WO2006103010A1 - Cyclic iminopeptide derivatives - Google Patents

Abstract

The invention concerns antibacterial cyclic iminopeptide derivatives, methods for producing same, use thereof for treating and/or preventing diseases, as well as their use for producing drugs for treating and/or preventing diseases, in particular bacterial infections.

Description

Cyclic iminopeptide derivatives

The invention relates to antibacterial cyclic iminopeptide derivatives and processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, especially of bacterial infections.

JP 43010998, JP 47010036, US 3650904, JP 49116297 and HU 52165 describe the fermentation of bottromycin. US 3380885 describes bottromycin as an antibiotic for the treatment of chickens and turkeys and JP 61165332 for the treatment of mycoplasmosis in porcine pets and dysentery. The structures described by bottromycin in the prior art show a false stereochemistry.

Amide and hydrazine derivatives of bottromycin are found assuming a false bottromycin backbone in JP 42006905, DE 1620027, J. Antibiotics 19, 1966, 149, J. Antibiotics 20, 1967, 162 and J. Med. Chem. 11, 1968 , 746 published as an antibiotic.

The natural substances do not correspond in their properties to the requirements placed on antibacterial drugs. Although structurally different antibacterial agents are present on the market, development of resistance can regularly occur. New means for a good and more effective therapy are therefore desirable.

An object of the present invention is therefore to provide new and alternative compounds having the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals.

Surprisingly, it has been found that certain derivatives of these natural products in which the ester group of the natural substances is replaced by substituted hydroxamates have antibacterial activity and improved pharmacokinetic properties over the natural substances. The invention relates to compounds of the formula

in which

R ¹ and R ^{2 are} hydrogen,

or

R ¹ and R ^{2 are} methyl,

or

R ¹ for methyl and

R ^{2 is} hydrogen,

and

R ³ and R ⁴ independently of one another are C 1 -C ₄ -alkyl,

Ci-C C which may be substituted with a substituent selected from the group consisting of cyano, hydroxycarbonyl, aminocarbonyl, ₄ alkoxycarbonyl, Ci-COE-alkylaminocarbonyl, C ₃ -C ₆ cycloalkyl, Cβ-Cio-aryl and 5- or 6 -membered heteroaryl

and, if it is not methyl in the case of C 1 -C ₄ -alkyl, may alternatively or additionally be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₄ -alkoxy and C ₁ -C ₆ -alkylamino,

or represents C ₃ -C ₆ -cycloalkyl,

which may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₄ -alkyl,

Ci-C ₄ -alkoxy, Ci-COE-alkylamino, cyano, hydroxycarbonyl, aminocarbonyl, C _r C ₄ alkoxycarbonyl and Ci-Cβ-alkylaminocarbonyl,

or

R ³ and R ⁴ together represent (CH ₂ ) ₃ or (CH ₂₎ and form, with the nitrogen or oxygen atom to which they are attached, a 5- or 6-membered ring, which ring may be substituted by 1 to 2 substituents independently selected from the group consisting of halogen, hydroxy, amino, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₆ -alkylamino, cyano, hydroxycarbonyl, aminocarbonyl, Ci-C ₄ alkoxycarbonyl and Ci-C _δ alkylamino carbonyl,

or

R ³ and R ⁴ together with the nitrogen or oxygen atom to which they are attached form a group of the formula

form,

in which

* is the point of attachment to the carbonyl group,

and their salts, their solvates, and the solvates of their salts.

Compounds according to the invention are the compounds of the formula (I) and (Ia) and salts thereof,

Solvates and solvates of the salts, as well as those of formula (I) and (Ia), hereinafter referred to as embodiment (e) compounds and their salts, solvates and solvates of the salts, - A - as far as the compounds of formulas (I) and (Ia) mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers can be isolated by known methods such as chromatography on chiral phase or crystallization with chiral amines or chiral acids, the stereoisomerically uniform components in a known manner.

The invention also relates to tautomers of the compounds, depending on the structure of the compounds.

As salts, physiologically acceptable salts of the compounds according to the invention are preferred in the context of the invention.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic, trifluoroacetic and benzoic acids.

Physiologically acceptable salts of the compounds (I) also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms. Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

Solvates in the context of the invention are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy. Alkylamino, alkoxycarbonyl and alkylaminocarbonyl are a linear or branched alkyl radical, generally of from 1 to 6, preferably 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N- Diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propyl-amino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl -N-methyl-amino. C ₁ -C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, the alkyl substituents independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n Propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N -diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn- propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Cycloalkyl is a cycloalkyl group having usually 3 to 6 carbon atoms, by way of example and preferably cycloalkyl are called cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Aryl is a mono- or bicyclic aromatic radical having usually 6 to 10 carbon atoms, by way of example and preferably aryl are called phenyl and Νaphthyl.

Heteroaryl is an aromatic, monocyclic radical having usually 5 to 6 ring atoms and up to 4 heteroatoms from the series S, O and Ν, wherein a nitrogen atom is also a Ν-oxide by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be mono- or polysubstituted or differently substituted. Substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which

R ¹ and R ^{2 are} hydrogen,

or

R ¹ and R ^{2 are} methyl,

or

R ¹ for methyl and

R ^{2 is} hydrogen,

and

R ³ and R ⁴ independently of one another are methyl or ethyl,

or

R ³ and R ⁴ together represent (CH ₂ ) ₃ or (CH ₂₎ and form, with the nitrogen or oxygen atom to which they are attached, a 5- or 6-membered ring which may be substituted with one Substituents selected from the group consisting of hydroxy and

ethoxycarbonyl,

or

R ³ and R ⁴ together with the nitrogen or oxygen atom to which they are attached form a group of the formula

form,

in which

* is the point of attachment to the carbonyl group,

and their salts, their solvates, and the solvates of their salts.

Also preferred in the context of the present invention are compounds of the formula (I) in which

R ¹ for methyl and

R ^{2 is} hydrogen,

and

R ³ and R ⁴ independently of one another are methyl or ethyl,

or

R ³ and R ⁴ together represent (CH ₂ ) ₃ or (CH ₂₎ and form, with the nitrogen or oxygen atom to which they are attached, a 5- or 6-membered ring which may be substituted with one Substituents selected from the group consisting of hydroxy and

ethoxycarbonyl,

and their salts, their solvates, and the solvates of their salts.

Also preferred in the context of the present invention are compounds of the formula (I) which are of the formula

correspond,

in which

R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning,

and their salts, their solvates, and the solvates of their salts.

The invention further provides a process for the preparation of the compounds of the formula (I) or their salts, their solvates or the solvates of their salts, wherein

[A] Compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning,

in the presence of one or more dehydrating reagents with compounds of the formula

in which R ³ and R ^{4 have} the abovementioned meaning,

to be implemented

or

[B] Compounds of the formula (II) in the first stage in the presence of one or more dehydrating reagents with compounds of the formula

wherein R ^{3 has} the meaning given above,

and in the second step with compounds of the formula

^{λ K} (πib),

wherein R ^{4 has} the meaning given above, and

X ^{1 is} halogen, preferably bromine or iodine,

be reacted in the presence of a base.

The reaction according to process [A] and the 1st step according to process [B] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from ⁰ ° C. to 40 ^° C. under normal pressure.

Suitable dehydrating reagents here are, for example, carbodiimides, such as, for example, N, N-diethyl, N, N'-dipropyl, N, N'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl-N'- ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxy-methyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazol-1-yl) -NN, N ', N'-tetra-methyluroniumhexafluorophosphat (HBTU), 2- (2-oxo-l- (2H) pyridyl) -l, l, ^{3,3-tetramethyluroni'} umtetrafluoroborat (TPTU) or O- (7-azabenzotriazol -l -yl) -N, N, N'-N-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures thereof , or mixture of these together with bases.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The condensation is preferably carried out with 1-hydroxybenzotriazole in the presence of a base, in particular diisopropylethylamine.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbon such as benzene, or omitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.

The reaction of the 2nd step according to process [B] is generally carried out in inert solvents, preferably in a temperature range from ⁰ ° C to 4O ⁰ C at atmospheric pressure.

Bases are, for example, alkali carbonates, e.g. Cesium, sodium or potassium carbonate, or bicarbonate, cesium carbonate is preferred.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, or ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, or mixtures of these solvents Water, preferably dioxane, dioxane / water or dimethylformamide.

The compounds of formulas (III), (IUa) and (HIb) are known or can be prepared analogously to known processes. The compounds of the formula (II) are known or can be prepared by reacting the compounds of the formula

R ¹ and R ^{2 have} the abovementioned meaning,

be reacted with a base.

The reaction is generally carried out in inert solvents, preferably in a temperature range from ⁰ ° C to 4O ⁰ C at atmospheric pressure.

Examples of bases are alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preferably lithium hydroxide.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of solvents, as solvents are preferably tetrahydrofuran and / or methanol.

The compounds of formula (IV) can be prepared by fermentation. They are produced, for example, when a strain of the species Streptomyces bottropensis (DSM 16814) or the species Streptomyces spec. (DSM 17025) in an aqueous nutrient medium under aerobic

Fermented conditions. Typically, the microorganism is in a nutrient medium, which contains a carbon source and optionally a proteinaceous material. Preferred carbon sources are, for example, glucose, brown sugar, sucrose, glycerol, starch, corn starch, lactose, dextrin and molasses. Preferred nitrogen sources are, for example, cottonseed meal, yeast, autolyzed baker's yeast, solid milk components, soybean meal, maize meal, pancreatic or papainic digestion products of casein, solid distillation components, broths of animal peptone and meat and bone pieces. Preferably, combinations of these carbon and nitrogen sources are used. Trace elements such as zinc, magnesium, manganese, cobalt and iron need not be added to the fermentation medium as long as tap water and non-purified components are used as the medium components.

The preparation can be induced at any temperature which ensures sufficient growth of the microorganisms. Preferably, the temperature is between 21 ⁰ C and 32 ⁰ C, more preferably about 28 ⁰ C.

In general, optimal production is obtained within 4 to 8 days, preferably in about 7 days. The fermentation broth normally remains weakly basic during the fermentation (pH 7.2 to pH 8.4). The final pH will depend, in part, on the buffer which may be used, and partly on the initial pH of the culture medium. Preferably, the pH is adjusted to about 6.5 to 7.5 before sterilization, more preferably to pH 7.2.

The production takes place both in shake flasks and in stirred fermenters. When culturing is carried out in shake flasks or large cauldrons and tanks, it is preferable to use the vegetative form instead of the spore form of the microorganisms for seeding in order to avoid a marked lag phase in the production of the metabolites and thus inefficient use of the equipment. Accordingly, it is advantageous to produce a vegetative inoculum in an aqueous nutrient medium by seeding this medium with an aliquot of a bottom or oblique tube culture. After a fresh, active, vegetative inoculum has been prepared in this way, it is aseptically transferred into further shake flasks or other suitable equipment for the fermentation of the microorganisms. The medium in which the vegetative inoculum is prepared may be identical or different from the medium used for the preparation of the compounds of the invention as long as it ensures sufficient microorganism growth.

In general, production is accomplished using the above-mentioned microorganisms under aerobic conditions in stirred fermentors. The production is however regardless of the fermenters and starter cultures used. The precursors can also be obtained via shake cultures. For large volume fermentations, preferably a vegetative inoculum is used. The vegetative inoculum is prepared by seeding a small volume of the culture medium with the spore form, mycelial fragments or a lyophilized pellet of the microorganism. The vegetative inoculum is then transferred to a fermentation vessel wherein, after a suitable incubation period, the compounds of formula (IV) are produced in optimal yield. Ordinarily, in an aerobic submersed fermentation process, sterile air is passed through the culture medium. For efficient growth of the microorganisms, the volume of air used ranges from about 0.25 to about 0.5 volume of air per volume of culture medium per minute (wm). An optimum ratio in a 30 liter kettle is about 0.3 wm with motion produced by a conventional propeller rotating at about 200-500 rpm, preferably at 240 rpm. The addition of a small amount, such as 1 ml / l, of antifoaming agent, such as silicone, to the fermentation medium is necessary if foaming is a problem.

Production generally begins after approximately 96 hours and takes place for at least 3 days during the fermentation period. Peak production is achieved between about 6 to 7 days fermentation time.

The compounds of formula (IV) can be isolated from the fermentation medium by conventional methods.

The compounds of the formula (IV) are present above all in the culture filtrate of the fermented microorganisms, but they can also occur in small amounts in the mycelium of the microorganisms. The culture broth can be easily obtained by separation by a separator.

Various methods can be used to isolate and purify the compounds of formula (IV) from the fermentation broth, such as by chromatographic adsorption methods (for example, by column chromatography, liquid-liquid partition chromatography, gel permeation chromatography) followed by elution with a suitable solvent. Crystallization from solvents, as well as combinations thereof. In a preferred purification method, the compounds of formula (FV) are extracted from the mycelia or extracts of the supernatant. The latter can be prepared using adsorption resins such as XAD, HP20 or Lewapol. Column chromatography methods, preferably Biotage Cl 8 KP are used to perform an initial purification perform. The final purification of the compounds is preferably achieved by preparative high performance liquid chromatography (HPLC) with Cl 8 column materials.

Preferred fermentation conditions and media are described in Examples IA to 3A.

The strains mentioned Streptomyces bottropensis DSM 16814 and Streptomyces spec. DSM 17025 are deposited with the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ), Mascheroder Weg Ib, D-38124 Braunschweig, Germany under the Budapest Treaty.

The compounds of the invention show unpredictable, valuable antibacterial and pharmacokinetic properties.

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

Because of their pharmacological properties, the compounds according to the invention can be used alone or in combination with other active compounds for the treatment and / or prophylaxis of infectious diseases, in particular of bacterial infections.

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

Gram-positive cocci, e.g. Staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept faecalis, Strept pneumoniae, Strept pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) as well as Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.friendii, Citrob. Divernis), Salmonella and Shigella; also Klebsiella (Klebs. pneumoniae, Klebs. oxytocy), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum comprises the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) as well as strictly anaerobic bacteria such as e.g. Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, e.g. Mycobacterium tuberculosis.

The above list of pathogens is merely exemplary and by no means restrictive. As diseases caused by the mentioned pathogens or mixed infections and can be prevented, ameliorated or cured by the applicable preparations according to the invention, may be mentioned, for example:

Infectious diseases in humans such. For example, septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, mouth infections, infections after dental surgery, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.

Apart from humans, bacterial infections can also be treated in other species. Examples include:

Pig: coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agactiae syndrome, mastitis;

Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

Horse: bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonellosis;

Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;

Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Likewise, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, wherein the antibacterial spectrum on the aforementioned pathogen addition to other pathogens such. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsie, Yersinia.

Another object of the present invention is the use of the compounds according to the invention fertilize for the treatment and / or prophylaxis of diseases, preferably of bacterial diseases, in particular of bacterial infections.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an antibacterially effective amount of the compounds of the invention.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example, inhalant medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), Milk, pastes, foams, scattering powders, implants or stents. The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (For example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

In general, it has been found to be beneficial to administer amounts of about 5 to 250 mg / kg of body weight per 24 h when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 100 mg / kg body weight per 24 h.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. A. Examples

Used abbreviations:

Section. absolutely aq. _ watery

CDCl ₃ chloroform

CH cyclohexane d doublet (in ¹ H-NMR) dd doublet of doublet (in ¹ H-NMR)

TLC thin layer chromatography

DCC dicyclohexylcarbodiimide

DIC diisopropylcarbodiimide

DIEA diisopropylethylamine (Hünig base)

DMSO dimethyl sulfoxide

DMAP 4-N, N-dimethylaminopyridine

DMF dimethylformamide d. Th. Of theory

EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl

EE ethyl acetate (ethyl acetate)

ESI electrospray ionization (in MS) sat. saturated

HATU O- (7-azabenzotriazol-1-yl) -N, N, N'-N-tetramethyluronium hexafluorophosphate

HBTU 0- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate

HOBt 1-hydroxy-1H-benzotriazole x H ₂ O h hour (s)

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectrometry m multiplied (in ¹ H-NMR) min

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy proz. Percent q quartet (in ¹ H NMR)

Rr retention index (at DC)

RP reverse phase (on HPLC) RT room temperature

R ₄ retention time (by HPLC)

Singlet (in ¹ H NMR) t triplet (in ¹ H NMR)

THF tetrahydrofuran

TPTU 2- (2-oxo-1 (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate

LC-MS and HPLC methods;

Method 1 (standard conditions for preparative HPLC for purifying bottromycin derivatives): Column: VP 250/21 nucleic acid 100-5, C18 ec, Macherey & Nagel: 762002; Eluent A: 0.01% trifluoroacetic acid in water, eluent B: acetonitrile / 0.01% trifluoroacetic acid; Gradient: 0 minutes 0% B, 20 minutes 20% B, 40 minutes 20% B, 60 minutes 30% B, 100 minutes 30% B, 110 minutes 100% B, 132 minutes 100% B; Flow: 5 ml / min; Oven: 30 ^° C; UV detection: 210 nm.

Method 2 (standard conditions for the analytical HPLC of bottromycin derivatives):

Column: XTerra 3.9 x 150 WAT 186000478; Temperature: 4O ⁰ C; Flow: 1 ml / min; Eluent A: 0.01% trifluoroacetic acid in water, eluent B: acetonitrile + 0.01% trifluoracetic acid, gradient: 0.0 min 20% B → 1 min 20% B → 4 min 90% B → 6 min 90% B → 6.2 min 20% B.

Method 3 (Standard Conditions for Analytical LC-MS Measurement of Bottromycin Derivatives): Instrument: Micromass LCT with HPLC Agilent Series 1100; Column: Waters Symmetry C18; 3.5 μm; 50mm x 2.1mm; Eluent A: 1 liter of water + 1 ml of 98-100% formic acid; Eluent B: 1 liter acetonitrile + 1 ml 98-100% formic acid; Gradient: 0 min 100% A -> 1 min 100% A -> 6 min 10% A -> 8 min 0% A - ^ 10 min 0% A - ^ 10.1 min 100% A -> 12 min 100% A; Flow 0 min to 10 min 0.5 ml / min -> 10.1 min 1 ml / min -> 12 min 0.5 ml / min; Oven: 40 ^° C; UV detection DAD: 208-500 nm.

NMR measurements: NMR measurements were performed on a Bruker DMX500 with the proton frequency 500.13 MHz. Solvent was DMSO-d ₆ , temperature 302K. Calibration was performed on the DMSO signal at 2.5 ppm. starting compounds

The structure of bottromycin A2 (Example IA) is confirmed by X-ray diffraction analysis. It is believed that the further mentioned bottromycins (Examples 2A to 5A) have the same stereochemistry since they show similar NMR spectra. These structures thus have a different stereochemistry than the prior art.

The resulting during the fermentation compound IA to 5 A are used in further reactions (see Example 1). If the assignment of the stereochemistry in the compounds IA to 5A actually be different, the stereochemistry of the secondary products is accordingly different.

Examples IA

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [l, 2-a] [1, 4, 7, 10] Tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3-methoxy-3-OXo-1- (1,3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalanine amide (bottromycin A2)

Example 2A

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1, 4, 7, 1] -tetraazacyclododecin-7 ( 8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3-methoxy-3-oxo-1- (1,3-thiazol-2-yl) -propyl] -beta -methyl-L-phenylalanine amide (bottromycin B2)

Example 3A

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl 1-14,14-dimethyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3-methoxy-3-oxo-l- (1,3-thiazole-2-one] yl) propyl] -beta-methyl-L-phenylalanine amide (bottromycin C2)

Example 4A

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(1R) -2-carboxy-1 - (1,3-thiazol-2-yl) ethyl] -beta -methyl-L-phenylalanine amide (bottromycin A2 as acid)

Example 5A

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-1,4,4-dimethyl-1,4,10-trioxododecahydropyrrolo [1, 2 a] [1, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -2-carboxy- l (1,3-thiazol-2-yl) -ethyl] β-methyl-L-phenylalanine amide (bottromycin C2 as acid)

Synthese der Verbindungen IA, 2A, 3A, 4A und 5A

Synthesis of compounds IA, 2A, 3A, 4A and 5A

Used strains

Table 1: Strains capable of producing the precursors Bottromycin A and B:

ATCC = American Type Culture Collection, Manassas, Va., U.S.A.

DSM = German Collection for Microorganisms and Cell Cultures, Braunschweig, Germany.

CBS = Centraalbureau voor Schimmelcultures, Baarn, The Netherlands

Streptomyces bottropensis was obtained from the Koninklijke Nederlandsche Gisten Spiritusfabriek, N.V. isolated, identified and deposited under CBS 163.64 at CBS, Baarn, The Netherlands (BP 762736, 1954). For the purpose of reviewing the present patent, the strain was again deposited with the German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany under the accession number DSM 16814.

Streptomyces spec. DSM 17025 was isolated from a soil sample from the Eifel / Germany and was included under the strain number BC 16019 in the strain collection of Bayer Healthcare AG.

Production of Examples IA, 2A and 3A

Preparation of the preculture of S. bottropensis DSM 16814

To prepare the preculture, strain S. bottropensis DSM 16814 was grown in the following medium: Medium 1: yeast malt Medium: D-glucose 0.4%, yeast extract 0.4%, malt extract 1.0%, ad 1 liter of tap water. The pH of the medium was adjusted to 7.2 with aqueous sodium hydroxide solution. The medium was sterilized in each case at 121 ^° C. and 1.1 bar overpressure for 20 minutes.

2 ml each of a mycelial suspension in 50% glycerol were prepared as an inoculum for 15 × 150 ml of medium 1 in a 1000 ml Erlenmeyer flask and for 96 hours at 240 revolutions per minute (U / min) and 28 ⁰ C incubated on a rotary shaker. These cultures were either used to produce new glycerin canned foods stored at -2O ⁰ C or served as an inoculum for the production cultures.

Production culture (30 liter scale) of S. bottropensis DSM 16814

To prepare the production culture, 15 × 150 ml of a preculture as described above was used as inoculum for 22 liters of the following medium 2: glucose (1%), starch (1.5%), yeast extract (0.5%), soya flour defatted (1.0%), Sodium chloride (0.5%), calcium carbonate (0.3%). Prior to inoculation, 1 ml defoamer SAG 5693 (Union Carbide, USA) per liter was added to the medium and sterilized with steam at 1.1 bar for 60 minutes. This production culture was incubated for 120-160 hours at 28 ⁰ C at a stirring speed of 240 U / min and with a ventilation rate of 0.3 wm in a 30 1 Bioengineering (Switzerland) stirred fermentor (blade stirrer). To track the production process, daily samples of 20 ml were used, which were taken sterile and analyzed by analytical HPLC. Under these conditions, yields of Bottromycin A (Example IA) of 20 mg / l were obtained.

Preparation of the preculture of S. spec. DSM 17025

For the preparation of the preculture, the strain S. spec. DSM 17025 in the following medium: Medium 1: yeast malt Medium: D-glucose 0.4%, yeast extract 0.4%, malt extract 1.0%, ad 1 liter of tap water. The pH of the medium was adjusted to 7.2 with aqueous sodium hydroxide solution. The medium was sterilized in each case at 121 ^° C. and 1.1 bar overpressure for 20 minutes.

Each 2 mL of a mycelial suspension in 50% glycerol were used as inoculum for 2 x 150 mL of medium 1 in a 1000 ml Erlenmeyer flask and incubated for 96 hours at 240 revolutions per minute (rev / min) and 28 ⁰ C on a rotary shaking machine. These cultures were either used to produce new glycerol preserves, which were stored at -20 ⁰ C, or they served as inoculum for the production cultures.

Production culture (30 liter scale) of S. spec DSM 17025

To prepare the production culture, 2 × 150 ml of a preculture as described above were used as the inoculum for 30 liters of the following medium 2: glucose (1%), starch (1.5%), yeast extract (0.5%), soya flour defatted (1.0%), Sodium chloride (0.5%), calcium carbonate (0.3%). Prior to inoculation, 1 ml defoamer SAG 5693 (Union Carbide, USA) per liter was added to the medium and sterilized with steam at 1.1 bar for 60 minutes. This production culture was 90-140 hours at 28 ° C at a stirring speed of 240 rev / min and with a Aeration rate of 0.3 wm in a 40 1 Bioengineering (Switzerland) stirred fermenter (paddle) incubated. To track the production process, daily samples of 20 ml were used, which were taken sterile and analyzed by analytical HPLC. Under these conditions, yields of Bottromycin A (Example IA) of 20 mg / l were obtained.

Analytical HPLC

For detection during biosynthesis analytical HPLC methods with UV / visual (HPLC-UV / Vis) and with mass spectrometric detection were used.

Prior to the HPLC analysis, the aqueous fermentation samples were separated into mycelium and culture supernatant and methanol was added to both products. The culture filtrate was diluted 1: 4 with methanol, and the centrifuged mycelium was extracted for 15 minutes with the original volume of methanol in an ultrasonic bath. The methanolic samples were filtered with an O.45μm filter and injected on the analytical HPLC or LC-MS.

HPLC-MS analyzes were performed on an HPI 100 HPLC system coupled with a Micromass LCT mass spectrometer (Micromass, Manchester, UK) in ESI ⁺ and ESF modes. Mass spectra were recorded in the range between m / z = 100 and 1650. The individual bottromycins have the following retention times:

Bottromycin A2 (Example IA): R _t = 4.54 min.

Bottromycin B2 (Example 2A): R _t = 4.51 min.

Bottromycin C2 (Example 3A): R _t = 4.61 min.

Bottromycin A2 free acid (Example 4A): R _t = 4.51 min.

Bottromycin C2 free acid (Example 5A): R _t = 4.48 min.

The HPLC-MS system used had the following parameters: Stationary phase: Waters Symmetry C18, 3.5 μm 2.1 x 50 mm; Mobile phase: Gradient water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B): 0-1 minutes 100% A; 1-6 minutes linear gradient to 90% B; 6-8 minutes 90% B-100% B; 8-10 min 100% B; Flow rate 0.5 ml / min; Column oven 40 ⁰ C, UV detection:. DAD 208-700 nm Evidence of Bottromycine was based on the protonated molecular ions (M + H) ⁺ and the deprotonated molecular ion (MH) ^", the doubly charged molecules (M + 2H) ⁺⁺ and the formic acid adducts (M + AS) ^" . Bottromycin A2 (Example IA): (M + H) ⁺ = 823.8; (M + 2H) ⁺⁺ = 412.5; (MH) - = 821.6; (M + AS) ^" = 867.7

Bottromycin B2 (Example 2A): (M + H) ⁺ = 809.8; (MH ^ H) ^{"1" 1 "} = 405.5; (MH) ^" = 807.6; (M + AS) ^" = 853.6

Bottromycin C2 (Example 3A): (M + H) ⁺ = 837.7; QΛ + 2H) ** = 419.5; (MH) ^" = 835.6; (M + AS) ^" = 881.6

Bottromycin A2 free acid (Example 4A): (M + H) ⁺ = 809.6; (M + 2H) ⁺⁺ = 405.5; (MH) ^' = 807.5

Bottromycin C2 free acid (Example 5A): (M + H) ⁺ = 823.7; (M + 2H) ⁺⁺ = 412.5; (MH) - = 821.5; (M + AS) ^" = 867.5

HPLC-UV / Vis analyzes were performed using a Hewlett Packard Series 1100 analytical HPLC system (HP, Waldbronn, Germany) consisting of a G 1312A binary pump system, a G 1315A diode array detector, a G 1316A column tempering system, a G 1322A degasser system and a G 1313A autoinjector. The mobile phase used water with 0.05% trifluoroacetic acid (A) and acetonitrile with 0.05% trifluoroacetic acid (B) at a flow of 0.4 ml / min, while a Waters Symmetry Cl 8, 3.5 μm 2.1 x 50 mm column with 10 mm precolumn served as a stationary phase. The samples were separated by a step gradient 0-100% B (25-25-45-45-65-100-25% B in 0-1-2-3.5-6.7-6.8-7.8-8.4 min). HPLC-UV chromatograms were recorded at 210 nm (detection of impurities), 225 nm and 254 nm. Diode array detection in the range of 200-600 nm yielded the HPLC UV / Vis spectra. The column oven was set at 45 ^° C.

The compounds described have the following UV spectrum: UV _raax at 206-207 nm and a weak shoulder at 230 nm and the following retention times:

Bottromycin A2 (Example IA): R _t = 4.68 min.

Bottromycin B2 (Example 2A): R _t = 4.54 min.

Bottromycin C2 (Example 3A): R, = 4.88 min.

Bottromycin A2 free acid (Example 4A): R _t = 3.44 min.

Bottromycin C2 free acid (Example 5A): R _t = 4.22 min. Isolation of Compounds of Examples IA, 2A, 3A, 4A and 5A from stirred fermentor cultures (30 liter scale)

The mycelia from fermentations of strain Streptomyces bottropensis DSM 16814 in 30 liter scale were separated from the supernatant by centrifugation (15 minutes at 2300 rpm).

The culture supernatant obtained after centrifugation was applied to a 2500 ml Lewapol column (adsorber resin, OC 1064, Bayer AG, Leverkusen, Germany). The run was discarded as well as the wash water (about 30 liters). Thereafter, 60% methanol and 3 column volumes of 80% methanol were washed with 6 column volumes. The resulting fractions were discarded and the bottromycins bound to the adsorbent resin were eluted with at least 10 column volumes of 100% methanol. The eluate was then dried in vacuo.

The mycelium obtained after the centrifugation was digested twice with 5 l of methanol each time in the Ultra-Turrax P50 DPX (Janke & Kunkel laboratory technique), then separated and discarded. The methanolic extract obtained from the digestion of the mycelium was concentrated in a rotary evaporator and the aqueous residue (about 2.6 l) was extracted four times with 2 l of ethyl acetate each time. The ethyl acetate phase was dried over sodium sulfate, filtered and dried in vacuo.

The residues from the processing of the mycelium (about 11 g, content of bottromycin A2 - $ ^■ main metabolite, about 3%) and the culture supernatant (about 5 g, content of bottromycin A2 about 10%) were combined, dissolved in methanol and further purified on a Biotage chromatography column (Flash 75, 75 x 300 mm, Biotage Cl 8 KP-WP, 15-20 μM). Use was made of a step gradient with the eluents water with 0.05% trifluoroacetic acid (A) and acetonitrile with 0.05% trifluoroacetic acid (B) at a flow rate of 80 ml / min with stages 12, 16, 20, 25, 28, 31, 31, 35 and 50% B. The bottromycins eluted at 31% B, were concentrated to dryness in vacuo (residue about 0.9 g, yield about 61% bottromycin A2) and dissolved in methanol. The total was cut in half and separated in three runs using a preparative HPLC system: Hardware Gilson Abimed HPLC (UV detector 210 nm, binary pump system, fraction collector); Solid phase: Inertsil ODS-3 Cl 8, 5μm; 30 x 250 mm with precolumn Nucleosil C18, 7μm, 20 x 30 mm; Flow rate: 41.2 ml / min; Fraction size 20.6ml / 0.5min from 50 min); Stepwise gradient of water with 0.05% trifluoroacetic acid (A) to acetonitrile with 0.05% trifluoroacetic acid (B): 0-15-75-105-115-125 min with 10-10-30-30-100-100% B.

The bottromycins eluted in the gradient range 31-35% B. The individual fractions were combined by HPLC and HPLC-MS analyzes according to the target substances and dried in vacuo. From the main metabolite bottromycin A2 (Example IA), a yield of 320 mg with> 97% purity could be achieved. Of the minor metabolites bottromycin B2 (Example 2A) and bottromycin C2 (Example 3A), 12 mg were obtained with> 98% purity and about 15 mg with> 90% purity. The free acids of bottromycin A2 (Example 4A) and bottromycin C2 (Example 5A) are present as minority components in amounts <5 mg. The minor metabolite (Example 3A) and the minority components (Example 4A), (Example 5A) were further purified to> 98% purity in a further separation step by the same preparative HPLC method.

After purification, the bottromycins are present as salts of trifluoroacetic acid, a resalting to mesyl and formate salts is quite possible.

Example 4A

Alternative synthesis:

265 mg (322 μmol) of bottromycin A2 are dissolved in 125 ml of methanol and treated with 2.4 ml of a 2M aqueous lithium hydroxide solution. The solution is refluxed for Ih, then cooled to RT and brought to pH 1-2 with 5.4 ml of 1M hydrochloric acid. It is concentrated and the residue is partitioned between 300 ml of ethyl acetate and 100 ml of water. The water phase is separated off, saturated with ammonium chloride and extracted once more with 100 ml of ethyl acetate. The combined ethyl acetate phases are concentrated and the residue taken up in dichloromethane / methanol 1: 1. In the cold, the target product is precipitated by addition of diethyl ether and petroleum ether. After filtration with suction and drying, 199 mg (76% of theory) of the acid are obtained.

HPLC (method 2): R _t = 4.14 min;

LC-MS (Method 3): R ₁ = 4.34 min; m / z = 809 (M + H) ⁺

Example 5A

Alternative synthesis:

Analogously to the alternative synthesis of Example 4A, the title compound is prepared from 28 mg (33.45 μM) bottromycin C2.

Yield: 20 mg (73% of theory)

HPLC (Method 2): R, = 4.16 min;

LC-MS (Method 3): R _t = 4.47 min; m / z = 821 (MH) ^" Example 6A

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-1,4,8-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraaza-cyclododecin-7 ( 8H) -ylidene] -3-methyl-L-valyl- (betas) -N - [(lR) -2-carboxy-l-

(L, 3-thiazol-2-yl) ethyl] -beta-methyl-L-phenylalaninamide

Analogously to the alternative synthesis of Example 4A, the title compound is prepared from 22 mg (27 μM) bottromycin B2.

Yield: 21 mg (97% of theory)

HPLC (Method 2): R _t = 4.01 min;

LC-MS (Method 3): R, = 4.34 min; m / z = 793 (MH) ^"

embodiments

example 1

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4,7,10 ] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3- [methoxy-methyl-amino-S-oxo-1-Clys-thiazole] -xypropyl- beta-methyl-L-phenylalaninamide

75 mg (92.7 μM) of the compound from Example 4A are dissolved in 3 ml of DMF and treated with 18.8 mg (139 μmol) of 1-hydroxy-1H-benzotriazole, 21.3 mg (111.2 μmol) of N- (3-dimethylaminopropyl) -N'- Ethylcarbodiimid hydrochloride and then with 28.3 mg (463.5 .mu.mol) of N, O-dimethyl hydroxylamine. The mixture is stirred for 16 h at room temperature. Then it is concentrated. The remaining residue is taken up in 300 ml of dichloromethane and shaken out with 50 ml of 5% citric acid. The water phase is separated, saturated with ammonium chloride and extracted again with dichloromethane. The combined organic phases are concentrated and the residue is purified by preparative HPLC (method 1). The appropriate fractions are combined, the solvent evaporated and the remaining residue from dioxane / water 1: 1 lyophilized. This gives 55 mg (70% of theory) of the target compound.

HPLC (Method 2): R _t = 4.31 min;

LC-MS (Method 3): R _t = 4.59 min; m / z = 852 (M + H) ⁺

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 0.8 and 0.89 (2d, 6H), 0.84 (s, 9H), 0.9 (s, 9H), 0.97 (d, 3H), 1.12 (d, 3H ), 1.68 (m, IH), 1.88 (m, IH), 2.2 (m, IH), 2.55 (m, IH), 2.9-3.3 (m, 6H), 3.65-3.8 (m,

5H), 3.4 and 3.9 (2m, 2H), 3.95 (d, IH), 4.12 (d, IH), 4.2 (dd, IH), 4.7 (t, IH), 5.0 (d, IH), 5.63 (m, IH), 6.7 (d, IH), 7.1-7.3 (m, 5H), 7.45 (m, IH), 7.63 and 7.73 (2d, 2H), 7.8-8.0 (m, 2H), 8.95 (i.e. , IH), 9.22 (d, lH).

Example 2

N - [(3S, 6S, 14R, 14AS) -6-tert-butyl-3-isopropyl-14-methyl-l, 4.10 trioxododecaliydropyrrolo _r [l, 2- a] [l, 4,7,10] Tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3-isoxazolidin-2-yl-3-oxo-l- (1,3-thiazole) 2-yl) propyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is obtained from 5 mg (6.2 μM) of the compound from Example 4A, 1.35 mg (12.4 μM) isoxazolidine hydrochloride (preparation analogous to Perkin 2, 2000, 1435 or J. Chem. Soc. 1942, 432), 1.25 mg of 1-hydroxy-1H-benzotriazole, 1.4 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 3 μl of ethyl diisopropylamine.

Yield: 2.1 mg (40% of theory)

HPLC (Method 2): R _t = 4.26 min;

LC-MS (Method 3): R, = 4.0 min; m / z = 864 (MH-H) ⁺ Example 3

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] Tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (beta-S) -beta-methyl-N - [(LR) -3- (1,2-oxazinan-2-yl) -3-oxo -l- (l, 3-thiazol-2-yl) propyl] -L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 μM) of the compound from Example 4A, 3.1 mg (24.7 μM) of 1,2-oxazinan hydrochloride (prepared analogously to Perkin 2, 2000, 1435 and J. Chem. Soc., 1942, 432), 2.5 mg of 1-hydroxy-1H-benzotriazole, 2.9 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, and 6.5 μl of ethyl diisopropylamine.

Yield: 3.8 mg (35% of theory)

HPLC (Method 2): R _t = 4.36 min;

LC-MS (Method 3): R _t = 4.6 min; m / z = 878 (M + H) ⁺ Example 4

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-1,4,8-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraaza-cyclododecin-7 ( 8H) -ylidene] -3-methyl-L-valyl- (betas) -beta-methyl-N - [(lR) -3-

(L, 2-oxazinan-2-yl) -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound of 11 mg (13.85 μM) of the compound from Example 6A, 5.1 mg (41.5 μM) of 1,2-oxazinan hydrochloride (prepared analogously to Perkin 2, 2000, 1435 and J. Chem. Soc., 1942, 432), 2.8 mg of 1-hydroxy-1H-benzotriazole, 3.2 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, and 7 μl of ethyl-diisopropylamine.

Yield: 1.7 mg (14% of theory)

HPLC (Method 2): R, = 4.26 min;

LC-MS (Method 3): R _t = 4.60 min; m / z = 864 (M + H) ⁺ Example 5

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-1,4,8-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraaza-cyclododecin-7 ( 8H) -ylidene] -3-methyl-L-valyl- (betas) -N - [(lR) -3-

[Methoxy (methyl) amino] -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is obtained from 11 mg (13.9 μM) of the compound from Example 6A, 4.2 mg (69 μM) N, O-dimethylhydroxylamine, 2.8 mg 1-hydroxy-1H-benzotriazole and 3.2 mg N- (3 Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

Yield: 8.8 mg (76% of theory)

HPLC (method 2): R, = 4.17 min;

LC-MS (Method 3): R, = 4.49 min; m / z = 838 (M + H) ⁺

Example 6

N - [(3S, 6S, 14aS) -6-tert-butyl-3-isopropyl-14,14-dimethyl-1,4,8-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betas) -N - [(lR) -3-

[Methoxy (methyl) amino] -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12 μM) of the compound from Example 5A, 3.7 mg (61 μM) N, O-dimethylhydroxylamine, 2.5 mg 1-hydroxy-1H-benzotriazole and 2.8 mg N- (3 Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

Yield: 1.7 mg (16% of theory)

HPLC (Method 2): R _t = 4.31 min;

LC-MS (Method 3): R ₄ = 4.54 min; m / z = 866 (M + H) ⁺

Example 7

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1, 4, 10-trioxododecahydropyrrolo [1, 2 a] [1, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3- [ethoxy (ethyl) amino] -3-oxo-l- (l, 3-thiazol-2-yl) ρropyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is obtained from 10 mg (12.4 μM) of the compound from Example 4A, 5.5 mg (62 μM) of N, O-diethylhydroxylamine (prepared analogously to DE 2113355 (1971)), 3.3 mg of 1-hydroxy-1H benzotriazole and 3.6 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

Yield: 5.4 mg (50% of theory)

HPLC (Method 2): R _t = 4.35 min;

LC-MS (Method 3): R, = 4.78 min; m / z = 880 (M + H) ⁺

Example 8

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1, 4, 10-trioxododecahydropyrrolo [1, 2 a] [1, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betas) -N - [(lR) -3-

[Ethoxy (methyl) amino] -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound from 10 mg (12.4 uM) of the compound from Example 4A, 4.6 mg (62 uM) N-methyl-O-ethylhydroxylamine (preparation according to DE 2113355 (1971)), 3.3 mg of 1-hydroxy -LH-benzotriazole and 3.6 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

Yield: 5 mg (47% of theory)

HPLC (Method 2): R ₁ = 4.23 min;

LC-MS (Method 3): R, = 4.63 min; m / z = 866 (M + H) ⁺

Example 9

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (beta) -N - [(lR) -3- (4-hydroxyisoxazolidin-2-yl) -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 μM) of the compound from Example 4A and 2.2 mg (25 μM) of isoxazolidin-4-ol (preparation according to Synthesis 1982, 5, 426). As a coupling reagent here instead of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride / 1-hydroxy-lH-benzotriazole 7.1 mg (18.6μM) of [O- (7-azabenzotriazol-1-yl) -l, l, 3,3-tetramethyluronium hexafluorophosphate] (HATU) in the presence of 3.2 mg of ethyldiisopropylamine. After stirring for 16 h at RT, the mixture is concentrated, the residue is purified directly by preparative HPLC (Method 1) and the title compound is isolated analogously to Example 1.

Yield: 6.8 mg (63% of theory)

HPLC (Method 2): R, = 3.86 min;

LC-MS (Method 3): R, = 4.7 min; m / z = 880 (M + H) ⁺ Example 10

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl, 1-3-isopropyl, 1-14-methyl, 1-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4] 7,10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(1R) -3- [5 (ethoxycarbonyl) -isoxazolidin-2-yl] -3-oxo -l- (l, 3-thiazol-2-yl) propyl] -beta-methyl-L-phenylalanine amide

Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 μM) of the compound from Example 4A and 3.6 mg (25 μM) of ethylisoxazolidine-5-carboxylate (preparation analogous to J. Chem. Soc. Chem. Commun. 1984, 9, 606). As a coupling reagent here instead of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride / 1-hydroxy-1H-benzotriazole 9.4 mg (24.7 μM) of [O- (7-Azabenzotriazo 1-1 -y I) - 1, 1,3, 3-tetramethyluronium hexafluorophosphate] (HATU) in the presence of 3.2 mg of ethyldiisopropylamine. After stirring for 16 h at RT, the mixture is concentrated, the residue is purified directly by preparative HPLC (Method 1) and the title compound is isolated analogously to Example 1.

Yield: 6 mg (52% of theory)

HPLC (Method 2): R _t = 4.3 min;

LC-MS (Method 3): R _t = 5.1 min; m / z = 936 (M + H) ⁺ Example 11

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-l 4-methyl-1,4,8-trioxododecahydropyrrolo [1,2-a] [l, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3- [6 (ethoxycarbonyl) O-1-oxazinan-1-yl-S-oxo l-Cl ^ -thiazole ^ -xy-propyl-beta-methyl-L-phenylalanine amide

Analogously to the synthesis of Example 1, the title compound from 17 mg (21 uM) of the compound from Example 4A and 6.7 mg (42 uM) ethyl 1, 2-oxazinan-6-carboxylate (prepared analogously to J. Org. Chem. 2000 , 65, 7667). As the coupling reagent, instead of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride / 1-hydroxy-1H-benzotriazole, 16 mg (42 μM) of [O- (7-azabenzotriazol-1-yl) -l, l, 3,3-tetramethyluronium hexafluorophosphate] (HATU) in the presence of 5.4 mg of ethyldiisopropylamine. After stirring for 16 h at RT, the mixture is concentrated, the residue is purified directly by preparative HPLC (Method 1) and the title compound is isolated analogously to Example 1.

Yield: 16.7 mg (84% of theory)

HPLC (Method 2): R, = 4.5 min;

LC-MS (Method 3): R _t = 5.3 min; m / z = 948 (MH) - Example 12

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1,4,10-trioxododecahydropyrrolo [1,2-a] [1,4,7,10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betas) -beta-methyl-N - [(lR) -3-

(2-oxa-3-azabicyclo [2.2.2] oct-5-en-3-yl) -3-oxo-l- (l, 3-thiazol-2-yl) propyl] -L-phenylalaninamide

Analogously to the synthesis of Example 1, the title compound is obtained from 5 mg (6.2 μM) of the compound from Example 4A and 4.2 mg (19 μM) of 2-oxa-3-azabicyclo [2.2.2] oct-5-ene trifluoroacetate (preparation analogous to Organic Letters 2004, 11, 1805). As a coupling reagent here instead of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimid hydrochloride / 1-hydroxy-1H-benzotriazole 3.5 mg (9.5 μM) of [O- (7-Azabenzotriazol-l-yl) -l, l, 3,3-tetramethyluronium hexafluorophosphate] (HATU) in the presence of 1.6 mg of ethyldiisopropylamine. After stirring for 16 h at RT, the mixture is concentrated, the residue is purified directly by preparative HPLC (Method 1) and the title compound is isolated analogously to Example 1.

Yield: 5 mg (90% of theory)

HPLC (Method 2): R _t = 4.3 min;

LC-MS (Method 3): R _t = 5.0 and 5.1 min; m / z = 902 (M + H) ⁺ Example 13

N - [(3S, 6S, 14R, 14aS) -6-tert-butyl-3-isopropyl-14-methyl-1, 4, 10-trioxododecahydropyrrolo [1,2-a] [l, 4,7, 10] tetraazacyclododecin-7 (8H) -ylidene] -3-methyl-L-valyl- (betaS) -N - [(lR) -3-ben2yl (methoxy) amino] -3-oxo-l- (l, 3 -thiazol-2-yl) propyl] -beta-methyl-L-phenylalaninamide

40 mg (49.4 μmol) of the compound from Example 4A are dissolved in 20 ml of DMF and 11.8 mg (74.2 μmol) of N-benzylhydroxylamine hydrochloride, 37.6 mg (98.8 μmol) of [O- (7-azabenzotriazol-1-yl) -l , l, 3,3-tetramethyluronium hexafluorophosphate] (HATU) and 12.8 mg ethyldiisopropylamine. After stirring at RT for 16 h, the mixture is concentrated, and the residue is taken up in acetonitrile / water 1: 2 and purified by preparative HPLC (method 1). The appropriate fractions are combined, the solvent is evaporated and the remaining residue is lyophilized from dioxane. This gives 44.8 mg (99% of theory) of the target compound.

HPLC (method 2): R _t = 4.38 min.

25 mg (27.3 .mu.mol) of this intermediate are dissolved in 10 ml dioxane / water 1: 1 and treated with 26.7 mg (82 .mu.mol) cesium carbonate. After stirring at RT for 10 min, the batch is lyophilized. The residue is taken up in 10 ml of DMF and used at room temperature with 85 μl (1.4 mmol) of methyl iodide. After 30 minutes, the reaction is complete. It is concentrated and the residue is purified by preparative HPLC (Method 1). 8.4 mg (33% of theory) of the title compound are obtained.

HPLC (method 2): R, = 4.3 min; LC-MS (Method 3): R ₁ = 5.65 min; m / z = 928 (M + H) ⁺ B ₁ Evaluation of physiological activity

Used abbreviations:

BHI Medium Brain heart infusion medium

DMSO dimethyl sulfoxide

HTM Haemophilus Test Medium i.p. intraperitoneal i.v. intravenous

MIC Minimum inhibitory concentration

MTP microtiter plate

PBS Phosphate Buffered Saline

PEG polyethylene glycol

The in vitro and in vivo effects of the compounds of the invention can be demonstrated in the following assays:

Determination of the Minimum Inhibitory Concentration (MIC)

The minimum inhibitory concentration (MIC) is the minimum concentration of antibiotic used to inhibit a test bacterium in its growth for 18-24 h. The inhibitor concentration can be determined according to standard microbiological procedures (see, for example, The National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobic, approved standard-fifth edition, NCCLS document M7-A5 [ISBN 1-56238-394 NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-98 USA, 2000). The MIC of the compounds of the invention is determined in the liquid dilution assay in 96-well microtiter plate scale. Fresh bacterial smears on Columbia blood platelets with 5% sheep blood (Becton Dickinson) [Chocolate agar plates (Becton Dickinson) for Haemophilus influenzae] are adjusted in physiological saline to OD ₅₇ g of 0.1. The test substances dissolved at 10 mM in DMSO are diluted further in 1: 2 dilution steps with DMSO. 1 μl each of the diluted test substances is placed in a 96-well microtiter plate and 100 μl of the 1: 300 Mueller-Hinton broth (HTM for Haemophilus influenzae) diluted germinal suspension are added. For S. pneumoniae and S. pyogenes, the germ dilution is 1: 100 in Mueller-Hinton broth supplemented with 2% lysed horse blood. The microtiter plates are aerobically incubated for 18-24 h at 37 ⁰ C; Streptococci and Haemophilus influenzae are incubated microaerophilically in the presence of 5% CO ₂ . The lowest substance concentration at which no visible bacterial growth occurs is defined as MIC.

Table A

Concentration data: MIC in μM.

Systemic infection with S. aureus 133

The suitability of the compounds of the invention for the treatment of bacterial infections can be demonstrated in various animal models. For this purpose, the animals are generally infected with a suitable virulent germ and then treated with the compound to be tested, which is present in a formulation adapted to the respective therapeutic model. Specifically, the suitability of the compounds of the invention for the treatment of bacterial infections in a sepsis model in mice after infection with S. aureus can be demonstrated.

For this purpose, S. Aureus 133 cells are grown overnight in BH broth (Oxoid, Germany). The overnight culture was diluted 1: 100 in fresh BH broth and spun for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. Thereafter, a cell suspension in saline solution with an extinction of 50 units is set on the photometer (Dr. Lange LP 2W). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.2 ml / 20 g mouse ip is administered from this infectious solution. This corresponds to a cell number of about 1-2 x 10 ⁶ germs / mouse. IV therapy is given 30 minutes after infection. For the infection trial female CFWl mice are used. The survival of the animals is recorded over 5 days. The animal model is adjusted so that untreated animals die within 24 hours of infection. The EDioo corresponds to the minimum dose at which all animals survive the infection during the observation period. Lung infection with S. pneumoniae L3TV

The suitability of the compounds according to the invention for the treatment of bacterial infections can also be demonstrated in a lung infection model in mice after infection with S. pneumoniae.

Here, female CFWl mice are infected intranasally with 8x10 ⁵ germs of S. pneumoniae L3TV. The inoculum is adjusted by diluting a frozen stock culture. On the first and second day after infection iv therapy is given twice a day. On the third day after the infection, the lung is removed, the tissue is homogenized and a germ count is carried out.

Determination of pharmacokinetic properties in vivo

In general, the pharmacokinetic properties of a compound (e.g., clearance, volume of distribution ...) are determined by measuring compound concentrations in plasma of the respective species. For this, blood is added at various times (e.g., 2, 5, 10, 20, 40 minutes, 1, 2, 4, 6, 8, 24 hours) after e.g. taken intravenous administration of the compound and centrifuged. The compound concentrations in plasma are then determined by a suitable analytical method using LC / MSMS.

In the mouse an animal is needed for each withdrawal time. Blood is taken from the vena cava caudalis. In the rat blood is obtained from catheterized animals: a silicone catheter is advanced over the right external jugular vein to the heart or into the vena cava caudalis and bound, fixed in the cervical mucus, subcutaneously transferred to the back, passed through the skin and with a plastic mandrin closed. The catheter allows for constant venous access, so it is possible to obtain complete kinetics in an animal.

In dogs, blood is taken from the jugular vein. Again, you get a complete kinetics in one animal. Exemplary embodiments of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Intravenous solution:

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.

production:

The compound of the present invention is dissolved in the water with stirring together with polyethylene glycol 400. The solution is sterile-filtered (pore diameter 0.22 μm) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

claims 1. Compound of the formula

in which R ¹ and R ^{2 are} hydrogen, or R ¹ and R ^{2 are} methyl, or R ¹ for methyl and R is hydrogen, and R ³ and R independently of one another are C 1 -C ₄ -alkyl, which may be substituted by a substituent selected from the group consisting of cyano, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, C ₃ -C ₆ -cycloalkyl, C ₆ -C 10 -aryl and 5- or 6-membered heteroaryl hydroxy, amino, C can be and, if it is not ₄ alkyl in Ci-C methyl, alternatively or additionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ -alkoxy and CrCβ alkylamino, or represents C ₃ -C ₆ -cycloalkyl, hydroxy, amino, Ci-C ₄ alkyl, C which may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C ₁ -C ₄ -alkoxy, C] _-C6 alkylamino, cyano, hydroxyl carbonyl, aminocarbonyl, C 1 -C ₄ -alkoxycarbonyl and C 1 -C 6 -alkylaminocarbonyl, or R ³ and R ⁴ together represent (CH ₂ ) ₃ or (CH ₂ ) ₄ and form with the nitrogen or oxygen atom to which they are attached a 5- or 6-membered ring, which ring may be substituted with 1 to 2 substituents independently of one another selected from the group consisting of halogen, hydroxy, amino, C 1 -C ₄ -alkyl, C] _-C4 alkoxy, Cj-Cβ alkylamino, cyano, hydroxycarbonyl, aminocarbonyl, C _r C ₄ alkoxycarbonyl and Ci-Cβ-alkylaminocarbonyl, or R ³ and R ⁴ together with the nitrogen or oxygen atom to which they are attached form a group of the formula

form, in which * is the point of attachment to the carbonyl group, or one of its salts, its solvates or the solvates of its salts. 2. A compound according to claim 1, characterized in that R ¹ and R ^{2 are} hydrogen, or R ¹ and R ^{2 are} methyl, or R ¹ for methyl and R ^{2 is} hydrogen, and R ³ and R ⁴ independently of one another are methyl or ethyl, or R ³ and R ⁴ together represent (CH ₂ ) ₃ or (CH ₂₎ and form, with the nitrogen or oxygen atom to which they are attached, a 5- or 6-membered ring which may be substituted with one Substituents selected from the group consisting of hydroxy and ethoxycarbonyl, or R ³ and R ⁴ together with the nitrogen or oxygen atom to which they are attached form a group of the formula

form, in which * is the point of attachment to the carbonyl group, or one of its salts, its solvates or the solvates of its salts. 3. A compound according to claim 1 or 2, characterized in that R ¹ for methyl and R ^{2 is} hydrogen, and R ³ and R ⁴ independently of one another are methyl or ethyl, or R ³ and R ⁴ together represent (CF 1 _{) 2} or (CH ₂₎ ⁴ and form, with the nitrogen or oxygen atom to which they are attached, a 5- or 6-membered ring, which ring may be substituted by a substituent from the group consisting of hydroxy and ethoxycarbonyl, or one of its salts, its solvates or the solvates of its salts. 4. A compound according to any one of claims 1 to 3, characterized in that they are of the formula

corresponds, in which R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim I ₅ 2 or 3, or one of its salts, its solvates or the solvates of its salts. Process for the preparation of a compound of formula (I) according to claim 1 or one of its salts, solvates or the solvates of its salts, characterized in that [A] a compound of the formula

in which R ¹ and R ^{2 have} the meaning given in claim 1, in the presence of one or more dehydrating reagents with a compound of the formula

wherein R ³ and R ^{4 have} the meaning given in claim 1, is implemented, or [B] a compound of the formula (II) in the first stage in the presence of one or more dehydrating reagents with a compound of the formula

wherein R ^{3 has} the meaning given in claim 1, and in the second stage with a compound of the formula ^{Λ K} (fflb), wherein R ^{4 has} the meaning given in claim 1, and X ^{1 is} halogen, preferably bromine or iodine, is reacted in the presence of a base. 6. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases. 7. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases. 8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of bacterial diseases. 9. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 in combination with at least one inert, non-toxic, pharmaceutically suitable Excipient. 10. Medicament according to claim 9 for the treatment and / or prophylaxis of bacterial infections. 11. A method for combating bacterial infections in humans and animals by administering an antibacterially effective amount of at least one compound according to any one of claims 1 to 4 or a medicament according to claim 9 or 10.