ES2629751T3 - Derivados de pirazol novedosos - Google Patents

Derivados de pirazol novedosos Download PDF

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ES2629751T3
ES2629751T3 ES14709590.5T ES14709590T ES2629751T3 ES 2629751 T3 ES2629751 T3 ES 2629751T3 ES 14709590 T ES14709590 T ES 14709590T ES 2629751 T3 ES2629751 T3 ES 2629751T3
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substituted
alkyl
alkoxy
cycloalkyl
halogen
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Uwe Grether
Atsushi KIMBARA
Matthias Nettekoven
Fabienne Ricklin
Stephan Roever
Mark Rogers-Evans
Tanja Schulz-Gasch
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Abstract

Un compuesto de fórmula (I)**Fórmula** en la que A1 es -CH- o nitrógeno; A2 es -CH- o nitrógeno; A3 es -(CH2)n- o -CH2C(O)-; R1 es alquilo, cicloalquilo, alcoxi o halógeno; R2 es alcoxi, pirrolidinilo sustituido o dihidropirrolilo sustituido, en el que pirrolidinilo sustituido y dihidropirrolilo sustituido son pirrolidinilo y dihidropirrolilo sustituidos con uno o dos sustituyentes independientemente seleccionados de halógeno, hidroxilo, hidroxialquilo, alcoxialquilo y alquilfurazanilalcoxi; R3 es fenilo, fenilo sustituido, furazanilo sustituido, piridinilo, piridinilo sustituido, dioxotietanilo, tetrahidrofuranilo, tetrazolilo sustituido o triazolilo sustituido, en el que fenilo sustituido, piridinilo sustituido y triazolilo sustituido son fenilo, piridinilo y triazolilo sustituidos con uno o dos sustituyentes independientemente seleccionados de alquilo, alcoxi, halógeno, haloalquilo, alquilsulfonilo y cicloalquilo, y en el que tetrazolilo sustituido y furazanilo sustituido son tetrazolilo y furazanilo sustituidos con un sustituyente seleccionado de alquilo, alcoxi, halógeno, haloalquilo, alquilsulfonilo y cicloalquilo; n es 1 o 2; siempre que A1 y A2 30 no sean ambos carbono al mismo tiempo; o una sal o éster farmacéuticamente aceptable del mismo; en la que "alquilo", solo o en combinación, es un grupo alquilo de cadena lineal o cadena ramificada con 1 a 8 átomos de carbono; "cicloalquilo", solo o en combinación, es un anillo cicloalquilo con 3 a 8 átomos de carbono; y "alcoxi", solo o en combinación, es un grupo de la fórmula alquil-O-.

Description

imagen1
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en presencia de R2H y una base;
(b) la reacción de un compuesto de fórmula (B)
imagen12
en presencia de R3-A3-X y una base;
(c) la reacción de un compuesto de fórmula (C)
imagen13
15 en presencia de MR1, un catalizador de paladio y una base;
(d) la reacción de un compuesto de fórmula (D)
imagen14
20 en presencia de MR1, un catalizador de paladio y una base;
en la que A1 a A3 y R1 a R3 son como se definen anteriormente, X es un grupo saliente y M es una especie de metal adecuadamente sustituida, como una especie de boro, borilo, trifluoro-borato o estannilo. 25 En la etapa (a), la base es por ejemplo DIEA.
La etapa (a) se lleva a cabo en particular ventajosamente en un disolvente inerte, tal como DMF. La etapa (a) se puede llevar a cabo convenientemente a 120 ºC. 30 En la etapa (b), la base es por ejemplo terc-butóxido, carbonato de cesio o carbonato de potasio.
La etapa (b) se lleva a cabo en particular ventajosamente en un disolvente inerte, como DMF o DMA. La etapa (b) se puede llevar a cabo convenientemente a 120 ºC.
35 En la etapa (c), el catalizador de paladio es por ejemplo acetato de paladio(II). La etapa (c) se lleva a cabo preferentemente en presencia de una fosfina, particularmente n-butil-di-adamantilfosfina.
12
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6-terc-butil-1-[(2-clorofenil)metil]-4-etoxi-1H-pirazolo[3,4-d]pirimidina
imagen20
5 El compuesto del título se sintetizó en analogía con los ejemplos 1c a 1f, usando 5-amino-1-[(2-clorofenil)metil]-1Hpirazol-4-carboxamida (CAN 106898-48-0), cloruro de pivaloílo y etanol como materiales de partida, y se aisló (15 mg) como un aceite incoloro; CLEM (área de pico UV, ESI) 83 %, 345,5 [MH+].
10 Ejemplo 6
6-terc-butil-1-[(2-cloro-4-fluorofenil)metil]-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina
a) 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina 15
imagen21
A una mezcla de 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1-(4-metoxi-bencil)-1H-pirazolo[3,4-d]pirimidina (0,174 g, 0,43 mmol) y TFA (870 µl, 11,3 mmol) en DCM (3 ml) se le añadió ácido metanosulfónico (141 µl, 2,17 mmol). La
20 mezcla se agitó durante 1 hora a 0 ºC y durante 1,5 horas a temperatura ambiente. Después de esto, la mezcla se volvió básica con solución de hidróxido de sodio (2,5 ml, 25 %, enfriamiento) y se repartió entre agua y DCM. Se mezclaron las fases orgánicas, se secó con MgSO4, se filtró y se concentró a vacío. El residuo, 135 mg del compuesto del título como un sólido amarillo claro, se usó sin purificación adicional; CLEM (área de pico UV, ESI) 80 %, 282,5 [MH+].
25 b) 6-terc-butil-1-(2-cloro-4-fluoro-bencil)-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo [3,4-d]pirimidina
imagen22
30 A una solución de 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina (30 mg, 107 µmol) en acetona (1 ml) y DMF (2 ml) se le añadió 2-cloro-1-(clorometil)-4-fluoro-benceno (23 mg, 128 µmol) y carbonato de potasio (44 mg, 318 µmol). La mezcla se sometió a microondas durante 45 minutos a 120 ºC, se enfrió y se repartió entre agua y acetato de etilo. Se mezclaron las fases orgánicas, se secó por filtración sobre ChemElut®, y se concentró a vacío. El residuo se purificó por HPLC preparativa (Gemini NX, gradiente de agua/acetonitrilo), para proporcionar el
18
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Ejemplo
CE50 de CB2 humano [µM] CE50 de CB1 humano [µM]
1
0,0048 >10
2
0,0033 >10
3
0,0051 >10
4
0,0042 >10
5
0,0255 >10
6
0,0059 >10
7
0,0011 >10
8
0,0054 >10
9
0,0005 >10
10
0,0007 0,3368
11
0,0187 >10
12
0,0016 1,5741
13
0,0196 >10
14
0,0013 >10
15
0,0009 >10
16
0,0006 >10
17
0.003 >10
18
0,0262 >10
19
0,0014 >10
20
0,0016 >10
21
0,0034 >10
22
0,0084 >10
23
0,0055 >10
24
0,0175 >10
25
0,0004 >10
26
0,0356 >10
27
0,0425 >10
28
0,0019 >10
29
0,0019 >10
30
0,0024 >10
31
0,0173 >10
32
0,0015 >10
33
0,0088 >10
34
0.005 >10
35
0,0133 >10
36
0,0014 >10
37
0,0172 >10
38
0,0160 >10
Ejemplo A
Los comprimidos recubiertos con película que contienen los siguientes ingredientes se pueden fabricar de manera convencional:
Ingredientes
Por comprimido
Núcleo:
Compuesto de fórmula (I)
10,0 mg 200,0 mg
Celulosa microcristalina
23,5 mg 43,5 mg
Lactosa hidratada
60,0 mg 70,0 mg
Povidona K30
12,5 mg 15,0 mg
Glicolato sódico de almidón
12,5 mg 17,0 mg
Estearato de magnesio
1,5 mg 4,5 mg
(Peso del núcleo)
120,0 mg 350,0 mg
Recubrimiento de película:
Hidroxipropilmetilcelulosa
3,5 mg 7,0 mg
Polietilenglicol 6000
0,8 mg 1,6 mg
Talco
1,3 mg 2,6 mg
Óxido de hierro (amarillo)
0,8 mg 1,6 mg
Dióxido de titanio
0,8 mg 1,6 mg
41
imagen45

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
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