AR063682A1 - PIRIDAZINONILOS MACROCICLICOS AS INHIBITORS OF SERINA PROTEASA of HCV, A PROCESS FOR ITS OBTAINING, A PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE TREATMENT OF THE VIRAL INFECTION OF HEPATITIS C. - Google Patents

PIRIDAZINONILOS MACROCICLICOS AS INHIBITORS OF SERINA PROTEASA of HCV, A PROCESS FOR ITS OBTAINING, A PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE TREATMENT OF THE VIRAL INFECTION OF HEPATITIS C.

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AR063682A1
AR063682A1 ARP070103465A AR063682A1 AR 063682 A1 AR063682 A1 AR 063682A1 AR P070103465 A ARP070103465 A AR P070103465A AR 063682 A1 AR063682 A1 AR 063682A1
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Argentina
Prior art keywords
substituted
heteroaryl
aryl
cycloalkyl
heterocycloalkyl
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Spanish (es)
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Zhe Wang
Joel D Moore
Datong Tang
Yat Sun
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Enanta Pharm Inc
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Publication of AR063682A1 publication Critical patent/AR063682A1/en

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Abstract

Compuestos de Fórmula (1), o sus sales aceptables para uso farmacéutico, ésteres o prodrogas, que inhiben la actividad de serina proteasa, particularmente la actividad de la NS3-NS4A proteasa del virus de hepatitis C (VHC). En consecuencia estos compuestos interfieren con el ciclo de vida del virus de hepatitis C y también son útiles como agentes antivirales. Composiciones farmacéuticas que comprenden dichos compuestos para su administración a un sujeto afectado por una infección por VHC y el uso de los mismos para tratar una infección por VHC administrando una composición farmacéutica que comprende a estos compuestos. Reivindicación 1: Un compuesto de fórmula (1); o sus sales aceptables para uso farmacéutico, ésteres o prodrogas, en donde A se selecciona entre el grupo que consiste de -(C=O)-O-R1, (C=O)-R2, -C(=O)-NR1R2, o S(O)2-R1, -S(O)2-NR1R2; en donde, R1 se selecciona en forma independiente en cada caso entre los siguientes grupos: (i) arilo; (ii) arilo sustituido; (iii) heteroarilo; (iv) heteroarilo sustituido; (v) heterocicloalquilo; (vi) heterocicloalquilo sustituido; y (vii) alquilo C1-8, alquenilo C2-8, o alquinilo C2-8 cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; en donde, R2 se selecciona en forma independiente en cada caso entre los siguientes grupos: (i) hidrógeno; (ii) arilo; (iii) arilo sustituido; (iv) heteroarilo; (v) heteroarilo sustituido; (vi) heterocicloalquilo; (vii) heterocicloalquilo sustituido; y (viii) alquilo C1-8, alquenilo C2-8, alquinilo C2-8 con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; G se selecciona entre el grupo que consiste de -NHS(O)2-R3 y NH(SO2)NR4R5 en donde, R3 se selecciona en forma independiente en cada caso entre los siguientes grupos: (i) arilo; (ii) arilo sustituido; (iii) heteroarilo; (iv) heteroarilo sustituido; (v) heterocicloalquilo; (vi) heterocicloalquilo sustituido; y (vii) alquilo C1-8, alquenilo C2-8, o alquinilo C2-8 cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; con la salvedad de que R3 no sea -CH2Ph o -CH2CH2Ph; en donde, R4 y R5 se seleccionan en forma independiente en cada caso entre los siguientes grupos: (i) hidrógeno; (ii) arilo; (iii) arilo sustituido; (iv) heteroarilo; (v) heteroarilo sustituido; (vi) heterocicloalquilo; (vii) heterocicloalquilo sustituido; y (viii) alquilo C1-8, alquenilo C2-8, alquinilo C2-8 cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; L se selecciona entre el grupo que consiste de -CH2-, -O-, -S-, y -S(O)2-; X, Y, y Z se seleccionan en forma independiente en cada caso entre los siguientes grupos: (i) hidrógeno; (ii) -CN; (iii) -N3; (iv) halógeno; (v) OR6; (vi) NR7R8; (vii) arilo; (viii) arilo sustituido; (ix) heteroarilo; (x) heteroarilo sustituido; (xi) cicloalquilo C3-12, cicloalquilo C3-12 sustituido, heterocicloalquilo, heterocicloalquilo sustituido; (xii) alquilo C1-6 con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N, opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, arilo, arilo sustituido, heteroarilo, o heteroarilo sustituido; (xiii) alquenilo C2-6 con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N, opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, arilo, arilo sustituido, heteroarilo, o heteroarilo sustituido; y (xiv) alquinilo C2-6 con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N, opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, arilo, arilo sustituido, heteroarilo, o heteroarilo sustituido; o, como alternativa, X y Y o Y y Z tomados junto con los átomos de carbono a los cuales están unidos forman una porción cíclica, que se selecciona entre arilo, arilo sustituido heteroarilo, o heteroarilo sustituido; en donde R6 se selecciona en forma independiente en cada caso entre los siguientes grupos: (i) hidrógeno (ii) arilo; (iii) arilo sustituido; (iv) heteroarilo; (v) heteroarilo sustituido; (vi) heterocicloalquilo; (vii) heterocicloalquilo sustituido; y (viii) alquilo C1-8, alquenilo C2-8, o alquinilo C2-8 cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; en donde, R7 y R8 se seleccionan en forma independiente en cada caso entre los siguientes grupos: (i) hidrógeno; (ii) arilo; (iii) arilo sustituido; (iv) heteroarilo; (v) heteroarilo sustituido; (vi) heterocicloalquilo; (vii) heterocicloalquilo sustituido; y (viii) alquilo C1-8, alquenilo C2-8, o alquinilo C2-8 cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S, o N; alquilo C1-8 sustituido, alquenilo C2-8 sustituido, o alquinilo C2-8 sustituido cada uno con 0, 1, 2, o 3 heteroátomos seleccionados entre O, S o N; cicloalquilo C3-12, o cicloalquilo C3-12 sustituido; cicloalquenilo C3-12, o cicloalquenilo C3-12 sustituido; ------ denota un enlace carbono-carbono simple o doble; j = 0, 1, 2, 3, o 4; k = 1, 2, o 3; m = 0, 1, o 2; n =1, 2, o 3. Reivindicación 12: Un proceso para obtener un compuesto caracterizado porque responde a una fórmula seleccionada entre las fórmulas (1), (2) o (3), tal como se describe en la memoria descriptiva, en conformidad con los esquemas y ejemplos que se describen en la misma.Compounds of Formula (1), or their salts acceptable for pharmaceutical use, esters or prodrugs, which inhibit the activity of serine protease, particularly the activity of the NS3-NS4A protease of hepatitis C virus (HCV). Consequently these compounds interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. Pharmaceutical compositions comprising said compounds for administration to a subject affected by an HCV infection and the use thereof to treat an HCV infection by administering a pharmaceutical composition comprising these compounds. Claim 1: A compound of formula (1); or its salts acceptable for pharmaceutical use, esters or prodrugs, wherein A is selected from the group consisting of - (C = O) -O-R1, (C = O) -R2, -C (= O) -NR1R2 , or S (O) 2-R1, -S (O) 2-NR1R2; where, R1 is independently selected in each case from the following groups: (i) aryl; (ii) substituted aryl; (iii) heteroaryl; (iv) substituted heteroaryl; (v) heterocycloalkyl; (vi) substituted heterocycloalkyl; and (vii) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl each with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl each substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; wherein, R2 is independently selected in each case from the following groups: (i) hydrogen; (ii) aryl; (iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocycloalkyl; (vii) substituted heterocycloalkyl; and (viii) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; G is selected from the group consisting of -NHS (O) 2-R3 and NH (SO2) NR4R5 where, R3 is independently selected in each case from the following groups: (i) aryl; (ii) substituted aryl; (iii) heteroaryl; (iv) substituted heteroaryl; (v) heterocycloalkyl; (vi) substituted heterocycloalkyl; and (vii) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl each with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl each substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; with the proviso that R3 is not -CH2Ph or -CH2CH2Ph; where, R4 and R5 are independently selected in each case from the following groups: (i) hydrogen; (ii) aryl; (iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocycloalkyl; (vii) substituted heterocycloalkyl; and (viii) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl each with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl each substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; L is selected from the group consisting of -CH2-, -O-, -S-, and -S (O) 2-; X, Y, and Z are independently selected in each case from the following groups: (i) hydrogen; (ii) -CN; (iii) -N3; (iv) halogen; (v) OR6; (vi) NR7R8; (vii) aryl; (viii) substituted aryl; (ix) heteroaryl; (x) substituted heteroaryl; (xi) C3-12 cycloalkyl, substituted C3-12 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl; (xii) C1-6 alkyl with 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; (xiii) C2-6 alkenyl with 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and (xiv) C2-6 alkynyl with 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or, alternatively, X and Y or Y and Z taken together with the carbon atoms to which they are attached form a cyclic portion, which is selected from aryl, heteroaryl substituted aryl, or substituted heteroaryl; wherein R6 is independently selected in each case from the following groups: (i) hydrogen (ii) aryl; (iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocycloalkyl; (vii) substituted heterocycloalkyl; and (viii) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl each with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl each substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; where, R7 and R8 are independently selected in each case from the following groups: (i) hydrogen; (ii) aryl; (iii) substituted aryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocycloalkyl; (vii) substituted heterocycloalkyl; and (viii) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl each with 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted C1-8 alkyl, substituted C2-8 alkenyl, or C2-8 alkynyl each substituted with 0, 1, 2, or 3 heteroatoms selected from O, S or N; C3-12 cycloalkyl, or substituted C3-12 cycloalkyl; C3-12 cycloalkenyl, or substituted C3-12 cycloalkenyl; ------ denotes a single or double carbon-carbon bond; j = 0, 1, 2, 3, or 4; k = 1, 2, or 3; m = 0, 1, or 2; n = 1, 2, or 3. Claim 12: A process for obtaining a compound characterized in that it responds to a formula selected from formulas (1), (2) or (3), as described in the specification, in compliance with the schemes and examples described therein.

ARP070103465 2006-08-04 2007-08-06 PIRIDAZINONILOS MACROCICLICOS AS INHIBITORS OF SERINA PROTEASA of HCV, A PROCESS FOR ITS OBTAINING, A PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE TREATMENT OF THE VIRAL INFECTION OF HEPATITIS C. AR063682A1 (en)

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ARP070103465 AR063682A1 (en) 2006-08-04 2007-08-06 PIRIDAZINONILOS MACROCICLICOS AS INHIBITORS OF SERINA PROTEASA of HCV, A PROCESS FOR ITS OBTAINING, A PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE TREATMENT OF THE VIRAL INFECTION OF HEPATITIS C.

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TW (1) TW200815025A (en)

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TW200815025A (en) 2008-04-01

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