ES2733348T3 - Derivados de purina para uso en el tratamiento de enfermedades relacionadas con FAP - Google Patents
Derivados de purina para uso en el tratamiento de enfermedades relacionadas con FAP Download PDFInfo
- Publication number
- ES2733348T3 ES2733348T3 ES08787268T ES08787268T ES2733348T3 ES 2733348 T3 ES2733348 T3 ES 2733348T3 ES 08787268 T ES08787268 T ES 08787268T ES 08787268 T ES08787268 T ES 08787268T ES 2733348 T3 ES2733348 T3 ES 2733348T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- met
- xanthine
- amino
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract
Uso de un compuesto seleccionado de - 1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, - 1-[(3-metil-isoquinolin-1-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-5 il)-8-((S)-3-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-fenil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 2-((R)-3-amino-piperidin-1-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin- 4-ona, - 1-[([1,5]naftiridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, - 1-[(1H-perimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-etil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-cyclopropil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-fenil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-ciano-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(11H-dibenzo[b,e]azepin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina, - 1-[(fenantridin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(dibenzo[b,f][1,4]oxazepin-11-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4,5-dimetil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(2-amino-etil)-methilamino]-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-fenil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(3-metil-2-buten-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-bencil-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(piperazin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(homopiperazin-1-il)-xantina, - 1-[(3-ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(S)-(2-amino-propil)-methilamino]- - 1-[(quinoxalin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina, - 1-[(quinoxalin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, - 1-[(4-morfolino-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina, - 1-[(4-ciano-isoquinolin-3-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, - 1-[(4-metil-quinazolin-2-il)metil]-3-carboximetil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, y - 1-[(4,6-dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina, o un tautómero, enantiómero o sal terapéuticamente eficaz del mismo, para preparar una composición farmacéutica para el tratamiento de enfermedades que responden a la inhibición de FAP, seleccionadas entre hipertrofia cardíaca, cirrosis, fibromatosis, trastornos de la cicatrización de heridas y acné.
Description
DESCRIPCIÓN
Derivados de purina para uso en el tratamiento de enfermedades relacionadas con FAP
La presente invención se refiere al uso de un compuesto seleccionado de
1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(3-metil-isoquinolin-1-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((S)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1- [(4-fenil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
2- ((R)-3-amino-piperidin-1-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin-4-ona, 1-[([1.5]naftir îdin-2-il)metM]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(1H-perimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-etil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-cyclopropil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-fenil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-ciano-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(11H-dibenzo[b,e]azepin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(fenantridin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(dibenzo[b,f][1,4]oxazepin-11-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4,5-dimetil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(2-amino-etil)-methilamino]-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-fenil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(3-metil-2-buten-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-bencil-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(piperazin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(homopiperazin-1-il)-xantina,
1-[(3-ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(S)-(2-amino-propil)-methilamino]-xantina,
1-[(quinoxalin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(quinoxalin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-morfolino-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(4-ciano-isoquinolin-3-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-carboximetil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, y
1-[(4,6-dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
o un tautómero, enantiómero o sal terapéuticamente eficaz del mismo,
para la preparación de una composición farmacéutica para el tratamiento de enfermedades que responden a la inhi bición de FAP, seleccionadas entre hipertrofia cardíaca, cirrosis, fibromatosis, trastornos de la cicatrización de heridas
y acné.
La presente invención se refiere además a un compuesto seleccionado de:
1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(3-metil-isoquinolin-1-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((S)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1- [(4-fenil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
2- ((R)-3-amino-piperidin-1-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin-4-ona, 1-[([1,5]naftiridin-2-M)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(1H-perimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-etil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-cyclopropil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-fenil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-ciano-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(11H-dibenzo[b,e]azepin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(fenantridin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(dibenzo[b,f][1,4]oxazepin-11-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4,5-dimetil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(2-amino-etil)-methilamino]-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-fenil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(3-metil-2-buten-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-bencil-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(piperazin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(homopiperazin-1-il)-xantina,
1-[(3-ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(S)-(2-amino-propil)-methilamino]-xantina,
1-[(quinoxalin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(quinoxalin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-morfolino-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
1-[(4-ciano-isoquinolin-3-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
1-[(4-metil-quinazolin-2-il)metil]-3-carboximetil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina, y
1-[(4,6-dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
o un tautómero, enantiómero o sal terapéuticamente eficaz del mismo;
para uso en el tratamiento de hipertrofia cardíaca, cirrosis o fibromatosis, o trastornos de la cicatrización de heridas o acné.
Se hace referencia a las presentes reivindicaciones para realizaciones adicionales de la presente invención.
Esta memoria descriptiva describe el uso de sustancias con capacidades inhibitorias para el tratamiento de todo tipo de condiciones patológicas.
La proteína de activación de los fibroblastos (FAP), también conocida como seprasa, pertenece a la familia de las serina proteasas. La FAP, como la enzima DPP IV (dipeptidilpeptidasa IV), por ejemplo, pertenece a las enzimas que rompen un dipéptido a partir de una proteína o péptido existente con la fórmula general X-Pro-XAA. La FAP es una proteína transmembrana que consiste en 760 aminoácidos. La FAP exhibe una alta homología con DPP IV y también forma heterodímeros con esta proteína. A diferencia de la DPP IV, la expresión y actividad de FAP son muy limitadas. Así, la FAP no se expresa en tejidos de adulto normales. La FAP se induce en fibroblastos activados después de un traumatismo o daño al tejido. La FAP también se expresa en tejidos estromales tumorales de todo tipo de tumores epiteliales humanos y en células malignas de diversos sarcomas de tejido óseo y blando. Estos incluyen, inter alia, más del 90% de los carcinomas de mama, de pulmón de células no pequeñas y colorrectal. La FAP se encuentra preferiblemente en este caso en los fibroblastos que aparecen cerca de vasos sanguíneos de nueva formación o formados y forma un compartimento celular específico entre el endotelio capilar tumoral y las células epiteliales malignas reales y agrupaciones de células. Los fibroblastos FAP-positivos se encuentran tanto en carcinomas primarios como en carcinomas metastizantes. El perfil de expresión de FAP sugiere que la FAP desempeña una función en la invasión tumoral en el tejido sano y en la formación del tumor y la metástasis. Los inhibidores de FAP, es decir, las sustancias que son capaces de reducir o inhibir la actividad proteolítica de FAP, son agentes terapéuticos útiles para el tratamiento de todo tipo de enfermedades tumorales. Los inhibidores de FAP pueden usarse preferiblemente para tratar tumores de origen epitelial tales como tumores de mama, carcinomas de pulmón de células no pequeñas, carcinomas colorrectal y carcinomas de tejido blando. Los inhibidores de FAP también están indicados en todo tipo de tumores metastizantes tales como, por ejemplo, melanomas.
Además, los inhibidores de FAP también están indicados en otras enfermedades hiperproliferativas. Estas incluyen, inter alia, hipertrofia cardiaca, cirrosis y fibromatosis.
Además, los inhibidores de FAP pueden usarse tambi'én como valiosos agentes terapéuticos para tratar enfermedades de rango reumático tales como, por ejemplo, artritis u osteoartritis y trastornos neurotraumáticos.
Los inhibidores de FAP también están indicados en el tratamiento de trastornos de curación de heridas y acné y dolencias de la piel proliferativas tales como, por ejemplo, la psoriasis.
Además, los inhibidores de FAP están indicados en el tratamiento de dolores de todos los orígenes y migrañas.
Derivados de purina seleccionados de acuerdo con la presente invención pueden definirse por la fórmula (I),
fórmula (III)
en las que
R1 significa piridinilmetilo, pirimidinilmetilo, quinolinilmetilo, (2-oxo-1,2-dihidro-quinolinil)metilo, isoquinolinilmetilo, quinazolinilmetilo, (4-oxo-3,4-dihidro-quinazolinil)metilo, quinoxalinilmetilo, [1,5]naftiridinilmetilo, (1H-perimidinil)metilo, fenantridinilmetilo, (11H-dibenzo[b,e]azepinil)metilo, (dibenzo[b,f][1,4]oxazepinil)metilo, (5H-dibenzo[b,e][1,4]diazepinil)metilo o (imidazo[1,2-a]quinolinil)metilo y los grupos heterocíclicos de los grupos anteriormente mencionados pueden estar mono- o disustituidos por Ra, donde los sustituyentes pueden ser idénticos o diferentes y Ra significa flúor, cloro, bromo, ciano, metilo, etilo, propilo, isopropilo, ciclopropilo, fenilo, metoxi, etiloxi, amino, metilamino, dimetilamino, pirrolidino, piperidino, morfolino, piperazino o N-metilpiperazino,
R2 significa metilo, etilo, propilo, isopropilo, ciclopropilo o fenilo y el grupo metilo, etilo, propilo e isopropilo puede sustituirse por carboxi, metoxicarbonilo, etiloxicarbonilo, aminocarbonilo, metilaminocarbonilo, dimetilaminocarbonilo, pirrolidinocarbonilo, piperidinocarbonilo, morfolinocarbonilo, piperazinocarbonilo o N-metilpiperazinocarbonilo,
R3 significa 2-buten-1-ilo, 3-metil-2-buten-1-ilo, 2-butin-1-ilo, bencilo, fluorobencilo, clorobencilo, bromobencilo o cianobencilo y
R4 significa piperazino, homopiperazino, 3-(R)-amino-piperidin-1-ilo, 3-(S)-amino-piperidin-1-ilo, (2-amino-etil)-metilamino, (2-amino-2-metil-propil)-metilamino, ((R)-2-amino-propil)-metilamino o ((S)-2-amino-propil)-metilamino,
los tautómeros, enantiómeros y sales de los mismos y sus mezclas.
De los derivados de purina de las fórmulas (I) a (IV) aquellos con fórmulas (I) y (II) son particularmente preferidos.
Significados preferidos de R1 son piridin-2-ilmetilo, piridin-3-ilmetilo, piridin-4-ilmetilo, pirimidin-2-ilmetilo, pirimidin-4-ilmetilo, quinolin-2-ilmetilo, quinolin-3-ilmetilo, quinolin-4-ilmetilo, quinolin-5-ilmetilo, quinolin-6-ilmetilo, quinolin-7-ilmetilo, quinolin-8-ilmetilo, (2-oxo-1,2-dihidro-quinolin-6-il)metilo, isoquinolin-1-ilmetilo, isoquinolin-3-ilmetilo, isoquinolin-4-ilmetilo, isoquinolin-8-ilmetilo, quinazolin-2-ilmetilo, quinazolin-4-ilmetilo, quinazolin-6-ilmetilo, quinazolin-7-ilmetilo, (4-oxo-3,4-dihidro-quinazolin-2-il)metilo, quinoxalin-2-ilmetilo, quinoxalin-5-ilmetilo, quinoxalin-6-ilmetilo, [1,5]naftiridin-2-ilmetilo, [1,5]naftiridin-3-ilmetilo, [1,5]naftiridin-4-ilmetilo, (1H-perimidin-2-il)metilo, fenantridin-6-ilmetilo, (11H-dibenzo[b,e]azepin-6-il)metilo, (dibenzo[b,f][1,4]oxazepin-11-il)metilo, (5H-dibenzo[b,e][1,4]diazepin-11-il)metilo o (imidazo[1,2-a]quinolin-2-il)metilo, donde los grupos heterocíclicos de los grupos anteriormente mencionados pueden estar monosustituidos por ciano, etilo, ciclopropilo, fenilo o morfolino o mono- o disustituidos por metilo,
particularmente 3-ciano-piridin-2-ilmetilo, (4-fenil-pirimidin-2-il)metilo, (4,6-dimetil-pirimidin-2-il)metilo, 3-cianoquinolin-2-ilmetilo, 3-metil-isoquinolin-l-ilmetilo, 4-ciano-isoquinolin-3-ilmetilo, quinazolin-2-ilmetilo, (1-metil-2-oxo-1,2-dihidro-quinolin-6-il)metilo, (4-metil-quinazolin-2-il)metilo, (4,5-dimetil-quinazolin-2-il)metilo, (4-etil-quinazolin-2-il)metilo, (4-ciclopropil-quinazolin-2-il)metilo, (4-ciano-quinazolin-2-il)metilo, (4-morfolino-quinazolin-2-il)metilo, (4-fenilquinazolin-2-il)metilo, (4-oxo-3,4-dihidro-quinazolin-2-il)metilo, quinoxalin-2-ilmetilo, quinoxalin-6-ilmetilo, [1,5]naftiridin-2-ilmetilo, (1H-perimidin-2-il)metilo, fenantridin-6-ilmetilo, (11H-dibenzo[b,e]azepin-6-il)metilo, (dibenzo[b,f][1,4]-oxazepin-11-il)metilo, (5-metil-5H-dibenzo[b,e][1,4]diazepin-11-il)metilo o (imidazo[1,2-a]quinolin-2-il)metilo.
Significados preferidos de R2 son metilo, carboximetilo, metoxicarbonilmetilo, etiloxicarbonilmetilo, ciclopropilo y fenilo,
particularmente metilo, carboximetilo y fenilo.
Significados preferidos de R3 son 2-buten-1-ilo, 3-metil-2-buten-1-ilo, 2-butin-1-ilo, bencilo, 2-clorobencilo, 2-bromobencilo o 2-cianobencilo,
particularmente 3-metil-2-buten-1-ilo, 2-butin-1-ilo o bencilo.
Significados preferidos de R4 son piperazino, homopiperazino, 3-(R)-amino-piperidin-1-ilo, 3-(S)-amino-piperidin-1-ilo, (2-amino-etil)-metilamino, ((R)-2-amino-propil)-metilamino o ((S)-2-amino-propil)-metilamino.
Los derivados de purina de las fórmulas generales (I) a (IV) pueden prepararse usando métodos conocidos de la bibliografía. Los derivados de purina de fórmula general (I) pueden prepararse, por ejemplo, como se describe en los documentos internacionales WO 2002/068420, WO 2004/018468, WO 2004/041820, WO 2005/051950, WO 2005/082906, WO 2005/085246, WO 2006/027204 y WO 2006/029769.
Los derivados de purina de fórmula general (II) pueden prepararse, por ejemplo, como se describe en los documentos internacionales WO 2004/050658, WO 2004/111051, WO 2005/058901, WO 2005/097798 y WO 2005/110999.
Los derivados de purina de fórmulas generales (III) y (IV) pueden prepararse, por ejemplo, como se describe en los documentos internacionales WO 2006/068163 y w O 2007/071738.
Son particularmente preferidos los derivados de purina de los siguientes compuestos, sus tautómeros, enantiómeros y sales terapéuticamente eficaces:
• 1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina (véase el documento internacional w O 2004/018468, Ejemplo 2(80)):
• 1-[(3-metil-isoquinolin-1-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina (cfr. el documento internacional WO 2004/018468, Ejemplo 2(130)):
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((S)-3-amino-piperidin-1-il)-xantina (cfr. el documento internacional WO 2004/018468, Ejemplo 2(141)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/018468, Ejemplo 2(142)):
-[(4-fen¡l-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/018468, Ejemplo 2(217)):
-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-3-(but-2-¡n¡l)-5-(4-met¡l-qu¡nazol¡n-2-ilmet¡l)-3,5-d¡h¡dro-¡m¡dazo[4,5-d]p¡r¡daz¡n-4-ona (véase el documento internacional WO 2004/050658, Ejemplo 136)):
-[([1,5]naft¡rid¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡perid¡n-1-il)-xant¡na (véase el documento internacional WO 2004/018468, Ejemplo 2(252)):
-[(1H-perim¡d¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/041820, Ejemplo 1(29)):
-[(4-et¡l-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/085246, Ejemplo 1(22)):
-[(4-c¡doprop¡l-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/085246, Ejemplo 1(23)):
-[(4-fen¡l-p¡rim¡d¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/085246, Ejemplo 1(31)):
-[(4-c¡ano-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡perid¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/085246, Ejemplo 1(37)):
-[(11H-d¡benzo[b,e]azep¡n-6-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/041820, Ejemplo 1(5)):
-[(fenantnd¡n-6-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/041820, Ejemplo 1(33)):
-[(d¡benzo[b,f][1,4]oxazep¡n-11-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-il)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/041820, Ejemplo 1(8)):
-[(5-metil-5H-dibenzo[b,e][1,4]diazepin-11-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina (véase el documento internacional WO 2004/041820, Ejemplo 1(12)):
-[(4,5-d¡met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional Wo 2005/085246, Ejemplo 1(28)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)metil]-3-met¡l-7-(2-but¡n-1-¡l)-8-[(2-am¡no-et¡l)-met¡lam¡no]-xant¡na (véase el documento internacional WO 2006/029769, Ejemplo 1(1)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-fenil-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/082906, Ejemplo 1(8)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(3-met¡l-2-buten-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento ¡nternadonal WO 2004/018468, análogamente al Ejemplo 2(20)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-bendl-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/018468, análogamente al Ejemplo 2(294)):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(p¡peraz¡n-1-¡l)-xant¡na (véase. el documento ¡nternac¡onal WO 2005/051950, Ejemplo 1):
-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(homop¡peraz¡n-1-¡l)-xant¡na (véase el documento ¡nternadonal WO 2005/051950, Ejemplo 1(3)):
1-[(3-dano-qu¡nol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional WO 2005/085246, Ejemplo 1(30)):
1-[(4-met¡l-qu¡nazol¡n-2-¡l)metil]-3-met¡l-7-(2-but¡n-1-¡l)-8-[(S)-(2-am¡no-prop¡l)-met¡lam¡no]-xant¡na (véase el documento ¡nternadonal WO 2006/029769, Ejemplo 2(4)):
1-[(¡m¡dazo[1,2-a]qu¡nol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na (véase el documento ¡nternadonal WO 2004/041820, Ejemplo 1(32)):
-[(quinoxalin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina (véase el documento internacional WO 2004/018468, Ejemplo 2(169)):
-[(qu¡noxal¡n-6-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional w O 2005/085246, Ejemplo 1(83)):
-[(4-morfol¡no-qu¡nazol¡n-2-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na (véase el documento internacional WO 2004/018468, Ejemplo 2(l80)):
-[(1-met¡l-2-oxo-1,2-d¡h¡dro-qu¡nol¡n-6-¡l)met¡l]-3-metil-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na (véase el documento internacional w O 2004/018468, Ejemplo 2(227)):
• 1-[(4-dano-¡soqu¡nol¡n-3-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento internacional W o 2005/085246, Ejemplo 1(88)):
1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-carbox¡met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento ¡nternac¡onal WO 2006/027204, Ejemplo 2):
1-[(4,6-d¡met¡l-p¡r¡m¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na (véase el documento ¡nternac¡onal WO 2005/085246, Ejemplo 1(82)):
1-[(3-dano-p¡nd¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na (véase el documento ¡nternadonal WO 2005/085246, Ejemplo 1(52)):
Las prop¡edades b¡ológ¡cas de los compuestos se ¡nvest¡gan como s¡gue:
Ensayo de FAP:
La fuente de FAP usada es una preparadón homogen¡zada de células CD8huFAP y esto se d¡luye con tampón en una relac¡ón 1:100. El sustrato usado para la reacc¡ón es H-Ala-Pro_7-am¡do-4-tr¡fluoromet¡lcoumar¡no (AlaPro-AFC) fabr¡cado por Bachem (Prod. No I-1680).
Las sustancias de ensayo se diluyen en DMSO (dimetilsulfóxido) y tampón y se pipetean en una placa de 96 pocilios.
70 uL de la enzima y 20 uL del sustrato se añaden a esto. La placa se incuba durante una hora a temperatura ambiente, luego se mide la fluorescencia usando un contador Victor 1420 Multilabel de Wallac a una longitud de onda de excitación de 405 nm y una longitud de onda de emisión de 535 nm.
Los resultados se calcularon comparando la fluorescencia en presencia de la sustancia de ensayo con la fluorescencia del control. La fluorescencia basal se deduce.
Los compuestos de acuerdo con la invención tienen una inhibición de FAP de >50% a una concentración de 100 j M, por ejemplo. Preferiblemente, los compuestos de acuerdo con la invención tienen una inhibición de FAP de >50% a una concentración de 3 j M.
Para uso farmacéutico, los compuestos de acuerdo con la invención se usan habitualmente para vertebrados de san gre caliente, particularmente seres humanos, en dosis de 0,001-100 mg/kg de peso corporal, preferiblemente 0,1-15 mg/kg, de 1a 4 veces al día. Con este fin, los compuestos, opcionalmente combinados con otras sustancias activas, se formulan con uno o más vehículos y/o diluyentes inertes convencionales, por ejemplo con almidón de maíz, lactosa, glucosa, celulosa microcristalina, estearato de magnesio, polivinilpirrolidona, ácido cítrico, ácido tartárico, agua, agua/etanol, agua/glicerol, agua/sorbitol, agua/polietilenglicol, propilenglicol, alcohol cetilestearílico, carboximetilcelulosa o sustancias grasas tales como grasa dura o mezclas adecuadas de los mismos para formar preparaciones ga lénicas convencionales tales como comprimidos sencillos o recubiertos, cápsulas, polvos, suspensiones o suposito rios.
La preparación farmacéutica se diseña de acuerdo con el método de administración deseado (oral, intravenosa, parenteral, etc), siendo la formulación preferida una preparación oral.
Las composiciones farmacéuticas de acuerdo con la invención que contienen los derivados de purina anteriormente mencionados son así preparados por el experto en la técnica usando excipientes de formulación permitidos mediante métodos como los descritos en la técnica anterior. Ejemplos de tales excipientes son diluyentes, aglomerantes, vehículos, cargas, lubricantes, agentes de flujo, retardantes de la cristalización, desintegrantes, solubilizantes, agentes colorantes, reguladores del pH, tensioactivos y emulsificantes.
Ejemplos de diluyentes adecuados incluyen polvo de celulosa, hidrogenofosfato de calcio, eritritol, hidroxipropilcelulosa (bajo-sustituida), mannitol, almidón pregelatinizado o xilitol.
Ejemplos de aglomerantes adecuados incluyen copolímeros de vinilpirrolidona con otros derivados de vinilo (copovidona), hidroxipropilmetilcelulosa (HPMC), hidroxipropilcelulosa (HPC) polivinilpirrolidona (povidona), almidón pregelatinizado o hidroxipropilcelulosa bajo-sustituida.
Ejemplos de lubricantes adecuados incluyen talco, polietilenglicol, behenato de calcio, estearato de calcio, aceite de ricino hidrogenado o estearato de magnesio.
Ejemplos de desintegrantes adecuados incluyen almidón de maíz o crospovidona.
Métodos adecuados para preparar formulaciones farmacéuticas de los inhibidores de DPP IV de acuerdo con la invención son:
• la formación directa de comprimidos de la sustancia activa en mezclas en polvo con excipientes de formación de comprimido adecuados;
• la granulación con excipientes adecuados y posterior mezclado con excipientes adecuados y posterior formación de comprimidos así como recubrimiento con película; o
• el envasado de mezclas en polvo o gránulos en cápsulas.
Son métodos de granulación adecuados:
• la granulación en húmedo en mezclador intensivo, seguido de secado en lecho fluidificado;
• la granulación en un recipiente;
• la granulación en lecho fluidificado; o
• la granulación en seco (por ejemplo, mediante compactación por rodillos) con excipientes adecuados y posterior formación de comprimidos o envasado en cápsulas.
Ya que a menudo aparecen simultáneamente diferentes trastornos funcionales, no es infrecuentemente aconsejable combinar una serie de principios activos diferentes entre sí. Así, dependiendo de los trastornos funcionales diagnosticados, pueden obtenerse mejores resultados de tratamiento si se combina un inhibidor de FAP con una sustancia activa (permitida) usada generalmente para la dolencia en cuestión, por ejemplo con una sustancia activa
que tenga propiedades anti-hiperproliferativas o con una sustancia activa que pueda usarse para el tratamiento de enfermedades hiperproliferativas (por ejemplo, cánceres).
Dicho tratamiento combinado puede administrarse en forma de una combinación sin las sustancias activas o en forma de una combinación fija, por ejemplo en un comprimido o cápsula. Formulaciones farmacéuticas del asociado de combinación necesarias para esto pueden obtenerse en el mercado en forma de composiciones farmacéuticas o pueden formularse por el experto en la técnica usando métodos convencionales. Las sustancias activas que pueden obtenerse en el mercado en forma de composiciones farmacéuticas se describen en numerosos lugares en la técnica anterior, por ejemplo en la lista de fármacos que aparece anualmente, la "Rote Liste ®" de la Asociación Federal de la Industria Farmacéutica, o en la recopilación actualizada anualmente de información de fabricantes sobre fármacos con receta conocida como "Physicians' Desk Reference".
El tratamiento anti-cáncer definido en este documento puede usarse como una terapia única o puede comprender, además del compuesto de acuerdo con la invención, cirugía convencional, radioterapia o quimioterapia. Dicha quimioterapia puede comprender una o varias de las siguientes categorías de agentes antitumorales quimioterapéuticos y/o de reconocimiento:
Las siguientes categorías y algunos representantes típicos de éstas pueden mencionarse como ejemplos de agentes antitumorales quimioterapéuticos conocidos:
(i) sustancias activas alquilantes/carbamilantes tales como ciclofosfamida (Endoxan), lfosfamida (Holoxan), tiotepa, melfalan (Alkeran) o cloroetilnitrosourea (CENU); (ii) derivados de platino tales como cisplatin (Platinex), oxaliplatin, satraplatin o carboplatin (Carboplat); (iii) sustancias activas antimitóticas / inhibidores de tubulina tales como alcaloides de la vinca (Vincristin, Vinblastin, Vinorelbin), taxanos tales como paclitaxel (Taxol), docetaxel (Taxotere) o sus análogos y conjugados, epotilonas tales como epotilona B (Patupilona), azaepotilona (Ixabepilona) o ZK-EPO; (iv) inhibidores de topoisomerasa tales como antraciclina (por ejemplo doxorubicin / Adriblastin), epipodofilotoxinas (por ejemplo, etoposid / Etopofos) y camptotecina y análogos de camptotecina (por ejemplo, lrinotecan / Camptosar o Topotecan / Hicamtin); (v) antagonistas de pirimidina tales como 5-fluorouracilo (5-FU), capecitabina (Xeloda), arabinosilcitosina / citarabina (Alexan) o gemcitabina (Gemzar); (vi) antagonistas de purina tales como 6-mercaptopurina (Puri-Nethol), 6-tioguanina o fludarabina (Fludara) y (vii) antagonistas del ácido fólico tales como el metotrexato (Farmitrexat) o premetrexed (Alimta).
Las siguientes categorías y algunos representantes típicos de éstas pueden mencionarse como ejemplos de agentes antitumorales de reconocimiento usados en terapia experimental o cáncer estándar:
(i) inhibidores de quinasa (por ejemplo, Abl, EGFR, VEGFR, PDGFR, etc.) tales como imatinib (Glivec), ZD-1839 / fefitinib (Iressa), Bay43-9006 (Sorafenib, Nexavar), SU11248 / sunitinib (Sutent) o OSI-774 / erlotinib (Tarceva), dasatinib (Sprycel), lLapatinib (Tykerb), o vatalanib, vandetanib (Zactima) o pazopanib; (ii) inhibidores de proteasoma tales como PS-341 / bortezumib (Velcade); (iii) inhibidores de proteína de choque térmico 90 tales como 17-alilaminogeldanamicina (17-AAG); (iv) agentes de reconocimiento vascular (VTA) tales como combretastin A4 Phosphat o AVE8062 / AC7700, así como sustancias activas anti-angiogénicas tales como anticuerpos de VEGF tales como bevacizumab (Avastin), inhibidores de angioquinasa o inhibidores de KDR tirosinaquinasa tales como PTK787 / ZK222584 (Vatalanib) o vandetanib (Zactima) o pazopanib; (v) anticuerpos monoclonales tales como trastuzumab (Herceptin), rituximab (MabThera / Rituxan), alemtuzumab (Campath), tositumomab (Bexxar), C225 / cetuximab (Erbitux), avastin o panitumumab, mutantes y conjugados de anticuerpos monoclonales tales como gemtuzumab ozogamicin (Milotarg) o ibritumomab tiuxetan (Zevalin), así como fragmentos de anticuerpos; (vi) sustancias activas basadas en oligonucleótidos tales como G-3139 / oblimersen (Genasense); (vii) receptores del tipo Toll / agonistas de TLR 9 tales como ProMune, agonistas de TLR 7 tales como imiquimod (Aldara) o isatoribina así como sus análogos, o agonistas de TLR 7/8 tales como resiquimod, así como ARN inmunoestimuladores como agonistas de TLR 7/8; (viii) inhibidores de proteasa (ix) sustancias activas hormonales tales como anti-estrógenos (tales como tamoxifen o raloxifen), anti-andrógenos (tales como flutamida o casodex), análogos de LHRH (tales como leuprolida, goserelin o triptorelin) así como inhibidores de aromatasa.
Las siguientes sustancias activas pueden nombrarse como ejemplos de otros agentes antitumorales de reconocimiento que pueden ser útiles en la terapia del cáncer: bleomicin, retinoides tales como ácido retinoico todotrans (ATRA), inhibidores de ADN metiltransferasa tales como decitabina (Docagen) o 5-azacitidina, alanosina, citoquinas tales como interleuquina-2, interferones tales como interferón-alfa2 o interferón-gamma, agonistas del receptor de muerte tales como TRAIL, anticuerpos agonísticos de DR4/5, agonistas de FasL y TNF-R (por ejemplo, agonistas del receptor de TRAIL tales como mapatumumab o lexatumumab), así como inhibidores de HDAC tales como SAHA.
Claims (11)
1. Uso de un compuesto seleccionado de
• 1-[(qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(3-met¡l-¡soqu¡nol¡n-1-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((S)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-fen¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 2-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-3-(but-2-¡n¡l)-5-(4-met¡l-qu¡nazol¡n-2-¡lmet¡l)-3,5-d¡h¡dro-¡m¡dazo[4,5-d]p¡r¡daz¡n-4-ona,
• 1-[([1,5]naft¡r¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(1H-per¡m¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-et¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-cydoprop¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-fen¡l-p¡r¡m¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-dano-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(11H-d¡benzo[b,e]azep¡n-6-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(fenantr¡d¡n-6-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(d¡benzo[b,f][1,4]oxazep¡n-11-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na, • 1-[(4,5-d¡met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-[(2-am¡no-et¡l)-meth¡lam¡no]-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-fen¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(3-met¡l-2-buten-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-bendl-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(p¡peraz¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(homop¡peraz¡n-1-¡l)-xant¡na,
• 1-[(3-dano-qu¡nol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-[(S)-(2-am¡no-prop¡l)-meth¡lam¡no]-xant¡na,
• 1-[(qu¡noxal¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(qu¡noxal¡n-6-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-morfol¡no-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-dano-¡soqu¡nol¡n-3-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-carbox¡met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡per¡d¡n-1-¡l)-xant¡na, y • 1-[(4,6-d¡met¡l-p¡r¡m¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
o un tautómero, enant¡ómero o sal terapéut¡camente ef¡caz del m¡smo,
para preparar una compos¡c¡ón farmacéut¡ca para el tratam¡ento de enfermedades que responden a la ¡nh¡b¡c¡ón de FAP, selecc¡onadas entre h¡pertrof¡a cardíaca, c¡rros¡s, f¡bromatos¡s, trastornos de la c¡catr¡zac¡ón de her¡das y acné.
2. El uso de acuerdo con la reivindicación 1, en el que la composición farmacéutica es para el tratamiento de una enfermedad hiperproliferativa que responde a la inhibición de FAP, seleccionada de hipertrofia cardíaca, cirrosis y fibromatosis.
3. El uso de acuerdo con la reivindicación 2, en el que la composición farmacéutica es para el tratamiento de la hiper trofia cardíaca.
4. El uso de acuerdo con la reivindicación 2, en el que la composición farmacéutica es para el tratamiento de cirrosis.
5. El uso de acuerdo con la reivindicación 2, en el que la composición farmacéutica es para el tratamiento de fibromatosis.
6. El uso de acuerdo con la reivindicación 1, en el que la composición farmacéutica es para el tratamiento de enfer medades que responden a la inhibición de FAP, seleccionadas de trastornos de cicatrización de heridas y acné.
7. El uso de acuerdo con la reivindicación 6, en el que la composición farmacéutica es para el tratamiento de un trastorno de cicatrización de heridas.
8. El uso de acuerdo con la reivindicación 6, en el que la composición farmacéutica es para el tratamiento del acné.
9. Un compuesto seleccionado de:
• 1-[(quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
• 1-[(3-metil-isoquinolin-1-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((S)-3-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-fenil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 2-((R)-3-amino-piperidin-1-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin-4-ona,
• H([1,5]naftiridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina,
• 1-[(1H-perimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-etil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-cyclopropil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-fenil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-ciano-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(11H-dibenzo[b,e]azepin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
• 1-[(fenantridin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(dibenzo[b,f][1,4]oxazepin-11-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4,5-dimetil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(2-amino-etil)-methilamino]-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-fenil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(3-metil-2-buten-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-bencil-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(piperazin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(homopiperazin-1-il)-xantina,
• 1-[(3-ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-1-il)-xantina,
• 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-[(S)-(2-amino-propil)-methilamino]-xantina,
• 1-[(quinoxalin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-amino-piperidin-1-il)-xantina,
• 1-[(qu¡noxal¡n-6-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na,
• 1-[(4-morfol¡no-qu¡nazol¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-(3-am¡no-p¡per¡d¡n-1-¡l)-xant¡na,
• 1-[(4-c¡ano-¡soqu¡nol¡n-3-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na,
• 1-[(4-met¡l-qu¡nazol¡n-2-¡l)met¡l]-3-carbox¡met¡l-7-(2-but¡n-1-¡l)-8-(3-(R)-am¡no-p¡pend¡n-1-¡l)-xant¡na, y • 1-[(4,6-d¡met¡l-p¡nm¡d¡n-2-¡l)met¡l]-3-met¡l-7-(2-but¡n-1-¡l)-8-((R)-3-am¡no-p¡pend¡n-1-¡l)-xant¡na,
o un tautómero, enant¡ómero o sal terapéut¡camente ef¡caz del m¡smo,
para uso en el tratam¡ento de h¡pertrof¡a cardíaca, c¡rros¡s, f¡bromatos¡s, trastornos de la c¡catr¡zac¡ón de her¡das y acné.
10. Un compuesto para uso según la re¡v¡nd¡cac¡ón 9, para uso en el tratam¡ento de h¡pertrof¡a cardíaca, c¡rros¡s o f¡bromatos¡s.
11. Un compuesto para uso según la re¡v¡nd¡cac¡ón 9, para uso en el tratam¡ento de un trastorno de c¡catr¡zac¡ón de her¡das o acné.
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EP07114494 | 2007-08-17 | ||
PCT/EP2008/060740 WO2009024542A2 (en) | 2007-08-17 | 2008-08-15 | Purin derivatives for use in the treatment of fab-related diseases |
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US (2) | US20110112069A1 (es) |
EP (2) | EP2190434B1 (es) |
JP (1) | JP5769966B2 (es) |
KR (1) | KR101610005B1 (es) |
CN (1) | CN101784278A (es) |
AU (1) | AU2008290582B2 (es) |
BR (1) | BRPI0815405A2 (es) |
CA (1) | CA2696579C (es) |
ES (1) | ES2733348T3 (es) |
MX (1) | MX2010001821A (es) |
NZ (1) | NZ600126A (es) |
RU (1) | RU2569749C2 (es) |
WO (1) | WO2009024542A2 (es) |
ZA (1) | ZA201000075B (es) |
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-
2008
- 2008-08-15 EP EP08787268.5A patent/EP2190434B1/en not_active Revoked
- 2008-08-15 KR KR1020107003508A patent/KR101610005B1/ko active IP Right Grant
- 2008-08-15 CA CA2696579A patent/CA2696579C/en active Active
- 2008-08-15 NZ NZ600126A patent/NZ600126A/en unknown
- 2008-08-15 US US12/673,176 patent/US20110112069A1/en not_active Abandoned
- 2008-08-15 BR BRPI0815405-8A2A patent/BRPI0815405A2/pt not_active Application Discontinuation
- 2008-08-15 RU RU2010109545/15A patent/RU2569749C2/ru active
- 2008-08-15 MX MX2010001821A patent/MX2010001821A/es active IP Right Grant
- 2008-08-15 WO PCT/EP2008/060740 patent/WO2009024542A2/en active Application Filing
- 2008-08-15 JP JP2010521404A patent/JP5769966B2/ja active Active
- 2008-08-15 EP EP19169300.1A patent/EP3542801A1/en not_active Withdrawn
- 2008-08-15 AU AU2008290582A patent/AU2008290582B2/en active Active
- 2008-08-15 ES ES08787268T patent/ES2733348T3/es active Active
- 2008-08-15 CN CN200880103199A patent/CN101784278A/zh active Pending
-
2010
- 2010-01-05 ZA ZA201000075A patent/ZA201000075B/xx unknown
-
2016
- 2016-01-20 US US15/001,301 patent/US20160136180A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JP5769966B2 (ja) | 2015-08-26 |
MX2010001821A (es) | 2010-03-10 |
EP2190434A2 (en) | 2010-06-02 |
US20160136180A1 (en) | 2016-05-19 |
AU2008290582B2 (en) | 2014-08-14 |
RU2569749C2 (ru) | 2015-11-27 |
RU2010109545A (ru) | 2011-09-27 |
CA2696579A1 (en) | 2009-02-26 |
ZA201000075B (en) | 2010-09-29 |
WO2009024542A3 (en) | 2009-05-22 |
NZ600126A (en) | 2013-12-20 |
AU2008290582A1 (en) | 2009-02-26 |
BRPI0815405A2 (pt) | 2015-02-03 |
CN101784278A (zh) | 2010-07-21 |
US20110112069A1 (en) | 2011-05-12 |
EP3542801A1 (en) | 2019-09-25 |
KR101610005B1 (ko) | 2016-04-08 |
EP2190434B1 (en) | 2019-04-17 |
CA2696579C (en) | 2017-01-24 |
JP2010536820A (ja) | 2010-12-02 |
WO2009024542A2 (en) | 2009-02-26 |
KR20100055423A (ko) | 2010-05-26 |
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