JPWO2019165951A5

JPWO2019165951A5 -

Info

Publication number: JPWO2019165951A5
Application number: JP2020542936A
Authority: JP
Publication date: 2022-02-22

Claims

5.9, 8.8, 9.6, 13.8, 15.7 and 16.8, and preferably 4.50, 5.86, 8.78, 9.60, 11.89, 12.57, 13.21, 13.76, 14.35, 15.68, 16.78, 18.01, 19.42, 19.95, 22.57, 23.76, 25.14 , 27.03 , 27.42 and 27.92 , a type A crystal of the compound of formula (I), characterized by having an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ.

7.0, 7.5, 12.4, 13.1, 13.6, 16.0, 16.8, 17.2, 18.1, 19.1, 19.9, 21.7, 22.7, 23.7, 23.9, 25.6, 26.0, 27.9, 28.5 and 29.0, and preferably 6.98, 7.53, 11.24, 12.36. , 13.13, 13.59, 16.02, 16.79, 17.21, 18.12, 19.06, 19.87, 20.56, 21.65, 22.70, 23.73, 23.94, 24.50, 25.58, 25.98, 26.33, 27.87, 28.48, 28.96, 30.19, 30.77, 33.01, 34. , 37.83, 38.74, 41.03, 41.74, 42.91, 44.03 and 45.46 of the compound of formula (I), characterized by having an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ. B-type crystal.

Method I: The compound of formula (I) is added to the solvent (III) and the mixture is pulped to give a B-type crystal; the solvent (III) is water, an alcohol solvent, a mixed solvent of alcohol solvent and water, ether. It is selected from the group consisting of a mixed solvent of a solvent and an alcohol solvent and a mixed solvent of an ether solvent and water; the alcohol solvent is preferably methanol; the ether solvent is preferably tetrahydrofuran; the ether solvent and alcohol. The mixed solvent of the solvent is preferably a mixed solvent of tetrahydrofuran and methanol; the mixed solvent of the alcohol solvent and water is preferably a mixed solvent of methanol and water; and Method II: the compound of the formula (I) is used as a solvent. Dissolve in (IV) and crystallize crystalline form B by adding solvent (V); the solvent (IV) is an ether solvent selected from tetrahydrofuran; the solvent (V) is water, It is selected from the group consisting of an alcohol solvent and a mixed solvent of alcohol solvent and water; the alcohol solvent is preferably methanol; the mixed solvent of the alcohol solvent and water is preferably a mixed solvent of methanol and water.
The method for producing a B-type crystal according to claim 2 , wherein the crystal is selected from the group consisting of.

7.4, 9.2, 13.3, 15.6, 15.9, 19.2, 21.7, 24.1, 24.9 and 27.3, and preferably 7.38, 9.15, 11.60, 12.82, 13.27, 14.36, 15.60, 15.91, 16.67, 17.21, 18.54, 19.18, 20.15, 21.65. , 22.27, 24.06, 24.92, 26.82, 27.34, 28.96, 29.96, 32.24 and 33.08 , and has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ. ) C-type crystal.

Features 5.3, 6.4, 8.7, 11.5, 15.9, 16.3, 20.0 and 24.7, and preferably 5.34, 6.44, 8.71, 10.85, 11.48, 12.02, 13.24, 15.91, 16.28, 18.08, 20.04, 23.22, 24.69, 25.95 and 27.30 . A D-type crystal of the compound of the formula (I), which comprises a typical peak and has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ.

6.6, 7.0, 8.9, 11.9, 15.1, 15.4, 16.3, 19.1, 19.9, 20.9, 23.5, 23.8, 24.3, 25.4, 26.6, 28.9 and 30.1, and preferably 3.60, 3.79, 4.76, 6.55, 6.98, 8.92, 11.86 , 13.18, 14.33, 15.14, 15.37, 16.32, 17.19, 19.05, 19.86, 20.88, 22.75, 23.50, 23.77, 24.26, 25.38, 26.56, 28.88, 30.05 and 32.19 . An E-type crystal of the compound of formula (I), characterized by having an X-ray powder diffraction spectrum.

6.5, 9.9, 11.3, 13.2, 13.6, 15.2, 16.5, 17.4, 17.9, 19.0, 20.1, 21.1, 23.7, 24.1 and 26.6, and preferably 6.46, 7.51, 9.92, 11.26, 13.15, 13.58, 15.20, 16.46 , 17.38. , 17.88, 19.02, 20.10, 21.10, 23.70, 24.10, 26.61, 28.78 and 29.80 , and has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ. ) F-type crystal.

Method I: The compound of formula (I) is added to the solvent (X) and the mixture is pulped to give F-type crystals; the solvent (X) is selected from alcohol solvents, preferably ethanol or isopropanol; And Method II: the compound of formula (I) is dissolved in solvent (XI) to crystallize F-type crystals; the solvent (XI) is selected from alcohol solvents, preferably ethanol or isopropanol; the crystals. The crystallization method is selected from the group consisting of room temperature crystallization, cooling crystallization, solvent volatile crystallization and induced crystallization by crystal species.
The method for producing an F-type crystal according to claim 7 , wherein the crystal is selected from the group consisting of.

The crystal according to any one of claims 1, 2, 4, 5, 6 and 7 , wherein the error range of 2θ is ± 0.2.

A pharmaceutical composition comprising the crystals according to any one of claims 1, 2, 4, 5, 6, 7 and 9 , and optionally pharmaceutically acceptable carriers, diluents and excipients.

A pharmaceutical composition produced from the crystals according to any one of claims 1, 2, 4, 5, 6, 7 and 9 , and optionally pharmaceutically acceptable carriers, diluents and excipients.

It comprises a step of mixing the crystal according to any one of claims 1, 2, 4, 5, 6, 7 and 9 with a pharmaceutically acceptable carrier, diluent or excipient. , The method for producing a pharmaceutical composition according to claim 10 or 11 .

Use of the crystals according to any one of claims 1, 2, 4, 5, 6, 7 and 9 in the manufacture of a drug for treating and / or preventing a disease or condition associated with inhibition of XIa factor. The disease or condition is cardiovascular disease, preferably thromboembolic disease, more preferably myocardial infarction, angina, reocclusion and restenosis, disseminated blood vessels after angioplasty or aortic coronary shunt. Select from the group consisting of internal coagulation, stroke, transient ischemic attack, peripheral arterial occlusion, pulmonary embolism and deep venous thrombosis, use.