn ions of the type described above.

IJi2 Starting compounds of the general formula III, in Rg has a meaning other than a hydrogen atom, are made from eina.Ti iX amino acid esters of the general formula VI

R-CH-COOY 1 ι

¹ ( VT )

NH " ^v '

25 2

in the R "has the above meaning and Y a slightly abspal table group, for example a diphenylmethyl, nitrophenyl, Dinitrophenyl, tert-butyl or trimethylsilyl groups means by reaction with an oxalyl halide, such as oxalyl chloride, with formation of an intermediate of the general formula XIII

R-CH-COOY 1 liter

NH

(XIII)

35 C = O

C = O hai

S09837 / 0673

In the shark one. Represents a halogen atom, preferably a chlorine atom, Made in a solvent such as dioxane. Then ^ ied this intermediate with a compound of general η Formal XIV

5 f ₄

NCC-NH-R _{3 (XIV)}

in an organic solvent, for example one of the solvents mentioned above, in the presence of an organic base, such as pearethylaniline, at low temperatures, for example about -2O ° C, and treatment of the intermediate product with an acid, such as trifluoroacetic acid and anisole, to give the free acid general formula III implemented. By reacting the compound of the general formula X with a Oxalylhalogenld such as oxalyl chloride, in a solvent such as üioxan, at elevated Temoeraturen, for example etvia OEO to 7O ⁰ C, a compound of the general formula V em al tan.

Alternatively, the starting compounds of the general formula III can also be derived from the starting compounds of the general formula VI by reaction with a compound of the general formula V

N-C-C-hal (γΛ

I Il Il

^R 8 OO

getting produced.

The salts of the carboxylic acids of the compounds of general formula I are obtained by reacting the carboxyl group of the cephalosporanic acid residue made with a salt-forming ion of the type described above.

The compounds of general formula I contain a further center of asymmetry in the remainder of the side chain acid, which is through

809837/0673

marked with an otern. By using the corresponding ci-jr. From ..rar.? Tö connections can be the connections of the general Formula I produced as Epimerencemiseh or as individual Spimers will. The invention relates to the mixtures as well as the

⁵ ei. ;;:;: 1λ = γ »Isor.eren,

Prior-u-ts compounds of the invention are the free carboxylic acids and alkali metal salsa of the compounds of the general Forr.ei I, in which R is a hydrogen atom, a sodium or potassium

^{1 (3} represents a union, X means an acetoxy or heterorhic group - ΐ3ΐ _3, in particular a 1-methyl-1H-tetrazol-5-ylthio group, R ₁ a cyelohexadienyl, phenyl, 2-thienyl, 3-thienyl, 2 -7urvl-j 3-? Uryi, 2-pyridyl, 3-? Yridyl or H -pyridyl group,? .-, ii .: "-asserstcf fatom or a methoxy group, in particular an oxygen atom and PU, R ₁ . and R_ water atoms or lower alkali radicals, in particular hydrogen atoms, mean “The D-isomers are preferred.

Particularly preferred compounds of the invention are the free carboxylic acids and alkali metal salts of the compounds of the general principles. Formula I in which R 1 is a 2-thienyl or phenyl group, in particular a 2-thienyl group, R ₂ , R ₁ , R 1. and R ^ water-3 ~ cr'fatone and X is a heterothio group, in particular the group NN

means,

Lie compounds of general formula I are broad spectrum antibiotics which both ^ egen gram-positive and gram-Ne -asive bacteria such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus rettgeri, Escherichia coil, Enterobacter Hafniae, Enterobacter cloacae, Klebsiella pneumoniae and Serratia marcescens, act. The connections

Ö09837 / 0673 SA f

can be in the form of medicinal preparations orally or parenterally in usual Dosage forines are given.

The examples illustrate the invention. 5

example 1

D-u "- / (2-iüthoxy-1,2-oxoethi / l) -amino--2-thiophenes sic acid diphanyir, ethyl ester

A solution of 3.2 g (20 mmol) of 2-D-thienylglycine diphenylmethyl ester in 50 ml of methylene chloride is mixed with 1 g of triethylamine and then at -20 ° C dropwise with 1.3 g (20 mmol) Ethyl oxalate in 20 ml of methylene chloride was added. After 2 hours the reaction mixture is shaken out with water, dried over sodium sulfate and reduced under reduced pressure Evaporated pressure. The remaining syrup is the pure titanium compound.

Example 2 ~ -; i-yf (2-zthoxy-1,2-dioxoethy1) -amino7-2-thiophenesic acid

9.5 g of D -!? - Zr (2-ethoxy-1,2-dioxoethyl) -aminoJ-2-thiophenes3igsaurediohenylmethylester v / ground with -ICC with 50 ml of a mixture of trifluoroacetic acid and anisole (4: 1). Thereafter. v. ^r he de η the trifluoroacetic acid and the anisole distilled off. Ea an oily residue in 100 ml of saturated vräiiri _r ~ he Natriumbicaroonatlösung added v / ill. Hintsrbleibt This solution is extracted twice with 20 ml of diethyl ether. The aqueous phase is then acidified with hydrochloric acid. After several extractions with ethyl acetate and evaporation of the ethyl acetate extract, the title compound remains as a brownish syrup which does not crystallize. Yield 6.5g.

Example 3 D-C <-ZT2-. \. 'Iino-1,2-dioxoethyl) -amino7-2-thiophenacetic acid

809837/0673

3in-2 solution of 0.5 g of D - # - £ (2-3thoxy-l, 2-dioxoethyl) -amino_7-2 - Dhiopaene33i ~ 3 acid in 100 ml of a 5N solution of ammonia in ethanol Λ-irü 10 hours in a glass autoclave at 40 to 50 ⁰ C allowed to stand. Thereafter \ ^r ith the Reaktionsgenisch evaporated.

δ 2-er residue obtained is dissolved in V / water and acidified. Eo v / iri the litelver'oindun ^ obtained in wide crystals, which are recrystallized from ',.' Water. Yield 4? g voa F, up to 175 ⁰ C

10 Example 4

7-3- / T _i O-ZT2-Äniino-1,2, -dioxoethyl) -ainino_7-2-fchienylacetyl7-a.-niria7-3- / Zr (l-niethyl-lH-tetrasol-4-yl) - thio7-methyl7-8-oxo-5- ^ hia-l-azabicycloC ⁱ l.2.0joct-2-en-2-carboxylic acid diphenylrr.etxiyiester

A solution of 1.2 g (5 nllol) OCR 2-amino-l, 2-dioxoethyl) -a ^v r _i inq7-2-thiopaena33ir; acid in 50 nl of anhydrous tetrahydrofuran: -; ird with 0.5 of triethylamine and nil then at -10 ° C drop-2n .-; ice3 With a solution of 0.55 g (6 ml) of chlorine iron acid ethyl ester in 10 ml of tetrahydrofuran. After 30 I: inuts: i "/ ira the header mixture in a solution of 2.5 g (5 ~ i .-: ol) 7-A.mino-3 - /" Z "(l-methyl-lH-tetrazole- 5-yl) -thio ^ -metnyi7-C2phalo3poran-3äurediphenylniethy! Ester in 30 ml tetrahydrofuran was added dropwise. The mixture: "Rir for 3 hours at 5 ° C. Then the reaction mixture is filtered and the filtrate evaporated. It What remains is a brown foam, which is dissolved in 25 nl. ethylene chloride and treated with activated charcoal. After the activated charcoal has been filtered off, 200 ml of diethyl ether are added to the filtrate. The title compound precipitates as a hall-yellow powder. Yield 3.2 s from P. 106 ° C (dec.).

Example 5

7A - / "^ (i --- / r (2-amino-1,2-dioxoethyl) -araino_7-2-thienylacetyl7-arninc_7-3- ^ Z (l-ni £ thyl-1H-tetrazo 1-5-yl) -thio_7-me thy 17-3-oxo-S-tnia-l-azabicycloZTf. 2.Q7oct-2-en-2-carbon3S.ure

^BAÖ original - ¹ 809837/0673

* 2.3 5 of the product from Example h are stirred for 10 minutes at ^{0 0} C la a mixture of trifluoroacetic acid and anisole (U : 1). The trifluoroacetic acid and the anisole are then distilled off under changed pressure. The oily residue is with

S diethyl ether added. The solid formed is filtered off, dissolved in 33 l aqueous sodium carbonate solution, the 1/3 Sunx filtered and the filtrate acidified to a pK V / srt of 3 with 2U hydrochloric acid. -Ls the tit el compound precipitates as a brown powder. The product is filtered off, dried, dissolved in tetrahydrofuran and treated with activated charcoal. After the activated charcoal has been filtered off, diethyl ether is added to the filtrate and the title verb is precipitated in darks. It is obtained as a light yellow powder in a yield of 0.7 ½ g and from 155 to 16 ° C.

Example 6 DZ <~ £ { 2-Aair _l ol, 2-dioxoethyl) -am.inqj ^ -thiophene acetyl chloride

Interest suspension of 2.3 g of D-0'-ZT (2-amino-1,2-dioxoethyl) -amino7-2-thioolien-33sic acid 1,2-thionyl chloride is rapidly added to 30 ml of acetonitrile at -20 ° C. The temperature will be on RauTiteiTiperatur increases and the solvent decreases

distilled off under reduced pressure. The sticky brown residue is digested with diethyl ether. A light yellow solid powder is obtained. The IR absorption spectrum is confirmed the anpenoninene structure of the title compound, which is immediately is used in the next stage, as it is in the case of storage: decomposed,

³⁰ Example 7

) -D, 2-Amino-1,2-dioxoethyl) -amino7-2-thienylacetyl7-ariino7-3-Z "ZTl-methyl-1H-tetrazol-5-yl) -thioJ-niethyl7-B-oxo-5 tnia -l-azabicycloZ ^ .2.Ojoct-2-en-2-carboxylic acid

Zine solution - of 2.5 g (7.5 iaHol) of 7-amino-3-ZZ (1-Kethyl-1K-tetra2oi-5-yl) -thio7-ethyl7 "-cephalo3poranoic acid and 3.7 g

L- ■ J

8 0 9 8 3 7/0673 bad original

Bistrimethylsilylacetamide in 100 ml of acetonitrile is added at -10 ⁰ C with 2.2 g (7.5 mmol) D-CC-ZT 2-amino-l, 2-dioxoethyl) -amino7-2-thiophenacetylehlorid. The mixture is stirred for 1 hour. The solvent is then distilled off. The residue is taken up in a mixture of 50 ml of methanol and 1 ml of 2N hydrochloric acid and treated with activated charcoal. After the activated charcoal has been filtered off, ether is added to the filtrate and the title compound is precipitated. It is obtained as a light yellow powder, which was further purified by reprecipitation from a mixture of tetrahydrofuran and diethyl ether wlrdj P. 156-158 ⁰ C. The compound is identical with the product of Example 5 "

Example "8

7ß-ZZD-ZT (2-amino-1,2-dioxoethyl) -aminoy ^ -thienylacetyl / amino7-3-ZZ (1-methyl-1H-tetrazol-5-yl) -thio7-methy17-3-oxo-5 -thia-l-azabicyclo ^ .2 .C ^ oct ^ -en ^ -carboxylic acid potassium salt

The product from Example 5 is reacted with an equimolar aqueous solution of potassium bicarbonate. The title compound is obtained as a brownish powder from P. 17 * 1 to 175 ^° C.

Example 9 7ß-Amino-3-Z "/ f (1-methyl-1H-tetrazol-5-yl) -thio7-methy 17-8-oxo-5-thia-1-azabicycloZ ¹ i.2.07oct-2- en-2-carboxylic acid

A suspension of 27.2 g (0.1 mole) of 7-aminocephalosporanic acid in 150 ml of acetone and 100 ml of water is treated under stirring at 0 to 5 ⁰ C and 50 ml of 2N sodium hydroxide solution. The pH should remain below 8.5. A solution of 12.7 g (0.11 mol) of 1-methyl-5-mercapto-1H-tetrazole in 50 ml of 2N sodium hydroxide solution is then added and the mixture is warmed to room temperature. The mixture is then stirred with further 3

^fs hours under nitrogen as protective gas to 6Q ⁰ O sle heated by ^. ^ entiichs adding v-sräünntep sodium hydroxide solution, the pH vjird ° We2 * t

set to 7 to 7.5. After that, the mixture is placed in an ice water bath cooled and adjusted to a pH of 3.9 with 3N hydrochloric acid while stirring. The mixture is left for an additional 15 minutes touched. The resulting precipitate is filtered off with water

'5 washed and acetone and finally dried. It will be 18.4 g obtained the title compound as a powder.

Example 10

7β-Amino-3-ZZ (1-methyl-1H-tetra2ol-5-yl) -thioJ-methyl7-8-oxo-5-thia-1-azabicycloZ? I .2.Q7oct-2-en-2-carboxylic acid diphenyl ester

A mixture of 16.4 g (0.05 mol) of the compound prepared according to Example 9, 10.3 (0.054 mol) of p-toluenesulfonic acid monohydrate, 350 ml of dioxane dehydrated from basic aluminum oxide and anhydrous methanol is used as a protective gas for 30 minutes under nitrogen stirred at room temperature. The clear solution obtained is then evaporated. Remaining water and methanol are separated off by 4 times evaporation of 100 ml quantities of dioxane. The residue is mixed with 300 ml of fresh dioxane and then with a solution of 19.4 g (0.10 mol) of crystalline Diphsnyldiazomethan in 150 ml of anhydrous dimethoxyethane. The mixture is first shaken vigorously for 10 to 15 minutes and then stirred for 3 hours at room temperature. After adding 25 ml of methanol, the resulting red solution is stirred until the color has turned yellow-orange, then the solvents are distilled off under reduced pressure. The residue is mixed with ¹ JOO ml of methylene chloride and a solution of 20 g KpHPO ^ in 250 ml of water The i'Iethylenchloridschicht is washed with water and saturated sodium = · brine and? 'Lagnesiumsulfat dried The solvent is distilled under reduced pressure _a the The residue obtained is digested with diethyl ether. 27 g of a solid are obtained. Column chromatography of this solid on silica gel with chloroform and then with a mixture of ethyl acetate and chloroform (4 si) as the eluent gives the title compound after evaporation of the eluate

80 9 8 37/0673

binding as residue, yield 12.9 g. Treatment of the raw product with ethyl acetate gives 4.8 g of the title compound as light yellow powder.

5 Example 11

DL - # - £ (2-ethoxy-1,2-dioxoethyl) -amino_7-phenylacetic acid diphenylmethyl ester

Example 1 is made with DL-ic-aminophenyl acetic acid diphenylmethyl ester repeated. The title compound is obtained as a viscous colorless oil.

Example 12

DL-C / - ^ 2-Amino-1,2-dioxoethyl) -amino-7-phenylacetic acid diphenylmethyl ester

A mixture of 10 mmol of DL- (V-TC 2-ethoxy-1,2-dioxoethyl) -aminoj-phenylacetic acid diphenylethyl ester in 50 ml of ethanol which contains 13 mmol of ammonia is stirred for 15 minutes. After a short time, a thick slurry of the title compound forms. The Tite compound is filtered off and recrystallized from toluene. The compound crystallizes in white threads with a temperature of 168 ^° C.

25 Example 1.3.

DIj-CX'-Zr (2-amino-1,2-dioxoethyl) -amino.7-phenylacetic acid

13 g of the compound prepared according to Example 12 is introduced into 250 ml of a 6N solution of hydrogen chloride in glacial acetic acid, After stirring for 15 minutes, everything went into solution. The resulting solution is evaporated at room temperature. The white crystalline residue is digested with diethyl ether. The crystals are suctioned off and recrystallized from water, It becomes the title compound in white crystals of P, 193 ° C

³⁵ received.

809837/0673

1 example l4

1 & -C / DL-ZI 2-Amino-1,2-dioxoethyl) -amino7-pheny Iacetyl7-amino7-3-r / ^ l-methyl-lH-tetrazol-5-yl) -thioj-methy 17-8- Oxo-5-thia-lazabicycloZTi .2.07oct-2-en-2-carboxylic acid diphenylmethyl ester

According to Example 4, 1.85 g (7.5 mmol) DL - # - / ~ (2-Amino-1,2-ciioxoethyl) -amino_7-phenylessio; acid with ethyl chloroformate and then with 7-amino-3-Z "Z" (1-raethyl-1H-tetrazol-5-yl) thioJ-methylJ-cephalosporanic acid diphenylmethyl ester converted to the title compound. The link falls as a light brown
Powder from P. 146 ° C.

Example 15

7S- / ZSIi- £ "(2-amino-1,2-dioxoethyl) -amino_7-phenylacetyl7-amino_7-3-ZZ" (1-methyl-1xH-tetrazol-5-yl) -thio7-ynethyl7-8-oxo -5-thia-l- azabicyclo / ?! .2.07oct-2-en-2-carboxylic acid

The compound prepared according to Example I ^ is reacted with trifluoroacetic acid and anisole according to Example 5. It becomes the title compound as a light brown powder with a melting point of 153 ° C
(Decomp.) Obtained.

The sodium salt is produced as a light yellow powder by freeze drying an equimolar aqueous solution of the title compound and sodium bicarbonate; M.p. 175 ° C (decomp.

3example 1 6 "

DL- (X- ^ "(ethoxy-1,2-dioxoethyl)» amino7-2 ~ for uranesic acid diphenyl methyl ester

Example 1 is repeated with 2-DL-furylglycine diphenylmethyl ester. The title compound is obtained as a colorless oil in 5 seconds
that does not crystallize ₀

1 example 7

DL- (X- / Γ (2-amino-1,2-dioxoethyl) -amino7-2-furanacetic acid diphenyl methyl ester

Example 12 2--aminoJ-furanessigsäurediphenylmethylester repeated with DL-0i-Z "(ethoxy-l, 2-dioxoethyl). After recrystallization from toluene, the title compound as white crystals. From? 163 to 17O ⁰ C is obtained.

10 Example 8

DL- (X- £ 12-amino-1,2-dioxoethyl) -amino7-2-furanacetic acid

Example 13 is repeated with DLWX- ^ 2-amino-1,2-dioxoethyl) -amino7-2-furanessi ~ acid diphenylmethyl ester. There is obtained the title compound as white crystals melting at 17 ¹ J ⁰ C after recrystallization from water.

Example 19

(oR-trans) -7-ZTDL-ZX2-amino-1,2-dioxoethyl) -amino7-2-furanylacetyl7-amino7-3-Z "> ai-methyl-1H-tetrazol-5-yl) -thio7-methyl7 - 3-oxo-5-thia-1-azabicycloZ7l.2, Q7oct-2-en-2-carboxylic acid diphenylmethyl ester

Example 4 is carried out with DL- (X-ZT (2-amino-1,2-dioxoethyl) -amino7-2-furanacetic acid repeated. The title compound is obtained as a light yellow powder from E. 31 ° C. (decomp.).

Example 20

(oR-trans) -7- £ fOL- £ { 2-amino-1,2-dioxoethyl) -amino7-2-furanylacetyl7-amino7-3-Z7 "(l-methyl-lH-tetrazol-5-yl) - thio7-methy] J- 8-oxo-5-thia-1-azabicycloZ7 ».2.0joct-2-en-2-carboxylic acid

Example 5 is repeated with the compound prepared according to Example 19. There is obtained the title compound as a pale yellow powder, melting at 154 ⁰ C (dec ₀₎

L J

The sodium salt according to Example "prepared 15 It is a light yellow powder from P, 171 ⁰ C (dec.).

Example 21

5 L - # - ZT 2-amino-1, 2-dioxoethyl) -aminoZ-thiophenacetic acid diphenylmethyl ester

a) A suspension of 3.5 g (10 mmol) of o-thienylglycine diphenylmethyl ester hydrochloride in 50 ml of a mixture of carbon tetrachloride and methylene chloride (2: 1) is with 1.2 g (10 mmol) of oxalyl chloride are added. Nitrogen is passed into the mixture at 35 ° C. with stirring until it is clear Solution is obtained. The greenish colored reaction solution containing the L-of - / "(2-chloro-1,2-dioxoethyl) -ami'noj-thiophenessigsäurediphenylmethylester contains, is decolorized with activated charcoal and used immediately in the next stage.

b) The reaction solution from step (a) is added dropwise to a cooled to -20 ⁰ C solution of iOmMol ammonia and 10 mmol of dimethylaniline in 500 ml of methylene chloride. After the addition has ended, the reaction mixture is stirred for a further 15 minutes, then washed with 100 ml v / ater, 100 ml 2N hydrochloric acid and again with 100 ml water, dried and evaporated. The residue is recrystallized from ethanol and then from toluene

the title compound is obtained in white crystals from P. 157 to 16O ⁰ C; CoQ ^ = + 59.0 ° (1 % in methylene chloride).

Example 22

L- (X-ZT 2-Amino-1,2-dioxoethyl) -amino7-2-thiophenacetic acid 30th

The compound produced according to Example 21 is according to Bei =. game 12 implemented with ammonia. The title compound is obtained from P. 140 to 14 ° C; ßxj ^ ⁰ = + 152 ° (1 % in tetra =

hydrofuran).
35

809837/0873

¹ example -23:

7β- ^ LT (2-amino-1,2-dioxoethyl) -amino7-2-thienylacetyl7-amino7-3-TZr (1-methyl-1H-tetrazol-5-yl) -thioJ-methyl7-8-oxo-1 -aza-

bicycloZ ¹ * .2.Q7oct-2-en-2-carboxylic acid 5

Example 4 is repeated with L- (V- / C (2-amino-1,2-dioxoethyl) -amino7-2-thiophenacetic acid. The product is recrystallized from isopropanol. The 7 & -ZTL-ZX2-amino-1, 2-dioxoethyl) -amino7'-2-thienylacetyl7-amine Q7-3-Z7r (1-methyl-1H-tetrazol-5-yl) -thio_7-methy 17-8-oxo-1-azabicyclo ^ .2, Q7oct -2-ene-2-carboxylic acid as pale yellow powder, melting at 94 ⁰ C (dec.). This compound is reacted according to Example 5 to give the title compound, melting at 150 ⁰ C (dec.). The sodium salt is prepared according to Example 15; F. 167 to 170 ⁰ C

¹⁵ (dec.).

Examples 24 to 75

According to Example 7 ₄ but using the acylating agents A listed below with the substituents listed in the table (which has been prepared according to Examples 1 to 3 and 6) with the 7β-aminocephalosporanic acid compound B listed below, the product C is obtained. Any protective groups and ester groups present are split off as in Example 5 or 7. The salts are according to

²⁵ Example 8 produced.

809837/0673

R ₁ -CH-COOH

¹ !

NH

C = O I C = O

COOR

NH-R.

20th

O h

R ₁ -CH-C-NH- ¹ I.
NH

U <

C = O

NH-R_

COOR

SB 3 7 / υ ο

cn

2— { 2 -

2-U

2- U

cn ι CO I

PS I W

-μ

cn EC α U O O I. 1

F = K

co

- /

co

Οι

N)

cn

cn

example

28

co 29 CD CD OO co O CD 30th

31

U-

O-

-OH.

-CH ₂ CCl ₃

CH.

^C 2 ^H 5

II

N ^<

CH.

N-

N
I.

CH.

N-

-4

-N

Il

, N

Il

.N

N '

^C 2 ^H 5

-s JP)

N
O

OO O CXJ CD

cn

, Z = Z

• ζ - ζ

\ ^M

^x te z — u

te

cn ι

ζ- ζ

TO

cn ι

10

ρΓ \ te

ιη

ro

15th

in

U I

20th

25th

CN pi

ro

te

U O

ro

U O I

30th

1 (Q) @

-f

35

L

r-J •H

CQ •H

CQ

CN

ro ro 809837/0673

in ro

VO

ro

O
OI ω
ο ^ o example 37 38

Ι3
cn

to

cn

^C 2 ^H 5

~ 0
Il
-OC-GH

-NS.

39

O)-

-OH.

-OCONH

■ 40

O-

-OH.

ONH,

N N

I Ί

-S —ι «

<X> CD

X I

υ ο

53 -

ro

TO

JS ί

cn ι

cn

cn ι

Ο — U

K U

I U)

O I

σ \

in

CN

Co

(ο)

Ι <Ν

CTl

K U

in

CJ

Z I

υ ο ι

O?

ιη

U I

LOj

• Η

«Η 0) 03

809837/0673

co cn

IV)

cn

ro ο

Oil

cn

example

50

OQ
SjJ

51

53

5 4 55

-OH.

-OH

-OH

-CH

-S-

H
-OH.

N
Il

N
Il
N

Ii
0-C-CH.

35

η E U

O-U Xl?

TO

cn

ro

z = A 2 - \

Z =

cn ι

ζ -

cn ι

20th

Pi I

25th

(N Pi I E

ro E U O I

CNJ

JL, -4

η (ο) D O4

Φ • Η

P. to

! 33

in in

CT

in

ι-4 VO

809837/06?

25th

CN

- 35 -

cn ι

- ζ

S-U

C / 5 I.

S-ι

cn

co

ro

15th

20th

CN

U I.

U U I O

ta

CN

U ι

30th

Oj

35

Φ • Η Q to

ro

09837/06?

- .50 -

- 2

S2-CJ

E U

cn ι

- 2 Ln

(N

2-U

ro

CN

PJ

E. U I.

(q:

OJ

frt

'■ -} i

co

P 'S ^' "^ C)

! a Lf S Ö

0 Ii S

10

35

- 37 -

- LP

υ cn

co

co

X

-

U I.

co

2-U

2-

CO

20th

ro S.

ro η

• Η CO

25th

(N

pi U O

30th

03

• Η

α)

CN

809837/0673

The acylating agent A can be in either the D or L form or as a DL isomer mixture.

Example 7o ⁵ £ (cyanometnyl) -aminoj-oxoacetyl chloride

A solution of 20 mmol of cyanomethylamine hydrochloride and 25 mmoles of oxalyl chloride in 100 rnliol anhydrous dioxane is heated at 60 to 70 ⁰ C. At the same time, nitrogen is passed through the solution. After 1 hour a clear solution is obtained and there is no longer any hydrogen chloride in the nitrogen flowing off. The solvent is distilled off under reduced pressure, and the remaining light brown oil in methylene chloride aufgenon-hem, filtered through activated charcoal and at -30 ⁰ C until

15 Use retained.

Example 77 D-0- £ Z7TCyanomethyl) aniineQ7-oxoacetyl7-amino7-2-thiophene acetic acid

acid diphenylmethyl ester 20th

A solution of 10 nmoles of 2-D-thienylglycine diphenylmethyl ester in 20 ml of methylene chloride is mixed with 10 mmoles of dimethylaniline. Then half of the product is dropped from Example 76 at -20 ⁰ C under stirring. After 30 minutes, the reaction solution is washed first with 50 ml of 1N hydrochloric acid and then with 50 ml of water. After drying over sodium sulfate, the solution is evaporated. A viscous yellow mass remains which solidifies on digestion with diethyl ether. The product is recrystallized from a little ethanol. The title compound is obtained in white crystals and in a yield of 63 % of theory; F. 160 to 16 ° C.

Example 78

D-CS ('- Z7Z "(cyanomethyl) -amino7-oxoacetyl_7-amino7-2-thiophenacetic acid

L _J

809837/0673

The compound prepared according to Example 77 is ^{treated with trifluoroacetic acid and anisole (1} I; 1). The titanium compound is obtained in 7 ^ percent yield. After recrystallization from anhydrous ethanol, white crystals become

• 5 from?. 199 to 2OO ° C obtained.

Example 79

7-3-Z "Z ^ -Z." / R2- <C (CyanoTn9thyl) -amino7-1,2-dioxoethyI / -amine§-2 « thienylacetyl7-amino7-3- / T (l-ynethyl - lH-tetrazol ™ 5-yl) -thio7 » nethyLZ-B-oxo-i-thiä-l-azabicyclo A. 2.Q7oct-2-en-2 ~ carbon = acid

A solution of 10 mmol of V-OC-CC (X cyanomethyl) ~ amino7 = oxo = acetyl7-amino7-2-thiophenacetic acid and 10 mmol of triethylamine in 100 ml of tetrahydrofuran is cooled to = 5 ° C and slowly added dropwise with a solution of 10 mmol Ethyl chloroformate in tetrahydrofuran added. After 20 minutes of reaction, a solution of 10 mmol of 7 "amino-2 = zT £ (1-methyllH-tetrazol-5-yl) -thio7-methy17-cephalosporanic acid diphenylmethyl ester in tetrahydrofuran is added -5 ⁰ C and lstündigem stirring at room temperature, di-3 eingedamnft solution under reduced pressure and the back = stand-in methylene chloride and water was added ,, the organ! = see phase is washed with 2N phosphoric acid and water _a ge "dries j Treated activated charcoal and evaporated. The 7-S = CCD-CC2-C ( cyanomethyl) -amino7 = 1 _s 2-dioxoeth; / l7-amino7- = 2 »thienylacetyl7 = -amino7 ~ 3-Z77 (l -niethyl = 1H = tetra = zol-5-yl) -thio7-methyl7 = '3 = oxo = 5 = thia = 1 = azabicycloAo2oa7oct = 2-en = 2 = car'oons acid diphenylmethyl ester as a solid brown foam ο Treatment of the product with trifluoroacetic acid and anisole (4 % 1) gives the title compound in the form of a "! IgeIben? ul \ ^?" ers ₃ which is recrystallized from a mixture of isopropanol and ethyl acetate. Po 15 ¹ I ⁰ C ₀

r. ^ *> Qnoc / ο ~ ι

1 3game S0

7-3- / 72 - ^ / 2- ^ Cyanonethy!) - ard.no7-l, 2-dioxoethyl7-aninq7-2-tr ^ enylac3tyl7-a: iiino7-3-ZZU-rnethyl-lH-tetrazole-5- yl) -thio7-nethyl7-3-oxo-5-tnia-1-azabicyclo, / Ti. 2.07oct-2-en-2-carbon-

5 acid

A suspension of 10 n.'icl 7 ^ -Aniino-3- ^ ZTl-niethyl-1H-tetrazol-5-yl) -thio7-niethy 17-3-oxo-5-thia-1-azabicyclo Z ⁷ J. 2.07 oct-2-sn-2-carboxylic acid 9-trifluoroacetate in acetonitrile is mixed with 3 nil 3is- (trimethylsilyl) -acetamide and 15 mKol propylene oxide. A clear solution is obtained within a few minutes. The solution is ^{cooled to 0} ° C. and a solution of 12 πΓ-iol chloroxoacetic acid cyanomethylamide in methylene chloride is added dropwise. The mixture is stirred for 1 hour.

The solvent is then distilled off under reduced pressure. The residue is stirred for 1 hour in 300 ml of ethyl acetate and 50 ml barrels. The organic phase is then dried, treated with activated charcoal and evaporated to 30 ml. The title compound crystallizes out in the process. The mother liquor is poured into diethyl ether. A further amount of the title compound precipitates out. 153 to 155 ° C

3eis? Iel 81

73-ZZD-Z "ZT2-r (Cyanoniethyl) -amino7-1,2-dioxoethyl7-amino7-2-thienylac9tyl7-amino7-3- / ZXl-methyl-1H-tetrazol-5-yl) -thio7- methyl7-3-oxo-5-thia-l-azabicyclo ^. 2.07oct-2-en-2-carboxylic acid sodium al ζ

An equimolar mixture of the aqueous solution of the compound prepared according to Example 79 or 30 and sodium bicarbonate is freeze-dried. There is obtained the title compound as a pale yellow powder, melting at 173 ⁰ C (dec.).

Examples 32 to 14 5

Example 79 is carried out using the acylation agents listed below Λ with those listed in the table below

^L 809837/0673

_ αϊ - & © Uöo43

• j substituents repeated. The acylating agent A is prepared according to Examples 70 to 73. In the reaction with the 7β-aminohalosporanic acid compound B, the product C ₀ is obtained. Any protective groups and ester groups present are split off from Example 79. The salts are prepared according to Bei soiei 31.

L -J

809837/0673

R ₁ -CH-COOH I NH I C = O I C = O

COOR

NO_

CEN Λ

H R ₁ -CH-C-NH-

¹ I.

NH

C = O

C = O

NO,

CH ₂ -X

COOR

R ₄ -CR ₅ C £ N

809837/0673

- H 3 -

ro U

Z - =

^ 2

Y '

cn

S3- U

vi

σ \

IC U

(N

ffi

U I

U O I

ro

υ ο ι

ai

cn

CN OO

ro oo

809837/0673

ο-ύ

O I

-

* 7 - ~ *

\ I.
co
I. K I. co
I. \ te 2 - O I. 2 -O 2

= 2

\ te

2-O

co

2 ~ 2 I ^

\ ^E CN

2 -U

• co

in I.

CN

CN

U I

τα υ

IT)

CN

U U

CN

te

U I

¹ b-

co

co

H (D • H D. W

oo

ΓΟΟ

OO OO

CTi

co

(Ti

809837/0673

30th

CN

20th

CN

25th

rc)
Z

υ ι

U O

χ ι

2 =

cn ι

—CJ

CO I.

I U

ι O

10

IT)

CN

CJ

15th

ffi ro

te

¹ ^!

= A

p. to

• Η

a>

CN CTl

ro cn

809837/0673

CTl

in

CTl

2- U

ro

ro

co

O =

a; Γ0 U I. U O = U I. I. CJ O I. I. O I.

ro

cn
ι

2 O U O I

OJ (^ U.

in pi

in

U U U U I. r I.

CN

U I

CMl

pi

U O I

U O

—Λ

tr

co

VO

approx σ> O fH CN cn CTl CTi O O O .H .H

809837/0673

K U

co

BW 8

2: zr

Ζ— U
Z- 2

pi I κ

ro i I

U I

20th

25th

OS

CJ

(Ti

CN

U X I. U I.

CN

(N X CJ

CN

pi I κ

30th

35

ro • Η O
D. to α τ

m ο

CXJ

809837/0673

U I

O-U ι

O I

- = ζ

I cn

W I

CN

■ Z- U

Z = /

in

r - SJ

ro U

33

33

pi

U \

CTi

33 U

33

CN

33

33

CN

CoJ

33 U

CN

ro

33

33

33

ro

U O I

U O I

30th

in 33

CN U

Co)

35

r- \
(U

•H
OW

"H

d)

CQ

(Ti O

O r-l

OJ

ro r-l r-)

809837/0673

co cn

co ο

ro cn

ro ο

cn

For example

116

117

118

119

120

S ''

-OH.

-CH _ (<g

R.

-Ci

Ii
-0-C-CH.

II -0-C-CH.

_ C

N N

121

122

2'2

N N

-s-

Ί CH

N · N

Il j!

" ³ ^ o -

PO 00 O CX) CT)

■ ο-

x:

Cfl

cn

• Ζ- =.

\ S I ZG

- 2

TO

cn ι

2 - ~ ι

CO

CTv

U ι

Ci

CQ)

CJ

C-I

te

O I

CMl

K i

U O I

O U

P. CO • Η α ·· cc

ro

CN

CN

LD CN

CN

809837/0673

ORIGINAL

X I

-υ

cn

- 51 -

ro

cn ι

in

JZ-CJ

cn ι

in pi

ro
pi

rg

ro U

PS I

Oj

U I

(N

<N Pi

PS

O U

ro

ffi

L = J CJ
O
I.

• Η ρ w • Η (U VQ

co

(N

r-l

O ro rl

809837/0673

ro

LT)

- ζ

U O \ ^s - ^s \ Z— 2 \ U
I. W. / co I. U) I. cn Cf) I. I.

TO

: - J

ιη

U ί

CN

U I

E U

• Η Ui

U O

O E

ρ CN m cn in η to η η •H ■ Η (U (T,

80 9837/0673

CN

CN

2 O O O I.

2 ο υ ο ι

O O

TO

\ ™

to

CN

- e.g.

U ι

O O Z-U

CO-U

CO
I.

co

W • Η α> CQ

C »

809837/0673

32 U ο O cn

2 -

<N

cn-u

te

- U

1 Z -

Z-

TO

10

in
pi

15 20 25 30

roi

Pi I

CN

cn ι

cn ι

35

• Η
Q

O)

cn

809837/0673

_i

1 The acylating agent A can either be in the D or L form or as a DL mixture.

L J

809837/067 3

Claims (1)

5. US: K 605 (Ya / ko) - "-Cases ^{1 year} CHEZ-EESGHE FiQEIE VOM HEYBEEi, S.m.b.H 8 leinenen 19, Yolkartstrasse Priority: 3/10/1977 * ¥ .St.A., Mr. 15th / Si 1. JSi-Ii Z-JiEiino-l, 2-diosoeth ^ I) -arainoj-aeyl cephalosporine of the allcensinam formula I 25th -CH-C-I ° C = O C = O CD in the H one hydrogen atom, one never its alkali radical, one Paeaj-I-nieaer-alkylresfc, a mphemyl-isledep-alkyl radical, a irl-C-lower-alk ^ D-silyl radical, a 1! ri-C-lower-alfejl) -stannyl radical or a Trihaogenetlaylgniippe or a Saizbildendes ! 09837/0673 BAD 2808843 Ion, R, a water atom, a lower alkyl radical, a saturated one or unsaturated cycloalkyl radical, one optionally by up to zv, "el halogen atoms, lower alkyl or alkali radicals or Hydra%> 'groups substituted pheny! group, a Ptierrjl-nleder-alkjrlrest or a 2-thlenyl-, 3-th-enyl-, 2-fur ^ l-, 3-furyl, 2-? Yridyl, 3-pyridyl or ^ -pyridyl group, R ^ a / iasserstoffatoiTi or a kethoxy group, Rx is a hydrogen atom, a lower alkyl radical, a piienyl IQ lower-alkyl or cycloalkyl radical and Eg a Ufas se rs to ffat on or a group of the general formula -GH ^ H ₁ --CJi means, where R ^ and R ₁ - represent hydrogen atoms or lower alkyl radicals and X is a hydrogen atom, a lower radical, the group or a carbaaoyloxy group, a lower Älko.x ^ · - or lower Älkjlthiorest or a Srupne of the general formula M - μ Ν— Ε -JLI ₁ -s- ¹ G ^S ~ ^ S ^ R. II - M jf P CH ₂ R ₇ or K s- O -S- *. Ί Ο ι η i ^R 6 - M -S means, where R ^ - a hydrogen atom or a lower one 309837/0673 PAD ÄlKylrest and R ^ a carboxyl group or this group in the Saizfors, a -COO-lower-alkyl-, SO, H-, -SOp-lower-alkyl- or cyano group, and their salts, 2. Compounds according to claim 1 of the general formula I, in FL means a thienyl group " 3. Veroindungen according to claim i of the general formula I, in which H. is a phenyl group. 10 4. Compounds according to claim 1 of the general formula I ₁ in which R. is a furyl group. 5 «compounds according to claim 1 of the general formula I, in which X is a methyltetrazolyl group. D. Compounds according to claim 1 of the general formula I, in which H ₁ , R ~, R ^, Hi. and Rj- represent hydrogen atoms. 7. Compounds according to claim 1 of the general formula I, in which R is a -tfassstoffatom or an alkali metal cation, R. is a cyclohexadienyl, phenyl, thienyl, furyl or pyridyl group, Rp is a hydrogen atom or a methoxy group, R, , R ₁ . and R_ "represent hydrogen atoms or lower alkyl radicals and ²⁵ X has the meaning given in claim 1. 3. Compounds according to claim 1 of the general formula I, in which R is a hydrogen atom, a sodium or potassium cation, R _{1 is} a phenyl or thienyl group, R _{2 is} a hydrogen atom, R, Place * a v-hydrogen atom or a methyl group, R ₁ . and R ^ are hydrogen atoms and X is an acetoxy or (1-methyl-1H-tetrazol-5-yl) -thio group. 9. Compounds according to claim 1 of the general formula I, in which R, R ₂ , R ,, R ^ and R, - hydrogen atoms, R. a 2-thienyl group and X a (l-methyl-lH-tetrazol-5-yl ) thio group 809837/0673 ca; ο-3- interpret. 10. Compounds according to claim 1 of the general formula I, in which R is a sodium cation, R _?> Fu, K _a and R ₁ . Hydrogen atoms, R "a Z-Ihienvlsrup-ce and X a (l -: - Iethyl-lH-tetrazol-5-yD- -Ir - ^R 6 -S O -i- ^R 6 -S ! 1 S. i V N
[I. ΐ 11. Compounds according to claim 1 of the general formula I in the X is a group of the formula NN?, -, ^N H. ".. _r i ¹ ■ 'ii il N "S ^R 6 i / R _{5 0} denotes, where R- is a hydrogen atom or a CL ^ -alkyl group represents 12. D-isomer of the compound according to claim 1. 13 · D-isomer of the compound according to claim 9t 14. D-13omer of the compound according to claim 10. 15. Intermediate product of the general formula R ₁ -CH-COOH R ₄ NH-CCN-C-C = N | 1 rl i I
OOR ₃ R ₅ in which R., R ,, R ₁ , and R ^ have the meaning given in claim 1, -have. 809837/0673 BADORiGiNAL 808643 lo. Compound according to Claim 15, in which R ₁ , R, Pu and R_ have the meaning given in Claim 7. 17. Compound: according to claim 15, in which R _{1 is} a 2-thienvl- ~ rup ~; - and R _? ,? .. and R signify hydrogen ratios. IS. Intermediate of the general formula ? 4? 3 N ^ c-C-N-C-C-hnl I ii Il 10 R _r OO in the R ^, R ^ and Ρ _{> Ε} . have the meaning given in claim 1 and Hal represents a Halo.cenatom. 19 · Veroinduns according to claim 13, in which R ,, R ₂ . and R _{1 represents} hydrogen stoffator.e or lower alkyl radicals. 20. A compound according to claim 1-3, in which R- ,, R ^. and R ₁ - Wasserotcffato .-. mean and Hai is a chlorinator, 21. Vsrci.idun ^ according to claim i, ir. The R ^ a Hassers to ff- 22. Compound according to claim 1, in which R _{Q is} the group of allr = ~ -iir.3n ror.-ael -0? _; , ^ Ρ ._- 0 :. ^Γ means. 2y. Process for the preparation of the compounds according to claim i, characterized in that a Ceohemverbindunp; of the general formula II 30 ti j .. * -, ^ r ι (H) COOR 35 809 8 37/0673 in the?., ?. ^ ^and ^ - ^ is given in claim 1, or ieran reactive derivative with a carboxylic acid of the general formula III _R CH COOH 5 ^λ \ NH I (in) C = O C = O I _{1 R} 10 ^R 8 ³ in which R ₁ , R, and R -> the meaning given in claim 1 habc-n, or its reactive derivative, and optionally converts the compound obtained into a salt with a 3ase. 2 * 4. Use of the compounds according to claim 1 in the 3eklrr.ofung bacterial infections. ■ η, λ ri i-.Tä; η '.' i F- 5 Lst .'- J - *; ■ "·.: - ν ■ .ί-.t» 809837/0673