ES2618352T3 - Antagonistas del receptor de prostaglandina D2 para el tratamiento de la alopecia androgenética - Google Patents

Antagonistas del receptor de prostaglandina D2 para el tratamiento de la alopecia androgenética Download PDF

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ES2618352T3
ES2618352T3 ES07809581.7T ES07809581T ES2618352T3 ES 2618352 T3 ES2618352 T3 ES 2618352T3 ES 07809581 T ES07809581 T ES 07809581T ES 2618352 T3 ES2618352 T3 ES 2618352T3
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methyl
benzoyl
ylmethoxy
indole
dihydro
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Luis Garza
George Cotsarelis
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University of Pennsylvania Penn
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Abstract

Un antagonista del receptor de prostaglandina D2 (receptor DP) para su uso en el tratamiento de la alopecia androgenética (AAG) en el cuero cabelludo de un sujeto.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
En otra realización, el antagonista del receptor DP es una variante de la estructura anterior, en la que el grupo ciclopentilo de la derecha arriba está sustituido por un grupo ciclohexilo. Cada uno de los sustituyentes enumerados 5 para la estructura anterior puede usarse para esta estructura que contiene ciclohexilo.
En otra realización, el antagonista del receptor DP tiene una de las siguientes estructuras:
imagen7
7
imagen8
imagen9
imagen10
imagen11
imagen12
imagen13
imagen14
imagen15
imagen16
imagen17
imagen18
imagen19
imagen20
En otras realizaciones, el antagonista del receptor DP es una sal no tóxica de uno de los compuestos anteriores.
En otras realizaciones, el antagonista del receptor DP se selecciona entre los siguientes compuestos: (1) éster bencílico del ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético,
(2)
ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (3) ácido 1-(4-((2R)-1,4-benzodioxan-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (4) ácido 1-(4-((2S)-1,4-benzodioxan-2ilmetoxi)benzoil)-2-metil-1H-indolo-4-il-acético, (5) ácido 1-(4-((2S)-1-metilindolin-2-ilmetoxi)benzoil)-2-metil-1H-indol4-il-acético, (6) ácido 1-(4-((2R)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (7) ácido 1-(4-((2S)-4,6-dimetil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (8) ácido 1-(4-((2S)-6-fluoro-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (9) ácido 1-(4-((2S)-6-metoxi-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (10) ácido 1-(4-((2S)-7-metoxi-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (11) ácido 1-(4-((2S)-4,7-dimetil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4ilacético, (12) ácido 1-(4-((2 S)-7-fluoro-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4il-acético, (13) ácido 1-(4-((2S)-1-etilindolin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (14) ácido 1-(4-((2S)-4,8dimetil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (15) ácido 1-(4-((2S)-5-metoxi4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (16) ácido 1-(4-((2S)-5-fluoro4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (17) ácido 1-(4-((2S)-2,3dihidrobenzofuran-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (18) ácido 1-(4-((2R)-2,3-dihidrobenzofuran-2ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (19) ácido 1-(4-((2S)-8-fluoro-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (20) ácido 1-(4-((2R)-1,4-benzoxatian-2-ilmetoxi)benzoil)-2-metil-1Hindol-4-il-acético, (21) ácido 1-(4-((3S)-2,3-dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (22) ácido 1-(4-((3R)-2,3-dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (23) ácido 1-(4-((3R)-5-fluoro2,3-dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (24) ácido 1-(4-((3R)-5-metil-2,3dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (25) ácido 1-(4-((3R)-6-fluoro-2,3dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (26) ácido 1-(4-((3R)-7-metil-2,3dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-ilacético, (27) ácido 1-(4-((2R)-5-fluoro-1,4-benzodioxan-2ilmetoxi)benzoil)-2-metil-1H-indol-4-il-acético, (28) ácido 1-(4-((2S)-8-fluoro-1,4-benzodioxan-2-ilmetoxi)benzoil)-2metil-1H-indol-4-il-acético, (29) ácido 1-(4-((3R)-7-fluoro-2,3-dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4il-acético, (30) éster alílico del ácido 3-(1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil1H-indol-4-il)acrílico, (31) ácido 3-(1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1Hindol-4-il)acrílico, (32) ácido 3-(1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol4-il)propanoico, (33) éster bencílico del ácido (1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2metil-1H-indol-4-il)oxiacético, (34) ácido (1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil1H-indol-4-il)oxiacético, (35) éster bencílico del ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2ilmetoxi)benzoil)-2-metil-1H-indol-4-carboxílico, (36) ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2ilmetoxi)benzoil)-2-metil-1H-indol-4-carboxílico, (37) éster bencílico del ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4benzoxazin-2-ilmetoxi)benzoil)-1H-indol-4-il-acético, (38) ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2ilmetoxi)benzoil)-1H-indol-4-il-acético, (39) ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)2,3-dihidro-1H-indol-4-il-acético, (40) ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2metil-2,3-dihidro-1H-indol-4-il-acético, (41) 2-(1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2metil-1H-indol-4-il)etanol, (42) 2-(1-(4-((2S)-4,6-dimetil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1Hindol-4-il)etanol, (43) 2-(1-(4-((2S)-6-fluoro-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1Hindol-4-il)etanol, (44) 2-(1-(4-((2S)-7-fluoro-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1Hindol-4-il)etanol, (45) 2-(1-(4-((2S)-2,3-dihidrobenzofuran-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il)etanol, (46) 2-(1-(4((3R)-2,3-dihidrobenzofuran-3-ilmetoxi)benzoil)-2-metil-1H-indol-4-il)etanol, (47) N-metilsulfonil-( 1-(4-((2S)-4-metil3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il)acetamida, (48) N-fenilsulfonil-(1-(4-((2S)-4metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il)acetamida, (49) acetato de 2-(1-(4-((2S)4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)benzoil)-2-metil-1H-indol-4-il)etilo, (50) éster bencílico del ácido 1(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)-2-metilbenzoil)-2-metil-1H-indol-4-il-acético, (51) éster bencílico del ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)-2-metilbenzoil)-1H-indol-4-il-acético,
(52)
ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)-2-metilbenzoil)-2-metil-1H-indol-4-il-acético, y
(53)
ácido 1-(4-((2S)-4-metil-3,4-dihidro-2H-1,4-benzoxazin-2-ilmetoxi)-2-metilbenzoil)-1H-indol-4-il-acético o una sal no tóxica de los mismos.
En otras realizaciones, el antagonista del receptor DP tiene la estructura:
21
imagen21
en la que
R.sup.1 representa hidroxi, alcoxi C1-6, o NR.sup.8R.sup.9, en la que cada uno de R.sup.8 y R.sup.9 representa independientemente un átomo de hidrógeno, alquilo C1-6, o SO.sub.2R.sup.13, en la que R.sup.13 representa alquilo C1-6, un anillo carbocíclico saturado o insaturado C3-15 o un anillo heterocíclico de 4 a 15 miembros que contiene de 1 a 5 átomos de nitrógeno, átomos de azufre y/o átomos de oxígeno; R.sup.2 representa un átomo de hidrógeno, alquilo C1-6, alcoxi C1-6, alcoxialquilo C2-6, un átomo de halógeno, amino, trihalometilo, ciano, hidroxi, bencilo, o 4-metoxibencilo; R.sup.3 representa un átomo de hidrógeno, alquilo C1-6, alcoxi C1-6, un átomo de halógeno, trihalometilo, ciano, o hidroxi; cada uno de R.sup.4 y R.sup.5 representa independientemente un átomo de hidrógeno, alquilo C1-6, alcoxi C1-6, alcoxialquilo C2-6, un átomo de halógeno, nitro, amino, trihalometilo, ciano, o hidroxi; D representa un enlace sencillo, alquileno C1-6, alquenileno C2-6, u oxialquileno C1-6; en --G--R.sup.6,
1) G representa un enlace sencillo, alquileno C1-6 que puede estar sustituido con 1 a 2 átomos de oxígeno y/o átomos de azufre, alquenileno C2-6 que puede estar sustituido con 1 a 2 átomos de oxígeno y/o átomos de azufre, en la que el alquileno y el alquenileno pueden estar sustituidos con hidroxi o alcoxi C1-4, --C(O)NH--, --NHC(O)--, -SO.sub.2NH--,-NHSO.sub.2--, o diazo; R.sup.6 representa un anillo carbocíclico saturado o insaturado C3-15, o un anillo heterocíclico de 4 a 15 miembros que contiene de 1 a 5 átomos de nitrógeno, átomos de azufre y/o átomos de oxígeno, en la que el anillo puede estar sustituido con 1 a 5 sustituyentes seleccionados entre alquilo C1-6, alcoxi C1-10, alcoxialquilo C2-6, un átomo de halógeno, hidroxi, trihalometilo, nitro, amino, fenilo, fenoxi, oxo, acilo C2-6, alcanosulfonilo C1-6 y ciano,
2) G y R.sup.6 se toman juntos para representar
(i)
alquilo C1-15 que puede estar sustituido con 1 a 5 átomos de oxígeno y/o átomos de azufre;
(ii)
alquenilo C2-15 que puede estar sustituido con 1 a 5 átomos de oxígeno y/o átomos de azufre; o
(iii) alquinilo C2-15 que puede estar sustituido con 1 a 5 átomos de oxígeno y/o átomos de azufre, en la que el alquilo, el alquenilo y el alquinilo pueden estar sustituidos con 1 a 12 sustituyentes seleccionados entre alcoxi C1-6, un átomo de halógeno, hidroxi, ciano, oxo y NR.sup.11R.sup.12, en la que cada uno de R.sup.11 y R.sup.12 representa independientemente un átomo de hidrógeno, alquilo C1-6, alquenilo C2-6, fenilo, benzoílo, naftilo, fenilo sustituido con alquilo C1-6, o alquilo C1-6 sustituido con fenilo o ciano; n representa de 1 a 3; m representa de 1 a 3; i representa de 1 a 4; y
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Claims (1)

  1. imagen1
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