WO1992011004A1 - Fenalamiden als therapeutische mittel zur bekämpfung von viruserkrankungen - Google Patents

Fenalamiden als therapeutische mittel zur bekämpfung von viruserkrankungen Download PDF

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Publication number
WO1992011004A1
WO1992011004A1 PCT/EP1991/002503 EP9102503W WO9211004A1 WO 1992011004 A1 WO1992011004 A1 WO 1992011004A1 EP 9102503 W EP9102503 W EP 9102503W WO 9211004 A1 WO9211004 A1 WO 9211004A1
Authority
WO
WIPO (PCT)
Prior art keywords
aromatic
methanol
fenalamide
protons
fenalamides
Prior art date
Application number
PCT/EP1991/002503
Other languages
German (de)
English (en)
French (fr)
Inventor
Gerhard Hunsmann
Elke Jurkiwicz
Hans Reichenbach
Edgar Forche
Klaus Gerth
Herbert Irschik
Brigitte Kunze
Florenz Sasse
Gerhard Höfle
Norbert Bedorf
Rolf Jansen
Heinrich Steinmetz
Wolfram Trowitzsch-Kienast
Original Assignee
Deutsches Primatenzentrum 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 Deutsches Primatenzentrum Gmbh filed Critical Deutsches Primatenzentrum Gmbh
Publication of WO1992011004A1 publication Critical patent/WO1992011004A1/de

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the invention relates to therapeutic agents for combating viral diseases, consisting of fenalamides of the following general formula or containing fenalamides of the following general formula, optionally in addition to conventional carriers and / or diluents:
  • the invention further relates to therapeutic agents for combating viral diseases, consisting of fenalamides of the following general formulas or containing fenalamides of the following general formulas, if appropriate hepenic carriers and / or diluents:
  • the invention further relates to a therapeutic agent for combating viral diseases, consisting of fenalamide (A) with one or more of the following parameters or containing fenalamide (A) with one or more of the following parameters, if appropriate in addition to a conventional carrier or diluent:
  • the invention further relates to a therapeutic agent for combating viral diseases, consisting of fenalamide (B) with one or more of the following parameters or containing fenalamide (B) with one or more of the following parameters, if appropriate in addition to a conventional carrier or diluent:
  • the invention further relates to a therapeutic agent for combating viral diseases, consisting of fenalamide (C) with one or more of the following parameters or containing fenalamide (C) with one or more of the following parameters, if appropriate in addition to a conventional carrier or diluents:
  • m / z (%) 507 (84) [M] + , 489 (100) [MH 2 O] + , 474 (30) [MH 2 O-CH 3 ] , 446 (69), 432 (76).
  • a special embodiment relates to such a therapeutic agent for combating diseases by retroviruses, in particular for combating HIV.
  • Fenalamides in particular the fenalamides mentioned above, in particular fenalamides A, B and / or C. can be obtained by
  • the adsorber resin is separated off and extracted with methanol
  • fenalamide A, B and / or C can be subjected to a treatment with UV light and the isomers obtained can be separated by chromatography and isolate if necessary.
  • the invention is explained in more detail below on the basis of experimental data.
  • the bacterium Myxococcus stipitatus belongs to the order of the
  • Myxobacterales subordination Cystobacterineae, family Myxococcaceae.
  • the production strain Myxococcus stipitatus Mx s40 was isolated at GBF in September 1988 from a soil sample from Jacobsburg State Park near Wind Gap, Pennsylvania, USA, deposited with the German Collection of Microorganisms (DSM) under the number DSM 6259.
  • DSM German Collection of Microorganisms
  • the stock culture is carried out on agar plates. preferably on yeast agar (VY / 2 agar). This medium contains 0.5% baker's yeast, 0.1% CaCl2 ⁇ H 2 O, 0.1 ⁇ g / 1 vitamin B12 and 1.2% agar. The pH is adjusted to 7.2. The plates are incubated at 30 °.
  • the vegetative sticks are slender and have slightly tapered ends. They are about 0.7 ⁇ m thick and 2 to 5 ⁇ m long.
  • the Myxospores are oval, strong light-speaking, about 1.1 to 1 .3 ⁇ 1.3 to 1.5 ⁇ m in size. Due to the sliding movement of the bacteria, the colonies spread quickly over the culture plate.
  • the swarm colony on yeast cooking is thin, film-like, reddish brown.
  • whitish to pale brown fruiting bodies are often formed. These consist of a soft, slimy head of about 100 to 200 ⁇ m in diameter, which often sits on a more or less long stem of 30 to 50 ⁇ m in diameter. After several vaccinations, the tendency to form fruiting bodies gradually subsides.
  • the Mx s40 strain produces substances, namely fenalamides, that inhibit the multiplication of HIV (Human Immunodeficiency Virus) (see below).
  • the antiviral substances can be isolated both from the cells and from the culture supernatant.
  • a typical fermentation proceeds as follows: A fermentor with 700 1 working volume is filled with 630 1 culture medium (composition: 0.6% peptone from casein, (digested tryptically) 0.05% CaCl2 ⁇ 2H 2 O, 0.2% MgSO 4 ⁇ 7H 2 O. pH 7. z adjusted with H 2 SO 4 ).
  • a fermentor with 700 1 working volume is filled with 630 1 culture medium (composition: 0.6% peptone from casein, (digested tryptically) 0.05% CaCl2 ⁇ 2H 2 O, 0.2% MgSO 4 ⁇ 7H 2 O. pH 7. z adjusted with H 2 SO 4 ).
  • released antiviral substances is the medium 1 to 2% (V / V) of an adsorbent resin e.g. XAD-1180 added. Inoculated with 70 1 one in the same medium in one accordingly
  • the pH is kept at 7.2 by the controlled addition of 5% strength H 2 SO 4 .
  • the fermentation is ended after three days.
  • the fermentation is carried out in the presence of 8 l of XAD-1180 adsorber resin. Towards the end of the fermentation, the resin is separated from the medium and the cells through a sieve. The resin is eluted in a column with 3 bed volumes of methanol. After concentrating on a rotary evaporator, 234 g of crude extract are obtained. The crude extract is dissolved in 20 l of ethyl acetate and 20 l of water and distributed in a countercurrent centrifuge. The
  • the fenalamide-containing fractions are between the
  • m / z 91 base ions.
  • Fenalamide A was examined in the MT-4-line system (Hara ⁇ a et al .; 1986) for the anti-HIV-1 effect and cell toxicity.
  • MT-4 is a human T cell line that is severely damaged and dies by an HIV-1 infection.
  • culture supernatants from the HIV-1-producing Jurkat cell line were used for the cell test carried out here, which were caused by infection of lymphocytic Jurkat cells (Wendler et al., 1987) with the HIV-1 type HTLLV-IIIB from H9 cells (Popovic et al .; 1984).
  • the MT-4 cell test was carried out in microtiter plates. 3 ⁇ 10 4 MT-4 cells with different substance dilutions with and without HIV-1 were cultivated per well. Fenalamide A was titrated at an initial concentration of 500 ⁇ g / ml followed by 1:10 dilutions. A virus dose of 100 TCID 30 which had previously been withdrawn was used for the virus infection. After three days of cultivation, fresh RPMI 1640 medium was added. Four days after the test batch, 0.1 ⁇ ci 3 H-thymidine were added per well of the microtiter plate.
  • the cells were 20 hours later harvested on glass fiber filters, washed with water and the 3 H-thymidine incorporation in the Zeil DNA measured after adding a liquid scintillator toluene / POPOP (Roth, Düsseldorf) in the ß counter (Packard, Frankfurt). Low installation rates indicate virus-related cell death or the toxicity of the substance, high ones indicate an inhibition of HIV-1 infection.
  • the 3 H-Thym ⁇ d ⁇ neinpau was shown graphically depending on the substance concentration and the toxicity and the maximum antiviral activity of the substance was determined. The results were compared with those of the nucleoside analog 3'-Az ⁇ do-3'-deoxythymidin (AZT).
  • Figure 1 the 3 H-thymidine incorporation rates of the MT-4 cells cultivated with HIV-1 and without virus addition were compared with the substance dilutions.
  • the 3 H-thyrmdine incorporation (com) was applied to the cell DNA against the substance concentration (nM) of (C) fenalamide and (D) AZT.
  • the cells were treated with substance in the presence (- - -) and in the absence of
  • HIV-1 (- - -) cultivated.
  • the maximum non-toxic substance concentration for MT-4 cells, as well as the maximum and therapeutic concentrations were determined from the graphics and summarized in Table 1. Fenalamid A was with one
  • Fenalamide A has not yet been diluted enough so that the minimum therapeutic substance concentration has not yet been determined. Fenalamide A was still effective in the concentration of 1.02 nM anti-HIV-1.
  • Table 1 shows the selectivity index (SI) of the investigated substance. It describes the ratio of the substance concentration, which has a toxic effect on the MT-4 cells, to the substance concentration at which an HIV-1 infection is 100% prevented. Fenalamid A is in its ability to prevent HIV-1 infection to compare with the high effectiveness of AZT with an SI of 10 4 .
  • Table 1 Comparison of the toxicity and anti-HIV-1 effectiveness of the pure substance with AZT.
  • selectivity index quotient from tox to TE.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/EP1991/002503 1990-12-24 1991-12-23 Fenalamiden als therapeutische mittel zur bekämpfung von viruserkrankungen WO1992011004A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4041688.7 1990-12-24
DE19904041688 DE4041688A1 (de) 1990-12-24 1990-12-24 Therapeutisches mittel zur bekaempfung von viruserkrankungen

Publications (1)

Publication Number Publication Date
WO1992011004A1 true WO1992011004A1 (de) 1992-07-09

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ID=6421374

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Application Number Title Priority Date Filing Date
PCT/EP1991/002503 WO1992011004A1 (de) 1990-12-24 1991-12-23 Fenalamiden als therapeutische mittel zur bekämpfung von viruserkrankungen

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DE (1) DE4041688A1 (enrdf_load_stackoverflow)
WO (1) WO1992011004A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2968556A1 (fr) * 2010-12-13 2012-06-15 Centre Nat Rech Scient Inhibiteurs des infections a vih et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Keine Entgegenhaltungen *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2968556A1 (fr) * 2010-12-13 2012-06-15 Centre Nat Rech Scient Inhibiteurs des infections a vih et leurs utilisations
WO2012080641A1 (fr) * 2010-12-13 2012-06-21 Centre National De La Recherche Scientifique - Cnrs - Agonistes des recepteurs sip et leur utilisation dans le traitement des infections du vin

Also Published As

Publication number Publication date
DE4041688A1 (de) 1992-07-09
DE4041688C2 (enrdf_load_stackoverflow) 1993-02-25

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