ES2638595T3 - Derivados de aminopirimidina como moduladores de LRRK2 - Google Patents

Derivados de aminopirimidina como moduladores de LRRK2 Download PDF

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ES2638595T3
ES2638595T3 ES12797826.0T ES12797826T ES2638595T3 ES 2638595 T3 ES2638595 T3 ES 2638595T3 ES 12797826 T ES12797826 T ES 12797826T ES 2638595 T3 ES2638595 T3 ES 2638595T3
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6alkyl
halo
chloro
methoxy
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Charles Baker-Glenn
Mark Chambers
Bryan K. Chan
Huifen Chen
Anthony Estrada
David Shore
Zachary Sweeney
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Genentech Inc
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    • 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
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract

Un compuesto de fórmula I:**Fórmula** o sales farmacéuticamente aceptables de los mismos, en donde: m es de 0 a 3; X es: -NRa-; -O-; o -S(O)r- en donde r es de 0 a 2 y Ra es hidrógeno o alquilo C1-6; R1 es: alquilo C1-6; R2 es: halo; alcoxi C1-6; ciano; alquinilo C2-6; alquenilo C2-6; halo-alquilo C1-6; halo-alcoxi C1-6; cicloalquilo C3-6 en donde la porción de cicloalquilo C3-6 está opcionalmente sustituida con alquilo C1-6; cicloalquil C3-6-alquilo C1-6 en donde la porción de cicloalquilo C3-6 está opcionalmente sustituida con alquilo C1-6; tetrahidrofuranilo; tetrahidrofuranoil-alquilo C1-6; acetilo; oxetanilo; u oxetan-alquilo C1-6; R3 y R4 cada uno independientemente son: halo; alquilo C1-6; alcoxi C1-6; cicloalquiloxi C3-6; halo-alquilo C1-6; o halo-alcoxi C1-6; o R3 y R4 junto con los átomos a los que están unidos pueden formar un anillo de cinco o seis miembros que incluye opcionalmente uno o dos heteroátomos seleccionados cada uno de ellos independientemente entre O, N y S, estando el anillo opcionalmente sustituido una o más veces con R6; R5 es: alquil-sulfonilo C1-6; o ciano; y R6 es: alquilo C1-6; halo; halo-alquilo C1-6; u oxo.

Description

imagen1
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En ciertas realizaciones de fórmula I, R2 es trifluorometilo. En ciertas realizaciones de fórmula I, R2 es metoxi.
5 En ciertas realizaciones de fórmula I, R2 es ciano. En ciertas realizaciones de fórmula I, R2 es alquinilo C2-6. En ciertas realizaciones de fórmula I, R2 es alquenilo C2-6.
10
En ciertas realizaciones de fórmula I, R3 es: alquilo C1-6; En ciertas realizaciones de fórmula I, R3 es halo.
15 En ciertas realizaciones de fórmula I, R3 es alquilo C1-6. En ciertas realizaciones de fórmula I, R3 es alcoxi C1-6. En ciertas realizaciones de fórmula I, R3 es halo o alcoxi C1-6.
20
En ciertas realizaciones de fórmula I, R3 es cicloalquiloxi C3-6. En ciertas realizaciones de fórmula I, R3 es halo-alquilo C1-6.
25 En ciertas realizaciones de fórmula I, R3 es halo-alcoxi C1-6. En ciertas realizaciones de fórmula I, R3 es halo o metoxi. En ciertas realizaciones de fórmula I, R3 es flúor, cloro o metoxi.
30
En ciertas realizaciones de fórmula I, R3 es flúor o cloro. En ciertas realizaciones de fórmula I, R3 es metoxi.
35 En ciertas realizaciones de fórmula I, R3 es metilo En ciertas realizaciones de fórmula I, R3 es cloro. En ciertas realizaciones de fórmula I, R3 es flúor.
40
En ciertas realizaciones de fórmula I, R4 es: alquilo C1-6; En ciertas realizaciones de fórmula I, R4 es halo.
45 En ciertas realizaciones de fórmula I, R4 es alquilo C1-6. En ciertas realizaciones de fórmula I, R4 es alcoxi C1-6. En ciertas realizaciones de fórmula I, R4 es halo-alquilo C1-6.
50
En ciertas realizaciones de fórmula I, R4 es halo-alcoxi C1-6. En ciertas realizaciones de fórmula I, R4 es halo o metoxi.
55 En ciertas realizaciones de fórmula I, R4 es R4 es flúor, cloro, metilo o metoxi. En ciertas realizaciones de fórmula I, R4 es flúor, cloro o metoxi. En ciertas realizaciones de fórmula I, R4 es flúor o cloro.
60
En ciertas realizaciones de fórmula I, R4 es metoxi. En ciertas realizaciones de fórmula I, R4 es metilo 65 En ciertas realizaciones de fórmula I, R4 es cloro.
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EtOH Etanol/Alcohol etílico EtOAc Acetato de etilo
5 HATU Hexafluorofosfato de metanaminio de 2-(1H-7-azabenzotriazol-1-il)--1,1,3,3-tetrametiluronio HBTU Hexafluorofosfato de O-benzotriazol-1-il-N,N,N',N'-tetrametiluronio HOBT 1-Hidroxibenzotriazol
10
HPLC Cromatografía líquida de alta presión RP HPLC Cromatografía líquida de alta presión de fase inversa
15 i-PrOH Isopropanol/alcohol isopropílico CLEM Cromatografía líquida/Espectrometría de masas MeOH Metanol/Alcohol metílico
20
MW Microondas NBS N-Bromosuccinimida
25 NMP 1-Metil-2-pirrolidinona PSI Libra por pulgada cuadrada TA Temperatura ambiente
30
TBDMS terc-Butildimetilsililo TFA Ácido trifluoroacético 35 THF Tetrahidrofurano TLC Cromatografía de capa fina Preparación 1: 2-cloro-5-fluoro-N-metilpirimidin-4-amina
imagen15
A un matraz de fondo redondo de 250 ml equipado con una barra agitadora, se le añadieron 9,0 g de 5-fluoro-2,4dicloropirimidina, 40 ml de metanol y 15 ml de metilamina 8 M en etanol. La reacción se calentó (exotérmico suave) y se dejó en agitación a temperatura ambiente durante ~30 minutos. Un control por TLC (1:1 de EtOAc: heptano) y
45 CLEM mostró la reacción completa. La reacción se concentró para dar 9,77 g de material en bruto que se purificó en una columna de sílice que ejecutó un gradiente de MeOH del 1 % al 10 % en DCM durante 35 minutos para dar 6,77 g de 2-cloro-5-fluoro-N-metilpirimidin-4-amina pura.
Se usó el mismo método para preparar los compuestos mostrados en la Tabla 1 a continuación, usando las 2,450 dicloropirimidinas y aminas sustituidas disponibles en el mercado apropiadas.
Tabla 1
1
2-cloro-5-cloro-N-metilpirimidin-4-amina
2
2-cloro-5-bromo-N-metilpirimidin-4-amina imagen16
3
2-cloro-5-trifluorometil-N-metilpirimidin-4-amina
6
2-cloro-5-metoxi-N-metilpirimidin-4-amina imagen17
8
2-cloro-5-fluoro-N,N-dimetilpirimidin-4-amina
9
2-cloro-5-cloro-N-etilpirimidin-4-amina imagen18
10
2-cloro-5-cloro-N-propilpirimidin-4-amina
11
2-cloro-5-cloro-N-isopropilpirimidin-4-amina
12
2-cloro-5-cloro-N-isobutilpirimidin-4-amina
13
4-(2,5-dicloropirimidin-4-il)morfolina
14
2,5-dicloropirimidin-4-amina
15
2,5-dicloro-N,N-dimetilpirimidin-4-amina
16
4-(azetidin-1-il)-2,5-dicloropirimidina
17
2,5-dicloro-4-(pirrolidin-1-il)pirimidina
18
2,5-dicloro-4-(piperidin-1-il)pirimidina
19
2,5-dicloro-4-(2-(metoximetil)piperidin-1-il)pirimidina
20
2,5-dicloro-4-(4-(metoximetil)piperidin-1-il)pirimidina imagen19
21
2,5-dicloro-N-(ciclopropilmetil)pirimidin-4-amina
22
2,5-dicloro-N-(ciclobutilmetil)pirimidin-4-amina imagen20
23
2,5-dicloro-N-(ciclopentilmetil)pirimidin-4-amina
24
2-cloro-N-metilpirimidin-4-amina
25
2,5-dicloro-N-(2-metoxietil)pirimidin-4-amina
Preparación 2: 2,5-dicloro-4-metoxipirimidina
imagen21
5 A un matraz de fondo redondo de 250 ml equipado con una barra agitadora se le añadieron 1 g de 5-cloro-2,4dicloropirimidina y 15 ml de éter dietílico. La mezcla se enfrió a 0 ºC en un baño de hielo y después se añadió lentamente 1 equivalente de metóxido sódico en metanol (preparado a partir de hacer reaccionar 120 mg de sodio con 4 ml de metanol a temperatura ambiente). La reacción se agitó durante una noche a temperatura ambiente y se
10 controló por CLEM. El precipitado de color blanco se filtró y el sólido se lavó con metanol frío. Después de secarse, se obtuvieron 0,98 g de 2,5-dicloro-4-metoxipirimidina y este material se usó sin purificación adicional.
Se usó el mismo método para preparar los compuestos mostrados en la Tabla 2 a continuación, usando los alcoholes disponibles en el mercado apropiados y las 2,4-dicloropirimidinas apropiadamente sustituidas. 15 Tabla 2
1
2,5-dicloro-4-etoxipirimidina
2
2,5-dicloro-4-propoxipirimidina imagen22
3
2,5-dicloro-4-isoprpoxipirimidina
6
5-bromo-2-cloro-4-metoxipirimidina
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Etapa 1: 1-Bromo-2-fluoro-5-metoxi-4-nitrobenceno
5 A una solución de 1-bromo-2,5-difluoro-4-nitrobenceno (2,56 g, 0,011 mmol) en metanol (20 ml) se le añadió una solución al 25 % de metóxido sódico en metanol (2,5 ml). La mezcla se agitó a temperatura ambiente durante 1,5 horas. Después, la reacción se concentró, se volvió a disolver en EtOAc y se lavó con agua. El lavado acuoso se extrajo de nuevo con EtOAc. Los extractos orgánicos combinados se lavaron con salmuera, se secaron sobre sulfato sódico, se filtraron y se concentraron para dar 1-bromo-2-fluoro-5-metoxi-4-nitrobenceno (2,65 g, 99 %).
10 Etapa 2: 4-Bromo-5-fluoro-2-metoxianilina
A una solución de 1-bromo-2-fluoro-5-metoxi-4-nitrobenceno (0,998 g, 3,99 mmol) en isopropanol (20 ml) se le añadieron hierro (0,7 g, 12 mmol), cloruro de amonio (0,64 g, 12 mmol) y agua (2 ml). La reacción se agitó a 75 ºC
15 durante 2 horas, después se filtró y se concentró. El residuo se diluyó con agua y se extrajo con EtOAc. Los extractos orgánicos combinados se lavaron con salmuera, se secaron sobre sulfato sódico, se filtraron y se concentraron para dar 4-bromo-5-fluoro-2-metoxianilina (0,82 g, 93 %).
Etapa 3: 4-Amino-2-fluoro-5-metoxibenzonitrilo
20 A un tubo de presión se le añadieron 4-bromo-5-fluoro-2-metoxianilina (0,24 g, 1,1 mmol), cianuro de cinc (0,10 g, 0,87 mmol), Pd2(dba)3 (100 mg, 0,11 mmol), DavePhos (86 mg, 0,22 mmol) y DMF (3 ml). La reacción se cerró herméticamente y se agitó a 100 ºC durante 6 horas. La reacción se diluyó con agua y se extrajo con EtOAc. Los extractos orgánicos combinados se lavaron con salmuera, se secaron sobre sulfato sódico, se filtraron y se
25 concentraron. El producto en bruto se purificó por cromatografía ultrarrápida para dar 4-amino-2-fluoro-5metoxibenzonitrilo (0,18 g, 77 %).
De forma análoga se prepararon: 4-amino-5-cloro-2-metilbenzonitrilo; 4-amino-5-metoxi-2-metilbenzonitrilo; y 4amino-3-metoxibenzonitrilo.
30 Los Ejemplos 9, 11, 12, 14, 21, 22, 24-26, 29-33 y 37 se enumeran como "ejemplos de referencia".
Ejemplo 1: N2-(2-Metoxi-4-(metilsulfonil)fenil)-N4-metil-5-(trifluorometil)pirimidina-2,4-diamina
imagen25
35 A una mezcla de 2-metoxi-4-(metilsulfonil)anilina (0,095 g, 0,47 mmol) y 2-cloro-N-metil-5-(trifluorometil)pirimidin-4amina (0,10 g, 0,47 mmol) en 1-butanol (1,5 ml) se le añadió TFA (0,036 ml, 0,047 mmol). La reacción se agitó en un tubo cerrado herméticamente a 100 ºC durante 1,5 h. La reacción se concentró y el producto se aisló por HPLC de fase inversa para dar N2-(2-metoxi-4-(metilsulfonil)fenil)-N4-metil-5-(trifluorometil)pirimidina-2,4-diamina (0,18 g,
40 20 %). RMN 1H (400 MHz, DMSO) δ 8,58 (d, J = 12,9, 1H), 8,24 (d, J = 5,0, 2H), 7,53 (d, J = 10,1, 1H), 7,48 (s, 1H), 7,38 -7,29 (m, 1H), 3,99 (s, 3H), 3,20 (s, 3H), 2,94 (d, J = 4,3, 3H); LRRK2 Ki = 0,002.
imagen26
7
N2-(2-Cloro-4-metanosulfonil-fenil)-N4-metil-5trifluorometil-pirimidina-2,4-diamina 0,008
8
5-Cloro-N2-(2-cloro-4-metanosulfonil-fenil)-N4metil-pirimidina-2,4-diamina 0,008
9
imagen27 N2-(2-Metoxi-4-morfolin-4-ilmetil-fenil)-N4-metil5-trifluorometil-pirimidina-2,4-diamina 0,003
10
5-Cloro-2-metil-4-(4-metilamino-5-trifluorometilpirimidin-2-ilamino)-benzonitrilo 0,046
11
2-(5-Fluoro-2-metoxi-4-morfolin-4-ilmetilfenilamino)-4-metilamino-pirimidina-5carbonitrilo 0,027
12
4-Etilamino-2-(5-fluoro-2-metoxi-4-morfolin-4ilmetilfenilamino)-pirimidina-5 -carbonitrilo 0,014
13
5-Metoxi-2-metil-4-(4-metilamino-5trifluorometil-pirimidin-2-ilamino)-benzonitrilo 0,012
14
5-Cloro-N2-[2-(2-fluoro-etoxi)-4-morfolin-4ilmetil-fenil]-N4-metilpirimidina-2,4-diamina 0,009
15
imagen28 N2-(5-Fluoro-4-metanosulfonil-2-metoxifenil)N4-metil-5-trifluorometil-pirimidina-2,4-diamina 0,003
16
N2-(2-Isopropoxi-4-metanosulfonil-fenil)-N4metil-5-trifluorometil-pirimidina-2,4-diamina 0,017
17
5-Cloro-N2-[2-(2-fluoro-etoxi)-4metanosulfonilfenil]-N4-metilpirimidina-2,4diamina 0,012
18
(5-Cloro-4-metoxi-pirimidin-2-il)-[2-(2-fluoroetoxi)-4-metanosulfonilfenil]-amina 0,012
19
N2-[2-(2-Fluoro-etoxi)-4-metanosulfonil-fenil]N4-metil-5-trifluorometilpirimidina-2,4-diamina 0,003
20
imagen29 N2-(5-Cloro-4-metanosulfonil-2-metoxifenil)-N4metil-5-trifluorometil-pirimidina-2,4-diamina 0,001
21
N2-[5-Fluoro-2-(2-fluoroetoxi)-4-morfolin-4ilmetil-fenil]-N4-metil-5-trifluorometil-pirimidina2,4-diamina 0,004
22
N4-Etil-N2-[5-fluoro-2-(2-fluoro-etoxi)-4morfolin-4-ilmetil-fenil]-5-trifluorometilpirimidina-2,4-diamina 0,002
23
N2-(4-Metanosulfonil-2-metoxi-5-metil-fenil)-N4metil-5-trifluorometil-pirimidina-2,4-diamina 0,0003
24
5-cloro-N2-(2-metoxi-4-morfolinofenil)-N4metilpirimidina-2,4-diamina 0,009
25
imagen30 ácido 4-(5-cloro-4-(metilamino)pirimidin-2ilamino)-3-metoxibenzoico 0,007
26
N2-(2-metoxi-4-(morfolinosulfonil)fenil)-N4metil-5-(trifluorometil)pirimidina-2,4-diamina 0,047
27
N2-(2-metoxi-4-(trifluorometil)fenil)-N4-metil-5(trifluorometil)pirimidina-2,4-diamina 0,023
28
5-cloro-N2-(2-metoxi-4-(trifluorometil)fenil)-N4metilpirimidina-2,4-diamina 0,035
29
ácido 2-cloro-4-(5-cloro-4-(metilamino)pirimidin2-ilamino)-5-metoxibenzoico 0,036
30
1-(2-fluoro-5-metoxi-4-(4-(metilamino)-5(trifluorometil)pirimidin-2-ilamino)fenil)pirrolidin2-ona 0,003
31
4-(2-fluoro-5-metoxi-4-(4-(metilamino)-5(trifluorometil)pirimidin-2-ilamino)fenil)morfolin3-ona 0,003
32
imagen31 1-(2-fluoro-5-metoxi-4-(4-(metilamino)-5(trifluorometil)pirimidin-2-ilamino)fenil)piperidin2-ona 0,0055
33
N2-(5-fluoro-2-metoxi-4-(oxetan-3-il)fenil)-N4metil-5-(trifluorometil)pirimidina-2,4-diamina 0,003
34
N4-etil-N2-(2-metoxi-5-metil-4(metilsulfonil)fenil)-5-(trifluorometil)pirimidina2,4-diamina 0,003
35
imagen32 N2-(4-(etilsulfonil)-2-metoxi-5-metilfenil)-N4metil-5-(trifluorometil)pirimidina-2,4-diamina 0,003
36
N2-(2-metoxi-5-metil-4-(metilsulfonil)fenil)-N4metil-5-(trifluorometil)pirimidina-2,4-diamina 0,003
37
imagen33 N2-(5-fluoro-2-metoxi-4-(morfolinometil)fenil)N4-metil-5-(trifluorometil)pirimidina-2,4-diamina 0,056
38
N4-etil-N2-(8-(metilsulfonil)-2,3dihidrobenzo[b][1,4]dioxin-5-il)-5(trifluorometil)pirimidina-2,4-diamina 0,003
Ejemplo 30 Ensayo LabChip de LRRK2 in vitro
Este ensayo se usó para determinar la potencia de un compuesto para inhibir la actividad de LRRK2, determinando,
5 Kiapp, CC50 o los valores de inhibición porcentual. EN una placa de polipropileno, se incubaron juntos LRRK2, sustrato péptido marcado fluorescentemente, ATP y el compuesto de prueba. Usando un LabChip 3000 (Caliper Life Sciences), después de la reacción el sustrato se separó por electroforesis capilar en dos poblaciones: fosforilado o sin fosforilar. Las cantidades relativas de cada uno se cuantificaron mediante la intensidad de fluorescencia. Se determinó el ki de LRRK2 Ki de acuerdo con la ecuación:
10 Y=V0*( 1 -((x+Ki*(1+S/Km)+Et)/(2*Et)-(((x+Ki*(1+S/Km)+Et)^2-(4*Et*x))^0,5)/(2 *Et))).
Los valores Ki en la Tabla 4 y en otras partes en el presente documento se muestran en µM.
15 Las condiciones de ensayo y los materiales usados fueron los siguientes:
Condiciones de ensayo finales:
LRRK2 G2019S en MgCl2 5 mM: 5,2 nM (Invitrogen lot n.º 567054A)
20
LRRK2 G2019S en MnCl2 1 mM: 11 nM (Invitrogen lot n.º 567054A)
LRRK2 de tipo salvaje en MgCl2 5 mM: 15 nM (Invitrogen lot n.º 500607F)
25 LRRK2 I2020T en MgCl2 5 mM: 25 nM (Invitrogen lot n.º 43594)
Sustrato: 1 µM ATP: 130 µM Tiempo de reacción quinasa: 2 horas Temperatura: ambiente Volumen total: 20 µl ATPapp Kms:
G2019S en MgCl2 5 mM: 130 µM
imagen34
imagen35

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