NO310915B1 - Fremstilling av Polymorfene B og C av 1-[2,4-diklor-<beta>- [(7-klorbenzo[b]tien-3-yl)metoksy]fenetyl]imidazol. mononitrat - Google Patents
Fremstilling av Polymorfene B og C av 1-[2,4-diklor-<beta>- [(7-klorbenzo[b]tien-3-yl)metoksy]fenetyl]imidazol. mononitrat Download PDFInfo
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- NO310915B1 NO310915B1 NO19963291A NO963291A NO310915B1 NO 310915 B1 NO310915 B1 NO 310915B1 NO 19963291 A NO19963291 A NO 19963291A NO 963291 A NO963291 A NO 963291A NO 310915 B1 NO310915 B1 NO 310915B1
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- mononitrate
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims description 18
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 title claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 10
- -1 7-chlorobenzo[b]thien-3-yl Chemical group 0.000 claims description 9
- 238000002844 melting Methods 0.000 claims description 9
- 230000008018 melting Effects 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 150000002460 imidazoles Chemical class 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims 2
- HAAITRDZHUANGT-UHFFFAOYSA-N 1-[2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 HAAITRDZHUANGT-UHFFFAOYSA-N 0.000 abstract description 11
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 13
- 229960005429 sertaconazole Drugs 0.000 description 13
- 239000000843 powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 239000006210 lotion Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000000003 vaginal tablet Substances 0.000 description 2
- QSWSKDXFOIOXKW-UHFFFAOYSA-N 1h-imidazole;nitric acid Chemical compound O[N+]([O-])=O.C1=CNC=N1 QSWSKDXFOIOXKW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003621 irrigation water Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940044977 vaginal tablet Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C07—ORGANIC CHEMISTRY
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Abstract
To nye polymorfer av l-[2,4-diklor-B-[(7-klorbenzo[b]-tien-3-yl)metoksy]fenetyl]imidazol mononitrat er identifisert. Det beskrives fremgangsmåter for fremstilling og anvendelse av begge polymorfer.
Description
Foreliggende oppfinnelse angår fremstilling av nye polymorfer B og C av l-[2,4-diklor-p<->[(7-klorbenzo[b]tien3yl) metoksy]fenetyl]imidazol mononitrat, forbindelser som er kjent som sertaconazol mononitrat (WHO).
Oppfinnelsen skal nedenfor beskrives under henvisning til de vedlagte figurer der: figur 1 er et infrarødt (IR) spektrum av sertaconazol.
mononitrat polymorf B; figur 2 er et differensialscanderende kalorimetri (DSC)
termogram av sertaconazol. mononitrat polymorf B; figur 3 er et røntgenpulverdiffraktogram av sertaconazol.
mononitrat polymorf B; figur 4 er et (IR) spektrum av sertaconazol. mononitrat
polymorf C; figur 5 er et differensialscanderende kalorimetri (DSC)
termogram av sertaconazol. mononitrat polymorf C; figur 6 er et røntgenpulverdiffraktogram av sertaconazol.
mononitrat polymorf C; figur 7 er et (IR) spektrum av sertaconazol. mononitrat
polymorf A; figur 8 er et differensialscanderende kalorimetri (DSC)
termogram av sertaconazol. mononitrat polymorf A; figur 9 er et røntgenpulverdiffraktogram av sertaconazol.
mononitrat polymorf A. l-[2,4-diklor-p-[ ( 7-klorbenzo[b] tien-3-yl )metoksy] f enetyl] - imidazol. mononitrat benyttes i terapien som et antifungal-middel. Fremstillingen av denne forbindelse er beskrevet i EP 0.151.477. Foreliggende søkere har funnet ut at sertaconazol. mononitrat har to nye polymorfer, B og C, som har smeltepunkt i områdene respektivt 163-164'C og 164,5-165,5°C.
Foreliggende oppfinnelse tilveiebringer en fremgangsmåte for selektivt å oppnå hver av polymorfene B og C av sertaconazol. mononitrat. I det ovenfor nevnte patent ble sertaconazol. mononitrat, herefter kalt polymorf A, oppnådd med et smeltepunkt på 156-157°C. Foreliggende søkere har under forskjellige krystalliseringsanalyser funnet ut at når polymorf A omkrystalliseres fra absolutt etanol gir dette den nye polymorf B og når polymorf A omkrystalliseres fra kloroform gir dette den nye polymorf C. Smeltepunktene for de tre polymorfer ligger i et nært område men er vel diffe-rensiert ved hjelp av de vedlagte IR-spektra, DSC-termo-grammer og røntgenpulver-diffraktogrammer.
Foreliggende oppfinnelse angår i henhold til dette i et første aspekt en fremgangsmåte for fremstilling av polymorf B av 1. [2,4-diklor-p<-> [(7-klorbenzo [b]tien-3-yl)metoksy] fenetyl]imidazol.mononitrat med et smeltepunkt i området 163-164°C, og denne fremgangsmåte karakteriseres ved oppløsning av polymorf A i absolutt etanol under tilbakeløp, filtrering av den varme, krystalliser ing ved romtemparatur og filtrering.
Oppfinnelsen angår i et andre aspekt enn fremgangsmåte for fremstilling av polymorf C av l-[2, 4-diklor-g-[tueb.3.yl)-metoksy] f enetyl ]unudazol .mononitrat med et smeltepunkt i området 164,5-165,5<0>C, og denne fremgangsmåte karakteriseres i oppløsning av polymorf A i kloroform under tilbakeløp, filtrering av den varme oppløsning, krystallisering ved romtemperatur og filtrering.
Figurene 7, 8 og 9 som gjelder polymorf A, vedlegges for å gi basis for forskjellene mellom de nye polymorfene B og C og primærpolymorf A.
De fysikalske egenskaper for polymorfene B og C av sertaconazol .mononitrat skiller seg fra de til pr imærpolymorf A. Således viser polymorf B en høyere stabilitet enn polymorf A mot en moderat tilførsel av ekstern energi (som siktings- og homogeniseringsprosesser) og er derfor egnet for topiske doseringer i fast form som pulvere. Polymorf C antas å være ennu mere stabil enn polymorf A mot ytre energitilførsel og kan derfor hensiktsmessig benyttes i prosesser som krever høyere energitilførsler som for eksempel kompresjons-prosesser, og er derfor velegnet for fremstilling av tabletter. Når det gjelder flytende formuleringer kan begge polymorfer B og C benyttes fordi de iboende egenskapene til et faststoff forsvinner i en oppløsning.
I tillegg til de ovenfor nevnte farmasøytiske former kan polymorfene B og C av sertaconazol.mononitrat, blandet med farmasøytisk akseptable bærere, administreres oralt til mennesker og dyr i form av kapsler, siruper, oppløsninger, pulvere og så videre, ved injeksjoner, rektalt eller ved vaginal intrauterine administreringsveier i form av ovolum, salver, kremer, pessarer, lotioner og så videre, i daglige doser fra 100 til 800 mg, og topisk i form av kremer, lotioner, salver, emulsjoner, oppløsninger, sjampo, gel og så videre, i konsentrasjoner fra 0,1 til 5 %.
Videre kan polymorfene B og C av sertaconazol.mononitrat i blanding med et fortynningsmiddel eller en bærer og i suspensjon med vanningsvann, benyttes mot avl ingssykdommer; de kan også anvendes ved forstøvning, spraying, støving eller i form av kremer, pastaer og så videre, i doser på 0,1 til 15 kg/hektar jord.
De følgende eksempler skal illustrere fremstilling av polymorfene B og C av sertaconazol.mononitrat og farma-søytiske formuleringer inneholdende forbindelsene.
Eksempel 1
Polymorf B av l-[2,4-diklor-p-[(7-klorbenzo[b]tien-3-yl)metoksy]fenetyl]imidazol.mononitrat (Sertaconazol.mononitrat polymorf B).
10 g sertaconazol.mononitrat (polymorf A) oppløses i 100 ml absolutt etanol under tilbakeløp. Den varme oppløsning filtreres og tillates krystallisering ved romtemperatur uten omrøring. Det krystallinske faststoff som dannes filtreres og tørkes og man oppnår 8,78 g polymorf B av 1-[2,4-diklor-P-[ ( 7-klorbenzo[b]tien-3-yl)metoksy]fenetyl]imidazol.mononitrat (Sertaconazol.mononitrat polymorf B).
Smeltepunkt: 163-164°C.
IR-spektrum (KBr): Figur 1
DSC-termogram: Figur 2
Røntgendiffraktogram: Figur 3.
Eksempel 2
Polymorf C av l-[2,4-diklor-3-[(7-klorbenzo[b] tien-3-yl)metoksy]fenetyl]imidazol.mononitrat (Sertaconazol mononitrat polymorf C). 5 g sertaconazol.mononitrat (polymorf A) oppløses i 150 ml kloroform under tilbakeløp. Den varme oppløsning filtreres og tillates krystallisering ved romtemperatur uten omrøring. Det dannede, krystallinske faststoff filtreres og tørkes og man oppnår 4,2 g polymorf C av l-[2,4-diklor-e-[(7-klorbenzo[b]-tien-3-yl)metoksy]fenetyl]imidazol.mononitrat (Sertaconazol mononitrat polymorf C).
Smeltepunkt: 164,5-165 , 5°C.
IR-spektrum (KBr): Figur 4
DSC-termogram: Figur 5
Røntgendiffraktogram: Figur 6.
Eksempel 3
2 % pulver for topisk applikering.
Sammensetning for 100 g:
Eksempel 4
Vaginaltabletter.
Sammensetning for 1 vaginaltablett:
Claims (2)
1.
Fremgangsmåte for fremstilling av polymorf B av l-[2,4-diklor-p-[ ( 7-klorbenzo [b]tien-3-yl )metoksy] fenetyl] imidazol mononitrat med et smeltepunkt i området 163-164<0>C, karakterisert ved oppløsning av polymorf A i absolutt etanol under tilbakeløp, filtrering av den varme oppløsning, krystallisering ved romtemperatur og filtrering.
2.
Fremgangsmåte for fremstilling av polymorf C av l-[2,4-diklor-p-[( 7-klorbenzo [b] ti en-3-yl )metoksy] f enetyl] imidazol mononitrat med et smeltepunkt i området 164,5-165,5<0>C, karakterisert ved oppløsning av polymorf A i kloroform under tilbakeløp, filtrering av den varme opp-løsning, krystallisering ved romtemperatur og filtrering.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/ES1995/000001 WO1996020939A1 (es) | 1995-01-04 | 1995-01-04 | POLYMORFOS B Y C DE MONONITRATO DE 1-[2,4-DICLORO-β-[(7-CLOROBENZO[b]TIEN-3-IL)METOXI]FENETIL]IMIDAZOL |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO963291D0 NO963291D0 (no) | 1996-08-07 |
| NO963291L NO963291L (no) | 1996-08-07 |
| NO310915B1 true NO310915B1 (no) | 2001-09-17 |
Family
ID=8289063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19963291A NO310915B1 (no) | 1995-01-04 | 1996-08-07 | Fremstilling av Polymorfene B og C av 1-[2,4-diklor-<beta>- [(7-klorbenzo[b]tien-3-yl)metoksy]fenetyl]imidazol. mononitrat |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5939555A (no) |
| EP (1) | EP0748806B1 (no) |
| JP (1) | JP3250809B2 (no) |
| KR (1) | KR100336642B1 (no) |
| AU (1) | AU691234B2 (no) |
| CA (1) | CA2184411C (no) |
| DE (1) | DE69503364T2 (no) |
| DK (1) | DK0748806T3 (no) |
| ES (1) | ES2120720T3 (no) |
| FI (1) | FI111366B (no) |
| NO (1) | NO310915B1 (no) |
| NZ (1) | NZ278402A (no) |
| WO (1) | WO1996020939A1 (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7056321B2 (en) | 2000-08-01 | 2006-06-06 | Endius, Incorporated | Method of securing vertebrae |
| ES2203316B1 (es) * | 2002-02-11 | 2005-03-01 | Ferrer Internacional, S.A. | R-(-)-1-(2-(7-cloro-benzo(b)tiofen-3-il-metoxi)-2-(2,4-dicloro-fenil)-etil)1h-imidazol. |
| DE10223913A1 (de) * | 2002-05-29 | 2003-12-11 | Bayer Cropscience Ag | Verfahren zur Herstellung spezifischer Kristallmodifikationen polymorpher Substanzen |
| ES2249991B1 (es) * | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | Procedimiento de fabricacion de compuestos imidazolicos, sus sales y sus pseudopolimorfos. |
| ES2249992B1 (es) * | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | Un procedimiento para fabricar compuestos enantiomericos del imidazol. |
| KR100738999B1 (ko) * | 2006-06-15 | 2007-07-25 | (주)대우건설 | 강재 덕트를 이용한 조립구조를 가지는 프리캐스트콘크리트 세그먼트 및 그 연결 조립구조 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT67416B (en) * | 1977-01-07 | 1979-05-22 | Smithkline Corp | New polymorphic forms |
| US5135943A (en) * | 1984-02-02 | 1992-08-04 | Ferrer Internacional S.A. | 1H-imidazole derivative compounds and pharmaceutical compositions containing the same |
-
1995
- 1995-01-04 WO PCT/ES1995/000001 patent/WO1996020939A1/es active IP Right Grant
- 1995-01-04 NZ NZ278402A patent/NZ278402A/en not_active IP Right Cessation
- 1995-01-04 KR KR1019960704405A patent/KR100336642B1/ko not_active IP Right Cessation
- 1995-01-04 CA CA002184411A patent/CA2184411C/en not_active Expired - Fee Related
- 1995-01-04 DK DK95905144T patent/DK0748806T3/da active
- 1995-01-04 JP JP52074296A patent/JP3250809B2/ja not_active Expired - Fee Related
- 1995-01-04 US US08/702,536 patent/US5939555A/en not_active Expired - Lifetime
- 1995-01-04 AU AU13872/95A patent/AU691234B2/en not_active Ceased
- 1995-01-04 ES ES95905144T patent/ES2120720T3/es not_active Expired - Lifetime
- 1995-01-04 EP EP95905144A patent/EP0748806B1/en not_active Expired - Lifetime
- 1995-01-04 DE DE69503364T patent/DE69503364T2/de not_active Expired - Lifetime
-
1996
- 1996-08-07 NO NO19963291A patent/NO310915B1/no not_active IP Right Cessation
- 1996-08-30 FI FI963392A patent/FI111366B/fi not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU1387295A (en) | 1996-07-24 |
| CA2184411C (en) | 2004-05-11 |
| KR100336642B1 (ko) | 2002-11-23 |
| ES2120720T3 (es) | 1998-11-01 |
| DE69503364D1 (de) | 1998-08-13 |
| NO963291D0 (no) | 1996-08-07 |
| JPH09510234A (ja) | 1997-10-14 |
| EP0748806A1 (en) | 1996-12-18 |
| KR970701187A (ko) | 1997-03-17 |
| AU691234B2 (en) | 1998-05-14 |
| NO963291L (no) | 1996-08-07 |
| DK0748806T3 (da) | 1999-04-19 |
| FI963392A (fi) | 1996-08-30 |
| NZ278402A (en) | 1997-10-24 |
| FI963392A0 (fi) | 1996-08-30 |
| CA2184411A1 (en) | 1996-07-11 |
| FI111366B (fi) | 2003-07-15 |
| US5939555A (en) | 1999-08-17 |
| DE69503364T2 (de) | 1999-04-15 |
| WO1996020939A1 (es) | 1996-07-11 |
| EP0748806B1 (en) | 1998-07-08 |
| JP3250809B2 (ja) | 2002-01-28 |
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