Crystal of benzoxazole derivative
Inventors
KUMURA, KO • Tamura, Keiji • Watanabe, Takashi • Takahashi, Michiko
Assignees
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Publication Number
US-11512091-B2
Publication Date
2022-11-29
Expiration Date
Abstract
Provided are crystals of 1-((2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl)oxy)-1,1-difluoro-2-methylpropan-2-ol represented by formula (1),
Core Innovation
The disclosed subject matter provides two polymorphic crystal forms, I type crystal and II type crystal, of a PDE4-inhibiting compound represented by formula (1): 1-((2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl)oxy)-1,1-difluoro-2-methylpropan-2-ol. Each polymorphic crystal form is defined by characteristic peaks in powder X-ray diffraction with diffraction angles (2θ) within ±0.2°.
For the I type crystal, an endothermic DSC peak at 205 ± 3°C is also reported as a defining thermal characteristic. The patent reports that both crystal forms exhibit high chemical stability, including results in thermal stability tests, photostability tests, and accelerated stability tests, and distinguishes the two polymorphic forms by hygroscopicity and water uptake at 95% RH.
The disclosed crystalline polymorphs are presented as suitable for pharmaceutical use. The document also states that pharmaceutical compositions contain the crystal forms, and it associates PDE4 with disease areas attributable to or related to PDE4, including asthma, COPD, fibrosis, inflammatory bowel disease, multiple sclerosis, depression, neurodegenerative diseases, and cancers.
Claims Coverage
The provided content includes one independent claim covering a crystal of the named compound by a powder X-ray diffraction peak pattern defined by characteristic diffraction angles (2θ) within ±0.2°, with two alternative peak sets. Dependent claims further add additional peak sets, a DSC thermal characteristic, and pharmaceutical composition coverage.
Powder X-ray diffraction peak-defined crystal polymorph sets
A crystal of 1-((2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl)oxy)-1,1-difluoro-2-methylpropan-2-ol represented by formula (1), wherein the crystal has characteristic powder X-ray diffraction peaks at diffraction angles (2θ ±0.2°) of 7.7°, 14.5°, 17.0°, 18.9°, 19.4°, 23.3°, and 25.7°, or alternatively at diffraction angles (2θ ±0.2°) of 7.8°, 14.7°, 15.7°, 19.3°, and 25.0°.
Additional powder X-ray diffraction peak sets within ±0.2°
The crystal further having characteristic peaks in powder X-ray diffraction at diffraction angles (2θ ±0.2°) including 7.4°, 7.8°, 8.2°, 12.7°, 13.6°, 14.3°, 14.7°, 15.7°, 16.5°, 19.3°, 22.1°, 25.0°, and 25.6°.
DSC endothermic peak temperature for the diffraction-defined crystal
The crystal having an endothermic peak temperature of 205 ± 3°C measured by differential scanning calorimetry (DSC).
Pharmaceutical composition comprising the crystal
A pharmaceutical composition comprising the crystal defined by the diffraction-defined crystal of claim 1.
Overall, the claim coverage is centered on identifying a specific crystalline polymorph of the named PDE4-inhibiting compound by powder X-ray diffraction peak positions within ±0.2°, with additional dependent coverage by adding alternative or expanded diffraction peak lists, a DSC endothermic peak temperature constraint, and pharmaceutical compositions containing the crystal.
Stated Advantages
High chemical stability in thermal stability tests, photostability tests, and accelerated stability tests as supported by HPLC residual ratios of approximately 99.5% to 100.1%.
Distinguishable hygroscopicity behavior, with lower water uptake for the I type crystal (0.6% at 95% RH) than for the II type crystal (10.7% at 95% RH).
Suitable for pharmaceutical use.
Documented Applications
Pharmaceutical compositions containing the crystal forms of the PDE4-inhibiting compound.
Disease areas attributable to or related to PDE4, including asthma, COPD, fibrosis, inflammatory bowel disease, multiple sclerosis, depression, neurodegenerative diseases, and cancers.
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