HRP20151255T1 - Izokinolinski modulatori atp-vezujuä†ih kasetnih transportera - Google Patents

Izokinolinski modulatori atp-vezujuä†ih kasetnih transportera Download PDF

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HRP20151255T1
HRP20151255T1 HRP20151255TT HRP20151255T HRP20151255T1 HR P20151255 T1 HRP20151255 T1 HR P20151255T1 HR P20151255T T HRP20151255T T HR P20151255TT HR P20151255 T HRP20151255 T HR P20151255T HR P20151255 T1 HRP20151255 T1 HR P20151255T1
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Croatia
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aliphatic
cycloaliphatic
heterocycloaliphatic
carbonyl
carbonylamino
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HRP20151255TT
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Sara Hadida Ruah
Mark Miller
Jinglan Zhou
Brian Bear
Peter D. J. Grootenhuis
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Vertex Pharmaceuticals Incorporated
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Publication of HRP20151255T1 publication Critical patent/HRP20151255T1/hr

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Claims (20)

1. Spoj s formulom (I): [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da neovisno za svako pojavljivanje: R1 je proizvoljno supstituirani C1-6 alifatski, proizvoljno supstituirani aril, proizvoljno supstituirani heteroaril, proizvoljno supstituirani 3 do 10 člani heterocikloalifatski, pod uvjetom da najmanje jedan R1 je proizvoljno supstituiran heterocikloalifatski, proizvoljno supstituirani aril, ili proizvoljno supstituirani heteroaril vezan na 1-položaj u izokinolinskom prstenu; R2 je vodik, ili proizvoljno supstituirani C1-6 alifatski; R3 i R'3 zajedno s atomom ugljika na koji su vezani tvore proizvoljno supstituiran C3-7 cikloalifatski; R4 je proizvoljno supstituirani fenil; i n je 1, pri čemu proizvoljni supstituenti za aril su alifatski [npr., alkil, alkenil, ili alkinil]; cikloalifatski; (cikloalifatski)alifatski; heterocikloalifatski; (heterocikloalifatski)alifatski; aril; heteroaril; alkoksi; (cikloalifatski)oksi; (heterocikloalifatski)oksi; ariloksi; heteroariloksi; (aralifatski)oksi; (heteroaralifatski)oksi; aroil; heteroaroil; amino; okso (na ne-aromatskom karbocikličkom prstenu benzokondenziranog bicikličkog ili tricikličkog arila); nitro; karboksi; amido; acil [npr., alifatskikarbonil; (cikloalifatski)karbonil; ((cikloalifatski)alifatski)karbonil; (aralifatski)karbonil; (heterocikloalifatski)karbonil; ((heterocikloalifatski)alifatski)karbonil; ili (heteroaralifatski)karbonil]; sulfonil [npr., alifatskisulfonil ili aminosulfonil]; sulfinil [npr., alifatskisulfinil ili cikloalifatskisulfinil]; sulfanil [npr., alifatskisulfanil]; cijano; halo; hidroksi; merkapto; sulfoksi; urea; tiourea; sulfamoil; sulfamid; ili karbamoil; pri čemu proizvoljni supstituenti za heteroaril su alifatski [npr., alkil, alkenil, ili alkinil]; cikloalifatski; (cikloalifatski)alifatski; heterocikloalifatski; (heterocikloalifatski)alifatski; aril; heteroaril; alkoksi; (cikloalifatski)oksi; (heterocikloalifatski)oksi; ariloksi; heteroariloksi; (aralifatski)oksi; (heteroaralifatski)oksi; aroil; heteroaroil; amino; okso (na ne-aromatskom karbocikličkom ili heterocikličkom prstenu bicikličkog ili tricikličkog heteroarila); karboksi; amido; acil [npr., alifatskikarbonil; (cikloalifatski)karbonil; ((cikloalifatski)alifatski)karbonil; (aralifatski)karbonil; (heterocikloalifatski)karbonil; ((heterocikloalifatski)alifatski)karbonil; ili (heteroaralifatski)karbonil]; sulfonil [npr., alifatskisulfonil ili aminosulfonil]; sulfinil [npr., alifatskisulfinil]; sulfanil [npr., alifatskisulfanil]; nitro; cijano; halo; hidroksi; merkapto; sulfoksi; urea; tiourea; sulfamoil; sulfamid; ili karbamoil; pri čemu proizvoljni supstituenti za heterocikloalifatski su alifatski [npr., alkil, alkenil, ili alkinil], cikloalifatski, (cikloalifatski)alifatski, heterocikloalifatski, (heterocikloalifatski)alifatski, aril, heteroaril, alkoksi, (cikloalifatski)oksi, (heterocikloalifatski)oksi, ariloksi, heteroariloksi, (aralifatski)oksi, (heteroaralifatski)oksi, aroil, heteroaroil, amino, amido [npr., (alifatski)karbonilamino, (cikloalifatski)karbonilamino, ((cikloalifatski) alifatski)karbonilamino, (aril)karbonilamino, (aralifatski)karbonilamino, (heterocikloalifatski)karbonilamino, ((heterocikloalifatski) alifatski)karbonilamino, (heteroaril)karbonilamino, ili (heteroaralifatski)karbonilamino], nitro, karboksi [npr., HOOC-, alkoksikarbonil, ili alkilkarboniloksi], acil [npr., (cikloalifatski)karbonil, ((cikloalifatski) alifatski)karbonil, (aralifatski)karbonil, (heterocikloalifatski)karbonil, ((heterocikloalifatski)alifatski)karbonil, ili (heteroaralifatski)karbonil], nitro, cijano, halo, hidroksi, merkapto, sulfonil [npr., alkilsulfonil ili arilsulfonil], sulfinil [npr., alkilsulfinil], sulfanil [npr., alkilsulfanil], sulfoksi, urea, tiourea, sulfamoil, sulfamid, okso, ili karbamoil; pri čemu izraz "alifatski' obuhvaća izraze alkil, alkenil, alkinil; pri čemu proizvoljni supstituenti za alkilnu skupinu su halo, cikloalifatski [npr., cikloalkil ili cikloalkenil], heterocikloalifatski [npr., heterocikloalkil ili heterocikloalkenil], aril, heteroaril, alkoksi, aroil, heteroaroil, acil [npr., (alifatski)karbonil, (cikloalifatski)karbonil, ili (heterocikloalifatski)karbonil], nitro, cijano, amido [npr., (cikloalkilalkil)karbonilamino, arilkarbonilamino, aralkilkarbonilamino, (heterocikloalkil)karbonilamino, (heterocikloalkilalkil)karbonilamino, heteroarilkarbonilamino, heteroaralkilkarbonilamino], amino [npr., alifatskiamino, cikloalifatskiamino, ili heterocikloalifatskiamino], sulfonil [npr., alifatskisulfonil], sulfinil, sulfanil, sulfoksi, urea, tiourea, sulfamoil, sulfamid, okso, karboksi, karbamoil, cikloalifatskioksi, heterocikloalifatskioksi, ariloksi, heteroariloksi, aralkiloksi, heteroarilalkoksi, alkoksikarbonil, alkilkarboniloksi, ili hidroksil; pri čemu proizvoljni supstituenti za alkenilnu skupinu su halo, cikloalifatski, heterocikloalifatski, aril, heteroaril, alkoksi, aroil, heteroaroil, acil [npr., (cikloalifatski)karbonil, ili (heterocikloalifatski)karbonil], nitro, cijano, acil [npr., alifatskikarbonil, cikloalifatskikarbonil, arilkarbonil, heterocikloalifatskikarbonil ili heteroarilkarbonil], amido [npr., (cikloalkilalkil)karbonilamino, arilkarbonilamino, aralkilkarbonilamino, (heterocikloalkil)karbonilamino, (heterocikloalkilalkil)karbonilamino, heteroarilkarbonilamino, heteroaralkilkarbonilamino alkilaminokarbonil, cikloalkilaminokarbonil, heterocikloalkilaminokarbonil, arilaminokarbonil, ili heteroarilaminokarbonil], amino [npr., alifatskiamino, ili alifatskisulfonilamino], sulfonil [npr., alkilsulfonil, cikloalifatskisulfonil, ili arilsulfonil], sulfinil, sulfanil, sulfoksi, urea, tiourea, sulfamoil, sulfamid, okso, karboksi, karbamoil, cikloalifatskioksi, heterocikloalifatskioksi, ariloksi, heteroariloksi, aralkiloksi, heteroarilalkoksi, alkoksikarbonil, alkilkarboniloksi, ili hidroksil; pri čemu proizvoljni supstituenti za alkinilnu skupinu su aroil, heteroaroil, alkoksi, cikloalkiloksi, heterocikloalkiloksi, ariloksi, heteroariloksi, aralkiloksi, nitro, karboksi, cijano, halo, hidroksi, sulfo, merkapto, sulfanil [npr., alifatskisulfanil ili cikloalifatskisulfanil], sulfinil [npr., alifatskisulfinil ili cikloalifatskisulfinil], sulfonil [npr., alifatskisulfonil, alifatskiaminosulfonil, ili cikloalifatskisulfonil], amido [npr., aminokarbonil, alkilaminokarbonil, alkilkarbonilamino, cikloalkilaminokarbonil, heterocikloalkilaminokarbonil, cikloalkilkarbonilamino, arilaminokarbonil, arilkarbonilamino, aralkilkarbonilamino, (heterocikloalkil)karbonilamino, (cikloalkilalkil)karbonilamino, heteroaralkilkarbonilamino, heteroarilkarbonilamino ili heteroarilaminokarbonil], urea, tiourea, sulfamoil, sulfamid, alkoksikarbonil, alkilkarboniloksi, cikloalifatski, heterocikloalifatski, aril, heteroaril, acil [npr., (cikloalifatski)karbonil ili (heterocikloalifatski)karbonil], amino [npr., alifatskiamino], sulfoksi, okso, karboksi, karbamoil, (cikloalifatski)oksi, (heterocikloalifatski)oksi, ili (heteroaril)alkoksi; pri čemu proizvoljni supstituenti za cikloalifatski su alifatski [npr., alkil, alkenil, ili alkinil], cikloalifatski, (cikloalifatski) alifatski, heterocikloalifatski, (heterocikloalifatski) alifatski, aril, heteroaril, alkoksi, (cikloalifatski)oksi, (heterocikloalifatski)oksi, ariloksi, heteroariloksi, (aralifatski)oksi, (heteroaralifatski)oksi, aroil, heteroaroil, amino, amido [npr., (alifatski)karbonilamino, (cikloalifatski)karbonilamino, ((cikloalifatski)alifatski)karbonilamino, (aril)karbonilamino, (aralifatski)karbonilamino, (heterocikloalifatski)karbonilamino, ((heterocikloalifatski)alifatski)karbonilamino, (heteroaril)karbonilamino, ili (heteroaralifatski)karbonilamino], nitro, karboksi [npr., HOOC-, alkoksikarbonil, ili alkilkarboniloksi], acil [npr., (cikloalifatski)karbonil, ((cikloalifatski) alifatski)karbonil, (aralifatski)karbonil, (heterocikloalifatski)karbonil, ((heterocikloalifatski)alifatski)karbonil, ili (heteroaralifatski)karbonil], cijano, halo, hidroksi, merkapto, sulfonil [npr., alkilsulfonil i arilsulfonil], sulfinil [npr., alkilsulfinil], sulfanil [npr., alkilsulfanil], sulfoksi, urea, tiourea, sulfamoil, sulfamid, okso, ili karbamoil.
2. Spoj prema zahtjevu 1, naznačen time da jedan R1 spojen na 1-položaju u izokinolinskom prstenu je supstituiran s 1, 2, ili 3 -ZDR9; pri čemu svaki ZD je neovisno veza ili proizvoljno supstituirani razgranati ili ravan C1-6 alifatski lanac pri čemu do dvije jedinice ugljika iz ZD su proizvoljno i neovisno zamijenjene s -CO-, -CONRE-, -CO2-, -O-, -NRECO-, -SO2-, -NRE-, -SO2NRE-, ili -NRESO2-; svaki R9 je neovisno RE, -OH, -NH2, -N(CH3)2, ili -N+(CH3)3; i svaki RE je neovisno vodik ili proizvoljno supstituirana C1-8 alifatska skupina.
3. Spoj prema zahtjevu 2, naznačen time da jedan R1 spojen na 1-položaju u izokinolinskom prstenu je fenil proizvoljno supstituiran s 1 ili 2 -ZDR9; heteroaril proizvoljno supstituiran s 1 -ZDR9; ili heterocikloalifatski, proizvoljno supstituiran s 1 -ZDR9.
4. Spoj prema zahtjevu 1, naznačen time da je jedan R1 spojen na 1-položaju u izokinolinskom prstenu odabran iz skupine koju čine [image] [image] [image] [image] i [image]
5. Spoj prema zahtjevu 1, naznačen time da R3 i R'3 zajedno s atomom ugljika na koji su vezani tvore C3-7 cikloalifatski, naročito ciklopropilni prsten.
6. Spoj prema zahtjevu 1, naznačen time da R4 je jedan odabran iz skupine koju čine [image]
7. Spoj prema zahtjevu 1, pri čemu navedeni spoj ima formulu (III): [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da neovisno za svako pojavljivanje: RD je -ZDR9, gdje svaki ZD je neovisno veza ili proizvoljno supstituirani razgranati ili ravan C1-6 alifatski lanac pri čemu do dvije jedinice ugljika iz ZD su proizvoljno i neovisno zamijenjene s -CO-, - CONRE-, -CO2-, -NReCO2-, -O-, -NRECO-, -SO2-, -NRE-, -SO2NRE-, ili - NRESO2-; R9 je RE, -OH, -NH2, -N(CH3)2, ili -N+(CH3)3; RE je vodik ili proizvoljno supstituirana C1-8 alifatska skupina; R2 je H ili C1-4 alifatski; R3 i R'3 zajedno s atomom ugljika na koji su vezani tvore C3-7 cikloalifatski; R4 je fenil, koji je proizvoljno supstituiran s 1, 2, ili 3 -ZCR8, pri čemu svaki ZC je neovisno veza ili proizvoljno supstituirani razgranati ili ravan C1-6 alifatski lanac pri čemu do dvije jedinice ugljika iz ZC su proizvoljno i neovisno zamijenjene s -O-; ili R4 je fenil supstituiran s dva pojavljivanja -ZCR8, koji uzeti zajedno s atomima ugljika na koje su vezani, tvore 4-8 člani zasićeni, djelomično nezasićeni, ili aromatski prsten s do 2 atoma u prstenu koji su O; i R8 je proizvoljno supstituirana C1-8alifatska skupina.
8. Spoj prema zahtjevu 1, pri čemu navedeni spoj ima formulu IV: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da neovisno za svako pojavljivanje: T je proizvoljno supstituiran C1-2 alifatski lanac, pri čemu svaka od jedinica ugljika je proizvoljno i neovisno zamijenjena s -CF2-; R1' je vodik; RD1 je vezan na ugljik broj 3" ili 4"; RD1 i RD2 su -ZDR9, pri čemu svaki ZD je neovisno veza ili proizvoljno supstituirani razgranati ili ravan C1-6 alifatski lanac pri čemu do dvije jedinice ugljika iz ZD su proizvoljno i neovisno zamijenjene s -CO-, - CONRE-, -CO2-, -O-, -NRECO-, -SO2-, -NRE-, -SO2NRE-, ili -NRESO2-; R9 je RE, -OH, -NH2, -N(CH3)2, ili -N+(CH3)3; ili RD1 i RD2, uzeti zajedno s atomima na koje su vezani, tvore 3-8 člani zasićeni, djelomično nezasićeni, ili aromatski prsten s do 3 člana prstena neovisno odabrana iz skupine koju čine O i NRE; i RE je vodik ili proizvoljno supstituirana C1-8 alifatska skupina.
9. Spoj prema zahtjevu 8, naznačen time da T je odabran iz skupine koju čine -CH2- i -CF2-, ili pri čemu RD1 je -CO2H vezan na ugljik broj 3", RD2 je H, T je -CF2-, i R1' je H, ili pri čemu RD1 je -CO2H vezan na ugljik broj 4", RD2 je H, T je -CF2-, i R1' je H.
10. Spoj prema zahtjevu 8, naznačen time da RD1 i RD2, uzeti zajedno s atomima ugljika na koje su vezani, tvore proizvoljno supstituirani 3-8 člani zasićeni, djelomično nezasićeni, ili aromatski prsten s 0-2 atoma u prstenu neovisno odabrana iz skupine koju čine O i NRE.
11. Spoj prema zahtjevu 10, naznačen time da RD1 i RD2, uzeti zajedno s fenilom koji sadrži ugljikove atome 3" i 4", je [image]
12. Spoj prema zahtjevu 1, pri čemu navedeni spoj ima formulu (VI): [image] naznačen time da G je -O-, -CHR9-, ili -NR9-; X je O ili H,H; R10 i R11 su neovisno H ili alkoksi; ili R10 i R11 uzeti zajedno tvore [image] T je -CH2-, -CF2-, ili -C(CH3)2-; R9 je vodik, proizvoljno supstituirana C1-8 alifatska skupina, ili proizvoljno supstituirani aril; i R1' je H.
13. Spoj prema zahtjevu 12, naznačen time da R9 je alifatski, aril, metil ili fenil ili gdje R11 je alkoksi.
14. Spoj prema zahtjevu 12, naznačen time da G je -NR9-, R9 je metil, i X je H,H, ili pri čemu G je -NR9-, R9 je fenil, i X je O, ili pri čemu G je -CHR9-, R9 je fenil, i X je H,H, ili pri čemu G je -NR9-, R9 je H, i X je O, ili pri čemu G je -NR9-, R9 je metil, X je H,H, R11 je metoksi, i R10 je H, ili pri čemu G je - CHR9-, R9 je fenil, X je H,H, R11 je metoksi, i R10 je H, ili pri čemu G je -NR9-, R9 je H, X je O, R11 je metoksi, i R10 je H.
15. Spoj prema zahtjevu 1, pri čemu navedeni spoj ima formulu (VII): [image] naznačen time da Y je CH ili N pod uvjetom da najmanje jedan Y je N; m je cijeli broj od 0 do uključivo 4; T je proizvoljno supstituirani C1-2 alifatski lanac, gdje svaka od jedinica ugljika je proizvoljno i neovisno zamijenjena s -CF2-; i R1' je vodik.
16. Spoj prema zahtjevu 15, naznačen time da T je -CH2- ili -CF2-, ili gdje meta Y je N, ili gdje m je 1.
17. Spoj prema zahtjevu 15, naznačen time da R1 je alkoksi, ili metoksi.
18. Spoj prema zahtjevu 1, naznačen time da spoj je jedan od slijedećih: [image] [image] [image]
19. Farmaceutski pripravak naznačen time da sadrži: (i) spoj prema zahtjevu 1; i (ii) farmaceutski prihvatljiv nosač
20. Pripravak prema zahtjevu 19, naznačen time da nadalje sadrži mukolitičko sredstvo, bronhodilatator, antibiotik, protuinfektivno sredstvo, protuupalno sredstvo, modulator CFTR, ili prehrambeno sredstvo.
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US20090143381A1 (en) 2009-06-04
JP5885359B2 (ja) 2016-03-15
HK1222847A1 (zh) 2017-07-14
DK2578571T3 (en) 2015-10-05
HK1177137A1 (en) 2013-08-16
EP2578571A1 (en) 2013-04-10
NZ585980A (en) 2012-04-27
CN102743385B (zh) 2014-09-17
PL2578571T3 (pl) 2016-03-31
DK2217572T3 (da) 2014-02-03
SI2217572T1 (sl) 2014-05-30
EP3012250B1 (en) 2017-11-08
US20130296364A1 (en) 2013-11-07
JP2014077021A (ja) 2014-05-01
NZ598941A (en) 2013-06-28
CN101952254B (zh) 2012-09-05
US9012473B2 (en) 2015-04-21
US8507524B2 (en) 2013-08-13
HUE026334T2 (en) 2016-06-28
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US8722704B2 (en) 2014-05-13
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HK1148006A1 (en) 2011-08-26

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