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ES2680550T3 - Combinaciones de inhibidores del virus de la hepatitis C - Google Patents

Combinaciones de inhibidores del virus de la hepatitis C Download PDF

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Publication number
ES2680550T3
ES2680550T3 ES13740435.6T ES13740435T ES2680550T3 ES 2680550 T3 ES2680550 T3 ES 2680550T3 ES 13740435 T ES13740435 T ES 13740435T ES 2680550 T3 ES2680550 T3 ES 2680550T3
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ns5a
combination
pharmaceutically acceptable
hcv
acceptable salt
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Inventor
Piyasena Hewawasam
Omar D. Lopez
Yong Tu
Alan Xiangdong Wang
Ningning Xu
John F. Kadow
Nicholas A. Meanwell
Samayamunthula Venkata Satya Arun Kumar Gupta
Indasi J. Gopi KUMAR
Suresh Kumar PUNUGUPATI
Makonen Belema
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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Abstract

Una combinación que comprende un compuesto dirigido a NS5A y un sinérgico de NS5A, que, cuando se administra, proporciona actividad sinérgica anti VHC frente a variantes que contienen una o más mutaciones que confieren resistencia al compuesto dirigido a NS5A solo, en la que el compuesto dirigido a NS5A es**Fórmula** y en la que el sinérgico de NS5A se selecciona entre: **Fórmula** o una sal farmacéuticamente aceptable de los mismos.

Description

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DESCRIPCION
Combinaciones de inhibidores del virus de la hepatitis C
La presente divulgación se refiere, en general, a compuestos antivíricos y más específicamente, se refiere a combinaciones de compuestos que pueden inhibir la función de la proteína NS5A codificada por el virus de la hepatitis C (VHC), a composiciones que comprenden dichas combinaciones y a métodos para inhibir la función de la proteína NS5A.
El VHC es un patógeno humano importante, que infecta, según las estimaciones, a 170 millones de personas en todo el mundo, aproximadamente cinco veces el número de personas infectadas por el virus de la inmunodeficiencia humana de tipo 1. Una parte sustancial de estos individuos infectados por VHC desarrolla enfermedades hepáticas progresivas graves, incluyendo cirrosis y carcinoma hepatocelular.
Durante la década pasada, el cuidado estándar para el tratamiento del VHC crónico empleó una combinación de interferón pegilado y ribavirina. El tratamiento tiene una tasa de éxito no óptima para lograr una respuesta vírica sostenida (SVR) contra los seis principales genotipos del VHC, con una tasa de éxito particularmente baja contra el genotipo 1 y provoca numerosos efectos secundarios. Los fármacos recientemente aprobados que actúan de manera selectiva sobre la proteasa NS3/4A (PI) del VHC (Victrelis ® e Incivek ®) se administran con interferón pegilado y ribavirina y proporcionan una gran mejora en el porcentaje de pacientes que experimentan SVR y en la duración del tratamiento necesaria para lograr la SVR. Sin embargo, existe una clara y urgente necesidad de desarrollar terapias adicionales para combatir la resistencia a los inhibidores de proteasas, para mejorar la eficacia entre todos los genotipos de VHC y para avanzar la terapia antivírica hacia el objetivo último de una cura sin interferón.
El VHC es un virus de ARN de hebra positiva de aproximadamente 9500 nucleótidos de longitud y tiene una sola fase abierta de lectura (ORF) que codifica una sola poliproteína grande de aproximadamente 3000 aminoácidos. En células infectadas, esta poliproteína se escinde en múltiples sitios por proteasas celulares y víricas para producir las proteínas estructurales y no estructurales (NS). En el caso de VHC, la generación de proteínas no estructurales maduras (NS2, NS3, NS4A, NS4B, NS5A, y NS5B) se efectúa mediante dos proteasas víricas. Se cree que la primera es una metaloproteasa y se escinde en la unión NS2-NS3; la segunda es una serina proteasa contenida entre la región N-terminal de NS3 (también citada en el presente documento como proteasa NS3) y media todas las escisiones posteriores cadena abajo de NS3, tanto en cis, en el sitio de escisión NS3-NS4A como en trans, para el resto de sitios NS4A-NS4B, NS4B-NS5A, NS5A-NS5B. La proteína NS4A es un cofactor para la proteasa NS3. Es necesaria la formación de un complejo NS3-NS4A para una actividad de proteasa adecuada. La proteína NS3 también presenta actividades de nucleósido trifosfatasa y ARN helicasa. NS5A es una proteína multifuncional necesaria para la replicación del ARN vírico y el ensamblaje del virión. NS5B (también citada en el presente documento con VHC polimerasa) es una ARN polimerasa dependiente de ARN que es responsable de la síntesis del ARN vírico.
Se ha observado una heterogeneidad considerable entre la secuencia de nucleótidos y la secuencia de aminoácidos codificada a lo largo del genoma del VHC debido a la alta tasa de error de la ARN polimerasa dependiente de ARN, que carece de capacidad de corrección de errores. El significado clínico de la heterogeneidad genética del VHC es la propensión a que surjan mutaciones durante el tratamiento con monoterapia, por lo tanto, se desean terapias combinadas con inhibidores del VHC que tienen cobertura para todos los genotipos y que actúen mediante mecanismos independientes.
Se desean compuestos que inhiben de manera selectiva la replicación vírica del VHC que sean útiles para tratar a pacientes infectados por VHC. En particular, se desean compuestos que inhiban de manera eficaz la función de la proteína NS5A. La función y el papel esencial de la proteína NS5A para la replicación del VHC se describen, por ejemplo, en las siguientes referencias: S. L. Tan, et al., Virology, 284:1-12 (2001); K.-J. Park, et al., J. Biol. Chem., 30711-30718 (2003); T. L. Tellinghuisen, et al., Nature, 435, 374 (2005); R. A. Love, et al., J. Virol, 83, 4395 (2009); N. Appel, et al., J. Biol. Chem., 281, 9833 (2006); L. Huang, J. Biol. Chem., 280, 36417 (2005); M. Gao, et al, Nature (2010); C. Rice, et al., documento WO2006093867.
Se ha descrito un método para identificar compuestos que demuestran inhibición sinérgica de la actividad de replicón del VHC cuando se combinan con el inhibidor de NS5A del VHC, tal como BMS-790052 (documento PCT/US2011/043785, presentado el 13 de julio de 2011). En resumen, cada compuesto, cuando se prueba individualmente frente a algunas variantes de NS5A resistentes, es esencialmente inactivo o mucho menos activo y solo tiene actividad inhibidora sinérgica cuando se prueba en combinación con un compuesto que actúa de manera selectiva sobre NS5A. Los compuestos sinérgicos se identificaron usando titulaciones de compuestos de ensayo en presencia de concentraciones fijas de inhibidores de NS5A de VHC, tales como BMS-790052.
En un primer aspecto, la presente divulgación proporciona una combinación que comprende un compuesto que actúa de manera selectiva sobre NS5A y un sinergista de NS5A, que, cuando se administra, proporciona actividad sinérgica anti-VHC frente a variantes que contienen mutaciones que confieren resistencia al compuesto que actúa de
manera selectiva sobre NS5A solo, en donde el compuesto que actúa de manera selectiva sobre NS5A es
imagen1
5 y en donde el sinergista NS5A se selecciona entre:
imagen2

Claims (5)

1. Una combinación que comprende un compuesto dirigido a NS5A y un sinérgico de NS5A, que, cuando se administra, proporciona actividad sinérgica anti VHC frente a variantes que contienen una o más mutaciones que 5 confieren resistencia al compuesto dirigido a NS5A solo, en la que el compuesto dirigido a NS5A es
imagen1
10 y en la que el sinérgico de NS5A se selecciona entre:
imagen2
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5 o una sal farmacéuticamente aceptable de los mismos.
2. Una composición que comprende una combinación de la reivindicación 1 o una sal farmacéuticamente aceptable de la misma y un vehículo farmacéuticamente aceptable.
10 3. La composición de la reivindicación 2, que además comprende uno o dos compuestos adicionales que tienen
actividad anti-VHC.
4. La composición de la reivindicación 3, en donde al menos uno de los compuestos adicionales es un interferón o una ribavirina.
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5. Una combinación de acuerdo con cualquiera de la reivindicación 1, para uso en el tratamiento de una infección por VHC en un paciente.
6. Una combinación para uso de acuerdo con la reivindicación 5, que comprende además administrar uno o dos
20 compuestos adicionales que tienen actividad anti-VHC antes de, después de o simultáneamente con la combinación o una sal farmacéuticamente aceptable de los mismos.
ES13740435.6T 2013-07-09 2013-07-09 Combinaciones de inhibidores del virus de la hepatitis C Active ES2680550T3 (es)

Applications Claiming Priority (1)

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PCT/US2013/049633 WO2015005901A1 (en) 2013-07-09 2013-07-09 Combinations of hepatitis c virus inhibitors

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