Salt of fused heterocyclic derivative and crystal thereof
Inventors
Jo, Kazumichi • Takeuchi, Hideki
Assignees
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Publication Number
US-9737539-B2
Publication Date
2017-08-22
Expiration Date
Abstract
The present invention provides 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 choline salt having excellent solubility and storage stability.
Core Innovation
The document discloses a choline salt form (compound A) of a fused tetrahydrothienopyrimidinone acid, identified as 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 choline salt. The compound is described as a gonadotropin releasing hormone antagonist for the prevention and/or treatment of sex hormone-dependent diseases. The disclosure emphasizes that compound A is crystalline.
Compound A is characterized by solid-state analytical fingerprints including powder X-ray diffraction (2θ peak values), 13C solid-state NMR chemical shifts, and 19F solid-state NMR chemical shifts. Differential thermal analysis is also described with an endothermic peak around 213°C. The document presents these solid-state characterization results to define and distinguish the crystalline choline salt form.
The disclosure compares compound A with other forms, including a free acid/crystal form (compound B) and another salt (compound C), and reports improved physical properties for compound A. The document states that compound A has markedly higher saturation solubility and improved oral absorbability/bioavailability in rats relative to compound B. The document further describes high storage stability based on retained HPLC purity after accelerated/forced conditions.
Claims Coverage
The provided independent claim covers a treatment method for a sex hormone-dependent disease selected from a listed group by administering an effective amount of a compound represented by a specified formula. The inventive features center on disease selection, administration, crystalline form, and solid-state characterization constraints.
Treating a listed sex hormone-dependent disease
A method for treating a sex hormone-dependent disease selected from benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, hirsutism, short stature, infertility, irritable bowel syndrome and prostate cancer.
Administering an effective amount of a specified-form compound
The method comprises administering an effective amount of a compound represented by the formula.
Selecting endometriosis within the disease group
The method is specified such that the sex-hormone dependent disease is endometriosis.
Oral administration
The method provides that the compound is administered orally.
Crystalline compound form
The method is further limited such that the compound is crystalline.
Powder X-ray diffraction peak constraints
The crystalline compound is defined by characteristic powder X-ray diffraction peaks at diffraction angles (2θ(°)) of 7.1, 11.5, 19.4, 20.3, 21.5, 22.0, 22.6, 23.5, and 26.2.
13C solid-state NMR chemical shift constraints
The method is defined by the compound exhibiting specified characteristic chemical-shift peak values (δ in ppm) in a 13C solid-state NMR spectrum.
Overall, the claim coverage centers on administering an effective amount of a specified-form compound to treat a selected sex hormone-dependent disease, with additional inventive constraints that narrow the method to oral dosing, a crystalline compound form, and identification by specific powder X-ray diffraction (2θ) and 13C solid-state NMR chemical shift peak values.
Stated Advantages
Markedly higher saturation solubility compared with compound B.
Improved oral absorbability/bioavailability in rats relative to compound B.
High storage stability based on retained HPLC purity after accelerated/forced conditions.
Documented Applications
Prevention and/or treatment of sex hormone-dependent diseases using the described gonadotropin releasing hormone antagonist compound A.
Treatment of sex-hormone dependent diseases selected from benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, hirsutism, short stature, infertility, irritable bowel syndrome, and prostate cancer.
Prevention/treatment context includes improved oral absorbability/bioavailability in rats and stability assessment using HPLC purity retention.
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