ES2310787T3 - Uso de 2-fluoro-3-cetoesteres para preparar 3-fluoro-6,7,8,9-tetrahidro-4h-pirimido(1,2-a)-pirimidin-4-onas. - Google Patents
Uso de 2-fluoro-3-cetoesteres para preparar 3-fluoro-6,7,8,9-tetrahidro-4h-pirimido(1,2-a)-pirimidin-4-onas. Download PDFInfo
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- ES2310787T3 ES2310787T3 ES05016160T ES05016160T ES2310787T3 ES 2310787 T3 ES2310787 T3 ES 2310787T3 ES 05016160 T ES05016160 T ES 05016160T ES 05016160 T ES05016160 T ES 05016160T ES 2310787 T3 ES2310787 T3 ES 2310787T3
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Abstract
Uso de un 3-cetoéster de fórmula (IV) (Ver fórmula) en la que R1 representa un anillo de 2,3 ó 4-piridina sustituido opcionalmente con un grupo cicloalquilo C3 - 6, un grupo alquilo C1 - 4, un grupo alcoxi C1 - 4, un grupo bencilo o un átomo de halógeno, R5 es un átomo de halógeno y R es un etilo. para preparar un compuesto de fórmula (II) (Ver fórmula) haciendo reaccionar un compuesto de fórmula (V) (Ver fórmula) en el que la definición de R1, R5 son las mismas que se han definido anteriormente, R3 representa un átomo de hidrógeno, un grupo alquilo C1 - 6, un grupo hidroxi, un grupo alcoxi C1 - 4, o un átomo de halógeno; R4 representa un átomo de hidrógeno, un grupo alquilo C1 - 6, un grupo hidroxi, un grupo alcoxi C1 - 4, o un átomo de halógeno; y cuando m es igual a 0, p es igual a 1, 2 ó 3, cuando m es igual a 1, p es igual a 0, 1 ó 2, cuando m es igual a 2, p es igual a 0 ó 1.
Description
Uso de
2-fluoro-3-cetoésteres
para preparar
3-fluoro-6,7,8,9-tetrahidro-4h-pirimido[1,2-a]-pirimidin-4-onas.
La presente invención se refiere a compuestos
que son útiles como un ingrediente activo de un medicamento para el
tratamiento preventivo y/o terapéutico de enfermedades
neurodegenerativas producidas por actividades anormales de la
GSK3\beta sola o por los efectos combinados de la GSK3\beta y la
cdk5/p25.
El objeto de la presente invención es el uso de
la reivindicación 1.
Esquema
1
(En el esquema anterior, las definiciones de R1,
R3, R4, R5, p y m son las mismas que las descritas
anteriormente).
Según este método, se hace reaccionar el
3-cetoéster de fórmula (IV) con un compuesto de
fórmula (V). La reacción puede realizarse en presencia de carbonato
de potasio, en un disolvente alcohólico, tal como metanol, etanol y
similares, o sin disolvente, a una temperatura adecuada que varía de
25ºC-140ºC en atmósfera ordinaria.
Los compuestos de fórmula (V) o (IV) están
disponibles comercialmente o se pueden sintetizar según métodos
bien conocidos por los expertos en la técnica.
Por ejemplo, los compuestos de fórmula (IV) en
la que R1 representa un anillo de piridina opcionalmente sustituido
con un grupo alquilo de C_{1-4}, un grupo alcoxi
de C_{1-4} o un átomo de halógeno, se pueden
preparar haciendo reaccionar un ácido nicotínico opcionalmente
sustituido con un grupo alquilo de C_{1-4}, un
grupo alcoxi de C_{1-4} o un átomo de halógeno,
con un monoéster del ácido malónico. La reacción se puede realizar
utilizando métodos bien conocidos por los expertos en la técnica,
tal como por ejemplo en presencia de un agente de acoplamiento, tal
como
1,1'-carbonilbis-1H-imidazol,
en un disolvente, tal como tetrahidrofurano, a una temperatura que
varía de 20 a 70ºC.
La presente invención se explicará más
específicamente con referencia al siguiente ejemplo, sin embargo el
alcance de la presente invención no se limita a estos ejemplos.
A una disolución de 134,88 mL (0,54 moles) de
tri-n-butilfosfina en 500 mL de
tetrahidrofurano anhidro en atmósfera de argón se le añadieron 63,8
mL (0,54 moles) de bromofluoroacetato de etilo y la mezcla
resultante se agitó a temperatura ambiente durante 40 horas.
La mezcla de reacción se enfrió a -78ºC y se
añadieron gota a gota 237,58 mL (0,594 moles) de
n-butil-litio (2,5M en hexano) y se
agitó durante 1 hora. Se añadieron 76,44 g (0,54 moles) de cloruro
de isonicotinoilo (Heterocyclic Chemistry, 18, 519, 1981) y
la mezcla se agitó durante 1 hora.
Se permitió que la temperatura subiese hasta
temperatura ambiente durante la noche y a 0ºC se añadieron 700 mL
de una disolución acuosa de bicarbonato de sodio al 5% y la mezcla
resultante se agitó durante una noche. Se evaporó el
tetrahidrofurano a presión reducida y la fase acuosa resultante se
extrajo con diclorometano, se lavó con salmuera y se secó sobre
sulfato de sodio anhidro y se evaporó para dar un residuo marrón
oscuro. Se realizó cromatografía ultra-rápida sobre
gel de sílice (eluyente: ciclohexano/acetato de etilo de 90/10 a
50/50). Este producto se trató con una disolución de ácido
clorhídrico en isopropanol (6N) para dar 20 g (17%) del producto.
P.F.: 142-144ºC.
Se calentó a temperatura de reflujo durante 18
horas una mezcla de 5,0 g (20,19 mmoles) del hidrocloruro de
piridin-4-il-3-oxo-2-fluoropropanoato
de etilo, 3,30 g (20,19 mmoles) de hidrocloruro de
5,5-dimetil-1,4,5,6-tetrahidro-2-pirimidinamina
(preparado de forma análoga al método descrito en la patente
estadounidense Nº 4.262.122) y 8,37 g (60,57 mmoles) de carbonato de
potasio en 30 mL de etanol.
La suspensión enfriada se filtró y se eliminó el
disolvente por evaporación. El residuo obtenido se trató con
diclorometano y se lavó con agua. La fase orgánica se secó y se
evaporó para dar 1,9 g (34%) del producto como un sólido beis. P.F.:
190-192ºC.
Claims (3)
1. Uso de un 3-cetoéster de
fórmula (IV)
en la que R1 representa un anillo
de 2,3 ó 4-piridina sustituido opcionalmente con un
grupo cicloalquilo C_{3-6}, un grupo alquilo
C_{1-4}, un grupo alcoxi
C_{1-4}, un grupo bencilo o un átomo de halógeno,
R5 es un átomo de halógeno y R es un
etilo.
para preparar un compuesto de fórmula (II)
haciendo reaccionar un compuesto de
fórmula
(V)
en el que la definición de R1, R5
son las mismas que se han definido
anteriormente,
R3 representa un átomo de hidrógeno, un grupo
alquilo C_{1-6}, un grupo hidroxi, un grupo alcoxi
C_{1-4}, o un átomo de halógeno;
R4 representa un átomo de hidrógeno, un grupo
alquilo C_{1-6}, un grupo hidroxi, un grupo alcoxi
C_{1-4}, o un átomo de halógeno; y
cuando m es igual a 0, p es igual a 1, 2 ó
3,
cuando m es igual a 1, p es igual a 0, 1 ó
2,
cuando m es igual a 2, p es igual a 0 ó 1.
2. Uso de un 3-cetoéster de
fórmula (IV) según la reivindicación 1, en la que R5 es un átomo de
flúor.
3. Uso de un 3-cetoéster de
fórmula (IV) según la reivindicación 2, que consiste en
2-fluoro-3-oxo-3-piridin-4-il
propanoato de etilo.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01402432 | 2001-09-21 | ||
| EP01402432A EP1295885A1 (en) | 2001-09-21 | 2001-09-21 | Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido(1,2-a)pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo(1,2-a)pyrimidin-5(1H)one derivatives |
| EP02290489A EP1340761A1 (en) | 2002-02-28 | 2002-02-28 | Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives |
| EP02290489 | 2002-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2310787T3 true ES2310787T3 (es) | 2009-01-16 |
Family
ID=26077256
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES05016160T Expired - Lifetime ES2310787T3 (es) | 2001-09-21 | 2002-09-19 | Uso de 2-fluoro-3-cetoesteres para preparar 3-fluoro-6,7,8,9-tetrahidro-4h-pirimido(1,2-a)-pirimidin-4-onas. |
| ES02785157T Expired - Lifetime ES2247398T3 (es) | 2001-09-21 | 2002-09-19 | Derivados de 2-piridini9l-6,7,8,9-tetrahidropirimido(1,2-a)pirimidin-4-ona y 7-piridinil-2,3-dihidroimidazo(1,2-a)pirimidin-5(1h)ona sustituidos. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02785157T Expired - Lifetime ES2247398T3 (es) | 2001-09-21 | 2002-09-19 | Derivados de 2-piridini9l-6,7,8,9-tetrahidropirimido(1,2-a)pirimidin-4-ona y 7-piridinil-2,3-dihidroimidazo(1,2-a)pirimidin-5(1h)ona sustituidos. |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US7214682B2 (es) |
| EP (2) | EP1674456B1 (es) |
| JP (3) | JP4570362B2 (es) |
| KR (1) | KR100868841B1 (es) |
| CN (2) | CN1247585C (es) |
| AR (1) | AR036600A1 (es) |
| AT (2) | ATE401309T1 (es) |
| AU (1) | AU2002350487C1 (es) |
| BR (1) | BR0212896A (es) |
| CA (1) | CA2457965C (es) |
| CY (1) | CY1108341T1 (es) |
| DE (2) | DE60227718D1 (es) |
| DK (2) | DK1430057T3 (es) |
| EA (1) | EA006859B1 (es) |
| ES (2) | ES2310787T3 (es) |
| HU (1) | HUP0500328A3 (es) |
| IL (2) | IL160402A0 (es) |
| MX (1) | MXPA04002629A (es) |
| NO (1) | NO329565B1 (es) |
| NZ (2) | NZ547205A (es) |
| PL (1) | PL370349A1 (es) |
| PT (1) | PT1674456E (es) |
| SI (1) | SI1430057T1 (es) |
| WO (1) | WO2003027116A2 (es) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ547205A (en) * | 2001-09-21 | 2007-11-30 | Sanofi Aventis | Intermediates of substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives |
| TWI335221B (en) | 2001-09-27 | 2011-01-01 | Alcon Inc | Inhibtors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma |
| EP1454909B1 (en) * | 2003-03-07 | 2008-08-20 | Sanofi Aventis | 8'-pyridinyl-dihydrospiro- (cycloalkyl) -pyrimido (1,2-a) pyrimidin-6-one and 8'-pyrimidinyl-dihydrospiro (cycloalkyl) -pyrimido (1,2-a) pyrimidin-6-one derivatives and their use against neurodegenerative diseases |
| EP1454900A1 (en) | 2003-03-07 | 2004-09-08 | Sanofi-Synthelabo | Process for the preparation of pyridinyl and pyrimidinyl mono-fluorinated beta keto-esters |
| EP1557417B1 (en) * | 2003-12-19 | 2007-03-07 | Sanofi-Aventis | Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2-a] pyrimidin-6-one derivatives |
| US7504403B2 (en) | 2004-01-22 | 2009-03-17 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
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| WO2007053596A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
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| CN101735211B (zh) * | 2008-11-04 | 2012-11-14 | 复旦大学 | 2,3-二氢[1,5]苯并噻氮杂*类化合物或其盐在制备GSK-3β抑制剂中的用途 |
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| MX2012000103A (es) * | 2009-07-02 | 2012-05-22 | Sanofi Sa | Nuevos derivados de 1,2,3,4-tetrahidro-pirimido (1,2-a) pirimidin-6-ona, su preparacion y su uso farmaceutica. |
| FR2947550B1 (fr) * | 2009-07-02 | 2012-05-18 | Sanofi Aventis | Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb) |
| ES2627428T3 (es) * | 2009-07-02 | 2017-07-28 | Sanofi | Nuevos derivados de 2,3-dihidro-1H-imidazo{1,2-a}pirimidin-5-ona, su preparación y su utilización farmacéutica |
| FR2947551B1 (fr) * | 2009-07-02 | 2012-05-18 | Sanofi Aventis | Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a)pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb) |
| US8815853B2 (en) | 2010-12-23 | 2014-08-26 | Sanofi | Pyrimidinone derivatives, preparation thereof and pharmaceutical use thereof |
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| WO1998016528A1 (en) * | 1996-10-11 | 1998-04-23 | Chiron Corporation | Purine inhibitors of glycogen synthase kinase 3 (gsk3) |
| HUP0001140A3 (en) * | 1996-12-05 | 2002-05-28 | Amgen Inc Thousand Oaks | Substituted pyrimidinone and pyridone compounds and methods of use |
| US6417185B1 (en) * | 1998-06-19 | 2002-07-09 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
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| MXPA01009615A (es) * | 1999-03-22 | 2003-07-21 | Johnson & Johnson | Procedimiento para la preparacion de acido [s -(r*s*)] -°-[[[1[1- oxo-3 -(4-piperidinil) propil]3 -piperidini] carbonil] amino] -3-piridinil] carbonil] amino] -3-piridinpropanoico, y derivados del mismo. |
| WO2001042224A1 (en) * | 1999-12-09 | 2001-06-14 | Mitsubishi Pharma Corporation | Carboxyamido derivatives |
| CN100335479C (zh) * | 1999-12-17 | 2007-09-05 | 希龙公司 | 糖元合成酶激酶3的双环抑制剂 |
| AU1224902A (en) * | 2000-09-01 | 2002-03-13 | Sanofi Synthelabo | 2-pyridinyl-6,7,8,9-tetrahydropyrimido(1,2-a)pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo(1,2-a)pyrimidin-5(1H)one derivatives |
| NZ547205A (en) * | 2001-09-21 | 2007-11-30 | Sanofi Aventis | Intermediates of substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives |
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