HRP20171688T1 - N-acil-(3-supstituirani)-(8-supstituirani)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazini kao selektivni antagonisti nk-3 receptora, farmaceutski sastav, metode za uporabu kod bolesti posredovane nk-3 receptorom - Google Patents

N-acil-(3-supstituirani)-(8-supstituirani)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazini kao selektivni antagonisti nk-3 receptora, farmaceutski sastav, metode za uporabu kod bolesti posredovane nk-3 receptorom Download PDF

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HRP20171688T1
HRP20171688T1 HRP20171688TT HRP20171688T HRP20171688T1 HR P20171688 T1 HRP20171688 T1 HR P20171688T1 HR P20171688T T HRP20171688T T HR P20171688TT HR P20171688 T HRP20171688 T HR P20171688T HR P20171688 T1 HRP20171688 T1 HR P20171688T1
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methyl
image
compound
formula
pharmaceutically acceptable
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HRP20171688TT
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Hamid Hoveyda
Guillaume Dutheuil
Graeme Fraser
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Ogeda S.A.
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Claims (23)

1. Spoj Formule I: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2’ je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil, hidroksietil, metoksietil, trifluorometil, difluorometil ili fluorometil; R5 je metil, etil, metoksimetil, trifluorometil, difluorometil, fluorometil, 1-fluoroetil, 1,1-difluoroetil ili 2,2,2-trifluoroetil; X1 je N i X2 je S ili O; ili X1 je S i X2 je N; [image] predstavlja jednostruku ili dvostruku vezu u ovisno o X1 i X2; [image] označava (R)-enantiomer ili racemat spoja Formule I.
2. Spoj sukladno zahtjevu 1, Formule I’ i I": [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu su R1, R1’, R2, R2’, R3, R4, R5, X1 i X2 onakvi kao što je definirano u zahtjevu 1; i [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2.
3. Spoj sukladno zahtjevu 1 ili zahtjevu 2, Formule Ia: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2’ je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil, hidroksietil, metoksietil, trifluorometil, difluorometil ili fluorometil; R5 je metil, etil, metoksimetil, trifluorometil, difluorometil ili fluorometil; [image] označava (R)-enantiomer ili racemat spoja Formule Ia.
4. Spoj sukladno bilo kojem od zahtjeva 1 do 3, odabrano između Formula Ia’ i Ia": [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu su R1, R1’, R2, R2’, R3, R4 i R5 onakvi kao što je definirano u zahtjevu 3.
5. Spoj sukladno bilo kojem od zahtjeva 1 do 4, koje ima Formulu Ia-1: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil, hidroksietil, metoksietil, trifluorometil, difluorometil ili fluorometil; R5 je metil, etil, metoksimetil, trifluorometil, difluorometil ili fluorometil; [image] označava (R)-enantiomer ili racemat spoja Formule Ia-1.
6. Spoj sukladno bilo kojem od zahtjeva 1 do 5, koje ima Formulu Ia-2: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2’ je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R5 je metil, etil, metoksimetil, trifluorometil, difluorometil ili fluorometil; *--- označava (R)-enantiomer ili racemat spoja Formule Ia-2.
7. Spoj sukladno bilo kojem od zahtjeva 1 do 6, koje ima Formulu Ia-3: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2’ je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil, hidroksietil, metoksietil, trifluorometil, difluorometil ili fluorometil; *--- označava (R)-enantiomer ili racemat spoja Formule Ia-3.
8. Spoj sukladno bilo kojem od zahtjeva 1 do 7, koje ima Formulu Ib: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R3 je F; R5 je metil, etil, trifluorometil, difluorometil, fluorometil, 1-fluoroetil, 1,1-difluoroetil ili 2,2,2-trifluoroetil; [image] označava (R)-enantiomer ili racemat spoja Formule Ib.
9. Spoj sukladno bilo kojem od zahtjeva 1 do 8 koje ima Formulu Ib’: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu su R3 i R5 definirani kao u zahtjevu 8.
10. Spoj sukladno bilo kojem od zahtjeva 1 do 9, koje ima Formulu Ic: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2" je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil ili hidroksietil; R5 je metil, etil ili trifluorometil; [image] označava (R)-enantiomer ili racemat spoja Formule Ic.
11. Spoj sukladno bilo kojem od zahtjeva 1 do 10, koje ima Formulu Ic’: [image] ili njegov farmaceutski prihvatljiv solvat, pri čemu: R1 je H, F ili metil; R1’ je H; R2 je H, F, Cl ili metoksi; R2’ je H ili F; R3 je H, F, Cl, metil, trifluorometil ili nitril; R4 je metil, etil, n-propil ili hidroksietil; R5 je metil, etil ili trifluorometil.
12. Spoj sukladno bilo kojem od zahtjeva 1 do 11, odabrano iz skupine sastavljenu od slijedećih: [image] [image] [image] [image] [image] [image] [image] [image] [image] i njihovih farmaceutski prihvatljivih solvata.
13. Spoj sukladno bilo kojem od zahtjeva 1 do 12, odabrano iz skupine sastavljenu od slijedećih: (R)-(3-(3-etil-1,2,4-tiadiazol-5-il)-8-metil-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)(4-fluorofenil)metanon; (R)-(4-hlorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon; (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon; (4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon; i (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-oksadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon, i njihovih farmaceutski prihvatljivih solvata.
14. Spoj sukladno bilo kojem od zahtjeva 1 do 13, koje je (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon, ili njegov farmaceutski prihvatljiv solvat.
15. Farmaceutski sastav koji sadrži spoj sukladno bilo kojem od zahtjeva 1 do 14, ili njegov farmaceutski prihvatljiv solvat, i najmanje jedan farmaceutski prihvatljiv nosač, diluent, ekscipijent i/ili ađuvans.
16. Spoj sukladno bilo kojem od zahtjeva 1 do 14 ili njegov farmaceutski prihvatljiv solvat za primjenu kao lijek.
17. Spoj sukladno bilo kojem od zahtjeva 1 do 14 ili njegov farmaceutski prihvatljiv solvat za liječenje i/ili prevenciju depresije, anksioznosti, psihoze, shizofrenije, psihotičnih poremećaja, bipolarnih poremećaja, kognitivnih poremećaja, Parkinsonove bolesti, Alzhajmerove bolesti, poremećaja deficita pažnje sa hiperaktivnosti (ADHD), boli, konvulzija, pretilosti, upalnih bolesti uključujući sindrom iritabilnog crijeva (IBS) i upalnih poremećaje crijeva, povraćanja, pre-eklampsije, bolesti dišnih puteva uključujući kroničnu opstruktivnu bolest pluća, astmu, hiperreaktivnost dišnih puteva, bronhokonstrikciju i kašalj, urinarne inkontinencije, reproduktivnih poremećaja, kontracepcije i bolesti ovisnih o seksualnim hormonima uključujući, ali bez ograničenja na benignu hiperplaziju prostate (BPH), hiperplaziju prostate, metastatski karcinom prostate, tumor testisa, tumor dojke, karcinom jajnika, akne ovisne o androgenu, muški tip ćelavosti, endometriozu, abnormalni pubertet, fibrozu maternice, fibroidni tumor maternice, lejomiom maternice, karcinom ovisan o hormonima, hiperandrogenizam, kirzutizam, virilizaciju, sindrom policističnih jajnika (PCOS), predmenstrualne disforične bolesti (PMDD), HAIR-AN sindrom (hiperandrogenizam, inzulinska rezistencija i acanthosis nigricans), hipertekozu jajnika (HAIR-AN s hiperplazijom luteiniziranih teka stanica u stromi jajnika), druge manifestacije visokih koncentracija androgena unutar jajnika (npr. prestanak sazrijevanja folikula, atresija, anovulacija, dismenoreja, disfunkcionalno materično krvarenje, neplodnost), tumor koji proizvodi androgen (virilizirajući tumor jajnika ili virilizirajući adrenalni tumor), menoragiju i adenomiozu.
18. Spoj za primjenu prema zahtjevu 17, pri čemu je spoj (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon ili njegov farmaceutski prihvatljiv solvat.
19. Spoj sukaldno bilo kojem od zahtjeva 1 do 14 ili njegov farmaceutski prihvatljiv solvat za liječenje i/ili prevenciji valunga.
20. Spoj za primjenu sukladno zahtjevu 19, pri čemu je spoj (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon ili njegov farmaceutski prihvatljiv solvat.
21. Spoj sukaldno bilo kojem od zahtjeva 1 do 14 ili njegov farmaceutski prihvatljiv solvat za primjenu kao agens za snižavanje razine cirkulirajućeg LH.
22. Spoj za primjenu sukladno zahtjevu 21, pri čemu je spoj (R)-(4-fluorofenil)(8-metil-3-(3-metil-1,2,4-tiadiazol-5-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon ili njegov farmaceutski prihvatljiv solvat.
23. Postupak za proizvodnju spoja sukladno bilo kojem od zahtjeva 1 do 14 ili njegovog farmaceutski prihvatljivog solvata, naznačen time što sadrži slijedeće korake: a) reakciju spoja Formule (i) [image] pri čemu: PG predstavlja pogodnu zaštitnu skupinu kao što je, na primjer, DMB, PMB, Boc, alil, difenil-fosfinamid ili 2-trimetilsililetansulfonil; R4’ je R4 onakav kao što je definirano u zahtjevu 1 ili reduktibilni prekursor hidroksietila i zato slijedeći prekursor metoksietila; *--- označava (R)-enantiomer ili racemat; sa spojem Formule (ii) [image] pri čemu: R5’ je R5 onakav kao što je definirano u zahtjevu 1, H ili 1-((terc. butildifenilsilil)oksi)etil; X1 i X2 su onakvi kao što je definirano u zahtjevu 1; [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2; tako da se dobije spoj Formule (iii) [image] pri čemu su PG, R4’, R5’, X1 i X2 onakvi kao što je gore definirano, [image] označava (R)-enantiomer ili racemat i [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2; b) deprotekciju spoja Formule (iii) s odgovarajućim agensom za deprotekciju da bi se dobio spoj Formule (iv) [image] pri čemu su R4’, R5’, X1 i X2 onakvi kao što je gore definirano, [image] označava (R)-enantiomer ili racemat i [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2; c) kada je R5’ H, onda uvođenje trifluorometil ili difluorometil skupine direktnom C-H trifluoro- ili difluorometilacijom, dovodi do spoja Formule (v) [image] pri čemu su R4’, X1 i X2 onakvi kao što je gore definirano i R5 je trifluorometil ili * difluorometil, [image] označava (R)-enantiomer ili racemat i [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2; d) N-aciliranje spoja Formule (iv), pri čemu R5’ nije H ili spoja Formule (v), sa spojem Formule (vi) [image] pri čemu su R1, R1’, R2, R2’ i R3 onakvi kao što je definirano u zahtjevu 1; što dovodi do spoja Formule (vii) [image] pri čemu su R1, R1’, R2, R2’, R3, R4’, X1 i X2 onakvi kao što je gore definirano, [image] označava (R)-enantiomer ili racemat, [image] predstavlja jednostruku ili dvostruku vezu ovisno o X1 i X2; i R5" je R5 onakvo kao što je definirano u zahtjevu 1 ili 1-((terc.butildifenilsilil)oksi)etil; e) opcijski dalje izvođenje jednog ili dva slijedeća koraka e’) i e"): e’) kada je R4’ reducirani prekursor hidroksietila i zato slijedeći prekursor metoksietila, za korakom redukcije opcijski slijedi tvorba metil etra; e") kada je R5" 1-((terc.butildifenilsilil)oksi)etil, onda sledi korak deprotekcije alkoholom i potom fluoriranje da bi se tvorila 1-fluoroetil R5 skupina; ili korak deprotekcije alkoholom, za kojim slijedi korak oksidacije i potom korak fluoriranja da bi se dobila 1,1-difluoroetil R5 skupina; da bi se dobio spoj Formule I sukladno bilo kojem od zahtjeva 1 do 14.
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