CZ307637B6 - 40-O-(2-Hydroxyethyl)rapamycin jako jediná účinná látka při léčení - Google Patents

40-O-(2-Hydroxyethyl)rapamycin jako jediná účinná látka při léčení Download PDF

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Publication number
CZ307637B6
CZ307637B6 CZ2005-91A CZ200591A CZ307637B6 CZ 307637 B6 CZ307637 B6 CZ 307637B6 CZ 200591 A CZ200591 A CZ 200591A CZ 307637 B6 CZ307637 B6 CZ 307637B6
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Czechia
Prior art keywords
rapamycin
hydroxyethyl
tumors
tumor
treatment
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CZ2005-91A
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English (en)
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CZ200591A3 (cs
Inventor
Heidi Lane
Terence O´Reilly
Jeanette Marjorie Wood
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Novartis Ag
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Priority claimed from GB0104072A external-priority patent/GB0104072D0/en
Priority claimed from GB0124957A external-priority patent/GB0124957D0/en
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of CZ200591A3 publication Critical patent/CZ200591A3/cs
Publication of CZ307637B6 publication Critical patent/CZ307637B6/cs

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Abstract

Vynález se týká 40-O-(2-hydroxyethyl)rapamycinu pro použití jako jediná účinná látka při léčení pevných nádorů jiných než lymfatický karcinom, přičemž pevným nádorem je ledvinový nádor.

Description

Tento vynález se týká 40-O-(2-hydroxyethyl)rapamycinu jako jediné účinné látky při léčení.
Dosavadní stav techniky
Rapamycin je známé makro lidové antibiotikum produkované organismem Streptomyces hygroscopicus. Mezi vhodné deriváty rapamycinu patři například sloučeniny obecného vzorce I
ve kterém
Ri znamená skupinu CH3 nebo alkynylovou skupinu obsahujíc! 3 až 6 uhlíkových atomů,
R2 znamená atom vodíku nebo skupinu -CH2-CH2-OH, a
X znamená skupinu =0, (Η, H) nebo (H, OH), s tou výhradou, že symbol R2 nabývá jiného významu než atomu vodíku, pokud X znamená skupinu =0 a Ri znamená skupinu CH3.
Sloučeniny obecného vzorce I jsou popsány např. v dokumentech WO 94/09010, WO 95/16691 nebo WO 96/41807, které jsou zde zahrnuty zmínkou. Lze je připravit způsoby popsanými v těchto dokumentech nebo analogicky k nim.
Výhodnými sloučeninami jsou 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-dihydrorapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2hydroxyethyl)rapamycin a, výhodněji, 40-O-(2-hydroxyethyl)rapamycin (dále označovaný jako sloučenina A, popsaná v přikladu 8 ve WO 94/09010.
Zjistilo se, že jsou sloučeniny obecného vzorce I, na základě pozorované aktivity, např. vazby na makrofilin-12 (též známý jako FK-506 vazebný protein nebo FKBP-12), např. jak se popisuje v dokumentech WO 94/09010, WO 95/16691 či WO 96/41807, použitelné např. jako imunosupresiva, např. při léčení akutní rejekce allotransplantátu. Nyní se zjistilo, že sloučenina A vykazuje silné antiproliferativní účinky, které jí činí použitelnou pro rakovinnou chemoterapii.
- 1 CZ 307637 B6
Podstata vynálezu
Předmětem vynálezu je 40-O-(2-hydroxyethyl)rapamycin pro použití jako jediná účinná látka při léčení pevných nádorů jiných než je lymfatický karcinom, přičemž pevným nádorem je ledvinový nádor.
Výhodně se 40-O-(2-hydroxyethyl)rapamycin podává orálně ve formě jednotkové dávky obsahující 10 mg 40-O-(2-hydroxyethyl)rapamycinu společně s jedním nebo více farmaceuticky přijatelnými ředidly nebo nosiči.
Termínem pevné nádory jsou míněny nádory nebo/a metastázy (kdekoliv umístěné), jiné než lymfatické karcinomy, např. nádory mozku a jiné nádory centrálního nervového systému (např. meningeální nádory, mozkové nádory, míšní nádory, nádory kraniálních nervů a jiných částí centrálního nervového systému, např. glioblastomy či meduloblastomy); karcinomy hlavy nebo/a krku; nádory hrudi; nádory oběhového systému (např. srdce, mediastina a pleury, a dalších nitrohrudních orgánů, vaskulámí nádory a s nádorem související vaskulámí tkáň); nádory vylučovacího systému (např. ledvin, ledvinných pánviček, močovodů, močového měchýře, dalších a nespecifikovaných močových orgánů); nádory gastrointestinálního traktu (např. jícnu, žaludku, tenkého střeva, tračníku, kolorektální nádory, nádory rektosigmoidního spojení, rekta, anu a análního kanálu), nádory postihující játra a nitrojatemí žlučové cesty, žlučník, dalších a nespecifikovaných částí žlučového traktu, pankreatu a dalších orgánů zažívacího traktu); hlavy a krku; dutiny ústní (rtu, jazyka, dásně, spodiny dutiny ústní, patra a dalších částí úst, příušních žláz a dalších částí slinných žláz, tonzil, orofaryngu, nasofaryngu, pyriformního sinu, hypofaryngu a dalších míst ve rtu, ústní dutině a hltanu); nádory reprodukčního systému (např. vulvy, vagíny, děložního krčku, děložního těla, dělohy, vaječníků a dalších míst spojených s ženskými pohlavními orgány, placenty, penisu, prostaty, varlete a dalších míst spojených s mužskými pohlavními orgány); nádory dýchacího traktu (např. dutiny nosní a středního ucha, akcesomích sinů, hrtanu, trachey, bronchů a plic, např. malobuněčný karcinom plic či nemalobuněčný karcinom plic); nádory kosterního systému (např. kostí a kloubní chrupavky končetin, kostí a kloubní chrupavky a dalších míst); nádory kůže (např. maligní melanom kůže, non-melanomové kožní karcinomy, karcinom kůže z bazálních buněk, karcinom kůže ze skvamózních buněk, mesotheliom, Kaposiho sarkom); a nádory postihující jiné tkáně, což zahrnuje periferní nervy a autonomní nervový systém, pojivové a měkké tkáně, retroperitoneum a peritoneum, oko a adnexa, štítnou žlázu, nadledvinu a další endokrinní žlázy a související struktury, sekundární a nespecifikované maligní novotvary lymfatických uzlin, sekundární maligní novotvary dýchacího a zažívacího traktu a sekundární maligní novotvary jiných míst.
Pokud jsou výše a níže zmíněny nádor, nádorové onemocněni, karcinom nebo rakovina, jsou alternativně nebo navíc míněny též metastázy v původním orgánu či tkáni nebo/a v libovolném jiném místě, ať již je umístění nádoru nebo/a metastázy jakékoliv.
Lymfatickým karcinomem jsou míněny např. nádory krevního a lymfatického systému (např. Hodgkinova choroba, non-Hodgkinův lymfom, Burkittův lymfom, lymfomy související s AIDS, maligní imunoproliferativní onemocnění, mnohočetný myelom a maligní neoplasmata plasmatických buněk, lymfoidní leukémie, myeloidní leukémie, akutní nebo chronická lymfocytámí leukémie, monocytámí leukémie, další leukémie specifikovaných typů buněk, leukémie nespecifikovaných typů buněk, další a nespecifikované maligní neoplasmata lymfoidní, hematopoetické a příbuzných tkání, například difůsní velkobuněčný lymfom, T-buněčný lymfom nebo kožní T-buněčný lymfom).
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Příklady uskutečnění vynálezu
Klinická studie
Výzkum klinického přínosu sloučeniny A jako monoterapie u solidních nádorů
Cíl studie: Identifikovat optimální dávku uvedené sloučeniny podávané jednou týdně v rámci studie se zvyšující se dávkou a účinnost optimální dávka u solidních nádorů.
Studie se dělí na 2 části:
Část 1:
Primární cil: Identifikovat optimální dávku sloučeniny I, např. sloučeniny A, podávané p.o. jednou týdně, za předpokladu, že touto by měla být minimální dávka spojená s prolongovanou inhibici mTOR a krevními hladinami uvedené sloučeniny alespoň ekvivalentními hladinám dosahujícím protinádorového účinku v in vivo preklinických studiích.
Sekundární cíl: Zhodnotit bezpečnost uvedené sloučeniny, pokud se podává samotná pacientům s rakovinou, a zhodnotit změny nádorové metabolické aktivity.
Plán: Po sobě jdoucí skupiny 4 pacientů s pokročilými maligními solidními nádory, refiraktomími nebo rezistentními vůči standardním terapiím užívají sloučeninu A, každých 7 dni různé dávky (skupina 1 užívá 5 mg; skupina 2 užívá 10 mg, skupina 3 užívá 20 mg) po dobu 4 týdnů. V týdnu 4 se stanovuje farmakokinetický profil a profil inhibice mTOR, jak ukazuje inhibice p70s6 kinázy v periferních lymfocytech. Provede se komparativní 18-fluor-deoxyglukózový (FDG) positron-emisní tomografické (FDG-PET) zobrazení (před první dávkou, po třetí dávce) za účelem vyšetření změny nádorového metabolismu.
Hlavní výběrová kritéria pacientů: Dospělí s pokročilým stadiem (III až V) solidních nádorů, resistentním nebo refiraktomím vůči standardním terapiím. Alespoň jedna nádorová léze by měla být měřitelná (> 20 mm v jednom rozměru).
Hlavní proměnné pro hodnocení: Bezpečnost (nepříznivé jevy), standardní biochemické vyšetření séra a hematologické vyšetření, krevní hladiny testované sloučeniny, lymfocytámí p70-s6kinázová aktivita, změny v nádorovém příjmu glukózy pomoci FDG-PET.
Část 2:
Primární cíl: Vyšetřit účinnost sloučeniny A, u pacientů s pokročilými solidními nádory, pokud se podává jednou týdně v optimální dávce, jak se identifikuje v části 1, jak ukazuje nádorová odpověď.
Sekundární cíl: Zhodnotit bezpečnost uvedené sloučeniny při této dávce.
Plán: 20 pacientů s progredujícím solidním nádorem v pokročilém stadiu, rezistentním nebo refiraktomím vůči standardním terapiím, užívá uvedenou sloučeninu v dávce doporučené jako výsledek části 1. Celkový klinický stav pacientů se vyšetřuje týdně pomoci fyzikálního a laboratorního vyšetření. Změny nádorové zátěže se hodnotí každé 2 měsíce pomocí radiologického vyšetření. Zpočátku pacienti užívají terapii po dobu 2 měsíců. Poté se ponechávají na terapii, dokud jejich onemocnění neprogreduje a léčivo je uspokojivě snášeno.
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Hlavní proměnné pro hodnocení: Bezpečnost (nepříznivé jevy), standardní biochemické vyšetření séra a hematologické vyšetření, rozměry nádoru pomocí snímkování za použití počítačové tomografie (CT) nebo zobrazování magnetickou resonanci (MRI).
PATENTOVÉ NÁROKY

Claims (2)

1. 40-O-(2-hydroxyethyl)rapamycin pro použití jako jediná účinná látka při léčení pevných ío nádorů jiných než lymfatický karcinom, přičemž pevným nádorem je ledvinový nádor.
2. 40-O-(2-hydroxyethyl)rapamycin pro použití jako jediná účinná látka při léčení pevných nádorů podle nároku 1, přičemž 40-O-(2-hydroxyethyl)rapamycin se podává orálně ve formě jednotkové dávky obsahující 10 mg 40-O-(2-hydroxyethyl)rapamycinu společně s jedním nebo
15 více farmaceuticky přijatelnými ředidly nebo nosiči.
CZ2005-91A 2001-02-19 2002-02-18 40-O-(2-Hydroxyethyl)rapamycin jako jediná účinná látka při léčení CZ307637B6 (cs)

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