EP0815120B1 - 17-difluormethylen-estratriene - Google Patents
17-difluormethylen-estratrieneInfo
- Publication number
- EP0815120B1 EP0815120B1 EP96907453A EP96907453A EP0815120B1 EP 0815120 B1 EP0815120 B1 EP 0815120B1 EP 96907453 A EP96907453 A EP 96907453A EP 96907453 A EP96907453 A EP 96907453A EP 0815120 B1 EP0815120 B1 EP 0815120B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- difluoromethylene
- estra
- hydrogen atom
- methyl
- estratienes
- 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.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/02—Halogenated hydrocarbons
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
Definitions
- the present invention relates to 17-Difluo ⁇ nethy len-estratrienes, processes for their preparation and the use thereof for the production of pharmaceutical products (pharmaceuticals).
- Rl is a hydrogen atom or a Cj - CJO alkyl group
- R is a methyl or ethyl group
- R 2 is a hydrogen atom or an ⁇ - or ⁇ -position CJ-CIO alkyl group
- R J is a hydrogen atom or an ⁇ - or ⁇ -position Ci-C ⁇ -alkyloxy group
- R 4 is an ⁇ or ⁇ hydrogen atom
- A, B, D, E and G each have a hydrogen atom, and optionally additionally at least one of the pairs of substituents
- G and R 2 , R 2 and R 4 , R 4 and A, A and R 3 , B and D, D and E represent a double bond.
- the invention preferably relates to those compounds of the general formula I in which
- R 1 is a hydrogen atom or a Cj - C ⁇ Q alkyl group
- R5 is a methyl or ethyl group
- A, B, D, E, G, R 2 and R 3 each have a hydrogen atom and R 4 has a ⁇ or ⁇ position
- R 2 is a ß-position C -CiQ alkyl group, in which case A, B, D, E, G, R 3 and R 4 each represent a hydrogen atom, or
- R J is a ⁇ -position -CC-alkyloxy group, in which case A, B, D, E, G and R 2 and R 4 each represent a hydrogen atom.
- R- and R J Dzw - alkoxy groups are a methyl, ethyl, ⁇ -propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl radical or their higher straight-chain or branched-chain homologs or im Case of R- 3 around a corresponding alkoxy radical.
- the methyl or methoxy radical is preferred.
- Rl is preferably a hydrogen atom.
- a methyl group is primarily suitable for R-5.
- E, G, R 2 , R 3 and R 4 are hydrogen atoms or wherein A, B, D, E, R 3 and R 4
- the structurally closest compounds to the present compounds are the 17-monohalomethylene estratrienes described in EP-A 0 320 438.
- the known 17-halomethylene-estratrienes have a lower affinity for the estrogen receptors than estradiol and, compared to estradiol, cause an increased cell membrane and blood / lymphatic permeability. These compounds are therefore particularly well suited for the treatment of symptoms that occur as a result of failure of the second phase of action of estradiol (climacteric complaints).
- the new 17-difluoromethylene-estratrienes according to the invention show new, completely unexpected pharmacological properties not previously described for the above-mentioned 17-monohalomethylene-estratrienes and other steroids.
- the 17-difluoromethvlen estratrienes are very weak estrogens, as was shown by standard binding studies on the estrogen receptor and in transactivation assays in which lTß-estradiol was used as a reference substance (MT Bocqucl et al. Nucleic Acid Research 17: 2581-95: S. Green et al., Nucleic Acid Research 16: 369, 1989; L. Tora et al., EMBO J. 8: 1981-86, 1989; JE Burch et al., Mol Cell. Biol 8: 1123-31. 1988).
- test methods are used to characterize compounds with presumed antioxidative and vasculoprotective properties, the results of which, taken together, allow a statement to be made as to whether the tested compounds have antioxidative and vasculoprotective properties.
- the antioxidative and vasculoprotective properties of the new compounds are based both on a direct effect by preventing the oxidation of the LDLs and on an indirect effect by releasing the vasodilatory nitrogen oxide (NO) from endothelial cells.
- NO vasodilatory nitrogen oxide
- Human LDL was obtained from Organon Teknika, Rockville M.D. It was diluted with Ca and Mg ions-free PBS (phosphate buffer solution) to a protein concentration of 0.5 mg / ml and, in order to remove EDTA (ethylenediamine tetraacetic acid) before the oxidation, dialyzed against this buffer at 4 ° C. .
- PBS phosphate buffer solution
- LDL was then determined by adding 10 uM copper sulfate and then incubating at 37 ° C in a water bath. in an open Eppi village vessel. oxidized.
- the test compound dissolved in DMSO (dimethyl sulfoxide), was added in a final volume of 1%.
- the oxidation was stopped by the addition of 1 mM EDTA.
- the samples were stored at 4 ° C. until FPLC (fast protein liquid chromatography) analysis. It was found that the chromatographic behavior of the oxidized LDL's remained constant for more than a week.
- the samples (0.1 ml with 0.5 mg LDL protein) were analyzed on a 1 ml Q-Sepharose column (Hi-Trap Q, Pharmacia). The absorption was measured constantly at 280 ⁇ m and the peaks were integrated for quantification.
- the initial buffer (Buffer A) consisted of 10 mM Tris-HC1, pH 7.5 with ImM EDTA. Under these conditions, LDL tied completely to the column. It was eluted with a step gradient from buffer B (buffer A + IM NaCl).
- the aorta of male Sprague - Daweley rats was removed, all adherent fat and associated tissue were removed and cut into 2 mm rings.
- the endothelium was mechanically removed from the inner surfaces of some aortic rings.
- the rings were individually hung in 10 ml organ baths at 37 ° C, containing the Krebs-Henseleit solution (KHS), which had a pH of 7.4 when saturated with 95% O- and 5% CO-.
- KHS Krebs-Henseleit solution
- the tissue was allowed to equilibrate for 90 minutes under 1 g tension.
- the isometric tension was measured with a "force transducer" (Grass FT03C) and recorded on a recorder (Gould TA 5000).
- the new -difluoromethyl-estratrienes on isolated rat aortae bring about relaxation of the smooth muscles; in contrast to 17ß-estradiol, which exerts its relaxing influence on the aorta independently of the endothelium, the new compounds induce vasorelaxation by releasing NO from the endothelium.
- Vascular relaxation protects the vessels from the consequences of increasing local (vasospasm in the coronary and cerebral arteries) or general (e.g. hypertension) muscle tone of the smooth muscles;
- the antioxidant properties of the compounds can cause vascular damage by free radicals, which are caused by activated leukocytes (polymorphonuclear and mononuclear) and vascular cells (e.g. endothelium) and the oxidative modification of LDL, and are the main cause of atherosclerotic lesion formation and progression (Steinberg et al. , N. Engl. J. Med. 320: 915, 19989).
- the new compounds of general formula I according to the invention are particularly suitable for the prevention and treatment of the following diseases: Atherosclerosis
- Vasospasm coronal and cerebral diabetic vasculopathies (e.g. neuropathy, nephropathy, retinopathy)
- Kidney disease e.g. glomerulonephritis
- Neurodegenerative diseases e.g. Alzheimer's disease
- the invention also relates to pharmaceutical preparations which contain compounds of the general formula I.
- the application takes place depending on the application:
- soft gelatin capsules which contain solutions which are used in soft gelatin capsules, aqueous or oily suspensions, emulsions, pills, troches, syrups, elixirs or sprays and the like.
- the compounds of the general formula I can be applied in the form of depo injections, implants or muscular, subcutaneous and intravenous injections.
- compositions which contain compounds of the general formula I are prepared by the methods known from the prior art (reference). Pharmaceutical preparations should contain 17-difluoromethylene-estratrienes in an active compound concentration of 0.1-100 mg / kg day. The respective active ingredient concentration depends on the illness to be treated or the severity of the respective illness
- the invention also relates to a process for the preparation of the compounds of the general formula I. They are prepared according to the invention by a 17-keto compound of the general formula II
- Rl is a hydroxy protecting group
- A, B, D, E, G, R 2 , R 3 , R 4 and R 3 can have the meaning given in formula I, with difluoromethyl-diphenyl-phosphine oxide or diethyl (difluoromethyl) phosphonate in
- THP tetrahydropyranyl
- lithium diisopropylamide, sodium hydride, potassium t-butoxide, butyllithium and the like are suitable as strong bases.
- the ketone of the general formula II is reacted in an aprotic solvent, such as, for example, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dioxane or a mixture of these solvents.
- an aprotic solvent such as, for example, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dioxane or a mixture of these solvents.
- the reaction temperature should preferably be between 50 ° C and 100 ° C.
- the conditions for splitting off the 3-hydroxy protecting group depend on their nature: protecting groups such as the THP group or a silyl radical can be removed under the action of a weak acid such as oxalic acid or an acidic ion exchanger, while the methyl group can be removed by the action of strong Lewis acids, e.g. Dibutylaluminiumhydrid, can be split off.
- a weak acid such as oxalic acid or an acidic ion exchanger
- strong Lewis acids e.g. Dibutylaluminiumhydrid
- the etherification of the free 3-hydroxy group takes place in a manner known per se with a reagent supplying the R 1 radical.
- the 17-ketones with a protected 3-hydroxy function required for the difluoromethyleneation are prepared by reacting the corresponding, known 3-hydroxy compound with dihydropyran under the influence of ⁇ r ⁇ -toluenesulfonic acid in tetrahydrofuran or other methods known to those skilled in the art for protecting hydroxy groups.
- a suspension of 2.0 g of llß-methoxy-3-hydroxy-estra-l, 3,5 (10) -trien-17-one in 20 ml of toluene, 5 ml of tetrahydrofuran and 3.0 ml of dihydropyran is mixed with 20 mg of ⁇ r ⁇ -toluenesulfonic acid for 24 hours Room temperature stirred. Then 0.5 ml of pyridine are added, diluted with ethyl acetate, washed with sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate, in vacuo. concentrated and on silica gel with hexane /
- a solution of 3 g of difluoromethyldiphenylphosphine oxide in 80 ml of tetrahydrofuran is slowly mixed with 5.85 ml of 2 molar lithium diisopropylamide solution at a bath temperature of -50 ° C. and stirred for 1 hour. Then a solution of 1.8 g of 11 ⁇ -methoxy-3-tetrahydropyranyloxy-estra-l, 3,5 (10) -trie ⁇ -17-one in 40 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly from -50 ° C. to 100 ° C bath temperature warmed and refluxed for 2.5 hours.
- a solution of 3 g of difluoromethyldiphenylphosphine oxide in 85 ml of tetrahydrofuran is slowly mixed with 6 ml of 2-molar lithium diisopropylamide solution at a bath temperature of -50 ° C. and stirred for 1 hour. Then a solution of 1.7 g of 3-tetrahydropyranyloxy-estral, 3.5 (10), 7-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly from -50 ° C. to 100 ° C. Bath temperature warmed and refluxed for 2.5 hours.
- a suspension of 2.0 g of 3-hydroxy-estra-1,3,5 (10), 8-tetraen-17-one in 20 ml of tetrahydrofuran and 2.0 ml of dihydropyran is mixed with 9.4 mg of ⁇ -toluenesulfonic acid for 3 hours at room temperature touched. Then 0.3 ml of pyridine is added, diluted with ethyl acetate, washed with sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate, in vacuo. concentrated and chromatographed on silica gel with hexane / acetone / triethylamine.
- a suspension of 1.2 g of 3-hydroxy-7ß-methyl-estra-l, 3,5 (10) -trien-17-one in 12 ml of toluene and 1.2 ml of dihydropyran is mixed with 5.6 mg /? ⁇ r ⁇ -toluenesulfonic acid for 2 hours at room temperature ⁇ rature stirred. Then it is diluted with ethyl acetate, washed with sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate, in vacuo. concentrated and chromatographed on silica gel with hexane / acetone.
- a solution of 2 g of difluoromethyldiphenylphosphine oxide in 55 ml of tetrahydrofuran is slowly mixed with 3.9 ml of 2-molar lithium diisopropylamide solution at a bath temperature of -50 ° C. and stirred for 1 hour. Then a solution of 1.15 g of 7 ⁇ -methyl-3-tetrahydropyranyloxy-estra-1,3,5 (10) -trien-17-one in 20 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly from -50 ° C. to 100 ° C. Bath temperature warmed and refluxed for 2.5 hours.
- a solution of 9.4 g of diethyl (difluoromethyl) phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2-molar lithium diisopropylamide solution at -50 ° C. bath temperature and stirred for 1 hour. Then a solution of 6 g of 3-methoxy-18-methyl-estra-l, 3,5 (10) - trien-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly from - 50 ° C to 100 ° C bath temperature warmed and refluxed for 6 hours.
- a solution of 5 g of 17-difluoromethylene-3-methoxy-18-methyl-estra-1,3,5 (10) -triene in 95 ml of toluene is mixed with 95 ml of a 1.6 molar diisobutyialuminum hydride solution in toluene for 3 hours at 140 ° C. Bath temperature refluxed.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Photoreceptors In Electrophotography (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Exhaust-Gas Circulating Devices (AREA)
- Electrical Control Of Air Or Fuel Supplied To Internal-Combustion Engine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Vehicle Body Suspensions (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Ceramic Products (AREA)
- Saccharide Compounds (AREA)
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19509729A DE19509729A1 (de) | 1995-03-13 | 1995-03-13 | 17-Difluormethylen-Estratriene |
DE19509729 | 1995-03-13 | ||
PCT/EP1996/001069 WO1996028462A1 (de) | 1995-03-13 | 1996-03-13 | 17-difluormethylen-estratriene |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0815120A1 EP0815120A1 (de) | 1998-01-07 |
EP0815120B1 true EP0815120B1 (de) | 2001-02-14 |
Family
ID=7756963
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96907453A Expired - Lifetime EP0815120B1 (de) | 1995-03-13 | 1996-03-13 | 17-difluormethylen-estratriene |
Country Status (21)
Country | Link |
---|---|
US (2) | US6018062A (de) |
EP (1) | EP0815120B1 (de) |
JP (1) | JPH11501644A (de) |
KR (1) | KR19980703002A (de) |
AT (1) | ATE199159T1 (de) |
AU (1) | AU693335B2 (de) |
BR (1) | BR9612787A (de) |
CA (1) | CA2215201A1 (de) |
CZ (1) | CZ281097A3 (de) |
DE (2) | DE19509729A1 (de) |
HU (1) | HUP9801846A3 (de) |
IL (1) | IL117497A (de) |
IS (1) | IS4556A (de) |
NO (1) | NO308306B1 (de) |
PL (1) | PL322199A1 (de) |
RU (1) | RU2155770C2 (de) |
SI (1) | SI9620030A (de) |
SK (1) | SK121697A3 (de) |
TR (1) | TR199700950T1 (de) |
WO (1) | WO1996028462A1 (de) |
ZA (1) | ZA962037B (de) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU703814B2 (en) * | 1995-12-04 | 1999-04-01 | Wyeth | Antioxidant |
US5773432A (en) * | 1996-10-30 | 1998-06-30 | Schering Aktiengesellschaft | Method for lowering plasma levels of lipoprotein(a) |
AU2003264866A1 (en) * | 2003-08-11 | 2005-02-25 | Industria Chimica Reggiana I.C.R. S.P.A. | Chemical composition and method of polymerisation thereof for use on vehicle bodywork repair |
AU2005259499A1 (en) * | 2004-06-29 | 2006-01-12 | Jado Technologies Gmbh | Use of steroid-derived pharmaceutical compositions for treating disorders relating to pathological processes in lipid rafts |
US8030298B2 (en) | 2005-05-26 | 2011-10-04 | Abbott Products Gmbh | 17β-HSD1 and STS inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3741800A1 (de) * | 1987-12-07 | 1989-06-15 | Schering Ag | 17-halogenmethylen-estratriene |
US5969168A (en) * | 1991-01-07 | 1999-10-19 | Pherin Corporation | Androstanes for inducing hypothalamic effects |
US5783571A (en) * | 1991-01-07 | 1998-07-21 | Pherin Corporation | Method of altering hypothalamic function by nasal administration of estrene steroids |
US5883087A (en) * | 1991-01-07 | 1999-03-16 | Pherin Corporation | Androstane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods |
US5773432A (en) * | 1996-10-30 | 1998-06-30 | Schering Aktiengesellschaft | Method for lowering plasma levels of lipoprotein(a) |
-
1995
- 1995-03-13 DE DE19509729A patent/DE19509729A1/de not_active Withdrawn
-
1996
- 1996-03-13 RU RU97116513/04A patent/RU2155770C2/ru active
- 1996-03-13 PL PL96322199A patent/PL322199A1/xx unknown
- 1996-03-13 BR BR9612787-2A patent/BR9612787A/pt not_active Application Discontinuation
- 1996-03-13 EP EP96907453A patent/EP0815120B1/de not_active Expired - Lifetime
- 1996-03-13 KR KR1019970706410A patent/KR19980703002A/ko not_active Application Discontinuation
- 1996-03-13 DE DE59606435T patent/DE59606435D1/de not_active Expired - Fee Related
- 1996-03-13 ZA ZA962037A patent/ZA962037B/xx unknown
- 1996-03-13 SI SI9620030A patent/SI9620030A/sl unknown
- 1996-03-13 AU AU51078/96A patent/AU693335B2/en not_active Ceased
- 1996-03-13 CA CA002215201A patent/CA2215201A1/en not_active Abandoned
- 1996-03-13 TR TR97/00950T patent/TR199700950T1/xx unknown
- 1996-03-13 WO PCT/EP1996/001069 patent/WO1996028462A1/de not_active Application Discontinuation
- 1996-03-13 US US08/913,325 patent/US6018062A/en not_active Expired - Fee Related
- 1996-03-13 JP JP8527276A patent/JPH11501644A/ja active Pending
- 1996-03-13 HU HU9801846A patent/HUP9801846A3/hu unknown
- 1996-03-13 CZ CZ972810A patent/CZ281097A3/cs unknown
- 1996-03-13 AT AT96907453T patent/ATE199159T1/de not_active IP Right Cessation
- 1996-03-13 SK SK1216-97A patent/SK121697A3/sk unknown
- 1996-03-14 IL IL11749796A patent/IL117497A/xx not_active IP Right Cessation
-
1997
- 1997-09-08 IS IS4556A patent/IS4556A/is unknown
- 1997-09-12 NO NO974206A patent/NO308306B1/no unknown
-
1999
- 1999-03-08 US US09/263,062 patent/US6136800A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
HUP9801846A2 (hu) | 1998-12-28 |
RU2155770C2 (ru) | 2000-09-10 |
ATE199159T1 (de) | 2001-02-15 |
BR9612787A (pt) | 1999-11-23 |
US6136800A (en) | 2000-10-24 |
NO974206D0 (no) | 1997-09-12 |
AU693335B2 (en) | 1998-06-25 |
TR199700950T1 (xx) | 1998-02-21 |
KR19980703002A (ko) | 1998-09-05 |
US6018062A (en) | 2000-01-25 |
SK121697A3 (en) | 1998-02-04 |
JPH11501644A (ja) | 1999-02-09 |
HUP9801846A3 (en) | 1999-03-01 |
DE19509729A1 (de) | 1996-09-19 |
WO1996028462A1 (de) | 1996-09-19 |
NO308306B1 (no) | 2000-08-28 |
DE59606435D1 (de) | 2001-03-22 |
CZ281097A3 (cs) | 1998-02-18 |
EP0815120A1 (de) | 1998-01-07 |
ZA962037B (en) | 1996-09-25 |
PL322199A1 (en) | 1998-01-19 |
SI9620030A (sl) | 1998-02-28 |
IL117497A0 (en) | 1996-07-23 |
IL117497A (en) | 1999-12-22 |
IS4556A (is) | 1997-09-08 |
CA2215201A1 (en) | 1996-09-19 |
AU5107896A (en) | 1996-10-02 |
NO974206L (no) | 1997-11-13 |
MX9707006A (es) | 1997-11-29 |
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