ES2526671T3 - Compuestos de benzotriazoldiazepina inhibidores de bromodominios - Google Patents

Compuestos de benzotriazoldiazepina inhibidores de bromodominios Download PDF

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Publication number
ES2526671T3
ES2526671T3 ES11725769.1T ES11725769T ES2526671T3 ES 2526671 T3 ES2526671 T3 ES 2526671T3 ES 11725769 T ES11725769 T ES 11725769T ES 2526671 T3 ES2526671 T3 ES 2526671T3
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alkyl
ring
carbocyclyl
groups
elements
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James Matthew Bailey
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Un compuesto de fórmula (I) o una sal del mismo**Fórmula** en la que R1 es alquilo C1-3; R2 es -NR2aR2a' o -OR2b; en los que uno de R2a o R2'a es hidrógeno, y R2b o el otro de R2a o R2'a son seleccionados de alquilo C1-6, haloalquilo C1-6, R2cR2'cN - alquilo C2-6, R2cO-alquilo C2-6, carbociclilo, carbociclilalquilo C1-4, heterociclilo y heterociclilalquilo C1- 4, en los que cualquiera de los grupos carbociclilo o heterociclilo está opcionalmente sustituido con uno o más grupos seleccionados de halógeno, alquilo C1-6, haloalquilo C1-6, alcoxi C1-6, haloalcoxi C1-6, carbonilo, -CO-carbociclilo, azido, amino, hidroxilo y ciano, o dos grupos adyacentes en cualquiera de los grupos carbociclilo o heterociclilo, junto con los átomos de interconexión forman un anillo de 5 ó 6 elementos cuyo anillo puede contener 1 ó 2 heteroátomos seleccionados independientemente de O, S y N; o R2a y R2'a junto con el átomo de N al que están unidos forman un anillo de 5, 6 ó 7 elementos, que puede contener opcionalmente 1 o 2 heteroátomos seleccionados independientemente de O, S y N; en el que el anillo de 5, 6 ó 7 elementos puede estar además opcionalmente sustituido con alquilo C1-6; R2c y R2'c son independientemente hidrógeno o alquilo C1-6; cada R3 es seleccionado independientemente de hidrógeno, hidroxi, halo, alquilo C1-6, haloalquilo C1-6, alcoxi C1-6, haloalcoxi C1-6, ciano, CF3, -OCF3, -COOR5, - aquilC1-4 NR6R7 y -aquil C1-4 OH; R4 es un grupo carbocíclico aromático o heterociclilo aromático; en el que el grupo carbociclilo o heterociclilo aromático está opcionalmente sustituido con uno o más grupos seleccionados de halo, alquilo C1-6, alcoxi C1-6 y un grupo aquil C1-4 NR6R7; R5 es alquilo C1-3; en cada aparición, R6 y R7 son independientemente hidrógeno, alquilo C1-6, o C(O) alquilo C1-6, o R6 y R7 junto con el átomo de N al que están unidos forman un anillo de 5, 6 ó 7 elementos que opcionalmente contiene 1 ó 2 heteroátomos adicionales seleccionados independientemente de O, S y N; en el que el anillo de 5, 6 ó 7 elementos puede estar además opcionalmente sustituido con uno o más grupos alquilo C1-6, -C(O) alquilo C1-6, amino o hidroxilo; y n es un entero entre 1 y 5.

Description

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E11725769
18-12-2014
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Se añadió ácido 4-metoxibencenoborónico (50,5 mg), carbonato de sodio (64,5 mg) y cloruro de bis (trifenilfosfina) paladio (II) (19,4 mg) a un vial de microondas de 2 -5 ml. Se añadió una solución de trifluorometanosulfonato de (4S) -6-(4-clorofenil) -4-[2-(etilamino) -2-oxoetil] -1-metil-4H-[1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-8-ilo (para 5 una preparación véase el Intermedio 3) (150 mg) en DME (3 ml) y agua (1 ml) y la mezcla de reacción se calentó a 120°C durante 20 min (microondas). La mezcla de reacción se repartió entre acetato de etilo (10 ml) y agua (10 ml). La fase orgánica se separó, se lavó con agua (10 ml) y salmuera (10 ml). La fase orgánica se secó y el disolvente se evaporó. El residuo se sometió a cromatografía (metanol al 0% -5%: DCM) para dar 2 -{(4S) -6-(4clorofenil) -1-metil-8-[4-(metiloxi) fenil] -4H [1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-4-il} -N-etilacetamida en
10 forma de un sólido marrón claro (84 mg).
LCMS (formiato): MH+ 500 / 502, TR 1,08 min.
Ejemplo 4: 2 -[(4S) -6-(4-clorofenil) -1-metil-8-(1H-pirazol-5-yi) -4H [1,2,4] triazolo [4,3-a ] [1,4] benzodiacepina 4-il] -N-etilacetamida
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15 Se añadió carbonato de sodio (43,0 mg), ácido 1 H-pirazol-5-borónico (24,8 mg) y cloruro de bis (trifenilfosfina) paladio (II) (13,0 mg) a un vial de microondas de 2 -5 ml. Se añadió una solución de trifluorometanosulfonato de (4S) -6-(4-clorofenil) -4-[2-(etilamino) -2-oxoetil] -1-metil-4H-[1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-8-ilo (para una preparación véase el Intermedio 3) (100 mg) en DME (3 ml) y agua (1 ml). La mezcla de reacción se calentó a 120°C durante 30 min (microondas). Se añadió acetato de etilo (2 ml) y la fase acuosa se separó. La fase orgánica
20 se secó y el disolvente se evaporó. El residuo se sometió a cromatografía (metanol al 0% -5%: DCM) y el producto se purificó adicionalmente por MDAP (modificador de formiato). La goma resultante se cargó en una columna SCX-2 de 1 g y se lavó con amoniaco en metanol (2 M) para dar 2-[(4S)-6-(4-clorofenil)-1-metil-8-(1H-pyrazol-5-il)4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-il] -N-etilacetamida en forma un aceite marrón (15,6 mg).
LCMS (formiato): MH+ 460 / 462, TR 0,80 min
25 Ejemplo 5: 2 -[(4S) -6-(4-clorofenil) -1-metil-8-(1H-pirazol-4-il) -4H [1,2,4] triazolo [4,3-a] [1,4] benzodiazepina4-il] -N-etilacetamida
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Claims (1)

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ES11725769.1T 2010-06-22 2011-06-20 Compuestos de benzotriazoldiazepina inhibidores de bromodominios Active ES2526671T3 (es)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB201010514 2010-06-22
GBGB1010514.6A GB201010514D0 (en) 2010-06-22 2010-06-22 Novel compounds
GB201106801 2011-04-21
GBGB1106801.2A GB201106801D0 (en) 2011-04-21 2011-04-21 Novel compounds
PCT/EP2011/060179 WO2011161031A1 (en) 2010-06-22 2011-06-20 Benzotriazolodiazepine compounds inhibitors of bromodomains

Publications (1)

Publication Number Publication Date
ES2526671T3 true ES2526671T3 (es) 2015-01-14

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ES11725769.1T Active ES2526671T3 (es) 2010-06-22 2011-06-20 Compuestos de benzotriazoldiazepina inhibidores de bromodominios

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US (1) US9085582B2 (es)
EP (1) EP2585465B1 (es)
JP (1) JP5844358B2 (es)
ES (1) ES2526671T3 (es)
WO (1) WO2011161031A1 (es)

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