ES2597834T3 - Antagonistas selectivos del receptor H4 de la histamina para el tratamiento de trastornos vestibulares - Google Patents

Antagonistas selectivos del receptor H4 de la histamina para el tratamiento de trastornos vestibulares Download PDF

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ES2597834T3
ES2597834T3 ES09798938.8T ES09798938T ES2597834T3 ES 2597834 T3 ES2597834 T3 ES 2597834T3 ES 09798938 T ES09798938 T ES 09798938T ES 2597834 T3 ES2597834 T3 ES 2597834T3
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methylamino
pyrimidin
diamine
pyrimidine
pyrrolidin
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Gilles Desmadryl
Christian Chabbert
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Abstract

Un antagonista selectivo del receptor H4 de histamina para uso en el tratamiento y/o la prevención de al menos un síntoma de trastornos vestibulares, en donde el antagonista selectivo del receptor H4 de histamina: - tiene una relación KiH3:KiH4 por encima de 10:1, y - se selecciona del grupo que consiste en: * 1-[(5-cloro-1H-bencimidazol-2-il)carbonil]-4-metilpiperazina, * 1-[(5-cloro-1H-indol-2-il)carbonil]-4-metilpiperazina, * 4-((3R)-3-Aminopirrolidin-1-il)-6,7-dihidro-5H-benzo[6,7]ciclohepta[1,2-d]pirimidin-2-ilamina, * cis-4-(Piperazin-1-il)-5,6,7a,8,9,10,11,11a-octahidrobenzofuro[2,3-h]quinazolin-2-amina, * 2-Isobutil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Isobutil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-Ciclohexilmetil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-(4-Fluorobencil)-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Ciclopropil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-tert-Butil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Isopropil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-(Ciclopropilmetil)-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 6-(3-(Metilamino)azetidin-1-il)-2-(fenoximetil)pirimidin-4-amina, * 2-Ciclopropil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-tert-Butil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-Isopropil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 6-((3R)-3-(Metilamino)pirrolidin-1-il)-2-(fenoximetil)pirimidin-4-amina, * 6-(3-Aminoazetidin-1-il)-2-isobutilpirimidin-4-amina, * 2-Isobutil-6-(3-metil-3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 6-((3R)-3-aminopirrolidin-1-il)-2-isobutilpirimidin-4-amina, * 2-Ciclobutil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Ciclobutil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-Ciclopentil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Ciclopentil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-(2,2-Dimetilpropil)-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-(2,2-Dimetilpropil)-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-(2-Ciclopentiletil)-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-Ciclohexilmetil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Ciclopropilmetil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-Ciclohexil-6-(3-(metilamino)azetidin-1-il)pirimidin-4-amina, * 2-Ciclohexil-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * 2-(4-Fluorobencil)-6-((3R)-3-(metilamino)pirrolidin-1-il)pirimidin-4-amina, * N4-(Ciclopropilmetil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina, * N4-(Ciclopropilmetil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina tartrato, * N4-Isobutil-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina * N-Isobutil-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidin-4-amina, * N-(Ciclopropilmetil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidin-4-amina, * N4-(2,2-Dimetilpropil)-6-[(4aR*,7aR*)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-Ciclopropil-6-[(4aR*,7aR*)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-Ciclobutil-6-[(4aR*,7aR*)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * 6-(3-Metilamino-azetidin-1-il)-N4-(3,3,3-trifluoro-propil)-pirimidina-2,4-diamina, * N4-Ciclopropilmetil-6-(3-metilamino-azetidin-1-il)-pirimidina-2,4-diamina, * N4-(3,3-Dimetil-butil)-6-(3-metilamino-azetidin-1-il)-pirimidina-2,4-diamina, * N4-(3-Fluoro-bencil)-6-(3-metilamino-azetidin-1-il)-pirimidina-2,4-diamina, * N4-Ciclopentilmetil-6-(3-metilamino-azetidin-1-il)-pirimidina-2,4-diamina, * N4-Isobutil-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * 6-[3-(Metilamino)azetidin-1-il]-N4-propil-pirimidina-2,4-diamina, * N4-(2-Metoxibencil)-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[(3R)-3-metilpiperazin-1-il]pirimidina-2,4-diamina, * N4-Etil-6-(4-metilpiperazin-1-il)pirimidina-2,4-diamina, * N4-(Ciclopropilmetil)-6-(4-metilpiperazin-1-il)pirimidina-2,4-diamina, * 6-[3-(Metilamino)azetidin-1-il]-N4-(2-metilbutil)pirimidina-2,4-diamina, * N4-(2,5-Difluorobencil)-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * N4-(2,3-Difluorobencil)-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * N4-Butil-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina, * 6-[(3R)-3-(Metilamino)pirrolidin-l-il]-N4-(2-metilciclopropil)pirimidina-2,4-diamina, * N4-Isobutil-6-(4-metil-1,4-diazepan-1-il)pirimidina-2,4-diamina, * N4-(Ciclopropilmetil)-6-(3-pirrolidin-1-il-azetidin-1-il)pirimidina-2,4-diamina, * N4-Biciclo[1.1.1]pent-1-il-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina, * 6-[3-Metil-3-(metilamino)azetidin-1-il]-N4-propilpirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-(hexahidropirrolo[1,2-a]pirazin-2(1H)-il)pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-(3-pirrolidin-1-il-azetidin-1-il)pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[3-(isopropilamino)azetidin-1-il]pirimidina-2,4-diamina, * N4-(tert-Butil)-6-[(3R)-3-(metilamino)pymolidin-1-il]pirimidina-2,4-diamina, * 6-[(3R)-3-(Metilamino)pirrolidin-1-il]-N4-(1-metilciclopropil)pirimidina-2,4-diamina, * N4-(tert-Butil)-6-[(4aS*,7aS*)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-piperazin-1-ilpirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[3-(metilamino)azetidin-1-il]pirimidina-2,4-diamina clorhidrato, * N4-(2,2-Dimetilpropil)-6-[(3aR*,7aS*)-octahidro-5H-pirrolo[3,2-c]piridin-5-il]pirimidina-2,4-diamina, * 6-Piperazin-1-il-N410 -propilpirimidina-2,4-diamina, * N4-(Ciclopropilmetil)-6-[4aR,7aR]-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-(2,2-Dimetilpropil)-6-[(4aS,7aS)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * N4-(Ciclopropilmetil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina, * N4-isopropil-6-[(4aS,7aS)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * 4-[3-(Metilamino)azetidin-1-il]-6-(4-metilpiperidin-1-il)pirimidin-2-amina, * N4-(Ciclopentilmetil)-6-[(3R)-3-(metilamino)pirrolidin-1-il]pirimidina-2,4-diamina, * N4-Ciclobutil-6-[(4aS,7aS)-octahidro-6H-pirrolo[3,4-b]piridin-6-il]pirimidina-2,4-diamina, * 6-[(3R)-3-(Metilamino)pirrolidin-1-il]-N4-propilpirimidina-2,4-diamina, y * N4-Etil-6-(4-metil-1,4-diazepan-1-il)pirimidina-2,4-diamina.

Description

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benzoimidazol; 4–Metil–2–[1–(3–piperidin–4–il–propil)–2,3–dihidro–1H–indol–5–il]–1H–benzoimidazol; 5– Fluoro–4– metil–2–{1–[3–(1–metil–piperidin–4–il)–propil]–2,3–dihidro–1H–indol–5–il}–1H–benzoimidazol; 5–Cloro–2–{1–[3–(1– metil–piperidin–4–il)–propil]–2,3–dihidro–1H–indol–5–il}–1H–benzoimidazol; 4–Metil–2–{1–[3–(1–metil–piperidin–4–il)– propil]–2,3–dihidro–1H–indol–5–il}–l H–benzoimidazol; 2–[6–Cloro–1–(3–piperidin–4–il–propil)–1H–indol–5–il]–4,6– difluoro–1H–benzoimidazol; 2–[6–Cloro–1–(3–piperidin–4–il–propil)–1H–indol–5–il]–4,5–dimetil–1H– benzoimidazol; 5– Cloro–2–[6–cloro–1–(3–piperidin–4–il–propil)–1H–indol–5–il]–1H–benzoimidazol; 5–Cloro–2–{6–cloro–1–[3–(1–metil– piperidin–4–il)–propil]–1H–indol–5–il}–1H–benzoimidazol; 2–{6–Cloro–1–[3–(1–metil–piperidin–4–il)–propil]–1H–indol– 5–il}–4,5–dimetil–1H–benzoimidazol; 6–Cloro–4–metil–2–[1–(4–piperidin–4–il–butil)–1H–indol–4–il]–1H–benzoimidazol; 5–tert–Butil–2–[1–(4–piperidin–4–il–butil)–1H–indol–4–il]–1H–benzoimidazol; 6,7–Dimetil–2–[1–(4–piperidin–4–il–butil)– 1H–indol–4–il]–1H–benzoimidazol; 4–Metil–2–[1–(4–piperidin–4–il–butil)–1H–indol–6–il]–1H–benzoimidazol; 6–Cloro–4– metil–2–[1–(4–piperidin–4–il–butil)–1H–indol–6–il]–1H–benzoimidazol; 5–tert–Butil–2–[1–(4–piperidin–4–il–butil)–1H– indol–6–il]–1H–benzoimidazol; 4,5–Difluoro–2–[1–(4–piperidin–4–il–butil)–1H–indol–4–il]–1H–benzoimidazol; 4,4’– Dimetil–1’–(3–piperidin–4–il–propil)–1H,1’H–[2,5l]bibenzoimidazolil; 6–Fluoro–4,4’–dimetil–1’–(3–piperidin–4–il–propil)– 1H,1’H–[2,5’]bibenzoimidazolil; 5–Cloro–4,4’–dimetil–1’–(3–piperidin–4–il–propil)–1H,1’H–[2,5’]bibenzoimidazolil; 5– Fluoro–4,4’–dimetil–1’–(3–piperidin–4–il–propil)–1H,1’H–[2,5’]bibenzoimidazolil; 5–Fluoro–2–[1–(4–piperidin–4–il–butil)– 1H–indol–4–il]–1H–benzoimidazol; 4,6–Difluoro–2–[1–(4–piperidin–4–il–butil)–1H–indol–4–il]–1H–benzoimidazol; 4– Metil–1’–(4–piperidin–4–il–butil)–1H,1’H–[2,5’]bibenzoimidazolil; 4,5–Dimetil–1’–(4–piperidin–4–il–butil)–1H,1’H– [2,5’]bibenzoimidazolil; 5–Fluoro–1’–(4–piperidin–4–il–butil)–1H,1’H–[2,4’]bibenzoimidazolil; 5–Fluoro–1’–[4–(1–metil– piperidin–4–il)–butil]–1H,1’H–[2,4’]bibenzoimidazolil; 4,5–Dimetil–1’–[4–(1–metil–piperidin–4–il)–butil]–1H,1’H– [2,5’]bibenzoimidazolil; 4–Metil–3’–(4–piperidin–4–il–butil)–1H,3H–[2,5’]bibenzoimidazolil; 4,5–Dimetil–3’–(4–piperidin– 4–il–butil)–1H,3H–[2,5’]bibenzoimidazolil; 5–Fluoro–3’–(4–piperidin–4–il–butil)–1H,3H–[2,5’]bibenzoimidazolil; 4,5– Dimetil–3’–[4–(1–metil–piperidin–4–il)–butil]–1H,3H–[2,5’]bibenzoimidazolil; 5–Fluoro–3’–[4–(1–metil–piperidin–4–il)– butil]–1H,3’H [2,5’]bibenzoimidazolil; 2–[1–(4–Piperidin–4–il–butil)–1H–indol–4–il]–1H–nafto[2,3–d]imidazol; 2–[1–(4– Piperidin–4–il–butil)–1H–indol–4–il]–1H–nafto[1,2–d]imidazol; {2–[3–Cloro–1–(4–piperidin–4–il–butil)–1H–indol–4–il]– 1H–benzoimidazol–5–il}–fenil–metanona; 2–[3–Cloro–1–(4–piperidin–4–il–butil)–1H–indol–4–il]–5–trifluorometil–1H– benzoimidazol; 2–[3–Cloro–1–(4–piperidin–4–il–butil)–1H–indol–4–il]–5,6–difluoro–1H–benzoimidazol; 2–[3–Cloro–1– (4–piperidin–4–il–butil)–1H–indol–4–il]–4,5–difluoro–1H–benzoimidazol; 2–[3–Cloro–1–(4–piperidin–4–il–butil)–1H– indol–4–il]–5–fluoro–4–metil–1H–benzoimidazol; éster metílico del ácido 7–[3–Cloro–1–(4–piperidin–4–il–butil)–1H– indol–4–il]–2–metil–8H–2–[3–Cloro–1–(4–piperidin–4–il–butil)–1H–indol–4–il]–3H–benzoimidazol–5–carboxílico; éster metílico del ácido 2–{3–Cloro–1–[4–(1–metil–piperidin–4–il)–butil]–1H–indol–4–il}–3H–benzoimidazol–5–carboxílico; 4,5,4’–Trimetil–1’–(3–piperidin–4–il–propil)–1’H,1H–[2,5’]bibenzoimidazolil; 4,6–Dimetil–2–[1–(4–piperidin–4–il–butil)– 1H–indol–4–il]–1H–benzoimidazol; 6–Cloro–2–[1–(4–piperidin–4–il–butil)–1H–indol–4–il]–1H–benzoimidazol; 2–[1–(4– Piperidin–4–il–butil)–1H–indol–4–il]–6–trifluorometil–1H–benzoimidazol; 4–Metil–1–[3–(1–metil–piperidin–4–il)–propil]– 5–[4–metil–5–(4–trifluorometil–fenil)–1H–imidazol–2–il]–1H–benzoimidazol; 5–[5–(4–Metoxi–fenil)–4–metil–1H– imidazol–2–il]–4–metil–1–[3–(1–metil–piperidin–4–il)–propil]–1H–benzoimidazol; y sales farmacéuticamente aceptables, profármacos, y metabolitos activos de los mismos.
Antagonistas selectivos del H4 de la Histamina adicionales de ejemplo se seleccionan de los descritos en la Solicitud de Patente Internacional WO2009/038673: 4–(4–Metil–piperazin–1–il)–tieno[3,2–d]pirimidin–2–ilamina; 4–(4–Metil– piperazin–1–il)–6,7,8,9–tetrahidro–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 4–Piperazin–1–il–6,7,8,9–tetrahidro– benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 4–[(3aR,6aR)–Hexahidropirrolo[3,4–b]pirrol–5(1H)–il]–6,7,8,9– tetrahidro[1]benzotieno[3,2–d]pirimidin–2–amina; 4–(4–Metil–piperazin–1–il)–6,7,8,9–tetrahidro–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 4–Piperazin–1–il–6,7,8,9–tetrahidro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–[(3aR,6aR)– Hexahidropirrolo[3,4–b]pirrol–5(1H)–il]–6,7,8,9–tetrahidro[1]benzofuro[3,2–d]pirimidin–2–amina; 4–(4–Metil–piperazin– 1–il)–6,7,8,9–tetrahidro–benzo[4,5]furo[3,2–d]pirimidina; 4–Piperazin–1–il–6,7,8,9–tetrahidro–benzo[4,5]furo[3,2– d]pirimidina; 4–(4–Metil–piperazin–1–il)–6,7,8,9–tetrahidro–benzo[4,5]tieno[3,2–d]pirimidina; 4–Piperazin–1–il–6,7,8,9– tetrahidro–benzo[4,5]tieno[3,2–d]pirimidina; 7–Metil–4–[(3R)–3–(metilamino)pirrolidin–1–il]tieno[3,2–d]pirimidin–2– amina; 7–Metil–4–(4–metilpiperazin–1–il)tieno[3,2–d]pirimidin–2–amina; 7–Bromo–4–[(3R)–3–(metilamino)pirrolidin–1– il]tieno[3,2–d]pirimidin–2–amina; 6–tert–Butil–4–(4–metilpiperazin–1–il)tieno[3,2–d]pirimidin–2–amina; 6–tert–Butil–4– [(3R)–3–(metilamino)pirrolidin–1–il]tieno[3,2–d]pirimidin–2–amina; 6–tert–Butil–4–piperazin–1–iltieno[3,2–d]pirimidin–2– amina; 4–[(3R)–3–Aminopirrolidin–1–il]–6–tert–butiltieno[3,2–d]pirimidin–2–amina; 6–tert–Butil–4–(octahidro– 6Hpirrolo[3,4–b]piridin–6–il)tieno[3,2–d]pirimidin–2–amina; 4–[(4aR,7aR)–Octahidro–6H–pirrolo[3,4–b]piridin–6–il]– 6,7,8,9–tetrahidro[1]benzofuro[3,2–d]pirimidin–2–amina; 4–[(3R)–3–(Metilamino)pirrolidin–1–il]–6,7,8,9– tetrahidro[1]benzofuro[3,2–d]pirimidin–2–amina; 4–(1,4–Diazepan–1–il)–6,7,8,9–tetrahidro[1]benzofuro [3,2–d]pirimidin– 2–amina; 4–(3–Aminoazetidin–1–il)–6,7,8,9–tetrahidro[1]benzofuro[3,2–d]pirimidin–2–amina; 4–[(3R)–3–Aminopirrolidin– 1–il]–6,7,8,9–tetrahidro[1]benzofuro[3,2–d]pirimidin–2–amina; N4–(2–Aminoetil)–6,7,8,9–tetrahidro[1] benzofuro[3,2– d]pirimidina–2,4–diamina; 4–(3,8–Diazabiciclo[3.2.1]oct–3–il)6,7,8,9–tetrahidro[1]benzofuro[3,2d]pirimidin–2–amina; N– (6,7,8,9–Tetrahidro[1]benzofuro[3,2d]pirimidin–4–il)etano–1,2–diamina; (3R)–N–Metil–1–(6,7,8,9–tetrahidro [1]benzofuro[3,2–d]pirimidin–4–il)pirrolidin–3–amina; N–(6,7,8,9–Tetrahidro[1]benzotieno[3,2–d]pirimidin–4–il)etano–1,2– diamina; (3R)–N–Metil–1–(6,7,8,9–tetrahidrotilbenzotieno[3,2d]pirimidin–4–il)pirrolidin–3–amina; 4–[(3R)–3–(Metilamino)
pirrolidin–1–il]
–6,7,8,9–tetrahidro[1]benzotieno[3,2–d]pirimidin–2–amina; 4–[(4aR,7aR)–Octahidro–6H–pirrolo[3,4–
b]piridin–6–il]–6,7,8,9–tetrahidro[1]
benzotieno[3,2–d]pirimidin–2–amina; 4–Hexahidropirrolo[3,4–c]pirrol–2(1H)–il]–
6,7,8,9–tetrahidro[1]benzotieno[3,2–d]
pirimidin –2–amina; 4–[(3S)–3–Aminopiperidin–1–il]–6,7,8,9–
tetrahidro[1]benzotieno[3,2–d]pirimidin–2–amina; 4–[(1 S,4S)–2,5–Diazabiciclo[2.2.1]hept–2–il]–6,7,8,9– tetrahidro[1]benzotieno[3,2–d]pirimidin–2–amina; 4–[(1R,4R)–2,5–Diazabiciclo [2.2.1]hept–2–il]–6,7,8,9–
11
imagen10
imagen11
imagen12
imagen13
5
10
15
20
25
30
35
40
45
50
55
60
1,7–diaza–spiro[4.4]non–7–il)–pirimidin–2–ilamina (enantiómero 1 ); 4–Ciclopentil–6–(cis–1,7–diaza–spiro[4.4]non–7– il)–pirimidin–2–ilamina (enantiómero 2); (R)–4–Isopropoximetil–6–(3–metilamino–pirrolidin–1–il)–pirimidin–2–ilamina; (R)–4–(3–Amino–pirrolidin–1–il)–6–isopropoximetil–pirimidin–2–ilamina; 4–Isopropoximetil–6–piperazin–1–il–pirimidin– 2–ilamina; 4–Isopropoximetil–6–(4–metil–piperazin–1–il)–pirimidin–2–ilamina; 4–(3–Amino–azetidin–1–il)–6– isopropoximetil–pirimidin–2–ilamina; 4–Isopropoximetil–6–(8–metil–3,8–diaza–biciclo[3.2.1]oct–3–il)–pirimidin–2– ilamina; (R)–4–Ciclopropoximetil–6–(3–metilamino–pirrolidin–1–il)–pirimidin–2–ilamina; (R)–(4–Amino–pirrolidin–1–il)–6– ciclopropoximetil–pirimidin–2–ilamina; 4–Ciclopropoximetil–6–piperazin–1–il–pirimidin–2–ilamina; 4–Ciclopropoximetil– 6–(4–metil–piperazin–1–il)–pirimidin–2–ilamina; 4–(3–Amino–azetidin–1–il)–6–ciclopropoximetil–pirimidin–2–ilamina; 4– Ciclopropoximetil–6*–(8–metil–3,8–diaza–biciclo[3.2.1]oct–3–il)–pirimidin–2–ilamina; (R)–4–tert–Butoximetil–6–(3– metilamino–pirrolidin–1–il)–pirimidin–2–ilamina; (R)–4–(3–Amino–pirrolidin–1–il)–6–tert–butoximetil–pirimidin–2–ilamina; 4–tert–Butoximetil–6–piperazin–1–il–pirimidin–2–ilamina; 4–tert–Butoximetil–6–(4–metil–piperazin–1–il)–pirimidin–2– ilamina; 4–(3–Amino–azetidin–1–il)–6–tert–butoximetil–pirimidin–2–ilamina; 4–tert–Butoximetil–6–(8–metil–3,8–diaza– biciclo[3.2.1]oct–3–il)–pirimidin–2–ilamina; 4–Etil–6–(8–metil–3,8–diaza–biciclo[3.2.1]oct–3–il)–pirimidin–2–ilamina; 4– (8–Metil–3,8–diaza–biciclo[3.2.1]oct–3–il)–6–propil–pirimidin–2–ilamina; 4–Isopropil–6–(8–metil–3,8–diaza– biciclo[3.2.1]oct–3–il)–pirimidin–2–ilamina; 4–Ciclopentil–6–(8–metil–3,8–diaza–biciclo[3.2.1]oct–3–il)–pirimidin–2– ilamina; y sales farmacéuticamente aceptables de los mismos.
Antagonistas selectivos del H4 de la Histamina adicionales de ejemplo se seleccionan de los descritos en la Solicitud de Patente Internacional WO2008/008359: 8–Cloro–4–(4–metil–piperazin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6,8–Dicloro–4–(octahidro–pirrolo[3,4–b]piridin–6–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(4–isopropil– [1,4]diazepan–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Amino–pirrolidin–1–il)–6,8–dicloro– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–6,8–Dicloro–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; (R)–4–(3–Metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4– [1,4]diazepan–1–il–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(octahidro–pirido[1,2–a]pirazin–2–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–8–(octahidro–pirrolo[3,4–b]piridin–6–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 8–Cloro–4–(4–metil–[1,4]diazepan–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (S,S)–8– Cloro–4–(2,5–diaza–biciclo[2.2.1]hept–2–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (S)–4–(3–Amino–piperidin–1–il)–8–cloro–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 8–Cloro–4–piperazin–1–il–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(3–dimetilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Amino–pirrolidin–1–il)–8–cloro–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; (S)–8–Cloro–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–8– Cloro–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–8–Bromo–4–(3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Bromo–4–(hexahidro–pirrolo[1,2–a]jpirazin–2–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Amino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–4– (3–Dimetilaminopirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–Piperazin–1–il–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; (R)–8–Cloro–4–(3–dimetilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–4– (3–Amino–pirrolidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (S)–4–(3–Aminometil–pirrolidin–1–il)–8– cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(hexahidro–pirrolo[3,4–c]pirrol–2–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; (R)–4–(3–Amino–piperidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3– Aminometil–pirrolidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (R)–4–(3–Aminometil–pirrolidin–1–il)–8– cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6,8–Dicloro–4–piperazin–1–il–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6,8–Dicloro–4–[1,4]diazepan–1–il–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (S,S)–4–(2,5–Diaza–biciclo[2.2.1]hept–2– il)–benzo[415]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–(4–isopropil–piperazin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2– ilamina; 6,8–Dicloro–4–(3–dimetilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(Octahidro– pirido[1,2–a]pirazin–2–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6,8–Dicloro–4–(octahidro–pirido[1,2–a]pirazin–2–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; (S,S)–6,8–Dicloro–4–(2,5–diaza–biciclo[2.2.1]hept–2–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; (R)–8–Fluoro–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8– Fluoro–4–(hexahidro–pirrolo[1,2–a]pirazin–2–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Fluoro–N4–metil–N4–(1– metil–pirrolidin–3–il)–benzo[4,5]furo[3,2–d]pirimidina–2,4–diamina; (R)–8–(3–Metilamino–pirrolidin–1–il)–9–oxa–1,5,7– triaza–fluoren–6–ilamina; 8–(Octahidro–pirrolo[3,4–b]piridin–6–il)–9–oxa–1,5,7–triaza–fluoren–6–ilamina; 4–(4–Metil– piperazin–1–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 8–Bromo–4–(octahidro–pirrolo[3,4–b]piridin–6–il)– benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 7–Bromo–4–(octahidro–pirrolo[3,4–b]piridin–6–il)–benzo[4,5]tieno[3,2– d]pirimidin–2–ilamina; (S)–8–Bromo–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (R)–8– Bromo–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (S,S)–8–Bromo–4–(2,5–diaza– biciclo[2.2.1]hept–2–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 8–Bromo–4–(4–metil–piperazin–1–il)– benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (S)–4–(3–Metilamino–pirrolidin–1–il)–7–trifluorometil–benzo[4,5]tieno[3,2– d]pirimidin–2–ilamina; (R)–4–(3–Metilamino–pirrolidin–1–il)–7–trifluorometil–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (S,S)–4–(2,5–Diaza–biciclo[2.2.1]hept–2–il)–7–trifluorometil–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 4–(4–Metil– piperazin–1–il)–7–trifluorometil–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 7–Bromo–4–(4–metil–piperazin–1–il])– benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (R)–7–Bromo4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]tieno[3,2– d]pirimidin–2–ilamina; (S)–7–Bromo–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 4– (Octahidro–pirrolo[3,4–b]piridin–6–il)–7–trifluorometil–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; 7–Cloro–4–(octahidro– pirrolo[3,4–b]piridin–6–il)–benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (R)–7–Cloro–4–(3–metilamino–pirrolidin–1–il)– benzo[4,5]tieno[3,2–d]pirimidin–2–ilamina; (S)–7–Cloro–4–(3–metilamino–pirrolidin–1–il)–benzo[4,5]tieno[3,2– d]pirimidin–2–ilamina; (S,S)–7–Cloro–4–(2,5–diaza–biciclo[2.2.1]hept–2–il)–benzo[415]tieno[3,2–d]pirimidin–2–ilamina;
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metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 7–Metoxi–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–((R)–3–Metilamino–pirrolidin–1–il)–7–trifluorometil–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 6–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Metil– 4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Metoxi–4–((R)–3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Metoxi–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 4–(3–Metilamino–azetidin–1–il)–8–trifluorometoxi–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9– Fluoro–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9–Metil–4–(3–metilamino–azetidin–1– il)–benzo[4,5] furo [3,2–d] pirimidin–2–ilamina; 9–Metoxi–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin– 2–ilamina; 7–Metil–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 7–Metoxi–4–(3– metilamino–azetidin–1–il)–benzo[4,5]furo [3,2–d] pirimidin–2–ilamina; 4–(3–Metilamino–azetidin–1–il)–7–trifluorometil– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Cloro–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2– ilamina; 6–Metil–4–(3–metilamino–azetidin–1–il)–benzo[4,5] furo[3,2–d]pirimidin–2–ilamina; 6–Metoxi–4–(3–metilamino– azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–[3–(ciclopropilmetil–amino)–pirrolidin–1–il]– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–((R)–3–dimetilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 4–((R)–3–Amino–pirrolidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4– (4–metilamino–piperidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(4–Amino–piperidin–1–il)–8–cloro– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Amino–azetidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; [8–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–il]–metil–amina; [8–Cloro–4–((R)–3– metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–il]–dimetil–amina; N–[8–Cloro–4–((R)–3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–il]–acetamida; N–[8–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–il]–metanosulfonamida; [8–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–il]–ciclopropil–amina ; [8–Cloro–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–il]–metil–amina; [8–Cloro–4–(3–metilaminoazetidin–1–il)benzo[4,5]furo[3,2–d]pirimidin–2–il]–dimetil– amina; N–[8–Cloro–4–(3–metilamino–azetidin–1–il)benzo[4,5]furo[3,2–d]pirimidin–2–il]–acetamida; N–[8–Cloro–4–(3– metilamino–azetidin–1–il)benzo[4,5]furo[3,2–d]pirimidin–2–il]–metanosulfonamida; [8–Cloro–4–(3–metilamino–azetidin– 1–il)benzo[4,5]furo[3,2–d]pirimidin–2–il]– ciclopropilamina y sales de los mismos.
Antagonistas selectivos del H4 de la Histamina adicionales de ejemplo se seleccionan de los descritos en la Solicitud de Patente Internacional WO2007/090853: [(R)–1–(2–Amino–8–clorobenzo[4,5]furo[3,2–d]–pirimidin–4–il)pirrolidin–3–il] N– metil amina; 4–((R)–3–Metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Metil–4–((R)–3– metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Fluoro–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Bromo–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 7–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8– Metoxi–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–((R)–3–Metilamino–pirrolidin– 1–il)–8–trifluorometoxi–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9–Fluoro–4–((R)–3–metilamino–pirrolidin–1l–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9–Metil–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin– 2–ilamina; 9–Metoxi–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 7–Metil–4–((R)–3– metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 7–Metoxi–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–((R)–3–Metilamino–pirrolidin–1–il)–7–trifluorometil–benzo[4,5]furo [3,2– d]pirimidin–2–ilamina; 6–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Metil– 4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Metoxi–4–((R)–3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–[3–(ciclopropilmetil–amino)–pirrolidin–1–il]– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Cloro–4–((R)–3–dimetilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 4–((R)–3–Amino–pirrolidin–1–il)–8–cloro–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; [8–Cloro–4– ((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–il]–metil–amina; [8–Cloro–4–((R)–3–metilamino– pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–il]–dimetil–amina; N–[8–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–il]–acetamida; N–[8–Cloro–4–((R)–3–metilamino –pirrolidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–il]–metanosulfonamida; [8–Cloro–4–((R)–3–metilamino–pirrolidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2– il]–ciclopropil–amina. Algunos de dichos compuestos y/o sales o ésteres de los mismos, existirán en diferentes formas estereoisoméricas.
Antagonistas selectivos del H4 de la Histamina adicionales de ejemplo se seleccionan de los descritos en la Solicitud de Patente Internacional WO2007/090854: [1–(2–Etilamino–8–clorobenzo[4,5]furo[3,2–d]–pirimidin–4–il)azetidin–3–il]N– etilamina; N–[1–(2–Amino–8–clorobenzo[4,5]furo[3,2–d]pirimidin–4–il)azetidin–3–il]N–metil amina; 4–(3–Metilamino– azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Bromo–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 8–Metil–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Fluoro–4– (3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 8–Metoxi–4–(3–metilamino–azetidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Metilamino–azetidin–1–il)–8–trifluorometoxi–benzo[4,5]furo[3,2– d]pirimidin–2–ilamina; 9–Fluoro–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9–Metil–4– (3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 9–Metoxi–4–(3–metilamino–azetidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 7–Metil–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2– ilamina; 7–Metoxi–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Metilamino–azetidin– 1–il)–7–trifluorometil–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Cloro–4–(3–metilamino–azetidin–1–il)– benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 6–Metil–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2– ilamina; 6–Metoxi–4–(3–metilamino–azetidin–1–il)–benzo[4,5]furo[3,2–d]pirimidin–2–ilamina; 4–(3–Amino–azetidin–1–
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