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ES2269467T3 - Tratamiento de transtornos afectivos por la accion combinada de un agonista del receptor nicotinico y una sustancia monoaminergenica. - Google Patents

Tratamiento de transtornos afectivos por la accion combinada de un agonista del receptor nicotinico y una sustancia monoaminergenica. Download PDF

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Publication number
ES2269467T3
ES2269467T3 ES01976043T ES01976043T ES2269467T3 ES 2269467 T3 ES2269467 T3 ES 2269467T3 ES 01976043 T ES01976043 T ES 01976043T ES 01976043 T ES01976043 T ES 01976043T ES 2269467 T3 ES2269467 T3 ES 2269467T3
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treatment
azabicyclo
oct
disorder
eno
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Gunnar M. Olsen
Dan Peters
Elsebet Stergaard Nielsen
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NTG Nordic Transport Group AS
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Neurosearch AS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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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    • A61K31/44—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
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Un derivado de 8-azabiciclo[3, 2, 1]oct-2-eno de Fórmula VI, en la que R es hidrógeno; y R1 es 2-benzotienilo; o un enantiómero o una mezcla de sus enantiómeros, o una sal farmacéuticamente aceptable del mismo.

Description

Tratamiento de trastornos afectivos por la acción combinada de un agonista del receptor nicotínico y una sustancia monoaminérgica.
Campo técnico
Esta invención se refiere a una nueva sustancia para el tratamiento de trastornos afectivos, así como a composiciones farmacéuticas que comprenden esta sustancia.
Técnica antecedente
Los inhibidores selectivos de la recaptación de monoamina, y en particular, los inhibidores de la recaptación de serotonina (SSRI), son la norma de oro para el tratamiento de la depresión. Sin embargo, su inconveniente más grave es que aunque los efectos secundarios aparecen casi inmediatamente, no se observará ningún efecto antidepresivo sustancial en las primeras 2 a 4 semanas, dejando una ventana de vulnerabilidad durante la que el paciente puede no estar conforme con la terapia. Aunque la coadministración de antidepresivos de actuación rápida puede superar esto, es más preferible contrarrestar el mecanismo auto-inhibidor que retarda la aparición de los efectos de los SSRI.
Hay buenas indicaciones de que esto puede conseguirse bloqueando ciertos receptores que regulan negativamente la descarga de serotonina según se eleva la concentración de neurotransmisor en la hendidura sináptica. Por tanto, el documento WO 96/33710 (Astra) describe una combinación de un inhibidor de la captación de 5-HT con un antagonista selectivo de 5-HT_{1A}, y el documento WO 00/15217 (AstraZeneca), el documento WO 00/15218 (AstraZeneca) y el documento WO 00/15219 (AstraZeneca) describen ejemplos específicos de dichas combinaciones.
Otra combinación que implica ligandos nicotínicos, sin embargo, para un uso completamente diferente, se describe en el documento WO 00/45846 (Synthelabo). Esta publicación de patente describe el uso de nicotina o un ligando nicotínico en combinación con un inhibidor de la monoamina oxidasa (MAO) para el tratamiento de los síntomas del síndrome de abstinencia del tabaco, mostrando dicha combinación efectos secundarios cardiovasculares reducidos.
El documento WO 00/25783 (Carlsson & Carlsson) describe el uso de un agonista del receptor nicotínico en el tratamiento del trastorno obsesivo compulsivo (OCD). No se describe una terapia de combinación y el tratamiento de otros trastornos afectivos.
El documento WO 98/54181 (NeuroSearch) describe derivados de 8-azabiciclo[3,2,1]oct-2-eno útiles como ligandos colinérgicos y/o para la inhibición de la recaptación de serotonina, incluyendo el compuesto 3-(2-benzotienil)-8-metil-8-azabiciclo[3,2,1]oct-2-eno.
Sumario de la invención
La invención se refiere a la provisión de un nuevo derivado de 8-azabiciclo[3,2,1]oct-2-eno de Fórmula VI,
1
en la que
R es hidrógeno; y
R^{1} es 2-benzotienilo;
o un enantiómero o una mezcla de sus enantiómeros, o un isótopo del mismo o una sal farmacéuticamente aceptable del mismo.
En un segundo aspecto, la invención proporciona una composición farmacéutica que comprende una cantidad terapéuticamente eficaz del derivado de 8-azabiciclo[3,2,1]oct-2-eno de la invención junto con al menos un vehículo o diluyente farmacéuticamente aceptable.
Vista desde otro aspecto, la invención se refiere al uso de un derivado de 8-azabiciclo[3,2,1]oct-2-eno de la invención para la fabricación de un medicamento para el tratamiento, prevención o alivio de un trastorno, enfermedad o afección afectiva en un sujeto.
Serán evidentes otros objetos de la invención para los especialistas en la técnica a partir de la siguiente descripción detallada y ejemplos.
Descripción detallada de la invención
La presente invención se refiere al uso de una sustancia que tiene la actividad dual de un agonista nicotínico de acetilcolina y un agonista o antagonista de monoamina o un inhibidor de la recaptación de monoamina para el tratamiento, prevención o alivio de un trastorno afectivo en un sujeto.
El sujeto a tratar de acuerdo con esta invención es un cuerpo vivo, preferiblemente un mamífero, más preferiblemente un ser humano, en necesidad de dicho tratamiento.
El trastorno, enfermedad o afección afectiva puede ser, en particular, depresión, ansiedad, trastorno obsesivo compulsivo (OCD), trastorno de pánico o dolor.
Sustancias Químicas de "Acción Dual"
El derivado de 8-azabiciclo[3,2,1]oct-2-eno de la invención es un compuesto de Fórmula VI,
2
cualquiera de sus enantiómeros o cualquier mezcla de sus enantiómeros, o una sal farmacéuticamente aceptable del mismo;
en el que
R es hidrógeno; y
R^{1} es 2-benzotienilo;
o un enantiómero o una mezcla de sus enantiómeros, o una sal farmacéuticamente aceptable del mismo.
En su realización más preferida, el derivado de 8-azabiciclo[3,2,1]oct-2-eno de la invención es (\pm)-3-(2-benzotienil)-8-H-8-azabiciclo[3,2,1]oct-2-eno.
Composiciones Farmacéuticas
Vista desde otro aspecto, la invención se refiere al uso de un agonista nicotínico de acetilcolina y un inhibidor de la recaptación de monoamina para la fabricación de un medicamento para el tratamiento, prevención o alivio de un trastorno, enfermedad o afección afectiva en un sujeto, incluyendo un ser humano.
Aunque puede administrarse un compuesto químico de la invención para su uso en terapia en forma del compuesto químico sin procesar, se prefiere introducir el ingrediente activo, opcionalmente en forma de una sal fisiológicamente aceptable, en una composición farmacéutica junto con uno o más adyuvantes, excipientes, vehículos, tampones, diluyentes y/u otros compuestos farmacéuticos auxiliares habituales.
En una realización preferida, la invención proporciona composiciones farmacéuticas que comprenden el compuesto químico de la invención, o una sal o derivado farmacéuticamente aceptable del mismo, junto con uno o más vehículos farmacéuticamente aceptables para el mismo y, opcionalmente, otros ingredientes terapéuticos y/o profilácticos, conocidos y usados en la técnica. El vehículo o vehículos deben ser "aceptables" en el sentido de ser compatibles con los demás ingredientes de la formulación y no dañinos para el destinatario del mismo.
La composición farmacéutica de la invención puede administrarse por cualquier vía conveniente, que sea adecuada para la terapia deseada. Las vías preferidas de administración incluyen administración oral, en particular en forma de comprimido, de cápsula, de gragea, de polvo, o líquida, y administración parenteral, en particular inyección cutánea, subcutánea, intramuscular, o intravenosa. La composición farmacéutica puede prepararse por un especialista en la técnica usando técnicas convencionales y tradicionales apropiadas para la formulación deseada. Cuando se desea, se pueden emplear composiciones adaptadas para dar una liberación sostenida del ingrediente activo.
Pueden encontrarse detalles y técnicas adicionales para la formulación y administración en la última edición de Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
La composición farmacéutica de la invención preferiblemente es para su uso en el tratamiento, prevención o alivio de un trastorno, enfermedad o afección afectiva en un sujeto. El trastorno, enfermedad o afección afectiva puede ser, en particular, depresión, ansiedad, trastorno obsesivo compulsivo (OCD), trastorno de pánico, o dolor.
La dosificación exacta depende de la naturaleza y gravedad de la enfermedad que se está tratando, y es a juicio del médico, y puede variarse por valoración de dosificación para las circunstancias particulares de esta invención para producir el efecto terapéutico deseado. Sin embargo, actualmente se contempla que las composiciones farmacéuticas que contienen de aproximadamente 0,01 a aproximadamente 500 mg de ingrediente activo por dosis individual, preferiblemente de aproximadamente 0,1 a aproximadamente 100 mg, más preferiblemente de aproximadamente 1 a aproximadamente 10 mg, son adecuadas para tratamientos terapéuticos.
El ingrediente activo puede administrarse en una o varias dosis al día. Un resultado satisfactorio puede, en ciertos casos, obtenerse a una dosificación de tan sólo 0,1 \mug/kg i.v. y 1 \mug/kg p.o. El límite superior del intervalo de dosificación está considerado actualmente de aproximadamente 10 mg/kg i.v. y 100 mg/kg p.o. Los intervalos preferidos son de aproximadamente 0,1 \mug/kg a aproximadamente 10 mg/kg/día i.v., y de aproximadamente 1 \mug/kg a aproximadamente 100 mg/kg/día p.o.
Ejemplos
La invención se ilustra adicionalmente con referencia a los siguientes ejemplos, que no se pretende que limiten de ningún modo el alcance de la invención reivindicada.
Ejemplo 1
Ejemplo Preparativo
General
Todas las reacciones que implican reactivos o intermedios sensibles al aire se realizaron en atmósfera de nitrógeno y en disolventes anhidros. Se usó sulfato de magnesio como agente de secado en los procedimientos de tratamiento y los disolventes se evaporaron a presión reducida.
Método D
(\pm)-3-(2-Benzotienil)-8-H-8-azabiciclo[3,2,1]oct-2-eno (Compuesto 1D1)
Se calentó una mezcla de (\pm)-3-(2-benzotienil)-8-metil-8-azabiciclo[3,2,1]oct-2-eno (24,4 g, 0,0955 mol), 1-cloroetil-cloroformiato (15,5 ml, 0,143 mol) y xileno (200 ml) y se agitó a temperatura de reflujo durante 24 horas. Se añadió metanol (300 ml) seguido de agitación y calentamiento a temperatura de reflujo durante 22 horas. La mezcla se enfrió a temperatura ambiente y se filtró el producto. El producto bruto se recristalizó en éter dietílico. Rendimiento 16 g (69%). Pf 252-259ºC.

Claims (5)

1. Un derivado de 8-azabiciclo[3,2,1]oct-2-eno de Fórmula VI,
3
en la que
R es hidrógeno; y
R^{1} es 2-benzotienilo;
o un enantiómero o una mezcla de sus enantiómeros, o una sal farmacéuticamente aceptable del mismo.
2. El derivado de 8-azabiciclo[3,2,1]oct-2-eno de la reivindicación 1, que es (\pm)-3-(2-benzotienil)-8-H-8-azabiciclo[3,2,1]oct-2-eno.
3. Una composición farmacéutica que comprende una cantidad terapéuticamente eficaz del derivado de 8-azabiciclo[3,2,1]oct-2-eno de la reivindicación 1, junto con al menos un vehículo o diluyente farmacéuticamente aceptable.
4. Uso del derivado de 8-azabiciclo[3,2,1]oct-2-eno de la reivindicación 1, para la fabricación de un medicamento para el tratamiento, prevención o alivio de un trastorno, enfermedad o afección afectiva en un sujeto.
5. El uso de acuerdo con la reivindicación 4, en el que el trastorno, enfermedad o afección afectiva es depresión, ansiedad, trastorno obsesivo compulsivo (OCD), trastorno de pánico o dolor.
ES01976043T 2000-10-13 2001-10-10 Tratamiento de transtornos afectivos por la accion combinada de un agonista del receptor nicotinico y una sustancia monoaminergenica. Expired - Lifetime ES2269467T3 (es)

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