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WO1997036852A1 - Nouveaux derives benzaldehyde extraits de hericeum erinaceus - Google Patents

Nouveaux derives benzaldehyde extraits de hericeum erinaceus Download PDF

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Publication number
WO1997036852A1
WO1997036852A1 PCT/EP1997/001504 EP9701504W WO9736852A1 WO 1997036852 A1 WO1997036852 A1 WO 1997036852A1 EP 9701504 W EP9701504 W EP 9701504W WO 9736852 A1 WO9736852 A1 WO 9736852A1
Authority
WO
WIPO (PCT)
Prior art keywords
erinaceus
hericeum
double bond
compound according
compound
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.)
Ceased
Application number
PCT/EP1997/001504
Other languages
German (de)
English (en)
Inventor
Heike Stump
Wilhelm Stahl
Joachim Wink
Irvin Winkler
Herbert Kogler
Jürgen Backhaus
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.)
Hoechst AG
Original Assignee
Hoechst AG
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 Hoechst AG filed Critical Hoechst AG
Priority to EP97914303A priority Critical patent/EP0891319A1/fr
Priority to JP9534897A priority patent/JP2000507447A/ja
Publication of WO1997036852A1 publication Critical patent/WO1997036852A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/74—Unsaturated compounds containing —CHO groups
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/42—Hydroxy-carboxylic acids

Definitions

  • the invention relates to new benzaldehyde derivatives, a process for their preparation and their use for the manufacture of a medicament, in particular for the treatment of a disease which is caused by an HIV infection.
  • HIV Human Immunodeficiency Virus
  • the diseases of the human body that are caused by the Human Immunodeficiency Virus (HIV) are life-threatening and are associated with a large number of secondary diseases.
  • the severity of the disease is directly linked to the virus titer, i.e. the number of viruses present in the body. Reducing the virus titer is one way to prevent the onset of the disease or to positively influence the course of the disease.
  • the enzyme reverse transcriptase is essential for the multiplication of the virus. Inhibitors of this enzyme have been shown to significantly slow virus replication (e.g. azidothymidine)
  • CONFIRMATION COPY Hericerin the effects of which are described as stimulating cytotoxicity or stimulating neurite outgrowth from nerve cells (cf. H. Kawagishi et al, Tetrahedr. Lett. (1990), 31, 373).
  • R 1 to R 10 are hydrogen or methyl, where two R 1 to R 10 located on adjacent carbon atoms together with a CC single bond can represent a CC double bond, with the proviso that in the group with R 1 to R 10 substituted carbon chain each means only one of the substituents R 1 to R 10 is methyl and in each case only an adjacent pair of these substituents contributes to a CC double bond.
  • R 5 in formula I is preferably methyl.
  • R 3 and R 6 (for example formula 1) or R 6 and R 7 (for example formula 2) are particularly preferably together with that between those of them substituted carbon atoms lie CC single bond a CC double bond.
  • the double bond of these compounds is preferably in the Z configuration.
  • the new compound of formula I in particular compounds 1 and 2, and their physiologically tolerable salts are distinguished by their action against HIV reverse transcriptase, which is clearly superior to that of other metabolites from basisiomycetes.
  • RT reverse transcriptase
  • SPA scintillation proximity assay
  • Bovine serum albumin was added to the "assay" buffer at the final concentration of 0.5 mg / ml.
  • the test was carried out in Eppendorf reaction vessels with a 100 I batch volume.
  • the manufacturer's RT concentrate (5000 U / ml) was dissolved in Tris-HCl buffer 20 mM; pH 7.2; Diluted 30% glycerol to an activity of 15 U / ml.
  • the incubation time for the batches was 60 min (37 C).
  • the present invention furthermore relates to a process for the preparation of the compounds mentioned.
  • a process for the preparation of the compounds mentioned is characterized in that the microorganism Hericeum erinaceus, preferably Hericeum erinaceus DSM 10600, is cultivated in an aqueous medium and the target compounds are then isolated and purified.
  • microorganism Hericeum erinaceus DSM 10600 was deposited on March 20, 1996 with the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ), Marscheroder Weg 1 b, D-38124 Braunschweig, according to the provisions of the Budapest Treaty.
  • mutants and variants can also be used, provided that they can synthesize compounds of the formula I.
  • Such mutants can be known in a manner known per se by physical means, for example radiation, such as with ultraviolet or X-rays, or chemical mutagens, for example ethyl methanesulfonate (EMS), 2-hydroxy-4-methoxy-benzophenone (MOB) or N-meth ⁇ l- N ' -nitro-N-nitrosoguanidine (MNNG) are generated.
  • EMS ethyl methanesulfonate
  • MOB 2-hydroxy-4-methoxy-benzophenone
  • MNNG N-meth ⁇ l- N ' -nitro-N-nitrosoguanidine
  • the fermentation conditions described below apply to Hericeum erinaceus and the deposited isolate.
  • the fermentation can take place on a laboratory scale (milliliter and liter scale) or on an industrial scale (cubic meter scale).
  • Henricium erinaceus in particular H. erinaceus DSM 10600, produces the compound of the formula I in a nutrient solution which contains a carbon source and a nitrogen source and the customary inorganic salts.
  • assimilable carbohydrates and sugar alcohols such as glucose, lactose or D-mnanite, and carbohydrate-containing natural products, such as, for. B. malt extract.
  • Suitable nitrogenous nutrients are: amino acids, peptides and proteins and their degradation products, such as peptones or tryptones, also meat extracts, ground seeds, for example from corn, wheat, beans, soybeans or the cotton plant, distillation residues from alcohol production, meat flours or yeast extracts, but also Ammonium salts and nitrates.
  • the inorganic solution of inorganic salts can contain, for example, chlorides, carbonates, sulfates or phasphates of the alkali or alkaline earth metals, iron, zinc, cobalt and manganese.
  • the trace element solution can have the following composition:
  • the cultivation is carried out aerobically, for example submerged with shaking or stirring or in fermenters, if appropriate with the introduction of air or hydrogen. It will be carried out in a temperature range from 15 to 30 ° C, preferably from 20 to 30 ° C, in particular from 23 to 28 ° C.
  • the pH is from pH 1 to 7, advantageously from pH 2.5 to 4.5.
  • the fungus is cultivated under these conditions over a period of 100 to 300 hours, preferably 120 to 168 hours.
  • Cultivation is advantageously carried out in several stages, i. H. one or more precultures are first prepared in a liquid nutrient medium, which are then inoculated into the actual production medium, the main culture, for example in a volume ratio of 1:10.
  • the preculture is obtained e.g. B. by inoculating mycelium in a nutrient solution and growing for about 100 to 200 hours, preferably 120 to 168 hours.
  • the mycelium can be obtained, for example, by allowing the strain to grow on a solid or liquid nutrient medium, for example yeast-malt agar or potato-dextrose agar, for 7 to 40 days, preferably 10 to 20 days.
  • the course of the fermentation can each be based on the pH of the culture or the mycelium volume as well as by chromatographic methods, such as. B. thin layer chromatography or high pressure liquid chromatography, are monitored.
  • the compound of formula I is predominantly contained in the culture filtrate.
  • the isolation of the formal I compound from the respective culture medium is carried out according to known methods, taking into account the chemical, physical and biological properties of the products. It can e.g. B. the adsorption, ion exchange or gel filtration process can be applied.
  • Ethyl acetate / methanol / water mixtures are used as mobile solvents in concentrations known to those skilled in the art.
  • Detection in thin-layer chromatographic separation can, for example, also bring UV quenching and coloring reagents such as anisaldehyde, tetraozole blue or orcine into the suitable administration form and / or additives and / or auxiliary substances.
  • Hericenals can be found in both the mycelium and the culture filtrate, usually the majority is in the culture filtrate. It is therefore advisable to separate the cell mass from the filtrate by filtration or centrifugation.
  • the filtrate is lyophilized and the lyophilisate extracted with a solvent such as methanol or acetonitrii or 1-butanol.
  • Hericenals can be extracted from the mycelium in the same way. The extractions can be carried out over a wide pH range, a range from pH 3.0 to pH 7.5 is appropriate.
  • Another method of isolation is the solution distribution in a manner known per se.
  • Another method of purification is chromatography on adsorption resins such as on Diaion * HP-20 (Mitsubishi Casei Corp., Tokyo) on Amberlite ® XAD 7 (Rohm and Haas, USA) to Amber Chrome ® CG (Toso Haas, Philadelphia, USA) or on similar supports.
  • Numerous reversed-phase supports, for example RP-18, are also suitable, as are generally used in hop pressure liquid chromatography.
  • Another cleaning option for the Hericenale is the use of so-called straight-phase carriers such.
  • Many solvents such as chloroform / methanol or dichloromethane / n-butanol mixtures, are suitable for elution.
  • An alternative method for isolating the texenomycins is the use of so-called.
  • Molecular sieves such as Fractogel ® TSK HW-40, Sephadex ® LH-20 and others in a known manner. It is also possible to obtain the Texenomycins from enriched material by crystallization. Suitable for this purpose are, for example, organic solvents and their mixtures, anhydrous or with added water. Additions of acids such as trifluoroacetic acid, sulfuric acid, hydrochloric acid, formic acid or others can also be advantageous.
  • the compounds of formula I and their physiologically tolerable salts are also suitable as therapeutic agents against diseases which are caused by an HIV infection. Accordingly, the present invention also relates to the compound of formula I or a physiologically tolerable salt thereof for use as a medicament, preferably for the manufacture of a medicament for the treatment of a disease which is caused by an HIV infection.
  • the medicaments can contain one or more compounds of the formula I or their physiologically tolerable salts and pharmaceutical auxiliaries.
  • the present invention further relates to Hericeum erinaceus DSM 10600 and its mutants and variants.
  • 100 ml nutrient solution (20 g malt extract, 2 g yeast extract, 10 g glucose, 0.5 g (NH 4 ) 2 HPO 4 in 1 l tap water, pH value before sterilization 6.0) in a 500 ml sterile Erlenmeyer flask are mixed with Inoculated the strain DSM 7427 and incubated for 240 hours at 25 ° C and 140 rpm on a rotating shaker.
  • a sterile 500 ml Erlenmeyer flask with 100 ml of the nutrient solution described under a) is inoculated with a culture grown on a slant tube or with a 1 square centimeter piece of agar and incubated on a shaker at 140 rpm and 25 ° C.
  • the maximum production a compound of formula I is reached after about 168 hours.
  • a 1 68 hour old submerged culture (inoculation amount approx. 5%) from the same nutrient solution is sufficient to inoculate 4 (500 ml in 200 ml Erlenmeyer).
  • the pH is adjusted with aqueous 2 N NaOH or HCl.
  • composition Quantity in percent
  • the culture solution obtained according to Example 2 is centrifuged off and the cell mass is freeze-dried.
  • the clear culture filtrate is adsorbed on Mitsubishi Diaion ® CHP20 (column dimensions 30 x 6 cm) and eluted with an isopropanol gradient 0 - 70% isopropanol (flow 50 ml / min).
  • the fractions containing the Hericenale are combined, concentrated to the water phase in vacuo and lyophilized.
  • 270 mg of the crude mixture obtained in Example 3 are dissolved in 20% aqueous Acetonitrii and initially on a column of Nucleosil 100-12 ® C 18 with a gradient 25-40% Acetonitrii in water with 0.05% trifluoroacetic acid (column dimensions 250 x 32 mm, Flow 50 ml / min) chromatographed.
  • the fractions containing the Hericenale are pooled, concentrated in vacuo and Nucleosil 100-10 ® C 18 AB with the same gradient cleaned on (column dimensions 250 x 20 mm, flow 25 ml / min). After concentration of the fractions and lyophilization, 17.6 mg of a mixture of Hercenal A and Hericenal B are obtained.
  • the mixture is obtained by column chromatography on silica gel 60 (Merck, 0.015-0.040 mm, column volume 5 ml) with dichloromethane / n-butanol 20: 1 as Eluens separated into the individual components.
  • This international depository accepts the microorganism referred to under 1, which it received on 1996-03-20 (date of first deposit) 1 .
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for conversion of this first deposit including a deposit in accordance with the Budapest Treaty was received on (date of receipt of the application for conversion).

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Wood Science & Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I), où R1 à R10 sont hydrogène ou méthyle, et où deux R1 à R10 placés sur des atomes de carbone adjacents peuvent représenter avec une simple liaison C-C une double liaison C-C, à condition que dans la chaîne carbonée substituée par R1 à R10, un seul des substituants R1 à R10 soit méthyle et qu'une seule paire adjacente de ces substituants participe à une double liaison C-C. L'invention concerne également un procédé permettant de produire ce composé, ainsi que son utilisation comme médicament, notamment pour le traitement des maladies entraînées par l'infection à VIH.
PCT/EP1997/001504 1996-04-01 1997-03-25 Nouveaux derives benzaldehyde extraits de hericeum erinaceus Ceased WO1997036852A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP97914303A EP0891319A1 (fr) 1996-04-01 1997-03-25 Nouveaux derives benzaldehyde extraits de hericeum erinaceus
JP9534897A JP2000507447A (ja) 1996-04-01 1997-03-25 ヘリシウム・エリナシウスからの新規ベンズアルデヒド誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19612807.2 1996-04-01
DE19612807A DE19612807A1 (de) 1996-04-01 1996-04-01 Neue Benzaldehyd-Derivate aus Hericeum erinaceus

Publications (1)

Publication Number Publication Date
WO1997036852A1 true WO1997036852A1 (fr) 1997-10-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001504 Ceased WO1997036852A1 (fr) 1996-04-01 1997-03-25 Nouveaux derives benzaldehyde extraits de hericeum erinaceus

Country Status (4)

Country Link
EP (1) EP0891319A1 (fr)
JP (1) JP2000507447A (fr)
DE (1) DE19612807A1 (fr)
WO (1) WO1997036852A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03157347A (ja) * 1989-11-14 1991-07-05 Kagome Kk オクタデセン酸誘導体及びこれを有効成分とする子宮頚癌細胞の殺細胞剤
JPH04266848A (ja) * 1991-02-21 1992-09-22 Kagome Co Ltd ベンジルアルコール誘導体及びこれを有効成分とするｐｇｅ２産生抑制剤並びにｎｇｆ産生誘導剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03157347A (ja) * 1989-11-14 1991-07-05 Kagome Kk オクタデセン酸誘導体及びこれを有効成分とする子宮頚癌細胞の殺細胞剤
JPH04266848A (ja) * 1991-02-21 1992-09-22 Kagome Co Ltd ベンジルアルコール誘導体及びこれを有効成分とするｐｇｅ２産生抑制剤並びにｎｇｆ産生誘導剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
G.T. TAN ET AL.: "HIV-1 AND HIV-2 REVERSE TRANSCRIPTASES: A COMPARATIVE STUDY OF SENSITIVITY TO INHIBITION BY SELECTED NATURAL PRODUCTS", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 185, no. 1, 1992, pages 370 - 378, XP000673652 *
H. HAWAGISHI ET AL.: "HERICENONE A AND B AS CYTOTOXIC PRINCIPLES FROM THE MUSHROOM HERICIUM ERINACEUM", TETRAHEDRON LETTERS, vol. 31, no. 3, 1990, OXFORD GB, pages 373 - 376, XP000673621 *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 388 (C - 0872) 2 October 1991 (1991-10-02) *
PATENT ABSTRACTS OF JAPAN vol. 017, no. 055 (C - 1023) 3 February 1993 (1993-02-03) *

Also Published As

Publication number Publication date
EP0891319A1 (fr) 1999-01-20
DE19612807A1 (de) 1997-10-02
JP2000507447A (ja) 2000-06-20

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