NO179515B - Analogifremgangsmåte for fremstilling av terapeutisk aktive 3,4-dihydroisokinolinderivater - Google Patents
Analogifremgangsmåte for fremstilling av terapeutisk aktive 3,4-dihydroisokinolinderivater Download PDFInfo
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- NO179515B NO179515B NO932279A NO932279A NO179515B NO 179515 B NO179515 B NO 179515B NO 932279 A NO932279 A NO 932279A NO 932279 A NO932279 A NO 932279A NO 179515 B NO179515 B NO 179515B
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- 238000004519 manufacturing process Methods 0.000 title description 8
- -1 2-phenyl-2-ethoxycarbonylacetyl Chemical group 0.000 claims abstract description 16
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
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- 238000000034 method Methods 0.000 claims description 13
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Description
Gjennom EP-A 37 934 er det blitt kjent dihydro-isokinoliner med den generelle formel Ia. De der nevnte forbindelser har kardioton virkning og oppviser en kontraktilitetsøkende og en blodtrykksinfluerende virkningskomponent. De er foreslått til forbedring av vevsgjennomblødningen og oksygentilførselen til vev. Disse anvendelsesmuligheter beror på forbindelsenes vaskulære effekt. I EP-A 251 194 er det beskrevet at karbocyklisk og hetero-cyklisk kondenserte dihydropyridiner er i besittelse av kardio-protektive virkninger og utgjør en helt ny type Ca-antagonistiske forbindelser.
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av nye 3,4-dihydrokinolinderivater som kan anvendes som hjernebeskyttende middel, særlig ved behandlingen av pasienter som har hatt et slag eller står i fare for å få slag. De nye forbindelser kan dessuten anvendes til behandling av kronisk inflammatoriske prosesser (f.eks. bronkial astma, artritt) og til hemming av blodkoagulasjon resp. blodplateaggregasjon.
Oppfinnelsen angår således en fremgangsmåte for fremstilling av 3,4-dihydroisokinolinderivater med formel
innbefattet de tautomere og enantiomere former,
hvor X er
hvor
X1 er fenyl som er mono- eller di-substituert med trifluormetyl eller etoksy, metoksy- og fluorsubstituert fenyl eller 2-metoksyfenyl,
X2 er -CH2-CH2- eller
-CH2-CH(CH3) -
og
X3 er 2,3,4-trimetoksyfenyl, 2,3-dimetoksyfenyl, 2,6-dimetoksyfenyl, 3,6-dimetoksyfenyl, tienyl, fenyl som er mono-eller di-substituert med trifluormetyl eller etoksy, eller metoksy- og fluorsubstituert fenyl,
eller deres farmasøytisk akseptable salter.
Foretrukket er forbindelsene (I), hvor X er
hvor
X1 er 2-metoksyfenyl som dessuten kan være substituert med
fluor,
X2 er -CH2-CH2-
og
X3 er 2,3,4-trimetoksyfenyl, 2,3-dimetoksyfenyl, 2,6-dimetoksyfenyl, 3,6-dimetoksyfenyl, 2- eller 3-tienyl, fenyl som er substituert med trifluormetyl eller etoksy, eller metoksy- og fluorsubstituert fenyl.
Forbindelsene med formel I er baser og kan på vanlig måte overføres med uorganiske eller organiske syrer, samt salt- og kompleksdannere, i ønskede fysiologisk akseptable addukter (salter).
Egnede syrer for saltdannelsen er eksempelvis saltsyre, hydrogenbromidsyre, hydrogenjodidsyre, flussyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzosyre, p-hydroksybenzosyre, ftalsyre, kanelsyre, salisylsyre, ascorbinsyre, metansulfonsyre og lignende.
Som allerede nevnt innledningsvis har de nye forbindelser hjernebeskyttende virkning. Forbindelsene er fordelaktige ved behandling av degenerative og nekrotiske hjernesykdommer. Forebyggende behandling av pasienter som trues av slike sykdommer er likeledes mulig. Som vist i nedenfor beskrevne forsøk beror forbindelsenes virkning ikke på en forbedring av vevsgjennom-blødningen. Forbindelsene er således egnet for en ny type behandling av epilepsi og av Alzheimers sykdom, spesielt ved behandling av pasienter som har hatt et slag eller står i fare for å få slag.
Videre er forbindelsene som nevnt innledningsvis, egnet ved behandling av kroniske inflammatoriske prosesser og for hemming av blodkoagulasj onen.
De følgende forsøksresultater viser forbindelsenes over-raskende virkning. Undersøkelsene ble særlig foretatt med forbindelse A som representant for forbindelser med den generelle formel I.
Ischemitoleranse hos ørkenrotte (Gerbille):
(f.eks. Suzuki, R. et al., Acta Neuropath. (Berl.) 1983, 60:207-216, 217-222; Yoshidomi, M. et al., J. Neurochem. 1989, 53:1589-1594). Ischemi ved okklusjon av arteria carotis i 10 minutter under eteranestesi. Forbindelsen A ble gitt som 1 og 10 mg/kg s.c. 4 x i løpet av 24 timer med start 2 timer etter gjenåpning av arteriene. 7 2 timer etter karokklusjonen ble dyrene avlivet og hjernen preparert for histologisk undersøkelse. Som påvisning av en ischemisk skade, respektivt redusering av denne, ble cellenes beskadigelse i et definert utsnitt av det histologiske preparat i CA1-regionen av hippocampus vurdert. Undersøkelsen ble foretatt på grupper på 5 dyr.
Innen gruppen av dyr som ikke var tilført noen testfor-bindelse, oppviste samtlige dyr en tydelig beskadigelse av den undersøkte CA.,-region. Derimot viste det seg ved administrasjon av forbindelse A en tydelig doseavhengig beskyttelse mot hypoksi-skadene. Ved administrasjon av 1 mg/kg av forbindelse A oppviste kun 2 av 5 dyr beskadigelse av CA1 -regionen. Ved administrasjon av 10 mg/kg av forbindelse A oppviste ingen av de 5 dyr beskadigelse.
Ut fra dette resultat kan det fastslås at forbindelsene med den generelle formel I kan benyttes til kurativ behandlig av nevrologiske skader, f.eks. forårsaket av slag. Resultatet av denne undersøkelse viser også at forbindelsene overvinner blod/ hjernebarrieren, hvilket er et vesentlig trekk ved oppfinnelsen.
De følgende undersøkelser på isolerte cellekulturer viser virkningen av de undersøkte forbindelser. Ut fra disse undersø-kelsesresultatene kan det likeledes (som ved undersøkelses-resultatene på ørkenrotter) fastslås at forbindelsen med den generelle formel I kan benyttes ved de behandlinger som er nevnt i foreliggende patentbeskrivelse.
I isolerte cellekulturer (f.eks. neutrofile granulocytter,
HL 60-celler, trombocytter, o.a.) kunne forbindelse A doseavhengig hemme (IC50-verdier i området 1 |iM) "calsiumoverload" og celledød frembragt gjennom forskjellige agonister (f.eks. PAF, leukotriener, endothelin, FMLP eller isoprenalin).
Den halvmaksimale hemmende konsentrasjon av testsubstansene som inhiberer FMLP (1 nM)-induserte kalsiumtransienter på FLU03-ladede HL60-celler ble målt.
Disse ovenfor nevnte undersøkelsesmetoder er beskrevet av W.K. Pollock, T.J. Rink, R.F. Irvine, Biochem. J. 235:869-877
(1986), resp. J.E. Merritt, R. Jacob, T.J. Hallam, J. of Biol. Chem. 264:1522-1527 (1989).
På HL-60 enkeltceller ble den transmembrane innstrømming gjennom "unselected cation channels" etter ATP-stimulering målt elektrofysiologisk ved hjelp av "patch clamp"-teknikk. Denne innstrømming inhiberes av Forbindelse A (IC50-verdi: 7 nM) .
Disse funn legger det direkte angrepspunkt på isolerte celler. I den levende organisme vandrer spesielt de i ytterligere undersøkelser anvendte granulocytter resp. leukocytter, etter en beskadigelse av hjerneceller (f.eks. ved slag) inn i det beskadigede areal hvor de aktiveres gjennom kalsiumformidlede prosesser og faller sammen og derved frigjør vevsødeleggende, herunder kjemotaktiske, mediatorer (f.eks. PAF, leukotrien, prostaglandin, FMLP, o.a.). Ytterligere leukocytter tillokket gjennom kjemotaksi, forstørrer det beskadigede areal. De ovenfor beskrevne resultater av undersøkelse viser at denne Circulus vitiosus kan blokkeres ved administrasjon av de ovenfor beskrevne virkestoffer. Derved begrenses de nevrologiske skadene.
Det har latt seg vise at klassiske kalsiumantagonister (f.eks. Verapamil, Nifedipine, Diltiazem) ikke hemmer leukocyttaktiveringen.
Videre undersøkelser med Forbindelse A understøtter ovennevnte iakttagelse: På isolerte corticale og hippocampale nerveceller fra føtale rottehjerner (preparering ifølge H.W. Muller og W. Seifert, Proe. Nati. Acad. Sei. USA 81: 1248-1252, 1984; J. Neurosci. Res. 8: 195-204, 1982; samt Muller et Seifert i "Methods for Serum Free Culture of Neuronal and Lymphoid Cells", s. 67-77, A.R. Liss Inc., 150 Fifth Ave., New York, N.Y. 10011, 1984) ble det direkte neuronale angrep av Forbindelse A påvist. I FURA2~ladede enkeltceller ble konsentrasjons/tids-kurvene (kalsiumtransient) av det cytoplasmatiske Ca<2+> registrert (metode: modifisert etter J.A. Connor, Proe. Nati. Acad. Sei. 83:6179-6183, 1986). Såvel etter mekanisk lesjon som etter administrasjon av eksitatoriske aminosyrer (E.A.A., glutamat, kainat, quisgualat og NMDA) ble det frembragt en sterk økning av de cytoplasmatiske kalsium-konsentrasjonene som i samtlige tilfeller lot seg hemme doseavhengig av Forbindelse A (IC50 ved 3 jxM) .
Virkningsmekanismen for denne hemming ble undersøkt på neuronale cellekulturer og også på humane neutrofile granulocytter og HL 60-celler og trombocytter. Det kunne vises at Forbindelse A hemmer den transmembrane kalsiuminnstrømming i cellene, som stimuleres gjennom reseptoragonister (f.eks. EAA, FMLP, leukotrien, PAF, endothelin, o.a.). Denne influks som av T.J. Hallam og T.J. Rink (tips 10:8-10, 1989) betegnet "receptor mediated Ca<2+> entry (RMCE)" lar seg ikke hemme gjennom klassiske kalsiumantagonister. Klassiske kalsiumantagonister kan ikke forhindre leukocytt- og trombocyttaktiveringen da disse celler ikke har spenningsavhengige Ca<2+> kanaler. Blokkeringen av den transmembrane kalsiuminnstrømming kunne verifiseres elektrofysiologisk (voltage clamp-teknikk) på HL 60-celler og nerveceller.
Hemmingen av blodkoaguleringen resp. blodplateaggregasjonen, kan vises gjennom standardundersøkelser: På QUIN 2 ladede humane blodplater som er stimulert med ADP, vasopressin, PGF2a, trombin eller serotonin, kan det vises at den intracellulære Ca-transient som fører til blodplateaggregasjonen, hemmes gjennom 3 /xmol av Forbindelse A.
I den allerede nevnte patentsøknad EP-A-251 194 er det nevnt at in vitro undersøkelser på glatt muskulatur (aortastrimler; C. van Breemen, P. Aaronson, R. Lautzenheiser, K. Meisheri, Chest 78: 157S-165S (1980); R. Casteels og G. Droogman, J. Physio. 317: 263-279 (1981) har gitt som resultat at det ved forbindelsen med formel I er tale om kalsiumantagonister med en ny virknings-mekanisme. Som forklaring understrekes at de nevnte undersøkelser viser forbindelsenes kardiovaskulære virkning. Undersøkelses-resultatene fra den gang gjør det imidlertid ikke på noen måte nærliggende at forbindelsene med den generelle formel I skulle virke på inflammatoriske celler eller nerveceller.
Forbindelsene kan administreres peroralt, parenteralt eller lokalt. Egnede anvendelsesformer er for eksempel tabletter, kapsler, stikkpiller, oppløsninger, safter, emulsjoner, aerosoler eller dispergerbare pulvere. Slike tabletter kan for eksempel oppnås ved å blande virkestoff(ene) med kjente hjelpestoffer, eksempelvis inerte fortynningsmidler som kalsiumkarbonat, kalsiumfosfat eller melkesukker, sprengmidler som maisstivelse eller alginsyre, bindemidler som stivelse eller gelatin, glatte-midler som magnesiumstearat eller talk, og/eller midler for å oppnå depoteffekt, så som karboksypolymetylen, karboksymetyl-cellulose, celluloseacetatftalat eller polyvinylacetat. Tablettene kan også bestå av flere skikt.
Tilsvarende kan drasjéer fremstilles ved drasjering av kjerner fremstillet analogt med tablettene, med midler som vanligvis benyttes i drasjeringslag som eksempelvis kollidon eller skjellakk, gummi arabicum, talk, titandioksyd eller sukker. For å oppnå en depoteffekt eller for å unngå uforlikelighet kan kjernen også bestå av flere skikt. Likeledes kan også drasjeringslaget bestå av flere skikt for å oppnå en depoteffekt, hvorunder ovennevnte hjelpestoffer for tabletter kan benyttes.
Safter av virkestoffene eller virkestoffkombinasjonene kan dessuten inneholde et søtningsmiddel som sakkarin, cyklamat, glycerol eller sukker, så vel som et smaksforbedrende middel, f.eks. aromastoff som vanillin eller appelsinekstrakt. De kan dessuten inneholde suspenderingshjelpestoffer eller fortyknings-midler som natriumkarboksymetylcellulose, fuktemidler, eksempelvis kondensasjonsprodukter av fettalkoholer med etylenoksyd, eller konserveringsmidler som p-hydroksybenzoat.
Injeksjonsoppløsninger fremstilles på vanlig måte, f.eks. under tilsetning av konserveringsmidler, som p-hydroksybenzoater, eller stabilisatorer, som alkalisalter av etylen-diamintetraeddiksyre, og påfylles injeksjonsglass eller ampuller.
Kapsler som inneholder ett eller flere virkestoff eller virkestoffkombinasjoner, kan eksempelvis fremstilles ved at virkestoffet blandes med inerte bæremidler, som melkesukker eller sorbitol, og innkapsles i gelatinkapsler.
Egnede stikkpiller lar seg eksempelvis fremstille ved sammen-blanding med bæremidler for formålet, som nøytralfett eller polyetylenglykol eller derivater derav.
Forbindelsene kan i henhold til oppfinnelsen administreres enteralt, parenteralt eller lokalt, hensiktsmessig i en mengde på 0. 05 til 500 mg per dose for voksne personer. Fortrinnsvis benyttes ved peroral administrasjon 0,1 til 500 mg per dose og ved 1. v. administrasjon 0,05 til 150 mg per dose.
Formulerin<q>seksempler
Fremstilling:
Virkestoffet blandes med en del av hjelpestoffene og granuleres med en oppløsning av den oppløselige stivelse i vann. Etter tørking av granulatet tilblandes resten av hjelpestoffene og blandingen presses til tabletter. Eksempel 2: Drasjéer
Fremstilling:
Virkestoff og hjelpestoffene presses til tablettkjerner som beskrevet i Eksempel 1 og drasjeres med sukker, talkum og gummi arabicum på vanlig måte.
Eksempel 3: Suppositorier
Fremstilling:
Virkestoff og melkesukker blandes med hverandre og blandingen suspenderes jevnt i den smeltede suppositoriemasse. Suspensjonen støtes i avkjølte former til suppositorier med en vekt på 1,7 g.
Eksempel 4: Ampuller
Fremstilling:
Virkestoff og natriumkloridet oppløses i dobbeltdestillert vann og oppløsningen fylles sterilt over på ampuller. Eksempel 5: Ampuller Eksempel 6; Dråper
Fremstilling:
Virkestoff og konserveringsmiddel oppløses i demineralisert vann og oppløsningen filtreres og fylles over på flasker på 100 ml.
Forbindelsene med den generelle formel I er nye. De kan fremstilles analogt med kjente fremgangsmåter som følger:
a) ved cyklisering av et fenylmalonsyrediamid med formel III
i nærvær av et kondensasjonsmiddel
eller
b) ved å gå ut fra karboksylsyrer eller karboksylsyrehalogenider med formel IV, hvor Y står for OH eller halogen,
ved omsetning med aminet med den generelle formel VI
i nærvær av et egnet kondensasjonsmiddel.
I de ovenfor angitte formler III og IV er gruppen X som definert for formel I.
Som kondensasjonsmiddel for fremgangsmåte a) egner seg en rekke Lewissyrer, som f.eks. fosforoksyklorid, bortrifluorid, tinntetraklorid eller titantetraklorid, og også sterke mineral-syrer som svovelsyre, fluorsulfonsyre, flussyre eller polyfosfor-syre. De benyttes vanligvis i overskudd. Fosforoksyklorid fore-trekkes .
Cykliseringsreaksjonen kan utføres med eller uten nærvær av oppløsningsmiddel. Alle inerte oppløsningsmidler egner seg i den utstrekning de har tilstrekkelig oppløselighet for reaktantene og oppviser et tilstrekkelig høyt kokepunkt. Eksempler er benzen, alkylbenzener, klorbenzener, dekalin, kloroform, metylenklorid, acetonitril og lignende. En variant av fremgangsmåten består i at kondensasjonsmidlet, eksempelvis fosforoksyklorid, selv benyttes som oppløsningsmiddel.
Når det gjelder reaksjonstemperaturen foreligger ingen spesielle betingelser. Omsetningen i henhold til oppfinnelsen kan utføres innenfor et stort temperaturområde, fortrinnsvis under oppvarming eventuelt til oppløsningsmidlets kokepunkt.
Amideringsreaksjonen b) kan prinsipielt foretas under de samme betingelser som ved reaksjon a). Som kondensasjonsmiddel skal dessuten nevnes karbodiimider - som cykloheksylkarbodiimid eller karbonyldiimidazol.
Eksempel
3,4-dihydro-l-benzyl-6,7-dimetoksy-a-[di-2-(2,3,4-trimetoksyfenyl)etyl]aminokarbonyl-isokinolin-hydroklorid
a) 2-(3,4-dimetoksyfenyl)etylaminokarbonyl-fenyl-eddiksyre-N,N-di-[2-(2,3,4-trimetoksyfenyl)etyl]amid
I en oppløsning av 18,0 g (52,4 mmol) fenylmalonsyremono-etylester-2- ( 3 , 4-dimetoksyf enyl ) etylamid i 150 ml vannfri dimetylformamid innrøres ved romtemperatur porsjonsvis 9,0 g (55,5 mmol) N,N'-karbonyldiimidazol. Etter 3 0 minutter tilsettes 18,0 g (44,3 mmol) di-[2-(2,3,4-trimetoksyfenyl)etyl]amin og blandingen omrøres i 30 minutter. Deretter avdestilleres oppløsningsmidlet i vakuum, hvorpå residuet tas opp i 1,5 liter CH2C12 og utrystes to ganger med 2 50 ml vann og med 2 ml IN HCl. Den organiske fase inndampes etter tørking over Na2S04, hvorpå residuet etter rensing over en kiselgelsøyle
(eluent: CH2Cl2/MeOH 100:2) krystalliserer fra etylacetat/eter. Utbytte: 35,5 g
b) 35,0 g (47,5 mmol) amid (fra trinn a) og 15 ml (164 mmol) fosforoksyklorid oppvarmes til koking i 150 ml vannfri acetonitril
i 30 minutter. Etter endt omsetning (tynnskiktskromatografi-kontroll) avdestilleres oppløsningsmidlet og ikke konsumert fosforoksyklorid i vakuum. Residuet tilsettes isvann, gjøres alkalisk med natriumkarbonatoppløsning og ekstraheres porsjonsvis med ca. 1 liter CH2C12. Den organiske fase vaskes med vann, tørkes over Na2S04 og inndampes. Residuet renses to ganger over en kiselgelsøyle (1. eluent: CH2Cl2:MeOH 100:2-*100:4 stigende;
2. eluent: CH2Cl2/etylaceta.t 1:1).
Av det rensede produkt (6,5 g) dannes hydrokloridet ved oppløsning i ca. 50 ml etanol og tilsetning av alkoholisk saltsyre. Etter inndampning og tørking i høyvakuum ved 50°C blir 11,5 g av det ønskede produkt tilbake. (Smp. 56-64°C, amorft).
Analogt kan for eksempel også forbindelsen i den følgende tabell fremstilles.
Claims (2)
1. Analogif remgangsmå.te for fremstilling av terapeutisk aktive 3,4-dihydroisokinolinderivater med den generelle formel I
hvor
X1 er fenyl som er mono- eller di-substituert med trifluormetyl
eller etoksy, metoksy- og fluorsubstituert fenyl eller 2-metoksyfenyl,
X2 er -CH2-CH2- eller -CH2-CH(CH3) -
og
X3 er 2,3,4-trimetoksyfenyl, 2,3-dimetoksyfenyl, 2,6-di
metoksyfenyl, 3,6-dimetoksyfenyl, tienyl, fenyl som er mono-eller di-substituert med trifluormetyl eller etoksy, eller metoksy- og fluorsubstituert fenyl,
eller deres farmasøytisk akseptable salter,
karakterisert veda) cyklisering av et fenylmalonsyrediamid med formel III
i nærvær av et kondensasjonsmiddel eller b) ved å gå ut fra karboksylsyrer eller karboksylsyrehalogenider med formel IV, hvor Y står for OH eller halogen,
omsetning med aminet med den generelle formel VI
i nærvær av et egnet kondensasjonsmiddel,
idet X i de ovenfor angitte formler er som definert for formel le, hvorpå den således oppnådde forbindelse eventuelt overføres i dens farmasøytisk akseptable salt.
2. Fremgangsmåte ifølge krav 1 for fremstilling av forbindelsen med formel
karakterisert ved at tilsvarende utgangs-materialer anvendes.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4041482A DE4041482A1 (de) | 1990-12-22 | 1990-12-22 | Neue pharmazeutische verwendung carbocyclisch und heterocyclisch annelierter dihydropyridine |
PCT/EP1991/002470 WO1992011010A1 (de) | 1990-12-22 | 1991-12-20 | Neue 3,4-dihydroisochinolinderivate und neue pharmazeutische verwendung carbocyclisch und heterocyclisch anellierter dihydropyridine |
Publications (4)
Publication Number | Publication Date |
---|---|
NO932279D0 NO932279D0 (no) | 1993-06-21 |
NO932279L NO932279L (no) | 1993-06-21 |
NO179515B true NO179515B (no) | 1996-07-15 |
NO179515C NO179515C (no) | 1996-10-23 |
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ID=6421218
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO932279A NO179515C (no) | 1990-12-22 | 1993-06-21 | Analogifremgangsmåte for fremstilling av terapeutisk aktive 3,4-dihydroisokinolinderivater |
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US (3) | US5686462A (no) |
EP (2) | EP0781556A1 (no) |
JP (1) | JP3283877B2 (no) |
KR (1) | KR100227953B1 (no) |
AT (1) | ATE177948T1 (no) |
AU (1) | AU666107B2 (no) |
BR (1) | BR1100520A (no) |
CA (1) | CA2098917A1 (no) |
CZ (3) | CZ289533B6 (no) |
DE (3) | DE4041482A1 (no) |
DK (1) | DK0563128T3 (no) |
ES (1) | ES2129040T3 (no) |
FI (1) | FI105026B (no) |
GR (1) | GR3030341T3 (no) |
HK (1) | HK1010683A1 (no) |
HR (1) | HRP940721B1 (no) |
HU (1) | HU217819B (no) |
ID (1) | ID16001A (no) |
IE (3) | IE990430A1 (no) |
IL (1) | IL100450A (no) |
MX (1) | MX9102765A (no) |
NO (1) | NO179515C (no) |
NZ (1) | NZ241140A (no) |
PL (1) | PL172262B1 (no) |
PT (1) | PT99901B (no) |
RU (2) | RU2115647C1 (no) |
SG (1) | SG43064A1 (no) |
SI (1) | SI9111975B (no) |
SK (1) | SK281017B6 (no) |
TW (1) | TW283145B (no) |
WO (1) | WO1992011010A1 (no) |
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CA2138788A1 (en) * | 1992-06-22 | 1994-01-06 | Dietrich Arndts | Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions |
DE4343683A1 (de) * | 1993-12-21 | 1995-06-22 | Boehringer Ingelheim Kg | Anellierte Dihydropyridine und deren Verwendung für die Herstellung von pharmazeutischen Zubereitungen |
AU688833B2 (en) * | 1993-12-21 | 1998-03-19 | Boehringer Ingelheim International Gmbh | Anellated dihydropyridines and their use in the production of pharmaceutical preparations |
GB2341318A (en) * | 1998-09-14 | 2000-03-15 | Boehringer Ingelheim Pharma | A Dihydroisoquinoline (LOE 908) and Traumatic Brain Injury. |
EP1482882B1 (en) * | 2002-02-11 | 2011-09-14 | Gold-T Tech, Inc. | Implantable device for preventing thrombus formation |
DE102004055633A1 (de) * | 2004-11-12 | 2006-05-18 | Schering Ag | 5-substituierte Chinolin- und Isochinolin-Derivate, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer |
JP5148636B2 (ja) * | 2007-03-15 | 2013-02-20 | エフ.ホフマン−ラ ロシュ アーゲー | オレキシンアンタゴニストとしてのマロンアミド |
CZ302637B6 (cs) * | 2010-01-05 | 2011-08-10 | Zentiva, K. S | Zpusob prípravy 6,7-dimethoxy-1-[2-(4-trifluormethylfenyl)ethyl]-3,4-dihydroisochinolinu |
EP2420237A1 (en) | 2010-08-11 | 2012-02-22 | Ville Takio | Fluorinated derivatives of endogenous isoquinolines for use in the treatment of diseases mediated through endogenous isoquinoline pathways |
KR101645930B1 (ko) | 2014-12-16 | 2016-08-05 | (주) 우수 | 타월 거치대 |
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DE3013906A1 (de) * | 1980-04-11 | 1981-10-15 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituierte (alpha) -aminocarbonyl-l-benzyl-3,4-dihydro-isochinoline, verfahren zu deren herstellung und deren verwendung |
DE3621413A1 (de) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | Verwendung carbocyclisch und heterocyclisch annelierter dihydropyridine als cardioprotektive mittel sowie neue heterocyclisch und carbocyclisch anellierte dihydropyridine, verfahren zu deren herstellung und zwischenstufen fuer deren herstellung |
IL86131A0 (en) * | 1987-04-24 | 1988-11-15 | Boehringer Ingelheim Kg | Benzo-and thieno-3,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
DE3827727A1 (de) * | 1988-08-16 | 1990-02-22 | Boehringer Ingelheim Kg | Anellierte tetrahydropyridinessigsaeurederivate, verfahren zu deren herstellung und verwendung solcher verbindungen zur kardioprotektion |
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1990
- 1990-12-22 DE DE4041482A patent/DE4041482A1/de not_active Ceased
- 1990-12-22 DE DE9017900U patent/DE9017900U1/de not_active Expired - Lifetime
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1991
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- 1991-12-20 EP EP96119881A patent/EP0781556A1/de not_active Withdrawn
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- 1991-12-20 DE DE59109115T patent/DE59109115D1/de not_active Expired - Fee Related
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- 1991-12-20 EP EP92901178A patent/EP0563128B1/de not_active Expired - Lifetime
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- 1991-12-20 CA CA002098917A patent/CA2098917A1/en not_active Abandoned
- 1991-12-20 KR KR1019930701908A patent/KR100227953B1/ko not_active IP Right Cessation
- 1991-12-20 AT AT92901178T patent/ATE177948T1/de not_active IP Right Cessation
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- 1991-12-20 IE IE20001043A patent/IE20001043A1/en unknown
- 1991-12-20 IE IE448691A patent/IE914486A1/en not_active Application Discontinuation
- 1991-12-23 NZ NZ241140A patent/NZ241140A/en unknown
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