TR202002325A2 - Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-4 - Google Patents
Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-4Info
- Publication number
- TR202002325A2 TR202002325A2 TR2020/02325A TR202002325A TR202002325A2 TR 202002325 A2 TR202002325 A2 TR 202002325A2 TR 2020/02325 A TR2020/02325 A TR 2020/02325A TR 202002325 A TR202002325 A TR 202002325A TR 202002325 A2 TR202002325 A2 TR 202002325A2
- Authority
- TR
- Turkey
- Prior art keywords
- agents
- compound
- mdm2
- formula
- inhibitors
- Prior art date
Links
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Buluş yeni bir MDM2 aktivitesi inhibitörü olarak kullanım için formül I ile gösterilen bileşik veya bunun farmasötik olarak kabul edilebilir bir türevi ile ilgilidir.
Description
TARIFNAME
YENI MOUSE DOUBLE MINUTE 2 (MDM2) INHIBITÖRÜ
OLARAK KULLANMAK IÇIN DRG-MDM2-4
Teknik Dayanak
PS3, hücre döngüsünü koruyan ve tümör baskilayici islevini üstlenen önemli bir
gendir. Hücresel fonksiyonlarin, DNA onariminin, nörodejeneratif hastaliklarin,
yaslanmanin, iskeminin, apoptozun ve hücre siklüsü durdurulmasinin düzenlenmesi
konularinda önemli islevlere sahiptir. Bu p53 aktivitelerinin bir çogu, onkojenik
hasari önleyerek, onkojenik ilerleyici hücreleri onararak veya ortadan kaldirarak
tümörün baskilanmasinda rol oynamaktadir. PS3 islevlerinin kaybi, çesitli organlarda
kanser gelisimi ile iliskilendirilmektedir. Metabolik stres ve onkojenlerin artmasi
durumunda, p53 seviyeleri de artmaktadir. P53 seviyelerinde meydana gelen optimum
artislar hayati önem tasimaktadir. Bununla birlikte, p53 seviyesinin asiri veya yetersiz
olmasi, genin hatali çalistiginin açik bir isaretidir. Asiri olmasi apoptoza neden
olurken, yetersiz olmasi tümör olusumuna yol açar. P53'ün dogal negatif regülatörü,
bir endojen p53 inhibitörü olan Mouse Double Minute 2'dir (MDM2). MDM2 geni,
p53'ün p53 ubikuitinasyonu ile transkripsiyonel aktivasyonunu negatif olarak
düzenleyen bir proto-onkojendir. Bu düzenleme, normal hücre döngüsü ilerlemesini
ve hücre sagkalimini koruyarak, düsük p53 seviyeleri saglamak açisindan çok
önemlidir. Bu nedenle, en yaygin p53 baskilama mekanizmasi MDMZ'yi
içermektedir.
PS3, normal hücrelerde stres olmadan 5-30 dakikalik yarilanma ömrüne sahip kararsiz
bir proteindir. Çekirdek ve sitoplazmada proteazomlar tarafindan parçalanmak üzere
MDM2 tarafindan sürekli olarak mono-bikitize edilmektedir. MDM2 çekirdekte
normal hücresel kosullar altinda eksprese edilmektedir; ancak sitoplazmada yer
degistirebilir ve p53 gibi bazi hedeflerin proteazomlari ile parçalanmaya katki
saglayabilmektedir. Hücresel stres olmasi halinde p53 yolu aktive edilir ve onkojenik
potansiyelli hücrelerin proliferasyonunu inhibe ederek, tümör hücresi inhibisyonu
meydana gelir. PS3 yolu, endojen negatif regülatörlerin (özellikle MDM2) daha fazla
okunmasindan dolayi etkisiz hale getirilmektedir. Tümörlerin %17'sinden fazlasi
kemoterapötiklerde kötü prognoza ve tedavi basarisizligina yol açan MDM2 gen
amplifikasyonu mevcut oldugunu göstermektedir.
P53-MDM2 etkilesiminin önemi, in Viva deneylerle gösterilmistir. Insan
sarkomlarinda MDM2 amplifikasyonu gözlenmistir. MDM2`nin p53 inhibisyon
etkisini tersine çevirmek (antagonize etmek) için çesitli yaklasimlar kullanilmistir. Bu
yöntemler, p53-MDM2 etkilesimlerini önleyen MDM2 antagonistlerinin
gelistirilmesini de kapsamaktadir. Dolayisiyla, MDMZ'nin dogrudan inhibisyonu,
MDMZ'nin hem p53-bagimli hem de p53-bagimsiz islevlerini inhibe edebildiginden
inhibitör ve terapötik aktivitelere neden olabilir. MDM2 düzeyleri yumurtalik
kanserlerinde artmaktadir; iyi huylu yumurtalik tümörlerinde ve normal
yumurtaliklarda ise çok düsüktür. Asiri okunan MDM2, p53'ün N-terminal alanina
dogrudan baglanir ve asagidaki mekanizmalardan biriyle inhibe olarak; (i) E3 ubikitin
ligazi olarak hareket ederek nükleer ve sitoplazmik 268 protizomlari içerisinde
ubikitine bagimli p53 degradasyonunu uyarir; (ii) p53'ün çekirdekten sitoplazmaya
tasinmasini saglayarak, p53'ün transkripsiyonel yeteneginin azaltilmasini saglar; (iii)
p53 ile kuvvetli etkilesime girerek DNA'ya baglanma yetenegini azaltir ve p53'ü
transkripsiyonel olarak islevsiz hale getirir. P53 mutasyonlari ve delesyonlari ve/veya
MDM2 amplifikasyonu ve asiri ekspresyonu dahil olmak üzere p53-MDM2 yolunun
düzensizligi, çesitli insan kanserlerinde en sik gözlenen moleküler degisiklik
niteligindedir. p53-MDM2 denge bozulmasi normal hücrelerin habis
transformasyonuna yol açabilir ve ayrica tümör hücrelerinin kemosensitivitesini
etkileyebilir. MDM2 asiri ekspresyonu, p53'ün apoptotik islevlerinin baskilanmasina
ve dolayisiyla kanser hücrelerinin kontrolsüz bir sekilde çogalmasina yol açar.
MDM2 proteini, p53'ün bagli oldugu N-terminal alani (nükleer lokalizasyon sekansi
(NLS), nükleer çikis sekansi (NES), Box-l alani) dahil olmak üzere dört fonksiyonel
bagimsiz alandan meydana gelmektedir (aa l9-102); merkezi asidik alan (aa 223-
Teknigin Bilinen Durumu
Küçük moleküllerle p53-MDM2 etkilesimlerinin engellenmesi siddetle tavsiye
edilmektedir ve son yillarda çok sayida MDM2 inhibitörü kesfedilmistir. P53-MDM2
kompleksinin yapisal özellikleri, p53-MDM2 etkilesimlerini önlemek için anahtar
kalintilarini taklit eden küçük moleküllerin tasarimina yol açmaktadir. Kanser
hücrelerinde apoptozu indükleyebilen ve p53-MDM2 etkilesimini bozan ve p53
fonksiyonlarini geri yükleyebilen nutlin bilesikleri, bilinen en iyi MDM2 antagonistleri
olarak nitelendirilmektedir.
Nutlinler, vahsi tip p53 hücrelerindeki antitümör profilleri için iyi bilinen bilesiklerdir.
P53-MDM2 etkilesiminin inhibisyonu için seçici nutlinler, küçük moleküllerin es
yönlü bir imidazolin sinifidir. Nutlin türevi MI-,
p53-MDM2 etkilesimlerini inhibe ederek kanser hücrelerinde in vitro ve in
vi'vo apoptozunu indüklemektedir. Ml-219'un, vahsi tip p53 içeren akciger kanseri
hücrelerinin büyümesini, Gl veya G2 fazinda hücre döngüsü durdurrnasi ile seçici bir
sekilde inhibe ettigi gösterilmistir. Ml-219 ve bir Oksindol türevi (Ml-319) olan
nutlin-3a analogu, MDM2 proteinini, dogal bir p53 peptidinden 500 kat daha yüksek
baglanma afinitesiyle baglayan sentetik ve küçük bir moleküldür. Çalismalar, Ml-
3l9'un kemoterapötik ilaç Cisplatin ile kombinasyon halinde hücre döngüsü
büyümesini sinerjik olarak baskiladigini ve pankreas kanseri hücre hatlarinda
apoptozu indükledigini göstermistir. 7-nitr0-5-deazailavin ve deazatlavin-S,
MDMZ'nin otoikuitini yapan güçlü MDM2 E3 ligaz inhibitörleridir. Oksindol ve indol
bilesiklerinin tibbi öneminden dolayi bu bilesiklerin kanser hücre hatlarina karsi
sitotoksik aktiviteye sahip türevleri bildirilmistir. Spirotetrahidrotiyopiran oksindol
iskelesi, p53-MDM2'nin bir inhibitörü olarak olusturulmustur ve MDM2 inhibitörü ve
antitümör aktivitesi olarak iyi bir kuvvet göstermistir. Insan akciger kanseri hücresi
A549, insan karaciger kanseri hücresi BEL7402 ve insan kolon kanseri hücresi HCT-
S'e karsi spirosiklik Oksindol iskeletinin antitümör aktivitesi arastirilmistir. Indol
türevlerinin güçlü oldugu ve farkli kanser türlerine karsi yüksek terapötik aktiviteye
sahip oldugu gösterilmistir. Halen kullanilan FDA onayli kemoterapötiklerden
bazilari, antitümör aktiviteleri klinik asamada degerlendirilen indol halkalari
içemiektedir.
P53 ve MDM2 etkilesimi ile etkilesen bazi moleküller olmasina ragmen, p53'ün
kontrolsüz tümör büyümesine karsi faydali etki gösterebilmesi için MDM2 inhibitörleri
olarak islev görebilen daha iyi farmakokinetik profillere sahip yeni ilaçlara halen
ihtiyaç duyulmaktadir.
Mucitler, formül I ile gösterilen yeni bilesigin, p53-MDM2 etkilesiminin bir
inhibitörü olarak islev gördügünü tespit etmistir.
Dolayisiyla, bu bulusa göre formül I ile gösterilen bilesik, p53-MDM2 yolunun bir
etkilesiminin rol oynadigi çesitli bozukluklarda kullanima müsait yeni bir bilesigin
temsilcisidir. 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.
Bulus, DRG-MDM2-4 olan formül I ile gösterilen bilesik veya bunun farmasötik
olarak kabul edilebilir bir türevi ile ilgilidir.
Bulusun Ayrintili Açiklamasi
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
l'e ait bilesik formlarini ifade etmektedir.
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
l:l karisimi "rasemik" karisim olarak adlandirilmaktadir. Mutlak stereokimya, Cahn-
lngold-Prelog RS sistemine göre belirlenmektedir. Bir bilesik saf bir enantiyomer
oldugunda, her bir kiral karbondaki stereokimya, R veya S ile belirtilebilir. Formül
bilesigi, R ve S enantiomerlerinin 1:1 rasemik karisimi formundadir. Formül l'e ait
bilesik ayrica saf R formunda veya saf S formunda veya bunlarin herhangi bir oranda
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'i 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.
tarafindan da belirtilmis oldugu gibi insan proteininin kendisini ifade etmektedir.
MDM2 (özellikle MDM2 veya bunlarin varyantlari olarak belirtildiginde) genellikle
MDM2, Mdm2, HDMZ, Hdm2 veya bunlarin bir varyanti adlariyla kodlanan tüm
genleri ve/veya proteinleri ifade etmektedir.
Baska bir yönünde mevcut bulus, formül I bilesigi, DRG-MDM2-4 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, faimasötik olarak kabul edilebilir eksipiyan
asagidakileri içeren bir gruptan seçilebilmektedir; çözücüler, antioksidanlar,
koruyucular (örn. 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 1 bilesigini içeren farrnasötik bilesimler, farkli uygulama yollari için formüle
edilebilmektedir. Bulusun bir düzeneginde formül l'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
farrnasötik 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 forrnülasyonlar
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.
Baska bir yönden bulus, p53-MDM2 etkilesiminin rol oynadigi bir bozuklugun
tedavisinde kullanilmak üzere formül I bilesigi, DRG-MDM2-4 veya bunun
farmasötik olarak kabul edilebilir bir türevi ile ilgili olmaktadir.
Tercih edilen bir düzenekte bulus, MDM2 aktivitesinin (normal aktivite veya özellikle
asiri aktivite dahil) aracilik ettigi bir bozuklugun tedavisinde kullanilmak üzere
formül I bilesigi, DRG- MDM2-4 veya bunun farmasötik açidan kabul gören bir
türevi ile ilgili olmaktadir.
Tercih edilen bir düzenekte MDM2 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 (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 orijini) ve diger organlardaki metastazlari içermektedir.
Baska bir yönden bulus, burada tanimlandigi gibi formül I'e ait bir bilesigin veya bir
tuzunun, MDMZ'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 bunun bir tuzunun, burada
tanimlandigi gibi, apoptoz ve/veya hücre döngüsü yavaslamasi veya durdurmasi
indükleyicileri gibi bir veya daha fazla ilave farmasötik olarak aktif maddeye
hücrelerin duyarlilastirilmasi için p53 veya bunun varyantlarini içeren hücrelerde
döngünün yavaslamasini veya tercihen durdurulmasini ve/veya apoptozu indüklemek
için kullanimi ile ilgilidir.
Baska bir yönden bulus, formül l bilesigi 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, trabectedin.
Antrasiklinler, bunlarla sinirli olmamak üzere asagidakileri içeren bir gruptan
seçilebilir; daunorubisin, doksorubisin, epirubisin, idarubisin, mitoksantron, valrubisin.
Taksanlar (hücre iskeleti bozuculari) asagidakileri içeren, ancak bunlarla sinirli
olmayan bir gruptan seçilebilir: paklitaksel, dosetaksel, abraksan, taksoter,
cabazitaksel,
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 farmasötik olarak kabul edilen bir türevi.
Histon deasetilaz inhibitörleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; belinostat, panobinostat, valproat, vorinostat, romidepsin.
Topoizomeraz I 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, tafluposit.
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, doksifluridin, desitabin, floksuridin, fludarabin, florourasil (5-
FU), florourasil, gemsitabin, hidroksurea, merkapupürin, metotreksatrintaintatan,
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, alitretionoin, beksaroten, izotretinoin, tamibaroten.
Vinkaalkaloidler ve türevleri, asagidakileri içeren, ancak bunlarla sinirli olmayan bir
gruptan seçilebilir; vinblastin, vinkristin, vinilunin, vinorelbin.
Diger ajanlar asagidakileri içeren ancak bunlarla sinirli olmayan bir gruptan
seçilebilir: metotreksat, pemetrexed, pralatrexed, 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, fluxymesterone, iobenguane, imiguimod,
interferon, ixazomib, lanreotid, lentinan, oktreotid, omasetaksin, tegafur, gimerazil,
oterasil, urasil, combretastatin.
Bulusun bir düzeneginde bu gibi kombinasyonlar, formül l'e ait bilesigin ve bir veya
daha fazla terapötik açidan aktif ajanin, tercihen anti-proliferatif ajanlarin birlikte
formüle edildigi bir formda olabilir.
Bulusun baska bir düzeneginde formül l'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.
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
HCT 116 kolon kanseri ve MDA-MB231 meme kanseri hücre dizileri hücre kültürü
deneylerinde kullanilir.
Hücreler, %10 PES (Gibco) ve 1)( penisilin/streptomisin (Multicell) ile takviye
edilmis yüksek glikozlu DMEM ortami (Biosera) ile tedavi edilmistir. Deney,
inhibitörlere maruz birakilmasindan önce 24 oyuklu hücre kültür plakalarinin her bir
oyugu için 10.000 hücre içerecek sekilde tasarlanmistir.
Formül I'e ait bilesik, 20 mM stok olarak DMSO ile çözündürülmüstür. 24 saat sonra
çözelti, %10 PES ile DMEM içerisinde seyreltilmis ve nihai araç DMSO
konsantrasyonu, maksimum %05 olmustur. Bu nedenle, araç grubu deneylerde %05
DMSO konsantrasyon içermistir. Hücrelerin yogun bir sekilde kü1tive edilmesi,
çogalma kapasitesinde bir azalmaya neden olur. Bu nedenle hücre doluluk orani, %60'1
asmamistir.
MTT hücre canliligi deneyi yari-maksimal inhibisyon konsantrasyonunun degerlerini
tespit etmek için kullanilmistir (ICso). 109 ila 10`4M arasinda degisen formül l
bilesiginin farkli konsantrasyonlari, tek doz tedavi ile MDA-MB231 hücre çizgileri
üzerinde test edildi. 570 nm absorbans degerleri kaydedilmis ve leo degerleri, doz
yanitlari - Graphpad Prism 8 yazilimi inhibisyon egrileri ve dogrusal olmayan
regresyon analizi kullanilarak hesaplanmistir. Formül 1 bilesiginin IC50 degerinin 24
uM (Seki1 1) oldugu belirlenmistir.
Örnek 2: Hücre Çogalmasi Inhibisyon Analizi
Proliferasyon inhibisyon analizi için, hücreler, 1 X 104 hücre/oyuklu hücre içerisinde
24 plaka ile gece boyunca ilaç tedavisi olmaksizin tohumlanmistir. Hücre çogalma
deneyleri sirasinda, her hücre hattinda bes günlük tedavi gerçeklestirilmis ve her bir
deneyi kontrol etmek için deneyler üç kez tekrarlanmistir. Üçüncü günden sonra hücre
canliliginda anlamli bir fark gözlenmemistir. Bu nedenle, farkli ilaç
konsantrasyonlarina sahip hücreler iki gün boyunca tedavi edilmistir. 48 saat sonra
hücrelere MTT uygulanmis ve 37°C'de 4 saat inkübe edilmistir, formazan DMSO
(Sigma-Aldrieh, St. Louis, ABD) ile çözündürülmüs ve absorbans, 570 nm'de
ölçülmüstür.
MTT hücresi çogalma tahlil sonuçlari Sekil 2'de gösterilmektedir. Molekül
konsantrasyonu 100 uM olmus ve daha düsük konsantrasyonlar gösterilmemistir.
Araç, sadece %0,5 DMSO ile tedavi edilen gruplari temsil eder ve islem yapilmamis
hiçbir molekül, islem yapilmis gruplari temsil etmemektedir. Molekül yanitlari, 12
saat, 24 saat, 48 saat ve 72 saatte MTT tedavisi üzerine hücrelerin spektrofotometrik
analizi ile elde edilen hücre yasayabilirligi ile degerlendirilmistir. Molekül gruplari,
tasit ve tedavi edilmemis gruplara göre istatistiksel olarak anlamli farklilik
göstermistir. Grafiklerdeki istatistiksel anlamlilik, ANOVA testi kullanilarak her bir
tedavi grubunun DMSO kontrolü ile karsilastirilmasiyla belirlenmis ve anlamlilik p
<0.001 olarak kabul edilmistir (Sekil 2).
HCT-116 hücrelerinin mikroskobik degerlendirmesi Sekil 3'te gösterilmektedir.
Hücreler fotograflanmis ve üç gün boyunca mikroskop altinda gözlenmistir. Araç
grubu, islenmemis grupta oldugu gibi hücrelerin düzgün proliferasyonunu gösterirken,
moleküle maruz birakilan grup, proliferasyonda azalma ve apoptotik hücre yapilari
göstermistir. Formül l'e ait bilesik, onikinci saatten itibaren net apoptotik aktivite
göstermistir (Sekil 3).
Sonuç olarak, hücre canliligi ilk günün sonunda %40 azalmis ve üçüncü günün
sonunda %60'a ulasmistir. Uygulama yapilmamis ve araç gruplarinda herhangi bir
hücre proliferasyon degisikligi ve apoptotik hücre morfolojisi gözlenmemistir. Ayrica,
hücre morfolojisinde farklilik da gözlenmistir. Normal hücrelerin aksine, apoptotik
hücrelerde dairesel hücre yapisi meydana gelmis oldugu gözlenmistir (Sekil 3).
Mevcut bulusa göre formül I bilesigi ile 100 uM konsantrasyonda islem
yapilmasindan sonra,3. saatten baslamak üzere apoptotik hücrelerin morfolojisine
sahip hücreler gözlenmistir.
Formüll
0.60'
0.554 n- v n fx
0.50`
0.45'
0.40' L.
0.35 1 i r i
-10 -8 -6 -4 -2
log (Konsantrasyon)
Formüll
Absorbans O UNT
1.5 5. I DMSO
1 .0 f..?
0.5 _ _,±-"ýý
Süre (Saat)
UNTREM'ED
Formula I
Claims (7)
1. DRG-MDM2-4 olan formül I ile gösterilen bir bilesik veya bunun fannasötik olarak kabul edilebilir bir türevi. Formül I
2. Formül I'e ait farmasötik açidan kabul edilebilir türev, hidratlari, solvatlari, ön ilaçlari, tüm stereoizomerleri, tuzlari, esterleri, totomerleri, izotopik olarak etiketlenmis türevleri veya insan vücudunun fizyoloj ik kosullari altinda olusan formül l'e ait bilesik formlari seklinde olabilecek, Isteml'e göre bir bilesik.
3. Bilesigin, R ve S enantiomerlerinin 1:1 rasemik karisimi formunda oldugu Istem l-2'ye göre bir bilesik.
4. PS3- MDM2 etkilesiminin rol oynadigi bir bozuklugun tedavisinde kullanilmak üzere lstem 1-3'e göre bir bilesik.
5. Rahatsizligin proliferatifbir hastalik oldugu Istem 4'te istenen kullanim için bir bilesik.
6. Proliferatif rahatsizligin kanser oldugu, Istem 5'te istendigi gibi kullanim için bir bilesik.
7. Kanserin, iyi huylu veya kötü huylu tümörler, yumusak doku sarkomu veya sarkom (örn. Liposarkom, rabdomiyosarkom) veya kemik kanseri (öm. Osteosarkomlar), karsinom (öm. 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 orijini) ve diger organlardaki metastazlari içermekte oldugu Istem 6'da istendigi gibi kullanim için bir bilesik. Bir veya daha fazla ilave farmasötik aktif ajan ile kombinasyon halinde kullanilmak üzere Istem 1-3'e göre bir bilesik. Farmasötik olarak aktif ilave ajanm, anti-proliferatif ajanlar, immünomodülatör ajanlar, antiviral ajanlar, antimikrobiyal ajanlar, anti-enfektif ajanlar, anestezik ajanlar, antiemetikler veya bunlarin kombinasyonlarini içeren bir gruptan seçildigi Istem 8'de istenen kullanim için bir bilesik. Antipoliferatif ajanlarin, antrasiklinler, taksanlar (sitoskeletal yikieilar), 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 seçildigi Istem 9'da istenen kullanim için bir bilesik. Istem 1-3'e göre bir bilesikten ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren farmasötik bir kompozisyondan meydana gelen bilesik. Istem 1-3'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 içeren bilesik.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/02325A TR202002325A2 (tr) | 2020-02-17 | 2020-02-17 | Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-4 |
| US17/800,378 US20230071340A1 (en) | 2020-02-17 | 2021-02-17 | Drg-mdm2-4 for use as a novel mouse double minute 2 (mdm2) inhibitor |
| PCT/TR2021/050146 WO2021167573A1 (en) | 2020-02-17 | 2021-02-17 | Drg-mdm2-4 for use as a novel mouse double minute 2 (mdm2) inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/02325A TR202002325A2 (tr) | 2020-02-17 | 2020-02-17 | Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-4 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR202002325A2 true TR202002325A2 (tr) | 2021-08-23 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TR2020/02325A TR202002325A2 (tr) | 2020-02-17 | 2020-02-17 | Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-4 |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US20230071340A1 (tr) |
| TR (1) | TR202002325A2 (tr) |
| WO (1) | WO2021167573A1 (tr) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ553646A (en) * | 2004-09-22 | 2010-07-30 | Janssen Pharmaceutica Nv | Inhibitors of the interaction between MDM2 and p53 |
| KR101725571B1 (ko) * | 2012-06-13 | 2017-04-11 | 가톨릭대학교 산학협력단 | Ｍｄｍ２ 억제제를 유효성분으로 포함하는 노화 억제용 조성물 |
-
2020
- 2020-02-17 TR TR2020/02325A patent/TR202002325A2/tr unknown
-
2021
- 2021-02-17 WO PCT/TR2021/050146 patent/WO2021167573A1/en active Application Filing
- 2021-02-17 US US17/800,378 patent/US20230071340A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021167573A1 (en) | 2021-08-26 |
| US20230071340A1 (en) | 2023-03-09 |
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