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WO2015067224A1 - Sels de 6-[2- (méthylcarbamoyl) phénylsulfanyl]-3-e-[2-(pyridin-2-yl) éthanyl]indazole - Google Patents

Sels de 6-[2- (méthylcarbamoyl) phénylsulfanyl]-3-e-[2-(pyridin-2-yl) éthanyl]indazole Download PDF

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Publication number
WO2015067224A1
WO2015067224A1 PCT/CZ2013/000146 CZ2013000146W WO2015067224A1 WO 2015067224 A1 WO2015067224 A1 WO 2015067224A1 CZ 2013000146 W CZ2013000146 W CZ 2013000146W WO 2015067224 A1 WO2015067224 A1 WO 2015067224A1
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Prior art keywords
acid
phenylsulfanyl
pyridin
methylcarbamoyl
indazole
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PCT/CZ2013/000146
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English (en)
Inventor
Violetta Kiss
Ludek Ridvan
Hana TOZICKOVA
Marcela Tkadlecova
Ondrej Dammer
Lukas KREJCIK
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Zentiva, K.S.
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Priority to PCT/CZ2013/000146 priority Critical patent/WO2015067224A1/fr
Publication of WO2015067224A1 publication Critical patent/WO2015067224A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole of Formula I:
  • vascular endothelias growth factor receptor VEGFR- 1, VEGFR-2 and VEGFR-3 is a tyrosine kinase inhibitor of vascular endothelias growth factor receptor VEGFR- 1, VEGFR-2 and VEGFR-3 as well as platelet derived growth factor receptor (PDGFR) and cKIT (CD117).
  • VEGFR Vascular endothelias growth factor receptors
  • VEGFR can be found on the surface of cancer cells and are involved into the growth and the spread of the cancer cells and in the development of blood vessels that supply the tumours.
  • Axitinib produced tumour growth delay and inhibition of metastases for the treatment of advanced renal cell carcinoma (RCC) after failure of prior systemic treatment.
  • Formula I was specifically described in WO0102369. Polymorphic forms and pharmaceutical compositions comprising Formula I are described in WO2006048745 and WO2006048751. Disclosed crystalline forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E- [2-(pyridin-2-yl)ethanyl]indazole are denominated therein as Form I, II, III, IV, VI, VII and VIII and processes for their preparation are also provided.
  • composition comprising amorphous 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole as solid amorphous dispersion obtained by spray solution is published in WO2006123223. Forced degradation studies exposing the active substance high intensity light conditions demonstrated that the active substance is sensitive to light and photo stability study performed confirmed that axitinib is photolabile. Photodegradants and oxidative degradants of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole are published in WO2013046133 related to pharmaceutical composition.
  • the objective of the present invention is to provide novel pharmaceutically acceptable salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole with good chemical purity and stability and good processability during its preparation as an active pharmaceutical ingredient or synthesis intermediate for purification purposes. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.
  • the invention provides new pharmaceutically acceptable salts of 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and methods of their production.
  • An advantage of the newly prepared salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form.
  • the present invention further relates to characterization of prepared salts using FTIR, 1 NMR, solid state NMR, DSC, XRPD and TGA techniques and to pharmaceutical formulations containing the novel salts of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole.
  • Figure 1 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 2 is a 1 H-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 3 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 4 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 5 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 6 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and benzenesulphonic acid.
  • Figure 7 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 8 is a ⁇ -NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 9 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 10 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 11 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 12 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid.
  • Figure 13 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 14 is a 1 H-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 15 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 16 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 17 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 18 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and methanesulphonic acid.
  • Figure 19 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 20 is a l-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 21 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 22 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 23 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 24 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and p-toluenesulphonic acid.
  • Figure 25 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and hydrobromic acid.
  • Figure 26 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and hydrobromic acid.
  • Figure 27 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and hydrobromic acid.
  • Figure 28 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and hydrobromic acid.
  • Figure 29 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and hydrobromic acid.
  • Figure 30 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and hydrochloric acid.
  • Figure 31 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyi)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and hydrochloric acid.
  • Figure 32 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and hydrochloric acid.
  • Figure 33 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and hydrochloric acid.
  • Figure 34 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and hydrochloric acid.
  • Figure 35 is a FTIR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and sulphuric acid.
  • Figure 36 is a solid state-NMR spectra of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3- E-[2-(pyridin-2-yl)ethanyl]indazole and sulphuric acid.
  • Figure 37 is a XRPD pattern of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and sulphuric acid.
  • Figure 38 is a DSC curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and sulphuric acid.
  • Figure 39 is a TGA curve of the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethanyl]indazole and sulphuric acid.
  • the aim of the present invention is to provide novel salts of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole with advantegous properties for pharmaceutical use regarding the physico-chemical properties and production of salts in a reproducible manner even in industrial scale.
  • the invention also relates to a method for preparing the salts of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole with pharmaceutically acceptable components.
  • a salt comprising Formula I - (6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and at least one acid selected from the group consisting of benzenesulphonic acid, 4-chlorobenzenesulphonic acid, methanesulphonic acid, p-toluenesulphonic acid, hydrobromic acid, hydrochloric acid and sulphuric acid.
  • inventive salts of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole can be obtained with high yields and high purity and preferably in a crystalline form.
  • the salts may be an anhydrous and/or solvent-free form or be a hydrated/solvated form. They may exist in different solid forms with different internal structures (polymorphism), which may have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt. Therefore, crystalline modifications of the inventive salt cover individual crystals and/or mixtures thereof in any ratio.
  • the selected solvents preferably 2-propanol are suitable for the preparation of the salts of 6- [2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole in a yield and purity which is favorable from efficient and safe production point of view of a pharmaceutically active compound.
  • the reaction was 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 crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and benzenesulphonic acid can be characterized by an FTIR spectroscopy and solid- state NMR investigations.
  • Figure 1 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 553.10, 565.60, 609.50, 691.60, 729.00, 753.90, 1013.50, 1626.90, 3061.40 and 3204.70 cm 1 wavenumbers
  • Figure 3 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and benzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 4. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the salt of 6-[2-(methylcarbamoyl)-phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyl]indazole and benzenesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 1, below:
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and benzenesulphonic acid can be further described by thermal analytical methods.
  • Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 6 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 250°C, respectively.
  • Benzenesulphonic acid salt shows a 2.4% weigth loss in the range of 20°C to 200°C, respectively.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and 4-chlorobenzenesulphonic acid can be characterized by an FTIR spectroscopy and solid-state NMR investigations.
  • Figure 7 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 553.00, 563.60, 606.40, 647.30, 744.90, 755.80, 1627.20, 2488.40, 3062.50 and 3224.40 cm "1 wavenumbers
  • Figure 9 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and 4-chlorobenzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 10.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the salt of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 2, below: Pos. [°2Th.] d-spacing [A] Rel. Int. [%]
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and 4-chlorobenzenesulphonic acid can be further characterized 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 250°C and 20°C to 250°C, respectively.
  • 4-Chlorobenzensulphonic acid salt shows a 2% weigth loss in the
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and 4-chlorobenzenesulphonic acid obtained by the process described above was isolated in a good yield (74%) and exhibits excellent purity (98.0%).
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and methanesulphonic acid can be characterized by an FTIR spectroscopy and solid- state MR investigations.
  • Figure 13 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 552.50, 623.00, 642.20, 752.70, 1036.10, 1148.00, 1228.70, 1328.80, 1631.70, 2493.40 and 3246.20 cm 1 wavenumbers and Figure 15 shows the sslMMR (Bruker AVANCE 250 MHz) spectrum.
  • FTIR Nicolet Thermo 6700
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and methanesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 16. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the salt of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and methanesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 3, below:
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and methanesulphonic acid can be further characterized 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 250°C and 20"C to 250°C, respectively.
  • Methanesulphonic acid salt shows a 4.4% weigth loss in the range of 20°C to 125°C and 1.4% weigth loss in the range of 125°C to 200°C.
  • the DSC measurement gives a melting process with
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and p-toluenesulphonic acid can be characterized by an FTIR spectroscopy and solid- state NMR investigations.
  • Figure 19 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 551.50, 564.00, 682.00, 1226.70, 1268.60, 1557.30, 1625.60, 2486.10, 3083.40 and 3222.90 cm 1 wavenumbers
  • Figure 21 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and p-toluenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 22.
  • XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and p-toluenesulphonic acid can be further characterized 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 of 50°C to 250°C and 20°C to 250°C respectively.
  • p-Toluenesulphonic acid salt shows a 1.6% weigth loss in the range of 20°C-to 200°C.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrobromic acid can be characterized by an FTIR spectroscopy and solid-state NMR investigations.
  • Figure 25 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 593.20, 620.00, 740.20, 754.50, 953.10, 961.70, 1618.30, 2624.90, 3218.50 and 3545.70 cm 1 wavenumbers and
  • Figure 26 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrobromic acid according to the invention has the characteristic XRPD pattern as shown in Figure 27. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • the salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2- (pyridin-2-yl)ethanyi]indazole and hydrobromic acid has the following most characteristic powder diffraction peaks illustrated in Table 5, below:
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and hydrobromic acid can be further characterized by thermal analytical methods.
  • Figure 28 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 29 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 250°C, respectively.
  • Hydrobromic acid salt shows a 4.2% weigth loss in the range of 20°C to 120°C and 3% weigth loss in the range of 120°C-to 210°C.
  • the DSC measurement gives a melting process with and
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrochloric acid can be characterized by an FTIR spectroscopy and solid-state NMR investigations.
  • Figure 30 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 620.50, 686.90, 722.50, 754.80, 953.60, 1266.60, 1552.70, 1621.60, 2557.20 and 3232.00 cm 1 wavenumbers
  • Figure 31 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and hydrochloric acid according to the invention has the characteristic XRPD pattern as shown in Figure 32. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
  • the salt of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and hydrochloric acid has the following most characteristic powder diffraction peaks illustrated in Table 6, below.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrochloric acid can be further characterized by thermal analytical methods.
  • Figure 33 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 34 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 250° ⁇ respectively.
  • Hydrochloric acid salt shows a 7% weigth loss in the range of 20 C C to 120°C and 2.1% weigth loss in the range of 120°C-to 200°C.
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and hydrochloric acid obtained by the process described above was isolated in a good yield (83%) and exhibits good purity (95%).
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and sulphuric acid can be characterized by an FTIR spectroscopy and solid-state NMR investigations.
  • Figure 35 shows the FTIR (Nicolet Thermo 6700) spectrum comprising characteristic peaks at 577.20, 757.10, 827.60, 849.40, 1160.70, 1231.80, 1452.50, 1618.90, 1666.40, 2523.00 and 3357.80 cm “1 wavenumbers and Figure 36 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.
  • FTIR Nicolet Thermo 6700
  • the crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and sulphuric acid 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 salt of 6-[2-(methylcarbamoyl)- phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]indazole and sulphuric acid has the following most characteristic powder diffraction peaks illustrated in Table 7, below:
  • Table 7 The crystalline salt of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole and sulphuric acid can be further characterized by thermal analytical methods.
  • Figure 38 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 39 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 250°C, respectively.
  • Sulphuric acid salt shows a 3.8% weigth loss in the range of 20°C to 250°C.
  • the DSC measurement gives a melting process with
  • novel salts of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethanyl]- indazole according to the invention are easily producible by a 1-step method in C1-C4 alkyl alcohols, preferebly in 2-propanol with a good or excellent yield.
  • ⁇ -NMR analysis complies with 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2- yl)ethanyl]indazole and methanesulphonic acid.
  • FTIR spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • step time 0.5 s.
  • Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1 4 ⁇ anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.1222, o.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
  • 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 220°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 specific heat is given in J/g.
  • the weight sample was about 3.5 mg.
  • 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 250°C with a heating rate of 10°C/min.
  • the weight sample was about 19-22 mg.

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Abstract

Sel comprenant un composé de formule I et au moins un constituant acide (HA), qui peut être choisi parmi l'acide benzènesulfonique, l'acide 4-chlorobenzènesulfonique, l'acide méthanesulfonique, l'acide p-toluènesulfonique, l'acide bromhydrique, l'acide chlorhydrique et l'acide sulfurique.
PCT/CZ2013/000146 2013-11-08 2013-11-08 Sels de 6-[2- (méthylcarbamoyl) phénylsulfanyl]-3-e-[2-(pyridin-2-yl) éthanyl]indazole WO2015067224A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106467512A (zh) * 2015-08-19 2017-03-01 浙江九洲药业股份有限公司 一种阿西替尼富马酸盐及其结晶形式和制备方法
WO2020212253A1 (fr) 2019-04-18 2020-10-22 Synthon B.V. Procédé de préparation d'axitinib, procédé de purification de l'intermédiaire 2-((3-iodo-1h-indazol-6-yl)thio)-n-méthylbenzamide, procédé de purification d'axitinib par l'intermédiaire du sel d'axitinib hcl, forme solide du sel d'axitinib hcl
WO2022000265A1 (fr) * 2020-06-30 2022-01-06 天津理工大学 Cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN114685432A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
CN114685434A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶
CN114685431A (zh) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型
CN114685435A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
KR20220102697A (ko) 2021-01-13 2022-07-21 조득형 마이크로버블 생성 혼합 수중 에어레이터 회전분사 조립체

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106467512A (zh) * 2015-08-19 2017-03-01 浙江九洲药业股份有限公司 一种阿西替尼富马酸盐及其结晶形式和制备方法
CN106467512B (zh) * 2015-08-19 2022-03-11 浙江九洲药业股份有限公司 一种阿西替尼富马酸盐及其结晶形式和制备方法
WO2020212253A1 (fr) 2019-04-18 2020-10-22 Synthon B.V. Procédé de préparation d'axitinib, procédé de purification de l'intermédiaire 2-((3-iodo-1h-indazol-6-yl)thio)-n-méthylbenzamide, procédé de purification d'axitinib par l'intermédiaire du sel d'axitinib hcl, forme solide du sel d'axitinib hcl
JP2022528994A (ja) * 2019-04-18 2022-06-16 シントン・ビー．ブイ． アキシチニブの製造方法、中間体２－（（３－ヨード－１ｈ－インダゾール－６－イル）チオ）－ｎ－メチルベンズアミドの精製方法、アキシチニブ塩酸塩によるアキシチニブの精製方法、アキシチニブ塩酸塩の固体形態
JP7200399B2 (ja) 2019-04-18 2023-01-06 シントン・ビー．ブイ． アキシチニブの製造方法、中間体２－（（３－ヨード－１ｈ－インダゾール－６－イル）チオ）－ｎ－メチルベンズアミドの精製方法、アキシチニブ塩酸塩によるアキシチニブの精製方法、アキシチニブ塩酸塩の固体形態
WO2022000265A1 (fr) * 2020-06-30 2022-01-06 天津理工大学 Cocristaux d'axitinib et d'acide glutarique, et leur procédé de préparation
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN113943271B (zh) * 2020-07-15 2023-11-14 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN114685431A (zh) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型
CN114685431B (zh) * 2020-12-26 2022-11-29 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型
CN114685435A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
CN114685432B (zh) * 2020-12-28 2022-11-25 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
CN114685434A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶
CN114685435B (zh) * 2020-12-28 2023-01-31 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
CN114685434B (zh) * 2020-12-28 2023-06-16 鲁南制药集团股份有限公司 一种阿昔替尼与戊二酸共晶
CN114685432A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
KR20220102697A (ko) 2021-01-13 2022-07-21 조득형 마이크로버블 생성 혼합 수중 에어레이터 회전분사 조립체

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