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WO2025132408A2 - Solvates de trametinib - Google Patents

Solvates de trametinib Download PDF

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Publication number
WO2025132408A2
WO2025132408A2 PCT/EP2024/086872 EP2024086872W WO2025132408A2 WO 2025132408 A2 WO2025132408 A2 WO 2025132408A2 EP 2024086872 W EP2024086872 W EP 2024086872W WO 2025132408 A2 WO2025132408 A2 WO 2025132408A2
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Prior art keywords
trametinib
solvate
solvent
solid form
methanol
Prior art date
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PCT/EP2024/086872
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English (en)
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WO2025132408A3 (fr
Inventor
Michal HEGEDUS
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Synthon BV
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Synthon BV
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Publication date
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Publication of WO2025132408A2 publication Critical patent/WO2025132408A2/fr
Publication of WO2025132408A3 publication Critical patent/WO2025132408A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to solvates of trametinib, compound of the formula (1), and to improved processes making of complexes of trametinib, compound of formula (1):
  • Trametinib N-(3- ⁇ 3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl ⁇ phenyl)acetamide , is an oral inhibitor of mitogen- activated protein kinase kinase 1 (MEK1) and of mitogen-activated protein kinase kinase 2 (MEK2).
  • MEK1 mitogen- activated protein kinase kinase 1
  • MEK2 mitogen-activated protein kinase kinase 2
  • W02005121142 discloses trametinib compound as well as complexes with common organic solvents including dimethyl sulfoxide. No particular examples of the form of solvent complexes are disclosed in the application.
  • WO2015081566 discloses a method for preparation of particular forms of trametinib solvent complexes utilizing ultrasound.
  • WO2016169532 and US20150152100 discloses a particular crystalline form and method of preparation of dimethyl sulfoxide complex of trametinib.
  • WO2020161654 discloses a particular crystalline form and method of preparation of acetic acid complex of trametinib.
  • WO2015128298 discloses pharmaceutical composition comprising trametinib embedded in a carrier matrix.
  • US20170020880 discloses pharmaceutical composition
  • pharmaceutical composition comprising trametinib, trametinib salt, or trametinib solvent complex and a solubility enhancer.
  • WO2014085371 discloses pharmaceutical composition comprising trametinib dimethyl sulfoxide complex and a solubilizer.
  • the prior art discloses solvates of trametinib with limited industrial usability as medicaments.
  • the disclosed solvates are both chemically and physically unstable and manifest low aqueous solubility.
  • the prior art discloses solvates of trametinib with limited industrial usability as medicaments.
  • the disclosed solvates are prepared by processes, which utilize physical methods with rather limited industrial scalability and with negative environmental impact.
  • trametinib solvates are carried out in solutions at very high dilution levels due to a very low solubility of trametinib in most of organic solvents.
  • the low solubility in organic solvents provides for a high environmental burden in the form of high amounts of organic solvent waste obtained after isolation of a desired solid form of trametinib solvate.
  • Trametinib as well as a solvate forms of trametinib exhibit unique properties, which render the use of trametinib or the solvated forms of trametinib in providing for a medicament, suitable for a treatment of life threatening conditions, cumbersome and not straightforward, particularly on a commercial scale.
  • the properties include but are not limited to a low aqueous solubility of trametinib and the instability of the solvate forms of trametinib typically when heated or in the presence of water or light.
  • Trametinib is practically insoluble in water in free desolvated form.
  • the poor water solubility of biologically active substance may lead to a slow absorption and to inadequate and variable bioavailability.
  • the solubility of the active substance is suitably increased by solvation providing for solvate complexes of the active substance with improved and robust bioavailability.
  • Trametinib was found to interact with a variety of solvents to form the solvates.
  • the solvate is formed when trametinib is brought in contact with a solvent.
  • trametinib is miscible with the solvent.
  • trametinib dissolves in the solvent.
  • Trametinib was found to be nearly immiscible with a variety of the solvents.
  • the present inventors have surprisingly found that a desired solvate of trametinib and a solvent can be prepared with a high yield and with a high chemical purity from a mixture of solvents in a way the overall amount of solvents is dramatically reduced.
  • the reduction in the overall amount of solvents diminishes the environmental impact of the process compared to a single solvent process.
  • the solvate complexes are suitably prepared in a solid form.
  • the bioavailability of the solvate of the active substance is further increased by a reduction of a particle size of the solid form.
  • the reduction of particle size is typically achieved for example by milling, bashing and/or grinding, to significantly reduce particle size over those produced naturally during chemical synthesis.
  • solvate complexes are complexes wherein the individual complex entities are attracted by weak intermolecular forces, the solvated complexes tend to dissociate typically upon exposure to heat during handling.
  • dissociation of solvate complex of the active substance can take place during manufacture of a medicament on a commercial scale.
  • the dissociation of trametinib active substance solvate can lead to the formation of the de solvated trametinib with a disadvantageous solubility characteristics with a negative impact on pharmacodynamics of trametinib medicament.
  • the present inventors have surprisingly found that a desired solvate of trametinib and a solvent with a reduced particle size of the solid form of the desired solvate can be produced with a high yield and with a high chemical purity by a chemical process without a need to use of mechanical particle size reducing means.
  • the particles of trametinib solvate providing for an acceptable solubility and bioavailability are provided for.
  • the present inventors have also found that anisol, butan-l-ol, cyclohexanol, and methanol solvents provide for the solvates of trametinib, which are stable and can be advantageously used in a manufacture of a medicament on a commercial scale.
  • the stable solvates of trametinib provide for the medicaments with desired and robust bioavailability.
  • the present invention is directed to a solvate comprising trametinib and a solvent selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.
  • the present invention further relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Freeze drying the solution obtained in the step a); c) Mixing a solid obtained in the step b) with the first solvent; d) Separating a solid form of the solvate from the mixture; and e) Drying the solid form of the complex.
  • the present invention also discloses a process for preparation of a solvate of trametinib and a solvent comprising: a) Mixing trametinib with the solvent and the solvate seed; b) Separating a solid form of the solvate from the mixture; and c) Drying the solid form of the complex.
  • the present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Mixing a solution obtained in step a) with the first solvent; c) Separating a solid form of the solvate from the mixture; and d) Drying the solid form.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib anisole solvate prepared according to the Example 1.
  • Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib butan-l-ol solvate prepared according to the Example 2.
  • XRPD X-Ray Powder Diffractogram
  • Figure 5 depicts the differential scanning calorimetry (DSC) curve of trametinib butan-l-ol solvate prepared according to the Example 2.
  • FIG. 6 depicts the thermogravimetric analysis (TGA) curve of trametinib butan-l-ol solvate prepared according to the Example 2.
  • Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib cyclohexanol solvate prepared according to the Example 3.
  • TGA thermogravimetric analysis
  • XRPD X-Ray Powder Diffractogram
  • Figure 9 depicts the thermogravimetric analysis (TGA) curve of trametinib cyclohexanol solvate prepared according to the Example 3.
  • Figure 11 depicts the differential scanning calorimetry (DSC) curve of trametinib methanol solvate prepared according to the Example 4.
  • Figure 12 depicts the thermogravimetric analysis (TGA) curve of trametinib methanol solvate prepared according to the Example 4.
  • Figure 20 depicts scanning electron microscope (SEM) image of trametinib propan-2 -ol solvate prepared according to Example 14.
  • SEM scanning electron microscope
  • the present invention relates to a solvate comprising trametinib and a solvent selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.
  • the solvate is solid.
  • the solvate wherein the solvent is anisole is solid form A-l.
  • the solid form A-l can be further characterized by XRPD pattern describe in the following table:
  • the solid A-l can be also characterized by XRPD pattern depicted in Figure 1.
  • the solid can be further characterized by DSC curve depicted in Figure 2 and by TGA curve depicted in Figure 3.
  • the solid form B-l can be further characterized by XRPD pattern describe in the following table:
  • the solid form B-l can be also characterized by XRPD pattern depicted in Figure 4.
  • the solid can be further characterized by DSC curve depicted in Figure 5 and by TGA curve depicted in Figure.
  • the solid form CX-1 can be further characterized by XRPD pattern describe in the following table:
  • the solid CX-1 can be also characterized by XRPD pattern depicted in Figure 7.
  • the solid can be further characterized by DSC curve depicted in Figure 8 and by TGA curve depicted in Figure 9.
  • the solvate wherein the solvent is methanol is solid form M-l.
  • the solid form M-l can be further characterized by XRPD pattern describe in the following table :
  • the solid M-l can be also characterized by XRPD pattern depicted in Figure 10.
  • the solid can be further characterized by DSC curve depicted in Figure 11 and by TGA curve depicted in Figure 12.
  • the solvates of trametinib according to presented invention can be prepared by a process comprising contacting trametinib with a solvent selected from group consisting of anisole, butan-l-ol, cyclohexanol and methanol.
  • a solvent selected from group consisting of anisole, butan-l-ol, cyclohexanol and methanol.
  • the solvates od the presented invention can be formulated into pharmaceutical composition comprising the solvate and one or more excipients.
  • the present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Freeze drying the solution obtained in the step a); c) Mixing the solid obtained in the step b) with the first solvent; d) Separating a solid form of the solvate from the mixture; and e) Drying the solid form of the complex.
  • trametinib is dissolving in the second solvent in the process of the present invention.
  • the suitable second solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloro- ethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2- dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxy- propane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydro- furan, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene
  • trametinib is dissolved in the second solvent at an elevated temperature in the process of the present invention.
  • Trametinib is dissolved at a temperature from 40 °C to 180 °C, preferably at temperature from 60 °C to 140 °C, or more preferably at temperature from 80 °C to 100
  • the solution of trametinib in the second solvent prepared in the process of the present invention contains from 0.5 % to 5 % of trametinib by weight based on the total weight of the solution.
  • the solution contains from 1 % to 4.5 %, more preferably 2 % to 3.5 %, of trametinib by weight based on the total weight of the solution.
  • a solution of trametinib in the second solvent is freeze-dried at a diminished pressure in the process of the present invention.
  • the solution is freeze-dried at the pressure from 0.5 mTorrto 100 mTorr, more preferably at the pressure from 1 mTorr to 75 mTorr.
  • the solution of trametinib in the second solvent is freeze dried at a diminished temperature in the process of the present invention.
  • the solution is freeze-dried at the temperature from -25 °C to 25 °C, more preferably at the temperature from -10 °C to 10 °C.
  • a material produced by free-drying is mixed with the first solvent in the process of the present invention.
  • the first solvent can be selected from 1,1,1 -trichloroethane, 1,1,2- trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2- dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2 -methyl - tetrahydrofuran, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole
  • ⁇ -dimcthylacctamidc. '. '-dimcthyl- formamide nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene.
  • methanol, ethanol, propan-2-ol, propan- I-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.
  • the mixing of the freeze-dried material and the first solvent is performed at ambient temperature in the process of the present invention.
  • the mixing is performed at a temperature from 10 °C to 30 °C. More preferably, the mixing is performed at a temperature from 15 °C to 25 °C.
  • a solid form of the solvate of trametinib and the first solvent is separated by filtration in the process of the present invention.
  • an isolated solid form of the solvate of trametinib and the first solvent is dried in the process of the present invention.
  • the drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure.
  • the solvate is at pressure lower than or equal to the atmospheric pressure.
  • the solid form of the solvate of trametinib and the first solvent is heated when dried in the process of the present invention.
  • the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.
  • the present invention further relates to a process for preparation of a solvate of trametinib and a solvent comprising: a) Mixing trametinib with the solvent and the solvate seed; b) Separating a solid form of the solvate from the mixture; and c) Drying the solid form of the complex.
  • trametinib and a seed of trametinib solvate with a solvent is mixed with the solvent in the process of the present invention.
  • the solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloro- ethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2- dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2 -methyl - tetrahydrofuran, 2-propanol, 3 -methyl- 1 -butanol, acetic acid
  • ⁇ -dimcthylacctamidc. '. '-dimcthyl- formamide nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene.
  • methanol, ethanol, propan-2-ol, propan- l-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.
  • the mixture of trametinib and the seed is cooled in the process of the present invention.
  • the mixing is performed at a temperature from -5 °C to 25 °C. More preferably, the mixing is performed at a temperature from 0 °C to 15 °C.
  • a solid form of the solvate of trametinib and the solvent is separated by filtration in the process of the present invention.
  • an isolated solid form of the solvate of trametinib and the solvent is dried in the process of the present invention.
  • the drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure.
  • the solvate is at pressure lower than or equal to the atmospheric pressure.
  • the solid form of the solvate of trametinib and the solvent is heated when dried in the process of the present invention.
  • the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.
  • the present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Mixing a solution obtained in step a) with the first solvent; c) Separating a solid form of the solvate from the mixture; and d) Drying the solid form.
  • trametinib is dissolving in the second solvent in the process of the present invention.
  • the suitable second solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloro- ethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2- dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxy- propane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydro- furan, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloro
  • dimethyl sulfoxide formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, sulfolane, or a mixture thereof is used. More preferably, N,N-dimethylformamide is used.
  • trametinib is dissolved at an elevated temperature in the process of the present invention.
  • Trametinib is dissolved at a temperature from 40 °C to 180 °C, preferably at temperature from 60 °C to 140 °C, or more preferably at temperature from 80 °C to 100 °C.
  • trametinib solution is mixed with the first solvent in the process of the present invention.
  • the first solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2-dichloro- ethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydrofuran, 2- propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene,
  • nitromethane N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert- butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene.
  • methanol, ethanol, propan-2 -ol, propan- l-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.
  • the first solvent is cooled in the process of the present invention.
  • the first solvent is cooled at a temperature from -20 °C to 20 °C, preferably at temperature from -10 °C to 10 °C, or more preferably at temperature from -10 °C to 10 °C.
  • a solid form of the solvate of trametinib and the first solvent is separated by filtration in the process of the present invention.
  • the solid form of the solvate of trametinib and the first solvent is dried in the process of the present invention.
  • the drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure.
  • the solvate is at pressure lower than or equal to the atmospheric pressure.
  • the solid form of the solvate of trametinib and the first solvent is heated when dried in the process of the present invention.
  • the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.
  • trametinib cyclo- hexanol solvate
  • trametinib 1.5 g was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled ethanol at 0 °C upon constant stirring. The mixture was seeded with trametinib ethanol solvate (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value
  • trametinib 1.5 g was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled 2-propanol at 0 °C upon constant stirring. The mixture was seeded with trametinib 2-propanol complex (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.
  • Trametinib was dissolved in 1,4-dioxane at concentration around 3 wt.% at elevated temperature. The solution was freeze dried at 0 °C/10-50 mTorr for 3 hours followed by secondary drying at 25 °C/10-50 mTorr. 1g of freeze dried trametinib was suspended at temperature of 25 °C upon constant stirring in 20 mb of ethanol. The resulting slurry was stirred for about two hours at 25 °C. The solids were fdtered off by suction fdtration, suck dried in air for one hour and then at 40 °C/vacuum/nitrogen bleed for 4 hours. The yield: 0.890 g (83 %).
  • Example 11 The propan-2-ol solvate
  • Trametinib was dissolved in 1,4-dioxane at concentration around 3 wt.% at elevated temperature. The solution was freeze dried at 0 °C/ 10-50 mTorr for 3 hours followed by secondary drying at 25 °C/10-50 mTorr. 0.87 g of freeze dried trametinib was suspended at temperature of 25 °C upon constant stirring in 20 mL of propan-2-ol. The resulting slurry was stirred for about two hours at 25 °C. The solids were filtered off by suction filtration, suck dried in air for one hour and then at 40 °C/vacuum/nitrogen bleed for 4 hours. The yield: 0.65 g (68 %).
  • trametinib 90 mg was mixed with approximately 20 mg of trametinib complex with methanol and 1 mL of methanol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.
  • trametinib 90 mg was mixed with approximately 20 mg of trametinib complex with ethanol and 1 ml of ethanol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.
  • trametinib 90 mg was mixed with approximately 20 mg of trametinib complex with propan- 2-ol and 1 ml of propan-2-ol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.
  • trametinib 1.5 g was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and filtered through PTFE (0.7 microns) filter into 40 ml of pre-cooled ethanol at 0 °C upon constant stirring. The mixture was seeded with trametinib ethanol solvate (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum filtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.
  • trametinib 1.5 g was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled 2-propanol at 0 °C upon constant stirring. The mixture was seeded with trametinib 2-propanol complex (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.
  • Example 22 The purity of solvates The trametinib and trametinib solvate samples were analyzed for a sum of area percent levels of impurities HPLC.
  • the column was eluted, using a gradient method, with aqueous ammonium dihydrogen phosphate (10 mM, pH 6.5) and acetonitrile-methanol (3: 1) at column temperature of 30 °C for 15 min.
  • Table 1 The material purities as detected by HPLC area % by internal normalization for the materials obtained as exemplified above.

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Abstract

La présente invention concerne des solvates d'un composé de formule (1) et leurs procédés de préparation.
PCT/EP2024/086872 2023-12-21 2024-12-17 Solvates de trametinib Pending WO2025132408A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP23219290.6 2023-12-21
EP23219262 2023-12-21
EP23219290 2023-12-21
EP23219262.5 2023-12-21
EP23219049 2023-12-21
EP23219049.6 2023-12-21

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WO2025132408A3 WO2025132408A3 (fr) 2025-08-21

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121142A1 (fr) 2004-06-11 2005-12-22 Japan Tobacco Inc. Dérivés de 5-amino-2,4,7-trioxo-3,4,7,8-tétrahydro-2h-pyrido’2,3-d! pyrimidine et composés apparentés pour le traitement du cancer
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