HRP20210960T1 - Spojevi i derivati spiro[3h-indol-3,2’-pirolidin]-2(1h)-ona kao inhibitori mdm2-p53 - Google Patents
Spojevi i derivati spiro[3h-indol-3,2’-pirolidin]-2(1h)-ona kao inhibitori mdm2-p53 Download PDFInfo
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Claims (36)
1. Spoj, naznačen time, da je predstavljen formulom (I)
[image]
,
u kojoj
--
R1 je skupina, opcionalno supstituirana s jednim ili više, istih ili različitih Rb1 i/ili Rc1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C16haloalkil, C3-7cikloalkil, C47cikloalkenil, C6-10aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rb1 se neovisno bira između sljedećih: -ORc1, -NRc1Rc1, halogen, CN, C(O)Rc1, C(O)ORc1, C(O)NRc1Rc1, S(O)2Rc1, S(O)2NRc1Rc1, NHC(O)Rc1, N(C14alkil)C(O)Rc1 i bivalentni supstituent =O, dok =O može biti supstituent samo u nearomatskim sustavima prstena;
svaki Rc1 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rd1 i/ili Re1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rd1 se neovisno bira između sljedećih: -ORe1, -NRe1Re1, halogen, CN, C(O)Re1, C(O)ORe1, C(O)NRe1Re1, S(O)2Re1, S(O)2NRe1Re1, NHC(O)Re1, N(C14alkil)C(O)Re1 i bivalentni supstituent =O, dok =O može biti supstituent samo u nearomatskim sustavima prstena;
svaki Re1 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rf1 i/ili Rg1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rf1 se neovisno bira između sljedećih: -ORg1, -NRg1Rg1, halogen, CN, C(O)Rg1, C(O)ORg1, C(O)NRg1Rg1, S(O)2Rg1, S(O)2NRg1Rg1, NHC(O)Rg1, N(C14alkil)C(O)Rg1 i bivalentni supstituent =O, dok =O može biti supstituent samo u nearomatskim sustavima prstena;
svaki Rg1 se neovisno bira od sljedećih: vodik, C1-6alkil, C2-6alkenil, C26alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C6-10aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
--
jedan od R2 i R3 je vodik a drugi se bira između fenila i 5-članog do 6-članog heteroarila, pri čemu su navedeni fenil i 5člani do 6-člani heteroaril su opcionalno supstituirani s jednim ili više, istih ili različitih Rb2 i/ili Rc2;
svaki Rb2 se neovisno bira između sljedećih: -ORc2, -NRc2Rc2, halogen, CN, C(O)Rc2, C(O)ORc2, C(O)NRc2Rc2, S(O)2Rc2, S(O)2NRc2Rc2, NHC(O)Rc2 i N(C14alkil)C(O)Rc2;
svaki Rc2 neovisno jedan od drugoga označava vodik ili skupinu koja se bira između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C36cikloalkil, C46cikloalkenil, phenil, 5-člani do 6-člani heteroaril i 3člani do 7-člani heterociklil;
--
A se bira između fenila i 5-članog do 6-članog heteroarila, ako je F ugljik ili
A je 5-člani do 6-člani heteroaril koji sadrži dušik, ako je F dušik;
svaki R4 se neovisno bira između Ra4 i Rb4;
svaki Ra4 neovisno jedan od drugoga predstavlja skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rb4 i/ili Rc4, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rb4 se neovisno bira između sljedećih: -ORc4, -NRc4Rc4, halogen, CN, C(O)Rc4, C(O)ORc4, C(O)NRc4Rc4, C(O)NRg4ORc4, S(O)2Rc4, S(O)2NRc4Rc4, -NHSO2Rc4, -N(C1-4alkil)SO2Rc4, NHC(O)Rc4 i N(C14alkil)C(O)Rc4;
svaki Rc4 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rd4 i/ili Re4, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rd4 se neovisno bira između sljedećih: -ORe4, -NRe4Re4, halogen, CN, C(O)Re4, C(O)ORe4, C(O)NRe4Re4, C(O)NRg4ORe4, S(O)2Re4, S(O)2NRe4Re4, NHC(O)Re4 i N(C14alkil)C(O)Re4;
svaki Re4 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rf4 i/ili Rg4, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rf4 se neovisno bira između sljedećih: -ORg4, -NRg4Rg4, halogen, CN, C(O)Rg4, C(O)ORg4, C(O)NRg4Rg4, C(O)NRg4ORg4, S(O)2Rg4, S(O)2NRg4Rg4, NHC(O)Rg4 i N(C14alkil)C(O)Rg4;
svaki Rg4 se neovisno bira između sljedećih: vodik, C1-6alkil, C2-6alkenil, C26alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C6-10aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
r označava broj 0, 1, 2 ili 3;
--
n označava broj 1 ili 2;
--
svaki R7 se neovisno bira između sljedećih: halogen, C1-4alkil, -CN, C14haloalkil, OC1-4alkil i OC1-4haloalkil;
q označava broj 0, 1, 2 ili 3;
--
W, X i Y su –CH= uz uvjet da vodik u svakom –CH= može biti zamijenjen sa supstituentom R7 ako je prisutan;
--
V je kisik ili sumpor;
--
D je dušik, E je ugljik i F je ugljik; ili
D je ugljik, E je dušik i F je ugljik; ili
D je ugljik, E je ugljik i F je dušik;
ili njegova sol.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom (Ia) ili (Ib) ili (Ic)
[image]
[image]
[image]
ili njegova sol.
3. Spoj prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom (Ia*) ili (Ib*) ili (Ic*)
[image]
[image]
[image]
ili njegova sol.
4. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da
R1 je skupina, opcionalno supstituirana s jednim ili više, istih ili različitih Rb1 i/ili Rc1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C16haloalkil, C3-7cikloalkil, C47cikloalkenil, C6-10aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rb1 se neovisno bira između sljedećih: -ORc1, -NRc1Rc1, halogen, CN, C(O)Rc1, C(O)ORc1, C(O)NRc1Rc1, S(O)2Rc1, S(O)2NRc1Rc1, NHC(O)Rc1 i N(C14alkil)C(O)Rc1;
svaki Rc1 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rd1 i/ili Re1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rd1 se neovisno bira između sljedećih: -ORe1, -NRe1Re1, halogen, CN, C(O)Re1, C(O)ORe1, C(O)NRe1Re1, S(O)2Re1, S(O)2NRe1Re1, NHC(O)Re1 i N(C14alkil)C(O)Re1;
svaki Re1 neovisno jedan od drugoga označava vodik ili skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rf1 i/ili Rg1, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rf1 se neovisno bira između sljedećih: -ORg1, -NRg1Rg1, halogen, CN, C(O)Rg1, C(O)ORg1, C(O)NRg1Rg1, S(O)2Rg1, S(O)2NRg1Rg1, NHC(O)Rg1 i N(C14alkil)C(O)Rg1;
svaki Rg1 se neovisno bira između slljedećih: vodik, C1-6alkil, C2-6alkenil, C26alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C6-10aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
ili njegova sol.
5. Spoj prema patentnom zahtjevu 1, naznačen time, da
jedan od R2 i R3 je vodik a drugi se bira između fenila i 5-članog do 6-članog heteroarila, pri čemu su navedeni fenil i 5-člani do 6-člani heteroaril opcionalno supstituirani s jednim ili više, istih ili različitih supstituenata koji se biraju između sljedećih: OC16alkil, halogen, C16alkil i C16haloalkil;
ili njegova sol.
6. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da
R3 jest vodik;
ili njegova sol.
7. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da
A se bira između fenila i 5-članog do 6-članog heteroarila, ako je F ugljik ili
A je 5-člani do 6-člani heteroaril koji sadrži dušik, ako je F dušik;
svaki R4 se neovisno bira između Ra4 i Rb4;
svaki Ra4 neovisno jedan od drugoga predstavlja skupinu, opcionalno supstituiranu s jednim ili više, istih ili različitih Rb4 i/ili Rc4, koji se biraju između sljedećih: C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
svaki Rb4 se neovisno bira između sljedećih: -ORc4, -NRc4Rc4, halogen, CN, C(O)Rc4, C(O)ORc4, C(O)NRc4Rc4, C(O)NHORc4, S(O)2Rc4, S(O)2NRc4Rc4, -NHSO2Rc4, -N(C1-4alkil)SO2Rc4, NHC(O)Rc4 i N(C14alkil)C(O)Rc4;
svaki Rc4 neovisno jedan od drugoga se bira između sljedećih: vodik, C1-6alkil, C26alkenil, C2-6alkinil, C1-6haloalkil, C37cikloalkil, C47cikloalkenil, C610aril, 5-člani do 10-člani heteroaril i 3člani do 10-člani heterociklil;
r označava broj 0, 1, 2 ili 3;
ili njegova sol.
8. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da
A zajedno s r supstituenata R4 predstavlja
[image]
;
R8 se bira između sljedećih: vodik, C1-6alkil, -OC1-6alkil, halogen, CN, C(O)OH, C(O)OC16alkil, C(O)NH2, C(O)NHC1-6alkil, C(O)N(C16alkil)2 i S(O)2C16alkil;
R9 se bira između sljedećih: vodik, C1-6alkil, -OC1-6alkil, halogen, CN, C(O)OH, C(O)OC16alkil, C(O)NH2, C(O)NHC1-6alkil, C(O)N(C16alkil)2 i S(O)2C16alkil;
R10 se bira između sljedećih: vodik, C1-6alkil, -OC1-6alkil, halogen, CN, C(O)OH, C(O)OC16alkil, C(O)NH2, C(O)NHC1-6alkil, C(O)N(C16alkil)2 i S(O)2C16alkil;
uz uvjet da najmanje jedan od R8 do R10 ali ne svi od R8 do R10 je/su vodik;
ili njegova sol.
9. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da
svaki R7 je neovisno halogen ili -CN i q je 1 ili 2;
ili njegova sol.
10. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da se bira između sljedećih:
[image]
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11. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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12. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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13. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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14. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
[image]
15. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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16. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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17. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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18. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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19. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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20. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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21. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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22. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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23. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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24. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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25. Spoj prema patentnom zahtjevu 10, naznačen time, da je predstavljen Formulom
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26. Farmaceutski prihvatljiva sol, naznačena time, da je od bilo kojega od spojeva u skladu s bilo kojim od patentnih zahtjeva 11 do 25.
27. Spoj prema bilo kojem od patentnih zahtjeva 1 do 25, ili njegova farmaceutski prihvatljiva sol, naznačeni time, da su za uporabu kao lijek.
28. Spoj prema bilo kojem od patentnih zahtjeva 1 do 25, ili njegova farmaceutski prihvatljiva sol, naznačeni time, da su za uporabu u liječenju i/ili prevenciji bolesti i/ili stanja koji se biraju od sljedećih:
virusne infekcije (primjerice HIV i Kaposijev sarkom); upalne i autoimune bolesti (primjerice kolitis, artritis, Alzheimerova bolest, glomerulonefritis i zacijeljivanje rana); bakterijske, gljivične i/ili parazitne infekcije; leukemije, limfomi i solidni tumori (primjerice karcinomi i sarkomi), kožne bolesti (primjerice psorijaza); bolesti zasnovane na hiperplaziji koje su naznačene time, da se povećava broj stanica (primjerice fibroblasti, hepatociti, koštane stanice i stanice koštane srži, stanice hrskavice ili glatkih mišića ili epitelne stanice (primjerice endometrijska hiperplazija); bolesti kostiju i kardiovaskularne bolesti (primjerice restenoza i hipertrofija); oni su također prikladni za zaštitu proliferacijskih stanica (primjerice kose, crijeva, krvi i progenitorskih stanica) od oštećenja DNA koje je prouzročeno radijacijom, UV obradom i/ili liječenjem citostaticima; tumori na mozgu kao što je na primjer akustični neurinom, astrocitomi kao što su pilocitički astrocitomi, fibrilarni astrocitom, protoplasmički astrocitom, gemistocitarni astrocitom, anaplastični astrocitom i glioblastom, gliom, limfomi mozga, metastaze na mozgu, hipofizalni tumor kao što je prolaktinom, tumor koji proizvodi HGH (ljudski hormon rasta) i tumor koji proizvodi ACTH (adrenokortikotropni hormon), kraniofaringiomi, meduloblastomi, meningeomi i oligodendrogliomi; tumori živaca (neoplazme) kao što su na primjer tumori vegetativnog živčanog sustava kao što je neuroblastom simpatikum, ganglioneurom, paragangliom (feokromocitom, kromafinom) i tumor glomus-karotikum, tumori na perifernom živčanom sustavu kao što jsu amputacijski neurom, neurofibrom, neurinom (neurilemom, Schwannom) i maligni Schwannom, kao i tumori središnjeg živčanog sustava kao što su tumori na mozgu i tumori koštane srži; intestinalni rak kao što je na primjer karcinom rektuma, karcinom debelog crijeva, kolorektalni karcinom, analni karcinom, karcinom velikog crijeva, tumori malog crijeva i duodenuma; tumori očnog kapka kao što je bazaliom ili karcinom bazalnih stanica; rak gušterače ili karcinom pankreasa; rak mokraćnog mjehura ili karcinom mokraćnog mjehura i ostali urotelijalni rakovi; rak pluća (bronhijalni karcinom) kao što su na primjer bronhijalni karcinomi malih stanica (karcinomi zobenih stanica) i bronhijalni karcinomi ne-malih stanica (NSCLC) kao što su karcinomi pločastih epitela, adenokarcinomi i bronhijalni karcinomi velikih stanica; rak dojke kao što je primjerice karcinom mliječnih žlijezda kao što su infiltrirani duktalni karcinom, koloidni karcinom, lobularni invazivni karcinom, tubularni karcinom, adenocistični karcinom i papilarni karcinom, rak dojke pozitivan na hormonski receptor (rak dojke pozitivan na estrogenski receptor, rak dojke pozitivan na progesteronski receptor), rak dojke pozitivan na Her2, trostruko negativni rak dojke; ne-Hodgkinovi limfomi (NHL) kao što su primjerice Burkittov limfom, ne-Hodgkinov limfom niske malignosti (NHL) i mukozni fungoidi; rak maternice ili endometrijski karcinom ili karcinom korpusa; CUP sindrom (prema engl. Cancer of Unknown Primary – rak nepoznatog izvora); rak jajnika ili karcinom jajnika kao što je mucinozni, endometrijski ili serozni rak; rak žučnog mjehura; rak žučnih vodova kao što je primjerice Klatskinov tumor; rak testisa kao što su na primjer seminomi i ne-seminomi; limfom (limfosarkom) kao što su primjerice maligni limfom, Hodgkinova bolest, ne-Hodgkinovi limfomi (NHL) kao što su kronična limfocitna leukemija, leukemijska retikuloendotelioza, imunocitom, plazmocitom, multipli mijelom (MM), imunoblastom, Burkittov limfom, mukozni fungoidi T-zone, anaplastični limfoblastom velikih stanica i limfoblastom; rak grkljana kao što su primjerice tumori glasnica, supraglotidni, glotidni i subglotidni tumori grkljana; rak kostiju kao što su na primjer osteohondrom, hondrom, hondroblastom, hondromiksoidni fibrom, osteom, osteoidni osteom, osteoblastom, eozinofilni granulom, tumor divovske stanice, hondrosarkom, osteosarkom, Ewingov sarkom, retikulo-sarkom, sarkom mekog tkiva, liposarkom, plazmocitom, fibrozna displazija, mladenačke ciste na kostima i aneurizmatične ciste kostiju; tumori glave i vrata kao što su na primjer tumori usana, jezika, dna usta, usne šupljine, desni, nepca, žlijezde slinovnice, grla, nosne šupljine, paranazalnih sinusa, grkljana i srednjeg uha; rak jetre kao što su primjerice karcinom jetrenih stanica ili hepatocelularni karcinom (HCC); leukemije, kao što su na primjer akutne leukemije kao primjerice akutna limfocitna / limfoblastična leukemija (ALL), akutna mijeloična leukemija (AML); kronične leukemije kao što su kronična limfocitna leukemija (CLL), kronična mijeloična leukemija (CML); mijelodisplastični sindromi (MDS); rak želuca ili gastrički karcinom kao što su primjerice papilarni, tubularni i mucinozni adenokarcinom, karcinom prstenastih stanica s pečatom, adenoskvamozni karcinom, karcinom malih stanica i nediferencirani karcinom; melanomi kao što su primjerice površinski rasprostranjeni, čvorasti, lentigo-maligna i akralni lentigni melanom; rak bubrega kao što su na primjer karcinom bubrežnih stanica ili hipernefrom ili Grawitzov tumor; rak jednjaka ili karcinom jednjaka; rak penisa; rak prostate (primjerice rak prostate otporan na kastraciju); rak grla ili karcinomi ždrijela kao što su na primjer karcinomi nazofarinksa, karcinomi orofarinksa i karcinomi hipofarinksa; retinoblastom, vaginalni rak ili vaginalni karcinom, mezoteliom; karcinomi pločastih epitela, adenokarcinomi, in situ karcinomi, maligni melanomi i sarkomi; tiroidni karcinomi kao što su primjerice papilarni, folikularni i medularni karcinom štitnjače, kao i anaplastični karcinomi; spinaliom, epidermoidni karcinom i karcinom pločastih epitela kože; timomi, rak uretre, rak cerviksa, adenoidni cistični karcinom (AdCC), adrenokortikalni karcinom i rak vulve.
29. Spoj za uporabu prema patentnom zahtjevu 28, naznačen time, da je za uporabu u liječenju i/ili prevenciji raka pluća koji se bira iz skupine koju čine bronhijalni karcinomi malih stanica i bronhijalni karcinomi ne-malih stanica (NSCLC) kao što su karcinomi pločastih epitelnih stanica, adenokarcinomi i bronhijalni karcinomi velikih stanica.
30. Spoj za uporabu prema patentnom zahtjevu 28, naznačen time, da je za uporabu u liječenju i/ili prevenciji bolesti ili stanja koji se biraju iz skupine koju čine sarkom mekog tkiva i liposarkom.
31. Spoj za uporabu prema patentnom zahtjevu 28, naznačen time, da je za uporabu u liječenju i/ili prevenciji tumora na mozgu koji se bira iz skupine koju čine akustični neurinom, astrocitomi, glioblastom, gliom, limfomi mozga, metastaze na mozgu, hipofizni tumor kao što je prolaktinom, tumor koji proizvodi HGH i tumor koji proizvodi ACTH, kraniofaringiomi, meduloblastomi, meningeomi i oligodendrogliomi.
32. Spoj prema bilo kojem od patentnih zahtjeva 1 do 25, ili njegova farmaceutski prihvatljiva sol, naznačeni time, da su za uporabu u liječenju i/ili prevenciji raka, zaraza, upala ili autoimunih bolesti.
33. Spoj ili njegova farmaceutski prihvatljiva sol, za uporabu prema patentnom zahtjevu 28, naznačeni time, da su za liječenje raka.
34. Farmaceutski pripravak, naznačen time, da sadrži najmanje jedan spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 25, ili njegovu farmaceutski prihvatljivu sol, i farmaceutski prihvatljiv nosač.
35. Farmaceutski pripravak, naznačen time, da sadrži najmanje jedan spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 25, ili njegovu farmaceutski prihvatljivu sol, i najmanje jednu, neku drugu citostatičku i/ili citotoksičnu aktivnu tvar.
36. Spoj prema bilo kojem od patentnih zahtjeva 1 do 25, ili njegova farmaceutski prihvatljiva sol, koji su za uporabu u liječenju i/ili prevenciji raka, zaraza, upala ili autoimunih bolesti, naznačeni time, da se navedeni spoj primjenjuje prije, poslije ili zajedno s najmanje jednom, nekom drugom citostatičkom ili citotoksičnom aktivnom tvari.
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| EP3129380B1 (en) | 2014-04-11 | 2018-11-28 | Boehringer Ingelheim International Gmbh | Spiro[3h-indole-3,2'-pyrrolidin]-2(1h)-one derivatives and their use as mdm2-p53 inhibitors |
| EP3164401B1 (en) | 2014-07-03 | 2018-12-26 | Boehringer Ingelheim International GmbH | New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
| CN107001385B (zh) | 2014-08-21 | 2020-03-13 | 勃林格殷格翰国际有限公司 | 作为mdm2-p53抑制剂的螺-[3h-吲哚-3，2’-吡咯烷]-2(1h)-酮化合物及其衍生物 |
| BR112018007155B1 (pt) * | 2015-10-09 | 2022-12-13 | Boehringer Ingelheim International Gmbh | Novos compostos de espiro[3h-indol-3,2-pirrolidin]-2(1h)-ona e derivados como inibidores de mdm2-p53 |
| TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療 |
| TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
| EP3606556A1 (en) | 2017-04-05 | 2020-02-12 | Boehringer Ingelheim International GmbH | Anticancer combination therapy |
| WO2019128877A1 (zh) * | 2017-12-29 | 2019-07-04 | 甘李药业股份有限公司 | 一种可用作肿瘤抑制剂的化合物及其制备方法与应用 |
| EP3511334A1 (en) * | 2018-01-16 | 2019-07-17 | Adamed sp. z o.o. | 1,2,3',5'-tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,3'-dione compounds as therapeutic agents activating tp53 |
| WO2020018611A1 (en) * | 2018-07-18 | 2020-01-23 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for identification, assessment, prevention, and treatment of ewing sarcoma using tp53 dependency biomarkers and modulators |
| US10590147B1 (en) | 2019-09-10 | 2020-03-17 | King Saud University | Spirooxindole-pyrrolothiazole heterocyclic hybrids |
| PH12022551091A1 (en) * | 2019-11-05 | 2024-06-24 | Abbvie Deutschland | Dosing regimens for use in treating myelofibrosis and mpn-related disorders with navitoclax |
| EP4157836B1 (en) | 2020-06-02 | 2025-10-29 | Boehringer Ingelheim International GmbH | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
| CN112047951A (zh) * | 2020-10-16 | 2020-12-08 | 吉林大学 | 手性螺[吡咯-2，2’-呋喃]化合物及其制备方法 |
| TW202309022A (zh) | 2021-04-13 | 2023-03-01 | 美商努法倫特公司 | 用於治療具egfr突變之癌症之胺基取代雜環 |
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