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EP1866312A1 - Derives d'iminopeptide cycliques - Google Patents

Derives d'iminopeptide cycliques

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Publication number
EP1866312A1
EP1866312A1 EP06723579A EP06723579A EP1866312A1 EP 1866312 A1 EP1866312 A1 EP 1866312A1 EP 06723579 A EP06723579 A EP 06723579A EP 06723579 A EP06723579 A EP 06723579A EP 1866312 A1 EP1866312 A1 EP 1866312A1
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EP
European Patent Office
Prior art keywords
methyl
salts
solvates
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06723579A
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German (de)
English (en)
Inventor
Hans-Georg Lerchen
Guido Schiffer
Heike BRÖTZ-ÖSTERHELT
Anke Mayer-Bartschmid
Stefan Eckermann
Christoph Freiberg
Rainer Endermann
Joachim Schuhmacher
Heinrich Meier
Niels Svenstrup
Stephan Seip
Matthias Gehling
Dieter Häbich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aicuris GmbH and Co KG
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Aicuris GmbH and Co KG
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Application filed by Aicuris GmbH and Co KG filed Critical Aicuris GmbH and Co KG
Publication of EP1866312A1 publication Critical patent/EP1866312A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 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.
  • 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.
  • R 1 and R 2 are hydrogen
  • R 1 and R 2 are methyl
  • R 2 is hydrogen
  • 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, C ⁇ -Cio-aryl and 5- or 6 -membered heteroaryl
  • 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,
  • 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 ⁇ alkylamino carbonyl,
  • R 3 and R 4 together with the nitrogen or oxygen atom to which they are attached form a group of the formula
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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-methylaminocarbon
  • 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 ⁇ aphthyl.
  • Heteroaryl is an aromatic, monocyclic radical having usually 5 to 6 ring atoms and up to 4 heteroatoms from the series S, O and ⁇ , wherein a nitrogen atom is also a ⁇ -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.
  • 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.
  • R 1 and R 2 are hydrogen
  • R 1 and R 2 are methyl
  • R 2 is hydrogen
  • R 3 and R 4 independently of one another are methyl or ethyl
  • 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
  • R 3 and R 4 together with the nitrogen or oxygen atom to which they are attached form a group of the formula
  • R 2 is hydrogen
  • R 3 and R 4 independently of one another are methyl or ethyl
  • 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
  • R 1 , R 2 , R 3 and R 4 have the abovementioned meaning
  • 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
  • R 3 has the meaning given above
  • R 4 has the meaning given above
  • X 1 is halogen, preferably bromine or iodine
  • 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,
  • 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.
  • alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate
  • 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.
  • 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.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, or mixtures of these solvents
  • Water preferably dioxane
  • 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
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C to 4O 0 C at atmospheric pressure.
  • 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
  • the microorganism is in a nutrient medium, which contains a carbon source and optionally a proteinaceous material.
  • a carbon source 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.
  • 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.
  • the temperature is between 21 0 C and 32 0 C, more preferably about 28 0 C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a vegetative inoculum is used for large volume fermentations.
  • 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.
  • sterile air is passed through the culture medium.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Staphylococci Staph aureus, Staph epidermidis
  • streptococci Strept agalactiae, Strept faecalis, Strept pneumoniae, Strept pyogenes
  • 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.
  • Pseudomonas Ps. Aeruginosa, Ps. Maltophilia
  • 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
  • pathogens are merely exemplary and by no means restrictive.
  • 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 as 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds according to the invention can be administered in suitable administration forms.
  • 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).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 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 ⁇ m; 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 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
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • the strain S. spec. DSM 17025 in the following medium Medium 1: yeast malt
  • 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.
  • 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.
  • a 40 1 Bioengineering (Switzerland) stirred fermenter (paddle) incubated.
  • 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.
  • the aqueous fermentation samples 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.45 ⁇ m filter and injected on the analytical HPLC or LC-MS.
  • the individual bottromycins have the following retention times:
  • the HPLC-MS system used had the following parameters: Stationary phase: Waters Symmetry C18, 3.5 ⁇ m 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:.
  • 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 ⁇ m 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.
  • UV raax at 206-207 nm and a weak shoulder at 230 nm and the following retention times:
  • 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 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.
  • bottromycins are present as salts of trifluoroacetic acid, a resalting to mesyl and formate salts is quite possible.
  • Example 4A Analogously to the alternative synthesis of Example 4A, the title compound is prepared from 28 mg (33.45 ⁇ M) bottromycin C2.
  • Example 4A Analogously to the alternative synthesis of Example 4A, the title compound is prepared from 22 mg (27 ⁇ M) bottromycin B2.
  • Example 1 Analogously to the synthesis of Example 1, the title compound is obtained from 5 mg (6.2 ⁇ M) of the compound from Example 4A, 1.35 mg (12.4 ⁇ M) 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 ⁇ l of ethyl diisopropylamine.
  • Example 1 Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 ⁇ M) of the compound from Example 4A, 3.1 mg (24.7 ⁇ M) 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 ⁇ l of ethyl diisopropylamine.
  • Example 1 Analogously to the synthesis of Example 1, the title compound of 11 mg (13.85 ⁇ M) of the compound from Example 6A, 5.1 mg (41.5 ⁇ M) 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 ⁇ l of ethyl-diisopropylamine.
  • 1,2-oxazinan hydrochloride prepared analogously to Perkin 2, 2000, 1435 and J. Chem. Soc., 1942, 432
  • 1-hydroxy-1H-benzotriazole 3.2 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • Example 2 Analogously to the synthesis of Example 1, the title compound is obtained from 11 mg (13.9 ⁇ M) of the compound from Example 6A, 4.2 mg (69 ⁇ M) N, O-dimethylhydroxylamine, 2.8 mg 1-hydroxy-1H-benzotriazole and 3.2 mg N- (3 Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.
  • Example 2 Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12 ⁇ M) of the compound from Example 5A, 3.7 mg (61 ⁇ M) N, O-dimethylhydroxylamine, 2.5 mg 1-hydroxy-1H-benzotriazole and 2.8 mg N- (3 Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.
  • Example 2 Analogously to the synthesis of Example 1, the title compound is obtained from 10 mg (12.4 ⁇ M) of the compound from Example 4A, 5.5 mg (62 ⁇ M) 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.
  • Example 1 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.
  • Example 2 Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 ⁇ M) of the compound from Example 4A and 2.2 mg (25 ⁇ M) of isoxazolidin-4-ol (preparation according to Synthesis 1982, 5, 426).
  • Example 2 Analogously to the synthesis of Example 1, the title compound is prepared from 10 mg (12.4 ⁇ M) of the compound from Example 4A and 3.6 mg (25 ⁇ M) of ethylisoxazolidine-5-carboxylate (preparation analogous to J. Chem. Soc. Chem. Commun. 1984, 9, 606).
  • Example 2 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).
  • Example 2 Analogously to the synthesis of Example 1, the title compound is obtained from 5 mg (6.2 ⁇ M) of the compound from Example 4A and 4.2 mg (19 ⁇ M) of 2-oxa-3-azabicyclo [2.2.2] oct-5-ene trifluoroacetate (preparation analogous to Organic Letters 2004, 11, 1805).
  • HTM Haemophilus Test Medium i.p. intraperitoneal i.v. intravenous
  • the minimum inhibitory concentration 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 ⁇ l each of the diluted test substances is placed in a 96-well microtiter plate and 100 ⁇ l of the 1: 300 Mueller-Hinton broth (HTM for Haemophilus influenzae) diluted germinal suspension are added.
  • HTM Mueller-Hinton broth
  • 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.
  • the suitability of the compounds of the invention for the treatment of bacterial infections can be demonstrated in various animal models.
  • 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.
  • 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.
  • 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.
  • mice are infected intranasally with 8x10 5 germs of S. pneumoniae L3TV.
  • the inoculum is adjusted by diluting a frozen stock culture.
  • iv therapy is given twice a day.
  • the lung is removed, the tissue is homogenized and a germ count is carried out.
  • the pharmacokinetic properties of a compound 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.
  • Blood is taken from the vena cava caudalis.
  • 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.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • 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 ⁇ m) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des dérivés d'iminopeptide cycliques antibactériens, des procédés pour leur production, leur utilisation pour le traitement et/ou la prévention de maladies, ainsi que leur utilisation pour produire des médicaments servant au traitement et/ou à la prévention de maladies, notamment d'infections bactériennes.
EP06723579A 2005-03-30 2006-03-21 Derives d'iminopeptide cycliques Withdrawn EP1866312A1 (fr)

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DE102005014243 2005-03-30
DE102005055946A DE102005055946A1 (de) 2005-03-30 2005-11-24 Cyclische Iminopeptid-Derivate
PCT/EP2006/002565 WO2006103010A1 (fr) 2005-03-30 2006-03-21 Derives d'iminopeptide cycliques

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