ES2622138T3 - Nuevos derivados de pirimidina condensados para la inhibición de la actividad tirosina quinasa - Google Patents
Nuevos derivados de pirimidina condensados para la inhibición de la actividad tirosina quinasa Download PDFInfo
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- ES2622138T3 ES2622138T3 ES11798350.2T ES11798350T ES2622138T3 ES 2622138 T3 ES2622138 T3 ES 2622138T3 ES 11798350 T ES11798350 T ES 11798350T ES 2622138 T3 ES2622138 T3 ES 2622138T3
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- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- Vascular Medicine (AREA)
Abstract
Un compuesto de fórmula (I) o una de sus sales farmacéuticamente aceptables:**Fórmula** en la que, W es O; X es O, NH, S, SO o SO2; Y es un átomo de hidrógeno, átomo de halógeno, alquilo C1-6 o alcoxi C1-6; A y B son cada uno independientemente un átomo de hidrógeno, átomo de halógeno, o di(alquil C1- 6)aminometilo; Z es arilo o heteroarilo que tiene uno o más sustituyente seleccionados entre el grupo que consiste en: átomo de hidrógeno, átomo de halógeno, hidroxi, nitro, ciano, alquilo C1-6, alcoxi C1-6, alquil C1-6carbonilo, alcoxi C1- 6carbonilo, di(alquil C1-6)aminoalcoxi C2-6carbonilo, amino, alquil C1-6 lamino, di(alquil C1-6)amino, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, di(alquil C1-6)aminoalquilC2-6carbamoilo, sulfamoílo, alquil C1- 6sulfamoilo, di(alquil C1-6)sulfamoilo, di(alquil C1-6)aminoalquil C2-6sulfamoilo, alquil C1-6sulfonilo, alquil C1- 6sulfinilo, di(alquil C1-6)fosfonilo, hidroxialquilo C1-6, hidroxicarbonilalquil C1-6, alcoxi C1-6alquilo C1-6, alquil C1-6 sulfonilalquilo C1-6, alquil C1-6sulfinilalquilo C1-6, di(alquil C1-6)fosfonilalquil C1-6, hidroxialcoxi 2-6, alcoxi C1-6alcoxi2-6, aminoalquilo C1-6, alquil C1-6aminoalquilo C1-6, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminoacetilo, aminoalcoxiC2-6, alquil C1-6aminoalcoxi C2-6, di(alquil C1-6)aminoalcoxi C2-6, hidroxialquil C2-6 amino, alcoxi C1- 20 6alquilC2-6amino, aminoalquil C2-6amino, alquil C1-6aminoalquilC2-6amino, di(alquil C1-6)aminoalquil C2-6amino, heteroarilo, heterociclo, oxi heterocíclico, tio heterocíclico, sulfinilo heterocíclico, sulfonilo heterocíclico, sulfamoilo heterocíclico, alquilo C1-6 heterocíclico, alcoxi C1-6 heterocíclico, amino heterocíclico, alquilamino C1-6 heterocíclico, aminoalquilo C1-6 heterocíclico, carbonilo heterocíclico, alquil C1-6 carbonilo heterocíclico, carbonilalquilo C1-6 heterocíclico, alquil C1-6 tio heterocíclico, alquil C1-6 sulfinilo heterocíclico, alquil C1-6 sulfonilo heterocíclico, aminocarbonilo heterocíclico, alquil C1-6aminocarbonilo heterocíclico, aminocarbonilalquilo C1-6 heterocíclico, carboxamido heterocíclico, y alquil C1-6carboxamido heterocíclico; el arilo se refiere a un anillo aromático C6-12 cíclico o bicíclico; cada uno de los heterarilos se refiere, independientemente a un heteroanillo aromático cíclico o bicíclico de 5 a 12 miembros que tienen uno o más átomos de N, O o S; cada uno de los heterociclos se refiere, independientemente, a un heteroanillo saturado o parcialmente saturado cíclico o bicíclico de 3 a 12 miembros que tiene uno o más átomos de N, 0, S, SO o SO2, en el que un átomo de carbono que forma el heterociclo tiene opcionalmente uno o más sustituyentes seleccionados entre el grupo que consiste en alquilo C1-6, hidroxi, hidroxialquilo C1-6, hidroxicarbonilo, alcoxi C1-6, amino, alquilamino C1-6, di(alquil C1-6)amino, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminocarbonilo, heterociclo, alquilo C1-6 heterocíclico, y heteroarilo, y en el que, a condición de que el heterociclo comprenda opcionalmente un átomo de nitrógeno, el átomo de nitrógeno tiene opcionalmente un sustituyente seleccionada entre el grupo que consiste en átomo de hidrógeno, alquilo C1-6, monohalogenoalquiloC1-6, dihalogenoalquiloC1-6, trihalogenoalquiloC1-6, cicloalquilo C3-6, hidroxialquilo C2-6, alcoxi C1-6alquilo C2-6, alquil C1-6carbonilo, hidroxialquil C1-6carbonilo, alcoxi C1-6carbonilo, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, sulfamoílo, alquil C1-6sulfamoilo, di(alquil C1- 6)sulfamoilo, alquil C1-6sulfonilo, aminoalquilo C2-6, alquil C1-6aminoalquilo C2-6, di(alquil C1-6)aminoalquilo C2-6, di(alquil C1-6)aminoalquilo C1-6, heterociclo, oxi heterocíclico, tio heterocíclico, sulfinilo heterocíclico, sulfonilo heterocíclico, alquilo C1-6 heterocíclico, carbonilo heterocíclico, alquil C1-6 carbonilo heterocíclico, alquil C1-6 sulfinilo heterocíclico, y alquil C1-6sulfonilo heterocíclico ( en el que, cuando el átomo de nitrógeno forma una amina terciaria, está opcionalmente en forma de N-óxido); y opcionalmente, el alquilo C1-6 está parcialmente insaturado o tiene un resto cicloalquilo C3-6, y un átomo de carbono del heterociclo se encuentra en forma de carbonilo.
Description
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DESCRIPCION
Nuevos derivados de pirimidina condensados para la inhibicion de la actividad tirosina quinasa Campo de la invencion
La presente invencion se refiere a un nuevo derivado de pirimidina que tiene actividad inhibidora de tirosina quinasas, y a una composicion farmaceutica que comprende el mismo como principio activo.
Antecedentes de la invencion
Las celulas disponen de muchos sistemas de transduccion de la senal que estan funcionalmente vinculados entre sf para controlar la proliferacion, crecimiento, metastasis y apoptosis de las celulas (William G. Kaelin Jr., Nature Reviews Cancer 5, 689, 2005). La descomposicion del sistema de control intracelular mediante factores geneticos y ambientales ocasiona una amplificacion o destruccion anomala del sistema de transduccion de la senal que conduce a la generacion de tumores celulares (Douglas Hanahan y Robert A. Weinberg, Cell 100, 57, 2000).
Las protemas tirosina quinasas desempenan importantes papeles en dicha regulacion celular (Irena Melnikova y James Golden, Nature Reviews Drug Discovery 3, 993, 2004), y se ha observado su expresion anomala o mutacion en celulas cancerosas o enfermedades autoinmunitarias. La protema tirosina quinasa es una enzima que cataliza el transporte de grupos fosfato desde el ATP a las tirosinas situadas sobre sustratos proteicos. Muchas protemas de receptores de factores de crecimiento funcionan como tirosina quinasas para transportar senales celulares. La interaccion entre factores de crecimiento y sus receptores controla normalmente el crecimiento celular, pero la transduccion de senal anomala causada por la mutacion o la expresion en exceso de cualquiera de los receptores induce frecuentemente varios ticos de canceres o enfermedades autoinmunitarias tales como la artritis reumatoide.
Con respecto a los papeles de estas tirosina quinasas, se han investigado una variedad de factores de crecimiento y receptores de los mismos, y, entre ellas, las tirosina quinasas de los factores de crecimiento epidermico (EGF) y el receptor de EGF (EGFR) se han estudiado intensamente (Nancy E. Hynes y Heidi A. Lane, Nature Reviews Cancer 5, 34l, 2005). Una tirosina quinasa EGFR se compone de un receptor y una tirosina quinasa, y suministra senales extracelulares al nucleo celular a traves de la membrana celular. Las diferentes tirosina quinasas EGFR se han clasificado dependiendo de sus diferencias estructurales en cuatro subtipos, es decir, EGFR (Erb-B1), Erb-B2, Erb- B3 y Erb-B4, y es sabido que las mutaciones que activan mutaciones en EGFR, como la mutacion puntual L858R en el exon 21 y las deleciones en marco en el exon 19 del dominio tirosina quinasa del EGFR, son la causa principal del cancer de pulmon no microcftico.
Gefitinib (AstraZeneca) fue desarrollado inicialmente como una molecula pequena para la inhibicion de las tirosina quinasas EGFR, que inhiben EGFR (Erb-B1) de forma selectiva y reversible. Erlotinib (Roche) tiene tambien caractensticas similares. Estos farmacos dirigidos a EGFR son eficaces en el cancer de pulmon no microcftico (NSCLC) y proporcionan comodidad terapeutica para pacientes con mutaciones activadoras de EGFR.
Sin embargo, se ha notificado que el desarrollo de resistencia disminuye la actividad de un farmaco concreto utilizado en terapias dirigidas contra el EGFR. Tambien se ha notificado que aproximadamente la mitad de los pacientes que reciben Gefitinib o Erlotinib muestran resistencia a los farmacos debido a la induccion de la mutacion secundaria T790M del EGFR (William Pao y col., Public Library of Science Medicine, 2(3), 225, 2005, Cancer Res, 67(24), 11924, 2007). Ademas, se ha descubierto recientemente que los inhibidores irreversibles dirigidos contra EGFR son mas ventajosos para garantizar una eficacia excelente y superar la aparicion de resistencia, en comparacion con los inhibidores reversibles convencionales tales como Gefitinib y Erlotinib (Danan Li y col., Cancer Cell 12, 81, 2007; y Anja Michalczyk y col., Bioorganic & Medicinal Chemistry l6, 3482, 2008). De este modo, los inhibidores irreversibles tales como BIBW-2992 (Afatinib, Boeringer Ingelheim) (C H Mom y col., British Journal of Cancer 98, 80, 2007), PF00299804 (Dacomitinib, Pfizer) (Engelman JA, y col., Cancer Res. 67, 11924, 2007), y AV- 412 (AVEO Pharmaceuticals) (Tsuyoshi Suzuki y col., Cancer Sci. 98(12), 1977, 2007) se han desarrollado y se encuentran actualmente en la fase de ensayo clmico. Se sabe que los compuestos forman un enlace covalente con la cistema 773 (Cys773) situada en un dominio ATP del EGFR, bloqueando asf de forma irreversible la autofosforilacion del EGFR e inhibiendo eficazmente de esta forma la transduccion de la senal en celulas cancerosas (David W. Fry y col., Proc. Natl. Acad. Sci. U.S.A. 95, 12022, 1998), y muestra mayores actividades inhibidoras en comparacion con los inhibidores reversibles comercialmente disponibles como inhibidores dobles EGFR/HER-2, o inhibidores pan-HER en actividades in vitro y en diferentes modelos in vivo de carcinomas (Jeff B. Smaill y col., J. Med. Chem. 42, 1803, 1999). Sin embargo, los compuestos pueden ocasionar graves efectos secundarios como erupciones cutaneas, diarrea y perdida de peso debido a la elevada actividad del EGFR WT (natural) presente en celulas normales, cuando se administran en dosis suficiente para superar la resistencia inducida por las mutaciones T790M en EGFR, y esto ha limitado su aplicacion clrnica, (Martin L. Sos, y col., Cancer Res. 70, 868, 2010).
Como se ha puesto en evidencia en los ensayos clmicos de inhibidores irreversibles realizados en cancer de pulmon no microcftico, los compuestos han mostrado actividades mejoradas, pero siguen teniendo efectos terapeuticos debiles en el desarrollo de la resistencia en pacientes de cancer, en comparacion con los inhibidores reversibles convencionales. De acuerdo con ello, existe una necesidad continuada de desarrollar un farmaco novedoso que sea
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eficaz en canceres resistentes a farmacos y que no tenga efectos secundarios adversos.
Entre tanto, existen varias evidencias de que las celulas B (linfocitos B) y las celulas T (linfocitos T) desempenan un papel fundamental en la patogenesis de enfermedades inflamatorias, enfermedades autoinmunitarias y/o enfermedades mediadas por el sistema inmunitario.
Por ejemplo, la senalizacion anomala puede inducir la proliferacion y diferenciacion de linfocitos B no regulada, y esto produce todo tipo de linfoma entre los que se incluyen varias leucemias linfoides agudas o cronicas y puede causar la formacion de autoanticuerpos que da lugar a diferentes enfermedades inflamatorias, enfermedades autoinmunitarias y/o enfermedades mediadas por el sistema inmunitario.
La tirosina quinasa de Bruton (BTK) es miembro de la familia BTK de tirosina quinasas, y desempena un importante papel en la activacion linfocitos B y en la transduccion de la senal. BTK desempena un papel fundamental en la ruta de senalizacion de linfocitos B que vincula la estimulacion del receptor de linfocitos B (BCR) situado en la superficie de los linfocitos B con la respuesta de las celulas posteriores. Ademas, se sabe que BTK es un regulador fundamental del desarrollo de linfocitos B y de la activacion y supervivencia de los linfocitos B maduros (Khan y col., Immunity 3, 283, 1995; Ellmeier y col., J. Exp. Med. 192, 1611, 2000; Kurosaki, Current Opinion in Immunology 12, 276, 20O0; Schaeffer y Schwartzberg, Current Opinion in Immunology 12, 282, 2000). Asf, la inhibicion de BTK podna ser un enfoque terapeutico para bloquear los procedimientos patologicos mediados por linfocitos B.
Por ejemplo, se ha conocido que los ratones deficientes en BTK son resistentes a la artritis inducida por colageno, y se ha demostrado que los inhibidores de BTK tienen eficacias dependientes de la dosis en un modelo de artritis en raton (Jansson y Holmdahl, Clin. Exp. Immunol. 94, 459, 1993; Pan y col., Chem. Med Chem. 2, 58, 2007). Asf, inhibidores de BTK eficaces pueden ser de utilidad en el tratamiento de la artritis reumatoide.
Ademas, otras celulas diferentes a los linfocitos B tambien expresan BTK, que pueden estar implicadas en otros procedimientos patologicos, es decir, mastocitos derivados de la medula osea. Se ha notificado que la granulacion inducida por antfgenos se suprime en mastocitos derivados de la medula osea deficiente en BTK (Iwaki y col., J. Biol. Chem. 280, 40261, 2005). Esto muestra que BTK podna ser util para tratar respuestas patologicas de mastocitos tales como alergia y asma.
Asimismo, monocitos, cuya actividad BTK es ausente, mostraron una disminucion en la produccion de TNF-a tras el estimulo (Horwood y col. J Exp Med. 197, 1603, 2003). Por lo tanto, la inflamacion mediada por TNF-a se podna modular mediante inhibidores de BTK.
Ademas, se ha notificado que BTK desempena un papel en la apoptosis, como algunos reguladores (Islam y Smith, Immunol. Rev. 178, 49, 2000). Asf, Los inhibidores de BTK senan utiles para el tratamiento de determinados linfomas y leucemias de linfocitos B (Feldhahn y col., J. Exp. Med. 201, 1837, 2005).
Entre tanto, Los linfocitos T desempenan un papel en la transmision de senales suministradas a traves del receptor de linfocitos T (TCR) situado en la superficie celular de las celulas presentadoras de antfgenos a los efectores posteriores mediante la activacion de diferentes quinasas intercelulares, como las quinasas janus. En este momento, secretan diferentes interleuquina (IL) o interferon-Y para activar varios leucocitos, asf como los linfocitos B. Las protemas quinasa implicadas en la transduccion de la senal en los linfocitos T son las quinasas janus (JAK) como JAK1, JAK2, JAK3 y TYK2, quinasas de linfocitos T inducibles por IL-2 (ITK), y la familia TEC de quinasas, tales como las quinasas de linfocitos en reposo (RLK).
Las quinasas janus que implican JAK3 se han investigado ampliamente como diana para enfermedades autoinmunitarias y/o inflamatorias. Entre ellos, a diferencia de JAK2 implicada en la hematosis y la homeostasia de eritrocitos, y de JAK1 expresada en varios tejidos, JAK3 se expresa en linfocitos, y desempena un papel muy importante en la transduccion de la senal mediante varias citoquinas, es decir, IL-2, IL-4, IL-7, IL-9 y IL-15, por lo que es mas atractiva (Flanagan y col, Journal of medicinal Chemistry, 53, 8468, 2010). De acuerdo con estudios con animales, JAK3 desempena un papel en la maduracion de linfocitos B y linfocitos T, asf como en el mantenimiento de las funciones de los linfocitos T.
Por lo tanto, los inhibidores de JAK3 pueden ser de utilidad en el tratamiento de la artritis reumatoide, psoriasis, dermatitis atopica, lupus, esclerosis multiple, diabetes de tipo I y complicaciones derivadas de diabetes, cancer, asma, trastornos del tiroides autoinmunitarios, colitis ulcerosa, enfermedad de Crohn, enfermedad de Alzheimer, leucemia, y otras indicaciones en las que la inmunosupresion sena deseable, tal como el trasplante de organos o el xenotransplante (Pesu M, Laurence A, Kishore N, y col., Immunol Rev 223, 132, 2008; Kawahara A, Minami Y, Miyazaki T, y col., Proc Natl Acad Sci USA 92, 8724, 1995; Nosaka T, van Deursen JMA, Tripp RA, y col., Science 270, 800, 1995; Papageorgiou Ac, Wikman LEK., y col., Trends Pharm Sci 25, 558, 2004).
Entre tanto, otra familia de quinasas TEC tambien desempena un papel importante en la activacion de linfocitos T (Pamela L. Schwartzberg, y col., Nature Reviews Immunology 5, 284, 2005). Por ejemplo, la delecion de ITK que se expresa de forma caractenstica en los linfocitos T de ratones lleva a una disminucion de la proliferacion celular que se induce mediante la estimulacion realizada de los receptores de linfocitos T y una disminucion en la secrecion de varias citoquinas tales como IL-2, IL-4, IL-5, IL-10 e IFN-y (Schaeffer y col., Science 284, 638, 1999; Fowell y col.,
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Immunity 11, 399, 1999; Schaffer y col., Nature Immunology 2, 1183, 2001).
Ademas, en ratones deficientes en ITK, los smtomas inmunitarios del asma alergica se atenuaron, y la inflamacion pulmonar, infiltracion de eosinofilos, y produccion de moco en respuesta al estimulo con la ovoalbumina alergenica se redujo de forma importante (Muller y col., Journal of Immunology 170, 5056, 2003). Esto muestra que los inhibidores de ITK podnan ser utiles en el tratamiento del asma.
Ademas, ITK tambien se ha implicado en la dermatitis atopica. Se ha notificado que este gen se expresa en mayor cantidad en los linfocitos T de sangre periferica procedentes de pacientes con dermatitis atopica severa, en comparacion con los controles, o con pacientes con dermatitis atopica leve (Matsumoto y col., International archives of Allergy and Immunology 129, 327, 2002).
Entre tanto, RLK funciona para activar la secrecion de IL-2, que se produce mediante la transduccion de la senal de los receptores de linfocitos T de los esplenocitos. Asf, la inhibicion de RLK puede reducir varias respuestas de los linfocitos T (Schaeffer y col., Nature Immunology 2, 1183, 2001; Schaeffer y col., Science 284, 638,1999).
Ademas, se sabe que la tirosina quinasa de la medula osea (BMX) esta implicada en la migracion de celulas epiteliales y endoteliales (Pan y col., Mol. Cell. Biol. 2002, 22, 7512). Por lo tanto, los inhibidores de BMK se pueden desarrollar como agentes antineoplasicos para inhibir la metastasis de celulas cancerosas y la angiogenesis.
Como anteriormente, como las quinasas de la familia TEC tales como BTK, ITK, RLK, BMX y otros, y las quinasas Janus tales como JAK3 desempenan un papel fundamental en la activacion de linfocitos B y/o linfocitos T que estan implicados en la patogenesis de las enfermedades inflamatorias, enfermedades autoinmunitarias, y enfermedades mediadas de forma inmunitaria, un compuesto para inhibir las quinasas de forma eficaz sena de utilidad como agente terapeutico para varias enfermedades inflamatorias, enfermedades autoinmunitarias, y enfermedades mediadas de forma inmunitaria.
Ademas, un compuesto para inhibir la BTK implicada en la activacion de linfocitos B que induce el linfoma de linfocitos B, y la BMX implicada en la metastasis de celulas cancerosas puede ser de utilidad como agente antineoplasico o agente antitumoral.
Por lo tanto, el desarrollo de un compuesto, que puede inhibir las quinasas anteriores e inhibir selectivamente EGFR variantes tales como mutaciones secundarias en T790M, asf como la mutacion puntual L858R en el exon 21 o la delecion en marco en el exon 19, es un desaffo muy importante.
Aunque se sugirio que los inhibidores de EGFR irreversibles, que forman un enlace covalente con la cistema 773 (Cys773) situada en un dominio ATP del EGFR, puede mostrar efectos inhibidores sobre las actividades de la familia de quinasas BTK tales como BTK, ITK, RLK y BMX donde la cistema esta presente en la misma posicion de la secuencia de aminoacidos, asf como quinasas tales como JAK3 o BLK (Wooyoung Hur, y col., Bioorg. Med. Chem. Lett. 18, 5916, 2008), no se ha desarrollado un compuesto que pueda inhibir de forma irreversible, selectiva y eficaz variantes de EGFR, BTK, JAK3, ITK, RLK, BMX y/o BLK.
Los documentos WO 2009/062258 y WO 2009/158571 se refieren a compuestos heterodclicos que contienen N que son inhibidores de protema quinasas. El documento WO 2010/054285 se refiere a compuestos de pirimidina bidclicos y tridclicos condensados como inhibidores de tirosina quinasas.
Sumario de la invencion
Por lo tanto, es un objeto de la presente invencion proporciona un novedoso derivado de pirimidina condensada que puede inhibir de forma selectiva y eficaz canceres o tumores inducidos por una tirosina quinasa del receptor de factor de crecimiento epidermico (EGFR) o un mutante del mismo con efectos secundarios adversos reducidos.
Es otro objeto de la presente invencion proporcionar un novedoso derivado de pirimidina condensada que pueda tratar canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria por linfocitos B o linfocitos T activados de forma anomala, o ambos, mediante la represion de tirosina quinasas no de receptor tales como quinasas de la familia TEC (por ejemplo, BTK, ITK, BMX o RLK) y quinasas janus (por ejemplo, JAK3).
Es otro objeto de la presente invencion proporcionar una composicion farmaceutica para prevenir o tratar canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria que comprende dicho novedoso derivado de pirimidina condensada.
De acuerdo con un aspecto de la presente invencion, se proporciona un compuesto de formula (I) o una sal del mismo farmaceuticamente aceptable:
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en la que,
W es O;
X es O, NH, S, SO o SO2;
Y es un atomo de hidrogeno, atomo de halogeno, alquilo C1-6 o alcoxi C1-6;
A y B son cada uno independientemente un atomo de hidrogeno, atomo de halogeno, o di(alquil Ci- 6)aminometilo;
Z es arilo o heteroarilo que tiene uno o mas sustituyente seleccionados entre el grupo que consiste en: atomo de hidrogeno, atomo de halogeno, hidroxi, nitro, ciano, alquilo C1-6, alcoxi C1-6, alquil Ci-6carbonilo, alcoxi Ci- 6carbonilo, di(alquil C1-6)aminoalcoxi C2-6carbonilo, amino, alquilamino C1-6, di(alquil C1-6)amino, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, di(alquil C1-6)aminoalquilC2-6carbamoilo, sulfamoflo, alquil C1- 6sulfamoilo, di(alquil C1-6)sulfamoilo, di(alquil C1-6)aminoalquil C2-6sulfamoilo, alquil C1-6sulfonilo, alquil C1- esulfinilo, di(alquil C1-6)fosfonilo, hidroxialquilo C1-6, hidroxicarbonilalquil C1-6, alcoxi C1-6alquilo C1-6, alquil C1-6 sulfonilalquilo C1-6, alquil C1-6sulfinilalquilo C1-6, di(alquil C1-6)fosfonilalquil C1-6, hidroxialcoxi 2-6, alcoxi C1-6alcoxi2-6, aminoalquilo C1-6, alquil C1-6aminoalquilo C1-6, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminoacetilo, aminoalcoxiC2-6, alquil C1-6aminoalcoxi C2-6, di(alquil C1-6)aminoalcoxi C2-6, hidroxialquil C2-6 amino, alcoxi C1- 6alquilC2-6amino, aminoalquil C2-6amino, alquil C1-6aminoalquilC2-6amino, di(alquil C1-6)aminoalquil C2-6amino, heteroarilo, heterociclo, oxi heterodclico, tio heterodclico, sulfinilo heterodclico, sulfonilo heterodclico, sulfamoilo heterodclico, alquilo C1-6 heterodclico, alcoxi C1-6 heterodclico, amino heterodclico, alquilamino C1-6 heterodclico, aminoalquilo C1-6 heterodclico, carbonilo heterodclico, alquil C1-6 carbonilo heterodclico,
carbonilalquilo C1-6 heterodclico, alquil C1-6 tio heterodclico, alquil C1-6 sulfinilo heterodclico, alquil C1-6 sulfonilo heterodclico, aminocarbonilo heterodclico, alquil C1-6aminocarbonilo heterodclico, aminocarbonilalquilo C1-6 heterodclico, carboxamido heterodclico, y alquil C1-6carboxamido heterodclico; el arilo se refiere a un anillo aromatico C6-12dclico o bidclico;
cada uno de los heterarilos se refiere, independientemente a un heteroanillo aromatico dclico o bidclico de 5 a 12 miembros que tienen uno o mas atomos de N, O o S;
cada uno de los heterociclos se refiere, independientemente, a un heteroanillo saturado o parcialmente saturado dclico o bidclico de 3 a 12 miembros que tiene uno o mas atomos de N, O, S, SO o SO2, en el que un atomo de carbono que forma el heterociclo tiene opcionalmente uno o mas sustituyentes seleccionados entre el grupo que consiste en alquilo C1-6, hidroxi, hidroxialquilo C1-6, hidroxicarbonilo, alcoxi C1-6, amino, alquilamino C1-6, di(alquil C1-6)amino, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminocarbonilo, heterociclo, alquilo C1-6 heterodclico, y heteroarilo, y en el que, a condicion de que el heterociclo comprenda opcionalmente un atomo de nitrogeno, el atomo de nitrogeno tiene opcionalmente un sustituyente seleccionada entre el grupo que consiste en atomo de hidrogeno, alquilo C1-6, monohalogenoalquiloC1-6, dihalogenoalquiloC1-6, trihalogenoalquiloC1-6, cicloalquilo C3-6, hidroxialquilo C2-6, alcoxi C1-@alquilo C2-6, alquil C1-6carbonilo, hidroxialquil C1-6carbonilo, alcoxi C1-6carbonilo, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, sulfamoflo, alquil C1-6sulfamoilo, di(alquil C1-6)sulfamoilo, alquil C1-6sulfonilo, aminoalquilo C2-6, alquil C1-6aminoalquilo C2-6, di(alquil C1- 6)aminoalquilo C2-6, di(alquil C1-6)aminoalquilo C1.6, heterociclo, oxi heterodclico, tio heterodclico, sulfinilo heterodclico, sulfonilo heterodclico, alquilo C1-6 heterodclico, carbonilo heterodclico, alquil C1-6 carbonilo heterodclico, alquil C1.6 sulfinilo heterodclico, y alquil C1-6sulfonilo heterodclico ( en el que, cuando el atomo de nitrogeno forma una amina terciaria, esta opcionalmente en forma de N-oxido); y
opcionalmente, el alquilo C1-6 esta parcialmente insaturado o tiene un resto cicloalquilo C3-6, y un atomo de carbono del heterociclo se encuentra en forma de carbonilo.
De acuerdo con otro aspecto de la presente invencion, se proporciona una composicion farmaceutica para prevenir o tratar canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria que comprenden el compuesto de formula (I) o una sal del mismo farmaceuticamente aceptable.
Breve descripcion de los dibujos
Los objetos y caractensticas anteriores de la presente invencion resultaran evidentes a partir de la siguiente descripcion de la invencion, cuando se toma junto con los dibujos, que muestran respectivamente:
Fig. 1: cambio de tamano de los tumores mediante administracion por via oral del compuesto obtenido en el Ejemplo 2 a ratones lampinos con un xenoinjerto de celulas cancerosas NCI-H1975;
Fig. 2: cambio en el peso corporal mediante administracion por v^a oral del compuesto obtenido en el Ejemplo 2 a ratones lampinos con un xenoinjerto de celulas cancerosas NCI-H1975; y
Fig. 3: cambio en la puntuacion clmica de la artritis mediante la administracion por via oral del compuesto obtenido en el Ejemplo 1 en un modelo de artritis inducida por colageno (CIA).
5 Descripcion detallada de la invencion
En el compuesto de formula (I), los ejemplos preferidos de Z incluyen sustituyentes seleccionados entre el grupo que consiste en las formulas Z1 a Z203, pero no estan limitados a lo anterior:
Claims (15)
- 510152025303540451. Un compuesto de formula (I) o una de sus sales farmaceuticamente aceptables:
imagen1 en la que,W es O;X es O, NH, S, SO o SO2;Y es un atomo de hidrogeno, atomo de halogeno, alquilo C1-6 o alcoxi C1-6;A y B son cada uno independientemente un atomo de hidrogeno, atomo de halogeno, o di(alquil C1- 6)aminometilo;Z es arilo o heteroarilo que tiene uno o mas sustituyente seleccionados entre el grupo que consiste en: atomo de hidrogeno, atomo de halogeno, hidroxi, nitro, ciano, alquilo C1-6, alcoxi C1-6, alquil C1-6carbonilo, alcoxi Ci- 6carbonilo, di(alquil C1-6)aminoalcoxi C2-6carbonilo, amino, alquil C1-6lamino, di(alquil C1-6)amino, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, di(alquil C1-6)aminoalquilC2-6carbamoilo, sulfamoMo, alquil C1- 6sulfamoilo, di(alquil C1-6)sulfamoilo, di(alquil C1-6)aminoalquil C2-6sulfamoilo, alquil C1-6sulfonilo, alquil C1- 6sulfinilo, di(alquil C1-6)fosfonilo, hidroxialquilo C1-6, hidroxicarbonilalquil C1-6, alcoxi C1-6alquilo C1-6, alquil C1-6 sulfonilalquilo C1-6, alquil C1-6sulfinilalquilo C1-6, di(alquil C1-e)fosfonilalquil C1-6, hidroxialcoxi 2-6, alcoxi C1-6alcoxi2-6, aminoalquilo C1-6, alquil C1-6aminoalquilo C1-6, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminoacetilo, aminoalcoxiC2-6, alquil C1-6aminoalcoxi C2-6, di(alquil C1-6)aminoalcoxi C2-6, hidroxialquil C2-6 amino, alcoxi C1- 6alquilC2-6amino, aminoalquil C2-6amino, alquil C1-6aminoalquilC2-6amino, di(alquil C1-6)aminoalquil C2-6amino, heteroarilo, heterociclo, oxi heterodclico, tio heterodclico, sulfinilo heterodclico, sulfonilo heterodclico, sulfamoilo heterodclico, alquilo C1-6 heterodclico, alcoxi C1-6 heterodclico, amino heterodclico, alquilamino C1-6heterodclico, aminoalquilo C1-6 heterodclico, carbonilo heterodclico, alquil C1-6 carbonilo heterodclico, carbonilalquilo C1-6 heterodclico, alquil C1-6 tio heterodclico, alquil C1-6 sulfinilo heterodclico, alquil C1-6 sulfonilo heterodclico, aminocarbonilo heterodclico, alquil C1-6aminocarbonilo heterodclico, aminocarbonilalquilo C1-6 heterodclico, carboxamido heterodclico, y alquil C^carboxamido heterodclico; el arilo se refiere a un anillo aromatico C6-12dclico o bidclico;cada uno de los heterarilos se refiere, independientemente a un heteroanillo aromatico dclico o bidclico de 5 a 12 miembros que tienen uno o mas atomos de N, O o S;cada uno de los heterociclos se refiere, independientemente, a un heteroanillo saturado o parcialmente saturado dclico o bidclico de 3 a 12 miembros que tiene uno o mas atomos de N, 0, S, SO o SO2, en el que un atomo de carbono que forma el heterociclo tiene opcionalmente uno o mas sustituyentes seleccionados entre el grupo que consiste en alquilo C1-6, hidroxi, hidroxialquilo C1-6, hidroxicarbonilo, alcoxi C1-6, amino, alquilamino C1-6, di(alquil C1-6)amino, di(alquil C1-6)aminoalquilo C1-6, di(alquil C1-6)aminocarbonilo, heterociclo, alquilo C1-6 heterodclico, y heteroarilo, y en el que, a condicion de que el heterociclo comprenda opcionalmente un atomo de nitrogeno, el atomo de nitrogeno tiene opcionalmente un sustituyente seleccionada entre el grupo que consiste en atomo de hidrogeno, alquilo C1-6, monohalogenoalquiloC1-6, dihalogenoalquiloC1-6, trihalogenoalquiloC1-6, cicloalquilo C3-6, hidroxialquilo C2-6, alcoxi C1-6alquilo C2-6, alquil C1-6carbonilo, hidroxialquil C1-6carbonilo, alcoxi C1-6carbonilo, carbamoilo, alquil C1-6carbamoilo, di(alquil C1-6)carbamoilo, sulfamoilo, alquil C1-6sulfamoilo, di(alquil C1- 6)sulfamoilo, alquil C1-6sulfonilo, aminoalquilo C2-6, alquil C1-6aminoalquilo C2-6, di(alquil C1-6)aminoalquilo C2-6, di(alquil C1-6)aminoalquilo C1-6, heterociclo, oxi heterodclico, tio heterodclico, sulfinilo heterodclico, sulfonilo heterodclico, alquilo C1-6 heterodclico, carbonilo heterodclico, alquil C1-6 carbonilo heterodclico, alquil C1-6 sulfinilo heterodclico, y alquil C1-6sulfonilo heterodclico ( en el que, cuando el atomo de nitrogeno forma una amina terciaria, esta opcionalmente en forma de N-oxido);y opcionalmente, el alquilo C1-6 esta parcialmente insaturado o tiene un resto cicloalquilo C3-6, y un atomo de carbono del heterociclo se encuentra en forma de carbonilo. - 2. El compuesto de la reivindicacion 1, en el que Z se selecciona entre el grupo que consiste en las formulas Z1 a Z203:
imagen2 imagen3 V~0Himagen4 imagen5 Z141 Z142 Z143 Z144 Z145 Z146 Z147 Z14B Z149 Z1500Z151Z152 Z153 Z154 Z1S5 Z156Cl5o oZ157 Z15BZ159 Z160- ,9 3
- 9 F 9 ,9 ^ <6 pj 9 j$> -j ?
- 0 0
- 0 “V HH Hhl HN I ™xx . H~xx 1 XX
- 0 0
- 0
- Z161 Z162
- Z1«3 Z164 Z165 Z166 Z167 Z1G8 Z169 Z170
- F-O V
- f9 ,j5 r§ 0o f9 f9 9
- Oy
- V L? \ i - A- k \ i \ ^ kh'> L k,o a ^ o3-
- Z171 Z172
- Z173 Z174 Z175 Z176 Z177 Z178 Z179 Z180
Z131 Z182 Z183 Z134 Z185 Z18G Z187 Z188 Z189 Z190F-0 9 f-6O IX TX T>Z191 Z192 Z193 Z194 Z195 Z196 Z197 Z198 Z199 Z2005101520253035imagen6 - 3. El compuesto de la reivindicacion 1, en el que el compuesto de formula (1) se selecciona entre el grupo que consiste en:W-(3-((2-((4-(4-metilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-(4-isopropilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-morfolinofenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-((dimetilamino)metil)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-((4-(dimetilamino)piperidin-1-il)metil)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((3-fluoro-4-(1-metilpiperazin-4-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-(2-dimetilamino)etil)amino)-3-fluorofenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((3-fluoro-4-((1-metilpiperidin-4-il)amino)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-(2-(3-metoxi-4-(4-metil-piperazin-1-il)-fenilamino)-furo[3,2-d]pirimidin-4-iloxi)-fenil)-acrilamida; yW-(3-((2-((4-sulfamoilfenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida.
- 4. Un compuesto de la reivindicacion 3 seleccionado entre el grupo que consiste en:W-(3-((2-((4-(4-isopropilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-morfolinofenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-((dimetilamino)metil)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-((4-(dimetilamino)piperidin-1-il)metil)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((3-fluoro-4-(1-metilpiperazin-4-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((4-(2-dimetilamino)etil)amino)-3-fluorofenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-((2-((3-fluoro-4-((1-metilpiperidin-4-il)amino)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida;W-(3-(2-(3-metoxi-4-(4-metil-piperazin-1-il)-fenilamino)-furo[3,2-d]pirimidin-4-iloxi)-fenil)-acrilamida; yW-(3-((2-((4-sulfamoilfenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida,o una de sus sales farmaceuticamente aceptables.
- 5. Un compuesto de la reivindicacion 3, en el que el compuesto es W-(3-((2-((4-(4-metilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida, o una de sus sales farmaceuticamente aceptables.
- 6. Un compuesto de la reivindicacion 3, en el que el compuesto es W-(3-((2-((4-(4-metilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil)acrilamida.
- 7. El compuesto de la reivindicacion 1, en el que el compuesto de formula (1) se selecciona entre el grupo que consiste en:
imagen7 - 8. Una composicion farmaceutica que comprende, como principio activo, un compuesto de formula (I) o una sal del mismo farmaceuticamente aceptable, de acuerdo con las reivindicaciones 1 a 7.
- 9. Un compuesto de cualquiera de las reivindicaciones 1 a 7, para su uso en terapia.
- 10. Un compuesto de cualquiera de las reivindicaciones 1 a 7, para su uso en la prevencion o el tratamiento de canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria.51015202530354045
- 11. Un compuesto para su uso de acuerdo con la reivindicacion 10, en el que los canceres o tumores estan inducidos por una tirosina quinasa del receptor del factor de crecimiento epidermico (EGFR) o un mutante del mismo.
- 12. Un compuesto para su uso de acuerdo con la reivindicacion 10, en el que los canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria, que estan mediados por al menos una quinasa seleccionada entre el grupo que consiste en tirosina quinasa de Bruton (BTK), quinasa janus 3 (JAK3), quinasa de linfocitos T que induce interleuquina 2 (ITK), quinasa de linfocitos en reposo (RLK), y tirosina quinasa de la medula osea (BMX).
- 13. Un compuesto para su uso de acuerdo con la reivindicacion 10, en el que los canceres, tumores, enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma inmunitaria, estan mediados por linfocitos B, linfocitos T activados de forma anomala, o ambos.
- 14. Un compuesto para su uso de acuerdo con la reivindicacion 10, en el que las enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma autoinmunitaria, son artritis, artritis reumatoide, espondiloartroparta, artritis gotosa, artrosis, artritis juvenil, otras afecciones artnticas, lupus, lupus eritematoso sistemico (LES), enfermedades relacionadas con la piel, psoriasis, eczema, dermatitis, dermatitis atopica, dolor, trastorno pulmonar, inflamacion pulmonar, smdrome de dificultad respiratoria del adulto (SRDA), sarcoidosis pulmonar, enfermedad inflamatoria pulmonar cronica, enfermedad pulmonar obstructiva cronica (EPOC), enfermedad cardiovascular, arterioesclerosis, infarto de miocardio, insuficiencia cardfaca congestiva, lesion por reperfusion cardiaca, enfermedad inflamatoria del intestino, enfermedad de Crohn, colitis ulcerosa, smdrome de intestino irritable, asma, smdrome de Sjogren, enfermedad del tiroides autoinmunitaria, urticaria (cnidosis), esclerosis multiple, escleroderma, rechazo del trasplante organo, injerto heteroplastico, purpura trombocitopenica idiopatica (ITP), enfermedad de Parkinson, enfermedad de Alzheimer, enfermedad asociada con diabetes, inflamacion, enfermedad inflamatoria pelvica, rinitis alergica, bronquitis alergica, sinusitis alergica, leucemia, linfoma, linfoma de linfocitos B, linfoma de linfocitos T, mieloma, leucemia linfoide aguda (ALL), leucemia linfoide cronica (CLL), leucemia mieloide aguda (AML), leucemia mielocftica cronica (CML), leucemia de celulas pilosas, enfermedad de Hodgkin, linfoma no de Hodgkin, mieloma multiple, smdrome mielodisplasico (MDS), neoplasias mioproliferativas (MPN), linfoma difuso de linfocitos B grandes, o linfoma folicular.
- 15. Un compuesto para su uso de acuerdo con la reivindicacion 10 en la prevencion o tratamiento de enfermedades inflamatorias, enfermedades autoinmunitarias, o enfermedades mediadas de forma autoinmunitaria, seleccionadas entre artritis, artritis reumatoide, espondiloartroparta, artritis gotosa, artrosis, artritis juvenil, otras afecciones artnticas, lupus, lupus eritematoso sistemico (LES), enfermedades relacionadas con la piel, psoriasis, eczema, dermatitis, dermatitis atopica, dolor, trastorno pulmonar, inflamacion pulmonar, smdrome de dificultad respiratoria del adulto (SRDA), sarcoidosis pulmonar, enfermedad inflamatoria pulmonar cronica, enfermedad pulmonar obstructiva cronica (EPOC), enfermedad cardiovascular, arterioesclerosis, infarto de miocardio, insuficiencia cardfaca congestiva, lesionpor reperfusion cardiaca, enfermedad inflamatoria del intestino, enfermedad de Crohn, colitis ulcerosa, smdrome de intestino irritable, asma, smdrome de Sjogren, enfermedad del tiroides autoinmunitaria, urticaria (cnidosis), esclerosis multiple, escleroderma, rechazo del trasplante organo, injerto heteroplastico, purpura trombocitopenica idiopatica(lTP), enfermedad de Parkinson, enfermedad de Alzheimer, enfermedad asociada con diabetes, inflamacion, enfermedad inflamatoria pelvica, rinitis alergica, bronquitis alergica, sinusitis alergica, leucemia, linfoma, linfoma de linfocitos B, linfoma de linfocitos T, mieloma, leucemia linfoide aguda (ALL), leucemia linfoide cronica (CLL), leucemia mieloide aguda (AML), leucemia mielocftica cronica (CML), leucemia de celulas pilosas, enfermedad de Hodgkin, linfoma no de Hodgkin, mieloma multiple, smdrome mielodisplasico (MDS), neoplasias mioproliferativas (MPN), linfoma difuso de linfocitos B grandes, o linfoma folicular, en el que el compuesto es N-(3-((2-((4-(4-metilpiperazin-1-il)fenil)amino)furo[3,2-d]pirimidin-4-il)oxi)fenil]acrilamida o una sal del mismo farmaceuticamente aceptable.
imagen8 Grupo de control- Comp. Ej. (BIBW2992 50 mg/kg/dia)Ejemplo 2 (70 mg/kg/dia)Tiempo despues de la administracion (dialimagen9 Grupo de controlComp. Ej. (BIBW2992 50 mg/kg/diaEjemplo 2 (70 mg/kg/dia)20i* -Tiempo despues de la administracion (dia)imagen10 Grupo de control regular 0 Grupo de control enfermedad A Ejemplo 1 (10 mg/kg/dia)— Ejemplo 1 (30 mg/kg/dia)Tiempo despues de la administracion (dia)
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CA3022256C (en) | 2010-06-03 | 2021-03-30 | Pharmacyclics Llc | The use of inhibitors of bruton's tyrosine kinase (btk) |
PL2585470T3 (pl) * | 2010-06-23 | 2017-07-31 | Hanmi Science Co., Ltd. | Nowe sprzężone pochodne pirymidyny do hamowania aktywności kinazy tyrozynowej |
KR20140005882A (ko) * | 2010-10-08 | 2014-01-15 | 애브비 인코포레이티드 | 푸로[3,2-d]피리미딘 화합물 |
JP2013539795A (ja) * | 2010-10-14 | 2013-10-28 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Egfr発動性がんの細胞増殖の阻害方法 |
CA2832504C (en) | 2011-05-04 | 2019-10-01 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
AU2012283775A1 (en) | 2011-07-13 | 2014-01-23 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
PT3333161T (pt) | 2011-07-27 | 2020-05-18 | Astrazeneca Ab | Derivados de 2-(2,4,5-anilino-substituídos)pirimidina como moduladores do egfr úteis para o tratamento do cancro |
KR20130076046A (ko) * | 2011-12-28 | 2013-07-08 | 한미약품 주식회사 | 타이로신 카이네이즈 억제 활성을 갖는 신규 이미다조피리딘 유도체 |
US8377946B1 (en) | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
US9464089B2 (en) | 2012-01-13 | 2016-10-11 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
US9586965B2 (en) | 2012-01-13 | 2017-03-07 | Acea Biosciences Inc. | Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases |
AU2013207712B2 (en) | 2012-01-13 | 2017-08-31 | Acea Biosciences Inc. | Heterocyclic compounds and uses as anticancer agents. |
US9034885B2 (en) | 2012-01-13 | 2015-05-19 | Acea Biosciences Inc. | EGFR modulators and uses thereof |
KR20130091464A (ko) * | 2012-02-08 | 2013-08-19 | 한미약품 주식회사 | 타이로신 카이네이즈 억제 활성을 갖는 트리아졸로피리딘 유도체 |
KR101660145B1 (ko) * | 2012-02-23 | 2016-09-26 | 다이호야쿠힌고교 가부시키가이샤 | 퀴놀릴피롤로피리미딜 축합환 화합물 또는 그의 염 |
AU2013204563B2 (en) * | 2012-05-05 | 2016-05-19 | Takeda Pharmaceutical Company Limited | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
JP6236071B2 (ja) | 2012-06-04 | 2017-11-22 | ファーマサイクリックス エルエルシー | ブルトン型チロシンキナーゼ阻害剤の結晶形態 |
CN104520291A (zh) * | 2012-06-06 | 2015-04-15 | Irm责任有限公司 | 用于调节egfr活性的化合物和组合物 |
WO2014018567A1 (en) | 2012-07-24 | 2014-01-30 | Pharmacyclics, Inc. | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
AU2013344656A1 (en) | 2012-11-15 | 2015-06-04 | Pharmacyclics Llc | Pyrrolopyrimidine compounds as kinase inhibitors |
CA2898274A1 (en) | 2013-02-22 | 2014-08-28 | Taiho Pharmaceutical Co., Ltd. | Method for producing tricyclic compound, and tricyclic compound capable of being produced by said production method |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
CN103242341B (zh) * | 2013-04-19 | 2015-12-09 | 中国科学院广州生物医药与健康研究院 | 噻吩并2,4取代嘧啶类化合物及其药物组合物与应用 |
WO2014175370A1 (ja) * | 2013-04-25 | 2014-10-30 | 塩野義製薬株式会社 | ピロリジン誘導体およびそれらを含有する医薬組成物 |
EA028756B1 (ru) | 2013-04-25 | 2017-12-29 | Бэйджин, Лтд. | Конденсированные гетероциклические соединения в качестве ингибиторов протеинкиназы |
AU2014287016B2 (en) * | 2013-07-11 | 2018-11-01 | Acea Biosciences Inc. | Pyrimidine derivatives as kinase inhibitors |
AR097204A1 (es) | 2013-08-02 | 2016-02-24 | Pharmacyclics Inc | Métodos de tratamiento de tumores sólidos |
EP2832358A1 (en) | 2013-08-02 | 2015-02-04 | Bionsil S.r.l. | Pharmaceutical kit for use in the treatment of colon and colorectal cancer |
EP3033079B1 (en) | 2013-08-12 | 2018-10-31 | Pharmacyclics LLC | Methods for the treatment of her2 amplified cancer |
CN107090041B (zh) | 2013-09-13 | 2018-11-16 | 百济神州有限公司 | 抗pd1抗体及其作为治疗剂与诊断剂的用途 |
BR112016005881A2 (pt) * | 2013-09-18 | 2017-09-12 | Beijing Hanmi Pharmaceutical Co Ltd | composto, composição farmacêutica e uso do composto |
EP3052486A1 (en) | 2013-09-30 | 2016-08-10 | Pharmacyclics LLC | Inhibitors of bruton's tyrosine kinase |
FR3015483B1 (fr) * | 2013-12-23 | 2016-01-01 | Servier Lab | Nouveaux derives de thienopyrimidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
WO2015148904A1 (en) * | 2014-03-28 | 2015-10-01 | Driver Group | Methods for predicting egfr tyrosine kinase inhibitor efficacy |
EP3125920B1 (en) | 2014-04-04 | 2020-12-23 | Del Mar Pharmaceuticals | Dianhydrogalactitol, diacetyldianhydrogalactitol or dibromodulcitol to treat non-small-cell carcinoma of the lung and ovarian cancer |
PT3137470T (pt) | 2014-05-01 | 2021-06-24 | Novartis Ag | Compostos e composições como agonistas do recetor tipo toll 7 |
SG11201608299TA (en) | 2014-05-01 | 2016-11-29 | Novartis Ag | Compounds and compositions as toll-like receptor 7 agonists |
SG11201609837WA (en) * | 2014-05-28 | 2016-12-29 | Astellas Pharma Inc | Pharmaceutical composition comprising pyrazine carboxamide compound as active ingredient |
CN106604742B (zh) | 2014-07-03 | 2019-01-11 | 百济神州有限公司 | 抗pd-l1抗体及其作为治疗剂及诊断剂的用途 |
EP2974729A1 (en) | 2014-07-17 | 2016-01-20 | Abivax | Quinoline derivatives for use in the treatment of inflammatory diseases |
AU2015296215A1 (en) | 2014-08-01 | 2017-03-23 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
WO2016020901A1 (en) | 2014-08-07 | 2016-02-11 | Acerta Pharma B.V. | Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate |
BR112017002231A2 (pt) | 2014-08-07 | 2018-07-17 | Pharmacyclics Llc | novas formulações de um inibidor de tirosina cinase de bruton |
KR20160082062A (ko) | 2014-12-30 | 2016-07-08 | 한미약품 주식회사 | 싸이옥소 퓨로피리미디논 유도체의 제조방법 및 이에 사용되는 중간체 |
EP3224257B1 (en) | 2014-12-30 | 2019-10-16 | Hanmi Pharm. Co., Ltd. | Novel method for preparing thienopyrimidine compound and intermediates used therein |
CN105837572B (zh) * | 2015-02-02 | 2019-04-19 | 四川大学 | N-取代苯基酰胺衍生物及其制备方法和用途 |
RU2572709C1 (ru) * | 2015-03-03 | 2016-01-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Способ коррекции структурно-функциональных нарушений артериального русла у больных ревматоидным артритом |
IL315294A (en) | 2015-03-03 | 2024-10-01 | Pharmacyclics Llc | Pharmaceutical formulations of bruton's tyrosine kinase inhibitor |
CA2988896C (en) | 2015-04-29 | 2023-08-15 | Guangdong Zhongsheng Pharmaceutical Co., Ltd. | Fused-ring or tricyclic aryl pyrimidine compound used as kinase inhibitor |
EP3799873A1 (en) | 2015-07-17 | 2021-04-07 | Institut Pasteur | 5-hydroxytryptamine 1b receptor-stimulating agent for use as a promoter of satellite cells self-renewal and/or differentiation |
MA44909A (fr) | 2015-09-15 | 2018-07-25 | Acerta Pharma Bv | Association thérapeutique d'un inhibiteur du cd19 et d'un inhibiteur de la btk |
CN107949388B (zh) | 2015-10-09 | 2021-10-26 | 艾森医药公司 | 吡咯并嘧啶激酶抑制剂的药用盐、物理形态和组合物及其制备方法 |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
KR20170050453A (ko) * | 2015-10-30 | 2017-05-11 | 한미약품 주식회사 | 싸이에노피리미딘 화합물의 신규 제조방법 및 이에 사용되는 중간체 |
WO2017092523A1 (zh) * | 2015-12-02 | 2017-06-08 | 深圳市塔吉瑞生物医药有限公司 | 一种稠合嘧啶化合物及包含该化合物的组合物及其用途 |
WO2017096095A1 (en) * | 2015-12-03 | 2017-06-08 | Shanghai Aeon Biotech Co., Ltd. | Thieno-pyrimidine derivatives and uses thereof |
AU2016362394B2 (en) | 2015-12-03 | 2021-01-14 | Zhejiang Jianfeng-Yien Biotechnology Co., Ltd. | Heterocycle compounds and uses thereof |
KR20180089903A (ko) * | 2015-12-31 | 2018-08-09 | 한미약품 주식회사 | 싸이에노피리미딘 화합물의 하이드로클로라이드 염의 결정형 |
EP3380482A4 (en) * | 2015-12-31 | 2019-05-15 | Hanmi Pharm. Co., Ltd. | CRYSTALLINE FORMS OF A THIENOPYRIMIDINE COMPOUND |
HUE052893T2 (hu) | 2016-01-13 | 2021-05-28 | Acerta Pharma Bv | Antifolát és BTK-gátló terápiás kombinációi |
US20190125751A1 (en) * | 2016-05-18 | 2019-05-02 | Boehringer Ingelheim International Gmbh | Anticancer combination therapy |
KR20190003805A (ko) * | 2016-05-27 | 2019-01-09 | 한미약품 주식회사 | 암 세포 성장을 저해하는 아민 유도체 또는 이의 약학적으로 허용가능한 염 및 저융점을 갖는 안정화제를 포함하는 약학적 조성물 |
PE20190811A1 (es) * | 2016-06-30 | 2019-06-13 | Dae Woong Pharma | Derivados de pirazolopirimidinas como inhibidor de quinasa |
US10864203B2 (en) | 2016-07-05 | 2020-12-15 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
JP2019524723A (ja) | 2016-07-15 | 2019-09-05 | アンスティテュ・パストゥール | 皮膚および/または毛の修復のための5−ヒドロキシトリプタミン1b受容体刺激剤 |
CN107698603B (zh) * | 2016-08-09 | 2022-04-08 | 南京红云生物科技有限公司 | 噻吩并嘧啶类化合物、其制备方法、药用组合物及其应用 |
TWI865873B (zh) | 2016-08-16 | 2024-12-11 | 瑞士商百濟神州瑞士有限責任公司 | (s)-7-(1-丙烯醯基六氫吡啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氫吡唑並[1,5-a]嘧啶-3-甲醯胺的晶型、其製備和用途 |
AU2017313085B2 (en) | 2016-08-19 | 2024-06-20 | Beigene Switzerland Gmbh | Use of a combination comprising a Btk inhibitor for treating cancers |
EP3515414B1 (en) | 2016-09-19 | 2022-11-30 | MEI Pharma, Inc. | Combination therapy |
CN106565612B (zh) * | 2016-10-25 | 2018-10-16 | 大连医科大学 | 二苯乙烯基嘧啶类化合物,组合物及其用途 |
CA3045339A1 (en) | 2016-12-03 | 2018-06-07 | Juno Therapeutics, Inc. | Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors |
KR20180075228A (ko) | 2016-12-26 | 2018-07-04 | 한미약품 주식회사 | 싸이에노피리미딘 화합물의 신규 제조방법 및 중간체 |
WO2018134786A1 (en) | 2017-01-19 | 2018-07-26 | Acerta Pharma B.V. | Compositions and methods for the assessment of drug target occupancy for bruton's tyrosine kinase |
US11555038B2 (en) | 2017-01-25 | 2023-01-17 | Beigene, Ltd. | Crystalline forms of (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
WO2018139883A1 (ko) * | 2017-01-26 | 2018-08-02 | 부광약품 주식회사 | 다중 표적 키나아제 저해제로서 융합피리미딘 유도체 |
CN106831814B (zh) * | 2017-02-15 | 2018-11-23 | 山东大学 | 一种噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂及其制备方法和应用 |
CN106916112B (zh) * | 2017-03-02 | 2019-12-20 | 四川海思科制药有限公司 | 嘧啶衍生物及其制备方法和在医药上的应用 |
CN106866699B (zh) * | 2017-03-29 | 2019-03-08 | 山东大学 | 一种二芳基噻吩并嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 |
US11498922B2 (en) | 2017-04-07 | 2022-11-15 | ACEA Therapeutics, Inc. | Pharmaceutical composition comprising N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenylacrylamide |
CN108727382B (zh) * | 2017-04-19 | 2022-07-19 | 华东理工大学 | 作为btk抑制剂的杂环化合物及其应用 |
EP3645569A4 (en) | 2017-06-26 | 2021-03-24 | BeiGene, Ltd. | IMMUNOTHERAPY FOR LIVER CELL CARCINOMA |
CN109206435B (zh) * | 2017-06-29 | 2020-09-08 | 中国医药研究开发中心有限公司 | 噻吩并[3,2-d]嘧啶类化合物及其制备方法和医药用途 |
WO2019034009A1 (en) | 2017-08-12 | 2019-02-21 | Beigene, Ltd. | BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY |
WO2019034153A1 (zh) * | 2017-08-18 | 2019-02-21 | 北京韩美药品有限公司 | 一种化合物,其药物组合物及其用途及应用 |
CN109575045B (zh) * | 2017-09-28 | 2021-02-12 | 南京红云生物科技有限公司 | 噻吩并嘧啶类化合物、其制备方法、药用组合物及其应用 |
KR102613433B1 (ko) * | 2017-10-11 | 2023-12-13 | 주식회사 대웅제약 | 신규한 페닐피리딘 유도체 및 이를 포함하는 약학 조성물 |
AU2018367909B2 (en) | 2017-11-17 | 2022-03-10 | Cellix Bio Private Limited | Compositions and methods for the treatment of eye disorders |
US11786529B2 (en) | 2017-11-29 | 2023-10-17 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors |
CN109627263B (zh) | 2017-12-21 | 2022-05-20 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制激酶活性的二苯氨基嘧啶类化合物 |
LT3733673T (lt) | 2017-12-28 | 2022-08-10 | Daewoong Pharmaceutical Co., Ltd. | Oksi-fluorpiperidino darinys, kaip kinazės inhibitorius |
KR102577241B1 (ko) * | 2017-12-28 | 2023-09-11 | 주식회사 대웅제약 | 카이네이즈 저해제로서의 아미노-플루오로피페리딘 유도체 |
KR102577242B1 (ko) | 2017-12-28 | 2023-09-11 | 주식회사 대웅제약 | 카이네이즈 저해제로서의 아미노-메틸피페리딘 유도체 |
CN111989322B (zh) | 2018-04-23 | 2024-04-02 | 细胞基因公司 | 取代的4-氨基异吲哚啉-1,3-二酮化合物以及它们用于治疗淋巴瘤的用途 |
WO2019208805A1 (ja) | 2018-04-27 | 2019-10-31 | 小野薬品工業株式会社 | Btk阻害活性を有する化合物を有効成分として含む自己免疫疾患の予防および/または治療剤 |
KR101954370B1 (ko) * | 2018-07-25 | 2019-03-05 | 한미약품 주식회사 | 피리미딘 화합물 및 이를 포함하는 암의 예방 또는 치료용 약학 조성물 |
PE20210406A1 (es) | 2018-07-25 | 2021-03-02 | Novartis Ag | Inhibidores de inflamasoma nlrp3 |
CA3111126A1 (en) | 2018-08-31 | 2020-03-05 | Stichting Katholieke Universiteit | Synergistic combinations of amino acid depletion agent sensitizers (aadas) and amino acid depletion agents (aada), and therapeutic methods of use thereof |
CN109265469A (zh) * | 2018-11-12 | 2019-01-25 | 大连医科大学附属第医院 | 嘧啶并噻唑类杂环化合物,组合物及其治疗淋巴细胞白血病的用途 |
EP3669873A1 (en) | 2018-12-20 | 2020-06-24 | Abivax | Quinoline derivatives for use ine the traeatment of inflammation diseases |
CN111747950B (zh) * | 2019-03-29 | 2024-01-23 | 深圳福沃药业有限公司 | 用于治疗癌症的嘧啶衍生物 |
KR20200114776A (ko) * | 2019-03-29 | 2020-10-07 | 한미약품 주식회사 | 퓨로피리미딘 화합물의 산 부가염의 결정형 |
CN111909101B (zh) * | 2019-05-10 | 2022-07-19 | 浙江大学 | 一种egfr激酶抑制剂及其在制备抗癌药物方面的应用 |
AR119731A1 (es) | 2019-05-17 | 2022-01-05 | Novartis Ag | Inhibidores del inflamasoma nlrp3 |
CA3133004A1 (en) * | 2019-05-31 | 2020-12-03 | Sichuan Haisco Pharmaceutical Co., Ltd. | Btk inhibitor ring derivative, preparation method therefor and pharmaceutical application thereof |
TWI856111B (zh) | 2019-06-10 | 2024-09-21 | 瑞士商百濟神州瑞士有限責任公司 | 一種含有布魯頓氏酪胺酸激酶抑制劑的口服固體錠劑及其製備方法 |
CA3139969A1 (en) * | 2019-06-20 | 2020-12-24 | Dana-Farber Cancer Institute, Inc. | Small molecule inhibitors of src tyrosine kinase |
CN110372529B (zh) * | 2019-08-08 | 2022-05-24 | 黄河水利职业技术学院 | N-[(3,4,5-三氟)苯基]丙烯酰胺及其制备方法 |
CN110511994B (zh) * | 2019-09-09 | 2023-05-26 | 中南大学湘雅二医院 | miRNA-4769-3p及其同源物的应用 |
CN115087655A (zh) * | 2019-12-20 | 2022-09-20 | 辉瑞公司 | 苯并咪唑衍生物 |
US11345681B1 (en) | 2020-06-05 | 2022-05-31 | Kinnate Biopharma Inc. | Inhibitors of fibroblast growth factor receptor kinases |
CN116239603A (zh) * | 2020-06-20 | 2023-06-09 | 江西科技师范大学 | 一种2-氨基嘧啶杂环类化合物及其应用 |
BR112023002031A2 (pt) | 2020-08-14 | 2023-03-07 | Novartis Ag | Derivados de espiropiperidinila substituídos por heteroarila e usos farmacêuticos dos mesmos |
AU2021371697B2 (en) * | 2020-10-29 | 2024-10-24 | Suzhou Yabao Pharmaceutical R&D Co., Ltd. | Substituted diarylamine compound, pharmaceutical composition thereof, preparation method therefor, and use thereof |
US20240216330A1 (en) | 2021-04-02 | 2024-07-04 | Biogen Ma Inc. | Combination treatment methods of multiple sclerosis |
US11786531B1 (en) | 2022-06-08 | 2023-10-17 | Beigene Switzerland Gmbh | Methods of treating B-cell proliferative disorder |
TW202406550A (zh) | 2022-08-03 | 2024-02-16 | 瑞士商諾華公司 | Nlrp3炎性小體抑制劑 |
WO2024123126A1 (ko) * | 2022-12-09 | 2024-06-13 | 재단법인대구경북과학기술원 | 올무티닙을 유효성분으로 포함하는 신경염증 또는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
AU2004267061A1 (en) * | 2003-08-19 | 2005-03-03 | Wyeth Holdings Corporation | Process for the preparation of 4-amino-3-quinolinecarbonitriles |
EP1979329A2 (en) | 2006-01-30 | 2008-10-15 | Exelixis, Inc. | 4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and methods of use |
JP2008013527A (ja) | 2006-07-10 | 2008-01-24 | Sankyo Co Ltd | チエノ[3,2−d]ピリミジン−2,4−ジアミン誘導体 |
KR101507182B1 (ko) * | 2006-12-07 | 2015-03-30 | 제넨테크, 인크. | 포스포이노시타이드 3-키나제 억제제 화합물 및 그의 사용 방법 |
WO2008152394A1 (en) | 2007-06-12 | 2008-12-18 | F.Hoffmann-La Roche Ag | Pharmaceutical compounds |
WO2009017838A2 (en) | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
WO2009062258A1 (en) * | 2007-11-15 | 2009-05-22 | Cytopia Research Pty Ltd | N-containing heterocyclic compounds |
JP5298187B2 (ja) * | 2008-04-07 | 2013-09-25 | アイアールエム・リミテッド・ライアビリティ・カンパニー | タンパク質キナーゼ阻害剤としての化合物および組成物 |
EP2361248B1 (en) | 2008-06-27 | 2018-09-19 | Celgene CAR LLC | Heteroaryl compounds and uses thereof |
WO2010054285A2 (en) * | 2008-11-10 | 2010-05-14 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
ES2659725T3 (es) * | 2009-05-05 | 2018-03-19 | Dana-Farber Cancer Institute, Inc. | Inhibidores de EGFR y procedimiento de tratamiento de trastornos |
WO2011079231A1 (en) | 2009-12-23 | 2011-06-30 | Gatekeeper Pharmaceutical, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
PL2585470T3 (pl) * | 2010-06-23 | 2017-07-31 | Hanmi Science Co., Ltd. | Nowe sprzężone pochodne pirymidyny do hamowania aktywności kinazy tyrozynowej |
MD20140023A2 (ro) * | 2011-09-22 | 2014-06-30 | Pfizer Inc. | Derivaţi de pirolpirimidină şi purină |
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