ME02656B - 2' -fluoro supstituisani karba-nukleozidni analozi za antiviralno lečenje - Google Patents

2' -fluoro supstituisani karba-nukleozidni analozi za antiviralno lečenje

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Publication number
ME02656B
ME02656B MEP-2017-35A MEP3517A ME02656B ME 02656 B ME02656 B ME 02656B ME P3517 A MEP3517 A ME P3517A ME 02656 B ME02656 B ME 02656B
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alkyl
independently
substituted
compound according
compound
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MEP-2017-35A
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German (de)
English (en)
French (fr)
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Aesop Cho
Choung U Kim
Samuel E Metobo
Adrian S Ray
Jie Xu
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Gilead Sciences Inc
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Publication of ME02656B publication Critical patent/ME02656B/me

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
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    • C07—ORGANIC CHEMISTRY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • G03C7/3825—Heterocyclic compounds with two heterocyclic rings the nuclei containing only nitrogen as hetero atoms
    • G03C7/3835—Heterocyclic compounds with two heterocyclic rings the nuclei containing only nitrogen as hetero atoms four nitrogen atoms

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Claims (26)

1. Jedinjenje Formule I: ili njegova farmaceutski prihvatljiva so; gde: R1 je (C1-C8)alkil, (C4-C8)karbociklilalkil, (C1-C8)supstituisani alkil, (C2-C8)alkenil, (C2-C8)supstituisani alkenil, (C2-C8)alkinil, (C2-C8)supstituisani alkinil, ili aril(C1-C8)alkil; 15 R2 je F; svaki R3, R4, ili R5 je nezavisno H, ORa N(Ra)2, N3, CN, NO2, S(O)nRa. halogen, (C1-C8)alkil, (C4-C8)karbociklilalkil, (C1-C8)supstituisani alkil, (C2-C8)alkenil, (C2-C8)supstituisani alkenil, (C2-C8)alkinil, (C2-C8)supstituisani alkinil, ili aril(C1-C8)alkil; 20 ili bilo koja dva od R3, R4 ili R5 na susednim atomima ugljenika kada su uzeti zajedno su - O(CO)O- ili kada uzeti zajedno sa atomom ugljenika u prstenu za koji su vezani grade dvostruku vezu; R6 je H, ORa, N(Ra)2, N3, CN, NO2, S(O)nRa, -C(=O)R11, -C(=O)OR11, - C(=O)NR11R12, -C(=O)SR11 -S(O)R11, -S(O)2R11, -S(O)(OR11), -S(O)2(OR11), 25 -SO2NR11R12, halogen, (C1-C8)alkil, (C4-C8)karbociklilalkil, (C1-C8)supstituisani alkil, (C2-C8)alkenil, (C2-C8)supstituisani alkenil, (C2-C8)alkinil, (C2-C8)supstituisani alkinil, ili aril(C1-C8)alkil; svaki n je nezavisno 0, 1, ili 2; svaki Ra je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, aril(C1-C8)alkil, (C4-C8)karbociklilalkil, -C(=O)R11 -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)R11, S(O)2R11 -S(O)(OR11), -S(O)2(OR11), ili -SO2NR11R12 R7 je H, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)R11, - S(O)2R11, -S(O)(OR11), -S(O)2(OR11), -SO2NR11R12, ili svaki Y ili Y1 je, nezavisno, 0, S, NR, +N(O)(R), N(OR), +N(O)(OR), ili N-NR2; W1 i W2, kada su uzeti zajedno, su -Y3(C(Ry)2)3Y3-; ili jedan od W1 ili W2 zajedno sa bilo R3 ili R4 je -Y3- i drugi od W1 ili W2 je Formula Ia; ili W1 i W2 su svaki, nezavisno, grupa Formule Ia: u kojoj: svaki Y2 je, nezavisno, hemijska veza, O, CR2, NR, +N(O)(R), N(OR), +N(O)(OR), N-NR2, S, S-S, S(O), ili S(O)2; svaki Y3 je, nezavisno, O, S, ili NR; M2 je 0, 1 ili 2; svaki Rx je, nezavisno, Ry ili formula: u kojoj: svaki M1a, M1c, i M1d je nezavisno 0 ili 1; M12c je 0, 1, 2, 3,4, 5, 6, 7, 8, 9,10, 11 ili 12; svaki Ry je nezavisno H, F, Cl, Br, I, OH, R, -C(=Y1)R, -C(=Y1)OR,-C(=Y1)N(R)2, -N(R)2, -+N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR),-OC(=Y1)R, -OC(=Y1)OR, -OC(=Y1)(N(R)2), -SC(=Y1)R, -SC(=Y1)OR,-SC(=Y1)(N(R)2), -N(R)C(=Y1)R, -N(R)C(=Y1)OR, -N(R)C(=Y1)N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, ili W3; ili kada uzeti zajedno, dva Ry na istom atomu ugljenika grade karbociklični prsten sa 3 do 7 atoma ugljenika; svaki R je nezavisno H, (C1-C8) alkil, (C1-C8) supstituisani alkil, (C2-C8)alkenil, (C2-C8) supstituisani alkenil, (C2-C8) alkinil, (C2-C8) supstituisani alkinil, C6-C20 aril, C6-C20 supstituisani aril, C2-C20 heterociklil, C2-C20 supstituisani heterociklil, arilalkil ili supstituisani arilalkil; W3 je W4 ili W5; W4 je R, -C(Y1)Ry, -C(Y1)W5, -SO2Ry, ili -SO2W5; i W5 je karbocikl ili heterocikl gde je W5 nezavisno supstituisan sa 0 do 3 Ry grupe; svaki X1 ili X2 je nezavisno C-R10 ili N; svaki R8 je halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NNHR11, -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR11, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C4-C8)karbociklilalkil, po izboru supstituisani aril, po izboru supstituisani heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil, aril(C1-C8)alkil, OR11 ili SR11; svaki R9 ili R10 je nezavisno H, halogen, NR11R12, N(R1)OR11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR11 ili SR11; svaki R11 ili R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C4-C8)karbociklilalkil, po izboru supstituisani aril, po izboru supstituisani heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil ili aril(C1-C8)alkil; ili R11 i R12 uzeti zajedno sa azotom za koji su oba vezani grade 3- do 7-člani heterociklični prsten u kom bilo koji atom ugljenika pomenutog heterocikličnog prstena može po izboru da bude zamenjen sa -O-, -S- ili -NRa-; gde je svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil ili aril(C1-C8)alkil svakog R1, R3, R4, R5, R6, R11 ili R12, nezavisno, po izboru supstituisan jednim ili više halo, hidroksi, CN, N3, N(Ra)2 ili ORa; i gde jedan ili više ne-terminalnih atoma ugljenika svakog pomenutog (C1-C8)alkila može po izboru da bude zamenjen sa -O-, -S- ili -NRa-, pod uslovom da jedinjenje Formule I nije jedinjenje predstavljeno bilo kojom od sledećih formula u kojima R označava H: ili
2. Jedinjenje prema patentnom zahtevu 1 predstavljeno Formulom II u kojoj svaki Y i Y1 je O; X1 je CR10 ili N i X2 je CH; ili njegova farmaceutski prihvatljiva so ili estar.
3. Jedinjenje prema patentnom zahtevu 1 ili 2 gde R8 je halogen, NR11R12, N(R11)OR11, NR11NR11R12, OR11 ili SR11.
4. Jedinjenje prema bilo kom od patentnih zahteva 1-3 i kom R9 je H, halogen, SR11 ili NR11R12.
5. Jedinjenje prema bilo kom od patentnih zahteva 1-4 u kom R6 je H, ORa, CN, metil, etenil, ili etinil.
6. Jedinjenje prema bilo kom od patentnih zahteva 1-5 u kom R6 je H.
7. Jedinjenje prema bilo kom od patentnih zahteva 1-5 u kom R6 je CN.
8. Jedinjenje prema bilo kom od patentnih zahteva 1-7 u kom R4 je ORa.
9. Jedinjenje prema bilo kom od patentnih zahteva 1-8 predstavljeno Formulom III u kom R1 je metil ili etinil; ili njegova farmaceutski prihvatljiva so ili estar.
10. Jedinjenje prema bilo kom od patentnih zahteva 1-9 u kom R7 je H ili
11. Jedinjenje prema bilo kom od patentnih zahteva 1-10 u kom R7 je
12. Jedinjenje prema bilo kom od patentnih zahteva 1-11 u kom R1 je CH3.
13. Jedinjenje prema Patentnom zahtevu 1 sledeće formule: ili Ili njegova prihvatljiva so ili estar.
14. Jedinjenje sledeće formule: ili ili njegova farmaceutski prihvatljiva so ili estar.
15. Jedinjenje korisno za pripremu jedinjenja Formule I odabrano iz grupe koja se sastoji od ili njegove soli ili estri.
16. Farmaceutska kompozicija koja sadrži terapijski efikasnu količinu jedinjenja patentnog zahteva 1 i farmaceutski prihvatljiv nosač.
17. Farmaceutska kompozicija patentnog zahteva 16 koja dalje sadrži najmanje jedan dodatni terapijski agens odabran iz grupe koja se sastoji od interferona, ribavirina ili njegovih analoga, HCV NS3 proteznog inhibitora, NS5a inhibitora, inhibitora alfa-glukozidaze 1, hepatoprotektanata, antagonista mevalonat dekarboksilaze, antagonista renin-angiotenzin sistema, antagonista endotelina, drugih antifibroznih agenasa, nukleozidnih ili nukleotidnih inhibitora HCV NS5B polimeraze, ne-nukleozidnih inhibitora HCV NS5B polimeraze, HCV NS5A inhibitora, agonista TLR-7, inhibitora ciklofilina, HCV IRES inhibitora, farmakokinetičkih pojačivača i drugih lekova za lečenje HCV; ili njihove smeše.
18. Jedinjenje prema jednom od patentnih zahteva 1 do 14 za primenu kao medikament.
19. Jedinjenje prema jednom od patentnih zahteva 1 do 14 za primenu u lečenju Flaviviridae virusne infekcije.
20. Jedinjenje patentnog zahteva 19 gde je viralna infekcija infekcija virusom hepatitisa C.
21. Jedinjenje patentnog zahteva 19 ili 20 gde je virusna infekcija izazvana mutantom S282T virusa hepatitisa C.
22. Smeša za primenu u lečenju infekcija virusom Flaviviridae koja sadrži jedinjenje bilo kog od patentnih zahteva 19 do 21 koja dodatno sadrži najmanje jedan dodatni terapijski agens odabran iz grupe koja se sastoji od interferona, ribavirina ili njegovih analoga, HCV NS3 proteaznih inhibitora, NS5a inhibitora, inhibitora alfa-glukozidaze 1, hepatoprotektanata, antagonista mevalonat dekarboksilaze, antagonista renin-angiotenzin sistema, antagonista endotelina, drugih antifibroznih agenasa, nukleozidnih ili nukleotidnih inhibitora HCV NS5B polimeraze, ne-nukleozidnih inhibitora HCV NS5B polimeraze, HCV NS5A inhibitora, agonista TLR-7, inhibitora ciklofilina, HCV IRES inhibitora, farmakokinetičkih pojačivača i drugih lekova za lečenje HCV; ili njihove smeše.
23. Primena jedinjenja bilo kog od patentnih zahteva 1-14 za izradu leka za lečenje infekcije virusima Flaviviridae.
24. Primena patentnog zahteva 23 gde je infekcija virusom Flaviviridae izazvana virusom hepatitisa C.
25. Primena patentnih zahteva 23 ili 24 gde je infekcija virusom Flaviviridae izazvana mutantom S282T virusa hepatitisa C.
26. Primena jedinjenja prema bilo kom od patentnih zahteva 1-15 za izradu leka za lečenje ili prevenciju Flaviviridae virusne infekcije, infekcije virusom hepatitisa C ili infekcije mutantom S282T virusa hepatitisa C.
MEP-2017-35A 2009-09-21 2010-09-20 2' -fluoro supstituisani karba-nukleozidni analozi za antiviralno lečenje ME02656B (me)

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JP3237884B2 (ja) 1991-12-27 2001-12-10 株式会社コーセー 美爪料
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