HRP20151141T1 - Derivati piridila kao modulatori cftr - Google Patents

Derivati piridila kao modulatori cftr Download PDF

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HRP20151141T1
HRP20151141T1 HRP20151141TT HRP20151141T HRP20151141T1 HR P20151141 T1 HRP20151141 T1 HR P20151141T1 HR P20151141T T HRP20151141T T HR P20151141TT HR P20151141 T HRP20151141 T HR P20151141T HR P20151141 T1 HRP20151141 T1 HR P20151141T1
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compound according
aryl
independently
alkylidene
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HRP20151141TT
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Sara Hadida-Ruah
Mark Miller
Jinglan Zhou
Brian Bear
Peter Grootenhuis
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Vertex Pharmaceuticals Incorporated
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Claims (36)

1. Spoj s formulom I: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: RN je H, alkil, aril, heteroaril, aralkil, cikloalkil, ili heterocikloalkil; A je 3 člani monociklički prsten; B je proizvoljno kondenziran na 5-7 člani prsten odabran iz skupine koju čine cikloalifatski prstenovi, aril, heterociklički prstenovi, i heteroaril; R1 je halogen, alkil, OH, alkoksi, tioalkil, trifluorometoksi; ili dva R1 na susjednim atomima, zajedno, tvore [image] pri čemu J je odabran iz skupine koju čine CH2, CF2, ili C(CH3)2; W je neovisno veza ili (C1-C6) alkilidenski lanac pri čemu su do dvije jedinice metilena iz W neovisno zamijenjene s -O-, -S-, -SO2-, ili-NR'-; R' je neovisno H, alkil, aril, heteroaril, aralkil, cikloalkil, ili heterociklil; RW je neovisno H, CN, NO2, N(R)2, CF3, OCF3, OH, OR, CO2R, C(O)N(R)2, -O(C1-C6)alkiliden-OR, -O(C1-C6)alkiliden-N(R)2, -O(C1-C6)alkiliden-heterociklil, ili alifatski, cikloalifatski, aril, ariloksi, heterociklički, ili heteroarilni ostatak, pri čemu, kada je supstituiran, Rw je supstituiran s do dva R2; R2 je halogen, CN, NO2, CF3, OCF3, OR, OC(O)R, OC(O)N(R)2, SR, S(O)R, SO2R, SO2N(R)2, SO3R, C(O)R, CO2R, C(O)N(R)2, N(R)2, NRC(O)R, NRCO2R, NRC(O)N(R)2, NRSO2R, B(OR)2, ili NRSO2N(R)2; R je neovisno H, alkil, cikloalkil, heterociklil, aril, ili heteroaril; n je 1 ili 2; w je cijeli broj od 0 do uključujući 4; i x je cijeli broj od 0 do uključujući 5; uz uvjet da kada W je veza i Rw je cikloalifatski, heterocikloalifatski, aril, ili heteroarilni ostatak, -W-Rw je vezan na 3- ili 4- položaj u piridil prstenu.
2. Spoj prema zahtjevu 1, naznačen time da J je CH2.
3. Spoj prema zahtjevu 1, naznačen time da J je CF2.
4. Spoj prema zahtjevu 1, naznačen time da RN je H ili alkil.
5. Spoj prema zahtjevu 1, naznačen time da W je veza.
6. Spoj prema zahtjevu 1, naznačen time da W je (C1-C6) alkilidenski lanac.
7. Spoj prema zahtjevu 1, naznačen time da W je odabran iz skupine koju čine -CH2-, -NH-, -O-, i -OCH2-.
8. Spoj prema zahtjevu 1, naznačen time da Rw je odabran iz skupine koju čine H, OH, heterociklil, aril, fenil, heteroaril, piridil, alkoksi, cikloalkil, i cikloheksil.
9. Spoj prema zahtjevu 1, naznačen time da-W-Rw je aciklički.
10. Spoj prema zahtjevu 1, naznačen time da -W-Rw je aril, heteroaril, cikloalifatski, ili heterocikloalifatski prsten.
11. Spoj prema zahtjevu 1, naznačen time da -W(Rw)n je odabran od slijedećeg: -F, -CH3, -CH2CH3, -CN, -CF3, -CONH2, -CH2CH(CH3)2, [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
12. Spoj prema zahtjevu 1, naznačen time da -W(Rw)n je odabran od slijedećeg: [image] [image]
13. Spoj prema zahtjevu 1, koji ima formulu Ia: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: J je CH2 ili CF2; W je neovisno veza ili (C1-C6) alkilidenski lanac po izboru supstituiran s R2 pri čemu su do dvije jedinice metilena iz W neovisno zamijenjene s -O-, ili -NR'-; R' je neovisno H ili alkil; RW je neovisno H, CN, N(R)2, CF3, OH, CO2R, C(O)N(R)2, -O(C1-C6)alkiliden-OR, -O(C1-C6)alkiliden-N(R)2, -O(C1-C6)alkiliden-heterociklil, ili alifatski, cikloalifatski, aril, ariloksi, heterociklički, ili heteroarilni ostatak, pri čemu, kada je supstituiran, Rw je supstituiran s do dva R2; R2 je halogen, OR, CO2R, C(O)N(R)2, SO2N(R)2, B(OR)2, ili N(R)2; R je neovisno H, alkil, cikloalkil, heterociklil, aril, ili heteroaril; n je 1 ili 2; i w je cijeli broj od 0 do uključujući 4; uz uvjet da kada W je veza i Rw je cikloalifatski, heterocikloalifatski, aril, ili heteroarilni ostatak, -W-Rw je vezan na 3- ili 4- položaj u piridil prstenu.
14. Spoj prema zahtjevu 13, naznačen time da J je CH2.
15. Spoj prema zahtjevu 13, naznačen time da J je CF2.
16. Spoj prema zahtjevu 13, naznačen time da -W-Rw je aciklički.
17. Spoj prema zahtjevu 13, naznačen time da -W-Rw je aril, heteroaril, cikloalifatski, ili heterocikloalifatski prsten.
18. Spoj prema zahtjevu 13, naznačen time da -W(Rw)n je je odabran od slijedećeg: -F, -CH3, -CH2CH3, -CN, -CF3, -CONH2, -CH2CH(CH3)2, [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
19. Spoj prema zahtjevu 13, naznačen time da -W(Rw)n je odabran od slijedećeg: [image] [image]
20. Spoj prema zahtjevu 1, koji ima formulu Ib: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: R1 je halogen, alkil, OH, alkoksi, tioalkil, trifluorometoksi; ili dva R1 na susjednim atomima, zajedno, tvore [image] pri čemu J je odabran iz skupine koju čine CH2, CF2, ili C(CH3)2; W je -NR' ili -CH2-; R' je neovisno H ili alkil; RW je neovisno H, CN, N(R)2, CF3, OH, CO2R, C(O)N(R)2, -O(C1-C6)alkiliden-OR, -O(C1-C6)alkiliden-N(R)2, -O(C1-C6)alkiliden-heterociklil, ili alifatski, cikloalifatski, aril, ariloksi, heterociklički, ili heteroarilni ostatak, pri čemu, kada je supstituiran, Rw je supstituiran s do dva R2; R2 je halogen, OR, CO2R, C(O)N(R)2, SO2N(R)2, B(OR)2, ili N(R)2; R je neovisno H, alkil, cikloalkil, heterociklil, aril, ili heteroaril; n je 1 ili 2; w je cijeli broj od 0 do uključujući 4; i x je cijeli broj od 0 do uključujući 5.
21. Spoj prema zahtjevu 20, naznačen time da dva R1 na susjednim atomima, zajedno, tvore [image] i J je CH2.
22. Spoj prema zahtjevu 20, naznačen time da dva R1 na susjednim atomima, zajedno, tvore [image] i J je CF2.
23. Spoj prema zahtjevu 20, naznačen time da -W(Rw)n je odabran od slijedećeg: -CH3, -CH2CH3, -CH2CH(CH3)2, [image] [image] [image] [image] [image] [image] [image] [image] [image]
24. Spoj prema zahtjevu 1, koji ima formulu Ic: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: R1 je halogen, alkil, OH, alkoksi, tioalkil, trifluorometoksi; ili dva R1 na susjednim atomima, zajedno, tvore [image] pri čemu J je odabran iz skupine koju čine CH2, CF2, ili C(CH3)2; W je -NR' ili -CH2-; R' je neovisno H ili alkil; RW je neovisno H, CN, N(R)2, CF3, OH, CO2R, C(O)N(R)2, -O(C1-C6)alkiliden-OR, -O(C1-C6)alkiliden-N(R)2, -O(C1-C6)alkiliden-heterociklil, ili alifatski, cikloalifatski, aril, ariloksi, heterociklički, ili heteroarilni ostatak, pri čemu, kada je supstituiran, Rw je supstituiran s do dva R2; R2 je halogen, OR, CO2R, C(O)N(R)2, SO2N(R)2, B(OR)2, ili N(R)2; R je neovisno H, alkil, cikloalkil, heterociklil, aril, ili heteroaril; n je 1 ili 2; w je cijeli broj od 0 do uključujući 4; i x je cijeli broj od 0 do uključujući 5.
25. Spoj prema zahtjevu 24, naznačen time da dva R1 na susjednim atomima, zajedno, tvore [image] i J je CH2.
26. Spoj prema zahtjevu 24, naznačen time da dva R1 na susjednim atomima, zajedno, tvore [image] i J je CF2.
27. Spoj prema zahtjevu 24, naznačen time da -W(Rw)n je odabran od slijedećeg: -CH3, -CH2CH3, -CH2CH(CH3)2, [image] [image] [image] [image] [image] [image] [image] [image] [image]
28. Spoj naznačen time da je odabran od sljedećih spojeva [image] [image] [image] [image] [image] [image]
29. Farmaceutski pripravak naznačen time da sadrži (i) spoj prema zahtjevu 1; i (ii) farmaceutski prihvatljiv nosač.
30. Pripravak prema zahtjevu 29, naznačen time da dodatno sadrži dodatno sredstvo koje je odabrano od mukolitičkog sredstva, bronhodilatatora, antibiotika, antiinfektivnog sredstva, protuupalnog sredstva, modulatora CFTR koji nije spoj prema zahtjevu 1, te nutritivnog sredstva.
31. Pripravak prema zahtjevu 30, naznačen time da dodatno sredstvo je N-(5-hidroksi-2,4-ditert-butil-fenil)-4-okso-1H-kinolin-3-karboksamid.
32. In vitro postupak za modulaciju ABC transportera u staničnoj membrani naznačen time da sadrži korak dovođenje u kontakt navedene stanice sa spojem prema zahtjevu 1.
33. In vitro postupak prema zahtjevu 31, naznačen time da ABC transporter je CFTR.
34. Pripravak prema bilo kojem zahtjevu od 1 do 28 ili farmaceutski pripravak prema zahtjevima 29 do 31 naznačen time da je za upotrebu za liječenje stanja, bolesti, ili poremećaja odabranih od cistične fibroze, nasljednog emfizema, nasljedne hemokromatoze, nedostataka koagulacije-fibrinolize, kao što je nedostatak proteina C, nasljedni angioedem tipa 1, nedostataka obrade lipida, kao što je obiteljska hiperkolesterolemija, kilomikronemija tip 1, abetalipoproteinemija, bolesti lizosomskog nakupljanja, kao što je bolest I-stanica/pseudo-Hurler, mukopolisaharidoze, Sandhof/Tay-Sachs, Crigler-Najjar tip II, poliendokrinopatija/ hiperinzulinemija, dijabetes melitus, Laronov sindrom patuljastog rasta, nedostatak mijeloperoksidaze, primarni hiperparatiroidizam, melanom, CDG glikogenoza tip I, nasljedni emfizem, kongenitalna hipertireoza, osteogenesis imperfecta, nasljedna hipofibrinogenemija, nedostatak ACT, dijabetes insipidus (DI), neurohipofizni DI, nefrogeni DI, Charcot-Marie Tooth sindrom, Pelizaeus-Merzbacherova bolest, neurodegenerativne bolesti kao što su Alzheimerova bolest, Parkinsonova bolest, amiotrofna lateralna skleroza, progresivna supranuklearna paraliza, Pickova bolest, nekoliko poliglutaminskih neuroloških poremećaja kao što su Huntingtonov poremećaj, spinocerebelarna ataksija tip I, spinalna i bulbarna mišićna atrofija, dentatorubralna palidolujzianska atrofija, te miotonična distrofija, kao i spongiformne encefalopatije, kao što je nasljedna Creutzfeldt-Jakobova bolest, Fabrijeva bolest, Gerstmann-Straussler-Scheinkerov sindrom, KOPB, bolest suhog oka, te Sjogrenova bolest.
35. Spoj prema bilo kojem od zahtjeva 1 do 28 ili farmaceutski pripravak prema bilo kojem od zahtjeva 29 do 31 naznačen time da je za upotrebu u liječenju cistične fibroze.
36. Komplet za uporabu za mjerenje aktivnosti ABC transportera ili njegovog fragmenta u biološkom uzorku in vitro ili in vivo, naznačen time da sadrži: (i) prvi pripravak koji sadrži spoj u skladu sa zahtjevom 1; te (ii) instrukcije za: a) dovođenje u kontakt pripravka s biološkim uzorkom; b) mjerenje aktivnosti navedenog ABC transportera ili njegovog fragmenta.
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