NEW FORMS OF PYRIDO[1,2-a]PYRIMIDIN-4-ONE DERIVATIVES, FORMULATION AND PROCESS OF MAKING THEREOF

Abstract

To provide a pharmaceutical composition for the treatment, prevention, delaying progression, and / or amelioration of diseases caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of SMN 1 gene function.SOLUTION: There is provided a solid form of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or its salt that is useful as a pharmaceutically active compound, wherein the solid form is a crystalline polymorph A type.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to crystalline forms of the compound 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, processes for their preparation, their compositions and their use as pharmaceutically active compounds.

Chemical Formula

Brief Description of the Drawings

[0002]

Figure 1

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DETAILED DESCRIPTION OF THE INVENTION

[0003] The present invention relates to crystalline polymorph A and crystalline hydrate D of the compound of formula (I)

CHEMICAL FORMULA

[0004] Crystalline polymorph A of the compound of formula (I) is a thermodynamically stable polymorph.

[0005] Crystalline hydrate D of the compound of formula (I) is a crystalline form obtained under high water activity conditions.

[0006] In another aspect, the present invention also relates to a composition or a medicament containing crystalline polymorph A. Its uses are also described. Such novel polymorphs have the property of being advantageous in terms of ease of production (formulation), have improved storage stability, and / or have dosage form stability in terms of ease of packaging.

[0007] In particular, Form A has improved chemical stability compared to Form D.

[0008] In particular, Form A has improved processability with respect to its filtration compared to Form D. This improvement enables the target compound to be isolated more quickly and can save solvents that can have a significant impact on the environment.

[0009] In one embodiment, the crystalline polymorphic Form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern comprising peaks characteristic of one or more of about 11.4 degrees two-theta, about 12.7 degrees two-theta, about 15.9 degrees two-theta, about 24.0 degrees two-theta, or about 25.6 degrees two-theta. In one embodiment, Form A comprises two or more, three or more, four or more, or all five of these characteristic peaks. For example, Form A may comprise a combination of X-ray powder diffraction pattern peaks characteristic of about 8.3 degrees two-theta, about 11.4 degrees two-theta, about 12.7 degrees two-theta, about 13.0 degrees two-theta, about 15.1 degrees two-theta, about 15.9 degrees two-theta, about 17.0 degrees two-theta, about 19.7 degrees two-theta, about 22.4 degrees two-theta, about 24.0 degrees two-theta, about 25.6 degrees two-theta and / or about 26.8 degrees two-theta. In another example, there may be three characteristic peaks at about 12.7 degrees two-theta, about 24.0 degrees two-theta, and about 25.6 degrees two-theta, which may be further combined with a fourth peak. Optionally, all five peaks may be present. For example, the crystalline polymorphic Form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern comprising peaks characteristic of one or more of 11.4 ± 0.2 degrees two-theta, 12.7 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, 24.0 ± 0.2 degrees two-theta, or 25.6 ± 0.2 degrees two-theta. In one embodiment, Form A comprises two or more, three or more, four or more, or all five of these peaks.For example, Type A may include a combination of X-ray powder diffraction pattern peaks characteristic of 2-theta of 8.3 ± 0.2 degrees, 2-theta of 11.4 ± 0.2 degrees, 2-theta of 12.7 ± 0.2 degrees, 2-theta of 13.0 ± 0.2 degrees, 2-theta of 15.1 ± 0.2 degrees, 2-theta of 15.9 ± 0.2 degrees, 2-theta of 17.0 ± 0.2 degrees, 2-theta of 19.7 ± 0.2 degrees, 2-theta of 22.4 ± 0.2 and 24.0 ± 0.2 degrees, or 2-theta of 25.6 ± 0.2 degrees and 2-theta of 26.8 ± 0.2 degrees. In another example, there may be three characteristic peaks at 2-theta of 12.7 ± 0.2 degrees, 2-theta of 24.0 ± 0.2 degrees, and 2-theta of 25.6 ± 0.2 degrees, which may be further combined with a fourth peak. Optionally, all five peaks may be present. In a further embodiment, Type A includes an XRPD peak at a diffraction angle of 2-theta of about 8.3 degrees (±0.2), and at least one, specifically two, more specifically three, even more specifically four, even more specifically five, and most specifically six additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 15.1 degrees (±0.2), 15.9 degrees (±0.2), 17.0 degrees (±0.2), 24.0 degrees (±0.2) or 25.6 degrees (±0.2). In another embodiment, Type A includes XRPD peaks at diffraction angles at 2-theta of about 11.4 degrees (±0.2), 15.1 degrees (±0.2) and 25.6 degrees (±0.2). In another embodiment, Type A includes XRPD peaks at diffraction angles at 2-theta of about 15.1 degrees (±0.2), 17.0 degrees (±0.2) and 25.6 degrees (±0.2). In another embodiment, Type A includes XRPD peaks at diffraction angles at 2-theta of about 15.1 degrees (±0.2), 24.0 degrees (±0.2) and 25.6 degrees (±0.2).In a more specific embodiment, Form A comprises XRPD peaks at a diffraction angle of 2 theta of about 8.3 degrees (±0.2), and at least one, specifically two, more specifically three, even more specifically four, even more specifically five, and most specifically six additional XRPD peaks at 2 theta of 11.4 degrees (±0.2), 15.1 degrees (±0.2), 15.9 degrees (±0.2), 17.0 degrees (±0.2), 24.0 degrees (±0.2), or 25.6 degrees (±0.2).

[0010] A specific embodiment of the present invention relates to crystalline polymorphic Form A of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern shown in FIG. 1.

[0011] A specific embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the infrared spectrum shown in FIG. 3.

[0012] A specific embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the Raman spectrum shown in FIG. 2.

[0013] In another embodiment, the crystalline polymorphic form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, has a melting point above 298 °C, specifically 298 °C to 302 °C, more specifically 299 °C to 301 °C, when measured by DSC using a heating rate of 10 K / min and a nitrogen flow. In one embodiment, the crystalline polymorphic form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is anhydrous, i.e., it does not contain water bound in the crystal lattice and is slightly hygroscopic from non-hygroscopic (less than 2% water absorption according to the European Pharmacopoeia). In another embodiment, the crystalline polymorphic form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is substantially free of water and other solvents (especially ethanol <5000 ppm; H2O <0.5 wt%).

[0014] In one embodiment, the crystalline polymorphic form A of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, prepared herein is at least 90% pure, specifically at least 95% pure, more specifically at least 97% pure, even more specifically at least 99% pure, even more specifically at least 99.5% pure, and most specifically at least 99.7% pure. "Pure" means, for example, not containing contaminants including solvents, organic impurities, or inorganic impurities.

[0015] In one embodiment, the crystalline hydrate D form of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern comprising peaks characteristic of one or more of about 8.4 degrees 2-theta, about 12.8 degrees 2-theta, about 13.9 degrees 2-theta, about 19.9 degrees 2-theta, about 20.8 degrees 2-theta, about 22.0 degrees 2-theta, about 22.6 degrees 2-theta, about 23.5 degrees 2-theta, about 24.4 degrees 2-theta, about 25.3 degrees 2-theta, about 26.1 degrees 2-theta and about 27.2 degrees 2-theta. In one embodiment, the D form comprises two or more, three or more, four or more, or all five of these characteristic peaks. For example, the D form may comprise a combination of characteristic peaks of the X-ray powder diffraction pattern selected from 8.4 degrees 2-theta, about 12.8 degrees 2-theta, about 13.9 degrees 2-theta, about 19.9 degrees 2-theta, about 20.8 degrees 2-theta, about 22.0 degrees 2-theta, about 22.6 degrees 2-theta, about 23.5 degrees 2-theta, about 24.4 degrees 2-theta, about 25.3 degrees 2-theta, about 26.1 degrees 2-theta or about 27.2 degrees 2-theta. In another example, there may be three characteristic peaks at 8.4 ± 0.2 degrees 2-theta, 23.5 ± 0.2 degrees 2-theta, 24.4 ± 0.2 degrees 2-theta, 25.3 ± 0.2 degrees 2-theta, or 27.2 ± 0.2 degrees 2-theta, and a fourth peak may be combined. Optionally, all five peaks may be present. For example, the crystalline hydrate D form of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is characterized by an X-ray powder diffraction pattern comprising peaks characteristic of one or more of 8.4 ± 0.2 degrees 2-theta, 23.5 ± 0.2 degrees 2-theta, 24.4 ± 0.2 degrees 2-theta, 25.3 ± 0.2 degrees 2-theta, or 27.2 ± 0.2 degrees 2-theta. In one embodiment, the D form comprises two or more, three or more, four or more, or all five of these peaks.For example, the D form may include a combination of X-ray powder diffraction patterns characteristic of 2 theta of 8.4 ± 0.2 degrees, 2 theta of 12.8 ± 0.2 degrees, 2 theta of 13.9 ± 0.2 degrees, 2 theta of 19.9 ± 0.2 degrees, 2 theta of 20.8 ± 0.2 degrees, 2 theta of 22.0 ± 0.2 degrees, 2 theta of 22.6 ± 0.2 degrees, 2 theta of 23.5 ± 0.2 degrees, 2 theta of 24.4 ± 0.2 degrees, 2 theta of 25.3 ± 0.2 degrees, or 2 theta of 26.1 ± 0.2 degrees, and 2 theta of 27.2 ± 0.2 degrees. In another example, there may be three characteristic peaks at 2 theta of 23.5 ± 0.2 degrees, 2 theta of 24.4 ± 0.2 degrees, and 2 theta of 25.3 ± 0.2 degrees, which may be further combined with a fourth peak. Optionally, all five peaks may be present.

[0016] A particular embodiment of the present invention relates to the crystalline hydrate D form of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern shown in FIG. 4.

[0017] A particular embodiment of the present invention relates to the crystalline D form of the compound of formula I described herein, characterized by the infrared spectrum shown in FIG. 6.

[0018] A particular embodiment of the present invention relates to the crystalline D form of the compound of formula (I) described herein, characterized by the Raman spectrum shown in FIG. 5.

[0019] In another embodiment, the crystalline hydrate D form of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, exhibits an endotherm of about 80 °C to 120 °C in an execution using a standard differential scanning calorimetry (DSC) with a heating rate of 10 K / min, indicating the loss of hydrate water. The crystalline hydrate D form of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is a trihydrate.

[0020] In one embodiment, the crystalline hydrate D form of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, is at least 90% pure, at least 95% pure, at least 97% pure, about 98% pure. In a further embodiment, the crystalline form D of the compound of formula (I), 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, contains up to 1% of a solvent, particularly ethanol and 1-propanol.

[0021] This application relates to a process for preparing a compound of formula (I)

Chemical formula

Chemical formula

[0022] In particular, the preparation of the compound of formula (I) is carried out in a solvent such as alcohol, aqueous alcohol, ethyl acetate, 1-propyl acetate, toluene, acetonitrile, THF or dichloromethane. More preferably, the preparation of the compound of formula (I) is carried out in the presence of 1-propanol and toluene.

[0023] Furthermore, this application discloses a process as described herein wherein 3 to 15 equivalents, more specifically 4 to 8 equivalents, most specifically 5 equivalents of a strong acid are used with respect to the compound of formula (II), particularly wherein the strong acid is HCl.

[0024] In particular, the present application discloses the above process for the preparation of a compound of formula (I), wherein the reaction is carried out at a temperature of 20 °C to 100 °C, specifically 60 °C to 80 °C, more specifically 75 °C.

[0025] 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is a valuable pharmaceutical compound as described in WO 2015 / 173181. It can be prepared according to WO 2015 / 173181.

[0026] Any open valence appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless otherwise indicated.

[0027] The present application also discloses further forms of the specified risedronate as follows. a) Form B as a metastable polymorph b) Form C as a monohydrate c) Form E as a trihydrate d) Form F as a hydrate e) Form G as a metastable polymorph.

[0028] The present application also discloses salts of risedronate such as the hydrochloride, tartrate and citrate salts of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. Unless otherwise specified, the following terms used in this specification and the claims have the meanings set forth below.

[0029] "About" or "approximately" refers to a range value that is within 5% greater than or less than the stated reference value. More specifically, "about" or "approximately" refers to ±0.2 °C 2 theta or ±0.5 °C.

[0030] "Ambient conditions" refers to the conditions experienced in a standard laboratory, for example, atmospheric pressure, air, ambient temperature of 18°C to 28°C, and humidity of 30% rH to 80% rH.

[0031] The "compound of formula (I)" is [Chemical formula] Also known as 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2a]pyrimidin-4-one. The compound of formula (I) is also known as ruzapladib, RG7916 or RO7034067. In this specification, the names or references to the compound of formula (I) can be used interchangeably.

[0032] As used herein, "Form A" refers to the crystalline anhydrous polymorph Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0033] As used herein, "Form D" refers to the crystalline hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one. Form D contains 3 molar equivalents of water. Form D is a trihydrate.

[0034] "(C1-C8)alkyl" refers to a branched or straight-chain hydrocarbon chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, pentyl, hexyl, heptyl or octyl. "(C1-C3)alkyl" refers to methyl, ethyl, n-propyl or isopropyl.

[0035] "Alcohol" refers to benzyl alcohol, aminoethanol, or (C1-8) alkyl (more specifically (C1-C alkyl) substituted with one or two hydroxy groups, more specifically substituted with one hydroxy group, as defined above). Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, propylene glycol, 1-butanol, 2-butanol, t-butanol, benzyl alcohol, 2-aminoethanol, and octanol. Specifically, alcohol refers to methanol, ethanol, 1-propanol, or benzyl alcohol, most specifically 1-propanol. 3) Alcohol examples include methanol, ethanol, isopropanol, 1-propanol, propylene glycol, 1-butanol, 2-butanol, t-butanol, benzyl alcohol, 2-aminoethanol, and octanol, but are not limited thereto. Specifically, alcohol refers to methanol, ethanol, 1-propanol, or benzyl alcohol, most specifically 1-propanol.

[0036] "Ambient conditions" refer to conditions experienced in a standard laboratory, such as atmospheric pressure, air, ambient temperature of 18°C to 28°C, and humidity of 30% rH to 80% rH.

[0037] "Base" refers to a compound that deprotonates another compound when reacting with it. Bases suitable for use according to the present disclosure include, but are not limited to, for example, organic bases and basic alkali metal salts. In particular, organic bases include nitrogen-containing heterocycles and tertiary amines. Examples of nitrogen-containing heterocycles include pyridine, imidazole, and benzimidazole. In some embodiments, tertiary amines include triethylamine, N-methylmorpholine, and diisopropylethylamine. In some embodiments, basic alkali metal salts include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), sodium and potassium alkoxides (including but not limited to sodium and potassium t-butoxides, 1-propoxides, 2-propoxides, ethoxides, methoxides, etc.), sodium amide (NaNH2), potassium amide (KNH2), and the like.

[0038] "Crystallization" and "recrystallization" can be used interchangeably and refer to the process by which a compound dissolved or suspended in a solvent system results in a stable polymorph or crystalline form of a particular compound. For example, the crystallization step can be carried out by forming crystals using a solvent and a poor solvent.

[0039] The terms "halo", "halogen", and "halide", which can be used interchangeably, refer to the substituents fluoro, chloro, bromo, or iodo.

[0040] "Strong acid" refers to an acid that completely dissociates in an aqueous solution with a pH of 2 or less. Examples of strong acids include, but are not limited to, sulfuric acid (H2SO4), hydrohalic acids (i.e., HX'' where X'' is I, Br, Cl, or F), nitric acid (HNO3), phosphoric acid (H3PO4), and combinations thereof. Specifically, a strong acid is a hydrohalic acid where X is Br or Cl. Most specifically, a strong acid is HCl.

[0041] "Nickel catalyst" refers to a catalyst containing nickel or nickel oxide or a mixture thereof. An example of a nickel catalyst is a Raney nickel catalyst (Ra-Ni).

[0042] The term "optional" or "optionally" means that the subsequently described event or situation may occur, but need not occur, and that its description includes both the case where the event or situation occurs and the case where it does not occur.

[0043] "Palladium catalyst" refers to a reagent that is a source of palladium 0 (Pd(0)). Suitable sources of Pd(0) include palladium bis(dibenzylideneacetone) (Pd(dba)2), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2), palladium chloride (PdCl2), tetrakis(triphenyl - phosphino)palladium (Pd(PPh3)4), 1,2 - bis(diphenylphosphino)ethane palladium (Pd(dppe)2), 1,3 - bis(diphenylphosphino) - propane palladium (Pd(dppp)2), dichloro - 1,3 - bis(diphenylphosphino) - propane palladium (PdCl2(dppp)), 1,4 - bis(diphenylphosphino)butane palladium, 1,1 - bis(diphenylphosphine) - ferrocene dichloropalladium (PdCl2(dppf)), palladium - supported carbon, Pd(OH)2 - supported carbon, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), bis(acetonitrile) - palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer ((Pd(allyl)Cl)2), (2 - butenyl)palladium chloride dimer, (2 - methylallyl)palladium(II) chloride dimer, palladium(1 - phenylallyl) chloride dimer, di - μ - chloro - bis[2’-(amino - N)[1,1’ - biphenyl] - 2 - yl - C]dipalladium(II), di - μ - chloro - bis[2 - [(dimethylamino)methyl]phenyl - C,N]dipalladium(II) or dichloro[9,9 - dimethyl - 4,5 - bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2), but are not limited thereto. Specifically, the palladium catalyst is Pd(OAc) 2、 refers to Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf). More specifically, the palladium catalyst is Pd(OAc)2, Pd2(dba)3, (Pd(XantPhos)Cl2) or PdCl2(dppf).

[0044] "XRPD" refers to the analytical method of X-ray powder diffraction. The reproducibility of the angular values is within the range of 2 theta ± 0.2°. The term "about" given in combination with the angular values indicates the reproducibility within the range of 2 theta ± 0.2°. The relative XRPD peak intensity depends on many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. The relative intensity can vary considerably from measurement to measurement due to the preferred orientation effect. According to USP941 (United States Pharmacopeia, 37th Edition, General Chapter 941), the relative intensity between two samples of the same material can vary considerably due to the "preferred orientation" effect. Anisotropic materials that adopt preferred orientation result in anisotropic distributions of properties such as elastic modulus, strength, ductility, toughness, conductivity, and thermal expansion, as described, for example, by Kocks U.F. et al. (Texture and Anisotropy: Preferred Orientation and Their Effects on the Properties of Polycrystals, Cambridge University Press, 2000). In Raman spectroscopy as well as in XRPD, preferred orientation causes a change in the intensity distribution. The preferred orientation effect is particularly prominent in crystalline APIs with relatively large particle sizes.

[0045] "Characteristic peak" refers to the presence of an X-ray powder diffraction peak that ultimately identifies 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as the reference crystal form (type A or type D). Typically, X-ray powder diffraction analysis is performed under ambient conditions in transmission geometry using a STOE STADI P diffractometer (CuKα1 radiation, primary monochromator, silicon strip detector, 2 theta angle range of 3 to 42 degrees, and a total measurement time of approximately 30 minutes). The sample (approximately 10 - 50 mg) is prepared between thin polymer films and analyzed without further processing of the substance (e.g., grinding or sieving).

[0046] "Polymorph" refers to crystal forms that have the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Generally, references throughout this specification are to polymorphs of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0047] The term "solvate" as used herein refers to a molecular complex comprising a compound of formula (I) and one or more solvent molecules (e.g., ethanol) in stoichiometric or non-stoichiometric amounts.

[0048] "Hydrate" as used herein refers to a solvate comprising a compound of formula (I) and water in stoichiometric or non-stoichiometric amounts.

[0049] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inert excipient" can be used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that has no therapeutic activity and is non-toxic to the subject to which it is administered, e.g., disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in the formulation of pharmaceuticals.

[0050] "Transition metal hydrogenation catalyst" refers to a transition metal hydrogenation catalyst that acts in a phase different from the substrate. In particular, the transition metal hydrogenation catalyst is in the solid phase. In particular, while the transition metal hydrogenation catalyst is in the solid phase, the reactants are in the liquid phase. The transition metal hydrogenation catalyst includes fibrous metals (i.e., Pd, Pt, Rh, Au, Ni, Co, Ru, Ir, V, Fe) that form one or more stable ions with incompletely filled d-orbitals, especially noble metals such as Pd, Pt, Rh or Au. In these catalysts, the transition metal is particularly "supported", which means that it is dispersed on a second material that enhances the effectiveness of the catalyst. The "support" can simply be a surface on which the metal is spread to increase the surface area. The support is a porous material with a large surface area, most commonly alumina or various types of carbon. Further examples of supports include, but are not limited to, silicon dioxide, titanium dioxide, calcium carbonate, barium sulfate, diatomaceous earth and clay. In the absence of other supports, the metal itself can also act as a support. More specifically, the term "transition metal hydrogenation catalyst" includes, but is not limited to, Raney catalysts (e.g., Ra-Ni, Ra-Co), Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C or Pt / C, especially Pt-V / C.

[0051] "Tertiary amine" refers to an amine of the formula R a N(R b )R c (wherein R a , R b and R c are independently selected from (C1-C6) alkyl or phenyl). Representative examples include, but are not limited to, triethylamine, tributylamine, diethyl-methylamine, dimethyl-ethylamine, di-isopropylethylamine, N,N-dimethylaniline and methylethylbutylamine. Preferably, the tertiary amine is selected from triethylamine or di-isopropylethylamine. The most preferred tertiary amine is triethylamine.

[0052] The terms "process", "contact", or "react", as used interchangeably, refer to adding, combining, or mixing two or more chemical substances (usually referred to as reagents or reactants), more specifically under appropriate conditions, to produce the indicated and / or desired product. It should be understood that the reaction to produce the indicated and / or desired product does not necessarily result directly from the combination of the two initially added reagents, i.e., there may be one or more intermediates formed in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0053] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition having a specific biological activity.

[0054] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and mean a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and pharmaceutically acceptable additives, which is administered to a mammal in need of treatment, such as a human.

[0055] The term "pharmaceutically acceptable" means a property of a material useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary and human pharmaceutical use.

[0056] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier", and "therapeutically inert excipient" can be used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that has no therapeutic activity and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceuticals.

[0057] The terms "individual" or "subject" refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0058] The term "therapeutically effective amount" means an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the medical condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0059] The term "treating" or "treatment" of a medical condition includes inhibiting the medical condition, i.e., arresting the development of the medical condition or its symptoms, or alleviating the medical condition, i.e., causing a temporary or permanent regression of the medical condition or its clinical symptoms.

[0060] The term "spinal muscular atrophy" (or SMA) relates to a disease caused by the inactivation mutation or deletion of both copies of the SMN1 gene on a chromosome, resulting in the loss of SMN1 gene function. Symptoms of SMA include muscle weakness, insufficient muscle tone, a weak cry, a weak cough, a limp or tendency to drag, difficulty sucking or swallowing, breathing difficulties, accumulation of secretions in the lungs or throat, clenched fists with sweaty hands, tongue twitching / vibrations, frequent tilting of the head to one side even when lying down, legs that tend to be weaker than the arms, legs that frequently assume the "frog-leg" position, difficulty eating, increased susceptibility to respiratory infections, bowel / bladder weakness, lower than normal weight, inability to sit unsupported, inability to walk, inability to crawl, and hypotonia, loss of appetite, as well as multiple congenital contractures (arthrogryposis) associated with the loss of anterior horn cells.

[0061] The term "treating spinal muscular atrophy (SMA)" or "treatment of spinal muscular atrophy (SMA)" includes one or more of the following effects. (i) Reduction or reversal of the severity of SMA; (ii) delay in the onset of SMA; (iii) inhibition of the progression of SMA; (iv) reduction in the need for inpatient hospitalization of the subject; (v) shortening of the inpatient stay of the subject; (vi) prolongation of the survival of the subject; (vii) improvement in the quality of life of the subject; (viii) decrease in the number of symptoms associated with SMA; (ix) reduction or reversal of the severity of one or more symptoms associated with SMA; (x) shortening of the duration of symptoms associated with SMA; (xi) prevention of recurrence of conditions associated with SMA; (xii) prevention or suppression of the onset of SMA; and / or (xiii) inhibition of the progression of symptoms associated with SMA.

[0062] More specifically, the term "treating SMA" means one or more of the following beneficial effects. (i) Decrease in muscle weakness; (ii) increase in muscle strength; (iii) reduction in muscle atrophy; (iv) reduction in loss of motor function; (v) increase in motor neurons; (vii) reduction in loss of motor neurons; (viii) protection from degeneration of SMN-deficient motor neurons; (ix) increase in motor function; (x) increase in lung function; and / or (xi) reduction in loss of lung function.

[0063] More specifically, the term "treating SMA" refers to the functional ability or maintenance of the functional ability of a human infant or toddler to sit without assistance, or a human infant, toddler, child or adult to stand up without assistance, walk without assistance, run without assistance, breathe without assistance, turn over during sleep without assistance, or swallow without assistance.

[0064] "Pharmaceutically acceptable carrier" refers to a component other than the active ingredient in a pharmaceutical composition that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0065] The term "buffer" or "buffer system" means a pharmaceutically acceptable excipient or excipient mixture that stabilizes the pH of a pharmaceutical formulation. Suitable buffers are well known in the art and can be found in the literature. Specific pharmaceutically acceptable buffers include citrate buffers, malate buffers, maleate buffers or tartrate buffers, most specifically tartrate buffers. Specific buffer systems of the present invention include combinations of organic acids and their selected salts, such as trisodium citrate and citric acid, malic acid and sodium malate, potassium sodium tartrate and tartaric acid, or disodium tartrate and tartaric acid, specifically potassium sodium tartrate and tartaric acid. Alternatively, the organic acid (specifically tartaric acid) may be used alone as an "acidifying agent" instead of a combination of an acid and its corresponding salt. Irrespective of the buffer used, the pH can be adjusted with acids or bases known in the art, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide. A specific acidifying agent is tartaric acid.

[0066] The term "antioxidant" means a pharmaceutically acceptable excipient that prevents oxidation of the active pharmaceutical ingredient. Antioxidants include ascorbic acid, glutathione, cysteine, methionine, vitamin E TPGS, EDTA.

[0067] The term "surfactant" means a pharmaceutically acceptable excipient used to protect a protein composition from mechanical stresses such as agitation and shear. Examples of pharmaceutically acceptable surfactants include poloxamers, polysorbates, polyoxyethylene alkyl ethers (BRIJ®), alkylphenyl polyoxyethylene ethers (TRITON®-X), or sodium dodecyl sulfate (SDS).

[0068] The term "poloxamer" means a nonionic triblock copolymer composed of a central hydrophobic chain of poly(propylene oxide) (PPO) flanked by two hydrophilic chains of poly(ethylene oxide) (PEO), and each PPO or PEO chain may have a different molecular weight. Poloxamers are also known by the trade name Pluronics. A specific poloxamer is poloxamer 188, which is a poloxamer in which the molecular mass of the PPO chain is 1800 g / mol and the PEO content is 80% by weight.

[0069] The term "polysorbate" typically means an oleic acid ester of sorbitol copolymerized with ethylene oxide and its anhydrides. Specific polysorbates are polysorbate 20 (poly(ethylene oxide)(20)sorbitan monolaurate, TWEEN® 20) or polysorbate 80 (poly(ethylene oxide)(80)sorbitan monolaurate, TWEEN® 80).

[0070] The "hydrophile-lipophile balance" (HLB) value means the degree of hydrophilicity of a nonionic surfactant. The HLB value is determined by the ratio of the molecular mass of the hydrophilic portion of the surfactant molecule to its total molecular mass, as described in Griffin W.C., Journal of the Society of Cosmetic Chemists (1949) 1:311. The term "hydrophilic" means the ability of a molecule or part of a molecule to interact with a polar solvent, particularly water, or other polar moieties driven by hydrogen bonding, dipole-ion interactions, and / or dipole-dipole interactions.

[0071] The terms "lipophilic" and "hydrophobic" can be used interchangeably and mean the tendency of a molecule or part of a molecule to dissolve in a nonpolar environment such as fats, oils, and nonpolar solvents driven by London dispersion forces.

[0072] The term "mg / ml" in the pharmaceutical composition of the present invention means the amount of either the compound of formula (I) or an individual excipient by the formulation in milligrams per volume of solvent, specifically in purified water in the constituent solution when the solvent is water, most specifically in milliliters.

[0073] This application relates to the preparation process of a compound of formula (II)

Chemical formula

Chemical formula

Chemical formula

[0074] More specifically, the present application relates to a process for preparing a compound of formula (II)

Chem.

Chem.

Chem.

[0075] The present application relates to a process for preparing a compound of formula (II)

Chem.

Chem.

Chem.

Chem.

Chemical formula

[0076] This application relates to a process for preparing a compound of formula (II)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0077] This application relates to a preparation process of formula (III) [Chemical formula] wherein a compound of formula (IV) (wherein X is an alkylsulfonic acid or an arylsulfonic acid (e.g., pTolSO3-, CH3SO3-, phenyl-SO3-), a fluorinated alkylsulfonic acid or an arylsulfonic acid (e.g., CF3SO3-, nonaflate), or a halide (such as Cl, Br, or I)) is reacted with tosyl chloride when X is pTol-SO3-, methanesulfonyl chloride when X is CH3SO3-, triflyl chloride when X is CF3SO3-, or phenylsulfonyl chloride when X is phenyl-SO3-, and in the presence of a base (especially, the base is an organic base or a basic alkali metal salt, more specifically, the base is a nitrogen-containing heterocyclic ring, a tertiary amine or a basic alkali metal salt, and most specifically, the base is a tertiary amine); [Chemical formula] - with POCl3 when X is Cl; - with POBr3 when X is Br; or - when X is I 、 ​Disclosed is a process comprising reacting with Ph3PI2 or POCl3 and subsequently with NaI or CuI.

[0078] This application is a process for preparing a compound of formula (III a ), which comprises

Chem.

Chem.

[0079] This application is a process for preparing a compound of formula (IV)

Chem.

Chem.

[0080] This application is a process for preparing a compound of formula (IV)

Chem.

Chem.

Chem.

[0081] This application relates to a process for preparing a compound of formula (IV)

Chem.

Chem.

Chem.

[0082] In particular, the process for preparing the compound of formula (IV) comprising reacting the compound of formula (V) with di-tert-butyl malonate is carried out in the presence of xylene, dichlorobenzene, toluene or anisole, particularly in the presence of anisole.

[0083] More specifically, the transition metal hydrogenation catalyst is Raney catalyst (e.g., Ra-Ni, Ra-Co), Pd / C, Pd(OH)2 / C, Au / TiO2, Rh / C, Ru / Al2O3, Ir / CaCO3, Pt-V / C or Pt / C or a combination thereof, particularly Pt-V / C, and more specifically 1% Pt and 2% V on activated carbon for the preparation of the compound of formula (IV).

[0084] This application relates to a compound of formula (VI)

Chem.

Chem.

Chem.

[0085] Particularly, a process for preparing a compound of formula (VI) which comprises reacting a compound of formula (VII) with a compound of formula (VIII) in the presence of lithium chloride, dimethyl sulfoxide and a base such as tetramethylguanidine, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), specifically tetramethylguanidine.

[0086] In a further embodiment, the present application discloses the preparation of a compound of formula (V) according to Scheme 1.

[0087] Scheme 1:

Chem.

[0088] In particular, the compound of formula (IX) can be prepared by reacting a compound of formula (X) with a compound of formula (VIII) in the presence of a catalyst (e.g., Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf), CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chlorobis[2’-(amino-N)[1,1’-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(xantphos)Cl2, etc., but not limited thereto), especially in the presence of dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium, and in the presence of a base (e.g., Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((CH3)3CONa) or KOAc; especially KOtBu, etc.), especially in the presence of 2-methyltetrahydrofuran, THF or dioxane, more specifically in the presence of 2-methyltetrahydrofuran.

[0089] Compound (V) is Pd(PPh3)4, PdCl 2、In the presence of catalysts such as Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), PdCl2(CH3CN), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chloro-bis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chloro-bis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), etc., especially in the presence of Pd2(dba)3, and in the presence of a base (e.g., Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((CH3)3CONa) or KOAc; especially KOtBu) and t-BuBrettPhos, it can be prepared by reacting compound (IX) with ammonia (NH3).

[0090] Preferably, this step is carried out in dioxane.

[0091] The compound of formula (V) can also be prepared according to Scheme 2. Scheme 2: [Chemical formula]

[0092] In particular, the compound of formula (V) is prepared by reacting a compound of formula (X) with a compound of formula (VIII) in the presence of a catalyst (e.g., Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3, PdCl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), allyl palladium(II) chloride dimer (Pd(allyl)Cl)2, (2-butenyl)chloropalladium dimer, (2-methylallyl) palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chloro bis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C] dipalladium(II), di-μ-chloro bis[2-[(dimethylamino)methyl]phenyl-C,N] dipalladium(II)), in particular in the presence of allyl palladium(II) chloride dimer (Pd(allyl)Cl)2 or palladium(1-phenylallyl) chloride dimer; and a ligand (e.g., 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl (tBuDavePhos), in particular: tBuDavePhos) and a base (e.g., Na2CO3, K2CO3, Cs2CO3, KOtBu, NaOtBu ((CH3)3CONa), KOAc or lithium-bis(trimethylsilyl)amide; in particular lithium-bis(trimethylsilyl)amide, in particular in the presence of tetrahydrofuran).

[0093] The present invention is carried out in the presence of an organic solvent such as an ether-like solvent (e.g., tetrahydrofuran, diisopropyl ether, t-butyl methyl ether, cyclopentyl-methyl-ether or dibutyl ether), a chlorinated solvent (e.g., dichloromethane, chloroform) or an aromatic solvent (e.g., anisole, toluene or t-butyl-benzene). In particular, the solvent used for the preparation of the compound of formula (I) according to embodiment 1 is toluene.

[0094] The reaction is carried out, in particular, under an inert gas atmosphere, more specifically under argon or nitrogen.

[0095] This application discloses a process for preparing a compound of formula (III'') according to Scheme 3.

[0096] Scheme 3:

Chemical formula

[0097] In particular, depending on the application, the compound of formula (XII) is prepared by reacting a compound of formula (XIII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromosuccinimide or bromine, optionally with sodium acetate or sodium bicarbonate, in the presence of a solvent such as an alcohol (e.g., methanol or ethanol). Further, the compound of (XI) is prepared by reacting the compound of formula (XII) with methylmagnesium chloride or bromide, methylboronic acid, methyl borate, dimethylzinc or methyllithium, optionally in the presence of zinc chloride, or in methyltetrahydrofuran or THF, in the presence of a catalyst (e.g., Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)2Cl2, PdCl2(dppf), PdCl2(dppf).CH2Cl2, PdCl2(dppp), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2 (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium (Pd(XantPhos)Cl2)), especially in the presence of Pd(PPh3)4) with dimethylzinc. The compound of formula (III'') is prepared by reacting chloroacetone with the compound of formula (XI) in the presence of a tertiary amine and sodium bromide.

[0098] Alternatively, the compound of formula (III'') can be prepared according to the process described in International Publication No. WO 2015 / 173181.

[0099] Furthermore, the present application discloses a process for preparing the compound of formula (III a ’) or (III b ’).

[0100] Scheme 4:

Chemical Structure

[0101] Certain specific embodiments of the present invention also relate to a pharmaceutical composition comprising a compound of formula (I) obtained as described herein and at least one pharmaceutically acceptable excipient.

[0102] Further specific embodiments of the present invention also relate to a compound of formula (I) obtained by the process described herein for use as a therapeutic active substance.

[0103] Manufacturing process of type A: Type A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained by dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in dioxane at a high temperature (e.g., above 22 °C, particularly 80 °C). Upon cooling, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one spontaneously crystallized as type A.

[0104] Alternatively, Form A can be obtained by equilibration of solid 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in an organic solvent or a mixture thereof for a long time. In particular, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is suspended in ethanol, methyl ethyl ketone, ethyl acetate or dioxane at ambient temperature or elevated temperature (e.g., 22-65 °C) for 2-3 weeks to obtain 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as Form A.

[0105] To obtain Form A, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one is dissolved in water using hydrochloric acid as the corresponding hydrochloride. This solution is slowly added to an ethanol solution of sodium hydroxide (sodium hydroxide in molar excess to the hydrochloric acid added) at elevated temperature (e.g., above 22 °C), in particular 60-70 °C, more specifically 60 °C. By spontaneous crystallization, a suspension containing a saturated solution and crystalline solid of Form A is formed. The suspension is cooled, filtered, washed to remove sodium chloride, and dried under reduced pressure at elevated temperature (e.g., above 22 °C, in particular 60 °C). To control the solid Form A, the final conditions in the suspension need to be controlled by controlling the maximum water concentration and the minimum temperature.

[0106] Alternatively, by applying the A-type crystal used as a seed crystal, the A-type can be further obtained during crystallization. 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be dissolved in water using hydrochloric acid as the corresponding hydrochloride. A portion of this solution is added to an ethanol solution of sodium hydroxide (sodium hydroxide in molar excess relative to the hydrochloric acid added) at a high temperature (20 - 70 °C, specifically 60 °C), and A-type crystals are added to the solution thus formed (either as dry crystals or suspended in an organic solvent such as ethanol). A suspension is formed. The remaining hydrochloride solution is slowly added at a high temperature. The suspension is cooled, filtered, washed to remove sodium chloride, and dried under reduced pressure at a high temperature (e.g., above 22 °C, particularly 60 °C). To control the solid A-type, the final conditions in the suspension need to be controlled by controlling the maximum water concentration and the minimum temperature (e.g., water below 12 wt% in ethanol above 40 °C).

[0107] Preparation process of D-type: The D form can be obtained by equilibrating solid 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one in water or an organic solvent containing water for a long time. 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be suspended in water or a mixture of an organic solvent and water, especially an ethanol / water mixture. In particular, by equilibrating the mixture in water at 65 °C or in ethanol / water (20 / 80 v / v) for 2 to 3 weeks, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained in the D form. In particular, by equilibrating the mixture in water at 22 °C or in ethanol / water (20 / 80 to 50 / 50 to 80 / 20) for 2 to 3 weeks, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained in the D form.

[0108] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the X-ray powder diffraction pattern shown in FIG. 1.

[0109] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the Raman spectrum shown in FIG. 2.

[0110] A particular embodiment of the present invention relates to crystalline Form A of the compound of formula I described herein, characterized by the infrared spectrum shown in FIG. 3.

[0111] Starting materials and reagents that do not have those synthetic routes explicitly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

[0112] 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one has been found to crystallize in various crystal structures as a pure compound (polymorph). Among these, Form A is a polymorph that is thermodynamically stable particularly at 5°C to 65°C.

[0113] In another aspect, 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one has been found to crystallize in various crystal structures as a hydrate. Form D, which has a sufficiently high water activity, is a stable hydrated form.

[0114] In another embodiment, the present invention provides crystalline Form A or Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0115] In a particular embodiment, the present invention provides polymorphic Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is characterized by an X-ray powder diffraction pattern (XRPD) having peaks at diffraction angles 2 theta of about 12.7°, 15.9°, 24.0° and 25.6° (±0.2°).

[0116] In a particular embodiment, Form A is characterized by an XRPD diffraction pattern including the XRPD peaks at diffraction angle 2 theta shown in Table 2.

[0117] In a particular embodiment, Form A is characterized by the XRPD of FIG. 1.

[0118] Table 1 shows the relevant crystal structure data of Form A.

[0119] The lattice constant, unit cell volume, and calculated density are based on the ambient temperature data.

[0120]

Table 1

[0121]

Table 2

[0122] In certain embodiments, the present invention includes at least one peak at one of the positions of 848 (±2) cm -1 , 885 (±2) cm -1 , 939 (±2) cm -1 , or 1218 (±2) cm -1 , specifically including at least two peaks at the positions of 848 (±2) cm -1 , 885 (±2) cm -1 , 939 (±2) cm -1 , or 1218 (±2) cm -1 , more specifically including at least three peaks at the positions of 848 (±2) cm -1 , 885 (±2) cm -1 , 939 (±2) cm -1 , or 1218 (±2) cm -1 , and most specifically including four peaks at the positions of 848 (±2) cm -1 , 885 (±2) cm -1 , 939 (±2) cm -1 , and 1218 (±2) cm -1 , to provide polymorphic Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one characterized by an infrared (IR) spectrum.

[0123] In a further embodiment, Form A is characterized by an IR spectrum including IR peaks at the positions shown in Table 3.

[0124]

Table 3

[0125] According to the invention described in this specification, ATR FTIR spectra were recorded without sample preparation using a Thermo Nicolet iS5 FTIR spectrometer equipped with an iD5 ATR accessory and a DTGS detector. The spectral range was 4000 cm -1 ~650 cm -1 and a resolution of 2 cm -1 and at least 50 co-added scans were collected. Happ-Genzel apodization was applied.

[0126] In certain embodiments, the invention includes at least one peak at one of the positions of 213 (±2) cm -1 , 257 (±2) cm -1 , 1061 (±2) cm -1 or 1570 (±2) cm -1 , specifically at least two peaks at the position of 213 (±2) cm -1 , 257 (±2) cm -1 , 1061 (±2) cm -1 or 1570 (±2) cm -1 , more specifically at least two peaks at the position of 213 (±2) cm -1 , 257 (±2) cm -1 , 1061 (±2) cm -1 or 1570 (±2) cm -1 , even more specifically at least two peaks at the position of 213 (±2) cm -1 , 257 (±2) cm -1 , 1061 (±2) cm -1 or 1570 (±2) cm -1 , most specifically at least three peaks at the position of 213 (±2) cm -1 , 257 (±2) cm -1 , 1061 (±2) cm -1 or 1570 (±2) cm -1Provided is polymorphic Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is characterized by a Raman spectrum including four peaks at the positions described below.

[0127] In a further embodiment, Form A is characterized by a Raman spectrum including Raman peaks at the positions shown in Table 4.

[0128] [Table 4]

[0129] According to the invention described herein, the FT-Raman spectrum was collected in the spectral range of 4000 - 50 cm -1 using a Bruker MultiRam FT-Raman spectrometer equipped with a NdYAG 1064 nm laser and a liquid nitrogen-cooled germanium detector. The laser output of the sample was about 200 mW, and a resolution of 2 cm -1 was used, with 1024 or 2048 scans added simultaneously. The apodization used was Blackman-Harris 4-term.

[0130] In certain embodiments, the invention provides hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is characterized by XRPD having peaks at diffraction angles of about 8.4 (±0.2) degrees 2-theta, 23.5 (±0.2) degrees 2-theta, 24.4 (±0.2) degrees 2-theta, and 25.3 (±0.2) degrees 2-theta.

[0131] In certain embodiments, Form D is characterized by an XRPD diffraction pattern including XRPD peaks at the diffraction angles 2-theta shown in Table 5.

[0132] In certain embodiments, Form D is characterized by the XRPD diffraction pattern of Figure 4.

[0133] [Table 5]

[0134] In certain embodiments, the present invention comprises at least one peak at a position of 800 (±2) cm -1 , 1212 (±2) cm -1 , 1349 (±2) cm -1 , or 1577 (±2) cm -1 , specifically at least two peaks at a position of 800 (±2) cm -1 , 1212 (±2) cm -1 , 1349 (±2) cm -1 , or 1577 (±2) cm -1 , more specifically at least two peaks at a position of 800 (±2) cm -1 , 1212 (±2) cm -1 , 1349 (±2) cm -1 , or 1577 (±2) cm -1 , even more specifically at least two peaks at a position of 800 (±2) cm -1 , 1212 (±2) cm -1 , 1349 (±2) cm -1 , or 1577 (±2) cm -1 , most specifically, it is characterized by an infrared (IR) spectrum comprising at least three peaks at a position of 800 (±2) cm -1 , 1212 (±2) cm -1 , 1349 (±2) cm -1 , or 1577 (±2) cm -1 , and provides the hydrate Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0135] In a further embodiment, Form D is characterized by an IR spectrum that includes an IR peak at the position shown in Table 6.

[0136]

Table 6

[0137] In certain embodiments, the present invention includes at least one peak at one of the positions of 452 (±2 cm -1 ), 870 (±2 cm -1 ), 1311 (±2 cm -1 ), or 1578 (±2 cm -1 ), specifically, at least two peaks at the positions of 452 (±2 cm -1 ), 870 (±2 cm -1 ), 1311 (±2 cm -1 ), or 1578 (±2 cm -1 ), more specifically, at least two peaks at the positions of 452 (±2 cm -1 ), 870 (±2 cm -1 ), 1311 (±2 cm -1 ), or 1578 (±2 cm -1 ), even more specifically, at least three peaks at the positions of 452 (±2 cm -1 ), 870 (±2 cm -1 ), 1311 (±2 cm -1 ), or 1578 (±2 cm -1 ), and most specifically, a Raman spectrum that includes four peaks at the positions of 452 (±2 cm -1 ), 870 (±2 cm -1 ), 1311 (±2 cm -1 ), or 1578 (±2 cm -1 ), is provided for the hydrated form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0138] In a further embodiment, the D form is characterized by a Raman spectrum comprising Raman peaks at the positions shown in Table 7.

[0139]

Table 7

[0140] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), in particular 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof, more specifically the A form of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, wherein the composition is an oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution.

[0141] The compound of formula (I) can be formulated as an oral aqueous solution by dissolving the drug substance in a buffer system having a pH below 4, specifically below pH 3.8, more specifically below pH 3.6, most specifically in the pH range of pH 3.0 to pH 3.2, such as a citrate buffer system, a malate buffer system, a maleate buffer system or a tartrate buffer system, most specifically a tartrate buffer system, in order to provide a sufficiently high drug concentration.

[0142] It has been found that the low pH improves the storage effect of the formulation and thereby helps to minimize the concentration of the compounds of the present invention described herein. This refers to the formulation once reconstituted as an aqueous solution.

[0143] The long-term stability of the formulation of the compound of formula (I) can be achieved by preparing a dry powder or granulating it to form an oral solution. The buffer system can be incorporated into the dry formulation by selecting an organic acid and its salt, such as trisodium citrate and citric acid, disodium malate and malic acid, sodium potassium tartrate and tartaric acid, or disodium tartrate and tartaric acid, specifically sodium potassium tartrate and tartaric acid as a fine powder. Alternatively, the organic acid (specifically tartaric acid) can be used alone as an acidifying agent instead of a combination of the acid and the corresponding salt.

[0144] The powder or granules containing the compound of formula (I) may contain diluents such as sorbitol, isomalt, or specifically mannitol, and combinations thereof, which ensures rapid dissolution of the powder blend during the constitution of the oral solution. In the introduction of the filler, the powder blend can be granulated by dry compression to improve fluidity and ensure firm uniformity.

[0145] The components for constituting the solvent system of the compound of formula (I) can be formulated as a separate formulation. The constituted solvent can be used to dissolve the compound of formula (I) in a bottle at the start of the use period of the oral solution.

[0146] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) in powder form or a pharmaceutically acceptable salt thereof for constituting an oral solution.

[0147] In a particular embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is filled into a multi-dose bottle equipped with an adapter for use with an oral dispenser. Such a multi-dose bottle equipped with an adapter for use with an oral dispenser has been found to enhance the flexibility of administration, for example, the dosage can be adjusted according to body weight, and provides safe and convenient dosage administration.

[0148] In certain embodiments of the present invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared by dry granulation by roller compression and then filled into bottles. Such processing has been found to be beneficial (specifically for water-soluble fillers) to prevent separation.

[0149] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is an oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution.

[0150] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a non-aerosol oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution.

[0151] In certain embodiments of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is not an aerosol.

[0152] In certain embodiments of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof does not contain an isotonic agent, such as a salt like sodium chloride.

[0153] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is an oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution, and the oral aqueous solution has a pH of less than 4, specifically less than 3.8, more specifically less than 3.6, and most specifically from pH 3.0 to pH 3.2.

[0154] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a citrate, malate, maleate or tartrate buffer system, specifically a malate or tartrate buffer system, most specifically a tartrate buffer system; or alternatively, a pharmaceutical composition comprising, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid, which is an oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution.

[0155] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is an oral aqueous solution.

[0156] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is an oral aqueous solution in a buffer system having a pH of less than 4, specifically less than pH 3.8, more specifically less than pH 3.6, and most specifically pH 3.0 to pH 3.2.

[0157] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a citrate, malate, maleate or tartrate buffer system, specifically a malate or tartrate buffer system, most specifically a tartrate buffer system; or alternatively, a pharmaceutical composition comprising, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid, which is an oral aqueous solution.

[0158] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a dry powder suitable for the constitution of an oral aqueous solution.

[0159] Certain embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a dry powder comprising a buffer system suitable for the constitution of an oral aqueous solution in a buffer system having a pH of less than 4, specifically less than pH 3.8, more specifically less than pH 3.6, and most specifically pH 3.0 to pH 3.2.

[0160] Certain embodiments of the present invention are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a citrate, malate, maleate or tartrate buffer system, specifically a malate or tartrate buffer system, most specifically a tartrate buffer system; or alternatively, a pharmaceutical composition comprising, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid, which is a dry powder suitable for the constitution of an oral aqueous solution.

[0161] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise an extragranular filler such as lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol or combinations thereof.

[0162] In certain embodiments of the present invention, the extragranular filler is sorbitol, isomalt, mannitol, or combinations thereof, specifically mannitol, more specifically crystalline mannitol, most specifically crystalline mannitol with an average diameter of 160 μm (Pearlitol® 160C).

[0163] In the introduction of the diluent, the powder blend can be granulated by dry compression to improve fluidity and ensure robust uniformity.

[0164] In one embodiment of the present invention, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise a diluent such as lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, isomalt (E953, (2ξ)-6-O-α-D-glucopyranosyl-D-arabino-hexitol), sorbitol, sucrose, dextrose, basic xylitol or combinations thereof.

[0165] In one embodiment of the present invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise a diluent such as lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol, or a combination thereof.

[0166] In a particular embodiment of the present invention, the diluent is mannitol, specifically D-mannitol suitable for direct compression, such as Parteck® M100.

[0167] In a particular embodiment of the present invention, the diluent is a mixture of mannitol and isomalt, specifically D-mannitol and (2ξ)-6-O-α-D-glucopyranosyl-D-arabino-hexitol.

[0168] Isomalt as the second diluent has been found by the inventors of the present invention to improve the granule properties.

[0169] An oral solution composed of the compound of formula (I) in a buffer can provide a use time exceeding two weeks by the use of preservatives, stabilizers and antioxidants such as vitamin A, vitamin C, vitamin E, vitamin E TPGS, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sodium benzoate, sorbic acid, potassium sorbate, disodium edetate, butylhydroxytoluene, riboflavin, ascorbic acid, or a combination thereof.

[0170] An oral solution composed of the compound of formula (I) in a buffer can provide a use time exceeding two weeks by the use of preservatives, stabilizers and antioxidants such as vitamin E TPGS, disodium edetate, butylhydroxytoluene, riboflavin, ascorbic acid, or a combination thereof.

[0171] In one embodiment of the present invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further optionally contain a preservative, antioxidant and / or stabilizer such as vitamin E TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate), disodium ethylenediaminetetraacetate (ethylenediaminetetraacetic acid disodium salt, Na2EDTA), butylhydroxytoluene, riboflavin, ascorbic acid, or a combination thereof. It has been found that preservatives, antioxidants and / or stabilizers can be beneficial for extending the shelf life in multi-dose containers or improving the drug stability in solution over time.

[0172] In a particular embodiment of the present invention, the preservative is potassium sorbate, sorbic acid or sodium benzoate (E211), specifically sodium benzoate.

[0173] In a particular embodiment of the present invention, the antioxidant is ascorbic acid ((5R)-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one).

[0174] In a particular embodiment of the present invention, the stabilizer is disodium ethylenediaminetetraacetate (ethylenediaminetetraacetic acid disodium salt, Na2EDTA).

[0175] In one embodiment of the present invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further optionally contain a lubricant. The lubricant has been found to be useful as a processing aid for roller compaction. Also, for water-soluble components such as PEG, a lubricant can be used to ensure the acceptability of the appearance.

[0176] In a particular embodiment of the present invention, the lubricant is poly(ethylene glycol), specifically poly(ethylene glycol) (PEG6000) with a number average molar mass M n of 6,000.

[0177] In one embodiment of the present invention, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise a sweetener and / or a fragrance to improve palatability, if necessary.

[0178] In a particular embodiment of the present invention, the fragrance is a strawberry fragrance or a vanilla fragrance.

[0179] In a particular embodiment of the present invention, the sweetener is sucralose (1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside, E955) or sodium saccharin.

[0180] In a particular embodiment of the present invention, the compound of formula (I) is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0181] In a particular embodiment of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; and ● a buffer system selected from citrate, malate, maleate, or tartrate, specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid.

[0182] In a particular embodiment of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; ● a buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; and ● a diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol.

[0183] In certain embodiments of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; and ● a diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol.

[0184] In certain embodiments of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; ● a buffer system, specifically citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● an antioxidant, specifically ascorbic acid; and ● a stabilizer, specifically sodium edetate.

[0185] In certain embodiments of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; ● a buffer system, specifically citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● a diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● an antioxidant, specifically ascorbic acid; and ● a stabilizer, specifically sodium edetate.

[0186] In certain embodiments of the present invention, the pharmaceutical composition comprises ● a compound of formula (I) or a pharmaceutically acceptable salt thereof; ● A buffer system, specifically a citrate, malate, maleate, or tartrate, more specifically a malate or tartrate, and most specifically a tartrate buffer system selected therefrom; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; and ● A lubricant, specifically containing PEG6000.

[0187] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● A compound of formula (I) or a pharmaceutically acceptable salt thereof; ● A buffer system, specifically a citrate, malate, maleate, or tartrate, more specifically a malate or tartrate, and most specifically a tartrate buffer system selected therefrom; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; and ● A lubricant, specifically containing PEG6000.

[0188] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● A compound of formula (I) in type A or D, particularly type A; ● A buffer system, specifically a citrate, malate, maleate, or tartrate, more specifically a malate or tartrate, and most specifically a tartrate buffer system selected therefrom; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; ● A lubricant, specifically PEG6000; ● Optionally, a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● Optionally, a flavoring, specifically strawberry flavor or vanilla flavor.

[0189] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● A compound of formula (I) in form A or D, especially form A; ● A buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; ● A lubricant, specifically PEG6000; ● A preservative selected from sorbic acid or sodium benzoate; ● Optionally, a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● Optionally, a flavoring, specifically strawberry flavor or vanilla flavor.

[0190] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● A compound of formula (I) in form A or D, especially form A; ● A buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically sodium edetate; ● A lubricant, specifically PEG6000; ● A preservative selected from potassium sorbate or sodium benzoate; ● Optionally a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● Optionally a flavoring, specifically strawberry flavor or vanilla flavor.

[0191] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● 1 to 10% by weight of a compound of formula (I) in form A or D, particularly form A; ● 2 to 15% by weight, particularly 4 to 6% by weight, of a buffer system, specifically citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● 40 to 90% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5 to 4% by weight of an antioxidant, specifically ascorbic acid; ● 0.2 to 2% by weight of a stabilizer, specifically sodium edetate; ● 0.5 to 2% by weight of a lubricant, specifically PEG6000; ● 1 to 8% by weight, particularly 1 to 4% by weight, of a preservative selected from potassium sorbate or sodium benzoate; ● 0 to 3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0 to 20% by weight of a fragrance, specifically strawberry fragrance or vanilla fragrance, with the total amount of the components not exceeding 100% by weight.

[0192] In certain embodiments of the present invention, the pharmaceutical composition comprises ● 1 to 10% by weight of a compound of formula (I) in form A or D, particularly form A; ● 2 to 15% by weight of a buffer system, specifically selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, and most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● 40 to 80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5 to 4% by weight of an antioxidant, specifically ascorbic acid; ● 0.2 to 2% by weight of a stabilizer, specifically disodium edetate; ● 0.5 to 2% by weight of a lubricant, specifically PEG6000; ● 0 to 3% by weight of a sweetening agent, specifically sucralose or sodium saccharin, and most specifically sucralose; and ● 0 to 20% by weight of a fragrance, specifically including strawberry fragrance or vanilla fragrance, wherein the total amount of the components does not exceed 100% by weight.

[0193] In certain embodiments of the present invention, the pharmaceutical composition comprises ● 1 to 10% by weight of a compound of formula (I) in form A or D, particularly form A; ● 2 to 15%, particularly 4 to 6% by weight of a buffer system, specifically selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, and most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● 40 to 80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5 to 4% by weight of an antioxidant, specifically ascorbic acid; ● 0.2 to 2% by weight of a stabilizer, specifically sodium edetate; ● 0.5 to 2% by weight of a lubricant, specifically PEG6000; ● 1 to 8% by weight, particularly 1 to 4% by weight, of a preservative selected from potassium sorbate or sodium benzoate; ● 0 to 3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0 to 20% by weight of a fragrance, specifically including strawberry fragrance or vanilla fragrance; The total amount of the components does not exceed 100% by weight.

[0194] In a specific embodiment of the present invention, the pharmaceutical composition comprises ● 1 to 10% by weight of a compound of formula (I) in type A or D, particularly type A; ● 2 to 15% by weight, particularly 4 to 6% by weight, of a buffer system, specifically selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● 40 to 80% by weight of a diluent, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● 0.5 to 4% by weight of an antioxidant, specifically ascorbic acid; ● 0.2 to 2% by weight of a stabilizer, specifically sodium edetate; ● 0.5 to 2% by weight of a lubricant, specifically PEG6000; ● 1 to 8% by weight, particularly 1 to 4% by weight, of a preservative selected from sorbic acid or sodium benzoate; ● 0 to 3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0 to 20% by weight of a fragrance, specifically including strawberry fragrance or vanilla fragrance; The total amount of the components does not exceed 100% by weight.

[0195] In a specific embodiment of the present invention, the pharmaceutical composition after being constituted in water (80 ml) as a solvent is, ● A compound of formula (I) of type A at 0.25 to 2.5 mg / ml, particularly 0.25 to 0.5 mg / ml; ● A buffer system at 0.5 to 3.8 mg / ml, particularly 0.9 to 1.4 mg / ml, specifically a citrate, malate, maleate or tartrate, more specifically a malate or tartrate, and most specifically a tartrate buffer system selected therefrom; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent at 10.0 to 22.5 mg / ml, particularly 18.0 to 22.0 mg / ml, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant at 0.1 to 1.0 mg / ml, particularly 0.15 to 0.5 mg / ml, specifically ascorbic acid; ● A stabilizer at 0.05 to 1.0 mg / ml, particularly 0.05 to 0.5 mg / ml, specifically disodium edetate; ● A lubricant at 0.1 to 0.5 mg / ml, particularly 0.2 to 0.3 mg / ml, specifically PEG6000; ● A preservative selected from sorbic acid or sodium benzoate at 0.3 to 1.0 mg / ml, particularly 0.3 to 0.5 mg / ml; ● A sweetener at 0.0 to 0.75 mg / ml, particularly 0.1 to 0.4 mg / ml, specifically sucralose or sodium saccharin, and most specifically sucralose; and ● A fragrance at 0.0 to 5.0 mg / ml, particularly 1.0 to 2.1 mg / ml, specifically containing a strawberry fragrance or a vanilla fragrance.

[0196] In a specific embodiment of the present invention, the pharmaceutical composition is, ● 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one of type A or D at 1 to 5% by weight, particularly of type A; ● A tartrate buffer system at 2 to 8% by weight; ● 60 to 75% by weight of mannitol as the first diluent, and 8 to 10% by weight of isomalt as the second diluent; ● 0.5 to 1.5% by weight of ascorbic acid as an antioxidant; ● 0.25 to 0.75% by weight of disodium edetate as a stabilizer; ● 0.5 to 2% by weight of PEG6000 as a lubricant; ● 0.5 to 1% by weight of sucralose as a sweetener; and ● containing 5 to 10% by weight of strawberry flavor; The total amount of the components does not exceed 100% by weight.

[0197] In a specific embodiment of the present invention, the pharmaceutical composition is ● 1 to 5% by weight of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one of type A or D, particularly type A; ● 2 to 8% by weight, particularly 4 to 6% by weight of tartrate buffer system; ● 60 to 75% by weight of mannitol as the first diluent, and 10 to 15% by weight of isomalt as the second diluent; ● 0.5 to 1.5% by weight of ascorbic acid as an antioxidant; ● 0.25 to 0.75% by weight of disodium edetate as a stabilizer; ● 0.5 to 2% by weight of PEG6000 as a lubricant; ● 1 to 8% by weight, particularly 1 to 4% by weight of sodium benzoate as a preservative; ● 0.5 to 1% by weight of sucralose as a sweetener; and ● containing 5 to 10% by weight of strawberry flavor; The total amount of the components does not exceed 100% by weight.

[0198] In a specific embodiment of the present invention, the pharmaceutical composition after being constituted in water (80 ml) as a solvent is ● 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one at 0.25 to 1.25 mg / ml, particularly 0.25 to 0.5 mg / ml, especially as type A; ● A tartrate buffer system at 0.5 to 2.0 mg / ml, particularly 0.9 to 1.4 mg / ml; ● Mannitol at 15.0 to 18.75 mg / ml as the first diluent, and isomalt at 2.0 to 3.75 mg / ml as the second diluent; ● Ascorbic acid at 0.18 to 0.53 mg / ml as an antioxidant; ● Disodium edetate at 0.05 to 0.15 mg / ml as a stabilizer; ● PEG6000 at 0.1 to 0.5 mg / ml, particularly 0.2 to 0.3 mg / ml, as a lubricant; ● Sodium benzoate at 0.3 to 0.8 mg / ml as a preservative; ● Sucralose at 0.13 to 0.25 mg / ml as a sweetener; and ● Contains strawberry flavor at 1.25 to 2.5 mg / ml.

[0199] In a particular embodiment of the present invention, the pharmaceutical composition is ● 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one at 1 to 5 wt% as type A; ● Tartaric acid at 2 to 8 wt%, particularly 4 to 6 wt%; ● Mannitol at 60 to 75 wt% and isomalt at 8 to 10 wt%; ● Ascorbic acid at 0.5 to 1.5 wt%; ● Disodium edetate at 0.25 to 0.75 wt%; ● PEG6000 at 0.5 to 2 wt% as a lubricant; ● Sodium benzoate at 1 to 8 wt%, particularly 1 to 4 wt%; ● Sucralose at 0.5 to 1 wt%; and ● containing 5 to 10% by weight of strawberry flavor; The total amount of the components does not exceed 100% by weight.

[0200] In a specific embodiment of the present invention, the pharmaceutical composition after being constituted in water (80 ml) as a solvent is ● 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as type A at 0.25 to 1.25 mg / ml, particularly 0.25 to 0.5 mg / ml; ● tartaric acid at 0.5 to 2.0 mg / ml, particularly 0.9 to 1.4 mg / ml; ● mannitol at 15.0 to 18.75 mg / ml and isomalt at 2.0 to 3.75 mg / ml; ● ascorbic acid at 0.18 to 0.53 mg / ml; ● disodium edetate at 0.05 to 0.15 mg / ml; ● PEG6000 at 0.1 to 0.5 mg / ml, particularly 0.2 to 0.3 mg / ml; ● sodium benzoate at 0.3 to 0.8 mg / ml; ● sucralose at 0.13 to 0.25 mg / ml; and ● containing 1.25 to 2.5 mg / ml of strawberry flavor.

[0201] Another embodiment of the present invention is a kit for preparing a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, ● a powder blend containing a compound of formula (I) in type A or D, particularly type A, and ● water as a solvent for constitution relates to a kit containing the same. Another embodiment of the present invention is a kit for preparing a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, ● a powder blend containing a compound of formula (I) in type A, and ● water as a solvent for specifically constituting at 80 ml relates to a kit containing the same.

[0202] Another embodiment of the present invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, ● a pharmaceutical composition as described herein comprising a compound of formula (I) as Form A, and water as a solvent for constituting specifically with 80 ml of purified water relates to a kit comprising.

[0203] Another embodiment of the present invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, ● a compound of formula (I) as Form A or D, particularly as Form A, ● a powder blend as a medium for constitution, and ● optionally, water as a solvent for constitution relates to a kit comprising.

[0204] Another embodiment of the present invention is a kit for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, ● a compound of formula (I) as Form A, ● a powder blend as a medium for constitution, and ● optionally, water as a solvent for constitution, particularly 80 ml of purified water relates to a kit comprising.

[0205] Another embodiment is a powder blend as a medium suitable for constitution of a compound of formula (I) as Form A or D, particularly as Form A, described herein, ● a buffer system, specifically a citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate, selected from a buffer system; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; and ● a diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol relates to a powder blend containing

[0206] Another embodiment is a powder blend as a medium suitable for the composition of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, ● A buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, and most specifically tartrate; alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; and ● A lubricant, specifically PEG6000 relates to a powder blend containing

[0207] Another embodiment is a powder blend as a medium suitable for the composition of a compound of formula (I) in type A or D, particularly type A, described herein, ● A buffer system, specifically a buffer system selected from citrate, malate, maleate, or tartrate, more specifically malate or tartrate, and most specifically tartrate; alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant, specifically ascorbic acid; ● A stabilizer, specifically disodium edetate; ● A lubricant, specifically PEG6000; ● Optionally a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● Optionally a flavor, specifically strawberry flavor or vanilla flavor relates to a powder blend containing

[0208] Another embodiment is a powder blend as a medium suitable for the composition of the compound of formula (I) in form A or D as described herein, ● A buffer system of 3 to 15% by weight, specifically a citrate, malate, maleate, or tartrate, more specifically a malate or tartrate, and most specifically a tartrate selected from the buffer systems; alternatively, individually, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent of 40 to 80% by weight, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant of 1 to 4% by weight, specifically ascorbic acid; ● A stabilizer of 0.2 to 2% by weight, specifically disodium edetate; ● A lubricant of 0.5 to 2% by weight, specifically PEG6000; ● A sweetener of 0 to 3% by weight, specifically sucralose or sodium saccharin, and most specifically sucralose; and ● A flavoring of 0 to 20% by weight, specifically including a strawberry flavor or a vanilla flavor; Regarding a powder blend in which the total amount of the components does not exceed 100% by weight.

[0209] Another embodiment is a powder blend as a medium suitable for the composition of the compound of formula (I) in form A or D as described herein, ● A buffer system of 3 to 15% by weight, specifically a citrate, malate, maleate, or tartrate, more specifically a malate or tartrate, and most specifically a tartrate selected from the buffer systems; alternatively, individually, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid; ● A diluent of 40 to 90% by weight, particularly 40 to 80% by weight, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol; ● An antioxidant of 1 to 4% by weight, specifically ascorbic acid; ● A stabilizer of 0.2 to 2% by weight, specifically disodium edetate; ● 0.5 to 2% by weight of a lubricant, specifically PEG6000; ● 1 to 8% by weight, particularly 1 to 4% by weight, of a preservative, specifically sodium benzoate; ● 0 to 3% by weight of a sweetener, specifically sucralose or sodium saccharin, most specifically sucralose; and ● 0 to 20% by weight of a fragrance, specifically strawberry fragrance or vanilla fragrance; Relates to a powder blend in which the total amount of the components does not exceed 100% by weight.

[0210] Another embodiment is a powder blend as a medium suitable for the composition of the compound of formula (I) in type A or type D, particularly type A, described herein, ● 3 to 7% by weight of tartaric acid; ● 60 to 75% by weight of mannitol as a first diluent, and 10 to 15% by weight of isomalt as a second diluent; ● 0.5 to 1.0% by weight of ascorbic acid as an antioxidant; ● 0.3 to 0.7% by weight of disodium edetate as a stabilizer; ● 0.5 to 2% by weight of PEG6000 as a lubricant; ● 0.6 to 1.0% by weight of sucralose as a sweetener; and ● 5 to 10% by weight of strawberry fragrance; Relates to a powder blend in which the total amount of the components does not exceed 100% by weight.

[0211] Another embodiment is a powder blend as a medium suitable for the composition of the compound of formula (I) in type A or type D, particularly type A, described herein, ● 3 to 7% by weight, particularly 4 to 6% by weight, of tartaric acid; ● 60 to 75% by weight of mannitol as a first diluent, and 10 to 15% by weight of isomalt as a second diluent; ● 0.5 to 1.0% by weight of ascorbic acid as an antioxidant; ● 0.3 to 0.7% by weight of disodium edetate as a stabilizer; ● 0.5 to 2% by weight of PEG6000 as a lubricant; ● 1 to 8% by weight of sodium benzoate as a preservative, particularly 1 to 4% by weight of sodium benzoate as a preservative; ● 0.6 to 1.0% by weight of sucralose as a sweetener; and ● containing 5 to 10% by weight of strawberry flavor; A powder blend in which the total amount of the components does not exceed 100% by weight.

[0212] Another embodiment is a powder blend as a medium suitable for the composition of a compound of formula (I) of type A or D, particularly type A, described herein, ● 3 to 7% by weight, particularly 4 to 6% by weight of tartaric acid; ● 60 to 75% by weight of mannitol, and 10 to 15% by weight of isomalt; ● 0.5 to 1.0% by weight of ascorbic acid; ● 0.3 to 0.7% by weight of disodium edetate; ● 0.5 to 2% by weight of PEG6000; ● 1 to 8% by weight of sodium benzoate, particularly 1 to 4% by weight of sodium benzoate; ● 0.6 to 1.0% by weight of sucralose; and ● containing 5 to 10% by weight of strawberry flavor; A powder blend in which the total amount of the components does not exceed 100% by weight.

[0213] Another embodiment is a powder blend as a medium suitable for the composition of a compound of formula (I) of type A described herein, after being constituted in water (80 ml) as a solvent, The pharmaceutical composition after being constituted in water (80 ml) as a solvent is, ● 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one of type A at 0.25 to 1.25 mg / ml, particularly 0.25 to 0.5 mg / ml; ● tartaric acid at 0.5 to 2.0 mg / ml, particularly 0.9 to 1.4 mg / ml; ● Mannitol at 15.0 - 18.75 mg / ml and isomalt at 2.0 - 3.75 mg / ml; ● Ascorbic acid at 0.18 - 0.53 mg / ml; ● Disodium edetate at 0.05 - 0.15 mg / ml; ● PEG6000 at 0.1 - 0.5 mg / ml, particularly 0.2 - 0.3 mg / ml; ● Sodium benzoate at 0.3 - 0.8 mg / ml; ● Sucralose at 0.13 - 0.25 mg / ml; and ● Strawberry flavor at 1.25 - 2.5 mg / ml relates to a powder blend containing the same.

[0214] The compound of formula (I) has beneficial pharmacological properties and has been found to promote the incorporation of exon 7 of SMN1 and / or SMN2 into the mRNA transcribed from the SMN1 and / or SMN2 gene, and as a result, increase the expression of SMN protein in human subjects in need thereof.

[0215] The compounds of the present invention can be used alone or in combination with other drugs for the treatment, prevention, delay of progression and / or improvement of diseases caused by inactivating mutations or deletions of the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function. These diseases include, but are not limited to, spinal muscular atrophy (SMA).

[0216] A specific embodiment of the present invention relates to a pharmaceutical composition for the treatment, prevention, delay of progression and / or improvement of diseases caused by inactivating mutations or deletions of the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function, specifically for the treatment, prevention, delay of progression and / or improvement of SMA, particularly a compound of formula (I) of form A as defined above and one or more pharmaceutically acceptable excipients.

[0217] Certain embodiments of the present invention relate to pharmaceutical compositions for use as therapeutic active substances, in particular for treating, preventing, delaying the progression and / or improving diseases caused by inactivating mutations or deletions of the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, specifically for treating, preventing, delaying the progression and / or improving spinal muscular atrophy (SMA), and containing compounds of formula (I) as defined above, in particular type A compounds.

[0218] Certain embodiments of the present invention relate to the use of pharmaceutical compositions containing compounds of formula (I) of type A as defined above, specifically for treating, preventing, delaying the progression and / or remission of diseases caused by inactivating mutations or deletions of the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, specifically for treating, preventing, delaying the progression and / or remission of spinal muscular atrophy (SMA).

[0219] Certain embodiments of the present invention relate to a method for treating, preventing, delaying the progression and / or remission of diseases caused by inactivating mutations or deletions of the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, specifically for treating, preventing, delaying the progression and / or remission of spinal muscular atrophy (SMA), the method comprising administering a pharmaceutical composition containing a compound of formula (I) as defined above, in particular type A compounds, to a subject.

[0220] Certain embodiments of the present invention relate to the use of pharmaceutical compositions containing compounds of formula (i) of type A as defined above, specifically for treating, preventing, delaying the progression and / or improving diseases caused by inactivating mutations or deletions of the SMN1 gene and / or diseases associated with loss or deficiency of SMN1 gene function, specifically for treating, preventing, delaying the progression and / or improving spinal muscular atrophy (SMA).

[0221] Certain embodiments of the present invention relate to the use of a pharmaceutical composition comprising a compound of formula (i), particularly of type A, for the treatment, prevention, delay in progression and / or improvement of a disease caused by an inactivating mutation or deletion of the SMN1 gene and / or a disease associated with loss or deficiency of SMN1 gene function, specifically for the treatment, prevention, delay in progression and / or improvement of spinal muscular atrophy (SMA). Such medicaments comprise a compound of formula (I), particularly of type A, as defined above.

[0222] In general, the nomenclature used in the present application is based on AUTONOM™ 2000, a computerized system of the Beilstein Institute for generating systematic IUPAC nomenclature. The chemical structures shown herein were created using MDL ISIS™ version 2.5 SP2. Any open valence appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0223] The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention.

[0224] The following abbreviations and definitions are used in this application: br (broad); BuLi (butyllithium); CDCl3 (deuterochloroform); d (doublet); eq (equivalent); g (gram); GC (gas chromatography); h (hour); HCl (hydrochloric acid); H2O (water); HPLC (high performance liquid chromatography); ISP (isotope spin population); KOH (potassium hydroxide); L (liter); LDA (lithium diisopropylamide); LCMS (liquid chromatography - mass spectrometry); M (mole); m (multiplet); MS (mass spectrometry); mL (milliliter); NaOH (sodium hydroxide); NMR (nuclear magnetic resonance); Pd(dba)3 (tris(dibenzylideneacetone)dipalladium(0)); Pd(xantphos)Cl2 (dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene]palladium(II)); s (singlet); sec (second); t (triplet); t-BuBrettPhos (2-(di-tert-butylphosphino)-2’,4’,6’-triisopropyl-3,6-dimethoxy-1,1’-biphenyl); THF (tetrahydrofuran);

[0225] Example 17-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (Form A without seed crystals) 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.81 g, 13.71 mmol) was dissolved in water (28 g) and aqueous hydrochloric acid solution (37%, 2.61 g, 26.49 mmol) at 30 - 33 °C. When the hydrochloride solution was added to a solution of NaOH (1.15 g, 28.75 mmol) in ethanol (220 g) at 60 °C within 100 minutes, spontaneous crystallization occurred. The apparatus of the hydrochloride solution was rinsed with water (1.2 g) and added to the suspension. The suspension was cooled to 40 °C and stirred overnight. The precipitate was filtered, washed three times with a mixture of water / ethanol 88:12 (16.5 g) and subsequently with ethanol (16.5 g), and dried under high vacuum at 60 °C for 21 hours to obtain 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (4.95 g, 90.0%) of Form A.

[0226] Example 27-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (Form A) 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.81 g, 13.71 mmol) was dissolved in water (28 g) and aqueous hydrochloric acid solution (37%, 2.57 g, 26.08 mmol) at 30 - 33 °C. The first portion of the hydrochloride solution (3.64 g) was added to a solution of NaOH (1.12 g, 28.00 mmol) in ethanol (220 g) at 60 °C. Seeding was carried out by adding a suspension of Form A crystals (0.055 g, 0.01 mmol) in ethanol (1.7 g). The remaining portion of the hydrochloride solution was added to the NaOH solution at 60 °C within 87 minutes. The apparatus of the hydrochloride solution was rinsed with water (1.2 g) and added to the suspension. The mixture was cooled to 40 °C and stirred overnight. The precipitate was filtered, washed 4 times with a mixture of water / ethanol 88:12 (16.5 g) and subsequently with ethanol (16.5 g), and dried under high vacuum at 60 °C for 21 hours to obtain Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (5.06 g, 91.1%).

[0227] Example 37-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (Form D) Form A of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (0.5 g, 1.23 mmol) was suspended in a mixture of ethanol / water (4:1 weight / weight) (2.1 g). The solution was stirred at 35 °C for 4 days. The solid was isolated and dried under reduced pressure (4 hours at 30 °C, 200 mbar, or 2 hours at 40 °C, 100 mbar) to obtain Form D of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.

[0228] Oral solution containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be formulated as an oral aqueous solution by dissolving the active ingredient in a buffer system with a pH below 4, specifically in the range of pH 3.0 to pH 3.2, such as citrate buffer, malate buffer, maleate buffer or tartrate buffer, more specifically malate buffer or tartrate buffer, and most specifically tartrate buffer, in order to provide a sufficiently high drug concentration.

[0229] The long-term stability of the formulation of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one can be obtained by preparing dry powders or granules for constituting the oral solution. The buffer system can be incorporated into the dry formulation by selecting as fine powders organic acids and their salts, such as trisodium citrate dihydrate and anhydrous citric acid, sodium malate and malic acid, or preferably sodium potassium tartrate and tartaric acid.

[0230] The powders or granules containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one may contain an extra-granular filler such as sorbitol, isomalt, or mannitol, and combinations thereof, which ensure rapid dissolution of the powder blend during the constitution of the oral solution. In the introduction of the diluent, the powder blend may be granulated by dry compression to improve fluidity and ensure robust uniformity.

[0231] 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically the components for constituting a solvent system of type A, may be formulated as separate preparations.

[0232] The constituted solvent can be used to dissolve 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically type A, in the bottle at the start of the use period of the oral solution.

[0233] 7-(4,7-Diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, more specifically the constituted oral solution of type A in buffer solution, can provide a use time exceeding two weeks by using stabilizers and antioxidants such as vitamin E TPGS, disodium edetate, butylhydroxytoluene, riboflavin, or preferably ascorbic acid, and combinations thereof.

[0234] Table 8 shows several oral solutions that provide stability in solution for more than two weeks.

[0235]

Table 8

[0236] Example 5 Powder blend as a medium for constituting an oral solution of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one Table 9 shows a granule blend for the composition of a solvent suitable for dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one to obtain an oral solution with a stable pH of 3.4 for more than two weeks. The blend specifically contains polyethylene glycol 6000 as a water-soluble lubricant, sodium benzoate as a preservative, sucralose as a sweetener, and strawberry flavor for the purpose of improving the taste, for use in pediatric patients.

[0237] The composition of Table 9 shows a constituent solvent suitable for dissolving 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one (20 mg and 60 mg respectively), both containing 79 ml of water.

[0238]

Table 9

[0239] Powder blend containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one for constituting the oral solution of Example 6

[0240] Table 10 shows an oral solution containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is constituted by using the constituted medium solution obtained in Example 4 for dissolving the active compound. The medium is suitable for constituting an oral solution at pH 3.4 that is stable for more than two weeks. The composition in Table 9 shows an oral solution containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one at 1 mg / ml and 3 mg / ml, which together contain 79 ml of water.

[0241]

Table 10

[0242] Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one for constituting the oral solution of Example 7 Table 11 shows a powder blend containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which can be used for constituting an oral solution and together contains 90 ml of water. Also, the composition in Table 10 can be constituted from the solvent prepared from the medium powder blend (similar to Example 4), and then the API can be dissolved.

[0243]

Table 11

[0244] Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one for constituting the oral solution of Example 8 Table 12 shows a powder blend containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which can be used to constitute an oral solution for obtaining an 80 ml solution containing water together. Also, the composition of Table 11 can be composed of a solvent prepared from a medium powder blend (similar to Example 5), and then the API can be dissolved therein.

[0245] [Table 12]

[0246] Powder blend of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one for constituting the oral solution of Example 9 Table 13 shows a powder blend containing 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, which is used to constitute an oral solution using water to obtain an 80 mL solution. Also, the composition of Table 12 can be composed of a solvent prepared from a medium powder blend (similar to Example 4), and then the API can be dissolved therein.

[0247] [Table 13]

Claims

**Claim 1** A solid form of a compound of formula (I) or a salt thereof, wherein the solid form is crystalline polymorphic Form A. 【Chemical Formula 1】 **Claim 2** The solid form according to claim 1, characterized by an XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of about 2θ (±0.2) of 8.3 degrees and at least one additional XRPD peak at 2θ (±0.2) of 11.4 degrees, 15.1 degrees, 15.9 degrees, 17.0 degrees, 24.0 degrees or 25.6 degrees. **Claim 3** The solid form according to any one of claims 1 to 2, characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles of about 2θ (±0.2) of 8.3 degrees and 11.4 degrees. **Claim 4** The solid form according to any one of claims 1 to 2, characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles of about 2θ (±0.2) of 8.3 degrees and 15.1 degrees. **Claim 5** The solid form according to any one of claims 1 to 2, characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles of about 2θ (±0.2) of 8.3 degrees and 15.9 degrees. **Claim 6** The solid form according to any one of claims 1 to 2, characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction angles of about 2θ (±0.2) of 8.3 degrees and 17.0 degrees. **Claim 7** The solid form according to claim 1, characterized by an XRPD diffraction pattern comprising at least three XRPD peaks at diffraction angles of about 2θ (±0.2) of 11.4 degrees, 12.7 degrees, 15.9 degrees, 24.0 degrees or 25.6 degrees. **Claim 8** The solid form according to claim 1 or 7, characterized by an XRPD diffraction pattern comprising at least four XRPD peaks at diffraction angles of about 2θ (±0.2) of 11.4 degrees, 12.7 degrees, 15.9 degrees, 24.0 degrees or 25.6 degrees. **Claim 9** ​ An XRPD diffraction pattern comprising at least five XRPD peaks at diffraction angles of about 2-theta of 11.4 degrees (±0.2), 2-theta of 12.7 degrees (±0.2), 2-theta of 15.9 degrees (±0.2), 2-theta of 24.0 degrees (±0.2), and 2-theta of 25.6 degrees (±0.2), characterizing the solid form according to claim 1 or 7.

10. An XRPD diffraction pattern comprising XRPD peaks at diffraction angles of 2-theta of 8.3 (±0.2) degrees, 2-theta of 11.4 (±0.2) degrees, 2-theta of 12.7 (±0.2) degrees, 2-theta of 13.0 (±0.2) degrees, 2-theta of 15.1 (±0.2) degrees, 2-theta of 15.9 (±0.2) degrees, 2-theta of 17.0 (±0.2) degrees, 2-theta of 19.7 (±0.2) degrees, 2-theta of 22.4 (±0.2) degrees, 2-theta of 24.0 (±0.2) degrees, and 2-theta of 25.6 (±0.2) degrees, characterizing the solid form according to any one of claims 1 to 8.

11. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of about 2-theta of 8.3 degrees (±0.2) and at least two additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 2-theta of 15.1 degrees (±0.2), 2-theta of 15.9 degrees (±0.2), 2-theta of 17.0 degrees (±0.2), 2-theta of 24.0 degrees (±0.2), or 2-theta of 25.6 degrees (±0.2), characterizing the solid form according to any one of claims 1 or 2.

12. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of about 2-theta of 8.3 degrees (±0.2) and at least two additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 2-theta of 15.1 degrees (±0.2), 2-theta of 15.9 degrees (±0.2), 2-theta of 17.0 degrees (±0.2), 2-theta of 24.0 degrees (±0.2), or 2-theta of 25.6 degrees (±0.2), characterizing the solid form according to any one of claims 1, 2, or 11.

13. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 2-theta of about 8.3 degrees (±0.2) and at least three additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 15.1 degrees (±0.2), 15.9 degrees (±0.2), 17.0 degrees (±0.2), 24.0 degrees (±0.2) or 25.6 degrees (±0.2), the solid form according to any one of claims 1, 2 or 11-12.

14. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 2-theta of about 8.3 degrees (±0.2) and at least four additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 15.1 degrees (±0.2), 15.9 degrees (±0.2), 17.0 degrees (±0.2), 24.0 degrees (±0.2) or 25.6 degrees (±0.2), the solid form according to any one of claims 1, 2 or 11-13.

15. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle of 2-theta of about 8.3 degrees (±0.2) and at least five additional XRPD peaks at 2-theta of 11.4 degrees (±0.2), 15.1 degrees (±0.2), 15.9 degrees (±0.2), 17.0 degrees (±0.2), 24.0 degrees (±0.2) or 25.6 degrees (±0.2), the solid form according to any one of claims 1, 2 or 11-14.

16. An XRPD diffraction pattern comprising an XRPD peak at a diffraction angle 2-theta as described in Table 2, the solid form according to any one of claims 1-15.

17. The solid form according to any one of claims 1-16, wherein the XRPD is obtained from a CuKα source.

18. 848 (±2) cm －１ 、885 (±2) cm －１ 、939 (±2) cm －１ 、or 1218 (±2) cm －１ at least one peak at one of the positions of 848 (±2) cm －１ 、885 (±2) cm －１ 、939 (±2) cm －１ 、or 1218 (±2) cm －１ at least two peaks at the position of 848 (±2) cm －１ 、885 (±2) cm －１ 、939 (±2) cm －１ 、or 1218 (±2) cm －１ at least two peaks at the position of 848 (±2) cm －１ 、885 (±2) cm －１ 、939 (±2) cm －１ 、or 1218 (±2) cm －１ at least three peaks at the position of 848 (±2) cm －１ 、and 885 (±2) cm －１ 、939 (±2) cm －１ 、and 1218 (±2) cm －１ A solid form according to any one of claims 1 to 17, characterized by an IR spectrum having four peaks at the positions of 848 (±2) cm

19. 213 (±2) cm －１ 、257 (±2) cm －１ 、1061 (±2) cm －１ 、or 1570 (±2) cm －１ at least one peak at one of the positions of 213 (±2) cm －１ 、257 (±2) cm －１ 、1061 (±2) cm －１ 、or 1570 (±2) cm －１ at least two peaks at the position of 213 (±2) cm －１ 、257 (±2) cm －１ 、1061 (±2) cm －１ 、or 1570 (±2) cm －１ at least two peaks at the position of 213 (±2) cm －１ 、257 (±2) cm －１ 、1061 (±2) cm －１ 、or 1570 (±2) cm －１ at least three peaks at the position of 213 (±2) cm －１ 、257 (±2) cm －１ 、1061 (±2) cm －１ 、or 1570 (±2) cm －１ The solid form according to any one of claims 1 to 18, characterized by a Raman spectrum having four peaks at the position of 213 (±2) cm

20. The solid form according to any one of claims 1-19, wherein the melting point measured using DSC at a heating rate of 10 K / min exceeds 298 °C, specifically the melting point is 299 °C to 301 °C.

21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein the composition is an oral aqueous solution or a dry powder suitable for the constitution of an oral aqueous solution.

22. The pharmaceutical composition according to claim 21, wherein the oral aqueous solution has a pH of less than 4, most specifically between pH 3.0 and pH 3.

2.

23. The pharmaceutical composition according to any one of claims 21 to 22, further comprising a buffer system of citrate, malate, maleate, or tartrate, or further comprising tartaric acid.

24. The pharmaceutical composition according to any one of claims 21 to 20, further comprising an extragranular filler selected from lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol, and combinations thereof.

25. The pharmaceutical composition according to any one of claims 21 to 24, further comprising a diluent selected from lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, isomalt, sorbitol, sucrose, dextrose, basic xylitol, and combinations thereof.

26. The pharmaceutical composition according to any one of claims 21 to 25, further comprising a diluent selected from lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, basic xylitol, and combinations thereof.

27. The pharmaceutical composition according to any one of claims 21 to 26, further comprising a stabilizer or antioxidant selected from vitamin A, vitamin C, vitamin E, vitamin E TPGS, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, disodium edetate, butylhydroxytoluene, riboflavin, ascorbic acid, and combinations thereof.

28. The pharmaceutical composition according to any one of claims 21 to 27, further comprising an antioxidant selected from ascorbic acid.

29. The pharmaceutical composition according to any one of claims 21 to 28, further comprising a stabilizer selected from disodium ethylenediaminetetraacetate.

30. The pharmaceutical composition according to any one of claims 21 to 29, wherein the composition further comprises a lubricant selected from poly(ethylene glycol).

31. 1 to 10% by weight of a compound of formula (I) of type A or D, particularly type A A buffer system of 2 to 15% by weight, particularly 4 to 6% by weight, specifically citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate, or alternatively an acid corresponding to the buffer system as an acidifying agent alone, specifically tartaric acid, and A diluent of 40 to 90% by weight, specifically mannitol or a mixture of mannitol and isomalt, more specifically mannitol, and An antioxidant of 0.5 to 4% by weight, specifically ascorbic acid, and A stabilizer of 0.2 to 2% by weight, specifically disodium edetate, and A lubricant of 0.5 to 2% by weight, specifically PEG6000, and A preservative selected from potassium sorbate or sodium benzoate of 1 to 8% by weight, particularly 1 to 4% by weight, and A sweetener of 0 to 3% by weight, specifically sucralose or sodium saccharin, most specifically sucralose, and A fragrance of 0 to 20% by weight, specifically strawberry fragrance or vanilla fragrance, and comprising The total amount of the components does not exceed 100% by weight, the total amount of the components does not exceed 100% by weight, The pharmaceutical composition according to any one of claims 21 to 30.

32. 1 to 5% by weight of type A or D, particularly 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one as type A, and A tartrate buffer system of 2 to 8% by weight, particularly 4 to 6% by weight, and 60 to 75% by weight of mannitol as the first diluent and 10 to 15% by weight of isomalt as the second diluent, and 0.5 to 1.5% by weight of ascorbic acid as an antioxidant, and 0.25 to 0.75% by weight of disodium edetate as a stabilizer, and 0.5 to 2% by weight of PEG6000 as a lubricant, and 1 to 8% by weight, particularly 1 to 4% by weight of sodium benzoate as a preservative, and 0.5 to 1% by weight of sucralose as a sweetener, and 5 to 10% by weight of strawberry fragrance, and comprising The total amount of the components does not exceed 100% by weight, the pharmaceutical composition according to any one of claims 21 to 31.

33. The pharmaceutical composition according to any one of claims 21 to 32, which is an oral aqueous solution.

34. The pharmaceutical composition according to any one of claims 24 to 33, which is a dry powder suitable for the constitution of an oral aqueous solution.

35. A kit for preparing a pharmaceutical composition, comprising the pharmaceutical composition according to any one of claims 21 to 34 and water as a solvent for constitution.

36. A kit for preparing a pharmaceutical composition, comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, a powder blend as a medium for constitution, and optionally water as a solvent for constitution.

37. The powder blend is a buffer system selected from 3 to 15% by weight, specifically citrate, malate, maleate, or tartrate, more specifically malate or tartrate, most specifically tartrate; or alternatively, alone, the corresponding acid of the buffer system as an acidifying agent, specifically tartaric acid, and a diluent of 40 to 90% by weight, especially 40 to 80% by weight, specifically mannitol, or a mixture of mannitol and isomalt, more specifically mannitol, and an antioxidant of 1 to 4% by weight, specifically ascorbic acid, and a stabilizer of 0.2 to 2% by weight, specifically disodium edetate, and a lubricant of 0.5 to 2% by weight, specifically PEG6000, and a preservative of 1 to 8% by weight, especially 1 to 4% by weight, specifically sodium benzoate, and a sweetening agent of 0 to 3% by weight, specifically sucralose or sodium saccharin, most specifically sucralose, and a flavor of 0 to 20% by weight, specifically strawberry flavor or vanilla flavor, and the total amount of the components does not exceed 100% by weight, the kit for preparing a pharmaceutical composition according to claim 36.

38. Use of the pharmaceutical composition according to any one of claims 21 to 34 for the treatment, prevention, delay of progression, and / or remission of a disease caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of the function of the SMN1 gene.

39. Use of the pharmaceutical composition according to any one of claims 21 to 34 for preparing a medicament for the treatment, prevention, delay of progression, and / or remission of a disease caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of the function of the SMN1 gene.

40. The pharmaceutical composition according to any one of claims 21 to 34 for use as a therapeutic active substance.

41. ​ The pharmaceutical composition according to any one of claims 21 to 34, which is caused by an inactivating mutation or deletion of the SMN1 gene and / or is used in the treatment, prevention, delay of progression, and / or remission of a disease associated with loss or deficiency of SMN1 gene function, and further for protecting cells involved in the pathophysiology of said disease.

42. A method for the treatment, prevention, delay of progression, and / or remission of a disease caused by an inactivating mutation or deletion of the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function, and further for protecting cells involved in the pathophysiology of said disease, the method comprising administering the pharmaceutical composition according to any one of claims 21 to 34.

43. The invention as described hereinbefore.

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