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HRP20140336T1 - Inhibitori glicin transportera-1 - Google Patents

Inhibitori glicin transportera-1 Download PDF

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Publication number
HRP20140336T1
HRP20140336T1 HRP20140336TT HRP20140336T HRP20140336T1 HR P20140336 T1 HRP20140336 T1 HR P20140336T1 HR P20140336T T HRP20140336T T HR P20140336TT HR P20140336 T HRP20140336 T HR P20140336T HR P20140336 T1 HRP20140336 T1 HR P20140336T1
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Croatia
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methyl
phenyl
acetic acid
piperazin
alkyl
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HRP20140336TT
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Stephen Hitchcock
Albert Amagadzie
Wenyuan Qian
Xiaoyang Xia
Scott S. Harried
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Amgen Inc.
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Application filed by Amgen Inc. filed Critical Amgen Inc.
Publication of HRP20140336T1 publication Critical patent/HRP20140336T1/hr

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Claims (23)

1. Spoj sa formulom (1): [image] naznačen time da: n je cijeli broj od 1 do 3; R1 i R2 su neovisno odabrani od vodika, alkila, haloalkila, alkoksi, haloalkoksi, arila, heteroarila, cikloalkila, ili heterociklila pri čemu su gore navedeni prstenovi proizvoljno supstituirani sa Ra, Rb, ili Rc neovisno odabranim od alkila, halo, haloalkila, alkoksi, haloalkoksi, hidroksi, cijano, monosupstituiranog amino, ili disupstituiranog amino; ili R1 i R2, kada su vezani na isti atom ugljika, mogu se kombinirati i tvorili cikloalkil ili monociklički zasićeni heterociklil da se dobije spiro prsten pri čemu cikloalkil ili monociklički zasićeni heterociklil mogu biti proizvoljno supstituirani sa Rd, Rc ili Rf neovisno odabranim od alkila, alkoksi, fluoro, fluoroalkil, fluoroalkoksi, hidroksi, monosupstituiranim amino, ili disupstituiranim amino; ili R1 i R2, kada su vezani na atome ugljika na 2 i 5 ili 3 i 6 položaju u piperazinskom prstenu, mogu se kombinirati da tvore-C1-C3-alkilenski lanac pri čemu jedan od ugljikovih atoma u alkilenskom lancu je proizvoljno zamijenjen sa -NR-, -O-, -S(O)n1, (gdje R je vodik ili alkil i n1 je 0-2) i dodatno pri čemu jedan ili dva atoma vodika u alkilenskom lancu mogu biti proizvoljno supstituirani sa jednim ili dva alkila; R3, R4 i R5 su neovisno vodik, alkil, fluoro, ili fluoroalkil; i Ar1 i Ar2 su neovisno aril, heteroaril, cikloalkil, ili heteroeiklil gdje je svaki gore navedeni prsten proizvoljno supstituiran sa Rg, Rh ili Ri gdje Rg je alkil, - C=C-R6 (pri čemu R6 je aril ili heteroaril), halo, haloalkil, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituirani amino, disupstituirani amino, sulfonil, acil, karboksi, alkoksikarbonil, hidroksi alkil, alkoksialkil, aminoalkil, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonil, aminokarbonil, ili acilamino i Rh i Ri su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila. hidroksialkoksi, alkoksialkoksi, aminoalkoksi. aminosulfonila, aminokarbonila, aeilamino, arila, heteroarila, cikloalkila, ili heterociklila gdje aromatski ili aliciklički prsten u Rg, Rh i Ri je proizvoljno supstituiran sa Rj, Rk ili Rl koji su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, ili aeilamino; ili njihova farmaceutski prihvatljiva sol uz uvjet da: spoj sa Formulom (1) nije 2-(4-benzhidrilpiperazin-1-il)octena kiselina, nije 2-(4-((4-klorofenil)(fenil)metil)piperazin-1-il)octena kiselina, te kada R1, R2, R3, R4 i R5 su vodik i Ar1 je 4-fluorofenil i n = 1, tada Ar2 nije 4-fluorofenil.
2. Spoj prema zahtjevu 1 naznačen time da: n je 1; R1 i R2 su neovisno odabrani od vodika, alkila, haloalkila, alkoksi, haloalkoksi, arila, heteroarila, cikloalkila, ili heterociklila pri čemu su gore navedeni prstenovi proizvoljno supstituirani sa Ra, Rb, ili Rc neovisno odabranim od alkila, halo, haloalkila, alkoksi, haloalkoksi, hidroksi, cijano, monosupstituiranim amino, ili disupstituiranim amino; ili R1 i R2, kada su vezani na isti atom ugljika, mogu se kombinirati i tvoriti cikloalkil ili monociklički zasićeni heterociklil da se dobije spiro prsten pri čemu cikloalkil ili monociklički zasićeni heterociklil može biti proizvoljno supstituiran sa Rd, Re, ili Rf neovisno odabranim od alkila, alkoksi, fluoro, fluoroalkil, fluoroalkoksi, hidroksi, monosupstituiranim amino, ili disupstituiranim amino; ili R1 i R2, kada su vezani na atome ugljika na 2 i 5 ili 3 i 6 položaju u piperazinskom prstenu, mogu se kombinirati da tvore-C1-C3-alkilenski lanac pri čemu je jedan od ugljikovih atoma u alkilenskom lancu proizvoljno zamijenjen sa -NR-, -O-, -S(O)n1-(gdje R je vodik ili alkil i ni je 0-2) i dodatno pri čemu jedan ili dva atoma vodika u alkilenskom lancu mogu biti proizvoljno supstituirani sa jednim ili dva alkila; i Ar1 i Ar2 su neovisno aril, heteroaril, eikloalkil, ili hctcrociklil gdje je svaki gore navedeni prsten proizvoljno supstituiran sa Rg, Rh ili Ri gdje Rg je alkil, halo, haloalkil, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituirani amino, disupstituirani amino, sulfonil, acil, karboksi, alkoksikarbonil, hidroksialkil, alkoksialkil, aminoalkil, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonil, aminokarbonil, ili acilamino i Rh i Ri su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi. alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, aeilamino, arila, heteroarila, cikloalkila, ili heterociklila gdje aromatski ili aliciklički prsten u Rg, Rh i Ri je proizvoljno supstituiran sa Rj, Rk ili Rl koji su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, ili aeilamino.
3. Spoj prema zahtjevu 2 naznačen time da R1 i R2 su vodik.
4. Spoj prema zahtjevu 2 naznačen time da: R1 i R2 su neovisno odabrani od vodika, alkila, haloalkila, alkoksi, ili haloalkoksi uz uvjet da najmanje jedan od R1 i R2 je različit od vodika; ili R1 je vodik i R2 je alkil.
5. Spoj prema zahtjevu 2 naznačen time da R1, R2, i R3, R4 i R5 su vodik i Ar1 i Ar2 su fenil, svaki fen ii je proizvoljno supstituiran sa Rg, Rh ili Ri.
6. Spoj prema zahtjevu 2 naznačen time da: R1, R3, R4, i R5 su vodik, R2 je alkil, i Ar1 i Ar2 su fenil proizvoljno supstituiran sa Rg, Rh ili Ri; ili R1, R2, R3, R4 i R5 su vodik, Ar1 je fenil proizvoljno supstituiran sa Rg, Rh ili Ri i Ar2 je cikloalkil; ili R1, R', R4, i R' su vodik, R2 je alkil, Ar1 je fenil proizvoljno supstituiran sa Rg, Rh ili Ri i Ar2 je cikloalkil; R1, R2, R3, R4 i R5 su vodik, Ar1 je fenil i Ar je heteroaril, svaki prstenje proizvoljno supstituiran sa Rs, Rh ili R1; ili R1. R3, R4, i R5 su vodik, R2 je alkil, Ar1 je fenil i Ar2 je heteroaril, svaki prsten je proizvoljno supstituiran sa Rg, Rh ili Ri.
7. Spoj prema zahtjevu 2 naznačen time da spoj ima slijedeću strukturu: [image] gdje: R1 i R2 su neovisno vodik ili alkil; i Ar1 i Ar2 su neovisno fenil, svaki prstenje proizvoljno supstituiran sa Rg, Rh ili Ri gdje Rg je alkil, halo, haloalkil, haloalkoksi, alkiltio, alkoksi, alkilkarbonil, ili alkoksikarbonil.
8. Spoj prema zahtjevu 2 naznačen time da spoj ima slijedeću strukturu: [image] Rg je alkil, halo. haloalkil. ili haloalkoksi je vezan na 3-položaj u fenilnom prstenu i stereokemija kod *C je (R).;
9. Spoj prema zahtjevu 2 naznačen time da spoj ima slijedeću strukturu: [image] gdje Rg i Rh su neovisno vodik, alkil. halo, haloalkil, ili haloalkoksi.;
10. Spoj prema zahtjevu 2 naznačen time da spoj sa Formulom (1) ima jednu od slijedećih struktura: [image] gdje R1 je vodik ili metil i Rg je cijano, heleroaril ili fenil, svaki prsten u Rg je proizvoljno supstituiran sa alkilom i Rh je alkil, halo, haloalkil, ili haloalkoksi.;
11. Spoj prema zahtjevu 10 naznačen time da Rg je smješten na 3-položaj u fenilnom prstenu i stereokemija je kod *C (R).
12. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koju čine: (R)-2-(4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-(4-((3-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-(4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-(4-((3,5-diklorofenil)(fenil)metil)piperazin-1-il)octena kiselina; (S)-2-(4-(fenil(3-(trifluorometil)fenil)metil)piperazin-]-il)octena kiselina; 2-(4-((4-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-(4-(fenil(4-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-(4-((2-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-(4-((3-bifenil)(fenil)metil)piperazin-1-il)octena kiselina; (S)-2-(4-((4-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; (R)-2-(4-((4-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; (S)-2-(4-((3-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; (R)-2-(4-((3-bromofenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-4-((3-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; (R)-2-(4-benzhidril-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(3-jodofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina: 2-((R)-4-((R)-(3-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((S)(3-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-(bifenil-3-il-fenil-metil)-piperazin-1-il)-octena kiselina; 2-((R)-2-metil-4-((S)-fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-4-((4-klorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-(bifenil-4-il-fenil-metil)-piperazin-1-il)-octena kiselina; 2-((R)-4-((4-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((4-cijanofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((3-klorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; [(R)-4-((R)-bifenil-3-il-fenil-metil)-2-metil-piperazin-1-il]-octena kiselina; 2-((R)-2-metil-4-((3-(metiltio)fenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-4-((S)-(2-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(2-bromofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(m-tolil)metil)piperazin-1-il)octena kiselina; 2-(R)-4-((R)-(3-izopropilfenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((4-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((3-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(3-(tiofen-2-il)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-(3-(metiltio)fenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((S)-(3-(metiltio)fenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-(4-(metiltio)fenil)(fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-4-((S)-(2-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(2-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((S)-fenil(3-(trifluorometoksi)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(3-(trifluorometoksi)fenil)metil)piperazin-1-il)octena kiselina; [(R)-4-((R)-bifenil-4-il-fenil-metil)-2-metil-piperazin-1-il]-octena kiselina; {(R)-2-metil-4-[(R)-(2'-metil-bifenil-4-il)-fenil-metil]-piperazin-1-il]-octena kiselina; {(R)-2-meti!-4-[(R)-(3'-metil-bifenil-4-il)-fenil-metil]-piperazin-1-il]-octena kiselina; {(R)-2-metil-4-[(R)-(4'-metil-bifenil-4-il)-fenil-metil]-piperazin-1-il]-octena kiselina; 2-((R)-4-((S)-(2,4-difluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(2,4-difluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((S)-(4-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(4-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((S)-(3-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-4-((R)-(3-fluorofenil)(fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(4-(2-feniletinil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(3-(2-piridin-3-iletinil)fenil)metil)-piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-fenil(3-(2-piridin-4-iletinil)fenil)metil)-piperazin-1-il)octena kiselina; (S)-2-(4-benzhidril-2-metilpiperazin-1-il)octena kiselina; 2-((S)-2-metil-4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; (S)-2-(4-benzhidril-3-metilpiperazin-1-il)octena kiselina; (R)-2-(4-benzhidril-3-metilpiperazin-1-il)octena kiselina; 2-((2,5-trans)-4-bcnzhidril-2,5-dimetilpiperazin-1-il)octena kiselina; 2-((2,5-cis)-4-benzhidril-2,5-dimetilpiperazin-1-il)octena kiselina; 2-((R)-3-metil-4-(fenil(4-difenil)metil)piperazin-1-il)octena kiselina; (R)-2-(4-(bis(3-klorofenil)metil)-2-metilpiperazin-1-il)octena kiselina; (R)-2-(4-(bis(3-fluorofenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-(4-((3-(trifluorometil)fenil)(4-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-(4-((4-fluorofenil)(3-(difenil)metil))-(R)-2-metilpiperazin-1-il)octena kiselina (R)-2-(4-(bis(4-klorofenil)metil)-2-metilpiperazin-1 -il)octena kiselina; 2-((R)-4-((3-bromofenil)(4-fluorofenil)metil)-2-metilpiperazin-1-il)octena kiselina; (R)-2-(4-(bis(4-fluorofenil)metil)-3-metilpiperazin-1-il)octena kiselina; (R)-2-(4-(bis(4-fluorofenil)metil)-2-metilpiperazin-1-il)octena kiselina; (R)-2-(4-(bis(3-(trifluorometil)fenil)metil)-2-metilpiperazin-1-il)octena kiselina; 2-(4-(bis(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-(tiofen-2-il(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; 2-((R)-2-metil-4-((R)-tiofen-2-il(3-(trifluorometil)fenil)metil)-piperazin-1- il)octena kiselina; 2-((R)-2-metil-4-((R)-tiofen-2-il(3-(trifluorometil)fenil)metil)-piperazin-1- il)octena kiselina: 2-((R)-4-(ciklopropil(3-(trifluorometil)fenil)metil)-2-metilpiperazin-1-il)octena kiselina; (R)-2-(4-(bis(4-klorofenil)metil)-2-metilpiperazin-1-il)octena kiselina; (S)-2-((R)-4-(bis(4-klorofenil)metil)-3-metilpiperazin-1-il)propanska kiselina; (S)-2-((R)-4-(bis(4-klorofenil)metil)-2-metilpiperazin-1-il)propanska kiselina; (R)-2-((R)-4-(bis(4-klorofenil)metil)-2-metilpiperazin-1-il)propanska kiselina; 2-((2R,6S)-4-(bis(4-klorofenil)metil)-2,6-dimetilpiperazin-1-il)octena kiselina; 2-(4-(bis(4-klorofenil)metil)-2,2-dimetilpiperazin-1-il)octena kiselina; 2-(4-(bis(4-klorofenil)metil)piperazin-1-il)propanska kiselina; (R)-2-(4-(bis(4-klorofenil)metil)-2-izopropilpiperazin-1-il)octena kiselina; 2-(4-(bis(4-klorofenil)metil)piperazin-1-il)octena kiselina ; i 2-(4-(fenil(3-(trifluorometil)fenil)metil)-1,4-diazepan-1-il)-octena kiselina; ili njihova farmaceutski prihvatljiva sol.
13. Spoj prema zahtjevu 1 naznačen time da je odabran od: (R)-2-(4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octene kiseline, ili njezine farmaceutski prihvatljive soli; dihidrokloridna sol 2-((R)-4-(ciklopropil(3-(trifluorometil)fenil)metil)-2- metilpiperazin-1-il)octene kiseline; i 2-((R)-2-metil-4-((R)-fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina; ili njihova farmaceutski prihvatljiva sol.
14. Farmaceutski pripravak naznačen time da sadrži spoj prema bilo kojem od zahtjeva 1- 13 ili smjesu spoja prema bilo kojem od zahtjeva 1-13 i njihove farmaceutski prihvatljive soli; te farmaceutski prihvatljivo pomoćno sredstvo.
15. Spoj sa formulom (I) naznačen time da se koristi kao lijek za uporabu kod liječenja bolesti koja se liječi inhibicijom GlyT1 receptora [image] gdje: n je cijeli broj od 1 do 3; R1 i R2 su neovisno odabrani od vodika, alkila, haloalkila, alkoksi, haloalkoksi, arila, heteroarila, cikloalkila, ili helerociklila pri čemu su gore navedeni prstenovi proizvoljno supstituirani sa Ra, Rb, ili Rc neovisno odabranim od alkila, halo, haloalkila, alkoksi, haloalkoksi, hidroksi, cijano, monosupstituiranim amino, ili disupstituiranim amino; ili R1 i R2, kada su vezani na isti atom ugljika, mogu se kombinirati i tvoriti cikloalkil ili monociklički zasićeni heterociklil da se dobije spiro prsten pri čemu cikloalkil ili monociklički zasićeni heterociklil mogu proizvoljno biti supstituirani sa Rd, Re, ili Rf neovisno odabranim od alkila, alkoksi, fluoro, fluoroalkila, fluoroalkoksi, hidroksi, monosupstituiranog amino, ili disupstituiranog amino; ili R1 i R2 kada su vezani na atome ugljika na 2 i 5 ili 3 i 6 položaju u piperazinskom prstenu, mogu se kombinirati da tvore-C1-C3-alkilenski lanac pri čemu je jedan od ugljikovih atoma u alkilenskom lancu proizvoljno zamijenjen sa -NR-, -O-, -S(O)n- (gdje R je vodik ili alkil i n je 0-2) i dodatno pri čemu jedan ili dva atoma vodika u alkilenskom lancu mogu biti proizvoljno supstituirani sa jednim ili dva alkila; R3, R4 i R5 su neovisno vodik, alkil, fluoro, ili fluoroalkil; i Ar1 i Ar2 su neovisno aril, heteroaril, cikloalkil, ili heterociklil gdje je svaki gore navedeni prsten proizvoljno supstituiran sa Rg, Rh ili Ri gdje Rg je alkil, -C=C-R6 (gdje R6 je aril ili heteroaril), halo, haloalkil, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituirani amino, disupstituirani amino, sulfonil, acil, karboksi, alkoksikarbonil, hidroksialkil, alkoksialkil, aminoalkil, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonil, aminokarbonil, ili acilamino i Rh i Ri su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila. alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, acilamino, arila, heteroarila, cikloalkila, ili heterociklila gdje aromatski ili aliciklički prsten u Rg, Rh i Ri je proizvoljno supstituiran sa Rj, Rk ili Rl koji su neovisno odabrani od alkila, halo. haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, ili acilamino; ili njihova farmaceutski prihvatljiva sol ili smjesa spoja sa formulom (1) i njihove farmaceutski prihvatljive soli, te farmaceutski prihvatljivo pomoćno sredstvo, pri čemu je bolest odabrana od shizofrenije ili psihoze uključujući shizofreniju (paranoidnu, dezorganiziranu, katatoničnu ili nediferenciranu), shizofreničkog poremećaja, shizoafektivnog poremećaja, deluzijskog poremećaja, kratkog psihotičnog poremećaja, podijeljenog psihotičnog poremećaja, psihotičnog poremećaja uslijed općeg zdravstvenog stanja i psihoznopsihotičnog poremećaja induciranog uzimanjem tvari ili lijekovima (fenciklidinom, ketaminom i ostalim disocijativnim anesteticima, amfetaminom i ostalim psihostimulansima i kokainom), psihoze povezane s afektivnim poremećajima, kratke reaktivne psihoze, shizoafektivne psihoze, poremećaji „shizofrenog spektra1" poput shizoidnih ili shizotipnih poremećaja ličnosti, ili bolesti povezane s psihozom (poput velike depresije, maničnog depresivnog (bipolarnog) poremećaja, Alzheimerove bolesti i post- traumatskog stresnog sindroma), uključujući i pozitivne i negativne simptome shizofrenije i drugih psihoza; kognitivne poremećaje, uključujući demenciju (povezane s Alzheimerovom bolesti, ishemijom, multi- infarktnom demencijom, traumom, vaskularnim problemima ili moždanim udarom, Parkinsonovom bolesti, Huntingtonovom bolesti, Pickovom bolesti, Creutzfeldt-Jacobovom bolesti, perinatalnom hipoksijom, drugim općim zdravstvenim stanjem, ili alkoholizmom); delirijum, poremećaji amnezije ili pad kognitivnih sposobnosti povezan sa starenjem; anksiozni poremećaji, uključujući akutni stresni poremećaj, agorafobiju, generalizirani anksiozni poremećaj, opsesivno - kompulzivni poremećaj, napad panike, poremećaj panike, post-traumatski stresni poremećaj, anksiozni poremećaj zbog odvajanja, socijalnu fobiju, specifičnu fobiju, anksiozni poremećaj izazvan supstancom i anksioznost zbog općeg zdravstvenog stanja; poremećaji i ovisnosti povezani s uzimanjem tvari (uključujući tvarima induciran delirij, trajnu demenciju, poremećaj trajne amnezije, psihotični poremećaj ili anksiozni poremećaj; toleranciju, ovisnost ili prestanak uzimanja tvari, uključujući alkohol, amfetamine. kanabis, kokain, halucinogene tvari, inhalante, nikotin, opioide, fenciklidin, sedative, hipnotičke tvari ili anksiolitike); bipolarne poremećaje, poremećaje raspoloženja, uključujući depresivne poremećaje; depresiju, uključujući unipolarnu depresiju, sezonsku depresiju i poslijeporođajnu depresiju, predmenstrualni sindrom (PMS ) i predmenstrualni disforični poremećaj (PDD), poremećaje raspoloženja zbog općeg zdravstvenog stanja, te tvarima inducirani poremećaj raspoloženja; poremećaje u učenju, pervazivni razvojni poremećaj uključujući autistični poremećaj, poremećaje pažnje, uključujući pomanjkanje pažnje s hiperaktivnošću ( ADHD ) i poremećaj ponašanja; poremećaje povezane sa NMDA receptorima poput autizma, depresije, benigne zaboravljivosti, poremećaja učenja u djetinjstvu i zatvorene ozljedu glave; poremećaje kretanja, uključujući akinezije i akinetičke-rigidne sindrome (uključujući Parkinsonovu bolest, lijekovima-izazvan parkinsonizam, posteneefalitički parkinsonizam, progresivnu i supranuklearnu paralizu, višestruku sistemsku atrofiju, kortikobazalnu degeneraciju, kompleks parkinsonizam-ALS demenciju i kalcifikaciju bazalnih ganglija), parkinsonizam izazvan uzimanjem lijekova (kao što su neuroleptički izazvan parkinsonizam, neuroleptički maligni sindrom, neuroleptički izazvana akutna distonija, neuroleptički izazvana akutna akatizija, neuroleptički izazvana tardivna diskinezija i lijekovima izazvan posturalni tremor), Gilles de la Touretteov sindrom, epilepsija, grčenje mišića i poremećaji povezani s grčenjem mišića ili slabošću uključujući tremore; diskinezije [uključujući tremor (kao što je tremor u mirovanju, posturalni tremor i intencioni tremor), koreja (kao Svdenhamova koreja, Huntingtonova bolest, benigna nasljedna koreja, neuroakantocitoza, simptomatska koreja, lijekovima izazvana koreja i hemibalizam), mioklonus (uključujući generalizirani mioklonus i lokalni mioklonus), tikovi (uključujući jednostavne tikove, kompleksne tikove i simptomatske tikove), te distoniju (uključujući generaliziranu distoniju kao stoje idiopatska distonija, distonija uzrokovana lijekovima, simptomatska distoniju i paroksizmalna distonija, te fokalna distonija kao što blefarospazam, oromandibularna distonija, spazmodička distonija, spazmodički tortikolis, aksijalna distonija, distonički piščev grč i hemiplegična distonija); urinarna inkontinencija; oštećenje neurona, uključujući oštećenje oka, retinopatiju ili makularnu degeneraciju oku, zujanje u ušima, oštećenje i gubitak sluha, te edem mozga; povraćanje; te poremećaje spavanja uključujući nesanicu i narkolepsiju.
16. Spoj za uporabu za liječenje bolesti kako je definirano u zahtjevu 15, naznačen time da spoj je bilo koji od spojeva iz patentnih zahtjeva 2-13 i 15 ili smjesa spoja prema zahtjevu 15 i njegove farmaceutski prihvatljive soli, te farmaceutski prihvatljivo pomoćno sredstvo.
17. Spoj za uporabu za liječenje bolesti ako je definirano u zahtjevu 15 ili 16 naznačen time da je bolest shizofrenija ili kognitivni poremećaj povezan sa shizofrenijom.
18. Postupak za pripremu spoja sa Formulom (I): [image] gdje: n je cijeli broj od 1 do 3; R1 i R2 su neovisno odabrani od vodika, alkila, haloalkila, alkoksi, haloalkoksi, arila, heteroarila, cikloalkila ili heterociklila pri čemu su gore navedeni prstenovi proizvoljno supstituirani sa Ra, Rb, ili Rc neovisno odabranim od alkila, halo, haloalkila, alkoksi, haloalkoksi, hidroksi, cijano, monosupstituiranog amino, ili disupstituiranog amino; ili R1 i R2 kada su vezani na isti atom ugljika, se mogu kombinirati i tvoriti cikloalkil ili monociklički zasićeni heterociklil da se dobije spiro prsten pri čemu cikloalkil ili monociklički zasićeni heterociklil može biti proizvoljno supstituiran sa Rd, Re, ili Rf neovisno odabranim od alkila, alkoksi, fluoro, fluoroalkila, fluoroalkoksi, hidroksi, monosupstituiranog amino ili disupstituiranog amino; ili R1 i R2 kada su vezani na atome ugljika na 2 i 5 ili 3 i 6 položaju u piperazinskom prstenu, se mogu kombinirati da tvore -C1-C3-alkilenski lanac pri čemu jedan od ugljikovih atoma u alkilenskom lancu je proizvoljno zamijenjen sa -NR-, -O-, -S(O)n1- (gdje R je vodik ili alkil i n1 je 0-2) i dodatno pri čemu jedan ili dva atoma vodika u alkilenskom lancu mogu biti proizvoljno supstituirani sa jednim ili dva alkila; R3, R4 i R5 su neovisno vodik, alkil, fluoro, ili fluoroalkil; i Ar1 i Ar2 su neovisno aril, heteroaril, cikloalkil, ili heterociklil gdje je svaki gore navedeni prsten proizvoljno supstituiran sa Rg, Rh ili Ri gdje Rg je alkil, -C=C-R6(gdje R6 je aril ili heteroaril), halo, haloalkil, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituirani amino, disupstituirani amino, sulfonil, acil, karboksi, alkoksikarbonil, hidroksialkil, alkoksialkil, aminoalkil, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonil, aminokarbonil, ili acilamino i Rh i Ri su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, acilamino, arila, heteroarila, cikloalkila, ili heterociklila gdje aromatski ili aliciklički prsten u Rg, Rh i Ri je proizvoljno supstituiran sa Rj, Rk ili Rl koji su neovisno odabrani od alkila, halo, haloalkila, haloalkoksi, alkiltio, cijano, alkoksi, amino, monosupstituiranog amino, disupstituiranog amino, sulfonila, acila, karboksi, alkoksikarbonila, hidroksialkila, alkoksialkila, aminoalkila, hidroksialkoksi, alkoksialkoksi, aminoalkoksi, aminosulfonila, aminokarbonila, ili acilamino; naznačen time da sadrži: (a) hidrolizu ester skupine u spoj sa formulom: [image] gdje R je alkil i R1, R2, R3, R4, R5, Ar1 i Ar2 skupine su kako je gore definirano; pod kiselim ili bazičnim uvjetima reakcije hidrolize; (b) proizvoljno modifikaciju bilo kojih R1, R2, R3, R4, R5, Ar1 i Ar2 skupina da se dobije spoj sa formulom (I); (c) proizvoljno formiranje kisele adicijske soli spoja sa Formulom (I) dobivenog u gore navedenom koraku (a) i/ili (b); (d) proizvoljno odvajanje stereoizomera spoja sa Formulom (I) dobivenog u gore navedenom koraku (a), (b), i/ili (c); uz uvjet da (i) kada R1, R2, R3, R4 i R5 su vodik i Ar1 je fenil tada Ar2 nije fenil ili 4-klorofenil; te (ii) kada R1, R2, R3, R4 i R5 su vodik i Ar1 je 4-fluorofenil i n = 1, tada Ar2 nije 4-fluorofenil.
19. Postupak prema zahtjevu 18 gdje je spoj sa Formulom (I) naznačen time da: R1 i R2 su neovisno vodik ili alkil; R3, R4, i R5 su vodik; i Ar1 i Ar2 su neovisno fenil, svaki prstenje proizvoljno supstituiran sa Rg ili Rh gdje Rgi Rh su neovisno alkil, halo, haloalkil, haloalkoksi, alkiltio, alkoksi, alkilkarbonil, ili alkoksikarbonil.
20. Postupak prema zahtjevu 18 gdje je spoj sa Formulom (1) naznačen time da: R1 i R2 su neovisno vodik ili alkil; R3, R4, i R5 su vodik; i Ar1 i Ar2 su neovisno fenil, svaki prstenje proizvoljno supstituiran sa Rg ili Rh gdje Rg i Rh su neovisno alkil, halo, haloalkil, haloalkoksi, alkiltio, alkoksi, alkilkarbonil, ili alkoksikarbonil i stereokemija na atomu ugljika koji nosi R3, Ar1 i Ar2 skupinu je (R).
21. Medikament naznačen time da sadrži spoj prema bilo kojem zahtjevu od 15 do 17 u kombinaciji sa antipsihotičkim sredstvom.
22. Medikament prema zahtjevu 21, naznačen time da je antipsihotičko sredstvo odabrano od acetofenazina, alentemola, aripiprazola, amisulprida, benzheksola, bromokriptina, biperidena, klorpromazina, klorprotiksena, klozapina, diazepama, fenoldopama, flufenazina, haloperidola, levodopa, levodopa sa benzerazidom, levodopa sa karbidopom, lizurida, loksapina, mezoridazina, molindolona, naksagolida, olanzapina, pergolida, perfenazina, pimozida, pramipeksola, kvetiapina, risperidona, sulpirida, tetrabenazina, triheksifenidila, lioridazina, tiotiksena, tritluoperazina ili ziprasidona.
23. Spoj prema zahtjevu 12, naznačen time da spoj je (R)-2-(4-(fenil(3-(trifluorometil)fenil)metil)piperazin-1-il)octena kiselina (Formula A) [image] ili (R)-2-(4-benzhidril-2-metilpiperazin-1-il)octena kiselina (Formula B) [image] ili njihova farmaceutski prihvatljiva sol.
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