AR045010A1 - Pirimidinas utiles como moduladores de canales ionicos cuya activacion es controlada por tension - Google Patents

Pirimidinas utiles como moduladores de canales ionicos cuya activacion es controlada por tension

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Publication number
AR045010A1
AR045010A1 ARP040102352A ARP040102352A AR045010A1 AR 045010 A1 AR045010 A1 AR 045010A1 AR P040102352 A ARP040102352 A AR P040102352A AR P040102352 A ARP040102352 A AR P040102352A AR 045010 A1 AR045010 A1 AR 045010A1
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Argentina
Prior art keywords
ring
hydrogen
phenyl
optionally substituted
methyl
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ARP040102352A
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English (en)
Inventor
Ester Martinborough
Andreas Peter Termin
Dean Mitchell Wilson
Nicole Zimmermann
Jesus E Gonzales Iii
Thimothy Neubert
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Vertex Pharma
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Publication of AR045010A1 publication Critical patent/AR045010A1/es

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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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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    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composiciones farmacéuticamente aceptables que comprenden los compuestos del presente y métodos par usar las composiciones en el tratamiento de varios desórdenes que afectan al sistema nervioso. Reivindicación 1: Un compuesto de la fórmula (1), o una sal farmacéuticamente aceptable del mismo en el cual: R1, y R2 son, cada uno, independientemente hidrógeno, o un grupo sustituido opcional seleccionado entre un alifático C1-6, un anillo arilo de 5-6 miembros que tiene 0-5 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno, o azufre; o un anillo saturado o parcial no saturado de 3-7 miembros que tiene 0-3 heteroátomos independientemente seleccionados entre nitrógeno oxígeno o azufre o R1 y R2, tomados conjuntamente con el átomo de nitrógeno al cual están ligados, forman un anillo heterocíclico o heteroarilo de 3-8 miembros opcionalmente sustituido que tiene 1-3 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno o azufre, siendo R1, R2, o cualquier anillo formado por R1 y R2 tomados conjuntamente, son , cada uno, independientemente, sustituidos opcionalmente con uno o más átomos de carbono con 0-4 ocurrencias de -R5, y uno o más átomos de nitrógeno sustituibles con -R6; el anillo A es un anillo arilo de 5-6 miembros que tiene 0-5 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno o azufre, o un anillo saturado o insaturado de 3-7 miembros que tiene 0-3 heteroátomos independientemente seleccionados entre nitrógeno, oxígeno o azufre, opcionalmente sustituido en uno o más átomos de nitrógeno sustituido en uno o más átomos de carbono con 0-5 ocurrencias de -R7, y en uno o más átomos de nitrógeno sustituibles con -R8; cada ocurrencia R3, R4, R5, y R7 es independientemente Q-Rx; donde Q es un enlace o es C1-6 donde hasta dos unidades Metileno no adyacentes de Q son opcionalmente reemplazadas por CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, o NR; y cada ocurrencia de Rx es independientemente seleccionada entre R', halógeno, NO2, CN; donde cada ocurrencia de R es independientemente seleccionada entre hidrógeno o un grupo alifático opcionalmente sustituido C1-6; y cada ocurrencia de R' es independientemente seleccionada entre hidrógeno o un grupo opcionalmente sustituido seleccionado entre alifático C1-8, arilo C6-10, un anillo heteroarilo que tiene 5-10 átomos en el anillo, o un anillo heterocíclico que tiene 3-10 átomos en el anillo, o donde R y R' tomados conjuntamente con el o los átomo(s) al cual o a los cuales están ligados, o dos ocurrencias de R' tomadas conjuntamente con el o los átomo(s) al cual ellos están ligados, forman un anillo cicloalquilico, heterocíclico, arílico o heteroarílico de 5-8 miembros que tiene 0-3 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno o azufre, y cada ocurrencia de R6 o R8 es independientemente R', -COR', -CO2(alifático C1-6), -CON(R')2, o -SO2R', con el próximo de que R3 esté ligado al átomo de carbono del grupo carbonilo a través de un átomo que no sea oxígeno, y con el provisto de que: a)cuando el anillo A es fenilo no sustituido, R3 es metilo, y R4 es =S, -SMe, entonces R1 y R2 tomados conjuntamente no pueden ser N-morfolino, N-pirrolidinilo, o piperazinilo opcionalmente sustituido; b) cuando el anillo A es N-morfolino, R3 es H, y R4 es Cl o Me, entonces R1 no es Et, cuando R2 es 4-Cl-fenil, o R1 y R2, tomados conjuntamente, no pueden ser N-morpholino; c) cuando el anillo A es N-pirrolidinilo y R3 es H, entonces: i) cuando R4 es -N(CH3)COPh, entonces R1 y R2, tomados conjuntamente, no pueden ser pirrolidinilo; y ii) cuando R4 es Cl, entonces R1 no es Et, cuando R2 es 4-Me-fenilo; d) cuando el anillo A es N-piperidinil, R3 hidrógeno, y R4 es metilo, entonces R1 y R2, tomados conjuntamente, no pueden ser piperidinil; e) cuando el anillo A es opcionalmente piperazidil, R3 es hidrógeno, y R4 es cloro, entonces cuando R1 es Et, entonces R2 no es 4-Cl-finilo, 4-Me-fenilo, o 4-F-fenilo, o R1 y R2, tomados conjuntamente no pueden ser tiomorfolino; f) cuando el anillo A es 2,5-dimetil-1H-pirrolidin-1-il, R3 es hidrógeno, y R4 es OMe, entonces R1 es Me, R2 no es benzilo; g) cuando el anillo A es 1-oxido-4-tiomorfolinilo, R3 es hidrógeno, y R4 es OEt, entonces R1 y R2, tomados conjuntamente, no pueden ser piperocinilo; h) cuando R3 es CH3 u opcionalmente sustituido R1 es hidrógeno, R2 es fenilo opcionalmente sustituido, metilo, etilo, COR', NR', o CONHR', y R4 es =S, ME, SME, o SCH2CO2Me, SCH2CN, entonces el anillo A no es fenilo o 4-Cl-fenilo no sustituido; i) cuando R3 es CH3, R1 es hidrógeno, R2 es etilo, y R4 es hidrógeno entonces el anillo A no es N-pirrolidinilo, piperacin-1-ilo, N-morfolinilo, o 1-piperidinilo; j) cuando R3 es N(R')2, R1 es hidrógeno R2 es 3-, 5-Cl-fenilo, 4-Cl-fenilo, metilo, o opcionalmente sustituido, ciclohexil, 3-Cl, 4-OME-bencilo, 4-Ac-fenilo, etilo, i-propilo, 4-OEt-fenilo, 4-OMe-fenilo, bencilo, o (CH2)OR, y R4 es CH3, hidrógeno, SMe, entonces el anillo A es fenilo no sustituido, piperidinilo, piperacinilo opcionalmente sustituido, morfolinilo, pirrolidinilo opcionalmente sustituido, 5,8-dihidro-1,7-naftiridino-7(6H)-il, o 5,6-dihidro-8-imidiazo[1,2-a]piracin-7-ilo; k) cuando R3 es -CH=CHN(CH3)2, CH3, -(CH2)2-N-morfolino, -(CH2)2-OMe, -(CH2)2-OH, -CH2OMe, n-butilo, piridin-2-ilmetil, piridin-2-ilo, pirimidin-5-ilo, CH2SO2Me, -(CH2)2-NMe2, -(CH2)2-N-(4-metilpiperacilo), -(CH2)2-NH-piridin-3-ilo, -(CH2)2-NH-CH2-piridin-3-ilo, 1-metil-1H-imidazol-2-ilo, 5-amino-1,2-dimetil-1H-imidazol-4-ilo, 4-(dimetilamino)fenilo, 3,4-(metilendioxi)fenil, -CH2=CH2, -CH=CH2, o -CH(CN)COOEt, R1 es hidrógeno, R2 es bencilo o etilo opcionalmente sustituido, R4 es SMe o hidrógeno, entonces el anillo A no es fenilo sustituido o pirrolidinilo opcionalmente sustituido; l) cuando R1 es hidrógeno y R2 es hidrógeno o 4,6-dimetilpirimidin-2-ilo, el anillo A es fenilo opcionalmente sustituido, R3 es Me o fenilo no sustituido, entonces R4 no es SMe, =S, Me, o fenilo no sustituido; m) cuando R1 es hidrógeno y R2 es benzilo opcionalmente sustituido, entonces R3 no es 3,4,5-trimetoxifenilo; n) cuando R1 y R2 son ambos hidrógeno, el anillo A es (2-fluorofenilmetil)-1H-pirazolo[3,4-b]piridin-3-ilo, R3 es etilo o 2-etoxietilo, entonces R4 no es hidrógeno; o) cuando R1 es hidrógeno, R2 es benzoilo, entonces R3, R4, y el anillo A no son simultáneamente fenilo no sustituido; p) cuando R1 y R2 son ambos hidrógeno, el anillo A es 4-(4'-morfolinil)-5-metil-2-feniltieno[2,3-d]pirimidin-6-ilo, 4-amino-5-metil-2-feniltieno[2,3-d]pirimidin-6-ilo, 4-(4-(4-fluorofenil)-piperacil)-5-metil-2-feniltieno[2,3-d]pirimidin-6-ilo, 4-(4,6-dimetil-pirimidin-2-il)amino-5-metil-2-feniltieno[2,3-d]pirimidin-6-ilo, 4-(N-pirrolidinil)-5-metil-2-feniltieno[2,3-d]pirimidin-6-ilo, o fenil no sustituido, R3 es metilo, entonces R4 no es metilo o SMe; q) cuando R1 y R2 son ambos hidrógeno, R3 no es metilo, R4 es =S o fenilo no sustituido, entonces el anillo A no es fenilo no sustituido; r) cuando R1 y R2 tomados conjuntamente forman un anillo a N-pirrolidinilo, R3 es -NHCH2(4-trifluorometilfenil), R4 es H, entonces el anillo A no es N-pirrolidinil, 3,4-dimetoxifenil, 2-metoxifenilo, tiofen-3-ilo, o tiofen-2-ilo.
ARP040102352A 2003-07-02 2004-07-02 Pirimidinas utiles como moduladores de canales ionicos cuya activacion es controlada por tension AR045010A1 (es)

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EP (1) EP1638955A2 (es)
JP (1) JP2007521287A (es)
KR (1) KR20060032190A (es)
AR (1) AR045010A1 (es)
AU (1) AU2004253962A1 (es)
CA (1) CA2531061A1 (es)
IL (1) IL172937A0 (es)
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PE (1) PE20051029A1 (es)
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Publication number Priority date Publication date Assignee Title
AU2004253962A1 (en) * 2003-07-02 2005-01-13 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
GB0415364D0 (en) 2004-07-09 2004-08-11 Astrazeneca Ab Pyrimidine derivatives
JP2008534472A (ja) * 2005-03-22 2008-08-28 ノイロサーチ アクティーゼルスカブ カリウムチャンネル調節剤としてのピラゾリル−ピリミジン及びその医学的使用
WO2006119451A1 (en) * 2005-05-04 2006-11-09 Vertex Pharmaceuticals Incorporated Pyrimidines and pyrazines useful as modulators of ion channels
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