Salt of fused heterocyclic derivative and crystal thereof
Inventors
Jo, Kazumichi • Takeuchi, Hideki
Assignees
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Publication Number
US-10576084-B2
Publication Date
2020-03-03
Expiration Date
Abstract
The present invention provides 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid choline salt having excellent solubility and storage stability.
Core Innovation
The invention relates to a gonadotropin releasing hormone (GnRH) antagonist choline salt of a fused heterocyclic acid, including its crystalline identity. The background problem addressed is that another form of the compound has solubility and stability issues that limit performance.
The choline salt is described as having substantially higher saturation solubility and improved oral absorbability, and it also provides storage stability. The crystalline form is characterized and distinguished using powder X-ray diffraction peak angles, 13C and 19F solid-state NMR chemical shifts, and a differential thermal analysis endothermic event around 213°C.
The invention further describes pharmaceutical compositions and their use for prevention or treatment of sex hormone-dependent diseases, including dysmenorrhea. Crystalline characterization and performance are supported by reported comparisons of solubility, bioavailability for the choline salt, and stability, together with formulation suitability for oral dosing forms.
Claims Coverage
The independent claim covers a treatment method for dysmenorrhea by administering a therapeutically effective amount of a compound represented by a specified formula, with six inventive features directed to the compound’s crystalline choline salt identity and administration in a pharmaceutical composition.
Treating dysmenorrhea by administering a therapeutically effective amount of a specified-formula compound
A method of treating dysmenorrhea in a subject by administering to the subject a therapeutically effective amount of a compound represented by the formula.
Crystalline identity defined by powder X-ray diffraction peak positions
The compound is characterized by a powder X-ray diffraction diagram having characteristic diffraction peaks at specified 2θ angles.
Crystalline identity defined by 13C solid-state NMR chemical shift peaks
The compound is characterized by a 13C solid-state NMR spectrum with characteristic chemical shift peak values at specified δ(ppm) positions.
Crystalline identity defined by 19F solid-state NMR chemical shift peaks
The compound is characterized by a 19F solid-state NMR spectrum with characteristic chemical shift peaks at specified δ(ppm) values.
Thermal behavior defined by an endothermic event near 213°C
The compound shows an endothermic event at about 213°C when measured by differential thermal analysis.
Administration via a pharmaceutical composition
The method further comprises administering to a subject a pharmaceutical composition that includes a therapeutically effective amount of the compound.
Overall claim coverage is grounded in a dysmenorrhea treatment method that administers a therapeutically effective amount of a specified-formula compound, while dependent limitations emphasize a defined crystalline choline salt identity using powder X-ray diffraction peak positions, 13C and 19F solid-state NMR chemical shift peaks, and differential thermal analysis behavior near 213°C, including administration via a pharmaceutical composition.
Stated Advantages
Substantially higher saturation solubility
Improved oral absorbability
Storage stability
Reported bioavailability of about 59% for the choline salt
Documented Applications
Prevention or treatment of sex hormone-dependent diseases, including dysmenorrhea.
Crystalline pharmaceutical use for sex hormone-dependent diseases such as benign prostatic hypertrophy, endometriosis, hysteromyoma/metrofibroma, precocious puberty, amenorrhea, and premenstrual syndrome.
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