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WO1999009028A1 - Crystalline polymorphic forms of 3-{2-[4-6-fluorobenzo[d] isoxazol-3-yl) -3,6-dihydro-2h-pyridine-1-yl] -ethyl]-2-methyl-6,7, 8,9-tetrahydropyrido [1,2-a]pyrimidine-4-one and process for producing the forms - Google Patents

Crystalline polymorphic forms of 3-{2-[4-6-fluorobenzo[d] isoxazol-3-yl) -3,6-dihydro-2h-pyridine-1-yl] -ethyl]-2-methyl-6,7, 8,9-tetrahydropyrido [1,2-a]pyrimidine-4-one and process for producing the forms Download PDF

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Publication number
WO1999009028A1
WO1999009028A1 PCT/ES1998/000227 ES9800227W WO9909028A1 WO 1999009028 A1 WO1999009028 A1 WO 1999009028A1 ES 9800227 W ES9800227 W ES 9800227W WO 9909028 A1 WO9909028 A1 WO 9909028A1
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WIPO (PCT)
Prior art keywords
polymorph
ethyl
isoxazol
dihydro
methyl
Prior art date
Application number
PCT/ES1998/000227
Other languages
Spanish (es)
French (fr)
Inventor
Ana Bosch Rovira
Ignacio Diez Martin
Joan Huguet Clotet
Original Assignee
Vita-Invest, S.A.
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Application filed by Vita-Invest, S.A. filed Critical Vita-Invest, S.A.
Priority to AU85432/98A priority Critical patent/AU8543298A/en
Publication of WO1999009028A1 publication Critical patent/WO1999009028A1/en

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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

Definitions

  • the present invention relates to two new crystalline polymorphic forms of 3- ⁇ 2- [4- ( ⁇ -fluorobenzo-
  • the present invention also relates to methods for obtaining said new polymorphs, as well as to pharmaceutical compositions containing them and to the use thereof as antipsychotics.
  • the objective of the present invention is to solve the drawbacks of the prior art, by providing the compound of formula (I) as a base, which has been obtained in two different polymorphic forms, methods for obtaining it and compositions that they contain.
  • the present invention provides the compound of formula (I) in the form of a crystallized base in two new polymorphic forms, referred to as polymorph I and polymorph II, clearly differentiated based on their IR, solid state and C- 13 NMR spectra, With application as antipsychotics.
  • Another object of the present invention is to provide a process for obtaining the compound of formula (I), as a base, as a crystalline solid, which It has the advantage of being easy to filter and dry.
  • the invention provides a process for obtaining the compound of formula (I), in the form of a base, as a crystalline product that can be precipitated to give two different polymorphic forms, obtaining one or the other according to the parameters used in the crystallization.
  • the crystallization of the compound of formula (I) as a base to obtain polymorph I can also be carried out by evaporation, at room temperature and pressure, of said saturated solution described above.
  • Crystallization of the compound of formula (I) as a base to obtain polymorph II can also be carried out by the addition, at room temperature and pressure, of water or an excess of a non-polar solvent, such as hexane, to a saturated solution of 3- ⁇ 2-
  • halogenated solvents such as chloroform or methylene chloride.
  • Crystallization of a solution of the compound of formula (I) as a base, at room temperature and pressure, can lead to either of the two polymorphs (I or II), or mixtures thereof, depending on the solvent. of the solution to which water or hexane is added.
  • the concentration of the base and / or the agitation used in the cooling influence the type of polymorph obtained.
  • Polymorph I has signals at 112.8, 117.3 and 127.8 ppm
  • Polymorph I has characteristic peaks for 2 theta (2 ⁇ ) values of 11.1 °, 13.9 °, 17.7 °, 21.7 °, 22.7 °, 23 , 7 °, 24.3 ° and 28.0 ° (Figure 8); Polymorph II has characteristic peaks for values of 2 theta (20) of 7.3 °, 10.8 °, 12.2 °, 14.7 °, 15.0 °, 15.6 °, 20.1 °, 21.9 °, 22.1 °, 22.4 °, 23.3 °, 24.0 °, 26.5 ° and 30.3 °. ( Figure 9).
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of crystalline polymorph I or II, in combination with a pharmaceutically acceptable carrier.
  • Preferred pharmaceutical compositions are in the form of an aqueous solution, such as tablets and capsules, although other forms such as: rectal, delayed-release, rapid-dissolving, or other compositions can also be prepared.
  • Figures 1 and 2 show the melting points of polymorphs I and II by DSC thermograms.
  • Figures 3 and 4 show the solid phase nuclear magnetic resonance spectrum of C 13 for polymorphs I and II respectively.
  • Figures 5 and 6 show the IR spectrum for polymorphs I and II respectively.
  • Figure 7 shows the superposition of the IR spectra of both polymorphs in the area where They have differences.
  • Figures 8 and 9 show the X-ray diffraction spectrum of crystalline powder for polymorphs I and II respectively.
  • Dissolve the tartaric acid in approximately 80% of the water of the formula then dissolve the product of the Example 1 and adjust the pH of the formulation with 1N sodium hydroxide.
  • sweeteners, colorants, preservatives, flavorings, etc. can be added or it can be sterilized if it is intended to be administered parenterally.
  • magnesium stearate lactose monohydrate c.s.p. 100.0%
  • the preparation of the tablets is carried out by a wet granulation process using a hydroxypropylmethylcellulose solution as a binder.
  • a wet granulate is prepared, using as an agent binder a solution of sodium lauryl sulfate. The granulate thus obtained in hard gelatin capsules of adequate size.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

T he invention relates to polymorphic forms I and II forms which are characterized by the powder X ray diffraction model, the nuclear magnetic resonance spectrum of C13 and the infrared spectrum of figures 3, 5 and 8, and figures 4, 6 and 9, polymorphic forms I and II respectively. The invention also relates to the process for producing the polymorphic forms I and II through crystallisation of a saturated solution of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl) -3,6-dihydro-2H-pyridine-1-yl] -(ethyl}-2-methyl-6,7, 8,9-tetrahydropyrido [1,2-a]pyrimidine-4-one as a base in solvents, alcohols, ketones, esters, ethers or halogenated derivatives, in adecuate pressure and temperature conditions.

Description

FORMAS POLIMORFICAS CRISTALINAS DE LA 3-{2-[4-(6-FLUOROBENZθrD] ISOXAZOL-3-IL) -3 6-DI- HIDRO-2H-PIRIDIN-1-IL] -EΗL}-2-METIL-6,7, 8,9-TETRAHIDROPIRIDO [1.2-A1PIRIMIDIN-4-ONA Y PROCEDIMIENTOS PARA SU OBTENCIÓNCRYSTALLINE POLYMORPHIC FORMS OF THE 3- {2- [4- (6-FLUOROBENZθrD] ISOXAZOL-3-IL) -3 6-DI- HIDRO-2H-PIRIDIN-1-IL] -EΗL} -2-METIL-6, 7, 8,9-TETRAHYDROPIRID [1.2-A1 PYRIMIDIN-4-ONA AND PROCEDURES FOR OBTAINING
CAMPO DE LA INVENCIÓNFIELD OF THE INVENTION
La presente invención se refiere a dos nuevas formas polimórficas cristalinas de la 3-{2- [4- (β-fluorobenzo-The present invention relates to two new crystalline polymorphic forms of 3- {2- [4- (β-fluorobenzo-
[d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l-il]-etil}-2-metil-[d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2-methyl-
6, 7, 8, 9-tetrahidropirido[l,2-a]pirimidin-4-ona, de fórmula6, 7, 8, 9-tetrahydropyrid [l, 2-a] pyrimidin-4-one, of formula
(I)(I)
Figure imgf000003_0001
Figure imgf000003_0001
La presente invención también se refiere a procedimientos para la obtención de dichos nuevos polimorfos, asi como a composiciones farmacéuticas que los contienen y a la utilización de los mismos como antipsicóticos.The present invention also relates to methods for obtaining said new polymorphs, as well as to pharmaceutical compositions containing them and to the use thereof as antipsychotics.
ANTECEDENTES DE LA INVENCIÓNBACKGROUND OF THE INVENTION
El compuesto 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- il)-3, 6-dihidro-2H-piridin-l-.il] -etil}-2-metil-6, 7,8,9- tetrahidropirido [1, 2-a]pirimidin-4-ona de fórmula (I) es conocido por la solicitud de patente española ES 9400362, solicitada el 24 de febrero de 1994, a nombre del mismo titular. Aunque en dicha patente se reivindica el producto de fórmula (I) y sus sales farmacéuticamente aceptables, sólo se describe la obtención del compuesto de fórmula (I) bajo la forma de diclorhidrato en los ejemplos de la misma.The compound 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- yl) -3, 6- dihydro-2H- pyridin-l-.yl] -ethyl} -2-methyl-6, 7 , 8,9-tetrahydropyrid [1,2-a] pyrimidin-4-one of formula (I) is known from Spanish patent application ES 9400362, filed on February 24, 1994, in the name of the same holder. Although said patent claims the product of formula (I) and its pharmaceutically acceptable salts, only the preparation of the compound of formula (I) in the form of dihydrochloride is described in the examples thereof.
HOJA DE SUSTITUCIÓN (REG.LA 26) Sin embargo, durante el procedimiento de obtención a escala industrial de dicho diclorhidrato del compuesto de fórmula (I) se observaron grandes dificultades en la etapa de filtración del mismo. Por otro lado, dicho diclorhidrato presentaba problemas de secado, no importantes a escala de laboratorio pero si a escala industrial, ya que dicho diclorhidrato comprende cantidades importantes de disolvente de muy difícil eliminación a dicha escala.SUBSTITUTE SHEET (REG.LA 26) However, during the process of obtaining the dihydrochloride of the compound of formula (I) on an industrial scale, great difficulties were observed in the filtration step thereof. On the other hand, said dihydrochloride presented drying problems, not important on a laboratory scale but on an industrial scale, since said dihydrochloride comprises significant amounts of solvent that is very difficult to remove at said scale.
Debido a las dificultades existentes en la técnica anterior para llevar a cabo la obtención a escala industrial del diclorhidrato de dicho compuesto de fórmula (I) , se han realizado numerosos ensayos para conseguir un buen procedimiento de cristalización de la base que superara los anteriores inconvenientes encontrándose sorprendentemente que dicha base cristaliza en dos formas polimórficas cristalinas distintas (I y II) del compuesto de fórmula (I) que presentan aplicación como antipsicóticos y que sustituyen al diclorhidrato del compuesto de fórmula (I) .Due to the difficulties existing in the prior art to carry out the industrial scale production of the dihydrochloride of said compound of formula (I), numerous tests have been carried out to achieve a good crystallization process of the base that will overcome the above-mentioned problems. Surprisingly, said base crystallizes in two different crystalline polymorphic forms (I and II) of the compound of formula (I) which have application as antipsychotics and which replace the dihydrochloride of the compound of formula (I).
Por tanto, el objetivo de la presente invención es resolver los inconvenientes de la técnica anterior, proporcionando el compuesto de fórmula (I) en forma de base, el cual se ha obtenido en dos formas polimórficas distintas, procedimientos para su obtención y composiciones que los contienen.Therefore, the objective of the present invention is to solve the drawbacks of the prior art, by providing the compound of formula (I) as a base, which has been obtained in two different polymorphic forms, methods for obtaining it and compositions that they contain.
DESCRIPCIÓN DE LA INVENCIÓNDESCRIPTION OF THE INVENTION
La presente invención proporciona el compuesto de fórmula (I) en forma de base cristalizado en dos nuevas formas polimórficas, denominadas polimorfo I y polimorfo II, claramente diferenciadas en base a sus espectros de IR, RMN-C13 en estado sólido y rayos X, con aplicación como antipsicóticos .The present invention provides the compound of formula (I) in the form of a crystallized base in two new polymorphic forms, referred to as polymorph I and polymorph II, clearly differentiated based on their IR, solid state and C- 13 NMR spectra, With application as antipsychotics.
Otro objetivo de la presente invención es proporcionar un procedimiento de obtención del compuesto de fórmula (I) , en forma de base, como un sólido cristalino, que presenta la ventaja de ser fácil de filtrar y de secar.Another object of the present invention is to provide a process for obtaining the compound of formula (I), as a base, as a crystalline solid, which It has the advantage of being easy to filter and dry.
En los ensayos de optimización del procedimiento de cristalización del compuesto de fórmula (I), en forma de base, se han obtenido, aislado e identificado dichas nuevas formas polimórficas I y II.In the optimization tests of the crystallization process of the compound of formula (I), in base form, said new polymorphic forms I and II have been obtained, isolated and identified.
La invención proporciona un procedimiento de obtención del compuesto de fórmula (I) , en forma de base, como un producto cristalino que puede precipitarse para dar dos formas polimórficas distintas, obteniéndose una u otra según los parámetros utilizados en la cristalización.The invention provides a process for obtaining the compound of formula (I), in the form of a base, as a crystalline product that can be precipitated to give two different polymorphic forms, obtaining one or the other according to the parameters used in the crystallization.
Asi, el enfriamiento hasta temperatura ambiente de una disolución saturada de la 3-{2- [4- (6-fluoro- benzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2- metil-6, 7, 8, 9-tetrahidropirido [1, 2-a]pirimidin-4-ona en forma de base, preparándose dicha disolución por calefacción a reflujo, en disolventes como el acetonitrilo; alcoholes como el metanol, etanol, isopropanol o semejantes; cetonas como la propanona; esteres como el acetato de etilo; éteres como el tetrahidrofurano, dioxano; o derivados halogenados como el cloruro de metileno, cloroformo o semejantes, conduce a la cristalización del compuesto de fórmula (I) en forma del polimorfo I.Thus, cooling to room temperature of a saturated solution of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl ] -ethyl} -2-methyl-6, 7, 8, 9-tetrahydropylido [1,2-a] pyrimidin-4-one as a base, said solution being prepared by heating under reflux, in solvents such as acetonitrile; alcohols such as methanol, ethanol, isopropanol or the like; ketones such as propanone; esters such as ethyl acetate; ethers such as tetrahydrofuran, dioxane; or halogenated derivatives such as methylene chloride, chloroform or the like, leads to the crystallization of the compound of formula (I) in the form of polymorph I.
La cristalización del compuesto de fórmula (I) en forma de base para obtener el polimorfo I también puede llevarse a cabo mediante evaporación, a presión y temperatura ambiente, de dicha disolución saturada descrita más arriba.The crystallization of the compound of formula (I) as a base to obtain polymorph I can also be carried out by evaporation, at room temperature and pressure, of said saturated solution described above.
Por otro lado, la eliminación total del disolvente, a presión reducida, de una disolución saturada de la 3-{2-[4- (6-fluoro-benzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l- il]-etil}-2-metil-6, 7, 8, 9-tetrahidropirido [1, 2-a]pirimidin- 4-ona en forma de base, en disolventes como el acetonitrilo; alcoholes como el etanol, isopropanol o semejantes; cetonas como la propanona; esteres como el acetato de etilo; éteres como el tetrahidrofurano, dioxano; o derivados halogenados como el cloruro de metileno, cloroformo o semejantes, conduce a la cristalización del compuesto de fórmula (I) en forma del polimorfo II, de forma cuantitativa o mayoritaria, con excepción del caso en que sea metanol el disolvente que se evapore en cuyo caso se obtendrá el polimorfo I .On the other hand, the total removal of the solvent, under reduced pressure, from a saturated solution of 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3-yl) -3,6-dihydro- 2H-pyridin-l-yl] -ethyl} -2-methyl-6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4-one as a base, in solvents such as acetonitrile; alcohols such as ethanol, isopropanol or the like; ketones such as propanone; esters such as ethyl acetate; ethers such as tetrahydrofuran, dioxane; or halogenated derivatives such as methylene chloride, chloroform or the like, leads to the crystallization of the compound of formula (I) in the form of Polymorph II, quantitatively or in a majority manner, with the exception of the case in which methanol is the solvent that evaporates in which case polymorph I will be obtained.
La cristalización del compuesto de fórmula (I) en forma de base para obtener el polimorfo II también puede llevarse a cabo mediante la adición, a presión y temperatura ambiente, de agua o un exceso de un disolvente apolar, como por ejemplo el hexano, a una disolución saturada de la 3-{2-Crystallization of the compound of formula (I) as a base to obtain polymorph II can also be carried out by the addition, at room temperature and pressure, of water or an excess of a non-polar solvent, such as hexane, to a saturated solution of 3- {2-
[4- (6-fluoro-benzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l- il] -etil}-2-metil-6, 7, 8, 9-tetrahidropirido [1, 2-a]pirimidin-[4- (6-fluoro-benzo [d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2-methyl-6,7,8,9-tetrahydropyrid [1,2-a] pyrimidin-
4-ona en disolventes halogenados, como el cloroformo o el cloruro de metileno.4-one in halogenated solvents, such as chloroform or methylene chloride.
La cristalización de una disolución del compuesto de fórmula (I) en forma de base, a presión y temperatura ambiente, puede conducir a cualquiera de los dos polimorfos (I o II) , o a mezclas de los mismos, en función de cuál sea el disolvente de la disolución a la que se añade el agua o el hexano .Crystallization of a solution of the compound of formula (I) as a base, at room temperature and pressure, can lead to either of the two polymorphs (I or II), or mixtures thereof, depending on the solvent. of the solution to which water or hexane is added.
Cuando la cristalización se lleva a cabo a partir de disoluciones preparadas por calefacción a reflujo, la concentración de la base y/o la agitación empleada en el enfriamiento influyen en el tipo de polimorfo obtenido.When the crystallization is carried out from solutions prepared by reflux heating, the concentration of the base and / or the agitation used in the cooling influence the type of polymorph obtained.
Ambos polimorfos (I y II) no muestran diferencias en sus puntos de fusión ni en los termogramas de DSC como se muestra en las figuras 1 y 2.Both polymorphs (I and II) do not show differences in their melting points or DSC thermograms as shown in Figures 1 and 2.
Las diferencias más importantes que se observan entre ambos polimorfos se encuentran en:The most important differences observed between both polymorphs are found in:
Espectro de resonancia magnética nuclear de C13 en fase sólida en la zona comprendida entre 110 y 131 ppm. El polimorfo I presenta señales a 112,8, 117,3 y 127,8 ppmNuclear magnetic resonance 13 C solid phase in the zone between 110 and 131 ppm. Polymorph I has signals at 112.8, 117.3 and 127.8 ppm
(Figura 3) , mientras que el polimorfo II las presenta a(Figure 3), while Polymorph II presents them at
114,4, 117,5, 118,4 y 130,5 ppm (Figura 4).114.4, 117.5, 118.4 and 130.5 ppm (Figure 4).
Espectro de IR: el polimorfo I tiene una banda característica a 1647 cm"1 (Figura 5) mientras que el polimorfo II la tiene a 1657 cm"1' (Figura 6) . En la Figura 7 se muestra la superposición de los espectros de IR en la zona en que presentan diferencias.IR spectrum: Polymorph I has a characteristic band at 1647 cm "1 (Figure 5) while Polymorph II has it at 1657 cm " 1 '(Figure 6). Figure 7 shows the overlapping the IR spectra in the area where they present differences.
Espectro de difracción de Rayos X de polvo cristalino: el polimorfo I tiene picos característicos para valores 2 theta (2Θ) de 11,1°, 13,9°, 17,7°, 21,7°, 22,7°, 23,7°, 24,3° y 28,0° (Figura 8) ; el polimorfo II tiene picos característicos para valores de 2 theta (20) de 7,3°, 10,8°, 12,2°, 14,7°, 15,0°, 15,6°, 20,1°, 21,9°, 22,1°, 22,4°, 23,3°, 24,0°, 26,5° y 30,3°. (Figura 9) .X-ray diffraction spectrum of crystalline powder: Polymorph I has characteristic peaks for 2 theta (2Θ) values of 11.1 °, 13.9 °, 17.7 °, 21.7 °, 22.7 °, 23 , 7 °, 24.3 ° and 28.0 ° (Figure 8); Polymorph II has characteristic peaks for values of 2 theta (20) of 7.3 °, 10.8 °, 12.2 °, 14.7 °, 15.0 °, 15.6 °, 20.1 °, 21.9 °, 22.1 °, 22.4 °, 23.3 °, 24.0 °, 26.5 ° and 30.3 °. (Figure 9).
La presente invención también proporciona composiciones farmacéuticas que comprenden una cantidad terapéuticamente eficaz del polimorfo cristalino I o II, en combinación con un vehículo farmacéuticamente aceptable . Las composiciones farmacéuticas preferidas se presentan en forma de solución acuosa, como comprimidos y cápsulas, aunque también pueden prepararse otras formas como: composiciones rectales, de liberación retardada, de disolución rápida, u otras . Los polimorfos cristalinos I y/o II de la 3-{2-[4- ( 6-fluoro-benzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l- il] -etil}-2-metil-6, 7, 8, 9-tetrahidropirido [1, 2-a]pirimidin-4- ona, tal como se han descrito, pueden utilizarse para preparar un medicamento de aplicación como antipsicótico.The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of crystalline polymorph I or II, in combination with a pharmaceutically acceptable carrier. Preferred pharmaceutical compositions are in the form of an aqueous solution, such as tablets and capsules, although other forms such as: rectal, delayed-release, rapid-dissolving, or other compositions can also be prepared. Crystalline polymorphs I and / or II of 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl } -2-methyl-6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4- one, as described, can be used to prepare an application medicine as an antipsychotic.
BREVE DESCRIPCIÓN DE LAS FIGURASBRIEF DESCRIPTION OF THE FIGURES
Las figuras 1 y 2 muestran los puntos de fusión de los polimorfos I y II mediante termogramas de DSC. Las figuras 3 y 4 muestran el espectro de resonancia magnética nuclear de C13 en fase sólida para los polimorfos I y II respectivamente.Figures 1 and 2 show the melting points of polymorphs I and II by DSC thermograms. Figures 3 and 4 show the solid phase nuclear magnetic resonance spectrum of C 13 for polymorphs I and II respectively.
Las figuras 5 y 6 muestran el espectro de IR para los polimorfos I y II respectivamente. La Figura 7 muestra la superposición de los espectros de IR de ambos polimorfos en la zona en que presentan diferencias.Figures 5 and 6 show the IR spectrum for polymorphs I and II respectively. Figure 7 shows the superposition of the IR spectra of both polymorphs in the area where They have differences.
Las figuras 8 y 9 muestran el espectro de difracción de Rayos X de polvo cristalino para los polimorfos I y II respectivamente .Figures 8 and 9 show the X-ray diffraction spectrum of crystalline powder for polymorphs I and II respectively.
EJEMPLOSEXAMPLES
Para mayor comprensión de cuanto se ha expuesto se acompañan unos ejemplos en los que, esquemáticamente y tan sólo a titulo de ejemplo no limitativo, se representa un caso práctico de realización de la invención.For a better understanding of what has been stated, some examples are attached in which, schematically and only by way of non-limiting example, a practical case of realization of the invention is represented.
EJEMPLO 1EXAMPLE 1
Preparación de 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2-metil-6, 7, 8, 9- tetrahidropirido [1, 2-a]pirimidin-4-ona, polimorfo I.Preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2-methyl-6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4-one, polymorph I.
Se añaden 4,5 g (0,119 mol) de NaBH4 en porciones de 0,5 g sobre una suspensión de 31,5 g (0,059 mol) de yoduro de l-[2- (2-metil-4-oxo-6, 7, 8, 9-tetrahidro-4H-pirido [1, 2-a]pirimidin- 3-il) etil] -4- (6-fluorobenzo [d] isoxazol-3-il]piridinio en 189 mi de MeOH y 189 mi de H20, dejando que la temperatura suba hasta 45°C. Acabada la adición se agita lh más a 45°C, se enfria a 0°C y se filtra. Después de secar a 35°C se obtienen 18,0 g (75% rendimiento) del compuesto del titulo en forma de sólido blanco.4.5 g (0.119 mol) of NaBH 4 are added in 0.5 g portions on a suspension of 31.5 g (0.059 mol) of l- [2- (2-methyl-4-oxo-6 iodide) , 7, 8, 9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) ethyl] -4- (6-fluorobenzo [d] isoxazol-3-yl] pyridinium in 189 ml of MeOH and 189 ml of H 2 0, allowing the temperature to rise to 45 ° C. After the addition is stirred, it is further stirred at 45 ° C, cooled to 0 ° C and filtered. After drying at 35 ° C, 18 are obtained, 0 g (75% yield) of the title compound as a white solid.
EJEMPLO 2EXAMPLE 2
Preparación de 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2-metil-6, 7, 8,9- tetrahidropirido [1, 2-a]pirimidin-4-ona, polimorfo I.Preparation of 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2-methyl-6, 7,8,9-tetrahydropyrid [1,2-a] pyrimidin-4-one, polymorph I.
Se añaden gota a gota 263 mi de NaOH 1N sobre una suspensión de 67,5 g de 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-il) -3, 6- dihidro-2H-piridin-l-il] etil}-2-metil-6, 7, 8, 9-tetrahidropi- rido [1, 2-a]pirimidin-4-ona, diclorhidrato, en 340 mi de MeOH y 80 mi de H20, precalentada a 60°C. Acabada la adición se agita lh a 25°C y se filtra a -5°C, obteniéndose después de secar 50,8 g (95% rendimiento) del compuesto del titulo en forma de sólido blanco.263 ml of 1N NaOH are added dropwise on a suspension of 67.5 g of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -3, 6- dihydro-2H-pyridin -l-yl] ethyl} -2-methyl-6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4-one, dihydrochloride, in 340 ml of MeOH and 80 ml of H 2 0 , preheated to 60 ° C. Finished the addition is Stir lh at 25 ° C and filter at -5 ° C, obtaining after drying 50.8 g (95% yield) of the title compound as a white solid.
EJEMPLO 3EXAMPLE 3
Preparación de 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2-metil-6, 7, 8, 9- tetrahidropirido [1, 2-a]pirimidin-4-ona, polimorfo II.Preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2-methyl-6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4-one, polymorph II.
Se disuelven 10 g del producto del ejemplo 2 en 100 mi de CH2CI2, y la solución se vierte con buena agitación sobre 1L de heptano. Después de filtrar y secar se obtienen 9 g del compuesto del titulo en forma de sólido blanco.10 g of the product of Example 2 are dissolved in 100 ml of CH2CI2, and the solution is poured with good stirring over 1L of heptane. After filtering and drying, 9 g of the title compound are obtained as a white solid.
EJEMPLO 4EXAMPLE 4
Preparación de 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- il) -3, 6-dihidro-2H-piridin-l-il-etil}-2-metil-6, 7, 8, 9- tetrahidropirido [1, 2-a]pirimidin-4-ona, polimorfo II.Preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3- yl) -3,6-dihydro-2H-pyridin-l-yl-ethyl} -2-methyl-6, 7, 8 , 9-tetrahydropyrid [1,2-a] pyrimidin-4-one, polymorph II.
Se disuelven 10 g del producto del ejemplo 2 en 200 mi de 2- propanol a 80°C y luego se enfria a 20°C sin agitación en el transcurso de 2 horas. Después de filtrar y secar se obtienen 8,9 g del compuesto del título en forma de sólido blanco.10 g of the product of Example 2 are dissolved in 200 ml of 2-propanol at 80 ° C and then cooled to 20 ° C without stirring within 2 hours. After filtering and drying, 8.9 g of the title compound are obtained as a white solid.
EJEMPLO 5 Solución acuosaEXAMPLE 5 Aqueous solution
Producto del ejemplo 1 0,20%Product of example 1 0.20%
Acido tartárico 0,74%0.74% tartaric acid
Hidróxido sódico (c.s.p. pH 3 ± 1)Sodium hydroxide (c.s.p. pH 3 ± 1)
Agua c.s.p. 100%Water c.s.p. 100%
Disolver el ácido tartárico en aproximadamente el 80% del agua de la fórmula, disolver a continuación el producto del ejemplo 1 y ajustar el pH de la formulación con hidróxido sódico 1N. Dependiendo del uso de la solución se le pueden adicionar edulcorantes, colorantes, conservantes, aromatizantes, etc, o puede ser esterilizado si va destinada a ser administrada por vía parenteral .Dissolve the tartaric acid in approximately 80% of the water of the formula, then dissolve the product of the Example 1 and adjust the pH of the formulation with 1N sodium hydroxide. Depending on the use of the solution, sweeteners, colorants, preservatives, flavorings, etc. can be added or it can be sterilized if it is intended to be administered parenterally.
Se han ensayado diversos rangos de concentraciones del principio activo en la solución, que van desde un 0,0002% hasta un 0,4%, distintos sistemas amortiguadores del pH y pH comprendidos entre 2 y 6.Various ranges of concentrations of the active substance in the solution have been tested, ranging from 0.0002% to 0.4%, different pH and pH buffer systems between 2 and 6.
EJEMPLO 6 ComprimidosEXAMPLE 6 Tablets
Producto del Ejemplo 1 1,0% Almidón de maíz 20,0%Product of Example 1 1.0% Corn Starch 20.0%
Hidroxipropilmetilcelulosa 1,0%1.0% hydroxypropyl methylcellulose
Lauril sulfato sódico 0,2%0.2% sodium lauryl sulfate
Celulosa microcristalina 15,0%15.3% microcrystalline cellulose
Estearato de magnesio 0,6% lactosa monohidrato c.s.p. 100,0%0.6% magnesium stearate lactose monohydrate c.s.p. 100.0%
La elaboración de los comprimidos se realiza por un proceso de granulación por vía húmeda empleando como aglutinante una solución hidroxipropilmetilcelulosa .The preparation of the tablets is carried out by a wet granulation process using a hydroxypropylmethylcellulose solution as a binder.
EJEMPLO 7 CápsulasEXAMPLE 7 Capsules
Producto del Ejemplo 1 5% Almidón de maíz 40%Product of Example 1 5% Corn Starch 40%
Celulosa microcristalina 10%10% microcrystalline cellulose
Lauril sulfato sódico 0, 6%0.6% sodium lauryl sulfate
Estearato de magnesio 0,5%0.5% magnesium stearate
Lactosa minohidrato c.s.p. 100%Lactose minohydrate c.s.p. 100%
Se prepara un granulado por vía húmeda, empleando como agente aglutinante una solución de lauril sulfato sódico. El granulado así obtenido en cápsulas de gelatina dura de tamaño adecuado . A wet granulate is prepared, using as an agent binder a solution of sodium lauryl sulfate. The granulate thus obtained in hard gelatin capsules of adequate size.

Claims

R E I V I N D I C A C I O N E S
1. Polimorfo cristalino de la 3-{2- [4- (6-fluorobenzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2- metil-6, 7, 8, 9-tetrahidropirido [1, 2-a]pirimidin-4-ona, que se denomina polimorfo I y que se caracteriza por el modelo de difracción de rayos X de polvo, el espectro de resonancia magnética nuclear de C13 y el espectro de infrarrojo de las figuras 3, 5 y 8 respectivamente. 2. Polimorfo cristalino de la 3-{2- [4- (6-fluorobenzo [d] isoxazol-3-il) -3, 6-dihidro-2H-piridin-l-il] -etil}-2- metil-6, 7, 8, 9-tetrahidropirido [1, 1. Crystalline polymorph of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2- methyl- 6, 7, 8, 9-tetrahydropyrid [1,2-a] pyrimidin-4-one, which is called polymorph I and which is characterized by the powder X-ray diffraction model, the nuclear magnetic resonance spectrum of C 13 and the infrared spectrum of Figures 3, 5 and 8 respectively. 2. Crystalline polymorph of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-l-yl] -ethyl} -2- methyl- 6, 7, 8, 9-tetrahydropyrid [1,
2-a]pirimidin-4-ona que se denomina polimorfo II y que se caracteriza por el modelo de difracción de rayos X de polvo, el espectro de resonancia magnética nuclear de C13 y el espectro de infrarrojo de las figuras 4, 6 y 9 respectivamente.2-a] pyrimidin-4-one called polymorph II and characterized by the X-ray powder diffraction model, the nuclear magnetic resonance spectrum of C 13 and the infrared spectrum of Figures 4, 6 and 9 respectively.
3. Procedimiento para la obtención del polimorfo según la reivindicación 1 o reivindicación 2, caracterizado por el hecho de que se lleva a cabo: la cristalización de una disolución saturada de la 3-{2- [4- (6-fluoro-benzo [d] isoxazol-3-il) -3, 6-dihidro-2H- piridin-1-il] -etil}-2-metil-6, 7, 8, 9-tetrahidropirido [1, 2- a]pirimidin-4-ona en forma de base, en disolventes como el acetonitrilo; alcoholes como el metanol, etanol, isopropanol o semejantes; cetonas como la propanona; esteres como el acetato de etilo; éteres como el tetrahidrofurano, dioxano; o derivados halogenados como el cloruro de metileno, cloroformo o semejantes.3. Method for obtaining the polymorph according to claim 1 or claim 2, characterized in that it is carried out: the crystallization of a saturated solution of 3- {2- [4- (6-fluoro-benzo [ d] isoxazol-3-yl) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -2-methyl-6, 7, 8, 9-tetrahydropyrido [1, 2- a] pyrimidin-4 -one as a base, in solvents such as acetonitrile; alcohols such as methanol, ethanol, isopropanol or the like; ketones such as propanone; esters such as ethyl acetate; ethers such as tetrahydrofuran, dioxane; or halogenated derivatives such as methylene chloride, chloroform or the like.
4. Procedimiento según la reivindicación 3, caracterizado por el hecho de que dicha cristalización se lleva a cabo por enfriamiento de dicha disolución a temperatura ambiente para obtener el polimorfo I.4. Method according to claim 3, characterized in that said crystallization is carried out by cooling said solution to room temperature to obtain polymorph I.
5. Procedimiento según la reivindicación 3, caracterizado por el hecho de que dicha cristalización se lleva a cabo por evaporación de dicha disolución saturada o no a presión y temperatura ambiente para obtener el polimorfo I .5. Method according to claim 3, characterized in that said crystallization is carried out by evaporation of said saturated solution or not at room temperature and pressure to obtain the polymorph I.
6. Procedimiento según la reivindicación 3, caracterizado por el hecho de que dicha cristalización se lleva a cabo por evaporación de dicha disolución saturada o no, a presión reducida, para obtener el polimorfo II.Method according to claim 3, characterized in that said crystallization is carried out by evaporation of said saturated solution or not, under reduced pressure, to obtain polymorph II.
7. Procedimiento según la reivindicación 3, caracterizado por el hecho de que dicha cristalización se lleva a cabo por adición de agua o un exceso de un disolvente apolar, preferiblemente hexano, a dicha disolución, estando dicha disolución preparada con disolventes halogenados como cloroformo o cloruro de metileno para obtener el polimorfo II.Method according to claim 3, characterized in that said crystallization is carried out by adding water or an excess of a non-polar solvent, preferably hexane, to said solution, said solution being prepared with halogenated solvents such as chloroform or chloride of methylene to obtain polymorph II.
8. Composición farmacéutica que incluye una cantidad terapéuticamente eficaz del compuesto definido en la reivindicación 1 en combinación con un vehículo farmacéuticamente aceptable.8. Pharmaceutical composition that includes a therapeutically effective amount of the compound defined in claim 1 in combination with a pharmaceutically acceptable carrier.
9. Composición farmacéutica que incluye una cantidad terapéuticamente eficaz del compuesto definido en la reivindicación 2 en combinación con un vehículo farmacéuticamente aceptable.9. Pharmaceutical composition that includes a therapeutically effective amount of the compound defined in claim 2 in combination with a pharmaceutically acceptable carrier.
10. Utilización del polimorfo cristalino definido en la reivindicación 1 para preparar un medicamento de aplicación como antipsicótico .10. Use of the crystalline polymorph defined in claim 1 to prepare an application medicine as an antipsychotic.
11. Utilización del polimorfo cristalino definido en la reivindicación 2 para preparar un medicamento áe aplicación como antipsicótico. 11. Use of the crystalline polymorph defined in claim 2 to prepare a medicament for application as an antipsychotic.
PCT/ES1998/000227 1997-08-14 1998-08-06 Crystalline polymorphic forms of 3-{2-[4-6-fluorobenzo[d] isoxazol-3-yl) -3,6-dihydro-2h-pyridine-1-yl] -ethyl]-2-methyl-6,7, 8,9-tetrahydropyrido [1,2-a]pyrimidine-4-one and process for producing the forms WO1999009028A1 (en)

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AU85432/98A AU8543298A (en) 1997-08-14 1998-08-06 Crystalline polymorphic forms of 3-{2-{4-6-fluorobenzo{d} isoxazol-3-yl) -3,6-dihydro-2h-pyridine-1-yl} -ethyl}-2-methyl-6,7, 8,9-tetrahydropyrido {1,2-a}pyrimidine-4-one and process for producing the forms

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ES9701795A ES2138908B1 (en) 1997-08-14 1997-08-14 POLYMORPHES OF 3- (2- (4- (6-FLUOROBENZO (D) ISOXAZOL-3-IL) 3.6. DIHIDRO-2H-PIRIDIN-1-IL) -ETIL) -2-METHYL-6.7, 8,9-TETRAHIDROPIRIDO (1,2-A) PIRIMIDIN-4-ONA AND PROCEDURES FOR ITS OBTAINING.
ESP9701795 1997-08-14

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Publication number Priority date Publication date Assignee Title
EP0695751A1 (en) * 1994-02-24 1996-02-07 Vita-Invest, S.A. Agent acting on the central nervous system, process for its preparation and pharmaceutical compositions containing it

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0695751A1 (en) * 1994-02-24 1996-02-07 Vita-Invest, S.A. Agent acting on the central nervous system, process for its preparation and pharmaceutical compositions containing it

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