ME01231B - Makrociklički inhibitori virusa hepatitisa C - Google Patents

Makrociklički inhibitori virusa hepatitisa C

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Publication number
ME01231B
ME01231B MEP-2011-58A MEP5811A ME01231B ME 01231 B ME01231 B ME 01231B ME P5811 A MEP5811 A ME P5811A ME 01231 B ME01231 B ME 01231B
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Montenegro
Prior art keywords
compound
compound according
formula
6alkyl
group
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MEP-2011-58A
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German (de)
English (en)
French (fr)
Inventor
Kock Herman Augustinus De
Anna Karin Gertrud Linnea Belfrage
Per-Ola Mikael Johansson
Lili Hu
Abdellah Tahri
Sandrine Marie Helene Vendeville
Bengt Bertil Samuelsson
Karl Magnus Nilsson
Åsa Annica Kristina Rosenquist
Pierre Jean-Marie Bernard Raboisson
Dominique Louis Nestor Ghislain Surleraux
Kenneth Alan Simmen
Vladimir Ivanov
Michael Pelcman
Original Assignee
Janssen Sciences Ireland Uc
Medivir Ab
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37067620&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ME01231(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Janssen Sciences Ireland Uc, Medivir Ab filed Critical Janssen Sciences Ireland Uc
Publication of ME01231B publication Critical patent/ME01231B/me

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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Claims (28)

1.Jedinjenje koje ima formulu neki njegov N-oksid, so ili stereoizomer, naznačeno time, da svaka isprekidana linija (predstavljena sa-----) ponekad predstavlja dvostruku vezu; X je N, CH, a kada X nosi dvostruku vezu, pomenuti je C; R1 je -OR7 -NH-SO2R8; R2 je vodonik, a kada X je C ili CH, R2 može takođe da bude C1-6alkil; R3 je vodonik, C1-6alkil, C1-6alkoksiC1-6alkil, C3-7cikloalkil; R4 je aril ili Het; n je 3, 4, 5 ili 6; R5 predstavlja halo, C1-6alkil, hidroksi, C1-6alkoksi, polihaloC1-6alkil, fenil ili Het; R6 predstavlja C1-6alkoksi ili dimetilamino; R7 je vodonik; aril; Het; C3-7cikloalkil koji je ponekad supstituisan sa C1-6alkilom; ili C1-6alkil koji je ponekad supstituisan sa C3-7cikloalkilom, arilom ili sa Het; R8 je aril; Het; C3-7cikloalkil koji je ponekad supstituisan sa C1-6alkilom; ili C1-6alkil koji je ponekad supstituisan sa C3-7cikloalkilom, arilom ili sa Het; aril kao grupa ili kao deo grupe je fenil koji je ponekad supstituisan sa jednim, dva ili tri supstituenata koji su izabrani iz halo, hidroksi, nitro, cijano, karboksila, C1-6alkila, C1-6alkoksi, C1-6alkoksiC1-6alkila, C1-6alkilkarbonila, amino, mono- ili di-C1-6alkilamino, azido, merkapto, polihaloC1-6alkila, polihaloC1-6alkoksi, C3-7cikloalkila, pirolidinila, piperidinila, piperazinila, 4-C1-6alkilpiperazinila, 4-C1-6alkilkarbonilpiperazinila i morfolinila; gde pomenuta morfolinilna i piperidinilna grupa može da ponekad bude supstituisan sa jednim ili sa dva C1-6alkil radikala; Het kao grupa ili kao deo grupe je 5- ili 6-člani zasićeni, delomično nezasićeni ili kompletno nezasićeni heterociklički prsten koji sadrži 1 do 4 heteroatoma od kojih je svaki nezavisno izabran iz azota, kiseonika i sumpora, pri čemu je pomenuti heterociklički prsten ponekad kondenzovan sa nekim benzenskim prstenom; i gde pomenuti het kao celina je ponekad supstituisan sa jednim, dva ili tri supstituenata od kojih je svaki nezavisno izabran iz grupe koja se sastoji od halo, hidroksi, nitro, cijano, karboksila, C1-6alkila, C1-6alkoksi, C1-6alkoksiC1-6alkila, C1-6alkilkarbonila, amino, mono- ili di-C1-6alkilamino, azido, merkapto, polihaloC1-6alkila, polihaloC1-6alkoksi, C3-7cikloalkila, pirolidinila, piperidinila, piperazinila, 4-C1-6alkilpiperazinila, 4-C1-6alkilearbonilpiperazinila i morfolinila; a gde morfolinilna i piperidinilna grupa mogu da ponekad budu supstituisane sa jednim ili dva C1-6alkil radikala.
2.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje ima formulu (I-c), (I-d) ili (I-e):
3.Jedinjenje u skladu sa bilo kojim od zahteva od 1-2, naznačeno time, da R1 je izabran iz grupe koja se sastoji od fenila, piridin-4-il, a gde R4a, svaki nezavisno, je vodonik, halo, C1-6alkil, amino ili mono- ili di-C1-6alkilamino.
4.Jedinjenje u skladu sa bilo kojim od zahteva od 1-3, naznačeno time, da R5 je metil, etil, izopropil, tert-butil, fluoro, hloro ili bromo; a R6 je metoksi.
5. Jedinjenje u skladu sa bilo kojim od zahteva od 1-4, naznačeno time, da (a)R1 je -OR7, gde R7 je C1-6alkil ili vodonik; (b)R1 je -NHS(=O)2R8, gde R8 je metil, ciklopropil ili fenil; ili (c)R1 je -NHS(=O)2R8, gde R8 je ciklopropil koji je supstituisan sa metilom.
6.Jedinjenje u skladu sa zahtevom 5, naznačeno time, da R1 je -NHS(=O)2R8, gde R8 je metil, ciklopropil ili fenil.
7.Jedinjenje u skladu sa bilo kojim od zahteva od 1-6, naznačeno time, da nje 4 ili 5.
8.Jedinjenje u skladu sa bilo kojim od zahteva od 1-7, naznačeno time, da n je 4.
9.Jedinjenje u skladu sa bilo kojim od zahteva od 1-8, naznačeno time, da R3 je vodonik ili C1-6alkil.
10.Jedinjenje u skladu sa zahtevom 9, naznačeno time, da R3 je vodonik ili metil.
11.Jedinjenje u skladu sa bilo kojim od zahteva od 1-2, naznačeno time, da R4 je radikal gde, kada je to moguće, azot može da nosi R4a supstituenat ili neku vezu prema ostatku molekula; svaki R4a u bilo kojem od R4 supstituenata može da bude izabran iz grupe onih supstituenata koji su pomenuti kao mogući supstituenti na Het, kao šta je specifikovano u zahtevu 1.
12.Jedinjenje u skladu sa bilo kojim od zahteva od 1-2, naznačeno time, da R4 je izabran iz grupe koja se sastoji od: gde svaki R4a je vodonik, halo, C1-6alkil, amino ili mono- ili di-C1-6alkilamino, pirolidinil, piperidinil, morfolinil, piperazinil, 4-C1-6alkilpiperazinil; i gde morfolinilna i piperidinilna grupa mogu da ponekad budu supstituisane sa jednim ili dva C1-6alkil radikala.
13.Jedinjenje u skladu sa zahtevom 12, naznačeno time, da u radikalima (q-l), (q-2), (q-3) ili (q-4) svaki R4a je nezavisno vodonik, halo, C1-6alkil, amino ili mono- ili di-C1-6alkilamino.
14.Jedinjenje u skladu sa bilo kojim od zahteva od 1-13, naznačeno time, da R6 je metoksi.
15.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje ima sledeću strukturu
16.Jedinjenje u skladu sa zahtevom 15, naznačeno time, da R2 je vodonik, a dvostruka veza je prisutna između atoma ugljenika 7 i 8.
17.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje sa formulom (I) je sledeće:
18.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje sa formulom (I) je sledeće:
19.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje sa formulom (I) je sledeće:
20.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje sa formulom (I) je sledeće:
21.Jedinjenje u skladu sa bilo kojim od zahteva od 1-20, naznačeno time, da je različito od N-oksida ili soli.
22.Jedinjenje u skladu sa bilo kojim od zahteva od 1-21, naznačeno time, da je različito od N- oksida.
23.Kombinacija, naznačena time, da obuhvata (a)jedinjenje kao šta je definisano u bilo kojem od zahteva od 1 do 22 ili neku njegovu farmaceutski prihvatljivu so; i (b)ritonavir ili neku njegovu farmaceutski prihvatljivu so.
24.Kombinacija, naznačena time, da obuhvata (a)jedinjenje kao šta je definisano u bilo kojem od zahteva od 1 do 22 ili neku njegovu farmaceutski prihvatljivu so; i (b)interferon-a, pegilovani interferon-α i/ili ribavirin.
25.Farmaceutska kompozicija, naznačena time, da obuhvata kerijer, a kao aktivni sastojak neku anti-viralno efektivnu količinu nekog jedinjenja kao šta se zahteva u bilo kojem od zahteva od 1-22 ili neku kombinacija u skladu sa bilo kojim od zahteva od 23-24.
26.Jedinjenje u skladu sa bilo kojim od zahteva od 1-22 ili kombinacija u skladu sa bilo kojim od zahteva od 23-24, naznačeni time, da se upotrebljavaju kao lek.
27.Jedinjenje u skladu sa bilo kojim od zahteva od 1-22 ili kombinacija u skladu sa bilo kojim od zahteva od 23-24, naznačeni time, da se koriste za inhibiranje HCV replikacije.
28.Proces za pripremanje jedinjenja kao šta se zahteva u bilo kojem od zahteva od 1 - 22, naznačen time, da pomenuti proces obuhvata: (a) preparaciju jedinjenja sa formulom (I) gde veza među C7 i C8 je dvostruka veza, šta u stvari predstavlja jedinjenje sa formulom (I-i), uz pomoć formiranja dvostruke veze među C7 i C8, a posebno preko olefin metatezne reakcije, a nakon toga uz pomoć ciklizovanja u makrocikal kao šta je opisano u sledećoj reakcionoj šemi: gde u gornjoj i u sledećim reakcionim šemama R9 predstavlja neki radikal (b) konvertovanje jedinjenja sa formulom (I-i) ujedinjenje sa formulom (I) gde veza među C7 i C8 u makrociklu je jednostruka veza, na primer neko jedinjenje sa formulom (I-j): uz pomoć redukcije C7-C8 dvostruke veze u jedinjenjima sa formulom (I-j); (c)preparaciju jedinjenja sa formulom (I) gde R1 predstavlja -NHSO2R8, pri čemu su pomenuta jedinjenja predstavljena sa formulom (I-k-1), uz pomoć formiranja amidne veze među intermedijara (2a) i sulfonilamina (2b) ili priprema jedinjenja sa formulom (I) gde R1 predstavlja -OR7, na primer jedinjenje (I-k-2), uz pomoć formiranja esterske veze među intermedijara (2a) i alkohola (2c) kao šta je navedeno u sledećoj šemi gde G predstavlja neku grupu: (d)priprema jedinjenja sa formulom (I) gde R3 je vodonik, a pomenuto jedinjenje je predstavljeno sa (1-1), iz odgovarajućeg azot-zaštićenog intermedijara (3a), gde PG predstavlja neku grupu koja štiti azot: (e)reagovanje intermedijara (4a) sa intermedijarom (4b) kao šta je navedeno u sledećoj reakcionoj šemi: gde Y u (4b) predstavlja hidroksi ili neku izlaznu grupu; pri čemu kada Y predstavlja hidroksi, reakcija (4a) sa (4b) je Mitsunobu-ova reakcija; pri čemu kada Y predstavlja izlaznu grupu, reakcija (4a) sa (4b) je supstitucijska reakcija; (f)konvertovanje jedinjenja sa formulom (I) jedno u drugo uz pomoć reakcije transformacije funkcionalne grupe; ili (g)priprema soli uz pomoć reagovanja slobodne forme jedinjenja sa formulom (I) sa nekom kiselinom ili bazom. [1]
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