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ME00561B - Derivati sulfonamida kao pro-ljekovi inhibitora aspartil proteaze - Google Patents

Derivati sulfonamida kao pro-ljekovi inhibitora aspartil proteaze

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Publication number
ME00561B
ME00561B MEP-2008-820A MEP82008A ME00561B ME 00561 B ME00561 B ME 00561B ME P82008 A MEP82008 A ME P82008A ME 00561 B ME00561 B ME 00561B
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Roger D Tung
Michael R Hale
Christopher T Baker
Eric Steven Furfine
Istvan Kaldor
Wieslaw Wieczyslaw Kazmierski
Andrew Spaltenstein
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Vertex Pharma
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    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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Abstract

Ovaj pronalazak se odnosi na pro-ljekove jedne klase sulfonamida koji su infibitori aspartil proteaze. U jednoj realizaciji, ovaj pronalazak se odnosi na novu klasu proljekova inhibitora HIV aspartil proteaze koje se karakterišu pogodnom rastvorljivošću u vodi, visokom bio-prihvastljivošću i lakim in vivo obrazovanjem aktivne komponente. Pronalazak se takođe odnosi na farmaceutske kompozicije koje sadrže ove pro-ljekove. Pro-ljekovi i farmaceutske kompozicije prema ovom pronalasku su izuzetno dobro pogodni za smanjenje tabletnog opterećenja (“pill burden”) i povećanje saglasnosti pacijenta. Ovaj pronalazak se takođe odnosi na postupak za tretiranje sisara sa ovim proljekovima i farmaceutskim kompozicijama.

Claims (32)

1. Jedinjenje formule I: naznačeno time, što je: A odabran od H; Ht; -R1-Ht; -R1-(C1-C6)-alkila,koji je opciono supstituisan sa jednom ili više grupa nezavisno odabranih odhidroksi, C1-C4 alkoksi, Ht, -O-Ht, -NR2 -CO-N (R2)2 ili -CO-N(R2)2; -R1-(C2-C6)-alkenila, koji je opciono supstituisan sa jednom ili više grupa nezavisno odabranih od hidroksi, C1-C4 alkoksi, Ht, -O-Ht, -NR2-C(O)-N (R2) 2 ili -CO-N(R2)2; ili R7; svaki R1 je nezavisno odabran od -C(O)-, -S(O)2-, -C(O)-C(O)-O-C(O)-, -O-S (O) 2, -N(R)2-S (O)2-, -NCR2)-(O)- ili -N(R)2-C(O)-C(O)-;svaki Ht je nezavisno odabran od C3-C7 cikloalkila;C5-H7 cikloalkenila; C6-C10 arila; ili 5-7 članog zasićenog ili nezasićenog heterociklusa, koji sadrži jedan ili više heteroatoma odabranih od N, N (R2 ), O, S i S(O)n;gde je navedeni aril ili navedeni heterociklus opciono kondenzovan Sa Q; i gde je bilo koji član navedenog Ht opciono supstituisan sa jednim ili više supstituenata nezavisno odabranih od okso, -OR2, SR2, -R2, -N(R2)2, -R2-OH, -CN, -C(O) O-R2, C (O) -N (R2 ) 2, -S(O)2-N(R2)2, -N(R2) C(O)-R2, -C (O)-R2, -S (O)n-R2, -OCF3, -S(O)n-Q, metilendioksi, -N(R2)-S(O)2(R2), halogena, -CF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N(R2)(R7) ili -N(R7) 2;svaki R2 je nazavisno odabran od H, ili C1-C4-alkila opciono supstituisanog sa Q; B, kada je prisutan, je -N(R2)-C(R )2-C(O)-; svaki x je nezavisno 0 ili 1; svaki R3 je nezavisno odabran od H, Ht,alkila, (C2-C6)-alkenila, (C3-C6)-cikloalkila ili (C5-C6)-ciklo-alkenila; gde je bilo koji član navedenog R3, osim H,opciono supstituisan sa jednim ili više supstituenata odabranih od -OR2, -C(O)-NH-R2, -S(O)n-N(R2)2, Ht, -CN, -SR2, -CO2R2, NR2 -C(O)-R2; svaki n je nezavisno 1 ili 2; G, kada je prisutan, je odabran od H, R7 ili (C1-C4)-alkila, ili, kada je G (C1-C4)-alkil, G i R7 su vezani jedan za drugog ili direktno ili preko veze tako da obrazuju heterociklični prsten; ili kada G nije prisutan, atom za koji je G vezan je vezan direktno na R7 grupu u -OR7 sa pratećim premeštanjem jedne -ZM grupe iz R7. D i D' su nezavisno odabrani od Q; (C1-C6)-alkila, koji je opciono supstituisan sa jednom ili više grupa odabranih od (C3-C6)-cikloalkila, -OR2, -R2, -O-Q ili Q; - (C2-C4)-alkenila, koji je opciono supstituisan sa jednom ili više grupa odabranih od (C3-C6)-cikloalkila, -OR2, -R3, -O-Q ili Q; (C3-C6)-cikloalkila, koji je opciono supstituisan sa, ili kondenzovan sa Q; ili(C5-C6) cikloalkenila, koji je opciono supstituisan sa ili kondenzovan sa Q; svaki Q je nezavisno odabran od 3-7 članog zasićenog deliruićno zasićenog ili nezasićenog karbocikličnog prstenastog sistema; ili 5-7 članog zasićenog, delimićno zasićenog ili nezasićenog heterocikličnog prstena koji sadrži jedan ili više heteroatoma odabranih od O, N, S, S(O)n ili NCR2 ); gde je bilo koji prsten u Q opciono supstituisan sa jednom ili više grupa odabranih od okso, -OR2, -R2, -N(R2)2, -N(R2)-C(O)-R2, -r2OH, -CN, -C(O)OR2, C(O)-N(R2)2, halogena ili -CF3; E je odabran od Ht; O-Ht; Ht-Ht; -OR3; -N(R2)(R3);(C1-C6)-alkila, koji je opciono supstituisan sa jednom ili više grupa odabranih od R ili Ht; (C2-C6)-alkenila, koji je opciono supstituisan sa jednom ili više grupa odabranih od R4 ili Ht;(C3-C6)-zasićenog karbociklusa koji je opciono supstituisan sa jednom ili više grupa odabranih od R4 ili Ht; ili (C5-C6)-nezasićenog karbociklusa koji je opciono supstituisan sa jednom ili više grupa odabranih od R4 ili Ht; svaki R4 je nezavisno odabran od -OR2, -SR2,-C(O)-NHR2, -S(O)2-NHR2, halogena, -NR2-C(O)-R2, -N(R2)2 ili -CN; svaki R je nezavisno odabran od gde je svaki M nezavisno odabran od H, Li, Na, K, Mg, Ca, Ba, -N(R2)4 (C1-C12)-alkila, (C2-C12)-alkenila, ili -R6; gde su 1 do 4 -CH2 radikala alkil ili alkenil grupe, drugojačiji od -CH2, koji je vezan za Z, opciono zamenjeni sa heteroatomskom grupom odabranomod O, S, S(O), S(O)2, ili N(R2); i gde je bilo koji vodonik u navedenom alkil, alkenil ili R6 opciono zamenjen sa supstituentom odabranim od okso,-OR2, -R, N (R )2, N(R2)3, R2OH, -CN, -C(O)OR2-C(O)-N (R2) 2, S(O)2-N (R2) 2, N (R2) -C (O) -R2, C(O)-R2, -S (O) -R2, OCF., -S(O) -R6, N(R2) -S (O)2 (R2), halogena, -CF3, ili -NO2; M2 je H, je (C1-C12)-alkil, (C2-C12)-alkenil, ili -R6;gde su 1 do 4 -CH2 radikal a alkil ili alkenil grupe opciono zamenjeni sa heteroatomskom grupom odabranom iz O, S, S(O), S(O2), ili NC(R2); i gde je bilo koji vodonik u navedenom alkil, alkenil ili R6 opciono zamenjen sa supstituentom odabranim od okso, -OR2, R2, -N(R2)2, N(R2)3, -R2 OH, -CN,-CO2R2, -C(O)-N(R2)2, -S(O)2-N(R2)2, -NCR2)-C(O)-R2, -C(O)R2, -S(O)n-R2, -OCF3, -S(O)n-R6, -N(R2)-S(O)2 R2, halogena, -CF3, ili -NO2; Z je CH3, O, S, N(R2)2 ili, kada je M odsutan, H; Y je P ili S; X je O ili S; i R9 je C(R2)2, O-ili N(R2); i gde kada je Y S, Z nije S; i R6 je 5-6 elani zasićen, delimično zasićen ili nezasićen karbociklični ili heterociklični prstenasti sistem, ili 8-10 člani zasićen, delimićno zasićen ili nezasićen biciklični prstenasti sistem, gde bilo koji od navedenih heterocikličnih prstenastih sistema sadrže jedan ili više hetero atoma odabranih od O, N, S, S(O) ili N(R2); i gde bilo koji prstenasti sistem opciono sadrži 1 do 4 supstituenta nezavisno odabrana od OH, (C1-C4) alkila, O-(C1-C4)-alkila, OC(O)C1-C4 alkila.
2. Jedinjenje prema zahtevu 1, naznačeno time, sto je najmanje jedan R odabran od:
3. Jedinjenje prema zahtevu 2, naznačeno time, što navedeno jedinjenje ima formulu XXII: gde su A, D, R7 i E kao što su definisani u zahtevu 1.
4. Jedinjenje prema zahtevu 3, naznačeno time, što je A odabran od 3-tetrahidrofuril-O-C(O)-, 3-(l, 5-dioksan)-O-C(O) - f ili 3-hidroksi-heksahidrofura/2, 3-b/-furanil-O-C-(O)-;D' je C1-C4 alkil koji je opciono supstituisan sa jednom ili više grupa odabranih iz grupe koja se sastoji od (C3-C6)-cikloalkila, -OR2, -R2, -O-O i O; E je(C6-C10)-aril opciono supstituisan sa jednim ili više supstituenata odabranih od okso, -OR2, SR2, -R2,-NCR2)2, -R2-OH, -CN, C(O)O-R2, -C(O)-N(R2)2, S(O)2-N(R2)2,-N(R2)-C(O)-r2, -C(O) -R2, -S(O)n-R2, -OCF3, -S(O)n-Q, raetilendioksi -N(R2)-S(O)2(R2), halogena, -CF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N(R2)(R7) ili -N(R7)2; ili 5-članog heterocikličnog prstena koji sadrži jedan S i opciono sadrži N kao dodatni heteroatom, gde je heterociklični prsten opciono supstituisan sa jednom do dve grupe nezavisno odabrane od -CH3, R4, ili Ht, i Ht, ukoliko je definisan kao deo R3, je definisan kao gore osim sa izuzećem heterociklusa.
5. Jedinjenje prema zahtevu 4, naznačeno time, što je:A 3-tetrahiđrofuril-O-C(O)-; G je vodonik; D' je izobutil; E je fenil supstituisan sa N(R1)2; svaki M je nezavisno odabran od E, Li, Na, K, Mg, Ca, Ba, C1-C4 alkila ili -N(R2)4; i svaki M' je H ili C1-C4 alkil.
6. Jedinjenje prema zahtevu 3, naznačeno time, što je: E 5-to člani heterociklični prsten koji sadrži jedan S i opciono sadrži N kao dodatni heteroatom i gde je navedeni heterociklični prsten opciono supstituisan sa jednom do dve grupe nezavisno odabrane od -CH3, R4, ili Ht.
7. Jedinjenje prema zahtevu 3, naznačeno time, što: E je Ht supstituisan sa N(R7)2; r7 u -OR7 grupi prikazanoj u formuli XXII je-PO(OM)2 ili C(O)CH2OCH2CH2OCH2CH2OCH3 i oba R7 u N(R7) supstituentu u Ht su H; ili R7 u -OR7 grupi prikazanoj u formuli XXII je C (O) CH2OCH2CH2OCH3, jedan R7 u-N(R7)- supstituentu u Ht je C (O) CH2OCH2CH2OCH3, a drugi R7 u -N(R7)2 supstituentu u Ht jeH; i gde M je H, Li, Na, K ili alkil
8. Jedinjenje prema zahtevu 3, naznačeno time, što ima strukturu: gde je svaki M Na ili K.
9. Jedinjenje prema zahtevu 8, naznačeno time, što je svaki M Na.
10. Jedinjenje prema zahtevu 2, naznačeno time, što navedeno jedinjenje ima formulu XXIII:
11. Jedinjenje prema zahtevu 10, naznačeno time, što; R3 je (C1-C6)-alkil, (C2-C6)-alkenil, (C5-C6)-cikloalkil, (C5-C6)-cikloalkenil ili 5-6 člani zasićen ili nezasićen heterociklus, gde bilo koji član navedenog R3 može da bude opciono supstituisan sa jednim ili više supstituenata odabranih iz grupe koja se sastoji od -OR2, -C(O)-NH-R2, -S(O)nN(R2)2, -Ht, -CN, -SR2,C(O)O-R2 i NR2-C CO) -R2; i D' je (C1-C3)-alkil ili C3 alkenil; gde je D' opcionosupstituisan sa jednom ili više grupa odabranih od (C3-C6)-ciklalkila, -OR2, -OQ ili O.
12. Jedinjenje prema zahtevu 11, naznačeno time, što je R7 u OR7 grupi opisanoj u formuli XXIII -PO(OM)2 ili-C(O)-M'
13. Jedinjenje prema zahtevu 2, naznačeno time, što navedeno jedinjenje ima formulu XXXI:
14. Jedinjenje prema zahtevu 13, naznačeno time, što: A je R1-Ht; svaki R3 je nezavisno (C1-C6)-alkil koji je opciono supstituisan sa -OR2, -C(O)-NH-R2, -S (O)nN(R2) 2, -Ht, -CN,-SR2, -CO2R2 ili -N(R2)-C(O)-R2; i D' je (C1-C4)-alkil, koji je opciono supstituisan sa (C3-C6)-cikloalkilom, -OR2, -O-Q; i E je Rt, Ht-Ht i -N(R2)(R2).
15. Jedinjenje prema zahtevu 14, naznačeno time, što je R7 u -OR7 grupi opisanoj u formuli XXXI -PO(OM)2 ili -C (O) -M'.
16. Jedinjenje prema zahtevu 1, naznačeno time, što je odabrano od bilo kojeg jedinjenja brojeva 198 do 231, 237 do 242, 245 do 267, ili 308, opisanih u Tabeli 1; bilo kojeg od jedinjenja brojeva 232 do 236 opisanih u Tabeli II; ili bilo kojeg od jedinjenja brojeva 243 do 244 opisanih u Tabeli III.
17. Jedinjenje prema zahtevu 1, naznačeno time, što je odabrano od; gde: R10 je odabran od izopropil ili ciklopentil; R11 je odabran od NHR7 ili OR7; u jedinjenju 1005, kada je R7 PO3M, (G)x nije H; i x, R7 i G su kao što su definisani u zahtevu 1.
18. Jedinjenje prema bilo kome od zahteva 1-3, naznačeno time, što: A je 3-heksahidrofura [2, 3-b]-furanil-O-C-(O)-; D' je (C1-C4)-alkil koji je opciono supstituisan sa jednom ili više grupa odabranih iz grupe koja se sastoji od (C3-C6) - cikloalkila, -OR2, -OR3, -0-Q i Q; E je (C6-C10)-aril opciono supstituisan sa jednim ili više supstituenata odabranih od okso, -OR2, SR2, -R2, -N(R2)2,- (C1-C4)-alkil koji je supstituisan sa OH i opciono supstituisan sa Q, CN, C(O)O-R2, -C (O)-N (R2) 2, -S (O) 2-N (R2) 2,-N (R2) -C (O) -R2, -C (O) -R2, -S(O)n-R2, -OCF3, -S(O)n-Q, metilendioksi, -N (R2)-S (O) 2-R2, halogena, -SF3, -NO2, Q, -OQ, -OR7, -SR7, -R7, -N(R2) (R7) ili -N(R7)2; ili 5-članog heterocikličnog prstena koji sadrži jedan S i opciono sadrži N kao dodatni heteroatom, gde je heterociklični prsten opciono supstituisan sa jednom do dve grupe nezavisno odabrane od -CH3, R4, ili Ht, i Ht, ukoliko je definisan kao deo R3, je definisan kao u zahtevu 1 osim sa izuzećem heterociklusa.
19. Jedinjenje prema zahtevu 18, naznačeno time, što: D' je izobutil; i E je fenil supstituisan sa -N(R2)2.
20. Jedinjenje prema bilo kom od zahteva 1-3, naznačeno time, što ima strukturu:
21. Jedinjenje prema bilo kom od zahteva 18 - 20, naznačeno time, što: svaki M je nezavisno odabran od H, Li, Na, K, Mg, Ca, Ba, C1-C4-alkil ili -N(R2)4; i svaki M' je H ili C1-C4-alkil.
22. Jedinjenje prema zahtevu 1 ili 3, naznačeno time, što ima strukturu:gde je svaki M Na ili K.
23. Jedinjenje prema zahtevu 1 ili 3, naznačeno time, što ima strukturu:
24. Jedinjenje prema zahtevu 1 ili 3, naznačeno time, što ima strukturu:
25. Farmaceutska kompozicija, naznačeno time, što sadrži jedinjenje prema bilo kojem od zahteva 1 do 24 i farmaceutski prihvatljiv nosač, adjuvant ili prenosioc.
26. Farmaceutska kompozicija prema zahtevu 25, naznačeno time, što dalje sadrži jedan ili više agenasa, odabranih od anti-virusnog agensa, inhibitora HIV proteaze drugojačijeg od jedinjenja prema zahtevu 1, i imunostimulator.
27. Farmaceutska kompozicija prema zahtevu 26, naznačeno time, što dalje sadrži jedan ili više agenasa odabranih od zidovudina (AZT), zalcitabina (ddC), didanosina (ddl), stavudina (d4T), lamivudina (3TC), abakavira (1592U89), sakvinavira (Ro 31-8959), indinavira (MK-639, L-735, 524), ritonavira (ABT 538, A84538), nelfinavira (AG 1343), XM 450, CGP 53, 437, polisulfonovanih polisaharida, ganciklovira, ribavirina, aciklovira, TIBO, nevirapina, IL-2,GM-CSF, interferon alfa, i eritropoietina (EPO).
28. Upotreba jedinjenja prema bilo kom od zahteva 1 - 24 za proizvodnju leka za inhibiranje aktivnosti aspartil proteaze kod sisara.
29. Upotreba jedinjenja prema bilo kom od zahteva 1 - 24 za proizvodnju leka za tretiranje HIV infekcije kod sisara.
30. Upotreba prema zahtevu 28 ili 29, s tim što navedeni lek sadrži jedan ili više dodatnih agenasa odabranih od anti-virusnog agensa, inhibitora HIV proteaze drugojačijeg od jedinjenja prema zahtevu 1, i imunostimulator bilo kao deo jednog oblika doze sa navedenim jedinjenjem ili kao odvojeni oblik doze.
31. Upotreba prema zahtevu 30, s tim što je navedeni dodatni agens zidovudin (AZT), zalcitabin (ddC), didanosin (ddI), stavudin (d4T), lamivudin (3TC), abakavir (1592U89), sakvinavir (Ro 31-8959), indinavir (MK-639, L-735, 524), ritonavir (ABT 538, A84538), nelfinavir (AG 1343), XM 450, CGP 53, 437, polisulfonovani polisaharidi, ganciklovir, ribavirin, aciklovir, TIBO, nevirapin, IL-2, GM-CSF, interferon alfa, ili eritropoietin (EPO).
32. Upotreba prema zahtevu 29, s tim što je navedeni lek za oralnu primenu.
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