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ES2529457T3 - Derivados de piridinas y pirimidinas como agonistas de mGluR2 - Google Patents

Derivados de piridinas y pirimidinas como agonistas de mGluR2 Download PDF

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Publication number
ES2529457T3
ES2529457T3 ES07727038.7T ES07727038T ES2529457T3 ES 2529457 T3 ES2529457 T3 ES 2529457T3 ES 07727038 T ES07727038 T ES 07727038T ES 2529457 T3 ES2529457 T3 ES 2529457T3
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Prior art keywords
alkyl
optionally substituted
bipyridinyl
phenyl
group
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Silvia Gatti Mcarthur
Erwin Goetschi
Juergen Wichmann
Thomas Johannes Woltering
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract

Un compuesto de fórmula (I):**Fórmula** que es en la que el heteroarilo de 5 o 6 miembros es imidazolilo, [1,2,4]oxadiazolilo, pirrolilo, 1H-pirazolilo, piridinilo, [1,2,4] triazolilo, tiazolilo, pirimidinilo o tiofenilo, cada uno de los cuales opcionalmente sustituido con alquilo C1-6; B es un arilo opcionalmente sustituido o un heteroarilo opcionalmente sustituido de 5 o 6 miembros, en el que los sustituyentes se seleccionan entre el grupo que consiste en: halo, nitro, alquilo C1-6 opcionalmente sustituido con hidroxi, NRaRb, en el que Ra y Rb son independientemente H, alquilo C1-6 o -(CO)-alquilo C1-6, -S-alquilo C1-6, -(SO2)-OH, -(SO2)-alquilo C1-6, -(SO2)-NRcRd, en el que Rc y Rd son independientemente: H, alquilo C1-6 opcionalmente sustituido con hidroxi, haloalquilo C1-6, alcoxi C1-6, -(CO)alquilo C1-6 opcionalmente sustituido con alcoxi C1-6, -(CH2CH2O)nCHRe, en el que Re es H o CH2OH y n es 1, 2, 3, 4, 5, 6, 7, 8, 9 o 10, -(CH2)m-arilo, en el que m es 1 o 2 y el arilo está opcionalmente sustituido con halo o alcoxi C1-6, -(CH2)p-cicloalquilo C3-6, en el que p es 0 o 1, heteroalquilo de 5 o 6 miembros, -(SO2)-NRfRg, en el que Rf y Rg junto con el átomo de nitrógeno al que están unidos forman un anillo heterocicloalquilo de 4, 5 o 6 miembros que contiene opcionalmente un heteroátomo adicional seleccionado entre nitrógeno, oxígeno, azufre o un grupo SO2, en el que dicho anillo heterocicloalquilo de 4, 5 o 6 miembros está opcionalmente sustituido con: un sustituyente seleccionado entre el grupo que consiste en hidroxi, alquilo C1-6, alcoxi C1-6 que está opcionalmente sustituido con hidroxi, y un heteroariloxi de 5 o 6 miembros, NHSO2-alquilo C1-6, y NHSO2-NRhRi en el que Rh y Ri son independientemente H, alquilo C1-6, -(CO)O- alquilo C1-6, o Rh y Ri junto con el átomo de nitrógeno al que están unidos forman un anillo heterocicloalquilo de 4, 5 o 6 miembros que contiene opcionalmente un heteroátomo adicional seleccionado entre nitrógeno, oxígeno o azufre, en el que dicho anillo heterocicloalquilo de 4, 5 o 6 miembros está opcionalmente sustituido con alquilo C1-6; R1 es H, halógeno, alquilo C1-6 opcionalmente sustituid 5 o con hidroxi, alcoxi C1-6, haloalquilo C1-6, cicloalquilo C1-6; R2 es H, ciano, halógeno, haloalquilo C1-6, alcoxi C1-6, haloalcoxi C1-6, alquilo C1-6 o cicloalquilo C3-6; R3 es halógeno, H, alcoxi C1-6, haloalquilo C1-6, alquilo C1-6, cicloalquilo C3-6, haloalcoxi C1-6, o es NRjRk en el que Rj y Rk se seleccionan independientemente entre el grupo que consiste en: H, cicloalquilo C3-8, arilo, heteroarilo que tiene de 5 a 12 átomos en el anillo y alquilo C1-6 que está opcionalmente sustituido con uno o más sustituyentes seleccionados entre el grupo que consiste en halógeno, hidroxi, cicloalquilo C3-8, arilo, heteroarilo que tiene de 5 a 12 átomos en el anillo y -NRlRm, en el que Rl y Rm se seleccionan independientemente entre el grupo que consiste en H y alquilo C1-6; o Rj y Rk pueden formar, junto con el átomo de nitrógeno al que están unidos, un grupo heterocíclico opcionalmente sustituido que comprende de 5 a 12 átomos, en el anillo que contiene opcionalmente un heteroátomo adicional seleccionado entre nitrógeno, oxígeno o azufre, en el que dicho grupo heteroarilo está opcionalmente sustituido con uno, dos, tres, cuatro o cinco sustituyentes que se seleccionan entre el grupo que consiste en halógeno, hidroxi, alquilo C1-6 y haloalquilo C1-6; o R2 y R3 juntos pueden formar un puente dioxo; R4 es H o halo; así como sales farmacéuticamente aceptables del mismo, excluyendo los siguientes compuestos de la fórmula (I): 6,6'-Dimetil-4,4'-difenil-[2,2']bipiridinilo, 6,6'-Dimetil-4,4'-di-p-tolil-[2,2']bipiridinilo, 4,4'-Difenil-[2,2']bipiridinilo, 4-Fenil-[2,2';6',2"]terpiridina, 4,4'-Di-p-tolil-[2,2']bipiridinilo, 6-Bromometil-6'-metil-4,4'-difenil-[2,2']bipiridinilo, 4,4'-Bis-(4-cloro-fenil)-6,6'-dimetil-[2,2']bipiridinilo, 4-Fenil-2-(4-piridin-2-il-tiazol-2-il)-piridina, 4,4'-Bis-(4-fluoro-fenil)-[2,2']bipiridinilo, 4,4'-Bis-(2,4-difluoro-fenil)-[2,2']bipiridinilo, 4,4'-Bis-(2,3,4-trifluoro-fenil)-[2,2']bipiridinilo, 4,4'-Bis-(4-cloro-fenil)-[2,2']bipiridinilo, 3-(4-fenil-2-piridil)-5-fenil-1,2,4-triazol, 4-p-tolil-[2,2';6',2"]terpiridina, y 4-((4-metoxifenil)-2,2':6',2"]-terpiridina.

Description

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E07727038
03-02-2015
Además, las preparaciones farmacéuticas pueden contener conservantes, solubilizantes, estabilizantes, agentes humectantes, emulsionantes, edulcorantes, colorantes, aromatizantes, sales para variar la presión osmótica, tampones, agentes enmascarantes o antioxidantes. También pueden contener otras sustancias terapéuticamente valiosas adicionales.
5 Como se menciona anteriormente, los medicamentos que contienen un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo y un excipiente terapéuticamente inerte también son un objeto de la presente invención, al igual que lo es un proceso para la producción de dichos medicamentos que comprende incorporar uno o más compuestos de fórmula (I) o sales farmacéuticamente aceptables de los mismos y, si se desea, una o más de
10 otras sustancias terapéuticamente valiosas, en una forma de dosificación galénica junto con uno o más vehículos terapéuticamente inertes.
La dosificación puede variar dentro de límites amplios y, por supuesto, puede ajustarse a los requerimientos individuales de cada caso particular. En general, la dosificación efectiva para la administración oral o parenteral está
15 entre 0,01-20 mg/kg/día, prefiriéndose una dosificación de 0,1-10 mg/kg/día para todos las indicaciones descritas. La dosis diaria para un humano adulto que pesa 70 kg, por consiguiente, se encuentra entre 0,7-1400 mg por día, preferentemente entre 7 y 700 mg por día.
La presente invención se refiere también al uso de compuestos de fórmula (I) y de sales farmacéuticamente 20 aceptables de los mismos para la producción de medicamentos, especialmente para el control o prevención de trastornos neurológicos agudos y/o crónicos del tipo anteriormente mencionado.
Los compuestos de la presente invención son antagonistas de receptores mGlu del grupo II. Los compuestos muestran actividades, medidas en el ensayo que se describe a continuación, de 0,250 μM o inferiores, típicamente de 0,100 μM 25 o inferiores, e idealmente de of 0,010 μM o inferiores. En la tabla a continuación se describen algunos de los valores específicos de Ki de algunos de los compuestos preferidos.
Nº de ejemplo
Ki mGlu2 (μM)
Nº de ejemplo
54
Ki mGlu2 (μM)
0,060
Nº de ejemplo
71 72 73
Ki mGlu2 (μM)
0,001 0,056 0,019
Nº de ejemplo
237
Ki mGlu2 (μM)
0,004
Nº de ejemplo
Nº de ejemplo
Ki mGlu2 (μM)
Nº de ejemplo
306 313 318 322 330
Ki mGlu2 (μM)
0,038 0,018 0,004 0,009 0,004
Nº de ejemplo
334 338 345 346 350 355 356 357 360
Ki mGlu2 (μM)
0,011 0,001 0,0007 0,004 0,022 0,001 0,001 0,039 0,005
Nº de ejemplo
445
Ki mGlu2 (μM)
0,003
Unión de [3H]-LY354740 en membranas de células CHO transfectadas con mGlu2 30
Transfección y cultivo celular
El ADNc que codifica la proteína del receptor mGLU2 de rata en pBluescript II se subclonó en el vector de expresión
eucariótico pcDNA I-amp de Invitrogen Ltd (Paisley, R.U.). Esta construcción de vector (pcD1mGR2 se cotransfectó 35 con un plásmido psvNeo que codifica el gen para la resistencia a neomicina, en células CHO por un método de fosfato
de calcio modificado por Chen & Okayama (1988). Las células se mantuvieron en medio Eagle modificado de
Dulbecco con L-glutamina reducida (concentración final 1 mM), 36 mg/l de L-prolina y suero fetal de ternera dializado
21
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Claims (1)

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ES07727038.7T 2006-03-29 2007-03-19 Derivados de piridinas y pirimidinas como agonistas de mGluR2 Active ES2529457T3 (es)

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