TR202002072A2 - Bcl-2 i̇nhi̇bi̇törü olarak kullanilan yeni̇ küçük terapöti̇k bi̇leşi̇kleri̇n fi̇zi̇k odakli olarak keşfi̇ - Google Patents
Bcl-2 i̇nhi̇bi̇törü olarak kullanilan yeni̇ küçük terapöti̇k bi̇leşi̇kleri̇n fi̇zi̇k odakli olarak keşfi̇Info
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
Buluş yeni bir BCL-2 inhibitörü olarak kullanılmak üzere formül I ile gösterilen bileşik veya bunun farmasötik olarak kabul edilebilir bir türevi ile ilgilidir
Description
TARIFNAME
BCL-Z INHIBITÖRÜ OLARAK KULLANILAN YENI KÜÇÜK
TERAPÖTIK BILESIKLERIN FIZIK ODAKLI OLARAK KESFI
Teknik Dayanak
1980'lerin ortalarindan beri kanser patolojisine katki saglayan moleküler
mekanizmalarin ve nedensel iliskilerin anlasilmis olmasina ragmen, kansere tedavi
bulunmasi zorlu bir is olmaya devam etmektedir. Apoptoz olarak da bilinen
programlanmis hücre ölümü, fizyolojik fonksiyonlarin sona ermesinin veya genetik
materyale verilen önemli bir hasarin ardindan hücrenin kendi kendini yok etmesiyle
sonuçlanan bir moleküler yoldur. Iyi tanimlanan temel apoptoz yollari, dissal ve içsel
yollar çesitli sekillerde uyarilir ve belirli sinyal elementleri kullanir. Dissal yol, ölüm
reseptörlerinin distan uyarilmasi ile aktive edilmektedir. Ölüm reseptörleri, kaspaz-8
biriktirip, tetikleyebilen ve sonrasinda kaspaz-3, -6 ya da -7 dahil olmak üzere effektör
kaspazlarin çalistirilmasi islemi meydana gelen hücre içi ölüm alanina sahip olan
tümör nekroz faktörü (TNF) reseptör ailesinin üyeleridir. Bu birikim, B-
Hücre lösemi /lenfoma -2 (BCL-2)'nin dogrudan katilimiyla sonuçlanmamaktadir.
Mitokondriyal yol olarak da adlandirilan intrinsik yol, bazilari genetik
kararsizlik, yetersiz gelisimsel stimülasyon, viral patojen istilasi olarak ortaya çikan
Çesitli sitotoksik hasarlar veya büyüme sinyalleri ile baslatilmaktadir. BCL-2 bu islemi
siki bir sekilde düzenlemekte ve daha sonra kaspaz-9 aktivasyonuna yol açmaktadir
BCL-2 protein ailesinin tüm üyeleri, BCL-2 homolojisi (BH) alanlari olarak kabul
edilen dizi düzenlerini muhafaza etmistir ve 3 ana sinifa ayrilabilmektedir. Birinci
protein sinifi, sadece BIM, BID, PUMA gibi pro-apoptotik aktivatör BH alan 3'ten
(BH3) meydana gelmektedir. Aktivasyonlarindan hemen sonra, dis mahmuzlari
mitokondriyal yola baglayan moleküler koruyucu görevi üstlenmektedirler. Asagidaki
grup BAX, BAK gibi çok alanli proteinler olan proapoptotik efektörleri içermektedir
ve her birinin üç BH alani bulunmaktadir. Bu proteinler, sitokrom C'nin sitoplazmaya
serbest dolasimina yol açan mitokondriyal dis zarin bütünlügünü bozarak, asagi akim
kaspaz aktivitesini baslatir ve sonuç olarak tetiklendiginde hücrenin
sonlandirilmasiyla sona erer. BCL-2 ailesinin son sinifi antiapoptotik protein, BCL-
XL, BCL-2, MCL-l vb. gibi proteinlerdir. Bu üyelerin tümü dört BH alanindan
olusmakta ve proapoptotik akranlarini ayirarak, hücreleri güvende tutmaktadir.
Apoptozun tesvik edilmesindeki en önemli nokta, sadece BH3 içeren protein
miktarini arttirmak veya antiapoptotik BCL-2 muadillerinden birini kapatmaktir.
Apoptotik hücre ölümü, tümör hücrelerinin büyümesi için dogustan gelen bir engeldir,
bu nedenle kanser hücrelerinin temel özelliklerinden biri de kemoterapötiklere karsi
dirençte önemli süreçleri içeren apoptozdan kaçinmaktir. Bu fenomen, çok sayida
malignite kapsaminda asiri üretildigi tespit edilen sagkalim faktörlerinin baskilanmasi
dahil olmak üzere apoptoza odaklanan antikanser tedavilerinde tuhaf yaklasimlara yol
açmistir.
Teknigin Bilinen Durumu
BH3 mimetiklerinin umut verici antikanser ilaçlari oldugu fikri, çok sayida kanserin
BCL-2 aile proteinlerine dayandigi ve bu proteinler arasindaki etkilesimin spesifik BH
alanlari üzerinden gerçeklestigi sonucundan kaynaklanmistir. Gerçek bir BH3
mimetiginin, proapoptotik BCL-2 proteininin BH3 alanini taklit etmesi ve bu sekilde
antiapoptotik aile üyelerini BH3 baglama ceplerini doldurarak deaktive etmesi
beklenmektedir.
Kanser hücrelerinde asiri üretilen anti-apoptotik protein BCL-Z'nin inhibisyonu,
kanser arastirmalarinda en çok çalisilan yaklasimlardan biridir. Su anda, venetoklaks,
Gida ve Ilaç Dairesi (FDA) tarafindan kronik lenfositik lösemi (KLL) tedavisi için
onaylanmis tek ilaçtir ve seçici bir BCL-2 protein inhibitörüdür. Farkli kanser hücre
dizileri üzerinde yapilan çesitli çalismalarda gösterildigi gibi BCL-2 için çok yüksek
bir afiniteye sahip olmasina ragmen, bu ilaca karsi direnç halihazirda gözlemlenmis
olmaktadir. Bu nedenle, BCL-2 inhibitörleri olarak hedef yapidaki mutasyonlara karsi
daha etkili olabilecek ve yan etkisi olmayan yeni bilesikler ve iskeleler önerilmesi
gerekmektedir.
Mucitler, formül I ile gösterilen yeni bilesigin, BCL-Z'nin inhibitörü olarak islev
gördügünü tespit etmistir.
Formül 1
Mevcut bulusa göre formül I ile gösterilen bilesik, BCL-2 protein inhibisyonunun
terapötik olarak arzu edilen bir sonuç ürettigi çesitli bozukluklarda kullanim için
uygun yeni bir bilesigin bir temsilcisi niteligindedir. Bu tür hastaliklar, örnegin
kanser gibi proliferatif hastaliklar olabilir. Bu nedenle, mevcut bulus sadece formül I
ile gösterilen yeni bilesiklerle degil, ayni zamanda bahsedilen bilesiklerin kanser gibi
proliferatif hastaliklarin tedavisinde kullanimiyla da ilgilidir.
Bulusun Ayrintili Açiklamasi
Bulus, DRG-BCL2-5 olan formül I ile gösterilen bilesik veya bunun farmasötik olarak
kabul edilebilir bir türevi ile ilgilidir.
Formül 1
Aksi belirtilmedikçe, "mevcut bulusa ait bilesik" veya "bulusa ait bilesik" veya
yerine kullanilabilir ve formül I'e ait bilesikler ve bunlarin tuzlari, hidratlar veya
formül I bilesiginin veya tuzlarinin solvatlari, tüm stereoizomerler (diastereomerler ve
enantiyomerler), totomerler, izotopik olarak etiketlenmis bilesikler (döteryum
sübstitüsyonlari dahil) veya insan Vücudunun fizyolojik kosullari altinda olusan
formlarin yani sira dogal olarak olusanlar (örnegin polimorflar, solvatlar ve/Veya
hidratlar) anlamina gelecektir.
Yani, "farmasötik olarak kabul edilebilir türev" terimi, hidratlari, solvatlari, ön
ilaçlari, tüm stereoizomerleri, tuzlari, esterleri, totomerleri, izotopik olarak
etiketlenmis türevleri veya insan vücudunun fizyolojik kosullari altinda olusan formül
Bulusun tercih edilen bir düzeneginde formül l bilesigi, Formül la ile gösterildigi gibi
spesifik bir stereoizomer seklinde olabilir.
Formül [a
Bulusun tercih edilen bir düzeneginde formül l bilesigi, Formül `lb ile gösterildigi gibi
spesifik bir stereoizomer seklinde olabilir.
Formül [[7
Bulusun çesitli düzenlemeleri burada tarif edilmektedir. Belirtilen her bir
düzenlemenin, baska düzenlemeler saglamak için diger belirlenmis
özelliklerle birlestirilebilecegi düsünülmelidir. Tekil olarak kullanilan terimler, çogul
formlarini da ifade edebilir.
Burada açiklandigi gibi "enantiomerler" terimi, birbirinin üzerine bindirilemeyen ayna
görüntüleri olan bir stereoizomer çifti anlamina gelmektedir. Bir çift enantiyomerin
lzl karisimi "rasemik" karisim olarak adlandirilmaktadir. Mutlak stereokimya, Cahn-
lngold-Prelog RS sistemine göre belirlenir. Bir bilesik saf bir enantiyomer oldugunda,
her bir kiral karbondaki stereokimya, R veya S ile belirtilebilir. Formül l'in bilesigi,
kiral bir merkeze sahiptir. Bulusun tercih edilen düzeneginde formül l bilesigi, R ve S
enantiomerlerinin 111 rasemik karisimi formundadir. Formül I'e ait bilesik ayrica saf
R formunda veya saf S formunda veya bunlarin herhangi bir oranda bir karisimi
halinde olabilir.
Mevcut bulus, rasematlar ve formül I'e ait bilesigin optik olarak saf formlari dahil
olmak üzere tüm olasi izomerleri içermektedir. Bahsedilen formlar, kiral reaktiflerin
veya baska yöntemlerin kullanilmasi gibi bilinen geleneksel teknikler kullanilarak
hazirlanabilir.
Burada açiklandigi gibi "tuzlar" terimi, bulus bilesiginin baz ilaveli tuzlarina asit ilave
edilen hallerini ifade etmektedir. Özellikle tuzlar, bulus bilesiginin biyolojik
etkinligini ve kendi etkinligini korurken, toksisite veya herhangi bir formülasyon
zorluguna neden olan herhangi bir biyolojik veya farkli istenmeyen özelliklere sahip
olmayan tuzlari ifade eden "farmasötik olarak kabul edilebilir tuzlari" içermektedir.
Farmasötik olarak kabul edilebilir asit ilaveli tuzlar, organik asitler ve/veya inorganik
asitler ile olusturulabilir. Mevcut bulusa göre bilesigin asit ilaveli tuzlari asagidakileri
içeren bir gruptan seçilebilmektedir; asetat, aspartat, benzoat, besilat, bromür /
hidrobromür, bikarbonat / karbonat, bisülfat / sülfat, kamforsülfonat, klorür /
hidroklorür, klortheofillonat, sitrat, etabisülfonat, fumarat, gluceptat, glukonat,
glukuronat, sitrat, etabisülfat, lakodiyot, lakodiyot laktobiyonat, laurilsülfat, malat,
maleat, malonat, mandelat, mesilat, metilsülfat, naftoat, naflat, nikotinat, nitrat,
oktadekanoat, oleat, oksalat, palmitat, pamoat, fosfat / hidrojen fosfat / dihidrojen
fosfat, poligalaktu steakat sülfosalisilat, tartarat, tosilat ve trifloroasetat tuzlari.
Farmasötik olarak kabul edilebilir baz ilaveli tuzlar organik bazlar ve/veya inorganik
bazlar ile olusturulabilir. Bulusa ait bilesigin baz ilaveli tuzlarinin hazirlanmasi için
uygun bazlar sodyum hidroksit, sodyum karbonat, sodyum bikarbonat, kalsiyum
hidroksit, kalsiyum karbonat, kalsiyum bikarbonat, magnezyum hidroksit,
magnezyum karbonat, magnezyum bikarbonat, potasyum hidroksit, potasyum
karbonat, potasyum bikarbonat ve benzerleri arasindan seçilebilir.
Burada açiklandigi gibi "izotopik olarak etiketlenmis bilesikler" terimi, bir veya daha
fazla atomun, seçilmis atomik kütle veya kütle sayisina sahip bir atom ile
degistirildigi formül I'e ait bilesikleri belirtmektedir. Bu tür degisimler, örnegin,
Bulusa ait bilesigin bu izotopik isaretli varyantlari, teknolojide bilinen saptama veya
görüntüleme teknikleri veya hastalarin radyoaktif tedavisi için kullanilabilir.
Baska bir yönünde mevcut bulus, formül I bilesigi, DRG-BCL2-5 veya bunun
farmasötik açidan kabul gören bir türevini ve farmasötik açidan kabul gören en az bir
eksipiyan içeren farmasötik kompozisyonlar ile ilgilidir.
Bulusun tercih edilen bir düzenlemesinde, farmasötik olarak kabul edilebilir eksipiyan
asagidakileri içeren bir gruptan seçilebilmektedir; çözücüler, antioksidanlar,
koruyucular (öm. antibakteriyel ajanlar, antifungal ajanlar), izotonik ajanlar, emilim
geciktirici ajanlar, doyurucu maddeler, koruyucular, stabilizatörler, baglayicilar,
parçalayicilar, yaglayicilar, tatlandirici ajanlar, aroma ajanlari ve bunlarin
kombinasyonlari. Her bir grubun özel örnekleri Remington's Pharmaceutical Sciences,
18th Ed. Mack Printing Company, 1990 ve buna eklenen belgeler kapsaminda
verilmistir.
Formül I'e ait bilesik veya bunun farmasötik açidan kabul edilen türevlerini içeren
farmasötik kompozisyonlar, farkli uygulama yollari için formüle edilebilir. Bulusun
bir düzeneginde formül I'e ait bilesikleri ihtiva eden farmasötik kompozisyonlar, oral
uygulama, parenteral uygulama, topikal uygulama veya rektal uygulama için formüle
edilebilmektedir.
Bulusun tercih edilen bir düzenegindeki oral uygulama için bulusa ait olan farmasötik
kompozisyonlar, tabletler, pastiller, sulu veya yagli süspansiyonlar, dagilabilir tozlar
veya granüller, emülsiyon, sert veya yumusak kapsüller veya suruplar ya da iksirler
formunda olabilmektedir.
Bulusun tercih edilen bir düzeneginde parenteral uygulama için bulusa ait olan
farmasötik kompozisyonlar, izotonik çözeltiler veya süspansiyonlar formunda veya
uygulamadan önce sulandirma için uygun liyofilize toz formunda olabilmektedir.
Parenteral uygulama için bulusa ait adi geçen farmasötik kompozisyonlar,
intramüsküler, intravenöz, subkütan, intraperitoneal, intratrakeal uygulama için
kullanilabilmektedir.
Bulusun tercih edilen bir düzeneginde topikal uygulama için bulusa ait farmasötik
kompozisyonlar, sulu çözeltiler, süspansiyonlar, merhemler, macunlar, losyonlar,
transdermal yamalar, jeller, kremler veya aerosoller gibi püskürtülebilir
formülasyonlar seklinde olabilir. Bu topikal uygulama cilt, göz veya burun yoluyla
uygulamalari kapsamaktadir (yani burun içi uygulamalar). Dolayisiyla, bulusun
farmasötik bilesimleri, uygun bir iticiyle veya itici olmaksizin, basinçli kaplar, pompa,
sprey, atomizer veya nebülizör yoluyla uygulama için kuru tozlar, çözeltiler veya
aerosoller formunda olabilir.
Mevcut bulusa ait farmasötik kompozisyon veya kombinasyon, yaklasik 50-70 kg
veya yaklasik 1-500 mg veya yaklasik 1-250 mg ya da yaklasik olarak bir denek için
aktif bilesen birim dozajinda olabilir. Bir bilesigin, farmasötik bilesimin veya bunlarin
kombinasyonlarinin terapötik olarak etkili dozaji, hastanin türüne, vücut agirligina,
yasina ve bireysel durumuna, bozukluklarina veya hastaliklarina veya uygulanan
tedavi agirligina baglidir. Siradan becerilere sahip bir doktor, klinik görevlisi veya
veteriner, bozuklugun veya hastaligin ilerlemesini önlemek, tedavi etmek veya inhibe
etmek için gerekli aktif bilesenlerin her birinin etkili miktarini kolay bir sekilde
belirleyebilmektedir.
Tercih edilen bir düzenekte bulus, BCL2 aktivitesinin (normal aktivite veya özellikle
asiri aktivite dahil) aracilik ettigi bir bozuklugun tedavisinde kullanilmak üzere
formül I bilesigi, DRG- BCL2-5 veya bunun farmasötik açidan kabul gören bir türevi
ile ilgili olmaktadir.
Bir düzenekte bulus, formül la, formül lb, formül lc veya formül ld bilesigi gibi
formülün bir bilesigi veya bunun, BH3 taklidi uygulamasi sirasinda arzu edilen bir
terapötik yanitin gözlendigi, farmasötik açidan kabul edilen bir türevi ile ilgilidir.
Bu basvuru kapsaminda ise "BCL-2 inhibitörü" ve "BH3 mimetik" terimleri ayni
bilesikleri ifade eder ve birbirlerinin yerine kullanilabilir.
Tercih edilen bir düzenekte BCL2 aktivitesinin aracilik ettigi bozukluk, kanser
gibi proliferatif bir hastaliktir.
Bulusun bir düzeneginde kanser, iyi huylu veya kötü huylu tümörler, yumusak doku
sarkomu veya sarkom (örn. Liposarkom, rabdomiyosarkom) veya kemik kanseri (öm.
Osteosarkomlar), karsinom (örn. Beyin, böbrek, karaciger, adrenal bezi, mesane,
meme, mide, yumurtalik, kolon, rektum, prostat, pankreas, akciger, vajina veya tiroid
gibi), glioblastom, meningioma, glioma, mezotelyoma, multipl miyelom,
gastrointestinal kanser (özellikle kolon karsinomu veya kolorektal adenom), bas ve
boyun tümörü, melanoma, prostat hiperplazisi, neoplazi, epitelyal karakterli neoplazi,
akut miyeloid lösemi veya B hücresi kronik lenfositik lösemi, lenfoma (8- veya T-
hücre orij ini) ve diger organlardaki metastazlari içermektedir.
Baska bir yönden bulus, burada tanimlandigi gibi formül l'e ait bir bilesigin veya bu
bilesigin farmasötik olarak kabul edilen bir türevinin, BCLZ'nin aktivitesinin aracilik
ettigi bir hastada bir bozuklugun veya hastaligin tedavisi için ilacin üretiminde
kullanimi ile ilgilidir.
Baska bir yönden bulus, formül l'e ait bir bilesigin veya bu bilesigin farmasötik olarak
kabul edilen bir türevinin ve asagidakileri içeren bir gruptan seçilen bir veya daha
fazla ilave aktif madde içeren kombinasyonlar ile ilgilidir; anti-proliferatif ajanlar,
immünomodülatör ajanlar, antiviral ajanlar, antimikrobiyal ajanlar, anti-enfektif
ajanlar, anti-enflamatuar ajanlar, anestezik ajanlar, antiemetikler veya uygun
oldugunda bunlarin kombinasyonlari. Tercih edilen bir düzenekte ilave aktif ajan, bir
veya daha fazla anti-proliferatif ajandir.
Bulusun bir düzeneginde anti-proliferatif aktif ajan, asagidakileri içeren ancak
bunlarla sinirli olmayan bir gruptan seçilen bir veya daha fazla ajan
olabilir; alkilleyici ajanlar, antrasiklinler, taksanlar (sitoskeletal yikicilar), epotilonlar,
histon deasetilaz inhibitörleri, topoizomeraz l inhibitörleri, topoizomeraz ll
inhibitörleri, kinaz inhibitörleri, tirozin kinaz inhibitörleri, nükleotit analoglari ve
prekürsör analoglari, peptit antibiyotikler, platinum türevleri, platinum, ve türevler
veya diger ajanlar.
Alkilleyici ajanlar asagidakileri içeren, ancak bunlarla sinirli olmayan bir gruptan
seçilebilir: bendamustin, siklofosfamid, mechlorethamine, klorambucil, melfalan,
dakarbazin, nitrosoureler, streptozotosin, temozolomid, trabeetedin.
Antrasiklinler, bunlarla sinirli olmamak üzere asagidakileri içeren bir gruptan
seçilebilir;daun0rubisin, doksorubisin, epirubisin, idarubisin, mitoksantron,
valrubisin.
Taksanlar (hücre iskeleti bozuculari) asagidakileri içeren, ancak bunlarla sinirli
olmayan bir gruptan seçilebilir: paklitaksel, dosetaksel, abraksan, eabazitaksel,
Epotilonlar, asagidakileri içeren, ancak bunlarla sinirli olmayan bir gruptan
seçilebilir; epotilon A, epotilon B, epotilon C, epotilon D, epotilon E, epotilon F veya
iksabepilon gibi fannasötik olarak kabul edilen bir türevi.
Histon deasetilaz inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; belinostat, panobinostat, valproat, vorinostat, romidepsin.
Topoizomeraz l inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; irinotekan, topotekan.
Topoizomeraz II inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir: etoposit, teniposit, tailuposit.
Kinaz inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir gruptan
seçilebilir; bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib.
Tirozin kinaz inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; afatinib, aksitinib, bosutinib, kobimetinib, crizotinib, dasatinib,
erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, ruxolitinib,
sunitinib, vandetanib.
Nükleotid analoglari ve öncü analoglari, asagidakileri içeren, ancak bunlarla sinirli
olmayan bir gruptan seçilebilir; azasitidin, azatiyoprin, kladribin, klofarabin,
kapesitabin, sitarabin, doksiIluridin, desitabin, Iloksuridin, Iludarabin, florourasil (5-
FU), Horourasil, gemsitabin, hidroksurea, metotreksatrintaintatan, tritatin,
Peptit antibiyotikler, asagidakileri içeren, ancak bunlarla sinirli olmayan bir gruptan
seçilebilir; bleomisin, aktinomisin.
Platin bazli ajanlar asagidakileri içeren ancak bunlarla sinirli olmayan bir gruptan
seçilebilir: karboplatin, cisplatin, oksaliplatin.
Retinoidler, asagidakileri içeren, ancak bunlarla sinirli olmayan bir gruptan
seçilebilir: tretinoin, beksaroten, izotretinoin, tamibaroten.
Vinka alkaloidleri ve türevleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; vinblastin, vinkristin, Vindesine, vinflunin, Vinorelbin.
Diger ajanlar asagidakileri içeren ancak bunlarla sinirli olmayan bir gruptan
seçilebilir: metotreksat, pemetrexed, raltitrexed, etoposide teniposid, abirateron,
bicalutamide, siproteron, degarelix, exemestane, fulvestrant, goserelin, histrelin,
leuprolid, mifepriston, triptorelin, lenalidomid, pomalidomid, talidomid, everolimus,
temsirolimus, anagrelid, ceritinib, dabrafenib, idelalisib, ibrutinib, palbociclib,
vemurafenib, bleomisin, daktinomisin, eribülin, estramustin, ixabepilone, mitomisin,
prokarbazin, alektinib, iobenguane, interferon, ixazomib, lanreotid, lentinan, oktreotid,
omasetaksin, tegafur, oterasil, urasil, combretastatin.
Bulusun bir düzeneginde bu gibi kombinasyonlar, formül I'e ait bilesigin veya bunun
farmasötik açidan kabul gören bir türevinin ve bir veya daha fazla terapötik açidan
aktif ajanin, tercihen anti-proliferatif ajanlarm birlikte formüle edildigi bir formda
olabilir.
Bulusun baska bir düzeneginde formül I'e ait bilesik ve bir veya daha fazla terapötik
açidan aktif ajan, tercihen anti-proliferatif ajanlar ayri ayri formüle edilir ancak buna
ihtiyaç duyan bir hastaya ayni anda veya sirayla uygulanir.
Mevcut özellikler kapsaminda içerme anlami da dahil edilebilmektedir.
Teknik olarak uygun olan yerlerde, bulusa iliskin düzenlemeler birlestirilebilir.
Burada, düzenlemelerin belirli özellikler/elemanlar içerdigi belirtilmektedir. Açiklama
ayrica temel olarak adi geçen özelliklerden/elemanlardan olusan ayri uygulamalara da
uzanmaktadir.
Patentler ve basvurular gibi teknik referanslar, isbu belgeye referans olarak dahil
edilmistir.
Burada spesifik olarak ve açikça belirtilen herhangi bir düzenleme, tek basina veya bir
veya daha fazla baska düzenleme ile kombinasyon halinde bir feragatnamenin
temelini olusturabilmektedir.
Mevcut bulusun diger amaçlari, özellikleri ve avantajlari asagida ayrintili bir sekilde
açiklanmistir. Bununla birlikte, bulusun tercih edilen düzenlemelerini gösterirken,
detayli bir sekilde açiklanan tarifin ve spesifik örneklerin sadece tanimlamak için
verildigi anlasilmalidir; çünkü bulusun özü ve kapsamindaki çesitli degisiklikler ve
modifikasyonlar, bu ayrintili açiklamalar konusunda teknik olarak uzman kisilere
verilmektedir.
Bulus su anda yalnizca açiklayici olan ve hiçbir sekilde asagidakilerin kapsamini
sinirlayici olarak yorumlanmamasi gereken, asagidaki örneklere referans verilmek
suretiyle tanimlanacaktir.
ÖRNEKLER
Örnek 1: Hücre Kültürü Deneyleri
Hücre kültürü deneyleri için çesitli kanser hücre dizileri, HCT-llö kolon kanseri,
U87- MG glial tümör, MCF7 meme kanseri hücre dizileri kullanilmistir. Hücreler,
glikoz DMEM ortami (Biosera) ile tohumlanmistir. Moleküler islemden yirmi dört
saat önce 24 oyuklu hücre kültür plakalarinin her bir oyuguna 10.000 hücre
tohumlanmistir. Moleküller, DMSO'da (Amresco) 4 mM stok çözeltisi hazirlanarak
kullanilmistir. Molekül tedavisi için molekül stok çözeltileri, %10 PES ile DMEM
içerisinde seyreltilmis ve karsilik gelen her oyuktaki hücrelere ilave edilmistir. Araç
DMSO'sunun nihai konsantrasyonu maksimum %2 olarak hesaplanmistir. Bu nedenle,
deneylerdeki araç grubu sadece maksimum %2 DMSO konsantrasyonu içermistir.
Daha yüksek plaka kontluens seviyeleri, moleküler tedaviden bagimsiz olarak hücre
proliferasyonunu yavaslatacagindan, tedavi süresince hücrelerin hiçbirinin %60'tan
fazla konfluansa ulasmadigindan emin olmak için tohumlanacak hücre sayisini
hesapladik.
Yari-maksimal inhibisyon konsantrasyonunun degerleri (1C50), MTT hücre çogalma
analizleri kapsaminda belirlenmistir. HCT-l 16 hücre hatlari üzerinde 10-9 ila 10-4 M
arasinda degisen farkli molekül konsantrasyonlari tek bir islemle test edilmistir. 570
nm absorbans degerleri kaydedilmis ve ICso degerleri, doz yanitlari - Graphpad Prism
8 yazilimi inhibisyon egrileri ve dogrusal olmayan regresyon analizi kullanilarak
hesaplanmistir. Hücre çogalma tahlilleri için bes günlük deneyler yapilmis ve tüm
hücre dizileri ile en az üç kez çalisilmistir. Uygulamanin üçüncü gününden sonra
sagkalim oranlari önemli ölçüde degismemistir. Bu nedenle, üç günlük sonuçlar
sunulmustur. MTT analizi, baslangiçta 1 X 104 hücre/oyuk ile 24 oyuklu plakalar
üzerinde gerçeklestirilmis ve gece boyunca gelistirilmistir; ardindan en az 3 gün
boyunca farkli konsantrasyonlarda seçilen moleküller ile islenmistir. Ilk inkübasyon
gününden sonra moleküller ilave edilmis ve MTT ile 37°C'de 4 saat inkübasyondan
sonra formazan, DMSO (Sigma-Aldrich, St. Louis, ABD) ile Çözündürülerek,
absorbans degeri, 570 nm'de ölçülmüstür. Sekil l'deki graIikte gösterildigi gibi, araç
grubu HCT-116 hücrelerinin düzgün çogaldigini gösterirken, formül I bilesigi ile
uygulamaya maruz birakilan grup daha az çogalma ve apoptotik hücre yapilari
göstermistir. leÜ Formül 1 bilesiginin degeri (Sekil 1) 130 uM olarak belirlenmistir.
2929-951& :gg
4. Tasiyici
1501 -v-mmsk
Hücre Canliligi (Kontrol'ün %'si olarak)
Süre (Saat)
Claims (9)
- l. DRG-BCL2-5 olan formül I ile gösterilen bir bilesik veya bunun farrnasötik olarak kabul edilebilir bir türevi. 5F ormüi' I
- 2. Istem 1`e göre bir bilesik olup, formül I'e ile gösterilen bilesigin farinasötik açidan kabul edilebilir türevleri, hidratlari, solvatlari, ön ilaçlari, tüm stereoizomerleri, tuzlari, esterleri, tautomerleri, izotopik olarak isaretlenmis türevleri veya insan 15 vücudunun fizyolojik kosullari altinda olusan formül I'e ait bilesik formlaridir.
- 3. Istem 2`ye göre bir bilesik Olup, Formül 1 ile gösetrilen bilesigin farmasötik olarak kabul edilebilir türevi Formül la ile gösterilir. 20 F ormi'il [a
- 4. Istem 2'ye göre bir bilesik olup, Formül 1 ile gösetrilen bilesigin farrnasötik olarak kabul edilebilir türevi Formül lb ile gösterilir. F ormüi' [b
- 5. BCLZ'nin aktivitesinin (normal aktivite veya özellikle asiri aktivite dahil olmak üzere) neden oldugu bir hastaligin tedavisinde kullanilmak üzere Istem 1-47e göre bir bilesik.
- 6. Istem 5'teki gibi bir kullanim için bir molekül olup, hastalik proliferatif bir hastaliktir.
- 7. Istem 6,deki gibi bir kullanim için bir molekül olup, proliferatif hastalik kanserdir
- 8. Istem ?deki gibi bir kullanim için bir molekül olup, kanser iyi huylu veya kötü huylu tümörler, yumusak doku sarkomu veya sarkom (öm. Liposarkom, rabdomiyosarkom) veya kemik kanseri (örn. Osteosarkomlar), karsinom (örn. Beyin, böbrek, karaciger. adrenal bezi, mesane, meme, mide, yumurtalik, kolon, rektum, prostat, pankreas, akciger, vajina veya tiroid gibi), glioblastom, meningioma, glioma, mezotelyoma, multipl miyelom, gastrointestinal kanser (özellikle kolon karsinomu veya kolorektal adenom), bas ve boyun tümörü, melanoma, prostat hiperplazisi, neoplazi, epitelyal karakterli neoplazi, akut miyeloid lösemi veya B hücresi kronik lenfositik lösemi, lenfoma (B- veya T- hücre orij ini) ve diger organlardaki metastazlardir.
- 9. Bir veya daha fazla ilave farmasötik aktif ajan ile kombinasyon halinde kullanilmak üzere Istem 1-4'e göre bir bilesik. Istem 9'a göre bir kullanim olup, farrnasötik olarak aktif ilave ajan, anti- proliferatif ajanlar, immünomodülatör ajanlar, antiviral ajanlar, antimikrobiyal ajanlar, anti-enfektif ajanlar, anestezik ajanlar, antiemetikler veya bunlarin kombinasyonlarini içeren bir gruptan seçilir. Istem 10,21 göre bir kulllamm olup, antipoliferatif ajanlar, antrasiklinler, taksanlar (sitoskeletal yikiçilar), epotilonlar, histon deasetilaz inhibitörleri, topoizomeraz I inhibitörleri, topoizomeraz II inhibitörleri, kinaz inhibitörleri, tirozin kinaz kinazlari içeren bir gruptan seçilir. inhibitörler, nükleotid analoglari ve öncü analoglari, peptit antibiyotikleri, platin bazli ajanlar, retinoidler, vinka alkaloidleri ve türevleri veya diger ajanlar arasindan seçilir. Istem 1-4'e göre bir bilesik ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren farmasötik bir kompozisyon. Istem 1-4'e göre bir bilesik ve anti-proliferatif ajanlar, immünomodülatör ajanlar, antiviral ajanlar, antimikrobiyal ajanlar, anti-enfektif ajanlar, anestezik ajanlar, antiemetikler veya kombinasyonlar içeren bir gruptan seçilen bir veya daha fazla ilave farmasötik aktif ajan içeren farmasötik bir kompozisyon.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/02072A TR202002072A2 (tr) | 2020-02-11 | 2020-02-11 | Bcl-2 i̇nhi̇bi̇törü olarak kullanilan yeni̇ küçük terapöti̇k bi̇leşi̇kleri̇n fi̇zi̇k odakli olarak keşfi̇ |
| PCT/TR2021/050122 WO2021162668A1 (en) | 2020-02-11 | 2021-02-10 | Physics-driven discovery of novel small therapeutic compounds for use as a bcl-2 inhibitor |
| US17/929,003 US20230099876A1 (en) | 2020-02-11 | 2021-02-10 | Physics-driven discovery of novel small therapeutic compounds for use as a bcl-2 inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
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| TR2020/02072A TR202002072A2 (tr) | 2020-02-11 | 2020-02-11 | Bcl-2 i̇nhi̇bi̇törü olarak kullanilan yeni̇ küçük terapöti̇k bi̇leşi̇kleri̇n fi̇zi̇k odakli olarak keşfi̇ |
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| TR202002072A2 true TR202002072A2 (tr) | 2021-08-23 |
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| US (1) | US20230099876A1 (tr) |
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| CA2577752A1 (en) * | 2004-08-20 | 2006-03-02 | The Regents Of The University Of Michigan | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| EP3319938B1 (en) * | 2015-07-10 | 2022-04-06 | University of Maryland, Baltimore | Small molecule inhibitors of the mcl-1 oncoprotein and uses thereof |
| US11419843B2 (en) * | 2016-12-01 | 2022-08-23 | Oregon State University | Small molecule BCL-2 functional converters as cancer therapeutics |
| US11053239B2 (en) * | 2017-01-07 | 2021-07-06 | Fochon Pharmaceuticals, Ltd. | Compounds as BLC-2-selective apoptosis-inducing agents |
| KR102630069B1 (ko) * | 2017-04-18 | 2024-01-26 | 포천 파마슈티컬즈, 엘티디. | 아폽토시스-유도제 |
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| US20230099876A1 (en) | 2023-03-30 |
| WO2021162668A1 (en) | 2021-08-19 |
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