EP0424504B1 - NOUVEAUX DERIVES D'ACIDE 9$g(a)-HYDROXY-3-OXO-4,24(25)-STIGMASTADIENE-26-O QUE, PROCEDE DE PREPARATION DE CES DERIVES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT DE TELS DERIVES - Google Patents
NOUVEAUX DERIVES D'ACIDE 9$g(a)-HYDROXY-3-OXO-4,24(25)-STIGMASTADIENE-26-O QUE, PROCEDE DE PREPARATION DE CES DERIVES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT DE TELS DERIVES Download PDFInfo
- Publication number
- EP0424504B1 EP0424504B1 EP90907364A EP90907364A EP0424504B1 EP 0424504 B1 EP0424504 B1 EP 0424504B1 EP 90907364 A EP90907364 A EP 90907364A EP 90907364 A EP90907364 A EP 90907364A EP 0424504 B1 EP0424504 B1 EP 0424504B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydroxy
- oxo
- stigmastadien
- oic acid
- general formula
- 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
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Definitions
- This invention relates to novel 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid derivatives of the general formula (I), wherein M stands for hydrogen C1 ⁇ 4 alkyl or a pharmaceutically acceptable cation, as well as pharmaceutical compositions containing these compounds.
- the invention also relates to processes for preparing the compounds of the general formula (I) by a microbial degradation of ⁇ -sitosterol or ⁇ -sitosterol-containing sterols of plant origin followed, if desired, by salt formation or esterification, and for preparing pharmaceutical compositions containing the compounds of the general formula (I).
- the pharmaceutically acceptable salts of the compounds of the general formula (I) include those formed with inorganic or organic cations such as sodium, potassium, calcium, magnesium, aluminium, zinc, ammonium, ethylenediaminium, tris(hydroxy-methyl)-aminomethane or tetramethylammonium.
- the degradation of the side-chain of ⁇ -sitosterol having an ethyl group on the carbon atom in position 24 differs from that of cholesterol in that the bacteria degrading the side-chain introduce a carboxyl group on the carbon atom in position 28 attached to the carbon atom in position 24, then cleave the bond between the carbon atoms in positions 24 and 28 by a ⁇ -oxidation mechanism.
- mutant strains such as those requiring various nutrients (adenine, proline, valine) or those resistent to various antibiotics (e. g. streptomycin).
- antibiotics e. g. streptomycin
- BCS 394 Under the code name BCS 394 a Mycobacterium strain of this type producing new and unpublished sitosterol degradation products as main products such as 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid (I, wherein M stands for hydrogen) and 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid-methylester (I, wherein M means a methyl group) was deposited with the National Collection of Agricultural apd Industrial Microorganisms (Budapest) under the number NCAIM B(P) 001038.
- Budapest National Collection of Agricultural apd Industrial Microorganisms
- the taxonomic characteristics of the Mycobacterium strain deposited under the number NCAIM B(P) 001038 are as follows: the colonies of the microorganism are greyish white; this organism proliferates at 45 °C, but fails to proliferate at 50 °C and in the absence of oxygen. It efficiently utilizes ammonium chloride, calcium nitrate, sodium nitrate and ammonium hydrogen phosphate as sole nitrogen source, as well as glucose, glycerol, fructose, maltose, xylose, sodium succinate, sodium pyruvate and sodium acetate as sole carbon source. It fails to utilize saccharose, starch and arabinose. The strain is unable to degrade tyrosine and is devoid of pigmentation.
- the cholesterol-biosynthesis-inhibiting effect of the compounds according to the invention is illustrated by the example of 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid (I, wherein M stands for hydrogen).
- the inhibitory effect of this compound was compared with that of 3 ⁇ -hydroxy-5 ⁇ -cholest-8(14)-en-15-one (Colestolone) by the method of A. Endo and co-workers [Eur. J. Biochem. 77 , 31 (1977); Biochim. Biophys. Acta 486 , 71 (1977)] studying in rat liver homogenate the incorporation of radiolabelled acetic acid into cholesterol.
- the animals were decapitated on the day of the experiment. Livers were immersed in ice cold Krebs/Ringer bicarbonate buffer (pH 7.4) and cut into small pieces. Using a tissue homogenizer in a gentle mode of operation we prepared a crude liver homogenate of which a portion equivalent to 100 mg of wet liver was weighed into glass-stoppered tubes. The operations were carried out under constant cooling. The incubation mixture included the liver homogenate, the Krebs/Ringer bicarbonate buffer, the sodium-(1-14C)acetate (supplied by IZINTA; specific activity: 14.86 MBq/mg) and the (3H)cholesterol oleate (supplied by Du Pont; specific activity: 3067 GBq/mmole).
- the steroids inhibiting cholesterol biosynthesis were added to the incubation mixture in an alcoholic solution containing albumin, as described by G. J. Schroepfer and co-workers [J. Biol. Chem. 24 , 8975 (1977)].
- the final volume of the incubation mixture was 2.0 ml. Incubation went on for 2 hours in a water bath of 37 °C, then 2 ml of alcohol containing 15% (w/v) of KOH were added to the mixture, which was then kept at 70-75 °C for further 2 hours.
- the lipids were extracted from the alkaline mixture by petroleum ether.
- this invention relates to a process for producing new 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid derivatives of the general formula (I), wherein M stands for hydrogen, C1 ⁇ 4 alkyl or a pharmaceutically acceptable cation, by submerged aerobic fermentation of a Mycobacterium sp. BCS-394 microorganism strain, deposited under the number NCAIM B(P) 001038, or a mutants of same with ⁇ -sitosterol or a sterol mixture of plant origin containing.
- ⁇ -sitosterol in a nutrient medium containing utilizable carbon and nitrogen sources as well as mineral salts, and, if desired, by isolating from the fermentation broth the compound or compounds of the general formula (I), wherein M means hydrogen and/or a methyl group, and, if desired, by transforming the compound of the general formula (I), wherein M stands for hydrogen, to a compound of the general formula (I), wherein M stands for a pharmaceutically acceptable cation or C1 ⁇ 4 alkyl group.
- the Mycobacterium strain BCS-394 deposited under the number NCAIM B(P) 001038 is cultivated in nutrient media which contain utilizable carbon and nitrogen sources as well as mineral salts, and which are suitable for the cultivation of fast-growing Mycobacteria.
- the carbon sources glucose and glycerol of the organic nitrogen sources soybean-meal, urea and yeast extract, of the inorganic nitrogen sources ammonium chloride were advantageously applied. It is advantageous to admix the sterol to be transformed in the form of a suspension prepared with Tween-80 and polypropylene-glycol with the nutrient medium. Pure ⁇ -sitosterol or a sterol mixture containing ⁇ -sitosterol, e. g. crude sitosterol obtained from soybean oil, which is a mixture of ⁇ -sitosterol and campesterol, serve as substrates for the microbial transformation.
- the cultivation of the microorganisms and the transformation of the sterols are carried out between 28 °C and 37 °C, preferably at 32 °C.
- a major proportion of the products of sterol transformation is adsorbed on the mycobacterium cells, a minor proportion is dissolved in the nutrient liquid.
- the steroids are desorbed from the cells using organic solvents miscible with water, preferably methanol, while the sterol transformation products in the filtrate of the fermentation broth are preferably isolated by extraction with ethyl acetate or chlorinated hydrocarbons, such as dichloromethane.
- ethyl acetate or chlorinated hydrocarbons such as dichloromethane.
- the crude product obtained after the evaporation of the solvent also contains several sterol degradation products present in minor quantities.
- column chromatography and/or thin-layer chromatography can be preferably used.
- the structures of the products were elucidated by UV, IR, 1H-NMR and 13C-NMR as well as mass spectrometry.
- salts can be formed for therapeutic application.
- These salts can be prepared in a manner known per se from the compound of the general formula (I), wherein M stands for hydrogen, and a base providing the suitable cation.
- ester derivatives according to the invention can be prepared also in a manner known per se from the compound of the general formula (I), wherein M means hydrogen, and a suitable C1 ⁇ 4 alcohol.
- M means hydrogen
- a representative of the compounds according to the invention, wherein M means a methyl group in the general formula (I) can be isolated directly from the fermentation broth.
- the compounds of the general formula (I) according to the invention are highly useful as active substances in antihypercholesteremic pharmaceutical compositions for the treatment of e. g. atherosclerosis or hyperlipemia in humans. They can be administered e. g. orally or parenterally, in the form of e. g. tablets, capsules or injectable compositions. The oral mode of administration is generally preferred.
- the dose may naturally depend on several factors, such as the age, body weight, the severity of the health problem of the person to be treated and on some other factors, but the daily dose for adults may generally range between about 100 and 3000 mg, preferably between 300 and 1000 mg, but higher doses may also be favourably used, if necessary.
- the active compounds according to the invention are suitably transformed to pharmaceutical compositions by mixing them with nontoxic, inert, solid or liquid carriers and/or additives commonly used for enteral or parenteral administration.
- solid forms of pharmaceutical compositions suitable for oral administration can be prepared from 9 ⁇ -hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid derivatives of the general formula (I), wherein M has the above meaning, by the following method:
- the pulverized active substance with an average particle size of 0.05-1.0 mm is homogenized with additives of similar particle size, used in preparing tablets and capsules, then the mixture is filled in hard gelatine capsules or pressed to form tablets directly or after dry or wet granulation.
- Vehicles used in the preparation of tablets and capsules were applied as additives, preferably starch, tribasic calcium phosphate, calcium hydrogen phosphate, lactose, glucose, cellulose, saccharose, mannitol, sorbitol or mixtures thereof; adsorbents, preferably colloidal silicon dioxide (protected names: Aerosil, Gesilite, Cab-o-sil, Syloid, Neosyl); excipients, preferably gelatine, acacia, cellulose ethers (methylcellulose, carboxy-methylcellulose, ethylcellulose, ethyl-hydroxyethyl-cellulose, hydroxypropyl-methylcellulose), pectin, sodium alginate, tragacanth, polyvinylpyrrolidone, polyvinylalcohol or their mixtures; disintegrants, preferably starch, sodium carboxymethyl-starch, ultra-amylopectin, alginic acid and alginates, formaldehyde-gelatine,
- a cell suspension is prepared with 10 ml of sterile water from the 5-day old culture of Mycobacterium sp. BCS-394 (NCAIM B(P) 001038) grown on a potato - glucose agar slant. Five ml of this suspension are used to inoculate 800 ml of sterile MI inoculum-medium in a 3000 ml Erlenmeyer flask.
- the MI medium has the following composition: Glucose 8.0 g Soybeanmeal 1.6 g Urea 0.4 g Yeast extract 0.8 g Ammonium chloride 2.4 g Potassium dihydrogen phosphate 0.4 g Magnesium sulfate.7H2O 0.4 g Ferric chloride.6H2O 0.4 g Tween-80 0.4 g in 800 ml of tap water.
- the pH of the nutritive medium is adjusted to 7.0 before sterilization and the mixture is sterilized at 121 °C for 45 minutes.
- the flask is incubated at 32 °C for 2 days on a rotary shaker (250 r.p.m., diameter 2.5 cm). The contents of this flask are used to inoculate, in a 10 l laboratory fermentor, 4.2 l of MF medium, sterilized at 121 °C for 60 minutes.
- the MF medium is prepared as follows: 50 g of glucose, 10 g of soybean-meal, 2.5 g of urea, 15 g of ammonium chloride and 2.5 g of potassium dihydrogen phosphate are brought to boil in 1.5 l of tap water.
- the basic medium prepared in this way is added, supplemented with 15 g of calcium carbonate, under constant stirring to the molten mixture of 100 g of ⁇ -sitosterol, 40 g of polypropylene glycol, 10 g of Tween-80 and 800 ml of tap water, sterilized at 121 °C for 1 hour, then the volume of the mixture is brought up to 4 l with boiling tap water.
- the nutrient medium thus obtained is sterilized at 121 °C for 1 hour.
- the inoculated culture is agitated at 32 °C for 24 hours at 750 r.p.m., while an air flow of 100 l/hour is introduced to the fermentor. Fermentation is continued for 6 days with aeration of 300 l/hour through the broth stirred at 750 r.p.m. After the termination of the fermentation the products of the sterol transformation are isolated as follows.
- a cell suspension is prepared with 10 ml of sterile water from the 4-5 day old culture of Mycobacterium sp. BCS-394 grown on a potato-glucose agar slant. Ten 100 ml portions each of sterile MY-5 inoculum-medium in ten 500 ml Erlenmeyer flasks are inoculated with 1 ml each of the above cell suspension.
- the MY-5 medium is prepared as follows: 10 g of glycerol, 1 g of soybeanmeal, 0.5 g of urea, 1 g of ammonium chloride, 0.5 g of dipotassium hydrogen phosphate, 0.5 g of magnesium sulfate.7H2O, 1 g of sodium citrate and 0.05 g of ferric chloride.6H2O are brought to boil in 300 ml of tap water.
- the basis medium prepared in this way is added, under stirring, to the molten mixture of 30 g of crude sitosterol (a 2:1 mixture of ⁇ -sitosterol and campesterol), 8 g of polypropyleneglycol, 2 g of Tween-80 and 150 ml of tap water, sterilized at 121 °C, then the volume of the mixture is brought up to 1 l with boiling tap water.
- the flasks are shaken at 32 °C for 7 days on a horizontal shaker (250 r.p.m., diameter: 2.5 cm), then the cells are separated from the broth by means of a centrifuge.
- the sterol conversion products and the unchanged crude sitosterol are washed off from the cells by washing them three times with 200 ml of methanol each.
- the methanol solution is evaporated under reduced pressure.
- the supernatant of the fermentation broth is extracted with 200 ml of ethyl acetate and the extract is evaporated under reduced pressure.
- By pooling the residue of the extracts 32 g of crude product are obtained.
- the crude product is subjected to chromatography on a column prepared from 500 g of silicic acid.
- Elution is carried out with an ethyl acetate - n-heptane mixture in which the proportion of ethyl acetate is increased step-wise.
- an eluent mixture containing 25% of ethyl acetate in n-heptane 2.5 g of unchanged starting material (a 2:1 mixture of ⁇ -sitosterol and campesterol) are eluted from the column.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (8)
- Acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque.
- Esters alkyliques en C₁₋₄ d'acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque.
- Ester méthylique d'acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque.
- Sels acceptables du point de vue pharmaceutique de l'acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque.
- Procédé pour préparer des dérivés d'acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque de formule générale (I), dans laquelle M est un atome d'hydrogène, un groupe alkyle en C₁₋₄ ou un cation acceptable du point de vue pharmaceutique, qui comprend la fermentation de β-sitostérol ou d'un mélange de stérols contenant du β-sitostérol d'origine végétale par une culture aérobie submergée de Mycobacterium sp. BCS-394 déposé sous le numéro NCAIM B(P) 001038 ou d'un mutant de celui-ci dans un milieu nourricier contenant des sources de carbone et d'azote utilisables ainsi que des sels minéraux et, si cela est désiré, l'isolation à partir du bouillon du ou des composés de formule générale (I) dans laquelle M est un atome d'hydrogène et/ou un groupe méthyle et, si cela est désiré, la conversion du composé de formule générale (I) dans laquelle M est un atome d'hydrogène, en un composé de formule générale (I) dans laquelle M est un groupe alkyle en C₁₋₄ ou un cation acceptable du point de vue pharmaceutique.
- Composition pharmaceutique qui comprend comme composant actif, un dérivé d'acide 9α-hydroxy-3-oxo-4,24 (25)-stigmastadièn-26-oïque de formule générale (I), dans laquelle M est un atome d'hydrogène, un groupe alkyle en C₁₋₄ ou un cation acceptable du point de vue pharmaceutique, en mélange avec des supports et/ou des additifs couramment utilisés dans la préparation de produits pharmaceutiques.
- Procédé pour préparer des compositions pharmaceutiques principalement antihypercholestérolémiques, qui comprend la mise d'un composé de formule générale (I), dans laquelle M est tel que défini dans la revendication 6, sous forme de composition pharmaceutique par une procédure connue dans la préparation de produits pharmaceutiques.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT90907364T ATE104313T1 (de) | 1989-05-11 | 1990-05-10 | Neue 9-g(a)-hydroxy-3-oxo-4,24(25)-stigmastadien26-s|urederivate,verfahren zur herstellung und heilmittel daraus. |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU235989 | 1989-05-11 | ||
HU235989 | 1989-05-11 | ||
PCT/HU1990/000033 WO1990013559A1 (fr) | 1989-05-11 | 1990-05-10 | NOUVEAUX DERIVES D'ACIDE 9α-HYDROXY-3-OXO-4,24(25)-STIGMASTADIENE-26-OÏQUE, PROCEDE DE PREPARATION DE CES DERIVES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT DE TELS DERIVES |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0424504A1 EP0424504A1 (fr) | 1991-05-02 |
EP0424504B1 true EP0424504B1 (fr) | 1994-04-13 |
Family
ID=10958990
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90907364A Expired - Lifetime EP0424504B1 (fr) | 1989-05-11 | 1990-05-10 | NOUVEAUX DERIVES D'ACIDE 9$g(a)-HYDROXY-3-OXO-4,24(25)-STIGMASTADIENE-26-O QUE, PROCEDE DE PREPARATION DE CES DERIVES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT DE TELS DERIVES |
Country Status (17)
Country | Link |
---|---|
US (1) | US5112815A (fr) |
EP (1) | EP0424504B1 (fr) |
KR (1) | KR920701232A (fr) |
CN (1) | CN1048857A (fr) |
AT (1) | ATE104313T1 (fr) |
AU (1) | AU638993B2 (fr) |
DE (1) | DE69008103T2 (fr) |
DK (1) | DK0424504T3 (fr) |
ES (1) | ES2055429T3 (fr) |
FI (1) | FI910159A0 (fr) |
GR (1) | GR1002174B (fr) |
HR (1) | HRP920777A2 (fr) |
IL (1) | IL94272A (fr) |
NZ (1) | NZ233657A (fr) |
WO (1) | WO1990013559A1 (fr) |
YU (1) | YU47914B (fr) |
ZA (1) | ZA903628B (fr) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7250694A (en) * | 1993-06-25 | 1995-01-17 | Biosphere Technologies Inc. | Dietary supplement incorporating beta-sitosterol and pectin |
JP3873097B2 (ja) * | 1997-11-06 | 2007-01-24 | 独立行政法人理化学研究所 | 抗肥満剤及び脂質代謝改善剤 |
US6531462B2 (en) | 1997-11-06 | 2003-03-11 | Riken | Medicament for treating obesity and improving lipid metabolism |
US5952393A (en) * | 1998-02-12 | 1999-09-14 | Sorkin, Jr.; Harlan Lee | Composition for reducing serum cholesterol levels |
WO2001055098A1 (fr) | 2000-01-28 | 2001-08-02 | The Procter & Gamble Company | Composes d'arginine d'un gout agreable et leurs utilisations pour la sante cardio-vasculaire |
US20030045473A1 (en) * | 2002-07-19 | 2003-03-06 | Sarama Robert Joseph | Compositions, kits, and methods for cardiovascular health |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4062880A (en) * | 1976-04-30 | 1977-12-13 | The Upjohn Company | 9α-Hydroxy-bis-nor-cholanic acid |
US4214051A (en) * | 1977-10-21 | 1980-07-22 | The Upjohn Company | Process for preparing 9α-OH BN acid methyl ester |
US4429041A (en) * | 1981-05-11 | 1984-01-31 | The Upjohn Company | Process of producing 9-hydroxy-3-oxo-4,17(20)-pregnadiene-20-carboxylic acid |
US4425429A (en) * | 1981-07-24 | 1984-01-10 | The Upjohn Company | Composition of matter and process |
US4755463A (en) * | 1982-05-25 | 1988-07-05 | Wisconsin Alumni Research Foundation | Process for preparing steroids |
-
1990
- 1990-05-03 IL IL9427290A patent/IL94272A/en not_active IP Right Cessation
- 1990-05-10 ES ES90907364T patent/ES2055429T3/es not_active Expired - Lifetime
- 1990-05-10 EP EP90907364A patent/EP0424504B1/fr not_active Expired - Lifetime
- 1990-05-10 WO PCT/HU1990/000033 patent/WO1990013559A1/fr active IP Right Grant
- 1990-05-10 US US07/635,623 patent/US5112815A/en not_active Expired - Fee Related
- 1990-05-10 AT AT90907364T patent/ATE104313T1/de not_active IP Right Cessation
- 1990-05-10 AU AU56363/90A patent/AU638993B2/en not_active Ceased
- 1990-05-10 DE DE69008103T patent/DE69008103T2/de not_active Expired - Fee Related
- 1990-05-10 DK DK90907364.5T patent/DK0424504T3/da active
- 1990-05-10 KR KR1019910700031A patent/KR920701232A/ko not_active IP Right Cessation
- 1990-05-11 ZA ZA903628A patent/ZA903628B/xx unknown
- 1990-05-11 GR GR900100356A patent/GR1002174B/el unknown
- 1990-05-11 YU YU92390A patent/YU47914B/sh unknown
- 1990-05-11 NZ NZ233657A patent/NZ233657A/en unknown
- 1990-05-11 CN CN90104386A patent/CN1048857A/zh active Pending
-
1991
- 1991-01-11 FI FI910159A patent/FI910159A0/fi not_active Application Discontinuation
-
1992
- 1992-10-01 HR HR920777A patent/HRP920777A2/hr not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CN1048857A (zh) | 1991-01-30 |
WO1990013559A1 (fr) | 1990-11-15 |
DK0424504T3 (da) | 1994-05-16 |
HRP920777A2 (en) | 1994-08-31 |
YU47914B (sh) | 1996-05-20 |
IL94272A0 (en) | 1991-03-10 |
DE69008103D1 (de) | 1994-05-19 |
FI910159A0 (fi) | 1991-01-11 |
US5112815A (en) | 1992-05-12 |
GR1002174B (en) | 1996-03-07 |
ZA903628B (en) | 1991-04-24 |
GR900100356A (el) | 1991-10-10 |
KR920701232A (ko) | 1992-08-11 |
EP0424504A1 (fr) | 1991-05-02 |
ATE104313T1 (de) | 1994-04-15 |
AU5636390A (en) | 1990-11-29 |
YU92390A (en) | 1991-10-31 |
NZ233657A (en) | 1992-03-26 |
ES2055429T3 (es) | 1994-08-16 |
AU638993B2 (en) | 1993-07-15 |
IL94272A (en) | 1994-04-12 |
DE69008103T2 (de) | 1994-07-28 |
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