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WO2018007842A1 - Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique. - Google Patents

Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique. Download PDF

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Publication number
WO2018007842A1
WO2018007842A1 PCT/HU2017/050027 HU2017050027W WO2018007842A1 WO 2018007842 A1 WO2018007842 A1 WO 2018007842A1 HU 2017050027 W HU2017050027 W HU 2017050027W WO 2018007842 A1 WO2018007842 A1 WO 2018007842A1
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Prior art keywords
pimavanserin
salt
crystalline
ray powder
monohydrate
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PCT/HU2017/050027
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Inventor
Mária TÓTHNÉ LAURITZ
Balázs VOLK
Katalin KÁTAINÉ FADGYAS
Zoltán VARGA
Tamás Nagy
Ádám Dezső DIETRICH
Erika MOLNÁRNÉ SAMU
Adrienn Keszthelyi
Norbert RÁCZ
László SZLÁVIK
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Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Pimavanserin salts useful for the production of a pharmaceutical preparation are useful for the production of a pharmaceutical preparation
  • the object of the present invention relates to the formula 1 l-(4-fluorobenzyl)-l-(l- methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]carbamide (pimavanserin)
  • the object of the present invention relates to the formula 2 benzene sulphonic acid salt (besylate) of pimavanserin
  • l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide (pimavanserin) of formula 1 is a pharmaceutical active substance with a selective serotonin inverse agonist effect mechanism for the treatment of the psychosis associated with Parkinson's and Alzheimer's disease.
  • Patent application number WO 2006036874 discloses the production of the pimavanserin base, and of its citrate, fumarate ("form A” and "form B"), maleate, malate, phosphate, succinate, sulphate, and edisylate salts.
  • the salts are characterised by x-ray powder diffraction data.
  • Patent application number WO 2007133802 describes the production of the "Form A” and “Form C” crystalline forms of the pimavanserin base and its hemitartrate salt, and methods for their purification. It also discloses the advantageous characteristics of the pharmaceutical preparations containing pimavanserin.
  • Patent application number WO 2008144326 discloses the production of the pimavanserin base and of its hemitartrate salt. In addition to the amorphous form of the pimavanserin base, it discloses the production of its "Form Y" crystalline form, supplemented with the information that the "Form Y" crystalline base is thermodynamically stable. In addition to the amorphous form of the pimavanserin hemitartrate salt, it discloses the production of the "A”, “B”, “C”, “D”, “E” and “F” crystalline forms, with the additional information in paragraph 0077 that among the hemitartrate salts, "Form C" is the most stable.
  • the aim when creating the pimavanserin salts according to the invention was to produce a highly pure form of pimavanserin salt with homogenous crystal structure, the polymorphic, chemical stability, and physical-chemical properties of which are more preferable than the known forms and that may be reproducibly produced at industrial scales, and especially that are more stable, among the previously produced pimavanserin forms, than the Y crystalline form of the pimavanserin base, and that are more stable and have lower hygroscopicity than the pimavanserin hemitartrate salt crystalline "Form C", which proved to be the most stable.
  • the set objective may be achieved with the production of the pimavanserin besylate (1: 1) "Form I", the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I”, the pimavanserin tosylate (1: 1) monohydrate, the pimavanserin benzoate (1: 1) monohydrate, the pimavanserin D-(-)-mandelate (1: 1) "Form I” and the pimavanserin L-(+)-mandelate (1: 1) "Form I” salts.
  • the salts according to the invention are also suitable for purification by pimavanserin salt formation.
  • the object of the invention are the pimavanserin besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as their amorphous and crystalline forms, hydrates and solvates.
  • the pimavanserin salt according to the object of the invention is preferably
  • the object of the invention also relates to a method for the production of the pimavanserin besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as of their amorphous and crystalline forms, their hydrates and solvates, in such a way that the pimavanserin base is reacted with an inorganic or organic acid in water, or in an organic solvent or in a mixture of an organic solvent and water, then the pimavanserin salt formed is isolated.
  • the object of the invention also relates to a pharmaceutical preparation that contains a pimavanserin salt according to the above.
  • the object of the invention also relates to the use of a pimavanserin salt according to the above in the treatment or prevention of any of the following neurodegenerative diseases: Parkinson's disease, including the treatment of hallucinations and delusions associated with the psychosis occurring in Parkinson's disease, Huntington's disease, Alzheimer's disease, Spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, dystonia, progressive supranuclear palsy and frontotemporal dementia.
  • Parkinson's disease including the treatment of hallucinations and delusions associated with the psychosis occurring in Parkinson's disease, Huntington's disease, Alzheimer's disease, Spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia,
  • the pimavanserin besylate salt (1 : 1) "Form I”, the pimavanserin cyclamate salt (1 : 1) monohydrate, the pimavanserin tosylate salt (1 : 1) "Form I”, the pimavanserin tosylate salt (1: 1) monohydrate, the pimavanserin benzoate salt (1: 1) monohydrate, the pimavanserin D-(-)-mandelate salt (1: 1) "Form ⁇ ' and the pimavanserin L-(+)-mandelate salt (1: 1) "Form I” according to the object of the invention are polymorphic ally and chemically stable, and may be produced in a reproducible and upscalable way.
  • Diffusion inhibitor slit Fixed slit 1/2 °
  • Diffusion inhibitor slit Programmable slit in fixed mode:
  • Type PIXcel 3D 1 x 1 area detector
  • Step gap 0.0131° 2 ⁇
  • Step duration 109.650 seconds
  • thermoanalytical methods thermogravimentric analysis and DSC: differential scanning calorimetry.
  • TGA thermogravimentric analysis
  • DSC differential scanning calorimetry
  • the amounts of the volatile components emitted from the materials due to the effect of heat were determined, which, in the case of hydrates, may be associated with the crystalline water content of the form.
  • DSC may be suitable for the precise determination of the melting point of the substances (as long as the substances have a well defined melting point).
  • the thermoanalytical testing of the samples was performed under the following measurement conditions (the end temperatures associated with the measurements were determined by the thermal properties of the currently tested sample):
  • thermogravimetric analysis TGA
  • thermogravimetric analyser Atmosphere flowing N 2 : 25 mL/min (furnace)
  • the measurement conditions of the differential scanning calorimetry were the following:
  • Atmosphere flowing N 2 (50 mL/min)
  • the hygroscopicity was examined with a DVS device, by recording the water sorption isotherms, under the following measurement conditions:
  • Figure 1 The x-ray powder diffractogram of the pimavanserin besylate salt (1: 1) "Form I”
  • Figure 2 The water sorption isotherm of the pimavanserin besylate salt (1: 1) "Form I” at 25 °C
  • Figure 3 The x-ray powder diffractogram of the pimavanserin cyclamate salt (1: 1) monohydrate
  • Figure 4 The water sorption isotherm of the pimavanserin cyclamate salt (1: 1) monohydrate at 25 °C
  • Figure 5 The x-ray powder diffractogram of the pimavanserin tosylate salt (1: 1) "Form I”
  • Figure 6 The water sorption isotherm of the pimavanserin tosylate salt (1: 1) "Form I” at 25 °C
  • Figure 7 The x-ray powder diffractogram of the pimavanserin tosylate salt (1: 1) monohydrate
  • Figure 8 The water sorption isotherm of the pimavanserin tosylate salt (1: 1) monohydrate at 25 °C
  • Figure 9 The x-ray powder diffractogram of the pimavanserin benzoate salt (1: 1) monohydrate
  • Figure 10 The water sorption isotherm of the pimavanserin benzoate salt (1: 1) monohydrate at 25
  • Figure 11 The x-ray powder diffractogram of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I” (The x-ray powder diffractogram of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" is identical to this)
  • Figure 13 The water sorption isotherm of the pimavanserin tartrate salt (2: 1) "Form C” at 25 °C
  • Figure 14 Comparison of the water sorption isotherms of the pimavanserin besylate salt (1: 1) "Form I” and the pimavanserin tartrate salt (2: 1) "Form C” (25 °C)
  • Figure 17 Comparison of the water sorption isotherms of the pimavanserin tosylate salt (1: 1) monohydrate and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C): In the interest of better depicting hygroscopicity, the mass measured at 25% RH was viewed as the initial value.
  • Figure 19 Comparison of the water sorption isotherms of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I” and the pimavanserin tartrate salt (2: 1) "Form C” (25 °C) (The water sorption isotherm of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I” at 25 °C is identical to that of the D-(-)-mandelate salt.)
  • the equilibrium moisture content of the individual samples can be seen on the sorption curves in figures 2, 4, 6, 8, 10 and 12 to 19 as a function of relative humidity.
  • the object of the invention is the crystalline pimavanserin besylate salt (1: 1) "Form I", the characteristic x-ray powder diffractogram of which can be seen in figure 1, and the 1% or greater intensity signals are summarised in table 1.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin besylate salt (1: 1) "Form I” are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.06; 8.14; 13.78; 16.44; 18.19; 21.86; 26.58, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.06; 16.44; 18.19; 21.86. Table 1
  • the object of the invention is the crystalline pimavanserin cyclamate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 3, and the 1% or greater intensity signals are summarised in table 2.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin cyclamate salt (1: 1) monohydrate are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 3.95; 7.90; 13.82; 17.39; 18.73; 20.13; 20.85; 23.06; 25.82, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 3.95; 7.90; 17.39; 18.73; 20.85.
  • thermogravimetric (TG) testing of the pimavanserin cyclamate salt (1: 1) monohydrate a 2.8% mass loss was determined up to a temperature of 140 °C, which corresponds well to the theoretical drop in mass (2.9%) associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.
  • the object of the invention is the crystalline pimavanserin tosylate salt (1: 1) "Form I", the characteristic x-ray powder diffractogram of which can be seen in figure 5, and the 1% or greater intensity signals are summarised in the following table 3.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin tosylate salt (1:1) "Form I” are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.00; 8.02; 13.71; 16.43; 18.15; 21.76; 22.23; 25.84, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.00; 8.02; 16.43; 21.76.
  • the object of the invention is the crystalline pimavanserin tosylate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 7, and the 1% or greater intensity signals are summarised in table 4.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin tosylate salt (1: 1) monohydrate are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.25; 8.51; 13.39; 14.59; 16.58; 17.65; 20.42; 21.99; 24.24, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.25; 8.51; 16.58; 17.65; 21.99.
  • thermogravimetric (TG) testing of the pimavanserin tosylate salt (1: 1) monohydrate a 2.7% mass loss was determined up to a temperature of 120 °C, which corresponds well to the theoretical drop in mass (2.9%) associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.
  • the water sorption isotherm of the pimavanserin tosylate salt (1:1) monohydrate at 25 °C is shown in figure 8. It is clearly visible that the substance gives up its water of crystallization under dry conditions (under 10% RH), presumably completely (drop in mass is around 2.6%, which corresponds well to the value determined during TG testing). The substance is able to regain its crystal water as the ambient humidity content increases (in other words the process is reversible).
  • the salt form does not display hygroscopicity in the 15-95% RH range: the maximum surplus water sorption (as compared to the crystal water) is just around 0.2%.
  • the object of the invention is the crystalline pimavanserin benzoate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 9, and the 1% or greater intensity signals are summarised in table 5.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin benzoate salt (1: 1) monohydrate are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.23; 8.46; 10.46; 14.41; 16.44; 17.96; 18.51; 22.22; 26.15, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.23; 8.46; 10.46; 17.96; 22.22.
  • thermogravimetric (TG) testing of the pimavanserin benzoate salt (1: 1) monohydrate a 3.2% mass loss was determined up to a temperature of 120 °C, which corresponds to the theoretical drop in mass associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.
  • the object of the invention is the crystalline pimavanserin D-(-)-mandelate salt (1: 1) "Form I", and the pimavanserin L-(+)-mandelate salt (1: 1) "Form I”.
  • the x-ray powder diffractograms of the pimavanserin D-(-)- and L-(+)-mandelate salts (1: 1) "Form I" are identical, the x-ray powder diffraction peaks are equally characteristic of both forms.
  • the characteristic x-ray powder diffractograms of the crystalline pimavanserin D-(-)- and L-(+)-mandelate salts (1: 1) "Form I" can be seen in in figure 11, and the 1% or greater intensity signals are summarised in table 6.
  • the characteristic x-ray powder diffractogram peaks of the pimavanserin D-(-)- and L-(+)-mandelate salts (1:1) "Form I" are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 6.94; 7.75; 17.82; 18.99; 20.73; 24.96, and the even more characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 6.94; 7.75; 18.99. Table 6
  • the water sorption isotherm of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I” at 25 °C is shown in figure 12.
  • the water sorption isotherm of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I” at 25 °C is identical to this. It is clearly visible that the substance does not display hygroscopicity under 90% RH: maximum water sorption is 0.2%. However, above 90% RH it becomes strongly hygroscopic: water sorption at 95% RH is 21.2%, the substance deliquesces.
  • the pimavanserin cyclamate salt monohydrate visible in figure 15 gives up a part of its crystal water (-0.2%) under completely dry conditions, while the tosylate salt monohydrate shown in figure 17 is able to give up all of its crystal water (-2.6%), but in the 15-95% RH range these salt forms display a lower water sorption tendency than the originator's pimavanserin hemitartrate salt (2: 1) "Form C".
  • the lower hygroscopicity experienced is preferable from the points of view of stability and preparation formulation as well.
  • the forced stability test essentially provides a model of accelerated mode for the degradations taking place in the pharmaceutical preparation during storage. The results of this predict whether the novel pimavanserin salts according to the invention will be stable in pharmaceutical preparations.
  • This preferable characteristic of the pimavanserin salts of the present invention is very important from the point of view of the formulation of the pharmaceutical preparation, its storage and the minimising of the damaging effects on the human body.
  • the pimavanserin cyclamate salt (1: 1) monohydrate and the pimavanserin tosylate salt (1: 1) "Form I" were shown to be significantly more stable than the "Form C" crystalline form of the pimavanserin hemitartrate salt (2: 1) is, which, according to patent application number WO 2008144326, is the most stable of the polymorphs of the hemitartrate salt.
  • the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I" and the pimavanserin benzoate (1: 1) monohydrate salts displayed a lower degree of decomposition as compared to both reference compounds.
  • the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I” and the pimavanserin benzoate (1: 1) monohydrate salts proved to be significantly more stable than the "Form C" crystalline form of the pimavanserin hemitartrate (2: 1) salt, and proved to be slightly more stable than the "Form Y" pimavanserin base.
  • the object of the invention also relates to a pharmaceutical preparation containing a therapeutically effective amount of any of the pimavanserin salts according to the invention and, optionally, one or more excipients used in the production of medical preparations, furthermore, a method for the production of a pharmaceutical preparation, in such a way that any pimavanserin salt according to the invention or a mixture of these is mixed with an appropriate amount of pharmaceutically acceptable carrier, solid or liquid diluents and, optionally, other excipients, and the mixture is then placed in a galenic formulation.
  • novel salts of pimavanserin according to the present invention are produced by reacting the amorphous, or crystalline, anhydrous, hydrate or solvate form of the pimavanserin base with the desired organic or inorganic acid in water, or in a suitable organic solvent, or solvent mixture, then the salt formed is isolated.
  • the reaction may be performed in water, or organic solvents, such as in 1-6 carbon atom aliphatic alcohols, in 1-5 carbon atom straight chain or cyclic ethers, in 1-6 carbon atom esters, in open chain asymmetric or symmetric ketones, and in dipolar aprotic solvents, in addition mixtures of the listed solvents, and mixtures and blends of the listed solvents also containing water may be used.
  • organic solvents such as in 1-6 carbon atom aliphatic alcohols, in 1-5 carbon atom straight chain or cyclic ethers, in 1-6 carbon atom esters, in open chain asymmetric or symmetric ketones, and in dipolar aprotic solvents, in addition mixtures of the listed solvents, and mixtures and blends of the listed solvents also containing water may be used.
  • an open chain ketone or a dipolar aprotic solvent may be preferably used, diisopropyl ether, ethyl acetate, acetonitrile, methanol, 2-propanol or a mixture of these, and mixtures and blends of the listed solvents also containing water may be especially preferably used.
  • An amount of 0.9-2.0 mol equivalents, preferably an amount of 1.0-1.2 mol equivalents of the acid serving for forming the salt calculated for the amount of pimavanserin is used.
  • the process involves that the organic acid is used as a solution, suspension or in solid form, and the salt formation reaction is carried out at a temperature between 0 °C and the boiling point of the solvent or at the boiling point of the solvent.
  • Any method used in the pharmaceutical industry may be used for isolating the salt that serves for separating the solid phase and the liquid phase, for example, it may be filtered under atmospheric conditions, or by using vacuum filtering, or even under pressure, and a centrifuge may even be used. If the salt precipitates at the temperature of addition of the acid or when cooled, after the required crystallization time, the product is filtered, washed and dried. If the salt does not precipitate, the solvent is evaporated in a vacuum, and the residue material is crystallized by adding a suitable solvent or solvent mixture, then finally the crystalline material is filtered, washed and dried.
  • the new salts according to the invention may be recrystallized in order to achieve the appropriate pharmaceutical active substance quality.
  • the recrystallization is performed by dissolving the product obtained according to the above in a polar aprotic solvent, or in a mixture of a polar aprotic solvent and an alcohol with 1 to 6 carbon atoms, preferably the dissolving is performed in ethyl acetate, acetonitrile or in a mixture of acetonitrile and methanol at boiling point, then by cooling the solution the desired salt is precipitated, or it is crystalized by adding an ether-type solvent, preferably diisopropyl ether.
  • novel salts of pimavanserin according to the present invention are produced by dissolving or suspending the pimavanserin base in a polar aprotic, straight carbon chain alcohol, nitrile or ester- type solvent, preferably in acetonitrile, 2-propanol or ethyl acetate at a temperature between 0 °C and the boiling point of the solvent, preferably at 20 to 50 °C, then 0.9-1.5 mol equivalents, preferably 1.0-1.2 mol equivalents, most preferably 1.0 mol equivalent of inorganic or organic acid calculated for the amount of pimavanserin base is added on its own or in the form of a solution or suspension,
  • the product is filtered, washed and dried. If the salt does not precipitate, the solvent is evaporated in a vacuum, and the residue material is crystallized by adding a suitable solvent or solvent mixture, then finally the crystalline material is filtered, washed and dried at an appropriate temperature.
  • pimavanserin salts according to the invention are high-purity substances with a homogenous morphology, a homogenous and preferable crystalline structure and have preferable and reproducible characteristics from the point of view of dissolution rate, bioavailability and processing - filtering, drying and tableting.
  • a further advantage of the pimavanserin salts according to the invention is that their polymorphic and chemical stability, and their physical-chemical characteristics are more preferable than those of the known forms, furthermore their production is reproducible and they may be produced on the industrial scale.
  • the pimavanserin salts according to the invention are especially preferable from the point of view of that they are more stable under the majority of conditions than the Y crystalline form of the pimavanserin base of the previously produced pimavanserin forms and the most stable "Form C" crystalline form of the pimavanserin hemitartrate (2: 1) salt.
  • the pimavanserin salts according to the invention are also especially preferable from the point of view of that they are less hygroscopic than the a pimavanserin hemitartrate salt (2: 1) "Form C" form in the humidity range of 15-85% RH relevant from the point of view of the pharmaceutical industry environment (crystallization, grinding, formulation, storage).
  • Example 1 The invention is illustrated through the following examples without limiting the invention to these examples.
  • Example 1 The invention is illustrated through the following examples without limiting the invention to these examples.
  • the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried for 4 hours in a drying cabinet at 40-42 °C and at a pressure of 15-20 mbar. In this way 13.46 g (98.2%) of a white solid product is obtained.
  • 10 g of the raw product besylate salt is dissolved in 180 ml of acetonitrile at boiling point, then the solution is filtered and left to cool to room temperature, and then stirred for 2 hours and then cooled to 10-12 °C.
  • the precipitated solid material is filtered, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 9.16 g of a white solid product is obtained.
  • the product is monohydrate.
  • the reaction mixture is stirred for 1 hour at 40-42 °C, then it is left to cool to room temperature and then stirred for 4 hours, then cooled to 10-12 °C.
  • the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried for 4 hours in a drying cabinet at 40-42 °C and at a pressure of 15-20 mbar. In this way 13.74 g (97.9%) of a white solid product is obtained.
  • the reaction mixture is evaporated to 40 ml and 60 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C.
  • the precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 9.6 g (72.3%) of a white solid product is obtained.
  • the product is monohydrate.
  • the reaction mixture is stirred for 1 hour at 40-42 °C, then is left to cool to room temperature.
  • the reaction mixture is evaporated to 40 ml and 10 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C.
  • the precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 8.81 g (65.0%) of a white solid product is obtained. Mp.: 112 °C (onset).
  • the reaction mixture is evaporated to 40 ml and 10 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C.
  • the precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 8.81 g (65.0%) of a white solid product is obtained. Mp.: 112 °C (onset).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'objet de la présente invention porte sur la formule (1) 1- (4-fluorobenzyl)-1-(1-méthylpipéridin-4-yl)-3-[4- (2-méthylpropoxy) benzyl] carbamide (pimavansérine) le bésylate, le cyclamate, le tosylate, le benzoate et les sels de mandelate, ainsi que sur leurs formes amorphes et cristallines, leurs hydrates et leurs solvates, sur la production de ces sels, sur des préparations pharmaceutiques les contenant, ainsi que sur leur utilisation thérapeutique.
PCT/HU2017/050027 2016-07-08 2017-07-07 Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique. Ceased WO2018007842A1 (fr)

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HU1600415A HU231097B1 (hu) 2016-07-08 2016-07-08 Gyógyászati készítmény előállítására alkalmazható pimavanserin sók
HUP1600415 2016-07-08

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WO2018007842A1 true WO2018007842A1 (fr) 2018-01-11

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PCT/HU2017/050027 Ceased WO2018007842A1 (fr) 2016-07-08 2017-07-07 Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique.

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HU (1) HU231097B1 (fr)
WO (1) WO2018007842A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022199707A1 (fr) * 2021-03-26 2022-09-29 上海博志研新药物技术有限公司 Sel pharmaceutiquement acceptable de pimavansérine, procédé de préparation associé, composition pharmaceutique la contenant et utilisation associée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006036874A1 (fr) * 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation
WO2008144326A2 (fr) * 2007-05-15 2008-11-27 Acadia Pharmaceuticals Inc. Synthèse de n-(4-fluorobenzyl)-n-(l-méthylpypéridine-4-yl)-n'-(4-2-méthylpropyloxy)phénylméthyl)carbamide et son sel de tartrate et des formes cristallines
WO2017054786A1 (fr) * 2015-10-02 2017-04-06 Zentiva, K. S. Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006036874A1 (fr) * 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation
WO2006037043A1 (fr) * 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Synthese de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, tartrate de ce compose et ses formes cristallines
WO2008144326A2 (fr) * 2007-05-15 2008-11-27 Acadia Pharmaceuticals Inc. Synthèse de n-(4-fluorobenzyl)-n-(l-méthylpypéridine-4-yl)-n'-(4-2-méthylpropyloxy)phénylméthyl)carbamide et son sel de tartrate et des formes cristallines
WO2017054786A1 (fr) * 2015-10-02 2017-04-06 Zentiva, K. S. Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022199707A1 (fr) * 2021-03-26 2022-09-29 上海博志研新药物技术有限公司 Sel pharmaceutiquement acceptable de pimavansérine, procédé de préparation associé, composition pharmaceutique la contenant et utilisation associée
CN115124456A (zh) * 2021-03-26 2022-09-30 上海博志研新药物技术有限公司 哌马色林药用盐、制备方法、含其的药物组合物及应用
CN115124456B (zh) * 2021-03-26 2024-05-10 上海云晟研新生物科技有限公司 哌马色林药用盐、制备方法、含其的药物组合物及应用

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HUP1600415A2 (en) 2018-01-29

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