HRP20010773A2 - Thiazolidinedione derivative and its use as antidiabetic - Google Patents
Thiazolidinedione derivative and its use as antidiabetic Download PDFInfo
- Publication number
- HRP20010773A2 HRP20010773A2 HR20010773A HRP20010773A HRP20010773A2 HR P20010773 A2 HRP20010773 A2 HR P20010773A2 HR 20010773 A HR20010773 A HR 20010773A HR P20010773 A HRP20010773 A HR P20010773A HR P20010773 A2 HRP20010773 A2 HR P20010773A2
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- polymorph
- diabetes mellitus
- compound
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- accordance
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Classifications
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- A61P9/12—Antihypertensives
Description
Ovaj izum odnosi se na novu farmaceutski aktivnu tvar, na postupak dobivanja farmaceutski aktivne tvari i upotrebu farmaceutski aktivne tvari u medicini.
Međunarodna patentna prijava, objavljena kao WO94/05659 opisuje izvjesne derivate tiazolidindiona s hipoglikemijskom i hiperlipidemijskom aktivnošću, uključujući 5[4[2(NmetilN(2piridil)amino)etoksi]benzil]tiazolidin2,4dion, sol maleinske kiseline (nadalje ga se navodi kao "spoj (I)").
Od Međunarodnih patentnih prijava, objavljenih kao WO99/31093, WO99/31094 i WO99/31095 svaka opisuje različite hidrate spoja (I).
U novije vrijeme otkriveno je da spoj (I) postoji u novoj polimorfnoj formi, koja je osobito pogodna za masovnu proizvodnju i rukovanje. Nova forma može se proizvesti djelotvornim, ekonomičnim i ponovljivim postupkom, osobito pogodnim za industrijsku proizvodnju.
Nova polimorfna forma ("polimorf") također posjeduje korisna farmaceutska svojstva, a osobito se navodi da je korisna u liječenju i/ili profilaksi dijabetes melitusa, stanja povezanih s dijabetes melitusom izvjesnih njihovih komplikacija.
Prema tome, ovaj izum se odnosi na polimorfnu formu 5[4[2(NmetilN(2piridil)amino)etoksi]benzil]tiazolidin2,4diona, sol maleinske kiseline, koja je karakterizirana time što:
(i) njen infracrveni spektar ima istaknute vrijednosti na 1360, 1326, 1241, 714 i 669 cm–1; i/ili
(i) njen Ramanov spektar ima istaknute vrijednosti na 1581, 768, 670, 271 i 226 cm–1; i/ili
(i) njen spektar nuklearne magnetske rezonancije čvrstog stanja ima istaknute vrijednosti kod kemijskih pomaka kako je uglavnom navedeno u tablici I; i/ili
(i) njen uzorak difrakcije Xzraka na prahu (X-ray powder diffraction, XRPD) ima istaknute vrijednosti kako je uglavnom navedeno u tablici II.
U jednom povoljnom aspektu polimorf ima infracrveni spektar uglavnom u skladu sa slikom I.
U jednom povoljnom aspektu polimorf ima Ramanov spektar uglavnom u skladu sa slikom II.
U jednom povoljnom aspektu polimorf ima spektar nuklearne magnetske rezonancije čvrstog stanja uglavnom u skladu sa slikom III.
U jednom povoljnom aspektu polimorf ima uzorak difrakcije Xzraka na prahu (XRPD) uglavnom u skladu sa slikom IV.
Ovaj izum obuhvaća polimorf izdvojen u čistoj formi ili u smjesi s drugim materijalima, primjerice poznatim formama spoja I spoja I ili bilo kojim drugim materijalom.
Prema tome, u jednom aspektu polimorf je u izdvojenoj formi.
U daljnjem aspektu polimorf je u čistoj formi.
U još daljnjem aspektu polimorf je u kristalnoj formi.
Ovaj izum također se odnosi na postupak dobivanja polimorfa, karakteriziran time što se gustu otopinu spoja (I) u smjesi etanola i vode, koja sadrži do oko 2,5 %, težinski, po jedinici volumena vode, osobito u smjesi denaturiranog etanola i vode, koja sadrži do oko 2,5 %, težinski, po jedinici volumena vode, grije, po mogućnosti na temperaturi raspona od 3560 °C, kao npr. od 4050 °C, npr. 45 °C, kroz dulji period vremena, primjerice 65 sati, nakon čega se polimorf prikuplja iz denaturiranog etanola. Izborno, reakcijsku smjesu se zasije polimorfom.
U daljnjem postupku iz ovog izuma, spoj (I) se umiješa u denaturirani etanol, grije na povišenoj temperaturi, po mogućnosti na temperaturi raspona od 3560 °C, kao npr. od 4050 °C, npr. 4547 °C, kroz dulji period vremena, primjerice 65 sati, nakon čega se polimorf prikuplja iz denaturiranog etanola. Izborno, reakcijsku smjesu se zasije polimorfom.
U daljnjem postupku otopinu spoja (I) u denaturiranom etanolu sadrži do oko 2,5 %, težinski, po jedinici volumena vode, primjerice od 0,82,5 %, težinski, po jedinici volumena vode, na 55 °C se zasije polimorfom, a zatim ohladi na temperaturu raspona od 2025 °C, kako bi se dobilo polimorf. Polimorf se zatim prikuplja iz denaturiranog etanola.
Otopinu spoja (I) u denaturiranom etanolu se dobije na pogodan način otapanjem spoja (I) u traženoj količini denaturiranog etanola na povišenoj temperaturi, primjerice 65 °C. Dalje se ovaj potonji postupak također djelotvorno provodi pomoću spoja (I) koji sadrži do 25 %, težinski, hidrata opisanog u gore navedenom dokumentu WO99/31093.
Polimorf se na pogodan način prikuplja iz reakcijskog otapala, poput denaturiranog etanola, filtracijom uz naknadno sušenje, po mogućnosti na povišenoj temperaturi, npr. 45 °C.
U daljnjem aspektu, ovaj izum se također odnosi na postupak dobivanja spoja (I) (kojeg se također, pogodnosti radi, navodi kao "izvorni polimorf") iz polimorfa iz ovog izuma, gdje se dotični postupak sastoji prije svega u pripremanju otopine polimorfa u smjesi (100:1 volumno) apsolutnog etanola i metanola na povišenoj temperaturi, po mogućnosti u rasponu od 6075 °C, npr. na 68 °C, a zatim se otopinu pusti neka se ohladi do temperature okoliša, npr. 2025 °C, omogućivši tako kristalizaciju izvornog polimorfa.
U poželjnoj varijanti navedenog postupka dobivanja izvornog polimorfa, otopinu polimorfa u smjesi apsolutni etanol/metanol se filtrira, obično kad se polimorf posve otopi, a dobivenu otopinu je ponovno zagrije na povišenu temperaturu, primjerice na 65 °C, zatim se navedenu otopinu pusti neka se ohladi na temperaturu okoliša, primjerice na 2025 °C.
U gore navedenom postupku dobivanja izvornog polimorfa otopinu se može zasijati izvornim polimorfom, no to nije obavezno.
Spoj (I) se dobiva poznatim postupcima, poput onih opisanih u dokumentu WO94/05659. Opisi iz dokumenta WO94/05659 ovdje su uključeni referencom.
Kako bi se izbjeglo dvojbu, izraz "spoj (I)", kao što se koristi u ovom dokumentu, odnosi se na 5[4[2(NmetilN(2piridil)amino)etoksi]benzil]tiazolidin2,4dion, sol maleinske kiseline, kao što je opisan i okarakteriziran u Međunarodnoj patentnoj prijavi, objavljenoj kao WO94/05659.
Kada se upotrebljava ovdje, izraz "denaturirani etanol" odnosi se na etanol koji sadrži male količine metanola, obično do 5 %, volumno, npr. od 0,95 %, volumno, metanola, npr. etanol koji sadrži 4 %, volumno, metanola.
Kada se upotrebljava ovdje, izraz "profilaksa stanja povezanih s dijabetes melitusom" uključuje liječenje stanja poput otpornosti na inzulin, smanjene tolerancije na glukozu, hiperinzulinemije i dijabetesa trudnica.
Dijabetes melitus po mogućnosti znači dijabetes melitus tipa II.
Stanja povezana s dijabetesom uključuju hiperglikemiju i otpornost na inzulin i pretilost. Daljnja stanja povezana s dijabetesom uključuju hipertenziju, kardiovaskularnu bolest, osobito aterosklerozu, izvjesne poremećaje hranjenja, uključujući reguliranje teka i unošenje hrane u subjekte koji pate od poremećaja povezanih sa smanjenim unosom hrane, poput anoreksije nervoze, i poremećaja povezanih s pretjeranim unosom hrane, poput pretilosti i anoreksije bulimije. Daljnji poremećaji povezani s dijabetesom uključuju sindrom policističnih jajnika i steroidima uzrokovanu otpornost na inzulin.
Komplikacije ovdje obuhvaćenih stanja povezanih dijabetes melitusom uključuju bubrežnu bolest, osobito bubrežnu bolest povezanu s razvojem dijabetesa tipa II, uključujući dijabetičku nefropatiju, glomerulonefritis, sklerozu glomerulosklerozu, nefrotski sindrom, hipertenzivnu nefrosklerozu i krajnji stadij bubrežne bolesti.
Kao što je navedeno gore, spoj iz ovog izuma ima korisna terapijska svojstva: ovaj izum odnosi se na upotrebu polimorfa kao terapijski aktivna tvar.
Specifičnije, ovaj izum odnosi se na upotrebu polimorfa u liječenju i profilaksi dijabetes melitusa i njegovih izvjesnih komplikacija.
Polimorf se može primijeniti sam za sebe ili, po mogućnosti, kao farmaceutski pripravak koji također sadrži farmaceutski prihvatljivu podlogu. Pripravak polimorfa i njegova doziranja su općenito opisani kao za spoj (I) u Međunarodnim patentnim prijavama, objavljenim kao WO94/05659 i WO98/55122.
Prema tome, ovaj izum se također odnosi na farmaceutski pripravak koji sadrži polimorf i farmaceutski prihvatljivu podlogu.
Polimorf se normalno primjenjuje u obliku jedinice doziranja.
Aktivni spoj može se primijeniti bilo kojim pogodnim načinom, no obično je to na oralni ili parenteralni način. Prilikom takve upotrebe, spoj će se normalno upotrijebiti u obliku farmaceutskog pripravka s dodatkom farmaceutske podloge, razrjeđivača i/ili ekscipijensa, iako će prirodno stvarni oblik pripravka ovisiti o načinu primjene.
Pripravke se pripravlja miješanjem i pogodno su prilagođeni oralnoj, parenteralnoj ili topikalnoj primjeni, te kao takvi mogu biti u obliku tableta, kapsula, oralnih tekućih pripravaka, praškova, granula, pilula, pastila, praškova za rekonstituciju, injektibilnih i infuzibilnih otopina ili suspenzija, supozitorija i transdermalnih terapijskih sustava. Preferira se oralno primjenjive pripravke, kao osobito oblikovani oralni pripravci, jer su tako pogodniji za opću primjenu.
Tablete i kapsule namijenjene oralnoj primjeni obično su u obliku jedinice doziranja i sadrže konvencionalne ekscipijense, poput veziva, punila, razrjeđivača, tabletirajućih tvari, maziva, dezintegransa, bojila, aroma i močila. Tablete mogu biti prevučene putem postupaka dobro poznatih u ovom području tehnike.
Pogodna punila namijenjena toj upotrebi uključuju celulozu, manitol, laktozu i druge slične tvari. Pogodni dezintegransi uključuju škrob, polivinilpirolidon i derivate škroba, poput natrijevog škrobnog glikolata. Pogodna maziva uključuju, primjerice, magnezijstearat. Pogodna farmaceutski prihvatljiva močila uključuju natrijlaurilsulfat.
Krute oralne pripravke može se pripraviti konvencionalnim postupcima miješanja, punjenja, tabletiranja i slično. Ponovljene postupke miješanja može se upotrijebiti u distribuciji aktivne tvari u pripravcima koji sadrže velike količine punila. Takvi postupci su, naravno, konvencionalni u ovom području tehnike.
Tekući oralni pripravci mogu biti u obliku, primjerice, vodenih ili uljnih suspenzija, otopina, emulzija, sirupa ili ljekovitih napitaka, ili mogu biti u obliku suhog proizvoda namijenjenog rekonstituciji s vodom ili drugim pogodnim vehikulumom prije upotrebe. Takvi tekući pripravci mogu sadržavati konvencionalne aditive, poput suspendirajućih tvari, primjerice sorbitola, sirupa, metilceluloze, želatine, hidroksietilceluloze, karboksimetilceluloze, aluminijstearatnog gela ili hidrogeniranih jestivih masti, emulgatora, primjerice lecitina, sorbitanmonooleata ili arapske gume; nevodenih vehikuluma (što može uključivati jestiva ulja), poput bademovog ulja, frakcioniranog kokosovog ulja, uljnih estera, poput estera glicerina, propilenglikola ili etilalkohola; konzervansa, primjerice metil ili propilphidroksi benzoata ili sorbinske kiseline, te, ako se želi, konvencionalnih aroma ili bojila.
Prilikom parenteralne primjene, tekuće oblike jedinica doziranja se pripravlja tako da sadrže spoj iz ovog izuma i sterilni vehikulum. Spoj, ovisno o vehikulumu i koncentraciji, može biti suspendiran ili otopljen. Parenteralne otopine se normalno pripravlja otapanjem aktivnog spoja u vehikulumu i steriliziranjem filtriranjem prije punjenja u odgovarajuće fijale ili ampule prije hermetičnog zatvaranja. Po mogućnost, adjuvansi, poput lokalnog anestetika, konzervansa i puferirajućih tvari, su također otopljeni u vehikulumu. Radi poboljšanja stabilnosti, pripravak se može zamrznuti nakon punjenja u fijalu, a vodu se ukloni pod vakuumom.
Parenteralne suspenzije se pripravlja na uglavnom isti način, s tim što se aktivni spoj suspendira u vehikulumu umjesto da ga se otopi, te sterilizira izlaganjem etilenoksidu prije suspendiranja u sterilnom vehikulumu. Po mogućnosti, surfaktant ili močilo je uključeno u pripravak, kako bi se pospješilo jednoličnu raspodjelu aktivnog spoja.
Osim toga, takvi pripravci mogu sadržavati još aktivnih tvari, poput antihipertenziva i diuretika.
Osim toga, polimorf se može upotrijebiti u kombinaciji s drugim antidijabeticima, poput sekretagoga inzulina, poput sulfonilureja, bigvanida, poput metmorfina, inhibitora alfaglukozidaze, poput akarboze, betaagonista, te inzulina, kao što je opisano u dokumentima WO98/57649, WO98/57634, WO98/57635 ili WO98/57636. Količine i postupci primjene drugih antidijabetika opisani su u gore navedenim dokumentima. Pripravak polimorfa i njegova doziranja u navedenim kombinacijama općenito su opisani za spoj (I) u gore navedenim dokumentima. Prema uobičajenoj praksi, uz pripravke će općenito biti pridodate pisane ili tiskane upute za upotrebu, koje se tiču upotrebe u medicinskom liječenju.
Kao što se ovdje upotrebljava, izraz "farmaceutski prihvatljiv" obuhvaća spojeve, pripravke i sastojke namijenjeni upotrebi na ljudima i u veterini: primjerice, izraz "farmaceutski prihvatljiva sol" obuhvaća veterinarski prihvatljivu sol.
Ovaj izum se još odnosi na postupak liječenja i/ili profilakse dijabetes melitusa, stanja povezanih dijabetes melitusom i izvjesnih njihovih komplikacija kod čovjeka ili sisavca koji nije čovjek, što obuhvaća primjenu djelotvorne, neotrovne količine polimorfa na čovjeku ili sisavcu koji nije čovjek, kojima je to potrebno.
Po mogućnost, aktivni sastojak se može primijeniti u obliku farmaceutskog pripravka koji je prethodno definiran u ovom dokumentu, a to predstavlja jedan aspekt ovog izuma.
Prilikom liječenja i/ili profilakse dijabetes melitusa, stanja povezanih s dijabetes melitusom i izvjesnih njihovih komplikacija, polimorf se može unijeti u dozama poput gore opisanih.
Slični režimi doziranja pogodni su u liječenju i/ili profilaksi sisavaca koji nisu ljudi.
U daljnjim aspektima, ovaj izum se odnosi na upotrebu polimorfa u proizvodnji lijeka namijenjenog liječenju i/ili profilaksi dijabetes melitusa, stanja povezanih s dijabetes melitusom i izvjesnih njihovih komplikacija.
U gore navedenom liječenju nema naznake nepovoljnog otrovnog djelovanja.
Slijedeći primjeri ilustriraju ovaj izum, no ne ograničuju ga ni na koji način.
PRIMJERI
Primjer 1
Gustu otopina spoja (I) (3,0 g, pripravljenog u skladu s dokumentom WO94/05659, u denaturiranom etanolu (30,5 ml, količina vode: 2,5 % težinski, po jedinici volumena)) grije se na 45 °C 65 sati. Produkt se filtrira na 45 °C i osuši na 50 °C pod vakuumom, kako bi se dobilo polimorf (1,55 g).
Primjer 2
U smjesu apsolutnog etanola (30 ml, voda <0,1 % težinski, po jedinici volumena) i metanola (1,2 ml) doda se spoj (I) (2,00 g). Dobivenu suspenziju se zagrije na 4547 °C i drži na toj temperaturi 65 sati. Krutinu se izdvoji na 45 °C i osuši na 50 °C pod vakuumom, kako bi se dobilo 0,83 g polimorfa (41 %).
Primjer 3
Spoj (I) (6,0 g, sadrži približno 25 %, težinski, hidrata opisanog u dokumentu WO99/31093) grije se na 60 °C u denaturiranom etanolu (60 ml, količina vode: 0,8 % težinski, po jedinici volumena) dok se posve ne otopi. Dobivenu otopinu ohladi se na 55 °C, zasije naslovnim spojem (0,06 g), a zatim ohladi na 2025 °C. Produkt se filtrira, ispere denaturiranim etanolom (10 ml) i osuši na 50 °C pod vakuumom, kako bi se dobilo polimorf (4,8 g, 80 %).
Primjer 4
Prevođenje polimorfa u spoj (I) (izvorni polimorf):
Polimorf (4,0 g) se grije na 68 °C u smjesi apsolutnog etanola (40 ml) i metanola (0,4 ml) dok se posve ne otopi. Dobivenu otopinu se filtrira, ponovno zagrije na 65 °C, zatim ohladi do 2025 °C. Produkt se filtrira, ispere apsolutnim etanolom (8 ml) i osuši na 50 °C pod vakuumom, kako bi se dobilo spoj (I), kao što je opisano u dokumentu WO94/05659 (3,32 g, 83 %).
KARAKTERISTIČNI PODACI
Ovo su karakteristični podaci dobiveni za polimorf:
A Količina vode
Određena je na 0,08 %, težinski, pomoću Karl Fischerovim uređajem.
B Infracrveni apsorpcijski spektar
Infracrveni apsorpcijski spektar disperzije polimorfa u mineralnom ulju dobiven je Nicolet 710 FTIR spektrometrom, u rezoluciji od 2 cm–1. Podaci su digitalizirani u intervalima od po 1 cm–1. Dobiveni spektar prikazan je na slici I. Položaji istaknutih vrijednosti su slijedeći: 2720, 1750, 1703, 1640, 1618, 1610, 1573, 1541, 1529, 1513, 1412, 1400, 1360, 1326, 1309, 1300, 1265, 1241, 1213, 1183, 1162, 1112, 1096, 1080, 1068, 1033, 1014, 989, 972, 933, 902, 866, 843, 832, 812, 774, 741, 734, 729, 669, 660, 636, 613, 605, 577, 558, 540, 527, 515, 508 i 473 cm–1.
C Ramanov spektar
Ramanov spektar polimorfa snimljen je kroz staklenu fijalu Perkin Elmer 2000R spektrometrom, u rezoluciji od 4 cm–1 i prikazan je na slici II (xos pokazuje intenzitet, a yos pokazuje Ramanov pomak u cm–1, 18002000 cm–1). Pobuda je vršena Nd:YAG laserom (1064 nm), izlazne snage 400 mW. Položaji istaknutih vrijednosti su slijedeći: 1749, 1706, 1683, 1611, 1581, 1546, 1511, 1468, 1445, 1435, 1388, 1361, 1327, 1301, 1269, 1250, 1229, 1210, 1179, 1149, 1103, 1056, 1036, 1024, 1005, 989, 920, 843, 827, 800, 782, 768, 744, 722, 670, 637, 605, 560, 541, 512, 473, 429, 408, 397, 347, 322, 298, 271 i 226 cm–1.
D NMR spektar
90,56 MHz 13C CPMAS NMR spektar polimorfa prikazan je na slici III. Kemijski pomaci su dani u tablici I. Podaci su snimljeni na sobnoj temperaturi, uz 10 kHz spinsku frekvenciju, na Bruker AMX360 spektrometru, uz ukriženu polarizaciju od 1,6 ms, te uz vrijeme ponavljanja 15 s. Kemijski pomaci se navode izvana u odnosu na karboksilatni signal u uzorku iz glicinskog testa, na 176,4 ppm u odnosu na tetrametilsilan i smatra ih se točnim u okviru ± 0,5 ppm. Istaknute vrijednosti nisu označene.
Tablica I.
13C kemijski pomaci polimorfa
[image]
E Difrakcija Xzraka na prahu (XRPD)
Uzorak XRPD polimorfa prikazan je niže, na slici IV, a sažeti prikaz XRPD kuteva i izračunatih razmaka rešetke karakterističnih za polimorf dani su tablici II.
U dobivanju uzorka na prahu upotrebljen je PW1710 difraktometar Xzraka na prahu (izvor CU Xzraka), uz slijedeće uvjete dobivanja:
[image]
Tablica II
Kutevi difrakcije Xzraka na prahu i izračunati razmaci rešetke karakteristični za polimorf
[image] [image]
Claims (14)
1. Polimorfna forma 5[4[2(NmetilN(2piridil)amino)etoksi]benzil]tiazolidin2,4diona, soli maleinske kiseline ("Polimorf"), naznačena time što:
(i) njen infracrveni spektar ima istaknute vrijednosti na 1360, 1326, 1241, 714 i 669 cm–1; i/ili
(i) njen Ramanov spektar ima istaknute vrijednosti na 1581, 768, 670, 271 i 226 cm–1; i/ili
(i) njen spektar nuklearne magnetske rezonancije čvrstog stanja ima istaknute vrijednosti kod kemijskih pomaka kako je uglavnom navedeno u tablici I; i/ili
(i) njen uzorak difrakcije Xzraka na prahu (X-ray powder diffraction, XRPD) ima istaknute vrijednosti kako je uglavnom navedeno u tablici II.
2. Polimorf prema zahtjevu 1, naznačen time što je njegov infracrveni spektar uglavnom u skladu sa slikom I.
3. Polimorf prema zahtjevu 1 ili zahtjevu 2, naznačen time što je njegov Ramanov spektar uglavnom u skladu sa slikom II.
4. Polimorf prema bilo kojem zahtjevu od 1-3, naznačen time što je njegov spektar nuklearne magnetske rezonancije čvrstog stanja uglavnom u skladu sa slikom III.
5. Polimorf prema bilo kojem zahtjevu od 1-4, naznačen time što je njegov uzorak difrakcije Xzraka na prahu (XRPD) uglavnom u skladu sa slikom IV.
6. Polimorf prema bilo kojem zahtjevu od 1-5, naznačen time što je u izdvojenoj formi.
7. Polimorf prema bilo kojem zahtjevu od 1-6, naznačen time što je u čistoj formi.
8. Polimorf prema bilo kojem zahtjevu od 1-7, naznačen time što je u kristalnoj formi.
9. Postupak dobivanja polimorfa prema zahtjevu 1, naznačen time što:
(a) gustu otopinu 5[4[2(NmetilN(2piridil)amino)etoksi]benzil]tiazolidin2,4diona, soli maleinske kiseline, (dalje se navodi kao "spoj (I)" ili "izvorni polimorf") u smjesi etanola i vode, koja sadrži do oko 2,5 %, težinski, po jedinici volumena vode, se grije kroz dulji period vremena; nakon toga se polimorf prikuplja iz denaturiranog etanola; ili
(a) spoj (I) se umiješa u denaturirani etanol, grije na povišenoj temperaturi kroz dulji period vremena, nakon čega se polimorf prikuplja iz otapala; ili
(a) spoj (I) u denaturiranom etanolu sadrži do oko 2,5 %, težinski, po jedinici volumena vode, na 55 °C se zasije polimorfom, a zatim ohladi na temperaturu raspona od 2025 °C, kako bi se dobilo polimorf;
polimorf se zatim prikuplja iz otapala.
10. Farmaceutski pripravak naznačen time što sadrži djelotvornu, neotrovnu količinu polimorfa prema zahtjevu 1 i odgovarajuću farmaceutski prihvatljivu podlogu.
11. Polimorf prema zahtjevu 1, naznačen time što je namijenjen upotrebi kao terapijski aktivna tvar.
12. Polimorf prema zahtjevu 1, naznačen time što je namijenjen liječenju i/ili profilaksi dijabetes melitusa, stanja povezanih s dijabetes melitusom i izvjesnih njihovih komplikacija.
13. Upotreba polimorfa prema zahtjevu 1, naznačen time što je namijenjena proizvodnji lijeka namijenjenog liječenju i/ili profilaksi dijabetes melitusa, stanja povezanih s dijabetes melitusom i izvjesnih njihovih komplikacija.
14. Postupak liječenja i/ili profilakse dijabetes melitusa, stanja povezanih s dijabetes melitusom i izvjesnih njihovih komplikacija kod čovjeka ili sisavca koji nije čovjek, naznačen time što se sastoji u primjeni djelotvorne, neotrovne količine polimorfa na čovjeku ili sisavcu koji nije čovjek, kojima je to potrebno.
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GBGB9909472.4A GB9909472D0 (en) | 1999-04-23 | 1999-04-23 | Novel compounds |
GBGB9912197.2A GB9912197D0 (en) | 1999-05-25 | 1999-05-25 | Novel pharmaceutical |
PCT/GB2000/001514 WO2000064892A2 (en) | 1999-04-23 | 2000-04-19 | Thiazolidinedione derivative and its use as antidiabetic |
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HRP20010773A2 true HRP20010773A2 (en) | 2002-10-31 |
HRP20010773B1 HRP20010773B1 (en) | 2005-06-30 |
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EP (3) | EP1284268B1 (hr) |
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GB9726568D0 (en) | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Novel pharmaceutical |
US20020137940A1 (en) * | 1997-12-16 | 2002-09-26 | Smithkline Beecham P.L.C. | 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical |
US6664278B2 (en) | 1997-12-16 | 2003-12-16 | Smithkline Beecham P.L.C. | Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt |
ATE246191T1 (de) | 1999-04-23 | 2003-08-15 | Smithkline Beecham Plc | Polymorph von 5-(4-(2-(n-methyl-n-(2- pyrdyl)amino)äthoxy)benzyl)thiazolidin-2,4-dion maleinsäuresalz |
US20040248945A1 (en) | 1999-04-23 | 2004-12-09 | Smithkline Beecham P.L.C. | Thiazolidinedione derivative and its use as antidiabetic |
AR023568A1 (es) | 1999-04-23 | 2002-09-04 | Smithkline Beecham Plc | Un procedimiento para preparar una forma polimorfica de sal de acido maleico derivado de tiazolidina-2,4-diona |
GB0006133D0 (en) | 2000-03-14 | 2000-05-03 | Smithkline Beecham Plc | Novel pharmaceutical |
WO2002026737A1 (en) * | 2000-09-26 | 2002-04-04 | Dr. Reddy's Research Foundation | Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation |
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AU2002352479A1 (en) * | 2001-12-20 | 2003-07-09 | Smithkline Beecham Plc | 5- (4- (2- (n-methyl-n- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2, 4-dione malic acid salt and use against diabetes mellitus |
GB0130511D0 (en) * | 2001-12-20 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
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US20020045649A1 (en) * | 1997-07-18 | 2002-04-18 | Smithkline Beecham P.L.C. | Treatment of diabetes with thiazolidinedione and sulphonylurea |
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ATE246191T1 (de) | 1999-04-23 | 2003-08-15 | Smithkline Beecham Plc | Polymorph von 5-(4-(2-(n-methyl-n-(2- pyrdyl)amino)äthoxy)benzyl)thiazolidin-2,4-dion maleinsäuresalz |
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