Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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 encompasses Sunitinib hemi-L-malate. In one embodiment, the invention encompasses a crystalline form of sunitinib hemi-
• Figure 8 illustrates a powder X-ray diffraction pattern of composition I containing Sunitinib base and L-malic acid.
• Figure 8a illustrates a powder X-ray diffraction pattern of composition I containing
• Figure lla illustrates a powder X-ray diffraction pattern of composition L containing Sunitinib base and L-malic acid (zoomed).
• Figure 21 illustrates a DSC thermogram of of sunitinib hemi-L-malate form U.
• Figure 37 illustrate a powder XRD pattern of crystalline Sunitinib base Form II.
• Sunitinib base characterized by crystalline Sunitinib base characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks selected from the list consisting of: 3.8, 7.8, 9.0, 10.2, 11.8, 15.8, 17.9, 20.3, 26.1 and 26.8 deg ⁇ 0.2 degrees 2-theta, a PXRD pattern having peaks at about 9.0 and 26.1 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of 3.8, 7.8, 10.2, 11.8, 15.8, 17.9, 20.3 and 26.8 deg ⁇ 0.2 degrees 2-thetaa PXRD pattern as depicted in Figure 37 and combination thereof.
• the crystalline racemic sunitinib malate Form A can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7, 8.0, 12.5, 14.7 and 18.3 ⁇ 0.2 degrees 2-theta; a PXRD pattern having peaks at about 5.7, 8.0, 9.3, 24.7 and 18.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having a single peak at about 27.4 ⁇ 0.2 degrees 2-theta.
• the crystalline racemic sunitinib malate Form A can be prepared by a process comprising reacting Sunitinib base and racemic malic acid in ethanol to obtain a suspension comprising the said crystalline form.
• the said solution is maintained at the said temperature for a period of about 15 minutes to about 2 hours. More preferably, the said solution is maintained at the said temperature for a period of about 30 minutes.
• the present inventions encompasses crystalline sunitinib hemi-L-malate designated form E characterized by a PXRD pattern having peaks at about 6.8 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 3.7, 11.9, 15.1, 25.9 and 26.6 ⁇ 0.2 degrees 2-theta.
• Crystalline sunitinib hemi-L-malate can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 3.7, 6.8, 11.3, 11.9 and 25.9 ⁇ 0.2 degrees 2-theta.
• the aqueous solution is provided by combining sunitinib base, water and L- malic acid, and heating the combination.
• the heating is done to a temperature of about 100 0 C.
• L-malic acid in water to obtain a solution, and lyophilizing the solution; wherein the ratio of L-malic acid to water is about 34:1 w/v, respectively.
• the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.0, 7.7, 9.2, 12.3, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta, a PXRD pattern as depicted in Figure 12, a PXRD pattern as depicted in Figure 12a and combination thereof.
• This composition can be designated as composition M.
• composition M can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.0, 9.2, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having peaks at about 7.7, 9.2, 12.3, 14.5 and 23.0 ⁇ 0.2 degrees 2-theta.
• Composition M can be prepared by a process comprising heating Sunitinib malate to a temperature of about 50°C to 100°C. Preferably, heating is done to a temperature of about 8O 0 C. Preferably, heating is done for a period of about 30 minutes to about 4 hours. More preferably, heating is done for a period of about 2 hours.
• Composition N can be prepared by a process comprising dissolving sunitinib malate in a mixture of dioxane and water, and lyophilizing the solution. In the lyophilization process, the said solution is subjected to a pressure of less than about one atmosphere, to remove solvent.
• composition O can be further characterized by a PXRD pattern having four peaks at about 6.0, 7.4, 8.9 and 11.9 ⁇ 0.2 degrees 2-theta.
• the composition O can be prepared by a process comprising combining sunitinib base, L-malic acid, and a mixture of water, and tetrahydrofuran and evaporating the solvent.
• the solution is provided by combining sunitinib base, L-malic acid and a mixture of water and dioxane, and heating the said combination to obtain a solution.
• the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern any 5 peaks at positions selected from the group consisting of: 3.4, 5.6, 9.6, 10.3,
• the invention encompasses a composition containing Sunitinib base and L-malic acid, characterized by a PXRD pattern having peaks at about 8.5 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks selected from a group consisting of 14.2, 23.2, 24.0 and 26.9 ⁇ 0.2 degrees 2-theta.
• Example 10 Preparation of composition H containing sunitinib base and L-malic acid. To sunitinib base (form VII, 300 mg) and L-malic acid (101 mg) was added TBME 10 ml) and the slurry was heated 10 min to reflux temperature facilitating formation of the titled composition (368 mg).
• Example 13 Preparation of composition O containing sunitinib base and L-malic acid.
• Sunitinib base (form X, dried 70°C, 2 h, 1 mBar, 150 mg)
• L-malic acid 50 mg in 3 ml of water, 1:1 molar
• THF 8 ml
• boiling to dissolution allowed to evaporate at 20°C to dryness in an open baker.
• Sunitinib base was dissolved in water (250 g) at about 40° by adjusting the pH to 1.5 with IN HCl. The solution was extracted with methyl isobutyl ketone (100 g), the phases were separated and to the aqueous phase dimethylacetamide (20 g) was added. Under strong stirring, the solution was adjusted to pH 8.5 by addition of 25% ammonium hydroxide solution. After one hour the suspension was filtered and the cake was rinsed with 200 g of water. The product was dried at 70° under vacuum overnight to give 12.6 g (56%) of Sunitinib base Form II.
• Sunitinib Base obtained by reaction of Sunitinib activated carboxylic acid derivative with excess of N,N'-diethylaminoethylamine in tetrahydrofuran, were dissolved with 150g of water and 5Og of HCl IM. The solution was washed with methyl isobutyl ketone at 50°C and then precipitated with ammonia 30% in water to pH 9, the product was filtered and dried in oven under vacuum at 60 0 C for 16 hours.
• the stirred suspension was cooled at room temperature for 2 hours and filtered; the cake was washed with 5O g of toluene and dried at 50° under vacuum overnight.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2008
  • 2008-11-21 CA CA2699306A patent/CA2699306A1/en not_active Abandoned
  • 2008-11-21 EP EP08851719A patent/EP2220071A2/de not_active Withdrawn
  • 2008-11-21 KR KR1020107010188A patent/KR20100069705A/ko not_active Application Discontinuation
  • 2008-11-21 CA CA2699305A patent/CA2699305A1/en not_active Abandoned
  • 2008-11-21 EP EP08852503A patent/EP2220072A2/de not_active Withdrawn
  • 2008-11-21 WO PCT/US2008/084386 patent/WO2009067686A2/en active Application Filing
  • 2008-11-21 EP EP10166182A patent/EP2253629A1/de not_active Withdrawn
  • 2008-11-21 WO PCT/US2008/084366 patent/WO2009067674A2/en active Application Filing

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