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NO20190725A1 - Polymorfer - Google Patents

Polymorfer

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Publication number
NO20190725A1
NO20190725A1 NO20190725A NO20190725A NO20190725A1 NO 20190725 A1 NO20190725 A1 NO 20190725A1 NO 20190725 A NO20190725 A NO 20190725A NO 20190725 A NO20190725 A NO 20190725A NO 20190725 A1 NO20190725 A1 NO 20190725A1
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Norway
Prior art keywords
methyl
polymorph
butyn
xanthine
quinazolin
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NO20190725A
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English (en)
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NO347644B1 (no
Inventor
Peter Sieger
Thomas Nicola
Dirk Kemmer
Peter Kohlbauer
Martin Renz
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Boehringer Ingelheim Int
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Application filed by Boehringer Ingelheim Int filed Critical Boehringer Ingelheim Int
Publication of NO20190725A1 publication Critical patent/NO20190725A1/no
Publication of NO347644B1 publication Critical patent/NO347644B1/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)

Description

Oppfinnelsen omhandler polymorfe krystallmodifikasjoner av en DPP-IV inhibitor, fremstillingen derav og anvendelsen derav for fremstilling av et medikament.
Enzymet DPP-IV, også kjent ved navnet CD26, er en serinprotease som fremmer spaltingen av dipeptider i proteiner med en prolin- eller alaningruppe ved den N-terminale enden. DPP-IV inhibitorer påvirker derved plasmanivået av bioaktive peptider inkludert peptidet GLP-1. Forbindelser av denne typen er nyttige for forhindringen eller behandlingen av sykdommer eller tilstander som er assosiert med en øket DPP-IV aktivitet eller som kan forhindres eller lindres ved å redusere DPP-IV aktiviteten, spesielt type I eller type II diabetes mellitus, prediabetes, eller redusert glukosetoleranse.
WO 2004/018468 beskriver DPP-IV inhibitorer med verdifulle farmakologiske egenskaper. Ett eksempel på inhibitorene som er vist der er 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin.
Innen omfanget av foreliggende oppfinnelse har det blitt funnet at 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin kan ha ulike polymorfe krystallmodifikasjoner og at forbindelsen fremstilt i WO 2004/018468 ved omgivelsestemperatur foreligger som en blanding av to enantiotropiske polymorfer. Temperaturen som de to polymorfene transformeres over i hverandre ved er 25±15 ºC (se figurene 1 og 2).
Den rene høytemperaturformen (polymorf A), som kan oppnås ved oppvarming av blandingen til temperaturer >40 ºC, smelter ved 206±3 ºC. I røntgenpulverdiagrammet (se figur 3) viser denne formen karakteristiske reflekser ved de følgende d-verdier: 11,49 Å, 7,60 Å, 7,15 Å, 3,86 Å, 3,54 Å og 3,47 Å (jf. også tabell 1 og 2).
Vannfri polymorf A kan fremstilles ved
(a) tilbakeløpskoking av 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin i absolutt etanol og eventuelt filtrering av blandingen,
(b) avkjøling av den varme løsningen eller det varme filtratet inntil krystallisering begynner,
(c) fortynning med et løsemiddel så som tert.-butylmetyleter,
(d) sugefiltrering av løsemiddelblandingen og
(e) tørking av polymorf A ved 45 ºC in vacuo.
Lavtemperaturformen (polymorf B) oppnås ved avkjøling til temperaturer <10 ºC. I røntgenpulverdiagrammet (se figur 4) viser denne formen karakteristiske reflekser ved de følgende d-verdier: 11,25 Å, 9,32 Å, 7,46 Å, 6,98 Å og 3,77 Å (jf. også tabell 3 og 4).
Vannfri polymorf B kan fremstilles ved
(a) oppløsning av 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin i absolutt etanol og tilbakeløpskoking og eventuelt filtrering av blandingen,
(b) avkjøling av den varme løsningen eller det varme filtratet for krystallisering til en temperatur under 10 ºC,
(c) fortynning med et løsemiddel så som tert.-butylmetyleter,
(d) sugefiltrering av løsemiddelblandingen og
(e) tørking av polymorfen ved en temperatur under 10 ºC in vacuo.
En annen polymorf (polymorf C) viser karakteristiske reflekser i røntgenpulverdiagrammet (se figur 5) ved de følgende d-verdier: 12,90 Å, 11,10 Å, 6,44 Å, 3,93 Å og 3,74 Å (jf. også tabell 5).
Polymorf C oppnås hvis
(a) 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xantin blir løst opp i metanol og tilbakeløpskokt og eventuelt filtrert i nærvær av aktivkull,
(b) den metanolholdige løsningen blir avkjølt til en temperatur på 40-60 ºC, (c) et løsemiddel så som tert.-butylmetyleter eller diisopropyleter blir tilsatt, (d) den resulterende suspensjon blir først langsomt avkjølt til 15-25 ºC og så senere til 0-5 ºC,
(e) de dannede krystallene blir sugefiltrert og vasket igjen med tert.-butylmetyleter eller diisopropyleter og
(f) krystallene som oppnås slik blir tørket ved en temperatur på 70 ºC i vakuumtørken.
En annen polymorf (polymorf D) smelter ved 150±3 ºC. Denne polymorfen oppnås hvis polymorf C blir varmet til en temperatur på 30-100 ºC eller tørket ved denne temperaturen.
Til slutt er det også polymorf E, som smelter ved en temperatur på 175±3 ºC. Vannfri polymorf E dannes hvis polymorf D blir smeltet. Ved videre oppvarming, krystalliserer polymorf E ut av smelten.
Polymorfene oppnådd slik kan anvendes på samme måte som blandingen av de to polymorfene A og B beskrevet i WO 2004/018468 for fremstilling av en farmasøytisk sammensetning som er egnet for behandling av pasienter med type I og type II diabetes mellitus, prediabetes eller redusert glukosetoleranse, med revmatoid artritt, obesitet, eller kalsitonin-indusert osteoporose, så vel som pasienter hvor det har blitt utført en allografttransplantasjon. Disse medikamentene inneholder i tillegg til én eller flere inerte bærere minst 0,1 % til 0,5 %, foretrukket minst 0,5 % til 1,5 % og spesielt foretrukket minst 1 % til 3 % av én av polymorfene A, B, eller C.
De følgende eksempler er tenkt å illustrere oppfinnelsen mer detaljert.
Eksempel 1 Krystallisering av polymorf A
Ubearbeidet 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin blir tilbakeløpskokt med 5 ganger så mye absolutt etanol og den varme løsningen blir filtrert klar gjennom aktivkull. Etter at filtratet har blitt avkjølt til 20 ºC og krystallisering har begynt, blir løsningen fortynnet for å doble volumet med tert.-butylmetyleter. Deretter blir suspensjonen avkjølt til 2 ºC, omrørt i 2 timer, sugefiltrert og tørket i vakuumtørken ved 45 ºC.
Polymorf A smelter ved 206 ± 3 ºC. I DSC diagrammet kan det sees et annet svakt endotermt signal ved omtr.25 ºC. Dette er en fullstendig reversibel fastfast faseovergang mellom de to enantiotropiske krystallmodifikasjoner A og B. Formen A er den termodynamisk stabile modifikasjon over denne transformasjonstemperaturen, mens form B er den termodynamisk stabile modifikasjon under denne transformasjonstemperaturen.
Figur 2 viser et syklisk DSC diagram, hvor faseovergangen fra -40 ºC til 120 ºC og vice versa har blitt kjørt gjennom totalt 3 ganger. I løpet av oppvarmingen, blir faseovergangen observert som et endotermt signal og tilsvarende blir den i løpet av avkjøling observert som et eksotermt signal. I løpet av den første oppvarmingssyklusen kan faseovergangen også observeres som et endotermt dobbelsignal eller som et svært bredt signal mens signalet i alle de andre syklusene forekommer som et svært skarpt endotermt eller eksotermt signal, avhengig av om det finner sted oppvarming eller avkjøling.
Tabell 1: Markerte røntgenreflekser opp til 30 º 2 θ med intensiteter (standardisert) for den vannfrie polymorf A
Tabell 2: Gittermål for den vannfrie form A
Eksempel 2 Krystallisering av polymorf B
Polymorf B oppnås ved avkjøling av form A fra eksempel 1 til temperaturer <10 ºC.
Tabell 3: Markerte røntgenreflekser opp til 30 º 2 θ med intensiteter (standardisert) for den vannfrie form B
Tabell 4: Gittermål for den vannfrie form B
Eksempel 3 Krystallisering av polymorf C
Ubearbeidet 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin (26 kg) blir tilbakeløpskokt med 157 l metanol, kombinert med 1,3 kg aktivkull og etter 30 minutters omrøring blir blandingen filtrert og vasket med 26 l metanol.122 l metanol blir destillert av fra filtratet, deretter blir resten avkjølt til 45-55 ºC.52 l tert.-butylmetyleter blir tilsatt til resten i løpet av 30 minutter. Deretter blir blandingen omrørt i ytterligere 60 minutter ved 45-55 ºC. Krystallisering finner sted i løpet av denne tiden. Ytterligere 78 l tert. butylmetyleter blir tilsatt til suspensjonen i løpet av 30 minutter og deretter blir det omrørt igjen i ytterligere 60 minutter ved 45-55 ºC. Det blir fortynnet til fire ganger volumet. Suspensjonen blir langsomt avkjølt til 15-25 ºC og omrørt over natten ved denne temperaturen. Etter at suspensjonen har blitt avkjølt til 0-5 ºC blir krystallene sugefiltrert, vasket med 2 porsjoner tert.-butylmetyleter og tørket ved 70 ºC i vakuumtørken.
Tabell 5: Røntgenreflekser opp til 30 º 2 θ med intensiteter (standardisert) for den vannfrie form C
Eksempel 4 Krystallisering av polymorf D
Polymorf C oppnås hvis polymorf C fra eksempel 3 blir varmet til en temperatur på 30-100 ºC eller tørket ved denne temperaturen.
Eksempel 5 Krystallisering av polymorf E
Vannfri polymorf E oppnås hvis polymorf D blir smeltet. Ved videre oppvarming, krystalliserer polymorf E ut av smelten.
I DSC diagrammet av form C kan det observeres et helt område med signaler. Det sterkeste signalet er smeltepunktet for den vannfrie form A ved omtr.
206 ºC, som fremstilles i DSC forsøket. Før smeltepunktet kan det observeres en rekke andre endoterme og eksoterme signaler. Derfor kan det for eksempel sees et svært bredt og svakt endotermt signal mellom 30 og 100 ºC, som korrelerer med hovedtapet av vekt i termogravimetri (TR). Et TG/IR koplingsforsøk tilveiebringer informasjonen at bare vann unnslipper fra prøven i dette temperaturområdet.
Et røntgenpulverdiagram tatt av en prøve opprettholdt ved en temperatur på 100 ºC viser forskjellige røntgenreflekser fra utgangsmaterialet, hvilket foreslår at form C er en hydratfase med støkiometri et sted i regionen til et hemihydrat eller monohydrat. Den temperaturkontrollerte prøven er en annen vannfri modifikasjon D, som bare er stabil under vannfrie betingelser. D formen smelter ved omtr. 150 ºC. En annen vannfri krystallmodifikasjon E krystalliserer fra smelten, og når den varmes videre smelter den ved omtr.175 ºC. Til slutt krystalliserer form A fra smelten av form E. Form E er også en metastabil krystallmodifikasjon som bare forekommer ved høye temperaturer.

Claims (12)

Patentkrav
1. Vannfri polymorf A av forbindelsen 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin,
k a r a k t e r i s e r t v e d a t den smelter ved 206±3 ºC.
2. Polymorf A ifølge krav 1,
k a r a k t e r i s e r t v e d a t i røntgenpulverdiagrammet har den blant annet karakteristiske reflekser ved de følgende d-verdier: 11,49 Å, 7,60 Å, 7,15 Å, 3,86 Å, 3,54 Å og 3,47.
3. Vannfri polymorf B av forbindelsen 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin,
k a r a k t e r i s e r t v e d a t ved en temperatur på 10-40 ºC transformerer den reversibelt til polymorfen A ifølge krav 1.
4. Polymorf B ifølge krav 3,
k a r a k t e r i s e r t v e d a t i røntgenpulverdiagrammet har den blant annet karakteristiske reflekser ved de følgende d-verdier: 11,25 Å, 9,32 Å, 7,46 Å, 6,98 Å og 3,77 Å.
5. Polymorf C av forbindelsen 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin,
k a r a k t e r i s e r t v e d a t den taper vann ved en temperatur på 30-100 ºC og i DSC diagrammet viser den videre termiske effekter ved omtr.150 ºC og 175 ºC.
6. Polymorf C ifølge krav 5,
k a r a k t e r i s e r t v e d a t i røntgenpulverdiagrammet har den blant annet karakteristiske reflekser ved de følgende d-verdier: 12,90 Å, 11,10 Å, 6,44 Å, 3,93 Å og 3,74 Å.
7. Vannfri polymorf D av forbindelsen 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin,
k a r a k t e r i s e r t v e d a t den smelter ved 150±3 ºC.
8. Vannfri polymorf E av forbindelsen 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin,
k a r a k t e r i s e r t v e d a t den smelter ved 175±3 ºC.
9. Fremgangsmåte for fremstilling av polymorf C ifølge krav 5,
k a r a k t e r i s e r t v e d a t
(a) 1-[(4-metyl-kinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xantin blir tilbakeløpskokt i metanol,
(b) den metanolholdige løsning blir avkjølt til en temperatur på 40-60 ºC, (c) et løsemiddel så som tert.-butylmetyleter blir tilsatt,
(d) den resulterende suspensjon blir avkjølt først til 15-25 ºC og deretter til 0-5 ºC,
(e) krystallene blir sugefiltrert og
(f) tørket in vacuo ved en temperatur på 70 ºC.
10. Fremgangsmåte ifølge krav 9,
k a r a k t e r i s e r t v e d a t etter trinn (a) blir den varme løsningen filtrert.
11. Anvendelse av én av polymorfene A, B, eller C av forbindelsen 1-[(4-metylkinazolin-2-yl)metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin for fremstilling av en farmasøytisk sammensetning for behandlingen av pasienter med type I og type II diabetes mellitus, prediabetes eller redusert glukosetoleranse, revmatoid artritt, obesitet, eller kalsitonin-indusert osteoporose, så vel som pasienter hvor en allografttransplantasjon har blitt utført.
12. Medikamenter som inneholder forbindelsen 1-[(4-metyl-kinazolin-2-yl)-metyl]-3-metyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xantin i tillegg til én eller flere inerte bærere og/eller fortynningsmidler,
k a r a k t e r i s e r t v e d a t det inneholder minst 0,1 % til 0,5 % av én av polymorfene A, B, eller C.
NO20190725A 2006-05-04 2007-04-30 Polymorfer NO347644B1 (no)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06009202 2006-05-04
PCT/EP2007/054201 WO2007128721A1 (de) 2006-05-04 2007-04-30 Polymorphe

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NO20190725A1 true NO20190725A1 (no) 2008-12-02
NO347644B1 NO347644B1 (no) 2024-02-12

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