SI2941432T1 - 2-amino-6-fluoro-n-(5-fluoro-4-(4-(4-(oksetan-3-il)piperazin-1-karbonil) piperidin-1-il)piridin-3-il)pirazolo(1,5alfa)pirimidin-3-karboksamid kot inhibitor atr kinaze - Google Patents

2-amino-6-fluoro-n-(5-fluoro-4-(4-(4-(oksetan-3-il)piperazin-1-karbonil) piperidin-1-il)piridin-3-il)pirazolo(1,5alfa)pirimidin-3-karboksamid kot inhibitor atr kinaze Download PDF

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SI2941432T1
SI2941432T1 SI201331041T SI201331041T SI2941432T1 SI 2941432 T1 SI2941432 T1 SI 2941432T1 SI 201331041 T SI201331041 T SI 201331041T SI 201331041 T SI201331041 T SI 201331041T SI 2941432 T1 SI2941432 T1 SI 2941432T1
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cancer
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
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Nadia Ahmad
Dean Boyall
Jean-Damien Charrier
Chris Davis
Rebecca Davis
Steven Durrant
I Jardi Gorka Etxebarria
Damien Fraysse
Juan-Miguel Jimenez
David Kay
Ronald Knegtel
Donald MIDDLETON
Michael Odonnell
Maninder Panesar
Francoise Pierard
Joanne Pinder
David Shaw
Pierre-Henri Storck
John Studley
Heather Twin
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Vertex Pharmaceuticals Incorporated
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Publication of SI2941432T1 publication Critical patent/SI2941432T1/sl

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Claims (31)

1. Spojina s strukturo l-G-32:
l-G-32 ali njena farmacevtsko sprejemljiva sol.
2. Spojina po zahtevku 1 s strukturo l-G-32:
I-G-32.
2-AMINO-6-FLUORO-N-(5-FLUORO-4-(4-(4-(OKSETAN-3-IL)PIPERAZIN-1- KARBONIL)PIPERIDIN-1-IL)PIRIDIN-3-IL)PIRAZOLO[1,5ALFA]PIRIMIDIN-3- KARBOKSAMID KOT INHIBITOR ATR KINAZE PATENTNI ZAHTEVKI
3. Spojina po zahtevku 1, kjer je spojina farmacevtsko sprejemljiva sol:
4. Farmacevtski sestavek, ki obsega spojino po zahtevku 1 ali njeno farmacevtsko sprejemljivo sol, in farmacevtsko sprejemljiv nosilec.
5. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo pri zdravljenju raka pri pacientu.
6. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevku 5, kjer je navedena spojina ali njena farmacevtsko sprejemljiva sol ali omenjeni farmacevtski sestavek za uporabo pri zdravljenju raka pri pacientu v kombinaciji z DNA-škodljivim sredstvom (ang.«DNA-damaging agent«); kjer je omenjeno DNA-škodljivo sredstvo primerno za zdravljenje bolezni, ki se zdravi; in omenjeno DNA-škodljivo sredstvo se daje skupaj z omenjeno spojino kot ekratni odmerni obliki ali ločeno od omenjene spojina kot del večkratne dozirne oblike.
7. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo kot po zahtevku 6, pri čemer je omenjeno DNA-škodljivo sredstvo kemoterapija ali radioterapija; po izbiri, kjer je omenjeno DNA-škodljivo sredstvo ionizirajoče sevanje, radiomimetični neokarzinostatin, sredstvo za platiniranje, inhibitor Topo I, inhibitor Topo II, antimetabolit, alkilirajoče sredstvo, alkil sulfonat ali antibiotik.
8. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevku 7, pri čemer je omenjeno sredstvo za platiniranje cisplatin, oksaliplatin, karboplatin, nedaplatin, lobaplatin, triplatin tetranitrat, pikoplatin, satraplatin, proLindac ali aroplatin; omenjeni Topo I inhibitor je kamptotecin, topotekan, irinotekan/SN38, rubitekan ali belotekan; omenjeni inhibitor Topo II etopozid, daunorubicin, doksorubicin, aklarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin ali tenipozid; omenjeni antimetabolit je izbran iz skupine, ki jo sestavljajo aminopterin, metotreksat, pemetreksed, raltitreksed, pentostatin, kladribin, klofarabin, fludarabin, tiogvanin, merkaptopurin, 6-merkaptopurin, fluorouracil, 5-fluorouracil, kapecitabin, tegafur, karmofur, floksuridin, citarabin, gemcitabin, azacitidin in hidroksiurea; omenjeno alkilirajoče sredstvo je izbrano iz skupine, ki jo sestavljajo dušikove gorčice, nitrozosečnine, triazeni, alkil sulfonati, aziridini; mekloroetamin, ciklofosfamid, ifosfamid, trofosfamid, klorambucil, melfalan, prednimustin, bendamustin, uramustin, estramustin, karmustin, lomustin, semustin, fotemustin, nimustin, ranimustin, streptozocin, busulfan, manosulfan, treosulfan, karbokvon, tioTEPA, triazikvon, trietilenmelamin, prokarbazin, dakarbazin, temozolomid, altretamin in mitobronitol; in omenjeni antibiotik je izbran iz skupine ki jo sestavljajo hidroksiurea, antraciklini, antracenedioni, družina Streptomyces, aktinomicin, bleomicin, mitomicin in plikamicin.
9. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo kot po zahtevku 7, kjer je DNA-škodljivo sredstvo sredstvo za platiniranje ali ionizirajoče sevanje; gemcitabin; ionizirajoče sevanje; sredstvo za platiniranje, neodvisno izbrano izmed cisplatina in karboplatina; etopozid; ali temozolomid.
10. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevku 7, kjer je DNA-škodljivo sredstvo eno ali več izmed naslednjih: cisplatin, karboplatin, gemcitabin, etopozid, temozolomid in ionizirajoče sevanje; na primer, kjer je DNA-škodljivo sredstvo eno ali več izmed naslednjih: gemcitabin, cisplatin ali karboplatin in etopozid.
11. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po katerem koli od zahtevkov 5 do 10, kjer je omenjeni rak soliden tumor izbran iz skupine, ki jo sestavljajo oralni rak, srčni rak, pljučni rak, rak genitourinarnega trakta, rak jeter, rak kosti, rak živčnega sistema, ginekološki/ženski rak, kožni rak, rak na žlezi ščitnici in rak nadledvične žleze; na primer, kjer je omenjeni oralni rak izbran iz skupine, ki jo sestavljajo: rak bukalne votline, rak ustnic, rak jezika, rak ustne votline in rak žrela; kjer je omenjeni srčni rak izbran iz skupine, ki jo sestavljajo: sarkom (angiosarkom, fibrosarkom, rabdomiosarkom, liposarkom), miksom, rabdomiom, fibrom, lipom in teratom; kjer je omenjeni rak pljuč izbran iz skupine, ki jo sestavljajo: bronhogeni karcinom (skvamozno celični ali epidermoid, nediferenciran drobno celični, nediferenciran velikih celic, adenokarcinom), alveolarni (bronhiolarni) karcinom, bronhialni adenom, sarkom, limfom, hondromatozen hamartom in mezoteliom; kjer je omenjeni gastrointestinalni rak izbran iz skupine, ki jo sestavljajo: esofagealni rak (skvamozni celični karcinom, larinksa, adenokarcinom, leiomiosarkom, limfom), rak želodca (karcinom, limfom, leiomiosarkom), rak trebušne slinavke (duktalni adenokarcinom, insulinom, glukagonom, gastrinom, karcinoidni tumorji, vipom(ang.«vipoma«)), rak tankega črevesa ali ozkega črevesa (adenokarcinom, limfom, karcinoidni tumorji, Karposijev sarkom, leiomiom, hemangiom, lipom, nevrofibrom, fibrom), rak debelega črevesja ali širokega črevesja (adenokarcinom, tubularni adenom, venski adenom, hamartom, leiomiom), rak kolona, rak kolon-rektum, kolorektalni rak; in rak rektuma; kjer je omenjeni rak genitourinarnega trakta izbran iz skupine ki jo sestavljajo_: ledvični rak (adenokarcinom, VVilmov tumor [nefroblastomj, limfom), rak mehurja in uretralni rak (skvamozno celični karcinom, prehodni celični karcinom, adenokarcinom), rak prostate (adenokarcinom, sarkom) in rak testisa (seminom, teratom, embrionalni karcinom, teratokarcinom, horiokarcinom, sarkom, intersticijski celični karcinom, fibrom, fibroadenom, adenomatoidni tumorji, lipom); kjer je omenjeni rak jeter je izbran iz skupine, ki jo sestavljajo: hepatom (hepatocelularni karcinom), holangiokarcinom, hepatoblastom.angiosarkom, hepatocelularni adenom, hemangiom in biliranih prehodov; kjer je navedeni kostni rak izbran iz skupine, ki jo sestavljajo: osteogeni sarkom (osteosarkom), fibrosarkom, maligni fibrozni histiocitom, hondrosarkom, Ewingov sarkom, maligni limfom (retikulum celični sarkom), multipli mielom, hordom maligni tumor velikanskih celic, osteohronfrom (ang.»osteochronfroma) (osteocartilaginous exostoses), benigni hondrom, hondroblastom, hondromiksofibrom, osteoidni osteom in tumorji velikanskih celic; kjer je omenjeni rak živčnega sistema izbran iz skupine, ki jo sestavljajo: rak lobanje (osteom, hemangiom, granulom, ksantom, osteitis deformans), meningiom (meningioma, meningiosarkom, gliomatoza), možganski rak (astrocitom, meduloblastom, gliom, ependimom, germinom [pinealomj, multiformni glioblastom, oligodendrogliom, švanom, retinoblastom, kongenitalni tumorji), rak hrbtenjače, nevrofibrom, meningiom, gliom in sarkom; pri čemer je omenjeni ginekološki/ženski rak izbran iz skupine, ki jo sestavljajo: rak maternice (karcinom endometrija), rak materničnega vratu (karcinom materničnega vratu, pred-tumorska displazija materničnega vratu), rak jajčnikov (karcinom jajčnikov [serozni cistadenokarcinom, mucinozni cistadenokarcinom, nerazvrščeni karcinom], granuloza-tekalni celični tumorji, Sertoli-Leydig celični tumorji, disgerminom, maligni teratom), vulvami rak (skvamozni celični karcinom, intraepitelijski karcinom, adenokarcinom, fibrosarkom, melanom), vaginalni rak (čisti celični karcinom, skvamozni celični karcinom, botrioidni sarkom (embrionalni rabdomiosarkom), jajcevodni rak (karcinom) in rak dojke; pri čemer je omenjeni kožni rak izbran iz skupine, ki jo sestavljajo: maligni melanom, bazalni celični karcinom, skvamozni celični karcinomom, Karposijevim sarkomom, keratoakantom, moli displastični nevus (ang.«moles dysplastic nevi«), lipom, angiom in dermatofibrom; kjer je omenjeni rak ščitnične žleze izbran iz skupine, ki jo sestavljajo papilarni karcinom ščitnice (ang.«papillary thyroid carcinoma«), folikularni karcinom ščitnice; medularni karcinom ščitnice, multipla endokrina neoplazija tipa 2A, multipla endokrina neoplazija tipa 2B, familiarni medularni rak ščitnice, feokromocitom in paragangliom; in pri čemer je omenjeni rak nadledvične žleze nevroblastom.
12. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po katerem koli od zahtevkov 5 do 10, pri čemer je omenjeni rak pljučni rak, rak glave in vratu, rak trebušne slinavke, rak želodca ali rak možganov; ali je navedeni rak nedrobnocelični pljučni rak, drobnocelični pljučni rak, rak trebušne slinavke, rak bilirnega trakta, rak sečnega mehurja, kolorektalni rak, glioblastom, ezofagalni rak, rak dojk, hepatocelularni karcinom ali rak jajčnikov; na primer, omenjeni rak je rak pljuč ali trebušne slinavke.
13. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevku 11, kjer je rak pljučni rak in je pljučni rak drobnocelični pljučni rak, in je DNA-škodljivo sredstvo, cisplatin in etopozid; ali kjer je pljučni rak nedrobnocelični pljučni rak in in je DNA-škodljivo sredstvo, gemcitabin in cisplatin, na primer, kjer je nedrobnocelični pljučni rak je skvamozni nedrobnocelični pljučni rak.
14. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevkih 5 do 10, kjer je rak rak dojke in je DNA-škodljivo sredstvo cisplatin; na primer, kjer je rak trojno negativni rak dojke.
15. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po zahtevku 7, pri čemer je rak rak trebušne slinavke in je DNA-škodljivo sredstvo gemcitabin.
16. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo pri zdravljenju raka trebušne slinavke v kombinaciji z DNA-škodljivim sredstvom, izbranim iz skupine, ki jo sestavljajo gemcitabin, radioterapija in obeh skupaj gemcitabina ter terapije z obsevanjem.
17. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo pri povečanju občutljivosti rakavih celic trebušne slinavke za izbrano terapijo raka od kemoterapije in radioterapije; na primer, kjer je a) kemoterapija gemcitabin; b) terapija raka je gemcitabin; c) terapija raka je radioterapija; ali d) terapija raka je gemcitabin in radioterapija.
18 z reagiranjem spojine s formulo 31:
18 pod ustreznimi pogoji za izmenjavo halogenov da se tvori spojina iz formule 32.
32 in 2) reagiranjem spojine s formulo 32:
32 s spojino s formulo 22: 22 pod ustreznimi premestitvenimi pogoji;
po izbiri, nadalje obsegajoč korak priprave spojine s formulo 18:
18. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, v kombinaciji z gemcitabinom (100 nM) in/ali sevanjem (6 Gy) za uporabo pri inhibiranju fosforilacije Chk1 (Ser 345) v rakasti celici trebušne slinavke.
19. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, v kombinaciji s kemoradiacijo za uporabo pri senzitizacijo rakavih celic pankreasa za kemoradiacijo; na primer, kjer je kemoradiacija gemcitabin in obsevanje.
20. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, v kombinaciji z radioterapijo, za uporabo pri radiosenzitizacijo hipoksičnih rakastih celic trebušne slinavke; ali v kombinaciji s kemoterapijo, za uporabo pri senzitizaciji hipoksičnih rakastih celic trebušne slinavke.
21. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, v kombinaciji z radioterapijo in/ali gemcitabinom, za uporabo v a) prekinitev kontrolnih točk celičnega cikla, povzročenih s škodo; ali b) inhibiranje popravila poškodbe DNA s homologno rekombinacijo v rakasti celici trebušne slinavke; na primer, kjer se spojina ali njena farmacevtsko sprejemljiva sol daje bolniku ali v rakasto celico trebušne slinavke.
22. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, v kombinaciji z enim ali več izmed naslednjih DNA-škodljivih sredstev: cisplatin ali karboplatin, etopozid in ionizirajočega sevanje, za uporabo pri zdravljenju nedrobnoceličnega pljučnega raka.
23. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo v a) spodbujanje celične smrti v rakavih celicah pri pacientu; b) preprečevanje celičnega popravila DNA poškodbe pri pacientu; ali c) senzitizacija celice na DNA-škodljivo sredstvo pri pacientu.
24. In vitro ali ex vivo metoda za inhibiranje ATR v biološkem vzorcu, ki obsega korak stika s spojino, ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3, ali farmacevtski sestavek po zahtevku 4, z navedenim biološkim vzorcem, na primer, kjer je navedeni biološki vzorec celica.
25 pod ustreznimi pogoji, da se tvori amidna vez; na primer, kjer ustrezni pogoji za tvorbo amidne vezi obsegajo reagiranje spojine s formulo 30 s spojino s formulo 25 v prisotnosti partnerja za amidno spajanje, aprotičnega topila in baze; na primer, kjer je aprotično topilo NMP, DMF ali tetrahidrofuran; na primer, kjer je baza alifatski amin, po izbiri kjer je baza DIPEA; in
na primer, kjer je partner za amidno spajanje TBTU ali TCTU.
25. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po katerem koli od zahtevkov 7-23, kjer ima navedeni rak, rakava celica ali celica pomanjkljivost v osnovnem popravljalnem proteinu z izrezom, pri čemer je osnovni popravljalni protein z izrezom PART1 ali PARP2.
26 z 1) reagiranjem spojine s formulo 18:
26 pod ustreznimi pogoji da se tvori amin; po izbiri pri čemer, proces nadalje obsega korak priprave spojine s formulo 26:
26. Spojina ali njena farmacevtsko sprejemljiva sol po katerem koli od zahtevkov 1-3 ali farmacevtski sestavek po zahtevku 4, za uporabo po katerem koli od zahtevkov 7-23, kjer uporaba nadalje obsega dajanje dodatnega terapevtskega sredstva, ki inhibira ali modulira osnovni popravljalni protein z izrezom, kjer je osnovni popravljalni protein z izrezom PART1 ali PARP2.
27 ki obsega korak reagiranja spojine s formulo 26:
27. Proces priprave spojine s formulo l-G-32:
l-G-32 ki obsega korak reagiranja spojine s formulo 30:
28 reagiranjem spojine s formulo 6a*:
6a* s spojino s formulo 27:
pod ustreznimi pogoji da se tvori amidna vez.
28. Proces po zahtevku 27, ki nadalje obsega korak priprave spojine s formulo 30:
29. Proces po zahtevku 28, kjer ustrezni deprotekcijski pogoji obsegajo reagiranje spojine s formulo 28 s kislino v prisotnosti topila; na primer, kjer je kislina HCI; in na primer, kjer je topilo 1,4-dioksan.
30. Proces po zahtevku 28, kjer ustrezni pogoji za tvorbo amidne vezi obsegajo reagiranje spojine s formulo 6a* s spojino s formulo 27 v aprotičnem topilu pod toploto; na primer, kjer je aprotično topilo NMP, piridin ali DMF; in na primer, kjer se reakcijo izvede pri temperaturi najmanj 80°C.
31. Proces za pripravo spojine s formulo 27:
30 z reagiranjem spojine s formulo 28:
28
pod ustreznimi deprotekcijskimi pogoji, da se tvori karboksilna kislina; na primer, ki nadalje obsega korak priprave spojine s formulo 28:
30 s spojino s formulo 25:
31 pod ustreznimi pogoji halogeniranja.
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RS62174B1 (sr) 2021-08-31
US20140249157A1 (en) 2014-09-04
US20180072735A1 (en) 2018-03-15
AU2018204431B2 (en) 2020-04-02
AU2018204431A1 (en) 2018-07-05
CN104903325B (zh) 2017-10-20
ES2884030T3 (es) 2021-12-10
SI3808749T1 (sl) 2023-07-31
ME03036B (me) 2018-10-20
JP6574859B2 (ja) 2019-09-11
DK2941432T3 (en) 2018-06-14
US20210047333A1 (en) 2021-02-18
LT3486245T (lt) 2021-08-25
WO2014089379A9 (en) 2015-01-15
RU2015127079A (ru) 2017-01-10
US9718827B2 (en) 2017-08-01
DK3808749T3 (da) 2023-06-06
CN107501274B (zh) 2019-11-22
CY1120232T1 (el) 2019-07-10
HRP20180859T1 (hr) 2018-07-13
EP3486245B1 (en) 2021-04-28
SG11201504467YA (en) 2015-07-30
DK3486245T3 (da) 2021-07-19
FI3808749T3 (fi) 2023-05-31
SI3418281T1 (sl) 2021-02-26
RS61319B1 (sr) 2021-02-26
RS57210B1 (sr) 2018-07-31
LT3808749T (lt) 2023-06-12
CN107501275B (zh) 2019-11-22
EP4190786A1 (en) 2023-06-07
EP3418281A1 (en) 2018-12-26
NZ630457A (en) 2017-05-26
PL3808749T3 (pl) 2023-07-10
ES2842876T3 (es) 2021-07-15
PL3486245T3 (pl) 2021-11-08
CN104903325A (zh) 2015-09-09
AU2013355124B2 (en) 2018-03-22
US9650381B2 (en) 2017-05-16
JP2018087213A (ja) 2018-06-07
US20160347754A1 (en) 2016-12-01
US20180155346A1 (en) 2018-06-07
CY1124291T1 (el) 2022-07-22

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