ES2548913T3 - Derivados heterocíclicos como inhibidores de glutaminil ciclasa - Google Patents
Derivados heterocíclicos como inhibidores de glutaminil ciclasa Download PDFInfo
- Publication number
- ES2548913T3 ES2548913T3 ES10751952.2T ES10751952T ES2548913T3 ES 2548913 T3 ES2548913 T3 ES 2548913T3 ES 10751952 T ES10751952 T ES 10751952T ES 2548913 T3 ES2548913 T3 ES 2548913T3
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- Prior art keywords
- phenyl
- alkyl
- benzo
- substituted
- imidazol
- Prior art date
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- 102000003642 glutaminyl-peptide cyclotransferase Human genes 0.000 title description 4
- 108010081484 glutaminyl-peptide cyclotransferase Proteins 0.000 title description 4
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract description 7
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- 150000003839 salts Chemical class 0.000 abstract description 6
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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Abstract
Un compuesto de fórmula (I):**Fórmula** o una sal farmacéuticamente aceptable, solvato o polimorfo del mismo, incluyendo todos los tautómeros y estereoisómeros del mismo en donde: R1 representa **Fórmula** o**Fórmula** R2 representa H, alquilo de C1-8, arilo, heteroarilo, carbociclilo, heterociclilo, alquilarilo de C1-4, alquilheteroarilo de C1-4, alquilcarbociclilo de C1-4 o alquilheterociclilo de C1-4; en el que cualquiera de los grupos arilo o heteroarilo anteriormente mencionados puede estar sustituido por uno o más grupos seleccionados de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, haloalquilo de C1-6, tioalquilo de C1-6, -SO-alquilo de C1-4, -SO2-alquilo de C1-4, alcoxi de C1-6, -O-cicloalquilo de C3-8, cicloalquilo de C3-8, -SO2-cicloalquilo de C3-8, -SO-cicloalquilo de C3-6, alqueniloxi de C3-6, alquiniloxi de C3-6, -C(O)-alquilo de C1-6, -C(O)O-alquilo de C1-6, alcoxi de C1-6-alquilo de C1-6, alcoxi de C1-6-alcoxi de C1-6, nitro, halógeno, haloalquilo de C1-6, halo-alcoxi de C1-6, ciano, hidroxilo, -C(O)OH, -NH2, -NH-alquilo de C1-4, -N(alquilo de C1- 4)(alquilo de C1-4), -N(alquilo de C1-4)(alquilo de C1-4)-N(alquilo de C1-4)(alquilo de C1-4), alquilo de C1-4-N- (alquilo de C1-4)(alquilo de C1-4), alcoxi de C1-4-N(alquilo de C1-4)(alquilo de C1-4), -N(cicloalquilo de C3- 8)(cicloalquilo de C3-8), -N(alquilo de C1-6-alcoxi de C1-6)(alquilo de C1-6-alcoxi de C1-6), -C(O)N(alquilo de C1- 4)(alquilo de C1-4), -C(O)NH2, -C(O)NH(alquilo de C1-4) y C(O)NH(cicloalquilo de C3-10); y en el que cualquiera de los grupos carbociclilo o heterociclilo anteriormente mencionados puede estar opcionalmente sustituido por uno o más grupos seleccionados de alquilo de C1-4, oxo, halógeno, -C(O)-alquilo de C1-6, y alcoxi de C1-4; o R2 representa fenilo sustituido por fenilo, fenilo sustituido por un grupo heteroarilo monocíclico, fenilo sustituido por fenoxi, fenilo sustituido por heterociclilo, fenilo sustituido por heterociclilo en donde dicho heterociclilo está sustituido por fenilo, fenilo sustituido por -O-alquilo de C1-4-heterociclilo, fenilo sustituido por benciloxi, fenilo sustituido por carbociclilo, fenilo sustituido por carbociclilo en donde dicho carbociclilo está sustituido por heterociclilo, fenilo sustituido por -O-carbociclilo, heterociclilo sustituido por fenilo, carbociclilo sustituido por fenilo, fenilo fusionado a carbociclilo, fenilo fusionado a heterociclilo, alquilo de C1-4-(fenilo sustituido por fenilo), alquilo de C1-4-(fenilo sustituido por un grupo heteroarilo monocíclico), alquilo de C1-4- (fenilo sustituido por un grupo heterociclilo monocíclico), alquilo de C1-4-(fenilo sustituido por un grupo -Ocarbociclilo), alquilo de C1-4-(fenilo sustituido por benciloxi), alquilo de C1-4-(fenilo opcionalmente sustituido fusionado a carbociclilo opcionalmente sustituido o alquilo de C1-4-(fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido); en el que cualquiera de los grupos fenilo, benciloxi y heteroarilo anteriormente mencionados puede estar opcionalmente sustituidos por uno o más grupos seleccionados de alquilo de C1-4, halógeno y alcoxi de C1-4; y en el que cualquiera de los de los grupos carbociclilo o heterociclilo anteriormente mencionados puede estar opcionalmente sustituidos por uno o más grupos seleccionados de metilo, fenilo, oxo, halógeno, hidroxilo y alcoxi de C1-4; R3 representa H, alquilo de C1-4 o arilo; en el que el arilo anteriormente mencionado puede estar opcionalmente sustituido por uno o más grupos seleccionados de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, haloalquilo de C1-6, tioalquilo de C1-6, -SO alquilo de C1-4, -SO2-alquilo de C1-4, alcoxi de C1-6, -O-cicloalquilo de C3-8, cicloalquilo de C3-8, -SO2-cicloalquilo
Description
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sulfámico, sulfanílico, succínico, oxálico, fumárico, maleico, málico, mandélico, glutámico, aspártico, oxaloacético, metanosulfónico, etanosulfónico, arilsulfónico (por ejemplo p-toluenosulfónico, bencenosulfónico, naftalenosulfónico
o naftalendisulfónico), salicílico, glutárico, glucónico, tricarbalílico, cinámico, cinámico sustituido (por ejemplo, cinámico sustituido con fenilo, metilo, metoxi o halo, incluyendo ácido 4-metil y 4-metoxicinámico), ascórbico, oleico, naftoico, hidroxinaftoico (por ejemplo, 1-o 3-hidroxi-2-naftoico), naftalenoacrílico (por ejemplo, naftaleno-2-acrílico), benzoico, 4-metoxibenzoico, 2-o 4-hidroxibenzoico, 4-clorobenzoico, 4-fenilbenzoico, bencenoacrílico (por ejemplo, 1,4-bencenodiacrílico), isetiónico, ácido perclórico, propiónico, glicólico, hidroxietanosulfónico, pamoico, ciclohexanosulfámico, salicílico, sacarínico y trifluoroacético. Las sales de bases farmacéuticamente aceptables incluyen sales de amonio, sales de metales alcalinos tales como las de sodio y potasio, sales de metales alcalinotérreos tales como las de calcio y magnesio y sales con bases orgánicas tales como diciclohexilamina y Nmetil-D-glucamina.
Todas las formas de sales de adición ácida farmacéuticamente aceptables de los compuestos de la presente invención se pretende que estén abarcadas por el ámbito de esta invención.
Formas cristalinas polimórficas:
Además, algunas de las formas cristalinas de los compuestos pueden existir como polimorfos y como tal se pretende que estén incluidas en la presente invención. Además, algunos de los compuestos pueden formar solvatos con agua (es decir, hidratos) o solventes orgánicos comunes, y también se pretende que tales solvatos estén abarcados dentro del ámbito de la esta invención. Los compuestos, incluyendo sus sales, también se pueden obtener en forma de sus hidratos, o incluir otros solventes usados para su cristalización.
Profármacos:
También se divulgan profármacos de los compuestos de esta invención. En general, tales profármacos serán derivados funcionales de los compuestos que son fácilmente convertibles in vivo al compuesto terapéuticamente activo deseado. Por tanto, en una divulgación adiconal, el término “administrar” abarca el tratamiento de varios trastornos descritos con versiones profármacos de uno o más de los compuestos reivindicados, pero que se convierte en el compuesto anteriormente especificado in vivo después de la administración al sujeto. Se describen procedimientos convencionales para la selección y preparación de derivados profármaco adecuados, por ejemplo, en "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Grupos protectores:
Durante cualquiera de los procesos para la preparación de los compuestos de la presente invención, puede ser necesario y/o deseable proteger grupos sensibles o reactivos en cualquiera de las moléculas concernidas. Esto se puede lograr por medio de grupos protectores convencionales, tales como los descritos en Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; y T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, incorporados por completo en el presente documento mediante referencia. Los grupos protectores se pueden eliminar en una fase posterior conveniente usando métodos conocidos en la técnica.
Un grupo protector se introduce en una molécula por modificación química de un grupo funcional para obtener quimioselectividad en una reacción química posterior. Los grupos protectores son, por ejemplo, grupos protectores de alcoholes, grupos protectores de amino, grupos protectores de carbonilo, grupos protectores de carboxílico y grupos protectores de fosfato.
Los ejemplos para grupos protectores de alcoholes son acetilo (Ac), benzoilo (Bz), bencilo (Bn, Bnl) βmetoxietoximetil éter (MEM), mimetoxitritil [bis-(4-metoxifenil)fenilmetil, DMT], metoximetil éter (MOM), metoxitritil [(4metoxifenil)difenilmetilo, MMT), p-metoxibencil éter (PMB), metiltiometil éter, pivaloilo (Piv), tetrahidropiranilo (THP), tritil (trifenilmetilo, Tr), éteres de sililo (tal como trimetilsilil éter (TMS), terc-butildimetilsilil éter (TBDMS), tercbutildimetilsililoximetil éter (TOM), y triisopropilsilil éter (TIPS)); éteres metílicos y éteres de etoxietilo (EE).
Los grupos protectores de amino adecuados se seleccionan de carbobenciloxi (Cbz), p-metoxibencil carbonilo (Moz
o MeOZ), terc-butiloxicarbonilo (BOC), 9-fluorenulmetiloxicarbonilo (FMOC), acetilo (Ac), benzoilo (Bz), bencilo (Bn), p-metoxibencilo (PMB), 3,4-dimetoxibencilo (DMPM), p-metoxifenilo (PMP), tosilo (Ts), y otras sulfonamidas (Nosilo & Nps).
Los grupos protectores de carbonilo adecuados se seleccionan de acetales y cetales, acilales y ditianos.
Los grupos protectores de carboxílico adecuados se seleccionan de ésteres metílicos, ésteres bencílicos, ésteres terc-butílicos, ésteres silílicos, ortoésteres y oxazolina.
Los ejemplos de grupos protectores de fosfato son 2-cianoetilo y metilo (Me).
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Cuando R2 representa alquil de C1-4-heteroarilo en el que el heteroarilo está opcionalmente sustituido, los ejemplo incluyen metilheteroarilo y etilheteroarilo (por ejemplo, 1-heteroariletilo y 2-heteroariletilo), -propilheteroarilo y butilheteroarilo en los que heteroarilo está opcionalmente sustituido. Los ejemplos específicos de grupos alquilheteroarilo incluyen piridinimetil-, N-metil-pirrol-2-metilo N-metil-pirrol-2-etilo, N-metil-pirrol-3-metilo, N-metilpirrol-3-etilo, 2-metil-pirrol-1-metilo, 2-metil-pirrol-1-etilo, 3-metil-pirrol-1-metilo, 3-metil-pirrol-1-etilo, 4-piridino-metilo, 4-piridino-etilo, 2-(tiazol-2-il)-etilo, 2-etil-indol-1-metilo, 2-etil-indol-1-etilo, 3-etil-indol-1-metilo, 3-etil-indol-1-etilo, 4metil-piridin-2-metilo, 4-metil-piridin-2-il-etilo, 4-metil-piridin-3-metilo, 4-metil-piridin-3-etilo.
Cuando R2 representa alquilo de C1-4-carbociclilo (que puede estar opcionalmente sustituido), los ejemplos incluyen metil-ciclopentilo, metil-ciclohexilo, -etil-ciclohexilo, -propil-ciclohexilo, -metil-ciclohexenilo, -etil-ciclohexenilo, -metil(4metilciclohexilo) y -propil (3-metilciclohexilo).
Cuando R2 representa alquilo de C1-4-heterociclilo (que puede estar opcionalmente sustituido), los ejemplos incluyen -metil-tetrahidrofuranilo (por ejemplo, -metil-tetrahidrofuran-2-ilo, metil-tetrahiudrofuran-3-ilo), -etil-tetrahidrofuranilo, metil-piperidinilo.
Cuando R2 representa fenilo sustituido por fenilo o fenilo sustituido por un grupo heteroarilo monocíclico, en el que cualquiera de los grupos fenilo y heteroarilo anteriormente mencionados puede estar opcionalmente sustituido, típicamente el anillo fenilo conectado directamente al átomo de nitrógeno está sin sustituir y el anillo fenilo terminal o el anillo heteroarilo monocíclico está opcionalmente sustituido por uno, dos o tres sustituyentes (por ejemplo, uno o dos, por ejemplo uno). Típicamente el fenilo o grupo heteroarilo monocíclico terminal está sin sustituir. Típicamente, el fenilo o grupo heteroarilo monocíclico terminal sustituye al otro fenilo en la posición 4.
Cuando R2 representa fenilo sustituido por fenilo en el que cualquiera de los grupos fenilo anteriormente mencionados puede estar opcionalmente sustituido, los ejemplos incluyen -bifenil-4-ilo.
Cuando R2 representa fenilo sustituido por un grupo heteroarilo monocíclico, en el que cualquiera de los grupos fenilo y heteroarilo anteriormente mencionados puede estar opcionalmente sustituido, los ejemplos incluyen 4(oxazol-5-il)fenilo.
Cuando R2 representa fenilo sustituido por benciloxi en el que cualquiera de los grupos fenilo y benciloxi anteriormente mencionados puede estar opcionalmente sustituido, los ejemplos incluyen 4-benciloxi-fenilo, 4-(3metilbenciloxi)fenilo y 4-(4-metilbenciloxi)fenilo.
Cuando R2 representa fenilo opcionalmente sustituido fusionado a carbociclilo opcionalmente sustituido, los ejemplos incluyen indanilo (por ejemplo, indan-4-ilo, 2-metil-indan-4-ilo), indenilo y tetralinilo.
Cuando R2 representa fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido, los ejemplos incluyen benzo[1,3]dioxo-4-ilo y 2,3-dihidro-benzo[1,4]dioxin-4-ilo.
Cuando R2 representa alquilo de C1-4(fenilo sustituido por fenilo), los ejemplos incluyen bifenil-4-il-metilo.
Cuando R2 representa alquilo de C1-4(fenilo sustituido por un grupo heteroarilo monocíclico), los ejemplos incluyen 4(oxazol-5-il)fenil-metilo.
Cuando R2 representa alquilo de C1-4(fenilo sustituido por benciloxi) en el que cualquiera de los grupos fenilo y benciloxi anteriormente mencionados pueden estar opcionalmente sustituidos, los ejemplos incluyen 4-benciloxifenil-metilo, 4-(3-metilbenciloxi)fenil-metilo y 4-(4-metilbenciloxi)fenil-metilo.
Cuando R2 representa alquilo de C1-4(fenilo opcionalmente sustituido fusionado a carbociclilo opcionalmente sustituido), los ejemplos incluyen indanil-metilo (por ejemplo, indan-4-il-metilo, 2-metil-indan-il-metilo), indenil-metilo y tetralinil-metilo.
Cuando R2 representa alquilo de C1-4(fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido), los ejemplos incluyen benzo[1,3]dioxo-4-il-metilo y 2,3-dihidro-benzo[1,4]dioxin-4-il-metilo.
Cuando R3 representa alquilo de C1-4 los ejemplos incluyen metilo, etilo, propilo (por ejemplo, n-propilo, isopropilo), butilo (por ejemplo, n-butilo, sec-butilo, isobutilo y terc-butilo).
Cuando R3 representa arilo opcionalmente sustituido, arilo puede representar típicamente fenilo. Los grupos fenilo sustituidos ejemplares incluyen 2,4-diclorofenilo, 2,4-difluororofenilo, 2,4-dimetoxifenilo, 2,4-bis(trifluorometil)fenilo, 2,4,6-trifluorofenilo, 2,4,6-trimetilfenilo, 2,6-diclorofenilo, 2,6-difluorofenilo, 2,6-dimetoxifenilo, 2-isopropil-6-metilfenilo, 3-(ciclopentiloxi)-4-metoxifenilo, 3,4,5-trimetoxifenilo, 3,4-dimetoxifenilo, 3,4-diclorofenilo, 3,4-dimetilfenilo, 3,4,5trifluorofenilo, 3,5-bis(trifluororometil)fenilo, 3,5-dimetoxifenilo, 3-metoxifenilo, 4-(trifluorometil)fenilo, 4-bromo-2(trifluorometil)fenilo, 4-bromofenilo, 4-cloro-3-(trifluorometil)fenilo, 4-clorofenilo, 4-cianofenilo, 4-etoxifenilo, 4
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mencionados están opcionalmente sustituidos, R2 representa adecuadamente fenilo sustituido por 3-fenilo, fenilo sustituido por 4-fenilo, fenilo sustituido por 3-(3-clorofenilo), fenilo sustituido por 4-(cloro-fenilo), fenilo sustituido por 4-(3,4-diclorofenilo) o 3-fluorofenilo sustituido por 4-fenilo. En una forma de realización alternativa, cuando R2 representa fenilo sustituido por fenilo, R2 representa adecuadamente fenilo sin sustituir sustituido por fenilo sin sustituir.
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por fenoxi opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por fenoxi opcionalmente sustituido, R2 representa adecuadamente fenilo sustituido por 4-fenoxi.
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido, R2 representa adecuadamente 3-clorofenilo sustituido por 4-morfolinilo, fenilo sustituido por 4-piperazinilo sustituido por 4N-metilo, 2-clorofenilo sustituido por 6-piperazinilo sustituido por 4N-etilo, fenilo sustituido por pirrolidinilo, fenilo sustituido por piperidinilo sustituido por 4N-metilo, fenilo sustituido por tetrahidropiranilo o fenilo sustituido por morfolinilo.
En una forma de realización adicional, R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido, R2 representa adecuadamente 3-clorofenilo sustituido por 4-morfolinilo, fenilo sustituido por 4-piperazinilo sustituido por 4N-metilo, fenilo sustituido por 4-piperazinilo sustituido por 4N-fenilo, fenilo sustituido por 3-piperazinilo sustituido por 4N-fenilo o 2-clorofenilo sustituido por 6-piperazinilo sustituido por 4N-etilo.
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo en donde dicho heterociclilo está sustituido por fenilo. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por heterociclilo en donde dicho heterociclilo está sustituido por fenilo, R2 representa adecuadamente fenilo sustituido por 4-piperazinilo sustituido por 4N-fenilo, fenilo sustituido por 3-piperazinilo sustituido por 4N-fenilo.
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por carbociclilo opcionalmente sustituido en donde dicho carbociclilo está sustituido por heterociclilo opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por carbociclilo opcionalmente sustituido en donde dicho carbociclilo está sustituido por heterociclilo opcionalmente sustituido, R2 representa adecuadamente fenilo sustituido por carbociclilo (es decir, ciclohexilo) sustituido por heterociclilo (es decir, morfolinilo).
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por -O-alquilo de C1-4heterociclilo. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por -O-alquilo de C1-4-heterociclilo, R2 representa adecuadamente fenilo sustituido por 4-O-(CH2)2-morfolinilo, 4-O-(CH2)3-morfolinilo, 2-O-(CH2)2-morfolinilo
o 4-O-(CH2)2-piperazinilo.
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por carbociclilo opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por carbociclilo opcionalmente sustituido, R2 representa adecuadamente fenilo sustituido por cicloalquilo de C3-8 (tal como ciclohexilo) en donde dicho cicloalquilo de C3-8 puede estar opcionalmente sustituido por uno o más grupos oxo, halógeno (es decir, flúor), hidroxilo o alcoxi de C1-4 (es decir metoxi).
En una forma de realización, R2 representa fenilo opcionalmente sustituido, sustituido por -O-carbociclilo. Cuando R2 representa fenilo opcionalmente sustituido, sustituido por -O-carbociclilo, R2 representa adecuadamente fenilo sin sustituir sustituido por un grupo -O-cicloalquilo de C3-8 (es decir, -O-ciclohexilo).
En una forma de realización, R2 representa heterociclilo opcionalmente sustituido, sustituido por fenilo opcionalmente sustituido. Cuando R2 representa heterociclilo opcionalmente sustituido, sustituido por fenilo opcionalmente sustituido, R2 representa adecuadamente piperidinilo sin sustituir sustituido por fenilo sin sustituir.
En una forma de realización, R2 representa carbociclilo opcionalmente sustituido, sustituido por fenilo opcionalmente sustituido. Cuando R2 representa carbociclilo opcionalmente sustituido, sustituido por fenilo opcionalmente sustituido, R2 representa adecuadamente cicloalquilo de C3-8 sin sustituir (es decir, ciclohexilo) sustituido por fenilo sin sustituir.
En una forma de realización, R2 representa fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido. Cuando R2 representa fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido, R2 representa adecuadamente benzo-1,3-dioxolanilo, 4-metoxi(benzo-1,3-dioxolanilo), 6-metoxi(benzo-1,3dioxolanilo), 2,2-difluoro(benzo-1,3-dioxolanilo), o benzo-1,4-dioxolanilo.
En una forma de realización, R2 representa alquilo de C1-4(fenilo sustituido por un grupo heterociclilo monocíclico). Cuando R2 representa alquilo de C1-4(fenilo sustituido por un grupo heterociclilo monocíclico), R2 representa adecuadamente bencilo sustituido por morfolinilo.
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En una forma de realización X representa C=O, Y representa CHR9 y Z representa -N-R4. En una forma de realización adicional, X representa C=O, Y representa CH2 y Z representa -NH.
Cuando X representa C=O, Y representa CHR9 y Z representa -N-R4, R1 representa adecuadamente 1Hbenzo[d]imidazolilo.
Cuando X representa C=O, Y representa CHR9 y Z representa -N-R4, R2 representa adecuadamente fenilo opcionalmente sustituido por uno o más átomos de halógeno (tal como fenilo sin sustituir o 2,3,5-trifluorofenilo).
Cuando X representa C=O, Y representa CHR9 y Z representa -N-R4, R3 adecuadamente representa hidrógeno.
En una forma de realización alternativa, X representa CR7R8, Y representa C=O y Z representa O. En una forma de realización adicional, X representa CH2, Y representa C=O y Z representa O. En una forma de realización adicional, X representa C(Me)2, Y representa C=O y Z representa O. En una forma de realización adicional, X representa CHfenilo, Y representa C=O y Z representa O.
Cuando X representa CR7R8, Y representa C=O y Z representa O, R1 representa adecuadamente 1Hbenzo[d]imidazolilo o 1H-imidazo[1,2-a]piridinilo.
Cuando X representa CR7R8, Y representa C=O y Z representa O, R2 representa adecuadamente:
alquilo de C1-8 (tal como i-propilo); fenilo opcionalmente sustituido por uno o más grupos halógeno (tal como flúor o cloro), alcoxi de C1-6 (tal como propoxi) o haloalquilo de C1-6 (tal como trifluorometilo); alquilo de C1-4-arilo (tal como bencilo); fenilo opcionalmente sustituido fusionado a heterociclilo opcionalmente sustituido (tal como 2,3 dihidrobenzo[b][1,4]dioxin-6-ilo o benzo[d][1,3]dioxo1-6-ilo); fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido (tal como fenilo sustituido por O-(CH2)2-piperazinilo o fenilo sustituido por -O-(CH2)2-morfolinilo); fenilo opcionalmente sustituido, sustituido por fenilo opcionalmente sustituido; o fenilo opcionalmente sustituido, sustituido por heterociclilo opcionalmente sustituido (tal como fenilo opcionalmente sustituido, sustituido por por piperazinilo sustituido por fenilo o fenilo opcionalmente sustituido, sustituido por piperazinilo sustituido por metilo).
Cuando X representa CR7R8, Y representa C=O y Z representa O, R3 adecuadamente representa hidrógeno.
En una forma de realización alternativa, X representa CR7R8, Y representa CHR9 y Z representa CHR10. En una forma de realización adicional, X representa CH2, Y representa CH2 y Z representa CH2.
Cuando X representa CR7R8, Y representa CHR9 y Z representa CHR10, R1 representa adecuadamente 1Hbenzo[d]imidazolilo.
Cuando X representa CR7R8, Y representa CHR9 y Z representa CHR10, R2 representa adecuadamente:
hidrógeno; fenilo opcionalmente sustituido por uno o más halógenos (tal como flúor o cloro), alcoxi de C1-6 (tal como metoxi); o alquilo de C1-4-arilo opcionalmente sustituido (tal como bencilo sin sustituir y bencilo sustituido por un átomo de halógeno tal como flúor o cloro o un alcoxi de C1-6 tal como metoxi).
Cuando X representa CR7R8, Y representa CHR9 y Z representa CHR10, R3 adecuadamente representa hidrógeno.
En una forma de realización alternativa, X representa S, Y representa C=O y Z representa CHR10. En una forma de realización adicional, X representa S, Y representa C=O y Z representa CH2. En una forma de realización adicional, X representa S, Y representa C=O y Z representa CH-metilo.
Cuando X representa S, Y representa C=O y Z representa CHR10, R1 representa adecuadamente 1Hbenzo[d]imidazolilo.
Cuando X representa S, Y representa C=O y Z representa CHR10, R2 representa adecuadamente:
fenilo opcionalmente sustituido por uno o más halógenos (tal como flúor o cloro); naftilo opcionalmente sustituido (tal como naftilo sin sustituir); fenilo opcionalmente sustituido, sustituido por fenoxi opcionalmente sustituido; o heteroarilo opcionalmente sustituido (tal como tiofenilo sin sustituir).
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Cuando X representa -CH2-CH2-, Y representa CO y Z representa O, R2 representa adecuadamente fenilo opcionalmente sustituido por un alcoxi de C1-6 (tal como propoxi).
Cuando X representa -CH2-CH2-, Y representa CO y Z representa O, R3 adecuadamente representa hidrógeno.
5 En una forma de realización, el compuesto de fórmula (I) es un compuesto seleccionado de los ejemplos 1 a 235. En una forma de realización adicional, el compuesto de fórmula (I) es un compuesto seleccionado de los ejemplos 1 a
147. En una forma de realización aún adicional, el compuesto de fórmula es un compuesto seleccionado de los
ejemplos 12 a 14. 10
Según un aspecto adicional de la invención se proporciona un proceso para preparar un compuesto de fórmula (I) que comprende:
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(a) preparar un compuesto de fórmula (I) a partir de un compuesto de fórmula (II):
20 en donde R2, R3, X, Y y Z son como se han definido anteriormente para los compuestos de fórmula (I). El proceso típicamente implica hacer reaccionar un compuesto de fórmula (II) con un compuesto de fórmula R1-L en el que L representa un grupo saliente, por ejemplo, un átomo de halógeno tal como yodo. Un ejemplo no limitante del proceso (a) se describe en los métodos 5-8 y 12 en el presente documento.
25 (b) preparar un compuesto de fórmula (I) en donde R3 representa hidrógeno, Y representa CO, Z representa -N-R4, y X representa CR7R8 y R8 representa hidrógeno por hidrogenación de un compuesto de fórmula (III):
30 en donde R1, R2, R4 y R7 son como se han definido anteriormente para los compuestos de fórmula (I). El proceso (b) típicamente comprende hidrogenación en condiciones adecuadas, tal como PdC, 10% sobre carbón a 4 baros a 40ºC durante 4 horas. Un ejemplo no limitante de la metodología del proceso (b) se describe en el método 1 del presente documento.
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(c) preparar un compuesto de fórmula (I) en donde R3 representa hidrógeno, Y representa CO, Z representa CH2, y X representa CH2 por hidrogenación de un compuesto de fórmula (IV):
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de la metodología del proceso (f) se describe en el método 3 en el presente documento.
(g) preparar un compuesto de fórmula (I) en donde R3 representa hidrógeno, Y representa CO y X y Z se unen para formar un anillo carbocíclico o también X y Z representan dos átomos de carbono adyacentes de una anillo fenilo que está fusionado en esa posición y está opcionalmente sustituido por uno o más halógenos o grupos alquilo de C12, a partir de un compuesto de fórmula (VIII):
en donde R1, R2, X y Z son como se han definido anteriormente para los compuestos de fórmula (I). El proceso (g) es esencialmente una reacción de deshidratación que típicamente comprende el uso de reactivos adecuados, tal como ácido trifluoroacético, trietilsilano y bicarbonato de sodio. Un ejemplo no limitante de la metodología del proceso (g) se describe en el método 11 en el presente documento.
- (h)
- preparar un compuesto de fórmula (I) en donde X representa S, por ejemplo, un compuesto de fórmula (I) en donde R3 representa hidrógeno, Y representa CO, Z representa -CH2 y X representa S a partir de un compuesto correspondiente en el que X representa O. El proceso (h) típicamente comprende el uso de reactivos adecuados tal como el reactivo de Lawesson. Un ejemplo no limitante de la metodología del proceso (h) se describe en el método 9 en el presente documento.
- (i)
- preparar un compuesto de fórmula (I) en donde R4 representa -NH2 y a partir de un compuesto correspondiente de fórmula (I) en donde R4 representa H por tratamiento con nitrito seguido por reducción. Típicamente el compuesto de fórmula (I) en donde R4 representa H se trata con nitrito de sodio (o potasio) en presencia de ácido (por ejemplo, ácido acético glacial) y después se reduce por tratamiento con polvo de zinc. Un ejemplo no limitante de la metodología del proceso (i) se describe en el método 65 en el presente documento.
- (j)
- preparar un compuesto de fórmula (I) en donde R4 representa alquilo de C1-8 o -C(O)-alquilo de C1-6 a partir de un compuesto correspondiente de fórmula (I) en donde R4 representa H por tratamiento con un agente alquilante o alcanoilante. Los agentes alquilantes típicos incluyen compuestos de fórmula R4-L en donde L es un grupo saliente tal como halógeno (por ejemplo, cloro) o un anhídrido ácido correspondiente.
- (k)
- interconversión de compuestos de formula (I). Los ejemplos de tal interconversión incluyen interconversión de un compuesto de fórmula (I) en donde Y representa CO a un compuesto de fórmula (I) en donde Y representa CS. Tal interconversión puede comprender típicamente el uso de reactivos adecuados, tal como toluol y el reactivo de Lawesson. Un ejemplo no limitante de la metodología del proceso (k) se describe en el método 9 en el presente documento; y
- (i)
- desproteger un compuesto de fórmula (I) que está protegido.
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Los compuestos de fórmula (I) y compuestos intermedios también se pueden preparar usando técnicas análogas a las que conoce el experto en la materia, o descritas en el presente documento.
Se reivindican intermedios novedosos como un aspecto de la presente invención. 5
Usos terapéuticos
Los sustratos fisiológicos de QC (EC) en mamíferos son, por ejemplo, péptidos beta amiloide (3-40), (3-42), (11-40 y (11-42), ABri, ADan, gastrina, neurotensina, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, fractalquina, orexina A,
10 [Gln3]-glucagón(3-29), [Gln5]-sustancia P(5-11) y el péptido QYNAD. Para detalles adicionales véase la tabla 1. Los compuestos y/o combinaciones según la presente invención y composiciones farmacéuticas que comprenden al menos un inhibidor de QC (EC) son útiles para el tratamiento de afecciones que se pueden tratar por modulación de la actividad QC.
15 Tabla 1: Secuencias de aminoácidos de péptidos fisiológicos activos con un residuo de glutamina Nterminal, que son propensos a ser ciclados a pGlu final
- Péptido
- Secuencia de aminoácidos Función
- Abeta(1-42)
- Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- Abeta(1-40)
- Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-lle-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- Abeta(3-42)
- Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-GIy-AIa-IIe-IIe-GIy-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- Abeta(3-40)
- Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-lle-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- Abeta(11-42)
- Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-lle-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- Abeta(11-40)
- Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-lle-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val Desempeña un papel en neurodegeneración, por ejemplo, en la enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, síndrome de Down.
- ABri
- EASNCFA IRHFENKFAV ETLIC SRTVKKNIIEEN La forma piroglutamada desempeña un papel en la demencia familiar británica.
- ADan
- EASNCFA IRHFENKFAV ETLIC FNLFLNSQEKHY La forma piroglutamada desempeña un papel en la demencia familiar danesa.
- Gastrina 17
- QGPWL EEEEEAYGWM DF (amida) La gastrina estimula que la mucosa del estómago produzca y secrete ácido clorhídrico y
- Swiss-Prot: P01350
- que el páncreas secrete sus enzimas digestivas. También estimula la contracción del músculo liso y aumenta la circulación de la sangre y la secreción de agua en el estómago y el intestino.
- Neurotensina Swiss-Prot: 30990
- QLYENKPRRP YIL La neurotensina desempaña un papel endocrino o paracrino en la regulación del metabolismo graso. Produce contracción del músculo liso.
- FPP
- QEP amida Un tripéptido relacionado con la hormona liberadora de tirotropina (TRH), se encuentra en plasma seminal. Evidencia reciente obtenida in vivo e in vitro mostró que FPP desempaña un papel importante en regular la fertilidad del semen.
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- Péptido
- Secuencia de aminoácidos Función
- TRH Swiss-Prot: P20396
- QHP amida TRH funciona como un regulador de la biosíntesis de TSH en la hipófisis anterior y como un neurotransmisor/neuromodulador en los sistemas nerviosos central y periférico.
- GnRH Swiss-Prot: P01148
- QHWSYGL RP(G) amida Estimula la secreción de gonadotropinas; estimula la secreción tanto de hormona luteinizante como foliculoestimulante.
- CCL16 (citoquina inducible pequeña A16) Swiss-Prot: O15467
- QPKVPEW VNTPSTCCLK YYEKVLPRRL VVGYRKALNC HLPAIIFVTK RNREVCTNPN DDWVQEYIKD PNLPLLPTRN LSTVKIITAK NGQPQLLNSQ Muestra actividad quimiotáctica para linfocitos y monocitos pero no neutrófilos. También muestra potente actividad mielosupresora, suprime la proliferación de células progenitoras mieloides. SCYA16 recombinante muestra actividad quimiotáctica para monocitos y monocitos THP1, pero no para linfocitos en reposo y neutrófilos. Induce un flujo de calcio en células THP-1 que se desensibilizaron por expresión anterior de RANTES
- CCL8 (citoquina inducible pequeña A8) Swiss-Prot: P80075
- QPDSVSI PITCCFNVIN RKIPIQRLES YTRITNIQCP KEAVIFKTKR GKEVCADPKE RWVRDSMKHL DQIFQNLKP Factor quimiotáctico que atrae monocitos, linfocitos, basófilos y eosinófilos. Puede desempeñar un papel en neoplasia y respuestas inflamatorias del huésped. Esta proteína se puede unir a heparina.
- CCL2 (MCP-1,
- QPDAINA PVTCCYNFTN Factor quimiotáctico que atrae monocitos y
- citoquina inducible
- RKISVQRLAS YRRITSSKCP basófilos pero no neutrófilos o eosinófilos.
- pequeña A2)
- KEAVIFKTIV AKEICADPKQ KWVQDSMDHL DKQTQTPKT Aumenta la actividad antitumoral de monocitos. Se ha implicado en la patogénesis de
- Swiss-Prot: P13500
- enfermedades caracterizadas por infiltrados monocíticos, como psoriasis, artritis reumatoide o ateroesclerosis. Puede estar implicada en el reclutamiento de monocitos en la pared arterial durante el proceso de enfermedad de ateroesclerosis. Se une a CCR2 y CCR4.
- CCL18 (citoquina inducible pequeña A18) Swiss-Prot: P55774
- QVGTNKELC CLVYTSWQIP QKFIVDYSET SPQCPKPGVI LLTKRGRQIC ADPNKKWVQK YISDLKLNA Factor quimiotáctico que atrae linfocitos pero no monocitos o granulocitos. Puede estar implicada en la migración de células B a folículos de células B en los ganglios linfáticos. Atrae linfocitos T indiferenciados hacia células dendríticas y macrófagos activados en ganglios linfáticos, tiene actividad quimiotáctica para células T indiferenciadas, células T CD4+ y CD8+ y por tanto puede desempañar un papel en las respuestas inmunitarias tanto humoral como celular.
- Fractalquina
- QHHGVT KCNITCSKMT SKIPVALLIH La forma soluble es quimiotáctica para células T
- (neurotactina)
- YQQNQASCGK RAIILETRQH RLFCADPKEQ WVKDAMQHLD y monocitos, pero no para neutrófilos. La forma unida a membrana fomenta la adhesión de esos
- Swiss-Prot: P78423
- RQAAALTRNG GTFEKQIGEV KPRTTPAAGG MDESWLEPE ATGESSSLEP TPSSQEAQRA LGTSPELPTG VTGSSGTRLP PTPKAQDGGP VGTELFRVPP VSTAATWQSS APHQPGPSLW AEAKTSEAPS TQDPSTQAST ASSPAPEENA PSEGQRVWGQ GQSPRPENSL EREEMGPVPA HTDAFQDWGP GSMAHVSVVP VSSEGTPSRE PVASGSWTPK AEEPIHATMD PQRLGVLITP VPDAQAATRR QAVGLLAFLG LLFCLGVAMF TYQSLQGCPR KMAGEMAEGL RYIPRSCGSN SYVLVPV leucocitos a células endoteliales. Puede desempeñar un papel en la regulación de los procesos de adhesión y migración de leucocitos en el endotelio se une a CX3CR1.
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- Péptido
- Secuencia de aminoácidos Función
- CCL7 (citoquina inducible pequeña A7) Swiss-Prot: P80098
- QPVGINT STTCCYRFIN KKIPKQRLES YRRTTSSHCP REAVIFKTKL DKEICADPTQ KWVQDFMKHL DKKTQTPKL Factor quimiotáctico que atrae monocitos y eosinófilos, pero no neutrófilos. Aumenta la actividad antitumoral de monocitos. También induce la liberación de gelatinasa B. Esta proteína se puede unir a heparina. Se une a CCR1, CCR2 y CCR3.
- Orexina A (hipocretina-1) Swiss-Prot: O43612
- QPLPDCCRQK TCSCRLYELL HGAGNHAAGI LTL Neuropéptido que desempeña un papel significativo en la regulación de la ingesta de alimentos y sueño-vigilia, posiblemente por coordinación de las respuestas conductuales y psicológicas complejas de estas funciones homeostáticas complementarias. También desempaña un papel más amplio en la regulación homeostática del metabolismo de energía, función autonómica, equilibrio hormonal y la regulación de líquidos corporales. Orexina-A se une tanto de OX1R como OX2R con una alta afinidad.
- Sustancia P
- RPK PQQFFGLM Pertenece a las taquicininas. Las taquicininas son péptidos activos que excitan neuronas, provocan respuestas conductuales, son potentes vasodilatadores y secretagogos, y contraen (directa o indirectamente) muchos músculos lisos.
- QYNAD
- Gln-Tyr-Asn-Ala-Asp Actúa sobre canales de sodio operados por voltaje.
El glutamato se encuentra en las posiciones 3, 11 y 22 del péptido β-amiloide. Entre ellos la mutación de ácido glutámico (E) a glutamina (Q) en la posición 22 (correspondiente a la proteína precursora de amiloide APP 6963, Swissprot P05067) se ha descrito como la denominada mutación de amiloidosis cerebroarterial de tipo holandés.
Se ha descrito que los péptidos β-amiloides con un residuo de ácido piroglutámico en la posición 3, 11 y/o 22 son más citotóxicos e hidrofóbicos que los péptidos β-amiloides 1-40(42/43) (Saido T.C. 2000 Medical Hypotheses 54(3): 427-429).
Se pueden generar las múltiples variaciones N-terminales, por ejemplo, Abeta(3-40), Abeta(3-42), Abeta(11-40) y Abeta(11-42), por la enzima β-secretasa enzima que corta la proteína precursora del amiloide en sitios β (BACE) en sitios diferentes (Huse J.T. et al. 2002 J. Biol. Chem. 277 (18): 16278-16284), y/o por procesamiento de aminopeptidasa o dipeptidilaminopeptidasa a partir de los péptidos de longitud completa Abeta(1-40) y Abeta(1-42). En todos los casos, la ciclación del residuo de ácido glutámico N-terminal entonces producido está catalizada por QC.
Las células transductoras transepiteliales, particularmente la célula de gastrina (G), coordinan la secreción de ácido gástrico con la llegada del alimento al estómago. Trabajo reciente mostró que se generan múltiples productos activos del precursor de gastrina, y que hay múltiples puntos de control en la biosíntesis de gastrina. Los precursores e intermedios biosintéticos (progastrina y Gly-gastrinas) son putativos factores de crecimiento; sus productos, las gastrinas amidadas, regulan la proliferación de células epiteliales, la diferenciación de células parietales productoras de ácido y células similares a enterocromafines (ECL) que secretan histamina, y la expresión de genes asociados con la síntesis y almacenamiento de histamina en las células ECL, así como estimulan intensamente la secreción de ácido. La gastrina también estimula la producción de miembros de la familia del factor de crecimiento epidérmico (EGF), que a su vez inhibe la función de células parietales pero estimula el crecimiento de células epiteliales de superficie. Las concentraciones de gastrina en plasma son elevadas en sujetos con Helicobacter pylori, que se sabe tienen riesgo aumentado de enfermedad de úlcera gastroduodenal y cáncer gástrico (Dockray, G.J. 1999 J Physiol 15 315-324).
La hormona peptídica gastrina, liberada de células G antrales, se sabe que estimula la síntesis y liberación de histamina de células ECL en la mucosa oxíntica a través de receptores CCK-2. La histamina movilizada induce la secreción ácida uniéndose a los receptores H(2) localizados en células parietales. Estudios recientes sugieren que la gastrina, tanto en sus formas completamente amidada como menos procesada (progastrina y gastrina extendida con glicina), también es un factor de crecimiento para el aparato digestivo. Se ha establecido que el principal efecto trófico de la gastrina amidada es para la mucosa oxíntica del estómago, donde produce proliferación aumentada de las células madre gástricas y células ECL, lo que produce masa de células parietales y ECL aumentada. Por otra parte, la principal diana trófica de la gastrina menos procesada (por ejemplo, gastrina extendida con glicina) parece ser la mucosa colónica (Koh, T.J. y Chen, D. 2000 Regul Pept 9337-44).
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terminal (AcELA) fallaron para provocar actividad de linfocitos T citotóxicos (LTC). A pesar de las aparentes modificaciones menores introducidas en PyrELA y AcELA, estos dos derivados probablemente tienen menor afinidad que ELA para el complejo de histocompatibilidad principal de clase I específico. Consecuentemente, para conservar la actividad completa de ELA, la formación de PyrELA se debe evitar (Beck A. et al. 2001, J Pept Res 57(6):528-38).
Orexina A es un neuropéptido que desempeña un papel significativo en la regulación de la ingesta de alimentos y sueño-vigilia, posiblemente por coordinación de respuestas conductuales y fisiológicas complejas de estas funciones homeostáticas complementarias. También desempeña un papel en la regulación homeostática del metabolismo de energía, función autonómica, equilibrio hormonal y la regulación de líquidos corporales.
Recientemente, se identificaron niveles aumentados del pentapéptido QYNAD en el líquido cefalorraquídeo (LCR) de pacientes que padecen esclerosis múltiple o síndrome de Guillain-Barré comparados con individuos sanos (Brinkmeier H. et al. 2000, Nature Medicine 6, 808-811). Hay una gran controversia en la bibliografía sobre el mecanismo de acción del pentapéptido Gln-Tyr-Asn-Ala-Asp (QYNAD), especialmente su eficacia para interaccionar con y bloquear canales de sodio lo que produce el fomento de disfunción axónica, que están implicados en enfermedades autoinmunitariass inflamatorias del sistema nervioso central. Pero recientemente, se pudo demostrar que no QYNAD, sino su forma ciclada, piroglutamada, pEYNAD, es la forma activa, que bloquea los canales de sodio lo que produce el fomento de la disfunción axónica. Los canales de sodio se expresan a alta densidad en axones mielinizados y desempañan un papel obligatorio en conducir los potenciales de acción a lo largo de los axones en el cerebro y la médula espinal de mamíferos. Por tanto, se especula que están implicados en varios aspectos de la patofisiología de enfermedades autoinmunitarias inflamatorias, especialmente esclerosis múltiple, el síndrome de Guillain-Barré y polirradiculoneuropatía desmielinizante inflamatoria crónica.
Además, QYNAD es un sustrato de la enzima glutaminil ciclasa (QC, EC 2.3.2.5), que también está presente en el cerebro de mamíferos, especialmente en cerebro humano. La glutaminil ciclasa cataliza eficazmente la formación de pEYNAD a partir de su precursor QYNAD.
Según esto, la presente invención proporciona el uso de compuestos de fórmula (I) para la preparación de un medicamento para la prevención o mejora o tratamiento de una enfermedad seleccionada del grupo que consiste en deterioro cognitivo leve, enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, neurodegeneración en síndrome de Down, enfermedad de Huntington, enfermedad de Kennedy, enfermedad de úlcera, cáncer duodenal con o sin infecciones por Helicobacter pylori, cáncer colorrectal, síndrome de Zolliger-Ellison, cáncer gástrico con o sin infecciones por Helicobacter pylori, afecciones psicóticas patogénicas, esquizofrenia, infertilidad, neoplasia, respuestas inflamatorias del huésped, cáncer, metástasis maligna, melanoma, psoriasis, artritis reumatoide, ateroesclerosis, pancreatitis, restenosis, respuestas inmunitarias humorales y celulares alteradas, procesos de adhesión y migración de leucocitos en el endotelio, ingesta de alimentos alterada, sueñovigilia alterado, regulación homeostática alterada del metabolismo de energía, función autonómica alterada, equilibrio hormonal alterado o regulación alterada de líquidos corporales, esclerosis múltiple, el síndrome de Guillain-Barré y polirradiculoneuropatía desmielinizante inflamatoria crónica.
Además, mediante la administración de un compuesto según la presente invención a un mamífero puede ser posible estimular la proliferación de células progenitoras mieloides.
Además, la administración de un inhibidor de QC según la presente invención puede producir una supresión de la fertilidad masculina.
En una forma de realización preferida, la presente invención proporciona el uso de inhibidores de la actividad QC (EC) en combinación con otros agentes, especialmente para el tratamiento de enfermedades neuronales, ateroesclerosis y esclerosis múltiple.
La presente invención también proporciona un método de tratamiento de las enfermedades anteriormente mencionadas que comprende la administración de un cantidad terapéuticamente activa de al menos un compuesto de fórmula (I) a un mamífero, preferiblemente un ser humano.
Lo más preferiblemente, dicho método y los usos correspondientes son para el tratamiento de un enfermedad seleccionada del grupo que consiste en deterioro cognitivo leve, enfermedad de Alzheimer, demencia familiar británica, demencia familiar danesa, neurodegeneración en síndrome de Down, enfermedad de Parkinson y Corea de Huntington, que comprende la administración de una cantidad terapéuticamente activa de al menos un compuesto de fórmula (I) a un mamífero, preferiblemente un ser humano.
Incluso preferiblemente, la presente invención proporciona un método de tratamiento y los usos correspondientes para el tratamiento de artritis reumatoide, ateroesclerosis, pancreatitis y restenosis.
Combinaciones farmacéuticas
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Por ejemplo, para la administración oral en forma de un comprimido o cápsula, el componente de fármaco activo se puede combinar con un soporte inerte farmacéuticamente aceptable no tóxico, oral, tal como etanol glicerol, agua y similares. Además, cuando se desee o sea necesario, también se pueden incorporar en la mezcla aglutinantes, lubricantes, agentes disgregantes y agentes colorantes adecuados. Los aglutinantes adecuados incluyen, sin limitación, almidón, gelatina, azúcares naturales tales como glucosa o betalactosa, edulcorantes de maíz, gomas naturales y sintéticas tales como goma arábiga, tragacanto u oleato de sodio, estearato de sodio, estearato de magnesio, benzoato de sodio, acetato de sodio, cloruro de sodio y similares. Los disgregantes incluyen, sin limitación, almidón, metilcelulosa, agar, bentonita, goma xantana y similares.
Las formas líquidas en agentes suspensores o dispersantes saborizados adecuados tales como las gomas sintéticas y naturales, por ejemplo, tragacanto, goma arábiga, metilcelulosa y similares. Para la administración parenteral, se desean suspensiones o soluciones estériles. Las preparaciones isotónicas que generalmente contienen conservantes adecuados se emplean cuando se desea la administración intravenosa.
Los compuestos o combinaciones de la presente invención también se pueden administrar en forma de sistemas de administración de liposomas, tal como vesículas unilamelares pequeñas, vesículas unilamelares grandes, y vesículas multilamelares. Los liposomas se pueden formar de una gran variedad de fosfolípidos, tal como colesterol, estearilamina o fosfatidilcolinas.
Los compuestos o combinaciones de la presente invención también se pueden administrar mediante el uso de anticuerpos monoclonales como soportes individuales a los que se acoplan las moléculas del compuesto. Los compuestos de la presente invención también se pueden acoplar con polímeros solubles como soportes de fármacos dirigibles. Tales polímeros pueden incluir polivinilpirrolidona, copolímero de pirano, polihidroxipropilmetacrilamidafenol, polihidroxietilaspartamida-fenol, o polietilenoxidopolilisina sustituida con residuo de palmitoilo. Además, los compuestos de la presente invención se pueden acoplar a una clase de polímeros biodegradables útiles en alcanzar la liberación controlada de un fármaco, por ejemplo, ácido poliláctico, poliepsilón caprolactona, ácido polihidroxibutiérico, poliortoésteres, poliacetales, polihidropiranos, policianoacrilatos y copolímeros en bloque entrecruzados o anfipáticos de hidrogeles.
Los compuestos o combinaciones de esta invención se pueden administrar en cualquiera de las combinaciones anteriores y según pautas de dosis establecidas en la técnica siempre que se requiera el tratamiento de los trastornos abordados.
La dosis diaria de los productos puede variar sobre un amplio intervalo desde 0,01 hasta 1.000 mg por mamífero al día. Para la administración oral, las composiciones preferiblemente se proporcionan en forma de comprimidos que contienen 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 150, 200, 250 y 500 mg de cada principio activo o combinaciones de los mismos para el ajuste sintomático de la dosis al paciente que se va a tratar. Una cantidad eficaz del fármaco se suministra normalmente a un nivel de dosis desde aproximadamente 0,1 mg/kg hasta aproximadamente 300 mg/kg de peso corporal al día. Preferiblemente, el intervalo es desde aproximadamente 1 hasta aproximadamente 50 mg/kg de peso corporal al día. Los compuestos o combinaciones se pueden administrar en una pauta de 1 a 4 veces al día.
La dosis óptima que se va a administrar la pueden determinar fácilmente los expertos en la materia, y variará con el compuesto particular usado, el modo de administración, la fuerza de la preparación, el modo de administración, y el progreso del estado de la enfermedad. Además, factores asociados con el paciente particular que se trata, incluyendo la edad del paciente, peso, dieta y tiempo de administración, producirán la necesidad de ajustar dosis.
En un aspecto más, la invención también proporciona un proceso para preparar una composición farmacéutica que comprende al menos un compuesto de fórmula (I), opcionalmente en combinación con al menos uno de los otros agentes anteriormente mencionados y un soporte farmacéuticamente aceptable.
Las composiciones están preferiblemente en una forma farmacéutica unitaria en una cantidad apropiada para la dosis diaria relevante.
Las dosis adecuadas, incluyendo especialmente dosis unitarias, de los compuestos de la presente invención incluyen las dosis conocidas incluyendo las dosis unitarias para estos compuestos como se describen o se refieren en un texto de referencia tal como las farmacopeas británica y estadounidense, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (Londres, The Pharmaceutical Press) (por ejemplo véase la 31ª edición página 341 y páginas citadas en las misma) o las publicaciones mencionadas anteriormente.
Ejemplos
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- 1
- 5-terc-butil-1-(1Hbenzo[d]imidazol-5il)imidazolidin-2-ona C14H18N4O 258,319
- 2
- 1-(1H-benzo[d]imidazol-5-il)5-ciclohexilimidazolidin-2ona C16H20N4O 284,356
- 3
- 1-(1H-benzo[d]imidazol-5-iI)5-fenilimidazolidin-2-ona C16H14N4O 278,309
- 4
- 1-(1H-benzo[d]imidazol-5-iI)5-m-tolilimidazolidin-2-ona C17H16N4O 292,335
- 5
- 1-(1H-benzo[d]imidazol-5-il)5-(4-metoxifenil)imidazolidin2-ona C17H16N4O2 308,335
- 6
- 1-(1H-benzo[d]imidazol-5-il)5-(4-metoxifenil)imidazolidin2-ona enantiómero 1 C17H16N4O2 308,335
- 7
- 1-(1H-benzo[d]imidazol-5-il)5-(4-metoxifenil)imidazolidin2-ona enantiómero 2 C17H16N4O2 308,335
- 8
- (4R,5S)-1-(1Hbenzo[d]imidazol-6-il)-5-(4metoxifenil)-4metilimidazolidin-2-ona C18H18N4O2 322,36
- 9
- 1-(1H-benzo[d]imidazol-5-il)5-(3-metoxifenil)imidazolidin2-ona C17H16N4O2 308,335
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- 10
-
1-(1H-benzo[d]imidazol-5-il)5-(2-metoxifenil)imidazolidin2-ona
imagen33 C17H16N4O2 308,335
- 11
- 1-(1H-benzo[d]imidazol-5-il)5-(4-etoxifenil)imidazolidin-2ona C18H18N4O2 322,361
- 12
- 1-(1H-benzo[d]imidazol-5-il)5-(4-propoxifenil) imidazolidin-2-ona C19H20N4O2 336,388
- 13
- (R)-1-(1H-benzo[d]imidazol5-il)-5-(4-propoxifenil) imidazolidin-2-ona C19H20N4O2 336,388
- 14
- (S)-1-(1H-benzo[d]imidazol5-il)-5-(4-propoxifenil) imidazolidin-2-ona C19H20N4O2 336,388
- 15
- 1-(1H-benzo[d]imidazol-5-il)5-(4-butoxifenil)imidazolidin2-ona C20H22N4O2 350,414
- 16
- 1-(1H-benzo[d]imidazol-5-il)5-(4-(pentiloxi)fenil) imidazolidin-2-ona C21H24N4O2 364,441
- 17
- 1-(1H-benzo[d]imidazol-5-il)5-(4-isopropoxifenil) imidazolidin-2-ona C19H20N4O2 336,388
- 18
- 1-(1H-benzo[d]imidazol-5-il)5-(4-metoxibenzo[d][1,3] dioxol-6-il)imidazolidin-2-ona C18H16N4O4 352,344
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- 19
-
1-(1H-benzo[d]imidazol-5-il)5-(2,3-dihidrobenzo[b][1,4] dioxin-6-il)imidazolidin-2-ona
imagen34 C18H16N4O3 336,345
- 20
- 5-(4-(1,1,2,2tetrafluoroetoxi)fenil)-1-(1Hbenzo[d]imidazol-5il)imidazolidin-2-ona C18H14F4N4O2 394,323
- 21
- 1-(1H-benzo[d]imidazol-5-il)5-(2,2-difluorobenzo[d][1,3] dioxol-5-il)imidazolidin-2-ona C17H12F2N4O3 358,299
- 22
- 1-(1H-benzo[d]imidazol-5-il)5-(3-fluoro-4-metoxifenil) imidazolidin-2-ona C17H15FN4O2 326,325
- 23
- 1-(1H-benzo[d]imidazol-5-il)5-(2,6-difluoro-4-metoxifenil) imidazolidin-2-ona C17H14F2N4O2 344,315
- 24
- 5-(4-(2-morfolinoetoxi)fenil-1(1H-benzo[d]imidazol-6il)imidazolidin-2-ona C22H25N5O3 407,466
- 25
- 5-(4-(3morfolinopropoxi)fenil)-1-(1Hbenzo[d]imidazol-5il)imidazolidin-2-ona C23H27N5O3 421,492
- 26
- 5-(2-(2-morfolinoetoxi)fenil-1(1H-benzo[d]imidazol-5il)imidazolidin-2-ona C22H25N5O3 407,466
- 27
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-fluorofenil)imidazolidin2-ona C16H13FN4O 296,299
42
E10751952
24-09-2015
- 28
- 1-(1H-benzo[d]imidazol-5-iI)5-(2-fluorofenil)imidazolidin2-ona C16H13FN4O 296,299
- 29
- 1-(1H-benzo[d]imidazol-5-iI)5-(3-fluorofenil)imidazolidin2-ona C16H13FN4O 296,299
- 30
- 1-(1H-benzo[d]imidazol-5-iI)5-(2,6difluorofenil)imidazolidin-2ona C16H12F2N4O 314,289
- 31
- 1-(1H-benzo[d]imidazol-5-iI)5-(3,4difluorofenil)imidazolidin-2ona C16H12F2N4O 314,289
- 32
- 1-(1H-benzo[d]imidazol-5-il)5-(2-fluoro-5(trifluorometil)fenil) imidazolidin-2-ona C17H12F4N4O 364,297
- 33
- 1-(1H-benzo[d]imidazol-5-il)5-(3-fluoro-5(trifluorometil)fenil) imidazolidin-2-ona C17H12F4N4O 364,297
- 34
- 1-(1H-benzo[d]imidazol-5-il)5-(2-fluoro-4(trifluorometil)fenil) imidazolidin-2-ona C17H12F4N4O 364,297
- 35
- 1-(1H-benzo[d]imidazol-5-il)5-(3-fluoro-4(trifluorometil)fenil) imidazolidin-2-ona C17H12F4N4O 364,297
43
E10751952
24-09-2015
- 36
- 1-(1H-benzo[d]imidazol-5-iI)5-(2-clorofenil)imidazolidin-2ona C16H13ClN4O 312,754
- 37
- 1-(1H-benzo[d]imidazol-5-iI)5-(3-clorofenil)imidazolidin-2ona C16H13ClN4O 312,754
- 38
- 1-(1H-benzo[d]imidazol-5-iI)5-(2,6diclorofenil)imidazolidin-2ona C16H12Cl2N4O 347,199
- 39
-
1-(1H-benzo[d]imidazol-5-iI)5-(2,3diclorofenil)imidazolidin-2ona
imagen35 C16H12Cl2N4O 347,199
- 40
- 1-(1H-benzo[d]imidazol-5-iI)5-(3,4diclorofenil)imidazolidin-2ona C16H12Cl2N4O 347,199
- 41
- (S)-1-(1H-benzo[d]imidazol5-iI)-5-(3,4diclorofenil)imidazolidin-2ona C16H12Cl2N4O 347,199
- 42
- 1-(1H-1,3-benzodiazol-5-iI)5-(4-bifenil)imidazolidin-2ona C22H18N4O 354,405
- 43
- (S)-1-(1H-1,3-benzodiazol-5iI)-5-(4-bifenil)imidazolidin-2ona C22H18N4O 354,405
44
E10751952
24-09-2015
- 44
- (R)-1-(1H-1,3-benzodiazol-5iI)-5-(4-bifenil)imidazolidin-2ona C22H18N4O 354,405
- 45
- 1-(1H-1,3-benzodiazol-5-iI)5-(3-fluoro-4bifenil)imidazolidin-2-ona C22H17FN4O 372,395
- 46
- 1-(1H-benzo[d]imidazol-5-iI)5-[4-(3clorofenil)fenil]imidazolidin-2ona C22H17ClN4O 388,85
- 47
- 1-(1H-benzo[d]imidazol-5-iI)5-(3',4'-dicloro-4bifenil)imidazolidin-2-ona C22H16Cl2N4O 423,295
- 48
- 1-(1H-benzo[d]imidazol-5-il)5-(3-fenilfenil)imidazolidin-2ona C22H18N4O 354,405
- 49
- 1-(1H-benzo[d]imidazol-5-il5-[3-(3-clorofenil)fenil] imidazolidin-2-ona C22H17ClN4O 388,85
- 50
- 1-(1H-benzo[d]imidazol-5-il)5-(3-cloro-4-morfolinofenil) imidazolidin-2-ona C20H20ClN5O2 397,858
- 51
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-(4-fenilpiperazin-1il)fenil)imidazolidin-2-ona C26H26N6O 438,524
45
E10751952
24-09-2015
- 52
- 1-(1H-benzo[d]imidazol-5-iI)5-(2-cloro-6-(4-etilpiperazin1-il)fenil)imidazolidin-2-ona C22H25ClN6O 424,297
- 53
- 1-(H-imidazo[1,2-a]piridin-7il)-5-fenilimidazolidin-2-ona C16H14N4O 278,309
- 54
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(4-propoxifenil) imidazolidin-2-ona C19H20N4O2 336,388
- 55
- 5-(4-butoxifenil)-1-(Himidazo[1,2-a]piridin-7il)imidazolidin-2-ona C20H22N4O2 350,414
- 56
- 5-(2,6-difluoro-4-metoxifenil)1-(H-imidazo[1,2-a]piridin-7il)imidazolidin-2-ona C17H14F2N4O2 344,315
- 57
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(4-metoxibenzo[d][1,3] dioxol-6-il)imidazolidin-2-ona C18H16N4O4 352,344
- 58
- 5-(4-(2-morfolinoetoxi)fenil)1-(H-imidazo[1,2-a]piridin-7il)imidazolidin-2-ona C22H25N5O3 407,466
- 59
- 5-(2,6-difluorofenil)-1-(Himidazo[1,2-a]piridin-7il)imidazolidin-2-ona C16H12F2N4O 314,28
- 60
-
5-(bifenil)-1-(H-imidazo[1,2a]piridin-7-il)imidazolidin-2ona
imagen36 C22H18N4O 354,405
46
E10751952
24-09-2015
- 61
-
5-(3-fluorobifenil)-1-(Himidazo[1,2-a]piridin-7il)imidazolidin-2-ona
imagen37 C22H17FN4O 372,395
- 62
-
1-(H-imidazo[1,2-a]piridin-7il)-5-(4-(4-fenilpiperazin-1il)fenil)imidazolidin-2-ona
imagen38 C26H26N6O 438,22
- 63
- 1-(1H-benzo[d]imidazol-5-iI)5-fenil)imidazolidin-4-ona C16H14N4O 278,30
- 64
- 1-(1H-benzo[d]imidazol-5-il)5-(2,3,5-trifluorofenil) imidazolidin-4-ona C16H11F3N4O 332,27
- 65
- 1-amino-3-(1Hbenzo[d]imidazol-5-il)-4-(4metoxifenil)imidazolidin-2ona C17H17N5O2 323,34
- 66
- (S)-3-(1H-benzo[d]imidazol6-il)-4-feniloxazolidin-2-ona C16H13N3O2 279,293
- 67
- (R)-3-(1H-benzo[d]imidazol6-il)-4-feniloxazolidin-2-ona C16H13N3O2 279,293
- 68
- (S)-3-(1H-benzo[d]imidazol5-il)-4-isopropiloxazolidin-2ona C13H15N3O2 245,27
47
E10751952
24-09-2015
- 69
- (S)-3-(1H-benzo[d]imidazol5-il)-4-benciloxazolidin-2-ona C17H15N3O2 293,31
- 70
- (4S,5R)-3-(1Hbenzo[d]imidazol-6-il)-4,5difeniloxazolidin-2-ona C22H17N3O2 355,389
- 71
- (4S,5S)-3-(1Hbenzo[d]imidazol-6-il)-5metil-4-feniloxazolidin-2-ona C17H15N3O2 293,32
- 72
- (S)-3-(1H-benzo[d]imidazol6-il)-5,5-dimetil-4feniloxazolidin-2-ona C18H17N3O2 307,346
- 73
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(4propoxifenil)oxazolidin-2-ona C19H19N3O3 337,372
- 74
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(2,3dihidrobenzo[b][1,4]dioxin-7il)oxazolidin-2-ona C18H15N3O4 337,11
- 75
- (S)-4-(benzo[d][1,3]dioxol-6il)-3-(1H-benzo[d]imidazol-6il)oxazolidin-2-ona C17H13N3O4 323,09
- 76
- (4S,5R)-3-(1Hbenzo[d]imidazol-6-il)-4,5bis(4-propoxifenil)oxazolidin2-ona diastereómero 1 C28H29N3O4 471,22
48
E10751952
24-09-2015
- 77
- (4S,5R)-3-(1Hbenzo[d]imidazol-6-il)-4,5bis(4-propoxifenil)oxazolidin2-ona diastereómero 2 C28H29N3O4 471,22
- 78
- 3-(1H-benzo[d]imidazol-6-il)5-fenil-4-(4propoxifenil)oxazolidin-2-ona diastereómero 1 C25H23N3O3 413,17
- 79
- -(1H-benzo[d]imidazol-6-il)-5fenil-4-(4propoxifenil)oxazolidin-2-ona diastereómero 2 C25H23N3O3 413,17
- 80
- (S)-4-(4-(2-(piperazin-1il)etoxi)fenil)-3-(1Hbenzo[d]imidazol-6il)oxazolidin-2-ona C22H25N5O3 407,2
- 81
- (S)-4-(4-(2morfolinoetoxi)fenil)-3-(1Hbenzo[d]imidazol-6il)oxazolidin-2-ona C22H24N4O4 408,18
- 82
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(2,3difluorofenil)oxazolidin-2-ona C16H11F2N3O2 315,08
49
E10751952
24-09-2015
- 83
-
(S)-3-(1H-benzo[d]imidazol6-il)-4-(3fluorofenil)oxazolidin-2-ona
imagen39 C16H12FN3O2 297,09
- 84
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(3-fluoro-5(trifluorometil)fenil)oxazolidin2-ona C17H11F4N3O2 365,08
- 85
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(3clorofenil)oxazolidin-2-ona C16H12ClN3O2 313,06
- 86
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(4clorofenil)oxazolidin-2-ona C16H12ClN3O2 313,06
- 87
- (S)-3-(1H-benzo[d]imidazol6-il)-4-[4-(3clorofenil)fenil]oxazolidin-2ona C22H16ClN3O2 389,09
- 88
- (S)-3-(1H-benzo[d]imidazol6-il)-4-[3-(3clorofenil)fenil]oxazolidin-2ona C22H16ClN3O2 389,09
- 89
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(4-(4-fenilpiperazin-1il)fenil)oxazolidin-2-ona C26H25N5O2 439,2
- 90
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(4-(4-metilpiperazin-1il)fenil)oxazolidin-2-ona C21H23N5O2 377,19
50
E10751952
24-09-2015
- 91
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(3-(4-fenilpiperazin-1il)fenil)oxazolidin-2-ona C26H25N5O2 439,50
- 92
- (S)-3-(2-metil-1Hbenzo[d]imidazol-6-il)-4feniloxazolidin-2-ona C17H15N3O2 293,31
- 93
- (S)-4-(1H-benzo[d]imidazol6-il)-5-(4propoxifenil)morfolin-3-ona C20H21N3O3 351,39
- 94
- 3-(1H-benzo[d]imidazol-6-il)4-(4-propoxifenil)-1,3oxazinan-2-ona C20H21N3O3 351,39
- 95
- (S)-3-(H-imidazo[1,2a]piridin-7-il)-4feniloxazolidin-2-ona C16H13N3O2 279,293
- 96
- (4S,5R)-3-(H-imidazo[1,2a]piridin-7-il)-4,5difeniloxazolidin-2-ona C22H17N3O2 355,389
- 97
- (4S,5R)-3-(imidazo[1,2a]piridin-6-il)-4,5difeniloxazolidin-2-ona C22H17N3O2 355,38
- 98
- (S)-3-(H-imidazo[1,2a]piridin-7-il)-4-(4propoxifenil)oxazolidin-2-ona C19H19N3O3 337,372
51
E10751952
24-09-2015
- 99
- (S)-4-(4-clorofenil)-3-(Himidazo[1,2-a]piridin-7il)oxazolidin-2-ona C16H12ClN3O2 313,06
- 100
- 3-(imidazo[1,2-a]piridin-7-il)4-(4-propoxifenil)-1,3oxazinan-2-ona C20H21N3O3 351,39
- 101
- 5-(2-fenilpirrolidin-1-iI)-1Hbenzo[d]imidazol C17H17N3 263,33
- 102
- 5-(2-(4-metoxifenil)pirrolidin1-iI)-1H-benzo[d]imidazol C18H19N3O 293,36
- 103
- 5-(2-(4-fluorofenil)pirrolidin-1il)-1H-benzo[d]imidazol C17H16FN3 281,32
- 104
- 5-(2-(4-clorofenil)pirrolidin-1il)-1H-benzo[d]imidazol C17H16ClN3 297,78
- 105
- 5-(2-bencilpirrolidin-1-iI)-1Hbenzo[d]imidazol C18H19N3 277,36
- 106
- 5-(2-(4-clorobencil)pirrolidin1-il)-1H-benzo[d]imidazol C18H18ClN3 311,80
- 107
- 5-(2-(4-fluorobencil)pirrolidin1-il)-1H-benzo[d]imidazol C18H18FN3 295,35
- 108
- 5-(pirrolidin-1-il)-1Hbenzo[d]imidazol C11H13N3 187,24
52
E10751952
24-09-2015
- 109
- 5-(2-(4metoxibencil)pirrolidin-1-il)1H-benzo[d]imidazol C19H21N3O 307,38
- 110
- 3-(1H-benzo[d]imidazol-6-il)2-(4-clorofenil)tiazolidin-4ona C16H12ClN3OS 329,80
- 111
- 3-(1H-benzo[d]imidazol-5-il)2-feniltiazolidin-4-ona C16H13N3OS 295,35
- 112
- 3-(1H-benzo[d]imidazol-6-il)2-(4-fluorofenil)tiazolidin-4ona C16H12FN3OS 313,34
- 113
- 3-(1H-benzo[d]imidazol-6-il)2-(naftalen-1-il)tiazolidin-4ona C20H15N3OS 345,41
- 114
- 3-(1H-benzo[d]imidazol-6-il)2-(4-fenoxifenil)tiazolidin-4ona C22H17N3O2S 387,45
- 115
- 3-(1H-benzo[d]imidazol-6-iI)2-(2,6-difluorofenil)tiazolidin4-ona C16H11F2N3OS 331,33
- 116
- 3-(1H-benzo[d]imidazol-6-il)2-(tiofen-3-il)tiazolidin-4-ona C14H11N3OS2 301,38
- 117
-
3-(1H-benzo[d]imidazol-6-il)5-metil-2-feniltiazolidin-4-ona
imagen40 C17H15N3OS 309,38
53
E10751952
24-09-2015
- 118
- 3-(1H-benzo[d]imidazol-5-il)2-feniltiazolidina-4-tiona C16H13N3S2 311,42
- 119
- 3-(1H-benzo[d]imidazol-6-il)2-(4-fenoxifeni)tiazolidina-4tiona C22H17N3OS2 403,51
- 120
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-fluorofenol)pirrolidin-2ona C17H14FN3O 295,31
- 121
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-metoxifenil)pirrolidin-2ona C18H17N3O2 307,34
- 122
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-propoxifenil)pirrolidin-2ona C20H21N3O2 335,39
- 123
- 1-(1H-benzo[d]imidazol-5-il)5-(2,3dihidrobenzo[b][1,4]dioxin-6il)pirrolidin-2-ona C19H17N3O3 335,35
- 124
- 1-(1H-benzo[d]imidazol-5-iI)5-fenilpirrolidin-2-ona C17H15N3O 227,32
- 125
- 2-(1H-benzo[d]imidazol-5-iI)3-fenilisoindolin-1-ona C21H15N3O 325,36
54
E10751952
24-09-2015
- 126
- 2-(1H-benzo[d]imidazol-5-il)3-(4-bifenil)isoindolin-1-ona C27H19N3O 401,45
- 127
- 2-(1H-benzo[d]imidazol-5-iI)3-(4-fluorofenil)isoindolin-1ona C21H14FN3O 343,35
- 128
- 2-(1H-benzo[d]imidazol-5-iI)3-(3-fluorofenil)isoindolin-1ona C21H14FN3O 343,35
- 129
- 2-(1H-benzo[d]imidazol-5-iI)3-(3,5-difluorofenil)isoindolin1-ona C21H13F2N3O 361,34
- 130
- 2-(1H-benzo[d]imidazol-5-iI)3-(4-clorofenil)isoindolin-1ona C21H14ClN3O 359,80
- 131
- 2-(1H-benzo[d]imidazol-5-iI)3-(3,4-diclorofenil)isoindolin1-ona C21H13Cl2N3O 394,25
- 132
- 2-(1H-benzo[d]imidazol-5-iI)3-(3-cloro-5fluorofenil)isoindolin-1-ona C21H13ClFN3O 377,79
55
E10751952
24-09-2015
- 133
- 2-(1H-benzo[d]imidazol-5-iI)3-(4-metoxifenil)isoindolin-1ona C22H17N3O2 355,38
- 134
- 2-(1H-benzo[d]imidazol-5-iI)3-(4-propoxifenil)isoindolin-1ona C24H21N3O2 383,44
- 135
- 2-(1H-benzo[d]imidazol-5-iI)3-(3-fluoro-4metoxifenil)isoindolin-1-ona C22H16FN3O2 373,37
- 136
- 2-(1H-benzo[d]imidazol-5-il)3-(3,4-dimetoxifenil) isoindolin-1-ona C23H19N3O3 385,41
- 137
- 3-(benzo[d][1,3]dioxol-6-il)-2(1H-benzo[d]imidazol-5il)isoindolin-1-ona C22H15N3O3 369,37
- 138
- 2-(1H-benzo[d]imidazol-5-iI)3-(4-fenoxifenil)isoindolin-1ona C27H19N3O2 417,45
- 139
- 2-(1H-benzo[d]imidazol-5-iI)4,7-dicloro-3-(4metoxifenil)isoindolin-1-ona C22H15Cl2N3O2 424,27
- 140
- 2-(1H-benzo[d]imidazol-5-iI)5,6-dicloro-3-(4metoxifenil)isoindolin-1-ona C22H15Cl2N3O2 424,27
56
E10751952
24-09-2015
- 141
- 2-(1H-benzo[d]imidazol-5-iI)5,6-dicloro-3-(4propoxifenil)isoindolin-1-ona C24H19Cl2N3O2 452,33
- 142
- (S)-2-(1H-benzo[d]imidazol5-il)-3-(3,4-dimetoxifenil) isoindolin-1-ona C23H19N3O2 385,41
- 143
- (R)-2-(1H-benzo[d]imidazol5-il)-3-(3,4-dimetoxifenil) isoindolin-1-ona C23H19N3O2 385,41
- 144
- (R)-2-(1H-benzo[d]imidazol5-il)-3-(4-propoxifenil) isoindolin-1-ona C24H21N3O2 383,44
- 145
- (S)-2-(1H-benzo[d]imidazol5-il)-3-(4-propoxifenil) isoindolin-1-ona C24H21N3O2 383,44
- 146
- (R)-2-(1H-benzo[d]imidazol5-il)-3-(4-clorofenil)isoindolin1-ona C21H14ClN3O 359,80
- 147
- (S)-2-(1H-benzo[d]imidazol5-il)-3-(4-clorofenil)isoindolin1-ona C21H14ClN3O 359,80
- 148
- 1-(1H-benzo[d]imidazol-5-il)5-(4-fenilciclohexil) imidazolidin-2-ona C22H24N4O 360,45
57
E10751952
24-09-2015
- 149
- 1-(1H-benzo[d]imidazol-6-il)5-(1-fenilpiperidin-4il)imidazolidin-2-ona C21H23N5O 361,41
- 150
- 1-(1H-benzo[d]imidazol-5-il)5-(4-(3-metoxipropil)fenil) imidazolidin-2-ona C20H22N4O2 350,41
- 151
- 1-(1H-benzo[d]imidazol-5-il)5-(4-hidroxifenil)imidazolidin2-ona C16H14N4O2 294,30
- 152
- 1-(1H-benzo[d]imidazol-5-il)5-(2-hidroxifenil)imidazolidin2-ona C16H14N4O2 294,30
- 153
- 1-(1H-benzo[d]imidazol-5-il)5-(2,4dihidroxifenil)imidazolidin-2ona C16H14N4O3 310,30
- 154
- 1-(1H-benzo[d]imidazol-5-il)5-(3,4dihidroxifenil)imidazolidin-2ona C16H14N4O3 310,30
- 155
- 1-(1H-benzo[d]imidazol-5-il)5-(3-hidroxifenil)imidazolidin2-ona C16H14N4O2 294,30
- 156
- 1-(1H-benzo[d]imidazol-5-il)5-(4-(ciclohexiloxi)fenil) imidazolidin-2-ona C22H24N4O2 376,45
- 157
- 5-(4-(2-metoxietoxi)fenil)-1(1H-benzo[d]imidazol-5il)imidazolidin-2-ona C19H20N4O3 352,38
58
E10751952
24-09-2015
- 158
- (S)-5-(4-(2(dimetilamino)etoxi)fenil)-1(1H-benzo[d]imidazol-5il)imidazolidin-2-ona C20H23N5O2 365,42
- 159
- 3-(1H-benzo[d]imidazol-5-il)1-fenetil-4-(4-propoxifenil) imidazolidin-2-ona C27H28N4O2 440,53
- 160
- 3-(1H-benzo[d]imidazol-5-il)1-((naftalen-2-il)metil)-4-(4propoxifenil)imidazolidin-2ona C30H28N4O2 476,56
- 161
- 3-(1H-benzo[d]imidazol-5-il)1-(3-fenilpropil)-4-(4propoxifenil)imidazolidin-2ona C28H30N4O2 454,56
- 162
- 3-(1H-benzo[d]imidazol-5-il)1-bencil-4-(4-propoxifenil) imidazolidin-2-ona C26H26N4O2 426,51
- 163
- 1-(1H-benzo[d]imidazol-5-il)5-(4-fluoro-3-metoxifenil) imidazolidin-2-ona C17H15FN4O2 326,32
- 164
- 1-(1H-benzo[d]imidazol-5-il)5-(3-fluoro-4-propoxifenil) imidazolidin-2-ona C19H19FN4O2 354,37
59
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- 165
- 1-(1H-benzo[d]imidazol-5-il)5-(2-fluoro-4-propoxifenil) imidazolidin-2-ona C19H19FN4O2 354,37
- 166
- (S)-1-(1H-benzo[d]imidazol5-il)-5-(4-(dietilamino)fenil) imidazolidin-2-ona C20H23N5O 349,42
- 167
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-clorofenil)imidazolidin-2ona C16H13ClN4O 312,75
- 168
- 1-(1H-benzo[d]imidazol-5-il)5-(4-ciclohexilfenil) imidazolidin-2-ona C22H24N4O 360,45
- 169
- 1-(1H-benzo[d]imidazol-5-il)5-(4-(4-morfolinociclohexil) fenil)imidazolidin-2-ona C26H31N5O2 445,55
- 170
- (S)-1-(1H-benzo[d]imidazol5-il)-5-(4-(1-metilpiperidin-4il)fenil)imidazolidin-2-ona C22H25N5O 375,46
- 171
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-(tetrahidro-2H-piran-4il)fenil)imidazolidin-2-ona C21H22N4O2 362,42
- 172
- 1-(1H-benzo[d]imidazol-5-il)5-(4-(4-oxociclohexil)fenil) imidazolidin-2-ona C22H22N4O2 374,43
60
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- 173
- (S)-1-(1H-benzo[d]imidazol5-il)-5-(4-(4,4difluorociclohexil)fenil) imidazolidin-2-ona C22H22F2N4O 396,43
- 174
- 1-(1H-benzo[d]imidazol-5-iI)5-(3-(pirrolidin-1il)fenil)imidazolidin-2-ona C20H21N5O 347,41
- 175
- 1-(1H-benzo[d]imidazol-5-iI)5-(4-(piperidin-1il)fenil)imidazolidin-2-ona C21H23N5O 361,44
- 176
- 1-(1H-benzo[d]imidazol-5-iI)5-(3-(piperidin-1il)fenil)imidazolidin-2-ona C21H23N5O 361,44
- 177
- 1-(1H-benzo[d]imidazol-5-il)5-(4-morfolinofenil) imidazolidin-2-ona C20H21N5O2 363,41
- 178
- 5-(4-ciclohexilfenil)-1-(Himidazo[1,2-a]piridin-7il)imidazolidin-2-ona C22H24N4O 360,45
- 179
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(4-(pirrolidin-1il)fenil)imidazolidin-2-ona C20H21N5O 347,41
- 180
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(3-(pirrolidin-1il)fenil)imidazolidin-2-ona C20H21N5O 347,41
61 62 63 64 65 66 67
- 181
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(4-(piperidin-1il)fenil)imidazolidin-2-ona C21H23N5O 361,44
- 182
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(3-(piperidin-1il)fenil)imidazolidin-2-ona C21H23N5O 361,44
- 183
- 1-(H-imidazo[1,2-a]piridin-7il)-5-(1-fenilpiperidin)-4il)imidazolidin-2-ona C21H23N5O 361,44
- 184
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-(3metoxipropil)fenil)oxazolidin2-ona C20H21N3O3 351,39
- 185
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(3-(dimetilamino)propil) fenil)oxazolidin-2-ona C21H24N4O2 364,44
- 186
- (S)-3-(7-metil-1Hbenzo[d]imidazol-5-il)-4feniloxazolidin-2-ona C17H15N3O2 293,31
- 187
- (S)-3-(6-fluoro-1Hbenzo[d]imidazol-5-il)-4feniloxazolidin-2-ona C16H12FN3O2 297,28
- 188
- (S)-3-(7-fluoro-1Hbenzo[d]imidazol-5-il)-4feniloxazolidin-2-ona C16H12FN3O2 297,28
- 189
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(ciclohexilmetil) oxazolidin-2-ona C17H21N3O2 299,36
- 190
- (S)-3-(1H-benzo[d]imidazol5-il)-4-ciclohexiloxazolidin-2ona C16H19N3O2 285,34
- 191
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-fenilciclohexil) oxazolidin-2-ona C22H23N3O2 361,41
- 192
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(1-fenilpiperidin-4il)oxazolidin-2-ona C21H22N4O2 362,42
- 193
- (S)-4-(1-acetilpiperidin-4-il)3-(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C17H20N4O3 328,36
- 194
- 3-(1H-benzo[d]imidazol-5-il)4-(1-feniletil)oxazolidin-2-ona C18H17N3O2 307,34
- 195
- (S)-4-(4-propoxibencil)-3(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C20H21N3O3 351,39
- 196
- (S)-4-(4-isopropoxibencil)-3(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C20H21N3O3 351,39
- 197
- (S)-4-(4-(ciclohexiloxi)bencil)3-(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C23H25N3O3 391,46
- 198
- 4-(4-morfolinobenciI)-3-(1Hbenzo[d]imidazol-5il)oxazolidin-2-ona C21H22N4O3 378,42
- 199
- (S)-3-(1H-benzo[d]imidazol5-il)-4-fenetiloxazolidin-2-ona C18H17N3O2 307,34
- 200
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(ciclohexiloxi)fenil) oxazolidin-2-ona C22H23N3O3 377,43
- 201
- (S)-3-(7-metil-1Hbenzo[d]imidazol-5-il)-4-(4propoxifenil)oxazolidin-2-ona C20H21N3O3 351,39
- 202
- (S)-3-(6,7-dimetil-1Hbenzo[d]imidazol-5-il)-4-(4propoxifenil)oxazolidin-2-ona C21H23N3O3 365,42
- 203
- (S)-4-(4-(2-metoxietoxi)feniI)3-(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C19H19N3O4 353,37
- 204
- (S)-4-(4-(2(dimetilamino)etoxi)fenil)-3(1H-benzo[d]imidazol-5il)oxazolidin-2-ona C20H22N4O3 366,41
- 205
- 3-(1H-benzo[d]imidazol-5-iI)4-(2,6-difluoro-4metoxifenil)oxazolidin-2-ona C17H13F2N3O3 345,30
- 206
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-(dietilamino)fenil) oxazolidin-2-ona C20H22N4O2 350,41
- 207
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-(bis(2-metoxietil) amino)fenil)oxazolidin-2-ona C22H26N4O4 410,46
- 208
-
(S)-3-(1H-benzo[d]imidazol5-il)-4-(4-(diciclopropilamino) fenil)oxazolidin-2-ona
imagen41 C22H22N4O2 374,43
- 209
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(bifenil-4-il)oxazolidin2-ona C22H17N3O2 355,38
- 210
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(4-oxociclohexil)fenil) oxazolidin-2-ona C22H21N3O3 375,42
- 211
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(4-metoxiciclohexil)fenil) oxazolidin-2-ona C23H25N3O3 391,46
- 212
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(4-hidroxiciclohexil)fenil) oxazolidin-2-ona C22H23N3O3 377,43
- 213
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(4-morfolinociclohexil) fenil)oxazolidin-2-ona C26H30N4O3 446,54
- 214
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(pirrolidin-1il)fenil)oxazolidin-2-ona C20H20N4O2 348,39
- 215
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-(piperidin-1il)fenil)oxazolidin-2-ona C21H22N4O2 362,46
- 216
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(3-(piperidin-1il)fenil)oxazolidin-2-ona C21H22N4O2 362,46
- 217
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(4-morfolinofenil) oxazolidin-2-ona C20H20N4O3 364,39
- 218
- (S)-3-(1H-benzo[d]imidazol5-il)-4-(3-morfolinofenil) oxazolidin-2-ona C20H20N4O3 364,39
- 219
- 3-(1H-benzo[d]imidazol-5-iI)4-(4-(tetrahidro-2H-piran-4il)fenil)oxazolidin-2-ona C21H21N3O3 363,40
- 220
- 3-(1H-benzo[d]imidazol-5-iI)4-(4-(1-metilpiperidin-4il)fenil)oxazolidin-2-ona C22H24N4O2 376,45
- 221
- (S)-3-(1H-benzo[d]imidazol6-il)-4-(3-(4-metilpiperazin-1il)fenil)oxazolidin-2-ona C21H23N5O3 377,43
- 222
- (S)-3-(3-metiIH-imidazo[1,2a]piridin-7-iI)-4feniloxazolidin-2-ona C17H15N3O2 293,31
- 223
- (S)-3-(3-(trifluorometil)Himidazo[1,2-a]piridin-7-iI)-4feniloxazolidin-2-ona C17H12F3N3O2 347,29
- 224
- (S)-4-(2,3dihidrobenzo[b][1,4]dioxin-6il)-3-(H-imidazo[1,2-a]piridin7-il)oxazolidin-2-ona C18H15N3O4 337,32
- 225
- (S)-4-(4-ciclohexilfenil)-3-(Himidazo[1,2-a]piridin-7il)oxazolidin-2-ona C22H23N3O2 361,43
- 226
- (S)-3-(H-imidazo[1,2a]piridin-7-il)-4-(4-(piperidin1-il)fenil)oxazolidin-2-ona C21H22N4O2 362,42
- 227
- (S)-3-(H-imidazo[1,2a]piridin-7-il)-4-(4morfolinofenil)oxazolidin-2ona C20H20N4O3 364,39
- 228
- (S)-3-(H-imidazo[1,2a]piridin-7-il)-4-(4-(4fenilpiperazin-1il)fenil)oxazolidin-2-ona C26H25N5O2 439,50
- 229
- (S)-1-(1H-benzo[d]imidazol5-il)-5-(4-(bis(2metoxietil)amino)fenil) imidazolidin-2-ona C22H27N5O3 409,48
- 230
- 5-(4-(N-(2-(dimetilamino)etil)-N-metilamino)feniI)-1-(1Hbenzo[d]imidazol-5il)imidazolidin-2-ona C21H26N6O 378,47
- 231
- 3-(1H-benzo[d]imidazol-5-il)4-(4-(4,4-difluorociclohexil) fenil)oxazolidin-2-ona C22H21F2N3O2 397,41
- 232
- 2-(1H-benzo[d]imidazol-5-iI)4,7-difluoro-3-(4propoxifenil)isoindolin-1-ona C24H19F2N3O2 419,42
- 233
- 2-(H-imidazo[1,2-a]piridin-7il)-3-(3,4dimetoxifenil)isoindolin-1-ona C23H19N3O3 385,41
- 234
- (S)-2-(H-imidazo[1,2a]piridin-7-il)-3-(3,4dimetoxifenil)isoindolin-1-ona C23H19N3O3 385,41
- Ejemplo de referencia 235
- (S)-3-(3,4-dimetoxifeniI)-2-(3metiIH-imidazo[1,2-a]piridin7-il)isoindolin-1-ona C24H21N3O3 399,44
Descripción de síntesis general
Método 1
68
El compuesto se sintetizó empezando del ejemplo 110 (0,122 g, 0,29 mmol), reactivo de Lawesson (0,6 g, 1,45 mmol), según el método 9, paso B, rendimiento: 44 mg (48,7%), MS m/z 312,3 (M+H)+; HPLC [A]): tr 7,32 min (87%)
Ejemplo 119: 3-(1H-benzo[d]imidazol-6-il)-2-(4-fenoxifenil)tiazolidina-4-tiona El compuesto se sintetizó empezando del ejemplo 113 (0,122 g, 0,284 mmol), reactivo de Lawesson (0,575 g, 1,42 mmol), según el método 9, paso B, rendimiento: 58 mg (50,7%), MS m/z 404,3 (M+H)+; HPLC [A]): tr 6,45 min (87%)
Ejemplo 120: 1-(1H-benzo[d]imidazol-5-il)-5-(4-fluorofenil)pirrolidin-2-ona El compuesto se sintetizó según el método 10 Paso A Ácido 4-(4-fluorofenil)-4-oxobutanoico (196 mg, 1 mmol, 1 eq.), carbonildiimidazol (162 mg, 1 mmol, 1 eq.) y
becimidazol-5(6)-amina (133 mg, 1 mmol, 1 eq.), rendimiento: 0,189 g (60,8%); MS m/z: 312,2 [M+H]+; HPLC ([A]): tr 10,45 min (81,9%)
Paso B, C rendimiento: 0,048 g (26,8%); MS m/z: 296,2 [M+H]+; 1H-RMN (CD3OD, 400 MHz): δ 2,02-2,10 (m, 1H); 2,67-2,82 (m, 3H); 5,39-5,43 (m, 1H); 6,95-6,99 (m, 2H); 7,21 (dd, 1H, 4J=2,1 Hz, 3J=8,7 Hz); 7,29-7,33 (m, 2H); 7,47 (d, 1H, 3J=8,7 Hz); 7,53 (d, 1H, 4J=2,1 Hz); 8,10 (s, 1H); HPLC ([A]): tr 11,47 min (97,4%)
Ejemplo 121: 1-(1H-benzo[d]imidazol-5-il)-5-(4-metoxifenil)pirrolidin-2-ona El compuesto se sintetizó según el método 10 Paso A Ácido 4-(4-metoxi)-4-oxobutanoico (208 mg, 1 mmol, 1 eq.), carbonildiimidazol (162 mg, 1 mmol, 1 eq.) y
becimidazol-5(6)-amina (133 mg, 1 mmol, 1 eq.), rendimiento: 0,207 g (64,1%); MS m/z: 324,2 [M+H]+; HPLC ([A]): tr 10,30 min (93,5%)
Paso B, C Purificación adicional por HPLC semipreparativa; rendimiento: 0,019 g (9,7%); MS m/z: 308,2 [M+H]+; 1H-RMN (CD3OD, 400 MHz): δ 2,03-2,11 (m, 1H); 2,64-2,83 (m, 3H); 3,69 (s, 3H); 5,42-5,45 (m, 1H); 6,79-6,82 (m, 2H); 7,207,23 (m, 2H); 7,58 (dd, 1H, 4J=2,1 Hz, 3J=9,1 Hz); 7,67 (d, 1H, 3J=9,5 Hz); 7,86 (d, 1H, 4J=2,1 Hz); 9,17 (s, 1H); HPLC ([A]): tr 9,65 min (100%)
Ejemplo 122: 1-(1H-benzo[d]imidazol-5-il)-5-(4-propoxifenil)pirrolidin-2-ona El compuesto se sintetizó según el método 10 Paso A Ácido 4-oxo-(4-propoxifenil)butanoico (236 mg, 1 mmol, 1 eq.), carbonildiimidazol (162 mg, 1 mmol, 1 eq.) y
becimidazol-5(6)-amina (133 mg, 1 mmol, 1 eq.), rendimiento: 0,215 g (61,3%); MS m/z: 352,3 [M+H]+; HPLC ([A]): tr 13,13 min (100%)
Paso B, C Purificación adicional por HPLC semipreparativa; rendimiento: 0,023 g (11,2%); MS m/z: 336,1 [M+H]+; 1H-RMN (CD3OD, 400 MHz): δ 0,97 (t, 3H, 3J=7,5 Hz); 1,67-1,75 (m, 2H); 2,05-2,08 (m, 1H); 2,66-2,80 (m, 3H); 3,82 (t, 2H, 3J=6,2 Hz); 5,41-5,44 (m, 1H); 6,78-6,81 (m, 2H); 7,18-7,21 (m, 2H); 7,56 (dd, 1H, 4J=2,1 Hz, 3J=9,1 Hz); 7,67 (d, 1H, 3J=9,1 Hz); 7,85 (d, 1H, 4J=2,1 Hz); 9,13 (s, 1H); HPLC ([A]): tr 12,44 min (100%)
Ejemplo 123: 1-(1H-benzo[d]imidazol-5-il)-5-(2,3-dihidrobenzo[b][1,4]dioxin-6-il)pirrolidin-2-ona El compuesto se sintetizó según el método 10 Paso A
114
4-Yodobencen-1,2-diamina (47 mg, 0,2 mmol); 3-(4-propoxifenil)isoindolinona (59 mg, 0,22 mmol), yoduro de cobre(I) (4 mg, 0,02 mmol), diaminociclohexano (2 mg, 0,02 mmol) y fluoruro de cesio (60 mg, 0,4 mmol); rendimiento: 0,016 g (20,5%); MS m/z 384,4 [M+H]+; 1H-RMN (DMSO-d6, 400 MHz): δ 0,84-0,88 (m, 3H); 1,55-1,64 (m, 2H); 3,74-3,77 (m, 2H); 6,51 (s, H); 6,73-6,76 (m, 2H); 7,10-7,13 (m, 2H); 7,26 (d, 1H, 3J=7,5 Hz); 7,40-7,42 (m, 1H); 7,47-7,59 (m, 3H); 7,80-7,82 (m, 2H); 8,15 (s, 1H); 12,41 (br s, 1H); HPLC (Gradiente 3): tr 14,35 min (100%)
Ejemplo 146: (R)-2-(1H-benzo[d]imidazol-5-il)-3-(4-clorofenil)isoindolin-1-ona
El compuesto se sintetizó según el método 12
Paso B, C
Ácido 4-clorofenilborónico (624 mg, 4 mmol), [RhCl(C2H4)2]2 (12 mg, 0,031 mmol), (3aR, 6aR)-3,6-difenil-1,3a,4,6atetra-hidroheptaleno (17 mg, 0,066 mmol), metil-2-(tosilimino-metil)benzoato (634 mg, 2 mmol) y TEA (0,56 ml; 4 mmol); rendimiento: 113 mg (23,3%); MS m/z 244,4 [M+H]+; 487,5 [2M+H]+; HPLC (Gradiente 3): tr 17,05 min (100%)
Paso D
4-Yodobencen-1,2-diamina (94 mg, 0,4 mmol); 3-(4-clorofenil)isoindolinona (107 mg, 0,44 mmol), yoduro de cobre(I) (8 mg, 0,04 mmol), diaminociclohexano (5 mg, 0,04 mmol) y fluoruro de cesio (121 mg, 0,8 mmol); rendimiento: 0,020 g (13,9%); MS m/z 360,2 [M+H]+; 1H-RMN (DMSO-d6, 400 MHz): δ 6,75 (s, 1H); 7,30-7,37 (m, H); 7,56-7,60 (m, 1H); 7,63-7,67 (m, 1H); 7,73-7,75 (m, 2H); 7,89 (d, 1H, 3J=7,5 Hz); 8,13 (s, 1H); 9,15 (s, 1H); HPLC (Gradiente 3): tr 13,60 min (100%)
Ejemplo 147: (S)-2-(1H-benzo[d]imidazol-5-il)-3-(4-clorofenil)isoindolin-1-ona
El compuesto se sintetizó según el método 12
Paso B, C
Ácido 4-clorofenilborónico (624 mg, 4 mmol), [RhCl(C2H4)2]2 (12 mg, 0,031 mmol), (3aS, 6aS)-3,6-difenil-1,3a,4,6atetra-hidroheptaleno (17 mg, 0,066 mmol), metil-2-(tosilimino-metil)benzoato (634 mg, 2 mmol) y TEA (0,56 ml; 4 mmol); rendimiento: 112 mg (23,0%); MS m/z 244,3 [M+H]+; 487,4 [2M+H]+; HPLC (Gradiente 3): tr 17,24 min (100%)
Paso D
4-Yodobencen-1,2-diamina (94 mg, 0,4 mmol); 3-(4-clorofenil)isoindolinona (107 mg, 0,44 mmol), yoduro de cobre(I) (8 mg, 0,04 mmol), diaminociclohexano (5 mg, 0,04 mmol) y fluoruro de cesio (121 mg, 0,8 mmol); rendimiento: 0,029 g (20,3%); MS m/z 360,2 [M+H]+; 1H-RMN (DMSO-d6, 400 MHz): δ 6,72 (s, 1H); 7,28-7,34 (m, 5H); 7,54-7,57 (m, 1H); 7,60-7,64 (m, 1H); 7,68-7,73 (m, 2H); 7,86 (d, 1H, 3J=7,1 Hz); 8,11 (s, 1H); 9,11 (br s, 1H); HPLC (Gradiente 3): tr 13,50 min (99,1%)
Ejemplo 148: 1-(1H-benzo[d]imidazol-5-il)-5-(4-fenilciclohexil)imidazolidin-2-ona
El compuesto se sintetizó como la sal trifluoroacetato empezando de 5-aminobencimidazol (848 mg, 6,38 mmol), fenilciclohexilcarbaldehído (1,0 g, 5,31 mmol), TMSCN (1,39 ml, 10,63 mmol), PdC (10%, 0,02 g), di-(imidazol-1il)metanona (812 mg, 5,01 mmol), como se describe en el método 2. El producto se purificó a través de HPLC preparativa usando un gradiente de agua-acetonitrilo con ácido trifluoroacético al 0,04%.
Rendimiento: 0,092 g (4,0%); Ms m/z 361,2 (M+H)+; 1H RMN (DMSO, 400 MHz): δ 8,53 (d, 1H); 8,07 (d, 1H); 7,297,14 (m, 5H); 4,27 (t, 1H); 4,15-4,10 (m, 2H); 2,42 (t, 1H); 1,83-1,62 (m, 5H); 1,50-1,41 (m, 2H); 1,37-1,21 (m, 1H), HPLC (λ = 214 nm, [A]: tr 13,01 min (98,6%).
Ejemplo 149: 1-(1H-benzo[d]imidazol-6-il)-5-(1-fenilpiperidin-4-il)imidazolidin-2-ona
El compuesto se sintetizó empezando de 1H-benzo[d]imidazol-5-amina (0,400 g, 3 mmol), 1-fenilpiperidina-4carbaldehído (0,570 g, 3 mmol), TMSCN (0,375 ml, 3 mmol), PdC (10%, 0,02 g), TEA (1,05 ml, 7,5 mmol), di(imidazol-1-il)metanona (0,730 g, 4,5 mmol), como se describe en el método 2.
Rendimiento: 0,082 g (7,6%); Ms m/z 362,3 (M+H)+, 181,7 (M+2H)2+; 1H-RMN (DMSO, 400 MHz): δ 1,63-1,80 (m, 3H); 1,81-1,89 (m, H); 2,03-2,15 (m, H); 2,90-3,00 (m, H); 3,03-3,15 (m, H); 3,42-3,49 (m, H); 3,59-3,73 (m, 3H); 4,70-4,77 (m, H); 7,12-7,18 (m, H); 7,24 (d, 2H, 3J=8,3 Hz); 7,35 (t, 2H, J=7,5 Hz); 7,66 (dd, H; 3J=9,1 Hz , 4J=1,7 Hz); 7,79 (d, H, 3J=9,1 Hz); 7,98 (s, H); 9,14 (s, H); HPLC (λ = 214 nm, [A]: tr. 5,87 min (99%)
119
Paso A
Una mezcla de 4-(4-cianofenil)ciclohexanona (3,0 g, 15,05 mmol), etilenglicol (2,1 ml, 37,64 mmol) y ácido ptoluenosulfónico catalítico (430 mg, 2,26 mmol) en tolueno (50 ml) se calentó a 125-130ºC durante 24 h. La masa de reacción se enfrió a temperatura ambiente, se diluyó con tolueno y se lavó sucesivamente con solución saturada de bicarbonato de sodio, agua, salmuera, se secó sobre sulfato de sodio anhidro y se concentró al vacío para dar crudo. La purificación por cromatografía en columna sobre gel de sílice (malla 60-120) usando acetato de etilo al 5% en éter de pet como eluyente dio 3,36 g del producto como sólido blanco.
Paso B
Se añadió hidruro de diisobutil aluminio al 25% en tolueno (17,3 ml, 27,65 mmol) a una solución del producto del paso A (3,36 g, 13,86 mmol) en tetrahidrofurano anhidro (60 ml) a -40ºC. La masa de reacción se calentó a temperatura ambiente y se agitó durante 3,5 h. La masa de reacción se enfrió a 0ºC y se extinguió con solución saturada de cloruro de amonio. Se filtraron las sales y se lavó con acetato de etilo. El filtrado y los lavados combinados se lavaron con salmuera, se secaron sobre sulfato de sodio anhidro y se concentraron al vacío para dar 3,36 g del producto crudo como jarabe amarillo pálido. Este se tomó para el siguiente paso sin purificación.
Paso C
Se añadió cianuro de trimetlsililo (0,87 ml, 6,50 mol) a una solución de 5-aminobencimidazol (433 mg, 3,25 mmol), el producto del paso B (800 g, 3,25 mmol) en ácido acético (20 ml) y se agitó durante 1 h 40 min. La masa de reacción se extinguió con solución acuosa fría de amoniaco y se extrajo con acetato de etilo (2x30 ml). La fase orgánica combinada se lavó con agua, salmuera, se secó sobre sulfato de sodio anhidro y se concentró al vacío para dar 1,0 g de producto crudo como sólido marrón amarillento.
Paso D
Una solución del producto del paso C (1,0 g, 2,58 mmol) en ácido acético (50 ml) se hidrogenó sobre Pd-C al 10% (250 mg) en aparato Parr durante 20 h a presión de 80 psi. La masa de reacción se filtró a través de celite y se lavó con ácido acético. El filtrado y los lavados combinados se concentraron al vacío para dar 2,56 g del producto crudo como líquido marrón. Este crudo se tomó directamente para el siguiente paso sin ninguna purificación.
Paso E
Se añadieron sucesivamente trietilamina (9,8 ml, 70,4 mmol), carbonildiimidazol (1,14, 7,04 mmol) a la solución del producto crudo del paso D (2,76 g, 7,04 mmol) en tetrahidrofurano (50 ml) y se sometió a reflujo durante 18,5 h. La masa de reacción se enfrió a temperatura ambiente, se echó en agua y se extrajo con acetato de etilo (2x50 ml). La fase orgánica combinada se lavó con agua, salmuera, se secó sobre sulfato de sodio anhidro y se concentró al vacío para dar crudo. La purificación por cromatografía en columna sobre alúmina neutra usando metanol al 6-7% en cloroformo como eluyente dio 270 mg del producto como sólido amarillo pálido. Este se tomó como tal al siguiente paso.
Paso F
128
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Also Published As
Publication number | Publication date |
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MX2012002993A (es) | 2012-04-19 |
JP5934645B2 (ja) | 2016-06-15 |
NZ598685A (en) | 2013-05-31 |
US20160039795A1 (en) | 2016-02-11 |
SG178953A1 (en) | 2012-04-27 |
US20110092501A1 (en) | 2011-04-21 |
BR112012008346A2 (pt) | 2020-09-15 |
PL2475428T3 (pl) | 2015-12-31 |
AU2010294214B2 (en) | 2015-05-07 |
US8486940B2 (en) | 2013-07-16 |
US9650362B2 (en) | 2017-05-16 |
EA201200474A1 (ru) | 2012-10-30 |
EP2475428B1 (en) | 2015-07-01 |
AU2010294214A1 (en) | 2012-03-29 |
CA2772488C (en) | 2018-04-17 |
IL218259A0 (en) | 2012-04-30 |
JP2013504544A (ja) | 2013-02-07 |
ZA201201366B (en) | 2013-09-25 |
DK2475428T3 (en) | 2015-09-28 |
KR20120105421A (ko) | 2012-09-25 |
CN102695546B (zh) | 2014-09-10 |
US9173885B2 (en) | 2015-11-03 |
CA2772488A1 (en) | 2011-03-17 |
IL218259A (en) | 2016-09-29 |
EP2475428A1 (en) | 2012-07-18 |
WO2011029920A1 (en) | 2011-03-17 |
EA022007B1 (ru) | 2015-10-30 |
KR101755737B1 (ko) | 2017-07-07 |
HK1175135A1 (en) | 2013-06-28 |
US20140065095A1 (en) | 2014-03-06 |
CN102695546A (zh) | 2012-09-26 |
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