ES2665964T3 - Compuestos de isoindolina sustituidos en posición 5 - Google Patents

Compuestos de isoindolina sustituidos en posición 5 Download PDF

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ES2665964T3
ES2665964T3 ES16160422.8T ES16160422T ES2665964T3 ES 2665964 T3 ES2665964 T3 ES 2665964T3 ES 16160422 T ES16160422 T ES 16160422T ES 2665964 T3 ES2665964 T3 ES 2665964T3
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George W. Muller
Shen-Chu Roger Chen
Alexander L. Ruchelman
Weihong Zhang
Ehab M. Khalil
Hon-Wah Man
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Celgene Corp
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Celgene Corp
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Abstract

Un compuesto que tiene la fórmula:**Fórmula**

Description

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Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "sal aceptable para
10 uso farmacéutico" se refiere a sales preparadas a partir de ácidos no tóxicos aceptables para uso farmacéutico, incluyendo ácidos inorgánicos y ácidos orgánicos. Los ácidos no tóxicos apropiados incluyen ácidos orgánicos e inorgánicas tal como, pero no limitado a, ácidos acético, algínico, antranílico, bencenosulfónico, benzoico, canforsulfónico, cítrico, etanosulfónico, fórmico, fumárico, furoico, glucónico, glutámico, glucorénico, galacturónico, glicıdico, bromhídrico, clorhídrico, isetiónico, láctico, maleico, málico, mandélico, metanosulfónico, múcico, nítrico,
15 pamoico, pantoténico, fenilacético, propiónico, fosfórico, salicílico, esteárico, succínico, sulfanílico, sulfúrico, tartárico, p-toluenosulfónico y similares. Son adecuados ácidos clorhídrico, bromhídrico, fosfórico y sulfúrico.
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "solvato" significa un compuesto de la presente invención o una sal del mismo, que incluye además una o cantidad estequiométrica o no estequiométrica de disolvente unido por fuerzas intermoleculares no covalentes. Cuando el disolvente es agua, el
20 solvato es un hidrato.
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "profármaco" significa un derivado de un compuesto que puede hidrolizar, oxidar o reaccionar de otra forma en condiciones biológicas (in vitro o in vivo) para dar lugar al compuesto. Ejemplos de profármacos incluyen, pero no se limitan a, compuestos que comprenden restos biohidrolizables tales como amides biohidrolizables, ésteres biohidrolizables, carbamatos 25 biohidrolizables, carbonatos biohidrolizables, ureidas biohidrolizables y análogos de fosfato biohidrolizables. Otros ejemplos de profármaco incluyen compuestos que comprenden restos de -NO, -NO2, -ONO o -ONO2. Los
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profármacos se pueden preparar típicamente usando mátodos bien conocidos, tales como los que se describen en Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Ed. Manfred E. Wolff, 5ª ed. 1995), y Design of Prodrugs (Ed. H. Bundgaard, Elselvier, New York 1985).
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, los términos "carbamato biohidrolizable", "carbonato biohidrolizable", "ureído biohidrolizable" y "fosfato biohidrolizable" significa un carbamato, carbonato, ureido y fosfato, respectivamente, de un compuesto que, o bien: 1) no interfiere con la actividad biológica del compuesto pero puede conferir propiedades ventajosas in vivo a ese compuesto, tal como captación, duración de acción, o aparición de acción; o 2) es biológicamente inactivo pero se convierte in vivo en el compuesto biológicamente activo. Los ejemplos de carbamatos biohidrolizables incluyen, pero no se limitan a, alquilaminas inferiores, etilenediaminas sustituidas, aminoácidos, hidroxialquilaminas, aminas heteroaromáticas y heterocíclicas, y aminas de poliéter.
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "estereoisómero" abarca todos los compuestos enantioméricamente/estereoméricamente puros y enantioméricamente / estereoméricamente enriquecidos de la presente invención.
Como se utiliza en la presente memoria y a menos que se indique lo contrario, el término "estereoméricamente puro" significa una composición que comprende un estereoisómero de un compuesto y está sustancialmente libre de otros estereoisómeros de ese compuesto. Por ejemplo, una composición estereoméricamente pura de un compuesto que tiene un centro quiral estará sustancialmente libre del enantiómero opuesto del compuesto. Una composición estereoméricamente pura de un compuesto que tiene dos centros quirales será sustancialmente libre de otros diastereómeros del compuesto. Un compuesto estereoméricamente puro típico comprende más que aproximadamente 80% en peso de un estereoisómero del compuesto y menos que aproximadamente 20% en peso de otros estereoisómeros del compuesto, más preferentemente más que aproximadamente 90% en peso de un estereoisómero del compuesto y menos que aproximadamente 10% en peso de los otros estereoisómeros del compuesto, aún más preferentemente más que aproximadamente 95% en peso de un estereoisómero del compuesto y menos que aproximadamente 5% en peso de los otros estereoisómeros del compuesto, y mucho más preferentemente más que aproximadamente 97% en peso de un estereoisómero del compuesto y menos que aproximadamente 3% en peso de los otros estereoisómeros del compuesto.
Como se utiliza en la presente memoria y a menos que se indique lo contrario, el término "estereoméricamente enriquecido" significa una composición que comprende más que aproximadamente 55% en peso de un estereoisómero de un compuesto, más que aproximadamente 60% en peso de un estereoisómero de un compuesto, preferentemente más que aproximadamente 70% en peso, más preferentemente más que aproximadamente 80% en peso de un estereoisómero de un compuesto.
Como se utiliza en la presente memoria, y a menos que se indique lo contrario, el término "enantioméricamente puro" significa una composición estereoméricamente pura de un compuesto que tiene un centro quiral. En forma similar, el término "enantioméricamente enriquecido" significa una composición estereoméricamente enriquecida de un compuesto que tiene un centro quiral.
Como se utiliza en la presente memoria, y a menos que se indique lo contrario, el término "alquilo" se refiere a un hidrocarburo ramificado o de cadena lineal saturados que tiene el número de átomos de carbono como se especifica en este documento. Los alquilos de cadena lineal saturada representativos incluyen -metilo, -etilo, n-propilo, -n-butilo, -n-pentilo, y -n-hexilo, mientras que los alquilos ramificados saturados incluyen -isopropilo, -sec-butilo, -isobutilo, -terc-butilo, -isopentilo, 2-metilbutilo, 3-metilbutilo, 2-metilpentilo, 3-metilpentilo, 4-metilpentilo, 2-metilhexilo, 3-metilhexilo, 4-metilhexilo, 5-metilhexilo, 2,3-dimetilbutilo, y similares. El término "alquilo" también contempla cicloalquilo.
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "cicloalquilo" significa una especie de alquilo que contiene de 3 a 15 átomos de carbono, sin enlaces dobles alternantes o resonantes entre los átomos de carbono. El mismo puede contener de I a 4 anillos. Los ejemplos de cicloalquilos sustituidos incluyen, pero no se limitan a, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, y adamantilo. Un cicloalquilo puede estar sustituido con uno o más de los sustituyentes como se define a continuación.
Como se utiliza en la presente memoria, y a menos que se especifique lo contrario, el término "alcoxi" se refiere a -O-(alquilo), en el que alquilo se define en la presente memoria. Los ejemplos de alcoxi incluyen, pero no se limitan a, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, y -O(CH2)3CH3.
Como se utiliza en la presente memoria, el término "arilo" significa un anillo aromático carbocíclico que contiene de 5 a 14 átomos anulares. Los átomos anulares de un grupo arilo carbocíclico son todos átomos de carbono. Las estructuras anulares de arilo incluyen compuestos que tienen una o más estructuras anulares tales como compuestos mono-, bi-, o tricíclico, así como restos carbocíclicos benzo-condensados tal como 5,6,7,8-tetrahidronaftilo y similares. Los grupos arilo representativos incluyen fenilo, antracenilo, fluorenilo, indenilo, azulenilo, fenantrenilo y naftilo.
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no se limitan a, lesiones/ daños del SNC y síndromes relacionados, incluyen, pero no se limitan a, lesión cerebral primaria, lesión cerebral secundaria, lesión cerebral traumática, lesión focal cerebral, lesión axonal difusa, lesión en la cabeza, conmoción cerebral, síndrome post-conmoción cerebral, contusión cerebral y laceración, hematoma subdural, hematoma epidérmico, epilepsia postraumática, estado vegetativo crónico, SCI completa, SCI incompleta,
5 SCI aguda, SCI subaguda, SCI crónica, síndrome de médula central, síndrome de Brown-Séquard, síndrome medular anterior, síndrome medular conal, síndrome de la cola de caballo, shock neurogénico, shock medular, alteración del nivel de conciencia, dolor de cabeza, náuseas, vómitos, pérdida de memoria, mareos, diplopía, visión borrosa, labilidad emocional, trastornos del sueño, irritabilidad, incapacidad para concentrarse, nerviosismo, alteraciones del comportamiento, déficit cognitivo, convulsiones.
10 Otros trastornos o enfermedades incluyen, pero no se limitan a, enfermedades víricas, genéticas, alérgicas y autoinmunes. Los ejemplos específicos incluyen, pero no se limitan a, VIH, hepatitis, síndrome de distrés respiratorio del adulto, enfermedades de resorción ósea, enfermedades inflamatorias pulmonares crónicas, dermatitis, fibrosis quística, shock séptico, sepsis, choque endotóxico, choque hemodinámico, síndrome de sepsis, lesión por reperfusión postisquémica , meningitis, psoriasis, enfermedad fibrótica, caquexia, enfermedad injerto contra huésped,
15 rechazo de injertos, enfermedad auto-inmune, espondilitis reumatoide, enfermedad de Crohn, colitis ulcerosa, enfermedad inflamatoria del intestino, esclerosis múltiple, lupus eritematoso sistémico, ENL en la lepra, daño por radiación, cáncer, asma, o lesión alveolar hiperóxica.
Los ejemplos de aterosclerosis y afecciones relacionadas incluyen, pero no se limitan a, los que se analizan en la publicación de EE.UU. No. 2002/0054899, publicada el 9 de mayo de 2002. Los ejemplos específicos incluyen, pero 20 no se limitan a, todas las formas de las afecciones que implican aterosclerosis, incluyendo restenosis después de intervención vascular, como la angioplastia, inhalación, aterectomía e injerto. Todas las formas de intervención vascular están contempladas por la invención, incluyendo enfermedades del sistema renal y cardiovascular, tales como, pero no limitadas a, angioplastia renal, intervención coronaria percutánea (PCI), angioplastia coronaria transluminal percutánea (PTCA), angioplastia transluminal percutánea de carótida (PTA), injerto de bypass coronario, 25 angioplastia con implantación de stent, intervención transluminal percutánea periférica de las arterias ilíaca, femoral
o poplítea, y intervención quirúrgica utilizando injertos artificiales impregnados. La siguiente tabla proporciona una lista de las principales arterias sistémicas que pueden necesitar tratamiento, todas las cuales están contempladas por la invención:
Arteria
Áreas corporales suministradas
Axilar
Hombro y axila
Braquial
Brazo superior
Braquiocefálica
Cabeza, cuello y brazo
Celíaca
Se divide en las arterias gástricas, esplénica y hepática
Carótida común
Cuello
Ilíaca común
Se divide en arterias ilíacas externa e interna
Coronaria
Corazón
Femoral profunda
Muslo
Digital
Dedos
Dorsal del pie
Pie
Carótida externa
Cuello y regiones externas de la cabeza
Ilíaca externa
Arteria femoral
Femoral
Muslo
Gástrica
Estómago
Hepática
Hígado, vesícula biliar, páncreas y duodeno
Mesentérica inferior
Colon descendente, recto y pared pélvica
Carótida interna
Cuello y regiones internas de la cabeza
Ilíaca interna
Recto, vejiga urinaria, genitales externos, glúteos, útero y vagina
Gástrica izquierda
Esófago y estómago
Sacral media
Sacro
Ovárica
Ovarios
Arco palmar
Mano
Peroneal
Pantorrilla
Popliteal
Rodilla
Tibial posterior
Pantorrilla
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