NO342153B1 - Forbindelsen 1-(3-(2-(1-benzotiofen-5-yl)etoksy)propyl)azetidin-3-ol, eller et salt derav for behandling eller forebygging av sykdom - Google Patents
Forbindelsen 1-(3-(2-(1-benzotiofen-5-yl)etoksy)propyl)azetidin-3-ol, eller et salt derav for behandling eller forebygging av sykdom Download PDFInfo
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- NO342153B1 NO342153B1 NO20084338A NO20084338A NO342153B1 NO 342153 B1 NO342153 B1 NO 342153B1 NO 20084338 A NO20084338 A NO 20084338A NO 20084338 A NO20084338 A NO 20084338A NO 342153 B1 NO342153 B1 NO 342153B1
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- 150000003839 salts Chemical class 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 title claims description 14
- HQNACSFBDBYLJP-UHFFFAOYSA-N 1-[3-[2-(1-benzothiophen-5-yl)ethoxy]propyl]azetidin-3-ol Chemical compound C1C(O)CN1CCCOCCC1=CC=C(SC=C2)C2=C1 HQNACSFBDBYLJP-UHFFFAOYSA-N 0.000 title claims description 7
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- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000003282 alkyl amino group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61P25/24—Antidepressants
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Abstract
117140/MFP Det beskrives et middel som omfatter et benzotiofenalkyleterderivat representert ved den generelle formel nedenfor, eller et salt derav: hvor R1 og R2 uavhengig representerer minst én gruppe valgt fra et hydrogenatom, et halogenatom, en alkylgruppe, en arylgruppe, en aralkylgruppe, en alkoksygruppe, en aryloksygruppe, en alkyltiogruppe, en aryltiogruppe, en alkenylgruppe, en alkenyloksygruppe, en aminogruppe, en alkylsulfonylgruppe, en arylsulfonylgruppe, en karbamoylgruppe, en heterocyklisk gruppe, en aminogruppe, en hydroksylgruppe, en karboksylgruppe, en nitrogruppe, en oksogruppe og lignende; R3 representerer en alkylaminogruppe som kan være substituert eller en amino- eller hydroksylgruppe som kan være beskyttet; og m og n representerer, uavhengig, et helt tall i området fra 1 til 6. Midlet er anvendelig som et nevrogenese-fremkallende middel eller som et terapeutisk middel mot nevropati.
Description
Foreliggende oppfinnelse angår forbindelsen 1-(3-(2-(1-benzotiofen-5-yl)etoksy)propyl)azetidin-3-ol, eller et salt derav for behandling eller forebygging av sykdom.
KJENT TEKNIKK.
Schizofreni, bipolar emosjonell lidelse, tilbakevendende depressiv lidelse, fobisk angstlidelse og lignende, er kjent som mentale lidelser (ikke-patentdokument 1). For tiden blir antipsykotiske medikamenter, antidepressive medikamenter, anti-angstmedikamenter og lignende anvendt klinisk for å behandle disse mentale lidelsene. Det er imidlertid behov for et medikament med øket effektivitet og færre ugunstige medikamentreaksjoner.
For eksempel er mange av de antipsykotiske medikamentene dopaminreseptorblokkere, og kan fremkalle ekstrapyramidale symptomer. Dessuten er effekten av disse medikamenter for å forbedre negative symptomer utilstrekkelig. Det er for antidepressive medikamenter kjent at omtrent mange uker er nødvendig for at deres terapeutiske effekt skal manifestere seg; noen pasienter er resistente mot terapi med dem, og remisjonsprosenten etter terapi med dem er 50% eller mindre. Mange antidepressive medikamenter er kjent for å være vanedannende, og de har ugunstige effekter, så som døsighet.
På den annen side er det blitt rapportert om redusert lokalt hjernevolum ved forskjellige patologiske tilstander, så som depresjon, schizofreni og stemningsleielidelse. Et redusert antall hjernenevroner observert ved mentale lidelser, er antatt å være nært forbundet med de patologiske tilstandene ved disse sykdommene (ikke-patentdokumenter 2-5).
Nylig er det blitt avslørt at nevroner blir dannet gjennom proliferasjon og differensiering av nerve-stamceller og nerve-progenitorceller som finnes i den voksne hjernen (ikke-patentdokument 6), og det er antydet en mulighet for at aktivering og differensiering av endogene nerve-stamceller og/eller nerveprogenitorceller vil rekonstruere nervevevet og funksjonen som er redusert ved forskjellige lidelser.
Videre, basert på det faktum at antidepressive medikamenter, antipsykotiske medikamenter og lignende faktisk oppviser en nevrogenese som fremkaller effekt, er det antydet at fokusering på den nevrogenese-fremkallende effekt vil føre til utvikling av mer effektive terapeutiske midler mot mentale lidelser (ikke-patentdokumenter 7 og 8).
Forbindelser som fremkaller proliferasjon og differensiering av nerve-stamcellene og/eller nerve-progenitorcellene, er ansett å være anvendelige som terapeutiske midler mot mentale lidelser på grunn av sin effekt på rekonstrueringen av nervevevet og -funksjonen, som er redusert ved forskjellige lidelser (patentdokument 2).
Hittil er alkyleterderivater blitt rapportert å ha effekt på nervebeskyttelse, nerve-regenerering og det å fremme nevritt-utvekst (patentdokument 1). Imidlertid har deres nevrogenese-fremkallende effekt ikke vært kjent i det hele tatt.
Patentdokument 1: WO 03/035647-pamflett,
patentdokument 2: US 6.294.346, beskrivelsen,
ikke-patentdokument 1: Michio Tohru, Yoshibumi Nakan, Minoru Komiyama, Yuuji Okazaki, Yoshirou Ohkubo, "ICD-10 Seishin oyobi koudou no syougai-Rinshou kijutu to sindan gaidorain-Shinteiban (ICD-10, mental og adferdsmessig lidelse - klinisk beskrivelse og retningslinjer for diagnose - en nylig revidert utgave)", Igaku-Shoin, Nov., 2005, s.23-49.
ikke-patentdokument 2: Br. J. Psychiatry., 1988, 172: s.527-532, ikke-patentdokument 3: Biol. Psychiatry., 1993, 33(4): s.236-246, ikke-patentdokument 4: Biol. Psychiatry., 1996, 40(11): s.1091-1099, ikke-patentdokument 5: Brain, 2002, 125: s.1428-1449,
ikke-patentdokument 6: Nat. Med., 1998, 11: s.1313-1317,
ikke-patentdokument 7: Science, 2003, 301: s.805-809,
ikke-patentdokument 8: J. Neurosci. Res., 2002, 69(1): s.72-79.
BESKRIVELSE AV OPPFINNELSEN.
Det er behov for en forbindelse som oppviser en nevrogenese som fremkaller effekt og som er anvendelig som et nevrogenese-fremkallende middel og et terapeutisk middel mot en mental lidelse.
Under slike omstendigheter har foreliggende oppfinnere funnet at forbindelsen 1-(3-(2-(1-benzotiofen-5-yl)etoksy)propyl)azetidin-3-ol, eller et salt derav for behandling eller forebygging av ryggmargskade eller for behandling eller forebygging av schizofreni og dens beslektede sykdommer, stemningsleielidelse og nevrotisk lidelse.
BESTE MÅTE Å UTFØRE OPPFINNELSEN PÅ.
Foreliggende oppfinnelse vil nå bli illustrert i detalj nedenfor.
Saltet av forbindelsen over omfatter et generelt kjent salt dannet ved en basisk gruppe, så som en aminogruppe, eller ved en sur gruppe, så som en hydroksyl- eller karboksylgruppe.
Salter dannet ved en basisk gruppe omfatter for eksempel salter med en mineralsyre, så som saltsyre, bromhydrogensyre, salpetersyre og svovelsyre; salter med en organisk karboksylsyre, så som maursyre, eddiksyre, sitronsyre, oksalsyre, fumarsyre, maleinsyre, ravsyre, eplesyre, vinsyre, asparaginsyre, trikloreddiksyre og trifluoreddiksyre; og salter med en sulfonsyre, så som metansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, mesitylenesulfonsyre og naftalensulfonsyre.
Salter dannet ved en sur gruppe omfatter for eksempel salter med et alkalimetall, så som natrium og kalium; salter med et jordalkalimetall, så som kalsium og magnesium; et ammonium-salt; og salter med en nitrogen-inneholdende organisk base, så som trimetylamin, trietylamin, tributylamin, pyridin, N,N-dimetylanilin, N-metylpiperidin, N-metylmorfolin, dietylamin, dicykloheksylamin, prokain, dibenzylamin, N-benzyl- β-fenetylamin, 1-efenamin og N,N'-dibenzyletylendiamin.
Blant ovennevnte salter innbefatter foretrukne salter farmakologisk akseptable salter.
Når en isomer, for eksempel en optisk isomer, en geometrisk isomer og en tautomer, eksisterer av forbindelsen over eller et salt derav, omfatter foreliggende oppfinnelse alle disse isomerene, og omfatter et hydrat, et solvat og alle krystallformer.
Det har vært kjent at et terapeutisk middel mot en mental lidelse kan være å finne basert på den nevrogenese-fremkallende effekt i dyrkede nerve-stamceller (patentdokument 2). For eksempel er valproinsyre anvendt som et terapeutisk middel for bipolar lidelse kjent for å vise den nevrogenese-fremkallende effekt i dyrkede nerve-stamceller (Proc. Natl. Acad. Sci. U.S.A., 2004, 101(47), s.16659-64).
Sykdommer hvor nevrogenese-fremkalling er effektivt for behandling eller forebygging, omfatter for eksempel mentale lidelser og ryggmargskade.
Foretrukne sykdommer omfatter mentale lidelser.
De mentale lidelsene i foreliggende oppfinnelse omfatter for eksempel schizofreni og dens beslektede sykdommer, så som schizofreni, lidelser av schizotype, schizoaffektiv lidelse og andre ikke-organiske psykotiske lidelser; stemningsleielidelser, så som manisk episode, bipolar affektiv lidelse (maniskdepressiv psykose), depressiv episode, tilbakevendende depressiv lidelse og vedvarende stemningsleielidelser; og nevrotiske lidelser, så som fobiske angstlidelser, obsessiv-kompulsiv lidelse og tilpasningslidelser, og fortrinnsvis schizofreni, bipolar affektiv lidelse (manisk-depressiv psykose), depressiv episode og tilbakevendende depressiv lidelse.
Foreliggende alkyleterderivat eller et salt derav, anvendt i foreliggende oppfinnelse, kan fremstilles ved allerede kjente metoder eller passende kombinasjoner av dem, eller ved metoden beskrevet i patentdokument 1.
Forbindelsen ifølge foreliggende oppfinnelse kan formuleres til farmasøytiske preparater, så som orale midler (tablett, kapsel, pulver, granuler, fint pulver, pille, suspensjon, emulsjon, løsning, sirup etc.) eller injeksjoner, ved å tilsette til dem forskjellige typer av farmasøytiske additiver, så som et tilsetningsmiddel, et bindemiddel, et desintegreringsmiddel, en desintegreringshemmer, et anti-kakedannelses/anti-klebemiddel, et glattemiddel, en absorpsjon/adsorpsjonsbærer, et løsningsmiddel, et ekstensjonsmiddel, et isotonisitetsmiddel, et solubiliseringsmiddel, et emulgeringsmiddel, et suspenderingsmiddel, et fortykningsmiddel, et belegningsmiddel, et absorbsjonsbevirkende middel (”absorbefacient”), en gelatinerings/agglutineringspromoter, et lett stabiliseringsmiddel, et konserveringsmiddel, et anti-fuktemiddel, et emulsjons/suspensjons/-dispersjonsstabiliserende middel, et fargeforhindrende middel (”coloration preventing agent”), et deoksiderings/antioksidantmiddel, forbedringsmidler (”correctives”), et fargemiddel, et ”whipping”-middel, et anti-skummemiddel, et lindrende middel, et antistatisk middel eller et buffer/pH-justerende middel.
Ovennevnte midler blir formulert på konvensjonell måte.
Orale faste preparater, så som en tablett, pulver eller granuler, kan fremstilles i henhold til vanlige metoder, ved anvendelse av følgende farmasøytiske additiver for slike faste preparater, for eksempel: tilsetningsmidler, så som laktose, sukrose, natriumklorid, glukose, stivelse, kalsiumkarbonat, kaolin, krystallinsk cellulose, vannfri dibasisk kalsiumfosfat, delvis pregelatinert stivelse, maisstivelse eller alginsyre; bindemidler, så som vanlig sirup, glukoseløsning, stivelsesløsning, gelatinløsning, polyvinylalkohol, polyvinyleter, polyvinylpyrrolidon, karboksymetylcellulose, skjellakk, metylcellulose, etylcellulose, natriumalginat, gummi arabicum, hydroksypropylmetylcellulose, hydroksypropylcellulose, vann eller etanol; desintegreringsmidler, så som tørr stivelse, alginsyre, agarpulvere, stivelse, kryssbundet polyvinylpyrrolidon, kryssbundet karboksymetylcellulose-natrium, karboksymetylcellulose-kalsium eller natriumstivelsesglykolat; desintegreringshemmende midler, så som stearylalkohol, stearinsyre, kakaosmør eller hydrogenert olje; anti-kakedannelses/anti-adhesjonsmidler, så som aluminiumsilikat, kalsiumhydrogenfosfat, magnesiumoksid, talk eller kiselsyreanhydrid; glattemidler, så som carnauba-voks, lett, vannfri kiselsyre, aluminiumsilikat, magnesiumsilikat, herdet olje, herdet vegetabilsk oljederivat, sesamolje, hvit bivoks, titanoksid, tørr aluminiumhydroksidgel, stearinsyre, kalsiumstearat, magnesiumstearat, talk, kalsiumhydrogenfosfat, natriumlaurylsulfat eller polyetylenglykol; absorpsjonspromotere, så som kvaternære ammoniumsalter, natriumlaurylsulfat, urinstoff eller enzym; og absorpsjons/-adsorpsjonsbærere, så som stivelse, laktose, kaolin, bentonitt, kiselsyreanhydrid, vandig silisiumdioksid, magnesium-aluminometasilikat eller kolloidal kiselsyre.
Videre, om nødvendig, kan en tablett bearbeides til en tablett belagt med et vanlig belegningsmiddel, så som en sukker-belagt tablett, en gelatin-belagt tablett, en gastrisk belagt tablett, en enterisk belagt tablett og en tablett belagt med vannoppløselig film.
En kapsel blir fremstilt ved å blande foreliggende forbindelse med de ovennevnte forskjellige typer av farmasøytiske midler, og å fylle den oppnådde blanding i en hard gelatinkapsel eller en myk kapsel.
Videre kan forbindelsen ifølge foreliggende oppfinnelse også formuleres til en vann- eller olje-type-suspensjon, løsning, sirup og eliksir, ved vanlige metoder, ved anvendelse av ovennevnte forskjellige typer av additiver for flytende prepara ter, så som et løsningsmiddel, ekstensjonsmiddel, isotonisitetsmiddel, solubiliseringsmiddel, emulgeringsmiddel, suspenderingsmiddel eller fortykningsmiddel.
En injeksjon kan fremstilles ved vanlige metoder, ved anvendelse av farmasøytiske additiver for flytende preparater, omfattende: fortynningsmidler, så som vann, etylalkohol, Macrogol, propylenglykol, sitronsyre, eddiksyre, fosforsyre, melkesyre, natriumlaktat, svovelsyre, natriumhydroksid; pH-justeringsmidler og buffere, så som natriumcitrat, natriumacetat eller natriumfosfat; stabiliseringsmidler, så som natriumpyrosulfitt, etylendiamintetraeddiksyre, tioglykolsyre eller tiomelkesyre; isotonisitetsmidler, så som natriumklorid, glukose, mannitol eller glycerin; solubiliseringsmidler, så som karboksymetylcellulose-natrium, propylenglykol, natriumbenzoat, benzylbenzoat, uretan, etanolamin eller glycerin; lindrende midler, så som kalsiumglukonat, klorbutanol, glukose eller benzylalkohol; og lokale anestetika.
En øyedråpe kan fremstilles i henhold til vanlige metoder, ved på passende måte å blande forbindelsen ifølge foreliggende oppfinnelse med konserveringsmidler, så som klorbutanol, natriumdehydroacetat, benzalkoniumklorid, cetylpyridiniumklorid, fenetylalkohol, metylparahydroksybenzoat eller benzetoniumklorid; buffere, så som borax, borsyre eller kaliumdihydrogenfosfat; fortykningsmidler, så som metylcellulose, hydroksyetylcellulose, karboksymetylcellulose, hydroksypropylmetylcellulose, polyvinylalkohol, karboksymetylcellulose-natrium eller kondroitinsulfat; solubiliseringsmidler, så som polysorbat 80 eller polyoksyetylen-herdet ricinusolje 60; stabiliseringsmidler, så som edetatnatrium eller natriumbisulfitt; eller isotonisitetsmidler, så som natriumklorid, kaliumklorid eller glycerin.
En metode for administrering av ovennevnte preparater er ikke spesielt begrenset. Den blir bestemt etter hva som passer, avhengig av formen av preparatet, alderen til pasienten, pasientens kjønn og graden av symptomene til pasienten, og andre betingelser.
Dosen av den aktive bestanddel i preparatet ifølge foreliggende oppfinnelse blir valgt etter hva som som passer, avhengig av praksis (”usage”), alderen til pasienten, pasientens kjønn, formen av sykdom og andre betingelser. Generelt kan foreliggende preparat administreres i en dose på mellom 1 og 1500 mg pr. voksen pr. dag, én gang eller fordelt på mange administreringer, og kan fortrinnsvis administreres i en dose på mellom 40 og 500 mg pr. voksen pr. dag, én gang eller fordelt på mange administreringer.
Eksempler.
Foreliggende oppfinnelse vil nå bli illustrert som et testeksempel og formuleringseksempler, som ikke på noen måte begrenser foreliggende oppfinnelse.
For å vise dens anvendelighet som et terapeutisk middel mot en mental lidelse, blir den nevrogenese-fremkallende effekt av forbindelsen ifølge foreliggende oppfinnelse vist i dyrkede nerve-stamceller.
Som testsubstans ble 1-(3-(2-(1-benzotiofen-5-yl)etoksy)propyl)azetidin-3-ol (nedenfor refererert til som T-817), maleat (nedenfor referert til som T-817MA) anvendt.
Test-eksempel: Effekt på differensiering av dyrkede nerve-stamceller.
Dyrkede nerve-stamceller ble fremstilt i henhold til den delvis modifiserte metode i Hirabayashi (Development, 2004, 131(12), s.2791-2801). Cerebrum ble fjernet fra et ICR-muse-embryo (embryonisk dag 14) og inkubert i kunstig cerebrospinalvæske (124 mM NaCl, 5 mM KCl, 1,3 mM MgCl2, 2 mM CaCl2, 26 mM NaHCO3, 10 mM D-glukose, pH 7,4) inneholdende 0,0625% trypsin og 0,1 mg/ml DNaseI ved 37 ºC i 5 min. En trypsinhemmer (endelig konsentrasjon: 0,35 mg/ml) ble deretter tilsatt, og blandingen ble sentrifugert ved 800 rpm i 5 min. Den oppnådde pellet ble dispergert ved pipettering i et nerve-stamcelle-dyrkningsmedium (DMEM/F-12-dyrkningsmedium inneholdende 20 ng/ml basisk fibroblast-vekstfaktor, 20 ng/ml epidermal vekstfaktor og B27-supplement (Invitrogen)) for å oppnå enkeltcellesuspensjon. Den oppnådde cellesuspensjonen ble fortynnet til 1 x 10<5>celler/ml i 10 ml av nerve-stamcelle-dyrkningsmediet og dyrket i 7 dager (ved anvendelse av en 10-cm skål). På dag 7 av dyrkningen ble de dannede nevrokulene (”neuro spheres”) fordøyet med trypsin og dispergert ved pipettering som beskrevet ovenfor, for å oppnå enkeltcellesuspensjon. De oppnådde, isolerte cellene ble dyrket i ytterligere 7 dager i nerve-stamcelle-dyrkningsmediet.
Etter 7 dagers dyrkning ble de dannede nevrokulene fordøyet med trypsin og dispergert ved pipettering som beskrevet ovenfor, for å oppnå enkeltcellesuspensjon. Cellesuspensjonen ble fortynnet til 2 x 10<5>celler/ml i et dyrkningsmedium (B27-supplert DMEM/F-12-dyrkningsmedium), og deretter ble den alikvotert med 100 μl/brønn til hver brønn av en T-817MA-behandlet gruppe og en kontrollgruppe. Til brønnen med den T-817MA-behandlede gruppen var 100 μl T-817MA-løsning blitt tilsatt (T-817MA ble oppløst i B27-supplemert DMEM/F-12-dyrkningsmedium til en endelig konsentrasjon på 10 μM). Til brønnen med kontrollgruppen var 100 μl av det B27-supplerte DMEM/F-12-dyrkningsmediet blitt tilsatt. Som dyrkningsplate ble en 0,5% polyetylenimin-belagt, 48-brønners plate anvendt.
Både den T-817MA-behandlede gruppen og kontrollgruppen ble dyrket i 3 dager.
Etter 3 dagers dyrkning ble cellene vasket med fosfat-bufret saltløsning (PBS), fiksert med 4% paraformaldehyd/fosfatbuffer, behandlet med 0,3% Triton X-100/PBS-løsning ved romtemperatur i 5 minutter, vasket med PBS og inkubert med 0,5% skummetmelk ved romtemperatur i 1 time. Et muse-Tuj1-antistoff (COVANCE), som var blitt fortynnet 500 ganger med 0,5% skummetmelk, ble tilsatt, og blandingen fikk stå ved 4 ºC natten over og deretter vasket med PBS. Videre ble et Alexa Fluor 546-merket anti-muse-IgG (Molecular Probes), som var blitt fortynnet 1000 ganger med PBS, tilsatt til cellene, og blandingen fikk stå ved romtemperatur i 1 time. Cellene ble vasket med PBS og observert under fluorescens-mikroskop og antallet Tuj1-positive celler som emitterer rød fluorescens tellet, og dets forhold til det totale celle-tall ble beregnet som differensieringsforholdet til nevroner som representerer en nevrogenese-fremkallende effekt. Resultatene er vist i tabell 1.
Tabell 1
Sammenlignet med nerve-stamcellene dyrket i de B27-supplerte DMEM/F-12-dyrkningsmediene alene (kontrollgruppe), viste cellene dyrket i mediet inneholdende T-817MA (10 μM) høyere differensieringsforhold, dvs. en nevrogenesefremkallende effekt av T-817MA.
Formuleringseksempel 1.
En blanding av 50 mg T-817MA, 20 mg laktose, 25 mg maisstivelse og 40 mg Avicel PH101 (Asahi Kasei Corporation) ble eltet med 5% polyvinylpyrrolidon K30 vandig løsning, tørket ved 60 ºC, blandet med en blanding av 10 mg Kollidon CL (BASF), 10 mg Avicel PH302 (Asahi Kasei Corporation), 18 mg lett, vannfri kiselsyre og 2 mg magnesiumstearat, sammenpresset, hvilket gir en rund tablett med diameter 7 mm og vekt 75 mg, inneholdende 50 mg T-817MA.
Formuleringseksempel 2.
En blanding av 50 mg T-817MA, 20 mg laktose og 53 mg maisstivelse ble eltet med 5% polyvinylpyrrolidon K30 vandig løsning, tørket ved 60 ºC, blandet med en blanding av 7 mg Kollidon CL (BASF), 18 mg Avicel PH302 (Asahi Kasei Corporation) og 2 mg magnesiumstearat, deretter ble 150 mg av dette pr. kapsel fylt i en nr.4 gelatinkapsel for å danne en kapsel.
INDUSTRIELL ANVENDELIGHET.
Alkyleterderivatet, eller saltet derav, ifølge foreliggende oppfinnelse, viser en nevrogenese-fremkallende effekt og er anvendelig som et nevrogenese-fremkallende middel og et terapeutisk middel mot en mental lidelse.
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ATE491705T1 (de) * | 2006-08-04 | 2011-01-15 | Toyama Chemical Co Ltd | Verstärker der aktivität von proteinkinase c, enthaltend ein alkyletherderivat oder ein salz davon |
CN102046620B (zh) * | 2008-05-28 | 2014-04-09 | 富山化学工业株式会社 | 新的苯并噻吩氧化物衍生物及其盐 |
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US10238632B2 (en) | 2015-06-11 | 2019-03-26 | Fujifilm Toyama Chemical Co., Ltd. | Sigma receptor-binding agent |
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