WO2012177708A1 - Oléate de palipéridone - Google Patents

Oléate de palipéridone Download PDF

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Publication number
WO2012177708A1
WO2012177708A1 PCT/US2012/043267 US2012043267W WO2012177708A1 WO 2012177708 A1 WO2012177708 A1 WO 2012177708A1 US 2012043267 W US2012043267 W US 2012043267W WO 2012177708 A1 WO2012177708 A1 WO 2012177708A1
Authority
WO
WIPO (PCT)
Prior art keywords
paliperidone
oleate
solid state
palmitate
paiiperidone
Prior art date
Application number
PCT/US2012/043267
Other languages
English (en)
Inventor
Wolfgang Albrecht
Ludovic Coutable
Original Assignee
Ratiopharm Gmbh
Teva Pharmaceuticals Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ratiopharm Gmbh, Teva Pharmaceuticals Usa, Inc. filed Critical Ratiopharm Gmbh
Publication of WO2012177708A1 publication Critical patent/WO2012177708A1/fr

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Classifications

    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention is directed to Paliperidone oleate, solid state forms thereof, and methods of preparation thereof.
  • Paliperidone is a metabolite of Risperidone. It is marketed under the trade name, Invega®. Paliperidone is an anti-psychotropic agent approved in the United States for the treatment of schizophrenia.
  • Patent No. 5,158,952 (“US '952”) and PCT application No. WO 96/23784 (“WO '784"). US '952 and WO '784 also describe a process for the synthesis of a precursor of Paliperidone, (3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2- a]- pyrimidine-4-one).
  • the present invention provides paliperidone oleate, a solid state form thereof, and processes for preparing paliperidone oleate and a solid state form of paliperidone oleate.
  • the invention further provides pharmaceutical compositions comprising the below described paliperidone oleate.
  • This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient.
  • the invention further provides the use of the paliperidone oleate described below for the manufacture of a medicament for the treatment of schizophrenia.
  • Figure 1 shows a DSC thermogram of Paliperidone oleate, as obtained in Example 2.
  • Figure 2 shows a DSC thermogram of Paliperidone oleate, as obtained in Example 3.
  • Figure 3 shows an XRD diffractogram of Paliperidone oleate, as obtained in Example 2.
  • Figure 4 shows an XRD diffractogram of Paliperidone oleate, as obtained in Example 3.
  • Figure 5 shows a 1H NMR spectrum of Paliperidone oleate.
  • a solid state form may be referred to herein as being characterized by graphical data "as shown in" a Figure.
  • Such data include, for example, powder X-ray diffractograms (XRD) and solid state nuclear magnetic resonance (NMR) spectra.
  • XRD powder X-ray diffractograms
  • NMR solid state nuclear magnetic resonance
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which factors are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirming whether the two sets of graphical data characterize the same solid state form or two different solid state forms.
  • the present invention provides paliperidone oleate, as shown in the following formula:
  • the paliperidone oleate of the present invention can be in a solid state form.
  • the paliperidone oleate and the solid state form of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • the present invention also provides a crystalline form of
  • Paliperidone oleate designated Form A.
  • Form A can be characterized by data selected from: a powder XRD pattern with peaks at 4.8°, 7.2°, 19. F, 19.4°, 20. F, 20.8°, and 24.0° ⁇ 0.2° 2 ⁇ ; a powder XRD pattern as shown in figures 2.1 or 2.2; and combinations thereof.
  • Form A may have a melting point of between about 84 and 88°C.
  • the mp of the oleate is substantially lower than that of the palmitate and if the particle size of both esters is reduced to ⁇ 1 ⁇ , the trend of particle agglomeration is much more pronounced for the oleate compared to the palmitate.
  • the above described Paliperidone oleate and the crystalline form can be used to prepare Paliperidone or Paliperidone palmitate, for example by hydrolyzing the oleate group, for example by reacting Paliperidone oleate with an aqueous solution, for example, an aqueous solution of acid.
  • the present invention provides a process for preparing Paliperidone
  • Paliperidone palmitate comprising preparing the above describes Paliperidone
  • the present invention further encompasses 1) a pharmaceutical
  • composition comprising Paliperidone oleate, as described above, and at least one
  • Paliperidone oleate in the manufacture of a pharmaceutical composition.
  • composition can be useful for the treatment of schizophrenia.
  • Aluminum crucible 40 ⁇ .
  • the sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker-AXS, Düsseldorf, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during the measurement. Further conditions for the measurements are summarized below. The raw data were analyzed with the program EVA (Bruker-AXS, Germany).
  • Crystalline paliperidone oleate was prepared and characterized by means of HPLC/UV, 1 H-NMR spectroscopy, differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD).
  • the crystal form is characterized by a m.p. of from 84 to 88°C (peak in DSC) and by the following characteristic X-ray powder diffraction (XRPD) angles (°2 ⁇ ): 4.85, 7.28, 19.11, 19.45, 20.12, 20.85 and 23.95 ( ⁇ 0.2).
  • Paliperidone 50 g, 117.2 mmol was dissolved in 500 ml tetrahydrofuran and 20 ml pyridine. While the solution was heated to reflux, 83.01 g (234.5 mmol, 2 eq.) were added dropwise and the mixture was refluxed for 20 h. The mixture was allowed to cool to r.t. followed by addition of 400 ml water and 100 ml brine. The aqueous phase was removed and the organic phase was washed with (3 X 700 ml). The organic layer was then dried over MgS0 4 and the solvent was evaporated to provide a residue.
  • Oleic acid (4.2 g, 14.87 mmol) and N,N'-dicyclohexylcarbodiimide (3 g, 14.5 mmol) were dissolved in 230 ml dichloromethane and the solution was stirred at r.t. After 10 minutes, 5 g paliperidone (11.7 mmol) and 180 mg N,N-dimethylamino- pyridine was added, and the mixture was stirred at r.t. for 24 h. The mixture was then washed sequentially with 100 ml water, with a solution of 30 ml saturated NaHCC"3 in 70 ml of water. The combined aqueous phase was extracted with dichloromethane (2 x 50 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un oléate palipéridone, une forme de celui-ci à l'état solide, des compositions pharmaceutiques comprenant l'oléate de palipéridone, l'utilisation de l'oléate de palipéridone pour traiter la schizophrénie, des procédés de préparation de l'oléate de palipéridone et une forme d'oléate de palipéridone à l'état solide.
PCT/US2012/043267 2011-06-20 2012-06-20 Oléate de palipéridone WO2012177708A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161498818P 2011-06-20 2011-06-20
US61/498,818 2011-06-20

Publications (1)

Publication Number Publication Date
WO2012177708A1 true WO2012177708A1 (fr) 2012-12-27

Family

ID=46458611

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/043267 WO2012177708A1 (fr) 2011-06-20 2012-06-20 Oléate de palipéridone

Country Status (1)

Country Link
WO (1) WO2012177708A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5158952A (en) 1988-11-07 1992-10-27 Janssen Pharmaceutica N.V. 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
WO1996023784A1 (fr) 1995-01-31 1996-08-08 Janssen Pharmaceutica N.V. Derives neuroleptiques de piperidine a substitution 4-(1h-indolyl-1-yl)-1
WO2009089076A2 (fr) * 2008-01-10 2009-07-16 Teva Pharmaceutical Industries Ltd. Procédés de préparation et de purification de palmitate de palipéridone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5158952A (en) 1988-11-07 1992-10-27 Janssen Pharmaceutica N.V. 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
WO1996023784A1 (fr) 1995-01-31 1996-08-08 Janssen Pharmaceutica N.V. Derives neuroleptiques de piperidine a substitution 4-(1h-indolyl-1-yl)-1
WO2009089076A2 (fr) * 2008-01-10 2009-07-16 Teva Pharmaceutical Industries Ltd. Procédés de préparation et de purification de palmitate de palipéridone

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