SK287276B6 - Kryštalická forma adičnej soli kyseliny monometánsulfónovej - Google Patents
Kryštalická forma adičnej soli kyseliny monometánsulfónovej Download PDFInfo
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Abstract
Opisuje sa kryštalická forma adičnej soli metánsulfónovej kyseliny 4-(4-metylpiperazin-1-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3- yl)pyrimidin-2-ylamino]fenyl}benzamidu vzorca (I), ktorá sa môže použiť napríklad pri liečení nádorov.
Description
Vynález sa týka špecifickej formy adičnej soli metánsulfónovej kyseliny so 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)amino]fenyl}benzamidom, obsahujúcej typické kryštály.
Doterajší stav techniky
Príprava 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu a jeho použitie, predovšetkým ako protinádorovo účinnej látky, je opísaná v príklade 21 spisu EP-A-0 564 409, ktorý bol zverejnený 6. októbra 1993 a súbežných prihláškach v mnohých ďalších štátoch. Táto zlúčenina je uvedená v príkladoch uvedených publikácií len vo voľnej forme (nie ako soľ).
Podstata vynálezu
Vynález sa týka kryštalickej formy adičnej soli monometánsulfónovej kyseliny so zlúčeninou vzorca (I)
(I) charakterizovanej bodom topenia okolo 226 °C, definovaným ako začiatok topenia v diagrame diferenčnej skenovacej kalorimetrie.
Táto kryštalická forma má ihličkovité kryštály.
Predovšetkým sa vynález týka v podstate čistej kryštalickej formy adičnej soli metánsulfónovej kyseliny so 4-(4-metylpiperazin-1 -ylmetyl)-N- {4-metyl- [ 3-(4-pyri d-3 -yl)pyrimidin-2-ylamino] fenyl} benzamidom vzorca (I).
Tam, kde sa už používa alebo sa bude používať termín soľ metánsulfónovej kyseliny so zlúčeninou vzorca (I) alebo so 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidm-2-ylamino]fenyl)benzamidom, rozumie sa tým predovšetkým soľ metánsulfónovej kyseliny vzorca (II)
(Π).
Termínom „v podstate čistý“ sa v kontexte tohto vynálezu rozumie to, že predovšetkým najmenej 90, výhodne 95 a najvýhodnejšie najmenej 99 % hmotn. kryštálov adičnej soli s kyselinou vzorca (I) je obsiahnuté v kryštalickej forme podľa vynálezu.
Vynález sa teda predovšetkým vzťahuje na také formy adičnej soli metánsulfónovej kyseliny so zlúčeninou vzorca (I), v ktorých kryštály kryštalickej formy podľa vynálezu sú obsiahnuté v podstate v čistej forme spolu s inými kryštalickými formami a/alebo amorfnými formami metánsulfonátu 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu.
Nová kryštalická forma má tieto vlastnosti:
Teplota topenia α-kryštalickej formy je 226 °C (začiatok topenia).
α-kryštalická forma adičnej soli metánsulfónovej kyseliny so 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidom sa získa napríklad vyzrážaním tejto soli z roztoku v inom rozpúšťadle, ako je alkohol, ako je metanol a bez prídavku očkovacích kryštálov β-kryštalickej formy.
Uvedené podmienky na selektívnu prípravu jednotlivých kryštalických foriem nie sú rozhodujúce. Všeobecne je napríklad možné meniť parametre, ako je hmotnostný pomer adičnej soli metánsulfónovej kyseliny so zlúčeninou vzorca (I) k rozpúšťadlu.
Skutočnosťou je, že α-kryštalická forma adičnej soli metánsulfónovej kyseliny so zlúčeninou vzorca (I) je pri teplote miestnosti metastabilná.
Je zrejmé, že pri teplote 25 °C je α-kryštalická forma hygroskopická a rýchlo prijíma vodu, takže pri 93 % relatívnej vlhkosti má vzorka určitý obsah amorfnej formy, α-kryštalická forma skvapalnieva pri 97 % relatívnej vlhkosti.
Adičná soľ metánsulfónovej kyseliny so zlúčeninou vzorca (I) a taktiež aj 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyI}benzamid vo voľnej forme má cenné farmakologické vlastnosti a môže sa napríklad používať ako protinádorovo účinná látka, ako látka na liečenie aterosklerózy, ako látka na liečenie restenózy, na prevenciu porúch vyvolaných transplantáciou, ako je obliteratívna bronchiolitída a/alebo na prevenciu napadnutia buniek teplokrvného živočícha niektorými baktériami, ako je Porphyromonas gingivalis.
Fosforylácia bielkovín je už dlho známa ako dôležitý stupeň pri rozlišovaní a rozdeľovaní buniek. Fosforylácia je katalyzovaná proteínkinázami, ďalej delenými na seríntreoninkmázy a tyrozínkinázy. Tyrozínkináza zahrnuje PDGF (Platelet-derived Growth Factor), receptor tyrozínkinázy.
PDGF je všeobecne veľmi často vyskytujúci sa rastový faktor, ktorý má významnú úlohu tak pri normálnom raste, ako aj pri patologickej proliferácii buniek, ako je to zrejmé pri karcinogenéze a pri ochorení buniek hladkého svalstva ciev, napríklad pri ateroskleróze a trombóze.
Inhibícia aktivity receptora tyrozínkinázy in vitro, stimulovanej PDGF, sa meria v komplexoch buniek BALB/c 3T3, imúnnych proti receptoru PDGF, ako opísal E. Andrejauskas-Buchdunger a U. Regenass v Cancer Research 52, 5353 až 5358 (1992). Zlúčenina vzorca (I), ktorá už bola podrobne opísaná, ako je najmä jej β-kryštalická forma, inhibuje fosforyláciu celulámeho receptora, ktorá je závislá od PDGF. Inhibícia receptora tyrozínkinázy PDGF sa meria mikrotitračným testom ELISA (pozri Trinks a kol., J. Med. Chem., 37, 1015 až 1027 (1994)). 4-(4-Metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamid inhibuje aktivitu tyrozínkinázy receptora PDGF pri IC50 (koncentrácia, pri ktorej je aktivita inhibovaná na 50 % v porovnaní s kontrolou) v koncentrácii asi 120 nM, prípadne 100 nM.
Vďaka inhibícii PDGF je zlúčenina vzorca (I) vhodná na liečenie nádorových ochorení, ako sú gliómy, sarkómy, nádory prostaty, nádory hrubého čreva, prsníkov a vaječníkov.
Tiež abl kináza, najmä v-abl kináza, je inhibovaná 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyI}benzamidom a jeho soľou s metánsulfónovou kyselinou. Inhibíciu v-abl tyrozínkinázy je možné stanoviť metódami podľa N. Lydona a kol., Oncogene Research 5, 161-173 (1990) a J. F. Geisslera a koľ, Cancer Research 52, 4492-4498 (1992). Pri týchto metódach sa ako substráty používajú [Val5]-angiotenzín II a [γ’32]-ΑΤΡ. 4-(4-Metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylaminojfenyljbenzamid tu má IC50 pri 38 nM.
Analogicky inhibuje soľ zlúčeniny vzorca (I) tiež BCR-abl-kinázu (pozri Náture Medicíne 2, 561-566 (1996)) a je teda vhodná na liečenie BCR-abl-pozitívnej rakoviny a nádorových ochorení, akým j e leukémia (najmä chronická myeloidná leukémia a akútna lymfoblastická leukémia, kde sa zistili aktívne apoptické mechanizmy), a taktiež má účinky na podskupinu leukemických kmeňových buniek a tiež možnosti čistenia týchto buniek in vitro po odstránení týchto buniek (napríklad odstránenie kostnej drene) a reimplantáciu týchto buniek, ak boli jednoznačne spoznané ako rakovinové bunky (napríklad reimplantácia čistených buniek kostnej drene).
Nie je treba zmieňovať sa o tom, že všetky uvedené inhibičné a farmakologické účinky má aj voľná báza 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu alebo jej ďalšie soli.
Farmakologicky účinné zlúčeniny podľa tohto vynálezu sa môžu používať vo forme prípravkov na parenterálne podanie alebo vo forme infúznych roztokov. Takéto roztoky sú výhodne izotonické vodné roztoky alebo suspenzie, ktoré sa môžu pripravovať pred podávaním, napríklad v prípade lyofilizovaných prípravkov, ktoré obsahujú účinnú substanciu buď samotnú, alebo spolu s nosičom, napríklad manitolom. Farmaceutické substancie sa môžu sterilizovať a/alebo môžu obsahovať excipienty, napríklad konzervačné látky, stabilizátory, zmáčadlá a/alebo emulgačné činidlá, solubilizačné činidlá, soli na reguláciu osmotického tlaku a/alebo pufre. Uvedené farmaceutické prípravky, ktoré ak je to žiaduce, môžu obsahovať ďalšie farmakologicky účinné látky, ako antibiotiká, sa pripravujú známym spôsobom, napríklad bežným miešaním, granuláciou, poťahovaním, rozpúšťaním alebo lyofilizáciou a obsahujú asi od 1 % do 100 %, najmä asi od 1 % do 20 %, jednej účinnej substancie alebo viac účinných substancií.
Prehľad obrázkov na výkresoch
Vynález ilustrujú nasledujúce výkresy.
Na obrázku 1 je znázornený rôntgenový difrakčný diagram α-kryštalickej formy adičnej soli metánsulfónovej kyseliny zlúčeniny vzorca (I).
Na obrázku 2 sú zobrazené kryštály α-kryštalickej formy a dole kryštály β-kryštalickej formy 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu (= adičná soľ metánsulfónovej kyseliny so zlúčeninou vzorca (I)).
Na diagrame je uhol refrakcie 2theta zakreslený na horizontálnej osi (os x) a relatívna intenzita línie (intenzita vrcholu korigovaná pozadím) na vertikálnej osi (os y). Diagramy sa získajú takto: najskôr sa rôntgenový difrakčný diagram zachytí na film použitím Guinierovej kamery (Enraf-Nonius model FR 552) s Guinierovým filmom 258-94c a výbojom medzi medenými elektródami (žiarenie Kal, vlnová dĺžka λ = = 1,54060 . 1O10 m). Optická hustota línií na filme je úmerná intenzite svetla. Film sa potom skenuje použitím riadkového skenera (LS 18, Johansson, Täby, Švédsko) so softvérom SCANPI.
Teploty topenia sa určujú DSC termogramom použitím prístroja Mettler-Toledo TA 8000. DSC („differential scaning calorimetry“) je technika dynamickej diferenciálnej kalorimetrie. Pri použití tejto techniky sa teplota topenia α-kryštalickej formy môže merať zahrievaním vzoriek, kým nie je možné detegovať termickú, t. j. endotermickú alebo exotermickú reakciu pomocou ultrasenzitívnych senzorov. Teploty topenia uvedené v tomto texte sa určujú použitím pristroja Mettler-Toledo TA 8000, keď sa asi 5,5 až 6,5 mg každej vzorky v hliníkovom tégliku s perforovaným vekom, v pokojnej atmosfére vzduchu, meria počas zahrievania rýchlosťou 10 °C/min. (začína sa od 20 °C).
α-Kryštalická forma metánsulfonátu 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu je charakterizovaná ihlicovito vytváranými kryštálmi a je hygroskopická. Táto forma nemá kryštály príliš vhodné pre farmaceutické prostriedky ako pevné dávkovacie formy, pretože ich fyzikálne vlastnosti, napríklad charakteristiky sypkosti, nie sú vhodné.
Nasledujúce príklady uskutočnenia vynález ilustrujú, ale neobmedzujú jeho obsah. Hodnoty Rf sa zisťujú na TLC platniach potiahnutých silikagélom (Merck, Darmstadt, Nemecko). Vzájomný pomer rozpúšťadiel v použitých systémoch rozpúšťadiel je vyjadrený objemovo (obj./obj.) a teploty sa udávajú v stupňoch Celzia (°C).
Príklady uskutočnenia vynálezu
Eluenty (gradienty)
Gradient HPLC:
% b) v a) počas 20 minút, potom 0 % 30 % b) v a) počas 10 minút, potom 30 % b) v a) počas 5 minút
Eluent a): iónové párové činidlo a metanol (420 ml a 580 ml) Eluent b): iónové párové činidlo a metanol (40 ml a 960 ml)
Iónové párové činidlo: 7,5 g 1-oktánsulfónovej kyseliny rozpustených asi v 800 ml vody, hodnota pH nastavená na 2,5 fosforečnou kyselinou, zriedené vodou do 1000 ml.
Stĺpec: 150 x 3,9 mm, plnený Symmetry C18 5 μ (Waters), vopred ekvilibrovaný eluentom a). Rýchlosť prietoku 1,2 ml/min., U V detekcia pri 267 nm.
Príklad 1
Príprava α-kryštalickej formy metánsulfonátu 4-(4-metylpiperazin-l-ylmetyl)-N-(4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu
Metánsulfonát 4-(4-metylpiperazin-1 -ylmetyl)-N - {4-metyl- [3 -(4-pyrid-3 -yl)pyrimidin-2-ylamino]fenyl} benzamid sa pripraví takto: 98,6 g (0,2 mol) voľného 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl}benzamidu (príprava pozri napríklad EP-A 0 564 409) sa dá do 1,4 1 etanolu. K tejto béžovej suspenzii sa prikvapkáva počas 20 minút 19,2 g (0,2 mol) metánsulfónovej kyseliny. Roztok sa varí pod spätným chladičom počas 20 minút a potom sa vyčíri filtráciou pri teplote 65 °C. Filtrát sa odparí na 50 % a odparok sa odfiltruje pri teplote 25 °C (filtrovaný materiál A). Materský lúh sa odparí do sucha. Tento odparok a filtrovaný materiál A sa suspendujú v 2,2 1 etanolu a rozpustí za varu pod spätným chladičom za prídavku 30 ml vody. Ochladením cez noc na teplotu 25 °C, filtráciou a sušením pri teplote 65 °C do konštantnej hmotnosti sa získa 4-(4-metylpiperazin-l-ylmetyl)-N-{4-metyl-[3-(4-pyrid-3-yl)pyrimidin-2-ylamino]fenyl)benzamid v podobe svetlo béžového kryštalického metánsulfonátu (α-kryštalické formy)·
Claims (2)
1. Kryštalická forma adičnej soli monometánsulfónovej kyseliny so zlúčeninou vzorca (I) charakterizovaná bodom topenia okolo 226 °C, definovaným ako začiatok topenia v diagrame diferenčnej skenovacej kalorimetrie.
2. Kryštalická forma podľa nároku 1,vyznačujúca sa tým, že má ihličkovité kryštály.
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Application Number | Priority Date | Filing Date | Title |
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CH176497 | 1997-07-18 | ||
PCT/EP1998/004427 WO1999003854A1 (en) | 1997-07-18 | 1998-07-16 | Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
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SK287276B6 true SK287276B6 (sk) | 2010-05-07 |
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SK5044-2005A SK287276B6 (sk) | 1997-07-18 | 1998-07-16 | Kryštalická forma adičnej soli kyseliny monometánsulfónovej |
SK43-2000A SK286551B6 (sk) | 1997-07-18 | 1998-07-16 | Kryštalická modifikácia derivátov N-fenyl-2-pyrimidínamínu, spôsob jej prípravy, farmaceutická kompozícia s jej obsahom a použitie kryštalickej modifikácie |
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SK43-2000A SK286551B6 (sk) | 1997-07-18 | 1998-07-16 | Kryštalická modifikácia derivátov N-fenyl-2-pyrimidínamínu, spôsob jej prípravy, farmaceutická kompozícia s jej obsahom a použitie kryštalickej modifikácie |
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