NO163857B - Analogifremgangsmaate for fremstilling av terapeutisk aktive tiazolidindionforbindelser. - Google Patents

Analogifremgangsmaate for fremstilling av terapeutisk aktive tiazolidindionforbindelser. Download PDF

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NO163857B
NO163857B NO86860141A NO860141A NO163857B NO 163857 B NO163857 B NO 163857B NO 86860141 A NO86860141 A NO 86860141A NO 860141 A NO860141 A NO 860141A NO 163857 B NO163857 B NO 163857B
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pyridyl
ethoxy
ethyl
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Kanji Meguro
Takeshi Fujita
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Tiazolidindionderivater med formel. eller farmakologisk akseptable salter derav, er nye forbindelser som utviser en blod-sukker- og lipid-senkende aktivitet hos pattedyr, og er verdifulle som terapeutiske midler for diabetes og som terapeutisk middel for hyperlipemia.

Description

Foreliggende oppfinnelse vedrører fremstilling av nye, terapeutisk aktive tiazolidindionforbindelser.
En rekke forskjellige biguanid- og sulfonylureaderivater
har blitt benyttet klinisk som antidiabetiske midler.
Biguanidene blir imidlertid nå nesten ikke brukt fordi de har tendens til å bevirke laktisk acidose, og bruken av sulfo-nylureaderivatene krever, selv om de har sterke hypoglycemiske aktiviteter, tilstrekkelig forsiktighet fordi de forårsaker ofte alvorlig hypoglycemi. En ny type antidiabetiske midler som ikke er forbundet med disse ulemper har derfor vært ønsket.
I japanske (ikke undersøkte) patentpublikasjoner nr. 22 636/ 1980 og 64 586/1980, Chemical and Pharmaceutical Bulletin, 30, side 3563, (1982), ibid 30, side 3580 (1982) og ibid 32, side 2267 (1984), vises det til en rekke forskjellige tiazolidin-dioner som har blodglukose- og lipidsenkende virkning. Antidiabetisk aktivitet for ciglitazon ble også rapportert i Diabetes, 32, side 804 (1983). Disse forbindelser har imidlertid enda ikke blitt benyttet i praksis. Som grunn kan 1) util-strekkelig aktivitet eller/og 2) alvorlig toksisitet, nevnes.
Man syntetiserte forskjellige forbindelser som ikke er konkret beskrevet i overnevnte publikasjoner og foretok studier med disse, og fant at forbindelser viste sterke farmakologiske effekter med lavere toksisitet.
Foreliggende oppfinnelse tilveiebringer forbindelsen som kan anvendes i praksis som antidiabetiske midler med god sikker-hetsmargin mellom farmakologisk effekt og toksisitet, eller ugunstige sidereaksjoner.
De ovennevnte nye, terapeutisk aktive tiazolidindionforbin-delsene har formelen:
eller et farmakologisk salt derav.
Ifølge oppfinnelsen fremstilles disse forbindelsene ved at man hydrolyserer en forbindelse med formelen:
eller et farmakologisk akseptabelt salt derav og, om nødvendig, omdannes et hydrolyseprodukt til et farmasøytisk akseptabelt salt derav.
Forbindelsene som kan representeres med den ovenfor angitte formel (I), innbefatter spesielt følgende forbindelser: 5-/~4-/~2-(3~etyl-2-pyridyl)etoksx/benzyl7-2,4-tiazolidin-dion ,
5- <l> 4-/~2-H-etyl-2-pyridyl)etoksy7benzyl7~2,4-tiazolidin-dion ,
5-/~4-/~2-(5-etyl-2-pyridyl)etoksY/benzyl/-2, 4-tiazolidin-dion>,
5~Z 4~Z 2-(6-etyl-2-pyridyl)etoksY7benzyl7-2,4-tiazolidin-dion .
Forbindelsen (I) inneholder både basisk nitrogen og surt nitrogen i sitt molekyl, og det kan omdannes til et farmakologisk akseptabelt salt, når dette er ønskelig, ved an-
vendelse av egnet syre eller base.
Slike syresalter er eksemplifisert av mineralsalter (f. eks. hydroklorid, hydrobromid, sulfat, osv), organiske syresalter (f. eks. succinat, maleat, fumarat, malat, tartrat, osv.) og sulfonater (f. eks. metansulfonat, benzensulfonat, toluen-sulfonat, osv.). Slike basiske salter er eksemplifisert av alkalimetallsalter, f.eks. natriumsalt, kaliumsalt, jordalkali-metallsalter, f.eks. kalsiumsalt, osv. Alle disse saltene kan fremstilles på i og for seg kjent måte.
Forbindelsen (I) eller et farmakologisk akseptabelt
salt derav viser blodglukose- og blodlipid-senkende virkning med lavere toksisitet, og kan benyttes som sådant eller i blanding med en i og for seg kjent farmakologisk akseptabel bærer, hjelpemiddel eller fyllstoff som et antidiabetisk middel for pattedyr inkludert mennesket.
Det antidiabetiske middel benyttes vanligvis administrert oralt som tabletter, kapsler (inkludert myke kapsler og mikrokapsler), pulvere, granulater, osv., og avhengig av tilstander, parenteralt som injeksjoner, suppositorier, pellets, osv. Oral administrasjon til en voksen pasient er helst 0,05-10 mg/kg legemsvekt/dag, og parenteralt 0,01-10 mg/kg legemsvekt/dag,
en gang daglig, eller delt i 2-4 ganger pr. uke.
Forbindelsene representerer i den ovenfor angitte generelle formel (I) og farmakologisk akseptable salter derav, (i det følgende kollektivt betegnet som "forbindelse (I)", kan fremstilles ved å utsette en forbindelse representert ved den generelle formel (II) for hydrolyse. Denne reaksjon forløper fordelaktig i et riktig oppløsningsmiddel ved anvendelse av en mineralsyre. Oppløsningsmidlet eksemplifiseres av alkoholer (f. eks. metanol, etanol, propanol, butanol, isobutanol, 2-metoksyetanol, osv), dimetylsulfoksyd, sulfolat, dioksan, tetrahydrofuran, dimetoksyetan, osv., og mineralsyrer er eksemplifisert av saltsyre, hydrobromsyre, svovelsyre, osv. Reaksjonstemperaturen varierer fra 20 til 150°C. Reaksjons-tiden er 0,5-2 0 timer.
Forbindelsene med formel (I) eller et farmakologisk akseptabelt salt derav, fremstilt som angitt ovenfor, kan isoleres og renses på konvensjonell måte slik som konsentrasjon, ekstraksjon, omkrystallisering, kromatografi, osv.
Forbindelsen representert ved den ovenfor angitte generelle formel (II), kan fremstilles ved følgende reaksjoner:
(hvor R betyr hydrogen eller laverealkyl).
Den laverealkylgruppen representert ved R, eksemplifiseres
av (C1~C4)-grupper slik som metyl, etyl, propyl, isopropyl og butyl.
Reaksjonen for fremstilling av forbindelse (V) fra forbindelse (III) og forbindelse (IV) utføres i nærvær av f. eks. natriumhydrid. Denne reaksjon kan utføres i et oppløsningsmiddel,
f. eks. dimetylformamid, og tetrahydrofuran ved en temperatur varierende fra -10 til 3 0°C. Reaksjonen fra forbindelse (V) til forbindelse (VI) kan lett utføres ved konvensjonell katalytisk reduksjon under anvendelse f. eks. av palladium-karbon, som katalysator. Forbindelse (VI) kan isoleres som det rene produktet, eller kan underkastes det etterfølgende reaksjonstrihn uten isolering og rensning. Forbindelse (VIII) kan fremstilles ved å underkaste forbindelsen (VI), for dia-zotering i nærvær av en vandig oppløsning av hydrobromsyre, hvoretter den resulterende forbindelse får reagere med akryl-syre, eller dens laverealkylrester (VII) i nærvær av en kobberkatalysator, f .eks. kuprooksyd, kuprioksyd, kupro-klorid, kupriklorid, kuprobromid, kupribromid, osv. (Meer-wein-arylering). Forbindelse (VIII) kan renses f. eks. ved kromatografi og underkastes den etterfølgende reaksjon uten isolering eller rensning.
Forbindelse (VIII) får deretter reagere med tiourea for oppnåelse av forbindelse (II) . Denne reaksjon utføres vanligvis 1 alkoholer (f. eks. metanol, etanol, propanol, butanol, isobutanol, 2-metoksyetanol, osv.), dimetylsulfoksyd, sulfolan, osv. Reaksjonstemperaturen er vanligvis 20 - 180°C, for-trinnsvis 60 - 150°C. Mengden av tiourea som anvendes er 1-
2 mol i forhold til 1 mol av forbindelse (VIII).
I denne reaksjonen blir, etter hvert som reaksjonen forløper, hydrogenbromid dannet som biprodukt, og for å ta vare på dette biproduktet kan reaksjonen utføres i nærvær av natriumacetat, kaliumacetat, osv., i en mengde på vanligvis 1-1,5 mol i forhold til 1 mol av forbindelse (VIII). Den reduserende forbindelse (II) fi.;.: isoleres, men kan føres til hydrolysetrinnet direkte uten isolering; forbindelse (I) har en utmerket blodglukose- og -lipid-senkende aktivitet, og har en bemerkelsesverdig lav toksisitet, hvilket understøttes av følgende forsøksdata.
Forsøksdata
1. Blodglukose- og - lipid- senkende aktivitet hos mus.
Til KKA Y-hann-mus. (8-10 dager gamle, 5 mus/gruppe), ble testforbindelsene (ved tre doseringsnivåer) gitt som en dietisk tilblanding i CE-2-pulverdiett (CLEA Japan) med fri adgang til vann i 4 dager.
Blodprøver ble tatt fra orbitalvenen den 5. dagen.
Blodglukose- og -plasmatriglycerid (TG) ble bestemt ved en glukose-oksidase-metode og ved anvendelse av et kommersielt tilgjendelig analyseutstyr, Cleantech TG-S (Iatron, Japan) resp. Basert på dose-respons-kurver for blodglukose- og -plasma-TG-senkende aktivitet, ble effektiv dose av hver testforbindelse for 2'5 % senkning fra kontrollverdien, beregnet som verdien for ED^ (mg/kg/dag) .
Resultatene er vist i tabell 1.
2. Lipid- senkende aktivitet i rotter.
Sprague-Dawley-hann-rotter (7 uker gamle, 5 rotter/gruppe)
ble gitt laboratorieforet (CE-2, Clea, Japan) med fri adgang til vann. Alle testforbindelsene (ved 3 doseringsnivåer) suspendert i 5 % gummi arabicum-oppløsning, ble tvangsforet til dyrene oralt i 4 dager. Blodprøver ble tatt fra nåle-venen den 5. dagen. Plasma-TG ble bestemt ved anvendelse av et kommersielt tilgjengelig analyseutstyr, Cleantech-TG-S
(Iatron). Basert på dose-respons-kurver for lipid-senkende aktivitet, ble effektiv dose for hver testforbindelse i 25
% senkning fra kontrollverdien, beregnet som verdien for ED2j. (mg/kg/dag) . Resultatene er vist i tabell 1.
3. To- ukers toksisitetsstudium i rotter.
Sprague-Dawley hann- og hunn-rotter (5 uker gamle, 5 rotter/ gruppe) ble gitt laboratorieforet (CE-2, Clea, Japan), med fri adgang til vann. Alle testforbindelsene suspendert i 5 % gummi arabicum-oppløsning ble tvangsforet oralt til dyrene i 2 uker 1 gang daglig. Dosen var 100 mg/kg/dag for hver testforbindelse. Dyrene ble avlivet ved ca. 2 0 timers faste etter avslutning av nevnte 2-ukers administrasjon ved fjerning av blodprøver fra bukaorta ved bruk av hepariniserte sprøyter under eterbedøvelse. Lever og hjerte ble fjernet og veid. Hematologianalyse ble også utført ved bruk av en automatisk celleteller. Dataene representerer % økning eller sekning i forhold til kontrollverdien (ikke-legemiddelbehand-let) som vist i tabell 1.
I tabell 1, er forbindelse (I) en forbindelse som omfattes
av foreliggende oppfinnelse, forbindelser (a) og (b) er kjente forbindelser som konkret angis i japansk (ikke under-søkt) patentpublikasjon nr. 22 636/1980.
Mens forbindelser (c) og (d) og (e) ikke er konkret referert til i ovennevnte patentpublikasjon, er de angitt av sammenlig-ningsgrunner fordi de er lik forbindelser (I) i foreliggende oppfinnelse i sine kjemiske strukturer. Det fremgår fra for-søksresultatene gitt i tabell 1, er forbindelse (I) overlegen i forhold til forbindelsene (a), (c), (d) og (e), og sammen-lignbar med forbindelse (b) med hensyn til hypoglycemiske og hypolipidemiske aktiviteter, mens den viser meget lav toksisitet sammenlignet med forbindelsene (a), (b), (d) og (e).
En slik effekt som den ovenfor angitte forårsakes av inn-føring av en etylgruppe, er ganske uventet. Forbindelsen (I) viser således utmerket hypoglycemisk og hypolipidemisk aktivitet og liten toksisitet overfor indre organer og blod, selv ved kontinuerlig administrasjon over et langt tidsrom. Derfor er forbindelse (I) verdifull som et terapeutisk middel for type II diabetes ledsaget av følgende eller hyperlipide-mia i pattedyr inkludert mennesket.
Eksempel 1
a) Til en oppløsning av 2-(5-etyl-2-pyridyl)etanol (53,0 g) og 4-fluornitrobenzen (47,0 g) i DMF (500 ml) ble det tilsatt porsjonsvis under isavkjøling 60 % natriumhydrid i olje (16,0 g). Blandingen ble omrøring under isavkjøling i 1 time, deretter ved romtemperatur i 3 0 minutter, helt i vann og ekstrahert med eter. Eterlaget ble vasket med vann og tørket. (MgSO^). Oppløsningsmidlet ble inndampet for oppnåelse av 4-/2-(5-etyl-2-pyridyl)etoksy/nitrobenzen samt krystaller (62,0 g, 62,9 %). Omkrystallisering fra eter-heksan ga farve-løse prismer, sm.p. 53-54°C. b) En oppløsning av 4-/ 2-(5-et<y>l-2-p<y>rid<y>l)etoksy/-nitro-benzen (60,0 g) i metanol (500 ml) ble hydrogenert ved romtemperatur under en atmosfære trykk i nærvær av 10 % Pd-C (50 % fuktig, 6,0 g). Katalysatoren ble fjernet ved filtrering, og filtratet konsentrert under redusert trykk. Den resterende oljen ble oppløst i aceton (300 ml)-metanol (200 ml). Til oppløsningen ble det satt en 47 % HBr vandig oppløsning (152 g). Blandingen ble avkjølt og det ble tilsatt dråpe-vis en oppløsning av NaNO^ (17,3 g) i vann (30 ml) ved en temperatur ikke høyere enn 5°C. Hele blandingen ble omrørt ved 5°C i 20 minutter, deretter ble metylakrylat (112 g) tilsatt og temperaturen ble hevet til 38°C. Cupro-oksyd (2,0 g) ble tilsatt til blandingen i små porsjoner under kraftig om-røring. Reaksjonsblandingen ble omrørt inntil nitrogenut-vikling opphørte, og konsentrasjonen ble foretatt under redusert trykk. Konsentratet ble gjort alkalisk med konsentert vandig ammoniakk, og ekstrahert med etylacetat. Etylacetatlaget ble vasket med vann og tørket (MgSO^). Oppløsnings-midlet ble avdampet, og dette ga metyl-2-brom-3- £4-/ 2-(5-etyl-2-pyridyl)etoksy/f enylj propionat som en uren olje (74,09 g) , 85,7 %). IR(neat)cm"-L: 1735. NM R 6 (ppm) i CDC13: 1,21 (3H,t,J=7), 2,60(2H,q,J=7), 3,0 - 3,6(4H,m), 3,66(3H,s),
4,30(2H,t,J=7), 4,3(lH,m), 6,7 - 7,5(6H,m), 8,35(1H,d,J=2).
c) En blanding av den urene oljen av metyl-2-brom-3- [ 4-/ 2-(5-etyl-2-pyridyl)etoksy/fenyl } propionat (73,0 g) opp-nådd i b), tiourea (14,2 g) natriumacetat (5,3 g) og etanol (500 ml) ble omrørt i 3 timer under tilbakeløp. Reaksjonsblandingen ble konsentrert under redusert trykk og konsentratet ble nøytralisert med en mettet vandig oppløsning av natriumhydrogenkarbonat til hvilken det ble tilsatt vann (200
ml) og eter (100 ml). Hele blandingen ble omrørt i 10 minutter, og dette ga 5-(4-/~2-(5-etyl-2-pyridyl)etoksy/fenyl} -2-imino-4-tiazolidinon som krystaller (0,3 g, 523,0 %). Omkrystallisering fra metanol ga fargeløse prismer, sm.p. 187-188°C (de.komp.)
Elementanalyse for cigH21N3^2<S>
Beregnet: C. 64.20; H. 5.95; N. 11,82
Funnet : C. 64,20; H. 5,84; N. 11,73
v
d) En oppløsning av 5-[4-/~2-(5-etyl-2-pyridyl)-etoksy/ benzyl] -2-imino-4-tiazolidinon (23,5 g) i 2N HC1 (200 ml)
ble tilbakeløpskokt i 6 timer. Oppløsningsmidlet ble avdampet under redusert trykk og resten ble nøytralisert med en mettet vandig oppløsning av natriumhydrogenkarbonat. Krystallene (23,5 g, 97,5 %) som ble utfelt, ble oppsamlet ved filtrering og omkrystallisering fra DMF-f^O for oppnåelse av 5-[4-/ 2-(5-etyl-2-pyridyl)etoksy/benzyl]-2,4-tiazolidin-dion som farveløse nåler (20,5 g, 86,9 %), sm.p. 183-184°C.
Elementanalyse for C, r.H„nN_0_.S
X y Z U Z J
Beregnet: C. 64,02; H. 5,66; N. 7,86
Funnet : C. 63,70; H. 5,88; N. 8,01
e) Til en suspensjon av 5-^4-/ 2-(5-etyl-2-pyridyl)etoksy/ benzyl} -2,4-tiazolidindion (356 mg) i metanol (10 ml) ble
det tilsatt 28 % natriummetylat/metanol-oppløsning (0,2 g)
for oppnåelse av en oppløsning. Denne oppløsning ble konsentrert og fortynnet med etyleter for oppnåelse av krystaller. Krystallene ble oppsamlet ved filtrering og omkrystallisert ved metanol-etanol for dannelse av natriumsaltet av 5-^,4-/2-(5-etyl-2-pyridyl)etoksy/benz<y>l ] -2,4-tiazolidindion som farve-løse krystaller (298 mg, 78,8 %), sm.p. 262-263°C (dekomp.)
Elementanalyse for C^g<H>^<glS>^<O>^<S>Na:
Referanseeksempel 1
Forbindelsene angitt i tabell 2 ble fremstilt i overensstemmelse med eksempel l-a).
Referanseeksempel 2
i overensstemmelse med eksempel 1-b), ble følgende forbindelse fremstilt: Metyl-2-brom-3-1 4-/ 2-(3-metyl-2-pyridyl)etoksy/fenyl) propionat, IR(neat)cm"<1>: 1735. NMR S(ppm) i CDC13: 2,34(3H,s), 3,.10(lH,dd, J=14 og 7), 3,25(2H,t,J=6),3,38(1H.dd, J=14 og 7), 3,67(3H,s), 4,29(lH,t,J=7), 4,37(2H,t,J=6), 6,8-7,5 (6H,m), 8,35(lH,dd, J=5 og 2).
2-brom-3-\4-/ 2-(4-metyl-2-pyridyl/etoksy/fenyl} propion-syremetylester; IR(neat)cm-<1>: 1735.
NMR 6 (ppm) i CDC13: 2,30(3H,s), 3,10(1H,dd,J=14 og 7), 3,26(3H,t,J=7), 3,37(lH,dd, J=14 og 7), 3,67(3H,s), 4,30(3H,t,J=7), 6,7-7,36(6H,m), 8,37(1H,d,J=6).
Referanseeksempel 3
En oppløsning av 2-(5-metyl-2-pyridyl)etoksy/-nitro-benzen (15,0 g) i metanol (150 ml) ble underkastet analytisk reduksjon under et trykk på 1 atmosfære i nærvær av 10 %
Pd-C (50 % fuktig, 2,0 g). Katalysatoren ble frafiltrert og filtratet ble konsentrert for oppnåelse av 4-/~2-(5-metyl-2-pyridyl)etoksy/anilin som krystaller (12,3 g, 92,5 %). Omkrystallisering fra etylacetat-heksan ga farveløse prismer, sm.p. 74-75°C.
Elementanalyse for C^H-^^O:
Referanseeksempel 4
Til en blanding av 4-/ 2-(5-metyl-2-pyridyl)etoksy/anilin
(12,0 g), 47 % vandig HBr-oppløsning (36,5 g) og metanol (40 ml)-aceton (80 ml), ble det dråpvis tilsatt en oppløs-
ning av NaN02 (4,0 g) i vann (10 ml) ved 5°C eller under dette. Hele blandingen ble omrørt ved 5°C i 20 minutter, deretter
ble metylakrylat (27,0 g) tilsatt, og temperaturen ble hevet til 38°C. Cupro-oksyd (1,0 g) ble tilsatt til blandingen i'små porsjoner under kraftig omrøring. Etter at nitrogen-gassutvikling hadde opphørt ble reaksjonsblandingen konsentert under redusert trykk. Konsentratet ble gjort alkalisk med konsentrert vandig ammoniakk og ekstrahert med etylacetat.
Etylacetatlaget ble vasket med vann, tørket (MgSO^). Opp-løsningsmidlet ble avdampet, og dette ga metyl-2-brom-3-(4-/ 2-(5-metyl-2-pyridyl)etoksy/fenyl } -propionat som en uren olje (17,5 g, 87,5 %). IR(neat)cm"<1>: 1735. NMR S (ppm)
i CDC13: 2,27(3H,s), 3,10(1H,dd,J=14 og 7), 3,22(2H, t,
J=6), 3,38(lH,dd,J=14 og 7), 3,66(3H,s), 4,29(2H,t,
J=6), 4,32(lH,t,J=7), 6,7-7,5(6H,m), 8,34(lH,d,J=2).
Referanseeksempel 5
Forbindelsene angitt i tabell 3 ble fremstilt i overensstemmelse med eksempel 1-c).
Referanseeksempel 6
Forbindelsene angitt i tabell 4 ble fremstilt i overensstemmelse med eksempel 1-d).
R ef eranseeksempel 7
En blanding av 2-imino-5-^4-/ 2-(5-metyl-2-pyridyl)-etoksy? benzyl} -4-tiazolidinon (8,0 g), 2N HC1 (80 ml) og etanol (80 ml) ble tilbakeløpskokt i 16 timer. Reaksjonsoppløsning-en ble nøytralisert med en mettet vandig oppløsning av natriumhydrogenkarbonat for oppnåelse av krystaller. Krystallene ble oppsamlet ved filtrering og omkrystallisert fra etanol for dannelse av 5-[4-/ 2-(5-metyl-2-pyridyl)etoksy7benzylj - 2,4-tiazolidindion som farveløse prismer. (7,0 g, 87,5 %), sm.p. 192-193°C
Elementanalyse for C^gH^g^O^:

Claims (1)

  1. Analogifremgangsmåte for fremstilling av terapeutisk aktive tiazolidindionforbindelser med formelen:
    i eller et farmakologisk akseptabelt salt derav, karakterisert ved at man hydrolyserer en forbindelse med formelen:
    eller et farmakologisk akseptabelt derav og, om nødvendig, omdanner et hydrolyseprodukt til et farmasøytisk akseptabelt salt derav.
NO86860141A 1985-01-19 1986-01-16 Analogifremgangsmaate for fremstilling av terapeutisk aktive tiazolidindionforbindelser. NO163857C (no)

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Families Citing this family (273)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES533668A0 (es) * 1983-06-24 1985-10-01 Yamanouchi Pharma Co Ltd Un compuesto fenoxi
CN1003445B (zh) * 1984-10-03 1989-03-01 武田药品工业株式会社 噻唑烷二酮衍生物，其制备方法和用途
US4812570A (en) * 1986-07-24 1989-03-14 Takeda Chemical Industries, Ltd. Method for producing thiazolidinedione derivatives
FI91869C (fi) * 1987-03-18 1994-08-25 Tanabe Seiyaku Co Menetelmä antidiabeettisena aineena käytettävien bensoksatsolijohdannaisten valmistamiseksi
HU203330B (en) * 1987-06-10 1991-07-29 Pfizer Process for producing oxazolidin-2-one derivatives and hypoglychemic pharmaceutical compositions containing them
GB8713861D0 (en) * 1987-06-13 1987-07-15 Beecham Group Plc Compounds
EP0295828A1 (en) * 1987-06-13 1988-12-21 Beecham Group Plc Novel compounds
US4798835A (en) * 1987-12-02 1989-01-17 Pfizer Inc. dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione as an anti-atherosclerosis agent
US4791125A (en) * 1987-12-02 1988-12-13 Pfizer Inc. Thiazolidinediones as hypoglycemic and anti-atherosclerosis agents
GB8820389D0 (en) * 1988-08-26 1988-09-28 Beecham Group Plc Novel compounds
GB8919417D0 (en) 1989-08-25 1989-10-11 Beecham Group Plc Novel compounds
US4997948A (en) * 1989-10-27 1991-03-05 American Home Products 5-[(1- and 2-naphthalenyl) sulfonyl]-2,4-thiazolidinediones and derivatives thereof
WO1991012003A1 (en) * 1990-02-09 1991-08-22 The Upjohn Company Use of insulin sensitizing agents to treat hypertension
US5356913A (en) * 1990-02-09 1994-10-18 The Upjohn Company Use of insulin sensitizing agents to treat hypertension
EP0454501B1 (en) * 1990-04-27 2001-09-05 Sankyo Company Limited Benzylidenethiazolidine derivatives, their preparation and their use for the inhibition of lipid peroxides
GB9023584D0 (en) * 1990-10-30 1990-12-12 Beecham Group Plc Novel compounds
US5158966A (en) * 1991-02-22 1992-10-27 The University Of Colorado Foundation, Inc. Method of treating type i diabetes
ES2161692T3 (es) * 1991-04-11 2001-12-16 Upjohn Co Derivados de tiazolidindiona, produccion y uso de los mismos.
US5183823A (en) * 1991-04-11 1993-02-02 Takeda Chemical Industries, Ltd. Pyridine n-oxide compounds which are useful as hypoglycemic and hypolipidemic agents
US5441971A (en) * 1991-04-11 1995-08-15 The Upjohn Company Thiazolidinedione derivatives, production and use thereof
FR2680512B1 (fr) * 1991-08-20 1995-01-20 Adir Nouveaux derives de 2,4-thiazolidinedione, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
GB9124513D0 (en) * 1991-11-19 1992-01-08 Smithkline Beecham Plc Novel process
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives
GB9218830D0 (en) * 1992-09-05 1992-10-21 Smithkline Beecham Plc Novel compounds
ZA936492B (en) * 1992-09-10 1995-03-02 Lilly Co Eli Compounds useful as hypoglycemic agents and for treating Alzheimer's disease.
US5594016A (en) * 1992-12-28 1997-01-14 Mitsubishi Chemical Corporation Naphthalene derivatives
JP2845743B2 (ja) * 1992-12-28 1999-01-13 三菱化学株式会社 新規なナフタレン誘導体
USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
HU228260B1 (en) * 1993-09-15 2013-02-28 Daiichi Sankyo Company Pharmaceutical compositions to treat impaired glucose tolerance
US6046222A (en) * 1993-09-15 2000-04-04 Warner-Lambert Company Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus
US5874454A (en) * 1993-09-15 1999-02-23 Warner-Lambert Company Use of thiazolidinedione derivatives in the treatment of polycystic ovary syndrome, gestational diabetes and disease states at risk for progressing to noninsulin-dependent diabetes mellitus
US5478852C1 (en) * 1993-09-15 2001-03-13 Sankyo Co Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of noninsulin-dependent diabetes mellitus
EP0749430B1 (en) * 1994-03-08 1999-08-25 American Home Products Corporation Thiazolidinedione derivatives as anti-hyperglycemic agents
US6251928B1 (en) 1994-03-16 2001-06-26 Eli Lilly And Company Treatment of alzheimer's disease employing inhibitors of cathepsin D
EP0787725B1 (en) * 1994-10-20 2003-04-23 Nippon Chemiphar Co., Ltd. Quinoline derivative
US5708012A (en) * 1995-04-28 1998-01-13 Sankyo Company, Limited Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of insulin resistant subjects with normal glucose tolerance in order to prevent or delay the onset of noninsulin-dependent mellitus
AU5121796A (en) * 1995-05-08 1996-11-29 Nippon Chemiphar Co. Ltd. 2,4-thiazolidinedione or oxazolidinedione derivatives and hy poglycemic agent
TW438587B (en) * 1995-06-20 2001-06-07 Takeda Chemical Industries Ltd A pharmaceutical composition for prophylaxis and treatment of diabetes
US5798375A (en) * 1995-07-03 1998-08-25 Sankyo Company, Limited Treatment of arteriosclerosis and xanthoma
EP0783888A1 (en) 1995-12-26 1997-07-16 Sankyo Company Limited Use of troglitazone and related thiazolidinediones in the manufacture of a medicament for the treatment and prophylaxis of osteoporosis
IL120443A (en) * 1996-03-18 2000-07-16 Sankyo Co Use of an insulin sensitizer for the manufacture of a medicament for the treatment or prophylaxis of pancreatitis
AU2381397A (en) * 1996-04-19 1997-11-12 Novo Nordisk A/S Modulators of molecules with phosphotyrosine recognition units
US5958957A (en) * 1996-04-19 1999-09-28 Novo Nordisk A/S Modulators of molecules with phosphotyrosine recognition units
CA2257284C (en) * 1996-05-31 2005-10-04 Sankyo Company Limited Remedy for autoimmune diseases
US5952509A (en) * 1996-06-27 1999-09-14 Takeda Chemical Industries, Ltd. Production of benzaldehyde compounds
DE69738809D1 (de) * 1996-11-08 2008-08-14 Nippon Chemiphar Co Mittel zur verringerung der eigeweidefette
JP2001514663A (ja) * 1997-03-12 2001-09-11 エスモンド，ロバート ダブリュー． アルツハイマー病を処置または予防するための方法
US5908859A (en) * 1997-08-11 1999-06-01 Eli Lilly And Company Benzothiophenes for inhibiting hyperlipidemia
HUP9902721A2 (hu) 1997-11-25 1999-12-28 The Procter & Gamble Co. Tömény textillágyító készítmény és ehhez alkalmazható magas telítetlenségű textillágyító vegyület
GB9726568D0 (en) * 1997-12-16 1998-02-11 Smithkline Beecham Plc Novel pharmaceutical
AU1507799A (en) * 1997-12-16 1999-07-05 Sankyo Company Limited Leukemia remedy
US20040058873A1 (en) * 1998-03-12 2004-03-25 Esmond Robert W. Method for treating or preventing Alzheimer's disease
CA2350599A1 (en) * 1998-11-20 2000-06-02 Genentech, Inc. Method of inhibiting angiogenesis
US6191154B1 (en) 1998-11-27 2001-02-20 Case Western Reserve University Compositions and methods for the treatment of Alzheimer's disease, central nervous system injury, and inflammatory diseases
TWI249401B (en) * 1999-04-14 2006-02-21 Takeda Chemical Industries Ltd Agent for improving ketosis
US6869959B1 (en) 1999-04-28 2005-03-22 Institute Of Medicinal Molecular Design Inc. Heterocyclic carboxylic acid derivatives
KR20010099634A (ko) * 1999-07-01 2001-11-09 할리 켈빈 비. 텔로머라제 저해제 및 그 사용 방법
JP2001072592A (ja) 1999-07-01 2001-03-21 Kyowa Hakko Kogyo Co Ltd テロメラーゼ阻害剤
US7390824B1 (en) * 1999-09-07 2008-06-24 Bristol-Myers Squibb Company Method for treating diabetes employing an aP2 inhibitor and combination
US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
AR028299A1 (es) 1999-09-17 2003-05-07 Novartis Ag Una composicion farmaceutica que comprende nateglinida, un proceso para su preparacion y el uso de dicha composicion para la preparacion de un medicamento para el tratamiento de desordenes metabolicos, especialmente diabetes, o de una enfermedad o condicion asociada con diabetes.
US6878749B2 (en) 1999-09-17 2005-04-12 Novartis Ag Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes
ES2156574B1 (es) * 1999-11-18 2002-02-01 Vita Invest Sa Nuevos derivados de tiazolidindiona como agentes antidiabeticos
PL356769A1 (en) 1999-12-03 2004-07-12 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic compounds and salts thereof and medicinal use of the same
ES2433476T3 (es) 2000-01-21 2013-12-11 Novartis Ag Combinaciones que contienen inhibidores de la dipeptidilpeptidasa-IV y agentes 5 antidiabéticos
US6680387B2 (en) * 2000-04-24 2004-01-20 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6958355B2 (en) * 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
CZ20023502A3 (cs) * 2000-04-25 2003-06-18 Kyorin Pharmaceutical Co., Ltd. Nová stabilní krystalická forma thiazolidionového derivátu a způsob jeho přípravy
AU2001294673A1 (en) * 2000-09-21 2002-04-02 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, andatherosclerosis
US6982251B2 (en) * 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US6452014B1 (en) 2000-12-22 2002-09-17 Geron Corporation Telomerase inhibitors and methods of their use
WO2002051441A1 (fr) * 2000-12-26 2002-07-04 Sankyo Company, Limited Compositions medicinales contenant un diuretique et un agent renforçant la resistance a l'insuline
CA2434504A1 (en) * 2001-01-26 2002-08-01 Teddy Kosoglou Combinations of sterol absorption inhibitor(s) with blood modifiers for treating vascular conditions
SI1363668T1 (sl) * 2001-01-26 2007-12-31 Schering Corp Kombinacija sekvestranta(-ov) in zaviralca(-ev) absorpcije sterola ter zdravljenje vaskularnih indikacij
WO2002058685A2 (en) * 2001-01-26 2002-08-01 Schering Corporation Combinations of nicotinic acid and derivatives thereof and sterol absorption inhibitor(s) and treatments for vascular indications
RU2003126186A (ru) * 2001-01-26 2005-03-10 Шеринг Корпорейшн (US) Комбинации ингибитора (ингибиторов) всасывания стерина с сердечно-сосудистым агентом (агентами), предназначенные для лечения патологических состояний сосудов
US7071181B2 (en) * 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
TWI337083B (en) * 2001-01-26 2011-02-11 Schering Corp Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
US7417039B2 (en) * 2001-01-26 2008-08-26 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
CN100408579C (zh) * 2001-02-24 2008-08-06 贝林格尔英格海姆法玛两合公司 黄嘌呤衍生物,其制法及其作为药物组合物的用途
KR200249057Y1 (ko) * 2001-03-22 2001-10-19 김진환 뚜껑, 받침대에 합체된 하수역류. 악취방지 장치
WO2002080936A1 (en) * 2001-04-04 2002-10-17 Ortho Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and ppar modulators
US20060047000A1 (en) * 2001-04-24 2006-03-02 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2002087580A1 (fr) * 2001-04-25 2002-11-07 Takeda Chemical Industries, Ltd. Promoteurs d'expression d'abc
US7009057B2 (en) 2001-04-26 2006-03-07 Zentiva A.S. Method for obtaining pioglitazone as an antidiabetic agent
PL367639A1 (en) * 2001-05-29 2005-03-07 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic compound and medicinal use thereof
EP1398313A4 (en) * 2001-05-29 2005-11-16 Kyoto Pharma Ind NEW HETEROCYCLIC DERIVATIVES AND THEIR MEDICAL USE
CA2456034A1 (en) * 2001-08-03 2003-02-20 Takeda Chemical Industries, Ltd. Sustained-release medicines
ATE345793T1 (de) * 2001-09-21 2006-12-15 Schering Corp Behandlung von xanthom mittels azetidinon- derivate als hemmer der sterol absorption
CN1556700A (zh) * 2001-09-21 2004-12-22 ���鹫˾ 使用甾醇吸收抑制剂治疗或预防脉管炎的方法
US7056906B2 (en) * 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
US7053080B2 (en) * 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
US20030119808A1 (en) * 2001-09-21 2003-06-26 Schering Corporation Methods of treating or preventing cardiovascular conditions while preventing or minimizing muscular degeneration side effects
AU2002337749A1 (en) * 2001-09-28 2003-04-07 Teva Pharmaceutical Industries Ltd. Pioglitazone hydrochloride
US20050101638A1 (en) * 2002-11-08 2005-05-12 Webb Randy L. Combination of organic compounds
CA2470075A1 (en) * 2001-12-20 2003-07-03 Teva Pharmaceutical Industries Ltd. Hydrogenation of precursors to thiazolidinedione antihyperglycemics
US20050187258A1 (en) * 2001-12-20 2005-08-25 Ben-Zion Dolitzky Hydrogenation of precursors to thiazolidinedione antihyperglycemics
ITRM20020016A1 (it) 2002-01-15 2003-07-15 Sigma Tau Ind Farmaceuti Derivati di acidi fenil(alchil)carbossilici e derivati fenilalchileterociclici dionici, loro uso come medicamenti ad attivita' ipoglicemizza
US20050084840A1 (en) * 2002-01-23 2005-04-21 Hideki Endoh Method for screening drug for improving insulin resistance
US7015345B2 (en) * 2002-02-21 2006-03-21 Asahi Kasei Pharma Corporation Propionic acid derivatives
KR100450700B1 (ko) * 2002-03-22 2004-10-01 주식회사종근당 티아졸리딘디온 유도체 화합물 및 이를 함유하는 약제학적조성물
US20050119314A1 (en) * 2002-04-05 2005-06-02 Sankyo Company, Limited Pharmaceutical composition comprising an ACAT inhibitor and an insulin resistance reducing agent
KR100897890B1 (ko) 2002-06-17 2009-05-18 인벤티아 헬스케어 피브이티. 엘티디. 티아졸리딘디온 및 바이구아나이드를 함유하는 다층 정제및 그의 제조 방법
US8993773B2 (en) 2002-07-16 2015-03-31 Cadila Healthcare Limited Process to prepare pioglitazone via several novel intermediates
WO2004007490A2 (en) * 2002-07-16 2004-01-22 Cadila Healthcare Limited A process to prepare pioglitazone via several intermediates.
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
AU2003260813A1 (en) * 2002-09-12 2004-04-30 Themis Laboratories Private Limited Improved process for preparation of thiazolidinedione derivatives
US7959946B2 (en) * 2002-09-20 2011-06-14 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8084058B2 (en) 2002-09-20 2011-12-27 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
KR20100137023A (ko) 2002-09-20 2010-12-29 안드렉스 랩스 엘엘씨 약제학적 정제
US9060941B2 (en) * 2002-09-20 2015-06-23 Actavis, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US7785627B2 (en) * 2002-09-20 2010-08-31 Watson Pharmaceuticals, Inc. Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US20040092499A1 (en) * 2002-11-06 2004-05-13 Schering Corporation Methods and therapeutic combinations for the treatment of autoimmune disorders
ATE406364T1 (de) * 2003-03-07 2008-09-15 Schering Corp Substituierte azetidinon-derivate, deren pharmazeutische formulierungen und deren verwendung zur behandlung von hypercholesterolemia
CN1756755A (zh) 2003-03-07 2006-04-05 先灵公司 取代的2－吖丁啶酮化合物、其制剂及其治疗高胆甾醇血症的用途
ES2318274T3 (es) 2003-03-07 2009-05-01 Schering Corporation Compuestos de azetidinona sustituida, formulaciones y uso de los mismos para el tratamiento de hipercolesterolemia.
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2004108721A1 (en) * 2003-04-01 2004-12-16 Sun Pharmaceutical Industries Limited Process for the preparation of 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl]-2,4-thiazolidinedione
ES2219180B1 (es) * 2003-05-09 2006-03-01 Medichem, S.A. Compuesto intermedio util para la preparacion de pioglitazona.
US20050059708A1 (en) * 2003-05-13 2005-03-17 Karel Pospisilik Processes for making thiazolidinedione derivatives and compounds thereof
SI1622899T1 (sl) * 2003-05-13 2007-10-31 Synthon Bv Pioglitazonsulfat, farmacevtski sestavki in njihova uporaba
US7230016B2 (en) * 2003-05-13 2007-06-12 Synthon Ip Inc. Pioglitazone salts, such as pioglitazone sulfate, and pharmaceutical compositions and processes using the same
US20050004179A1 (en) * 2003-05-22 2005-01-06 Pedersen Ward A. Methods and materials for treating, detecting, and reducing the risk of developing Alzheimer's Disease
US7718377B2 (en) * 2003-05-29 2010-05-18 Kyoto Pharmaceutical Industries, Ltd. Insulin resistance curative and method of screening the same
KR20110117731A (ko) 2003-05-30 2011-10-27 랜박시 래보러터리스 리미티드 치환된 피롤 유도체와 ｈｍｇ―ｃｏ 억제제로서의 이의 용도
ZA200602051B (en) 2003-08-13 2007-10-31 Takeda Pharmaceutical 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors
US20070078170A1 (en) * 2003-08-28 2007-04-05 Khanduri Chandra H Process for the preparation of pioglitazone
AU2003269479A1 (en) * 2003-09-03 2005-03-16 Biocon Limited Phosphoric acid salt of 5-((4-(2-(5-ethyl-2-pyridinyl) ethoxy) phenyl) methyl)-2, 4-thiazolidinedione
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
AU2003266526A1 (en) * 2003-09-17 2005-04-11 Kaname Kawasugi Medicinal composition
US20050096307A1 (en) * 2003-11-05 2005-05-05 Schering Corporation Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
US7501426B2 (en) * 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
WO2005080387A2 (en) * 2004-02-20 2005-09-01 Synthon B.V. Processes for making pioglitazone and compounds of the processes
CN102127053A (zh) * 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
EP1731170A1 (en) * 2004-03-29 2006-12-13 Sankyo Company, Limited Therapeutic agent for diabetes containing insulin resistance improving agent
US7161756B2 (en) * 2004-05-10 2007-01-09 Tandberg Data Storage Asa Method and system for communication between a tape drive and an external device
US20060025478A1 (en) * 2004-07-27 2006-02-02 Keisuke Inoue Medicine for prevention or treatment of diabetes
TW200608967A (en) * 2004-07-29 2006-03-16 Sankyo Co Pharmaceutical compositions containing with diabetic agent
US20070259927A1 (en) * 2004-08-26 2007-11-08 Takeda Pharmaceutical Company Limited Remedy for Diabetes
WO2006035459A1 (en) * 2004-09-28 2006-04-06 Morepen Laboratories Limited An improved process for the production of derivatives of thiozolidinediones and their precursors
US20060089387A1 (en) * 2004-10-26 2006-04-27 Le Huang Stabilized pharmaceutical composition comprising antidiabetic agent
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
US7833513B2 (en) 2004-12-03 2010-11-16 Rhode Island Hospital Treatment of Alzheimer's Disease
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
BRPI0609371A2 (pt) * 2005-03-08 2010-03-30 Nycomed Gmbh usos de roflumilast na produção de composições farmacêuticas para o tratamento de diabetes mellitus
US20070269486A1 (en) * 2005-03-14 2007-11-22 Conor Medsystems, Llc. Methods and Devices for Reducing Tissue Damage After Ischemic Injury
EP1858845A2 (en) * 2005-03-18 2007-11-28 Orchid Chemicals and Pharmaceuticals Limited Novel tyrosine derivatives
WO2006117654A1 (en) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Processes for the preparation of pioglitazone or salts thereof
CN101272805A (zh) * 2005-07-12 2008-09-24 第一三共株式会社 包含PPARγ激动剂的药物组合物
US20090203744A1 (en) * 2005-07-29 2009-08-13 Pande Y Surendrakumar Satyanarayan Novel pyridine derivatives
DE102005035891A1 (de) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DK1942898T4 (da) * 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidylpeptidase-inhibitorer til behandling af diabetes
KR101368988B1 (ko) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 디펩티딜 펩티다제 억제제
TW200738266A (en) * 2005-09-29 2007-10-16 Sankyo Co Pharmaceutical agent containing insulin resistance improving agent
AU2006313430B2 (en) 2005-11-08 2012-09-06 Ranbaxy Laboratories Limited Process for (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
TW200730173A (en) * 2005-12-16 2007-08-16 Sankyo Co Pharmaceutical composition enhancing production of adiponectin
JP2009530293A (ja) * 2006-03-16 2009-08-27 メタボリック ソリューションズ ディベロップメント カンパニー チアゾリジンジオン類似体およびグルココルチコイドアゴニストの併用療法
ES2397944T3 (es) * 2006-03-16 2013-03-12 Metabolic Solutions Development Company Llc Análogos de tiazolidindiona
ES2388555T3 (es) * 2006-03-16 2012-10-16 Metabolic Solutions Development Company Llc Análogos de tiazolidindiona
NO347644B1 (no) 2006-05-04 2024-02-12 Boehringer Ingelheim Int Polymorfer
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
EP1852108A1 (en) * 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
US20080096900A1 (en) 2006-06-26 2008-04-24 Amgen Inc. Methods for treating atherosclerosis
KR100791399B1 (ko) 2006-09-06 2008-01-07 동우신테크 주식회사 염산 피오글리타존의 제조방법
NZ574710A (en) 2006-09-07 2012-02-24 Nycomed Gmbh Combination treatment comprising the PDE4 inhibitor Compound A ((2R,4aR, 10bR)6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a,10b-hexahydrophenanthridin-2-ol) for diabetes mellitus
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US20080182880A1 (en) * 2006-09-28 2008-07-31 Mailatur Sivaraman Mohan Pioglitazone composition
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
CA2670730A1 (en) * 2006-12-13 2008-06-26 Gilead Sciences, Inc. Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (aistm's) and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction
WO2008075380A2 (en) * 2006-12-21 2008-06-26 Ind-Swift Laboratories Limited Process for the preparation of thiazolidine derivatives
WO2008091624A2 (en) * 2007-01-22 2008-07-31 Teva Pharmaceutical Industries Ltd. Polymorphic forms of rosiglitazone hydrobromide and processes for preparation thereof
PL2107905T3 (pl) * 2007-02-01 2011-04-29 Takeda Pharmaceuticals Co Stały preparat zawierający alogliptynę i pioglitazon
KR101126383B1 (ko) 2007-02-07 2012-04-12 교와 핫꼬 기린 가부시키가이샤 3환계 화합물
WO2008105326A1 (ja) * 2007-02-28 2008-09-04 Ohara Chemical Industries, Ltd. ２－イミノ－４－チアゾリジノン誘導体及び２，４－チアゾリジンジオン誘導体の製造方法
TW200901959A (en) 2007-03-09 2009-01-16 Indigene Pharmaceuticals Inc Combination of metformin R-(+) lipoate and antihyperlipidemic agents for the treatment of diabetic hyperglycemia and diabetic complications
US8093236B2 (en) * 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
CN104163864B (zh) 2007-03-30 2017-08-01 Ambrx公司 经修饰fgf‑21多肽和其用途
US20080249156A1 (en) * 2007-04-09 2008-10-09 Palepu Nageswara R Combinations of statins and anti-obesity agent and glitazones
US20160331729A9 (en) 2007-04-11 2016-11-17 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
EP3053440B1 (en) 2007-04-11 2020-08-12 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
CA2690004C (en) 2007-06-04 2018-01-23 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
MX354786B (es) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc Agonistas de guanilato ciclasa utiles para el tratamiento de trastornos gastrointestinales, inflamacion, cancer y otros trastornos.
ES2449483T3 (es) 2007-07-26 2014-03-19 Amgen, Inc Enzimas lecitina-colesterol aciltransferasa modificadas
WO2009024542A2 (en) * 2007-08-17 2009-02-26 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
US7960376B2 (en) * 2007-09-14 2011-06-14 Cara Therapeutics, Inc. Benzo-fused heterocycles
US8304441B2 (en) 2007-09-14 2012-11-06 Metabolic Solutions Development Company, Llc Thiazolidinedione analogues for the treatment of metabolic diseases
ES2398313T3 (es) 2007-09-14 2013-03-15 Metabolic Solutions Development Company Llc 5-(4-(2-(3-metoxifenil)-2-oxoetoxi)bencil)tiazolidin-2,4-diona para uso en el tratamiento de la diabetes
US8722710B2 (en) * 2007-09-26 2014-05-13 Deuterx, Llc Deuterium-enriched pioglitazone
US20090118514A1 (en) * 2007-11-06 2009-05-07 Raghupathi Reddy Anumula Processes for preparing pioglitazone and its pharmaceutically acceptable salts
JP5334422B2 (ja) * 2008-02-13 2013-11-06 株式会社トクヤマ ５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝−２−イミノ−４−チアゾリジノンの製造方法
JP5197063B2 (ja) * 2008-02-21 2013-05-15 株式会社トクヤマ ２−ブロモ−３−｛４−［２−（５−エチル−２−ピリジル）エトキシ］フェニル｝プロピオン酸メチルの製造方法
AR071175A1 (es) 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
US20110046382A1 (en) * 2008-04-28 2011-02-24 Erregierre S.P.A. Process for the preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene and pioglitazone
PE20100156A1 (es) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int Tratamiento de nafld
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
KR20200118243A (ko) 2008-08-06 2020-10-14 베링거 인겔하임 인터내셔날 게엠베하 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
EP3081213B1 (en) 2008-08-06 2020-04-01 Kyowa Kirin Co., Ltd. Tricyclic compound
EP2324126B1 (en) 2008-08-12 2014-04-23 Zinfandel Pharmaceuticals, Inc. METHOD OF IDENTIFYING Alzheimer's DISEASE RISK FACTORS
US8846315B2 (en) 2008-08-12 2014-09-30 Zinfandel Pharmaceuticals, Inc. Disease risk factors and methods of use
BRPI0917675A2 (pt) * 2008-08-15 2015-12-01 Boehringer Ingelheim Int compostos orgânicos para cura de ferida
CN102112444A (zh) * 2008-09-02 2011-06-29 株式会社德山 脱溴化氢化抑制剂
MX2011002558A (es) 2008-09-10 2011-04-26 Boehringer Ingelheim Int Terapia de combinacion para el tratamiento de diabetes y estados relacionados.
WO2010041538A1 (ja) * 2008-10-10 2010-04-15 株式会社トクヤマ カルボニルオキシ化合物の製造方法
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
JP5473303B2 (ja) * 2008-12-01 2014-04-16 株式会社トクヤマ ２−ブロモ−３−｛４−［２−（５−エチル−２−ピリジル）エトキシ］フェニル｝プロピオン酸メチルの製造方法
US20100144140A1 (en) * 2008-12-10 2010-06-10 Novellus Systems, Inc. Methods for depositing tungsten films having low resistivity for gapfill applications
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
TW201036975A (en) 2009-01-07 2010-10-16 Boehringer Ingelheim Int Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy
CN102227408A (zh) * 2009-01-20 2011-10-26 株式会社德山 抑制2-溴-3-{4-[2-(5-乙基-2-吡啶基)乙氧基]苯基}丙酸甲酯的脱溴化氢化的方法
JP2010208957A (ja) * 2009-03-06 2010-09-24 Tokuyama Corp 結晶構造を有する５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝−２−イミノ−４−チアゾリジノン及びその製造方法
BRPI1009141A2 (pt) 2009-03-11 2016-03-08 Omeros Corp composições e métodos para profilaxia e tratamento de vícios
EP2445343B1 (en) * 2009-06-25 2021-08-04 Alkermes Pharma Ireland Limited Prodrugs of nh-acidic compounds
AU2010266018B2 (en) 2009-06-25 2014-01-09 Alkermes Pharma Ireland Limited Heterocyclic compounds for the treatment of neurological and psychological disorders
US20110065756A1 (en) * 2009-09-17 2011-03-17 De Taeye Bart M Methods and compositions for treatment of obesity-related diseases
TWI513462B (zh) 2009-11-13 2015-12-21 Toray Industries 糖尿病之治療或預防藥
AU2010323068B2 (en) 2009-11-27 2015-09-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
KR102029611B1 (ko) 2009-12-15 2019-10-07 씨리우스 테라퓨틱스, 엘엘씨 대사성 질환의 치료를 위한 ｐｐａｒ 절약형 티아졸리딘디온염
AU2011207210A1 (en) 2010-01-22 2012-08-16 Dana-Farber Cancer Institute, Inc. Compositions,kits, and methods for identification, assessment, prevention, and therapy of metabolic disorders
WO2011120923A1 (en) 2010-03-30 2011-10-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
KR20190050871A (ko) 2010-06-24 2019-05-13 베링거 인겔하임 인터내셔날 게엠베하 당뇨병 요법
JP2013538807A (ja) 2010-09-01 2013-10-17 ルピン・リミテッド メトホルミンおよびピオグリタゾンを含む医薬組成物
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
MA34828B1 (fr) 2011-01-10 2014-01-02 Zinfandel Pharmaceuticals Inc Procédés et produits médicamenteux destinés au traitement de la maladie d'alzheimer
WO2012153312A1 (en) 2011-05-11 2012-11-15 Ranbaxy Laboratories Limited Process for the purification of pioglitazone
KR101985384B1 (ko) 2011-07-15 2019-06-03 베링거 인겔하임 인터내셔날 게엠베하 치환된 퀴나졸린, 이의 제조 및 약제학적 조성물에서의 이의 용도
WO2013018899A1 (ja) 2011-08-03 2013-02-07 協和発酵キリン株式会社 ジベンゾオキセピン誘導体
WO2013068486A1 (en) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the diagnosis and treatment of male infertility
EP2788384B1 (en) 2011-12-08 2017-08-09 Amgen Inc. Agonistic human lcat antigen binding proteins and their use in therapy
US8969337B2 (en) 2011-12-15 2015-03-03 Alkermes Pharma Ireland Limited Prodrugs of secondary amine compounds
US9504679B2 (en) 2011-12-19 2016-11-29 Bjoern Colin Kahrs Pharmaceutical compositions comprising glitazones and Nrf2 activators
US20130158077A1 (en) 2011-12-19 2013-06-20 Ares Trading S.A. Pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2638898A1 (en) 2012-03-16 2013-09-18 Sanovel Ilac Sanayi ve Ticaret A.S. Metformin and Pioglitazone Formulation with Different Release Profiles
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
WO2014068397A1 (en) 2012-11-05 2014-05-08 Commissariat A L'energie Atomique Et Aux Energies Atlternatives (Cea) Combination of an anti-cancer agent such as a tyrosinekinase inhibitor and a stat5 antagonist, preferably a thiazolidinedione, for eliminating hematologic cancer stem cells in vivo and for preventing hematologic cancer relapse
US8969581B2 (en) 2013-03-14 2015-03-03 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
WO2014150512A1 (en) * 2013-03-15 2014-09-25 Cba Pharma, Inc. Method and products for treating diabetes
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
JP6606491B2 (ja) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼｃの超高純度アゴニスト、その作成および使用方法
US9815777B2 (en) 2013-09-22 2017-11-14 Jiva Pharma, Inc. Metformin salts to treat Type2 diabetes
CA2926685A1 (en) 2013-10-09 2015-04-16 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for downregulation of pro-inflammatory cytokines
KR20160094956A (ko) 2013-11-05 2016-08-10 벤-구리온 유니버시티 오브 더 네게브 리서치 앤드 디벨럽먼트 어쏘러티 당뇨병 및 당뇨병으로부터 발생하는 합병증 질환의 치료를 위한 화합물
US10188639B2 (en) 2014-01-15 2019-01-29 Deuterx, Llc Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
WO2015128453A1 (en) 2014-02-28 2015-09-03 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor
KR101606547B1 (ko) * 2014-06-02 2016-03-28 김동연 공항 탑승객 위치조회시스템
PL3412302T3 (pl) 2014-10-24 2021-11-02 Bristol-Myers Squibb Company Zmodyfikowane polipeptydy fgf-21 i ich zastosowania
WO2016071727A1 (en) 2014-11-04 2016-05-12 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prevention and the treatment of rapidly progressive glomerulonephritis
MA39929A (fr) 2014-11-27 2016-06-01 Arven Ilac Sanayi Ve Ticaret As Comprimé multicouche comprenant de la metformine et du pioglitazone
PE20190376A1 (es) 2016-06-08 2019-03-08 Support Venture Gmbh Combinaciones farmaceuticas para el tratamiento del cancer
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
EA201990220A1 (ru) 2016-08-17 2019-08-30 Суппорт-Венче Гмбх Способ предотвращения или лечения потери слуха
TR201620309A2 (tr) 2016-12-30 2018-07-23 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Metformi̇n hi̇droklori̇t ve pi̇ogli̇tazon hi̇droklori̇ti̇n farmasöti̇k bi̇leşi̇mleri̇
US11576916B2 (en) 2017-04-04 2023-02-14 Kinarus Ag Methods of preventing or treating ophthalmic diseases
WO2019154893A1 (en) 2018-02-08 2019-08-15 Strekin Ag Oral extended release pharmaceutical compositions for preventing or treating hearing loss
WO2019154895A1 (en) 2018-02-08 2019-08-15 Strekin Ag Gel formulation for preventing or treating hearing loss
US11273158B2 (en) 2018-03-05 2022-03-15 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy
WO2020011661A1 (en) 2018-07-13 2020-01-16 Kinarus Ag Combinations of ppar agonists and p38 kinase inhibitors for preventing or treating fibrotic diseases
CN111875598B (zh) * 2020-05-23 2023-10-10 白银京宇新药业有限公司 一种吡格亚胺的制备方法
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
US20230263803A1 (en) 2020-08-11 2023-08-24 Kinarus Ag Methods of preventing or treating covid-19 and related viral diseases or disorders
WO2022068878A1 (zh) 2020-09-30 2022-04-07 映恩生物制药（苏州）有限公司 一种抗肿瘤化合物及其制备方法和应用
EP4385501A1 (en) 2022-12-15 2024-06-19 Sanovel Ilac Sanayi Ve Ticaret A.S. A pharmaceutical formulation comprising linagliptin, pioglitazone and a sglt-2 inhibitor
EP4385502A1 (en) 2022-12-15 2024-06-19 Sanovel Ilac Sanayi Ve Ticaret A.S. A pharmaceutical formulation comprising metformin, pioglitazone and a sglt-2 inhibitor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) * 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative
US4582839A (en) * 1984-03-21 1986-04-15 Takeda Chemical Industries, Ltd. 2,4-thiazolidinediones
CN1003445B (zh) * 1984-10-03 1989-03-01 武田药品工业株式会社 噻唑烷二酮衍生物，其制备方法和用途

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HK3692A (en) 1992-01-17
EP0193256A1 (en) 1986-09-03
SG105691G (en) 1992-02-14
DK171614B1 (da) 1997-02-24
BR1100325A (pt) 2000-06-27
ES8705886A1 (es) 1987-05-16
AU5246786A (en) 1986-07-24
JPS61267580A (ja) 1986-11-27

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