ES2359564T3 - Derivados de benzamida útiles como inductores de diferenciación celular. - Google Patents

Derivados de benzamida útiles como inductores de diferenciación celular. Download PDF

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ES2359564T3
ES2359564T3 ES04008185T ES04008185T ES2359564T3 ES 2359564 T3 ES2359564 T3 ES 2359564T3 ES 04008185 T ES04008185 T ES 04008185T ES 04008185 T ES04008185 T ES 04008185T ES 2359564 T3 ES2359564 T3 ES 2359564T3
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group
carbons
compound
formula
pharmaceutically acceptable
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Tsuneji Suzuki
Tomoyuki Ando
Tsuchiya Katsutoshi
Osamu Nakanishi
Akiko Saito
Yoshinori Shiraishi
Takashi Yamashita
Eishi Tanaka
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Bayer Pharma AG
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Bayer Schering Pharma AG
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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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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Abstract

Un compuesto representado por la fórmula (1): en la que A es un grupo heterocíclico, o un grupo heterocíclico que tiene de 1 a 4 sustituyentes, en el que el o los sustituyentes para el grupo heterocíclico se seleccionan del grupo constituido por un átomo de halógeno, un grupo hidroxilo, un grupo amino, un grupo nitro, un grupo ciano, un grupo alquilo que tiene de 1 a 4 carbonos, un grupo alcoxi que tiene de 1 a 4 carbonos, un grupo aminoalquilo que tiene de 1 a 4 carbonos, un grupo alquilamino que tiene de 1 a 4 carbonos, un grupo acilo que tiene de 1 a 4 carbonos, un grupo acilamino que tiene de 1 a 4 carbonos, un grupo alquiltio que tiene de 1 a 4 carbonos, un grupo perfluoroalquilo que tiene de 1 a 4 carbonos, un grupo perfluoroalquiloxi que tiene de 1 a 4 carbonos, un grupo carboxilo, un grupo alcoxicarbonilo que tiene de 1 a 4 carbonos, un grupo fenilo y un grupo heterocíclico; X es un resto que tiene una estructura seleccionada de: -(CH2)e- y -(CH2)g-O-(CH2)een las que e es un número entero de 1 a 4; y g un número entero de 0 a 4; Q es un resto que tiene la estructura en las que R7 es un átomo de hidrógeno o un grupo alquilo que tiene de 1 a 4 carbonos o un grupo alquilo que tiene de 1 a 4 carbonos que tiene de 1 a 4 sustituyentes seleccionados del grupo constituido por un halógeno, hidroxilo, amino, nitro, ciano, fenilo y un heterociclo; R2 es un átomo de hidrógeno, un grupo hidroxilo, un grupo alquilo que tiene de 1 a 4 carbonos, o un grupo alcoxi que tiene de 1 a 4 carbonos, o una sal del mismo farmacéuticamente aceptable.

Description

Esta invención se refiere a un agente inductor de diferenciación. En particular, esta invención se refiere al uso de un nuevo derivado de benzamida para un fármaco anticancerígeno u otros fármacos, basado en su actividad inductora de diferenciación.
Los cánceres ahora se han convertido en una causa principal de muerte superando a las enfermedades cardiacas y cerebrovasculares, y por lo tanto se han llevado a cabo muchos estudios para vencer al cáncer, con un gran desembolso y mucho tiempo. Sin embargo, no se ha vencido a pesar de la gran variedad de investigaciones de terapias tales como la operación quirúrgica, terapia con radiación y termoterapia. Entre estas terapias, la quimioterapia es una de las áreas principales para el tratamiento del cáncer. Sin embargo, hasta la fecha no se han descubierto fármacos satisfactorios, y por lo tanto se desea un fármaco anticancerígeno con poca toxicidad y un efecto terapéutico alto. Muchos de los fármacos anticancerígenos convencionales muestran su efecto afectando principalmente al ADN para expresar su citotoxicidad y después dañan a las células del carcinoma. Sin embargo, puesto que no tienen suficiente selectividad entre las células de carcinoma y las células normales, las reacciones adversas expresadas en células normales han limitado su uso en terapia.
Entretanto, los agentes inductores de diferenciación entre los fármacos anticancerígenos se dirigen a la inducción de la diferenciación de células de carcinoma para controlar su proliferación infinita, en lugar de matar a las células directamente.
Por lo tanto, los agentes pueden ser inferiores a los fármacos anticancerígenos que matan directamente las células de carcinoma, con respecto a la reducción de un carcinoma, pero se puede esperar que tengan una menor toxicidad y una selectividad diferente. De hecho, es bien conocido que se puede usar el ácido retinoico, un agente inductor de diferenciación, para el tratamiento de la leucemia promielocítica presentando un efecto superior [Huang y col., Blood, 72, 567-572(1988); Castaign y col., Blood, 76, 1704-1709 (1990); Warrell y col., New Engl. J. Med. 324, 1385-1393(1991) etc.]. Además, los derivados de la vitamina D presentan un efecto inductor de diferenciación, y por lo tanto se ha investigado su aplicación para fármacos anticancerígenos (p. ej., Olsson y col., Cancer Res. 43., 5862-5867 (1983) etc.).
Como resultado de estas investigaciones, se han publicado aplicaciones para fármacos anticancerígenos de una variedad de agentes inductores de diferenciación tales como derivados de vitamina D (documento JP-A6-179622), derivados de isopreno (documento JP-A6-192073), tocoferol (documento JP-A6-256181), derivados de quinona (documento JP-A6-305955), poliisoprenoides no cíclicos (documento JP-A6-316520), derivados de ácido benzoico (documento JP-A7-206765) y glucolípidos (documento JP-A7-258100). A pesar de las investigaciones no hay agentes que tengan un nivel suficiente de efecto para el tratamiento del cáncer, y por lo tanto se desea un agente muy seguro y eficaz para una variedad de cánceres.
Las realizaciones preferidas de esta invención pueden proporcionar compuestos que presentan efectos inductores de diferenciación y son útiles como agentes farmacéuticos, tales como agentes terapéuticos o agentes de mejora de tumores malignos, enfermedades autoinmunes, enfermedades dermatológicas y parasitismo.
Los autores de la invención han investigado intensamente y han encontrado que nuevos derivados de benzamida que tienen efecto inductor de diferenciación, presentan efecto antitumoral.
Esta invención proporciona un compuesto representado por la fórmula (1) o una sal del mismo farmacéuticamente aceptable:
imagen1
en la que A es un grupo heterocíclico, opcionalmente sustituido con 1 a 4 sustituyentes seleccionados del grupo constituido por un átomo de halógeno, un grupo hidroxilo, un grupo amino, un grupo nitro, un grupo ciano, un grupo alquilo que tiene de 1 a 4 carbonos, un grupo alcoxi que tiene de 1 a 4 carbonos, un grupo aminoalquilo que tiene de 1 a 4 carbonos, un grupo alquilamino que tiene de 1 a 4 carbonos, un grupo acilo que tiene de 1 a 4 carbonos, un grupo acilamino que tiene de 1 a 4 carbonos, un grupo alquiltio que tiene de 1 a 4 carbonos, un grupo perfluoroalquilo que tiene de 1 a 4 carbonos, un grupo perfluoroalquiloxi que tiene de 1 a 4 carbonos, un grupo carboxilo, un grupo alcoxicarbonilo que tiene de 1 a 4 carbonos, un grupo fenilo y un grupo heterocíclico;
X es un resto que tiene una estructura seleccionada de:
-(CH2)e- y -(CH2)g-O-(CH2)e-,
imagen2
en las que e es un número entero de 1 a 4; y g un número entero de 0 a 4; Q es un resto que tiene la estructura
imagen1
en las que R7 es hidrógeno o un alquilo que tiene de 1 a 4 carbonos y que tiene opcionalmente de 1 a 4 sustituyentes seleccionados de halógeno, hidroxilo, amino, nitro, ciano, fenilo y heterociclilo;
y R2 es un átomo de hidrógeno, un grupo hidroxilo, un grupo alquilo que tiene de 1 a 4 carbonos, o un grupo alcoxi que tiene de 1 a 4 carbonos.
Los derivados de benzamida de esta invención tienen efecto inductor de diferenciación y son útiles como fármacos, tal como un agente terapéutico o de mejora de tumores malignos, enfermedades autoinmunes, enfermedades dermatológicas y parasitismo. En particular, son muy eficaces como agente carcinostático, específicamente frente a un tumor maligno hematológico y un carcinoma sólido.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN Y REALIZACIONES PREFERIDAS
En la fórmula (1) anterior, n puede ser cero o un número entero de 1 a 4.
Q en la fórmula (1) anterior es un resto seleccionado de:
imagen1
en los que R7 es como se ha definido antes.
X en la fórmula (1) anterior puede ser un resto que tiene la estructura representada por la fórmula (6):
-(CH2)e- (6)
en la que e es como se ha definido antes.
X en la fórmula (1) anterior también puede ser un resto que tiene la estructura ilustrada en la fórmula (7):
-(CH2)g-O-(CH2)e- (7)
en la que e y g son como se han definido antes.
Como se usa en el presente documento, “de 1 a 4 átomos de carbono” significa un número de carbonos para un solo sustituyente; por ejemplo, para la sustitución dialquilo significa de 2 a 8 carbonos.
Un heterociclo en el compuesto representado por la fórmula (1) puede ser un heterociclo monocíclico que tiene 5 ó 6 miembros, que contiene de 1 a 4 átomos de nitrógeno, oxígeno o azufre, o un heterociclo bicíclico condensado. El heterociclo monocíclico incluye piridina, pirazina, pirimidina, piridazina, tiofeno, furano, pirrol, pirazol, isoxazol, isotiazol, imidazol, oxazol, tiazol, piperidina, piperazina, pirrolidina, quinuclidina, tetrahidrofurano, morfolina y tiomorfolina. El heterociclo bicíclico condensado incluye quinolina; isoquinolina; naftiridina; piridinas condensadas tales como furopiridina, tienopiridina, pirrolopiridina, oxazolopiridina, imidazolopiridina y tiazolopiridina; benzofurano; benzotiofeno; y bencimidazol.
Un halógeno puede ser flúor, cloro, bromo o yodo.
Un alquilo que tiene de 1 a 4 carbonos incluye metilo, etilo, n-propilo, isopropilo, n-butilo, isobutilo, sec-butilo y terc-butilo.
Un alcoxi que tiene de 1 a 4 carbonos incluye metoxi, etoxi, n-propoxi, isopropoxi, aliloxi, n-butoxi, isobutoxi, sec-butoxi y terc-butoxi.
Un aminoalquilo que tiene de 1 a 4 carbonos incluye aminometilo, 1-aminoetilo y 2-aminopropilo.
Un alquilamino que tiene de 1 a 4 carbonos incluye N-metilamino, N,N-dimetilamino, N,N-dietilamino, N-metil-Netilamino y N,N-diisopropilamino.
Un acilo que tiene de 1 a 4 carbonos incluye acetilo, propanoilo y butanoilo.
imagen3
Un acilamino que tiene de 1 a 4 carbonos incluye acetilamino, propanoilamino y butanoilamino.
Un alquiltio que tiene de 1 a 4 carbonos incluye metiltio, etiltio y propiltio.
Un perfluoroalquilo que tiene de 1 a 4 carbonos incluye trifluorometilo y pentafluoroetilo.
Un perfluoroalquiloxi que tiene de 1 a 4 carbonos incluye trifluorometoxi y pentafluoroetoxi.
5 Un alcoxicarbonilo que tiene de 1 a 4 carbonos incluye metoxicarbonilo y etoxicarbonilo.
Un alquilo opcionalmente sustituido que tiene de 1 a 4 carbonos incluye metilo, etilo, n-propilo, isopropilo, nbutilo, isobutilo, sec-butilo y terc-butilo y éstos tienen de 1 a 4 sustituyentes seleccionados del grupo constituido por un halógeno, hidroxilo, amino, nitro, ciano, fenilo y un heterociclo.
Una sal farmacéuticamente aceptable del compuesto de esta invención incluye sales con un ácido inorgánico
10 tal como ácido clorhídrico, ácido bromhídrico, ácido sulfúrico y ácido fosfórico; y con un ácido orgánico tal como ácido acético, ácido láctico, ácido tartárico, ácido málico, ácido succínico, ácido fumárico, ácido maleico, ácido cítrico, ácido benzoico, ácido trifluoroacético, ácido p-toluenosulfónico y ácido metanosulfónico.
Como se usa en el presente documento, un “fármaco” incluye un agente terapéutico y/o agente de mejora, por ejemplo, para una enfermedad autoinmune, enfermedad dermatológica o parasitismo, además de un fármaco 15 anticancerígeno.
Cuando hay un carbono o carbonos asimétricos, el compuesto representado por la fórmula (1) se puede obtener en forma de estereoisómeros individuales o una mezcla de estereoisómeros incluyendo una modificación racémica. Esta invención abarca las diferentes formas especificadas antes, que también se pueden usar como un principio activo.
20 Los compuestos representativos de esta invención representados por la fórmula (1) se muestran específicamente en la tabla 1, pero no se pretende que esta invención se límite a estos.
imagen4
imagen1
El compuesto de esta invención se puede preparar como se describe a continuación.
(a) Un compuesto representado por la fórmula (14),
A-X-R9 (14)
en la que A y X son como se han definido antes; R9 es -C(=O)OH, se condensa con un compuesto representado por la fórmula (15),
imagen5
imagen1
en la que R2 es como se ha definido antes; R10 es -NH2; R11 uno que un hidroxilo protegido con un grupo protector usado habitualmente en una reacción de formación de péptido, incluyendo bencilo; o
(b) Un compuesto representado por la fórmula (16)
A-X-OH (16),
en la que A y X son como se han definido antes, se condensa con un compuesto representado por la fórmula (17):
imagen1
en la que R2 y R11 son como se han definido antes; R13 es -NH2;
usando un agente tal como N,N’-carbonildiimidazol, N,N’-tiocarbonildiimidazol, fosgeno o tiofosgeno, para dar un compuesto representado por la fórmula (18):
imagen1
en la que A, X, Q, R2 y R11 son como se han definido antes, cuyo grupo protector después se elimina para dar el compuesto de esta invención; o
Con el fin de producir un compuesto de fórmula (21), o bien:
(c) (i) un compuesto representado por la fórmula (14) se condensa con un compuesto representado por la fórmula (19),
imagen1
en la que R10 es como se ha definido antes; R14 es un grupo metilo, etilo o terc-butilo; o bien
imagen6
(ii) un compuesto representado por la fórmula (16) se condensa con un compuesto representado por la fórmula
(20),
imagen1
en la que R13 y R14 son como se han definido antes;
usando un agente tal como N,N’-carbonildiimidazol, N,N’-tiocarbonildiimidazol, fosgeno o tiofosgeno, para dar dicho compuesto representado por la fórmula (21):
imagen1
en la que A, X, Q y R14 son como se han definido antes. Después, el compuesto de fórmula (21) se hidroliza para dar un compuesto representado por la fórmula (22),
imagen1
en la que A, X y Q son como se han definido antes. El producto se condensa con un compuesto representado por la fórmula (23),
imagen1
en la que R2 y R11 son como se han definido antes;
para dar un compuesto representado por la fórmula (18) cuyo grupo protector después se elimina para dar el compuesto de esta invención; o
(d) Un compuesto representado por la fórmula (22) se condensa con un compuesto representado por la fórmula (24),
imagen7
imagen1
en la que R2 es como se ha definido antes; para dar el compuesto de esta invención. A continuación se muestran los procedimientos de preparación para productos intermedios típicos. Un compuesto representado por la fórmula (15) se puede preparar introduciendo un grupo protector adecuado
en un derivado de ácido benzoico representado por la fórmula (25);
imagen1
en la que R10 es como se ha definido antes;
condensando el producto con un compuesto representado por la fórmula (23), y eliminando el grupo protector 10 del producto de condensación.
Un compuesto representado por la fórmula (17) se puede preparar introduciendo un grupo protector adecuado en un derivado de ácido benzoico representado por la fórmula (26);
imagen1
en la que R13 es como se ha definido antes;
15 condensando el producto con un compuesto representado por la fórmula (23), y eliminando el grupo protector del producto de condensación.
Un compuesto representado por la fórmula (23) se puede preparar introduciendo un grupo protector en un compuesto representado por la fórmula (24).
A continuación, se describirán las reacciones usadas para preparar el compuesto de esta invención.
20 La reacción de condensación de (a) puede ser una reacción de formación de enlace amida para un péptido habitual, usando, por ejemplo, un éster activado, un anhídrido de ácido mixto o un haluro de ácido. Por ejemplo, un ácido carboxílico, es decir, un compuesto representado por la fórmula (14), se puede condensar con un derivado de fenol tal como 2,4,5-triclorofenol, pentaclorofenol y 4-nitrofenol, o un compuesto N-hidroxi tal como N-hidroxisuccinimida y N-hidroxibenzotriazol, en presencia de diciclohexilcarbodiimida, para convertirlo en un éster activado que después se
25 condensa con una amina representada por la fórmula (15) para dar el producto deseado.
Alternativamente, un ácido carboxílico representado por la fórmula (14) se puede hacer reaccionar, por ejemplo, con cloruro de oxalilo, cloruro de tionilo u oxicloruro de fósforo para convertirlo en un cloruro de ácido, el cual después se condensa con una amina representada por la fórmula (15) para dar el producto deseado.
Además, un ácido carboxílico representado por la fórmula (14) se puede hacer reaccionar, por ejemplo, con clorocarbonato de isobutilo o cloruro de metanosulfonilo para convertirlo en un anhídrido de ácido mixto, el cual después se condensa con una amina representada por la fórmula (15), para dar el producto deseado.
imagen8
La reacción de condensación anterior se puede llevar a cabo usando solo un agente de condensación de péptidos tal como diciclohexilcarbodiimida, N,N’-carbonildiimidazol, azida difenilfosfórica, cianuro de dietilfosforilo, cloruro de 2-cloro-1,3-dimetilimidazolonio, etc.
La reacción se puede llevar a cabo normalmente de -20 a +50ºC durante de 0,5 a 48 horas. Los disolventes que se pueden usar incluyen hidrocarburos aromáticos tales como benceno y tolueno; éteres tales como tetrahidrofurano, dioxano y éter dietílico; hidrocarburos halogenados tales como diclorometano y cloroformo; N,Ndimetilformamida; alcoholes tales como metanol y etanol; y mezclas de los mismos. Si es necesario, se puede añadir una base orgánica tal como trietilamina y piridina.
La reacción de condensación en (b) se puede llevar a cabo activando un compuesto representado por la fórmula (16) o (17), por ejemplo, con fosgeno, tiofosgeno, N,N-carbonildiimidazol o N,N’-tiocarbonildiimidazol, y después haciendo reaccionar el producto activado con el otro compuesto. La reacción se puede llevar a cabo normalmente de -20 a +50ºC durante de 0,5 a 48 horas. Los disolventes que se pueden usar incluyen hidrocarburos aromáticos tales como benceno y tolueno; éteres tales como tetrahidrofurano, dioxano y éter dietílico; hidrocarburos halogenados tales como diclorometano y cloroformo; N,N-dimetilformamida; y mezclas. Si es necesario, se puede añadir una base orgánica tal como trietilamina o piridina.
La reacción de condensación en (a) se puede llevar a cabo como la condensación en (b).
El grupo protector del compuesto representado por la fórmula (17) se puede eliminar en condiciones usadas en una reacción de formación de péptido habitual.
Una sal de un compuesto representado por la fórmula (1) se puede formar durante la preparación del compuesto, pero normalmente se forma tratando el compuesto con un ácido farmacéuticamente aceptable. Dicho ácido incluye ácidos inorgánicos tales como ácido clorhídrico, ácido bromhídrico, ácido sulfúrico y ácido fosfórico; y ácidos orgánicos tales como ácido acético, ácido tartárico, ácido fumárico, ácido maleico, ácido cítrico, ácido benzoico, ácido trifluoroacético y ácido p-toluenosulfónico.
Un compuesto representado por la fórmula (1) se puede purificar o aislar por un procedimiento de separación habitual tal como extracción, recristalización o cromatografía en columna.
El nuevo derivado de benzamida de esta invención tiene efecto inductor de diferenciación y por lo tanto es útil como un agente terapéutico y/o de mejora para una variedad de enfermedades tales como tumores malignos, enfermedades autoinmunes, enfermedades dermatológicas y parasitismo.
Como se usa en el presente documento, un “tumor maligno” incluye tumores malignos hematológicos tales como leucemia aguda, linfoma maligno, mieloma múltiple y macroglobulinemia, así como tumores sólidos tales como cáncer de colon, tumor cerebral, tumor de cabeza y cuello, carcinoma de mama, cáncer pulmonar, cáncer esofágico, cáncer gástrico, cáncer hepático, cáncer de la vesícula biliar, cáncer de los conductos biliares, cáncer pancreático, nesidioblastoma, carcinoma de células renales, cáncer corticosuprarrenal, carcinoma de vejiga urinaria, cáncer prostático, tumor testicular, carcinoma de ovario, cáncer uterino, carcinoma coriónico, cáncer de tiroides, tumor carcinoide maligno, cáncer de piel, melanoma maligno, sarcoma osteogénico, sarcoma de tejido blando, neuroblastoma, tumor de Wilms y retinoblastoma.
Una enfermedad autoinmune incluye reumatismo, diabetes, lupus eritematoso sistémico, linfadenopatía linfocítica autoimmune humana, linfoadenopatía inmunoblástica, enfermedad de Crohn y colitis ulcerativa.
Una enfermedad dermatológica incluye psoriasis, acné, eczema y dermatitis atópica.
El parasitismo incluye enfermedades tales como malaria.
Las indicaciones para el compuesto de esta invención no están limitadas a estos ejemplos específicos.
El principio activo de esta invención útil como fármaco se puede usar en forma de una composición farmacéutica general. La composición farmacéutica se puede preparar con diluyentes o excipientes usados generalmente tales como cargas, aditivos, aglutinantes, agentes humectantes, disgregantes, tensioactivos y lubricantes. La composición farmacéutica puede tener una variedad de formas de dosificación dependiendo de su propósito terapéutico; típicamente forma de comprimido, píldora, polvo, disolución, suspensión, emulsión, gránulo, cápsula, inyección (p. ej., disolución, suspensión) y supositorio.
Para preparar comprimidos, se puede usar una variedad de vehículos conocidos en la técnica. Dicho vehículo incluye excipientes tales como lactosa, glucosa, almidón, carbonato de calcio, caolín, celulosa cristalina y ácido silícico; aglutinantes tales como agua, etanol, propanol, jarabe simple, disolución de glucosa, disolución de almidón, disolución de gelatina, carboximetilcelulosa, goma de laca, metilcelulosa y polivinilpirrolidona; disgregantes tales como almidón seco, alginato sódico, agar en polvo, carmelosa cálcica, almidón y lactosa; retardantes de la disgregación tales como sacarosa, manteca de cacao y aceite hidrogenado; promotores de la absorción tales como base de amonio cuaternario y laurilsulfato sódico; agentes humectantes tales como glicerina y almidón; adsorbentes tales como almidón, lactosa, caolín, bentonita, ácido silícico coloidal; y deslizantes tales como talco, estearatos y polietilenglicol. Si es necesario, el comprimido se puede recubrir con un recubrimiento común; por ejemplo, comprimido recubierto con azúcar, comprimido recubierto con gelatina, comprimido recubierto entérico, comprimido recubierto con película, comprimido de doble capa y comprimido de múltiples capas.
imagen9
En la formación de píldoras, se puede usar una variedad de vehículos conocidos en la técnica. Dicho vehículo incluye excipientes tales como celulosa cristalina, lactosa, almidón, aceite vegetal hidrogenado, caolín y talco; aglutinantes tales como goma arábiga en polvo, goma de tragacanto en polvo y gelatina; disgregantes tales como carmelosa cálcica y agar.
La cápsula se puede preparar mezclando un principio activo con una variedad de los vehículos anteriores como es habitual y cargando la mezcla resultante, por ejemplo, en una cápsula de gelatina dura o blanda, o similar.
Para preparar una inyección, la disolución, emulsión y suspensión se estabilizan y preferiblemente se hacen isotónicas con la sangre. Se puede preparar usando diluyentes usados habitualmente en la técnica; por ejemplo, agua, etanol, macrogol, propilenglicol, alcohol isoestearílico etoxilado, alcohol polioxiestearílico y ésteres de ácido graso y sorbitán polioxietilénico. La preparación farmacéutica puede contener cloruro sódico necesario para preparar una disolución isotónica, glucosa o glicerina, así como solubilizantes, tampones y agentes emolientes habituales.
El supositorio se puede formar usando una variedad de vehículos conocidos; por ejemplo, glicérido semisintético, manteca de cacao, alcoholes superiores, ésteres de alcohol superior y polietilenglicol.
Además, la composición farmacéutica puede contener agentes colorantes, conservantes, perfumes, agentes de sabor, edulcorantes y/u otros fármacos.
La cantidad de principio activo en la composición farmacéutica de esta invención se puede seleccionar, según sea adecuado, de un amplio intervalo sin limitaciones, y en general es aproximadamente de 1 a 70% en peso en la composición, preferiblemente aproximadamente de 5 a 50% en peso.
La vía de administración de la composición farmacéutica no está limitada, y se selecciona dependiendo de la edad, sexo, gravedad de la enfermedad y otras afecciones del paciente. Por ejemplo, el comprimido, píldora, disolución, suspensión, emulsión, gránulos y cápsula, se pueden administrar por vía oral; la inyección se puede administrar por vía intravenosa sola o en combinación con un ingrediente fluido de infusión común tal como glucosa o aminoácidos, o si es necesario, por vía intramuscular, subcutánea o intraperitoneal como una sola preparación. El supositorio se puede administrar por vía intrarrectal.
La dosis de la preparación farmacéutica de esta invención se puede seleccionar, dependiendo de su forma de dosificación, edad, sexo y gravedad de la enfermedad del paciente y otras afecciones, según sea adecuado, pero la cantidad del principio activo puede ser en general aproximadamente de 0,0001 a 100 mg/kg al día. Se recomienda que una forma de dosificación unitaria contenga aproximadamente de 0,001 a 1000 mg del principio activo.
El compuesto representado por la fórmula (1) de esta invención o una sal del mismo, no presenta o presenta una toxicidad baja que es aceptable como agente anticancerígeno con la dosis que presenta los efectos farmacológicos.
Ejemplos
Esta invención se ilustrará específicamente, pero sin limitación, con los siguientes ejemplos, en los que los números entre paréntesis indican los de los compuestos mostrados en la descripción detallada anterior.
Procedimiento de ejemplo M1
Preparación de hidrocloruro de N-(2-aminofenil)-4-(N-benzoilaminometil)benzamida
[NOTA: este no es un compuesto de la presente invención pero es un procedimiento de preparación que se usa]
(M1-1) A una suspensión de 21,16 g de ácido 4-aminometilbenzoico (140 mmol) en 450 ml de diclorometano se añadieron 42 ml de trietilamina (300 mmol). Enfriando con hielo, se añadieron gota a gota 60,4 g de anhídrido trifluoroacético (287 mmol) en 50 ml de diclorometano, manteniendo la temperatura interior de 3 a 8ºC, y después la mezcla se agitó durante 3 horas. La mezcla de reacción se vertió en una disolución acuosa saturada de bicarbonato sódico, y se acidificó con ácido clorhídrico al 10%. El gel que precipitó se recogió por filtración y se secó para dar 30,4 g de ácido 4-(N- trifluoroacetilaminometil)benzoico (Rendimiento: 87,8%) en forma de un sólido opalescente.
imagen10
RMN lH (270 MHz, DMSO-d6)  ppm: 4,47 (2H, d, J=5,8 Hz), 7,39 (2H, d, J=8,1 Hz), 7,93 (2H, d, J=8,1 Hz), 10,08 (1H, t, J=5,8 Hz), 12,95 (1H, s ancho).
(M1-2) A una disolución de 108 g de o-fenilendiamina (1,0 mol) en 1000 ml de dioxano se añadieron 500 ml de hidróxido sódico acuoso 1 N, y después 218 g de dicarbonato de terc-butilo (1,1 mol) en 500 ml de dioxano enfriando con hielo. Después de agitar durante 6 horas a temperatura ambiente, la mezcla se dejó durante la noche. La mezcla se concentró a la 1/2 del volumen por evaporación y se extrajo con acetato de etilo. La capa orgánica se lavó con salmuera saturada, se secó y se evaporó. El residuo se purificó por cromatografía en columna (eluyente: cloroformo) para dar un sólido, el cual después se lavó con éter dietílico para dar 68,4 g de N-terc-butoxicarbonil-o-fenilendiamina (Rendimiento: 32,8%) en forma de un sólido blanco.
RMN lH (270 MHz, CDCl3)  ppm: 1,51 (9H, s), 3,75 (2H, s), 6,26 (1H, s), 6,77 (1H , d, J=8,1 Hz), 6,79 (1H, dd, J=7,3, 8,1 Hz), 7,00 (1H, dd, J=7,3, 8,1 Hz), 7,27 (1H, d, J=8,1 Hz).
(M1-3) A una suspensión de 30 g del compuesto del procedimiento (1-1) (121 mmol) en 200 ml de diclorometano se añadieron lentamente gota a gota 21 g de cloruro de oxalilo (165 mmol) añadiendo DMF de forma intermitente (0,1 ml por 2 ml de adición), manteniendo la temperatura interior de 10 a 15ºC enfriando con hielo. Tras completar la adición, la mezcla se agitó hasta que cesó la generación de burbujas, y después a 40ºC durante una hora adicional. Después de evaporación, el exceso de cloruro de oxalilo se separó formando el azeótropo con tolueno, y después el residuo se volvió a disolver en 100 ml de diclorometano. La disolución de cloruro de ácido preparada se añadió gota a gota a una disolución de 22,88 g del compuesto del procedimiento (1-2) (110 mmol) en 100 ml de diclorometano y 200 ml de piridina, manteniendo la temperatura interior de 7 a 9ºC enfriando con hielo.
Después de la adición, la mezcla se calentó a temperatura ambiente y se dejó durante la noche. Después de añadir disolución acuosa saturada de bicarbonato sódico a la mezcla de reacción, la mezcla resultante se extrajo con cloroformo y la capa orgánica se lavó con salmuera saturada, se secó y se evaporó. Al residuo se añadió metanol-éter diisopropílico, y el sólido precipitado se recogió por filtración y se secó para dar 28,1 g de N-[2-(N-tercbutoxiearbonil)aminofenil]-4-(N- trifluoroacetilaminometil)benzamida (Rendimiento: 58%) en forma de un sólido amarillo claro.
RMN 1H (270 MHz, DMSO-d6)  ppm: 1,44 (9H, s), 4,48 (2H, d, J= 5,9 Hz), 7,12-7,23 (2H, m), 7,44 (2H, d, J = 8,1 Hz), 7,54 (2H, d, J=8,1 Hz), 7,94 (2H, d, J=8,1 Hz), 8,68 (1H, s ancho), 9,83 (1H, s), 10,10 (1H, t ancho, J=5,9 Hz)
(M1-4) A una suspensión de 13,12 g del compuesto del procedimiento (1-3) (30 mmol) en 120 ml de metanol y 180 ml de agua, se añadieron 4,70 g de carbonato potásico (34,0 mmol), y la mezcla se calentó con agitación a 70ºC durante 4 h. Se extrajo con cloroformo, y la capa orgánica se lavó con salmuera saturada, se secó, se evaporó y se secó para dar 10,3 g de 4-aminometil-N-[2-(N-terc-butoxicarbonil)aminofenil]benzamida (Rendimiento: cuantitativo) en forma de un sólido amorfo amarillo claro.
RMN 1H (270 MHz, DMSO-d6)  ppm: 3,80 (2H, s), 7,13-7,23 (2H, m), 7,48-7,58 (4H, m), 7,90 (2H, d, J=8,1 Hz), 8,69 (1H, s ancho), 9,77 (1H, s ancho).
(M1-5) A una disolución de 0,11 g del compuesto del procedimiento (1-4) (0,44 mmol) en 5 ml de piridina se añadieron 0,08 g de cloruro de benzoilo (0,53 mmol), y la mezcla se calentó gradualmente a temperatura ambiente y después se agitó durante 8 horas. Se añadió disolución acuosa saturada de bicarbonato sódico, y después la mezcla se extrajo con acetato de etilo. La capa orgánica se lavó con salmuera saturada, se secó y se evaporó. El residuo se lavó con éter diisopropílico, y el sólido obtenido se secó para dar 0,14 g de N-[2-(N-terc- butoxicarbonil)aminofenil]-4-(Nbenzoilaminometil)-benzamida (Rendimiento: 71,4%) en forma de un sólido blanco.
RMN 1H (270 MHz, DMSO-d6)  ppm: 1,44 (9H, s), 4,56 (2H, d, J=5,9 Hz), 7,11-7,22 (2H, m), 7,46-7,56 (7H, m), 7,90-7,94 (4H, m), 8,67 (1H, s), 9,15 (1H, t, J=5,9 Hz), 9,81 (1H, s).
(M1-6) A una disolución de 0,10 g del compuesto del procedimiento (1-5) (0,224 mmol) en 5 ml de dioxano y 1 ml de metanol, se añadieron 5 ml de ácido clorhídrico-dioxano, y la mezcla se agitó a temperatura ambiente durante 7 horas. Se añadió al residuo después de evaporación éter diisopropílico y el sólido formado se recogió por filtración y se secó para dar 0,08 g de hidrocloruro de N-(2-aminofenil)-4-(benzoilaminometil)-benzamida (Rendimientos 93%) en forma de un sólido marrón claro.
P.f.: 206-209ºC
RMN 1H (270 MHz, DMSO-d6)  ppm: 4,57 (2H, d, J= 5,8 Hz), 7,27-7,38 (4H, m), 7,47-7,59 (5H, m), 7,92 (1H, d, J= 8,1 Hz), 8,05 (1H, d, J=8,1 Hz), 9,19 (1H, t, J=5,8 Hz), 10,38 (1H, s ancho).
IR (KBr, cm-1): 3286, 3003(ancho), 1630, 1551, 1492, 1306, 1250, 749, 695.
Los compuestos de los ejemplos 1 a 3 se prepararon en general como se ha descrito en el procedimiento de
imagen11
ejemplo M1. A continuación se describen sus puntos de fusión (p.f.), datos de RMN 1H y/o datos de IR. Ejemplo 1 N-(2-hidroxifenil)-4-[N-[3-(piridin-3-il)propionil]-aminometil]benzamida (Tabla 1: Compuesto 8)
P.f.: (amorfo)
RMN 1H (270 MHz, CD3OD)  ppm: 2,61 (2H, t, J=7,3 Hz), 3,00 (2H, t, J=7,3 Hz), 4,39 (2H, s), 7,04 (1H, ddd, J=1,5, 8,1, 8,1 Hz), 7,25 (2H, d, J=8,1 Hz), 7,33 (1H, dd, J=5,1, 8,1 Hz), 7,69 (1H, d, J=8,1 Hz), 7,85 (2H, d, J=8,1 Hz), 7,86 (1H, d, J=8,1 Hz), 8,41 (2H, s ancho).
IR (puro) cm-1: 3276, 1645, 1614, 1536, 1509, 1435, 1415, 1385, 1333, 1280, 1247, 1091, 737. Ejemplo 2 N-(2-hidroxifenil)-4-[N-(piridin-3-il)oxiacetilaminometil]benzamida (Tabla 1: Compuesto l)
P.f.: (amorfo) RMN 1H (270 MHz, DMSO-d6): 4,43 (2H, d, J=6,6 Hz), 4,69 (2H, s), 6,83 (1H, t, J=6,6 Hz), 6,91 (1H, d, J=8,1 Hz), 7,68 (1H, d, J=6,6 Hz), 7,82 (2H, d, J=8,1 Hz), 8,21 (1H, d, J=4,4 Hz), 8,35 (1H , d, J=2,2 Hz), 8,81 (1H, t, J=6,6 Hz), 9,48 (1H, s), 9,75 (1H, s).
IR (KBr) cm-1: 3399, 1664, 1535, 1236, 1064. Ejemplo 3 N-(2-hidroxifenil)-4-[N-(piridin-3-il)acetilaminometil]benzamida (Tabla 1: Compuesto 5)
P.f.: 201-202ºC
RMN 1H (270 MHz, DMSO-d6)  ppm: 3,56 (2H, s), 4,37 (2H, d, J=5,9 Hz), 6,83 (1H, ddd, J=1,5, 8,1, 8,1 Hz), 6,92 (1H , d ancho, J=8,1 Hz), 7,03 (1H, ddd, J=1,5, 8,1, 8,1 Hz), 7,34 (1H, dd, J=3,7 ,8,1 Hz), 7,37 (2H, d, J=8,1 Hz), 7,70 (2H, d, J=8,1 Hz), 7,91 (2H, d, J=8,1 Hz), 8,45 (1H, d ancho, J=3,7 Hz), 8,49 (1H, s), 8,73 (1H, t, J=5,9 Hz), 9,47 (1H, s), 9,73 (1H, s ancho).
IR (KBr) cm-1: 3272, 3067, 1661, 1647, 1598, 1536, 1455, 1334, 1288, 1194, 1024, 742. Procedimiento de ejemplo M2 Preparación de N-(2-aminofenil)-4-[N-(piridin-3-il)metoxicarbonilaminometil]benzamida
[NOTA: este no es un compuesto de la presente invención pero es un procedimiento de preparación que se usa]
(M2-1) A una disolución de 384 mg de 3- piridinametanol (3,52 mmol) en 5 ml de THF seco, se añadieron 523 mg de N,N'-carbonildiimidazol (3,22 mmol) a temperatura ambiente. Después de agitar durante una hora, se añadió a la mezcla 1,0 g del compuesto del procedimiento de ejemplo 1, el procedimiento (M1-4) (2,93 mmol) en 6 ml de THF seco.
La mezcla se dejó a temperatura ambiente durante la noche, se añadieron 100 ml de cloroformo, y la mezcla se lavó con agua (3 x 20 ml) y después salmuera saturada, y se secó sobre sulfato magnésico anhidro. Después de evaporar el disolvente a presión reducida, el residuo se purificó por cromatografía en columna en gel de sílice (eluyente: cloroformo:metanol = 30:1) para dar 1,27 g de N-[2-(N-terc-butoxicarbonil)aminofenil]-4-[N-(piridin-3- il)metoxicarbonilaminometil]benzamida (Rendimiento: cuantitativo) en forma de un sólido amorfo.
RMN 1H (270 MHz, CDCl3)  ppm: 1,51 (9H, s), 4,45 (2H, d, J=5,9 Hz), 5,16 (1H, s), 7,10-7,50 (7H, m), 7,70 (1H, d, J=8,1 Hz), 7,80 (1H, d, J=7,3 Hz), 7,93 (1H, d, J=8,1 Hz), 8,57 (1H, d, J= 4,4 Hz), 8,63 (1H, s), 9,17 (1H, s).
(M2-2) El compuesto del procedimiento (M2-1) (1,2 g, 2,8 mmol) se disolvió en 10 ml de metanol. A la disolución se añadieron 20 ml de ácido clorhídrico-dioxano 4 N. La mezcla se agitó a temperatura ambiente durante 1,5 h, y después se vertió en hidróxido sódico acuoso diluido y se extrajo con cloroformo (3 x 60 ml). Las capas orgánicas combinadas se lavaron dos veces con salmuera saturada, se secaron sobre sulfato magnésico anhidro y se concentraron para dar 0,88 g de cristales, los cuales después se recristalizaron en 16 ml etanol, para dar 668 mg de N(2-aminofenil)-4-[N-(piridin-3-il)metoxicarbonilaminometil]benzamida (Rendimiento: 73%).
P.f.: 159-160ºC
RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,28 (2H, d, J=5,9 Hz), 4,86 (2H, s), 5,10 (2H, s), 6,60 (1H, t, J=7,3 Hz),
imagen12
6,78 (1H, d, J=7 Hz), 6,97 (1H, t, J=7 Hz), 7,17 (1H, d, J=8 Hz), 7,30-7,50 (3H, m), 7,78 (1H, d, J=8 Hz), 7,93 (2H, d, J=8 Hz), 8,53 (1H, d, J=3,7 Hz), 8,59 (1H, s), 9,61 (1H, s). IR (KBr) cm-1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742 Los compuestos de los ejemplos 4 a 8 se prepararon como se describe en el procedimiento de ejemplo M2. Sus puntos de fusión (p.f.), datos de RMN 1H y/o IR, se muestran a continuación. Ejemplo 4 N-(2-hidroxifenil)-4-[N-(piridin-3-il)metil-N(piridin-3-il)metoxicarbonilaminometil]benzamida (Tabla 1; compuesto 3) P.f.: amorfo
RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,52 (2H, s), 4,57 (2H, s), 5,20 (2H, s), 6,84 (1H, t, J=6,6 Hz), 6,93 (1H d, J=6,6 Hz), 7,03 (1H, d, J=7,3 Hz), 7,37 (4H, m), 7,68 (2H, dd, J=1,5, 8,1 Hz), 7,92 (2H, s ancho), 8,53 (4H, m), 9,49 (1H, s), 9,77 (1H, s ancho).
IR (KBr) cm-1: 3035, 1698, 1243, 1118, 754, 640. Ejemplo 5 N-(2-hidroxifenil)-4-[N-(piridin-3-il)metoxi-carbonilaminometil]benzamida (Tabla 1; compuesto 2)
P.f.: 162-164ºC RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,29 (1H, d, J=5,9 Hz), 5,10 (2H, s), 6,83 (1H, t, J=8,1 Hz), 6,92 (1H, d, J=6,6 Hz), 7,07 (1H, t, J=6,6 Hz), 7,39 (2H, d, J=8,8 Hz), 7,43 (1H, d, J=5,1 Hz), 7,68 (2H, d, J=8,1 Hz), 7,80 (1H, d, J=8,1 Hz), 7,92 (2H, d, J=8,1 Hz), 7,99 (1H, t, J= 5,9 Hz), 8,54 (1H, d, J=4,4 Hz), 8,60 (1H, s), 9,49 (1H, s), 9,76 (1H, s ancho).
IR (KBr) cm-1: 3333, 3259, 1694, 1645, 1529, 1267, 720. Ejemplo 6 N-(2,4-dihidroxifenil)-4-[N-(piridin-3-il)metoxi-carbonilaminometil]benzamida (Tabla 1; compuesto 4)
P.f.: (amorfo) RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,27 (2H, d, J=6,6 Hz), 5,10 (2H, s), 6,20 (2H, dd, J=2,2, 8,1 Hz), 6,39 (2H, d, J=2,9 Hz), 6,88 (2H, d, J=8,8 Hz), 7,33 (1H, d, J=8,1 Hz), 7,41 (1H, dd, J=5,1, 7,1 Hz), 7,89 (1H, d, J=8,8 Hz), 7,98 (1H, t, J=6,6 Hz), 8,05 (2H, s), 8,52 (1H, m) , 8,59 (1H, s), 9,30 (2H, s ancho)
IR (KBr) cm-1: 3387, 1702, 1612, 1311, 1169, 845. Ejemplo 7 N-(2-hidroxi-5-metilfenil)-4-[N-(piridin-3-il)metoxicarbonilaminometil]benzamida (Tabla 1; compuesto 6)
P.f.: 155-155,5°C RMN 1H: (270 MHz, DMSO-d6)  ppm: 2,22 (3H, s), 4,29 (2H, d, J=5,8 Hz), 5,11 (2H, s), 6,82 (2H, m) , 7,39 (2H, d, J=8,8 Hz), 7,42 (2H , m), 7,51 (1H, s), 7,79 (1H, d, J=8,1 Hz), 7,92 (1H, d, J=8,1 Hz), 7,98 (1H, t, J=5,9 Hz), 8,54 (1H, d, J=4,4 Hz), 8,60 (1H, s), 9,48 (2H, d, J=8,1 Hz)
IR (KBr) cm-1: 3306, 1723, 1655, 1525, 801, 639. Ejemplo 8 N-(2-hidroxi-5-metoxifenil)-4-[N-(piridin-3-il)metoxicarbonilaminometil]benzamida (Tabla 1; compuesto 7)
P.f.: 175-176ºC RMN 1H: (270 MHz, DMSO-d6)  ppm: 3,69 (3H, s), 4,29 (2H, d, J=5,9 Hz), 5,10 (2H, s), 6,63 (1H, dd, J=2,9, 8,7 Hz), 6,84 (1H, d, J=8,8 Hz), 7,41 (4H, m), 7,79 (1H, d, J=8,1 Hz), 7,91 (1H, d, J= 8,1 Hz), 7,99 (1H, t, J=5,9 Hz), 8,54 (1H, d, J=5,1 Hz), 8,60 (1H, s), 9,31 (1H, s), 9,45(1H, s). IR (KBr) cm-1: 3305, 1687, 1573, 1262, 1039, 868.
imagen13
Ejemplo comparativo 1
N-(3-aminofenil)-4-[N-(piridin-3-il)metoxicarbonil-aminometil]benzamida
El compuesto del título se preparó por el procedimiento del procedimiento de ejemplo M2.
P.f.: 156ºC
RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,27 (2H, d, J=6,6 Hz), 5,06 (2H, s), 5,10 (2H, s), 6,20-6,40 (1H, m),
6,80-7,10 (3H, m), 7,30-7,50 (3H, m), 7,70-8,00 (4H, m), 8,53 (1H, d, J=3,6 Hz), 8,59 (1H, s), 9,88 (1H, s)
IR (KBr) cm-1: 3327, 3218, 1708, 1639, 1536, 1279, 1147, 1050, 859, 788. Ejemplo comparativo 2 N-(4-aminofenil)-4-[N-(piridin-3-il)metoxicarbonil-aminometil]benzamida
El compuesto del título se preparó por el procedimiento del procedimiento de ejemplo M2.
P.f.: 204-205ºC
RMN 1H: (270 MHz, DMSO-d6)  ppm: 4,27 (2H, d, J=6,6 Hz), 4,91 (2H, s), 5,10 (2H, s), 6,52 (2H, d, J=8,8 Hz),
7,30-7,50 (5H, m), 7,70-8,00 (4H, m), 8,50-8,60 (2H, m), 9,80 (1H, s)
IR (KBr) cm-1: 3336, 3224, 1706, 1638, 1530, 1279, 1145, 1050, 1005, 827. Ejemplo de ensayo farmacológico 1 Ensayo de inducción de la diferenciación en células A2780
Se sabe que el aumento de la actividad de la fosfatasa alcalina (ALP) es un indicador de la diferenciación de las células de cáncer de colon humano. Por ejemplo, se sabe que el butilato sódico puede aumentar la actividad de la ALP (Young y col., Cancer Res., 45, 2976 (1985); Morita y col., Cancer Res., 42, 4540 (1982)). Por lo tanto, la acción de inducción de la diferenciación se evaluó usando la actividad de la ALP como un indicador.
Procedimiento experimental
En cada pocillo de una placa de 96 pocillos se pusieron 0,1 ml de células A2780 (15.000 células/pocillo) y al día siguiente se añadieron 0,1 ml de una disolución de ensayo diluida secuencialmente con el medio. Después de incubar durante 3 días, las células de la placa se lavaron dos veces con un tampón de TBS (Tris 20 mM, NaCl 137 mM, pH 7,6). Después, se añadieron a cada pocillo 0,05 ml de disolución de fosfato de p-nitrofenilo 0,6 mg/ml (dietanolamina al 9,6%, MgCl2 0,5 mM (pH 9,6)) y la placa se incubó a temperatura ambiente durante 30 minutos. La reacción se inactivó con
0,05 ml/pocillo de hidróxido sódico acuoso 3 N. Se midió para cada pocillo la absorbancia a 405 nm para determinar la concentración mínima de fármaco que inducía aumento de la actividad de la ALP (ALPmin). Resultados
Los resultados se muestran en la tabla 2.
Tabla 2: Acción de inducción de la diferenciación en células A2780
imagen14
Compuesto de ensayo
ALPmin (M)
Ejemplo 1
10
Ejemplo 2
0,3
Ejemplo 3
10
Ejemplo 4
10
Ejemplo 5
1
Ejemplo 8
3
Ejemplo comparativo 1
>100
Ejemplo comparativo 2
>100
imagen15
5
10
15
20
25
30
35

Claims (6)

  1. REIVINDICACIONES
    1. Un compuesto representado por la fórmula (1):
    imagen1
    en la que A es un grupo heterocíclico, o un grupo heterocíclico que tiene de 1 a 4 sustituyentes, en el que el o los sustituyentes para el grupo heterocíclico se seleccionan del grupo constituido por un átomo de halógeno, un grupo hidroxilo, un grupo amino, un grupo nitro, un grupo ciano, un grupo alquilo que tiene de 1 a 4 carbonos, un grupo alcoxi que tiene de 1 a 4 carbonos, un grupo aminoalquilo que tiene de 1 a 4 carbonos, un grupo alquilamino que tiene de 1 a 4 carbonos, un grupo acilo que tiene de 1 a 4 carbonos, un grupo acilamino que tiene de 1 a 4 carbonos, un grupo alquiltio que tiene de 1 a 4 carbonos, un grupo perfluoroalquilo que tiene de 1 a 4 carbonos, un grupo perfluoroalquiloxi que tiene de 1 a 4 carbonos, un grupo carboxilo, un grupo alcoxicarbonilo que tiene de 1 a 4 carbonos, un grupo fenilo y un grupo heterocíclico;
    X es un resto que tiene una estructura seleccionada de:
    -(CH2)e- y -(CH2)g-O-(CH2)e-
    en las que e es un número entero de 1 a 4; y g un número entero de 0 a 4;
    Q es un resto que tiene la estructura
    imagen1
    en las que R7 es un átomo de hidrógeno o un grupo alquilo que tiene de 1 a 4 carbonos o un grupo alquilo que tiene de 1 a 4 carbonos que tiene de 1 a 4 sustituyentes seleccionados del grupo constituido por un halógeno, hidroxilo, amino, nitro, ciano, fenilo y un heterociclo;
    R2 es un átomo de hidrógeno, un grupo hidroxilo, un grupo alquilo que tiene de 1 a 4 carbonos, o un grupo alcoxi que tiene de 1 a 4 carbonos,
    o una sal del mismo farmacéuticamente aceptable.
  2. 2.
    Un compuesto o una sal del mismo farmacéuticamente aceptable según la reivindicación 1, en el que A es un grupo piridilo, o un grupo piridilo que tiene de 1 a 4 sustituyentes seleccionados del grupo constituido por un átomo de halógeno, un grupo hidroxilo, un grupo amino, un grupo nitro, un grupo ciano, un grupo alquilo que tiene de 1 a 4 carbonos, un grupo alcoxi que tiene de 1 a 4 carbonos, un grupo aminoalquilo que tiene de 1 a 4 carbonos, un grupo alquilamino que tiene de 1 a 4 carbonos, un grupo acilo que tiene de 1 a 4 carbonos, un grupo acilamino que tiene de 1 a 4 carbonos, un grupo alquiltio que tiene de 1 a 4 carbonos, un grupo perfluoroalquilo que tiene de 1 a 4 carbonos, un grupo perfluoroalquiloxi que tiene de 1 a 4 carbonos, un grupo carboxilo, un grupo alcoxicarbonilo que tiene de 1 a 4 carbonos, un grupo fenilo y un grupo heterocíclico.
  3. 3.
    Un compuesto o una sal del mismo farmacéuticamente aceptable según la reivindicación 1 o reivindicación 2, en el que R2 es un átomo de hidrógeno.
  4. 4.
    Una composición farmacéutica que comprende, como principio activo, uno o más compuestos o sales de los mismos farmacéuticamente aceptables, según una cualquiera de las reivindicaciones 1 a 3.
  5. 5.
    Un fármaco anticancerígeno que comprende, como principio activo, uno o más compuestos o sales de los mismos farmacéuticamente aceptables, según una cualquiera de las reivindicaciones 1 a 3.
  6. 6.
    Uso de un compuesto o una sal del mismo farmacéuticamente aceptable, representado por la fórmula (1) como se define en la reivindicación 1, en la fabricación de una composición para usar para tratar el cáncer, una enfermedad autoinmune, una enfermedad dermatológica o el parasitismo.
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