NO853694L - Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav. - Google Patents
Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav.Info
- Publication number
- NO853694L NO853694L NO853694A NO853694A NO853694L NO 853694 L NO853694 L NO 853694L NO 853694 A NO853694 A NO 853694A NO 853694 A NO853694 A NO 853694A NO 853694 L NO853694 L NO 853694L
- Authority
- NO
- Norway
- Prior art keywords
- tetrazol
- phenyl
- tetramethyl
- propene
- indenyl
- Prior art date
Links
- -1 VINYLTETRAZOLYLPHENYL Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001540 azides Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
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- 239000005977 Ethylene Chemical group 0.000 claims description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 31
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
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- 210000002268 wool Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
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- Engineering & Computer Science (AREA)
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- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av nye vinyl-tetrazolfenylderivater.
Fra tysk OS 28 54 354 og 32 02 118 er det f.eks. kjent at vinylbenzosyrederivater har farmakologiske virkninger ved topisk og systemisk terapi av neoplasier, akne, psoriasis og andre dermatologiske forstyrrelser. Disse vinylbenzosyrederivatene er imidlertid ikke alltid tilfredsstillende. Fremfor alt er deres utpregede toksiske (bi)virkning uheldig, hvilke gjør disse forbindelser lite egnet som middel i topisk og systemisk terapi av neoplasier, akne, psoriasis og andre dermatologiske forstyrrelser. Det uheldige ved forbindelsene fra tysk OS 28 54 354 beskrives f.eks. av A. Kistler i Calcified Tissue International 33, 249-254 (1981) og viser seg ved flere gangers applikasjon på gnagere ifølge den metodikk som er beskrevet av R. C. Moon et al i Cancer Research 39, 1339-1346 (1979).
Oppgaven for foreliggende oppfinnelse er å tilveiebringe forbindelser med sammenlignbar virkningsgrad og mindre toksiske bivirkninger.
Man har nå funnet at vinyltetrazolylfenylderivater med
formel (I)
hvori R 1 og R 2 er hydrogen eller en metylgruppe,
3 4
R og R hydrogen, halogen, en C^_^-alkyl eller C-^_^-alkoksy-gruppe,
R^ hydrogen, en C^_g-alkyl- eller en C-^g-cykloalkylgruppe og
A en likeledes med C, .-alkylgruppe substituert metylen- eller
1 2
etylenrest eller - når R og R utgjør metylgrupper - også betyr
restene -CH2-C0- eller -Cr^-CH-, og deres fysiologisk fordragelige salter egner seg godt for behandling av sykdommer.
Som den bølgeformige viste C-H-binding i formel I angir,
kan forbindelsene fremstilt ifølge oppfinnelsen foreligge i
cis-(Z)- eller trans-(E)-formen. Trans-E-formene er foretrukne. Som foretrukket alkylgruppe på A må metylgruppen nevnes. For
3 4 5
R og R er hydrogen, metyl og metoksy foretrukket. R er fortrinnsvis hydrogen eller metyl.
Typiske eksempler på forbindelser ifølge oppfinnelsen er foruten de substanser som er nevnt i eksemplene: 2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1- £4-(lH-tetrazol-5-yl)fenylj -eten
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)fenylj-eten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1- U~
(lH-tetrazol-5-yl)fenyl} -1-buten
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)f enyl]-1-buten
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)f enyl]-1-buten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-1-octen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-f4-(lH-tetrazol-5-yl)fenyl}-1-octen
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenylj-1-octen
2-(1,1,4,4,7-Pentametyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(lH-tetrazol-5-yl)fenyl}-1-propen
2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-1^4-(lH-tetrazol-5-yl)fenylj -1-propen
2-(7-Etyl-l,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)
-l-[4- (lH-tetrazol-5-yl)fenyl}-1-propen
2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-f4-(lH-tetrazol-5-yl)fenyj-1-propen
2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)
-l-£4-(lH-tetrazol-5-yl)f enyl] -1-propen
2-[7-(2)-Metyletyl)-1,1,4,4-tetrametyl-l,2,3,4-tetrahydronaf t-6-yl] -1-C4-(lH-tetrazol-5-yl)fenyl} -1-propen
2-T6-(2-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-1-C4-(lH-tetrazol-5-yl)fenyl3-1-propen 2-[6-(2-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)-
indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-X3-lH-tetrazol-5-yl)fenyl} -1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[3-(1H-tetrazol-5-yl)fenyl] -1-propen
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T3-(1H-tetrazol-5-yl)fenyl]-1-propen
2-(7-butyl-l,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenylj-1-propen
2-(6-Butyl-l,1,3,3-tetrametyl-2,3-dihydro-5(lH-indenyl)-1--[4-(lH-tetrazol-5-yl)fenyl}-1-propen
2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-l-£4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-2-cyklo-propyl-l-f4-(lH-tetrazol-5-yl)f enyl}eten
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l~C4-(lH-tetrazol-5-yl)fenyl] -eten
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l-t 4-tetrazol-5-yl)fenyl] -eten
2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklopropyl-l-t4-(lH-tetrazol-5-yl)fenyl]-eten
2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l-[4-(lH-tetrazol-5-yl)fenyl] -1- [4-(lH-tetrazol-5-yl)-fenyl} -eten
2- r (1,1, 3 , 3 , 7-Pentametyl-l ,2,3, 4-tetrahydronaf t-6-yl) -2-cyklo-propyl-l-[4-(lH-tetrazol-5-yl)fenyl}-1- Ia-(lH-tetrazol-5-yl)-fenyl] -eten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-(3-metyl)-buten-1
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl} -(3-metyl)-buten-1
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(lH-tetrazol-5-yl)fenyl]-(3-metyl)-buten-1
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-heksyl-l-f4-(lH-tetrazol-5-yl)fenyl} -eten
2-(1,1,2,,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-heksyl-l-C4-(lH-tetrazol-5-yl)fenyl] -eten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-2-cyklo-heksyl-l-[4-(lH-tetrazol-5-yl)fenyl] -eten
2-(4,4,7-Trimetyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(1H-tetrazol-5-yl)fenyl] -1-propen
2-(4,4-Dimetyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetra-zol-5-yl) fenyl] -1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2,3-diokso-naft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl] -1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-okso-indenyl)-1--£4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-hydroksy-indenyl)--l-[4-(lH-tetrazol-5-yl)fenyl] -1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-hydroksy-naft--6yl)-l-t 4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-hydroksy-naft--6-yl) -l-["4- (lH-tetrazol-5-yl) fenyl] -1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl}-eten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-eten
2-(1,1,4,4-Tetraetyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)--1-T4-(lH-tetrazol-5-yl)fenyl]-1-buten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-buten
Forbindelsene fremstilles ifølge oppfinnelsen ved omsetning av et azid med et nitril med formel (II)
1 2 3 4 5
hvori R , R , R , R , R og A har de ovenfor angitte betydninger.
Omsetningen med azidet under tetrazoldannelse forløper ved en temperatur fra ca. romtemperatur til ca. 200°C, fortrinnsvis ved 60 til 100°C. Omsetningen kan finne sted ved normalt trykk eller i lukket apparatur under forhøyet trykk, hensiktsmessig under oppvarming til det angitte temperaturområdet.
Hensiktsmessig foretas omsetningen i nærvær av et fortyn-nings- eller løsningmiddel, f.eks. en av de lavere mettede dialkyletere, dialkylglykoletere eller cykliske etere, såsom dietyleter, etyl-tert.-butyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon, såsom benzen eller et alkylbenzen, såsom toluen eller xylen, eller et mettet alifa-tisk hydrokarbon, såsom heksan, heptan eller isooctan, et alkyl-formamid, såsom dimetyl- eller dietylformamid, i protiske løs-ningsmidler såsom alkoholer eller i blandinger av de nevnte løs-ningsmidler. Fortrinnsvis anvender man cykliske etere, såsom dioksan eller tetrahydrofuran samt spesielt dimetylformamid eller blandinger derav, hvorunder omsetningen generelt forløper ved en temperatur fra 60 til 100°C.
Det anbefales å foreta omsetningen i nærvær av et uorganisk halogenid. Som uorganiske halogenider kommer ammoniumklorid, litiumklorid, aluminium(III)klorid spesielt på tale.
Som azider kommer fortrinnsvis alkaliazider, såsom litium-azid, natriumazid eller kaliumazid, fortrinnsvis natriumazid eller 1,1,3,3-tetrametylguanidiniumazid i betraktning.
Utgangsforbindelsene med formel (II) kan enhetlig ha cis-eller transstruktur eller være blandinger av de to E-/Z-isomere. En isomerisering ved fremstilling av de nye forbindelser i sterisk enhetlig form kan ikke utelukkes. Isomerblandingen som dannes i slike tilfeller av forbindelsene med formel (I) fremstilt ifølge oppfinnelsen kan bestemmes kvantitativt ved HPLC-13
analyse eller med et C-NMR-spektrum, og den ønskede isomere eventuelt isoleres ved fraksjonert krystallisering eller kromato-grafi med f.eks. kiselgelsøyler eller med preparativ HPLC-kroma-tografi i ren form.
Fremstillingen av utgangsnitrilene med formel (II) er beskrevet i tysk OS 32 02 125 eller kan fremstilles etter den deri angitte arbeidsforskrift. For eksempel kan en karbonylforbindel-se med formel (III) hvori R"1", R^, R^, R4, R5 og A har de ovenfor angitte betydninger omsettes med en para- eller meta-substituert fosforforbindel-se formel (IV)
i en Horner-Emmons-reaksjon.
Forbindelsen fremstilt ifølge oppfinnelsen er et surt hydrogenatom på tetrazolringen og kan derfor med base på vanlig måte overføres i et fysiologisk fordragelig, vannløselig salt. Egnede salter er f. eks. ammonium-y alkalimetall- (spesielt nat-rium, kalium og litium) og jordalkalimetallsalter, spesielt av kalsium eller magnesium samt salter med egnede organiske baser såsom ved lavere alkylaminer, f.eks. metylamin eller etylamin, med substituerte lavere alkylaminer, spesielt hydroksysubstituer-te alkylaminer såsom dietanolamin, trietanolamin eller tris-hydroksymetylaminometan, piperidin eller morfolin.
Forbindelsen fremstilt ifølge oppfinnelsen og deres fysio-logiske fordragelige salter kan på grunn av deres farmakologiske egenskaper anvendes ved en topisk og systemisk terapi og også profylakse av prekanzeroser og karzinomer i huden, slimhinnene og innvendige organer samt ved topisk og systemisk terapi av akne, psoriasis og andre dermatologiske sykdommer som har forbindelse med patologisk forandret horndannelse samt ved behandling av revmatiske sykdommer, spesielt slike av betennelses-eller degenerativ type som angriper ledd, muskler, sener og andre deler av bevegelsesapparatet. Foretrukne indikasjonsom-råder er ved siden av terapi av dermatologiske sykdommer den profylaktiskeog terapeutiske behandling av prekanzeroser og tumorer, samt behandling av artritiske sykdommer. Den dermatologiske aktivitet, f.eks. for behandling av akne, kan blant annet påvises ved bestemmelse av den komedolytiske aktivitet og evnen til å redusere antall utrikuli i Rhino-mus modellen. Denne metoden er beskrevet av L.H. Kligman et al. i The Journal of Investigative Dermatology 73, 354 til 38 (1979) og av J.A. Mezick et al. i "Models of Dermatology (Ed. Maibach, Lowe) Vol. 2, s. 59-63, Karger, Basch 1985. Antiartritisk virkningen til forbindelsen fremstilt ifølge oppfinnelsen kan bestemmes på vanlig måte i dyre-eksperiment i Adjuvans-artritis-modellen. Den preventive virkning ved dannelse og utvikling av premalig-gende lesjoner kan f.eks. påvises i de etterfølgende forsøks-modeller. Forbindelsen fremstilt ifølge oppfinnelsen opphever på hamster-treakealvev in vitro keratiniseringen som begynner ved vitamin-A-mangel. Denne keratiniseringen tilhører en tidlig fase av karcinogenese som i en lignende teknikk in vivo etter initiering med kjemiske forbindelser inhiberes ved energirik stråling eller etter virale celletransformasjoner med forbindelsen med formel (I) fremstilt ifølge foreliggende oppfinnelse. Denne metodikken kan man lese i Cancer Res. 36, 96 4 til 972
(1976) eller i Nature 250, 64 til 66 (1974) og Nature 253, 47 til 50 (1975).
Dertil inhiberes formeringshastigheten til bestemte ond-artede forandrede celler ved forbindelsen fremstilt ifølge oppfinnelsen. Denne metodikken fremgår av J. Nati. Cancer Inst. 60, 1035 til 1041 (1978), Experimental Cell Research 117, 15 til 22 (1978) og Proe. Nati.Acad.Sei.USA 77, 2936 til 2940 (1980). Videre vises til bestemmelsen av de antagonistiske virkningene overfor forbolester som beskrives i Cancer Res. 37, 2196 til 2201 (1977).
Som terapeutiske midler for topisk og systemisk anvendelse blandes en forbindelse med formel (I) med vanlig bærestoffer eller fortynningsmidler og kan anvendes ved bekjempelse av sykdommer .
Fremstillingen av de terapeutiske midler eller preparater skjer med de vanlige flytende eller faste bærestoffer eller fortynningsmidler og de på vanlig måte anvendte farmasøytiske tekniske hjelpestoffer avhengig av den ønskede applikasjonstype og med en egnet dosering for anvendelsen på vanlig måte, f.eks. ved blanding av virkestoffet med de vanlige faste eller flytende bære- og hjelpestoffer i slike preparater.
Midlene kan følgelig gis peroralt, parenteralt eller topisk. Slike preparater er f.eks. tabletter, filmtabletter, drageer, kapsler, piller, pulvere, løsninger eller suspensjoner, infusjons-eller injeksjonsløsninger samt pastaer, salver, geleer,kremer, lotioner, puddere, løsninger eller emulsjoner og sprays.
De terapeutiske midler kan inneholde forbindelsene fremstilt ifølge foreliggende oppfinnelse ved lokale anvendelser i 0,001 til 1%-ig konsentrasjoner, fortrinnsvis i 0,001 til 0,1%-
ig konsentrasjon og ved systemiske anvendelser fortrinnsvis i en enkel dose på 0,1 til 50 mg, og gis daglig i en eller flere doser avhengig av sykdommens art og grad.
Vanlig anvendte farmasøytiske tekniske hjelpestoffer er f.eks. for lokale anvendelser.alkoholer, såsom isopropanol, oksetylert ricinusolje eller oksetylert hydrogenert ricinusolje, polyakrylsyre, glycerolmonostearat, paraffinolje, vaseliner, ullfett, polyetylenglykol 400, polyetylenglykol 400-stearat samt etoksylert fettalkohol, for systemiske anvendelser melke-sukker, propylenglykol og etanol, stivelse, talkum, polyvinyl-pyrrolidon. Preparatene kan eventuelt tilsettes et antioksida-sjonsmiddel, f.eks. tokoferol samt butylert hydroksyanisol eller butylert hydroksytoluen eller smaksforbedrende tilsetninger, stabiliseringsmidler, emulgeringsmidler, glidemidler osv. En forutsetning er at alle stoffer som anvendes ved fremstillingen av de farmasøytiske preparater er toksikologisk ubetenkelige og forenelige med de anvendte virkestoffer.
De følgende eksempler illustrerer oppfinnelsen.
Eksempel 1
(E)-2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
Til en suspensjon av 65 g natriumazid i 500 ml tetrahydrofuran innførtes ved 0°C i små porsjoner 33,5 g vannfritt alumi-niumklorid. Deretter oppvarmet man ca. 4 5 minutter ved tilbake-løp, blandet med 16,5 g (E)-4-£2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftalenyl)-1-propenyl]-benzonitril og rørte deretter igjen 24 timer ved tilbakeløpstemperatur. Etter avkjølin-gen ble reaksjonsblandingen helt på 2,5 1 isvann, blandet med 250 ml etanol og surgjort med 2 N saltsyre. Det dannede faste stoff ble filtrert fra og vasket på filteret med 100 ml kald metanol. Etter tørking i nitrogenstrøm ble 12,2 g (66% d.Th.) (E)-2-(1,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1- [4-(1H-tetrazol-5-yl)fenyl]-1-propen, smp. 227 til 230°C tilbake.<13>C-NMR-spektrumet viser at det dreier seg om den isomerrene tittel-forbindelse i trans-konfigurasjon.
Analogt ble substansene i den etterfølgende tabell fremstilt .
Claims (2)
1. Fremgangsmåte ved fremstilling av vinyltetrazolylfenylderivater med formel (I)
1 2
hvor R og R er hydrogen eller en metylgruppe,
R 3 og R 4hydrogen, halogen, en C^ _^ -alkyl eller C^ _^ -alkoksy-gruppe,
R 5hydrogen, en C^ _g-alkyl- eller en C-^ g-cykloalkylgruppe og A en eventuelt med C,_4 -alkylgruppe substituert metylen-eller etylenrest, eller - når R 1 09q§ 2 er metylgruppe - også betyr restene -Cr^-CO- eller -Cr^ -CH-, og deres fysiologisk fordragelige salter, karakterisert ved at man omset-ter et azid med et nitril med formel (II)
1 2 3 4 5
hvori R , R , R , R , R og A har de ovenfor angitte betydninger .
2. Fremgangsmåte ifølge krav 1, ved fremstilling av forbindelse med formel (I) som foreligger i E-form og hvori R 1 og R 2 har 3 4
de forutangitte betydninger og R og R betyr hydrogen, metyl og/eller metoksy og R hydrogen eller metyl, karakterisert ved at man anvender tilsvarende substituerte utgangsforbindelser.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843434948 DE3434948A1 (de) | 1984-09-22 | 1984-09-22 | Vinyltetrazolylphenyl-derivate, ihre herstellung und verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO853694L true NO853694L (no) | 1986-03-24 |
Family
ID=6246164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853694A NO853694L (no) | 1984-09-22 | 1985-09-20 | Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav. |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0176875A3 (no) |
| JP (1) | JPS6185371A (no) |
| AU (1) | AU578739B2 (no) |
| DE (1) | DE3434948A1 (no) |
| FI (1) | FI853621L (no) |
| HU (1) | HU192363B (no) |
| IL (1) | IL76452A0 (no) |
| NO (1) | NO853694L (no) |
| ZA (1) | ZA857272B (no) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3434946A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
| DE3434944A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | L-substituierte tetralinderivate, ihre herstellung und verwendung |
| AU587994B2 (en) * | 1984-09-27 | 1989-09-07 | Processing Technologies International Limited | Low alcohol wine |
| ZW7487A1 (en) * | 1986-05-23 | 1987-12-16 | Hoffmann La Roche | Tetrahydronaphthaline and indane derivatives |
| US5030764A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
| US5030765A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
| AT388728B (de) * | 1987-03-17 | 1989-08-25 | Hoffmann La Roche | Neue tetrahydronaphthalin- und indanderivate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK159967C (da) * | 1977-12-22 | 1991-06-03 | Hoffmann La Roche | Analogifremgangsmaade til fremstilling af terapeutisk aktive stilbenderivater |
| EP0084667B1 (de) * | 1982-01-23 | 1985-09-18 | BASF Aktiengesellschaft | Phenylethylen-Derivate, ihre Herstellung und Verwendung als Arzneimittel |
-
1984
- 1984-09-22 DE DE19843434948 patent/DE3434948A1/de not_active Withdrawn
-
1985
- 1985-09-19 EP EP85111834A patent/EP0176875A3/de not_active Withdrawn
- 1985-09-20 HU HU853547A patent/HU192363B/hu unknown
- 1985-09-20 FI FI853621A patent/FI853621L/fi not_active Application Discontinuation
- 1985-09-20 NO NO853694A patent/NO853694L/no unknown
- 1985-09-22 IL IL76452A patent/IL76452A0/xx unknown
- 1985-09-23 ZA ZA857272A patent/ZA857272B/xx unknown
- 1985-09-24 JP JP60209008A patent/JPS6185371A/ja active Pending
- 1985-09-24 AU AU47834/85A patent/AU578739B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP0176875A3 (de) | 1987-05-27 |
| HU192363B (en) | 1987-05-28 |
| FI853621L (fi) | 1986-03-23 |
| FI853621A0 (fi) | 1985-09-20 |
| IL76452A0 (en) | 1986-01-31 |
| JPS6185371A (ja) | 1986-04-30 |
| AU578739B2 (en) | 1988-11-03 |
| AU4783485A (en) | 1986-03-27 |
| EP0176875A2 (de) | 1986-04-09 |
| DE3434948A1 (de) | 1986-04-03 |
| ZA857272B (en) | 1986-05-28 |
| HUT39434A (en) | 1986-09-29 |
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