ES2658766T3 - Dímero de buprenorfina y uso en el tratamiento de trastornos gastrointestinales - Google Patents
Dímero de buprenorfina y uso en el tratamiento de trastornos gastrointestinales Download PDFInfo
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- ES2658766T3 ES2658766T3 ES15720244.1T ES15720244T ES2658766T3 ES 2658766 T3 ES2658766 T3 ES 2658766T3 ES 15720244 T ES15720244 T ES 15720244T ES 2658766 T3 ES2658766 T3 ES 2658766T3
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
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- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
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- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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Abstract
Un compuesto de un dímero de buprenorfina con la Fórmula (I): **(Ver fórmula)** o una sal o solvato farmacéuticamente aceptable de la misma.
Description
[0045] En otra realización de este documento, se proporcionan composiciones que comprenden una cantidad efectiva del dímero y un vehículo o portador farmacéuticamente aceptable, donde el vehículo o portador farmacéuticamente aceptable puede comprender un excipiente, diluyente o una mezcla de estos.
[0046] Las composiciones orales pueden adoptar la forma de comprimidos, comprimidos masticables, cápsulas, soluciones, pastillas, suspensiones y similares. Se pueden formular composiciones que contengan una dosis diaria, o una fracción conveniente de una dosis diaria, en una dosis unitaria, que puede ser un único comprimido o cápsula o un volumen conveniente de un líquido. En una realización, las soluciones se preparan a partir de sales solubles en agua, como sal de hidrocloruro. En general, todas las composiciones se preparan según los métodos conocidos en la química farmacéutica. Se pueden preparar cápsulas mezclando el dímero presentado en este documento con un vehículo o diluyente adecuado y rellenando las cápsulas con la cantidad adecuada de la mezcla. Los vehículos y diluyentes habituales incluyen, entre otros, sustancias inertes en polvo, como almidón de muchos tipos diferentes, celulosa en polvo, especialmente celulosa cristalina y microcristalina, azúcares como fructosa, manitol y sacarosa, harinas de trigo y polvos comestibles similares.
[0047] Los comprimidos se pueden preparar por compresión directa, por granulación húmeda o por granulación seca. Por lo general sus formulaciones incorporan diluyentes, aglutinantes, lubricantes y desintegradores, además del compuesto. Típicamente los diluyentes incluyen, por ej., diversos tipos de almidón, lactosa, manitol, caolín, fosfato cálcico o sulfato cálcico, sales inorgánicas como cloruro de sodio y azúcar en polvo. También se pueden utilizar derivados de celulosa en polvo. Los aglutinantes típicos para comprimidos son sustancias como el almidón, la gelatina y azúcares como la lactosa, la fructosa, la glucosa y similares. Las gomas naturales y sintéticas también resultan convenientes, incluyendo la goma arábiga, alginatos, metilcelulosa, polivinilpirrolidina y similares. El polietilenglicol, la etilcelulosa y las ceras también pueden utilizarse como aglutinantes.
[0048] Para la formulación de un comprimido puede resultar necesario un lubricante, a fin de evitar que el comprimido y las perforaciones se adhieran en el molde. El lubricante se puede seleccionar entre sólidos deslizantes como talco, magnesio y estearato cálcico, ácido esteárico y aceites vegetales hidrogenados. Los desintegradores de comprimidos son sustancias que se hinchan cuando se humedecen para romper el comprimido y liberar el compuesto. Estos incluyen almidones, arcillas, celulosas, alginas y gomas. Más concretamente, se pueden utilizar almidones de maíz y de patata, metilcelulosa, agar, bentonita, celulosa de madera, esponja natural en polvo, resinas de intercambio iónico, ácido algínico, goma guar, pulpa de cítricos y celulosa de carboximetilo, por ej., así como lauril sulfato de sodio. Los comprimidos pueden estar recubiertos de azúcar como aromatizante y sellante, o con agente protectores formadores de película, para modificar las propiedades de disolución del comprimido. Las composiciones también se pueden formular en forma de comprimidos masticables, por ej., utilizando sustancias como manitol en la formulación.
[0049] Cuando se desee administrar el fármaco presentado en este documento en forma de supositorio, se pueden utilizar las bases típicas. La manteca de cacao es una base de supositorio tradicional, que se puede modificar mediante la adición de ceras para elevar ligeramente su punto de fusión. Las bases de supositorio miscibles con agua que comprenden, particularmente, polietilenglicoles de diversos pesos moleculares son de uso muy extendido.
[0050] El efecto del fármaco proporcionado aquí se puede retrasar o prolongar mediante una formulación adecuada. Por ejemplo, se puede utilizar un gránulo de disolución lenta del dímero e incorporarse a un comprimido o cápsula, o un dispositivo implantable de liberación lenta. La técnica también incluye la producción de gránulos con varios índices de disolución diferentes y el rellenado de las cápsulas con una mezcla de los gránulos. Los comprimidos o cápsulas pueden estar revestidos con una película resistente a la disolución durante un periodo de tiempo predecible.
[0051] Los ejemplos siguientes se ofrecen para ilustrar, sin carácter limitador, la invención reivindicada.
[0052] El dímero de buprenorfina se sintetizó como se muestra a continuación.
8
[0053] Se colocó HCl de buprenorfina-sal (5,0 g, 10,68 mmol, 1 equiv) y carbonato de potasio (42,73 mmol, 4 equiv) en un matraz de fondo redondo de tres cuellos y, a continuación, DMSO anhidro (50 ml, 10 vol). La mezcla se calentó hasta 60°C y se añadió 1,2-dibromoetano (9,2 mL, 106,8 mmol, 10 equiv) lentamente. La
5 mezcla de la reacción se agitó a 60°C durante 16 h y, a continuación, se enfrió hasta la temperatura ambiente, se diluyó con agua y se extrajo con diclorometano. Las porciones orgánicas combinadas se lavaron con agua salada, se secaron (Na2SO4 anhidroso) y se concentraron bajo presión reducida para obtener un líquido viscoso. El producto crudo se purificó por cromatografía en gel de silicio utilizando 0-5% MeOH/ DCM para obtener 4,2 g (69%) de Intermedio 1 en forma de un sólido espumoso de color crudo.
10 [0054] Se colocó HCl de buprenorfina-sal (1,74 g, 3,72 mmol) y carbonato de potasio (2,0 g, 14,87 mmol) en un matraz de fondo redondo de tres cuellos y, a continuación, DMSO anhidro (10 mL). La mezcla se calentó hasta 60°C y el Intermedio 1 (3 g, 5,22 mmol, 1,4 equiv) se disolvió en 7 mL de DMSO anhidro, añadido gota a gota durante 2 h. La mezcla de la reacción se agitó a 60 °C durante 16 h y, a continuación, se enfrió hasta la temperatura ambiente, se diluyó con agua y se extrajo con diclorometano. La capa orgánica se lavó con
15 agua salada, se secó (Na2SO4 anhidroso), se filtró y se concentró bajo presión reducida para obtener un líquido viscoso. El producto crudo se purificó por cromatografía en gel de silicio utilizando 0-5% MeOH/ DCM para obtener un dímero de buprenorfina-FB (base libre) en forma de un sólido espumoso (2,8 g, 77%).
[0055] Se disolvieron 5,5 g (5,7 mmol) del biconjugado (dímero de buprenorfina-FB) en 50 mL de acetato de etilo a temperatura ambiente bajo nitrógeno. Se añadieron 3,43 mL (6,9 mmol, 1,2 equiv) de 2N HCI en éter 20 gota a gota a temperatura ambiente. La mezcla de la reacción se agitó a temperatura ambiente durante otra hora y se filtró para obtener un sólido. El sólido se lavó de nuevo con 100 ml de acetato de etilo y se secó bajo vacío para obtener el dímero de buprenorfina (sal bis HC1) en forma de sólido de color blanco (5,8 g, 98 %). 1H NMR (300 MHz, DMSO-d6): δ 9,75 (br, 2H), 6,88 (d, J = 9,2 Hz, 2H), 6,67 (d, J= 9,2 Hz, 2H), 4,66 (s, 2H), 4,23-4,42 (m, 4H), 3,84-3,92 (m, 2H), 3,40 (s, 6H), 3,21-3,35 (m, 5H), 2,98-3,20 (m, 7H), 2,64-2,85 (m,
25 4H), 2,12-2,26 (m, 4H), 1,72-1,94 (m, 4H), 1,38-1,52 (m, 4H), 1,26 (s, 6H), 0,99 (s, 20H), 0,48-0,76 (m, 10H), 0,32-0,42 (m, 4H); MS: m/z 962 (M + 1)+
EJEMPLO 2
[0056] La siguiente composición se puede utilizar para un comprimido oral del dímero de buprenorfina.
9
EJEMPLO 6
[0078] Los estudios farmacocinéticos con animales se realizaron en el John Hopkins Medical Institute. Los animales utilizados fueron ratones CD-1 (unos 35 gms, n = 3 por punto temporal). Los fármacos testados fueron buprenorfina y dímero de buprenorfina. Dosis 10 mg/kg IV y sonda nasogástrica. Se tomaron muestras de sangre cuando habían transcurrido 0 y 30 minutos, y 1, 2, 6 y 24 horas. Las muestras de sangre para el fármaco se analizaron tras obtener el plasma y por LC/MS/MS como sigue:
[0079] Se preparó una curva estándar en plasma de ratón salpicado con el fármaco de ensayo (10-25000 nM). Las muestras de plasma (50 µL) se extrajeron en 300 µL de acetonitrilo que contenía losartán o buprenorfina-d4 como estándar interno. Los extractos se centrifugaron a 16000 x g a 4°C durante 5 minutos. Los supernatantes (250 µL) se transfirieron a un nuevo tubo y se secaron bajo N2 a 45°C durante 1 hora. Las muestras se reconstituyeron con 100 µL de 30% acetonitrilo, se agitaron y se centrifugaron. Los supernatantes (90 µL) se tranfirieron a viales LC y 10µL se inyectaron en LC/MS. Ver la Figura 7.
[0080] Resultados: La Figura 7 ilustra los perfiles de concentración de plasma del dímero de buprenorfina tras 10 mg de dosis oral e intravenosa. El gráfico indica que la biodisponibilidad absoluta del dímero, medida como un ratio de la superficie bajo la curva de concentración tras la dosis oral e IV, era del 1% o inferior, mientras que la del monómero era aproximadamente del 30%.
EJEMPLO 7
[0081] Los animales utilizados en los estudios eran machos de ratones CD-1, con un peso medio de 30-35 gramos, con una media de 5 ratones por grupo de dosis. Por lo general los ratones convivían en colonias, con unos 3 animales por jaula de policarbonato con acceso a alimentos y agua a voluntad. El día del experimento fueron transportados a la sala de procesos donde se colocaron individualmente en jaulas de 20 cm de ancho x 20 cm de profundidad por 15 cm de alto, equipadas con un suelo de malla metálica, tras la administración intragástrica del compuesto de ensayo. Durante el ensayo los animales tuvieron acceso a agua a voluntad. El suelo de malla metálica de la jaula crea un entorno novedoso que provoca estrés a los ratones. El número de gránulos excretados se determinó cada hora. Los resultados se muestran en las Figuras 8-10.
[0082] Resultados: Las Figuras 8 y 9 muestran que las dosis orales del dímero de buprenorfina redujeron de forma significativa la producción fecal de los ratones respecto del placebo (vehículo). Las dosis investigadas eran de 25 y 50 mg por kg. Los resultados no variaron incluso cuando los animales con producción fecal cero (lo que sugiere sensibilidad extrema) fueron retirados del análisis. La Figura 10 muestra que la producción fecal en ratones desciende con la dosis, lo que indica un verdadero efecto farmacológico.
Ensayo in vivo: Efecto sobre un tiempo de tránsito GI alterado tras un proceso inflamatorio
[0083] Este ensayo fue diseñado para medir el efecto de la sustancia de ensayo sobre la hipersensibilidad gastrointestinal que se produce tras la inflamación. El tránsito GI alterado postinflamatorio se indujo en machos de ratones CD-1 inyectando aceite de mostaza recién abierto (95% isotiocianato de alilo puro, 0,5% etanol) El efecto del estrés sobre la motilidad GI se evaluó 3 o 4 semanas más tarde, cuando a pesar de que ya no había inflamación, el tracto GI continuaba en un estado hipersensible. El efecto de la sustancia de ensayo se midió tras la administración oral (sonda intragástrica) y sometiendo a los animales a estrés ambiental, al alojarlos en jaulas de 20 cm de ancho x 20 cm de profundidad x 15 cm de alto, equipadas con un suelo de malla metálica. Durante el ensayo los animales tuvieron acceso a agua a voluntad. El suelo de malla metálica de la jaula crea un entorno novedoso que provoca estrés a los ratones. El número de gránulos excretados se determinó cada hora/dos horas. Ver la Figura 11.
[0084] Tal y como se muestra en la Figura 11, el dímero de buprenorfina a 25 mg por kg redujo de forma significativa la motilidad gastrointestinal, medida por la producción fecal en modelos postinflamatorios. El gráfico también muestra que el aumento de la producción fecal en los ratones no tratados con aceite de mostaza fue transitorio y no duró más de una hora. El aumento de la producción fecal de los animales tratados con aceite de mostaza persistía incluso a las dos horas. El dímero continuó controlando la motilidad gastrointestinal incluso a las dos horas y los resultados fueron estadísticamente significativos.
[0085] Se entiende que los ejemplos y realizaciones descritos en el presente documento se incluyen únicamente a título ilustrativo. En la medida en que exista un conflicto entre las solicitudes de prioridad y la presente solicitud, cualquier incoherencia se resolverá en favor de la presente solicitud.
13
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