WO2012016266A2 - Dérivé de tétrahydroanthracénone - Google Patents

Dérivé de tétrahydroanthracénone Download PDF

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Publication number
WO2012016266A2
WO2012016266A2 PCT/AT2011/000334 AT2011000334W WO2012016266A2 WO 2012016266 A2 WO2012016266 A2 WO 2012016266A2 AT 2011000334 W AT2011000334 W AT 2011000334W WO 2012016266 A2 WO2012016266 A2 WO 2012016266A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
use according
resistant
salmonella
talaromanin
Prior art date
Application number
PCT/AT2011/000334
Other languages
German (de)
English (en)
Other versions
WO2012016266A3 (fr
Inventor
Alexander Pretsch
Heinz Burgmann
Apostolos Georgopoulos
Peter Proksch
Abdessamad Debbab
Original Assignee
Sealife Pharma Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sealife Pharma Gmbh filed Critical Sealife Pharma Gmbh
Publication of WO2012016266A2 publication Critical patent/WO2012016266A2/fr
Publication of WO2012016266A3 publication Critical patent/WO2012016266A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
    • C12P7/26—Ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel tetrahydroanthracenone derivative, a process for its preparation and its use as an anti-infective agent, above all against multiple drug-resistant pathogens.
  • methicillin-resistant Staphylococcus aureus (also abbreviated as MRSA, although more commonly used for "multidrug-resistant Staphylococcus aureus”) means that the use of ⁇ -lactams is ineffective in the therapy of S. aureus, while - For example, glycopeptides show most effect.
  • Altersolanols generally correspond to one (2):
  • R 1 to R 4 may each be H or OH, which in the case of OH in formula (2) in each case gives a chiral carbon atom which may be present both in the R and in the S configuration.
  • the "dimeric" aged porcines are generally of the following formula (3):
  • Flavomannin Such compounds have at least one chiral center in the molecule and are therefore present in the form of enantiomers, with atropisomerism generally also occurring.
  • reports on the antimicrobial efficacy of such compounds are largely missing.
  • only one study is known in which the two atropisomers of atrovirin B, isolated from Talaromyces wortmannii, were tested against microorganisms.
  • the object of the invention was the identification, isolation and preparation of new substances for use as antimicrobial agents in pharmaceutical compositions, especially compounds which show activity against multiple drug resistant (MDR) pathogens.
  • MDR multiple drug resistant
  • the inventors have isolated and characterized from a Talaromyces worfman / culture solution the new chemical compound shown in the formula below: e.ö'-dimethyl ⁇ 'a.S'.e.e' ⁇ '-octahydroxy-ö.S'.e.e'-tetrahydro-l, 1'-bianthracenyl-8,8' (7W, 77- /) -dione.
  • This compound is most likely in the form of several optical isomers because of the two asymmetric carbon atoms at positions 6/6 'and the limited freedom of rotation around the bond between the two anthracenone moieties, their separation and structure elucidation are still not satisfactory a successful degree.
  • the new compound was called by the inventors because of their origin as "Talaromanin":
  • a second aspect of the invention is the use of this novel compound as an anti-infective agent, preferably against Gram-positive and Gram-negative bacteria, in particular as anti-infective agents against multiple drug resistant, MDR) pathogens, propionibacteria and salmonella.
  • the compound is preferably against multiple drug-resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Klebsiella sp., Pseudomonas aeruginosa, Enterococcus faecalis or faecium, Streptococcus pneumoniae, Staphylococcus epidermis, Acinetobacter baumannii, Enterobacter, Propionibacterium acnes, Clostridium difficile and Enterobacter sp. and against Salmonella enteritidis and Salmonella typhimurium, as evidenced by the later embodiments in detail. As noted in various tests, the new compound is virtually nontoxic.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Escherichia coli Escherichia coli
  • Klebsiella sp. Pseudomonas aeruginosa
  • the present invention also relates to a process for the preparation of the novel compound which consists in fermenting a microorganism producing the compound or a precursor thereof under growth conditions, and the compound, optionally after destruction of the cells of the microorganism to increase the yield to win the culture.
  • a pure strain of Talaromyces wortmannii is preferably used as microorganism since the inventors were able to obtain the best yields with this species.
  • any other microorganisms capable of producing the new compound or precursors thereof can also be used for the fermentation.
  • precursors are obtained by the fermentation, these can be converted into the desired new compound by any method well known to those skilled in the art of organic synthesis, wherein optionally also enzyme catalysis process steps can be used to ensure higher stereoselectivity.
  • a possible synthetic route is to isolate a compound from the fermentation broth having a methyl group at C6 and one or more groups (eg, OH groups) at C5, C6 and C7, respectively, which can be conveniently eliminated to form a double bond between C5 and C6 or C6 and C7, and thus to obtain a prochiral center at C6.
  • this double bond can be enzymatically (re) hydrated, which results in a suitable choice of the stereospecificity of the enzyme (eg hydratase, peroxygenase) the desired compound of the present invention.
  • the enzyme eg hydratase, peroxygenase
  • the same procedure can, of course, also be carried out on the corresponding atoms of the second anthracenone main body in the molecule.
  • Suitable enzymes for the synthesis steps for the reaction of precursors of the desired compound can in some cases also be isolated from that used for fermentation or else from another microorganism. The latter case may be useful if, for example, a microorganism produces the desired product, but e.g. in so small amounts or so heavily contaminated that it is more economical to obtain a precursor of the product by culturing another strain (or even another species or genus) and to convert it to the target compound by enzymatic synthesis.
  • the extraction of the compound is carried out according to the present invention, however, preferably by extraction and subsequent isolation from a crude extract of a culture, for example by fractional crystallization or chromatography, more preferably preparative HPLC, which has so far again yielded the best yields with the highest purity.
  • a crude extract of a culture for example by fractional crystallization or chromatography, more preferably preparative HPLC, which has so far again yielded the best yields with the highest purity.
  • other isolation methods such as direct fractional crystallization of the crude extract or absorption methods, conceivable.
  • the person skilled in the art can determine the isolation method suitable for the particular culture (or synthesis or partial synthesis) step without undue experimentation.
  • novel compound of the invention was obtained by cultivating Talaromyces worfmannii and subsequent extraction.
  • Aloe vera The leaves of Aloe vera (true aloe) minced into small pieces were used to insulate the endophytic fungus. The surface of the pieces was sterilized twice with 70% ethanol for 2 minutes and then rinsed with sterile water to remove the alcohol. To distinguish any remaining epiphytic fungi from endophytic fungi, an imprint of the leaf surface on biomalt agar was made. Small tissue samples from the interior were aseptically sliced and pressed into petri dishes on malt agar medium containing antibiotic to suppress bacterial growth.
  • the composition of the insulating medium was as follows: 15 g / l malt extract, 15 g / l agar and 0.2 g / l chloramphenicol in distilled water, pH 7.4-7.8). From the cultures, a pure mushroom strain was obtained by repeated inoculation on malt agar plates.
  • the fungal culture was determined according to a molecular biological protocol by DNA amplification and sequencing of the ITS region as Talaromyces sp. identified. To clarify the species, a sample was sent to the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ) in Braunschweig, Germany, where the fungal strain was identified as Talaromyces wortmannii. Sequence data were deposited with GenBank under accession number HM 807532.
  • the fractions containing the desired compound were pooled and subjected to semipreparation HPLC (Merck, Hitachi L-7100) using a Eurosphere 100-10 C18 column (300 x 8 mm, L x id) and a linear water-methanol gradient subjected to increasing polarity as eluent. In this way the novel compound of the invention was obtained in pure form.
  • the 1 H-NMR spectrum shows signals of a tertiary methyl group at ⁇ 1, 43 (3H, s, H-1 1), two methylene groups at ⁇ 2.83 (2H, m, H-7) and ⁇ 3.05 ( 2H, m, H-5) and two aromatic protons at ⁇ 6.72 (1H, s, H-4) and ⁇ 6.87 (1H, s, H-10).
  • the 13 C spectrum comprises 15 carbon signals which are measured by DEPT measurements of a methyl group, two methylene groups, two methine groups and ten quaternary carbon atoms can be assigned.
  • the HMBC data confirm this and show proton-carbon distance correlations within the compound.
  • the aromatic proton at ⁇ 6.72 (1 H, s, H-4) correlates with three oxygen-bearing aromatic carbon atoms at ⁇ 159.0, 161, 5, and 167.8, corresponding to C2, C3, and C9. Furthermore, H-4 correlates via ⁇ -correlations also with the carbon atoms C10 and C10a.
  • the COZY spectrum shows far-distance correlations between protons H-5 in an aliphatic ring and proton H-10 in an aromatic ring, which was confirmed by ROESY. Confirmation of the spin system in the aliphatic ring was made by the observed COZY crosspeaks and HMBC measurement.
  • MIC stands for the "minimal inhibitory concentration" (MIC for "minimal inhibitory concentration ”) and refers to the lowest concentration of a substance that can not be observed by the naked eye to increase the number of microorganisms.
  • the MIC is determined by a so-called titer method, in which the substance is diluted out and then the pathogen is added determines the concentration of an antibiotic that just barely inhibits the growth of a bacterial strain.
  • MIC is expressed in micrograms per milliliter (pg / ml) and dilutions are usually in log2 increments.
  • a starting concentration of 250 g / ml was in each case doubled, which consequently resulted in test concentrations of 250 ⁇ g / ml, 125 ⁇ g / ml, 62.5 ⁇ g / ml, 31, 25 ⁇ g / ml, 15.6 ⁇ g / ml, 7.8 pg / ml and so on. Lower values therefore reflect better activity as an anti-infective agent.
  • a new compound which shows very good activity against multi-drug-resistant bacterial pathogens as well as Salmonella and Propionibakterien and therefore broad application as anti-infective agent, as well as feed additive or as an antibacterial agent in medical or cosmetic preparations, eg against acne, can find.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne le nouveau composé chimique 6,6'-diméthyl-2,2',3,3',6,6',9,9'- octahydroxy-5,5',6,6'-tétrahydro-1,1'-bianthracényl-8,8'(7H,7'H)-dione ("talaromanine"), son utilisation en tant qu'agent antiinfectieux, ainsi que son procédé de production (formule A).
PCT/AT2011/000334 2010-08-04 2011-08-03 Dérivé de tétrahydroanthracénone WO2012016266A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA1303/2010 2010-08-04
AT0130310A AT509716B1 (de) 2010-08-04 2010-08-04 Neue tetrahydroanthracenon-derivate

Publications (2)

Publication Number Publication Date
WO2012016266A2 true WO2012016266A2 (fr) 2012-02-09
WO2012016266A3 WO2012016266A3 (fr) 2012-04-26

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Application Number Title Priority Date Filing Date
PCT/AT2011/000334 WO2012016266A2 (fr) 2010-08-04 2011-08-03 Dérivé de tétrahydroanthracénone

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AT (1) AT509716B1 (fr)
WO (1) WO2012016266A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112111410B (zh) * 2018-03-14 2022-06-14 扬州大学 二苯并氧杂环庚酮类化合物的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT5072B (fr) 1900-08-03 1901-08-26 Siemens Ag

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5655334A (en) * 1979-10-12 1981-05-15 Suntory Ltd Dimeric tetrahydroanthracene compound
JP2001031564A (ja) * 1999-05-19 2001-02-06 Mitsubishi Chemicals Corp テロメレース阻害剤
AT507298B1 (de) * 2009-05-29 2010-04-15 Sealife Pharma Gmbh Neue anthrachinon-derivate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT5072B (fr) 1900-08-03 1901-08-26 Siemens Ag

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOUCHER ET AL.: "CID 2009", vol. 48, 1 January 2009, INFECTIOUS DISEASE SOCIETY OF AMERICA, article "IDSA Report on Development Pipeline"
G. A. STROBEL, CRIT. REV. BIOTECHNOL., vol. 22, 2002, pages 315 - 333
I.D. INTRIANI: "Diss.", 2007, HEINRICH-HEINE-UNIVERSITÄT DÜSSELDORF, article "Biodiversität von Pilzen mariner Herkunft und Identifizierung ihrer Sekundärstoffe"

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AT509716B1 (de) 2011-11-15
AT509716A4 (de) 2011-11-15
WO2012016266A3 (fr) 2012-04-26

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