Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles

Definitions

• Thiangazole as a therapeutic agent to fight viral diseases
• the invention relates to therapeutic agents for combating viral diseases, consisting of or containing thiangazole of the following general formula (optionally in each case as a therapeutically acceptable acid addition salt), optionally new carriers and / or diluents:
• the invention relates to an agent of this type with a thiangazole, if appropriate, as therapeutically tolerable
• Acid addition salt which is characterized by one or more parameters according to claim 2.
• a special embodiment relates to such a therapeutic agent for combating diseases of your retroviruses. especially to fight HIV.
• thiangazoles are obtainable by: - Polyangium DSM 6267 cultivated in a medium containing carbon sources, nitrogen sources and mineral salts.
• the aqueous phase is separated off and, if necessary, extracted with ether,
• Cis-trans isomers of this thiangazois which fall under the general formula given above, are thus obtainable. that the thiangazole obtainable by the stated process is subjected to a treatment with UV light. All thiangazoles according to the invention can be converted into pharmaceutically acceptable acid addition salts in a manner known per se.
• the vegetative cells are cylindrical with broadly rounded ends (polyangium type), mostly around 0.6-0.8 ⁇ 4-6 ⁇ m. If there is a lack of nutrients. e.g. when cultivated on a smear of living Escherichiacoli bacteria on water agar, the organism forms
• Fruit corer These are plate-shaped heaps of small to medium-sized, spherical ooer ovoid, gold to red raunchy sporangioles, the diameter of which is usually around 30-80 ⁇ m.
• the sporangiola noses can get quite large, but vary widely in their extent, usually between 100 and 600 ⁇ m.
• Pl 3007 grows well on living Escherichia coli bacteria on water agar, whereby the feed bacteria are broken down. The colony gradually spreads as a swarm over the culture plate due to the sliding movement of the ba ⁇ ter ⁇ en ⁇ ellen.
• the organism also grows well on grooved agar (VY / 2 agar: 0.5% baker's yeast: 0.1% CaCl 2 .2H 2 O; 0.5 mg / l cyanocobalamin; pH 7.2). It also penetrates deep into the growing medium and largely degrades the yeast cells. Catalase and oxidase are positive. In liquid media, the strain grows in small lumps of cells, both in shaking flasks at 160 rpm (100 ml medium in 250 ml Erlenmeyer flasks or 500 ml medium in 1000 ml Erlenmeyer flasks), as well as in bioreactors (tested up to 300 1 scale).
• Pol! Medium is suitable as a culture medium: Probion PS (single-cell protein from Methylomonas clarae:
• Preserve e.g. by freezing vegetative cells from agar plates or liquid cultures in PeDtonlös ⁇ ng at -80 C or in liquid nitrogen.
• the production strain is registered with the German Collection of Microorganisms in Braunschweig as a patent strain under the number DSM 6267.
• the ventilation rate is set to 200 Nl / hour, the speed to 200 rpm, the pO 2 . which is 100% saturation at the beginning of the fermentation, decreases continuously to 85% by the end of the fermentation after 95 hours.
• HD-Sil-15-60 and HD-Sil-18-5-100 Kelzanwald; see plant Florisil (Floridin Corp .; magnesium silicate gel)
• MT-4 Thiangazole was tested in the MT-4 cell system (Harada et al .; 1986) for the anti-HIV-1 effect and cell toxicity.
• MT-4 is a human T cell line that is severely damaged by an HIV-1 infection and dies.
• 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. Thiangazole was titrated at an initial concentration of 250 ⁇ g / ml followed by 1:10 dilutions. A virus dose of 100 TCID 30 previously titrated 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-thyme was added per well of the microtiterolatte.
• the cells were harvested 20 hours later on glass fiber filters, washed with water and the 3 H-thymidine incorporation in the cell DNA after the addition of a liquid scintillator toluene / POPOP (Roth. Düsseldorf) measured 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-thymine incorporation was shown graphically as a function of the substance concentration and the toxicity and the maximum anti-viral activity of the substance were determined. The results were compared with those of the nucleoside analog 3'-azido-3'-deoxythymi di n (AZT).
• 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.
• the toxicity of the Thiangazois was outside the test concentrations and therefore above 46.5 ⁇ M.
• Thiangazole has not yet been thinned out sufficiently so that the minimum therapeutic substance concentration has not yet been determined. Thiangazole still showed anti-HIV activity in the concentration of 0.047 nM.
• 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. In its ability to prevent HIV-1 infection, thiangazole can be compared 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.
• HTLV-III / LAV antibodies against AIDS-related viruses

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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)

Applications Claiming Priority (2)

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Country Status (2)

• 1990
  • 1990-12-24 DE DE19904041687 patent/DE4041687C1/de not_active Expired - Lifetime
• 1991
  • 1991-12-23 WO PCT/EP1991/002504 patent/WO1992011008A1/de not_active Ceased

Non-Patent Citations (1)

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