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ES2580803T3 - Moduladores de transportadores del casete de unión a ATP - Google Patents

Moduladores de transportadores del casete de unión a ATP Download PDF

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Publication number
ES2580803T3
ES2580803T3 ES13167785.8T ES13167785T ES2580803T3 ES 2580803 T3 ES2580803 T3 ES 2580803T3 ES 13167785 T ES13167785 T ES 13167785T ES 2580803 T3 ES2580803 T3 ES 2580803T3
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Spain
Prior art keywords
optionally substituted
independently
ring
carboxylic acid
aliphatic
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ES13167785.8T
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Inventor
Sara S. Hadida Ruah
Peter D.J. Grootenhuis
Fredrick Van Goor
Jinglan Zhou
Brian Bear
Mark T. Miller
Jason Mccartney
Mehdi Michel Jamel Numa
Xiaoqing Yang
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Abstract

Un compuesto de fórmula Ic:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que R1 es -ZAR4, en el que cada ZA es independientemente un enlace o una cadena alifática C1-6 ramificada o lineal opcionalmente sustituida en la que hasta dos unidades de carbono de ZA están opcional e independientemente sustituidas con -CO-, -CS-, -CONRA-, -CONRANRA-, -CO2- -OCO-, -NRACO2-, -O-, -NRACONRA-, -OCONRA-, - NRANRA-, -NRACO-, -S-, -SO-, -SO2- -NRA-, -SO2NRA-, -NRASO2- o -NRASO2NRA-, Cada R4 es independientemente RA, halógeno, -OH, -NH2, -NO2, -CN o -OCF3, Cada RA es independientemente hidrógeno, un alifático opcionalmente sustituido, un cicloalifático opcionalmente sustituido, un heterocicloalifático opcionalmente sustituido, un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido; Cada R2 es independientemente -ZBR5, en el que cada ZB es independientemente un enlace o una cadena alifática C1-6 ramificada o lineal opcionalmente sustituida en la que hasta dos unidades de carbono de ZB están opcional e independientemente sustituidas con -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -OCO-, -NRBCO2-, - O-, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -NRB-, -SO2NRB-, -NRBSO2- o - NRBSO2NRB-, Cada R5 es independientemente RB30 , halógeno, -OH, -NH2, -NO2, -CN, -CF3 o -OCF3, Cada RB es independientemente hidrógeno, un alifático opcionalmente sustituido, un cicloalifático opcionalmente sustituido, un heterocicloalifático opcionalmente sustituido, un arilo opcionalmente sustituido, o un heteroarilo opcionalmente sustituido; o, dos grupos R2 cualquiera adyacentes junto con los átomos a los que están unidos forman un carbociclo opcionalmente sustituido o un heterociclo opcionalmente sustituido; El Anillo A es un anillo monocíclico de 3-7 miembros que tiene 0-3 heteroátomos seleccionados de N, O y S; El Anillo B es un grupo que tiene la fórmula Ia:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que p es 0-2, Cada R3 y R'3 es independientemente -ZCR6, en el que cada ZC es independientemente un enlace o una cadena alifática C1-6 ramificada o lineal opcionalmente sustituidaen la que hasta dos unidades de carbono de ZC están opcional e independientemente sustituidas con -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, - OCO-, -NRCCO2-, -O-, -NRCCONRC-, -OCONRC-, -NRCNRC-, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -SO2NRC-, - NRCSO2- o -NRCSO2NRC-, Cada R6 es independientemente RC, halógeno, -OH, -NH2, -NO2, -CN o -OCF3, Cada RC es independientemente hidrógeno, un alifático opcionalmente sustituido, un cicloalifático opcionalmente sustituido,un heterocicloalifático opcionalmente sustituido, un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido, o, dos grupos R3 cualquiera adyacentes junto con los átomos a los que están unidos forman un heterociclo opcionalmente sustituido; y n es 1-3, a condición de que Cuando el anillo A es ciclopentilo sin sustituir, n es 1, R2 es 4-cloro y R1 es hidrógeno, entonces el anillo B no es 2-(terc-butil)indol-5-ilo, o (2,6-diclorofenil(carbonil))-3-metil-1H-indol-5-ilo; y cuando el anillo A es ciclopentilo sin sustituir, n es 0 y R1 es hidrógeno, entonces el anillo B no es**Fórmula** para su uso en el tratamiento de la infertilidad masculina o insuficiencia pancreática.

Description

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En otras realizaciones, R1 es -ZAR4, en el que cada ZA es un enlace y cada R4 es hidrógeno.
2. Grupo R2
Cada R2 es independientemente -ZBR5, en el que cada ZB es independientemente un enlace o una cadena alifática C1-6 ramificada o lineal opcionalmente sustituida en la que hasta dos unidades de carbono de ZB están opcionalmente e independientemente sustituidas con -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -OCO-, -NRBCO2-, -O-, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -NRB-, -SO2NRB-, -NRBSO2-o -NRBSO2NRB-.
RB RB
Cada R5 es independientemente , halógeno, -OH,-NH2, -NO2, -CN, -CF3, o -OCF3. Cada es independientemente hidrógeno, un alifático opcionalmente sustituido, un cicloalifático opcionalmente sustituido, un heterocicloalifático opcionalmente sustituido, un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido. Alternativamente, dos grupos R2 cualquiera adyacentes junto con los átomos a los que están unidos forman un carbociclo opcionalmente sustituido o un heterociclo o heteroarilo opcionalmente sustituido.
En varias realizaciones, R2 es un alifático opcionalmente sustituido. Por ejemplo, R2 es una cadena alifática C1-6 ramificada o lineal opcionalmente sustituida. En otros ejemplos, R2 es una cadena de alquilo C1-6 ramificada o lineal opcionalmente sustituida, una cadena de alquenilo C2-6 ramificada o lineal opcionalmente sustituida, o una cadena de alquinilo C2-6 ramificada o lineal opcionalmente sustituida. En realizaciones alternativas, R2 es una cadena alifática C1-6 ramificada o lineal que está opcionalmente sustituida con 1-3 de halógeno, hidroxi, ciano, cicloalifático, heterocicloalifático, arilo, heteroarilo, o combinaciones de los mismos. Por ejemplo, R2 es un alquilo C1-6 ramificado o lineal que está opcionalmente sustituido con 1-3 de halógeno, hidroxi, ciano, cicloalifático, heterocicloalifático, arilo, heteroarilo, o combinaciones de los mismos. En todavía otros ejemplos, R2 es un metilo, etilo, propilo, butilo, isopropilo o terc-butilo, cada uno de los cuales está opcionalmente sustituido con 1-3 de halógeno, hidroxi, ciano, arilo, heteroarilo, cicloalifático o heterocicloalifático. En todavía otros ejemplos, R2 es un metilo, etilo, propilo, butilo, isopropilo o terc-butilo, cada uno de los cuales está sin sustituir.
En varias otras realizaciones, R2 es un alcoxi C1-5 ramificado o lineal opcionalmente sustituido. Por ejemplo, R2 es un alcoxi C1-5 que está opcionalmente sustituido con 1-3 de hidroxi, arilo, heteroarilo, cicloalifático, heterocicloalifático o combinaciones de los mismos. En otros ejemplos, R2 es un metoxi, etoxi, propoxi, butoxi o pentoxi, cada uno de los cuales está opcionalmente sustituido con 1-3 de hidroxi, arilo, heteroarilo, cicloalifático, heterocicloalifático, o combinaciones de los mismos.
En otras realizaciones, R2 es hidroxi, halógeno o ciano.
En varias realizaciones, R2 es -ZBR5, y ZB es independientemente un enlace o una cadena alifática C1-4 ramificada o lineal opcionalmente sustituida en la que hasta dos unidades de carbono de ZB están opcionalmente e independientemente sustituidas con -C(O)-, -O-, -S-, -S(O)2-o -NH-, y R5 es RB, halógeno, -OH, -NH2, -NO2, -CN, -CF3 o -OCF3, y RB es hidrógeno o arilo.
En varias realizaciones, dos grupos R2 adyacentes forman un carbociclo opcionalmente sustituido o un heterociclo opcionalmente sustituido. Por ejemplo, dos grupos R2 adyacentes forman un carbociclo opcionalmente sustituido o un heterociclo opcionalmente sustituido, cualquiera de los cuales está condensado con el fenilo de fórmula I, en el que el carbociclo o heterociclo tiene la fórmula Ib:
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Cada uno de Z1, Z2, Z3, Z4 y Z5 es independientemente un enlace, -CR7R'7-, -C(O)-, -NR7-o -O-; cada R7 es independientemente -ZDR8, en el que cada ZD es independientemente un enlace o una cadena alifática C1-6 ramificada o lineal opcionalmente sustituida en la que hasta dos unidades de carbono de ZD están opcionalmente e independientemente sustituidas con -CO-, -CS-, -CONRD-, -CO2-, -OCO-, -NRDCO2-, -O-, -NRDCONRD-, -OCONRD-, -NRDNRD-, -NRDCO-, -S-, -SO-, -SO2-, -NRD-, -SO2NRD-, -NRDSO2-o -NRDSO2NRD-. Cada R8 es independientemente RD, halógeno, -OH, -NH2, -NO2, -CN,-CF3 o -OCF3. Cada RD es independientemente hidrógeno, un cicloalifático opcionalmente sustituido, un heterocicloalifático opcionalmente sustituido, un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido. Cada R'7 es independientemente hidrógeno, alifático C1-6 opcionalmente sustituido, hidroxi, halógeno, ciano, nitro, o combinaciones de los mismos. Alternativamente, dos grupos R7 cualquiera adyacentes junto con los átomos a los que están unidos forman un anillo carbocíclico de 3-7 miembros opcionalmente sustituido, tal como un anillo de ciclobutilo opcionalmente sustituido, o dos grupos R7 y R'7 cualquiera junto con el átomo o átomos a los que están unidos forman un anillo carbocíclico o un anillo
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5
6-Clorometil-2,3-dihidro-benzo[1,4]dioxina
Se agitó una mezcla de (2,3-dihidro-benzo[1,4]dioxin-6-il)metanol (10,6 g) en SOCl2 (10 ml) a temperatura ambiente durante 10 min y luego se vertió en agua con hielo. Se separó la fase orgánica y la fase acuosa se extrajo
10 con diclorometano (50 ml × 3). Las fases orgánicas combinadas se lavaron con NaHCO3 (disolución sat), agua y salmuera, se secaron sobre Na2SO4 y se concentraron a sequedad para obtener 6-clorometil-2,3-dihidrobenzo[1,4]dioxina (12 g, 88 % durante dos etapas), que se usó directamente en la siguiente etapa.
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2-(2,3-Dihidrobenzo[b][1,4]dioxin-6-il)acetonitrilo
20 Se agitó una mezcla de 6-clorometil-2,3-dihidro-benzo[1,4]dioxina (12,5 g, 67,7 mmoles) y NaCN (4,30 g, 87,8 mmoles) en DMSO (50 ml) a ta durante 1 h. La mezcla se vertió en agua (150 ml) y a continuación se extrajo con diclorometano (50 ml × 4). Las fases orgánicas combinadas se lavaron con agua (50 ml × 2) y salmuera (50 ml), se secaron sobre Na2SO4 y se concentraron a sequedad. El residuo se purificó por columna (éter de petróleo/acetato de etilo 50:1) sobre gel de sílice para obtener 2-(2,3-dihidrobenzo[b][1,4]dioxin-6-il)acetonitrilo como un aceite
25 amarillo (10,2 g, 86 %), RMN 1H (300 MHz, CDCl3) δ 6,78-6,86 (m, 3H), 4,25 (s, 4H), 3,63 (s, 2H).
La siguiente Tabla 2 contiene una lista de elementos estructurales de ácido carboxílico que estuvieron comercialmente disponibles, o se prepararon por uno de los tres métodos descritos anteriormente:
30 Tabla 2: Elementos estructurales de ácido carboxílico.
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Nombre
Estructura
1-benzo[1,3]dioxol-5-ilciclopropano-1-ácido carboxílico
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1-(2,2-difluorobenzo[1,3]dioxol-5-il)ciclopropano-1-ácido carboxílico
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1-(3,4-dihidroxifenil)ciclopropano acido carboxílico
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1-(3-metoxifenil)ciclopropano-1-ácido carboxilico
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1-(2-metoxifenil)ciclopropano-1-ácido carboxílico
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1-[4-(trifluorometoxi)fenil]ciclopropano-1-ácido carboxílico
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1-(2,2-dimetilbenzo[d][1,3]dioxol-5-il)ciclopropano ácido carboxílico
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Nombre
Estructura
tetrahidro-4-(4-metoxifenil)-2H-piran-4-ácido carboxílico
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1-fenilciclopropano-1-ácido carboxílico
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1-(4-metoxifenil)ciclopropano-1-ácido carboxílico
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1-(4-clorofenil)ciclopropano-1-ácido carboxílico
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1-(3-hidroxifenil)ciclopropano ácido carboxílico
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1-fenilciclopentano ácido carboxílico
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1-(2-oxo-2,3-dihidrobenzo[d]oxazol-5-il)ciclopropano ácido carboxílico
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1-(benzofuran-5-il)ciclopropano ácido carboxílico
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1-(4-metoxifenil)ciclohexano ácido carboxílico
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1-(4-clorofenil)ciclohexano ácido carboxílico
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1-(2,3-dihidrobenzofuran-5-il)ciclopropano ácido carboxílico
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1-(3,3-dimethil-2,3-dihidrobenzofuran-5-il)ciclopropano ácido carboxílico
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Nombre
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1-(7-metoxibenzo[d][1,3]dioxol-5-il)ciclopropano ácido carboxílico
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1-(3-hidroxi-4-metoxifenil)ciclopropano ácido carboxílico
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1-(4-cloro-3-hidroxifenil)ciclopropano ácido carboxílico
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1-(3-(benziloxi)-4-clorofenil)ciclopropano ácido carboxílico
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1-(4-clorofenil)ciclopentano ácido carboxílico
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1-(3-(benziloxi)-4-metoxifenil)ciclopropano ácido carboxílico
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1-(3-cloro-4-metoxifenil)ciclopropano ácido carboxílico
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1-(3-fluoro-4-metoxifenil)ciclopropano ácido carboxílico
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1-(4-metoxi-3-metilfenil)ciclopropano ácido carboxílico
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1-(4-(benziloxi)-3-metoxifenil)ciclopropano ácido carboxílico
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1-(4-cloro-3-metoxifenil)ciclopropano ácido carboxílico
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1-(3-cloro-4-hidroxifenil)ciclopropano ácido carboxílico
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Nombre
Estructura
1-(3-(hidroximetil)-4-metoxifenil)ciclopropano ácido carboxilico
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1-(4-metoxifenil)ciclopentano ácido carboxilico
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1-fenilciclohexano ácido carboxilico
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1-(3,4-dimetoxifenil)ciclopropano ácido carboxilico
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1-(7-chlorobenzo[d][1,3]dioxol-5-il)ciclopropano ácido carboxilico
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1-(benzo[djoxazol-5-il)ciclopropano ácido carboxilico
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1-(7-fluorobenzo[d][1,3]dioxol-5-il)ciclopropano ácido carboxilico
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1-(3,4-difluorofenil)ciclopropano ácido carboxilico
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1-(1H-indol-5-il)ciclopropano ácido carboxilico
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1-(1H-benzo[d]imidazol-5-il)ciclopropano ácido carboxilico
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1-(2-metil-1H-benzo[d]imidazol-5-il)ciclopropano ácido carboxilico
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1-(-metil-1H-benzo[d]imidazol-5-il)ciclopropano ácido carboxilico
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1-(3-metilbenzo[d]isoxazol-5-il)ciclopropano ácido carboxilico
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Nombre
Estructura
1-(spiro[benzo[d][1,3]dioxol-2,1’-ciclobutano]-5-il)ciclopropano ácido carboxílico
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1-(1H-benzo[d][1,2,3]triazol-5-il)ciclopropano ácido carboxílico
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1-(1-metil-1H-benzo[d][1,2,3]triazol-5-il)ciclopropano ácido carboxílico
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1-(1,3-dihidroisobenzofuran-5-il)ciclopropano ácido carboxílico
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1-(6-fluorobenzo[d][1,3]dioxol-5-il)ciclopropano ácido carboxílico
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1-(2,3-dihidrobenzofuran-6-il)ciclopropano ácido carboxílico
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1-(chroman-6-il)ciclopropano ácido carboxílico
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1-(4-hidroxy-4-methoxychroman-6-il)ciclopropano ácido carboxílico
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1-(4-oxochroman-6-il)ciclopropano ácido carboxílico
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1-(3,4-dicloorofenil)ciclopropano ácido carboxílico
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1-(2,3-dihidrobenzo[b][1,4]dioxin-6-il)ciclopropano ácido carboxílico
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1-(benzofuran-6-il)ciclopropano ácido carboxílico
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Claims (1)

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US7407976B2 (en) * 2003-11-14 2008-08-05 Vertex Pharmaceuticals Incorporated Thiazoles and oxazoles useful as modulators of ATP-Binding Cassette transporters
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