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WO2025126143A1 - Formes cristallines d'antagoniste du récepteur a2a, procédés de préparation et utilisations associées - Google Patents

Formes cristallines d'antagoniste du récepteur a2a, procédés de préparation et utilisations associées Download PDF

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Publication number
WO2025126143A1
WO2025126143A1 PCT/IB2024/062638 IB2024062638W WO2025126143A1 WO 2025126143 A1 WO2025126143 A1 WO 2025126143A1 IB 2024062638 W IB2024062638 W IB 2024062638W WO 2025126143 A1 WO2025126143 A1 WO 2025126143A1
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Prior art keywords
ray powder
pyrimidine
cyanophenyl
pyrazolo
differential scanning
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Alicia Tee Fuay Ng
Lisa McQUEEN
Eszter TIEGER
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Johnson and Johnson Enterprise Innovation Inc
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Johnson and Johnson Enterprise Innovation Inc
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 compound of Formula (I) is an orally bioavailable small molecule selective A2a receptor antagonist. In vitro, it enhanced T cell activation and cytokine secretion in primary CD4+ and CD8+ T cells. In vivo, it potentiated anti-tumor response to radiation therapy in combination with anti-PD-1 in 3 different mouse tumor models (CT-26, B 16F 10, and EG7 -OVA) resulting in enhanced tumor growth inhibition, tumor regression, and increased survival compared to monotherapy with either agent or the combination.
  • CT-26, B 16F 10, and EG7 -OVA 3 different mouse tumor models
  • a crystalline form of a compound can improve the thermodynamic stability, and has the technological operation advantage of easy further purification, easy filtration, drying and so on.
  • Some crystalline forms provide advantages of stability, ease of manufacture and/or formulating. Therefore, it is necessary to further research and develop crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)- 3- hydroxy-3 -methylbutan-2-yl]pyrazolo[l, 5 -a]pyrimidine-5 -carboxamide, which possess characteristics such as high melting point and better stability, suitable for drug formulations.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form C.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form D.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form E.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form F.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form H.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form J.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form K.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form L.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form M.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form N.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form O.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form P.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form Q.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form R.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form S.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form U.
  • crystalline 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl ]pyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide is Form V.
  • FIG. 1 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 3 illustrates the thermogravimetric analysis (TGA) curve of crystalline Form A of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 7B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form C of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • FIG. 8 illustrates the DVS isotherm plot of crystalline Form C of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • FIG. 9 illustrates the X-ray powder diffraction curve of crystalline Form G of 2- (3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • FIG. 10A illustrates the differential scanning calorimetry (DSC) curve of crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 10B illustrates the TGA curve crystalline Form G of 2-(3-cyanophenyl)-3- (2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide .
  • FIG. 11 illustrates the sorption isotherm of crystalline Form G of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • FIG. 12 depicts the crystal structure of crystalline Form G of 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide ; water molecules are depicted in spacefilled style for better visibility.
  • FIG. 13 illustrates the XRPD overlay of the samples obtained from VT-XRPD experiments on crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 14 illustrates the differential scanning calorimetry (DSC) curve of crystalline Form N of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • FIG. 16 illustrates the PLM image of Form C crystallized from the crystallization process in 2-methyltetrahydrofuran /heptane.
  • FIG. 17A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 17B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 17C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form B of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 18A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 18B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 18C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form D of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 19A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 19B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 19C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form E of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 20A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 20B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 20C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form F of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 21 A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 2 IB illustrates the differential scanning calorimetry (DSC) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 21C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form H of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 22A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 22B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 22C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form I of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 23A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 23B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 23C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form J of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 24A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 24B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 24C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form K of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 25A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 25B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 25C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form L of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 26 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form M of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 27 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form O of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 28 illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form P of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 29A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 29B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 29C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form Q of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 30A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 30B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 30C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form R of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 31 A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 3 IB illustrates the differential scanning calorimetry (DSC) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 31C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form S of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 32A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 32B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 32C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form T of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 33A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 33B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 33C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form U of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 34A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 34B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 34C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form V of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 35A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 35B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 35C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form W of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • TGA thermogravimetric analysis
  • FIG. 36A illustrates the X-ray powder diffraction (XRPD) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • XRPD X-ray powder diffraction
  • FIG. 36B illustrates the differential scanning calorimetry (DSC) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • FIG. 36C illustrates the thermogravimetric analysis (TGA) curve of crystalline Form X of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.
  • TGA thermogravimetric analysis
  • FIG. 37 illustrates an XRD overlay of simulated SXRD data from Form C of 2- (3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (bottom plot) and Form Y of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide (top plot).
  • compositions and methods may be understood more readily by reference to the following detailed description, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.
  • the term “about” preceding a numerical value or a series of numerical values means ⁇ 10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg.
  • the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or.”
  • treatment refers to the treatment of a disease, disorder, or medical condition (such as a gastrointestinal inflammatory disease), in a patient, such as a mammal (particularly a human) which includes one or more of the following:
  • Efficacy and “effective” as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention.
  • 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide can be administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated.
  • indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient.
  • Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question.
  • the degree of improvement generally is determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease.
  • an effective amount means an amount sufficient to affect treatment when administered to a patient in need of treatment.
  • subject includes any human or nonhuman animal
  • non-human animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • subject and patient can be used interchangeably herein.
  • the peaks of the XRPD pattern can be obtained from the pattern by conventional methods, which are known to those skilled in the field.
  • a Form such as Form A, Form B, etc. throughout refers to a polymorphic form of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N-
  • substantially pure is used herein to describe a crystalline form that has a purity in crystalline structure or form (such as, for example Form A substantial pure of Form S) of greater than 90%, greater than 96% pure, greater than 97% pure, greater than 98% pure, or greater than 99% pure.
  • 20 or 20 angle used in the present invention refers to the diffraction angle, 0 is the Bragg angle, and the unit of which is ° or degree.
  • the error range of 20 is from ⁇ 0.1 to ⁇ 0.5, preferably from ⁇ 0.1 to ⁇ 0.3, and more preferably ⁇ 0.2.
  • interplanar spacing or interplanar distance (d value) used in the present invention means that the space lattice selects three unit vectors a, b, c, wherein the each of the them connects two adjacent lattice dots, and the three vectors divide the lattice into juxtaposed parallel juxtagonal units, called the interplanar spacing.
  • the space lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, which is called a space lattice or a lattice.
  • the lattice reflects the periodicity of the crystal structure with geometric points and lines. Different crystal planes have different interplanar spacings (i.e., distance between two adjacent parallel crystal planes); the unit is A or angstrom.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis means to measure the thermal stability of a sample, in which changes in the weight of a sample are measured while its temperature is increased. Moisture and volatile contents of a sample can be measured by TGA. This measurement provides information about physical phenomena, such as phase transitions, absorption, adsorption and desorption; as well as chemical phenomena including chemisorptions, thermal decomposition, and solid-gas reactions (e.g., oxidation or reduction).
  • Form A of 2-(3-cyanophenyI)-3-(2,6-dimethyIpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methyIbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide is characterized as having:
  • crystalline Form A is a metastable form.
  • crystalline Form A can convert to crystalline Form C in an organic solvent at 25°C and 50°C.
  • organic solvent include, but not limited to, ethanol, acetone, t-butyl methyl ester, tetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, and heptane.
  • the invention relates to crystalline Form S of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.
  • Form S can be obtained from storing Form A at ambient condition for about 2 months or exposure of Form A to 92%RH for 1 day.
  • DSC of Form S shows a dehydration peak at Tonset of 14.3°C with an enthalpy of about 33J/g, and a melting peak at Tonset of 120.6°C and a recrystallization peak at Tonset of 133.1°C. Then it melts at Tonset of 190.9°C with an enthalpy of about 80J/g.
  • crystalline Form S of 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4 yl)- N- [ (2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide is characterized as having:
  • differential scanning calorimetry curve comprises a dehydration peak at Tonset of 14.3°C with an enthalpy of about 33J/g, and a melting peak at Tonset of 120.6°C and a recrystallization peak at Tonset of 133.1°C. Then it melts at Tonset of 190.9°C with an enthalpy of about 80J/g;
  • Form S is characterized as having at least two, or at least three of the properties selected from (a) to (c). In Some embodiments Form S is characterized as having properties (a), (b) and (c). In some embodiments, Form S is characterized as having at least two of the properties selected from (a), (b) and (c). In some embodiments. Form S is characterized as having each of the properties (a), (b) and (c). In some embodiments, crystalline Form S is a hydrate.
  • the invention relates to crystalline Form C of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • crystalline Form C is an anhydrate.
  • Form C is characterized as having:
  • differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about
  • a differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 7B ;
  • thermogravimetric analysis curve (h) a thermogravimetric analysis curve, wherein the thermogravimetric analysis curve is substantially similar to the thermogravimetric analysis curve in FIG. 7A.
  • thermogravimetric analysis curve shows about 0.6% weight loss at about 200.0°C
  • Form C is characterized as having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, nine, ten or all eleven of the properties selected from (a) to (k). In Some embodiments Form C is characterized as having properties (a), (b), (c), (e), (f), and (i). In other embodiments Form C is characterized as having properties one, two, or three of the properties (b), (f) and (i).
  • Form C is characterized as having properties (a), (d),(e) and (h).
  • crystalline Form C is a thermodynamically stable anhydrate. In certain embodiments, crystalline Form C is stable in a.w. ⁇ 0.4 at 25°C, and it converts to crystalline Form G in a.w. > 0.6 at 25°C.
  • the invention relates to crystalline Form G of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.
  • crystalline Form G is a dihydrate.
  • Form G is characterized as having:
  • differential scanning calorimetry curve comprises a dehydration peak at T onS et of 33.3°C with an enthalpy of about 206 J/g and an exothermic peak at T onS et of 168.1°C with an enthalpy of about 23 J/g, and an endothermic peak at T onS etof 193.7°C with an enthalpy of about 76 J/g.
  • differential scanning calorimetry curve comprises a melting endothermic peak of from 190°C to 200 °C, preferably from 190°C to 195°C, and more preferably about 194.4°C.
  • differential scanning calorimetry curve is substantially similar to the differential scanning calorimetry curve in FIG. 10A;
  • Form G is characterized as having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, nine, ten or all eleven of the properties selected from (a) to (k). In Some embodiments Form G is characterized as having properties (a), (b), (c), (e), (f), and (i). In other embodiments Form G is characterized as having properties one, two, or three of the properties (b), (f) and (i). In other embodiments Form G is characterized as having properties (a), (d),(e) and (h).
  • crystalline Form G is stable in a.w. > 0.6 at 25°C.
  • the invention relates to crystalline Form N of 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.
  • crystalline Form N is an anhydrate.
  • Form N is characterized by
  • Form N is characterized as having at least two, at least three, at least four, or all least five of the properties selected from (a) to (e). In some embodiments Form N is characterized as having one two or three of the properties selected from (a), (b), and (d). In some embodiments, crystalline Form N is metastable. In certain embodiments, crystalline Form N is not stable at ambient condition.
  • Crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.
  • Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent.
  • Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.
  • Class 1 solvents, which are to be avoided, include: benzene: carbon tetrachloride; 1 ,2-dichloroethane; 1,1 -di chloroethene; and 1,1,1 -trichloroethane.
  • Class 2 solvents are: acetonitrile, chloroben Zene, chloroform, cyclohexane, 1,2-dichloroethene, dichlo romethane, 1 ,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxy ethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxy ethanol, methylbutyl ketone, methylcyclohexane, N-meth ylpyrrolidine, nitromethane, pyridine, Sulfolane, tetralin, toluene, 1.1.2-trichloroethene and Xylene.
  • Class 3 solvents which possess low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l -propanol, pentane, 1 -pentanol.
  • compositions comprising 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide include a residual amount of an organic solvent(s).
  • compositions comprising 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide include a detectable amount of an organic solvent(s).
  • the organic solvent is a Class 3 solvent.
  • the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1- butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l -propanol, pentane, 1 -pentanol.
  • the Class 3 solvent is ethanol.
  • the methods and compositions described herein include the use of crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide.
  • the crystalline forms of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents Such as water, ethanol, and the like, include a residual amount of a Class 3 solvent.
  • the organic solvent is a Class 3 solvent.
  • the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, methylethyl ketone, methylisobutyl ketone,
  • the Class 3 solvent is ethanol.
  • crystalline forms can be prepared by recrystallization or equilibration with a solvent or a solvent mixture.
  • the recrystallization method is not particularly limited, and can be carried out by a conventional recrystallization process.
  • the material i.e., 2-(3- cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2- yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide
  • the material can be dissolved in a solvent or a solvent mixture under heating, and then the solution is cooled slowly to precipitate a crystal. After the completion of crystallization, the desired crystal can be obtained via filtering and drying.
  • the crystallization method of the present invention includes room temperature crystallization, cooling crystallization and the like.
  • the equilibration method can be carried out in a solvent or a solvent mixture at a room temperature (about 20 -30 °C) or at an elevated temperature (such as 50-80 °C).
  • the compound of Formula (I) and the solvent or solvent mixture are mixed to forma a suspension, and the suspension is allowed to stir for a suitable amount of time to obtain the desired crystalline form.
  • Examples of the solvent that can be used in the recrystallization or the equilibration include, but not limited to, water, methanol, ethanol, isopropyl acetate, acetone, t-butyl methyl ether, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, methyl ethyl ketone, toluene, 2-propanol, heptane, heptane, 1,4-dioxnae, or any combinations thereof.
  • the starting material used in the methods for preparing the crystalline forms of the present invention can be 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)- 3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in any form, and the specific forms include, but are not limited to, amorphous form, arbitrary crystal forms and the like.
  • the invention presents a method of preparing crystalline Form A.
  • the method of preparing crystalline Form A comprises recrystallizing 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l ,5-a]pyrimidine-5-carboxamide .
  • the method comprises dissolving 2-(3-cyanophenyl)-3- (2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide in acetonitrile or a mixture of acetonitrile and water to form a solution under heating, preferably under refluxing, and then cooling the solution to obtain crystalline Form A.
  • the invention presents a method of preparing crystalline Form C.
  • the method of preparing crystalline Form C comprises suspending 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3- methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide in ethyl acetate to form a suspension, optionally adding a Form C seed, and stirring the suspension at a suitable temperature for a suitable period of time to obtain crystalline Form C.
  • the suitable temperature is about 30-70 °C, preferably about 40-60 °C, more preferably about 50 °C.
  • the method comprises optionally adding a Form C seed when the solution is cooled to a temperature of about 50 to 60 °C, preferably about 55 °C.
  • the ratio of the volume (ml) of the mixture of acetone and water to the weight (gram) of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide is about 2 to 10, preferably about 4-6, more preferably about 5.
  • the method of preparing crystalline Form N comprises heating crystalline Form G of 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5-a]pyrimidine-5-carboxamide .
  • compositions in one another general aspect, presents a pharmaceutical composition comprising an effective amount of, in particular a therapeutically effective amount of, at least one of the crystalline forms described herein, and a pharmaceutically acceptable carrier.
  • carrier refers to any excipient, diluent, buffer, stabilizer, or other material well known in the art for pharmaceutical formulations.
  • Pharmaceutically acceptable carriers in particular are non-toxic and should not interfere with the efficacy of the active ingredient.
  • the pharmaceutically acceptable carriers include excipients and/or additives suitable for use in the pharmaceutical compositions known in the art, e.g., as listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), the disclosures of which are entirely incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.
  • a particular carrier or excipient, or combinations of carriers or excipients will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state.
  • preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts.
  • the carriers or excipients used in the pharmaceutical compositions of this invention are commercially- available.
  • conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid;
  • compositions of the disclosure are preferably packaged in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units.
  • unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration.
  • the pharmaceutical composition disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject in need thereof.
  • the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
  • the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.
  • the pharmaceutical composition can be a single unit administration with an accurate dosage.
  • the pharmaceutical composition may further comprise additional active ingredients.
  • compositions disclosed herein can be produced by the conventional methods in the pharmaceutical field.
  • the active ingredient can be mixed with one or more excipients, then to make the desired formulation.
  • the invention presents the uses of crystalline forms or the pharmaceutical compositions of the invention, particularly the uses as A2a receptor antagonists.
  • the invention presents a method of treating a disease or disorder in which A2a is implicated, comprising administering to a subject in need thereof an effective amount of crystalline form or the pharmaceutical composition described herein.
  • the invention presents a use of crystalline form or the pharmaceutical composition in the preparation of a medicament for the treatment of a disease or disorder.
  • the disease or disorder is one in which A2a receptor activity is implicated.
  • the disease or disorder is cancer, particularly solid tumors such as lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • Ethyl 7-chloro-2-(3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (53.43 g, 163.52mmol) was placed in a flat-bottomed 3-neck 5L flask equipped with a triangular cross- section rod stirrer bar. Palladium on carbon (10%) (4.35 g, 4.09mmol) was then added, followed by ethyl acetate (3200mL) and triethylamine (113.96 mL, 817.62mmol), and the necks sealed.
  • Activated Manganese dioxide (142.18 g, 1635.4mmol) was added to the solution of a crude mixture of ethyl 2-(3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5- carboxylate and ethyl 2-(3- cyanophenyl)-4,7-dihydropyrazolo[l,5- a]pyrimidine-5-carboxylate (95.71 g, 327.08mmol) in chloroform (3200mL) and the resulting mixture stirred vigorously at room temperature for 3 hours, after which time UPLCMS analysis showed no visible change in the UV trace but complete consumption of the SM and formation of the desired product on manual analysis of the mass data.
  • NBS (67.88 g, 381.4mmol) was added in one-portion to a stirred partial suspension of ethyl 2- (3-cyanophenyl)pyrazolo[l,5-a]pyrimidine-5-carboxylate (92.9 g, 317.84mmol) in DMF (1590mL) after which the solids soon dissolved and the mixture was stirred at room temperature for 60 mins, after which time UPLCMS analysis showed complete consumption of SM and formation of the DP as the sole UV active species. The mixture was cooled in an ice bath before water (3200 mL) was added slowly [NB - moderate exotherm. Maximum internal temperature reached was 35 °C].
  • Product (2) of Table 9 prepared according to Example 11 was used as starting material. One temperature cycle was applied. Initial XRPD analyses were carried out in ambient conditions. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature.
  • Cycle 1 25°C (initial)- 125 °C (10min)-160°C (10min)-25°C (lOmin).
  • the water activity experiments were conducted at 25 °C in EtOH/water and EA/water systems to determine critical water activity between free form Form B, Form C and Form G.
  • Table 19 water activity is calculated by UNIFAC method.
  • Table 20 water activity is calculated by UNIFAC method.
  • the Infrared (IR) spectrum of Form C prepared in accordance with Example 2 is substantially similar to the one set forth in Figure 18 having weak peaks at about 3357cm" ⁇ 2977 cm" 1 , 2932 cm” 1 , 2231 cm” 1 , 1585 cm" 1 , 860 cm” 1 , 833 cm” 1 .
  • Form C is a crystalline anhydrate. It was obtained from: • equilibration in ethanol (EtOH), acetone, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), ethyl acetate (EA), toluene, heptane;
  • Form C prepared in accordance with Example 2 is a crystalline (FIG. 5) anhydrous form with a melting point of 192.6°C (FIG. 7) with an enthalpy of about 94 J/g.
  • TGA shows about 0.5% weight loss at about 200.0°C.
  • HPLC shows 99.6% chemical purity.
  • 1H-NMR shows no solvent residue and is slightly hygroscopic (FIG. 8). Characterization of Form C is summarized in Table 23.
  • a summary of the structural data can be found in Table 23.
  • the asymmetric unit contains two molecules of 2-(3-cyanophenyl)-3-(2,6- dimethylpyridin-4 yl)- N- [(2S)-3- hydroxy-3-methylbutan-2-yl]pyrazolo[l,5- a]pyrimidine-5-carboxamide (Table 24, FIG. 6).
  • Form C is a thermodynamically stable anhydrate at 15°C and at higher temperatures.
  • Form C has an enantiotropic form that is stable at lower temperatures.
  • This low temperature enantiotropic form is Form Y.
  • the SCXRD structures of Form C and Form Y were compared to produce an overlay of simulated XRD patterns of Form C and Form Y shown in Figure 37.
  • SXRD, heat-cool-heat DSC and variable temperature XRD confirmed that there is an enaniotropic relationship between Form Y and Form C.
  • Heat-cool-heat DSC analysis showed reversible enantiotropic transformation in the temperature range of 15-22 °C in all analysed batches.
  • Variable temperature XRD confirmed that the transition temperature is between 5 and 15 °C.
  • Form G prepared in accordance with Example 3 is a crystalline (FIG. 9) dihydrate that desolvates upon heating (FIG. 10) and the resulting anhydrate (Form N) recrystallizes to Form C around 168°C (FIGs. 10 and 13).
  • the sorption isotherm of Form G shows that Form G dehydrates below 30% RH, forming Form N, but its dehydration and rehydration is reversible, in agreement with the channel-like arrangement of water molecules in the lattice as seen in the crystal structure (FIG. 12, Table 24).
  • Form N was an anhydrate and was obtained from heating Form G to 80°C by hot- stage XRPD.
  • Form N is a metastable phase (Table 3) that converts to Form C upon heating (FIG. 14).
  • the XRPD of Form N is shown in FIG. 15.
  • Hydrogen atoms attached to a heteroatom were located in a difference Fourier map and were allowed to refine freely with an isotropic displacement parameter.
  • a reference diffractogram for the crystal structure was generated using Mercury (C. F. a. Macrae, “Mercury: visualization and analysis of crystal structures,” J. Appl. Cryst., vol. 39, pp. 453-457, 2006).
  • Samples were studied on a Nikon SMZ1500 polarised light microscope with a digital video camera connected to a DS Camera control unit DS-L2 for image capture. The sample was viewed with appropriate magnification and partially polarised light, coupled to a I false-colour filter.
  • VT-XRPD Temperature X-Ray Powder Diffractometer

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Abstract

L'invention concerne des formes cristallines du 2-(3-cyanophényl)-3-(2,6-diméthylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-méthylbutan-2-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide, antagoniste du récepteur A2A, ainsi que des procédés de préparation et des utilisations de celles-ci.
PCT/IB2024/062638 2023-12-13 2024-12-13 Formes cristallines d'antagoniste du récepteur a2a, procédés de préparation et utilisations associées Pending WO2025126143A1 (fr)

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PCT/IB2024/062638 Pending WO2025126143A1 (fr) 2023-12-13 2024-12-13 Formes cristallines d'antagoniste du récepteur a2a, procédés de préparation et utilisations associées

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021224636A1 (fr) 2020-05-07 2021-11-11 AdoRx Therapeutics Limited Antagonistes du récepteur a2a de l'adénosine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021224636A1 (fr) 2020-05-07 2021-11-11 AdoRx Therapeutics Limited Antagonistes du récepteur a2a de l'adénosine

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Impurities: Guidelines for Residual Solvents", INTERNATIONAL CONFERENCE ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH, November 2005 (2005-11-01)
"Physician's Desk Reference", 1998, MEDICAL ECONOMICS
"Remington: The Science & Practice of Pharmacy", 1995, WILLIAMS & WILLIAMS
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WHITE
H.C. ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WHITE
MACRAE: "Mercury: visualization and analysis of crystal structures", J. APPL. CRYST., vol. 39, 2006, pages 453 - 457

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