ES2564204T3 - Derivados de pirrolopiridinil-pirimidin-2-il-amina - Google Patents

Derivados de pirrolopiridinil-pirimidin-2-il-amina

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Publication number
ES2564204T3
ES2564204T3 ES09772064.3T ES09772064T ES2564204T3 ES 2564204 T3 ES2564204 T3 ES 2564204T3 ES 09772064 T ES09772064 T ES 09772064T ES 2564204 T3 ES2564204 T3 ES 2564204T3
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Prior art keywords
pyrimidin
pyrrolo
pyrazol
pyridin
ethyl
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Inventor
Margarita Wucherer-Plietker
David Bruge
Dirk Finsinger
Ulrich Graedler
Dieter Dorsch
Christina Esdar
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/14—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 three or more hetero rings

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Compuestos, seleccionados del grupo 4-etil-6-{5-[1-(tetrahidro-furan-2-ilmetil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A2"), 4-etil-6-{5-[1-(1-metil-piperidin-4-il)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A5"), 4-etil-6-[5-(1-piperidin-4-il-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-2-ilamina ("A6"), 4-etil-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A7"), 4-etil-6-{5-[1-(2-morfolin-4-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A8"), 4-etil-6-[5-(1-pirrolidin-3-il-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-2-ilamina ("A9"), 4-(3-amino-propil)-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A20"), 4-(3-amino-propil)-6-{5-[1-(2-morfolin-4-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A21"), 4-morfolin-4-ilmetil-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A22"), 4-piperazin-1-ilmetil-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A23"), 4-(3-dimetilamino-propil)-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A26"), 2-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-(4-metil-piperazin-1-il)-etanona ("A29"), 2-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-N-(1-metil-piperidin-4-il)-acetamida ("A30"), ácido {4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-acético ("A31"), 2-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-morfolin-4-il-etanona ("A32"), 4-etil-6-{5-[1-(1-metanosulfonil-piperidin-4-il)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A44"), 1-(4-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-piperidin-1-il)-etanona ("A46"), 4-metilaminometil-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A56"); 4-(3-metilamino-propil)-6-{5-[1-(2-pirrolidin-1-il-etil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A57"), {4-etil-6-[5-(1-piperidin-4-il-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-2-il}-metil-amina ("A64"), 2-{4-[3-(6-etil-2-metilamino-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-piperidin-1-il-etanona ("A65"), 2-{4-[3-(6-etil-2-metilamino-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-pirrolidin-1-il-etanona (A66"), (4-etil-6-{5-[1-(1-metil-piperidin-4-il)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-il)-metil-amina ("A69"), {4-butil-6-[5-(1-piperidin-4-il-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-2-il}-metil-amina ("A70"), (4-butil-6-{5-[1-(1-metil-piperidin-4-il)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-il)-metil-amina ("A71"), 2-{4-[3-(6-etil-2-metilamino-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-N-(1H-indol-5-il)-propionamida ("A72"), 1-(3,4-dihidro-2H-quinolin-1-il)-2-{4-[3-(6-etil-2-metilamino-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}- etanona ("A73"), 1-(4-{4-[3-(2-amino-6-butil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-piperidin-1-il)-etanona ("A86"), 4-butil-6-[5-(1-piperidin-4-il-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-2-ilamina ("A87"), 4-butil-6-{5-[1-(1-metil-piperidin-4-il)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A89"), 4-etil-6-{5-[1-(3-fluoro-bencil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-pirimidin-2-ilamina ("A98"), 4-{5-[1-(3,4-difluoro-bencil)-1H-pirazol-4-il]-1H-pirrolo[2,3-b]piridin-3-il}-6-etil-pirimidin-2-ilamina ("A99"), 2-{4-[3-(2-amino-6-butil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-pirrolidin-1-il-etanona ("A106"), 2-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-N-(1H-indol-5-il)-propionamida ("A121"), o 2-{4-[3-(2-amino-6-etil-pirimidin-4-il)-1H-pirrolo[2,3-b]piridin-5-il]-pirazol-1-il}-1-(3,4-dihidro-2H-quinolin-1-il)-etanona ("A128"), así como sus sales, tautómeros y estereoisómeros farmacéuticamente útiles, incluyendo sus mezclas en todas las proporciones.

Description

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acetato de etilo y se succiona. Se diluye la fase orgánica combinada con acetato de etilo, se lava 2 veces con agua, se seca sobre sulfato de sodio, se filtra y se concentra. Se digiere el residuo con acetato de etilo y éter de petróleo y se succiona. Se obtiene el producto como cristales de color naranja (857 mg, rendimiento del 48%).
1.4 Para la producción de “A1” se desgasifica una mezcla de 100 mg (0,315 mmol) de “E3”, 1,8 equivalentes de ácido borónico “E2”, 36,4 mg (0,032 mmol) de tetrakis(trifenilfosfin)-paladio(0) y 0,9 ml de una disolución de carbonato de sodio 2 molar en 1,2 ml de N,N-dimetilformamida con nitrógeno durante 2 min y a continuación se calienta 30 min hasta 120ºC en un aparato de síntesis de microondas (CEM, Discover). Se diluye la mezcla de reacción con acetato de etilo y agua y se separa mediante filtración. Se pasa el filtrado a un embudo de decantación y se separan las fases. Se extrae la fase acuosa 2 veces más con acetato de etilo. Se seca la fase orgánica con sulfato de sodio, se filtra y se concentra. Se disuelve el residuo en 1 ml de N,N-dimetilformamida y se purifica a través de una columna de cromatografía de fase inversa. Se combinan las fracciones, se vuelven básicas con una disolución concentrada de hidróxido de sodio y se extraen 3 veces con acetato de etilo. Se seca la fase orgánica sobre sulfato de sodio, se filtra y se concentra. Se liofilizó el producto. Se obtuvieron 28 mg en forma de cristales blancos (rendimiento del 24%) de “A1”.
Materia sólida; ESI 376.
1H-RMN (d6-DMSO, 500 MHz): δ = 1,24 (t, J = 7,65 Hz, 3H), 2,21 (s, 6H), 2,53 (q, J = 7,61 Hz, 2H), 2,73 (t, J = 6,65 Hz, 2H), 4,24 (t, J = 6,63 Hz, 2H), 6,48 (s, 2H), 6,99 (s, 1 H), 8,07 (s, 1 H), 8,31 (s, 2H), 8,55 (d, J = 2,17 Hz, 1 H), 9,03 (d, J = 2,20 Hz, 1 H), 12,09 (s, 1 H) ppm.
Ejemplo 2
Producción de 1-{2-amino-6-[5-(1-isopropil-1H-pirazol-4-il)-1H-pirrolo[2,3-b]piridin-3-il]-pirimidin-4-il}-1-fenilpropan-1ol (“A57”)
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A una disolución de bromuro de etinilmagnesio (4 ml, 2,0 mmol, 0,5 M en THF) en THF (5 ml) se le añade gota a gota lentamente a temperatura ambiente con agitación una disolución de propiofenona en THF (0,2 ml, 1,505 mmol). Se agitó la disolución de reacción ligeramente amarilla 1 h a TA. Se acidifica la mezcla de reacción con HCl 1 N, a este respecto se produjo inicialmente turbidez, que desapareció con el aumento del valor de pH en el intervalo ácido. Se mezcló la disolución con dietil éter, se separó la fase acuosa y se extrajo la orgánica una vez con agua. Se secó la fase orgánica con sulfato de sodio, se separó mediante filtración y se concentró hasta obtener el residuo. Se obtuvo 3-fenil-pent-1-in-3-ol (233 mg, 0,001 mol) con un rendimiento del 65%. Se hace reaccionar adicionalmente la mezcla bruta sin purificación adicional.
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A una disolución de 3-fenil-pent-1-in-3-ol (3,4 g, 21,2 mmol) en diclorometano (80 ml) se le añade 2,6-dimetilpiridina (4,950 ml, 45,5 mmol). Se enfría hasta 0ºC y entonces se añade lentamente triflato de TIPS (8,5 ml, 31,9 mmol). Se calienta hasta temperatura ambiente y se deja agitar 18 h más. A la mezcla de reacción se le añade una disolución saturada de cloruro de amonio, se separa la fase orgánica y se extrae la acuosa dos veces con diclorometano. Se secan las fases orgánicas combinadas sobre sulfato de magnesio, se separa mediante filtración la materia sólida y se concentra hasta obtener el residuo. Se somete a cromatografía con heptano (Companion, columna RediSep 330 g, duración de ejecución 30,0 min, longitud de onda de detección 254 nm, caudal: 100 ml/min). Se obtiene el producto como aceite (880 mg, 5,879 mmol) con un rendimiento del 28%.
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Claims (1)

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ES09772064.3T 2008-07-03 2009-06-04 Derivados de pirrolopiridinil-pirimidin-2-il-amina Active ES2564204T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102008031517 2008-07-03
DE102008031517A DE102008031517A1 (de) 2008-07-03 2008-07-03 Pyrrolopyridinyl-pyrimidin-2-yl-amin-derivate
PCT/EP2009/004013 WO2010000364A1 (de) 2008-07-03 2009-06-04 Pyrrolopyridinyl-pyrimidin-2-yl-amin-derivate

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ES2564204T3 true ES2564204T3 (es) 2016-03-18

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US (1) US8420820B2 (es)
EP (1) EP2291375B1 (es)
JP (2) JP5587874B2 (es)
KR (1) KR20110027835A (es)
CN (1) CN102056926B (es)
AR (1) AR072792A1 (es)
AU (1) AU2009266090B2 (es)
BR (1) BRPI0913832A2 (es)
CA (1) CA2729725C (es)
DE (1) DE102008031517A1 (es)
EA (1) EA201100125A1 (es)
ES (1) ES2564204T3 (es)
IL (1) IL210406A (es)
MX (1) MX2010013919A (es)
WO (1) WO2010000364A1 (es)
ZA (1) ZA201100876B (es)

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CN102056926A (zh) 2011-05-11
WO2010000364A8 (de) 2011-01-06
CN102056926B (zh) 2013-10-16
IL210406A0 (en) 2011-03-31
BRPI0913832A2 (pt) 2015-10-20
EA201100125A1 (ru) 2011-08-30
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WO2010000364A1 (de) 2010-01-07
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AU2009266090A1 (en) 2010-01-07
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EP2291375A1 (de) 2011-03-09
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