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WO2015085973A1 - Modifications de sel de chlorhydrate de 3-(2-imidazo[1,2-b]pyridazine-3-yléthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl] benzamide - Google Patents

Modifications de sel de chlorhydrate de 3-(2-imidazo[1,2-b]pyridazine-3-yléthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl] benzamide Download PDF

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Publication number
WO2015085973A1
WO2015085973A1 PCT/CZ2013/000164 CZ2013000164W WO2015085973A1 WO 2015085973 A1 WO2015085973 A1 WO 2015085973A1 CZ 2013000164 W CZ2013000164 W CZ 2013000164W WO 2015085973 A1 WO2015085973 A1 WO 2015085973A1
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Prior art keywords
methyl
ponatinib hydrochloride
crystal modification
ponatinib
room temperature
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Inventor
Violetta Kiss
Eszter TIEGER
Ludek Ridvan
Marcela Tkadlecova
Ondrej Dammer
Lukas KREJCIK
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Zentiva KS
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Zentiva KS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel modifications of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt of Formula I
  • ponatinib (trifluoromethyl)phenyl] benzamide compound which is also known as ponatinib (CAS no.: 943319- 70-8) has a tyrosine kinase inhibitor activity which is effectively used for the treatment of chronic myeloid leukaemia (CML) as well as Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL).
  • CML chronic myeloid leukaemia
  • Ph+ Philadelphia chromosome positive acute lymphoblastic leukaemia
  • tyrosine kinase is a subclass of protein kinase and it plays an important role in the phosphate group transfer in form adenosine triphosphate (ATP) to a protein in the cell.
  • ATP adenosine triphosphate
  • the phosphate group is attached to the appropriate amino acid, tyrosine on the protein.
  • Tyrosine kinases act as an "on” and “off' switch, however, can easily undergo mutation by sticking in the "on” position resulting in uncontrolled growth of the cell that leads to the development of cancer. Consequently, tyrosine kinase inhibitors are often used as effective agents for cancer treatments.
  • WO2007075869 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases.
  • One example of the compounds disclosed is 3-(2-imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide; preparation of the base and the hydrochloride salt thereof are described.
  • the object of the present invention is to provide novel modifications of 3-(2-imidazo[l,2-b]pyridazin- 3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt suitable for oral administration which meet the pharmaceutical requirements.
  • the present invention further relates to a pharmaceutical formulations containing the modifications of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt and the use thereof for the treatment of cancer.
  • Crystal modification 1 Crystal modification 2, Crystal modification 3, Crystal modification 4, Crystal modification 5, Crystal modification 6, Crystal modification 7, Crystal modification 8, Crystal modification 9, Crystal modification 10 and amorphous phase
  • Crystal modification 1 Crystal modification 2, Crystal modification 3, Crystal modification 4, Crystal modification 5 and the amorphous phase
  • Crystal modification 2 Crystal modification 3, Crystal modification 4, Crystal modification 5 and the amorphous phase were identified furthermore by solid state NMR spectra and differ in their Differential Scanning Calorimetry and Thermal Gravimetric Analysis curves, too.
  • Figure 1 is an XRPD pattern of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 2 is a FTIR spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 3 is a Raman spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 4 is a ssNMR spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 5 is a DSC curve of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 6 is a TGA curve of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 7 is an XRPD pattern of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 8 is a FTIR spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 9 is a Raman spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 10 is a ssN R spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 11 is a DSC curve of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 12 is a TGA curve of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 13 is an XRPD pattern of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 14 is a FTIR spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 15 is a Raman spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 16 is a ssNMR spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 17 is a DSC curve of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 18 is a TGA curve of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 19 is an XRPD pattern of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 20 is a FTIR spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 21 is a Raman spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 22 is a ssNMR spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 23 is a DSC curve of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 24 is a TGA curve of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 25 is an XRPD pattern of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 26 is a FTIR spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 27 is a Raman spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 28 is a ssNMR spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 29 is a DSC curve of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 30 is a TGA curve of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 31 is an XRPD pattern of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 32 is a FTIR spectra of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 33 is a Raman spectra of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 34 is an XRPD pattern of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 35 is a FTIR spectra of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 36 is a Raman spectra of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 37 is an XRPD pattern of the Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 38 is a Raman spectra of the Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 39 is an XRPD pattern of the Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 40 is a Raman spectra of the Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 41 is an XRPD pattern of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 42 is a FTIR spectra of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 43 is a Raman spectra of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 44 is an XRPD pattern of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 45 is a FTIR spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 46 is a Raman spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 47 is a ssN R spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 48 is a DSC curve of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;
  • Figure 49 is a TGA curve of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt.
  • the aim of the present invention is to provide novel modifications of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride (ponatinib hydrochloride) of formula I with advantegous properties for pharmaceutical use regarding the physico-chemical properties and can be produced in a reproducible manner even in industrial scale.
  • Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was prepared and indentified when the process of the patent application WO2007/075869 was reproduced.
  • This crystalline modification has the characteristic XRPD pattern as shown in Figure 1.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:
  • Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 3 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2924, 2219, 1671, 1620, 1397, 1190, 1153, 1103, 903 and 468 cm "1 wavenumbers
  • Figure 4 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA).
  • Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC)
  • Figure 6 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively.
  • Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt shows a 0.9% weigth loss in the range of 20°C-to 100°C.
  • an alternative process for preparation of the crystalline modification 1 is provided.
  • ponatinib hydrochloride is suspended in a suitable organic solvent by heating of the system to a temperature close to the boiling point of the solvent. The suspension is then stirred at this temperature for 10-15 minutes, then cooled back to room temperature and left for stirring overnight. After filtering off and drying at laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of ponatinib hydrochloride.
  • the suitable organic solvent is a solvent selected form the group of acetone, acetonitrile, butyl acetate, 2-butanone, cyclohexane, diethyl ether, toluene, xylene, dioxane, ethyl acetate, 4-methyl-2- pentanone, n-hexane and tetrahydrofurane.
  • the process of preparation of the Crystal modification 1 of ponatinib hydrochloride thus comprises the steps of: a/ suspending ponatinib hydrochloride in a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, cyclohexane, diethyl ether, toluene, xylene, dioxane, ethyl acetate, 4-methyl-2-pentanone, n-hexane and tetrahydrofurane by heating close to the boiling point of the respective solvent:
  • Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 7. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical). The Crystal modification 2 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-
  • Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 9 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2967, 2214, 1655, 1617, 1524, 1155, 999, 912, 839 and 459 cm 1 wavenumbers
  • Figure 10 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods.
  • Figure 11 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 12 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 350°C and 20°C to 300°C, respectively.
  • the crystalline Modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-t(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate that shows a 11.1% weigth loss in the range of 20°C-to 230°C. The rresponding to water loss),
  • Crystal modification 2 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • a/ dissolving ponatinib hydrochloride in a solvent selected form the group consisting of 75 v/v % ethanol-water mixture; water; and water-dioxane in 1:1 ratio by volume at room temperature; b/ evaporating the solvent at laboratory conditions.
  • Another process of preparation of the Crystal modification 2 of ponatinib hydrochloride comprises the steps of:
  • Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 13. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 3 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride exhibits the following diffraction peaks in XRPD pattern, see Table 4, below:
  • Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 15 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3045, 2958, 2216, 1654, 1619, 1156, 1024, 1000, 888 and 471 cm-1 wavenumbers
  • Figure 16 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-t4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods.
  • Figure 17 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 18 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 350°C and 20°C to 300°C, respectively.
  • the crystalline Modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate and shows a 9.0% weigth loss in the range of 20°C-to 150°C.
  • the DSC measurement gives a melting process with and
  • Crystal modification 3 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • the solution resulting from the step a/ can be optionally filtered in order to remove the possible undissolved solids prior to the cooling step b/.
  • Another process of preparation of the Crystal modification 3 of ponatinib hydrochloride comprises the steps of:
  • Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 19.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • Crystal modification 4 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 5, below: Pos. [ e 2Th.] d-spacing [A] el. Int. [%]
  • Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 21 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2969, 2220, 1659, 1162, 1071, 1005, 910, 738, 555 and 463 cm "1 wavenumbers
  • Figure 22 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods.
  • Figure 23 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 24 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively.
  • Crystal modification 4 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 25. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO PD PANalytical).
  • Crystal modification 5 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 6, below:
  • Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 27 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2959, 2216, 1660, 1617, 1421, 1233, 1162, 1003, 903 and 460 cm 1 wavenumbers
  • Figure 28 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods.
  • Figure 29 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 30 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively.
  • Crystal modification 5 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 31. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical). The Crystal modification 6 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-
  • Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy.
  • Figure 33 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3067, 2960, 2214, 1672, 1313, 1269, 1053, 911, 765 and 436 cm "1 wavenumbers.
  • Crystal modification 6 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • the Crystal modification 6 of ponatinib hydrochloride is prepared by a process comprising the steps of:
  • Crystal modification 6 of ponatinib hydrochloride is prepared by a process comprising the steps of:
  • Another process of preparation of the Crystal modification 6 of ponatinib hydrochloride comprises the steps of:
  • Crystal modification 7 of S-f -imidazofl ⁇ -bJpyridazin-B-ylethyny ⁇ -methyl-N-f -ff ⁇ methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic X PD pattern as shown in Figure 34.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • Crystal modification 7 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 8, below:
  • Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy.
  • Figure 36 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3008, 2958, 2208, 1665, 1360, 1258, 1069, 1001, 771 and 460 cm "1 wavenumbers.
  • Crystal modification 7 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 37. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the XRPD pattern of Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt corresponds to a semi- crystalline form and exhibits the following diffraction peaks in XRPD pattern, see Table 9, below:
  • Crystal modification 8 of 3-(2-imidazofl,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy.
  • Figure 38 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 3962, 2215, 1656, 1310, 1263, 1067, 996, 762 and 456 cm "1 wavenumbers.
  • Crystal modification 8 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 39.
  • XRPD pattern was recorded on an X- ay Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • the XRPD pattern of Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt corresponds to a semi- crystalline form and exhibits the following diffraction peaks in XRPD pattern, see Table 10, below:
  • Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy.
  • Figure 40 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3068, 2929, 2217, 1671, 1607, 1539, 1398, 1308, 1154 and 776 cm 1 wavenumbers.
  • Crystal modification 9 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 41.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • Crystal modification 10 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 11, below:
  • Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy.
  • Figure 43 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3965, 3922, 2217, 1659, 1606, 1478, 1359, 1313, 761 and 463 cm "1 wavenumbers.
  • Crystal modification 10 of ponatinib hydrochloride can be prepared by a process comprising the steps of:
  • the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 44. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations.
  • Figure 46 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3069, 2963, 2216, 1667, 1606, 1399, 1154, 1000, 904 and 463 cm 1 wavenumbers and
  • Figure 47 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods.
  • Figure 48 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 49 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively.
  • the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate that shows a 8.2% weigth loss in the range of 20°C-to 160°C.
  • the amorphous ponatinib hydrochloride can be prepared by a process comprising the steps of: a/ dissolving ponatinib hydrochloride in a solvent selected form the group of consisting of water; ethanol; and water-dioxane in 1:1 ratio by volume at room temperature;
  • Another process for preparation of the amorphous ponatinib hydrochloride comprisese the steps of: a/ dissolving the ponatinib hydrochloride in ethanol at room temperature;
  • step c/ optionally, drying of the product of the step b/ at laboratory conditions until the constant weight of the product is reached.
  • the term “bulroom temperature” is defined as a temperature between 15°C and 29°C for the purpose of this document; preferably it is between 20-23°C.
  • step time 0.5 s.
  • Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/42 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 5 . 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
  • FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • the sample were weighed in aluminium pans and covers (20 ⁇ ) and measured in a nitrogen flow. Investigations were performed in a temperature range of 50°C to 300-350°C with a heating rate of 10°C/min.
  • the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks.
  • the peak temperature is obviously the temperature at the maximum/minimum of the thermal event.
  • the onset temperature is defined as the intersection of the tangents of the peak with the extrapolated baseline.
  • TGA were performed on a Perkin Elmer TGA 6.
  • the samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 20°C to 300°C with a heating rate of 10°C/min.
  • the weight sample was about 3-21 mg.
  • the vial was agitated during heating to the boiling point (95°C) to ensure adequate dissolution of the 3-(2-imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt. Then the solution was filtered to remove the remaining solid particles and it was left to cool slowly down to room temperature. Finally the resulting precipitate was filtered off and dried at laboratory condition.

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Abstract

L'invention concerne des modifications cristallines et une forme amorphe de chlorhydrate de ponatinib. Formule (I).
PCT/CZ2013/000164 2013-12-09 2013-12-09 Modifications de sel de chlorhydrate de 3-(2-imidazo[1,2-b]pyridazine-3-yléthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl] benzamide Ceased WO2015085973A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019246479A1 (fr) 2018-06-22 2019-12-26 Johnson Matthey Public Limited Company Forme de ponatinib
US11072620B2 (en) 2017-06-20 2021-07-27 Apotex Inc. Crystalline forms of Ponatinib hydrochloride
WO2022090953A1 (fr) * 2020-10-29 2022-05-05 Alembic Pharmaceuticals Limited Dispersion solide de chlorhydrate de ponatinib et son procédé de préparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2011053938A1 (fr) * 2009-10-30 2011-05-05 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement du cancer
WO2013101281A1 (fr) * 2011-04-07 2013-07-04 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de la maladie de parkinson

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2011053938A1 (fr) * 2009-10-30 2011-05-05 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement du cancer
WO2013101281A1 (fr) * 2011-04-07 2013-07-04 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de la maladie de parkinson

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11072620B2 (en) 2017-06-20 2021-07-27 Apotex Inc. Crystalline forms of Ponatinib hydrochloride
WO2019246479A1 (fr) 2018-06-22 2019-12-26 Johnson Matthey Public Limited Company Forme de ponatinib
US12030886B2 (en) 2018-06-22 2024-07-09 Macfarlan Smith Limited Form of ponatinib
WO2022090953A1 (fr) * 2020-10-29 2022-05-05 Alembic Pharmaceuticals Limited Dispersion solide de chlorhydrate de ponatinib et son procédé de préparation

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