WO1992011008A1 - Thiangazol als therapeutisches mittel zur bekämpfung von viruserkrankungen - Google Patents
Thiangazol als therapeutisches mittel zur bekämpfung von viruserkrankungen Download PDFInfo
- Publication number
- WO1992011008A1 WO1992011008A1 PCT/EP1991/002504 EP9102504W WO9211008A1 WO 1992011008 A1 WO1992011008 A1 WO 1992011008A1 EP 9102504 W EP9102504 W EP 9102504W WO 9211008 A1 WO9211008 A1 WO 9211008A1
- Authority
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- WIPO (PCT)
- Prior art keywords
- calc
- found
- thiangazole
- therapeutic agent
- viral diseases
- Prior art date
Links
- 201000010099 disease Diseases 0.000 title claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 8
- 230000003612 virological effect Effects 0.000 title claims abstract description 7
- IPNBHSCJCMEBFX-UHFFFAOYSA-N Thiangazole Natural products O1C(C)=C(C(=O)NC)N=C1C1(C)N=C(C2(C)N=C(SC2)C2(C)N=C(C=CC=3C=CC=CC=3)SC2)SC1 IPNBHSCJCMEBFX-UHFFFAOYSA-N 0.000 title claims description 23
- IPNBHSCJCMEBFX-WMXIMKIMSA-N n,5-dimethyl-2-[(4r)-4-methyl-2-[(4s)-4-methyl-2-[(4s)-4-methyl-2-[(e)-2-phenylethenyl]-5h-1,3-thiazol-4-yl]-5h-1,3-thiazol-4-yl]-5h-1,3-thiazol-4-yl]-1,3-oxazole-4-carboxamide Chemical compound O1C(C)=C(C(=O)NC)N=C1[C@@]1(C)N=C([C@@]2(C)N=C(SC2)[C@@]2(C)N=C(\C=C\C=3C=CC=CC=3)SC2)SC1 IPNBHSCJCMEBFX-WMXIMKIMSA-N 0.000 title claims description 22
- 239000003814 drug Substances 0.000 title claims description 8
- 229940124597 therapeutic agent Drugs 0.000 title claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000002451 electron ionisation mass spectrometry Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 2
- CWNPOQFCIIFQDM-UHFFFAOYSA-N 3-nitrobenzyl alcohol Chemical compound OCC1=CC=CC([N+]([O-])=O)=C1 CWNPOQFCIIFQDM-UHFFFAOYSA-N 0.000 claims description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 229910052724 xenon Inorganic materials 0.000 claims description 2
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 27
- 239000000126 substance Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000002609 medium Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 6
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 6
- 208000031886 HIV Infections Diseases 0.000 description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 241000862998 Polyangium Species 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000589344 Methylomonas Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229960002104 cyanocobalamin Drugs 0.000 description 2
- 235000000639 cyanocobalamin Nutrition 0.000 description 2
- 239000011666 cyanocobalamin Substances 0.000 description 2
- 230000035418 detection of UV Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
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- 239000011573 trace mineral Substances 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- JLPUISACQXFVRC-UHFFFAOYSA-N 2,5-dihydro-1,3-thiazole Chemical compound C1SCN=C1 JLPUISACQXFVRC-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- CZTQZXZIADLWOZ-UHFFFAOYSA-O 8-oxo-3-(pyridin-1-ium-1-ylmethyl)-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1SC2C(NC(=O)CC=3SC=CC=3)C(=O)N2C(C(=O)O)=C1C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-UHFFFAOYSA-O 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
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- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- MASVCBBIUQRUKL-UHFFFAOYSA-N POPOP Chemical compound C=1N=C(C=2C=CC(=CC=2)C=2OC(=CN=2)C=2C=CC=CC=2)OC=1C1=CC=CC=C1 MASVCBBIUQRUKL-UHFFFAOYSA-N 0.000 description 1
- 241000863008 Polyangiaceae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 108010027322 single cell proteins Proteins 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (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)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4041687.9 | 1990-12-24 | ||
| DE19904041687 DE4041687C1 (enrdf_load_stackoverflow) | 1990-12-24 | 1990-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992011008A1 true WO1992011008A1 (de) | 1992-07-09 |
Family
ID=6421373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1991/002504 WO1992011008A1 (de) | 1990-12-24 | 1991-12-23 | Thiangazol als therapeutisches mittel zur bekämpfung von viruserkrankungen |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE4041687C1 (enrdf_load_stackoverflow) |
| WO (1) | WO1992011008A1 (enrdf_load_stackoverflow) |
-
1990
- 1990-12-24 DE DE19904041687 patent/DE4041687C1/de not_active Expired - Lifetime
-
1991
- 1991-12-23 WO PCT/EP1991/002504 patent/WO1992011008A1/de active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| Keine Entgegenhaltungen * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4041687C1 (enrdf_load_stackoverflow) | 1992-08-13 |
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| 122 | Ep: pct application non-entry in european phase |