AR086096A1 - Derivados de nucleosidos 2’-ciano sustituidos y metodos de uso de los mismos para el tratamiento de enfermedades virales - Google Patents

Derivados de nucleosidos 2’-ciano sustituidos y metodos de uso de los mismos para el tratamiento de enfermedades virales

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AR086096A1
AR086096A1 ARP120101283A ARP120101283A AR086096A1 AR 086096 A1 AR086096 A1 AR 086096A1 AR P120101283 A ARP120101283 A AR P120101283A AR P120101283 A ARP120101283 A AR P120101283A AR 086096 A1 AR086096 A1 AR 086096A1
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alkylene
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Abstract

Reivindicación 1: Un compuesto que tiene la estructura de fórmula (1) o una sal farmacéuticamente aceptable del mismo, en la que: X es O, S o CH2; B es una base de purina o pirimidina natural o no natural, o B se selecciona entre uno de los restos del grupo de fórmulas (2); Y es N o -C(R19)-; R1 es H, o un resto del grupo de fórmulas (3); R2 es H, o el resto de fórmula (4), o R1 y R2 se unen para formar un compuesto del grupo de fórmulas (5); R3 es alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, alquenilo C2-6, alquinilo C2-6 o cicloalquilo C3-7; cada uno de R4, R5, R7 y R8 es independientemente H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, halo, -OR20, -SR20 o -N(R20)2; cada uno de R6, R9, R10, R11 se selecciona independientemente entre H, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, heteroarilo monocíclico de 5 ó 6 miembros, heteroarilo bicíclico de 9 ó 10 miembros, halo, -OR20, -SR20, -S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -NHC(O)OR20, -NHC(O)N(R20)2, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R20)2, -NH(alquileno C1-6)-(heteroarilo monocíclico de 5 ó 6 miembros), -NH(alquileno C1-6)-(heteroarilo bicíclico de 9 ó 10 miembros), -C(O)R20, -C(O)OR20, -C(O)N(R20)2 y -NHC(O)R20, en la que dicho grupo alquenilo C2-6 y dicho grupo alquinilo C2-6 pueden estar opcionalmente sustituidos con un grupo halo; R12 es H o -(alquileno C1-6)-T-R21; R13 es H o -(alquileno C1-6)-T-R21, o R12 y R13 pueden unirse para formar un grupo alquileno C2-4 entre los átomos de oxígeno a los que R12 y R13 están unidos, en la que dicho grupo alquileno C2-4 está sustituido con al menos un grupo arilo C6-10; R14 es H, arilo C6-10, heteroarilo monocíclico de 5 ó 6 miembros o heteroarilo bicíclico de 9 ó 10 miembros, en la que dicho grupo arilo C6-10, dicho grupo heteroarilo monocíclico de 5 ó 6 miembros y dicho grupo heteroarilo bicíclico de 9 ó 10 miembros puede estar opcionalmente sustituido con R22; R15 es H, alquilo C1-6, cicloalquilo C3-7, fenilo o bencilo, en la que dicho alquilo C1-6 puede estar opcionalmente sustituido con un grupo seleccionado entre halo, -OR20, -SR20, guanidino, -N(R20)2, -C(O)OR20, -C(O)N(R20)2, -NHC(O)R20, heteroarilo monocíclico de 5 ó 6 miembros y heteroarilo bicíclico de 9 ó 10 miembros, y en la que dicho grupo fenilo y dicho grupo bencilo pueden estar opcionalmente sustituidos con hasta 2 grupos, cada uno seleccionado independientemente entre alquilo C1-6, halo y -OR20; R16 es H, alquilo C1-6, cicloalquilo C3-7, fenilo o bencilo, en la que dicho alquilo C1-6 puede estar opcionalmente sustituido con un grupo seleccionado entre halo, -OR20, -SR20, guanidino, -N(R20)2, -C(O)OR20, -C(O)N(R20)2, -NHC(O)R20, heteroarilo monocíclico de 5 ó 6 miembros y heteroarilo bicíclico de 9 ó 10 miembros, y en la que dicho grupo fenilo y dicho grupo bencilo pueden estar opcionalmente sustituidos con hasta 2 grupos, cada uno seleccionado independientemente entre alquilo C1-6, halo y -OR20; R17 es H, alquilo C1-20, alquenilo C2-20, -(alquileno C1-3)m-cicloalquilo C3-7, -(alquileno C1-3)m-arilo C6-10 o adamantilo, en la que dicho grupo alquilo C1-20, dicho grupo alquenilo C2-20, dicho grupo arilo C6-10 y dicho grupo adamantilo pueden estar opcionalmente sustituidos con hasta tres grupos, cada uno seleccionado independientemente entre halo, -OR20, -C(O)OR20, CN, NO2, haloalquilo C1-6, hidroxialquilo C1-6, cicloalquilo C3-7, arilo C6-10, heteroarilo monocíclico de 5 ó 6 miembros, heteroarilo bicíclico de 9 ó 10 miembros, -N(R20)2, -C(O)N(R20)2, -SR20, -S(O)R20, -S(O)2R20, -S(O)2N(R20)2, -NHC(O)R20, -NHC(O)OR20 y -NHC(O)N(R20)2; y R18 es H, alquilo C1-6, cicloalquilo C3-7, -(alquileno C1-3)m-arilo C6-10, heteroarilo monocíclico de 5 ó 6 miembros, heteroarilo bicíclico de 9 ó 10 miembros o un resto de fórmula (6), en la que dicho grupo arilo C6-10, dicho grupo heteroarilo monocíclico de 5 ó 6 miembros y dicho grupo heteroarilo bicíclico de 9 ó 10 miembros pueden estar opcionalmente sustituidos con hasta cinco grupos, cada uno seleccionado independientemente entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, -OR20, -SR20, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R20)2, -C(O)OR20, -C(O)N(R20)2 y -NHC(O)R20; R19 es H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, halo, -OR20, -SR20, N(R20)2, cicloalquilo C3-7, arilo C6-10, heteroarilo monocíclico de 5 ó 6 miembros o heteroarilo bicíclico de 9 ó 10 miembros; cada aparición de R20 es independientemente H, alquilo C1-10, haloalquilo C1-6, hidroxialquilo C1-6, -(alquileno C1-3)m-(cicloalquilo C3-7), -(alquileno C1-3)m-(arilo C6-10), -(alquileno C1-3)m-(heterocicloalquilo de 4 a 7 miembros), -(alquileno C1-3)m-(heteroarilo monocíclico de 5 ó 6 miembros) o -(alquileno C1-3)m-(heteroarilo bicíclico de 9 ó 10 miembros), en la que dicho grupo cicloalquilo C3-7, dicho grupo arilo C6-10, dicho grupo heterocicloalquilo de 4 a 7 miembros, dicho -(grupo heteroarilo monocíclico de 5 ó 6 miembros) o dicho grupo heteroarilo bicíclico de 9 ó 10 miembros puede estar opcionalmente sustituido con R26; cada aparición de R21 es independientemente H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, cicloalquenilo C3-7, heteroarilo monocíclico de 5 ó 6 miembros, heteroarilo bicíclico de 9 ó 10 miembros, -OR20, -O-(haloalquilo C1-6) o -N(R20)2, en la que dicho grupo alquenilo C2-6, dicho grupo alquinilo C2-6, dicho grupo cicloalquilo C3-7, dicho grupo cicloalquenilo C3-7, dicho grupo arilo C6-10, dicho grupo heteroarilo monocíclico de 5 ó 6 miembros y dicho grupo heteroarilo bicíclico de 9 ó 10 miembros pueden estar opcionalmente sustituidos con hasta cinco grupos, cada uno seleccionado independientemente entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, -OR20, -SR20, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2 y -NHC(O)R20; R22 representa de uno a cinco grupos de sustituyentes, cada uno seleccionado independientemente entre alquilo C1-6, halo, -OR20, -SR20, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R20)2, -C(O)OR20, -C(O)N(R20)2 y -NHC(O)R20, o dos grupos R22 cualesquiera en los átomos de carbono adyacentes del anillo pueden combinarse para formar -O-R23-O-; R23 es -[C(R24)2]n-; cada aparición de R24 es independientemente H o alquilo C1-6; cada aparición de R25 es independientemente H, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, -(alquileno C1-3)m-(arilo C6-10), heterocicloalquilo de 4 a 7 miembros, heteroarilo monocíclico de 5 ó 6 miembros o heteroarilo bicíclico de 9 ó 10 miembros, en la que dicho grupo alquilo C1-6, dicho grupo alquenilo C2-6, dicho grupo alquinilo C2-6, dicho grupo cicloalquilo C3-7, dicho grupo arilo C6-10, dicho grupo heterocicloalquilo de 4 a 7 miembros, dicho -(grupo heteroarilo monocíclico de 5 ó 6 miembros) o dicho grupo heteroarilo bicíclico de 9 ó 10 miembros puede estar opcionalmente sustituido con R26; o dos grupos R25, junto con el átomo de nitrógeno común al que están unidos, se unen para formar un grupo heterocicloalquilo de 4 a 7 miembros; R26 representa de uno a cinco grupos de sustituyentes, cada uno seleccionado independientemente entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, -OR27, -SR27, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R27)2, -C(O)OR27, -C(O)N(R27)2 y -NHC(O)R27; cada aparición de R27 es independientemente H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, -(alquileno C1-3)m-(cicloalquilo C3-7), -(alquileno C1-3)m-(arilo C6-10), -(alquileno C1-3)m-(heterocicloalquilo de 4 a 7 miembros), -(alquileno C1-3)m-(heteroarilo monocíclico de 5 ó 6 miembros) o -(alquileno C1-3)m-(heteroarilo bicíclico de 9 ó 10 miembros); R28 es H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, cicloalquenilo C3-7, heteroarilo monocíclico de 5 ó 6 miembros, heteroarilo bicíclico de 9 ó 10 miembros, -OR20, -O-(haloalquilo C1-6) o -N(R20)2, en la que dicho grupo alquenilo C2-6, dicho grupo alquinilo C2-6, dicho grupo cicloalquilo C3-7, dicho grupo cicloalquenilo C3-7, dicho grupo arilo C6-10, dicho grupo heteroarilo monocíclico de 5 ó 6 miembros y dicho grupo heteroarilo bicíclico de 9 ó 10 miembros pueden estar opcionalmente sustituidos con hasta cinco grupos, cada uno seleccionado independientemente entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, -OR20, -SR20, haloalquilo C1-6, hidroxialquilo C1-6, -O-(haloalquilo C1-6), -CN, -NO2, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2 y -NHC(O)R20; cada aparición de R29 es independientemente H, alquilo C1-6, haloalquilo C1-6, hidroxialquilo C1-6, -(alquileno C1-3)m-(cicloalquilo C3-7), -(alquileno C1-3)m-(arilo C6-10), -(alquileno C1-3)m-(heterocicloalquilo de 4 a 7 miembros), -(alquileno C1-3)m-(heteroarilo monocíclico de 5 ó 6 miembros) o -(alquileno C1-3)m-(heteroarilo bicíclico de 9 ó 10 miembros), en la que dicho grupo cicloalquilo C3-7, dicho grupo arilo C6-10, dicho grupo heterocicloalquilo de 4 a 7 miembros, dicho -(grupo heteroarilo monocíclico de 5 ó 6 miembros) o dicho grupo heteroarilo bicíclico de 9 ó 10 miembros puede estar opcionalmente sustituido con R26; cada aparición de T es independientemente -S-, -O-, -SC(O)-, -SC(S)-, -OC(O)- y -OC(S)-; cada aparición de m es independientemente 0 ó 1; y cada aparición de n es independientemente 1 ó 2.Reivindicación 16: Una composición farmacéutica que comprende una cantidad eficaz del compuesto de cualquiera de las reivindicaciones 1 a 15, o una sal farmacéuticamente aceptable del mismo, y un vehículo farmacéuticamente aceptable. Reivindicación 20: Un método para tratar a un paciente infectado con VHC que comprende el paso de administrar una cantidad de (i) el compuesto de acuerdo con cualquiera de las reivindicaciones de 1 a 15, o una sal farmacéuticamente aceptable del mismo, o
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