Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D475/00—Heterocyclic compounds containing pteridine ring systems
  • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
  • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
• • 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 present invention relates to salts of Pralatrexate and their polymorphic forms, process for the preparation thereof, pharmaceutical compositions thereof and the use of pharmaceutical composition for the treatment of conditions related to human tumors.
• 25)-2-[[4-[(lR5)-l-[(2,4-diaminopteridin-6- yl)methyl]but-3-ynyl]benzoyl]amino]- pentanedioic acid has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory peripheral T-cell lymphoma.
• FDA U.S. Food and Drug Administration
• Pralatrexate molecule (I) was first disclosed in Journal of Medicinal Chemistry. 36: 2228- 2231 (1993) by DeGraw et al, and subsequently in US 5374726, US 5354741 and US 6028071.
• Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
• a single molecule like Pralatrexate, may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, Raman spectrum, density, crystal group, and solid state NMR spectrum.
• One polymorphic form may give rise to thermal behavior different from that of another polymorphic form.
• Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• the difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound or complex.
• the present invention addresses a need in the art by providing salts of Pralatrexate in different polymorphic forms, which are believed to provide significant advantages for making pharmaceutical compositions, as compared to the polymorphic form of Pralatrexate free acid disclosed in the prior art.
• salts of Pralatrexate and their Polymorphic forms such as the crystalline forms and amorphous form of the present invention are believed to provide advantages over Pralatrexate free acid disclosed in the prior art.
• Pralatrexate has been described as the free acid of formula (I) in US 6028071, as a treatment for relapsed and refractory peripheral T-cell lymphoma.
• the present invention provides salts of Pralatrexate.
• the present invention also provides processes for their preparation, which is robust and reproducible.
• the present invention further provides pharmaceutical compositions comprising said salts of Pralatrexate and at least one pharmaceutically acceptable excipient.
• the present invention still further provides a method for treatment of tumors using pharmaceutical composition comprising salts of Pralatrexate.
• First aspect of the present invention provides a salt of Pralatrexate of formula (II), wherein M is an alkali or alkaline earth metal.
• the salt of Formula (IF) is Crystalline.
• the salt of Formula (IF) is Amorphous.
• the salt is represented by formula (Ila)
• the salt is represented by the formula (lib)
• Second aspect of the present invention provides a process for producing a salt of formula (II) comprising the steps of
• step (a) is followed by addition of a second suitable solvent.
• step (b) is followed by cooling.
• salt of step (c) is isolated by freeze drying or filtration.
• the compound of Formula (II) is converted to a compound of Formula (I).
• Third aspect of the present invention provides pharmaceutical composition comprising salt of formula (II) and at least one pharmaceutically acceptable excipient.
• Fourth aspect of the present invention provides a method for treatment of tumors using pharmaceutical composition comprising salt of formula (II).
• Figure 1 depicts the X-ray Powder diffractogram of Pralatrexate.
• Figure 2 depicts the X-ray Powder diffractogram of crystalline Pralatrexate disodium of formula (IF).
• Figure 3 depicts the X-ray Powder diffractogram of amorphous Pralatrexate disodium of formula (IF).
• Figure 4 depicts the X-ray Powder diffractogram of amorphous Pralatrexate dilithium of formula (Ila).
• Figure 5 depicts the X-ray Powder diffractogram of amorphous Pralatrexate dipotassium of formula (lib).
• Figure 6 depicts the DSC thermogram of amorphous Pralatrexate dilithium of formula (Ila).
• Figure 7 depicts the TGA profile of amorphous Pralatrexate dilithium of formula (Ila).
• Figure 8 depicts the DSC thermogram of amorphous Pralatrexate dipotassium of formula (lib).
• Figure 9 depicts the TGA profile of amorphous Pralatrexate dipotassium of formula (lib).
• the alkali metal in the compound of formula II may be selected from the group comprising of sodium, lithium, potassium and the like.
• the alkaline -earth metal in the compound of formula II may be selected from the group comprising of calcium, magnesium and the like.
• the salt of Formula (II) may be characterized using various techniques, which are well known to those of ordinary skill in the art. Examples of characterization methods include, but are not limited to, single crystal X-ray diffraction, powder X-ray diffraction (PXRD), simulated powder X-ray patterns, differential scanning calorimetry (DSC), solid-state 13 C- NMR, Raman spectroscopy, infrared spectroscopy, moisture sorption isotherms, thermal gravimetric analysis (TGA), and hot stage techniques.
• characterization methods include, but are not limited to, single crystal X-ray diffraction, powder X-ray diffraction (PXRD), simulated powder X-ray patterns, differential scanning calorimetry (DSC), solid-state 13 C- NMR, Raman spectroscopy, infrared spectroscopy, moisture sorption isotherms, thermal gravimetric analysis (TGA), and hot stage techniques.
• the crystalline salt of Formula (IF) may be characterized as having powder X-ray diffraction pattern peaks of 2 ⁇ at 4.32, 6.08, 6.81, 9.93, 17.4, 23.13, 25.48, 27.82 ⁇ 0.2°.
• the crystalline salt of formula (IF) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 2.
• the crystalline polymorphic form of formula (IF) may be further characterized by having water content between about 1% and about 20 %.
• the amorphous salt of formula (IF) may be characterized by powder X-ray diffraction of one broad halo at 2 ⁇ of about 26°.
• the amorphous polymorphic form of salt of formula (IF) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 3.
• the amorphous form may be further characterized by having water content between about 1% and about 20 %.
• the amorphous salt of formula (Ila) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 4.
• the amorphous form may be further characterized by having water content between about 1% and about 20 %.
• the amorphous salt of formula (Ila) may be further characterized by having a DSC thermogram substantially as shown in Figure 6.
• the amorphous salt of formula (Ila) may be still further characterized by having a TGA profile substantially as shown in Figure 7.
• the amorphous form may be further characterized by having water content between about 1% and about 20 %.
• the amorphous salt of formula (lib) may be characterized by having a powder X-ray diffraction pattern substantially as shown in Figure 5.
• the amorphous form may be further characterized by having water content between about 1% and about 20 %.
• the amorphous salt of formula (lib) may be further characterized by having a DSC thermogram substantially as shown in Figure 8.
• the amorphous salt of formula (lib) may be still further characterized by having a TGA Profile substantially as shown in Figure 9.
• the amorphous form may be further characterized by having water content between about 1% and about 20 %.
• the present salt forms may be anhydrous or contain solvent(s), such as water.
• the present salt forms comprise solvate, such as hydrate.
• Pralatrexate used as starting material may be obtained by any of the methods known in the art including as described in Example- 1.
• the source of alkali or alkaline earth metal, used in the process for producing salt of formula (II) may be selected from inorganic bases like metallic hydroxides such as but not limited to those of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide; metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate.
• metallic hydroxides such as but not limited to those of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide
• metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate
• metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate.
• the suitable solvent, used in the process for producing salt of formula (II) may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.
• the process for producing a salt of formula (II) may be carried out by reacting Pralatrexate of formula (I) at a temperature range of 0°C-60°C. Preferably the temperature is between 20-30°C.
• the process for producing a salt of formula (II) may be carried out by reacting Pralatrexate of formula (I) for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 8 Hours.
• a second suitable solvent may be used in the process for producing salt of formula (II) as defined herein above.
• the reaction mixture may be further cooled in the process for producing salt of formula (II) at a temperature range of -80° to 20°C.
• the salt of formula (II) may be isolated from the reaction mixture by freeze drying or filtration.
• the salt of formula (II) may be isolated from the reaction mixture at a temperature range of - 200°C to 30°C.
• the Salt of formula (II) may be converted to compound of formula (I).
• the process for producing crystalline of salt of formula (IF) may be carried out in an aqueous medium.
• the crystalline salt of formula (IF) may be obtained by adding a suitable second solvent to the reaction mixture.
• the second solvent may be selected from methanol, ethanol, 2-propanol, Tetrahydrofuran, acetic acid, acetonitrile and acetone.
• the process for producing a crystalline salt of formula (IF) may be carried out at a temperature range of 0°C - 60°C. Preferably the temperature is between 20-30°C.
• the process for producing a crystalline salt of formula (IF) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 15 minutes. The reaction mixture may be isolated by filtration to obtain a crystalline salt of formula ( ⁇ ').
• the process for producing an amorphous salt of formula (IF) may be carried out in an aqueous medium.
• the process for producing an amorphous salt of formula (IF) may be carried out at a temperature range of 0°C - 60°C. Preferably the temperature is between 20-30°C.
• the process for producing an amorphous salt of formula (IF) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 10 minutes to 20 minutes.
• the amorphous salt of formula (IF) may be obtained by isolating the reaction mixture by freeze drying.
• the process for producing an amorphous salt of formula (Ila) may be carried out in a suitable solvent.
• the reaction mixture may be cooled in the process for producing salt of formula (Ila) in the temperature range of -80° to 20°C. Preferably the temperature is between -20 to 15°C.
• the process for producing an amorphous salt of formula (Ila) may be carried out for about 1 minute to 24 hours. Preferably reaction is carried out for 1 hour to 8 hours.
• reaction mixture may be isolated by filtration to obtain amorphous salt of formula (Ila).
• the process for producing an amorphous salt of formula (lib) may be carried out in an aqueous medium.
• the amorphous salt of formula (lib) may be obtained by adding a suitable second solvent to the reaction mixture.
• the second solvent may be selected from methanol, ethanol, 2- propanol, Tetrahydrofuran, acetic acid, acetonitrile and acetone.
• the process for producing an amorphous salt of formula (lib) may be obtained by cooling the reaction mixture in the temperature range of -25°C to 25°C.
• the reaction mixture may be isolated by filtration to obtain a salt of formula (lib).
• isolation includes filtration, filtration under vacuum, freeze drying, and decantation.
• freeze drying describes a process in which a solution or slurry containing the salt of formula (IF) is placed within a container and cooled or frozen under vacuum.
• the container is connected to one or more vacuum sources, and a vacuum (pressure less than 760 torr) is applied.
• the container is then cooled to a temperature less than 0°C, preferably between -200° C and 0° C.
• composition comprising salts of formula (II) and at least one pharmaceutically acceptable excipient.
• composition comprising salt of formula (II), including both solid tumors and leukemias.
• the composition may be used in the treatment of human mammary tumors and human lung cancer, particularly in the treatment of T-cell lymphomas.

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Citations (6)

• 2013
  • 2013-07-31 WO PCT/IB2013/056285 patent/WO2014020553A1/fr not_active Ceased

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