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HRP20161495T1 - Novi derivati pirimidina kao inhibitori fosfodiesteraze 10 (pde-10) - Google Patents

Novi derivati pirimidina kao inhibitori fosfodiesteraze 10 (pde-10) Download PDF

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HRP20161495T1
HRP20161495T1 HRP20161495TT HRP20161495T HRP20161495T1 HR P20161495 T1 HRP20161495 T1 HR P20161495T1 HR P20161495T T HRP20161495T T HR P20161495TT HR P20161495 T HRP20161495 T HR P20161495T HR P20161495 T1 HRP20161495 T1 HR P20161495T1
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bromo
diamine
pyrimidin
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pyrazol
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Juan CAMACHO GÓMEZ
Julio Castro Palomino Laria
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Palobiofarma S.L.
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Claims (22)

1. Spoj formule (I): [image] , naznačen time što: – R1 se bira iz skupine koju čine vodik, halogen, cikloalkil i alkil s tri ili četiri atoma ugljika, nerazgranat ili razgranat; – Y se bira iz skupine koju čine C-R2 i atom dušika; – R2 se bira iz skupine koju čine: (a) arilna ili heteroarilna skupina, koja može biti supstituirana s jednim ili više atoma halogena, ili s jednom ili više cikloalkilnih, hidroksi, (C1-C8) alkoksi, (C1-C8) alkiltio, amino, mono- ili dialkilamino, alkoksialkilnih, hidroksikarbonilnih i alkoksikarbonilnih skupina; (b) alkoksikarbonilna skupina formule (-CO(R7), gdje R7 predstavlja hidroksilnu skupinu ili skupinu [-N(R8)(R9)]; R8 i R9 se neovisno bira iz skupine koju čine atom vodika, cikloalkil i alkil s tri ili četiri atoma ugljika, nerazgranat ili razgranat i može biti supstituiran s halogenom ili arilnom ili heterocikličkom skupinom; ili R8 i R9, zajedno s atomom dušika na kojeg su vezani, tvore zasićeni pet- ili šesteročlani prsten, koji može sadržavati dodatni heteroatom, kojeg se bira iz skupine koju čine kisik i dušik, može biti supstituiran s (C1-C8) alkilnom skupinom; – R3 se bira iz skupine koju čine vodik, halogen, cikloalkilna skupina i (C1-C8) alkilna skupina, nerazgranata ili razgranata, koja može biti supstituirana s atomima halogena; ili R2 i R3, zajedno s atomima ugljika na kojeg su vezani, tvore šesteročlani arilni ili heteroarilni prsten, koji može biti supstituiran s jednim ili više atoma halogena, ili s jednom ili više skupina koje se bira između cikloalkila, hidroksi, (C1-C8) alkoksi, (C1-C8) alkiltio, amino, mono- ili dialkilamino, alkoksialkila, hidroksikarbonila i alkoksikarbonila; – X se bira iz skupine koju čine atom halogena i cijano skupina; – R4, R5 i R6 se neovisno bira iz skupine koju čine: (a) atom vodika; (b) alkilna, cikloalkilna ili cikloalkilalkilna skupina s najviše pet atoma ugljika, nerazgranata ili razgranata i može biti supstituirana s jednim ili više atoma halogena, metoksi skupina ili heteroarilnih skupina, gdje navedena heteroarilna skupina može biti supstituirana s atomima halogena ili (C1-C8) alkilnim skupinama; (c) alilna ili propargilna skupina, koja može biti supstituirana s jednim ili više atoma halogena ili s jednom ili više skupina koje se bira iz skupine koju čine cikloalkil, hidroksi, (C1-C8) alkoksi, (C1-C8) alkiltio, amino, mono- ili dialkilamino, alkoksialkil, hidroksikarbonil i alkoksikarbonil; i (d) tetrahidropiranilna skupina; ili R5 i R6 mogu, zajedno s atomom dušika na kojeg su vezani, tvoriti pirazolni ili triazolni prsten, koji može biti supstituiran s atomima halogena i njegove farmaceutski prihvatljive soli.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R4 predstavlja atom vodika.
3. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R1, R3 i R5 predstavljaju atom vodika, X predstavlja atom broma, a Y predstavlja atom dušika.
4. Spoj u skladu s patentnim zahtjevom 3, naznačen time što se R6 bira iz skupine koju čine alkil, cikloalkilalkil i alkilcikloalkil, koji može biti supstituiran s metoksi skupinom ili heteroarilom, koji pak može biti supstituiran s (C1-C8) alkilnom skupinom.
5. Spoj u skladu s patentnim zahtjevom 4, naznačen time što se R6 bira iz skupine koju čine etil, propil, i ciklopropilmetil, od kojih sve mogu biti supstituirane s metoksi skupinom ili peteročlanom heteroarilnom skupinom, koja pak može biti supstituirana s jednom ili više metilnih skupina.
6. Spoj u skladu s patentnim zahtjevom 3, naznačen time što se R6 bira iz skupine koja se sastoji od skupine alil, propargil i tetrahidropiranil od kojih sve mogu biti supstituirane s alkilnom skupinom, nerazgranatom ili razgranatom, s najviše tri atoma ugljika.
7. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R1, R3 i R5 predstavlja atom vodika, X predstavlja atom broma, Y predstavlja ostatak C-R2, a R2 predstavlja heteroarilnu skupinu, koja može biti supstituirana s atomima halogena.
8. Spoj u skladu s patentnim zahtjevom 7, naznačen time što R2 se bira između piridina, kinolina, pirimidina ili pirazina, koji su mogu biti supstituirani s atomima halogena.
9. Spoj u skladu s patentnim zahtjevom 8, naznačen time što se R6 bira iz skupine koju čine alkilna, cikloalkilalkilna i alkilcikloalkilna skupina, od kojih sve mogu biti supstituirane s metoksi skupinom ili s heteroarilnom skupinom, koja pak može biti supstituirana s (C1-C8) alkilnom skupinom.
10. Spoj u skladu s patentnim zahtjevom 8, naznačen time što se R6 bira iz skupine koju čine etil, propil, i ciklopropilmetil, koji može biti supstituiran s metoksi skupinom ili s peteročlanom heteroarilnom skupinom, koja može biti supstituirana s jednom ili više metilnih skupina.
11. Spoj u skladu s patentnim zahtjevom 8, naznačen time što se R6 bira iz skupine koju čine alilnu, propargilnu i tetrahidropiranilnu skupinu, koje mogu biti supstituirane s atomima halogena.
12. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R1 i R5 predstavlja atom vodika, X predstavlja atom broma, Y predstavlja atom ugljika, a R2 i R3, zajedno s atomima ugljika na kojeg su vezani, tvore izborno supstituiranu arilnu ili heteroarilnu skupinu.
13. Spoj u skladu s patentnim zahtjevom 12, naznačen time što R2 i R3, zajedno s atomima ugljika na kojeg su vezani, tvore fenilni ili piridinski prsten, koji mogu biti supstituirani s atomima halogena.
14. Spoj u skladu s patentnim zahtjevom 13, naznačen time što se R6 bira iz skupine koju čine alkil, cikloalkilalkil i alkilcikloalkil, koji može biti supstituiran s metoksi skupinom ili heteroarilnom skupinom, koja pak može biti supstituirana s (C1-C8) alkilnom skupinom.
15. Spoj u skladu s patentnim zahtjevom 14, naznačen time što se R6 bira iz skupine koju čine etil, propil i ciklopropilmetil, može biti supstituiran s metoksi skupinom ili s peteročlanom heteroarilnom skupinom, koja može biti supstituirana s jednom ili više metilnih skupina.
16. Spoj u skladu s patentnim zahtjevom 13, naznačen time što se R6 bira iz skupine koju čine izborno supstituirani alil, propargil i tetrahidropiranil.
17. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R1 i R5 predstavljaju atom vodika, X predstavlja atom broma, Y predstavlja ostatak CR2, R2 i R3, zajedno s atomima ugljika na koje su vezani, tvore fenilni ili piridinski prsten, a R6 se bira iz skupine koju čine etil, propil i ciklopropilmetil, koji može biti supstituiran s tiazolnim prstenom, koji može biti supstituiran s jednom ili više metilnih skupina.
18. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R1, R3 i R5 predstavljaju atom vodika, X predstavlja atom broma, Y predstavlja atom dušika, a R6 se bira iz skupine koju čine etil, propil, propargil i ciklopropilmetil, koji može biti supstituiran s tiazolnim prstenom, koji pak može biti supstituiran s jednom ili više metilnih skupina.
19. Spoj u skladu s patentnim zahtjevom 1, naznačen time što se bira iz skupine koju čine: 5-brom-N4-(ciklopropilmetil)-2-(1H-indazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-etil-2-(1H-indazol-1-il)pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-(prop-2-inil)pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-6-(1H-pirazol-1-il)pirimidin-4-amin; N4-[(1H-benzo[d]imidazol-2-il)metil]-5-brom-2-(1H-indazol-1-il)pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-[(2-metiltiazol-4-il)metil]pirimidin-4,6-diamin; 5-brom-N4-(tetrahidro-2H-piran-4-il)-2-(1H-indazol-1-il)pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-[(1-metil-1H-pirazol-4-il)metil]pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-[(tiazol-5-il)metil]pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-[(4-metiltiazol-5-il)metil]pirimidin-4,6-diamin; 5-brom-2-(1H-indazol-1-il)-N4-(2-metoksietil)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-pirazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-(2-metoksietil)-2-(1H-pirazol-1-il)pirimidin-4,6-diamin; N4-[(1H-benzo[d]imidazol-2-il)metil]-5-brom-2-(1H-pirazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-[4-(piridin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-2-(4-(piridin-4-il)-1H-pirazol-1-il)-N4-[(tiazol-5-il)metil]pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(4-(piridin-2-il)-1H-pirazol-1-il)pirimidin-4,6-diamin; 5-brom-2-[4-(piridin-2-il)-1H-pirazol-1-il]-N4-[(tiazol-5-il)metil]pirimidin-4,6-diamin; 5-brom-N4-(2-metoksietil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-[4-(kinolin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(tetrahidro-2H-piran-4-il)-2-[4-(kinolin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-[(2-metiltiazol-4-il)metil]-2-[4-(kinolin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-[4-(kinolin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-etil-2-(4-fenil-1H-pirazol-1-il)pirimidin-4,6-diamin; 5-brom-2-[4-(4-klorfenil)-1H-pirazol-1-il]-N4-etilpirimidin-4,6-diamin; 5-brom-2-[4-(4-klorfenil)-1H-pirazol-1-il]-N4-(prop-2-inil)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-[4-(pirazin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-[4-(pirazin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-(1H-pirazolo[3,4-b]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-pirazolo[3,4-b]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-(1H-pirazolo[3,4-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-pirazolo[3,4-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-2-(1H-pirazolo[3,4-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-2-(1H-pirazolo[3,4-c]piridin-1-il)-N4-[(tiazol-5-il)metil]pirimidin-4,6-diamin; 5-brom-N4-(2-metoksietil)-2-(1H-pirazolo[3,4-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-(1H-pirazolo[4,3-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-pirazolo[4,3-c]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-(1H-pirazolo[4,3-b]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-pirazolo[4,3-b]piridin-1-il)pirimidin-4,6-diamin; 5-brom-N4-(prop-2-inil)-2-(1H-1,2,4-triazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(4-metiltiazol-5-il)metil]-2-(1H-1,2,4-triazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-(2-metoksietil)-2-(1H-1,2,4-triazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-[(tiazol-5-il)metil]-2-(1H-1,2,4-triazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-2-(1H-1,2,4-triazol-1-il)pirimidin-4,6-diamin; 1-[4-amino-5-brom-6-(prop-2-inilamino)pirimidin-2-il]-1H-pirazol-4-karboksilna kiselina; 1-[4-amino-5-brom-6-(etilamino)pirimidin-2-il]-1H-pirazol-4-karboksilna kiselina; 1-{4-[(4-metiltiazol-5-il)metilamino]-6-amino-5-brompirimidin-2-il}-1H-pirazol-4-karboksilna kiselina; {1-[4-amino-5-brom-6-(etilamino)pirimidin-2-il]-1H-pirazol-4-il}(morfolino)metanon; 5-brom-6-(1H-pirazol-1-il)-2-[4-(piridin-4-il)-1H-pirazol-1-il]pirimidin-4-amin; 5-brom-6-(1H-pirazol-1-il)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4-amin; 5-brom-2-[4-(pirazin-2-il)-1H-pirazol-1-il)-6-(1H-pirazol-1-il]pirimidin-4-amin; 5-brom-6-(1H-pirazol-1-il)-2-(1H-1,2,4-triazol-1-il)pirimidin-4-amin; 1-[4-(2-metoksietilamino)-6-amino-5-brompirimidin-2-il]-1H-pirazol-4-karboksilna kiselina; 1-[4-amino-5-brom-6-(ciklopropilmetilamino)pirimidin-2-il]-1H-pirazol-4-karboksilna kiselina; 1-[4-amino-5-brom-6-(isopropilamino)pirimidin-2-il]-1H-pirazol-4-karboksilna kiselina; 5-brom-N4-etil-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-etil-2-[4-(pirimidin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-etil-2-[4-(kinolin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-klor-N4-etil-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-klor-N4-etil-2-(1H-indazol-1-il)pirimidin-4,6-diamin; 5-klor-N4-etil-2-(5-fluor-1H-indazol-1-il)pirimidin-4,6-diamin; 5-brom-N4-etil-2-(1H-indazol-1-il)-N6-(prop-2-inil)pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-2-(1H-indazol-1-il)-N6-(prop-2-inil)pirimidin-4,6-diamin; 5-brom-N4-(tetrahidro-2H-piran-4-il)-2-(1H-indazol-1-il)-N6-(prop-2-inil)pirimidin-4,6-diamin; N4-[(1H-benzo[d]imidazol-2-il)metil]-5-brom-2-(1H-indazol-1-il)-N6-(prop-2-inil)pirimidin-4,6-diamin; 5-brom-N4-etil-N6-(prop-2-inil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-N6-(prop-2-inil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(tetrahidro-2H-piran-4-il)-N6-(prop-2-inil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; N4-[(1H-benzo[d]imidazol-2-il)metil]-5-brom-N6-(prop-2-inil)-2-[4-(piridin-2-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-etil-N6-(prop-2-inil)-2-[4-(pirimidin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-(ciklopropilmetil)-N6-etil-2-[4-(pirimidin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; 5-brom-N4-etil-N6-(tetrahidro-2H-piran-4-il)-2-[4-(pirimidin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin; i N4-[(1H-benzo[d]imidazol-2-il)metil]-5-brom-N6-etil-2-[4-(pirimidin-4-il)-1H-pirazol-1-il]pirimidin-4,6-diamin.
20. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 19, zajedno s farmaceutski prihvatljivom pomoćnom tvari.
21. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 19, naznačen time što je namijenjen upotrebi u liječenju bolesti ili patološkom stanju podložnom poboljšanju inhibiranju fosfodiesteraze 10, gdje se bolest ili patološko stanje podložno poboljšanju inhibiranju fosfodiesteraze 10 bira iz skupine koju čine bolesti i patološka stanja središnjeg živčanog sustava, poput shizofrenije, Huntingtonove bolesti, Parkinsonove bolesti, Alzheimerove bolesti i depresije, te respiratorni poremećaji, poput plućne hipertenzije, astme i COPD-a.
22. Kombinacijski produkt, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 19, te najmanje još jedan lijek, gdje se navedeni lijek bira između lijekova korisni u liječenju bolesti središnjeg živčanog sustava, poput shizofrenije, Parkinsonove bolesti, Huntingtonove bolesti, Alzheimerove bolesti i depresije, te respiratornih poremećaja, poput plućne hipertenzije, astme i COPD-a.
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