HRP20170572T1 - Derivati pirazina kao agonisti receptora cb2 - Google Patents

Derivati pirazina kao agonisti receptora cb2 Download PDF

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HRP20170572T1
HRP20170572T1 HRP20170572TT HRP20170572T HRP20170572T1 HR P20170572 T1 HRP20170572 T1 HR P20170572T1 HR P20170572T T HRP20170572T T HR P20170572TT HR P20170572 T HRP20170572 T HR P20170572T HR P20170572 T1 HRP20170572 T1 HR P20170572T1
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cyclopropylmethoxy
difluoro
azetidin
pyrazine
carbonyl
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HRP20170572TT
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Baledi DHURWASULU
Uwe Grether
Matthias Nettekoven
Stephan Roever
Mark Rogers-Evans
Tanja Schulz-Gasch
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F. Hoffmann - La Roche Ag
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Publication of HRP20170572T1 publication Critical patent/HRP20170572T1/hr

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Claims (12)

1. Spoj, naznačen time, da ima sljedeću formulu (I): [image] u kojoj R1 je cikloalkilalkoksi ili haloalkoksi; R2 je cikloalkil ili haloazetidinil; R3 i R4 su neovisno odabrani od sljedećih: alkil, alkoksi, alkoksialkil i alkoksikarbonilalkil; ili R3 i R4 zajedno s atomom dušika na kojega su priključeni, tvore heterociklil ili supstituirani heterociklil, pri čemu je heterociklil sljedeći: pirolidinil, morfolinil, oksomorfolinil, 2-okso-5-aza-biciklo[2.2.1]heptil, 7-oksa-4-aza-spiro[2.5]oktil, piperazinil, 2-oksa-6-aza-spiro[3.4]oktil, piperidinil, tiomorfolinil ili 5-aza-spiro[2.4]heptil, te je pritom supstituirani heterociklil takav heterociklil koji je supstituiran s jednim do četiri supstituenta neovisno odabrana od sljedećih: alkil, halogen, aminokarbonil, hidroksialkil, alkoksikarbonil, alkiltiokarbamoil, alkilkarboniloksi i hidroksil; ili njegova farmaceutski prihvatljiva sol.
2. Spoj prema zahtjevu 1, naznačen time, da R1 je cikloalkilalkoksi.
3. Spoj prema zahtjevu 1 ili 2, naznačen time, da R1 je ciklopropilmetoksi.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time, da R2 je ciklopropil ili difluoroazetidinil.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time, da su R3 i R4 neovisno odabrani od sljedećih: alkil, alkoksi i alkoksialkil, ili R3 i R4 zajedno s atomom dušika na kojega su priključeni, tvore heterociklil ili supstituirani heterociklil, pri čemu je heterociklil sljedeći: pirolidinil, morfolinil ili 5-azaspiro[2.4]heptil, te je pritom supstituirani heterociklil takav heterociklil koji je supstituiran s jednim do tri supstituenta neovisno odabrana od sljedećih: alkil, halogen i aminokarbonil.
6. Spoj prema bilo kojem od zahtjeva 1 do 5, naznačen time, da su R3 i R4 neovisno odabrani od sljedećih: metil, tert-butil, metoksietil ili metoksibutil, ili R3 i R4 zajedno s atomom dušika na kojega su priključeni, tvore sljedeće: dimetilmorfolinil, dimetilpirolidinil, (aminokarbonil)(difluoro) pirolidinil, (aminokarbonil)(dimetil)pirolidinil, ili (aminokarbonil)-5-azaspiro[2.4]heptil.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, naznačen time, da je odabran od sljedećih: (5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-il)-((R)-2-metil-pirolidin-1-il)-metanon; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-((R)-2-metil-pirolidin-1-il)-metanon; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-tert-butil-(2-metoksi-etil)-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(3,3-dimetil-morfolin-4-il)-metanon; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-((S)-2-metil-pirolidin-1-il)-metanon; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-((1R,4R)-2-oksa-5-aza-biciklo[2.2.1]hept-5-il)-metanon; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-tert-butil-metil-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(3,3-difluoro-pirolidin-1-il)-metanon; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-etil-izopropil-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(7-oksa-4-aza-spiro[2.5]okt-4-il)-metanon; {tert-butil-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-amino}-octena kiselina-etilester; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-(2-metoksi-1,1-dimetil-etil)-metil-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(2,2-dimetil-morfolin-4-il)-metanon; 5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karboksilna kiselina-(2-metoksi-1,1-dimetil-etil)-metil-amid; (5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-il)-(2,2-dimetil-pirolidin-1-il)-metanon; (S)-1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-pirolidin-2-karboksilna kiselina-metil-ester; (5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-il)-(7-oksa-4-aza-spiro[2.5]okt-4-il)-metanon; (S)-1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-4,4-difluoro-pirolidin-2-karboksilna kiselina-amid; (S)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4,4-difluoro-pirolidin-2-karboksilna kiselina-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-[4-(2-hidroksietil)-piperazin-1-il]-metanon; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(2,2-dimetil-pirolidin-1-il)-metanon; (R)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-pirolidin-2-karboksilna kiselina-metil-ester; 4-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-morfolin-2-on; (R)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-pirolidin-2-karbotioična kiselina-dimetil-amid; octena kiselina-1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-3-metilpirolidin-3-il-ester; (5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-il)-(3,3,4,4-tetrafluoro-pirolidin-1-il)-metanon; octena kiselina-(S)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-pirolidin-3-il-ester; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(2-oksa-6-aza-spiro[3.4]okt-6-il)-metanon; octena kiselina-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-3-metil-pirolidin-3-il-ester; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(3,3,4,4-tetrafluoro-pirolidin-1-il)-metanon; 5-(3,3-difluoro-azetidin-1-il)-6-(2,2,2-trifluoro-etoksi)-pirazin-2-karboksilna kiselina-tert-butil-metil-amid; [5-(3,3-difluoro-azetidin-1-il)-6-(2,2,2-trifluoro-etoksi)-pirazin-2-il]-(2,2-dimetil-pirolidin-1-il)-metanon; 1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-piperidin-2-karboksilna kiselina-amid; 1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; 1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; (-)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-piperidin-2-karboksilna kiselina-amid; (-)-4-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-tiomorfolin-3-karboksilna kiselina-amid; (-)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; (-)-1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; (±)-5-[6-(ciklopropilmetoksi)-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-5-azaspiro[2.4]heptan-6-karboksamid; (2S)-1-[6-(ciklopropilmetoksi)-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4-hidroksi-4-metil-pirolidin-2-karboksamid; i (2S)-1-[5-(3,3-difluoro-azetidin-1-il)-6-(2,2-difluoro-etoksi)-pirazin-2-karbonil]-4,4-difluoro-pirolidin-2-karboksamid.
8. Spoj prema bilo kojem od zahtjeva 1 do 7, naznačen time, da je odabran od sljedećih: 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-tert-butil-(2-metoksi-etil)-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(3,3-dimetil-morfolin-4-il)-metanon; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-tert-butil-metil-amid; 6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karboksilna kiselina-(2-metoksi-1,1-dimetil-etil)-metil-amid; (5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-il)-(2,2-dimetil-pirolidin-1-il)-metanon; (S)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4,4-difluoro-pirolidin-2-karboksilna kiselina-amid; [6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-il]-(2,2-dimetil-pirolidin-1-il)-metanon; 1-(5-ciklopropil-6-ciklopropilmetoksi-pirazin-2-karbonil)-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; (-)-1-[6-ciklopropilmetoksi-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-4,4-dimetil-pirolidin-2-karboksilna kiselina-amid; i (±)-5-[6-(ciklopropilmetoksi)-5-(3,3-difluoro-azetidin-1-il)-pirazin-2-karbonil]-5-azaspiro[2.4]heptan-6-karboksamid.
9. Postupak za proizvodnju spoja prema bilo kojem od zahtjeva 1 do 8, naznačen time, da obuhvaća reakciju spoja sljedeće formule (II): [image] u prisutnosti NHR3R4, amidnog sredstva za vezanje te baze, pri čemu su R1 do R4 isti kao što su definirani u bilo kojem od zahtjeva 1 do 6.
10. Spoj prema bilo kojem od zahtjeva 1 do 8, naznačen time, da se upotrebljava kao terapeutski djelotvorna tvar.
11. Farmaceutski sastav, naznačen time, da obuhvaća spoj prema bilo kojem od zahtjeva 1 do 8, te terapeutski inertan nosač.
12. Spoj prema bilo kojem od zahtjeva 1 do 8, naznačen time, da se upotrebljava u liječenju ili profilaksi sljedećih stanja: bol, ateroskleroza, makularna degeneracija povezana sa starošću, dijabetska retinopatija, glaukom, okluzija retinalne vene, retinopatija kod prerano rođene djece, okularni ishemijski sindrom, geografska atrofija, dijabetes melitus, upala, upalna bolest crijeva, ishemijsko-reperfuzijska ozljeda, akutno zatajenje jetre, fibroza jetre, fibroza pluća, fibroza bubrega, sustavna fibroza, akutno odbacivanje alogenskih presadaka, kronična alogenska nefropatija, dijabetska nefropatija, glomerulonefropatija, kardiomiopatija, zatajenje srca, ishemija miokarda, infarkt miokarda, sustavna skleroza, termalna ozljeda, opekotina, hipertrofični ožiljci, keloidi, gingivitis pireksija, ciroza jetre ili tumori jetre, regulacija koštane mase, neurodegeneracija, amiotrofna lateralna skleroza, moždani udar, prolazni ishemijski napad ili uveitis.
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