ES2683355T3 - Profármacos de fumaratos y su uso en el tratamiento de diversas enfermedades - Google Patents

Profármacos de fumaratos y su uso en el tratamiento de diversas enfermedades Download PDF

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ES2683355T3
ES2683355T3 ES14767892.4T ES14767892T ES2683355T3 ES 2683355 T3 ES2683355 T3 ES 2683355T3 ES 14767892 T ES14767892 T ES 14767892T ES 2683355 T3 ES2683355 T3 ES 2683355T3
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substituted
unsubstituted
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pharmaceutically acceptable
rings
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Tarek A. Zeidan
Scott Duncan
Christopher P. HENCKEN
Thomas Andrew WYNN
Carlos N. SANRAME
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Alkermes Pharma Ireland Ltd
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Alkermes Pharma Ireland Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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Abstract

Un compuesto de Fórmula (III), o una sal farmacéuticamente aceptable del mismo:**Fórmula** en donde:**Fórmula** R1 es alquilo C1-C6 no sustituido; R6, R7, R8 y R9 son cada uno, independientemente, H, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido o C(O)ORa; Ra es H o alquilo C1-C6 sustituido o no sustituido; m es 0, 1, 2 o 3; t es 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10; y cada R10 es, independientemente, H, halógeno, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S; o, alternativamente, dos R10 anclados al mismo átomo de carbono, junto con el átomo de carbono al que están anclados, forman un carbonilo, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S; o, alternativamente, dos R10 anclados a diferentes átomos, junto con los átomos a los que están anclados, forman un carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroátomos seleccionados entre N, O y S.

Description

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DESCRIPCION
Profarmacos de fumaratos y su uso en el tratamiento de diversas enfermedades Solicitudes relacionadas
Esta solicitud reivindica prioridad sobre la Solicitud Provisional de los Estados Unidos Num. 61/782.445, presentada el 14 de marzo de 2013 y la Solicitud Provisional de los Estados Unidos Num. 61/934.365, presentada el 31 de enero de 2014.
Campo de la invencion
La presente invencion se refiere a diversos profarmacos de fumarato de monometilo definidos en las reivindicaciones. En particular, la presente invencion se refiere a derivados de fumarato de monometilo definidos en las reivindicaciones que ofrecen mejores propiedades con respecto al fumarato de dimetilo. La invencion tambien se refiere al uso de dichos compuestos en metodos para el tratamiento de diversas enfermedades.
Antecedentes de la invencion
Los esteres de acido fumarico (FAE) estan aprobados en Alemania para el tratamiento de la psoriasis, estan siendo evaluados en los Estados Unidos para el tratamiento de la psoriasis y la esclerosis multiple, y se han propuesto para su uso en el tratamiento de una amplia gama de enfermedades inmunitarias, autoinmunitarias e inflamatorias y el documento WO2010022177 describe derivados de Fumarato utiles para el tratamiento de la esclerosis multiple. Los FAE y otros derivados de acido fumarico se han propuesto para su uso en el tratamiento de una amplia variedad de enfermedades y afecciones que implican procesos inmunitarios, autoinmunitarios y/o inflamatorios, incluyendo la psoriasis (Joshi y Strebel, documento WO 1999/49858; Patente de los Estados Unidos Num. 6.277.882; Mrowietz y Asadullah, Trends Mol Med 2005, 111 (1), 43-48; y Yazdi y Mrowietz, Clinics Dermatology 2008, 26, 522-526); el asma y enfermedad pulmonar obstructiva cronica (Joshi et al., documentos WO 2005/023241 y US 2007/0027076); la insuficiencia cardfaca que incluye insuficiencia ventricular izquierda, infarto de miocardio y angina de pecho (Joshi et al., documento WO 2005/023241; Joshi et al., documento US 2007/0027076); las enfermedades mitocondriales y neurodegenerativas tales como la enfermedad de Parkinson, la enfermedad de Alzheimer, la enfermedad de Huntington, la retinopatfa pigmentosa y la encefalomiopatfa mitocondrial (Joshi y Strebel, documentos WO 2002/055063, US 2006/0205659, Patente de los Estados Unidos Num. 6.509.376, Patente de los Estados Unidos Num. 6.858.750 y Patente de los Estados Unidos Num. 7.157.423); los trasplantes (Joshi y Strebel, documentos WO 2002/055063, uS 2006/0205659, Patente de los Estados Unidos Num. 6.359.003, Patente de los Estados Unidos Num. 6.509.376 y Patente de los Estados Unidos Num. 7.157.423; y Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); las enfermedades autoinmunitarias (Joshi y Strebel, documento WO 2002/055063, Patente de los Estados Unidos Num. 6.509.376, Patente de los Estados Unidos Num. 7.157.423 y documento US 2006/0205659) incluyendo la esclerosis multiple (EM) (Joshi y Strebel, documento WO 1998/52549 y Patente de los Estados Unidos Num. 6.436.992; Went y Lieberburg, documento US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; y Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); la isquemia y lesion por reperfusion (Joshi et al., documento US 2007/0027076); el dano del genoma inducido por Age (Heidland, documento Wo 2005/027899); las enfermedades inflamatorias intestinales tales como la enfermedad de Crohn y la colitis ulcerosa; la artritis; y otras (Nilsson et al., documento WO 2006/037342 y Nilsson and Muller, documento Wo 2007/042034).
El Fumaderm®, un comprimido con recubrimiento enterico que contiene una mezcla de sal de fumarato de monoetilo y fumarato de dimetilo (DMF) que se hidroliza rapidamente a fumarato de monometilo, considerado como el principal metabolito bioactivo, se aprobo en Alemania en 1994 para el tratamiento de la psoriasis. El Fumaderm® se dosifica TID con 1-2 gramos/dfa administrados para el tratamiento de la psoriasis. El Fumaderm® muestra un alto grado de variabilidad entre pacientes con respecto a la absorcion del farmaco y los alimentos reducen fuertemente la biodisponibilidad. Se cree que la absorcion se produce en el intestino delgado alcanzandose los niveles maximos 5-6 horas despues de la administracion oral. Se producen efectos secundarios significativos en 70-90% de los pacientes (Brewer y Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; y Hoefnagel et al., Br J Dermatology 2003, 149, 363369). Los efectos secundarios de la terapia con FAE actual incluyen malestar gastrointestinal que incluye nauseas, vomitos, diarrea y/o enrojecimiento transitorio de la piel.
La esclerosis multiple (EM) es una enfermedad autoinmunitaria con actividad autoinmunitaria dirigida contra los antfgenos del sistema nervioso central (SNC). La enfermedad se caracteriza por inflamacion en algunas partes del SNC, lo que lleva a la perdida del revestimiento de mielina alrededor de los axones neuronales (desmielinizacion gradual), perdida axonal y la muerte eventual de neuronas, oligodendrocitos y celulas gliales.
El fumarato de dimetilo (DMF) es el componente activo del agente terapeutico experimental, BG-12, estudiado para el tratamiento de EM recidivante-remitente (EMRR). En un estudio de fase IIb en EMRR, BG-12 redujo significativamente las lesiones cerebrales que potencia el gadolinio. En estudios preclmicos, se ha demostrado que la administracion de DMF inhibe la inflamacion del SNC en la EAE murina y de rata. Tambien se ha encontrado que DMF puede inhibir la astrogliosis y las activaciones microgliales asociadas con EAE. Vease, por ejemplo, la Solicitud
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Publicada de los Estados Unidos Num. 2012/0165404.
Existen cuatro tipos clmicos principales de EM: 1) EM recidivante-remitente (EMRR), que se caracteriza por recafdas claramente definidas con recuperacion total o con secuelas y deficit residual tras la recuperacion; penodos entre las recafdas de la enfermedad caracterizados por la falta de progresion de la enfermedad; 2) EM progresiva secundaria (EMSP), que se caracteriza por un curso recidivante remitente inicial seguido de progresion con o sin recafdas ocasionales, remisiones menores y mesetas; 3) EM progresiva primaria (EMPP), que se caracteriza por la progresion de la enfermedad desde el inicio con mesetas ocasionales y permite pequenas mejonas temporales; y 4) EM progresiva recidivante (EMPR), que se caracteriza por el inicio progresivo de la enfermedad, con claras recafdas agudas, con o sin recuperacion completa; penodos entre recafdas caracterizados por una progresion continua.
Clmicamente, la enfermedad se presenta con mayor frecuencia como una enfermedad recidivante-remitente y, en menor medida, como una progresion constante de la discapacidad neurologica. La EM recidivante-remitente (EMRR) se presenta en forma de ataques recurrentes de disfuncion neurologica focal o multifocal. Los ataques pueden ocurrir, remitir y recurrir, aparentemente al azar durante muchos anos. La remision a menudo es incompleta y como un ataque sigue a otro, se produce un avance progresivo descendente con un aumento del deficit neurologico permanente. El curso habitual de la EMRR se caracteriza por recafdas repetidas asociadas, para la mayona de los pacientes, con el inicio eventual de la progresion de la enfermedad. El curso posterior de la enfermedad es impredecible, aunque la mayona de los pacientes con una enfermedad recidivante-remitente eventualmente desarrollaran una enfermedad progresiva secundaria. En la fase recidivante-remitente, las recafdas se alternan con periodos de inactividad clmica y pueden estar marcadas o no por secuelas dependiendo de la presencia de deficits neurologicos entre episodios. Los penodos entre las recafdas durante la fase recidivante- remitente son clmicamente estables. Por otro lado, los pacientes con EM progresiva muestran un aumento constante de los deficits, como se definio anteriormente, y desde el inicio o despues de un penodo de episodios, pero esta designacion no excluye la aparicion posterior de nuevas recafdas.
No obstante lo anterior, el fumarato de dimetilo tambien esta asociado con inconvenientes significativos.
Por ejemplo, se sabe que el fumarato de dimetilo causa efectos secundarios tras la administracion oral, tal como enrojecimiento y eventos gastrointestinales que incluyen nauseas, diarrea y/o dolor abdominal superior en sujetos. Vease, p. ej., Gold et al., N. Eng. J. Med, 2012, 367 (12), 1098-1107. El fumarato de dimetilo se dosifica BID o TID con una dosis diaria total de aproximadamente 480 mg a aproximadamente 1 gramo o mas.
Adicionalmente, en el uso de un farmaco para la terapia a largo plazo, es deseable que el farmaco se formule de modo que sea adecuado para su administracion una o dos veces al dfa para ayudar al cumplimiento por parte del paciente. Es aun mas deseable una frecuencia de dosificacion de una vez al dfa o menos.
Otro problema con la terapia a largo plazo es el requerimiento de determinar una dosis optima que pueda ser tolerada por el paciente. Si no se determina semejante dosis, esto puede conducir a una disminucion en la eficacia del medicamento que se administra.
En consecuencia, un objeto de la presente invencion es proporcionar compuestos y/o composiciones que sean adecuados para su administracion a largo plazo.
Un objeto adicional de la presente invencion es proporcionar el uso de un agente activo farmaceutico de una manera que permita alcanzar un nivel de estado estacionario tolerable para el farmaco en un sujeto que se esta tratando con el mismo.
Debido a las desventajas del fumarato de dimetilo descritas anteriormente, sigue existiendo la necesidad de disminuir la frecuencia de dosificacion, reducir los efectos secundarios y/o mejorar las propiedades fisicoqmmicas asociadas con el DMF. Sigue existiendo, por lo tanto, una necesidad real en el tratamiento de enfermedades neurologicas, tales como la EM, de un producto que conserve las ventajas farmacologicas del DMF pero que supere sus defectos en la formulacion y/o en los efectos adversos de su administracion. La presente invencion aborda estas necesidades.
Breve descripcion de los dibujos
La Figura 1 representa la hidrolisis del Compuesto 16 a pH 7,9, 25°C, que muestra la region vimlica, segun se observa por RMN durante 90 minutos.
La Figura 2 representa la hidrolisis del Compuesto 16 a pH 7,9, 25°C, que muestra la region vimlica, como se observo por RMN durante 19 horas.
La Figura 3 representa la hidrolisis del Compuesto 16 a pH 7,9, 25°C, que muestra la region alifatica, segun se observa por RMN durante 19 horas.
La Figura 4 representa la hidrolisis del Compuesto de Referencia A a pH 7,9, 37°C, que muestra la region vimlica, segun se observa por RMN durante 15 horas.
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La Figura 5 representa la hidrolisis del Compuesto de Referencia A a pH 7,9, 37°C, que muestra la region alifatica, segun se observa por RMN durante 15 horas.
La Figura 6 representa un grafico de la perdida de peso frente al tiempo para el Compuesto 14 y DMF.
La Figura 7 representa la celda unitaria para el Compuesto 14 cristalino.
Compendio de la invencion
Esta invencion se refiere al descubrimiento sorprendente e inesperado de nuevos profarmacos y metodos relacionados utiles en el tratamiento de enfermedades neurologicas. Los metodos y composiciones descritos en la presente memoria comprenden uno o mas profarmacos (p.ej, profarmacos de aminoalquilo) de fumarato de monometilo (MMF). Los metodos y composiciones proporcionan una cantidad terapeuticamente eficaz de un radical activo en un sujeto durante un penodo de tiempo de al menos aproximadamente 8 horas a al menos aproximadamente 24 horas.
Mas espedficamente, los compuestos de la invencion se pueden convertir in vivo, tras la administracion oral, en fumarato de monometilo. Tras la conversion, el radical activo (es decir, el fumarato de monometilo) es eficaz en el tratamiento de sujetos que padecen una enfermedad neurologica.
La presente invencion se refiere al uso de los compuestos definidos en las reivindicaciones en metodos para el tratamiento de una enfermedad neurologica administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de semejante compuesto, de manera que se trata la enfermedad.
La presente invencion tambien se refiere al uso de los compuestos definidos en las reivindicaciones en metodos para el tratamiento de la esclerosis multiple administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de semejante compuesto, de manera que se trata la esclerosis multiple.
La presente invencion tambien se refiere al uso de los compuestos definidos en las reivindicaciones en metodos para el tratamiento de la esclerosis multiple recidivante-remitente (EMRR) administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de semejante compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la esclerosis multiple.
La presente invencion tambien proporciona los compuestos definidos en las reivindicaciones para su uso en metodos para el tratamiento de la esclerosis multiple progresiva secundaria (EMPS) administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de un compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la esclerosis multiple.
La presente invencion tambien proporciona metodos para el tratamiento de la esclerosis multiple progresiva primaria (EMPP) administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de un compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la esclerosis multiple. La presente invencion tambien proporciona metodos para el tratamiento de la esclerosis multiple progresiva recidivante (EMPR) administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de un compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la esclerosis multiple.
La presente invencion tambien proporciona metodos para el tratamiento de la enfermedad de Alzheimer administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de un compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la enfermedad de Alzheimer.
La presente invencion tambien proporciona metodos para el tratamiento de la paralisis cerebral administrando a un sujeto que lo necesita, una cantidad terapeuticamente eficaz de un compuesto de la formula descrita en la presente memoria, o una sal, forma polimorfa, hidrato, solvato o cocristal del mismo farmaceuticamente aceptable, de manera que se trata la paralisis cerebral.
La presente invencion tambien proporciona compuestos y composiciones que permiten formulaciones con mejor liberacion oral, controlada o sostenida. Espedficamente, el fumarato de dimetilo se administra dos o tres veces al dfa para el tratamiento de la esclerosis multiple recidivante-remitente. Por el contrario, los compuestos y composiciones de la presente invencion pueden permitir formulaciones con una duracion modificada de la eficacia terapeutica para reducir las tasas de recafda en sujetos con esclerosis multiple. Por ejemplo, los presentes compuestos y composiciones proporcionan cantidades terapeuticamente eficaces de fumarato de monometilo en sujetos durante al menos aproximadamente 8 horas, al menos aproximadamente 12 horas, al menos aproximadamente 16 horas, al menos aproximadamente 20 horas o al menos aproximadamente 24 horas.
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La presente invencion tambien proporciona compuestos, composiciones y metodos que pueden dar como resultado una disminucion de los efectos secundarios tras la administracion a un sujeto con respecto al fumarato de dimetilo. Por ejemplo, la irritacion gastrica y el enrojecimiento son efectos secundarios conocidos de la administracion oral de fumarato de dimetilo en algunos sujetos. Los compuestos, composiciones y metodos de la presente invencion se pueden utilizar en sujetos que han experimentado o estan en riesgo de desarrollar tales efectos secundarios.
La presente invencion tambien proporciona compuestos y composiciones que muestran una mayor estabilidad ffsica con respecto al fumarato de dimetilo. Espedficamente, se conoce en la tecnica que el fumarato de dimetilo experimenta sublimacion en condiciones de temperatura ambiente y elevada. Los compuestos de la invencion poseen una mayor estabilidad ffsica que el fumarato de dimetilo bajo condiciones controladas de temperatura y humedad relativa. Espedficamente, en una realizacion, los compuestos de la formula descrita en la presente memoria muestran una disminucion de la sublimacion con respecto al fumarato de dimetilo.
Adicionalmente, tambien se sabe que el fumarato de dimetilo es un irritante de contacto. Vease, por ejemplo, Material Safety Data Sheet para DMF. En una realizacion, los compuestos de la presente invencion muestran una disminucion de la irritacion de contacto con respecto al fumarato de dimetilo. Por ejemplo, los compuestos de la formula descrita en la presente memoria muestran una reduccion de la irritacion de contacto con respecto al fumarato de dimetilo.
La presente invencion tambien proporciona compuestos y composiciones que muestran una disminucion del efecto de los alimentos con respecto al fumarato de dimetilo. Se sabe en la tecnica que la biodisponibilidad del fumarato de dimetilo se reduce cuando se administra con alimentos. Espedficamente, en una realizacion, los compuestos de la formula descrita en la presente memoria muestran una disminucion del efecto de los alimentos con respecto al fumarato de dimetilo.
A menos que se defina lo contrario, todos los terminos tecnicos y cienffficos utilizados en la presente memoria tienen el mismo significado que entiende comunmente un experto habitual en la tecnica a la que pertenece esta invencion. En la memoria descriptiva, las formas en singular tambien incluyen el plural a menos que el contexto indique claramente lo contrario. Aunque se pueden utilizar metodos y materiales similares o equivalentes a los descritos en la presente memoria en la practica o el ensayo de la presente invencion, los metodos y materiales adecuados se describen a continuacion. Las referencias citadas en la presente memoria no se admiten como tecnica anterior de la invencion reivindicada. En caso de conflicto prevalecera la presente memoria descriptiva, incluidas las definiciones. Ademas, los materiales, metodos y ejemplos son solo ilustrativos y no se pretende que sean limitantes.
Otras caractensticas y ventajas de la invencion seran evidentes a partir de la siguiente descripcion detallada y de las reivindicaciones.
Descripcion detallada de la invencion
La presente invencion proporciona nuevos compuestos y metodos para el tratamiento de una enfermedad neurologica administrando un compuesto de Formula (III) y composiciones farmaceuticas que contienen un compuesto de Formula (III).
La presente invencion tambien se refiere al uso de los compuestos definidos en las reivindicaciones en metodos para el tratamiento de la psoriasis mediante la administracion a un sujeto que lo necesita, de una cantidad terapeuticamente eficaz de dicho compuesto, o una sal farmaceuticamente aceptable del mismo.
La enfermedad neurologica puede ser esclerosis multiple. La presente invencion proporciona ademas el uso de un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo, para la preparacion de un medicamento util para el tratamiento de una enfermedad neurologica.
De acuerdo con la presente invencion, una enfermedad neurologica es un trastorno del cerebro, la medula espinal o los nervios en un sujeto. En una realizacion, la enfermedad neurologica se caracteriza por desmielinizacion, o degeneracion de la vaina de mielina, del sistema nervioso central. La vaina de mielina facilita la transmision de impulsos nerviosos a traves de una fibra nerviosa o axon. En otra realizacion, la enfermedad neurologica se selecciona del grupo que consiste en esclerosis multiple, enfermedad de Alzheimer, paralisis cerebral, lesion de la medula espinal, esclerosis lateral amiotrofica (ELA), accidente cerebrovascular, enfermedad de Huntington, enfermedad de Parkinson, neuritis optica, enfermedad de Devic, mielitis transversa, encefalomielitis diseminada aguda, adrenoleucodistrofia y adrenomieloneuropaffa, polineuropaffa desmielinizante inflamatoria aguda (PDIA), polineuropaffa desmielinizante inflamatoria cronica (PDIC), mielitis transversa aguda, leucoencefalopaffa multifocal progresiva (LMP), encefalomielitis diseminada aguda (EMDA) y otros trastornos hereditarios, tales como leucodistrofias, atrofia optica de Leber y enfermedad de Charcot-Marie-Tooth. En algunas realizaciones, el trastorno neurologico es una enfermedad autoinmunitaria. En una realizacion, la enfermedad neurologica es esclerosis multiple. En otra realizacion, la enfermedad neurologica es un accidente cerebrovascular. En otra realizacion, la enfermedad neurologica es la enfermedad de Alzheimer. En otra realizacion, la enfermedad neurologica es paralisis cerebral. En otra realizacion, la enfermedad neurologica es una lesion de la medula espinal. En otra realizacion, la
enfermedad neurologica es ELA. En otra realization, la enfermedad neurologica es la enfermedad de Huntington. Vease, por ejemplo, la Patente de los Estados Unidos Num. 8.007.826, y los documentos WO2005/099701 y WO2004/082684.
En una realizacion adicional, la presente invention proporciona el uso de los compuestos definidos en las 5 reivindicaciones en metodos para el tratamiento de una enfermedad o un smtoma de una enfermedad descritos en la presente memoria mediante la administration a un sujeto que lo necesita, de una cantidad terapeuticamente eficaz de una compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo. La presente invencion proporciona adicionalmente el uso de un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo, para la preparation de un medicamento util para el tratamiento de una enfermedad o un smtoma de una 10 enfermedad descritos en la presente memoria.
La presente invencion proporciona un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo, y el uso de dicho compuesto en un metodo para el tratamiento de una enfermedad neurologica mediante la administracion a un sujeto que lo necesita de una cantidad terapeuticamente eficaz de un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo:
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imagen1
en donde:
Ri es alquilo Ci-C6 no sustituido;
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m es 0, 1,2 o 3;
tes 0, 1,2, 3, 4, 5, 6, 7, 8,9o10;
R6, R7, Rs y R9 son cada uno, independientemente, H, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido o C(O)ORa; y
25 Ra es H o alquilo C1-C6 sustituido o no sustituido; y
cada R10 es, independientemente, H, halogeno, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos 30 anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S;
o, alternativamente, dos R10 anclados al mismo atomo de carbono, junto con el atomo de carbono al que estan anclados, forman un carbonilo, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 35 heteroatomos seleccionados entre N, O y S;
o, alternativamente, dos R10 anclados a diferentes atomos, junto con los atomos a los que estan anclados, forman un carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende
imagen2
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uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, Oy S.
Por ejemplo, la enfermedad neurologica es la esclerosis multiple.
Por ejemplo, la enfermedad neurologica es la esclerosis multiple recidivante-remitente (EMRR).
Por ejemplo, en el compuesto de Formula (III), R1 es metilo.
Por ejemplo, en el compuesto de Formula (III), R1 es etilo
En el compuesto de Formula (III),
Por ejemplo, en el compuesto de Formula (III), R6 es alquilo C1-C6 sustituido o no sustituido y R7, R8 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R6 es alquilo C1-C6 no sustituido y R7, R8 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R8 es alquilo C1-C6 sustituido o no sustituido y R6, R7 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R8 es alquilo C1-C6 no sustituido y R6, R7 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R6y R8 son cada uno, independientemente, alquilo C1-C6 sustituido o no sustituido y R7 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R6 y R8 son cada uno, independientemente, alquilo C1-C6 no sustituido y R7 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R6y R7 son cada uno, independientemente, alquilo C1-C6 sustituido o no sustituido y R8 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R6 y R7 son cada uno, independientemente, alquilo C1-C6 no sustituido y R8 y R9 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R8y R9 son cada uno, independientemente, alquilo C1-C6 sustituido o no sustituido y R6 y R7 son cada uno H.
Por ejemplo, en el compuesto de Formula (III), R8 y R9 son cada uno, independientemente, alquilo C1-C6 no sustituido y R6 y R7 son cada uno H.
En una realizacion de Formula (III):
R1 es alquilo C1-C6 no sustituido;
imagen3
imagen4
m es 0, 1, 2 o 3;
t es 2, 4 o 6;
R6, R7, R8 y R9 son cada uno, independientemente, H, alquilo C1-C6 no sustituido, o C(O)ORa, en donde Ra es H o alquilo C1-C6 no sustituido; y
dos Ri0 anclados al mismo atomo de carbono, junto con el atomo de carbono al que estan anclados, forman un carbonilo.
Por ejemplo, el compuesto es un compuesto enumerado en la Tabla 1 en la presente memoria.
Los compuestos representativos de la presente invention incluyen compuestos enumerados en la Tabla 1 y en la 5 Tabla 2.
Tabla 1.
5
0
14
,0 o o ....
15
0
17
r~Q vpi § k^N^QA^YOMe O
18
0
21
F F ° 0 ■
22
^,0 o NyN>i/^0A>^yOMe 0 0

Claims (14)

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    REIVINDICACIONES
    1. Un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo:
    en donde:
    imagen1
    imagen2
    Ri es alquilo Ci-C6 no sustituido;
    R6, R7, R8 y R9 son cada uno, independientemente, H, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido o C(O)ORa;
    Ra es H o alquilo C1-C6 sustituido o no sustituido;
    m es 0, 1,2 o 3;
    tes 0, 1,2, 3, 4, 5, 6, 7, 8,9o10;y
    cada R10 es, independientemente, H, halogeno, alquilo C1-C6 sustituido o no sustituido, alquenilo C2-C6 sustituido o no sustituido, alquinilo C2-C6 sustituido o no sustituido, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S;
    o, alternativamente, dos R10 anclados al mismo atomo de carbono, junto con el atomo de carbono al que estan anclados, forman un carbonilo, carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S;
    o, alternativamente, dos R10 anclados a diferentes atomos, junto con los atomos a los que estan anclados, forman un carbociclo C3-C10 sustituido o no sustituido, heterociclo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, O y S, o heteroarilo sustituido o no sustituido que comprende uno o dos anillos de 5 o 6 miembros y 1-4 heteroatomos seleccionados entre N, Oy S.
  2. 2. El compuesto de la reivindicacion 1, en donde R1 es metilo.
  3. 3. El compuesto de la reivindicacion 1 o 2, en donde R6, R7, R8 y R9 son cada uno H.
  4. 4. El compuesto de acuerdo con una cualquiera de las reivindicaciones precedentes, en donde m es 2 o 3.
  5. 5. El compuesto de acuerdo con una cualquiera de las reivindicaciones precedentes, en donde t es 0, 1, 2, 3 o 4.
  6. 6. El compuesto de acuerdo con una cualquiera de las reivindicaciones precedentes, en donde dos R10 estan anclados al mismo atomo de carbono, junto con el atomo de carbono al que estan anclados, forman un carbonilo.
  7. 7. El compuesto de la revindication 1, en donde el compuesto es:
    imagen3
    o una sal farmaceuticamente aceptable de los mismos.
    5 8. El compuesto de la reivindicacion 1, en donde el compuesto es:
    imagen4
    o una sal farmaceuticamente aceptable del mismo.
  8. 9. El compuesto de la reivindicacion 1, en donde el compuesto es:
    10
    imagen5
    o una sal farmaceuticamente aceptable del mismo.
  9. 10. El compuesto de la reivindicacion 1, en donde el compuesto se selecciona del grupo que consiste en:
    imagen6
    15
    20
    imagen7
    imagen8
    y
    imagen9
    o una sal farmaceuticamente aceptable de los mismos.
  10. 11. El compuesto de la revindication 1, en donde el compuesto se selecciona del grupo que consiste en:
    5
    10
    15
    20
    imagen10
    5
    imagen11
    o una sal farmaceuticamente aceptable de los mismos.
  11. 12. Una composicion farmaceutica que comprende:
    (i) un compuesto de Formula (III), o una sal farmaceuticamente aceptable del mismo, de acuerdo con una cualquiera de las reivindicaciones 1-11; y
    10 (ii) un portador farmaceuticamente aceptable.
  12. 13. Un compuesto de Formula (III), una sal farmaceuticamente aceptable del mismo, de acuerdo con una cualquiera de las reivindicaciones 1-11, o una composicion de acuerdo con la reivindicacion 12, para su uso en el tratamiento de una enfermedad neurologica.
  13. 14. El compuesto o composicion para el uso de la reivindicacion 13, en donde la enfermedad neurologica es
    15 esclerosis multiple.
  14. 15. El compuesto o composicion para el uso de la reivindicacion 13, en donde la enfermedad neurologica se selecciona entre esclerosis multiple recidivante-remitente, esclerosis multiple progresiva secundaria, esclerosis multiple progresiva primaria o esclerosis multiple progresiva recidivante.
    20
    'Me
    imagen12
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    imagen13
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    Q
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    2
    a
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    Figura 2
    (sbjolO odw9!j_
    imagen16
    imagen17
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    imagen18
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    imagen19
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    imagen20
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    imagen22
    Figura 7
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