EP0000392A2 - Cephalosporins and penicillins, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

β-lactam compounds of the formula I: <IMAGE> Process for their preparation and their use as medicaments, in particular as antimicrobial agents and as agents for promoting the growth and improving the feed conversion in animals. In addition to good compatibility and solubility, the compounds according to the invention have a broad antibacterial effect.

Description

The present invention relates to novel β-lactam compounds, processes for their preparation and their use as medicaments, in particular as antimicrobial agents and as agents for promoting the growth and improving the feed conversion in animals.

It has already become known that certain α- (imidasolidin-2-oxo-1-yl-carbonylamino) -benzylpenieillins are antibacterial (cf. BE-PS 767 647 and 767 648 and DT-OB 2 152 968).

The novel β-lactam antibiotics according to the invention differ chemically from the known compounds of the prior art, above all by the α-position heterocyclic ring in the acyl side chain.

in welcher

• R für Wasserstoff oder Niederalkoxy steht,
• Z für die Gruppen
  
  steht, worin
  • R¹ und _R ² gleich oder verschieden sind und Wasserstoff, gegebenenfalls substituiertes Alkyl oder Alkenyl, gegebenenfalls substituiartes Cycloalkyl, Cycloalkenyl und Cycloalkadienyl, gegebenenfalls substituiertes Aralkyl, gegebenenfalls substituiertes Aryl, gegebenenfalls substituiartes Heterocyclyl, Carboxy, Methoxycarbonyl, Xthoxycarbonyl, Cyano, Nitro, Niedrigalkylcarbonyl, -CONH₂, -CONHCH₃, CON(CH₃)2, -SO₂NH₂, -SO₂-NHCH₃ oder -SO₂N(CH₃)₂ bedeuten
    und
  • R¹ und R² gemeinsam mit dem Kohlenstoffatom, an welches sie gebunden sind, einen 3- bis 7-gliedrigen gesattigten oder ungesättigten carbocyclischen oder heterocyclischen Ring bilden können, welcher substituiert sein kennt
• A für -CH₂-CH₂-, -CH₂-CH₂-CH₂- oder
  
  steht,
• n 1 und 2 ist,
• B für einen gesättigten oder ungesättigten gegebenenfalls substituierten heterocyclischen Ring steht,
• X für S, O, SO, SO₂ oder -CH₂- steht; und
• Y für die Gruppen
  
  steht, in welchen das Kohlenatoffatom, welches die Gruppe -COOE trägt, an das Stickstoffatom des β-Lactamringes gebunden ist und
• T Wasserstoff, Alkyl-CO-0-, Pyridinium, 4-Ctrboxtmidopyridinium, Aminopyridinium, Carbamoyloxy, Asido, Cyano, Hydroxy, die Gruppe -S-Phenyl, welche substituiert sein kann, oder die Gruppe -S-Het bedeutet" in wlecher Het für einen gegebenenfells substituierten heterocyclitehan 5- oder 6-gliedrigen Ring steht;
  und wobei
• E für Wassarstoff, eine pharmazeutisch wedbare Estergruppierung wie z.B. die pivaloylgruppe, ein salsbildendes Kation oder eine geeignete schutsgruppe staht;

wobei diese Verbindungen der Formel I bezüglich des Chirelitätszentrums C in den beiden möglichen R- und S-Konfiguretionen sowie als Gemische der daraus resultierenden Diastereomeren vorliegen können, und wobei die Verbindungen der Formel I, falls Z für die Gruppe

steht und R¹ und R² verschieden sind, bezuglich der Iminogruppe sowohl in der syn-Form als auch in der anti-Form vorliegen können und wobei diese Verbindungen der Formel 1 auch in den verschiedenen Hydretformen vorliegen können,The invention relates to new β-lactam compounds of the formula (I)

in which

• R represents hydrogen or lower alkoxy,
• Z for the groups
  
  stands in what
  • R ¹ and _R ^{2 are} identical or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, methoxycarbonyl, xthoxycarbonyl, cyano, nitro, lower alkylcarbonyl, -CONH ₂ , -CONHCH ₃ , CON (CH ₃ ) 2, -SO ₂ NH ₂ , -SO ₂ -NHCH ₃ or -SO ₂ N (CH ₃ ) ₂ mean
    and
  • R ¹ and R ² together with the carbon atom to which they are attached can form a 3 to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring which is known to be substituted
• A for -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or
  
  stands,
• n is 1 and 2,
• B represents a saturated or unsaturated, optionally substituted heterocyclic ring,
• X represents S, O, SO, SO ₂ or -CH ₂ -; and
• Y for the groups
  
  is in which the carbon atom, which carries the group -COOE, is bound to the nitrogen atom of the β-lactam ring and
• T is hydrogen, alkyl-CO-0-, pyridinium, 4-ctrboxtmidopyridinium, aminopyridinium, carbamoyloxy, asido, cyano, hydroxy, the group -S-phenyl, which can be substituted, or the group -S-Het means "in which Het represents a given fur-substituted heterocyclite 5- or 6-membered ring;
  and where
• E stands for hydrogen, a pharmaceutically applicable ester grouping such as the pivaloyl group, a salsifying cation or a suitable protective group;

where these compounds of the formula I with respect to the chiral center C can be present in the two possible R and S configurations and as mixtures of the resulting diastereomers, and where the compounds of the formula I, if Z for the group

is and R ¹ and R ^{2 are} different, with respect to the imino group, can be both in the syn form and in the anti form, and these compounds of the formula 1 can also be present in the various hydret forms,

in welcher

• R, B,
  
  , X und Y die oben angegebene Bedeutung haben oder deren Salze,

mit Verbindungen der Fermel III

in welcher

• Z und A die oben angegebene Bedautung haben und
• W für Halogene Azid oder eine andere nukleofuge Abgangagruppe steht,

in Gegenwart eines Lösungsmittels und gegebenenfalls eines Säurebindemittels bei Temperaturen von etwa -20^oC bis etwa +50°C umsetzt und die erhaltenen B-Lactam-Antibiotica gegebenenfalls in ihre pharmazeutisch verwendbaren Salze oder Ester überführt oder aus den erhaltenen Salzen gewünschtenfalls die freien Säuren hergestellt.It has also been found that the new β-leetem antibiotic of formula 1 can be obtained when compounds of formula II

in which

• R, B,
  
  , X and Y have the meaning given above or their salts,

with compounds of Fermel III

in which

• Z and A have the above-mentioned condition and
• W represents halogens azide or another nucleofugic leaving group,

in the presence of a solvent and optionally of an acid binder at temperatures of about -20 ^o C to about + 50 ° C, and the B-lactam antibiotics obtained are optionally converted into their pharmaceutically usable salts or esters or, if desired made, the free acids from the resulting salts .

The compounds of formula (I) in which R represents lower alkoxy can also be prepared by alkoxylation of the corresponding hydrogen derivatives (R-H), it being advantageous to use those compounds in the alkoxylation in which E is a suitable protective group.

In addition to being well tolerated and soluble, the compounds according to the invention have a broad antibacterial action, i.e. Effect against several bacterial families in the gram-negative area and against β-lactamase formers. Because of their strong antibacterial properties and because of their ability to improve the growth and feed conversion in animals, the compounds according to the invention thus represent an enrichment of the technology.

If, for example, α-amino-furfurylacetylpenicillin and 1-chlorocarbonyl-3-furfurylideneamino-imidazolidin-2-one are used as starting materials, the course of the reaction can be represented by the following formula:

In the general formulas, the optionally substituted alkyl R ¹ and R ^{2 is} straight-chain or branched alkyl having preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl may be mentioned.

As optionally substituted alkenyl R ¹ and R ² there is straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4, carbon atoms. Examples include substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3). Called butenyl-2.

Optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl R ¹ and R ² is mono-, $ i- and tricyclic and preferably contains 3 to 10, in particular 3, 5 or 6 carbon atoms. Example book selenium optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclobexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, bicyclo- [2.2.1] -heptyl, bicyclo- [2.2.2] -octyl and adasantyl.

Aryl R ¹ and R which are optionally substituted are aryl having preferably 6 to 10 carbon atoms in the aryl part. Substituted phenyl or naphthyl may be mentioned as examples. Substituents in the phenyl ring are in the o, m or p position. The residues are also mentioned.

Is as optionally substituted aralkyl, R ¹ and R ² optionally in the aryl moiety and / or alkyl moiety substituted aralkyl having preferably 6 or 1 _0, in particular 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl moiety wherein the alkyl portion straight-chain or can be branched. Substituted benzyl and phenylethyl may be mentioned as examples.

Optionally substituted heterocyclyl R ¹ and R ² are heteroparaffinic, heteroaromatic and heterooletinic 5- to 7-membered, preferably 5- or 6-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroatoms. Oxygen, sulfur or nitrogen are the heteroatoms. Examples include optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, thinolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxdiasolyl, thiadiazolyl, triasolyl, oxtriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridyl. Tetrahydroturanyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyronyl-2 and -4.

Alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl and aralkyl R ¹ and R ² can carry one or more, preferably 1 to 3, in particular 1 or 2 identical or different radicals R. The radicals R ¹ and R ² mentioned are very particularly preferably unsubstituted or contain a substituent _R ³ _.

Heterocyclyl R ¹ and _R ² can carry one or more, preferably 1 to 3, in particular 1 or 2 identical or different radicals R. Heterocyelyl R ¹ and R ² is very particularly preferably unsubstituted or contains a substituent R ⁴ ,

In the following statements, the term "lower alkyl" means everywhere, also in connection with other atoms or groups (for example lower alkoxy, HCON- (lower alkyl), etc.) straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 Carbon atoms. Examples of optionally substituted methyl, ethyl, n- and i-propyl, n-, i- and t-butyl may be mentioned. "Lower alkyl" can be substituted by 1 to 5, in particular 1 to 3, identical or different halogen atoms, the halogen atoms preferably being fluorine, chlorine and bromine, in particular fluorine and chlorine. Examples include trifluoromethyl, chlorodifluoromethyl, bromomethyl, 2,2,2-trifluoroethyl and pentafluoroethyl.

Guanido, Nitro, Azido, Hydroxy, Niederalkyl-oxy-, vorzugsweise CH₃-O-, C₂H₅-O-, insbesondere CH₃O-, H-CO-0-, Niederalkyl-CO-0-, vorzugsweise CH,-CO-0, C₂H₅-CO-O-, (CH₃)₅C-CO-O-; Niederalkyl-O-CO-0-, vorzugsweise CH₃-O-CO-O-, C₂H₅-O-CO-O-, (CH₃ )₃C-O-CO-O-; H₂N-CO-O-; Niederalkyl-NH-CO-0-, vorzugsweise CH₃ -NH-CO-O-, C.H.-NH-CO-O-, (Niederalkvl),N-CQ-O-, vorzugsweise (CH₃ )₂=N-CO-O-, (C₂H₃)₂N-CO-O-,

H₂ N-SO₂-O-; Niederalkyl-NH-SO₂-O-, vorzugsweise CH₃-NH-SO₂-O-, C₂H₃-NH-SO₂-O-; (Niederalkyl)₂ N-SO₂-O-, vorzugsweise (CH₃ )₂ N-SO₂-O-, (C₂H₃ )₂ N-SO₂-O-; HOOC-, H₂ N-CO-; (Niederalkyl)₂ N-CO-, insbesondere (CH₃ )₂ N-CO- und (C₂H₃)₂ N-CO-; OHC-, HO-SO₂-O-, HS-; Niederalkyl-S-, vorzugsweise CH₃-S-, CF₃-S-, C₂H₃-S-, (CH₃ )₂ CH-S-; Niederalkyl

R ³ preferably denotes halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine; Ataino; Mono-lower alkylamino, preferably methylamino, ethylamino, especially methylamino; Di-lower alkylamino, preferably dimethylamino, diathylamino, especially dimethyladino; Pyrrolidyl; Piperidyl; HCO-NH-; Lower alkyl-CO-NH-, preferably CH ₃ -CO-NH-; H-CO-N (lower alkyl) -, preferably H-CO-N (H ₃ ) -, H-CO-N (C ₂ H ₅ ) -; Lower alkyl-CO-N (lower alkyl) -, preferably CH ₃ -CO-N (CH ₃ ) -; (Lower alkyl) ₂ CN-; Lower alkyl-SO ₂ -NH-, preferably CH ₃ -SO ₂ -NH-, C ₂ H ₅ -SO ₂ -NH-, in particular CH ₃ -SO ₂ -NH-; Hiederalkyl-SO ₂ - H (lower alkyl) -, preferably CH ₃ -SO ₂ -N (CH ₃ ) -; HO-SO ₂ -HH-; HO-SO ₂ -N (lower alkyl) -, preferably HO-S ₂ -N (CH ₃ ) -, HO-SO ₂ -N (C ₂ H ₅ ) -; Amidino; (Lower alkyl) ₂ -N-GH-N-; in particular (CH ₃ ) ₂ N-CH = N-;

Guanido, nitro, azido, hydroxy, lower alkyloxy, preferably CH ₃ -O-, C ₂ H ₅ -O-, in particular CH ₃ O-, H-CO-0-, lower alkyl-CO-0-, preferably CH , -CO-0, C ₂ H ₅ -CO-O-, (CH ₃ ) ₅ C-CO-O-; Lower alkyl-O-CO-0-, preferably CH ₃ -O-CO-O-, C ₂ H ₅ -O-CO-O-, (CH ₃ ) ₃ CO-CO-O-; H ₂ N-CO-O-; Lower alkyl-NH-CO-0-, preferably CH ₃ -NH-CO-O-, CH-NH-CO-O-, (lower alkylene), N-CQ-O-, preferably (CH ₃ ) ₂ = N-CO -O-, (C ₂ H ₃ ) ₂ N-CO-O-,

H ₂ N-SO ₂ -O-; Lower alkyl-NH-SO ₂ -O-, preferably CH ₃ -NH-SO ₂ -O-, C ₂ H ₃ -NH-SO ₂ -O-; (Lower alkyl) ₂ N-SO ₂ -O-, preferably (CH ₃ ) ₂ N-SO ₂ -O-, (C ₂ H ₃ ) ₂ N-SO ₂ -O-; HOOC-, H ₂ N-CO-; (Lower alkyl) ₂ N-CO-, especially (CH ₃ ) ₂ N-CO- and (C ₂ H ₃ ) ₂ N-CO-; OHC-, HO-SO ₂ -O-, HS-; Lower alkyl-S-, preferably CH ₃ -S-, CF ₃ -S-, C ₂ H ₃ -S-, (CH ₃ ) ₂ CH-S-; Lower alkyl

die Gruppe HO-SO₂-S-; geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, insbesondere Methyl, Aethyl, Propyl, Isopropyl, n-Butyl, sekrButyl oder tert.-Butyl, vorzugsweise Methyl; und Phenyl oder Phenoxy.Lower alkyl-SO ₂ -, preferably CH ₃ -SO ₂ -; CF ₃ SO ₂ -, C ₂ H ₃ -SO ₂ -; the group H ₂ N-SO ₂ -; Lower alkyl-NH-SO ₂ -, preferably CH ₃ -NH-SO ₂ -, C ₂ H ₃ -NH-SO ₂ -; (Lower alkyl) ₂ N-SO ₂ -, preferably (CH ₃ ) ₂ N-SO ₂ -, (C ₂ H ₃ ) ₂ N-SO ₂ -;

the group HO-SO ₂ -S-; straight-chain or branched alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, sekr-butyl or tert-butyl, preferably methyl; and phenyl or phenoxy.

In case that R ⁴ is at one or more carbon atoms in the heterocyclyl R ¹ and R ^2, R ⁴ is preferably lower alkyl, vorzugswise methyl, _A is methyl, isopropyl, especially methyl; the group trifluoromethyl; Halogen, preferably fluorine, chlorine, bromine; Amino; Re-alkylamino, preferably CH ₃ -NH-, C ₂ H ₅ -NH-; Diniederlkylamino, preferably (CH ₃ ) ₂ N-, (C ₂ H ₅ ) ₂ N-; formylamino; Acetylamino; CH ₃ -O-CO-NH-, C ₂ H ₅ O-CO-NH-; CH ₃ -SO ₂ -NH-; Hydroxy; Methoxy, athoxy; Methylthio, athlylthio; CH ₃ -SO ₂ -; CH ₃ -SO-; the Groups HOOC-; HO ₃ S-; HCO-; Lower alkyl-CO-, preferably CH ₃ -CO-; Lower alkyl-O-CO-, preferably CH ₃ -O-CO-, C ₂ H ₅ 0-CO-; and -CN.

In the event that R ⁴ in a nitrogen-containing heterocyclyl R ¹ and R ^{2 is} a substituent on one or more nitrogen atoms, R ^{4 is} preferably lower alkyl, preferably methyl, ethyl, propyl, isopropyl, especially methyl and ethyl; the group -C≡ N; -CHO; -COO-lower alkyl, preferably -COO-CH ₃ , -COOC ₂ H ₅ , -COOCH (CH ₃ ) ₂ , -COO-C (CH ₃ ) ₃ ; - ^CO-NH ₂ ; -CO-NH-lower alkyl, preferably -CO-NH-CH ₃ , -CO-NH-C ₂ H ₅ , -CO-NH-CH (CH ₃ ) ₂ ; and -CO-lower alkyl, preferably -CO-CH ₃ , -CO-C ₂ H ₅ , -CO-CH (CH ₃ ) ₂ .

The rings which can be formed by R ¹ and R ² together with the carbon atom to which they are attached are saturated or unsaturated. Unsaturated rings preferably contain 1 or 2 double bonds. The rings can contain 1 or more, preferably 1 or 2, in particular 1 hetero atom or hetero group. Oxygen, sulfur and / or nitrogen may be mentioned as heteroatoms. Examples of hetero groups are the SO ₂ group and the lower alkyl N group, in the case of 6 rings preferably a hetero atom or a hetero group in the 4-position (based on the carbon atom to which R and R ^{2 are} bonded) ) is located. The following are particularly preferred rings:

The rings which are formed by R ¹ and R ² together with the carbon atom to which they are attached can contain one or more, preferably 1 to 3, in particular 1 or 2 identical or different subatituents R ⁵ . R ⁵ is preferably halogen, preferably fluorine, chlorine, bromine; Hydroxy; Lower alkoxy, preferably methoxy and xthoxy; Lower alkylthio, preferably methylthio, ethylthio; Amino; Lower alkylamino, preferably CH ₃ -NH-, C ₂ H ₅ -NH-; Lower alkylamino, preferably dimethylamino and diethylamino; the groups -CN; -COOH; -COOCH ₃ , -COOC ₂ H ₅ ; and straight-chain or branched lower alkyl, preferably methyl and ethyl.

At least one of the radicals R and R ^{2 is} particularly preferably hydrogen.

Z particularly preferably represents the group

enthalten entstehen, wenn dieser Rest bereits in den Verbindungen der Formel III enthalten ist oder können entstehen, wenn in wasserhaltigen Lösungsmitteln gearbeitet wird.

• B steht bevorzugt für einen gesättigten oder ungesättigten, vorzugsweise jedoch ungesättigten, gegebenenfalls substituierten heterocyclischen Rest, der 1 bis 4, vorzugsweise jedoch 1 bis 3 gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Schwefel und/oder Stickstoff enthalten kann.

Compounds which are the radical R ¹ R ²

Contain arise when this residue is already contained in the compounds of formula III or can arise when working in water-based solvents.

• B preferably represents a saturated or unsaturated, but preferably unsaturated, optionally substituted heterocyclic radical which can contain 1 to 4, but preferably 1 to 3 identical or different heteroatoms from the series oxygen, sulfur and / or nitrogen.

⁴-thiazolinyl, Tetrazolyl, Sydnonyl sowie die im'Rahmen dieser Erfindung besonders wertvollen Furyl-Thienyl-, Pyrrolyl-, Thiazolyl-, Isothiazolyl-, Isoxazolyl-und Thiadiazolyl-Reste. Der heterocyclische Rest B kann einen oder mehrere, vorzugsweise 1 bis 2, insbesondere gleiche oder verschiedene Substituenten tragen. Als Substituenten seien beispielhaft Halogen, wie Fluor, Chlor und Brom, vorzugsweise Fluor und Chlor, Alkyl mit 1 bis 6, vorzugsweise 1 bis 4, insbesondere 1 oder 2 Kohlenstoffatomen; Cyano, Sulfo und Methylsulfonyl aufgeführt.Examples of suitable residues of this type are: pyrazolyl, imidazolyl, oxazolyl, oxidazolyl, 2-amino and 2-oxo-

⁴ -thiazolinyl, tetrazolyl, sydnonyl and the furyl-thienyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl and thiadiazolyl radicals which are particularly valuable in the context of this invention. The heterocyclic radical B can carry one or more, preferably 1 to 2, in particular identical or different substituents. Examples of substituents are halogen, such as fluorine, chlorine and bromine, preferably fluorine and chlorine, alkyl having 1 to 6, preferably 1 to 4, in particular 1 or 2, carbon atoms; Cyano, Sulfo and Methylsulfonyl listed.

In the definition of T, alkyl in alkyl-CO-0- preferably denotes alkyl having 1 to 4, in particular 1 or 2, carbon atoms. Examples include methyl and ethyl, with methyl being particularly preferred.

The heterocyclic ring Het in -S-Het (definition of T) consists of 5 or 6 ring members and contains 1 to 4, preferably 1 to 3 identical or different heteroatoms; where the heteroatoms are oxygen, sulfur and nitrogen. the heterocyclic ring is preferably unsaturated and particularly preferably contains 2 double bonds. The heterocyclic ring can contain one or more, preferably 1 or 2, in particular one, substituent. Substituents which may be listed by way of example: halogen, such as fluorine, chlorine and bromine, preferably chlorine and bromine, amino, Niederalkylaetino, di-lower alkylamino, lower alkyl, cycloalkyl ((3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl moiety), _N iederalkyloxy meaning of " Lower alkyl "see above), trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5, in particular 2 or 3 carbon atoms. The following are listed as -S-Het as particularly preferred:

The -S-phenyl radical in the definition of T can carry one or more, preferably 1 to 3, in particular 1 or 2 identical or different substituents, preference being given to those which are listed above as possible substituents for the -S-Het radical .

R in the meaning of lower alkoxy preferably denotes an alkoxy group having 1 to 6, in particular 1 to 4, carbon atoms, but in particular methoxy or ethoxy.

Compounds according to the invention in which C is in the D- - R configuration are very particularly preferred.

All crystal forms and hydrate forms of the compounds of the general formula (I) and their salts according to the invention are equally antibacterial.

Halogen W represents fluorine, chlorine and bromine, preferably bromine or chlorine, in particular chlorine.

Nucleofugic leaving groups in the definition of W are to be understood as meaning all nucleofugic groups commonly used in organic chemistry and, above all, those described in Angewandte Chemie, 81 (1969), page 543.

The compounds of the formula (I) are often obtained in the form of salts during manufacture or can be easily converted into them. The pharmaceutically usable salts of the compounds of the formula (I) are particularly important for use as medicaments.

Pharmaceutically usable salts of the compounds of formula (I) are salts of these compounds with inorganic and organic bases on the acidic carboxyl group or the acidic carboxyl and sulfonic acid groups. All bases normally used in pharmaceutical chemistry, in particular in the chemistry of antibiotics, can be used as bases for this purpose. Examples of inorganic bases are: alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates and alkali metal hydrogen carbonates, such as sodium and potassium hydroxide, calcium and magnesium hydroxide, sodium and potassium carbonate, calcium carbonate, sodium and potassium hydrogen carbonate; Aluminum hydroxide and ammonium hydroxide. Primary, secondary and tertiary aliphatic amines and heterocyclic amines can be used as organic amines. Examples include: di- and tri-lower alkylamines, e.g. B. diethylamine, triethylamine, tri-β-hydroxyethylamine, procain, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-β-phenyl-ethylamine, N-methyl and N-ethylorpholine, 1-ephenamine, dehydroabietylamine, N, N'-bis-dehydroabietylathylenediamine, N-lower alkyl piperidine. So-called basic amino acids such as lysine or arginine can also advantageously be used as bases. Particularly preferred salts are the sodium salts.

• R steht für Wasserstoff oder Methoxy;
• Z steht für die Gruppen
  
  worin
• R wasserstoff bedeutet; und
• n² gegebenenfalls durch Halogen (insbesondere Fluor, Chlor und brom), Alkyl mit 1 bis 4 Kohlenstoffatomen (insbesondere Methyl), Alkoxy mit 1 bis 4 Kohlenstoffatomen, insbesondere Methoxy), Nitro, Cyano, Alkylsulfonyl mit 1 bis 4 hohlenstoffatomen (insbesondere Methylsulfonyl) oder CH₃COC-, substituiertes Phenyl bedeutet oder gegebenenfalls durch Halogen (insbesondere Chlor oder Brom), NO₂, Alkyl oder Alkoxycarbonyl mit 1 bis 4 Kohlenstoffatomen oder CH₃COOCH₂-, vorzugsweise in der 4- oder 5-Stellung substituiertes Furyl oder Thienyl bedeutet, wobei der Furyl- und Thienylring bevorzugt in 2- und 3-Stellung gebunden ist; oder Pyridyl (vorzugsweise Pyridyl-3); oder
  für gegebenenfalls substituiertes, geradkettiges, verzweigtes oder cyclisches Alkyl oder Alkenyl mit bis zu 7 Kohlenstoffatomen, insbesondere für Cyclohexenyl oder Alkyl oder Alkenyl mit bis zu 4 Kohlenstoffatomen steht, wobei die genannten Alkyl- und Alkenylgruppen gegebenenfalls substituiert sind, wobei als vorzugsweise Substituenten Halogen und Alkoxy mit 1 bis 4 Kohlenstoffatomen,insbesondere Methoxy, in Frage kommen; und
• A steht für -CH₂-CH₂-; und
• B steht für Furyl, Thienyl, Pyrrolyl, Imidazolyl, Thiazolyl, Isothiazolyl, Isoxazolyl, Thiadiazolyl und
• Y steht für die Gruppen
  
  wobei
• T für Wasserstoff, -O-CC-CH₃, Hydroxyl oder für gegebenenfalls durch Alkyl mit 1 bis 4 Kohlenstoffatomen oder CF₃ substituiertes Thiadfazolylthio oder Tetrazolylthio steht; und
• C liegt in der b-R-kenfiguration vor;

sowie die Natriumsalzo dieser Verbindungen.Very particularly preferred compounds of formula 1 are those in which the definition of the radicals is as follows:

• R represents hydrogen or methoxy;
• Z stands for the groups
  
  wherein
• R represents hydrogen; and
• n ² optionally by halogen (in particular fluorine, chlorine and bromine), alkyl with 1 to 4 carbon atoms (in particular methyl), alkoxy with 1 to 4 carbon atoms, in particular methoxy), nitro, cyano, alkylsulfonyl with 1 to 4 carbon atoms (in particular methylsulfonyl) or CH ₃ COC-, substituted phenyl or optionally substituted by halogen (in particular chlorine or bromine), NO ₂ , alkyl or alkoxycarbonyl having 1 to 4 carbon atoms or CH ₃ COOCH ₂ -, preferably in the 4- or 5-position furyl or Means thienyl, the furyl and thienyl ring preferably being bonded in the 2- and 3-positions; or pyridyl (preferably pyridyl-3); or
  for optionally substituted, straight-chain, branched or cyclic alkyl or alkenyl with up to 7 carbon atoms, in particular for cyclohexenyl or alkyl or alkenyl having up to 4 carbon atoms, the alkyl and alkenyl groups mentioned being optionally substituted, halogen and alkoxy having 1 to 4 carbon atoms, in particular methoxy, being preferred as substituents; and
• A stands for -CH ₂ -CH ₂ -; and
• B is furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl and
• Y stands for the groups
  
  in which
• T represents hydrogen, -O-CC-CH ₃ , hydroxyl or thiadfazolylthio or tetrazolylthio optionally substituted by alkyl having 1 to 4 carbon atoms or CF ₃ ; and
• C is in the BR configuration;

as well as the sodium salt of these compounds.

The compounds of the general formula II related to the starting compound are already known or can be obtained by known methods.

All crystal forms, hydroforms and salts of the compounds of the general Ferrol II are suitable as Ausgergmaterial for the inventive method.

• 
  -Amino-furfurylacetyl-penicilin, 7-(2-Amino-furfuryl- acetamido-3-aaetoxymethyl-ceph-3-em-4-carbonsäure.

Examples include:

• 
  -Amino-furfurylacetyl-penicilin, 7- (2-amino-furfuryl-acetamido-3-aaetoxymethyl-ceph-3-em-4-carboxylic acid.

Salts of the compounds of the formula II which can be used are preferably salts with bases which are listed as being suitable for salt formation with compounds of the formula I. The sodium salts are particularly preferred.

Die Phosgenierung ist auch ohne vorherige Silylierung direkt in einem inerten organischen Lösungsmittel in Gegenwart einer Base möglich.The compounds of general formula III used as starting materials can be obtained by known methods. You can e.g. B. can be obtained in the following way (see also JACS 78 (1956) 5349):

Phosgenation is also possible without prior silylation directly in an inert organic solvent in the presence of a base.

• 1-Chlorcarbonyl-2-oxo-3-furfurylidenamino-imidazolidin
• 1-Azidocarbonyl-2-oxo-3-furfurylidenamino-imidazolidin
• 1-Chlorcarbonyl-2-oxo-3-crotonylidenamino-imidazolidin

The following may be mentioned as examples of starting compounds of the general formula (II) according to the invention:

• 1-chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine
• 1-azidocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine
• 1-chlorocarbonyl-2-oxo-3-crotonylideneamino-imidazolidine

Those compounds of the general formula (III) in which W is azide are customarily e.g. obtained from the corresponding compounds (III) in which W is halogen by reaction with, for example, alkali metal azides.

The compounds of formula II used as starting materials are known or can be prepared by methods known per se (cf. DOS 2 555 159).

Suitable diluents in the process according to the invention are water and all inert organic solvents, preferably those which are miscible with water. These include especially lower dialkyl ketones, e.g. B. acetone, methyl ethyl ketone, cyclic ether, for example tetrahydrofuran and dioxane; Nitriles, for example acetonitrile; lower dialkylformamides, for example dimethylformamide; lower alkyl alcohols, for example ethanol and isopropanol and dimethyl sulfoxide. These solvents can also be used in mixtures with one another and in any mixtures of one or more of these solvents with water. The process according to the invention can therefore be carried out in the presence of: (a) exclusively water, (b) exclusively one or several organic solvents or (c) water and one or more organic solvents. If a pH measurement is possible during the reaction according to the invention due to the presence of water, the pH of the reaction mixture is preferably kept between 6.5 to 7.5 by adding bases or by using buffer mixtures. However, the process according to the invention can also be carried out very well in another pH range, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. It is also possible to remove the heat in water-immiscible solvents, e.g. B. halogenated hydrocarbons, such as chloroform or methylene chloride, with the addition of organic bases, preferably Miederalkylaminen, z. B. triethylamine, diethylamine or cyclic bases, e.g. B. N-ethyl piperidine. Furthermore, the reaction can be carried out in a mixture of water and a water-immiscible solvent, such as. B. lower alkyl ethers such as diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride; Carbon disulfide; Isobutyl methyl ketone; Esters such as ethyl acetate; perform aromatic hydrocarbons such as benzene, it being advisable to stir vigorously and to adjust the pH by adding a base or using conventional buffer solutions, e.g. B. phosphate, acetate or citrate buffer, between 4.5 and 9.0 or z. B. 2, o and 4.5 to keep. However, the reaction can also be carried out in water alone in the absence of organic solvents in the presence of an organic or inorganic base or with the addition of customary buffer substances.

All acid binders customarily used in the chemistry of antibiotics can be used as acid binders. These include inorganic bases and organic bases, which, for. B. are difficult to acylate due to steric hindrance. Examples of inorganic bases include sodium and potassium hydroxide. Practically all open-chain or cyclic ones which are difficult or difficult to acylate come as organic bases Amines and also heteroaromatic bases in question. Examples of bases which may be mentioned are tertiary amines, preferably lower alkylamines, for example triethylamine and / or cyclic bases, for example pyridine, and dicyclohexylamine as secondary amine which is difficult to acylate.

In the process according to the invention, the addition of a base is only necessary if acidic compounds are formed during the reaction, e.g. in the case where W is halogen or azide.

The reaction temperatures can be varied within a wide range. Generally one works between about -20 ° C and about + 50 ° C, preferably between 0 and + 20 ° C. As with most chemical reactions, higher or lower temperatures can in principle be used.

The reaction can be carried out under normal pressure, but also under reduced or elevated pressure. Generally one works at normal pressure.

When carrying out the process according to the invention, the proportions of the reactants of the formulas (II) and (III) can be varied within wide limits without the result being adversely affected. The starting materials can e.g. are reacted with one another in equimolecular amounts. However, it may be expedient to use one of the two reactants in excess in order to facilitate the purification or purification of the desired penicillin and to increase the yield.

For example, you can use the reactants of the general formula II with an excess of 0.1 to 0.3 mol _d equivalents and thereby achieve a lower decomposition of the reactants of the general formula III in a water-containing solvent mixture. The excess of the reactants of the general formula II can be easily removed because of the good solubility in aqueous mineral acids when working up the reaction mixture.

On the other hand, it is also advantageous to use the reactants of general formula III with an excess of, for example, 0.1 to 1.0 molar equivalents. As a result, the reactants of the general formula II Lesser are used and the decomposition of the reactants of the general formula III taking place as a side reaction in water-containing solvents is compensated. Since the compounds of the general formula III added in excess quickly convert into neutral nitrogen-containing heterocycles in water which can be easily removed, the purity of the antibiotics is hardly impaired thereby.

The amount of bases that may be used is e.g. B. determined by the required compliance with a certain pH. Where there is no pH measurement and adjustment, or because of the lack of sufficient amounts of water in the diluent, it is not possible or is not reasonable, 2 molar equivalents of base are preferably added.

The reaction batches for the preparation of the compounds according to the invention and their salts are worked up in the manner generally known for these bodies. Also the isolation and purification of the compounds according to the invention and the release of the free acids from salts or the conversion of the free acids into salts are carried out according to generally accepted methods of organic chemistry, which are familiar to any person skilled in the art.

Alternatively, the compounds of formula (I) in which R denotes lower alkoxy can also be obtained by alkoxylation of the corresponding hydrogen derivatives (RH), where E denotes a suitable protective group such as an easily removable ester-forming group, an acetoxymethyl group, the cationic radical of a base, preferably one Alkali or alkaline earth metal hydroxide or hydrogen.

In this process, an 8-lactam compound of the formula (I) in which R is hydrogen is introduced with 2-10 X equivalents per equivalent of B-lactam compound of a base in the presence of an excess of an alcohol of the formula R'OH the R 'denotes lower alkyl in an inert organic solvent, adds between about 1 to about 8 equivalents of an N-halogenating agent and isolates the compound of the formula (I) in which R denotes lower alkoxy, optionally after prior splitting off of the acid protecting group, top transfer into a Salt or a pharmaceutically usable ester isolated.

In this process according to the invention, compounds which transmit positive chlorine, such as t-butyl hypochlorite or chloroacetamide, are preferably used as the N-halogenating agent.

Suitable bases are complex and simple, but preferably simple, alkali and alkaline earth hydrides, organometallic compounds and Grignard compounds. Examples include: lithium hydride, sodium hydride, butyl lithium, phenyl lithium, alkyl magnesium bromide, for example methyl magnesium bromide, or other known acid binders such as alkali and alkaline earth metal alcoholates or carbonates, alkali and alkaline earth metal bicarbonates or oxides such as sodium carbonate or other acid binders such as borax or open-chain or cyclic organic bases such as trialkyl or aralkylamines or cyclic amidines such as 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (DBN) or 2,3,4,6,7,8,9,10-octahydro-pyrimido [1,2-a] azepine (DBU).

Suitable solvents are, for example, open-chain or cyclic ethers, aliphatic and aromatic hydrocarbons or halogenated hydrocarbons or the alcohols R'OH. Tetrahydrofuran is particularly suitable.

The reaction temperatures should be kept below 0 ° C, preferably between -70 ° C and -45 ° C.

The compounds of general formula 1 are in the form of the free acid both crystalline and amorphous and both anhydrous and in different hydrate forums in the same way antibacterial. The compounds of general formula I are also in the form of their salts, e.g. B. sodium salts, both crystalline and amorphous and both anhydrous and hydrous, for example as a hydrate, antibacterial in the same way

Examples of new active substances are (formulas (IV) to (VII)

With low toxicity, the active compounds according to the invention have a strong and broad antimicrobial activity. These properties enable their use as chemotherapeutic agents in medicine and as substances for the preservation of inorganic and organic materials, in particular of all kinds of organic materials, e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

The active compounds according to the invention are active against a very broad spectrum of microorganisms. With their help, Eram-negative and gram-positive bacteria and bacteria-like microorganisms can be fought and all diseases caused by these pathogens prevented, improved and / or cured.

The active compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

• Micrococcaceae, wie Staphylokokken, z.B. Staphylococcus aureus, Staph.epidermidis, Staph.aerogenes und Gaffkya tetragena (Staph. = Staphylococcus);
• Lactobacteriaceae, wie Streptokokken, z.B. Streptococcus pyogenes, α-bzw. β-hämolysierende Streptokokken, nicht (γ-)-hämolysierende Streptokokken, Str.viridans, Str. faecalis (Enterokokken), Str.agalactiae, Str.lactis, Str.equi, Str.anaerobie und Diplococcus pneumoniae (Pneumokokken) (Str. = Streptococcus);
• Neisseriacsae, wie Neisserie, z.B. Neisseria gonorrhocea. (Conokokken), N.seningitidia (Meningokokken), N.catarrhalis und N.flava (N. = Neisseria);
• Corynebacteriaceae, wie Corynebakterien, z.B. çorynebacterium diphtheriae, C.pyogenes, C.diphtheroidea, C.acnes, C.parvum, C.bovis, C.renale, C.ovis, C.muri- septicum.
• Mycobacteriaceae, wie Erreger von Mykobakteriosen, z.B. Mycobacterium tuberculosis, M.bovis, M.avium, sogenannte atypische Mykobakterien der Runyon-Gruppen I, II, III und IV, M.leprae (M. = Mycobacterium);
• Enterobacteriaceae, wie Escherichiae-Bakterien der Coli-Gruppe: Escherichia-Bakterien, z.B. Escherichia coli, Enterobacter-Bakterien, z.B. E.aerogenes, E.cloacae, Klebsiella-Bakterien, z.B. K.pneusoniae, K.pneumoniae, K.ozaenae, Erwiniae, z.B. Erwinia spec., Serratia, z.B. Serratia marcescens (E. = Enterobacter) (K. = Klebsiella), Proteae-Bakterien der Proteus-Gruppe: Proteus, z.B. Proteus vulgaris, Pr.morganii, Pr.rettgeri, Pr.mirabilis, Providencia, z.B. Providencia sp. (Pr. = Proteus), Salmonellene: Salmonella-Bakterien, z.B. Salmonella paratyphi A und B, S.typhi, S.enteritidis, S.cholerae suis, S.typhimurium (S. = Salmonella, Shigella-Bakterien, z.B. Shigella dysenteriae, Sh. ambigua, Sh.flexneri, Sh.boydii, Sh.sonnei (Sh. = Shigella);
• Pseudomonadaceae, wie Pseudomonas-Bakterien, z.B. Pseudomonas aeruginosa, Ps.pseudomallei (Ps. = Pseudomonas), Aeromonas-Bakterien, z.B. Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas);
• Parvobacteriaceae, wie Pasteurella-Bakterien, z.B. Pasteurella multocida, Past.pestis (Yersinia), Past.pseudotuberculosis, Haemophilus-Bakterien, z.B. Haemophilus influenzae, H.ducreyi, H.suis, H.canis, H.aegypitcus (H. = Haemophilus), Bordetella-Bakterien, z.B. B.bronchiseptica (B. = Bordetella).
• Bacteroidaceae, wie Bacteroides-Bakterien, z.B. Bacteroides fragilis, B.serpens (B. = Bacteroides), Fusiforme-Bakterien, z.B. Fusobacterium fusiforme, Sphaerophorus-Bakterien, z.B. Sphaerophorus necrophorus, Sph.necroticus, Sph.pyrogenes (Sph. = Sphaerophorus);
• Bacillaceae, wie aerobe Sporenbildner, z.B. Bacillus anthracis (B.subtilis, B.cereus) B. = 8acillus), Anaerobe Sporenbildner-Chlostridien, z.B. Clostridium perfringens, Cl.septicium, Cl.oedematien, Cl.histolyticum, Cl.tetani, Cl.botulinum (C1. = Clostridium).

For example, local and / or systemic diseases that are caused by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

• Micrococcaceae, such as Staphylococci, for example Staphylococcus aureus, Staph.epidermidis, Staph.aerogenes and Gaffkya t Traga (Staph. = Staphylococcus);
• Lactobacteriaceae, such as streptococci, for example Streptococcus pyogenes, α- or. β-hemolytic streptococci, non (γ -) - hemolytic streptococci, Str.viridans, Str.faecalis (Enterococci), Str.agalactiae, Str.lactis, Str.equi, Str.anaerobie and Diplococcus pneumoniae (Pneumococci) (Str. = Streptococcus);
• Neisseriacsae, such as Neisserie, for example Neisseria gonorrhocea. (Conococcal), N. seningitidia (meningococcal), N. catarrhalis and N. flava (N. = Neisseria);
• Corynebacteriaceae, such as Corynebacteria, for example çorynebacterium diphtheriae, C.pyogenes, C.diphtheroidea, C.acnes, C.parvum, C.bovis, C.renale, C.ovis, C.muri-septicum.
• Mycobacteriaceae, such as mycobacterial pathogens, for example Mycobacterium tuberculosis, M.bovis, M.avium, so-called atypical mycobacteria of Runyon groups I, II, III and IV, M.leprae (M. = Mycobacterium);
• Enterobacteriaceae, such as Escherichiae bacteria from the Coli group: Escherichia bacteria, for example Escherichia coli, Enterobacter bacteria, for example E. aerogenes, E. cloacae, Klebsiella bacteria, for example K.pneusoniae, K.pneumoniae, K.ozaenae, Erwiniae , e.g. Erwinia spec., Serratia, e.g. Serratia marcescens (E. = Enterobacter) (K. = Klebsiella), Proteae bacteria of the Proteus group: Proteus, e.g. Proteus vulgaris, Pr.morganii, Pr.rettgeri, Pr.mirabilis, Providencia, e.g. Providencia sp. (Pr. = Proteus), Salmonellene: Salmonella bacteria, e.g. Salmonella paratyphi A and B, S.typhi, S.enteritidis, S.cholerae suis, S.typhimurium (S. = Salmonella, Shigella bacteria, e.g. Shigella dysenteriae, Sh. Ambigua, Sh.flexneri, Sh.boydii, Sh.sonnei (Sh. = Shigella);
• Pseudomonadaceae, such as Pseudomonas bacteria, for example Pseudomonas aeruginosa, Ps.pseudomallei (Ps. = Pseudomonas), Aeromonas bacteria, for example Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas);
• Parvobacteriaceae, such as Pasteurella bacteria, e.g. Pasteurella multocida, Past.pestis (Yersinia), Past.pseudotuberculosis, Haemophilus bacteria, e.g. Haemophilus influenzae, H.ducreyi, H.suis, H.canis, H.aegypitcus (H. = Haemophilus ), Bordetella bacteria, e.g. B.bronchiseptica (B. = Bordetella).
• Bacteroidaceae such as Bacteroides bacteria, e.g. Bacteroides fragilis, B.serpens (B. = Bacteroides), Fusiforme bacteria, e.g. Fusobacterium fusiforme, Sphaerophorus bacteria, e.g. Sphaerophorus necrophorus, Sph.necroticus, Sph.pyrogenes (Spoph. ;
• Bacillaceae, such as aerobic spore-forming agents, e.g. Bacillus anthracis (B.subtilis, B.cereus) B. = 8acillus), anaerobic spore-forming chlorostridia, e.g. Clostridium perfringens, Cl.septicium, Cl.oedematien, Cl.histolyticum, Cl.tetani, Cl .botulinum (C1. = Clostridium).

The above list of pathogens is only an example and is by no means restrictive.

• Erkrankungen der Atmungswege und des Rachenraumes;

Examples of diseases which can be prevented, improved and / or cured by the active compounds according to the invention are:

• Diseases of the respiratory tract and throat;

Otitis; Pheryngitis; Pneumonia; Peritonitis; Pyelonephritis; Cystitis; Endocarditis; System infections; Bronchitis; Arthritis; local infections.

For the present. The invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosing units. This means that the preparations are in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampoules lie whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can contain, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a lance, a hold or a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all types.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual excipients, such as (a) fillers and excipients, e.g. starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, Alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, eg cetyl alcohol, glycerol monostearate, (h) adsorbents, eg kaolin and bentonite and (i) lubricants, eg talc, calcium and magnesium stearate and strong polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed in such a way that they release the active ingredient (s) only, or preferably in a certain part of the intestinal tract, if necessary with a delay, using as the fat-removing compounds e.g. Polymer substances and waxes can be used.

If appropriate, the active ingredient (s) can also be present in microencapsulated form with one or more of the carrier substances specified above.

In addition to the active substance or substances, dollositories can contain the comparable water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C ₁₄ alcohol with C ₁₆ fatty acid) or mixtures of these substances.

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

In addition to the active ingredient (s), powders and sprays can contain the usual carriers, e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual propellants e.g. Contain chlorofluorocarbons.

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. .water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cotton saatol. Peanut oil, corn oil, olive oil, castor oil and sesame oil. Glycerin, clycerin formal. Contain tetrahydrofurfuryl alcohol, Polyethylenylykole and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carrier substances such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. Contain athoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptua oil and sweeteners, e.g. Saccharin.

The therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95 percent by weight of the total mixture.

In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in contraception in human and veterinary medicine; improvement and / or healing of the diseases listed above.

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.

seines Fachwissens leicht erfolgen.In general, both in human and in veterinary medicine, it has proven to be advantageous to use the active compound (s) according to the invention in total amounts of about 5 to about 1000, preferably 20 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to deliver the results you want. A single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to about 250, in particular 10 to 100 mg / kg of body weight. However, it may be necessary. deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and the application of the drug and the time period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. Any specialist can determine the optimum dosage and type of application of the active ingredients required in each case.

of his specialist knowledge easily.

When used as a feed additive, the new compounds can be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. This can prevent, ameliorate and / or cure infection by gram-negative or gram-positive bacteria and also promote growth and improve the utilization of the feed.

The new penicillins and cephalosporins are characterized by strong antibacterial effects that have been tested in vivo and in vitro.

The penicillins and cephilosporins according to the invention can be used with other antimicrobial agents, e.g. can be combined with penicillins that are particularly resistant to penicillinase. Such a combination would be e.g. those with oxacillin or dicloxacillin.

The penicillins and cephalosporins according to the invention can also be used with aminoglycoside antibiotics, such as, for the purpose of widening the spectrum of effects and to achieve an increase in activity. B. Gentamicin, Kanamicin, Sisomicin, Amikacin or Tobramicin, are combined.

The effectiveness of the ß-lactam antibiotics according to the invention can be demonstrated by way of example by the following in vitro and in vivo uses:

1. In vitro experiments

• Klebsiella pneumoniae; Enterobacter aerogenea sp.; Providencia; Serratia marcescens; E.coli BE; Salmonella ap.; Shigella ap.; Proteus, indolnegativ und indolpoaitiv; Pasteurella pseudotuberculosis; Brucella sp.; Haemophilua influenzao; Bordetella bronchiaeptica; Staphylococcua aureus 133; Neisseria catarrhalia ap.; Diplococcus pneumoniae sp.; Streptococcus pyogenes W.; Enterococcus sp.; Lactobacillus ap.; Corynebacterium diphteriae gravia; Corynebacterium pyogenes M; Cloatridium tetani; Pseudomonas aeruginosa sp.

Examples 2.3 and 3.1, which can be regarded as typical representatives of the compounds according to the invention, were diluted to a content of 100 μg / ml with Müller-Hinton nutrient broth with the addition of 0.1% clucose. There were 1 x 10 ⁵ to? x 10 ⁵ bacteria per milliliter. The tubes with this approach were each incubated for 24 hours and then the degree of turbidity was determined. Freedom from turbidity indicates effect. At the dosage of 100 µg / ml, the following bacterial cultures were cloudy (sp. = Apecies):

• Klebsiella pneumoniae; Enterobacter aerogenea sp .; Providencia; Serratia marcescens; E. coli BE; Salmonella ap .; Shigella ap .; Proteus, indole-negative and indole-negative; Pasteurella pseudotuberculosis; Brucella sp .; Haemophilua influenzao; Bordetella bronchiaeptica; Staphylococcua aureus 133; Neisseria catarrhalia ap .; Diplococcus pneumoniae sp .; Streptococcus pyogenes W .; Enterococcus sp .; Lactobacillus ap .; Corynebacterium diphteriae gravia; Corynebacterium pyogenes M; Cloatridium tetani; Pseudomonas aeruginosa sp.

In the NMR spectra of the compounds according to the invention, the names mean:

Explanation of the abbreviations used in the examples:

The yield data in% mean yields in% of theory.

example 1 2-t-butoxycarbonylamino-furfurylacetic acid

• IR(KBr): 3357, 1720, 1686, 1513, 1154, 74₇ cm^-1.
• NMR(CD₃OD): pseudo-s 7.42(1H), paeudo-s 6.35(2H), s 5.30(1H), s 1.45(9H) ppm (i) .

5.0 parts by weight 2-Amino-furfurylacetic acid (Röhm and Haas, Neth.Appl. 66.07754) in 100 vol. 80 percent aqueous dioxane are brought to pH 8 with 4N sodium hydroxide solution. 8.0 parts by weight of 2- (t-butoxycarbonyloxyimino) -2-phenylacetonitrile are added and the mixture is heated at 70 ° for 2 hours. During this time, the above pH is maintained by adding 4N sodium hydroxide solution. Then 80 vol. Parts of water are added, the dioxane is stripped off and extracted several times with ethyl acetate. The aqueous phase is with 10 percent. Citric acid brought to pH 4, saturated with sodium chloride and shaken out with ethyl acetate. The ethyl acetate phases are dried over sodium sulfate and concentrated. The residue is made up of little abs. Carbon tetrachloride recrystallized. 4.3 parts by weight are obtained. 2-t-Butoxycarbonylamino-furfurylacetic acid, mp 99-101 °.

• IR (KBr): 3357, 1720, 1686, 1513, 1154, 74 ₇ cm ^-1 .
• NMR (CD ₃ OD): pseudo-s 7.42 (1H), paeudo-s 6.35 (2H), s 5.30 (1H), s 1.45 (9H) ppm (i).

Example 2.1 7- [α- (t-Butyloxycarbonylamino) furfurylacetamide] -3-acetoxymethyl-ceph-3-em-4-carboxylic acid

To a solution of 3.7 parts by weight. 2-t-Butoxycarbonylamino-furfurylacetic acid in 60 Vol.Tln. Section. THF will be 1.7 parts by weight. Triethylamine and 0.1 part by weight. Given N-methylmorpholine. It is cooled to -25 °, a solution of 1.8 parts by weight. Chloroformic acid ethyl ester in 10 parts by volume. Section. THF added and stirred for 15 min at this temperature. Then a solution of silylated 7-aminocephalosporanic acid (7-ACS), pre-cooled to -20 °, in 40 parts by volume. Section. THF (prepared from 5.0 parts by weight of 7-ACS and 5.6 parts by weight of bistrimethylsilylacetamide) was added, the mixture was stirred at -20 ° for 10 minutes and allowed to come to RT. There will be 80 Vol.Tle. Ice water added, adjusted to pH 7.3 and the THF removed. The aqueous phase is extracted with ethyl acetate and acidified at 0-5 ° and extracted again with ethyl acetate. The latter extracts of ethyl acetate are dried over magnesium sulfate and concentrated. The product (7.5 parts by weight) is obtained as a yellow foam which is processed directly.

Example 2.2 7 - [(α-Amino) -furfurylacetamido] -3-acetoxymethyl-Ceph-3-em-4-carboxylic acid, trifluoroacetate

7.5 parts by weight 7- [α- (t-Butyloxycarbonylamino) furfuryl acetamide] -3-acetoxymethyl-ceph-3-em-4-carboxylic acid are dissolved in 30 parts by volume. ice-cold trifluoroacetic acid dissolved and stirred at 0 ° for 15 min. The solution is poured into a mixture of 120 parts by volume. Petroleum ether and 60 Vol.Tln. Poured ether, the product precipitates as trifluoroacetate. It is filtered off, washed with ether and dried over phoaphor pentoxide and potassium hydroxide. 5.8 parts by weight from Zers.p.115-12:

Example 2.3 Sodium 7- {α - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino] furfurylacetamido} -3-acetoxymethyl-ceph-3-em-4-carboxylate

• IR (KBr): 3420, 1765, 17₂5, 16₇5, 1605, 1415, 1₂35 cm^-1.
• NMR(CD₃OD): s 7.75(1H), pseudo-a 7.64(1H), pseudo-s 7.50(1H), d 6.8.9(1H), m um 6.5(3H), m um 5.65(2H), m um 5.0(teilweise verdeckt vom Signal der austauschbaren Protonen), s(breit) 3.93(4H), AB bei 3.4 und 3.6 (verdeckt vom Lösungsmittelsignal), s 2.02(3H) ppm (δ).
  

A solution of 5.8 parts by weight. 7 - [(α-Amino) -furturylacetamido] 7-3-acetoxymothyl-ceph-3-em-4-carboxylic acid as trifluoroacetate in 100 parts by volume 80 percent aqueous THF is cooled to 5 ° and brought to pH 8 with 1N sodium hydroxide solution. 2.8 parts by weight 1-Chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazole are added in portions, during which the pH is kept at 7.5 with 0.5 N sodium hydroxide solution. If the pH is constant, 100 Vol.Tle. Water was added and the THF was stripped off. The aqueous solution is extracted with ethyl acetate, cooled to 5 °, with 150 parts by volume. Layered ethyl acetate and acidified with 1N hydrochloric acid, the product acid precipitating (3.5 parts by weight). It is in 35 Vol.Tln. Suspended water, dissolved with 0.5 N sodium hydroxide solution and lyophilized this solution. 3.0 parts by weight are obtained. Sodium salt from Zers.p. 170-180 °.

• IR (KBr): 3420, 1765, 17 ₂ 5, 16 ₇ 5, 1605, 1415, 1 ₂ 35 cm ^-1 .
• NMR (CD ₃ OD): s 7.75 (1H), pseudo-a 7.64 (1H), pseudo-s 7.50 (1H), d 6.8.9 (1H), m around 6.5 (3H), m around 5.65 (2H) , m around 5.0 (partially covered by the interchangeable proton signal), s (broad) 3.93 (4H), AB at 3.4 and 3.6 (hidden by the solvent signal), s 2.02 (3H) ppm (δ).
  

Example 3.1 Sodium 6- {α- [2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino] -furfurylacetamido} penicillanate

• IR(KBr): 1760, 1715, 166₀, 16₀₅ cm^-1.
• NMR(CD₃OD): s 7.72(1H, d 7.70(1H), pseudo-s 7.50(1H), d 6.85(1H), m um 6.60(3H), a 5.55(1H), AB 5.38 und 5.42(2H), s 4.12(1H), s(breit) 3.80(4H), s 1.53(3H), s 1.48(3H) ppm (δ).

2.4 parts by weight α-Amino-furfurylacetamido-penicillanic acid (Beecham, USP 3,120,514) and 2.4 parts by weight. 1-Chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazole are reacted and worked up as in Example 2.3. 3.3 parts by weight are obtained. from Zers.p. 180-185 ° with a β-lactam content of 82%.

• IR (KBr): 1760, 1715, 166 ₀ , 16 ₀₅ cm ^-1 .
• NMR (CD ₃ OD): s 7.72 (1H, d 7.70 (1H), pseudo-s 7.50 (1H), d 6.85 (1H), m around 6.60 (3H), a 5.55 (1H), AB 5.38 and 5.42 ( 2H), s 4.12 (1H), s (broad) 3.80 (4H), s 1.53 (3H), s 1.48 (3H) ppm (δ).

Example 4 Sodium 6- {δ [(- 2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino-7-thiazolyl-4-acetamido} penicillanate.

• Ausbeute: 1,1 Gew.-Teile
• Zers. p.: ca. 215°C
• ß-Lactamgehalt 74 %
• IR (_Nujol, Carbonylbereich): 1765, 1715 1665 cm^-1.
• NMR (CD₃OD): δ 8,9 (1H, Thiazol), s 7,7 (18) und
• s (2H) (Furan, Thiazol und -CN-N-), m 6,85 (1H, Furan),
• m 6,5 (1H, Furan) m 5,6-5,35 (3H), m 3,8 (4H) 1,70-145 (6H) ppm (δ).

4.3 parts by weight of δ-amino-thiazolyl-4-acetamido-penicillanic acid (crude product; M. Hatanaka, T. Ishimaru, J. Medicinal Chemistry 1973, 16 pp. 978-84) are added in about 120 parts by volume . Dissolved 80 s aqueous tetrahydrofuran and the pH of the mixture adjusted to 7.5 by adding an appropriate amount of triethylamine. Then 3.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-furfurylideneaminoimidazole are introduced and the pH is kept at 7.5 by adding triethylamine. If the pH remains constant on its own, it is diluted with 100 parts by volume of water, shaken twice with ethyl acetate, covered with fresh ethyl acetate, acidified to pH 1.5 with 2N HC1 with stirring. Part of the released pnicillic acid precipitates as an oil. The ethyl acetate phase is dried and the pnicillin sought is precipitated from it by adding a 1 molar solution of sodium 2-ethylhexanate in ether containing methanol.

• Yield: 1.1 parts by weight
• Decay p .: approx. 215 ° C
• ß-lactam content 74%
• IR ( _N ujol, carbonyl range): 1765, 1715 1665 cm ^-1 .
• NMR (CD ₃ OD): δ 8.9 (1H, thiazole), s 7.7 (18) and
• s (2H) (furan, thiazole and -CN-N-), m 6.85 (1H, furan),
• m 6.5 (1H, furan) m 5.6-5.35 (3H), m 3.8 (4H) 1.70-145 (6H) ppm (δ).

Example 5 Sodium 6- {α - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino] thienyl-2-acetamido} penicillanate

• Ausbeute: 0,7 Gew.-Tle.
• ß-Lactamgehalts : 85 % (Substanz enthält ca. 6 % ß-Lactamoffenes Produkt)
• IR (Nujol: Carbonylbereich): 1760 (Schulter), 1750, 1715, 1655, 1595, 1520-10 cm^-1.
• NMR (CD₃OD/D₂O)s 7,7-6,9 m (5H, Thiophen, Furan, -CH-N-), 6,8 d (1H, Furan), 6,5 m (18, Furan), 5,8 s (1H, N-CH-CO-), 5,5 pseudo-s (2H, 5,6-H), 4,2 s (1H, 3-8), 3,9-3,6 s, breit (4H,
  
  ), 1,55 s (3H) und 1,45 s (3H) ppm
  
  .
• ⁺) Aufgrund des NMR-Spektrums und der guten Wirksamkeit muß man annehmen, daß die D-Form vorliegt. Da vom Racemat der α-Amino-thienylessigsäure ausgegangen wurde, muß auf der Stufe des α-Amino-thienylmethylpenicillins eine Diastereomerentrennung eingetreten sein.

0.6 part by weight of δ-amino-thienyl- (2) -acetamido-penicillanic acid (M. Hatanaka, T. Ishimaru, J. Medicinal Chemistry 1973, 16, pp. 978-84) are dissolved in 40 parts by volume . 80% aqueous tetrahydrofuran dissolved by adding the just necessary amount of triethylamine at pH 7.5-8.0. Then with 0.42 parts by weight. 1-Chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazole implemented and worked up in the manner described in Example 2.3.

• Yield: 0.7 part by weight.
• ß-lactam content: 85% (substance contains approx. 6% ß-lactam open product)
• IR (nujol: carbonyl range): 1760 (shoulder), 1750, 1715, 1655, 1595, 1520-10 cm ^-1 .
• NMR (CD ₃ OD / D ₂ O) s 7.7-6.9 m (5H, thiophene, furan, -CH-N-), 6.8 d (1H, furan), 6.5 m (18, Furan), 5.8 s (1H, N-CH-CO-), 5.5 pseudo-s (2H, 5.6-H), 4.2 s (1H, 3-8), 3.9 -3.6 s, wide (4H,
  
  ), 1.55 s (3H) and 1.45 s (3H) ppm
  
  .
• ⁺ ) Due to the NMR spectrum and the good effectiveness, one must assume that the D form is present. Since the racemate of α-aminothienylacetic acid was used as the starting material, a separation of the diastereomers must have occurred at the stage of α-aminothienylmethylpenicillin.

According to the NMR spectrum, the substance contains about 0.08 molar equivalents of sodium 2-ethylhexanoate and about 3.2 molar equivalents of water.

Example 6 Sodium-6-} α - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino] - (5-methyl-isoxazol-3-yl) -acetamido} - penicillanate

• IR (KBr): 1770, 1725, 1675, 1605, 1525, 1475, 1410, 1270, 1235 cm^-1.
• NMR (CD₃OD): s. 7.71 (1H), d 7.62 (1H), d 6.89 (1H), dd 6.54 (1H), breites 6.22 (1H), m zwischen 5.7 und 5.3 (3H), s 4.2 2 (1H), s 3.90 (4H), s 2,37 (2H), s 1.62 (3H), s 1.56 (3H) ppm (δ).

The representation is analogous to Example 3; Zp. 205-210 ° C.

• IR (KBr): 1770, 1725, 1675, 1605, 1525, 1475, 1410, 1270, 1235 cm ^-1 .
• NMR (CD ₃ OD): s. 7.71 (1H), d 7.62 (1H), d 6.89 (1H), dd 6.54 (1H), broad 6.22 (1H), m between 5.7 and 5.3 (3H), s 4.2 2 (1H), s 3.90 (4H) , s 2.37 (2H), s 1.62 (3H), s 1.56 (3H) ppm (δ).

Example 7.1 2- (1,3,5-trimethylpyrazol-4-yl) -2-aminoacetic acid

A mixture of 13.8 parts by weight. 1,3,5-trimethylpyrazole-4-aldehyde, 5 parts by weight. Sodium cyanide, 5.9 parts by weight.

Ammonium chloride, 13.4 vol parts. concentrated ammonia solution, 30 Vol.Tle. Water and 30 Vol.Tle. Ethanol is left for 5 hours at 60 ° C in a closed flask with occasional swiveling.

Then the reaction solution is poured into 80 parts by volume. ice-cold concentrated hydrochloric acid, rinsed with water and passes 50-60 g of HC21 gas into the solution at 0-5 ° C, which is then left overnight (fume cupboard). After dilution with 100 parts by volume. Water, 2.5 hours: reflux and concentration, the residue is smoked twice with water in a porcelain dish (to remove HCl).

Finally, the mixture is taken up in ethanol, the undissolved solution is filtered off, the mixture is evaporated to dryness, taken up again in water and stirred with about 50 g of acidic ion exchanger (Dowex from Serva, Heidelberg) (5 hours).

Then the loaded ion exchanger is suctioned off, washed well with water and finally eluted with ammonium carbonate solution. This solution is evaporated to dryness.

• 60 MHz-NMR-Spektrum (D₂0): 2,05 ppm s (3H), 2,15 s (3H), 3,6 s (3H), 4,8 (Wasser), 4,9 s (1H).
• Dünnschichtchromatographisch einheitlich R_f = O.
• (Laufmittel: 200 ml n-Butylacetat, 36 ml n-Butanol, 100 ml Essigsäure (behandelt mit 150 ml Phosphatpuffer pH 6)).

The residue is washed with ethanol and 7.4 parts by weight from the mother liquors. (40%) of the desired amino acid.

• 60 MHz NMR spectrum (D ₂ 0): 2.05 ppm s (3H), 2.15 s (3H), 3.6 s (3H), 4.8 (water), 4.9 s (1H ).
• Thin layer chromatography uniformly R _f = O.
• (Mobile solvent: 200 ml n-butyl acetate, 36 ml n-butanol, 100 ml acetic acid (treated with 150 ml phosphate buffer pH 6)).

Example 7.2 2- (1,3,5-trimethylpyrazol-4-yl) -2-tert-butoxycarbonylaminoacetic acid

• Eine Mischung aus 16,1 Gew.-Tln. Aminosäure aus Beispiel 7.1. 3,52 Gew.-Tln. Natriumhydroxid 18 Vol.-Tln. t-Butanol 9 Vol.-Tln. Wasser

wird bei O°C mit 20,3 Gew.-Tln. Di-t-butyl-dicarbonat langsam versetzt, noch weitere 18 Vol.-Tle. t-Butanol hinzugefügt und 14 Stunden bei 25°C, dann 12 Stunden bei 50°C nachgerührt. Man verdünnt mit 50 Vol.-Tln. Wasser, wäscht je 3mal mit n-Pentan und Xhter und säuert auf pH 2,4 an. Nach Extraktion mit Essigsäureäthylester (4 ml), Trocknen über Na₂SO₄ und Einengen wird im Hochvakuum getrocknet.

• 60 MH₂-NMR-Spektrum (CDCl₃): 1,4 ppm s (9H), 2,4 s (3H), 2,45 s (3H), 3,7 s (3H), 5,1 d (1H), 5,8 d (1H), 12,6 s (1H).
• Ausbeute: 15 Gew.-Tle. (63 t) 2-(1,3,5-Trimethylpyrazol-4-yl)-2-tert.-butoxycarbonylaminoessigsäure.

• A mixture of 16.1 parts by weight. Amino acid from example 7.1. 3.52 parts by weight Sodium hydroxide 18 parts by volume t-butanol 9 parts by volume water

is at 20 ° C with 20.3 parts by weight. Di-t-butyl dicarbonate slowly added, another 18 parts by volume. Added t-butanol and stirred for 14 hours at 25 ° C, then for 12 hours at 50 ° C. It is diluted with 50 parts by volume. Water, wash 3 times with n-pentane and xhter and acidify to pH 2.4. After extraction with ethyl acetate (4 ml), drying over Na ₂ SO ₄ and concentration, the mixture is dried under high vacuum.

• 60 MH ₂ NMR spectrum (CDCl ₃ ): 1.4 ppm s (9H), 2.4 s (3H), 2.45 s (3H), 3.7 s (3H), 5.1 d ( 1H), 5.8 d (1H), 12.6 s (1H).
• Yield: 15 parts by weight. (63 t) 2- (1,3,5-trimethylpyrazol-4-yl) -2-tert-butoxycarbonylaminoacetic acid.

Example 7.3 7- [2- (1,3,5-Trimethylpyrazol-4-yl) -2-t-butoxycarbonylamino-acetamido7-cephalosporanoic acid

5.36 parts by weight the compound from Example 7.2 are dissolved in 150 parts by volume of tetrahydrofuran, 2 parts by weight of triethylamine, 2.75 parts by weight of isobutyl chloroformate are added at -15 ° C. and 1.5 hours Stirred -10 ° C (solution A).

Solution B:

5.44 parts by weight 7-Aminocephalosporanic acid are in 100 vol. 80% aqueous tetrahydrofuran and 2 parts by weight. Triethylamine dissolved and cooled to -10 ° C. For this drips solution A at -10 ° C. The mixture is stirred for a further 1.5 hours at −1 ° C. and for a further 2 hours, while allowing to come to room temperature.

The reaction solution is in 100 parts by volume. Water, washed with ethyl acetate, acidified (pH 1.8), extracted with ethyl acetate and this ethyl acetate solution washed with saturated NaCl solution. After drying over MgSO ₄ , the mixture is concentrated and the residue is dried under high vacuum.

Yield: 7.5 parts by weight. (70%) of the above compound.

• 100 MHz-NMR-Spektrum (CDC13): 1,4 ppm s (9H), 2,1 s (3H) 2,3 m (6H), 3,4 a,b (2H) 3,7 m(3H), 4,95 a,b (2H), 5,05 d (1H) (I=3Hz), 5,3 d (1H) (I=3Hz) . 5,8 d (1H), 7,3 d (1H), 10,8 s (1H) .

Thin layer chromatogram uniformly R _f value 0.3 (solvent mixture as in Example 7.1)

• 100 MHz NMR spectrum (CDC13): 1.4 ppm s (9H), 2.1 s (3H) 2.3 m (6H), 3.4 a, b (2H) 3.7 m (3H) , 4.95 a, b (2H), 5.05 d (1H) (I = 3Hz), 5.3 d (1H) (I = 3Hz). 5.8 d (1H), 7.3 d (1H), 10.8 s (1H).

Example 7.4 7- [2- (1,3,5-Trimethylpyrazol-4-yl) -2-amino7-acetamido-cephalosporanic acid

12.3 vol. Trilfuacetic acid and 1.4 parts by volume Anisole are cooled to O ^o C and with stirring, 4 parts by weight. added to the compound from Example 7.3.

The trifluoroacetic acid is then largely distilled off (initial charge cooled to -70 ° C., high vacuum) and the residue in 10 parts by volume. Dissolved methylene chloride and stirred for 20 min. Then 100 parts by volume of ether / ligroin 1: 1 are added and the mixture is stirred for a further 30 minutes, the precipitate is filtered off with suction and taken up in water.

After top layers with ethyl acetate / ether, the pH is adjusted to 7 with amberlite (liquid ion exchanger, chloride as counterion), the phases are separated and the aqueous phase is washed very thoroughly with ether. The aqueous phase is freeze-dried.

Yield: 3 parts by weight. 7- [ 2nd - (1,3,5-Trimethylpyrazol-4-yl) -2-amino7-acetamidocephalosporanic acid.

• IR (KBr) 3422, 2923, 1763, 1689, 1599, 1383, 1235, 1064, 1026, 739.
• 100 MHz-NMR-Spektrum (D₂O) : 2,1 ppm 2 s (Abstand 0,5 Hz) 3H (Verhältnis 1:1 ) , 2,2 m (3H) 2,3 m (3H), 3,4 u 3,6 a,b (2H), 3,7 s (3H), 4,7 s (4 ausgetauschte H + 1 x H₂O), 5,15 m (3H), 5,7 m (1H).

Thin layer chromatogram (eluent see example 7.1) a substance stain at the starting point.

• IR (KBr) 3422, 2923, 1763, 1689, 1599, 1383, 1235, 1064, 1026, 739.
• 100 MHz NMR spectrum (D ₂ O): 2.1 ppm 2 s (distance 0.5 Hz) 3H (ratio 1: 1), 2.2 m (3H) 2.3 m (3H), 3, 4 u 3.6 a, b (2H), 3.7 s (3H), 4.7 s (4 exchanged H + 1 x H ₂ O), 5.15 m (3H), 5.7 m (1H ).

Example 7.5 a ± rium-7- {2- (1,3,5-trimethylpyrazol-4-yl) -2 - [(2-oxo-3-furfurylideneaminoimidazolidin-l-yl) carbonylamino] acetamido} cephalosporanate

• Aufarbeitung wie in Beispiel 2.3. beschrieben.
• Ausbeute: 1,2 Gew.Tle. (78 %) der oben bezeichneten Verbindung.
• IR-Spektrum (Nujol) ß-Lactambande bei 1765.
• Dünnschichtchromatogramm (Laufmittel wie Beispiel 7.1.) R_f-wert : 0, 2 ( einheitlich) .
• 100 (CD₃CD+D₂O): 2,15 ppm : (3H) 2,3 m (3H), 2,45 = (3H), 3,4 a,b (verdeckt durch Lösugsmittelsignal und folgende Signale) (2H), 3,8 s (3H), 4,0 s(breit)(4H), 4,9-5,2 m (teihweise verdeckt durch ausgetauschte Wasserstoffe) (48), 5, 5 d (J=0,5Hz) (1H), 6,65. q (1H), 7,0 d (1H), 7,8 d (1H), 7,85 a (1H).

1 part by weight of the cephaloaporin described above is in 80 Vol.Tln. 80% aqueous tetrahydrofuran dissolved and 0.53 parts by weight and 0.53 parts by weight. 1-chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazole added, keeping the pH at 7-8 with NaOH; Temperature 5 ° C.

• Refurbishment as in example 2.3. described.
• Yield: 1.2 parts by weight. (78%) of the compound mentioned above.
• IR spectrum (nujol) ß-lactam band at 1765.
• Thin layer chromatogram (eluent as in Example 7.1.) R _f value: 0, 2 (uniform).
• 100 (CD ₃ CD + D ₂ O): 2.15 ppm: (3H) 2.3 m (3H), 2.45 = (3H), 3.4 a, b (covered by solvent signal and following signals) ( 2H), 3.8 s (3H), 4.0 s (wide) (4H), 4.9-5.2 m (partly covered by exchanged hydrogens) (48), 5, 5 d (J = 0, 5Hz) (1H), 6.65. q (1H), 7.0 d (1H), 7.8 d (1H), 7.85 a (1H).

Example- 8 Sodium 6α-methoxy-6β- {D-2 - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) carbonylamino] thienyl-2-acetamido] penicillinate

1.9 parts by weight 6- {D-2 - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) -carbonylamino] -thienyl-2-acetamido} -penicillanic acid in 40 parts by volume. absolute tetrahydrofuran at -80 ° C with 0.067 parts by weight. Lithium hydride in 20 ml of methanol; then 0.4 part by weight is added. t-Butyl hypochlorite and stirred for 2 hours at -60 ° C.

The reaction solution is then placed in a 10% ammonium chloride solution and keeps the pH at 7 with further addition of dilute hydrochloric acid. The tetrahydrofuran is distilled off in vacuo, and the aqueous phase is washed with ethyl acetate. Then 10 parts by volume are added. Acetone and, while stirring, slowly adjust the pH to 4 with dilute hydrochloric acid. The penicillanic acid slowly crystallizes out. The precipitate is filtered off and dissolved in water with the addition of 1N sodium hydroxide solution at pH 7. The solution is finally lyophilized.

1.8 parts by weight are obtained. (86%) of the above compound.

• IR-Spektrum (KBr): 3436, 1762, 1726, 1674, 1604, 1529, 1476, 1413, 1270, 1235, 1136, 740.
• 100 MHz-NMR-Spektrum (CD₃CD) 1,3 ppm s (3H), 1,5 s (3H), 3,6 s (3H), 4,0 s (breit) (4H), 4,3 s (1H), 5,65 s (1H), 6,0 d (1H), 6,65 q (1H), 7,0 d (1H), 7,1-7,5 m (5H), 7,75 d (1H), 7,8 s (1H).

Thin layer chromatogram: R _f value 0.6 uniform.

• IR spectrum (KBr): 3436, 1762, 1726, 1674, 1604, 1529, 1476, 1413, 1270, 1235, 1136, 740.
• 100 MHz NMR spectrum (CD ₃ CD) 1.3 ppm s (3H), 1.5 s (3H), 3.6 s (3H), 4.0 s (broad) (4H), 4.3 s (1H), 5.65 s (1H), 6.0 d (1H), 6.65 q (1H), 7.0 d (1H), 7.1-7.5 m (5H), 7 , 75 d (1H), 7.8 s (1H).

Example 9.1 2- (2-tert-Butoxycarbonylimino-4-thiazolin-4-yl) -2-methoxyiminoacetic acid ethyl ester (syn form):

• Schmelzpunkt 122-24°C
• NMR (60 MHz; δ in CC14) 7,05 (s: Thiazolin 5-H)

65 g of di-tert are added to the mixture of 50 g of 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid ethyl ester (syn form) and 150 ml of tert-butanol, which has been heated and stirred at 40-45 ° C. . -Butylpyrocarbonate was added dropwise, and the mixture was subsequently stirred at 40 ° C. for 30 minutes and the solvent was then removed in vacuo. The substance is then dissolved in ether, this solution is washed with dilute hydrochloric acid, 13 g of unreacted starting material precipitating. It is suctioned off, the filtrate is mixed with a little petroleum ether, whereupon a further 4.5 g of starting material precipitate out. The filtrate from this precipitation is then evaporated again in vacuo, the residue is dissolved in a mixture of petroleum ether and acetone (9: 1) and chromatographed on a silica gel column. The sought compound is eluted as a second substance.

• Melting point 122-24 ° C
• NMR (60 MHz; δ in CC14) 7.05 (s: thiazoline 5-H)

Example 9.2 2- (2-tert.-butoxycarbonylimino-4-thiazolin-4-yl) -2 - ethyl acetate hydrochloride:

• Ausbeute 4,15 g
• IR(Nujol: Carboxylbereich) 1730; 1710; 1540 cm^-1 . Schmelzpunkt: ab etwa 130°C Zers.

5.6 g of zinc dust are added to the ice-cooled mixture of 7.0 g of a substance prepared according to Example 9.1 and 80 ml of 90% aqueous acetic acid, the mixture is stirred for 40 minutes in an ice bath, then unreacted zinc dust is suctioned off (1.6 g) and washed well with 50% aqueous acetic acid. The filtrate is evaporated in vacuo. The residue is suspended in water of pH 8, hydrogen sulfide passed through, suction filtered and the filtrate extracted at pH 10 with ethyl acetate. The ethyl acetate solution is stirred with water of pH 3 and this aqueous solution is freeze-dried.

• Yield 4.15 g
• IR (nujol: carboxyl range) 1730; 1710; 1540 cm ^-1 . Melting point: from about 130 ° C dec.

Example 9.3 2- (2-tert-butoxycarbonylimino-4-thiazolin-4-yl) -2-aminoacetic acid:

The solution of 4.15 g of a substance shown in Example 9.2 in 80 ml of 50% aqueous ethanol is brought to pH 13 with 2N sodium hydroxide solution and this pH is maintained until it no longer changes (about 15-20 minutes). . Then the pH is adjusted to 7.5 with hydrochloric acid and the solution is evaporated in vacuo. The residue consists of the substance sought, mixed with NaCl. IR (nujol; carbonyl range) 1715; 1600; 1545 cm ^-1 .

Example 9.4 2- (2-tert-Butoxycarbonylimino-4-thiazolin-4-yl) -2 - [(2-oxo-3-furylidenaminoimidazolidin-1-yl) carbonylamino] acetic acid:

• Ausbeute 3,8 g
• Schmelzpunkt 226°C
• NMR(60 MHz; in d₆-DMSO-CD₃OD) 7,55-7,8 (s breit;
• Furan 5-H; -N=_CH-) 7,05 (s;Thiazolin 5-H) 6,75 (d; Furan 3-H) 6,5 (m; Furan 4-H) 5,4 (s; CH-N) 3,75 (s breit;
• -CH₂-CH₂) 1,45 (s; -C(CH₃)₃) ppm.

5.0 g of a substance prepared according to Example 9.3 (contains 2.0 g of NaCl) are suspended or dissolved in 70 ml of 60% aqueous tetrahydrofuran and the mixture is brought to pH 7.5 using 2N sodium hydroxide solution. Then be 2.72 g of 1-chlorocarbonyl-2-oxo-3-furylideneaminoimidazolidine entered and the pH kept at 7.5 with sodium hydroxide solution. When the pH no longer changes, the tetrahydrofuran is removed in vacuo, acidified to pH 2.3 with 2N hydrochloric acid, the precipitate which has separated out is filtered off with suction and washed with water. The precipitate is suspended in hot aqueous ethanol, cooled and suction filtered.

• Yield 3.8 g
• Melting point 226 ° C
• NMR (60 MHz; in d ₆ -DMSO-CD ₃ OD) 7.55-7.8 (broad s;
• Furan 5-H; -N = _CH -) 7.05 (s; thiazoline 5-H) 6.75 (d; furan 3-H) 6.5 (m; furan 4-H) 5.4 (s; CH-N) 3 , 75 (s wide;
• -CH ₂ -CH ₂ ) 1.45 (s; -C (CH ₃ ) ₃ ) ppm.

Example 9.5 7- {2- (2-tert-Butoxycarbonylimino-4-thiazolin-4-yl) -2 - [(2-oxo-3-furylidenaminoimidazolidin-1-yl) -carbonylamino] -acetamido} -cephalosporanoic acid:

(Mixture A):

1.0 g of the substance prepared according to Example 9.4 is mixed with 0.29 ml of triethylamine in 30 ml of dichloromethane, the solution is cooled to -40 ° C., mixed with 0.02 ml of 3-dimethylaminopropanol and 0.26 ml of ethyl chloroformate, 60 min stirred at the same temperature, a further 0.13 ml of chloroformate and 0.15 ml of triethylamine were added and this was repeated after 30 minutes.

(Mix B):

2.0 ml of triethylamine and 20 ml of acetone precooled to -10 ° C. are added to the suspension of 0.77 g of 7-aminocephalosporanic acid in 20 ml of dichloromethane, which is stirred in an ice bath. The mixture is then cooled to -20 ° C.

Mixture A and B are combined and stirred without a cold bath. After 2 hours, the mixture is diluted with water, the pH is brought to 7.5, extracted twice with ethyl acetate and the aqueous phase is acidified to pH 2. It is shaken out three times with ethyl acetate, the combined and dried organic phases are evaporated in vacuo and the residue is dried in a desiccator over P ₄ O ₁₀ . Yield 1.05 g

Example 9.6 7- {(2-Aminothiazol-4-yl) -2 - [(2 oxo-3-furylidenamino-imidazolidin-1-yl) -carbonylamino] -acetamido-cepholosporanoic acid:

• über P₄0₁₀ getrocknet.
• Ausbeute 0, 6 g
• IR-Spektrum(Carbonylbereich) 1740, 1715, 1660 und 1520-1500 cm^-1 (Nujol) .
  

0.7 g of the substance shown in Example 9.5 are suspended in 2.8 ml of anisole, cooled in ice / water, mixed with 14 ml of trifluoroacetic acid and the mixture is left to stand at 4 ° C. overnight. The solution is then evaporated in vacuo at -25 ⁰ C, the residue triturated with ether, suction filtered and in a desiccator

• dried over P ₄ 0 ₁₀ .
• Yield 0.6 g
• IR spectrum (carbonyl range) 1740, 1715, 1660 and 1520-1500 cm ^-1 (Nujol).
  

Claims (10)

1. Compounds of formula (I)

in which R represents hydrogen or lower alkoxy, Z for the groups

stands in what R ¹ and R ^{2 are} identical or different and are hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, nitro, lower alkylcarbonyl, -CONH ₂ , -CONHCH ₃ , CON (CH ₃ ) ₂ , -SO ₂ NH ₂ , -SO ₂ -NHCH ₃ or -SO ₂ H (CH ₃ ) ₂ mean
and R and R ² together with the carbon atom to which they are attached can form a 3- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring, which can be substituted: A for -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or

stands, n is 1 and 2 B represents a saturated or unsaturated, optionally substituted heterocyclic ring, X represents S, O, SO, SO ₂ or -CH ₂ -; and Y for the groups

is in which the carbon atom, which carries the group -COOE, is bound to the nitrogen atom of the β-lactam ring and T is hydrogen, alkyl-CO-O-, pyridinium, 4-carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxy, the group -S-phenyl, which may be substituted, or the group -S-Het, in which Het represents an optionally substituted heterocyclic 5- or 6-membered ring;
and where E represents hydrogen, a pharmaceutically usable ester group such as the pivalcyl group, a salt-forming cation or a suitable protective group;
these compounds of the formula I can be present in the two possible R and S configurations with respect to the chiral center C and as mixtures of the resulting diastereomers, and the compounds of the formula I. if Z for the group

stands and R ¹ and R ^{2 are} different, with respect to the imino group can be both in the syn form and in the anti form and these compounds of the formula I can also be present in the different hydrate forms, 2. Compounds of formula (I) in which R represents hydrogen or methoxy Z for the groups

stands in what R ^{1 represents} hydrogen; and R ² optionally through halogen (in particular fluorine, chlorine and bromine), alkyl with 1 to 4 carbon atoms (in particular methyl), alkoxy with 1 to 4 carbon atoms, (in particular methoxy), nitro, cyano, Alkylsulfonyl with 1 to 4 carbon atoms (in particular methylsulfonyl) or CH ₃ OOC-, substituted phenyl or optionally by halogen (in particular chlorine or bromine), HO ₂ , alkyl or alkoxycarbonyl with 1 to 4 carbon atoms or CH ₃ COOCH ₂ -, preferably in the 4- or 5-position substituted furyl or thienyl, the furyl and thienyl ring preferably being bonded in the 2- and 3-position or pyridyl (preferably pyridyl-3): or for optionally substituted, straight-chain, branched or cyclic alkyl or Alkenyl having up to 7 carbon atoms, in particular cyclohexenyl or alkyl or alkenyl having up to 4 carbon atoms, the alkyl and alkenyl groups mentioned being optionally substituted, halogen and alkoxy having 1 to 4 carbon atoms, in particular methoxy, being preferred as substituents come and A represents -CH ₂ CH ₂ -; and B is furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl and n is 1 and 2, Y stands for the groups

in which T represents hydrogen, -O-CO-CH ₃ , hydroxyl or thiadiazolylthio or tetra- ₊ zolylthio optionally substituted by alkyl having 1 to 4 carbon atoms or CF ₃ ; and C is in the D = R configuration;
and the pharmaceutically acceptable salts of these compounds. 3. Process for the preparation of compounds of formula I.

in the 2, A, n, C, B, R, X and Y or their salts have the meaning given above, characterized in that compounds of the formula II

in which R, B, C, X and Y have the meaning given above or their salts, with Compounds of formula III

in which Z, n and A have the meaning given above and W represents halogen, azide or another nucleofugic leaving group,
in the presence of a solvent and optionally an acid binder at temperatures of about -20 to about + 50 ° C and the resulting ß-lactam antibiotics optionally converted into their salts or pharmaceutically acceptable esters or, if desired, the free acids are prepared from the salts obtained. Process for the preparation of compounds of the formula

in the Z, A, n, C, B and X have the meaning given above, R stands for lower alkoxy and Y for the groups

is in which T has the meaning given above and E is an easily removable ester-forming group, an acetoxymethyl group, the cationic radical of a base or hydrogen with 2-10 equivalents per equivalent of B-lactam antibiotic of the formula (VIII) of a base in the presence an excess of an alcohol of the formula

in the R 'means lower alkyl in an inert organic solvent with the addition of an N-halogenating agent and the compound of the formula I is isolated, if appropriate after prior removal of the protective group, conversion into a salt or a pharmaceutically usable ester. ₅ . Medicament, characterized by a content of a compound according to claims 1 to 8. 6. A process for the preparation of a medicament, characterized in that a compound according to claims 1 to 8 is mixed with pharmaceutically suitable carriers and / or additives. 7. A method for the treatment of diseases caused by bacteria, characterized in that compounds according to claims 1 to 8 are applied to people or animals suffering from these diseases. 8. Use of compounds according to claims 1 to 8 in the control of diseases. ₉ . Feed additive, characterized by a content of a compound according to claims 1 to 8. _10. Use of compounds according to claims 1 to 8 to promote growth and improve the utilization of the feed in animals.