WO2015085971A1 - Hydrobromide salt of 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide - Google Patents
Hydrobromide salt of 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide Download PDFInfo
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- WO2015085971A1 WO2015085971A1 PCT/CZ2013/000162 CZ2013000162W WO2015085971A1 WO 2015085971 A1 WO2015085971 A1 WO 2015085971A1 CZ 2013000162 W CZ2013000162 W CZ 2013000162W WO 2015085971 A1 WO2015085971 A1 WO 2015085971A1
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- methyl
- salt
- ylethynyl
- benzamide
- piperazinyl
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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 salt of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N- [4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide of Formula I,
- 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-lmidazo[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 a novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid of Formula la, in particular in a solid form suitable for oral administration and a method of the preparation thereof.
- An advantage of the newly prepared salt consists in its good physical and chemical characteristics, which make it suitable for preparation of a dosage form.
- the present invention further relates to a pharmaceutical formulations containing the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide and hydrobromic acid and the use thereof for the treatment of cancer.
- novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide is as follow: the salt of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid.
- Figure 1 is an XRPD pattern of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid according to the invention;
- Figure 2 is a FTIR spectra of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)pKenyl] benzamide and hydrobromic acid according to the invention;
- Figure 3 is a ssNMR spectra of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid according to the invention.
- the aim of the present invention is to provide a novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid with advantegous properties for pharmaceutical use regarding the physico- chemical properties and can be produced in a reproducible manner even in industrial scale.
- the inventive salt formed from 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl- l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be in crystalline or amorphous form.
- the inventively claimed salt may be an anhydrous and/or solvent-free form or be a hydrated/solvated form.
- the inventive salt exhibits polymorphism, i.e. it exists in different solid forms with different internal structures (crystalline or amorphous), which have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt.
- Substantially pure crystalline forms and substantially pure amorphous form can be prepared, as well as mixtures of different crystalline forms in any ratio or mixtures of crystalline form(s) with the amorphous form.
- the salt of the persent invention can be prepared by the reaction of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid in the solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixture, preferebly in 2-propanol.
- the solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixture, preferably 2-propanol are suitable for the preparation of the bromide of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide in a yield and purity which is favorable from efficient and safe production point of view of a pharmaceutically active compound.
- the reaction can be carried out in the range of temperature 40-60°C, preferably at temperature 50°C.
- the resulting salt was isolated from the reaction mixture at room temperature.
- the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be obtained by a process comprising following steps: a/ dissolving the 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide in a solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixtures at 40-60°C; b/ addition of hydrobromic acid in 1 equimolar ratio dissolved in the same solvent that was used in the step a/ to the solution formed in the step a c/ stirring the solution obtained in the step b/ at 40-60°C
- the term “bulroom temperature” is defined as a temperature between 15°C and 29°C for the purpose of this invention; preferably it is between 20-23°C.
- This crystalline salt was designated as the polymorphic Form I.
- the polymorphic Form I of the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be further characterized by a Fourier-Transformed Infra-Red (FTIR) spectroscopy and solid-state NMR invesitgations.
- FTIR Fourier-Transformed Infra-Red
- the polymorphic Form I of the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be further characterized by the solid-state NMR invesitgations.
- Figure 3 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
- 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 1.122°. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
- FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
Abstract
A salt of 3-(2-lmidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide and hydrobromic acid (ponatinib hydrobromide) of formula (la), or a solvate or a hydrate thereof.
Description
HYDROBROMIDE SALT OF 3-(2-IMIDAZO[1 ,2-B]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-[4- [(4-METHYL-1 -PIPERAZINYL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL] BENZAMIDE
Background of the invention
1. Field of the invention
The present invention relates to a novel salt of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N- [4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide of Formula I,
2. Background information
3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (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).
The enzyme 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. 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-lmidazo[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.
Summary of the invention
The object of the present invention is to provide a novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid of Formula la, in particular in a solid form suitable for oral administration and a method of the preparation thereof.
la
An advantage of the newly prepared salt consists in its good physical and chemical characteristics, which make it suitable for preparation of a dosage form.
The present invention further relates to a pharmaceutical formulations containing the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide and hydrobromic acid and the use thereof for the treatment of cancer.
The novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide is as follow: the salt of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid.
Brief description of the figures
Figure 1 is an XRPD pattern of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid according to the invention;
Figure 2 is a FTIR spectra of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)pKenyl] benzamide and hydrobromic acid according to the invention;
Figure 3 is a ssNMR spectra of the salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid according to the invention.
Detailed description of the invention
The aim of the present invention is to provide a novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid with advantegous properties for pharmaceutical use regarding the physico- chemical properties and can be produced in a reproducible manner even in industrial scale.
It has been surprisingly found that the above-mentioned chemically and morphologically stable salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide and hydrobromic acid can be prepared and have not been described in the literature; no analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X- Ray Diffraction data etc.) serving to characterize the crystalline salt have been provided.
The invented salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be obtained with acceptable yields.
The inventive salt formed from 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl- l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be in crystalline or amorphous form.
The inventively claimed salt may be an anhydrous and/or solvent-free form or be a hydrated/solvated form.
The inventive salt exhibits polymorphism, i.e. it exists in different solid forms with different internal structures (crystalline or amorphous), which have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt. Substantially pure crystalline forms and substantially pure amorphous form can be prepared, as well as mixtures of different crystalline forms in any ratio or mixtures of crystalline form(s) with the amorphous form.
The salt of the persent invention can be prepared by the reaction of 3-(2-lmidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid in the solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixture, preferebly in 2-propanol.
The solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixture, preferably 2-propanol are suitable for the preparation of the bromide of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide in a yield and purity which is favorable from efficient and safe production point of view of a pharmaceutically active compound.
The reaction can be carried out in the range of temperature 40-60°C, preferably at temperature 50°C. The resulting salt was isolated from the reaction mixture at room temperature.
The salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be obtained by a process comprising following steps: a/ dissolving the 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide in a solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixtures at 40-60°C; b/ addition of hydrobromic acid in 1 equimolar ratio dissolved in the same solvent that was used in the step a/ to the solution formed in the step a c/ stirring the solution obtained in the step b/ at 40-60°C for 1 hour; d/ cooling the mixture of the step c/ to the room temperature e/ stirring the the mixture of the step d/ at room temperature; f/ filtration of the suspension formed in the step e/; g/ drying the crystals obtained in the step f/ at laboratory conditions;
h/ optionally, recrystallization by dissolving the crystals in a solvent selected from the group consisting of C1-C4 alkyl alcohols and repetition of the steps of c/ - g/.
The term„room temperature" is defined as a temperature between 15°C and 29°C for the purpose of this invention; preferably it is between 20-23°C.
The term„overnight" as used in this patent application is related to the duration of the given process step. The process that is to be carried out„ovemight" has to be performed for at least 10 hours, preferably 12-16 hours.
The term„drying at laboratory condition" means drying at room temperature and relative humidity 20-60%.
The FTIR spectrum (measured by Nicolet Thermo 6700) of the the salt of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid is shown in Figure 2. The novel salt of 3-(2-lmidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid by peaks at 2936, 2701, 2218, 1670, 1529, 1315, 1152, 1122, 1103 and 789 cm"1 wavenumbers.
In one embodiment of this invention, the novel salt of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid in a crystalline state that is characterised by X-Ray Powder Diffraction (XRPD) pattern shown in Figure 1 (recorded on an X-Ray Powder Diffractometer X'PERT PRO MPD PANalytical) has the following most characteristic powder diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 10.97, 15.68, 18.72, 19.24, 21.20, 23.88 and 25.82. This crystalline salt was designated as the polymorphic Form I.
3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trif!uoromethyl)phenyl] benzamide hydrobromide shows the following powder diffraction peaks as illustrated in Table 1, below:
Pos. [°2Th.] d-spacing [A] Rel. Int. [%]
6.48 13.620 10.7
10.97 8.062 11.2
13.35 6.629 8.4
13.76 6.428 10.8
15.68 5.646 20.1
17.93 4.942 8.6
18.72 4.737 42.7
19.24 4.609 41.0
21.20 4.188 30.3
21.84 4.067 10.5
22.14 4.012 13.7
23.52 3.779 35.2
23.69 3.752 42.2
23.88 3.723 47.9
24.72 3.598 17.1
25.10 3.545 10.2
25.82 3.448 100.0
27.48 3.244 22.1
29.20 3.056 19.9
30.02 2.975 27.9
Table 1
The polymorphic Form I of the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be further characterized by a Fourier-Transformed Infra-Red (FTIR) spectroscopy and solid-state NMR invesitgations.
The polymorphic Form I of the novel salt of 3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid can be further characterized by the solid-state NMR invesitgations. Figure 3 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
The used analytical methods were performed as follows:
Analysis - XRPD (X-Ray Powder Diffractometry)
Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ = 1.542A).
Generator settings:
excitation voltage 45 kV
anodic current 40 mA.
Scan description:
scan type - gonio
measurement range 2 - 403 2Θ
- step size 0.012 2Θ
step time: 0.5 s.
Samples were measured as received on Si plate (zero background holder).
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 1.122°. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
Analysis - FTIR (Fourier-Transformed Infra-Red) spectroscopy
FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
General settings:
Number of sample scans: 45
Number of background scans: 45
Resolution: 4.000
Sample gain: 4.0
Optical velocity: 0.6329
Aperture: 100.00
Analysis - Solid state NMR spectroscopy
C CP-MAS ss NMR spectra were meausred on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency. The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of coformer.
Example
Example 1
100 mg (0.188 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide was dissolved in 3 mL of 2-propanol by heating to 50°C. 22 μί (0.189 mmol) of hydrobromic acid (48% solution) was diluted with 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C.
The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition until constant weight is reached.
Yield: 71.2 mg (62%)
FTIR spectrum confirmed the structure.
Claims
1. A salt of 3-(2-lmidazo[l,2-b]pyndazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide and hydrobromic acid (ponatinib hydrobromide) of formula la, or a solvate or a hydrate thereof.
2. The salt according to the claim 1, wherein the salt is crystalline or amorphous.
3. The salt according to the claim 1 or 2, wherein the salt is crystalline.
4. The salt according to any of the claims 1-3, having characteristic absorptions at 2936, 2701, 2218, 1670, 1529, 1315, 1152, 1122, 1103 and 789 cm'1 in Fourier-Transformed Infrared spectroscopic analysis.
5. The salt according to any of the claims 1-4, wherein the salt is in crystalline polymorphic Form I characterised by an x-ray powder diffraction pattern having characteristic peaks, using radiation CuKa (λ = 1.542A), at a reflection angle 2Θ (± 0.2° 2Θ) of 10.97, 15.68, 18.72, 19.24, 21.20, 23.88 and 25.82.
6. A process for the preparation of the salt according to claims 1 - 5, the process comprising the steps a-h: a/ dissolving the 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide in a solvent selected from the group consisting of C1-C4 alkyl alcohols and any their mixtures at 40-60°C; b/ addition of hydrobromic acid in 1 equimolar ratio dissolved in the same solvent that was used in the step a/ to the solution formed in the step a, c/ stirring the solution obtained in the step b/ at 40-60°C for 1 hour; d/ cooling the mixture of the step c/ to the room temperature e/ stirring the the mixture of the step d/; f/ filtration of the suspension formed in the step e/; g/ drying the crystals obtained in the step f/ at laboratory conditions;
h/ optionally, recrystallization by dissolving the crystals in a solvent selected from the group consisting of C1-C4 alkyl alcohols and repetition of the steps of c/ - g/.
7. The process according to the claim 6, wherein the temperature in the steps a/ and c/ is 50°C.
8. The process according to the claim 6 or 7, wherein the used solvent is 2-propanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9725454B2 (en) | 2013-07-04 | 2017-08-08 | Sandoz Ag | Crystalline forms of ponatinib hydrochloride |
| US11072620B2 (en) | 2017-06-20 | 2021-07-27 | Apotex Inc. | Crystalline forms of Ponatinib hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007075869A2 (en) | 2005-12-23 | 2007-07-05 | Ariad Pharmaceuticals, Inc. | Bicyclic heteroaryl compounds |
| WO2011053938A1 (en) * | 2009-10-30 | 2011-05-05 | Ariad Pharmaceuticals, Inc. | Methods and compositions for treating cancer |
| WO2012139027A1 (en) * | 2011-04-07 | 2012-10-11 | Ariad Pharmaceuticals, Inc. | Methods and compositions for treating neurodegenerative diseases |
-
2013
- 2013-12-09 WO PCT/CZ2013/000162 patent/WO2015085971A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007075869A2 (en) | 2005-12-23 | 2007-07-05 | Ariad Pharmaceuticals, Inc. | Bicyclic heteroaryl compounds |
| WO2011053938A1 (en) * | 2009-10-30 | 2011-05-05 | Ariad Pharmaceuticals, Inc. | Methods and compositions for treating cancer |
| WO2012139027A1 (en) * | 2011-04-07 | 2012-10-11 | Ariad Pharmaceuticals, Inc. | Methods and compositions for treating neurodegenerative diseases |
Non-Patent Citations (1)
| Title |
|---|
| HUANG WEI-SHENG ET AL: "Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{ 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 53, no. 12, 24 June 2010 (2010-06-24), pages 4701 - 4719, XP002615777, ISSN: 0022-2623, [retrieved on 20100601], DOI: 10.1021/JM100395Q * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9725454B2 (en) | 2013-07-04 | 2017-08-08 | Sandoz Ag | Crystalline forms of ponatinib hydrochloride |
| US11072620B2 (en) | 2017-06-20 | 2021-07-27 | Apotex Inc. | Crystalline forms of Ponatinib hydrochloride |
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