HRP20160396T1 - Novi kiralni n-acil-5,6,7(8-susupstituirani)-tetrahidro-/1,2,4/triazolo/4,3-a/pirazini kao selektivni nk-3 receptor antagonisti, farmaceutski pripravak, i metode za upor - Google Patents

Novi kiralni n-acil-5,6,7(8-susupstituirani)-tetrahidro-/1,2,4/triazolo/4,3-a/pirazini kao selektivni nk-3 receptor antagonisti, farmaceutski pripravak, i metode za upor Download PDF

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HRP20160396T1
HRP20160396T1 HRP20160396TT HRP20160396T HRP20160396T1 HR P20160396 T1 HRP20160396 T1 HR P20160396T1 HR P20160396T T HRP20160396T T HR P20160396TT HR P20160396 T HRP20160396 T HR P20160396T HR P20160396 T1 HRP20160396 T1 HR P20160396T1
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formula
alkyl
compound
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Hamid HOVEYEDA
Guillaume Dutheuil
Graeme Fraser
Marie-Odile Roy
Mohamed El Bousmaqui
Frédéric BATT
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Euroscreen S.A.
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Claims (38)

1. Spoj Formule I: [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1 je nesupstituirani tiofen-2-il, nesupstituirani fenil, ili 4-fluorofenil; R1 je H ili metil; Ar2 je opće Formule (i), (ii) ili (iii): [image] gdje R2 je linearni ili razgranati C1-C4 alkil, C1-C2 haloalkil, linearni ili razgranati C2-C3 alkenil, C3-C4 cikloalkil ili di(C1-C2 alkil)amino; X1 je N ili C-R6 gdje R6 je H, fluoro ili C1-C2 alkil; X2 je O ili S; X3 je N, ili X3 je CH pod uvjetom da X1 je N i X2 je N-R7 gdje R7 je linearni ili razgranati C1-C3 alkil ili ciklopropil; R3 je linearni ili razgranati C1-C4 alkil ili C3-C4 cikloalkil; X4 je N ili C-R8 gdje R8 je H ili C 1-C2 alkil; X5 je O ili S; X6 je N, ili X6 je CH pod uvjetom da X4 je N i X5 je N-R9 gdje R9 je linearni ili razgranati C1-C3 alkil ili ciklopropil; R4 je halo, cijano, metil, ili hidroksil; R5 je H ili halo; pod uvjetom da kada Ar2 je Formula (iii), tada R1 je metil; i spoj Formule I nije (3-(2-izobutiltiazol-4-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)(4-(tiofen-2-il)fenil)metanon; [1,1’-bifenil]-4-il(8-metil-3-(6-metilpiridin-2-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)metanon; (8-metil-3-(6-metilpiridin-2-il)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazin-7(8H)-il)(4-(tiofen-2-il)fenil)metanon.
2. Spoj prema zahtjevu 1 Formule I’: [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1 je nesupstituirani tiofen-2-il, nesupstituirani fenil, ili 4-fluorofenil; R1 je H ili metil; R2 je linearni ili razgranati C1-C4 alkil, C1-C2 haloalkil, linearni ili razgranati C2-C3 alkenil, C3-C4 cikloalkil ili di(C1-C2 alkil)amino; X1 je N ili C- R6 gdje R6 je H, fluoro ili C 1-C2 alkil; X2 je O ili S; X3 je N, ili X3 je CH pod uvjetom da X1 je N i X2 je N-R7 gdje R7 je linearni ili razgranati C1-C3 alkil ili ciklopropil.
3. Spoj prema zahtjevu 1 ili zahtjevu 2 Formule I’1 [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R1, R2, X1 i X2 su kao što je definirano gore u zahtjevu 1.
4. Spoj prema zahtjevu 3 izabran iz Formula I’a i I’b [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R2, X1 i X2 su kao što je definirano u zahtjevu 1.
5. Spoj prema zahtjevu 3 izabran iz Formula I’c, I’d [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R1, R2, X1 i X2 su kao što je definirano u zahtjevu 1.
6. Spoj prema zahtjevu 3 izabran iz Formula I’e, I’f [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R1, R2 i R6 su kao što je definirano u zahtjevu 1.
7. Spoj prema zahtjevu 6 izabran iz Formula I’e-1, I’e-2, I’f-1, I’f-2 [image] [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R1, R2 i R6 je kao što je definirano u zahtjevu 1.
8. Spoj prema zahtjevu 7 koji ima Formulu I’e-3 [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R2 je kao što je definirano u zahtjevu 1.
9. Spoj prema zahtjevu 7 koji ima Formulu I’f-3 [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R2 je kao što je definirano u zahtjevu 1.
10. Spoj prema bilo kojem od zahtjeva 1 do 3 koji ima Formule I’g, I’h i I’i [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R1, R2 i R7 su kao što je definirano u zahtjevu 1.
11. Spoj prema zahtjevu 1 koji ima Formulu I": [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1 je nesupstituirani tiofen-2-il, nesupstituirani fenil, ili 4-fluorofenil; R1 is H ili metil; R3 je linearni ili razgranati C1-C4 alkil ili C3-C4 cikloalkil; X4 je N ili C- R8 gdje R8 je H ili C1-C2 alkil; X5 je O ili S; X6 je N, ili X6 je CH pod uvjetom da X4 je N i X5 je N-R9 gdje R9 je linearni ili razgranati C1-C3 alkil or ciklopropil.
12. Spoj prema zahtjevu 11 izabran iz Formula I"a, I"b [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R3, X4, X5 i X6 su kao što je definrano u zahtjevu 1.
13. The compound of claim 11 selected from Formulae I"c, I"d [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R1, R3, X4, X5 i X6 su kao što je definirano u zahtjevu 1.
14. Spoj prema zahtjevu 11 izabran iz Formula I"e, I"f, I"g, I"h i I"i [image] [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1, R1, R3, R8 i R9 su kao što je definirano u zahtjevu 1.
15. Spoj prema zahtjevu 14 izabran iz Formula I"e-1, I"f-1, I"g-1, I"h-1, I"i-1, I"e-2, I"f-2, I"g-2, I"h-2 i I"i-2 [image] [image] [image] [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R1, R3, R8 i R9 su kao što je definirano u zahtjevu 1.
16. Spoj prema zahtjevu 1 koji ima Formulu I"’: [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da Ar1 je nesupstituirani fenil, nesupstituirani tiofen-2-il ili 4-fluorofenil; R4 je halo, cijano, metil, ili hidroksil; R5 je H ili halo.
17. Spoj prema zahtjevu 16 izabran iz Formula I"’a i I"’b [image] i njegovi farmaceutski prihvatljivi solvati, naznačen time da R4 i R5 su kao što je definirano u zahtjevu 1.
18. Spoj prema zahtjevu 1 izabran iz grupe koja se sastoji od: [image] [image] [image] [image] [image] [image] [image] [image] i njegovi farmaceutski prihvatljivi solvati.
19. Farmaceutski pripravak koji sadrži spoj prema bilo kojem od zahtjeva 1 do 18 ili njegov farmaceutski prihvatljiv solvat i najmanje jedan farmaceutski prihvatljiv nosač, otapalo, ekscipijent i / ili adjuvans.
20. Lijek koji sadrži spoj prema bilo kojem od zahtjeva 1 do 18 ili njegov farmaceutski prihvatljiv solvat.
21. Spoj prema bilo kojem od patentnih zahtjeva 1 do 18 ili njegov farmaceutski prihvatljiv solvat za uporabu u liječenju i / ili prevenciji depresije, anksioznosti, psihoze, shizofrenije, psihotičnih poremećaja, bipolarnih poremećaja, kognitivnih poremećaja, Parkinsonove bolesti, Alzheimerove bolesti, deficita pažnje i poremećaja hiperaktivnosti (ADHD), boli, konvulzija, pretilosti, upalnih bolesti uključujući sindrom iritabilnog crijeva i upalne bolesti crijeva, mučnine, preeklampsije, bolesti povezanih s dišnim uključujući kroničnu opstruktivnu bolest pluća, astmu, preosjetljivost dišnih puteva, bronhokonstrikciju i kašalj, poremećaje reprodukcije, kontracepcije i bolesti ovisne o spolnim hormonima uključujući ali ne ograničavajući se na benignu hiperplaziju prostate (BPH), hiperplazije prostate, metastaze karcinoma prostate, rak testisa, rak dojke, rak jajnika, androgen ovisne akne, muške ćelavosti, endometrioze, abnormalnog puberteta, fibroze maternice, fibroznog tumora maternice, hormon-ovisnog raka, hiperandrogenizma, hirzutizma, virilizacije, sindroma policističnih jajnika (PCOS), predmenstrualne disforične bolesti (PMDD), HAIRAN sindroma (hiperandrogenizam, inzulinska rezistencija i Acantosis nigricans) hipertekoze jajnika (HAIR-AN s hiperplazijom luteinskih teka stanica u stromi jajnika), druge manifestacije visokih intraovariijskih androgenih koncentracija (npr. arest folikulrnog sazrijevanja, atrezija, anovulacija, dismenoreja, disfunkcionalnog krvarenja iz maternice, neplodnosti), androgen proizvodećeg tumora ((virilizacijski tumor jajnika ili tumor nadbubrežne žlijezde), menoragija i adenomioza.
22. Spoj prema bilo kojem od zahtjeva 1 do 18 ili njihov farmaceutski prihvatljiv solvat za uporabu u supresiji LH-toka pri asistiranoj oplodnji pacijenata.
23. Spoj prema bilo kojem od zahtjeva 1 do 18 ili njihov farmaceutski prihvatljiv solvat za uporabu u izazivanju muške kastracije i inhibicije seksualnog poriva kod muškaraca.
24. Postupak priprave 5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin spoja Formule II [image] ili njegove soli ili sovata, naznačen time da puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese; R1 je linearni ili razgranati C1-C4 alkil ili C3-C4 cikloalkil, svaka od navedenih alkil ili cikloalkil groupa je po izboru supstituirana s jednom ili više grupa izabranih iz halo ili esteri; i Ar2’ je 5- do 6-člana aril ili heteroaril groupa, svaka od aril, ili heteroaril grups je po izboru supstituirana s jednom ili više grupa izabranih iz halo, alkil, haloalkil, cikloalkil, heteroalkil, heterociklil, aril, heteroaril, hidroksil, alkoksi, alkilamino, karbamoil, alkilkarbamoil, karbamoilalkil, karbamoilamino, alkilkarbamoilamino, alkilsulfonil, haloalkilsulfonil, arilsulfonilalkil, sulfamoil, alkilsulfamoil, alkilsulfonilamino, haloalkilsulfonilamino, fuzionizani na aril ili heteroaril grupu mogu biti jedna ili više cikloalkil, aril, heterociklil ili heteroaril grupa, svaki od navedenih supstituenata je po izboru supstituiran jednim ili više daljnjih supstituenata izabranih iz halo, alkil, haloalkil, alkoksi, haloalkoksi; navedeni postupak obuhvaća slijedeće korake: a) reakcijom spoja Formule A [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese; R1’ je kao što je definirano u svezi s Formulom II; s reagensom rezultirajući N-sp3 zaštitnom grupom (PG) na aminskom dušiku spoja Formule A, u prisutnosti reducirajućeg agensa dajući spoj Formule C [image] b) prevođenjem spoja Formule C s tri(C1-C2 alkil) oksonij soli kako bi se dobio spoj Formule D [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, R1 je kao što je definirano u svezi Formule II, PG je kao što je definirano u svezi Formule C, i R10 je C1-C2 alkil, u prisutnosti baze; c) reakcijom spoja Formule D sa spojem Formula E [image] ili njegove soli ili solvata, gdje Ar2’ je kao što je difinirano u svezi Formule II; Kako bi se dobio spoj Formule F [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, R1 je kao što je definirano u svezi Formule II, PG je kao što je definirano u svezi Formule C, i Ar2’ je kao što je definirano u svezi Formule E; i d) deprotekcijom spoja Formule F s odgovarajućim deprotekcijskim reagensom kako bi se dobio spoj Formule II ili njegova sol ili solvat.
25. Proces prema zahtjevu 24, naznačen time da su koraci a) do d) kao što slijedi: a) reakcijom spoja Formule A [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, i R1’ je kao što je definirano u zahtjevu 24; s reagensom rezultirajući N-sp3 zaštitnom grupom na amino dušiku spoja Formule A Formule B1 ili Formule B2 [image] gdje, R12, R12’, R13, R13’ i R14 su H, ili R14 je metoksi i R12, R12’, R13 i R13’ su H, ili R12 i R14 su metoksi i R12’, R13 i R13’ su H, ili R12, R12’ i R14 su metoksi i R13 i R13’ su H, X je Cl, Br, I, OMs, OTs, OTf, bilo direktnom alkilaciom amino dušika kad se koristi spoj Formule B2, ili u prisutnosti redukcijskog agensa kad se koristi spoj Formule B1 kako bi se na kraju dobio spoj Formule C-1 [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, i R1’, R12, R12’, R13, R13’ i R14 su kao što je definirano gore; b) prevođenjem spoja Formule C-1 s tri(C1-C2 alkil)oxonijevom soli (Meerwein-tip reagensa), ili (C1-C2)alkilsulfatom, ili (C1-C2)kloroformatom, ili uporabom PCl5/POCl3/(C1-C2)hidroksialkila kako bi se dobio spoj Formule D-1 [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, i R1’, R12, R12’, R13, R13’ i R14 su kao što je definirano gore i R10 je C1-C2 alkil, u prisutnosti baze; c) reakcijom spoja Formule D-1 sa spojem Formule E [image] ili njegova sol ili solvat, gdje Ar2’ kao što je definirano u svezi Formule II; kako bi se dobio spoj Formule F-1 [image] gdje puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, i R1’, R12, R12’, R13, R13’ i R14 su kao što je definirano gore i Ar2’ je kao što je definirano gore; i d) deprotekcijom spoja Formule F-1 s deprotekcijiskim reagensom kako bi se dobio spoj Formule II ili njegova sol ili sovat.
26. Postupak prema zahtjevu 25, naznačen time da R12 i R14 su metoksi i R12’, R13 i R13’ su H, ili R12, R12’ i R14 su metoksi i R13 i R13’ su H.
27. Proces prema bilo kojem od zahtjeva 24 do 26, naznačen time da je baza u koraku b) izabrana iz grupe koja se sastoji od natrij karbonata, natrij bikarbonata, kalij karbonata, cezij karbonata.
28. Proces prema bilo kojem od zahtjeva 24 do 27, naznačen time da Ar2’ je 5- do 6-člana heteroaril grupa izabrana iz skupine koja se sastoji od prstenova (i), (ii) i (iii) [image] gdje X1 je N ili C-R6 gdje R6 je H, fluoro ili metil; X2 je O ili S; X3 je N, ili X3 je CH pod uvjetom da X1 je N i X2 je N-R7 gdje R7 je linearni ili razgranati C1-C3 alkil ili ciklopropil; R2’ je linearni ili razgranati C1-C4 alkil, C1-C2 haloalkil, linearni ili razgranati C2-C3 alkenil, C3-C4 cikloalkil, di(C1-C2 alkil)amino, fenil, 4-fluorofenil, 2,4-difluorofenil ili N-morfolinil; X4 je N ili C-R8 gdje R8 je H ili C1-C2 alkil; X5 je O ili S; X6 je N ili X6 je CH pod uvjetom da X4 je N i X5 je N-R9 gdje R9 je C1-C2 alkil ili C3 alkil ili C3 cikloalkil, ili X4 je N, X5 je N-R9 gdje R9 je metil i X6 je CH; R3’ je linearni ili razgranati C1-C4 alkil, C1-C2 haloalkil, linearni ili razgranati C2-C3 alkenil, C3-C4 cikloalkil, di(C1-C2 alkil)amino, fenil, 4-fluorofenil, 2,4-difluorofenil ili N-morfolinil; R4’ je cijano, C1-C2 alkil ili hidroksil.
29. Postupak prema bilo kojem od zahtjeva 24 do 28, naznačen time da R1’ je C1-C2 alkil po izboru supstituiran jednom esterskom groupom.
30. Spoj Formule D [image] ili njegova sol ili solvat, naznačen time da puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese, R1’ je linearni ili razgranati C1-C4 alkil ili C3-C4 cikloalkil, svaki od navedenih alkil ili cikloakil groupa je po izboru supstituirana jednom ili više groupa izabranih iz halo ili esteri; PG je N-sp3 zaštitna groupa koja je benzil groupa po izboru supstituirana s jednom ili više elektron donirajućih groupa izabranih iz alkohol, alkoksi, amino, i alkil; i R10 je C1-C2 alkil.
31. Spoj prema zahtjevu 30 koji ima Formulu D-1 [image] ili njegova sol ili sovat, naznačen time da puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese; R12, R12’, R13, R13’ i R14 su H, ili R14 je metoksi i R12, R12’, R13 i R13’ je H, ili R12 i R14 su metoksi i R12’, R13 i R13’ je H, ili R12, R12’ i R14 su metoksi je R13 i R13’ su H; i R1’ i R10 su kao što je definirano u zahtjevu 30.
32. Spoj prema zahtjevu 30 ili 31, naznačen time da R1’ je C1-C2 alkil po izboru supstituiran jednom esterskom grupom.
33. Spoj prema bilo kojem od zahtjeva 30 do 31 koji je (R)-1-(2,4-dimetoksibenzil)-5-etoksi-6-metil-1,2,3,6-tetrahidropirazin ili (S)-1-(2,4-dimetoksibenzil)-5-etoksi-6-metil-1,2,3,6-tetrahidropirazin.
34. Spoj Formule III [image] ili njegove soli ili solvati, naznačen time da puna linija sa zvjezdicom označava da se misli na pojedinačne enantiomere, isklučujući njihove racemične smjese; R1’ je linearni ili razgranati C1-C4 alkil ili C3-C4 cikloalkil, svaka od navedenih alkil ili cikloakil grupe sup o izboru supstituirane jednom ili više grupa izabranih iz halo ili esteri; Ar2’ je 5- do 6-člana aril ili heteroaril groupa, svaka od aril, ili heteroaril groupa je po izboru supstituirana jednom ili više grupa izabranih iz halo, alkil, haloalkil, cikloalkil, heteroalkil, heterociklil, aril, heteroaril, hidroksil, alkoksi, alkilamino, karbamoil, alkilkarbamoil, karbamoilalkil, karbamoilamino, alkilkarbamoilamino, alkilsulfonil, haloalkilsulfonil, arilsulfonilalkil, sulfamoil, alkilsulfamoil, alkilsulfonilamino,haloalkilsulfonilamino, ili fuzioniran na aril ili heteroaril grupu može biti jedan ili više cikloalkil, aril, heterociklil ili heteroaril grupa, svaki od navedenih supstituenata je po izboru supstituiran sa jednom ili više daljnjih supstituenata izabranih iz halo, alkil, haloalkil, alkoksi, haloalkoksi; i R11 je H ili N-sp3 zaštitna grupa koja je benzilna groupa po izboru supstituirana sa jednom ili više elektron donirajućih groupa izabranih iz alkohol, alkoksi, amino, i alkil; pod uvjetom da spoj Formule III nije - (R)-4-(8-metil-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin-3-il)-2-feniltiazol hidroklorid, - (R)-8-metil-3-(piudin-2-il)-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin dihidrokloridna sol, - (R)-2-(4-klorofenil)-4-(8-metil-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin-3-il)tiazol hidroklorid na sol, - (R)-2-(4-fluorofenil)-4-(8-metil-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin-3-il)tiazol hidrokloridna sol, - (S)-8-metil-3-(piridin-2-il)-5,6,7,8-tetrahidro-[1,2,4]tuazolo[4,3-a]pirazine, - (S)-2-(4-fluorofenil)-4-(8-metil-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin-3-il)tiazol, - (S)-4-(4-(8-metil-5,6,7,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirazin-3-il)tiazol-2-il)morfolin.
35. Spoj prema zahtjevu 34 ili njegova sol ili solvat, naznačen time da R11 je H ili [image] gdje R12, R12’, R13, R13’ i R14 je H, ili R14 je metoksi i R12, R12’, R13 i R13’ je H, ili R12 i R14 su metoksi i R12’, R13 i R13’ je H, ili R12, R12’ i R14 su metoksi i R13 i R13’ su H; i R1’ i Ar2’ su kao što je definirano u zahtjevu 34.
36. Spoj prema zahtjevima 34 ili 35, naznačen time da R1’ je C1-C2 alkil po izboru supstituiran s jednom esterskom groupom.
37. Spoj prema bilo kojem od zahtjeva 34 do 36 izabran iz grupe koja se sastoji od [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image]
38. Uporaba spoja prema bilo kojem od zahtjeva 30 do 37 ili njegove soli ili solvata za sintezu farmaceutski aktivnog sastojka.
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