ES2572615T3 - Nuevos inhibidores pirrólicos de S-nitrosoglutatión reductasa como agentes terapéuticos - Google Patents

Nuevos inhibidores pirrólicos de S-nitrosoglutatión reductasa como agentes terapéuticos Download PDF

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ES2572615T3
ES2572615T3 ES09807383.6T ES09807383T ES2572615T3 ES 2572615 T3 ES2572615 T3 ES 2572615T3 ES 09807383 T ES09807383 T ES 09807383T ES 2572615 T3 ES2572615 T3 ES 2572615T3
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mmol
synthesis
compound
scheme
carbamoyl
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Jan Wasley
Gary J. Rosenthal
Xicheng Sun
Sarah Strong
Jian Qiu
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Nivalis Therapeutics Inc
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Nivalis Therapeutics Inc
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Abstract

Un compuesto de formula I o sales farmaceuticamente aceptables del mismo:**Fórmula** en la que: Ar se selecciona entre el grupo que consiste en fenilo y tiofen-ilo; R1 se selecciona entre el grupo que consiste en imidazolilo sin sustituir e imidazolilo sustituido, en donde el grupo imidazolilo sustituido esta sustituido con alquilo C1-C6; R2 se selecciona entre el grupo que consiste en hidrogeno, metilo, cloro, fluor, hidroxi, metoxi, etoxi, propoxi, carbamoilo, dimetilamino, amino, formamido y trifluorometilo; y X se selecciona entre el grupo que consiste en CO y SO2.

Description

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una cantidad eficaz que consigue o mantiene la erección; para obesidad, una cantidad terapéuticamente eficaz es una cantidad eficaz que causa saciedad; para apoplejía, una cantidad terapéuticamente eficaz es una cantidad eficaz que aumenta el flujo sanguíneo o una cantidad eficaz que protege de TIA; para lesión por reperfusión, una cantidad terapéuticamente eficaz es una cantidad eficaz que aumenta la función; y para acondicionar previamente el
5 corazón y el cerebro, una cantidad terapéuticamente eficaz es una cantidad eficaz protectora, por ejemplo, tal como se mide con triponina o CPK.
La cantidad terapéuticamente eficaz para el tratamiento de sujeto afectado con células que proliferan de forma patológica se refiere a una cantidad de inhibición de GSNOR in vivo que es una cantidad eficaz antiproliferativa. Tal
10 cantidad eficaz antiproliferativa, como se usa en el presente documento, se refiere a una cantidad que causa una reducción de la tasa de proliferación de al menos aproximadamente un 20 %, al menos aproximadamente un 10 %, al menos aproximadamente un 5 %, o al menos aproximadamente un 1 %.
En general, la dosificación, es decir, la cantidad terapéuticamente eficaz, varía de 1 µg a 10 g/kg y a menudo varía 15 de 10 µg a 1 g/kg o de 10 µg a 100 mg/kg de peso corporal del sujeto que se está tratando, al día.
H. Otros Usos
Los compuestos que se describen en el presente documento o una sal farmacéuticamente aceptable de los mismos,
20 o un profármaco o metabolito de los mismos, se puede aplicar a diversos aparatos en circunstancias en las que la presencia de compuestos de este tipo sería beneficiosa. Un aparato de este tipo puede ser cualquier dispositivo o recipiente, por ejemplo, dispositivos implantables en los que un inhibidor de GSNOR se puede usar para revestir una malla quirúrgica o endoprótesis cardiovascular antes del implante en un paciente. Los inhibidores de GSNOR que se describen en el presente documento también se pueden aplicar a diversos aparatos para fines de ensayos in vitro o
25 para cultivo de células.
Los compuestos que se describen en el presente documento o una sal farmacéuticamente aceptable de los mismos,
o un profármaco o metabolito de los mismos, también se pueden usar como un agente para el desarrollo, aislamiento o purificación de compañeros de unión para compuestos inhibidores de GSNOR, tales como anticuerpos
30 y ligandos naturales. Los expertos en la materia pueden determinar fácilmente husos relacionados para los compuestos que se describen en el presente documento.
Ejemplos
35 Ejemplo 1: métodos generales y específicos para preparar nuevos inhibidores pirrólicos de GSNOR
Este ejemplo describe esquemas para la preparación de los inhibidores de GSNOR representados en la Tabla 1. Algunos esquemas son específicos para un compuesto en particular, mientras que otros son esquemas generales que incluyen un método a modo de ejemplo para la preparación de un compuesto representativo. Siguiendo los
40 esquemas hay métodos que describen la preparación de compuestos intermedios que se usaron en esquemas seleccionados.
Esquema 1: Un esquema general para preparar inhibidores de GSNOR con estructura 1D
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Procedimiento representativo para el Esquema 1: Síntesis de Ácido 3[1(4carbamoil2metilfenil)5(4metoxifenil)1Hpirrol2il]propanoico.
50 Etapa 1: Síntesis de (E)3Furan2il1(4metoxifenil)propenona. Una solución de 2-furaldehído (5,85 g, 60,92 mmol) se añadió a una solución de 4-metoxi acetofenona (8,5 g, 56,6 mmol) en metanol (120 ml), seguido de
46
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Etapa 5: Síntesis de ácido 3(5(4(1Himidazol1il)fenil)1(4carbamoil2metilfenil)1Hpirrol2il)propanoico (5E, Ar1 = 4carbamoil2metilfenilo, R = H). A una solución del compuesto 3-(5-(4-(1H-imidazol-1-il)fenil)-1-(4carbamoil-2-metilfenil)-1H-pirrol-2-il)propanoato de etilo (22,0 g, 48,3 mmol) en THF/H2O (v/v = 1/1, 220 ml) se añadió LiOH·H2O (4,15 g, 96,6 mmol). La solución de reacción se agitó a temperatura ambiente durante 5 h. El THF
5 se retiró a presión reducida y la solución acuosa se acidificó con HCl al 10 % a pH = 5. El sólido se filtró y se recristalizó a partir de THF y agua [1:1 (v/v)] para proporcionar ácido 3-(5-(4-(1H-imidazol-1-il)fenil)-1-(4-carbamoil-2metilfenil)-1H-pirrol-2-il)propanoico en forma de un sólido de color amarillo (11,35 g, 55 %).
Esquema 6: Un esquema general para preparar inhibidores de GSNOR con estructura 6H
10
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Procedimiento representativo para el Esquema 6: Síntesis de ácido 3(5(benzo[d][1,3]dioxol5il)1(4carbamoil2metilfenil)1Hpirrol2il)propanoico.
15 Etapa 1: Síntesis de 3metil4(1Hpirrol1il)benzamida (6A). El 2,5-dimetoxi-tetrahidrofurano (106 g, 80 mmol) se añadió a la solución de 4-amino-3-metilbenzamida (100 g, 66,7 mmol) en AcOH (300 ml). La mezcla se agitó a 80 ºC durante aproximadamente 1,5 h y a continuación se enfrió a temperatura ambiente. La solución de Na2CO3 se añadió gota a gota a 0 ºC y se extrajo con acetato de etilo tres veces. Las fases orgánicas combinadas se lavaron
20 con salmuera, se secaron sobre Na2SO4, se concentraron y se lavaron con éter de petróleo. El sólido resultante se filtró y se secó para proporcionar 3-metil-4-(1H-pirrol-1-il)benzamida en forma de un sólido de color pálido (89,7 g, rendimiento de un 67 %).
Etapa 2: Síntesis de 4(2formil1Hpirrol1il)3metilbenzonitrilo (6B). Se añadió POCl3 (65 g, 427 mmol) a DMF
25 (34 ml) a 0 ºC durante 30 min. Después de la adición, la mezcla se agitó a temperatura ambiente durante 1,1 h, y a continuación se enfrió a 0 ºC. Una solución de 3-metil-4-(1H-pirrol-1-il)benzamida (6A) (42,7 g, 213,5 mmol) en DMF (150 ml) se añadió a 0 ºC y la mezcla resultante se agitó a temperatura ambiente durante 20 min, y a continuación se calentó a 80 ºC durante 1 h. La solución se enfrió a temperatura ambiente y a continuación se añadió Na2CO3 sat. a 0 ºC hasta pH = 8. La mezcla se extrajo con acetato de etilo tres veces. Las fases orgánicas combinadas se
30 lavaron con NaHCO3 sat. y salmuera, se secaron sobre Na2SO4, se concentraron y se purificaron por cromatografía en columna sobre gel de sílice (PE:EA = 10:1) para proporcionar 4-(2-formil-1H-pirrol-1-il)-3-metilbenzonitrilo en forma de un sólido de color amarillo (30,5 g, rendimiento de un 68 %).
Etapa 3: Síntesis de 3(1(4ciano2metilfenil)1Hpirrol2il)acrilato de etilo (6C).
35 Método A: La mezcla de 4-(2-formil-1H-pirrol-1-il)-3-metilbenzonitrilo (15 g, 71,4 mmol) y (carbotoximetilen)trifenilfosforano (27,5 g, 78,6 mmol) en tolueno se calentó a 100 ºC durante una noche. A continuación se enfrió a
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Procedimiento representativo para el Esquema 9a: Síntesis de ácido 3[1[(4carbamoil2metilfenil)5(4pirazol1il)1Hpirrol2il]propiónico.
Síntesis de éster de etilo del ácido 3[1(4carbamoil2metilfenil)5(4pirazol1ilfenil)1Hpirrol2il]
5 propiónico (9aB, Ar = 1Hpirazol1ilo). Se disolvió N,N-dimetil-ciclohexano-1,2-diamina (11 mg, 0,08 mmol) en DMSO y se les clasificó con burbujeó de argón a través de la solución durante 2 minutos. A continuación, la solución resultante se añadió a una mezcla de éster de etilo del ácido 3-[1-(4-carbamoil-2-metil-fenil)-5-(4-yodo-fenil)-1Hpirrol-2-il]-propiónico (que se preparó de acuerdo con las primeras 3 etapas del Esquema 1, R2 = 4-yodo-fenilo, y R1= 4-carbamoil-2-metilfenilo) (150 mg, 0,29 mmol), pirazol (500 mg, 7,5 mmol), yoduro de cobre (11 mg,
10 0,06 mmol), y carbonato potásico (86 mg (0,61 mmol) y la mezcla de reacción resultante se desgasificó de nuevo durante 2 minutos con burbujeo de gas argón a través de la solución. A continuación, la mezcla de reacción se sometió a radiación de microondas durante 30 minutos a 120 ºC. A continuación, la mezcla de reacción se añadió a agua (10 ml), se extrajo en acetato de etilo (3 x 10 ml). Los extractos de acetato de etilo se combinaron, se lavaron con agua (5 ml) y a continuación con salmuera (5 ml). A continuación, la fase orgánica se secó sobre MgSO4. La
15 cromatografía (cartucho Sep-Pak de 5 g de sílice) con diclorometano y a continuación con metanol al 1 % en diclorometano proporciona compuesto intermedio puro, éster de etilo del ácido 3-[1[(4-carbamoil-2-metil-fenil)-5-(4pirazol-1-il)-1Hpirrol-2-il]-propiónico (26 mg, 20 %).
Síntesis de ácido 3(5(4(1Hpirazol1il)fenil)1(4carbamoil2metilfenil)1Hpirrol2il)propanoico (9aC,
20 Ar = 1Hpirazol1ilo). El éster de etilo del ácido 3-[1-(4-carbamoil-2-metil-fenil)-5-(4-pirazol-1-il-fenil)-1H-pirrol-2-il]propiónico (24 mg, 0,06 mmol) se hidrolizó usando el procedimiento que se ha descrito anteriormente en la etapa final del esquema 1 para dar el compuesto del título, ácido 3-[1[(4-carbamoil-2-metil-fenil)-5-(4-pirazol-1-il)-1H-pirrol2-il]-propiónico (18 mg, 75 %).
25 Esquema 9b: Un esquema general para preparar inhibidores de GSNOR con estructura 9b-C
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Procedimiento representativo para el Esquema 9b: Síntesis de ácido 3[1(4carbamoil2metilfenil)5(530 imidazol1iltiofen2il)1Hpirrol2il]propiónico.
Síntesis de éster de etilo del ácido 3[1(4carbamoil2metilfenil)5(5imidazol1iltiofen2il)1Hpirrol2il]propiónico. Se preparó usando el mismo protocolo que en la Etapa 1 del Esquema 9a excepto en que se parte de 3-(5-(5-bromotiofen-2-il)-1-(4-carbamoil-2-metilfenil)-1H-pirrol-2-il)propanoato de etilo (que se preparó de acuerdo
35 con las primeras 3 etapas del Esquema 1, R2 = 5-bromotiofen-2-ilo, y R1= 4-carbamoil-2-metilfenilo).
Síntesis de ácido 3[1(4carbamoil2metilfenil)5(5imidazol1iltiofen2il)1Hpirrol2il]propiónico. El éster de etilo del ácido 3-[1-(4-carbamoil-2-metil-fenil)-5-(5-imidazol-1-il-tiofen-2-il)-1H-pirrol-2-il]-propiónico se hidrolizó de acuerdo con el procedimiento descrito en la etapa final del esquema 1 para dar el compuesto del título,
40 ácido 3-[1-(4-carbamoil-2-metil-fenil)-5-(5-imidazol-1-il-tiofen-2-il)-1H-pirrol-2-il]-propiónico.
51
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mezcla se purificó por cromatografía ultrarrápida sobre gel de sílice, eluyendo con EtOAc, para proporcionar el producto deseado, 7-(3-fluoro-4-(1H-imidazol-1-il)fenil)-4,7-dioxoheptanoato de etilo (279 mg, 68 %) en forma de sólidos de color marrón.
Esquema 37 - El Esquema 38 se omitió de forma intencionada.
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Síntesis de 39A. A una mezcla de 164 (Método 16) (200 mg, 0,419 mmol), NaBH3CN (53 mg, 0,838 mmol), HCHO al 37 % (1,5 ml, 2,095 mmol) en CH3CN (5 ml) se añadió AcOH (0,5 ml). Después de agitar a temperatura ambiente durante una noche, la solución se concentró y se diluyó con agua (15 ml), se extrajo con acetato de etilo (10 ml 3 4).
15 La fase orgánica se separó y se secó, se purificó con TLC preparativa (PE : EA = 1 : 1) para proporcionar 39A en forma de un aceite de color amarillo (97 mg, 49 %).
Síntesis de 39B. Se siguió el procedimiento descrito en las dos últimas etapas del Esquema 6 (etapas 7 y 8), con una purificación del producto final con HPLC preparativa.
20 Esquema 40: Síntesis de ácido 3(1(4carbamoil2metilfenil)5(4cloro2formamidofenil)1Hpirrol2il)propanoico
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25
Síntesis de 3(5(4cloro2formamidofenil)1(4ciano2metilfenil)1Hpirrol2il)propanoato de etilo (40A):
Una mezcla de Ac2O (301 mg, 2,948 mmol) y HCO2H (226 mg, 4,914 mmol) se agitó a 55 ºC durante 5 min. La mezcla se añadió a la solución de 164 (para la síntesis véase el método 16) (300 mg, 0,737 mmol) en THF (6 ml) y se agitó a 55 ºC durante 10 min. La TLC mostraba que la reacción era completa. Los compuestos volátiles se
30 retiraron a presión reducida, y el residuo se disolvió en EA (50 ml), se lavó con NaHCO3 sat. (10 ml x 3) y salmuera (10 ml). La fase orgánica se secó sobre Na2SO4 anhidro, se filtró y se concentró para proporcionar el producto en bruto en forma de un sólido de color amarillo (320 mg, rendimiento: 99 %) que se usó para la siguiente etapa directamente.
35 Síntesis de ácido 3(1(4carbamoil2metilfenil)5(4cloro2formamidofenil)1Hpirrol2il)propanoico (40B): Véase la metodología descrita en las últimas etapas del Esquema 6 (6F → 6H).
Los siguientes métodos se usaron para preparar compuestos intermedios que se usaron en los Esquemas mencionados anteriormente como se indica en la Tabla.
40
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que se usó para la siguiente etapa directamente.
Síntesis de 1(5bromo4clorotiofen2il)etanona (282). A una mezcla de 281 (10,0 g, 50,6 mmol) y AlCl3 (8,09 g, 60,7 mmol) en DCM (120 ml) se añadió gota a gota cloruro de acetilo (4,76 g, 60,7 mmol) durante 5 min a
5 0 ºC. Después de la adición, la mezcla se agitó durante una noche a temperatura ambiente, se lavó con ácido clorhídrico diluido (1,2 N, 150 ml) y salmuera (150 ml), se secó sobre Na2SO4 anhidro, se filtró y se concentró y se purificaron por cromatografía en columna sobre gel de sílice (PE/EA = 20/1 a 3/1) para proporcionar 282 en forma de un sólido de color marrón (8,0 mg, rendimiento: 66 %).
10 Síntesis de 1(4clorotiofen2il)etanona (283). A una solución de 282 (3,20 mg, 13,36 mmol) en EtOH (70 ml) se añadió Pd al 10 %/C (2,50 g) y AcONa (1,10 g, 13,36 mmol). La mezcla de reacción se agitó en una atmósfera de hidrógeno a temperatura ambiente durante 3 h, se filtró, y el filtrado se concentró. El residuo resultante se disolvió en EA (100 ml) se lavó con NaHCO3 sat. (40 ml) y salmuera (30 ml), se secó sobre Na2SO4 se filtró, se concentró y se purificó por cromatografía en columna sobre gel de sílice (PE/EA = 30/1 a 5/1) para proporcionar 283 en forma de
15 un aceite de color amarillo (1,32 g, rendimiento: 62 %).
Método 29 - El Método 32 se omitió de forma intencionada.
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Síntesis del Compuesto 332: una mezcla de HCO2H (644 mg, 14 mmol) y Ac2O (1,16 g, 11,4 mmol) se calentó a 55 ºC durante 2 h y a continuación se enfrió a temperatura ambiente. El THF (1 ml) y 331 (880 mg, 4,38 mmol) en
25 THF (1 ml) se añadieron en etapas y la mezcla resultante se agitó continuamente a temperatura ambiente durante 3 h. Después de la evaporación, el residuo se extrajo con EA (5 ml x 3). La fase orgánica se lavó sucesivamente con bicarbonato sódico acuoso saturado (10 ml) y cloruro sódico (10 ml), se secó sobre sulfato sódico anhidro, se filtró y se concentró para proporcionar 332 en forma de un líquido (845 mg, rendimiento: 85 %), que se usó directamente para la siguiente etapa.
30 Síntesis del Compuesto 333: a una mezcla de 332 (845 mg, 4,38 mmol), KOAc (726 mg, 7,4 mmol), B(pin)2 (1,41 g, 5,6 mmol) y dioxano se añadió Pd(dppf)2Cl2 (20 mg, 0,02 mmol). Después de su desgasificación y recarga con nitrógeno, la mezcla se calentó a reflujo a 90 ºC durante una noche. La TLC mostraba que la reacción era completa. Se añadió agua (10 ml) y la mezcla se extrajo con acetato de etilo (10 ml x 3). Las fases orgánicas
35 combinadas se secaron sobre Na2SO4, se filtraron, se concentraron y se purificaron por cromatografía en columna sobre gel de sílice (PE : EA = 4:1) para proporcionar 333 en forma de un sólido incoloro (220 mg, rendimiento: 29 %).
El Método 34 se omitió de forma intencionada.
40 Método 35: Síntesis de 4aminobencenosulfonamida. Se siguió el procedimiento/esquema que se describe en el Método 27, Síntesis de 4-amino-3-metilbencenosulfonamida.
Los Métodos 36-40 se omitieron de forma intencionada. 45
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50 Compuesto 412. A una solución de 411 (2,0 g, 13,32 mmol) en acetona (25 ml) se añadió NBS (2,37 g, 13,32 mmol) y HCl ac. 1 M (0,13 ml, 0,13 mmol). La mezcla de reacción se agitó a temperatura ambiente durante
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Resultados del Compuesto 26
El Compuesto 26 administrado por vía intravenosa (IV) o por vía oral era eficaz frente al asma experimental como se observa mediante una atenuación de broncoconstricción e inflamación pulmonar inducidas por metacolina (MCh). La eficacia significativa del Compuesto 26 se observó con una sola dosis IV de 0,1, 1, y 10 mg/kg a 24 h antes de MCh. El área bajo la curva (AUC) para la respuesta de Paum indicada como un porcentaje del control de vehículo (AUC = 100 %) era de un 64,2 ± 7,6 % (p = 0,0007); 60,2 ± 7,9 % (p = 0,0002); y 40,7 ± 2,4 % (p < 0,0001) para 0,0 mg/kg, 1 mg/kg, y 10 mg/kg, respectivamente, de Compuesto 26. La infiltración de eosinófilos en el fluido de lavado broncoaveolar (BALF) se redujo en un 79 % (p = 0,0064); 100 % (p = 0,0007); y 100 % (p = 0,0007) para 0,0 mg/kg, 1 mg/kg, y 10 mg/kg, respectivamente, de Compuesto 26. La eficacia significativa del Compuesto 26 también se observó tan pronto como los 30 min. (AUC = 35,2 ± 9,3; p < 0,0001) antes de MCh a una sola dosis IV de 10 mg/kg. La infiltración de eosinófilos en el BALF se redujo en un 94 % (p < 0,0001). La eficacia significativa con el Compuesto 26 también se observó con una sola dosis oral de 30 mg/kg a 24 h antes de MCh. El área bajo la curva (AUC) para la respuesta de Paum indicada como un porcentaje del control de vehículo (AUC = 100 %) era de un 26,7 ± 1,4 % (p < 0,0001). La infiltración de eosinófilos en el fluido de lavado broncoaveolar (BALF) se redujo en un 100 % (p = 0,0019).
Resultados del Compuesto 33
El Compuesto 33 administrado por vía intravenosa era eficaz frente al asma experimental como se observa mediante una atenuación de broncoconstricción e inflamación pulmonar inducidas por metacolina (MCh). La eficacia significativa del Compuesto 33 se observó con una sola dosis IV de 1 mg/kg a 24 h antes de MCh. El área bajo la curva (AUC) para la respuesta de Paum indicada como un porcentaje del control de vehículo (AUC = 100 %) era de un 72,9 ± 8,7 % (p = 0,0089). La infiltración de eosinófilos en el fluido de lavado broncoaveolar (BALF) se redujo en un 61 % (p < 0,0001).
Resultados del Compuesto 67
El Compuesto 67 administrado por vía intravenosa (IV) era eficaz frente al asma experimental como se observa mediante una atenuación de broncoconstricción e inflamación pulmonar inducidas por metacolina (MCh). La eficacia significativa del Compuesto 67 se observó con una sola dosis IV de 1 mg/kg a 24 h antes de MCh. El área bajo la curva (AUC) para la respuesta de Paum indicada como un porcentaje del control de vehículo (AUC = 100 %) era de un 78,7 ± 8,1 % (p = 0,0323). La infiltración de eosinófilos en el fluido de lavado broncoaveolar (BALF) se redujo en un 63 % (p < 0,0001).
66

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