FI106556B - Förfarande för framställning av semisyntetiska glykosaminoglykaner - Google Patents
Förfarande för framställning av semisyntetiska glykosaminoglykaner Download PDFInfo
- Publication number
- FI106556B FI106556B FI931741A FI931741A FI106556B FI 106556 B FI106556 B FI 106556B FI 931741 A FI931741 A FI 931741A FI 931741 A FI931741 A FI 931741A FI 106556 B FI106556 B FI 106556B
- Authority
- FI
- Finland
- Prior art keywords
- water
- nucleophilic
- semi
- heparin
- acid
- Prior art date
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- 229920002683 Glycosaminoglycan Polymers 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims description 16
- 230000008569 process Effects 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title description 3
- 229920000669 heparin Polymers 0.000 claims abstract description 44
- 229960002897 heparin Drugs 0.000 claims abstract description 44
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical group OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229920002971 Heparan sulfate Chemical group 0.000 claims abstract description 38
- 239000002253 acid Substances 0.000 claims abstract description 18
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 239000012434 nucleophilic reagent Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 16
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 230000002378 acidificating effect Effects 0.000 description 4
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- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
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- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
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- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000008320 venous blood flow Effects 0.000 description 1
- GSQBIOQCECCMOQ-UHFFFAOYSA-N β-alanine ethyl ester Chemical compound CCOC(=O)CCN GSQBIOQCECCMOQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Materials Engineering (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Claims (5)
1. Förfarande för syntetisering av heparin- eller heparanstruktur uppvisande halvsyntetiska glykosamino- g-5 lykaner med formeIn OP es . °1 0J\qh ^/L _6J\qh ^4 _0 J^h Χί/\°Η ^/L t WHSO,' CSO,1 M.HSOj' CH WHCOCH, < N
10. Jp L J, L J« IV väri p + q = m, varvid p är annat än 0 och m och n är hel-15 tai 1 - 100, R betecknar väte eller en sulfatgrupp (S03‘) och -Z(R2)R1 betecknar en nukleofil radikal, som härstammar frän en nukleofil reagens, som är vald ur gruppen primära och sekundära aminer, sekundära heterocykliska aminer, aminoalkoholer, aminotioler, aminosyror, aminoestrar, pep-20 tider, alkoholer, fenoler, merkaptaner, ditioler, tio-fenoler, hydroxylaminer, hydraziner, hydrazider och nat-, riumazid, kännetecknat av att en halvsyntetisk * i « · glykosaminoglykan med 2,3-gulonstruktur, vilken har for-meln • « • 1· 25 r- n r “I • ^ ^ Γ op OS 1 s0% V.'. A»7 Voi\ Z™7 \ J\oX TlisoH X • 1 K o / J\0H /|_ JVI» / LJ/ l— -0J \i / u \ / w
0 KHSO,” 050,- «HSO,· ON NHCOCH, • · · L J. L -I. 30 ' 1···1 III • · · • · *!1 väri p, q, n och R betecknar samma som ovan, och vilken • · :.1·· har erhällits genom att behandla en vattenhaltig lösning av ett heparinmaterial med en alkalimetall- eller jordal- • 1·. 35 kalimetallbas, vars koncentration är 0,01 - 1 N, varvid * « · # > > · · • · • e · 106556 närvarande är ett sait av en alkalimetall eller en jordal-kalimetall, vars koncentration är 0 - 1 N, och varvid närvarande är eventuellt en katalytisk mängd natriumborhyd-ridreduktionsmedel, i 0,5 - 24 timmar vid en temperatur av 5 35-70 °C; bringas att reagera med ovannämnda nukleofila reagens, varvid närvarande är ett polariskt lösningsmedel och en sadan mängd oorganisk eller organisk bas, sora för-mär bilda ett sait av vilka syragrupper som heist, som är närvarande i de nukleofila reagenserna, och/eller att fri-10 göra dessa nukleofila reagenser frän vilka salt som heist, som de kan ha med ämnen med karaktären av en syra, eventuellt i en inert gasatmosfär; genom att blanda 24 - 96 timmar vid en temperatur av 10 - 3 0 °C, reaktionsblandnin-gen utspäds med vatten, när reaktionslösningen är annan än 15 vatten, den vattenhaltiga lösningens pH regleras tili neutral genom att tillsätta en vattenlösning av klorvä-tesyra, överskottet av nukleofil reagens avlägsnas eventuellt genom att extrahera med ett lösningsmedel, som inte är blandbart med vatten, eller genom att filtrera, den 20 vattenhaltiga lösningen underkastas eventuellt dialys med rinnande vatten och med destillerat vatten och produkten isoleras genom att lyofilisera den vattenhaltiga lösningen : ·i innehällande densamma eller genom utfällning genom till- 5. sättning av ett lämpligt lösningsmedel. 4 4 < I ;·. 25
2. Förfarande enligt patentkrav 1, k ä n n e - • « « tecknat av att mängden nukleofil reagens är 1 - 200 • ♦ .. . molekvivalenter i förhällande tili dimerenheten av den • · · *..* epoxigruppen innehällande halvsyntetiska glykosaminoglyka- • · · *·* * nen med formeln III. 30
3. Förfarande enligt patentkrav 1, k ä n n e - • · · ·...· tecknat av att det polära lösningsmedlet är dime- ··· tylacetamid, dimetylformamid, acetonitril, dioxan, tetra- : hydrofuran eller en blandning därav med vatten. • · · ’ j 4. Förfarande enligt patentkrav 1, kanne- » · . 35 tecknat av att basen som används är natriumhydr- • · ♦,· ; oxid, kalciumhydroxid eller trietylamin.
4 t > • · • · 106556
5. Förfarande enligt patentkrav 1, kanne -tecknat av att den med uppvisande halvsyntetiska glykosaminoglykanen med formdln III 2,3-epoxigulonstruktur loses i vatten, sätts under blandning eventuellt i en 5 inert gasatmosfär tili en vattenhaltig lösning, som inne-häller 10 - 100 molekvivalenter nukleofil reagens i för-hällande tili dimerenheten av glykosaminoglykanen med for-meln III, vilken glykan innehäller en epoxigrupp, och en sadan mängd natriumhydroxid, som förmär bilda ett sait av 10 vilka syragrupper som heist, som är närvarande i den nuk-leofila reagensen, och/eller att frigöra den nukleofila reagensen frän ett eventuellt sait med ett ämne med karak-tären av en syra, reaktionsblandningen därefter hälls i rumstemperaturen 24-96 timmar, att reaktionsblandningens 15 pH därefter regleras neutral med en vattenhaltig klorväte-syra, da reaktionsblandningens pH inte är neutral, att överskottet av nukleofil reagens eventuellt kan avlägsnas genom en passiv extraktion med ett lösningsmedel, som inte är blandbart med vatten, eller genom filtrering, att 20 reaktionslösningen eventuellt kan underkastas dialys med rinnande vatten och med destillerat vatten i 6 - 24 timmar och att produkten isoleras frän lösningen medelst lyofi-:·: lisering eller genom att tillsätta ett lämpligt lös- ningsmedel. • · · · • « • « • « · • ♦ • · * « · · • · t · • · · • · · • · · M» 0 · 0 0 00 0 0 0 0 0 0 00 0 0 ft * 0 0 0 0 « · » 0 0
0 I » « ♦ 0 e • · « 0 · 0 0 » * 0 0 > * • · I t «
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITBO920141A IT1260137B (it) | 1992-04-17 | 1992-04-17 | Glicosaminoglicani semisintetici a struttura eparinica od eparanica modificati nella posizione 2 dell'acido alfa-l-iduronico-2-0-solfato |
| ITBO920141 | 1992-04-17 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI931741A0 FI931741A0 (fi) | 1993-04-16 |
| FI931741A FI931741A (fi) | 1993-10-18 |
| FI106556B true FI106556B (sv) | 2001-02-28 |
Family
ID=11338176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI931741A FI106556B (sv) | 1992-04-17 | 1993-04-16 | Förfarande för framställning av semisyntetiska glykosaminoglykaner |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5430133A (sv) |
| EP (1) | EP0565863B1 (sv) |
| JP (1) | JP2702376B2 (sv) |
| KR (1) | KR0171624B1 (sv) |
| AT (1) | ATE154616T1 (sv) |
| AU (1) | AU658498B2 (sv) |
| CA (1) | CA2093147C (sv) |
| DE (1) | DE69311619T2 (sv) |
| DK (1) | DK0565863T3 (sv) |
| ES (1) | ES2103992T3 (sv) |
| FI (1) | FI106556B (sv) |
| GR (1) | GR3024419T3 (sv) |
| IL (1) | IL105112A (sv) |
| IT (1) | IT1260137B (sv) |
| NO (1) | NO305992B1 (sv) |
| NZ (1) | NZ247196A (sv) |
| TW (1) | TW239148B (sv) |
| ZA (1) | ZA931798B (sv) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696100A (en) * | 1992-12-22 | 1997-12-09 | Glycomed Incorporated | Method for controlling O-desulfation of heparin and compositions produced thereby |
| IT1264101B1 (it) * | 1993-03-29 | 1996-09-10 | Alfa Wassermann Spa | Processo per la sintesi di glicosaminoglicani semisintetici a struttura eparinica od eparanica modificati nella posizione 2 |
| IT1264102B1 (it) * | 1993-03-29 | 1996-09-10 | Alfa Wassermann Spa | Processo per la sintesi di glicosaminoglicani semisintetici contenenti acido alfa-l-galatturonico sostituito con radicali |
| US6127347A (en) * | 1994-01-12 | 2000-10-03 | Univ Michigan | Non-anticoagulant chemically modified heparinoids for treating hypovolemic shock and related shock syndromes |
| US5583121A (en) * | 1994-01-12 | 1996-12-10 | Michigan State University | Non-anticoagulant chemically modified heparinoids for treating hypovolemic shock and related shock syndromes |
| US6255295B1 (en) | 1996-12-23 | 2001-07-03 | Nutramax Laboratories, Inc. | Aminosugar, glycosaminoglycan or glycosaminoglycan-like compounds, and s-adenosylmethionine composition for the protection, treatment, repair, and reduction of inflammation of connective tissue |
| HUP0201712A3 (en) * | 1999-06-30 | 2003-03-28 | Weitz Jeffrey I Ancaster | Clot associated coagulation factors inhibiting heparin compositions |
| US7259152B2 (en) | 2000-06-07 | 2007-08-21 | Alfa Wasserman, Inc. | Methods and compositions using sulodexide for the treatment of diabetic nephropathy |
| JP2004507562A (ja) * | 2000-09-08 | 2004-03-11 | ハミルトン シビック ホスピタルズ リサーチ ディベロップメント インコーポレイテッド | 抗血栓性組成物 |
| EP2284535A1 (en) | 2002-03-11 | 2011-02-16 | Momenta Pharmaceuticals, Inc. | Low molecular weight heparins |
| GB0216861D0 (en) * | 2002-07-19 | 2002-08-28 | Univ Birmingham | Saccharide libraries |
| US9139876B1 (en) | 2007-05-03 | 2015-09-22 | Momenta Pharmacueticals, Inc. | Method of analyzing a preparation of a low molecular weight heparin |
| WO2009014715A2 (en) * | 2007-07-23 | 2009-01-29 | The University Of North Carolina At Chapel Hill | Enzymatic synthesis of sulfated polysaccharides without iduronic acid residues |
| US8435795B2 (en) * | 2010-01-19 | 2013-05-07 | Momenta Pharmaceuticals, Inc. | Evaluating heparin preparations |
| CN103209997B (zh) * | 2010-09-14 | 2016-03-16 | 国立大学法人宫崎大学 | 高纯度肝素及其制备方法 |
| ES2910476T3 (es) | 2010-12-23 | 2022-05-12 | Univ North Carolina Chapel Hill | Síntesis quimioenzimática de heparinas de peso molecular ultra bajo estructuralmente homogéneas |
| WO2012115952A1 (en) | 2011-02-21 | 2012-08-30 | Momenta Pharmaceuticals, Inc. | Evaluating heparin preparations |
| DE102011077393A1 (de) * | 2011-06-10 | 2012-12-13 | Johannes Reinmüller | Antiinfektives Mittel |
| JP6670235B2 (ja) | 2013-06-17 | 2020-03-18 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒルＴｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｎｏｒｔｈ Ｃａｒｏｌｉｎａ Ａｔ Ｃｈａｐｅｌ Ｈｉｌｌ | 可逆的ヘパリン分子、その製法及びその使用方法 |
| CN116622006A (zh) | 2017-03-10 | 2023-08-22 | 北卡罗来纳大学查珀尔希尔分校 | 短效的基于肝素的抗凝血剂化合物和方法 |
| WO2019010216A1 (en) | 2017-07-03 | 2019-01-10 | The University Of North Carolina At Chapel Hill | ENZYMATIC SYNTHESIS OF HOMOGENEOUS CHONDROITIN SULFATE OLIGOSACCHARIDES |
| JP7495061B2 (ja) | 2017-11-03 | 2024-06-04 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | 抗炎症作用を有する硫酸化オリゴ糖 |
| CN112437667B (zh) | 2018-06-20 | 2024-05-28 | 北卡罗来纳大学查珀尔希尔分校 | 细胞保护方法和组合物 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4987223A (en) * | 1981-12-23 | 1991-01-22 | Choay S.A. | Derivatives of the uronic acid |
| IT1234508B (it) * | 1988-06-10 | 1992-05-19 | Alfa Wassermann Spa | Derivati eparinici e procedimento per la loro preparazione |
| DE3821271A1 (de) * | 1988-06-23 | 1989-12-28 | Solco Basel Ag | Derivatisiertes heparin, verfahren zu dessen herstellung und arzneimittel, welches dieses enthaelt |
| IT1234826B (it) * | 1989-01-30 | 1992-05-29 | Alfa Wassermann Spa | Derivati eparinici e procedimento per la loro preparazione |
| US5464942A (en) * | 1990-07-24 | 1995-11-07 | Seikagaku Kogyo Kabushiki Kaisha | Phospholipid- or lipid-linked glycosaminoglycan and process for producing the same |
| US5200523A (en) * | 1990-10-10 | 1993-04-06 | Monsanto Company | Synthesis of nojirimycin derivatives |
| IT1260136B (it) * | 1992-04-17 | 1996-03-28 | Alfa Wassermann Spa | Glicosaminoglicani semisintetici contenenti acido alfa-l-galatturonicosostituito con radicali nucleofili in posizione 3 |
-
1992
- 1992-04-17 IT ITBO920141A patent/IT1260137B/it active IP Right Grant
-
1993
- 1993-03-10 AT AT93103848T patent/ATE154616T1/de not_active IP Right Cessation
- 1993-03-10 ES ES93103848T patent/ES2103992T3/es not_active Expired - Lifetime
- 1993-03-10 DK DK93103848.3T patent/DK0565863T3/da active
- 1993-03-10 EP EP93103848A patent/EP0565863B1/en not_active Expired - Lifetime
- 1993-03-10 DE DE69311619T patent/DE69311619T2/de not_active Expired - Fee Related
- 1993-03-12 ZA ZA931798A patent/ZA931798B/xx unknown
- 1993-03-18 NZ NZ247196A patent/NZ247196A/en unknown
- 1993-03-19 TW TW082102014A patent/TW239148B/zh active
- 1993-03-19 IL IL10511293A patent/IL105112A/xx not_active IP Right Cessation
- 1993-03-30 NO NO931184A patent/NO305992B1/no not_active IP Right Cessation
- 1993-04-01 CA CA002093147A patent/CA2093147C/en not_active Expired - Fee Related
- 1993-04-13 US US08/046,248 patent/US5430133A/en not_active Expired - Lifetime
- 1993-04-13 AU AU36895/93A patent/AU658498B2/en not_active Ceased
- 1993-04-16 JP JP5089976A patent/JP2702376B2/ja not_active Expired - Fee Related
- 1993-04-16 FI FI931741A patent/FI106556B/sv not_active IP Right Cessation
- 1993-04-17 KR KR1019930006473A patent/KR0171624B1/ko not_active IP Right Cessation
-
1997
- 1997-08-13 GR GR970402062T patent/GR3024419T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2702376B2 (ja) | 1998-01-21 |
| ITBO920141A1 (it) | 1993-10-17 |
| IL105112A0 (en) | 1993-07-08 |
| KR0171624B1 (ko) | 1999-02-01 |
| DE69311619D1 (de) | 1997-07-24 |
| ZA931798B (en) | 1993-11-22 |
| EP0565863B1 (en) | 1997-06-18 |
| FI931741A0 (fi) | 1993-04-16 |
| DK0565863T3 (da) | 1997-12-15 |
| IT1260137B (it) | 1996-03-28 |
| EP0565863A3 (en) | 1993-11-10 |
| US5430133A (en) | 1995-07-04 |
| EP0565863A2 (en) | 1993-10-20 |
| AU3689593A (en) | 1993-10-21 |
| NO931184L (no) | 1993-10-18 |
| NO931184D0 (no) | 1993-03-30 |
| TW239148B (sv) | 1995-01-21 |
| CA2093147C (en) | 1999-01-26 |
| AU658498B2 (en) | 1995-04-13 |
| DE69311619T2 (de) | 1997-12-11 |
| IL105112A (en) | 1997-01-10 |
| GR3024419T3 (en) | 1997-11-28 |
| JPH0616703A (ja) | 1994-01-25 |
| KR930021650A (ko) | 1993-11-22 |
| CA2093147A1 (en) | 1993-10-18 |
| NZ247196A (en) | 1995-02-24 |
| ES2103992T3 (es) | 1997-10-01 |
| ATE154616T1 (de) | 1997-07-15 |
| FI931741A (fi) | 1993-10-18 |
| ITBO920141A0 (it) | 1992-04-17 |
| NO305992B1 (no) | 1999-08-30 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MA | Patent expired |