HRP20220268T1 - Spojevi i pripravci za unutarstaničnu isporuku sredstava - Google Patents

Spojevi i pripravci za unutarstaničnu isporuku sredstava Download PDF

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HRP20220268T1
HRP20220268T1 HRP20220268TT HRP20220268T HRP20220268T1 HR P20220268 T1 HRP20220268 T1 HR P20220268T1 HR P20220268T T HRP20220268T T HR P20220268TT HR P20220268 T HRP20220268 T HR P20220268T HR P20220268 T1 HRP20220268 T1 HR P20220268T1
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Kerry E. BENENATO
William BUTCHER
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Modernatx, Inc.
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Claims (28)

1. Spoj formule (I) ili formule (Ib): [image] ili njegova sol ili izomer, naznačen time što prsten A je [image] t je 1 ili 2; A1 i A2 su svaki nezavisno odabrani od CH ili N; A6 i A7 su svaki nezavisno odabrani od CH ili N, naznačen time što barem jedan od A6 i A7 je N; Z je CH2 ili odsutan, naznačen time što je Z CH2, isprekidane linije (1) i (2) svaka predstavljaju jednu vezu; a kada je Z odsutan, isprekidane linije (1) i (2) su obje odsutne; R1, R2, R3, R4, i R5 su nezavisno odabrani iż skupine koja sadrži C5-20 alkil, C5-20 alkenil, -R"MR', -R∗YR", -YR", i -R∗OR"; svaki M je nezavisno odabran iz skupine koja se sastoji od -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, skupine arila, i skupine heteroarila; naznačen time što kada je spoj formule (Ib), tada M nije -OC(O)O-; X1, X2, i X3 su nezavisno odabrani iż skupine koja se sastoji od veze, -CH2-, -(CH2)2-, -CHR-, -CHY-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)-CH2-, -CH2-C(O)-, -C(O)O-CH2-, -OC(O)-CH2-, -CH2-C(O)O-, -CH2-OC(O)-, -CH(OH)-, -C(S)-, i -CH(SH)-; X4 i X5 su nezavisno odabrani iż skupine koja se sastoji od -CH2-, -(CH2)2-, -CHR-, -CHY-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)-CH2-, -CH2-C(O)-, -C(O)O-CH2-, -OC(O)-CH2-, -CH2-C(O)O-, -CH2-OC(O)-, -CH(OH)-, -C(S)-, i -CH(SH)-; svaki Y je nezavisno C3-6 karbociklil; svaki R∗ je nezavisno odabran iż skupine koja se sastoji od C1-12 alkila i C2-12 alkenila; svaki R je nezavisno odabran iż skupine koja se sastoji od C1-3 alkila i C3-6 karbociklila; svaki R' je nezavisno odabran iz skupine koja se satoji od C1-12 alkila, C2-12 alkenila, i H; i svaki R" je nezavisno odabran iz skupine koja se sastoji od C3-12 alkila i C3-12 alkenila; naznačen time što kada je spoj formule (I), i kada je prsten A [image] tada i) barem jedan od X1, X2, i X3 nije -CH2-; i/ili ii) barem jedan od R1, R2, R3, R4, i R5 je -R"MR'; i kada je spoj formule (I) i prsten A je [image] i X1, X2, i X3 su svaki -CH2, tada barem jedan od A1 i A2 je N, R1, R2, R3, R4 i R5 su nezavisno odabrani iż skupine koja se sastoji od C6-20 alkila i C6-20 alkenila, te kada je prsten A [image] tada i) R1, R2, R3, R4, i R5 su isti, pri čemu R1 nije C12 alkil, C18 alkil, ili C18 alkenil; ii) samo jedan od R1, R2, R3, R4 i R5 je odabran od C6-20 alkenila; iii) barem jedan od R1, R2, R3, R4, i R5 ima različit broj atoma ugljika od barem još jednog od R1, R2, R3, R4, i R5; iv) R1, R2, i R3 su odabrani od C6-20 alkenila, i R4 i R5 su odabrani od C6-20 alkila; ili v) R1, R2, i R3 su odabrani od C6-20 alkila, i R4 i R5 su odabrani od C6-20 alkenila.
2. Spoj sukladno zahtjevu 1, naznačen time što je spoj formule (I) i: (i) prsten A je [image] poželjno [image] ili [image] (ii) prsten A je [image] poželjno [image] ili [image] (iii) prsten A je [image] , u kojem je N atom spojen sa X2; ili (iv) prsten A je [image] u kojem je N atom spojen sa X2.
3. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što (i) barem jedan od A1 i A2 u formuli (I) je N; (ii) u formuli (I) A1 je N i A2 je CH; (iii) u formuli (I) A1 je CH i A2 je N, i/ili u formuli (Ib) A6 je CH i A7 je N; (iv) u formuli (I) A1 je N i A2 je N, i/ili u formuli (Ib) A6 je N i A7 je N; ili (v) u formuli (I) svaki od A1 i A2 je CH.
4. Spoj sukladno bilo kojem od prethodnih zahtjeva, jedne od formula (Ia1)-(Ia6): [image] [image] ili [image]
5. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time što je spoj odabran između: [image] i njegovih soli ili izomera.
6. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time što je formule (IIa) [image]
7. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što R1, R2, i R3 su: (i) neovisno odabrani iz skupine koju čine C5-20 alkil i C5-20 alkenil; (ii) isti; (iii) C6 alkil; (iv) C9 alkil; (v) C12 alkil; (vi) C14 alkil; (vii) C18 alkenil; ili (viii) linoleil.
8. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što (i) barem jedan od X1 i X2 nije -CH2-; (ii) X1 nije -CH2-; (iii) X1 je -C(O)-; (iv) X2 nije -CH2-; ili (v) X2 je -C(O)-.
9. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što kada A6 je N i A7 je N, tada (i) barem jedan od X4 i X5 nije -CH2-, (ii) barem jedan od X4 i X5 je -C(O)-; i/ili (iii) barem jedan od R1, R2, R3, R4, i R5 je -R"MR'.
10. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što (i) X4 je-CH2- i X5 je -C(O)-; ili (ii) X4 i X5 su -C(O)-.
11. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što R2, R3, R4, i R5 su isti.
12. Spoj sukladno bilo kojem od prethodnih zahtjeva, naznačen time što R2, R3, R4, i R5 su C9 alkil.
13. Spoj u bilo kojem od prethodnih zahtjeva, naznačen time što je spoj odabran između spoja 67: [image] i njegovih soli i izomera.
14. Spoj prema kojem od zahtjeva 1-12, naznačen time što je spoj odabran između Spoja 4: [image] i njegovih soli i izomera.
15. Pripravak nanočestica koja sadrži lipidnu komponentu koja sadrži spoj prema bilo kojem od prethodnih zahtjeva.
16. Pripravak nanočestica prema zahtjevu 15, naznačen time, da lipidna komponenta dalje sadrži: (i) fosfolipid; (ii) strukturni lipid, i/ili (iii) PEG lipid.
17. Pripravak nanočestica prema bilo kojem od zahtjeva 15-16, naznačen time, da je strukturni lipid odabran iz skupine koju čine kolesterol, fekosterol, sitosterol, ergosterol, kampesterol, stigmasterol, brasikasterol, tomatidin, ursolna kiselina, alfa-tokoferol, smjesu istih.
18. Pripravak nanočestica prema bilo kojem od zahtjeva 15-17, naznačena time, da nadalje sadrži terapeutsko i/ili profilaktičko sredstvo; izborno pri čemu je terapeutski i/ili profilaktički agens (i) cjepivo ili spoj koji može izazvati imunološki odgovor; (ii) nukleinska kiselina; ili (iii) ribonukleinska kiselina (RNA), izborno pri čemu je RNA odabrana iz skupine koja se sastoji od male interferirajuće RNA (siRNA), asimetrične interferirajuće RNA (aiRNA), mikroRNA (miRNA), RNA supstrata Dicera (dsRNA), mala ukosna RNA (shRNA), glasnička RNA (mRNA), i njihove mješavine.
19. Farmaceutski pripravak, naznačen time, da sadrži sastav nanočestica prema bilo kojem od zahtjeva 15-18 i farmaceutski prihvatljivu podlogu.
20. Pripravak nanočestica prema bilo kojem od zahtjeva 15-18, naznačena time, da se koristi u postupku liječenja bolesti ili poremećaja u sisavca kojem je to potrebno, izborno pri čemu je sisavac čovjek.
21. Pripravak nanočestica za uporabu prema zahtjevu 20, naznačena time što je bolest ili poremećaj karakteriziran disfunkcionalnom ili aberantnom aktivnošću proteina ili polipeptida, ili gdje je bolest ili poremećaj odabran iz skupine koju čine zarazne bolesti, rak i proliferativne bolesti, genetske bolesti , autoimune bolesti, dijabetes, neurodegenerativne bolesti, kardio- i reno-vaskularne bolesti, i metaboličke bolesti.
22. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-21, naznačena time što sastav nanočestica sadrži spoj 4: [image]
23. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-22, naznačen time, da se pripravak nanočestica primjenjuje intravenozno, intramuskularno, intradermalno, supkutano, intranazalno ili inhalacijom.
24. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-23, naznačen time, da se sisavcu daje doza od oko 0,01 mg/kg do oko 10 mg/kg terapeutskog i/ili profilaktičkog sredstva.
25. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-24, naznačena time što metoda nadalje uključuje, prije stupnja kontakta ili davanja, prethodnu obradu navedenog sisavca s jednim ili više dodatnih spojeva, pri čemu prethodna obrada uključuje davanje jednog ili više dodatnih spojeva navedenom sisavcu; izborno pri čemu je navedeni sisavac prethodno tretiran 24 ili manje sata prije stupnja kontakta ili davanja, izborno oko jedan sat prije stupnja kontakta ili davanja.
26. Pripravak nanočestica za uporabu prema zahtjevu 25, naznačena time što je naveden jedan ili više dodatnih spojeva odabrano iz skupine koja se sastoji od protuupalnih spojeva, steroida, statina, estradiola, BTK inhibitora, S1P1 agonista, modulatora glukokortikoidnih receptora (GRM), i antihistaminici; izborno pri čemu je naveden jedan ili više dodatnih spojeva odabran iz skupine koju čine deksametazon, metotreksat, acetaminofen, blokator H1 receptora, i blokator H2 receptora.
27. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-26, naznačena time što sisavac (a) ima nedostatak LDLR; (b) nedostatak apoE; i/ili (c) ima abnormalnu interakciju LDLR-apoE.
28. Pripravak nanočestica za uporabu prema bilo kojem od zahtjeva 20-26, naznačena time, da sisavac (a) nema LDLR deficit; (b) nema apoE-deficit; i/ili (c) ima normalnu interakciju LDLR-apoE.
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