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AR047793A1 - Inhibidores de la serina proteasa ns-3 del vhc - Google Patents

Inhibidores de la serina proteasa ns-3 del vhc

Info

Publication number
AR047793A1
AR047793A1 ARP050100341A ARP050100341A AR047793A1 AR 047793 A1 AR047793 A1 AR 047793A1 AR P050100341 A ARP050100341 A AR P050100341A AR P050100341 A ARP050100341 A AR P050100341A AR 047793 A1 AR047793 A1 AR 047793A1
Authority
AR
Argentina
Prior art keywords
alkyl
alkylcarbocyclyl
alkylheterocyclyl
nrarb
nrac
Prior art date
Application number
ARP050100341A
Other languages
English (en)
Inventor
Asa Rosenquist
Fredrik Thorstensson
Per-Ola Johansson
Ingemar Kvarnstrom
Bertil Samuelsson
Lazlo Rakos
Susana Ayesa
Original Assignee
Medivir Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34831013&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AR047793(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from SE0400199A external-priority patent/SE0400199D0/xx
Priority claimed from SE0401288A external-priority patent/SE0401288D0/xx
Priority claimed from SE0402562A external-priority patent/SE0402562D0/xx
Application filed by Medivir Ab filed Critical Medivir Ab
Publication of AR047793A1 publication Critical patent/AR047793A1/es

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract

Inhibe la NS3 proteasa de flavivirus, tal como del virus de la hepatitis C (VHC). Los compuestos comprenden una union entre una unidad heterocíclica P2 y las porciones del inhibidor más distales del sitio de clivaje nominal del sustrato nativo, y dicha union revierte la orientacion de las uniones peptídicas sobre el lado distal con respecto a los proximales al sitio de clivaje. Composicion farmacéutica que comprende dicho compuesto y uso del mismo. Reivindicacion 1: Un compuesto de la formula (1), donde: A es C(=OO)R1, C(=O)NHSO2R2, C(=O)NHR3, o CR4R4' donde: R1 es hidrogeno, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo; R2 es C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo; R3 es C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, -OC1-6alquilo, -OC0-3alquilcarbociclilo, -OC0-3alquilheterociclilo; R4 es =O, halo, amino, o OH; O R4 y R4' juntos son =O; R4' es C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo; donde R2, R3, y R4' están cada uno opcionalmente sustituido con entre 1 y 3 sustituyentes seleccionados en forma independiente entre el grupo que comprende halo, oxo, nitrilo, azido, nitro, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, NH2CO-, Y-NRaRb, Y-O-Rb, Y-C(=O)Rb, Y-C(=O)NRaRb, Y-NRaC(=O)Rb, Y-NHSOpRb, Y-S(=O)pRb y Y-S(=O)pNRaRb, Y-C(=O)ORb, Y-NRaC(=O)ORb; Y es en forma independiente un enlace o C1-3 alquileno; Ra es en forma independiente H o C1-3 alquilo; Rb es en forma independiente H, C1-6 alquilo, C0-3 alquilcarbociclilo o C0-3 alquilheterociclilo; p es en forma independiente 1 o 2; M es CR7R7' o NRu; R7 es C1-6 alquilo, C0-3alquilC3-7cicloalquilo, o C2-6 alquenilo, cualquiera de los cuales está opcionalmente sustituido con 1-3 átomos de halo, o un grupo amino, -SH, o C0-3 alquilcicloalquilo; o R7 es J; R7' es H o tomado junto con R7 toma un anillo C3-6 cicloalquilo opcionalmente sustituido con R7'a donde; R7'a es C1-6 alquilo, C3-5 cicloalquilo, C2-6 alquenilo cualquiera de los cuales puede estar opcionalmente sustituido con halo; o R7'a puede ser J; q es entre 0 y 3 y k es entre 0 y 3; donde q + k >= 1; W es -CH2-, -O-, -OC(=O)H-, -OC(=O)-, -S-, -NH-, -NRa, -NHSO2-, - NHC(=O)NH- o -NHC(=O)-, -NHC(=S)NH- o un enlace; R8 es un sistema de anillos que contiene 1 o 2 anillos saturados, parcialmente saturados o insaturados cada uno de los cuales tiene entre 4 y 7 átomos de anillo y cada uno de los cuales tiene entre 0 y 4 heteroátomos seleccionados en forma independiente entre S, O y N, donde el sistema de anillos está separado opcionalmente de W por un grupo C1-3 alquileno; o R8 es C1-6 alquilo; cualquiera de dichos grupos R8 puede estar opcionalmente mono-, di- , o tri-sustituido con R9, donde R9 se selecciona en forma independiente entre el grupo que comprende halo, oxo, nitrilo, azido, nitro, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, NH2C(=O)-, Y-NRaRb, Y-O-Rb, Y-C(=O)Rb, Y- C(=O)NRaRb, Y-NRaC(=O)Rb, Y-NHSOpRb, Y-S(=O)pRb, Y-S(=O)pNRaRb, Y-C(=O)ORb, Y-NRaC(=O)ORb; en donde dicho carbociclilo o heterociclilo está opcionalmente sustituido con R10; en donde R10 es C1-6 C3-7 cicloalquilo, C1-6 alcoxi, amino, amido, sulfonilo, (C1-3 alquil)sulfonilo, NO2, OH, SH, halo, haloalquilo, carboxilo; E es -C(=O)-, -C(=S)-, -S(=O)2-, -S(=O)-, C(=N-Rf)-; Rf es H, -CN, -C(=O)NRaRb; -C(=O)C1-3alquilo; X es -NRx- donde Rx es H, C1-5 alquilo o J; o en el caso donde E es - C(=O), X también puede ser -O- o -NRjNRj-; en donde uno de Rj es H y el otro es H, C1-5 alquilo o J; R11 es H, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, cualquiera de los cuales puede estar sustituido con halo, oxo, nitrilo, azido, nitro, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, NH2C(=O)-, Y-NRaRb, Y-O-Rb, Y-C(=O)Rb, Y-C(=O)NRaRb, Y-NRaC(=O)Rb, Y-NHSOpRb, Y-S(=O)pRb, Y-S(=O)pNRaRb, Y-C(=O)ORb, Y-NRaC(=O)ORb; o R11 es J; de estar presente, es una cadena alquileno simple saturada o parcialmente insaturada de entre 3 y 10 miembros que se extiende desde el R7/R7' cicloalquilo o desde el átomo de carbono al cual R7 está unido a uno de Rj, Rx, Ry o R11 para formar un macrociclo, donde la cadena está opcionalmente interrumpida por entre uno y tres heteroátomos seleccionados en forma independiente entre: -O-, -S- o -NR12-, y donde entre 0 y 3 átomos de carbono en la cadena están opcionalmente sustituidos con R14, donde: R12 es H, C1-6 alquilo, C3-6 cicloalquilo, o-C(=O)R13; R13 es C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo; R14 se selecciona en forma independiente entre el grupo que comprende H, C1-6 alquilo, C1-6 haloalquilo, C1-6 alcoxi, hidroxi, halo, amino, oxo, tio, y C1-6 tioalquilo; Ru es en forma independiente H o C1-3 alquilo; m es 0 o 1; n es 0 o 1; U es =O o está ausente; R15 es H, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, cualquiera de los cuales puede estar sustituido con halo, oxo, nitrilo, azido, nitro, C1-6 alquilo, C0-3 alquilheterociclilo, C0-3 alquilcarbociclilo, NH2CO-, Y-NRaRb, Y-O-Rb, Y-C(=O)Rb, Y-C(=O)NRaRb, Y-NRaC(=O)Rb, Y-NHSOpRb, Y-S(=O)pRb, Y-S(=O)pNRaRb, Y-C(=O)ORb, Y-NRaC(=O)ORb; G es - O-, -NRy-, -NRjNRj-: donde un Rj es H y el otro Rj es H, C1-5 alquilo o J; Ry es H, C1-3 alquilo; o Ry es J; R16 es H; o C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, cualquiera de los cuales puede estar sustituido con halo, oxo, nitrilo, azido, nitro, C1-6 alquilo, C0-3 alquilcarbociclilo, C0-3 alquilheterociclilo, NH2CO-, Y-NRaRb, Y-O-Rb, Y-C(=O)Rb, Y-C(=O)NRaRb, Y-NRaC(=O)Rb, Y-NHSOpRb, Y-S(=O)pRb, Y-S(=O)pNRaRb, Y-C(=O)ORb, Y-NRaC(=O)ORb; con la salvedad de que cuando m = n = o y G es O entonces R16 no es tert-butilo o fenilo; o su sal o prodroga aceptable para uso farmacéutico.
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