NO173990B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 9-amino-1,4-etan-1,2,3,4-tetrahydroakridiner - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 9-amino-1,4-etan-1,2,3,4-tetrahydroakridiner Download PDFInfo
- Publication number
- NO173990B NO173990B NO88880627A NO880627A NO173990B NO 173990 B NO173990 B NO 173990B NO 88880627 A NO88880627 A NO 88880627A NO 880627 A NO880627 A NO 880627A NO 173990 B NO173990 B NO 173990B
- Authority
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- Norway
- Prior art keywords
- acid
- formula
- preparation
- pharmaceutically acceptable
- hydrogen
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
- C07D219/10—Nitrogen atoms attached in position 9
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
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- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse vedrører fremstillingen av nye, terapeutisk aktive forbindelser som har formelen
hvori
Ri er hydrogen, benzyl eller fenyl;
X er hydrogen, laverealkyl, halogen, trifluormetyl;
eller et farmasøytisk akseptabelt syreaddisjonssalt derav.
Disse forbindelsene har en hukommelsesforbedrende virkning og forbedrer den kolinergiske funksjonen i pattedyr.
Forbindelsene med formel I fremstilles ifølge oppfinnelsen ved en fremgangsmåte som innbefatter oppvarming av en blanding av fosforpentoksyd, N,N-dimetylcykloheksylamin og hydrokloridet av aminet ENRR^ og deretter tilsetning av en forbindelse av formel IV
hvor
R^3 er hydrogen eller C^-C^-alkyl, etterfulgt av 2-norbonanon av formelen og eventuelt overføres en oppnådd forbindelse på kjent måte til et farmasøytisk akseptabelt syreaddisjonssalt.
Denne reaksjonen kan gjennomføres i et egnet oppløsnings-middel, såsom benzen, toluen eller xylen, ved en temperatur på 80-150"C i nærvær av en syrekatalysator, såsom p-toluen-sulfonsyre, benzensulfonsyre eller metansulfonsyre.
Forbindelsene av formel I som fremstilles ifølge foreliggende oppfinnelse kan benyttes for behandling av forskjellige hukommelsesdysfunksjoner som er kjennetegnet ved en nedsatt kolinergisk funksjon, såsom Alzheimer's sykdom.
Denne anvendeligheten kan fastslås ved å bestemme disse forbindelsenes evne til å inhibere aktiviteten av enzymet acetylkolinesterase og derved øke acetylkolin-nivåene i hjernen.
Denne anvendeligheten kan også fastslås ved å bestemme disse forbindelsenes evne til å gjenopprette kolinergisk svekket hukommelse i "Dark Avoidance" analysen. I denne analysen undersøkes mus med henblikk på deres evne til å huske en ubehagelig stimulus i et tidsrom på 24 timer. En mus plas-seres i et kammer som inneholder en mørk underavdeling; et sterkt hvitglødende lys driver den til den mørke underavdelingen hvor et elektrisk sjokk administreres gjennom metallplater på gulvet. Dyret fjernes fra forsøksapparaturen og undersøkes igjen, 24 timer senere, vedrørende evnen til å huske det elektriske sjokket.
Dersom skopolamin, et anti-kolinergisk middel som er kjent for å forårsake hukommeIsessvekke1se, administreres før et dyrs innledende eksponering i forsøkskammeret, vil dyret igjen tre inn i den mørke underavdelingen kort tid etter at det er plassert i forsøkskammeret 24 timer senere. Denne virkningen av skopolamin blokkeres av en aktiv forsøksfor-bindelse, hvilket resulterer i et lengere intervall før gjeninntreden i den mørke underavdelingen.
Effektive mengder av forbindelsen fremstilt ifølge oppfinnelsen kan administreres til en pasient ved en hvilken som helst av de forskjellige fremgangsmåtene, f.eks. oralt som i kapsler eller tabletter, parenteralt i form av sterile oppløsninger eller suspensjoner, og i noen tilfeller intravenøst i form av sterile oppløsninger. Sluttprodukter i form av frie baser kan, selv om de i seg selv er effektive, formuleres og administreres i form av deres farmasøytisk akseptable syreaddisjonssalter for å oppnå stabilitet, hensiktsmessig krystallisasjon, forbedret oppløselighet o.l.
Syrer som er nyttige for fremstilling av de farmasøytisk akseptable syreaddisjonssaltene ifølge oppfinnelsen, innbefatter uorganiske syrer såsom saltsyre, hydrobromsyre, svovelsyre, salpetersyre, fosforsyre og perklorsyrer, så vel som organiske syrer såsom vinsyre, sitronsyre, eddiksyre, ravsyre, maleinsyre, fumarsyre og oksalsyre.
De aktive forbindelsene fremstilt ifølge oppfinnelsen kan administreres oralt, f.eks. med et inert fortynningsmiddel eller med en spiselig bærer, eller de kan være innesluttet i gelatinkapsler, eller de kan være komprimert til tabletter. For oral terapeutisk administrering kan de aktive forbindelsene fremstilt ifølge oppfinnelsen være inkorporert med eksipienser og benyttes i form av tabletter, pastiller, kapsler, eleksirer, suspensjoner, siruper, kjeks, tyggegummi o.l. Disse preparatene bør inneholde minst 0,556 aktiv forbindelse, men mengden kan variere avhengig av den spesielle formen og kan hensiktsmessig være mellom 4 og 70 vekt-# av enheten. Mengden aktiv forbindelse i slike preparater er slik at det oppnås en egnet dose. Fordelaktige sammensetninger og preparater fremstilles på en slik måte at en oral doseringsenhetsform inneholder mellom 1,0 og 300 mg aktiv forbindelse.
Tablettene, pillene, kapslene, pastillene o.l. kan også inneholde følgende bestanddeler: et bindemiddel, såsom mikrokrystallinsk cellulose, tragantgummi eller gelatin; en eksipiens, såsom stivelse eller laktose; et sprengmiddel, såsom alginsyre, "Primogel", maisstivelse o.l.; et smøre-middel, såsom magnesiumstearat eller "Sterotex"; et glide-middel, såsom kolloidalt silisiumdioksyd; og et søtnings-middel, såsom sukrose eller sakkarin kan tilsettes, eller et smaksstoff, såsom peppermynte, metylsalisylat eller appelsin-smak. Når doser ingsenhetsf ormen er en kapsel kan den, i tillegg til materialene av typen angitt ovenfor, inneholde en flytende bærer såsom en fettolje. Andre doseringsenhetsformer kan inneholde forskjellige materialer som modifiserer den fysikalske formen av doseringsenheten, som f.eks. belegg. Følgelig kan tabletter eller piller være belagt med sukker, skjellakk eller andre enteriske beleggingsmidler. En sirup kan, i tillegg til de aktive forbindelsene, inneholde sukrose som et søtningsmiddel og visse konserveringsmidler, fargestoffer og smaksstoffer. Materialene som benyttes ved fremstilling av disse forskjellige preparatene bør være farmasøytisk rene og ikke-toksiske i mengdene som benyttes.
For formålet parenteral terapeutisk administrering kan de aktive forbindelsene med formel I være inkorporert i en oppløsning eller en suspensjon. Disse preparatene bør inneholde minst 0,1$ aktiv forbindelse, men mengden kan variere mellom 0,5 og 30 vekt-#. Mengden av aktiv forbindelse i slike preparater er slik at det oppnås en egnet dose. Fordelaktige sammensetninger og preparater fremstilles på en slik måte at en parenteral doseringsenhet inneholder mellom 0,5 og 100 mg aktiv forbindelse.
Oppløsningene eller suspensjonene kan også innbefatte følgende komponenter: et sterilt fortynningsmiddel såsom vann for injeksjon, saltvannsoppløsning, fikserte oljer, poly-etylenglykoler, glyserin, propylenglykol eller andre synte-tiske oppløsningsmidler; anti-bakterielle midler, såsom benzylalkohol eller metylparabener; anti-oksydanter, såsom askorbinsyre eller natriumbisulfitt; gelateringsmidler, såsom etylendiamintetraeddiksyre; buffere, såsom acetater, citrater eller fosfater og midler for regulering av tonisiteten, såsom natriumklorid eller dekstrose. De parenterale preparatene kan være innesluttet i en engangssprøyte eller flerdoseflasker fremstilt av glass eller plast.
Det følgende eksemplet er angitt for å illustrere oppfinnelsen .
EKSEMPEL
9- anilin- l, 4- metan- l. 2. 3. 4- tetrahvdroakridin
Fosforpentoksyd (28,4 g), N,N-dimetylcykloheksylamin (25,4 g) og anilinhydroklorid (25,9 g) ble blandet sammen ved romtemperatur og deretter oppvarmet på et oljebad ved 220° C inntil en klar, homogen oppløsning var oppnådd. Blandingen fikk avkjøles til under 150"C, og metylantranilat (7,58 g) ble tilsatt dråpevis etterfulgt av 2-norbonanon (6,61 g). Blandingen ble gjenoppvarmet til 220°C under omrøring i 20 timer. Etter avkjøling til 100"C ble 450 ml 2M NaOH tilsatt og omrøring ble fortsatt ved 100°C i 30 minutter. Reaksjons-blandingen fikk deretter avkjøles til romtemperatur og ble ekstrahert med etylacetat. Inndampning og triturering med etyleter ga 6,28 g krystaller av 9-anilin-l,4-metan-l,2,3,4-tetrahydroakridin, smeltepunkt 223-225°C. Smeltepunktet av den analytiske prøven var uendret etter rekrystallisasjon fra etylacetat.
ANALYSE:
Claims (2)
1.
Analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse av formel I
hvori R^ er hydrogen, benzyl eller fenyl;
X er hydrogen, laverealkyl, halogen, trifluormetyl;
eller et farmasøytisk akseptabelt syreaddisjonssalt derav, karakterisert ved at den innbefatter oppvarming av en blanding av fosforpentoksyd, N,N-dimetyl-cykloheksylamin og hydrokloridet av aminet HNRR^ og deretter tilsetning av en forbindelse av formel IV
hvor
R13 er hydrogen eller Ci-C^-alkyl, etterfulgt av 2-norbonanon av formelen
og eventuelt overføres en oppnådd forbindelse på kjent måte til et farmasøytisk akseptabelt syreaddisjonssalt.
2.
Analogifremgangsmåte ifølge krav 1 for fremstilling av 9-anilin-1,4-metan-l,2,3,4-tetrahydroakridin eller et farma-søuytisk akseptabelt syreaddisjonssalt derav, karakterisert ved at tilsvarende utgangsmaterialer anvendes.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/014,753 US4897400A (en) | 1987-02-13 | 1987-02-13 | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO880627D0 NO880627D0 (no) | 1988-02-12 |
| NO880627L NO880627L (no) | 1988-08-15 |
| NO173990B true NO173990B (no) | 1993-11-22 |
| NO173990C NO173990C (no) | 1994-03-02 |
Family
ID=21767514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO880627A NO173990C (no) | 1987-02-13 | 1988-02-12 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 9-amino-1,4-etan-1,2,3,4-tetrahydroakridiner |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US4897400A (no) |
| EP (1) | EP0278499B1 (no) |
| JP (1) | JP2736254B2 (no) |
| KR (1) | KR960012366B1 (no) |
| AT (1) | ATE112270T1 (no) |
| AU (1) | AU596887B2 (no) |
| CA (1) | CA1341335C (no) |
| DE (1) | DE3851643T2 (no) |
| DK (1) | DK168011B1 (no) |
| ES (1) | ES2061530T3 (no) |
| FI (1) | FI90416C (no) |
| HU (1) | HU205908B (no) |
| IE (1) | IE64493B1 (no) |
| IL (1) | IL85401A (no) |
| NO (1) | NO173990C (no) |
| NZ (1) | NZ223485A (no) |
| PH (1) | PH24725A (no) |
| PT (1) | PT86749B (no) |
| ZA (1) | ZA88989B (no) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4897400A (en) * | 1987-02-13 | 1990-01-30 | Hoeschst-Roussel Pharmaceuticals, Inc. | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
| US5037833A (en) * | 1988-07-25 | 1991-08-06 | Hoechst-Roussel Pharmaceuticals Inc. | N-[substituted alkylidene]fused-bicycloalkylidene quinolinamines useful for enhancing the cholinergic function in a mammal |
| US5202440A (en) * | 1987-10-05 | 1993-04-13 | Pfizer Inc. | Certain 9-amino-2-(or 4)-oxa 1,2,3,4-tetrahydro- or 1,2,3,4,5,6,7,8-octahydro-acridines |
| IL87861A0 (en) * | 1987-10-05 | 1989-03-31 | Pfizer | 4-aminopyridine derivatives |
| US5008853A (en) | 1987-12-02 | 1991-04-16 | Xerox Corporation | Representation of collaborative multi-user activities relative to shared structured data objects in a networked workstation environment |
| US4985430A (en) | 1987-12-03 | 1991-01-15 | Mitsubishi Kasei Corporation | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| JP2720517B2 (ja) * | 1989-05-31 | 1998-03-04 | 三菱化学株式会社 | ９―アシルアミノーテトラヒドロアクリジン誘導体および該誘導体を有効成分とする記憶障害改善剤 |
| ES2100129B1 (es) * | 1995-10-11 | 1998-02-16 | Medichem Sa | Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion. |
| KR101953366B1 (ko) | 2018-12-26 | 2019-02-28 | 정종문 | 침향을 포함하는 기억력 및 인지능력을 향상시키는 기능성 건강식품 및 이의 제조방법 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3232945A (en) * | 1962-08-13 | 1966-02-01 | S E Massengill Company | 7,8,9,10-tetrahalo-6h-cyclohepta-(b)-quinolines |
| US3318895A (en) * | 1963-12-05 | 1967-05-09 | Squibb & Sons Inc | Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[b]quinolines |
| US3318896A (en) * | 1963-12-05 | 1967-05-09 | Squibb & Sons Inc | Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[b]quinolines |
| BE658695A (no) * | 1964-02-03 | 1965-07-22 | ||
| US3541066A (en) * | 1968-09-16 | 1970-11-17 | American Home Prod | 2,3-dihydro-1,4-ethanobenzo(b)(1,5)naphthyridine derivatives |
| US3580915A (en) * | 1968-09-16 | 1971-05-25 | American Home Prod | 1,2,3,4-tetrahydrobenzol(b)(1,6)naphthyridine derivatives |
| US3647800A (en) * | 1970-04-30 | 1972-03-07 | American Home Prod | 10-substituted - 1 2 3 4 - tetrahydrobenzo(b)(1 6)naphthyridines useful as cns depressants |
| US3637706A (en) * | 1970-04-30 | 1972-01-25 | American Home Prod | 10-(4 - (lower)alkylpiperazino) - 1 2 3 4-tetrahydrobenzo(b)(1 6) naphthyridine derivatives useful as cns depressants |
| US3657233A (en) * | 1970-04-30 | 1972-04-18 | American Home Prod | 10-morpholino-1 2 3 4-tetrahydrobenzo(b)(1 6)naphthyridine derivatives |
| US3674790A (en) * | 1970-05-01 | 1972-07-04 | American Home Prod | 2,10-disubstituted-1,2,3,4-tetrahydrobenzo(bhq (1,6)naphthyridines useful as cns depressants |
| ES431307A1 (es) * | 1973-11-16 | 1976-09-01 | Thomae Gmbh Dr K | Procedimiento para la preparacion de nuevos derivados de quinoleina. |
| US4108998A (en) * | 1976-11-08 | 1978-08-22 | American Home Products Corp. | Furo[3,4-b]quinoline derivatives and pharmaceutical compositions and methods employing them |
| US4695573A (en) * | 1984-10-25 | 1987-09-22 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| US4631286A (en) * | 1984-10-25 | 1986-12-23 | Hoechst-Roussel Pharmaceuticals Inc. | 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds |
| ATE63903T1 (de) * | 1984-10-25 | 1991-06-15 | Hoechst Roussel Pharma | 9-amino-1,2,3,4-tetrahydroacridin-1-ol und verwandte verbindungen, verfahren zu ihrer herstellung und verwendung als arzneimittel. |
| US4816456A (en) * | 1986-10-01 | 1989-03-28 | Summers William K | Administration of monoamine acridines in cholinergic neuronal deficit states |
| JPS6473A (en) * | 1986-10-31 | 1989-01-05 | Sumitomo Pharmaceut Co Ltd | Novel aminoacridine derivative |
| DK569087A (da) * | 1986-10-31 | 1988-05-01 | Sumitomo Pharma | Quinolin-derivater, deres fremstilling og anvendelse |
| US4897400A (en) * | 1987-02-13 | 1990-01-30 | Hoeschst-Roussel Pharmaceuticals, Inc. | 9-amino-1,4-ethano-1,2,3,4-tetrahydroacridine and related compounds useful for incresing the cholinergic function in a mammal |
| US4851536A (en) * | 1987-05-07 | 1989-07-25 | American Home Products Corporation | Cyclohexylquinolines as inhibitors of interleukin 1 |
| WO1989002739A1 (en) * | 1987-10-05 | 1989-04-06 | Pfizer Inc. | 4-aminopyridine derivatives |
| US4985430A (en) * | 1987-12-03 | 1991-01-15 | Mitsubishi Kasei Corporation | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
-
1987
- 1987-02-13 US US07/014,753 patent/US4897400A/en not_active Expired - Lifetime
-
1988
- 1988-02-11 ES ES88101973T patent/ES2061530T3/es not_active Expired - Lifetime
- 1988-02-11 EP EP88101973A patent/EP0278499B1/en not_active Expired - Lifetime
- 1988-02-11 FI FI880634A patent/FI90416C/fi not_active IP Right Cessation
- 1988-02-11 PH PH36487A patent/PH24725A/en unknown
- 1988-02-11 PT PT86749A patent/PT86749B/pt not_active IP Right Cessation
- 1988-02-11 IL IL85401A patent/IL85401A/xx not_active IP Right Cessation
- 1988-02-11 NZ NZ223485A patent/NZ223485A/en unknown
- 1988-02-11 AT AT88101973T patent/ATE112270T1/de not_active IP Right Cessation
- 1988-02-11 DE DE3851643T patent/DE3851643T2/de not_active Expired - Fee Related
- 1988-02-12 IE IE39188A patent/IE64493B1/en not_active IP Right Cessation
- 1988-02-12 HU HU88686A patent/HU205908B/hu not_active IP Right Cessation
- 1988-02-12 CA CA000558816A patent/CA1341335C/en not_active Expired - Fee Related
- 1988-02-12 ZA ZA88989A patent/ZA88989B/xx unknown
- 1988-02-12 JP JP63029044A patent/JP2736254B2/ja not_active Expired - Fee Related
- 1988-02-12 KR KR1019880001341A patent/KR960012366B1/ko not_active IP Right Cessation
- 1988-02-12 NO NO880627A patent/NO173990C/no unknown
- 1988-02-12 AU AU11670/88A patent/AU596887B2/en not_active Ceased
- 1988-02-12 DK DK072388A patent/DK168011B1/da not_active IP Right Cessation
- 1988-07-08 US US07/218,755 patent/US5401749A/en not_active Expired - Fee Related
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