ES2535166T3 - Pirimidinil-aminas sustituidas como inhibidores de proteína-quinasas - Google Patents
Pirimidinil-aminas sustituidas como inhibidores de proteína-quinasas Download PDFInfo
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- ES2535166T3 ES2535166T3 ES08829943.3T ES08829943T ES2535166T3 ES 2535166 T3 ES2535166 T3 ES 2535166T3 ES 08829943 T ES08829943 T ES 08829943T ES 2535166 T3 ES2535166 T3 ES 2535166T3
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Un compuesto o sal farmacéuticamente aceptable del mismo de fórmula Ib:**Fórmula** donde: Z1 y Z2 son cada uno CH; R1 es anillo heterocíclico de 4-10 miembros que tiene entre 1 y 4 miembros del anillo heteroatómicos seleccionados entre O, S(O)q, y N, donde el anillo heterocíclico está sustituido con 0-2 R5; R2, cuando está presente, es en forma independiente Cl, F, Br, I, CF3, OCF3, C1-4alquilo, C2-4alquenilo, C2-4-alquinilo, NO2, -CN, ORa, N(Ra)2, CORa, CO2Ra; R3 es H, CH3, CH2CH3, ciano, Cl, F, Br, o I; R4 es un anillo fenilo sustituido con 1-2 grupos R4a; cada R4a es en forma independiente >=O, Cl, F, Br, I, CF3, OCF3, C1-6alquilo sustituido con 0-3 R5, C2-6alquenilo sustituido con 0-3 R5, C2-6alquinilo sustituido con 0-3 R5, (CH2)pNO2, (CH2)pCN, (CH2)pOR, (CH2)pN(R)2, (CH2)pCOR, (CH2)pOCOR, (CH2)pCO2R, (CH2)pCON(R)2, (CH2)pOCON(R)2, (CH2)pNRCOR, (CH2)pNRCO2R, (CH2)pNRCON(R)2, (CH2)pC(>=NH)NH2, (CH2)pSO2R, (CH2)pSO2N(R)2, (CH2)pNRSO2R, (CH2)pNRSO2N(R)2, CH(CF3)NH2, o (CH2)p-(anillo heterocíclico de 5-6 miembros que tiene entre 1 y 4 miembros del anillo heteroatómicos seleccionados entre O, S(O)q, y N), donde el anillo heterocíclico está sustituido con 0-3 R5a, donde un primer grupo R4a es un anillo heteroaromático de 5-6 miembros; cada R es en forma independiente H, C1-6alquilo sustituido con 0-2 R5, C2-6alquenilo sustituido con 0-2 R5, C2- 6alquinilo sustituido con 0-2 R5, anillo carbocíclico de 3-10 miembros sustituido con 0-2 R5, o anillo heterocíclico de 5-10 miembros que tiene entre 1 y 4 miembros del anillo heteroatómicos seleccionados entre O, S(O)q, y N, donde el anillo heterocíclico está sustituido con 0-2 R5; o dos R unidos al mismo átomo de N se toman junto con el átomo de nitrógeno al cual están unidos para formar un heterocicloalquilo de 5-8 miembros sustituido con 0-2 R5; cada R5 es en forma independiente >=O, Cl, F, Br, I, CF3, OCF3, C1-4alquilo, C2-4alquenilo, C2-4alquinilo, NO2, -CN, ORa, N(Ra)2, CORa, CO2Ra, CON(Ra)2, NRaCORa, NRaCO2Ra, NRaCON(Ra)2, C(>=NH)NH2, SO2Ra, SO2N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, (CH2)P-(anillo carbocíclico de 3-10 miembros sustituido con 0-2 Rb), o (CH2)p-(anillo heterocíclico de 5-10 miembros que tiene entre 1 y 4 miembros del anillo heteroatómicos seleccionados entre O, S(O)q, y N), donde el anillo heterocíclico está sustituido con 0-2 Rb; o dos R5 tomados junto con el átomo de carbono al cual ambos están conectados forman un anillo 1,3-dioxolano donde los dos átomos de oxígeno del anillo se unen al átomo de carbono que los conecta; R5a se selecciona entre >=O, Cl, F, Br, I, CF3, OCF3, C1-4alquilo, C2-4alquenilo, C2-4alquinilo, NO2, -CN, (CH2)pORa, N(Ra)2, CORa, CO2Ra, CON(Ra)2, NRaCORa, NRaCO2Ra, NRaCON(Ra)2, C(>=NH)NH2, SO2Ra, SO2N(Ra)2, NRaSO2Ra, NRaSO2N(Ra)2, (CH2)p-(anillo carbocíclico de 3-10 miembros sustituido con 0-2 Rb), o (CH2)p-(anillo heterocíclico de 5-10 miembros que tiene entre 1 y 4 miembros del anillo heteroatómicos seleccionados entre O, S(O)q, y N), donde el anillo heterocíclico está sustituido con 0-2 Rb; cada Ra es en forma independiente H, C1-4alquilo, C3-6 cicloalquilo, CH2-C3-6 cicloalquilo, fenilo, o bencilo; o dos Ra unidos al mismo átomo de N se toman junto con el átomo de nitrógeno al cual están unidos para formar un heterocicloalquilo de 5-8 miembros; Rb es H, Cl, F, Br, I, CF3, OCF3, C1-4alquilo opcionalmente sustituido con ORa, C2-4alquenilo, C2-4alquinilo, NO2, -CN, ORa, N(Ra)2, CORa, CO2Ra, o CON(Ra)2; p es 0, 1, 2, 3, o 4; q es 0, 1, o 2; y m es 1 y n es 0, o 1; con las siguientes condiciones: el primer grupo R4a tiene 3 o 4 miembros del anillo heteroatómicos; y el compuesto de fórmula I o sal farmacéuticamente aceptable del mismo no es: N-[3-({4-[4-(acetilamino)fenil]pirimidin-2-il}amino)ciclohexil] -2,6-diclorobenzamida; N-[4-(2-{[4-(1,4-dioxa-8-azaespiro[4.5]dec-8-il)fenil]amino}pirimidin-4-il)fenil]acetamida; N-{4-[2-(lH-indazol-6-ilamino)-5-metilpirimidin-4-il]fenil}acetamida; N-{4-[2-(lH-indol-5-ilamino)-5-metilpirimidin-4-il]fenil}acetamida; N-{4-[2-(lH-indazol-5-ilamino)-5-metilpirimidin-4-il]fenil}acetamida; 'N-[6-({4-[4-(acetilamino)fenil]pirimidin-2-il}amino)piridin-2-il]-2,6-diclorobenzamida 'N-[6-({4-[4-(acetilamino)fenil]pirimidin-2-il}amino)pirimidin-4-il]-2,6-diclorobenzamida; N-(4-{2-[(6-aminopiridin-2-il)amino]pirimidin-4-il}fenil)acetamida; N-(4-{2-[(6-aminopirimidm-4-il)amino]pirimidin-4-il}fenil)acetamida; (R)-N-(4-(2-(1,2,3,4-tetrahidroquinolin-6-ilamino)pirimidin-4-il)fenil)pirrolidin-2-carboxamida; (R)-N-(4-(2-(6-morfolinopiridin-3-ilamino)pirimidin-4-il)fenil)pirrolidin-2-carboxamida; N-{4-[2-(lH-bencimidazol-6-ilamino)-5-metilpirimidin-4-il]fenil}acetamida; 4-({4-[(acetilamino)fenil]pirimidin-2-il}aminopiperidin-1-carboxilato de etilo; 4-({4-[4-(acetilamino)fenil]pirimidin-2-il}amino)piperidin-1-carboxilato de 1,1-dimetiletilo; N-{4-[2-(piperidin-4-ilamino)pirimidin-4-il]fenil}acetamida; o N-{4-[2-({1-[(2,6-diclorofenil)carbonil]piperidin-4-il}amino)pirimidin-4-il]fenil}acetamida.
Description
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En la cápsula anterior, el ingrediente activo toma la forma de partículas que tienen un tamaño apropiado. La lactosa cristalina y la celulosa microcristalina se mezclan de manera homogénea y se tamizan, y luego se introduce el talco y el estearato de magnesio y se los mezcla. La mezcla final se introduce en cápsulas de gelatina dura que tienen un tamaño apropiado.
A continuación se detalla un ejemplo posible de una solución inyectable de la presente invención.
- Ingrediente
- cantidad
- Sustancia activa
- 1,0 mg
- HCl 1 N
- 20,0 µl
- Ácido acético
- 0,5 mg
- NaCl
- 8,0 mg
- Fenol
- 10,0 mg
- NaOH 1 N
- una cantidad apropiada hasta alcanzar un pH de 5
- H2O
- una cantidad apropiada hasta alcanzar 1 ml
Síntesis
Los compuestos de la presente invención se pueden preparar de varias maneras conocidas por aquellos con experiencia en el arte de la síntesis orgánica (por ejemplo, véase la Patente de los EE.UU. N° 6.476.060 B2, J Med Chem 2004, 47, 627). Los compuestos de la presente invención se pueden sintetizar usando los métodos que se describen a continuación, junto con los métodos de síntesis conocidos en el arte de síntesis química orgánica, o por variaciones de la misma como podrán apreciar aquellos con experiencia en el arte. Los métodos preferidos incluyen, pero de manera no taxativa a, aquellos que se describen a continuación. Se contemplan que todos los procesos que se divulgan en asociación con la presente invención se pueden llevar a la práctica en cualquier escala, incluyendo de miligramos, gramos, de varios gramos, kilogramos, de varios kilogramos o a escala comercial o industrial. Las reacciones se llevan a cabo en un solvente apropiado para los reactivos y materiales que se emplean y que son apropiados para las transformaciones que se llevan a cabo. Aquellos con experiencia en el arte de la síntesis orgánica comprenderán que la funcionalidad presente en las moléculas debería ser consistente con las transformaciones propuestas. Esto a veces requerirá tomar una decisión sobre si se debe modificar el orden de los pasos de síntesis o seleccionar un esquema de proceso en particular con preferencia sobre otro para obtener un compuesto de la invención que se desea. Como se comprenderá fácilmente, los grupos funcionales presentes pueden contener grupos protectores durante el transcurso de la síntesis. Los grupos protectores son conocidos per se como grupos funcionales químicos que se pueden unir selectivamente a funcionalidades, como por ejemplo un grupos hidroxilo y grupos carboxilo y se pueden eliminar de las mismas. Dichos grupos están presentes en un compuesto químico para hacer que dicha funcionalidad sea inerte ante las condiciones de reacción de la reacción a las cuales se expone el compuesto. Con la presente invención se puede emplear cualquiera de una variedad de grupos protectores. Los grupos protectores preferidos incluyen el grupo benciloxicarbonilo y los grupos tertbutiloxicarbonilo. Los grupos protectores de hidroxilo preferidos incluyen a los grupos bencilo y el butildimetilsililo terciario. Otros grupos protectores preferidos que se pueden emplear de acuerdo con la presente invención han sido descritos en Greene, T.W. y Wuts, P.G.M., Protective Groups in Organic Synthesis 3a. Ed., Wiley & Sons, 1991, o Kocienski, P. J., Protecting Groups, 3a Ed., Georg Thieme Verlag, Stuttgart, 2005.
Los compuestos de la presente invención se pueden preparar de acuerdo con los siguientes métodos. Los sustituyentes son los mismos que en la Fórmula (I) excepto donde se los defina de otra manera, o según sea evidente para alguien con experiencia en el arte. Otros métodos representativos se pueden ver en la Sección de Ejemplos Experimentales que se da más adelante.
En el Esquema que se describe a continuación, R1, R2, R3, X y Z son según se definieron anteriormente. Alguien con experiencia en el arte comprenderá que pueden existir otras variables en base al contexto en el cual se las utiliza.
Por lo tanto, en el Esquema 1, una pirimidina apropiadamente sustituida que contiene un átomo de halógeno Z (Cl, Br, o I) se puede acoplar con una anilina sustituida en la posición 3- o 4- funcionalizada apropiadamente en presencia de una cantidad estequiométrica o catalítica de un catalizador de paladio tal como Pd(Ph3P)4,
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Se obtuvo 3-(2-metoxietilamino)-5-(2-(4-(3-metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)benzonitrilo siguiendo el
5 procedimiento G usando N-(4-(3-metil-1H-1,2,4-triazol-1-il)fenil)-4-(trimetilestannil)pirimidin-2-amina y 3-bromo-5-(2metoxietilamino)benzonitrilo que se preparó siguiendo el procedimiento general F usando 2-metoxietanamina y 3bromo-5-fluorobenzonitrilo. MS (ESI) 427 (M+H).
Ejemplo 192
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3-(Ciclohexilamino)-5-(2-(4-(3-metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)benzonitrilo
15 [Se obtuvo 3-(ciclohexilamino)-5-(2-(4-(3-metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)benzonitrilo siguiendo el procedimiento G usando N-(4-(3-metil-1H-1,2,4-triazol-1-il)fenil)-4-(trimetilestannil)pirimidin-2-amina y 3-bromo-5(ciclohexilamino)benzonitrilo que se preparó siguiendo el procedimiento general F usando ciclohexanamina y 3bromo-5-fluorobenzonitrilo. MS (ESI) 451 (M+H).
20 Ejemplo 193
3-(2-(4-(3-Metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)-5-(tetrahidro-2H-piran-4-ilamino)benzonitrilo
25 Se obtuvo 3-(2-(4-(3-metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)-5-(tetrahidro-2H-piran-4-ilamino)benzonitrilo siguiendo el procedimiento G usando N-(4-(3-metil-1H-1,2,4-triazol-1-il)fenil)-4-(trimetilestannil)pirimidin-2-amina y 3bromo-5-(tetrahidro-2H-piran-4-ilamino)benzonitrilo que se preparó siguiendo el procedimiento general F usando tetrahidro-2H-piran-4-amina y 3-bromo-5-fluorobenzonitrilo. MS (ESI) 453 (M+H).
30
Ejemplo 194
3-(Isopropilamino)-5-(2-(4-(3-metil-1H-1,2,4-triazol-1-il)fenilamino)pirimidin-4-il)benzonitrilo
104
Claims (1)
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imagen1 imagen2 imagen3 imagen4 imagen5 imagen6
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US969849P | 2007-09-04 | ||
PCT/US2008/075151 WO2009032861A1 (en) | 2007-09-04 | 2008-09-03 | Substituted pyrimidinyl-amines as protein kinase inhibitors |
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US (3) | US8530480B2 (es) |
EP (1) | EP2200436B1 (es) |
JP (2) | JP5611826B2 (es) |
CA (1) | CA2698511C (es) |
ES (1) | ES2535166T3 (es) |
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-
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- 2008-09-03 ES ES08829943.3T patent/ES2535166T3/es active Active
- 2008-09-03 US US12/676,411 patent/US8530480B2/en not_active Expired - Fee Related
- 2008-09-03 PT PT88299433T patent/PT2200436E/pt unknown
- 2008-09-03 EP EP08829943.3A patent/EP2200436B1/en not_active Not-in-force
- 2008-09-03 WO PCT/US2008/075151 patent/WO2009032861A1/en active Application Filing
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2013
- 2013-02-13 US US13/766,075 patent/US9018205B2/en not_active Expired - Fee Related
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US9018205B2 (en) | 2015-04-28 |
US8530480B2 (en) | 2013-09-10 |
EP2200436A4 (en) | 2011-12-28 |
EP2200436A1 (en) | 2010-06-30 |
WO2009032861A1 (en) | 2009-03-12 |
JP5611826B2 (ja) | 2014-10-22 |
US20150232429A1 (en) | 2015-08-20 |
US20130231336A1 (en) | 2013-09-05 |
JP2015007102A (ja) | 2015-01-15 |
EP2200436B1 (en) | 2015-01-21 |
CA2698511A1 (en) | 2009-03-12 |
JP5937648B2 (ja) | 2016-06-22 |
CA2698511C (en) | 2016-10-11 |
PT2200436E (pt) | 2015-04-29 |
JP2010538076A (ja) | 2010-12-09 |
US20100298312A1 (en) | 2010-11-25 |
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