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WO2003068946A1 - Derives de phenalenone, leur procede de production et leur utilisation - Google Patents

Derives de phenalenone, leur procede de production et leur utilisation Download PDF

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WO2003068946A1
WO2003068946A1 PCT/EP2003/001060 EP0301060W WO03068946A1 WO 2003068946 A1 WO2003068946 A1 WO 2003068946A1 EP 0301060 W EP0301060 W EP 0301060W WO 03068946 A1 WO03068946 A1 WO 03068946A1
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formula
compound
alkyl
alkenyl
compounds
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PCT/EP2003/001060
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German (de)
English (en)
Inventor
Laszlo Vertesy
Michael Kurz
Ziyu Li
Luigi Toti
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Aventis Pharma Deutschland Gmbh
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Priority to AU2003210205A priority Critical patent/AU2003210205B2/en
Priority to CA002476618A priority patent/CA2476618A1/fr
Priority to MXPA04007918A priority patent/MXPA04007918A/es
Priority to JP2003568061A priority patent/JP2005517710A/ja
Priority to BR0307733-0A priority patent/BR0307733A/pt
Priority to EP03739452A priority patent/EP1478731A1/fr
Publication of WO2003068946A1 publication Critical patent/WO2003068946A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • 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
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
    • 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
    • C12R2001/80—Penicillium

Definitions

  • Phenalenone derivatives process for making and using same.
  • the present invention relates to phenalenone derivatives, processes for their preparation, and their use as medicaments.
  • Cancer is a mostly fatal disease of humans and animals, which is caused by the uncontrolled growth of endogenous cells. Cancer is the name given to the formation of malignant tumors (malignancies), neoplasms (tumors or carcinomas) or malignant degeneration and maturation disorders of white blood cells (leukemia, blood cancer). Cancer or tumor cells are formed by the transformation of the body's own cells. The malignancy of the cancerous cell is expressed in the autonomy of growth, that is, in its capacity to be uninhibited and unclassified in the blueprint of the organs and under
  • Tissue destruction infiltrating to grow A sure sign of malignancy is the formation of tumor-distant colonies (metastases) after haematogenous or lymphogenic spread of tumor cells. Cancer is one of the most common causes of death in humans and therefore there is a great need for methods and means of curing or treating malignant degeneration.
  • the possibility of treating malignant tumors includes not only radical removal of the tumor, but also radiological therapy with X-rays, ⁇ -, ⁇ -, ⁇ -rays, immunotherapy and chemotherapy. Immunotherapy is currently only applicable to a limited extent. Under the
  • Chemotherapy of tumors is the administration of cytotoxic agents for the treatment of tumors and residual tumor cells after local surgical treatment or radiation. These substances specifically engage in certain processes of cell division, so that tissues with a high proportion of dividing cells, such as the rapidly growing tumor tissue, react more sensitively.
  • alkylating compounds such as cyclophosphamide (The Merck Index, 12th Ed., Page 463), antimetabolites such as methotrexate (The Merck Index, 12th ed.
  • Phenalen is a condensed, not completely aromatic ring system, which decomposes in the air. Phenalenone is its oxidation product with a carbonyl group in position 1.
  • Japanese Patent Application JP 60199849 describes the phenalenone derivative 2,7,8,9-tetrahydroxy-4-methoxy-5-methyl-phenale ⁇ -1-one, which is effective as a PDE inhibitor and for the treatment of arteriosclerosis, bronchial asthma, diabetes and cancers can be used.
  • the invention has for its object to provide alternative phenalenone derivatives that can be used in tumor therapy.
  • the invention relates to a compound of the formula (I-A)
  • 2.0 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, in which alkyl, alkenyl and alkynyl are straight or branched and are optionally monosubstituted or disubstituted by
  • R 1 and R 2 are H or C 1 -C 6 -alkyl.
  • Chirality centers may be in the R or S configuration unless otherwise specified.
  • the invention relates to both the optically pure compounds and stereoisomer mixtures, such as mixtures of enantiomers and Diasteromerengemische, in any ratio.
  • the compounds according to the invention differ from substances known from the literature by the polarity, the chemical structure, the biological activity or by further physical properties.
  • the strain Penicillium herquei Bainer & Sartory, DSM 14142 forms on glucose, starch, oatmeal or glycerol-containing nutrient solutions the compounds of the formulas (II-A) and (IIB) called Penilenone, which are summarized below as compounds of the formula (II ),
  • the compounds of formulas (II-A) and (II-B) are tautomers and can not be isolated separately from one another under customary conditions (eg room temperature). Compounds of formulas (II-A) and (II-B) are referred to collectively below as the compound of formula (II).
  • the compounds of the formulas (III-A) and (III-B) are also tautomers and can not be isolated separately from one another under customary conditions (for example room temperature).
  • Compounds of formulas (III-A) and (III-B) are hereinafter referred to collectively as the compound of formula (III).
  • the invention therefore furthermore relates to a compound of the formula (I), which has the formula (II), or a pharmacologically acceptable one
  • the invention therefore further relates to a process for the preparation of a compound of the formula (II), characterized in that
  • the compound of formula (II) is optionally converted into a pharmacologically acceptable salt.
  • the invention relates to a process for the preparation of a compound of formula (I), characterized in that
  • microorganism Penicillium herquei Bainer & Sartory, DSM 14142, or one of its variants or mutants is cultivated in an aqueous nutrient medium, 2. a) a compound of the formula (II) is isolated and purified, or b) the compound of the formula (III) is isolated and purified,
  • the compound of formula (I) is optionally converted into a pharmacologically acceptable salt.
  • strain Penicillium herquei Bainer & Sartory forms the penilenone and the by-products on glucose, starch, oatmeal or glycerol-containing nutrient solutions.
  • the fungus Penicillium herquei Bainer & Sartory, DSM 14142 has a gray to bright green substrate mycelium and very little aerial mycelium. Exudates are not formed on malt medium and colors are not eliminated in the medium.
  • the strain, in culture forms the compact sporangia characteristic of Penicillium, 200-400 x 3.5-4.0 ⁇ m, which are rough on the surface.
  • the "Metulae" are relatively short, usually 4-6 10-12 x 3.0-5.0 microns and club-shaped.
  • the phialides are arranged in 6-10 "verticilli", 7-10 x 3.0 microns, ampoule-shaped.
  • the conidia are elliptical to apiculate, 3.5-5.0 x 3.0-3.5 ⁇ m, with a smooth cell wall
  • the conidia are formed in parallel chains up to 100 ⁇ m long.
  • the said method comprises the cultivation of Penicillium herquei Bainer & Sartory, DSM 14142, its mutants and / or variants under aerobic conditions in a culture medium containing at least one carbon and nitrogen source, inorganic salts and optionally trace elements.
  • the cultivation is carried out at a temperature between 20 ° and 35 ° C and at a pH between 2 and 9.
  • strain DSM 14142 and their mutants and variants can be used, as far as they produce the compounds of the invention.
  • Such mutants can be prepared in a manner known per se by physical means, for example irradiation, such as ultraviolet or X-ray, or chemical mutagens, such as ethyl methanesulfonate (EMS); 2-hydroxy-4-methoxy-benzophenone (MOB) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
  • EMS ethyl methanesulfonate
  • MOB 2-hydroxy-4-methoxy-benzophenone
  • MNNG N-methyl-N'-nitro-N-nitrosoguanidine
  • Suitable carbon sources for the fermentation are assimilable carbohydrates and sugar alcohols, such as glucose, lactose, sucrose or D-mannitol, as well as carbohydrate-containing natural products, e.g. Malt extract or yeast extract.
  • nitrogen-containing nutrients are: amino acids, peptides and proteins and their degradation products, such as casein, peptones or tryptones, also meat extracts, yeast extracts, ground seeds, such as corn, wheat, beans, soy, rice or cotton plant, distillation residues of Alcohol production, meat flours or yeast extracts, but also ammonium salts and nitrates, in particular but also synthetically or biosynthetically derived peptides.
  • the nutrient solution may contain, for example, chlorides, carbonates, sulfates or phosphates of the alkali metals or alkaline earth metals, iron, zinc, cobalt and manganese.
  • the formation of the compounds according to the invention proceeds particularly well, e.g. in a nutrient solution containing about 0.05 to 5%, preferably 1 to 2% malt extract; and 0.05 to 3%, preferably 0.05 to 1% yeast extract; 0.2 to 5%, preferably 0.5 to 2% glucose; and 0.5 to 3%, preferably 1.5% to 3% oatmeal contains.
  • the percentages are in each case based on the weight of the entire nutrient solution.
  • Penicillium herquei Bainer & Sartory forms a mixture of the compounds according to the invention.
  • the composition of the Nutrient solution may vary the quantitative proportion of one or more of the compounds of the invention.
  • the synthesis of individual compounds can be controlled by the composition of the media, so that a compound is not prepared or in an amount below the detection limit of the microorganism.
  • the cultivation of the microorganism takes place aerobically, that is, for example, submerged with shaking or stirring in shake flasks or fermenters or on solid medium, optionally with the introduction of air or oxygen. It can be carried out in a temperature range of about 15 to 30 ° C, preferably at about 20 to 30 ° C, especially at 25 to 30 ° C.
  • the pH range should be between 4 and 10, preferably between 6.5 and 7.5.
  • the microorganism is cultivated under these conditions generally over a period of 48 to 720 hours, preferably 72 to 350 hours.
  • the preculture is obtained z. B., by inoculating the mycelium in a nutrient solution and about 20 to 120 hours, preferably 48 to 72 hours to grow.
  • the mycelium can be obtained, for example, by growing the stem for about 1 to 42 days, preferably 21 to 35 days, on a solid or liquid nutrient medium, for example yeast malt agar, oatmeal agar or potato dextrose agar.
  • the fungus Penicillium herquei Bainer & Sartory, DSM 14142 the compounds of the invention by a surface or stand culture on form solid nutrient media.
  • Solid nutrient media are prepared by adding, for example, agar or gelatin to aqueous nutrient media.
  • the compounds according to the invention can occur both in the mycelium and in the culture filtrate, usually the major amount is in the cell mass. It is therefore appropriate to separate the fermentation solution by filtration or centrifugation.
  • the filtrate is extracted with an adsorption resin as a solid phase.
  • the mycelium, but also the surface culture is suitably extracted with an organic solvent, for example methanol or propanol-2.
  • the extractions can be carried out in a wide pH range, but it is expedient to work in a neutral or slightly acidic medium, preferably between pH 3 and pH 7.
  • the extracts can z. B. concentrated in vacuo and dried.
  • the compounds of formula (II) and formula (III) are substances which are unstable unless special measures are taken during the isolation and purification process. It has been found that the Penilenone can be obtained in very good yields from the cultures of the strain DSM 14142, if 1) during the isolation and purification process is carried out under reducing conditions, eg. B. always in the presence of ascorbic acid, is carried out 2) isolation in an acid medium at a pH of less than 7, preferably in the pH range of 2 to 5) during the cleaning step only mild agents are used 3 ", such For example, adsorption resins as chromatographic supports, and 4) the presence of amines is excluded throughout the process.
  • reducing conditions eg. B. always in the presence of ascorbic acid
  • a suitable method of isolating the compounds of the invention is the solvent distribution in a conventional manner.
  • Another method of purification is the chromatography on adsorption resins such. On Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo), Amberlite® XAD 7 (Rohm and Haas, USA), Amberchrom® CG, (Toso Haas, Philadelphia, USA) or the like.
  • phase carrier z. B. RP ⁇ and RPi ⁇ , as z. B. in the context of high pressure liquid chromatography (HPLC) have become well known.
  • HPLC high pressure liquid chromatography
  • Normal-phase chromatography supports such as.
  • silica gel or Al 2 0 3 or others in a conventional manner.
  • An alternative isolation method is the use of molecular sieves, such as. B. Fractogel® TSK HW-40, Sephadex® G-25 and others, in a conventional manner.
  • An additional process for the isolation and purification of the compounds according to the invention consists in the use of anion exchangers, preferably in the pH range from 4 to 7; and cation exchangers, preferably in the pH range from 2 to 5.
  • anion exchangers preferably in the pH range from 4 to 7
  • cation exchangers preferably in the pH range from 2 to 5.
  • buffer solutions to which parts of organic solvents have been added.
  • a particularly advantageous purification method for isolating the compounds according to the invention is crystallization, which is carried out in a manner known per se.
  • the compounds of the formula (I) according to the invention can be converted into the corresponding pharmacologically acceptable salts by methods known to the person skilled in the art.
  • pharmacologically acceptable salts of the invention Compounds according to the invention are understood as meaning both inorganic and organic salts, as described in Remington's Pharmaceutical Sciences (17th Edition, page 1418 [1985]). Salts are in particular alkali, ammonium, alkaline earth salts, salts with physiologically acceptable amines and salts with inorganic or organic acids such.
  • HCI, HBr, H 2 S0 4 maleic acid, fumaric acid in question.
  • metal ions such as with calcium, magnesium, zinc, iron or others in question.
  • the compounds of formula (I) have a pronounced tendency to complex ions, preferably cations.
  • the compounds of the formula (I) according to the invention have potent cytostatic effects, they are therefore suitable for the therapy and / or prophylaxis of diseases caused by uncontrolled growth of tissue or cells, or tumor diseases. It is particularly noteworthy that the compounds of the invention have no cross-resistance with conventional cytostatics.
  • the kinases are among the transferases that transfer phosphate residues from adenosine triphosphate to other substrates. Proteins and enzymes are usually phosphorylated and modified in their activity by the protein kinases on serine, threonine or tyrosine side chains, which has been recognized as a common regulatory principle in metabolism and signal transduction. In the case of cancers, the diseased tissue proliferates unchecked; an intervention in the regulation of kinase-driven proliferation is therefore desirable.
  • the cascade of cell proliferation involves a number of kinases. Several of these kinases are inhibited by the compounds of the invention.
  • an antimicrobial inhibitory effect of the compounds of formula (I) according to the invention on bacteria such as Staphylococcus aureus, Streptomyces murinus and against fungi such as Aspergillus niger, which can cause persistent, life-threatening infectious diseases.
  • the Antimicrobial activity can be detected, for example, by so-called agar-diffusion tests.
  • penilenone on an agar plate containing Streptomyces murinus culture in a solution of 1 mg per mL produces an inhibition zone of 11 mm and in a solution of 0.1 mg per mL a zone of inhibition of 8 mm.
  • the compounds of the formula (I) according to the invention are therefore also suitable for the therapy and / or prophylaxis of bacterial infections and / or fungal diseases.
  • the compounds of formula (I) can also be used as antioxidants.
  • Antioxidants oxidation inhibitors
  • Antioxidants are organic compounds that inhibit or prevent undesirable changes in the substances to be protected due to oxygen effects. Antioxidants are needed, for example, in plastics for protection against aging, in fats for protection against rancidity, in oils against gumming, in odor-deteriorating flavors, in foods, and in medicines.
  • the effect of the antioxidants is usually that they act as a radical scavenger for the occurring during the oxidation of free radicals.
  • the antioxidant activity of atrovenetin (compound of formula (III)) has already been described by Y. Ishikawa et al. J. Am. Oil Chem. Soc. 68, 666-668, 1991.
  • the compounds of the formula (I) are highly active antioxidants which significantly exceed the activity of the atrovenetin: while the atrovenetin in solution and in solid form reacts only slowly with atmospheric oxygen (for example in hours), for example the penilenone of the formula ( II) with oxygen within seconds or in a few minutes.
  • atmospheric oxygen for example in hours
  • penilenone of the formula ( II) with oxygen within seconds or in a few minutes.
  • this increased affinity of penilenone for oxygen is of decisive advantage for very oxidation-sensitive substances.
  • Another chemical property of the compounds of the invention is the ability to complex with polyvalent, preferably 2- and 3-valent cations, such as Ca 2+ , Mg 2+ , Zn 2+ , Fe 3+ .
  • Complexing ability may be beneficial for the preparation of drugs, for example, inhibitors of matrix metallo-proteases (MMP 's ) have become known are to bind the zinc of these enzymes.
  • MMP 's matrix metallo-proteases
  • other possible uses for diseases are also conceivable, the expression of which manifests itself in an abnormal metal ion concentration in the organism.
  • the compounds of the formula (I) according to the invention may likewise be active in the treatment of rheumatic diseases, for example rheumatoid arthritis.
  • rheumatic diseases for example rheumatoid arthritis.
  • the mechanism of action of reducing oxidative stress in rheumatoid arthritis by radical scavengers or antioxidants has been described, for example, by Ostrakhovitch and Afanas (Biochemical Pharmacology, 2001, 743-746).
  • the present invention accordingly also relates to the use of the compounds of the formula (I) according to the invention as medicaments, in particular for the treatment and / or prophylaxis of tumor diseases, bacterial infections, mycoses, rheumatic diseases and diseases which are manifested by the inhibition of matrix metalloids. Treat proteases.
  • the present invention relates to a pharmaceutical composition containing at least one of the compounds according to the invention.
  • Said drug is prepared by mixing at least one compound of formula (I) with one or more physiologically acceptable excipients and placed in a suitable dosage form.
  • the medicaments according to the invention can be administered enterally (orally), parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders (tablets, capsules including microcapsules), ointments (creams or gel), or suppositories.
  • physiologically acceptable excipients for such formulations are the pharmaceutical customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, dyes and / or buffer substances in question.
  • nutrient solution malt extract 2.0%, yeast extract 0.2%, glucose 1.0% (NH 4 ) 2 HP0 4 0.05%, pH 6.0
  • a sterile 300 ml Erlenmeyer flask 100 ml of nutrient solution (malt extract 2.0%, yeast extract 0.2%, glucose 1.0% (NH 4 ) 2 HP0 4 0.05%, pH 6.0) in a sterile 300 ml Erlenmeyer flask are prepared with the strain Penicillium Bainer & Sartory, DSM 14142, and incubated for 4 days at 25 ° C and 140 rpm on a rotary shaker. 2 ml of this preculture are then inoculated for the production of the main cultures.
  • Example 3 Preparation of a major culture culture of Penicillium herquei Bainer & Sartory, DSM 14142.
  • the maximum production of one or more compounds of Penilenons invention is reached after about 144 hours.
  • a 96-144 h old submersed culture inoculation amount approx. 10% from the same nutrient solution is sufficient.
  • the conditions for these fermenters are: 0 temperature 25 ° C
  • the penilenone-containing fractions 23 to 26 (mixture of the compounds of the formulas (II-A) and (II-B), comprising compounds of the formula (II)) and the atrovenetin-containing fractions 43 to 51 (mixture of the compounds of the formulas ( III-A) and (III-B), 0 summarizing compounds of the formulas (III) mentioned), which by HPLC-
  • Example 5 Isolation or purification by HPLC.
  • penilenone The physicochemical and spectroscopic properties of penilenone can be summarized as follows:
  • Appearance Yellow, in medium polar and polar organic solvents soluble, in water little soluble crystalline substance.
  • the melting point is not determinable because of the decomposition. Stable in a mildly acidic environment under reducing conditions. Under the influence of oxygen, in a neutral environment or in the presence of amines, penilenone turns green.
  • UV maxima 215 nm, 248 (Sh) nm, 275 (Sh), 389 nm.
  • Example 7 Obtaining the penilenone monomethyl ether derivatives of the formulas (IV-A) 5 and (IV-B).
  • reaction ended by addition of water and the solvent distilled off in vacuo.
  • the reaction product is then separated on a Nucleosil HD® column (21 mm x 250 mm).
  • the eluent used was a gradient of 10% to 99% acetonitrile in 0.1% acetic acid.
  • UV maxima 216 nm, 242 nm, 280 nm (Sh), 387 nm.
  • UV maxima 213 nm, 241 nm and 390 nm.
  • Example 8 Obtaining the Atrovenetin Derivatives (V-A) and (V-B).
  • VA atrovenetin monomethyl ether
  • VB atrovenetin monomethyl ether
  • V-A Atrovenetin monomethyl ether
  • UV maxima 218 nm, 260 nm (Sh), 394 nm.
  • V-B Atrovenetin monomethyl ether
  • UV maxima 222 nm, 282 nm, 385 nm.

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Abstract

L'invention concerne des dérivés de phénalénone et leur production par fermentation du micro-organisme Penicillium herquei Bainer & Sartory, DSM 14142, ainsi que par dérivatisation des phénalénones obtenues pendant la fermentation. L'invention concerne également l'utilisation de ces dérivés de phénalénone comme médicaments, par exemple pour le traitement de maladies tumorales, d'infections ou de mycoses bactériennes et d'affections rhumatismales.
PCT/EP2003/001060 2002-02-18 2003-02-04 Derives de phenalenone, leur procede de production et leur utilisation WO2003068946A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2003210205A AU2003210205B2 (en) 2002-02-18 2003-02-04 Phenalenone derivatives, method for the production thereof and use of the same
CA002476618A CA2476618A1 (fr) 2002-02-18 2003-02-04 Derives de phenalenone, leur procede de production et leur utilisation
MXPA04007918A MXPA04007918A (es) 2002-02-18 2003-02-04 Derivados de fenalenona, procedimientos para su preparacion y utilizacion de los mismos.
JP2003568061A JP2005517710A (ja) 2002-02-18 2003-02-04 フェナレノン誘導体、その製造方法および使用
BR0307733-0A BR0307733A (pt) 2002-02-18 2003-02-04 Derivados de fenalenona, processo para sua preparação e seu uso
EP03739452A EP1478731A1 (fr) 2002-02-18 2003-02-04 Derives de phenalenone, leur procede de production et leur utilisation

Applications Claiming Priority (2)

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DE10206849.6 2002-02-18
DE10206849A DE10206849A1 (de) 2002-02-18 2002-02-18 Phenalenon-Derivate, Verfahren zur Herstellung und Verwendung derselben

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JP (1) JP2005517710A (fr)
AR (1) AR038524A1 (fr)
AU (1) AU2003210205B2 (fr)
BR (1) BR0307733A (fr)
CA (1) CA2476618A1 (fr)
DE (1) DE10206849A1 (fr)
MX (1) MXPA04007918A (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011009899A3 (fr) * 2009-07-22 2011-09-22 Instituto Biomar, S.A. Phénalénones comme agents antitumoraux
FR2987622A1 (fr) * 2012-03-02 2013-09-06 Centre Nat Rech Scient Composes oxo-phenalenes, leur preparation et utilisation dans les domaines des materiaux et therapeutique
US9376415B2 (en) 2009-03-30 2016-06-28 Nippon Suisan Kaisha, Ltd. Tricyclic condensed heterocyclic compound, process of producing same, and use thereof

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JPH03124791A (ja) * 1989-10-06 1991-05-28 Nisshin Oil Mills Ltd:The アトロベネチンの用途
WO2000045165A1 (fr) * 1999-02-01 2000-08-03 Cytovia, Inc. Techniques d'identification d'agents antineoplasiques therapeutiquement efficaces avec des cellules de culture a membrane cellulaire intacte et produits correspondants

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JPH03124791A (ja) * 1989-10-06 1991-05-28 Nisshin Oil Mills Ltd:The アトロベネチンの用途
WO2000045165A1 (fr) * 1999-02-01 2000-08-03 Cytovia, Inc. Techniques d'identification d'agents antineoplasiques therapeutiquement efficaces avec des cellules de culture a membrane cellulaire intacte et produits correspondants

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AYER, W.A. ET AL.: "Metabolites produced by the Scleroderris canker fungus, Gremmeniella abietina. Part 4. Biosynthetic studies", CANADIAN JOURNAL OF CHEMISTRY, vol. 65, 1987, pages 760 - 764, XP009008544 *
BÜCHI, G. ET AL.: "Total Syntheses of Atrovenetin and Scleroderondione", JOURNAL OF ORGANIC CHEMISTRY, vol. 51, 1986, pages 4813 - 4818, XP002237220 *
FROST, DA ET AL.: "Metabolitc Product of P. Herquei", TETRAHEDRON LETTERS, vol. 46, 1972, pages 4729 - 4732, XP009008542 *
NARASIMHACHARI, N ET AL: "Herqueichrysin, A new Phenalenone Antibiotic from Penicillum Herquei", JOURNAL OF ANTIBIOTIC, vol. XXV, no. 3, 1972, pages 155 - 162, XP009008687 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9376415B2 (en) 2009-03-30 2016-06-28 Nippon Suisan Kaisha, Ltd. Tricyclic condensed heterocyclic compound, process of producing same, and use thereof
WO2011009899A3 (fr) * 2009-07-22 2011-09-22 Instituto Biomar, S.A. Phénalénones comme agents antitumoraux
FR2987622A1 (fr) * 2012-03-02 2013-09-06 Centre Nat Rech Scient Composes oxo-phenalenes, leur preparation et utilisation dans les domaines des materiaux et therapeutique
WO2013128425A1 (fr) * 2012-03-02 2013-09-06 Centre National De La Recherche Scientifique Composés oxo-phénalènes, leur préparation et utilisation dans les domaines des matériaux et thérapeutique

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AU2003210205B2 (en) 2007-06-14
MXPA04007918A (es) 2004-11-26
JP2005517710A (ja) 2005-06-16
PE20030904A1 (es) 2003-11-18
CA2476618A1 (fr) 2003-08-21
BR0307733A (pt) 2005-01-25
DE10206849A1 (de) 2005-07-28
AU2003210205A1 (en) 2003-09-04
EP1478731A1 (fr) 2004-11-24
AR038524A1 (es) 2005-01-19

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