ES2646759T3 - Derivados de aminopirimidina para uso como moduladores de la actividad de la quinasa - Google Patents

Derivados de aminopirimidina para uso como moduladores de la actividad de la quinasa Download PDF

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Publication number
ES2646759T3
ES2646759T3 ES12766773.1T ES12766773T ES2646759T3 ES 2646759 T3 ES2646759 T3 ES 2646759T3 ES 12766773 T ES12766773 T ES 12766773T ES 2646759 T3 ES2646759 T3 ES 2646759T3
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hal
mono
atoms
cyc2
disubstituted
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Inventor
Ruoxi Lan
Bayard R. Huck
Xiaoling Chen
Lizbeth Celeste DESELM
Yufang Xiao
Hui QIU
Constantin Neagu
Igor Mochalkin
Theresa L. Johnson
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Merck Patent GmbH
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Un compuesto de fórmula (I)**Fórmula** o sal, solvato, o solvato de sal farmacéuticamente aceptable, del mismo, en la que: X es N o CH; Y es N o CR2; E es un enlazante de alquilo ramificado o no ramificado que tiene 1, 2, 3, 4, 5, 6 o 7 átomos de C, que puede estar no sustituido o mono- o disustituido con Hal, OH, CN o NH2, en el que un grupo CH3 puede estar sustituido por Cyc1, Cyc2, CONH2, CF3, y en el que uno, dos o tres grupos CH2 pueden estar sustituido por -O- o -NH-, y en el que un grupo CH puede estar sustituido por -N-; o si Y es CNH2, E también puede ser -CH(R3)-NH-CO- o -CO-NH-CH(R3)-; R1 es CN, CONH2, Hal, LA, O(LA), Ar, Cyc1 o Cyc2; R2 es H, NH2, Hal o CN; R3 es H o LA, Hal es F, Cl, Br o I; LA es una cadena hidrocarburo lineal saturada o parcialmente insaturada, no ramificada o ramificada que tiene 1, 2, 3 4, 5 o 6 átomos de C, en la que 1, 2 o 3 H átomos puede estar sustituido por Hal u OH; Ar es un homo- o heterociclo aromático mono- o bicíclico que tiene 0, 1, 2, 3 o 4 átomos de N, O y/o S y 5, 6, 7, 8, 9, o 10 átomos de esqueleto, que pueden estar no sustituidos o, independientemente uno del otro, mono- o disustituidos por Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), NHCONH(LA), NHCONH2, CHO y CO(LA), y/o monosustituidos por Cyc2 o OCyc2; Cyc1 es un homo- o heterociclo alifático monocíclico de 3, 4, 5 o 6 miembros que tiene 0-2 heteroátomos, seleccionados entre O, S y N, que puede estar mono- o disustituido por Hal, LA, NH2, NH(LA), N(LA)2, HO(LA)-; Cyc2 es un homo- o heterociclo alifático monocíclico de 5 o 6 miembros que tiene 0-3 heteroátomos, seleccionados entre O, S y N, que puede estar mono- o disustituido por Hal o LA; y n es 1 o 2.

Description

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líquidos y mezclas de los mismos en aceites. En condiciones normales de almacenamiento y uso, estas preparaciones contienen un conservante para prevenir el crecimiento de microorganismos.
Las formas farmacéuticas apropiadas para uso inyectable incluyen soluciones o dispersiones acuosas estériles y polvos estériles para la preparación extemporánea de soluciones o dispersiones inyectables estériles. En todos los casos, la forma debe ser estéril y debe ser fluida en la medida en que exista una facilidad de inyección. Debe ser estable en las condiciones de fabricación y almacenamiento y se debe preservar contra la acción contaminante de microorganismos tales como bacterias y hongos. El portador puede ser un solvente o medio de dispersión que contiene, por ejemplo, agua, etanol, poliol (por ejemplo, glicerol, propilenglicol y polietilenglicol líquido), mezclas apropiadas de los mismos y aceites vegetales.
Se puede emplear cualquier ruta de administración apropiada para proporcionar un mamífero, especialmente un ser humano, con una dosis eficaz de un compuesto de la presente invención. Por ejemplo, se pueden emplear vía oral, rectal, tópica, parenteral, ocular, pulmonar, nasal y similares. Las formas de dosificación incluyen comprimidos, trociscos, dispersiones, suspensiones, soluciones, cápsulas, cremas, ungüentos, aerosoles y similares. Preferiblemente, los compuestos de la presente invención se administran por vía oral.
La dosificación eficaz del ingrediente activo empleado puede variar dependiendo del compuesto particular empleado, del modo de administración, de la afección que se está tratando y de la gravedad de la afección que se está tratando. Dicha dosificación puede ser determinada fácilmente por un experto en el arte.
Cuando se trata o previene el cáncer, la inflamación u otras enfermedades proliferativas para las que se indican los compuestos de la presente invención, se obtienen resultados generalmente satisfactorios cuando los compuestos de la presente invención se administran a una dosis diaria de aproximadamente 0.01 miligramo a aproximadamente 100 miligramo por kilogramo de peso corporal del animal, preferiblemente suministrado como una dosis diaria única. Para la mayoría de los mamíferos grandes, la dosificación diaria total es de aproximadamente 0.2 miligramos a aproximadamente 2000 miligramos, preferiblemente de aproximadamente 0.5 miligramos a aproximadamente 1000 miligramos. En el caso de un ser humano adulto de 70 kg, la dosis diaria total será generalmente de aproximadamente 0.5 miligramos a aproximadamente 1000 miligramos. Estos regímenes de dosificación mencionados anteriormente se pueden ajustar para proporcionar la respuesta terapéutica óptima.
La invención se refiere también a un juego (kit) que consiste en paquetes separados de
a) una cantidad eficaz de un compuesto de acuerdo con la invención o una sal, o solvato fisiológicamente aceptable del mismo, y
b) una cantidad eficaz de un ingrediente activo adicional del medicamento.
El juego comprende recipientes apropiados, tales como cajas, botellas individuales, bolsas o ampollas. El juego puede comprender, por ejemplo, ampollas separadas, cada una de las cuales contiene una cantidad eficaz de un compuesto de acuerdo con la invención y/o solvatos y estereoisómeros farmacéuticamente que se pueden usar, incluyendo mezclas de los mismos en todas las proporciones y una cantidad eficaz de un ingrediente activo adicional del medicamento en forma disuelta o liofilizada.
Sección experimental
Algunas abreviaturas que pueden aparecer en esta solicitud son las siguientes:
Abreviaturas
Designación
ACN
acetonitrilo
ATP
Adenosina trifosfato
b
Pico amplio
D
Doblete
DMSO
dimetilsulfóxido
DIEA
N, N-Diisopropiletilamina
DTT
ditiotreitol
11
EDTA
Ácido etilendiaminotetraacético
Equiv.
Equivalentes
Et
etílico
h
hora
HEPES
Ácido 4-(2-hidroxietil)-1-piperazinoetanosulfónico
HPLC
Cromatografía líquida de alta resolución
LC/MS
Cromatografía líquida acoplada a espectrometría de masas
m
multipleto
M
iones moleculares
m/z
Proporción masa/carga
Me
Metilo
min
minuto
MS
Espectrometría de masas
N
Normal (unidad de concentración)
NMO
4-metilmorfolina N-óxido
RMN
Resonancia Magnética Nuclear
PG
Grupo de protección
Psi
Libras por pulgada cuadrada
Q
Cuarteto (o cuarteto)
Rf
Factor de retención
RT
Temperatura ambiente
Rt.
Tiempo de retención
S
Singlete
Tert
Terciario
TEA
Trietilamina
TFA
Ácido trifluoroacético
THAB
Bromuro de tetrahexilamonio
THF
Tetrahidrofurano
UV
ultravioleta
VIS
visible
Los compuestos de la presente invención se pueden preparar de acuerdo con los procedimientos de los siguientes esquemas y ejemplos, mediante el uso de materiales apropiados y se ejemplifican adicionalmente mediante los siguientes ejemplos específicos.
12
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Se hizo reaccionar 5-(4-fluorofenil)-6-(piperazin-1-il)pirimidin-4-amina con aril aldehídos o cetonas en condiciones de aminación reductora para generar los compuestos 10 deseados.
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El desplazamiento de los bromuros 11 con aminas secundarias 12 proporcionó las cetonas 13, que se redujo a alcoholes 14. Los alcoholes 14 se convirtieron en los correspondientes cloruros 15 por cloruro de tionilo. Los cloruros 15 se hicieron reaccionar con productos intermedios 16 de piperazina para proporcionar los productos 17 deseados.
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Se hizo reaccionar 5-bromo-6-cloro-pirimidina-4-ilamina con aminas 29 secundarias en presencia de una base para proporcionar los bromuros 30. Después se realizó un acoplamiento de Suzuki con los bromuros 30 y ácido o éster borónico para proporcionar los compuestos 31.
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El acoplamiento de amida del ácido 1-(tert-butoxicarbonil)-4-((tert-butoxicarbonil)amino)piperidina-4-carboxílico con aminas 32 seguido por la desprotección de Boc generó el intermedio 33 de amina, el cual se hizo reaccionar con 4cloro pirimidinas sustituidas con 6-amino-5 proporcionaron los compuestos 34. Se realizó entonces un acoplamiento de Suzuki si R1 de los compuestos 34 es bromo para proporcionar los compuestos 35.
10 Ejemplos:
Los ejemplos 136 y 209-213 han sido omitidos deliberadamente dada una discontinuidad en la numeración clerical de los compuestos como se describe en la presente solicitud.
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Claims (1)

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ES12766773.1T 2011-09-12 2012-09-12 Derivados de aminopirimidina para uso como moduladores de la actividad de la quinasa Active ES2646759T3 (es)

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US201161533606P 2011-09-12 2011-09-12
US201161533606P 2011-09-12
PCT/US2012/054877 WO2013040044A1 (en) 2011-09-12 2012-09-12 Aminopyrimidine derivatives for use as modulators of kinase activity

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US (3) US9321760B2 (es)
EP (1) EP2755958B9 (es)
JP (1) JP6082011B2 (es)
KR (1) KR101992505B1 (es)
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