AR045700A1 - Derivados de combretastatina que presentan actividad citotoxica - Google Patents

Derivados de combretastatina que presentan actividad citotoxica

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Publication number
AR045700A1
AR045700A1 ARP040102518A ARP040102518A AR045700A1 AR 045700 A1 AR045700 A1 AR 045700A1 AR P040102518 A ARP040102518 A AR P040102518A AR P040102518 A ARP040102518 A AR P040102518A AR 045700 A1 AR045700 A1 AR 045700A1
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Argentina
Prior art keywords
hydrogen
phenyl
methoxy
trimethoxy
double
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ARP040102518A
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English (en)
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Daniele Simoni
Romeo Romagnoli
Giuseppe Giannini
Domenico Alloati
Claudio Pisano
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Sigma Tau Ind Farmaceuti
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Publication of AR045700A1 publication Critical patent/AR045700A1/es

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Abstract

Dichos compuestos, aunque están relacionados químicamente con la estructura de cis/trans-combretastatina, no siempre ligan a la tubulina, pero sin embargo presentan actividad citotóxica de interés en el campo oncológico como agentes anticáncer y/o antiangiogénicos. Reivindicación 1: Compuestos de fórmula (1) caracterizados porque: los diversos R1, R2, R3 y R4, que pueden ser iguales o diferentes, son H, OH, OPO3H2 u OCH2OPO3H2 y su sal disódica, OMe, OCH2O, NO2, F, Cl, Br; -R1-R2- también pueden ser juntos: -CR8=CR9-X-; Y es un radical seleccionado del grupo (2); R5 y R6, que pueden ser iguales o diferentes, son H o halógeno; R7 es H, OMe, SO2Ph; Ar es una estructura seleccionada del grupo (3); R8, R9 y R10, que pueden ser iguales o diferentes, son H, OH, OPO3H2 o OCH2OPO3H2 y su sal disódica, OR11, OCH2O, NH2, NHR11, NO2, alquilo C1-4, C6H5, C5H4N o halógeno; R11 es alquilo C1-4 o acilo, residuo de aminoácidos; X es O, S, N, NR12; R12 es H, CH3, CH2Ph; Z es CH, N; con la condición de que el compuesto de fórmula (1) no sea combretastatina A-1, combretastatin A-2, combretastatin A-4, y sus derivados fosfatos disódicos y con la exclusión de los siguientes compuestos: 2-fenil-6-trans-estiril-benzo[b]furano; 2,3-difenil- 6-trans-estiril-benzo[b]furano; 2-fenil-6-(4-metoxi)-trans-estiril-benzo[b]furano; 2-fenil-6-(3,4-dimetoxi)-trans-estiril-benzo[b]furano; 2-fenil-6-(3,4,5-trimetoxi)-trans-estiril-benzo[b]furano; 2-fenil-6-(3,4-metilendioxi)-trans-estiril- benzo[b]furano; 2,3-difenil-6-(4-metoxi)-trans-estiril-benzo[b]furano; 2-fenil-5-(3,4-metilendioxi)-trans-estiril-benzo[b]tiofeno; 2-fenil-6-trans-estiril-benzo[b]tiofeno; 2-fenil-6-(4-metoxi)-trans-estiril-benzo[b]tiofeno; 2-fenil-6-(4-cloro)-trans- estiril-benzo[b]tiofeno; Piceatanol; 1-(3-furanil)-2-(3,4,5-trimetoxifenil)eteno; 1-(3-tiofenil)-2-(3,4,5-trimetoxifenil)eteno; 1-(2-furanil)-2-(3,4,5-trimetoxifenil)eteno; y con la condición de que: - cuando R1 es hidrógeno y R2-R4 son 3,4,5- trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 2-cloro, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R4 son trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, por lo menos uno de R8-R10 no es hidrógeno; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es ninguno de 4-cloro, 4-bromo, 4-nitro, 4-hidroxi, 4-acetilo, 4-etoxi, 4-alquilo C1-4; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-nitro o 4-amino, R10 no es ninguno de 3-cloro, 3-metoxi, 3-metilo; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-nitro o 3-amino, R10 no es ninguno de 3- cloro, 3-metoxi, 3-metilo; - cuando R1 es hidrógeno y R2-R4 son 2,3,4-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, por lo menos uno de R8 es hidrógeno, R9 es 3-metoxi, R10 no es 5-metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8-R10 no son metoxi; - cuando R1 y R2 son hidrógeno y R3-R4 son 3,4-dimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es 4-metoxi; - cuando R1 y R2 son hidrógeno y R3-R4 son 3,4-dimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9-R10 no son 3,5-dimetoxi; - cuando R1 y R2 son hidrógeno y R3-R4 son 3, 4-dimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, por lo menos uno de R8-R10 no es hidrógeno; - cuando R1 y R2 son hidrógeno y R3-R4 son 3,5-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es 4-metoxi; - cuando R1 y R2 son hidrógeno y R3-R4 son 3,5-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, Rio no es 4-acetilo; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar no es piridilo; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-amino, R10 es 4-NHR11, R11 no es el residuo de serina; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-amino, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-amino, R10 no es un grupo 4-alquiloxi que tiene de 1 a 3 átomos de carbono, o un grupo 4-alquilo que tiene de 1 a 4 átomos de carbono, o un átomo de halógeno; - cuando R1 es hidrógeno y R2-R3 son 3,4-metilendioxi, R4 es 5-metoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-amino, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R4 son 2,3, 4-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-amino, R10 no es 4-metoxi;- cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es NHR11, R11 es el residuo de serina, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R3 son 3,4-metilendioxi, R4 es 4- metoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es NHR11, R11 es el residuo del aminoácido cisteina, glicina, fenilalanina, serina, triptofano, tirosina, valina, R10 no es 4- metoxi; - cuando R1 es hidrógeno y R2-R3 son 3,4-metilendioxi, R4 es 4-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es NO2 o NH2, R10 no es 4-metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, por lo menos uno de R8-R10 no es hidrógeno;- cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metoxi, R10 no es 3-fluoro; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metilo, R10 no es 3-fluoro o 3-hidroxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metoxi, R10 no es 3-metoxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es 3-fluoro, R9 es 4-metoxi, R10 no es 2- o 5-fluoro; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metoxi, R10 no es 3-hidroxi o 3-amino; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metoxi, R10 no es 3-fluoro o 3-bromo; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 y R9 son hidrógeno, R10 no es 4-hidroxi; - cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-metilo, R10 no es 4-metilo;- cuando R1 es hidrógeno y R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace cis, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 4-metoxi, R10 no es 3-hidroxi;- cuando R1-R2 son hidrógeno y R3-R4 son 3,5-dihidroxi, Y es un doble enlace trans, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 es 3-hidroxi, R10 no es 5-hidroxi; - cuando R1-R3 son hidrógeno, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 y R10 son 3,4-dimetilo, y R4 no es 4-metoxi;- cuando R1-R2 son hidrógeno, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8 es hidrógeno, R9 y R10 son 3,4-dimetilo, R4 es 4-metoxi,R3 no es 3-fluoro o 3-bromo o 3-nitro o 3-hidroxi; - cuando R1-R2 son hidrógeno, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8-R10 son 3,4,5-trietoxi, R4 es 4-metoxi, R3 no es 3-fluoro o 3-cloro o 3-bromo o 3-hidroxi;- cuando R1-R2 son hidrógeno, R4 es 4-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8-R9 son 4,5-dimetoxi, R10 es 3-hidroxi, R3 no es 3-fluoro o 3- hidroxi; - cuando R1-R2 son hidrógeno, R4 es 4-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es fenilo, R8-R9 son 4,5-dimetoxi, R10 es 3-metoxi, R3 no es 3-fluoro; - cuando R1 es hidrógeno, R2-R4 son 3,4,5-trimetoxi, Y es un doble enlace, R5 y R6 son H, Ar es 2-naftilo, por lo menos uno de R8-R10 no es hidrógeno; - cuando R1 y R2 son hidrógeno, R3 es 3-hidroxi, R4 es 4-metoxi, Y es un doble enlace, R5 y R6 son H, Ar es 2-naftilo, por lo menos uno de R8-R10 no es hidrógeno; - cuando R1 es hidrógeno, R2-R4 son 3,4,5-trimetoxi, Y es de fórmula (4), Ar es indolilo, en donde por lo menos uno de R8-R10 es diferente de hidrógeno; sus enantiómeros, diastereoisómeros, las mezclas respectivas y sus sales farmacéuticamente aceptables.
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