Salt of fused heterocyclic derivative and crystal thereof
Inventors
Jo, Kazumichi • Takeuchi, Hideki
Assignees
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Publication Number
US-9169266-B2
Publication Date
2015-10-27
Expiration Date
Abstract
An objective of the present invention is to improve the solubility of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid.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 has excellent solubility and storage stability.
Core Innovation
The disclosure describes a choline salt (compound A) of a fused tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid derivative, including the corresponding free acid (compound B). The choline salt is presented as crystalline and characterizable by powder XRD, solid-state 13C NMR, solid-state 19F NMR, and differential thermal analysis.
The problem addressed is that the corresponding free acid (compound B) has insufficient solubility and storage stability, motivating development of a salt form to improve these properties. The disclosure reports that compound A has improved solubility compared with crystals of compound B and another salt form, and improved storage stability including retained purity after heat stability testing.
The compound is also described as functioning as a gonadotropin releasing hormone antagonist for preventing or treating sex hormone-dependent diseases and associated conditions. The disclosure further links the choline salt form to improved oral absorbability/bioavailability and related pharmacokinetic behavior, including a faster Tmax.
Claims Coverage
The partial content indicates one independent claim covering a compound represented by a formula, with dependent claims specifying crystalline characterization and NMR/XRD peak parameters, and a dependent claim extending the subject matter to a pharmaceutical composition. The inventive coverage centers on the formula-defined choline salt compound and its specific crystalline form.
Compound represented by the formula
A compound represented by the formula (formula content not provided in the partial content).
Crystalline choline salt compound defined by powder X-ray diffraction
The compound is crystalline and is defined by characteristic powder X-ray diffraction peaks at specified diffraction angles (2θ).
Crystalline compound defined by solid-state 13C NMR chemical-shift peaks
The compound has characteristic chemical-shift peak values in a 13C solid-state NMR spectrum.
Crystalline compound defined by solid-state 19F NMR chemical-shift peaks
The compound has characteristic peaks at specific 19F solid-state NMR chemical shift values.
Pharmaceutical composition comprising the compound as active ingredient
A pharmaceutical composition containing, as its active ingredient, the compound defined by claim 1.
Across the partial claims content, the inventive coverage centers on a formula-defined choline salt compound, further constrained to a specific crystalline form characterized by powder XRD peak positions and solid-state 13C and 19F NMR chemical-shift peaks, with additional coverage for a pharmaceutical composition that includes the compound as the active ingredient.
Stated Advantages
Improved solubility, including saturation solubility up to about 600× versus compound B crystals and large improvements versus another salt form.
Improved storage stability, including retained purity after heat stability testing.
Improved oral absorbability/bioavailability (about 59%).
Faster Tmax.
Documented Applications
Preventing or treating sex hormone-dependent diseases using the gonadotropin releasing hormone antagonist, including benign prostatic hypertrophy, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, and dysmenorrhea.
Pharmaceutical composition use cases in which the compound is used as an active ingredient.
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