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EP0000393A1 - Beta-lactam compounds, process for their preparation and their use - Google Patents

Beta-lactam compounds, process for their preparation and their use Download PDF

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Publication number
EP0000393A1
EP0000393A1 EP78100356A EP78100356A EP0000393A1 EP 0000393 A1 EP0000393 A1 EP 0000393A1 EP 78100356 A EP78100356 A EP 78100356A EP 78100356 A EP78100356 A EP 78100356A EP 0000393 A1 EP0000393 A1 EP 0000393A1
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EP
European Patent Office
Prior art keywords
compounds
formula
salts
group
bacteria
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EP78100356A
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German (de)
French (fr)
Inventor
Michael Dr. Preiss
Hans-Bodo Dr. König
Karl Georg Dr. Metzger
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Bayer AG
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Bayer AG
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to new ⁇ -lactam compounds, a process for their preparation and their use as medicaments, in particular as antibacterial agents and as agents for promoting the growth and improving the feed conversion in animals.
  • the compounds according to the invention have excellent tolerability.
  • alkyl in alkyl-CO-O 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, with oxygen, sulfur and nitrogen as heteroatoms.
  • 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 are: halogen, such as fluorine, chlorine and bromine, preferably chlorine and bromine, amino, lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl part), lower alkyloxy, trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5, in particular 2 or 3, carbon atoms.
  • halogen such as fluorine, chlorine and bromine, preferably chlorine and bromine
  • amino lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl part), lower alkyloxy, trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5, in particular 2 or 3, carbon atoms.
  • -S-Het as particularly
  • 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 .
  • 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 which are described in Angewandte Chemie, 81 (1969), page 543.
  • Pharmaceutically usable salts of the compounds of the 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.
  • 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.
  • organic amines examples include: di- and tri-lower alkylamines, e.g. B. diethylamine, triethylamine, tri-ß-hydroxyethylamine, procain, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-ß-phenyl-ethylamine, N-methyl and N-ethylmorpholine, 1-ephenamine, dehydroabiet y l- amine, N, N'-bis-dehydroabietylethylenediamine, 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.
  • Preferred salts of the compounds of the formula II are salts with bases which are listed as being suitable for salt formation with compounds of the formula I.
  • the sodium salts are particularly preferred.
  • 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):
  • 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 ethers, 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 more organic solvents or (c) water and one or more organic solvents. If, due to the presence in front of water, a pH measurement is hesitant during the reaction according to the invention, the pH of the reaction mixture is preferably kept between 6.5 to 7.5 by adding bases or by using buffer mixtures.
  • the Ver But driving can also be carried out very well in a different pH range, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. It is also possible to react in water-immiscible solvents, e.g. B.
  • halogenated hydrocarbons such as chloroform or methylene chloride
  • organic bases preferably lower alkylamines, for. B. triethylamine, diethylamine or cyclic bases, e.g. B. N-ethyl piperidine.
  • 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, o or z. B. 2, 0 and 4.5 to keep.
  • 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.
  • 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 are tertiary amines, preferably lower alkylamines, e.g. B. Triethylamine and / or cyclic bases, e.g. B. Pyridine and dicyclohexylamine called secondary amine, which is difficult to acylate.
  • bases are tertiary amines, preferably lower alkylamines, e.g. B. Triethylamine and / or cyclic bases, e.g. B. Pyridine and dicyclohexylamine called secondary amine, which is difficult to
  • 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 s +.
  • reaction temperatures can be varied within a wide range. In general, between about -20 ° C and about + 50 ° C, preferably between 0 and +20 0 C. However, as with most chemical reactions, higher or lower temperatures can in principle also be used.
  • the reaction can be carried out under normal pressure, but also under reduced or elevated pressure. Generally one works at normal pressure.
  • 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.
  • 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.
  • the reactants of the general formula III are also advantageous to use with an excess of, for example, 0.1 to 1.0 molar equivalents.
  • the reactants of the general formula II are better utilized 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 desired compliance with a certain pH value. 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 sensible, 2 molar equivalents of base are preferably added.
  • 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.
  • the compounds of the general formula I are both crystalline and amorphous in the form of the free acid and are both antibacterially active in the same way both anhydrous and in various forms of hydrate.
  • 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 water-containing, for example as a hydrate, antibacterial in the same way.
  • 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.
  • 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, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.
  • the active compounds according to the invention are particularly effective against bacteria and bacterial-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.
  • Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • 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 carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. Glycerin, (d) disintegrant, e.g. Agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g.
  • fillers and extenders e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone
  • humectants e
  • quaternary ammonium compounds (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and eentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • wetting agents e.g. Cetyl alcohol, glycerol monostearate
  • adsorbent e.g. Kaolin and eentonite
  • lubricants e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, capsules, pills and granules can be provided with the customary 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, possibly with a delay, with embedding materials e.g. Polymer substances and waxes can be used.
  • the active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the carrier substances specified above.
  • suppositories can contain the usual water-soluble or water-insoluble excipients, 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.
  • water-soluble or water-insoluble excipients 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.
  • ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • carriers e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • Powders and sprays can contain the usual excipients in addition to the active ingredient (s), 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.
  • solutions and emulsions can include the usual carrier substances such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils, in particular cottonseedol, Contain peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. Contain water, ethyl alcohol, propylene glycol, suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. Contain water, ethyl alcohol, propylene glycol
  • suspending agents e.g., ethoxylated 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 eucalyptus 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.
  • 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 human and veterinary medicine for preventing, ameliorating and / or curing the diseases mentioned above.
  • the active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.
  • the active ingredient (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.
  • the new compounds 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 an infection by gram-negative or gram-positive bacteria and also promote growth and improve the utilization of the feed.
  • the new cephalosporins are characterized by strong antibacterial effects, which have been tested in vivo and in vitro, and by oral resorbability.
  • cephalosporins 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.
  • cephalosporins according to the invention can also be combined with aminoglycoside antibiotics, such as, for example, gentamicin, kanamicin, amikacin or tobramycin, for the purpose of widening the spectrum of activity and to achieve an increase in activity.
  • aminoglycoside antibiotics such as, for example, gentamicin, kanamicin, amikacin or tobramycin
  • the ED 100 is the dose at which 100% of the infected animals survive after 24 hours.
  • aqueous solution is extracted once with ethyl acetate, cooled to 5 °, covered with 1CO vol.
  • the acid is suspended in 50 parts by volume of water (5 °) and 0.3N sodium hydroxide solution is added dropwise in such a way that a pH range between 6.0 and 7.5 can be maintained. After the acid has almost completely dissolved (final pH 7.5), the mixture is filtered and the light brown solution is freeze-dried. 5.0 parts by weight are obtained. (59.3%) with a decomp. of 235 °.
  • the ß-lactam content is 95% (HPLC).

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Abstract

beta -Lactam compounds of the formula <IMAGE> in which T is hydrogen, alkyl-CO-O-, pyridinium, 4-carbamoylpyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be substituted, or the group -S-Het in which Het is an optionally substituted heterocyclic 5- or 6-membered ring; are used as medicaments, especially as antibacterial agents and as agents for promoting growth and for improving feed conversion in livestock.

Description

Die vorliegende Erfindung betrifft neue β-Lactam-Verbindungen, ein Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel, insbesondere als antibakterielle Mittel und als Mittel zur Förderung des Wachstums und zur Verbesserung der Futterverwertung bei Tieren.The present invention relates to new β-lactam compounds, a process for their preparation and their use as medicaments, in particular as antibacterial agents and as agents for promoting the growth and improving the feed conversion in animals.

Es ist bereits bekannt geworden, daß bestimmte α-(3-Hetary- lidenamino-2-oxo-imidazolidin-1-yl)-carbonylamino)-benzyl- penicilline antibakteriell wirksam sind (vgl. Deutsche Offenlegungsschrift 2 525 541).It has already become known that certain α- (3-hetarylenidamino-2-oxo-imidazolidin-1-yl) carbonylamino) benzyl penicillins have antibacterial activity (cf. German Offenlegungsschrift 2,525,541).

Es wurde gefunden, daß die neuen β-Lactam-Verbindungen der Formel I

Figure imgb0001
in der

  • T Wasserstoff, Alkyl-CO-O-, Pyridinium, 4-Carbamoylpyridinium, Aminopyridinium, Carbamoyloxy, Azido, Cyano, Hydroxy, die Gruppe -S-Phenyl, welche substituiert sein kann, oder die Gruppe -S-Het bedeutet, in welcher Het für einen gegebenenfalls substituierten heterocyclischen 5- oder 6-gliedrigen Ring steht;
  • wobei diese Verbindungen der Formel I bezüglich des Chiralitätszentrums C in den beiden möglichen R- und S-Konfigurationen sowie als Gemische der daraus resultierenden Diastereomeren vorliegen können, und wobei die Verbindungen der Formel I, bezüglich der Iminogruppe sowohl in der syn-Form als auch in der anti-Form vorliegen können und wobei diese Verbindungen der Formel I auch in den verschiedenen Hydratformen vorliegen können, und die pharmazeutisch verwendbaren Salze dieser Verbindungen der Formel r starke antibakterielle Eigenschaften aufweisen sowie die Eigenschaften besitzen, das Wachstum und die Futterverwertung bei Tieren zu verbessern.
It has been found that the new β-lactam compounds of the formula I
Figure imgb0001
 in the
  • T is hydrogen, alkyl-CO-O-, pyridinium, 4-carbamoylpyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxy, the group -S-phenyl, which can be substituted, or the group -S-Het, in which Het represents an optionally substituted heterocyclic 5- or 6-membered ring;
  • where 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 where the compounds of the formula I, with respect to the imino group, both in the syn form and in can be present in the anti form and these compounds of the formula I can also be present in the various hydrate forms, and the pharmaceutically acceptable salts of these compounds of the formula r have strong antibacterial properties and also have the properties of improving the growth and feed conversion in animals.

Weiterhin wurde gefunden, daß man die neuen ß-Lactam-Antibiotica der Formel I erhält, wenn man Verbindungen der Formel II

Figure imgb0002
in welcher

  • und T die oben angegebene Bedeutung haben, oder deren Salze, mit Verbindungen der Formel III
Figure imgb0003
in welcher
  • W für Halogen, Azid oder eine andere nukleofuge Abgangsgruppe steht,

in Gegenwart eines Lösungsmittels und gegebenenfalls eines Säurebindemittels bei Temperaturen von etwa -20°C bis etwa +50°C umsetzt und die erhaltenen β-Lactam-Antibiotica gegebenenfalls in ihre pharmazeutisch verwendbaren Salze überführt oder aus den erhaltenen Salzen gewünschtenfalls die freien Säuren herstellt.Furthermore, it was found that the new β-lactam antibiotics of the formula I can be obtained if compounds of the formula II
Figure imgb0002
 in which
  • and T have the meaning given above, or their salts, with compounds of the formula III
Figure imgb0003
 in which
  • W represents halogen, azide or another nucleofugic leaving group,

in the presence of a solvent and, if appropriate, an acid binder at temperatures of from about -20 ° C. to about + 50 ° C., and the β-lactam antibiotics obtained are optionally converted into their pharmaceutically acceptable salts or, if desired, the free acids are prepared from the salts obtained.

Die erfindungsgemäßen Verbindungen zeigen neben guter antibakterieller Wirksamkeit eine ausgezeichnete Verträglichkeit.In addition to good antibacterial activity, the compounds according to the invention have excellent tolerability.

Verwendet man beispielsweise 7--[D-α-Amino-(4-hydroxyphenyl)-acetamido]-3-acetoxymethyl-ceph-3-em-4-carbonsäure und 1-Chlorcarbonyl-3-furfurylidenamino-imidazolidin-2-on als Ausgangsstoffe, so kann der Reaktionsablauf durch das folgende Formelschema wiedergegeben werden:

Figure imgb0004
If, for example, 7 - [D-α-amino- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-ceph-3-em-4-carboxylic acid 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:
Figure imgb0004

In der Definition von T bedeutet Alkyl in Alkyl-CO-O-vorzugsweise Alkyl mit 1 bis 4, insbesondere 1 oder 2 Kohlenstoffatomen.Beispielhaft seien Methyl und Äthyl genannt, wobei Methyl besonders bevorzugt ist.In the definition of T, alkyl in alkyl-CO-O preferably denotes alkyl having 1 to 4, in particular 1 or 2, carbon atoms. Examples include methyl and ethyl, with methyl being particularly preferred.

Der heterocyclische Ring Het in -S-Het (Definition von T) besteht aus 5 oder 6 Ringgliedern und enthält 1 bis 4, vorzugsweise 1 bis 3 gleiche oder verschiedene Heteroatome, wobei als Heteroatome Sauerstoff, Schwefel und Stickstoff stehen. Bevorzugt ist der heterocyclische Ring ungesättigt und enthält besonders bevorzugt 2 Doppelbindungen. Der heterocyclische Ring kann einen oder mehrere, vorzugsweise 1 oder 2, insbesondere einen Substituenten enthalten. Als Substituenten seien beispielhaft aufgeführt: Halogen, wie Fluor, Chlor und Brom, vorzugsweise Chlor und Brom, Amino, Niederalkylamino, Diniederalkylamino, Niederalkyl, Cycloalkyl (mit 3 bis 7, vorzugsweise 5 oder 6 Kohlenstoffatomen im Cycloalkylteil), Niederalkyloxy, Trifluormethyl, Phenyl, Benzyl und Acylamino mit vorzugsweise 2 bis 5, insbesondere 2 oder 3 Kohlenstoffatomen. Als -S-Het seien als besonders bevorzugt aufgeführt:

Figure imgb0005
Figure imgb0006
Figure imgb0007
Figure imgb0008
 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, with oxygen, sulfur and nitrogen as heteroatoms. 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. Examples of substituents are: halogen, such as fluorine, chlorine and bromine, preferably chlorine and bromine, amino, lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7, preferably 5 or 6 carbon atoms in the cycloalkyl part), lower alkyloxy, 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:
Figure imgb0005
Figure imgb0006
Figure imgb0007
Figure imgb0008

Der -S-Phenylrest in der Definition von T kann einen oder mehrere, vorzugsweise 1 bis 3, insbesondere 1 oder 2 gleiche oder verschiedene Substituenten tragen, wobei als Substituenten diejenigen bevorzugt werden, welche oben als mögliche Substituenten des Restes -S-Het aufgeführt werden.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 .

Ganz besonders bevorzugt sind erfindungsgemäße Verbindungen, in welchen C in der R-Konfiguration vorliegt.Compounds according to the invention in which C is present in the R configuration are very particularly preferred.

Alle Kristallformen und Hydratformen der erfindungsgemäßen Verbindungen der allgemeinen Formel I und ihrer Salze sind in gleicher Weise antibakteriell wirksam.All crystal forms and hydrate forms of the compounds of general formula I and their salts according to the invention have antibacterial activity in the same way.

Halogen W steht für Fluor, Chlor und Brom, vorzugsweise für Brom oder Chlor, insbesondere für Chlor.Halogen W represents fluorine, chlorine and bromine, preferably bromine or chlorine, in particular chlorine.

Unter nukleofugen Abgangsgruppen in der Definition von W sind alle üblicherweise in der organischen Chemie verwendeten nukleofugen Gruppen und vor allem solche zu verstehen, welche in Angewandte Chemie, 81 (1969), Seite 543 beschrieben sind.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 which are described in Angewandte Chemie, 81 (1969), page 543.

Pharmazeutisch verwendbare Salze der Verbindungen der Formel I sind Salze dieser Verbindungen mit anorganischen und organischen Basen an der sauren Carboxylgruppe beziehungsweise den sauren Carboxyl- und Sulfonsäuregruppen. Als Basen können hierzu alle in der pharmazeutischen Chemie, insbesondere in der Chemie der Antibiotika, üblicherweise verwendeten Basen eingesetzt werden. Als anorganische Basen seien beispielhaft genannt: Alkali- und Erdalkalihydroxide, Alkali- und Erdalkalicarbonate und Alkalihydrogencarbonate, wie Natrium- und Kaliumhydroxid, Calcium- und Magnesiumhydroxid, Natrium- und Kaliumcarbonat, Calciumcarbonat, Natrium- und Kaliumhydrogencarbonat; Aluminiumhydroxid und Ammoniumhydroxid. Als organische Amine können primäre, sekundäre und tertiäre aliphatische Amine sowie heterocyclische Amine eingesetzt werden. Beispielhaft seien genannt: Di- und Triniedrigalkylamine, z. B. Diäthylamin, Triäthylamin, Tri-ß-hydroxyäthylamin, Procain, Dibenzylamin, N,N'-Dibenzyläthylendiamin, N-Benzyl-ß-phenyl-äthylamin, N-Methyl- und N-Äthylmorpholin, 1-Ephenamin, Dehydroabietyl-amin, N,N'-Bis-dehydroabietyläthylendiamin, N-Niedrigalkylpiperidin. Auch sogenannte basische Aminosäuren wie Lysin oder Arginin können vorteilhaft als Basen Verwendung finden. Besonders bevorzugte Salze sind die Natriumsalze.Pharmaceutically usable salts of the compounds of the 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-ß-hydroxyethylamine, procain, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-ß-phenyl-ethylamine, N-methyl and N-ethylmorpholine, 1-ephenamine, dehydroabiet y l- amine, N, N'-bis-dehydroabietylethylenediamine, 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.

Ganz besonders bevorzugte Verbindungen der Formel I sind solche, bei denen T für einen Rest aus der Gruppe

Figure imgb0009
Figure imgb0010
steht und

  • C in der R-Konfiguration vorliegt sowie die pharmazeutisch verwendbaren Salze dieser Verbindungen, insbesondere die Natriumsalze.
Very particularly preferred compounds of the formula I are those in which T is a radical from the group
Figure imgb0009
Figure imgb0010
 stands and
  • C is in the R configuration and the pharmaceutically usable salts of these compounds, in particular the sodium salts.

Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formel II sind bereits bekannt oder nach bekannten Methoden erhältlich.The compounds of general formula II used as starting materials are already known or can be obtained by known methods.

Alle Kristallformen, Hydratforman und Salze der Verbindungen der allgemeinen Formel II sind als Ausgangsmaterialien für das erfindungsgemäße Verfahren geeignet.All crystal forms, hydrate formane and salts of the compounds of the general formula II are suitable as starting materials for the process according to the invention.

Als Beispiele seien genannt:

  • 7-[α-Amino-(4-hydroxyphenyl)acetamido]-3-methyl-ceph-3-em-4-carbonsäure, 7-[α-Amino-(4-hydroxyphenyl)-acetamido-3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-ceph-3-em-4-carbonsäure, 7-[α-Amino-(4-hydroxyphenyl)-acetamido]-3-[(1H-1,2,3-triazol-5-yl)-thiomethyl]-ceph-3-em-4-carbonsäure.
Examples include:
  • 7- [α-amino- (4-hydroxyphenyl) acetamido] -3-methyl-ceph-3-em-4-carboxylic acid, 7- [α-amino- (4-hydroxyphenyl) acetamido-3 - [(1- methyl-tetrazol-5-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid, 7- [α-amino- (4-hydroxyphenyl) -acetamido] -3 - [(1H-1,2,3- triazol-5-yl) thiomethyl] ceph-3-em-4-carboxylic acid.

Als Salze der Verbindungen der Formel II körren vorzugsweise Salze mit Basen eingesetzt werden, welche als für die Salzbildung mit Verbindungen der Formel I geeignet aufgeführt werden. Besonders bevorzugt sind die Natriumsalze.Preferred salts of the compounds of the formula II are 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 als Ausgangstoffe verwendeten Verbindungen der allgemeinen Formel III sind nach bekannten Methoden erhältlich. Sie können z. B. auf folgendem Wege erhalten werden (vgl. auch J.A.C.S. 78 (1956) 5349):

Figure imgb0011
Figure imgb0012
 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):
Figure imgb0011
Figure imgb0012

Diejenigen Verbindungen der allgemeinen Formel III, in denen W Azid ist, werden in üblicher Weise z. B. aus den entsprechenden Verbindungen III, in denen W Halogen ist, durch Umsetzung beispielsweise mit Alkaliaziden erhalten.Those compounds of general formula III, in which W is azide, are z. B. from the corresponding compounds III, in which W is halogen, obtained by reaction, for example, with alkali azides.

Als Verdünnungsmittel kommen beim erfindungsgemäßen Verfahren Wasser sowie alle inerten organischen Lösungsmittel, vorzugsweise solche, welche mit Wasser mischbar sind, in Frage. Hierzu gehören vor allem niedere Dialkylketone, z. B. Aceton, Methylathylketon, cyclische Aether, z.B. Tetrahydrofuran und Dioxan; Nitrile, z.B. Acetonitril; niedere Dialkylformamide, z.B. Dimethylformamid; niedere AlkylalKohole, z.B, Aethanol und Isopropanol sowie Dimethylsulfoxid. Diese Lösungsmittel können auch in Mischungen untereinander sowie in beliebigen Mischungen einzelner oder mehrerer dieser Lösungsmittel mit Wasser verwendet werden. Das erfindungsgemäße Verfahren kann also durchgeführt werden in Gegenwart von: (a) ausschließlich wasser, (b) ausschließlich einem oder mehreren organischen Lösungsmitteln oder (c) Wasser und einem oder mehreren organischen Lösungsmitteln. Ist wegen des Vorhandenseins vor Wasser eine pH-Messung während der erfindungsgemäßen Reaktion zölich, wird der pH der Reaktionsmischung durch Zusatz von Basen oder durch Verwendung von Puffergemischen vorzugsweise zwischen 6,5 bis 7,5 gehalten. Das erfindungsgemäße Verfahren läßt sich aber auch sehr gut in einem anderen pH-Bereich, beispielsweise zwischen 4,5 und 9,o oder bei pH 2,o bis 4,5, durchführen. Ferner ist es möglich, die keaktion in mit Wasser nicht mischbaren Lösungsmitteln, z. B. halogenierten Kohlenwasserstoffen, wie Chloroform oder Methylenchlorid, unter Zusatz von organischen Basen, vorzugsweise Niederalkylaminen, z. B. Triäthylamin, Diäthylamin oder cyclischen Basen, z. B. N-Äthylpiperidin durchzuführen. Weiterhin läßt sich die Reaktion in einer Mischung aus Wasser und einem mit Wasser nicht cischbaren Lösungsmittel, wie z. B. Niederalkyläthern, wie Diäthyläther, halogenierten Kohlenwasserstoffen, wie Chloroform und Methylenchlorid; Schwefelkohlenstoff; Isobutylmethylketon; Estern wie Essigsäureäthylester; aromatischen Kohlenwasserstoffen wie Benzol, ausführen, wobei es zweckmäßig ist, kräftig zu rühren und den pH-Wert durch Basenzusatz oder Verwendung von üblichen Pufferlösungen, z. B. Phosphat-, Acetat- oder Citratpuffer, zwischen 4,5 und 9,o oder z. B. 2, 0 und 4,5 zu halten. Man kann die Reaktion aber auch in Wasser allein in Abwesenheit von organischen Lösungsmitteln in Gegenwart einer organischen oder anorganischen Base oder unter Zusatz von üblichen Pufferstoffen durchführen.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 ethers, 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 more organic solvents or (c) water and one or more organic solvents. If, due to the presence in front of water, a pH measurement is hesitant during the reaction according to the invention, the pH of the reaction mixture is preferably kept between 6.5 to 7.5 by adding bases or by using buffer mixtures. The Ver But driving can also be carried out very well in a different pH range, for example between 4.5 and 9.0 or at pH 2.0 to 4.5. It is also possible to react in water-immiscible solvents, e.g. B. halogenated hydrocarbons, such as chloroform or methylene chloride, with the addition of organic bases, preferably lower alkylamines, for. 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, o or z. B. 2, 0 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.

Als Säurebindemittel können alle in der Chemie der Antibiotica üblicherweise verwendeten Säurebinder verwendet werden. Hierzu gehören anorganische Basen und organische Basen, welche z. B. durch sterische Hinderung schwer acylierbar sind. Als Beispiele für anorganische Basen seien Natrium- und Kaliumhydroxid genannt. Als organische Basen kommen praktisch alle nicht oder schwer acylierbaren offenkettigen oder cyclischen Amine und auch heteroaromatische Basen in Frage. Als Basen seien beispielhaft tertiäre Amine, vorzugsweise Niederalkylamine, z.B. Triäthylamin und/oder cyclische Basen, z.B. Pyridin sowie als schwer acylierbares sekundäres Amin Dicyclohexylamin genannt.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 are tertiary amines, preferably lower alkylamines, e.g. B. Triethylamine and / or cyclic bases, e.g. B. Pyridine and dicyclohexylamine called secondary amine, which is difficult to acylate.

Beim erfindungsgemäßen Verfahren ist der Zusatz einer Base nur dann erforderlich, wenn während der Reaktion saure Verbindungen entstehen, z.B. im Falle, daß W für Halogen oder Azid s+eht.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 s +.

Die Reaktionstemperaturen können in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man zwischen etwa -20°C und etwa +50°C, vorzugsweise zwischen O und +200C. Wie bei den meisten chemischen Reaktionen können jedoch prinzipiell auch höhere oder niedrigere Temperaturen verwendet werden.The reaction temperatures can be varied within a wide range. In general, between about -20 ° C and about + 50 ° C, preferably between 0 and +20 0 C. However, as with most chemical reactions, higher or lower temperatures can in principle also be used.

Die Umsetzung kann bei Normaldruck, aber auch bei vermindertem oder erhöhten Druck ausgeführt werden. Im allgemeinen arbeitet man bei Normaldruck.The reaction can be carried out under normal pressure, but also under reduced or elevated pressure. Generally one works at normal pressure.

Bei der Durchführung der erfindungsgemäßen Verfahren können die Anteile der Reaktionspartner der Formeln II und III in weiten Grenzen variiert werden, ohne daß das Ergebnis nachteilig beeinflußt wird. Die Ausgangsstoffe können z.B. in äquimolekularen Mengen miteinander zur Reaktion gebracht werden. Es kann jedoch zweckmäßig sein, einen der beiden Reaktionspartner im Überschuß zu verwenden, um sich die Reinigung oder Reindarstellung des gewünschten Penicillins zu erleichtern und die Ausbeute zu erhöhen.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.

Beispielsweise kann man die Reaktionspartner der allgemeinen Formel II mit einem Ueberschuß von 0,1 bis 0,3 Moläquivalenten einsetzen und dadurch eine geringere Zersetzung der Reaktionspartner der allgemeinen Formel III. in einem wasserhaltigen Lösungsmittelgemisch erreichen. Der Ueberschuß der Reaktionspartner der allgemeinen Formel II laßt sich wegen der guten Löslichkeit in wäßrigen Mineralsäuren beim Aufarbeiten des Reaktionsgemisches leicht entfernen.For example, you can use the reactants of the general formula II with an excess of 0.1 to 0.3 molar equivalents and thereby a lower decomposition of the reactants of the general formula III. in a water-based 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.

Andererseits kann man aber auch mit Vorteil die Reaktionspartner der allgemeinen Formel III mit einem Ueberschuß von beispielsweise 0,1 bis 1,0 Moläquivalenten einsetzen. Dadurch werden die Reaktionspartner der allgemeinen Formel II besser ausgenützt und die als Nebenreaktion in wasserhaltigen Lösungsmitteln ablaufende Zersetzung der Reaktionsteilnehmer der allgemeinen Formel III kompensiert. Da die im Ueberschuß zugesetzten Verbindungen der allgemeinen Formel III sich in Wasser rasch in neutrale stickstoffhaltige Heterocyclen umwandeln, die sich leicht entfernen lassen, wird die Reinheit der Antibiotica hierdurch kaum beeinträchtigt.On the other hand, it is also advantageous to use the reactants of the 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 are better utilized 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.

Die Menge der gegebenenfalls verwendeten Basen ist z. B, durch die gewünschte Einhaltung eines bestimmten pH-Wertes festgelegt. Wo eine pH-Messung und Einstellung nicht erfolgt oder wegen des Fehlens von ausreichenden Mengen Wasser im Verdünnungsmittel nicht möglich ist oder nicht sinnvoll ist, werden vorzugsweise 2 Moläquivalente Base zugesetzt.The amount of bases that may be used is e.g. B, determined by the desired compliance with a certain pH value. 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 sensible, 2 molar equivalents of base are preferably added.

Die Aufarbeitung der Reaktionsansätze zur Herstellung der erfindungsgemäßen Verbindungen und ihrer Salze erfolgt durchweg in der bei diesen Körpern allgemein bekannten Art und Weise. Auch die Isolierung und Reinigung der erfindungsgemäßen Verbindungen sowie die Freisetzung der freien Säuren aus Salzen oder die Umwandlung der freien Säuren in Salze werden nach allgemein üblichen Methoden der organischen Chemie, welche jedem Fachmann geläufig sind, vorgenommen.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.

Die Verbindungen der allgemeinen Formel I sind in Form der freien Säure sowohl kristallin wie amorph und sowohl wasserfrei wie in verschiedenen Hydratformen in gleicher Weise antibakteriell wirksam. Ebenfalls sind die Verbindungen der allgemeinen Formel I in Form ihrer Salze, z. B. Natriumsalze, sowohl kristallin wie amorph und sowohl wasserfrei wie wasserhaltig, beispielsweise als Hydrat, in gleicher Weise antibakteriell wirksam.The compounds of the general formula I are both crystalline and amorphous in the form of the free acid and are both antibacterially active in the same way both anhydrous and in various forms of hydrate. 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 water-containing, for example as a hydrate, antibacterial in the same way.

Als neue Wirkstoffe seien beispielhaft genannt (Formel IV):

Figure imgb0013
Figure imgb0014
Figure imgb0015
Figure imgb0016
Figure imgb0017
 Examples of new active ingredients (Formula IV) are:
Figure imgb0013
Figure imgb0014
Figure imgb0015
Figure imgb0016
Figure imgb0017

Die erfindungsgemäßen Wirkstoffe weisen bei geringer Toxizität eine starke und breite antimikrobielle Wirksamkeit auf. Diese Eigenschaften ermöglichen ihre Verwendung als chemotherapeutische Wirkstoffe in der Medizin sowie als Stoffe zur Konservierung von anorganischen und organischen Materialien, insbesondere von organischen Materialien aller Art, z.B. Polymeren, Schmiermitteln, Farben, Fasern, Leder, Papier und Holz, von Lebensmitteln und von Wasser.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.

Die erfindungsgemäßen Wirkstoffe sind gegen ein sehr breites Spektrum von Mikroorganismen wirksam. Mit ihrer Hilfe können gramnegative und grampositive Bakterien und bakterienähnliche Mikroorganismen bekampft sowie die durch diese Erreger hervorgerufenen Erkrankungen verhindert, gebessert und/oder geheilt werden.The active compounds according to the invention are active against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

besonders wirksam sind die erfindungsgemäßen Wirkstoffe gegen Bakterien und bakterienähnliche Mikroorganismen. Sie sind daher besonders gut zur Prophylaxe und Chemotherapie von lokalen und systemischen Infektionen in der Human- und Tiermedizin geeignet, die durch diese Erreger hervorgerufen werden.The active compounds according to the invention are particularly effective against bacteria and bacterial-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.

Beispielsweise können lokale und/oder systemische Erkrankungen behandelt und/oder verhindert werden, die durch die folgenden Erreger oder durch Mischungen der folgenden Erreger verursacht werden:

  • Micrococcaceae, wie Staphylokokken, z.B. Staphylococcus aureus, Staph.epidermidis, Staph.aerogenes und Gaffkya tetragena (Staph. = Staphylococcus);
  • Lactobacteriaceae, wie Streptokokken, z.B. Streptoccccus pyogenes, α-bzw. β-hamolysierende Streptokokken, nicht (y-)-hämolysierende Streptokokken, Str.viridans, Str. faecalis (Enterokokken), Str.agalactiae, Str.lactis, Str.equi, Str.anaerobis und Diplococcus pneumoniae (Pneumokokken) (Str. = Streptococcus);
  • Neisseriaceae, wie Neisserien, z.B. Neisseria gonorrhoeae (Gonokokken), N.meningitidis (Meningokokken), N.catarrhalis und N.flava (N. = Neisseria);
  • (Corynebacteriaceae, wie Corynebakterien, z.B. Corynebacterium diphtheriat, C.pyogenes, C.diphtheroides, C.acnes, C.parvum, C.bovis, C.renale, C.ovis, C.muri- septicum, Listeria-Bakterien, z.B. Listeria monocytogenes, Erysipelothrix-Bakterien, z.B. Erysipelothrix insidiosa, Kurthia-Bakterien, z.B, Kurthia zopfii (C. = Corynebacterium);
  • 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.pneumoniae, 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), Salmonelleae: Salmonella-Bäkterien, 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 (Fs. = Pseudomonas). Aeromonas-Bakterien, z.B. Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas);
  • Spiriliaceae, wie Vibrio-Bakterien, z.B. Vibrio cholerae, V.proteus, V.fetus (V. = Vibrio), Spirillum-Bakterien, z.B. Spirillum minus;
  • Parvobacteriacene oder Brucellaceae, wie Pasteurella-Bakterien, z.B. Pasteurella multocida, Fast. pestis (Yersinia), Fast.pseudotuberculosis, Past.tularensis (Past. = Pasteurella), Brucella-Bakterien, z.B. Brucella atortus, Br.melitensis, Br.suis (Er. = Brucella), Haemophilus-Bakterien, z.B. Haemophilus influenzae, H.ducreyi, H.suis, H.canis, H.aegypiteus (H. =Haemophllus), Fordetella-Bakterien, z.B. Bordetella pertussis, B.bronchiseptica (B. = Bordetella), Moraxella-Bakterien, z.B. Moraxella lacunata;
  • Bacterioidaceae, 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. = Bacillus), Anaerobe Sporenbildner-Chlostridien, z.B. Clostridium perfringens, Cl.septicium, Cl.oedematien, Cl.histolyticum, Cl.tetani, Cl.botulinum (Cl. = Clostridium);
  • Spirochaetaceae, wie Borrelia-Bakterien, z.B. Borrelia recurrentia, B.vincentii (B. = Borrelia), Treponema-Bakterien, z.B. Treponema pallidum, Tr.pertinue, Tr. carateum (Tr. = Treponema), Leptospira-Eakterien, Leptospira interrogans, z.b. Leptospira icterohaemorrhagiae, L.canicola, L.grippotyphosa, L.pomona, L.mitis, L.bovis (L. = Leptospira);
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 Streptoccccus pyogenes, α- or. β-hamolyzing streptococci, non (y -) - hemolytic streptococci, Str.viridans, Str.faecalis (enterococci), Str.agalactiae, Str.lactis, Str.equi, Str.anaerobis and Diplococcus pneumoniae (pneumococci) (Str. = Streptococcus);
  • Neisseriaceae, such as Neisseria, for example Neisseria gonorrhoeae (gonococci), N. meningitidis (meningococci), N. catarrhalis and N. flava (N. = Neisseria);
  • (Corynebacteriaceae, such as Corynebacteria, for example Corynebacterium diphtheriat, C.pyogenes, C.diphtheroides, C.acnes, C.parvum, C.bovis, C.renale, C.ovis, C.murisepticum, Listeria bacteria, for example Listeria monocytogenes, Erysipelothrix bacteria, for example Erysipelothrix insidiosa, Kurthia bacteria, for example, Kurthia zopfii (C. = Corynebacterium);
  • 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. pneumoniae, 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 vul G aris, Pr.morganii, Pr.rettgeri, Pr.mirabilis, Providencia, e.g. Providencia sp. (Pr. = Proteus), Salmonelleae: 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 (Fs. = Pseudomonas). Aeromonas bacteria, for example Aeromonas liquefaciens, A. hydrophila (A. = Aeromonas);
  • Spiriliaceae, such as Vibrio bacteria, for example Vibrio cholerae, V. proteus, V. fetus (V. = Vibrio), Spirillum bacteria, for example Spirillum minus;
  • Parvobacteriacene or Brucellaceae, such as Pasteurella bacteria, e.g. Pasteurella multocida, Fast. pestis (Yersinia), Fast.pseudotuberculosis, Past.tularensis (Past. = Pasteurella), Brucella bacteria, e.g. Brucella atortus, Br.melitensis, Br.suis (Er. = Brucella), Haemophilus bacteria, e.g. Haemophilus influenzae, H .ducreyi, H.suis, H.canis, H.aegypiteus (H. = Haemophllus), Fordetella bacteria, e.g. Bordetella pertussis, B.bronchiseptica (B. = Bordetella), Moraxella bacteria, e.g. Moraxella lacunata;
  • Bacterioidaceae, 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.pyrogenha (Sp. ;
  • Bacillaceae, such as aerobic spore-forming agents, for example Bacillus anthracis (B.subtilis, B.cereus) B. = Bacillus), anaerobic spore-forming chlorostridia, for example Clostridium perfringens, Cl.septicium, Cl.oedematien, Cl.histolyticum, Cl.tetani, Cl botulinum (Cl. = Clostridium);
  • Spirochaetaceae, such as Borrelia bacteria, for example Borrelia recurrentia, B.vincentii (B. = Borrelia), Treponema bacteria, for example Treponema pallidum, Tr.pertinue, Tr. carateum (Tr. = Treponema), Leptospira bacteria, Leptospira interrogans, e.g. Leptospira icterohaemorrhagiae, L.canicola, L.grippotyphosa, L.pomona, L.mitis, L.bovis (L. = Leptospira);

Die obige Aufzählung von Erregern ist lediglich beispielhaft und keineswegs beschränkend aufzufassen.The above list of pathogens is only an example and is in no way to be interpreted as limiting.

Als Krankheiten, die durch die erfindungsgemäßen Wirkstoffe verhindert, gebessert und/oder geheilt werden können, seien beispielsweise genannt:

  • Erkrankungen der Atmungswege und des Rachenraumes;
  • Otitis; Pharyngitis; Pneumonie; Peritonitis; Pyelonephritis; Cystitis; Endocarditis; Systeminfektionen; Bronchitis; Arthritis;lokale Infektionen.
  • Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nichttoxischen, inerten pharmazeutisch geeigneten Trägerstoffen einen oder mehrere erfindungsgemäße Wirkstoffe enthalten oder die aus einem oder mehreren erfindungsgemäßen Wirkstoffen bestehen sowie Verfahren zur Herstellung dieser Zubereitungen.
  • Zur vorliegenden Erfindung gehören auch pharmazeutische Zubereitungen in Dosierungseinheiten. Dies bedeutet, daß die Zubereitungen in Form einzelner Teile, z.B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z.B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.
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; Pharyngitis; Pneumonia; Peritonitis; Pyelonephritis; Cystitis; Endocarditis; System infections; Bronchitis; Arthritis; local infections.
  • The present 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 dosage units. This means that the preparations are in the form of individual parts, for example tablets, coated tablets, 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 whole, a half or a third or a quarter of a daily dose.

Unter nichttoxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Als bevorzugte pharmazeutische Zubereitungen seien Tabletten,Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt.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.

Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z.B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z.B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z.B. Glycerin, (d) Sprengmittel, z.B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z.B. Paraffin und (f) Resorptionsbeschleuniger, z.B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z.B. Cetylalkohol, Glycerinmonostearat, (h) Adsorptionsmittel, z.B. Kaolin und Eentonit und (i) Gleitmittel, z.B. Talkum, Calcium-und Magnesiumstearat und feste Polyäthylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. Glycerin, (d) disintegrant, e.g. Agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and eentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen gegebenenfalls Opakisierungsmittel enthaltenden Ueberzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinaltraktes gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen z.B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can be provided with the customary 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, possibly with a delay, with embedding materials e.g. Polymer substances and waxes can be used.

Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Tragerstoffen auch in mikroverkapselter Form vorliegen.The active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the carrier substances specified above.

Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z.B. Polyäthylenglykole, Fette, z.B. Kakaofett und höhere Ester (z.B. C14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble excipients, 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.

Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z.B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyäthylenglykole, Silicone, Bentonite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.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, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z.B. Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel z'.b. Chlorfluorkohlenwasserstoffe enthalten.Powders and sprays can contain the usual excipients in addition to the active ingredient (s), 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.

Losungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Tragerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z.B. Wasser, Aethylalkohol, Isopropylalkohol, Aethylcarbonat, Aethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3- - ButylenGlykol, Dimethylformamid, Oele, insbesondere Baumwollsaatol, Erdnußol, Maiskeimol, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfurylalkohol, Polyathylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can include the usual carrier substances such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils, in particular cottonseedol, Contain peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

Suspensionen können neben dem oder den wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z.B. Wasser, Aethylalkohol, Propylenglykol, Suspendiermittel, z.B, äthoxylierte Isostearylalkohole, Polyoxyäthylensorbit-und Sorbitanester, mikrokristallineCellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. Contain water, ethyl alcohol, propylene glycol, suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.

Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbessernde Zusätze, z.B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z.B. Saccharin, enthalten.The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Saccharin.

Die therapeutisch wirksamen Verbindungen sollen in den oben aufgeführten pharmazeutischen Zubereitungen vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 , vorzugsweise von etwa 0,5 bis 95 Gewichtsprozent der Gesamtmischung vorhanden sein.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.

Die oben aufgeführten pharmazeutischen Zubereitungen können außer den erfindungsgemäßen Wirkstoffen auch weitere pharcazeutische Wirkstoffe enthalten.In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.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.

Zur vorliegenden Erfindung gehört auch die Verwendung der erfindungsgemäßen Wirkstoffe sowie von pharmazeutischen Zubereitungen, die einen oder mehrere erfindungsgemäße Wirkstoffe enthalten, in der Human- und Veterinärmedizin zur Verhütung, Besserung und/oder Heilung der oben angeführten Erkrankungen.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 human and veterinary medicine for preventing, ameliorating and / or curing the diseases mentioned above.

Die Wirkstoffe oder die pharmazeutischen Zubereitungen können lokal, oral, parenteral, intraperitoneal und/oder rectal, vorzugsweise oral oder parenteral wie intravenös oder intramuskulär appliziert werden.The active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.

Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die erfindungsgenäßen Wirkstoffe in Gesamtmengen von etwa 5 bis etwa 1000, vorzugsweise 20 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben, zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder die erfindungsgemäßen Wirkstoffe, vorzugsweise in Mengen von etwa 1 bis etwa 250, insbesondere 10 bis 100 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Objekts, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einiger. Füllen ausreichend sein, mit weniger als der oben genannten Menge Wirkstoff auszukommen, während in anderen Fallen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.In general, it has proven to be advantageous both in human and in veterinary medicine to use the active ingredient (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 to 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. So it can be in some. Filling be sufficient to get by with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

Im Falle der Anwendung als Futterzusatzmittel können die neuen Verbindungen in den üblichen Konzentrationen und Zubereitungen zusammen mit dem Futter bzw. mit Futterzubereitungen oder mit dem Trinkwasser gegeben werden. Dadurch kann eine Infektion durch gramnegative oder grampositive Bakterien verhindert, gebessert und/oder geheilt werden und ebenso eine Förderung des Wachstums und eine Verbesserung der Verwertung des Futters erreicht werden.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 an infection by gram-negative or gram-positive bacteria and also promote growth and improve the utilization of the feed.

Die neuen Cephalosporine zeichnen sich durch starke antibakterielle Wirkungen, die in vivo und in vitro geprüft wurden, und durch orale Resorbierbarkeit aus.The new cephalosporins are characterized by strong antibacterial effects, which have been tested in vivo and in vitro, and by oral resorbability.

Die erfindungsgemäßen Cephalosporine können zum Zwecke der Erweiterung des Wirkungsspektrums und um eine Wirkungssteigerung speziell bei ß-lactamasebildenden Bakterien zu erzielen mit anderen antimikrobiellen Wirkstoffen z.B. mit Penicillinen, die besonders penicillinasefest sind, kombiniert werden. Eine solche Kombination wäre z.B. die mit Oxacillin oder Dicloxacillin.The cephalosporins 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.

Die erfindungsgemäßen Cephalosporine können zum Zweck der Erweiterung des Wirkungsspektrums und um eine Wirkungssteigerung zu erreichen auch mit Aminoglykosidantibiotica, wie z.B. Gentamicin, Kanamicin, Amikacin oder Tobramicin, kombiniert werden.The cephalosporins according to the invention can also be combined with aminoglycoside antibiotics, such as, for example, gentamicin, kanamicin, amikacin or tobramycin, for the purpose of widening the spectrum of activity and to achieve an increase in activity.

In vivo-VersucheIn vivo experiments

Aus der folgenden Tabelle 1 geht die Wirkung einer der' erfindungsgemußen Verbindungen gegen eine Reihe von Bakterien im Tierversuch mit der weisen Maus hervor. Die weißen Mäuse vom Stamm CF, wurden intraperitoneal mit der jeweils angegebenen Bakterienart infiziert.

Figure imgb0018
The effect of one of the compounds according to the invention against a number of bacteria in animal experiments with the white mouse is shown in Table 1 below. The white mice from the CF strain were infected intraperitoneally with the specified bacterial species.
Figure imgb0018

Therapie : zweimalig: 30 und 90 Minuten nach der Infektion. Die ED100 ist die Dosis, bei der 100% der infizierten Tiere nach 24 Stunden noch überleben.Therapy: twice: 30 and 90 minutes after infection. The ED 100 is the dose at which 100% of the infected animals survive after 24 hours.

Das erfindungsmäße Verfahren sei durch die folgenden Beispiele erläutert:

  • Bei den NMR-Spektren der erfindungsgemäßen Verbindungen bedeuten die Bezeichnungen in den Klammern:
    • s = Singulett
    • d = Dublett
    • dd = Doppeldublett
    • A2B2 = A2B2-System
The process according to the invention is illustrated by the following examples:
  • In the NMR spectra of the compounds according to the invention, the designations in the parentheses mean:
    • s = singlet
    • d = doublet
    • dd = double doublet
    • A 2 B 2 = A 2 B 2 system

Erläuterungen der in den Beispielen verwendeten Abkürzungen:

  • Gew.-Tle. = Gewichtsteile
  • Vol.-Tle. = Volumenteile
  • THF = Tetrahydrofuran
  • Essigester = Essigsäureäthylester
  • Zers.-p = Zersetzungspunkt
Explanations of the abbreviations used in the examples:
  • Parts by weight = Parts by weight
  • Vol.-Tle. = Parts by volume
  • THF = tetrahydrofuran
  • Ethyl acetate = ethyl acetate
  • Decomposition-p = decomposition point

Die Ausbeuteangaben in % bedeuten Ausbeuten in % der Theorie.The yield data in% mean yields in% of theory.

Beispiel 1example 1 Natrium-7-{(D-α-[(2-oxo-3-furfurylidenamino-imidazolidin-1-yl)-carbonylamino%-4-hydro yphenyl-aceZamido}-3-acetoxymethyl-ceph-3-em-4-carboxylatSodium 7 - {(D-α - [(2-oxo-3-furfurylideneamino-imidazolidin-1-yl) -carbonylamino% -4-hydrophenyl-aceZamido} -3-acetoxymethyl-ceph-3-em-4- carboxylate

Figure imgb0019
Figure imgb0019

Eine auf 5° gekühlte Lösung vcn 7,0 Gew.Tln. 7-(D-α-Amino-4-hydroxyphenyl-acetamido)-3-acetoxymethyl-ceph-3-em-4-carbonsäure in 120 Vol.Tln. 80-proz. wäßrigem THF wird mit lN Natronlauge bis zum konstanten pH von 8 versetzt. Dazu werden portionsweise 3,1 Gew.Tle. 1-Chlorcarbonyl-2-oxo-3-furfurylidenamino-imidazolidin gegeben, währenddessen der pH durch Zugabe von 0,5N Natronlauge auf 7,5 gehalten wird. Wenn keine Lauge mehr verbraucht wird, wird von einer geringen Menge Unlöslichem abgesaugt, 120 Vol.Tle. Wasser zugegeben und das THF schonend abgezogen. Die verbleibende wäßrige Lösung wird einmal mit Essigester extrahiert, auf 5° gekühlt,mit 1C0 Vol.Tlneiskaltem Essigester überschichtet und mit 0,5N Salzsäure auf pH 1,8 angesäuert, wobei die Säure ausfällt. Sie wird abgesaugt, einmal mit Essigester gewaschen, auf Ton abgepreßt und im Exsiccator über Phosphorpentoxid und Kaliumhydroxid getrocknet (5,7 Gew.Tle. = 69,9 %). Die Säure wird in 50 Vol.Tln.Wasser (5°) suspendiert und derart tropfenweise mit 0,3N Natronlauge versetzt, daß ein pH-Bereich zwischen 6,0 und 7,5 eingehalten werden kann. Nach der nahezu vollständigen Auflösung der Säure (End-pH 7,5) wird filtriert und die hellbraune Lösung gefriergetrocknet. Man erhält 5,0 Gew.Tle. (59,3 %) mit einem Zers.p. von 235°.A solution cooled to 5 ° of 7.0 parts by weight. 7- (D-α-Amino-4-hydroxyphenyl-acetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid in 120 parts by volume. 80 percent 1N sodium hydroxide solution is added to aqueous THF up to a constant pH of 8. For this purpose, 3.1 parts by weight. 1-Chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine added, during which the pH is kept at 7.5 by adding 0.5N sodium hydroxide solution. When no more alkali is used, a small amount of insoluble matter is sucked off, 120 vol. Parts. Water added and the THF carefully removed. The remaining aqueous solution is extracted once with ethyl acetate, cooled to 5 °, covered with 1CO vol. Of ice-cold ethyl acetate and acidified to pH 1.8 with 0.5N hydrochloric acid, the acid precipitating. It is suctioned off, washed once with ethyl acetate, pressed onto clay and dried in a desiccator over phosphorus pentoxide and potassium hydroxide (5.7 parts by weight = 69.9%). The acid is suspended in 50 parts by volume of water (5 °) and 0.3N sodium hydroxide solution is added dropwise in such a way that a pH range between 6.0 and 7.5 can be maintained. After the acid has almost completely dissolved (final pH 7.5), the mixture is filtered and the light brown solution is freeze-dried. 5.0 parts by weight are obtained. (59.3%) with a decomp. of 235 °.

IR(KBr.): 1765, 1725, 1660, 1600, 1415, 1230 cm-1
NMR(CD3OD/D2O): s 7.70(1H), d 7.66(lH,I=lHz), A2B2 7.33 und 6.86 (4H) mit überlagertem H3 des Furanrirges bei ca. 6.88, dd zentr. 6.56(I=lHz und 3Hz; 1H), d 5.70(1H), s 5.30(1H); s(breit) 3.90(4H), s 2.10(3H) ppm (δ).
Die übrigen Protonen sind verdeckt von Lösungsmittelsignal und vom Signal der austauschtaren Protonen.IR (KBr.): 1765, 1725, 1660, 160 0 , 14 15 , 1 230 cm -1
NMR (CD 3 OD / D 2 O): s 7.70 (1H), d 7.66 (lH, I = lHz), A 2 B 2 7.33 and 6.86 (4H) with superimposed H 3 of the furan range at approx. 6.88, dd centr . 6.56 (I = 1Hz and 3Hz; 1H), d 5.70 (1H), s 5.30 (1H); s (broad) 3.90 (4H), s 2.10 (3H) ppm (δ).
The remaining protons are hidden by the solvent signal and the signal of the exchangeable protons.

Der ß-Lactamgehalt beträgt 95 % (HPLC).The ß-lactam content is 95% (HPLC).

Beispiel 2Example 2

Figure imgb0020
Figure imgb0020

1,0 Gew.Tle. 7-[D-α-Amino-(4-hydroxyprenyl)-acetamido]-3-[(1H-1,2,3-triazol-5-yl)-methylthio]-ceph-3-em-4-carbonsäure (DOS 2 500 386) und 0,6 Gew.Tle. 1-Chlorcarbonyl-2-oxo-3-furfurylidenamino-imidazolidin werden wie in Beispiel 1 umgesetzt und aufgearbeitet. Man erhält 0,9 Gew.Tle. Natrium-7-{D-α-[(2-oxo-3-furfurylidenainino-imidazolidin-l-yl) carbonylaminö]-(4-hydroxyphenyl)-acetamido}-3-CH-1,2,3-triazol-5-yl)-methylthio]-ceph-3-em-4-carboxylat vom Zersp. 230°.1.0 part by weight 7- [D-α-Amino- (4-hydroxyprenyl) acetamido] -3 - [(1H-1,2,3-triazol-5-yl) methylthio] ceph-3-em-4-carboxylic acid ( DOS 2 500 386) and 0.6 part by weight. 1-Chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine are reacted and worked up as in Example 1. 0.9 parts by weight is obtained. Sodium-7- {D-α - [(2-oxo-3-furfurylidenainino-imidazolidin-l-yl) carbonylamino] - (4-hydroxyphenyl) acetamido} -3-CH-1,2,3-triazole-5 -yl) -methylthio] -ceph-3-em-4-carboxylate from mach. 230 °.

Claims (12)

1. Verbindunqen der Formel (I)
Figure imgb0021
in der T Wasserstoff, Alkyl-CO-O-, Pyridinium, 4-Carbamoylpyridinium, Aminopyridinium, Carbamoyloxy, Azido, Cyano, Hydroxy, die Gruppe -S-Phenyl, welche substituiert sein kann, oder die Gruppe -S-Het bedeutet, in welcher Het für einen gegebenenfalls substituierten heterocyclischen 5- oder 6-gliedrigen Ring steht; wobei diese Verbindungen der Formel I bezüglich des Chiralitätszentrums e in den beiden möglichen R- und S-Konfigurationen sowie als Gemische der daraus resultierenden Diastereomeren vorliegen können, und wobei die Verbindungen der Formel I, bezüglich der Iminogruppe sowohl in der syn-Form als auch in der anti-Form vorliegen können und wobei diese Verbindungen der Formel I auch in den verschiedenen Hydratformen vorliegen können, und die pharmazeutisch verwendbaren Salze dieser Verbindungen. 1. Compounds of formula (I)
Figure imgb0021
 in the T is hydrogen, alkyl-CO-O-, pyridinium, 4-carbamoylpyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxy, the group -S-phenyl, which can be substituted, or the group -S-Het, in which Het represents an optionally substituted heterocyclic 5- or 6-membered ring; where these compounds of the formula I can be present in the two possible R and S configurations with respect to the chirality center e and as mixtures of the resulting diastereomers, and where the compounds of the formula I with respect to the imino group both in the syn form and in can be in the anti form and these compounds of the formula I can also be in the various hydrate forms, and the pharmaceutically acceptable salts of these compounds. 2. Verbindungen gemäß Anspruch 1, bei denen T einen Rest aus der Gruppe
Figure imgb0022
Figure imgb0023
bedeutet und
Figure imgb0024
in der R-Konfiguration vorliegt. 2. Compounds according to claim 1, in which T is a radical from the group
Figure imgb0022
Figure imgb0023
 means and
Figure imgb0024
is in the R configuration. 3. Verbindung der Formel
Figure imgb0025
sowie ihre pharmazeutisch verwendbaren Salze.3. Compound of the formula
Figure imgb0025
 and their pharmaceutically acceptable salts. 4. Verbindung der Formel
Figure imgb0026
sowie ihre pharmazeutisch verwendbaren Salze.4. Compound of the formula
Figure imgb0026
 and their pharmaceutically acceptable salts. 5. Die Natriumsalze der Verbindungen gemäß den Ansprüchen 1 bis 4.5. The sodium salts of the compounds according to claims 1 to 4. 6. Verfahren zur Herstellung von Verbindungen der Formel I, dadurch gekennzeichnet, daß man Verbindungen der Formel II
Figure imgb0027
in welcher
Figure imgb0028
und T die oben angegebene Bedeutung haben, oder deren Salze mit Verbindungen der Formel III
Figure imgb0029
in welcher W für Halogen, Azid oder eine andere nukleofuge Abgangsgruppe steht,
in Gegenwart eines Lösungsmittels und gegebenenfalls eines Säurebindemittels bei Temperaturen von etwa -20°C bis etwa +50°C umsetzt und die erhaltenen ß-Lactam-Antibiotica gegebenenfalls in ihre pharmazeutisch verwendbaren Salze überführt oder aus den erhaltenen Salzen gewünschtenfalls die freien Säuren herstellt.6. A process for the preparation of compounds of formula I, characterized in that compounds of formula II
Figure imgb0027
 in which
Figure imgb0028
and T have the meaning given above, or their salts with compounds of the formula III
Figure imgb0029
 in which W represents halogen, azide or another nucleofugic leaving group,
in the presence of a solvent and, if appropriate, an acid binder at temperatures of from about -20 ° C. to about + 50 ° C., and the β-lactam antibiotics obtained are optionally converted into their pharmaceutically acceptable salts or, if desired, the free acids are prepared from the salts obtained. 7. Arzneimittel, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß den Ansprüchen 1 bis 5.7. Medicament, characterized by a content of a compound according to claims 1 to 5. 8. Verfahren zur Herstellung eines Arzneimittels, dadurch gekennzeichnet, daß man eine Verbindung gemäß den Ansprüchen 1 bis 5 mit pharmazeutisch geeigneten Träger- und/oder Zusatzstoffen vermischt.8. A process for the preparation of a medicament, characterized in that a compound according to claims 1 to 5 is mixed with pharmaceutically suitable carriers and / or additives. 9. Verfahren zur Behandlung von durch Bakterien hervorgerufenen Erkrankungen, dadurch gekennzeichnet, daß man Verbindungen gemäß den Ansprüchen 1 bis 5 Menschen oder Tieren appliziert, die an diesen Erkrankungen leiden. -9. A method for the treatment of diseases caused by bacteria, characterized in that compounds according to claims 1 to 5 are applied to people or animals suffering from these diseases. - 10. Verwendung von Verbindungen gemäß den Ansprüchen 1 bis 5 bei der Bekämpfung von Erkrankungen.10. Use of compounds according to claims 1 to 5 in combating diseases. 11. Futterzusatzmittel, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß den Ansprüchen 1 bis 5.11. Feed additive, characterized by a content of a compound according to claims 1 to 5. 12. Verwendung von Verbindungen gemäß den Ansprüchen 1 bis 5 zur Förderung des Wachstums und zur Verbesserung der Verwertung des Futters bei Tieren.12. Use of compounds according to claims 1 to 5 for promoting the growth and improving the utilization of the feed in animals.
EP78100356A 1977-07-16 1978-07-11 Beta-lactam compounds, process for their preparation and their use Withdrawn EP0000393A1 (en)

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EP0176716A1 (en) * 1984-08-25 1986-04-09 Bayer Ag Crystalline sodium salt of D-6-(alpha-[(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)carbonylamine]-thienyl-2-acetamido)-penicillanic acid, process for its preparation and its use in pharmaceutical compounds

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JPS5850799A (en) * 1981-09-21 1983-03-25 株式会社栄工業所 Method of electrically plating panel

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DE2456307A1 (en) * 1974-11-28 1976-08-12 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
DE2512998A1 (en) * 1975-03-25 1976-10-07 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
DE2525541A1 (en) * 1975-06-07 1976-12-16 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
FR2359145A1 (en) * 1976-07-23 1978-02-17 Bayer Ag NEW ANTIBIOTICS OF THE B-LACTAM TYPE, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM
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DE2456307A1 (en) * 1974-11-28 1976-08-12 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
DE2512998A1 (en) * 1975-03-25 1976-10-07 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
DE2525541A1 (en) * 1975-06-07 1976-12-16 Bayer Ag Alpha-(imidazolidinonyl carbonylamino) penicillins and cephalosporins - active against gram negative species and useful e.g. as feed additives
FR2359145A1 (en) * 1976-07-23 1978-02-17 Bayer Ag NEW ANTIBIOTICS OF THE B-LACTAM TYPE, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM
DE2658718A1 (en) * 1976-12-24 1978-06-29 Bayer Ag Beta lactam antibacterials - with 2-oxo-imidazolidine type substit. in the side chain, are useful e.g. for increasing growth rate of animals

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176716A1 (en) * 1984-08-25 1986-04-09 Bayer Ag Crystalline sodium salt of D-6-(alpha-[(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)carbonylamine]-thienyl-2-acetamido)-penicillanic acid, process for its preparation and its use in pharmaceutical compounds

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JPS5419992A (en) 1979-02-15
AU3796078A (en) 1980-01-17
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