Salt crystals

Abstract

To provide a crystal of 2 - (4-acetylbenzyl) - 3 - ((4-fluorophenyl) amino) - 577 - trimethyl-7, 8-dihydro-pyrazolo-imidazo [1, 2-a] 2H [4, 3-e] pyrimidin-4 (5H) - one.SOLUTION: Provided is a crystal of an acid addition salt form selected from, for example, succinate form, citrate form, adipate form, tartrate form (e.g., L-tartrate form), malate form, gluconate form (e.g., D-gluconate form), maleate form, fumarate form, aspartate form (e.g., L-aspartate form), hippurate form, sebacate form, glycolate form, galactarate form, benzoate form, pamoate form, oxalate form and malonate form.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Field of the Disclosure The present disclosure relates to acid addition salts and salt crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one, compositions containing same, and methods of making and using the salts and salt crystals. [Background technology]

[0002] Background of the Disclosure The compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one is disclosed in WO 2014 / 151409. This compound has been found to be a potent and selective phosphodiesterase 1 (PDE1) inhibitor useful for the treatment or prevention of disorders characterized by low levels of cAMP and / or cGMP in cells expressing PDE1, neurodegenerative disorders, psychiatric disorders, circulatory and cardiovascular disorders, respiratory and inflammatory disorders, diseases that can be alleviated by enhancing progesterone signaling, such as female sexual dysfunction, traumatic brain injury, or diseases or conditions characterized by reduced dopamine D1 receptor signaling activity. This list of disorders is illustrative and not intended to be exhaustive.

[0003] WO 2014 / 151409 discloses 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one, but does not demonstrate that a specific salt has particular stability or desirable properties. Because many pharmaceutical compounds can exist in various physical forms (e.g., liquid or solid in various crystalline, amorphous, polymorphic, hydrated, or solvated forms) that can alter the drug's stability, solubility, bioavailability, or pharmacokinetics (absorption, distribution, metabolism, excretion, or the like) and / or bioequivalence, identifying a pharmaceutical compound in an optimal physical form (e.g., free base or salt in a solid, liquid, crystalline, hydrated, solvated, amorphous, or polymorphic form) is crucial in drug development. Summary of the Invention

[0004] Summary of the Disclosure In a first aspect, the present disclosure is directed to a crystalline form of the compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one free base ("Compound A") [Free Base Crystalline 1]. These free base crystals are stable and particularly advantageous in the preparation of salt crystals of Compound A, such as succinate crystals, adipate crystals, and / or citrate crystals. Thus, in a first aspect, the present disclosure provides:

[0005] 1.1 Crystalline free base 1, wherein the crystallized free base is in a non-solvated form.

[0006] 1.2 Any of the above crystalline free bases, wherein the crystalline free base is in a solvate form.

[0007] 1.3 Any of the above crystalline free bases, wherein the crystalline free base is in the form of a solvate with an alcohol.

[0008] 1.4 Any of the above free base crystals, wherein the free base crystals are in the form of a solvate with methanol, ethanol, propanol (e.g., n-propanol or isopropanol), or butanol (e.g., n-butanol).

[0009] 1.5 Any of the foregoing free base crystals, wherein the free base crystals are in an anhydrate form or a hydrate form.

[0010] 1.6 Any of the preceding free base crystals, wherein the free base crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 9.3°, 14.0°, 14.7°, 17.3°, 17.9°, 18.7°, 21.2°, 23.2°, 23.3°, and 23.7°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0011] 1.7 Any of the preceding crystalline free bases, wherein the crystalline free base exhibits a powder X-ray diffraction pattern comprising peaks having 2θ angle values ​​selected from the group consisting of 9.3°, 14.0°, 23.2°, 23.3°, and 23.7°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0012] 1.8 The free base crystals are listed in Table 1 below: [Table 1] wherein the XRPD pattern is measured using a diffractometer with a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0013] 1.9 Any of the preceding free base crystals, wherein the free base crystals exhibit an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 9.53 Å, 6.33 Å, 6.02 Å, 5.11 Å, 4.95 Å, 4.74 Å, 4.19 Å, 3.83 Å, 3.82 Å, and 3.79 Å.

[0014] 1.10 Any of the preceding free base crystals, wherein the free base crystals exhibit a powder X-ray diffraction pattern comprising peaks having d-spacing values ​​selected from the group consisting of 9.53 Å, 6.33 Å, 3.83 Å, 3.82 Å, 3.79 Å.

[0015] 1.11 Any of the foregoing free base crystals, wherein the free base crystals exhibit a powder X-ray diffraction pattern corresponding to or substantially as shown in FIG. 1.

[0016] 1.12 Any of the preceding free base crystals, wherein the free base crystals exhibit a differential scanning calorimetry (DSC) pattern containing an endothermic peak at about 195°C-196°C.

[0017] 1.13 Any of the preceding free base crystals, wherein the crystals exhibit a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 2.

[0018] 1.14 Any of the foregoing free base crystals, wherein the crystals exhibit a thermogravimetric analysis (TGA) pattern corresponding to or substantially as shown in FIG. 3.

[0019] 1.15 Any of the preceding free base crystals, wherein the crystals have a platelet shape.

[0020] In a further aspect, the present disclosure is directed to stable acid addition salt crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one ("Compound A"), e.g., crystalline acid addition salts with certain acids. These salt crystals are particularly advantageous for the preparation of various types of galenic formulations. Thus, in a first aspect, the present disclosure provides:

[0021] 1.1 Compound A in the form of an acid addition salt, for example selected from the group consisting of citrate, adipate, tartrate (e.g., L-tartrate), malate, succinate, gluconate (e.g., D-gluconate), maleate, fumarate, aspartate (e.g., L-aspartate), hippurate, sebacate, glycolate, galactarate, benzoate, pamoate, oxalate, and malonate.

[0022] 1.2 A salt according to formula 1.1, wherein the salt is a succinate salt.

[0023] 1.3 A salt according to formula 1.1 or 1.2, wherein the salt is a succinate salt having a molar ratio of free base to succinic acid of 1:1 (i.e., monosuccinate) or 2:1.

[0024] 1.4 A salt according to formula 1.1, wherein the salt is a citrate.

[0025] 1.5 A salt according to formula 1.1, wherein the salt is an adipate.

[0026] 1.6 A salt according to formula 1.1, wherein the salt is a tartrate (e.g., L-tartrate).

[0027] 1.7 A salt according to formula 1.1, wherein the salt is a malate (e.g., L-malate).

[0028] 1.8 A salt according to formula 1.1, wherein the salt is a gluconate (e.g., D-gluconate).

[0029] Salts according to any of Formulas 1.1-1.8 are referred to herein as salts of the present disclosure.

[0030] It has also surprisingly been found that certain salts of the present disclosure are in crystalline form and are therefore preferred for galenical and / or therapeutic use. Thus, in further embodiments, the present disclosure provides:

[0031] 1.9 A salt according to any of formulas 1.1-1.8 in crystalline form (hereinafter "salt crystal").

[0032] 1.10 A salt crystal according to formula 1.9, where the salt is a succinate.

[0033] 1.11 Salt crystals according to formulas 1.9-1.10, where the salt is a succinate salt with a molar ratio of free base to succinic acid of 1:1 (i.e., monosuccinate) or 2:1.

[0034] 1.12 Salt crystals according to formulas 1.9-1.11, where the salt is the monosuccinate.

[0035] 1.13 Salt crystals according to formulas 1.9-1.12, in which the salt crystals have plate-like morphology.

[0036] 1.14 A salt crystal according to any of Formulas 1.9-1.13, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 7.8°, 8.2°, 11.6°, 14.5°, 16.5°, 18.6°, 19.7°, 20.4°, 20.6°, 22.1°, 23.3°, 24.8°, 26.0°, and 28.5°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0037] 1.15 A salt crystal according to any of Formulas 1.9-1.14, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​selected from the group consisting of 7.8°, 8.2°, 11.6°, 16.5°, and 20.4°, the XRPD pattern being measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0038] 1.16 The salt crystals are as shown in Table 2 below: [Table 2-1] [Table 2-2] 1.9-1.15, wherein the XRPD pattern is measured with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0039] 1.17 A salt crystal according to any of Formulas 1.9-1.16, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 11.37 Å, 10.77 Å, 7.62 Å, 6.09 Å, 5.38 Å, 4.77 Å, 4.50 Å, 4.36 Å, 4.31 Å, 4.02 Å, 3.81 Å, 3.59 Å, 3.43 Å, and 3.13 Å.

[0040] 1.18 A salt crystal according to any of Formulas 1.9-1.17, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having d-spacing values ​​selected from the group consisting of 11.37 Å, 10.77 Å, 7.62 Å, 5.38 Å, and 4.36 Å.

[0041] 1.19 A salt crystal according to any of Formulas 1.9-1.18, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from those set forth in Table 2 for Formula 1.16.

[0042] 1.20 A salt crystal according to any of formulas 1.9-1.19, wherein the salt crystal exhibits a powder X-ray diffraction pattern corresponding to or substantially as shown in Table 2 for formula 1.16.

[0043] 1.21 A salt crystal according to any of formulas 1.9-1.20, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG. 4.

[0044] 1.22 A salt crystal according to any of formulas 1.9-1.21, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern containing an endothermic peak at about 177°C-178°C.

[0045] 1.23 A salt crystal according to any of Formulas 1.9-1.22, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 5.

[0046] 1.24 A salt crystal according to any of Formulas 1.9-1.23, wherein the salt crystal exhibits a thermogravimetric analysis (TGA) pattern corresponding to or substantially as shown in FIG. 6.

[0047] 1.25 A salt crystal according to any of Formulas 1.9-1.24, wherein the salt crystal is prepared by reacting 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one free base crystals in ethanol with succinic acid.

[0048] 1.26 Salt crystals according to formula 1.9, where the salt is citrate.

[0049] 1.27 A salt crystal according to formula 1.26, where the salt is a monocitrate.

[0050] 1.28 A salt crystal according to any of Formulas 1.26-1.27, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.9°, 7.0°, 7.8°, 8.8°, 11.7°, 11.9°, 13.2°, 13.8°, 14.4°, 15.7°, 16.1°, 16.3°, 16.8°, 18.1°, 19.0°, 19.9°, 20.2°, 20.7°, 21.0°, 21.3°, 22.4°, 23.6°, 24.9°, 25.3°, and 27.2°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0051] 1.29 A salt crystal according to any of Formulas 1.26-1.28, which exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.9°, 7.0°, 7.8°, 8.8°, 11.7°, 11.9°, 14.4°, 15.6°, 16.1°, 16.8°, 18.1°, 19.0°, 21.0°, and 24.9°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0052] 1.30 A salt crystal according to any of Formulas 1.26-1.29, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​selected from the group consisting of 5.9°, 7.0°, 8.8°, 16.1°, and 16.8°, the XRPD pattern being measured, for example, with a diffractometer using a copper anode at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0053] 1.31 The salt crystals are as shown in Table 3 below: [Table 3] 1.26-1.30, wherein the XRPD pattern is measured with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0054] 1.32 A salt crystal according to any of Formulas 1.26-1.31, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 14.97 Å, 12.67 Å, ​​11.33 Å, 10.08 Å, 7.59 Å, 7.41 Å, 6.72 Å, 6.41 Å, 6.14 Å, 5.67 Å, ​​5.48 Å, 5.42 Å, 5.27 Å, 4.90 Å, 4.67 Å, ​​4.47 Å, 4.39 Å, 4.29 Å, 4.22 Å, 4.18 Å, 3.97 Å, 3.76 Å, 3.57 Å, 3.51 Å, and 3.27 Å.

[0055] 1.33 A salt crystal according to any of Formulas 1.26-1.31, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 14.97 Å, 12.67 Å, ​​11.33 Å, 10.08 Å, 7.59 Å, 7.41 Å, 6.14 Å, 5.67 Å, ​​5.48 Å, 5.27 Å, 4.90 Å, 4.67 Å, ​​4.22 Å, and 3.57 Å.

[0056] 1.34 A salt crystal according to any of Formulas 1.26-1.31, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having d-spacing values ​​selected from the group consisting of 14.97 Å, 12.67 Å, ​​10.08 Å, 5.48 Å, and 5.27 Å.

[0057] 1.35 A salt crystal according to any of Formulas 1.26-1.34, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from those set forth in Table 3 for Formula 1.31.

[0058] 1.36 A salt crystal according to any of formulas 1.26-1.35, wherein the salt crystal exhibits a powder X-ray diffraction pattern corresponding to or substantially as shown in Table 3 for formula 1.31.

[0059] 1.37 A salt crystal according to any of formulas 1.26-1.36, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG.

[0060] 1.38 A salt crystal according to any of Formulas 1.26-1.37, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 142°C-144°C.

[0061] 1.39 A salt crystal according to any of formulas 1.26-1.37, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 8.

[0062] 1.40 A salt crystal according to any of formulas 1.26-1.39, wherein the salt crystal exhibits a thermogravimetric analysis (TGA) pattern corresponding to or substantially as shown in FIG. 9.

[0063] 1.41 A salt crystal according to any of Formulas 1.26-1.40, prepared by reacting 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one free base crystals in acetone with citric acid.

[0064] 1.42 Salt crystals according to formula 1.9, where the salt is adipate.

[0065] 1.43 A salt crystal according to any of Formulas 1.42, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.4°, 6.4°, 7.1°, 9.6°, 10.9°, 14.2°, 15.5°, 15.7°, 16.1°, 16.5°, 17.9°, 20.8°, 21.8°, 22.4°, 23.9°, 24.7°, 26.3°, and 27.8°, wherein the XRPD pattern is measured, for example, on a diffractometer using a copper anode at wavelengths α1 of 1.5406 Å and α2 of 1.5444 Å.

[0066] 1.44 A salt crystal according to any of Formulas 1.42-1.43, which exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.4°, 6.4°, 7.1°, 9.6°, 10.9°, 16.1°, 16.45°, 17.9°, 23.9°, and 24.7°, wherein the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0067] 1.45 A salt crystal according to any of Formulas 1.42 to 1.44, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having 2θ angle values ​​selected from the group consisting of 5.4°, 6.4°, 9.6°, 16.5°, and 24.7°, the XRPD pattern being measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0068] 1.46 Salt crystals are prepared according to the following Table 4: [Table 4] 1.42-1.45, wherein the XRPD pattern is measured with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

[0069] 1.47 A salt crystal according to any of Formulas 1.42-1.46, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 16.23 Å, 13.72 Å, 12.49 Å, 9.18 Å, 8.10 Å, 6.23 Å, 5.70 Å, 5.65 Å, 5.50 Å, 5.38 Å, 4.94 Å, 4.26 Å, 4.08 Å, 3.96 Å, 3.72 Å, 3.60 Å, 3.38 Å, and 3.21 Å.

[0070] 1.48 A salt crystal according to any of Formulas 1.42-1.46, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 16.23 Å, 13.72 Å, 12.49 Å, 9.18 Å, 8.10 Å, 5.50 Å, 5.38 Å, 4.94 Å, 3.72 Å, and 3.60 Å.

[0071] 1.49 A salt crystal according to any of formulas 1.42-1.46, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising peaks having d-spacing values ​​selected from the group consisting of 16.23 Å, 13.72 Å, 9.18 Å, 5.38 Å, and 3.60 Å.

[0072] 1.50 A salt crystal according to any of formulas 1.42-1.49, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from those set forth in Table 4 for formula 1.46.

[0073] 1.51 A salt crystal according to any of formulas 1.42-1.50, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in Table 4 of formula 1.46.

[0074] 1.52 A salt crystal according to any of formulas 1.42-1.51, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG. 10.

[0075] 1.53 A salt crystal according to any of formulas 1.42-1.52, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 170°C-172°C.

[0076] 1.54 A salt crystal according to any of formulas 1.42-1.53, wherein the salt crystal exhibits thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) patterns corresponding to or substantially as shown in FIG. 11.

[0077] 1.55 A salt crystal according to any of Formulas 1.42-1.54, wherein the salt crystal is prepared by reacting 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one free base crystals with adipic acid in a solvent (e.g., ethanol, acetone, or ethyl acetate).

[0078] 1.56 Salt crystals according to formula 1.9, where the salt is malate.

[0079] 1.57 A salt crystal according to formula 1.56, where the salt is L-malate.

[0080] 1.58 A salt crystal according to any of formulas 1.56-1.57, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG. 12.

[0081] 1.59 A salt crystal according to any of formulas 1.56-1.58, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 214°C-215°C.

[0082] 1.60 A salt crystal according to any of formulas 1.56-1.59, wherein the salt crystal exhibits thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) patterns corresponding to or substantially as shown in FIG. 13.

[0083] 1.61 Salt crystals according to formula 1.9, where the salt is a tartrate.

[0084] 1.62 Salt crystals according to formula 1.61, where the salt is the L-tartrate.

[0085] 1.63 A salt crystal according to any of formulas 1.61-1.62, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG. 14.

[0086] 1.64 A salt crystal according to any of formulas 1.61-1.63, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 240°C-242°C.

[0087] 1.65 A salt crystal according to any of formulas 1.61-1.64, wherein the salt crystal exhibits thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) patterns corresponding to or substantially as shown in FIG. 15.

[0088] 1.66 A salt crystal according to formula 1.9, where the salt is a gluconate.

[0089] 1.67 A salt crystal according to formula 1.66, where the salt is D-gluconate.

[0090] 1.68 A salt crystal according to any of formulas 1.66-1.67, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in FIG. 16.

[0091] 1.69 A salt crystal according to any of formulas 1.66-1.68, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 195°C-196°C.

[0092] 1.70 A salt crystal according to any of formulas 1.66-1.69, wherein the salt crystal exhibits thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) patterns corresponding to or substantially as shown in FIG. 17.

[0093] 1.71 A salt crystal according to any of the above formulas, wherein the salt crystal is in a single crystalline form and is free or substantially free of other forms, e.g., less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of amorphous form.

[0094] 1.72 Salt crystals according to any of the above formulas, wherein the salt crystals are in a single crystalline form and are free or substantially free of other forms, e.g., have less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight of other crystalline forms.

[0095] 1.73 A salt crystal according to any of the above formulas, wherein the salt crystal is in a single crystalline form and is free or substantially free of other forms, e.g., amorphous and other crystalline forms comprise less than 10% by weight, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight.

[0096] 1.74 Salt crystals according to any of the above formulas when produced by any of the processes described or similarly described in any of Methods 1 et seq. or in any of Examples 1-6.

[0097] In a further aspect, the present disclosure also provides a method [Method 1] for preparing a stable acid addition salt, e.g., a crystalline acid addition salt, of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one ("Compound A") with a particular acid, comprising reacting the free base form of Compound A with the acid in a solvent and isolating the resulting salt. In certain embodiments, the present disclosure provides:

[0098] 1.1 Method 1, wherein the acid is selected from citric acid, adipic acid, tartaric acid (e.g., L-tartaric acid), malic acid, succinic acid, gluconic acid (e.g., D-gluconic acid), maleic acid, fumaric acid, aspartic acid (e.g., L-aspartic acid), hippuric acid, sebacic acid, glycolic acid, galactaric acid, benzoic acid, pamoic acid, oxalic acid, and malonic acid.

[0099] 1.2 Any of the preceding methods wherein the solvent is an alcohol (e.g., methanol and / or ethanol), acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethyl acetate, and / or toluene.

[0100] 1.3 Any of the preceding processes wherein 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (Compound A) is in crystalline form.

[0101] 1.4 Method 1.3, wherein Compound A is in a non-solvated form.

[0102] 1.5 Any of Methods 1.1-1.3, wherein Compound A is in the form of a solvate.

[0103] 1.6 Method 1.5, wherein Compound A is in the form of a solvate with an alcohol (e.g., methanol, ethanol, propanol (e.g., n-propanol or isopropanol) or butanol (e.g., n-butanol)).

[0104] 1.7 Any of Methods 1.3-1.6, wherein Compound A is in the form of a solvate with methanol, ethanol, a propanol (eg, n-propanol or isopropanol), or a butanol (eg, n-butanol).

[0105] 1.8 Any of Methods 1.3-1.7, wherein Compound A is in the non-hydrated or hydrated form.

[0106] 1.9 Any of Methods 1.3-1.8, wherein Compound A exhibits a powder X-ray diffraction pattern corresponding to or substantially as shown in FIG. 1.

[0107] 1.10 Any of Methods 1.3-1.9, wherein Compound A exhibits a differential scanning calorimetry (DSC) pattern that includes an endothermic peak at about 195°C-196°C.

[0108] 1.11 Any of Methods 1.3-1.10, wherein Compound A exhibits a differential scanning calorimetry (DSC) pattern corresponding to or substantially as shown in FIG. 2.

[0109] 1.12 Any of Methods 1.3-1.11, wherein Compound A has a platelet shape.

[0110] 1.13 Any of the preceding processes wherein the acid is about 2 molar equivalents relative to compound A.

[0111] 1.14 Any of Methods 1.1-1.12, wherein the acid is about 1 molar equivalent relative to Compound A.

[0112] 1.15 Any of Methods 1.1-1.12, wherein the acid is about 0.5 molar equivalents relative to Compound A.

[0113] 1.16 Any of the preceding processes wherein the acid is in aqueous, hydrated, or crystalline form.

[0114] 1.17 Any of the preceding processes wherein the acid is succinic acid.

[0115] 1.18 Method 1.17, in which the solvent is an alcohol.

[0116] 1.19 Any of Methods 1.17-1.18, where the solvent is ethanol.

[0117] 1.20 Compound A is dissolved in ethanol, as in any of methods 1.17-1.19.

[0118] 1.21 Any of Methods 1.17-1.20, wherein the solution of Compound A in ethanol is further heated to an elevated temperature (e.g., to a temperature of about 65°C to about 70°C, e.g., to a temperature of about 67°C, e.g., until all solids have dissolved).

[0119] 1.22 Succinic acid is dissolved in ethanol, any of methods 1.17-1.21.

[0120] 1.23 Any of Methods 1.17-1.18 further comprising the step of heating the mixture of Compound A and an acid in a solvent to about 75°C to about 80°C (e.g., about 78°C).

[0121] 1.24 Any of Methods 1.1-1.16, wherein the acid is citric acid.

[0122] 1.25 Method 1.24, where the solvent is acetone.

[0123] 1.26 Any of the preceding methods further comprising the optional step of seeding the reaction mixture.

[0124] 1.27 Any of the preceding methods wherein the reaction mixture / solution may be sonicated.

[0125] 1.28 Any of the preceding methods further comprising the step of isolating the crystals thus obtained.

[0126] 1.29 Any of the preceding methods further comprising the step of drying the crystals thus obtained (e.g., in an oven at about 45°C, by vacuum, or a combination thereof).

[0127] 1.30 Any of Methods 1.1 to 1.16, wherein the acid is adipic acid.

[0128] 1.31 Method 1.30, wherein the solvent is ethanol, acetone, or ethyl acetate.

[0129] 1.32 Methods 1.30 or 1.31, where the resulting solution is heated to about 50°C.

[0130] 1. A method for the prevention or treatment of a patient, for example a human suffering from a disorder selected from the following disorders, comprising administering to a patient in need of said prevention or treatment a therapeutically effective amount of the compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one in the form of an acid addition salt with either the free base crystalline 1 or later or salt crystalline 1 or later of the present disclosure [Method 2]: A. Neurodegenerative diseases, including Parkinson's disease, restless legs, tremors, dyskinesia, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; B. Psychiatric disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety disorders, sleep disorders, e.g., narcolepsy, cognitive dysfunction, e.g., cognitive dysfunction in schizophrenia, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction; C. Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, e.g., pulmonary arterial hypertension, and sexual dysfunction, including cardiovascular diseases and related disorders described in International Application No. PCT / US2014 / 16741, the contents of which are incorporated herein by reference; D. Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases; E. Diseases that can be alleviated by enhancing progesterone signaling, such as female sexual dysfunction; F. Diseases or disorders such as psychiatric illness, glaucoma, or elevated intraocular pressure; G. traumatic brain injury; H. Cancer or tumor, e.g., brain tumor, glioma (e.g., ependymoma, astrocytoma, oligodendroglioma, brain stem glioma, optic nerve glioma, or mixed glioma, e.g., oligodendroglioma), astrocytoma (e.g., glioblastoma multiforme), osteosarcoma, melanoma, leukemia, neuroblastoma, or leukemia; I. Renal disorders, such as renal fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis; J. A disease or condition characterized by low levels of cAMP and / or cGMP (or inhibition of the cAMP and / or cGMP signaling pathway) in cells expressing PDE1; and / or K. A disease or condition characterized by decreased dopamine D1 receptor signaling activity.

[0131] 2.1 A pharmaceutical composition comprising either the free base crystalline 1 or later or the salt crystalline 1 or later for use as a medicament, for example for use in the manufacture of a medicament for the treatment or prevention of a disease as described in Method 2. [Brief explanation of the drawings]

[0132] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern of the free base crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0133] [Figure 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of the free base crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0134] [Figure 3] FIG. 3 shows a thermogravimetric analysis (TGA) thermograph of the free base crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0135] [Figure 4]FIG. 4 shows the powder X-ray diffraction pattern of the succinate crystal of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0136] [Figure 5] FIG. 5 shows a differential scanning calorimetry (DSC) thermograph pattern of the succinate salt crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0137] [Figure 6] FIG. 6 shows a thermogravimetric analysis (TGA) thermograph pattern of the succinate salt crystal of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0138] [Figure 7] FIG. 7 shows the powder X-ray diffraction pattern of the crystalline citrate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0139] [Figure 8] FIG. 8 shows a differential scanning calorimetry (DSC) thermogram of the crystalline citrate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0140] [Figure 9]FIG. 9 shows a thermogravimetric analysis (TGA) thermograph of the citrate salt crystal of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0141] [Figure 10] FIG. 10 shows the powder X-ray diffraction pattern of the crystalline adipate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0142] [Figure 11] FIG. 11 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograph patterns of the crystalline adipate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0143] [Figure 12] FIG. 12 shows the powder X-ray diffraction pattern of crystalline malate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0144] [Figure 13] FIG. 13 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograph patterns of crystalline malate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0145] [Figure 14]FIG. 14 shows the powder X-ray diffraction pattern of the crystalline tartrate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0146] [Figure 15] FIG. 15 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograph patterns of the crystalline tartrate salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0147] [Figure 16] FIG. 16 shows the powder X-ray diffraction pattern of the gluconate salt crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one.

[0148] [Figure 17] FIG. 17 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograph patterns of the gluconate salt crystals of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one. DETAILED DESCRIPTION OF THE INVENTION

[0149] Detailed Description As used herein, the terms "crystal" or "crystals" or "crystalline" or "crystallinic" refer to a solid having short-range or long-range order of molecules, atoms, or ions in a fixed lattice arrangement. The salt crystals of the present disclosure may be in a single crystal form. Thus, the salt crystals of the present disclosure may be in a triclinic, monoclinic, orthorhombic, tetragonal, rhombohedral, hexagonal, or cubic crystalline form, or a mixture thereof. In particular, the salt crystals of the present disclosure are in a dry crystalline form. In another embodiment, the salt crystals of the present disclosure are in a needle-like form. In yet another embodiment, the salt crystals of the present disclosure are in a plate-like form. In certain embodiments, the salt crystals of the present disclosure are substantially free of other forms, for example, substantially free of amorphous or other crystalline forms.

[0150] The term "substantially free" of other crystalline forms refers to less than about 10% by weight of other forms or other crystalline forms, such as amorphous forms or other crystalline forms, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight.

[0151] The terms "predominantly" or "substantially entirely in a single form" refer to less than about 10% by weight of other crystalline forms, such as amorphous or other crystalline forms, preferably less than about 5% by weight, more preferably less than about 2% by weight, even more preferably less than about 1% by weight, even more preferably less than about 0.1% by weight, and most preferably less than about 0.01% by weight.

[0152] In certain embodiments, the crystal of the present disclosure may contain a trace amount of solvent, for example, may be in the form of a solvate, or may contain a trace amount of water, for example, may be in the form of a hydrate.Preferably, the salt crystal of the present disclosure is in a non-solvate form.More preferably, the crystal of the present disclosure is in a non-solvate form and a non-hydrate form.

[0153] The salt crystals of the present disclosure may have a free base to acid ratio of 1 to 1, 1 to 0.5, or 1 to > 1, such as 1 to 1.3 or 1 to 2. For example, the succinate crystals of the present disclosure may contain 1 molar equivalent of free base for every molar equivalent of succinic acid. Preferably, the succinate crystals of the present disclosure contain 1 molar equivalent of free base for every molar equivalent of succinic acid, and when the acid is a diacid such as fumaric acid or tartaric acid, the ratio of free base to acid may be 1 molar equivalent of free base for every 0.5 equivalents of diacid, for example, to form a hemifumarate or hemitartrate.

[0154] The term "solvate" refers to a crystalline solid adduct containing a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal structure. Thus, the term "non-solvate" form, as used herein, refers to a salt crystal that does not contain or is substantially free of solvent molecules within the crystal structure of the present disclosure. Similarly, the term "non-hydrate" form, as used herein, refers to a salt crystal that does not contain or is substantially free of water molecules within the crystal structure of the present disclosure.

[0155] The term "amorphous" morphology refers to a solid in which the molecules are arranged in a disordered manner and do not have a discernible crystal lattice.

[0156] The crystallinity or morphology of the crystals of the present disclosure can be determined by a number of methods, including, but not limited to, single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared adsorption spectroscopy, and Raman spectroscopy. The properties of solvates or hydrates, or the lack thereof, can also be determined by DSC and / or TGA.

[0157] It should be understood that the powder X-ray diffraction pattern or differential scanning calorimetry pattern of a sample may vary slightly (standard deviation) depending on the equipment used, the time and temperature of the sample during measurement, and standard experimental error. Therefore, the temperatures or 2θ values, d-spacing values, peak heights, and relative intensities listed in the tables or figures herein have an acceptable level of deviation. For example, the values ​​may have an acceptable deviation of, for example, about 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In certain embodiments, the 2θ values ​​or d-spacing values ​​of the XRPD pattern of the crystals of the present disclosure may have an acceptable deviation of ±0.2° and / or ±0.2 Å. The XRPD pattern of the crystals of the present disclosure may also be identified by characteristic peaks that would be recognized by a person skilled in the art. For example, the crystals of the present disclosure may be identified by, for example, at least five characteristic peaks, for example, at least three or at least five peaks, for example, at least three or at least five 2θ values ​​and / or at least three or at least five d-spacing values, as listed in the XRPD pattern described herein. Thus, the term "corresponding to or substantially corresponding to" as set forth in any of the tables or depicted in any of the figures refers to a crystal having an XRPD with the predominant or characteristic peak set forth in the table / figure.

[0158] The term "about" preceding a numerical value refers to ±20%, ±15%, ±10%, preferably ±5%, preferably ±3%, preferably ±2%, preferably ±1% of the numerical value itself. When referring to temperature, the term about refers to ±10°C, preferably ±5°C, preferably ±3°C of the temperature value itself. In another example, when referring to a 2-theta angle value, the term "about" refers to ±0.2° of the numerical 2-theta angle value itself. In yet another example, when referring to a d-spacing value, the term "about" refers to ±0.2 Å of the numerical 2-theta angle value itself.

[0159] The crystal of the present disclosure is a selective PDE1 inhibitor.Therefore, the crystal of the present disclosure is useful for treating PDE1-related disorders, such as those described in International Publication No. 2014 / 151409, International Publication No. 2018 / 049417, International Publication No. 2019 / 227004, International Publication No. 2019 / 152697, International Publication No. 2009 / 075784, International Publication No. 2010 / 132127, International Publication No. 2006 / 133261 and International Publication No. 2011 / 153129 (each of which is incorporated herein by reference in its entirety).

[0160] The term "patient" includes humans and non-humans. In one embodiment, the patient is a human. In another embodiment, the patient is a non-human. [Example]

[0161] Example 1 - Preparation of succinate salt crystals. The succinate salt crystals of the present disclosure can be prepared as described herein or similarly. In a 20 L round-bottom flask equipped with a reflux condenser, overhead stirrer, and temperature probe, 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (776.00 g, 1 eq, 1.6851 mol) was suspended in 7.5 L of absolute ethanol. The mixture was heated to 67°C (internal), and succinic acid (200.00 g, 1.0051 eq, 1.6936 mol) was added to the suspension. Upon addition, the suspension began to dissolve. The reaction mixture was heated to 78°C, yielding a clear orange / red solution after 15 minutes. The reaction was filtered hot through a P3 filter to remove undissolved particles. The mixture was then seeded, cooled to room temperature, and left for 48 hours for crystallization. The reaction mixture was filtered through a P2 filter and washed twice with 500 mL of EtOH. The solid was collected and dried to constant weight in a circulating oven at 45°C. Yield: 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-on succinate (804.8 g, 82.54%). Recrystallization afforded an additional 110 g of material.

[0162] A 3 L round-bottom flask was charged with 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-on succinate (745.0 g, 1 equivalent, 1.288 mol) from the initial crystallization and 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-on succinate (110.0 g, 0.1477 equivalents, 190.1 mmol) from the recrystallization. Ethanol (1.0 L) was added to the flask, and the slurry was stirred on a rotary evaporator at 65°C for 1 hour to obtain a uniform suspension. The water bath temperature was adjusted to 50°C, and the ethanol was removed under reduced pressure (distillation started from 220 mbar to 25 mbar) to dryness. The remaining solid (wet weight: 909.5 g) was transferred to a tray and dried in a circulating oven at 45°C for 5 days. 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-on succinate (845.5 g, 1.461 mol, 98.89%) was obtained as an off-white solid.

[0163] XRPD of the succinate crystals was obtained as described herein or similarly. The results are shown in Figure 4. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step. All measurement conditions were recorded in the instrument control file.

[0164] The XRPD pattern of the succinate salt crystals is shown in Figure 4 and has the following peaks: [Table 5-1] [Table 5-2]

[0165] A differential scanning calorimetry (DSC) thermogram of the succinate crystals was obtained as described herein or similarly as described herein, and the DSC is shown in Figure 5. DSC experiments were performed using a Mettler Toledo DSC1 STARe System. Samples were prepared using Al crucibles (40 μl; perforated). 1-8 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min and held at 350°C for 1 minute. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668. No corrections were applied to the thermograms.

[0166] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the succinate crystals were obtained as described herein or similarly as described herein and are shown in Figure 6. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0167] The succinate salt crystals are particularly stable, have good solubility, low hygroscopicity, a single melting event, definable stoichiometry, plate-like morphology, are non-solvated and non-hydrated, all of which are desirable properties for a galenic formulation.

[0168] A method for producing the compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one is generally described in WO 2014 / 151409, the contents of which are incorporated herein by reference in their entirety. This compound can be prepared as summarized in the following reaction scheme or analogously to the scheme summarized in the following reaction scheme.

[0169] [ka]

[0170] In particular, 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one can be prepared as described below or analogously as described below.

[0171] Preparation of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one

[0172] 2-(4-Bromobenzyl)-7-(4-methoxybenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (3). [ka]

[0173] To a clean 70 L reaction mixture was added DMAc (10 L), and under stirring (137 rpm), 7-(4-methoxybenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (1477 g, 1 eq., 5.159 mol), 1-bromo-4-(bromomethyl)benzene (1292 g, 1.002 eq., 5.169 mol), and potassium carbonate (713.0 g, 1 eq., 5.159 mol) were added under nitrogen. DMAc (2.5 L) was added to rinse the inside of the reaction vessel. The mixture (suspension) was warmed to 50°C and stirred at this temperature for 45 minutes. The mixture was warmed to 80°C and stirred for 30 minutes. IPC (by LC-MS) showed complete conversion. The mixture was cooled to 30°C, resulting in a thick white suspension. The suspension was suctioned from the reaction vessel into a work-up vessel. Water (35 L) was added to the reaction mixture with vigorous stirring (320 rpm). The suspension was filtered through two large Buchner funnels, washed with water (2 L each x 2), and dried in an oven at 45°C for 20 hours. The material weighed: 3222 g (yield >100%). The batch was split: 120 g was dried in a small rotary evaporator and in an oven at 45°C overnight. The larger batch was dried in a large rotary evaporator and oven overnight. Yield of the small batch: 81.6 g (3%). Yield of the large batch: 2276 g (96%).

[0174] 2-(4-Bromobenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione [ka]

[0175] A 20 L reaction vessel was charged with 2-(4-bromobenzyl)-7-(4-methoxybenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (2276 g, 1 equivalent, 4.999 mol). With mechanical stirring, 2,2,2-trifluoroacetic acid (10 kg, 6.7 L, 18 equivalents, 88 mol) was added and the mixture was stirred until completely dissolved. end = 25°C. Trifluoromethanesulfonic acid (2251 g, 3.001 equiv., 15.00 mol) was added dropwise. An exothermic effect was observed. T max =43.4°C. A reddish-purple solution was obtained. The reaction mixture was stirred for an additional 16 hours. The mixture was transferred to a 70 L reaction vessel and cooled to 15°C. Acetonitrile (20 L) was added using a dropping funnel and stirred for 30 minutes, and the red suspension was collected in a 10 L tank. A mixture of 28% ammonia in water (21 L) and acetonitrile (10 L) was charged to the reaction vessel and cooled to 0°C. The reaction mixture from the 10 L tank was added in small portions. The mixture (yellow suspension) was stirred for 30 minutes, filtered through an 8 L P2 glass funnel, and washed with acetonitrile / water (1:1; 10 L). The yellow solid was stirred in ethyl acetate (10 L) for 1 hour, filtered, and washed with ethyl acetate (3.5 L). The solid was dried at 45°C. Yield: 2-(4-bromobenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (1437 g, 4.288 mol, 85.79%) white / tan solid.

[0176] 2-(4-Bromobenzyl)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one [ka]

[0177] A 20 L flask equipped with a stirrer and temperature probe was placed under a nitrogen atmosphere and heated with a heat gun to remove moisture. DMF (4 L) was added, and with stirring, 2-(4-bromobenzyl)-5-methyl-2,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dione (736.0 g, 1 equiv., 2.196 mol) was added. A suspension formed. The funnel was rinsed with DMF (200 mL). ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (1166 g, 1.201 equiv., 2.636 mol) was added, and the funnel was rinsed with DMF (200 mL). 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (401.2 g, 1.2 equivalents, 2.635 mol) (weighed into a 100 mL beaker and washed with DMF (600 mL)) was added. The suspension became a clear brown solution and an exothermic effect was observed: T = 19.6 °C; T max =29.7°C. The mixture was stirred for 16 hours. 2-Amino-2-methylpropan-1-ol (822.1 g, 4.2 equivalents, 9.223 mol) melted in a sealed bottle in warm water was added, and the mixture became slightly endothermic. The vessel was warmed to 60°C and stirred for 4 days. The reaction mixture was cooled to 0°C with ice salt. Add dropwise thionyl chloride (1810 g, 6.929 equivalents, 15.22 mol). The temperature was maintained below 20°C. A light brown suspension was formed. Stirring was continued for 1 hour after the addition.

[0178] Alternatively, this step can be carried out as follows: In a 50 L extraction vessel equipped with a mechanical stirrer, 24 L of ice / water and 7 L of 25% ammonia were added. The reaction mixture was added portionwise under stirring (120 rpm). During the addition, ice was added portionwise to keep the mixture cool (<15°C). After the addition, the organic layer was extracted with ethyl acetate (3 L x 1: sticky solid on the bottom extraction vessel; 1 x 10 L, 5 L x 1). The ethyl acetate layer was washed with 0.5 M NaOH solution (5 L x 2: yellow after the first extraction, colorless after the second) to remove starting material, 5% NaCl solution (5 L x 3; after two extractions, the aqueous layer remained light basic), and brine (5 L x 1; pH was neutral, the organic layer was clear). The organic layer was dried over Na2SO4, filtered, and concentrated on a rotary evaporator, but not completely; the last 1.5 L was not concentrated due to the precipitation of a white solid. The vessel was cooled in an ice bath and the solid was filtered and washed with cold EtOAc (50 mL x 2). The solid was air-dried overnight. Yield: 566 g (66%) of a white solid. Further yield after further evaporation of the filtrate: 19.1 g.

[0179] 2-(4-Bromobenzyl)-3-chloro-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one [ka]

[0180] DCM (15 L) was added to a 50 L reaction vessel, followed by 2-(4-bromobenzyl)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (1790 g, 1 equiv., 4.610 mol). Perchloromethane (1.418 kg, 892 mL, 2 equiv., 9.22 mol) was added, and the reaction mixture was cooled to -10 °C. Lithium bis(trimethylsilyl)amide (1.466 kg, 8.8 L, 1.9 equiv., 8.76 mol) was added via an addition funnel, maintaining the temperature between -5 °C and -10 °C. The addition was complete after 1 h 50 min. A sample was checked by HPLC-MS (1 drop of the reaction mixture in acetonitrile), which showed complete conversion.

[0181] The reaction was quenched by the addition of saturated aqueous ammonium chloride (15 L). The temperature rose from -6 to 5°C. The mixture was stirred at 5°C for 10 minutes and then warmed to 18°C. The layers were separated. The aqueous layer was extracted with dichloromethane (5 L). The combined organic layers were washed with water (5 L x 2). The organic layers were then dried over sodium sulfate and evaporated to dryness. This yielded a dark brown / black sticky solid (2520 g). NMR indicated that the desired product was combined with toluene and ethylbenzene. Additional solvent was removed by using a high vacuum (oil) pump. This gave a crude yield of 2335 g (120% yield). Overnight, the material solidified in the evaporation flask. The material was removed from the flask, powdered, and further dried at room temperature in an open container. Compound 6 was obtained as a dark brown solid (2178 g, 5.15 mol, 110%).

[0182] 2-(4-Bromobenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one [ka]

[0183] To a 50 L reaction vessel under a nitrogen atmosphere was added THF (11 L) and 4-fluoroaniline (1.6 kg, 1.3 L, 3.1 equiv., 14 mol). The mixture was cooled to -6°C. Butyllithium (2.5 M in hexanes, 0.72 kg, 4.5 L, 2.5 equiv., 11 mol) was added over 70 minutes, maintaining the temperature between -5°C and -2°C. The reaction mixture was warmed to 15°C over 1 hour. Starting material (compound 6) (2126 g, 1 equiv., 4.5 mol) was dissolved in pyridine (10 L). This resulted in a black solution. This solution was added quickly (within 10 minutes) to the reaction mixture. An exotherm to 29°C was observed. The reaction mixture was heated at 70°C for 2 hours. The reaction was cooled to 55°C (below reflux) and the solution was collected (1 drop of reaction mixture in acetonitrile). The reaction mixture was heated at 70°C for an additional 2 hours and stirred overnight. Saturated NH4Cl (11 L) was added to the reaction mixture and the mixture was stirred for 10 minutes. The layers were separated. The aqueous layer (approximately 22 L), containing the solids, was extracted with ethyl acetate (3 L). Additional water (3 L) was added and stirred again. This gave two clear layers, which were then separated. The aqueous layer (approximately 16 L) was extracted with ethyl acetate (2 L). The combined organic layer (black) was washed with 5 L of half-saturated brine. The aqueous layer (7 L) was separated. The organic layer was washed with 3 L of half-saturated brine. The aqueous layer (3 L) was removed. The organic layer was dried over sodium sulfate, filtered through a fritted funnel, and evaporated to dryness on a large rotary evaporator at 50°C. A brown oil (3346 g) was obtained.

[0184] The crude material was purified on silica gel in four portions. A 20 kg silica gel column was prepared by loading the material as a slurry in dichloromethane. 3346 g of crude material was dissolved in 1.5 L of dichloromethane to obtain a 60% stock solution. 1500 g of this stock solution (approximately 900 g of product) was applied to the column. The solution was first eluted with 30 L of dichloromethane, followed by collection in 10 fractions. Next, the solution was eluted with 20% dichloromethane / acetone (50 L), collected in 4.5 L fractions. Each fraction was checked by TLC (eluted with 20% DCM / acetone, colored with PMA dip). The column was then eluted with 40 L of 30% DCM / acetone, collecting 2 L fractions each. Fractions 14-20 were very brown and contained 4-fluoroaniline by TLC. Finally, elution with DCM / acetone 40% (approximately 110 L) yielded 73.7 g of starting compound 6 combined with compound 7, 95 g of compound 7 containing traces of compound 6, and 187.9 g of pure product 7.

[0185] After the four columns were completed, several batches of similar purity were combined to give a total of 803.6 g of pure Compound 7. Fractions containing greater than 80% pure Compound 7 were combined and pooled (303 g).

[0186] 2-(4-Acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one [ka]

[0187] A 20 L reactor equipped with a Teflon-coated metal stirring propeller, reflux condenser, and temperature probe was flushed with nitrogen. 2700 mL of a 1:15 mixture of water and DMF (170 mL demi-water + 2530 mL DMF) was prepared. Most of the solvent mixture was charged to the reactor.

[0188] Compound 7 (800.0 g, 1 equivalent, 1.608 mol) was added, followed by 1,3-bis(diphenylphosphanyl)propane (66.34 g, 0.1 equivalent, 160.8 mmol), potassium carbonate (448 g, 2.02 equivalents, 3.24 mol), and 1-(vinyloxy)butane (4.833 kg, 6.24 L, 30 equivalents, 48.25 mol). The solid was washed with the remaining solvent mixture.

[0189] The resulting mixture was degassed by bubbling nitrogen through it with stirring for 1 hour. Palladium(II) acetate (18.06 g, 0.05 equiv., 80.42 mmol) was added and heated to 70°C over 1 hour. The internal temperature rose to 84°C (the reaction is likely exothermic!). The heating mantel was lowered to cool to 70°C. The reaction mixture was stirred at 70°C overnight.

[0190] HPLC analysis indicated complete conversion. The reaction mixture was cooled to 50°C and then transferred to a 20 L evaporating flask (1.5 L of water was used to dissolve the solids) and concentrated to water (5.8 L of butyl vinyl ether / water azeotrope was recovered). A solution of phosphoric acid (1.1 kg, 0.66 L, 6 equiv., 9.651 mol) and acetylcysteine ​​(131 g, 0.5 equiv., 804.2 mmol) in water (3.2 L) was prepared. The concentrated reaction mixture was poured into a 20 L reaction vessel. The flask was washed with water (1.5 L) and toluene (1.5 L). Both washes were added to the reaction vessel. The reaction mixture was cooled to 20°C in an ice / water bath. The phosphoric acid and acetylcysteine ​​solution was slowly added to the reaction mixture via an addition funnel. A small exotherm to 25°C and gas evolution were observed. The temperature was maintained below 25°C. The addition was complete after 1.5 hours. A brown suspension was obtained which was stirred for 30 min.

[0191] The solid was collected by filtration through a 4 L P2 fritted glass funnel. The solid was washed three times with 2 L of toluene (each wash was kept separate). The filter cake was orange in color. The acidic aqueous layer (dark brown / black) was washed successively with the toluene washes obtained after washing the filter cake.

[0192] The acidic aqueous layer and filter cake were added to a 50 L separatory funnel. Additional compound 7 (35 g) and toluene (6 L) were added. The mixture was made basic (pH 9.5) by adding 25% ammonia (using 1-1.5 L) and stirred for 30 minutes. The layers separated easily, but the aqueous layer still contained solids and some black tar-like material. The mixture was filtered through a pad of Celite (5 cm thick). The pad was then washed with toluene (2 L x 2), resulting in the formation of solids on top of the Celite. These solids were dissolved in hot toluene (approximately 5 L at 60 °C) and filtered again. The combined organic layers were washed with water (2 L x 4). The final aqueous layer had a pH of 7-8. The organic layer (approximately 26 L) was concentrated to approximately 15 L on a rotary evaporator at 50 °C. The mixture was transferred to a 20 L reaction vessel equipped with a Teflon-coated metal stirring propeller, a reflux condenser, and a temperature probe. Demineralized water (3 L) and acetylcysteine ​​(131 g, 0.5 eq, 804.2 mmol) were added to the mixture and stirred at 45°C overnight. The mixture was transferred to a 50 L separatory funnel, and additional toluene (8 L) was added to dissolve the remaining solids. 25% aqueous ammonia (160 mL) was added and stirred for 10 minutes. The layers were separated. The solids present in the aqueous layer were dissolved by stirring with hot toluene (4 L x 2) and then extracted. The combined organic layers were washed again with water (2 L x 4). The final washes had a pH of 7-8. The organic layers were dried over sodium sulfate and stored (total volume approximately 36 L). The combined organic layers were dried over sodium sulfate and filtered through a 4 L P2 fritted glass funnel. The mixture was concentrated to approximately 3 L under reduced pressure at 50°C on a large rotary evaporator. A thick suspension was obtained and cooled to 15°C. The solid was collected by filtration through a 4 L P2 fritted glass funnel. The solid was washed with cold toluene (1-2 L). The solid was dried in an open container at room temperature. The mother liquor was evaporated to dryness. This gave a dark brown sticky solid (114 g).

[0193] The crude product (617 g) was checked by NMR and shown to be the desired product 8 of high purity. Compound 8 (617.5 g) was dissolved in dichloromethane (8 L) and stirred in a 20 L reaction vessel equipped with a Teflon-coated metal stirring propeller, a reflux condenser, and a temperature probe. Approximately 21 wt % SiliaMET DMT (131 g) was added to the reaction vessel. The vessel was heated at 37 °C overnight. The reaction mixture was allowed to cool to room temperature. The mixture was then filtered through a pad of Celite (2 cm thick in a 4 L P2 fritted glass funnel). The solid on the filter was washed with dichloromethane (2 L). The combined filtrate was evaporated to dryness under reduced pressure at 45 °C. This gave compound 8 (602 g) as an off-white solid. The Pd content was determined to be 48.8 ppm.

[0194] Example 2 - Preparation of Citrate Crystals 2-(4-Acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (500 mg) was prepared as outlined in Example 1 and mixed with citric acid (232.1 mg). The mixture was dissolved in 16 mL of acetone and stirred overnight. The next day, the acetone was removed under vacuum. The product was dried under vacuum at 40°C for 2 days.

[0195] XRPD of the citrate crystals was obtained as described herein or similarly. The results are shown in Figure 7. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step. All measurement conditions were recorded in the instrument control file.

[0196] The XRPD pattern of the citrate salt crystals is shown in Figure 7 and has the following peaks: [Table 6]

[0197] A differential scanning calorimetry (DSC) thermogram of the citrate crystals was obtained as described herein or similarly as described herein, and the DSC is shown in Figure 8. DSC experiments were performed using a Mettler Toledo DSC1 STARe System. Samples were prepared using Al crucibles (40 μl; perforated). 1-8 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min and held at 350°C for 1 minute. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668. No corrections were applied to the thermograms.

[0198] Thermogravimetric analysis (TGA) of the citrate crystals was performed as described herein or similarly as described herein and is shown in Figure 6. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5-10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0199] Example 3 - Preparation of adipate crystals 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one is prepared as summarized in Example 1 and mixed with adipic acid. The mixture is dissolved in ethanol, acetone, or ethyl acetate at 50°C. The slurry is then cooled to a temperature of 20°C, and the solid is removed.

[0200] XRPD of the adipate crystals was obtained as described herein or similarly. The results are shown in Figure 7. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step. All measurement conditions were recorded in the instrument control file.

[0201] The XRPD pattern of the adipate crystals is shown in Figure 10 and has the following peaks: [Table 7]

[0202] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the adipate crystals were obtained as described herein or similarly as described herein and are shown in Figure 11. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0203] Example 4 – Preparation of Malate Crystals 2-(4-Acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one was prepared as outlined in Example 1 and mixed with malic acid. The mixture was dissolved in acetonitrile at room temperature for 16 hours. The acetonitrile was removed by pipette, and the remaining solvent was removed under vacuum. The product was further dried under vacuum at room temperature for 1 day.

[0204] XRPD of the malate crystals was obtained as described herein or similarly. The results are shown in Figure 12. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step. All measurement conditions were recorded in the instrument control file.

[0205] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the malate crystals were obtained as described herein or similarly as described herein and are shown in Figure 13. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0206] Example 5 – Preparation of tartrate crystals 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one is prepared as summarized in Example 1 and mixed with tartaric acid. The mixture is dissolved in acetone or acetonitrile at 50°C. The slurry is then cooled to a temperature of 20°C, and the solid is removed.

[0207] XRPD of the tartrate salt crystals was obtained as described herein or similarly. The results are shown in Figure 14. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step, and all measurement conditions were recorded in the instrument control file.

[0208] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the tartrate salt crystals were obtained as described herein or similarly as described herein and are shown in Figure 15. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0209] Example 6 - Preparation of gluconate crystals 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one was prepared as outlined in Example 1 and mixed with gluconic acid. The mixture was dissolved in DMSO at room temperature for 16 hours. Excess DMSO was removed, and the product was further dried under vacuum at room temperature for 1 day.

[0210] XRPD of the gluconate crystals was obtained as described herein or similarly. The results are shown in Figure 16. Powder X-ray diffraction experiments were performed using a Bruker AXS D8 discover HTS. A Cu anode was used at 40 kV and 40 mA; a Goebel mirror was used; and linear optics were used. Detector: Linear detector LYNXEYE XE with a receiving slit and a 2.95° detector aperture. Measurement conditions: scan range 2-45° 2θ, 1 sec / step, 0.005° / step, and all measurement conditions were recorded in the instrument control file.

[0211] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the gluconate crystals were obtained as described herein or similarly as described herein and are shown in Figure 17. TGA / DSC experiments were performed using a Mettler Toledo TGA / DSC-01 / 03 STARe System equipped with a 34-position autosampler. Samples were prepared using Al crucibles (40 μl; perforated). 5–10 mg of sample was placed in a pre-weighed Al crucible and held at 20°C for 5 minutes, then heated from 20°C to 350°C at 10°C / min. A 40 ml / min nitrogen purge was maintained over the sample. The software used for data collection and evaluation was STARe Software v15.00 build 8668.

[0212] Example 7 – Solubility experiments with succinate salt crystals The solubilities of the free base and succinate crystalline forms of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one are compared. Samples are titrated in water or under cosolvent conditions for a minimum of three titrations from the pH at which the sample completely dissolves. Sample precipitation from solution is detected by a UV-turbidity probe, which corresponds to kinetic solubility. After precipitation, base and acid titrants are added alternately to move the sample around the equilibrium solubility of the neutral species (intrinsic solubility). At this point, the sample exists in a supersaturated or subsaturated state (i.e., chase equilibrium). The intrinsic solubility is determined from the pH between the supersaturated and subsaturated states, which corresponds to the intrinsic solubility. If co-solvent conditions are used, the sample can be determined by extrapolation to aqueous media.

[0213] The solubility of the succinate salt is approximately 7 mg / mL, significantly higher than that of the free base (0.285 mg / mL). This degree of aqueous solubility predicts faster dissolution rates in vitro and in vivo.

[0214] Example 8 – Pharmacokinetic study of succinate crystalline salt in dogs Dogs were orally administered 5 mg / kg of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one succinate salt. Another group of dogs was orally administered 5 mg / kg of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one free base. Plasma samples were collected and analyzed for drug concentrations.

[0215] Pharmacokinetic (PK) parameters are determined from plasma concentration versus time data by non-compartmental methods using uniform weighting. Maximum observed concentration (C max ) and the time of maximum observed concentration (T max ) are obtained from the raw bioanalytical data. The area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable sample is calculated by the trapezoidal rule. The plasma pharmacokinetic profiles of the free base and succinate crystalline salt at a 5 mg / kg dose are shown in Table 5 below.

[0216] [Table 8]

Claims

1. Crystals of the compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one in free base form.

2. The crystal of claim 1, wherein the crystal is in a non-solvated form.

3. 2. The crystal of claim 1, wherein the free base crystal is in the form of a solvate with methanol, ethanol, propanol (eg, n-propanol or isopropanol), or butanol (eg, n-butanol).

4. 10. The crystal according to claim 9, wherein the crystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 9.3°, 14.0°, 14.7°, 17.3°, 17.9°, 18.7°, 21.2°, 23.2°, 23.3°, and 23.7°, and the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

5. 2. A crystal according to any preceding claim, wherein the crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 9.53 Å, 6.33 Å, 6.02 Å, 5.11 Å, 4.95 Å, 4.74 Å, 4.19 Å, 3.83 Å, 3.82 Å, and 3.79 Å.

6. 10. The crystal of any preceding claim, wherein the free base crystal exhibits a differential scanning calorimetry (DSC) pattern comprising an endothermic peak at about 195°C to 196°C.

7. For example, a crystal of the compound 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one in the form of an acid addition salt selected from citrate, adipate, tartrate (e.g., L-tartrate), malate, succinate, gluconate (e.g., D-gluconate), maleate, fumarate, aspartate (e.g., L-aspartate), hippurate, sebacate, glycolate, galactarate, benzoate, pamoate, oxalate, and malonate.

8. The crystal of claim 7, wherein the salt is a succinate salt.

9. 9. The crystal of claim 8, wherein the salt is a succinate salt having a molar ratio of free base to succinic acid of 1:1 (i.e., monosuccinate salt) or 2:

1.

10. 10. The crystal according to claim 8 or 9, wherein the salt is a monosuccinate salt.

11. The crystal according to any one of claims 8 to 10, wherein the salt crystal exhibits a powder X-ray diffraction pattern including at least five peaks having 2θ angle values ​​selected from the group consisting of 7.8°, 8.2°, 11.6°, 14.5°, 16.5°, 18.6°, 19.7°, 20.4°, 20.6°, 22.1°, 23.3°, 24.8°, 26.0°, and 28.5°, and the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

12. 12. The crystal of any one of claims 8 to 11, wherein the salt crystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 11.37 Å, 10.77 Å, 7.62 Å, 6.09 Å, 5.38 Å, 4.77 Å, 4.50 Å, 4.36 Å, 4.31 Å, 4.02 Å, 3.81 Å, 3.59 Å, 3.43 Å, and 3.13 Å.

13. The crystal according to any one of claims 8 to 12, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 177°C to 178°C.

14. The crystal of claim 7, wherein the salt is a citrate salt.

15. 15. The crystal of claim 14, wherein the salt is a monocitrate salt.

16. 16. The crystal according to claim 14 or 15, wherein the salt crystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.9°, 7.0°, 7.8°, 8.8°, 11.7°, 11.9°, 13.2°, 13.8°, 14.4°, 15.7°, 16.1°, 16.3°, 16.8°, 18.1°, 19.0°, 19.9°, 20.2°, 20.7°, 21.0°, 21.3°, 22.4°, 23.6°, 24.9°, 25.3°, and 27.2°, and the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

17. 17. The crystal of any one of claims 14 to 16, wherein the salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 14.97 Å, 12.67 Å, ​​11.33 Å, 10.08 Å, 7.59 Å, 7.41 Å, 6.72 Å, 6.41 Å, 6.14 Å, 5.67 Å, ​​5.48 Å, 5.42 Å, 5.27 Å, 4.90 Å, 4.67 Å, ​​4.47 Å, 4.39 Å, 4.29 Å, 4.22 Å, 4.18 Å, 3.97 Å, 3.76 Å, 3.57 Å, 3.51 Å, and 3.27 Å.

18. The crystal according to any one of claims 14 to 17, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 142°C to 144°C.

19. 8. The crystal of claim 7, wherein the salt is an adipate salt.

20. 20. The crystal according to claim 19, wherein the salt crystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having 2θ angle values ​​selected from the group consisting of 5.4°, 6.4°, 7.1°, 9.6°, 10.9°, 14.2°, 15.5°, 15.7°, 16.1°, 16.5°, 17.9°, 20.8°, 21.8°, 22.4°, 23.9°, 24.7°, 26.3°, and 27.8°, and the XRPD pattern is measured, for example, with a diffractometer using a copper anode at a wavelength α1 of 1.5406 Å and a wavelength α2 of 1.5444 Å.

21. 21. The crystal of claim 19 or 20, wherein the salt crystal exhibits a powder X-ray diffraction pattern comprising at least five peaks having d-spacing values ​​selected from the group consisting of 16.23 Å, 13.72 Å, 12.49 Å, 9.18 Å, 8.10 Å, 6.23 Å, 5.70 Å, 5.65 Å, 5.50 Å, 5.38 Å, 4.94 Å, 4.26 Å, 4.08 Å, 3.96 Å, 3.72 Å, 3.60 Å, 3.38 Å and 3.21 Å.

22. The crystal according to any one of claims 19 to 21, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 170°C to 172°C.

23. The crystal of claim 7, wherein the salt is a malate salt.

24. 24. The crystal of claim 23, wherein the salt is an L-malate salt.

25. 25. The crystal of claim 23 or 24, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in Figure 11.

26. The crystal according to any one of claims 23 to 25, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 214°C to 215°C.

27. The crystal according to any one of claims 23 to 26, wherein the salt crystal exhibits a thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) pattern corresponding to or substantially shown in Figure 12.

28. The crystal of claim 7, wherein the salt is a tartrate salt.

29. 29. The crystal of claim 28, wherein the salt is an L-tartrate salt.

30. 30. The crystal of claim 28 or 29, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in Figure 13.

31. The crystal according to any one of claims 28 to 30, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 240°C to 242°C.

32. 32. The crystal of any one of claims 28 to 31, wherein the salt crystal exhibits a thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) pattern corresponding to or substantially shown in Figure 14.

33. The crystal of claim 7, wherein the salt is a gluconate salt.

34. 34. The crystal of claim 33, wherein the salt is a D-gluconate salt.

35. 35. The crystal of claim 33 or 34, wherein the salt crystal exhibits an X-ray powder diffraction pattern corresponding to or substantially as shown in Figure 15.

36. The crystal according to any one of claims 33 to 35, wherein the salt crystal exhibits a differential scanning calorimetry (DSC) pattern including an endothermic peak at about 195°C to 196°C.

37. The crystal according to any one of claims 33 to 36, wherein the salt crystal exhibits a thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) pattern corresponding to or substantially shown in Figure 16.

38. A method for producing an acid addition salt of 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one ("Compound A"), for example, a crystalline acid addition salt with a particular acid, the method comprising the steps of reacting Compound A with the acid in a solvent and isolating the resulting salt.

39. 39. The method of claim 38, wherein the acid is selected from citric acid, adipic acid, tartaric acid (e.g., L-tartaric acid), malic acid, succinic acid, gluconic acid (e.g., D-gluconic acid), maleic acid, fumaric acid, aspartic acid (e.g., L-aspartic acid), hippuric acid, sebacic acid, glycolic acid, galactaric acid, benzoic acid, pamoic acid, oxalic acid, and malonic acid.

40. 40. The method of claim 38 or 39, wherein the solvent is an alcohol (e.g., methanol and / or ethanol), acetone, acetonitrile, dimethyl sulfoxide (DMSO), ethyl acetate, and / or toluene.

41. The method of any one of claims 38 to 40, wherein 2-(4-acetylbenzyl)-3-((4-fluorophenyl)amino)-5,7,7-trimethyl-7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (Compound A) is in crystalline form.

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