RU2021129952A - CRYSTAL FORM OF PHOSPHODIESTERASE INHIBITOR, METHOD OF ITS OBTAINING AND ITS APPLICATION - Google Patents

Claims (31)

1. Crystal form I of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3 -carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 7.3 ± 0.2°, 13.6 ± 0.2°, 14.5 ± 0.2°, 18.0 ± 0, 2°, 19.1 ± 0.2°, 22.0 ± 0.2° and 23.4 ± 0.2° as determined using Cu-Kα radiation,

(I). 2. Crystal form I according to claim 1, where the X-ray powder diffraction pattern additionally contains characteristic peaks at 2θ values of 14.2 ± 0.2°, 16.1 ± 0.2°, 19.4 ± 0.2° and 25, 6 ± 0.2° as determined using Cu-Kα radiation. 3. Crystal form I according to claim 2, wherein the crystal form is characterized by an X-ray powder diffraction pattern, which is essentially depicted in FIG. 1 using Cu-Kα radiation. 4. Method for obtaining crystalline form I according to claim 1, wherein the method comprises dissolving a compound of formula (I) in a single or mixed solvent, raising the temperature to reflux until complete dissolution, and slowly lowering the temperature until crystalline Form I precipitates or complete dissolution of the compound of formula (I) in one or a mixed solvent, and evaporation of one or a mixed solvent until the system is saturated and crystalline Form I precipitates; wherein the single or mixed solvent is selected from one of methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, methyl t-butyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water, or mixtures thereof; preferably the single or mixed solvent is selected from methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, water/ethanol, water/isopropanol, dichloromethane, ethyl acetate, acetonitrile, dichloromethane/acetone, dichloromethane/acetonitrile, dichloromethane/ethyl acetate, dichloromethane/methyl -tert-butyl ether, dichloromethane/tetrahydrofuran, dichloromethane/ethanol, dichloromethane/isopropanol, dichloromethane/toluene, dichloromethane/water/ethanol and dichloromethane/water/isopropanol. 5. Crystal Form II of the hydrochloride of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene 3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 4.0 ± 0.2°, 6.7 ± 0.2°, 7.9 ± 0.2°, 13.5 ± 0 .2°, 14.2 ± 0.2°, 15.4 ± 0.2°, 20.2 ± 0.2° and 22.0 ± 0.2° as determined using Cu-Kα radiation,

(I). 6. Crystal form II according to claim 5, where the X-ray powder diffraction pattern additionally contains characteristic peaks at 2θ values of 10.2 ± 0.2°, 13.8 ± 0.2°, 14.6 ± 0.2°, 26, 40 ± 0.2° and 26.80 ± 0.2° as determined using Cu-Kα radiation. 7. Crystal form II according to claim 6, wherein the crystal form is characterized by an X-ray powder diffraction pattern, which is essentially depicted in FIG. 6 using Cu-Kα radiation. 8. Method for obtaining crystalline form II according to claim 5, where the method includes adding one or a mixed solvent to the hydrochloride of the compounds of formula (I), heating the mixture until complete dissolution and slowly cooling the heated mixture until the precipitation of crystalline form II; wherein the single or mixed solvent is selected from one of methanol, ethanol, isopropanol and water, or mixtures thereof; preferably the single or mixed solvent is selected from methanol, ethanol, isopropanol, water/methanol, water/ethanol and water/isopropanol. 9. Crystal form III of the hydrochloride of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene- 3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 5.2 ± 0.2°, 6.4 ± 0.2°, 15.3 ± 0.2°, 18.6 ± 0 .2°, 22.0 ± 0.2° and 26.4 ± 0.2° as determined using Cu-Kα radiation,

(I). 10. Crystal form III according to claim 9, where the X-ray powder diffraction pattern additionally contains characteristic peaks at 2θ values of 8.0 ± 0.2°, 10.3 ± 0.2°, 13.5 ± 0.2° and 25, 0 ± 0.2° as determined using Cu-Kα radiation. 11. Crystal form III according to claim 10, wherein the crystal form is characterized by an X-ray powder diffraction pattern, which is essentially depicted in FIG. 9 using Cu-Kα radiation. 12. The method of obtaining crystalline form III according to claim 11, where the method includes adding one or mixed solvent to the hydrochloride of the compound of formula (I), heating the mixture until complete dissolution, conducting hot filtration and concentrating the filtrate to precipitate crystalline form III; wherein the single or mixed solvent is selected from one of acetonitrile, acetone, tetrahydrofuran and ethyl acetate, or mixtures thereof. 13. Crystal form IV of p-toluenesulfonate of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7- diazanaphthalene-3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 5.8 ± 0.2°, 7.8 ± 0.2°, 9.3 ± 0.2°, 11.3 ± 0.2°, 13.7 ± 0.2°, 14.8 ± 0.2° and 15.7 ± 0.2° and additionally containing characteristic peaks at 2θ values of 17.1 ± 0.2°, 18 .7 ± 0.2°, 20.0 ± 0.2° and 22.4 ± 0.2° as determined using Cu-Kα radiation,

(I). 14. Crystal form V of the methanesulfonate of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalen 3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 7.0 ± 0.2°, 9.7 ± 0.2°, 13.2 ± 0.2°, 18.1 ± 0 .2°, 19.5 ± 0.2°, 20.7 ± 0.2° and 21.7 ± 0.2° and additionally containing characteristic peaks at 2θ values of 16.9 ± 0.2°, 18.6 ± 0.2°, 19.1 ± 0.2°, 20.2 ± 0.2° and 28.0 ± 0.2° as determined using Cu-Kα radiation,

(I). 15. Crystal form VI of the sulfate of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene 3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 4.4 ± 0.2°, 7.1 ± 0.2°, 8.8 ± 0.2°, 14.3 ± 0 .2°, 17.8 ± 0.2°, 19.6 ± 0.2° and 21.6 ± 0.2° and additionally containing characteristic peaks at 2θ values of 25.5 ± 0.2° and 27.7 ± 0.2° as determined using Cu-Kα radiation,

(I). 16. Crystal Form VII of the sulfate of the compound represented by formula (I), 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene- 3-carbonitrile, where the crystalline form is characterized by an X-ray powder diffraction pattern containing characteristic peaks at 2θ values of 7.1 ± 0.2°, 13.6 ± 0.2°, 14.5 ± 0.2°, 18.0 ± 0 .2°, 19.0 ± 0.2°, 22.0 ± 0.2° and 23.4 ± 0.2° and additionally containing characteristic peaks at 2θ values of 15.0 ± 0.2°, 16.1 ± 0.2°, 17.4 ± 0.2° and 19.4 ± 0.2° as determined using Cu-Kα radiation,

(I). 17. Pharmaceutical composition containing crystalline form I according to any one of paragraphs. 1-3, crystalline form II according to any one of paragraphs. 5-7, crystalline form III according to any one of paragraphs. 9-11, crystalline form IV according to claim 13, crystalline form V according to claim 14, crystalline form VI according to claim 15, or crystalline form VII according to claim 16, and one or more additional therapeutically active agents. 18. Pharmaceutical preparation containing crystalline form I according to any one of paragraphs. 1-3, crystalline form II according to any one of paragraphs. 5-7, crystalline form III according to any one of paragraphs. 9-11, a crystalline form IV according to claim 13, a crystalline form V according to claim 14, a crystalline form VI according to claim 15, or a crystalline form VII according to claim 16, and one or more pharmaceutical carriers. 19. The use of crystalline form I according to any one of paragraphs. 1-3, crystalline form II according to any one of paragraphs. 5-7, crystalline form III according to any one of paragraphs. 9-11, crystalline form IV according to claim 13, crystalline form V according to item 14, crystalline form VI according to item 15, crystalline form VII according to item 16, pharmaceutical composition according to item 17 or pharmaceutical preparation according to item 18 for manufacturing a medicinal product for the treatment or prevention of diseases mediated by PDE9.