Amorphous solid dispersion of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

Abstract

The present invention relates to an amorphous solid dispersion comprising ABX464 and at least one pharmaceutically acceptable carrier. The present invention also relates to pharmaceutical compositions comprising the ASDs described above, to methods for their preparation, to ASDs obtainable by the specific methods, and to their use as medicines, more particularly to their use in the treatment and / or prevention of inflammatory diseases, diseases caused by viruses, and / or cancer or dysplasia.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical industry and to an amorphous solid dispersion (herein also named ASD) comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (also named (8-chloroquinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine or ABX464) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising said ASD, processes for their preparation, their use as medicaments, and more particularly their use in the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia. [Background technology]

[0002] Application WO 2010 / 143169 describes such preparation and uses of compounds, particularly quinoline derivatives or pharmaceutically acceptable salts thereof, including ABX464, which is currently in clinical development.

[0003] The inventors state that ABX464 is highly crystalline in nature and therefore spontaneously exists in a specific, unique, stable crystalline form. Summary of the Invention [Problem to be solved by the invention]

[0004] In the pharmaceutical field, formulations in which the active ingredient is in crystalline form are generally the primary intended formulations due to the general physical stability, chemical nature of the API (active pharmaceutical ingredient), low hygroscopicity, simplified control testing, robustness and ease of implementation of the formulation, and purification process. However, the active ingredient may face solubility problems, i.e., has low solubility in aqueous solution, as in the case of ABX464. The main drawback of this low solubility is that if the drug remains undissolved in the digestive system, the active ingredient cannot fully reach its target in the body.

[0005] Therefore, there is a need to provide new means to improve the solubility of ABX464.

[0006] SUMMARY OF THE INVENTION The present inventors have surprisingly found that the incorporation of ABX464 into ASD formulations offers new opportunities to improve pharmaceutical performance. [Means for solving the problem]

[0007] The present invention is intended to provide an ASD comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and pharmaceutical compositions comprising said ASD, which can be used both as a medicament and, more particularly, for treating and / or preventing inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia.

[0008] The ASD technology allows ABX464 to be maintained in a stable amorphous form up to 100°C, particularly up to 80°C, particularly during storage for at least two weeks and during administration of the pharmaceutical product to a subject in need thereof, as shown in the experimental part (XRPD (X-ray powder diffraction), mDSC (modulated differential scanning calorimetry), and TGA (thermogravimetric analysis) characterization). Furthermore, the amorphous form of ABX464 in the ASD can be maintained after administration to a subject in need thereof, and the ASD according to the present invention exhibits significantly improved solubility compared to the intrinsic crystalline form of ABX464, as demonstrated in the experimental part using fasted and fed human in vitro models. Furthermore, we show that the loading of ABX464 in the ASD is desirably maintained, more particularly after the spray-drying process (UV-HPLC (ultraviolet high performance liquid chromatography) characterization).

[0009] Therefore, the present invention provides an ASD comprising, or consisting of, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0010] According to one embodiment, the ASD may comprise 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and additional solvents or ingredients, such as water and / or a solvent, such as methanol.

[0011] The experimental section (see Example 6) demonstrates the synthesis of ABX464 ASDs produced by a rapid evaporation process and their physical stability (more than 24 hours) with various carriers. It is further demonstrated in the examples that the formed ASDs remain stable even in the presence of residual solvents and / or water dedicated to the synthesis of the ASDs, and even in a hygroscopic atmosphere. In other words, the claimed ASDs may actually contain, for example, a solvent, including water, in addition to the ABX464 and one or more carriers.

[0012] Example 4 also shows that even in the presence of residual water and / or solvent, the ASD according to the invention remains stable.

[0013] It should be understood that when water and / or one or more solvents are present in an ASD according to the present invention, they are present in an amount of from 0.5% to 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and even more preferably less than 2% by weight, relative to the total weight of the ASD.

[0014] According to a particular embodiment, the ASD according to the present invention can consist exclusively of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In this particular embodiment, water and / or one or more solvents can be present in an amount of less than 0.5% by weight, based on the total weight of the ASD.

[0015] Also provided herein are: a pharmaceutical composition comprising the ASD as defined in the present invention; a method for preparing the ASD and the pharmaceutical composition as defined in the present invention; an amorphous solid dispersion comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof obtainable by the process according to the present disclosure and at least one pharmaceutically acceptable carrier; the ASD as defined in the present invention and the pharmaceutical composition for use as a medicament; The ASD as defined in the present invention and the pharmaceutical composition for use in treating and / or preventing inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia.

[0016] As used herein, the term "pharmaceutically acceptable" refers to a compound, ingredient, excipient, carrier, adjuvant, vehicle, composition or dosage form that is suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem complications, commensurate with a reasonable benefit / risk ratio.

[0017] In the context of the present invention, the term "treat" or "treatment" as used herein means to reverse, alleviate, inhibit progression of or prevent inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia.

[0018] The term "prevent" as used herein means reducing the risk of developing or slowing the rate of onset of a given phenomenon, i.e., in the present invention, inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH, and multiple sclerosis, viral diseases, and / or cancer or dysplasia. As used herein, "prevent" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0019] As used herein, the term "ambient temperature" or "room temperature" refers to a temperature in the range of 15°C to 30°C, more particularly 18°C ​​to 25°C. [Brief explanation of the drawings]

[0020] [Figure 1a]Figure 1a shows an SEM image of ABX464 at 100x magnification (see Example 2.3). [Figure 1b] Figure 1b shows an SEM image of ABX464 at 1000x magnification (see Example 2.3). [Figure 2a] FIG. 2a shows an SEM micrograph at 10 kx magnification of ABX464:VA64 SDD after preparation by spray-drying (t=0 h) (see Example 2.3). [Figure 2b] FIG. 2b shows an SEM micrograph at 1.5 kx magnification of ABX464:VA64 SDD after preparation by spray-drying (t=0 h) (see Example 2.3). [Figure 2c] FIG. 2c shows an SEM micrograph at 10 kx magnification of ABX464:K30 SDD after preparation by spray-drying (t=0 h) (see Example 2.3). [Figure 2d] FIG. 2d shows an SEM micrograph at 1.5 kx magnification of ABX464:K30 SDD after preparation by spray-drying (t=0 h) (see Example 2.3). [Figure 3] Figure 3 shows the XRPD diffractograms of two different ASDs, ABX464:VA64 (middle diffractogram) and ABX464:K30 (top diffractogram), and the unique crystalline form of ABX464 (bottom diffractogram) (see Example 2.2). [Figure 4] FIG. 4 shows the reversible M-DSC pattern recorded for a 35 / 65 weight ratio (at 35 wt % ABX464 drug loading) ASD in PVP K30 (see Example 2.2). [Figure 5] FIG. 5 shows the reversible M-DSC pattern recorded for a 35 / 65 weight ratio (at 35 wt % ABX464 drug loading) ASD in PVP-VA64 (see Example 2.2). [Figure 6] Figure 6 shows TGA thermograms showing the % weight loss obtained for the ABX464:VA64 ASD (middle line, circles), ABX464:K30 SDD (lower line, diamonds) and the native crystalline form of ABX464 (upper line, crosses) (see Example 2.4). [Figure 7]FIG. 7 illustrates a two-stage dissolution / precipitation fasted human "in vitro" model of ABX464:VA64 ASD (top line, squares) and its native crystalline form ABX464 (bottom line, triangles) (see Example 3). [Figure 8] Figure 8 shows a two-step dissolution / precipitation feeding human "in vitro" model of ABX464:VA64 ASD (top line, squares) and its native crystalline form ABX464 (bottom line, triangles) (see Example 3). [Figure 9] FIG. 9 shows XRPD diffractograms in a simulated intestinal compartment of NaCl (top line, i.e., first line), ABX464:VA64 ASD in suspension at the end of a fasted human in vitro model, i.e., Fassif (second line), ABX464:VA64 ASD in suspension at the end of a fed human in vitro model, i.e., Fessif (third line), and the native crystalline form of ABX464 (bottom line, i.e., fourth line) (see Example 3). [Figure 10] Figure 10 shows XRPD diffractograms of the native crystalline form of ABX464 (bottom line) and ABX464:VA64 ASD subjected to two different stress conditions: a temperature of 25°C and 60% relative humidity (middle line); and a temperature of 40°C and 75% relative humidity (top line), respectively. These diffractograms were performed after two weeks under these stress conditions (see Example 4). [Figure 11] Figure 11 shows XRPD diffractograms of the native crystalline form of ABX464 (bottom line) and ABX464:K30 ASD subjected to two different stress conditions: a temperature of 25°C and 60% relative humidity (middle line); and a temperature of 40°C and 75% relative humidity (top line), respectively. These diffractograms were performed after two weeks under these stress conditions (see Example 4). [Figure 12]FIG. 12 shows the XRPD diffractogram of ABX464:Eudragit L100-55 ASD after storage under vacuum at 40° C. for 24 hours (see Example 6, Preparation 1). [Figure 13] FIG. 13 shows the XRPD diffractogram of ABX464:HPMCAS-MF ASD after storage under vacuum at 40° C. for 24 hours (see Example 6, Preparation 2). [Figure 14] FIG. 14 shows the XRPD diffractograms of ABX464:VA64:K30 ASD immediately after fast evaporation (bottom line), after 24 hours of storage at 40° C. under vacuum (middle line), and after 24 hours of storage at 40° C. under vacuum followed by 24 hours of storage at room temperature (RT) under 75% relative humidity (RH) (top line) (see Example 6, Preparation 4). [Figure 15] FIG. 15 shows the XRPD diffractograms of ABX464:VA64:citric acid ASD immediately after fast evaporation (bottom line), after 24 hours of storage at 40° C. under vacuum (middle line), and after 24 hours of storage at 40° C. under vacuum followed by 24 hours of storage at room temperature (RT) under 75% relative humidity (RH) (top line) (see Example 6, Preparation 5). [Figure 16] FIG. 16 shows the XRPD diffractogram of ABX464:K30:citric acid ASD after storage under vacuum at 40° C. for 24 hours (see Example 6, Preparation 6). [Figure 17] FIG. 17 shows the XRPD diffractogram of ABX464:VA64:Tween 80 ASD after storage under vacuum at 40° C. for 24 hours (see Example 6, Preparation 8). [Figure 18] FIG. 18 shows the XRPD diffractograms of ABX464:VA64:HPMCAS-MF ASD immediately after fast evaporation (bottom line), after 24 hours of storage at 40° C. under vacuum (middle line), and after 24 hours of storage at 40° C. under vacuum followed by 24 hours of storage at room temperature (RT) under 75% relative humidity (RH) (top line) (see Example 6, Preparation 9). DETAILED DESCRIPTION OF THE INVENTION

[0021] Amorphous solid dispersions according to the present invention As described above, provided herein is an ASD comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0022] In the context of the present invention, "ASD" refers to a glass solution, i.e., ABX464 (active pharmaceutical ingredient or API) in an amorphous form. The pharmaceutically acceptable carrier is also in an amorphous form in which the ABX464 molecules (solute molecules) are molecularly dispersed. Thus, the glass solution forms a homogeneous one-phase system. ASD in the sense of the present invention encompasses three categories depending on the presence of two or only one of the following two aspects: intermolecular interactions and molecular mobility. These three types are called eutectic ASD, amorphous solid solution, and stabilized ASD. A "eutectic ASD" is an ASD that has strong intermolecular interactions between the components that form the ASD, but high molecular mobility. An "amorphous solid solution" is an ASD that has low molecular mobility but very weak intermolecular interactions between the components that form the ASD. A "stabilized ASD" is an ASD that has low molecular mobility but strong intermolecular interactions between the components that form the ASD. "Amorphous" refers to a solid compound or mixture of solid compounds that is not crystalline. An amorphous compound or mixture of amorphous compounds has no long-range order and exhibits only short-range order, and therefore does not exhibit a distinct X-ray diffraction pattern with reflections, only broad scattering. "Matrix" refers to a homogeneous solid material that is not a powder. "ABX464:VA64" is an abbreviation for an ASD containing ABX464 and polyvinylpyrrolidone-polyvinyl acetate copolymer as the pharmaceutically acceptable carrier (binary mixture). "ABX464:K30" is an abbreviation for an ASD containing ABX464 and polyvinylpyrrolidone as the pharmaceutically acceptable carrier (binary mixture). "ABX464:Eudragit L100-55" is the abbreviation for an ASD containing ABX464 and poly(methacrylic acid-co-ethyl acrylate) 1:1 as the pharmaceutically acceptable carrier (binary mixture). "ABX464:HPMCAS-MF" is the abbreviation for an ASD containing ABX464 and hydroxypropyl methylcellulose acetate succinate (fine particle size grades M and F) as the pharmaceutically acceptable carrier (binary mixture). "ABX464:VA64:K30" is an abbreviation for an ASD containing ABX464, polyvinylpyrrolidone-polyvinyl acetate copolymer and polyvinylpyrrolidone as the pharmaceutically acceptable carriers (ternary mixture). "ABX464:VA64:citric acid" is an abbreviation for an ASD containing ABX464, polyvinylpyrrolidone-polyvinyl acetate copolymer, and citric acid as the pharmaceutically acceptable carriers (ternary mixture). "ABX464:K30:citric acid" is an abbreviation for an ASD containing ABX464, polyvinylpyrrolidone, and citric acid as the pharmaceutically acceptable carriers (ternary mixture). "ABX464:VA64:Tween 80" is an abbreviation for an ASD containing ABX464, polyvinylpyrrolidone-polyvinyl acetate copolymer, and Tween 80 as the pharmaceutically acceptable carriers (ternary mixture). "ABX464:VA64:HPMCAS-MF" is the abbreviation for an ASD containing ABX464 and polyvinylpyrrolidone-polyvinyl acetate copolymer and hydroxypropyl methylcellulose acetate succinate (fine particle size grades M and F) as the pharmaceutically acceptable carriers (ternary mixture).

[0023] Therefore, ASD according to the present invention encompasses the three types described above.

[0024] According to one embodiment, the present invention relates to a eutectic ASD comprising or consisting of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0025] According to another embodiment, the present invention relates to an amorphous solid solution comprising or consisting of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0026] According to another embodiment, the present invention relates to a stabilized ASD comprising, or consisting of, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0027] As detailed below, the properties of the pharmaceutically acceptable carrier may play a role in the properties of the resulting ASD (eutectic ASD, stabilized ASD, or amorphous solid solution).

[0028] According to a particular embodiment, the present invention relates to an amorphous solid dispersion comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0029] According to another particular embodiment, the present invention relates to an amorphous solid dispersion comprising, or consisting of, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer.

[0030] 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its salts As stated above, the ASD according to the present invention comprises ABX464 or a pharmaceutically acceptable salt thereof.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, salts of organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- These include naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, pantothenate, picrate, bitartrate, mandelate, edetate, gluceptate, salicylate, disalicylate, mucate, estolate, napsylate, esylate, napadisylate, and the like.

[0032] ABX464 and its salts may be prepared by any method known to those skilled in the art, such as the method disclosed in WO 2010 / 143169.

[0033] ABX464 (when not included in an ASD according to the present invention) is in a unique crystalline form having a melting point of 120.5°C (±2°C) and exhibits by XRPD analysis the following major peaks, expressed as order 2-theta angles: 7.3; 14.6; 23.5 and 28.4 (each time ±0.2), and may also exhibit the following additional peaks, expressed as order 2-theta angles: 12.1; 17.3; 18.4; 23.0; 24.2; 24.9; 27.4 and 29.1 (each time ±0.2), and optionally the following additional peaks, expressed as order 2-theta angles: 13.7; 16.3; 16.9; 18.1; 22.4 and 29.6 (each time ±0.2),

[0034] A characteristic X-ray powder diffraction pattern of this unique crystalline form of gently ground 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine can be given in FIG.

[0035] In contrast, when ABX464 is included in the ASD according to the present invention, it is in amorphous form, as detailed below. This has been demonstrated in the experimental part by means of mDSC (Figures 4 and 5 and Example 2.2) and XRPD characterization (Figure 3 and Example 2.2), under specific stress conditions after 2 weeks (see Figures 10 and 11 and Example 4), and in the Fassif and Fessif in vitro models (see Figure 9 and Example 3), which simulate the gastrointestinal fluids in the fasted and fed states, respectively.

[0036] Pharmaceutically Acceptable Carriers As noted above, the ASD according to the present invention comprises at least one pharmaceutically acceptable carrier.

[0037] In one embodiment, the pharmaceutically acceptable carrier is selected from a polymer, a sugar, an acid, a surfactant, a cyclodextrin or a cyclodextrin derivative, pentaerythritol, pentaerythrityl tetraacetate, urea, a urethane, a hydroxyalkylxanthine, and mixtures thereof, particularly selected from a polymer, an acid, a surfactant, urea, and mixtures thereof, more particularly selected from a polymer, an acid, a surfactant, and mixtures thereof.

[0038] In another embodiment, the pharmaceutically acceptable carrier is selected from polymers, sugars, acids, surfactants, cyclodextrins, pentaerythritol, pentaerythrityl tetraacetate, urea, urethane, hydroxyalkylxanthines, and mixtures thereof.

[0039] Among the sugars suitable for use in the solid amorphous dispersions of the present invention, mention may be made of dextrose, sucrose, galactose, sorbitol, maltose, xylitol, mannitol, lactose, and mixtures thereof.

[0040] Among the surfactants suitable for use in the amorphous solid dispersions of the present invention, mention may be made of polyoxyethylene stearate, poloxamer 188 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer), deoxycholic acid, Tween, e.g., Tween 80 (also named polysorbate 80), Span, Solutol (Macrogol-15 hydroxystearate), sodium lauryl sulfate, vitamin E, lauryl sulfate, and mixtures thereof.

[0041] Among the acids suitable for use in the amorphous solid dispersions of the present invention can be mentioned carboxylic acids or other acidic compounds commonly used to form pharmaceutically acceptable salts, such as citric acid, succinic acid, malic acid, fumaric acid, tartaric acid, and mixtures thereof.

[0042] Among the cyclodextrins suitable for use in the amorphous solid dispersions of the present invention, mention may be made of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin (i.e., chemically unmodified cyclodextrins), polymers of cyclodextrin (i.e., chemically modified cyclodextrins), and mixtures thereof.

[0043] Among the cyclodextrin derivatives suitable for use in the amorphous solid dispersions of the present invention, mention may be made, for example, of sulfobutyl ether β-cyclodextrin and its salts, such as the sodium salt.

[0044] The polymers suitable for use in the amorphous solid dispersions of the present invention may have a Tg of at least 50°C, and particularly at least 80°C, more particularly at least 100°C.

[0045] In one embodiment, the polymer suitable for use in the amorphous solid dispersions of the invention is a homopolymer or copolymer of an N-vinyl lactam, such as a homopolymer or copolymer of N-vinylpyrrolidone (e.g., polyvinylpyrrolidone (also named PVP or povidone), or a copolymer of N-vinylpyrrolidone with vinyl acetate or vinyl propionate); a cellulose ester or ether, such as an alkylcellulose (e.g., methylcellulose or ethylcellulose), a hydroxyalkylcellulose (e.g., hydroxypropylcellulose or hydroxyethylcellulose), a hydroxyalkylalkylcellulose (e.g., hydroxypropylmethylcellulose (HPMC)), and a phthalate or succinate of cellulose (e.g., cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate (also named HPMCP), hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose acetate succinate, also named HPMCAS); a polymeric polyalkylene oxide, such as poly Polyacrylates or polymethacrylates, such as methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), and poly(hydroxyalkyl methacrylate); polyacrylamide; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, and partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligo- or polysaccharides, such as carrageenan, galactomannan, pectin, and xanthan gum; polyhydroxyalkyl acrylate; polyhydroxyalkyl-methacrylate; copolymers of methyl methacrylate and acrylic acid; polyethylene glycol (PEG); graft copolymers of polyethylene glycol / polyvinyl caprolactam / polyvinyl acetate, or any mixture or combination thereof.

[0046] Non-limiting examples of cellulose-based polymers are hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10, Ethocel 14, Ethocel 20.

[0047] Non-limiting examples of polyethylene glycols are polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

[0048] Non-limiting examples of polyacrylates or polymethacrylates are (meth)acrylate / (meth)acrylic acid copolymers (Eudragit) L100-55, Eudragit L100, Eudragit S100.

[0049] According to a particular embodiment, the pharmaceutically acceptable carrier is a polymer, forming a binary or ternary mixture (if different polymers are present), as shown in the experimental part.

[0050] According to a particular embodiment, the polymers suitable for use in the amorphous solid dispersions of the present invention are selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose succinate, polymethacrylates, and mixtures thereof.

[0051] As indicated above, among the cellulose succinates, mention may be made of hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g. HPMCAS-MF), which may be, for example, that sold by Ashland under the name AquaSolve™.

[0052] As indicated above, among the polymethacrylates, mention may be made of methacrylic acid / ethyl acrylate copolymers, such as poly(methacrylic acid-co-ethyl acrylate) 1:1, which may be, for example, that sold by Evonik under the name Eudragit L100-55.

[0053] As indicated above, among the homopolymers of N-vinyl lactams, mention may be made of polyvinylpyrrolidone (also named povidone or PVP), which may be, for example, that sold by BASF under the names Kollidon® 30 (also named PVP K30), PVP K17, PVP K25 or PVP K90.

[0054] As indicated above, among the copolymers of N-vinyllactams, mention may be made of the copolymer of N-vinylpyrrolidone and vinyl acetate (also named copovidone or PVP-VA), such as that sold under the name Kollidon® VA64 by BASF, or the copolymer of N-vinylcaprolactam, vinyl acetate and ethylene glycol, such as that sold under the name Soluplus® by BASF.

[0055] According to a particular embodiment, the polymers suitable for use in the amorphous solid dispersions of the present invention are selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof.

[0056] In the sense of the present invention, the term "lactam" can include beta-lactams, gamma-lactams, delta-lactams and epsilon-lactams, i.e., respectively, 4-, 5-, 6- and 7-membered carbocyclic rings containing one amide function.

[0057] According to another particular embodiment, the polymer suitable for use in the amorphous solid dispersion of the present invention is selected from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, and mixtures thereof.

[0058] According to another particular embodiment, the polymer suitable for use in the amorphous solid dispersion of the present invention is selected from homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone, cellulose succinate, polymethacrylate, and mixtures thereof.

[0059] According to another particular embodiment, the polymer suitable for use in the amorphous solid dispersion of the present invention is selected from povidone, copovidone, polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, and mixtures thereof.

[0060] According to another particular embodiment, the polymers suitable for use in the amorphous solid dispersions of the present invention are selected from homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone, and mixtures thereof.

[0061] Thus, according to one embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a polymer selected from homopolymers of N-vinyl lactams, N-vinyl lactams, cellulose succinate, copolymers of polymethacrylates, and mixtures thereof, in particular from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, and mixtures thereof, more in particular from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, acrylic acid / ethyl acrylate copolymers, and mixtures thereof.

[0062] According to one particular embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a polymer selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof, in particular from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, and mixtures thereof, more particularly from povidone, copovidone, and mixtures thereof, and even more particularly copovidone.

[0063] According to another particular embodiment, the pharmaceutically acceptable carrier is a surfactant, forming a binary mixture as shown in the experimental part.

[0064] According to a particular embodiment, the surfactants suitable for use in the amorphous solid dispersions of the present invention are selected from poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers.

[0065] As indicated above, among the poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, mention may be made of poloxamer 188, poloxamer 407 and mixtures thereof, in particular poloxamer 407.

[0066] Thus, according to one particular embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a surfactant selected from poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, in particular selected from poloxamer 188, poloxamer 407 and mixtures thereof, in particular poloxamer 407.

[0067] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of a polymer and an acid to form a ternary mixture as shown in the experimental part.

[0068] According to a particular embodiment, the acid suitable for use in the amorphous solid dispersion of the present invention is a carboxylic acid.

[0069] As indicated above, among the carboxylic acids, mention may be made of citric acid, succinic acid, malic acid, fumaric acid, tartaric acid and mixtures thereof, in particular citric acid.

[0070] Thus, according to another embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a combination of a polymer and an acid, wherein the polymer is selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof, and the acid is selected from carboxylic acids, in particular the polymer is selected from homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, and mixtures thereof, and the acid is selected from citric acid, succinic acid, malic acid, fumaric acid, tartaric acid, and mixtures thereof, more particularly the polymer is povidone, copovidone, and mixtures thereof, and the acid is citric acid.

[0071] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of a polymer and urea, forming a ternary mixture.

[0072] Thus, according to another embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a combination of a polymer and urea, the polymer being selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof, in particular the polymer being selected from homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, and mixtures thereof, more in particular the polymer is copovidone.

[0073] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of a polymer and a surfactant, forming a ternary mixture, as shown in the experimental part.

[0074] Thus, according to another embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is a combination of a polymer and a surfactant, wherein the polymer is selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof, and the surfactant is selected from Tween (polysorbates), in particular the polymer is selected from homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, and mixtures thereof, and the surfactant is Tween 80 (polysorbate 80), more particularly the polymer is copovidone and the surfactant is Tween 80.

[0075] According to a particularly preferred embodiment, in the amorphous solid dispersion according to the invention, the pharmaceutically acceptable carrier is selected from polymers, acids, surfactants, urea, and mixtures thereof, more particularly from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose succinate, polymethacrylates, carboxylic acids, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, Tween (polysorbates), urea, and mixtures thereof, in particular from homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, citric acid. acid, succinic acid, malic acid, fumaric acid, tartaric acid, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, Tweens (polysorbates), urea, and mixtures thereof, more particularly povidone, covidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, citric acid, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, Tweens, urea, and mixtures thereof, even more preferably povidone, copovidone, poly(methacrylic acid-co-ethyl acrylate) 1:1, HPMCAS MF, citric acid, poloxamer 407, Tween 80, urea and mixtures thereof, and even more preferably selected from povidone, copovidone, poly(methacrylic acid-co-ethyl acrylate) 1:1, HPMCAS MF, citric acid, Tween 80, and mixtures thereof.

[0076] Thus, according to a particularly preferred embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier selected from polymers, acids, surfactants, urea, and mixtures thereof, more particularly selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose succinate, polymethacrylates, carboxylic acids, copolymers of poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), Tween (polysorbate), urea, and mixtures thereof, in particular homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, hydroxypropyl methylcellulose acetate. and mixtures thereof, more particularly selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, citric acid, succinic acid, malic acid, fumaric acid, tartaric acid, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer, Tweens (polysorbates), urea, and mixtures thereof, and even more particularly selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, citric acid, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer, Tweens, urea, and mixtures thereof, and even more preferably selected from povidone, copovidone, poly(methacrylic acid-co-ethyl acrylate) 1:1, HPMCAS. MF, citric acid, poloxamer 407, Tween 80, urea and mixtures thereof, and even more preferably selected from povidone, copovidone, poly(methacrylic acid-co-ethyl acrylate) 1:1, HPMCAS MF, citric acid, Tween 80, and mixtures thereof.

[0077] According to a particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, The carrier may be a polymer selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose succinate, polymethacrylates, and mixtures thereof, in particular selected from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, and mixtures thereof, more in particular selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, and mixtures thereof, and even more in particular copovidone; or The carrier may be a surfactant selected from Tweens, in particular Tween 80; or The carrier may be an acid selected from citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof, more particularly citric acid.

[0078] According to a particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, which may be one or more polymers, optionally in admixture with one or more acids as defined in the invention and / or one or more surfactants as defined in the invention, wherein the acids are in particular citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof, more in particular citric acid, and wherein the surfactant is in particular a Tween, more in particular Tween 80.

[0079] According to another particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, The carrier may be a polymer selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, and mixtures thereof; or The carrier may be a surfactant selected from Tweens; or The carrier may be an acid selected from citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof.

[0080] According to another particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, which may be one or more polymers, optionally in admixture with one or more acids as defined in the invention and / or one or more surfactants as defined in the invention, the acids being in particular citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof, and the surfactants being in particular Tweens.

[0081] According to another particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, The carrier may be a polymer selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, and mixtures thereof; or The carrier may be a surfactant, wherein the surfactant may be Tween 80; or The carrier may be an acid, where the acid may be citric acid.

[0082] According to another particular embodiment, the amorphous solid dispersion according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, which may be one or more polymers, optionally in admixture with one or more acids as defined in the present invention and / or one or more surfactants as defined in the present invention, wherein the acid may be citric acid and the surfactant may be Tween 80.

[0083] According to a particular embodiment, the amorphous solid according to the invention is a glassy solution forming a homogeneous monophasic system, and 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is in amorphous form.

[0084] According to a particular embodiment, the weight ratio of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof to the one or more pharmaceutically acceptable carriers ranges from 1:20 to 1:0.5, in particular from 1:10 to 1:1, and more in particular from 1:2 to 1:1.5.

[0085] It should be understood that for the calculation of the weight ratio of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof to the one or more pharmaceutically acceptable carriers, only the amount of ABX464 forming the ASD according to the present invention and the amount of the one or more pharmaceutically acceptable carriers defined in the present invention are taken into account. In other words, this weight ratio calculation does not take into account the amount of excipients that may be added later to obtain a pharmaceutical composition according to the present invention.

[0086] According to a particular embodiment, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is present in an amount of 5% to 70% by weight, in particular 30% to 40% by weight, and more in particular 33% to 37% by weight, relative to the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

[0087] According to a particular embodiment, the one or more pharmaceutically acceptable carriers are present in an amount of 30% to 95% by weight, in particular 60% to 70% by weight, and more in particular 63% to 67% by weight, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

[0088] According to a specific embodiment, the ASD according to the present invention comprises 5% to 70% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 30% to 95% by weight of one or more pharmaceutically acceptable carriers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

[0089] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of one or more pharmaceutically acceptable carriers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

[0090] According to a specific embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of one or more pharmaceutically acceptable carriers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

[0091] According to a specific embodiment, the ASD according to the present invention comprises 5% to 70% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 30% to 95% by weight of one or more pharmaceutically acceptable polymers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0092] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of one or more pharmaceutically acceptable polymers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0093] According to a particular embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of one or more pharmaceutically acceptable polymers, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0094] According to a particular embodiment, the ASD according to the present invention comprises 5% to 70% by weight of ABX464 or a pharmaceutically acceptable salt thereof, and 30% to 95% by weight of one or more pharmaceutically acceptable polymers selected from N-vinyl lactam homopolymers, N-vinyl lactam copolymers, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0095] According to a particular embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of one or more pharmaceutically acceptable polymers selected from N-vinyl lactam homopolymers, N-vinyl lactam copolymers, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0096] According to a particular embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of one or more pharmaceutically acceptable polymers selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0097] According to a specific embodiment, the ASD according to the present invention comprises 5% to 70% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 30% to 95% by weight of one or more pharmaceutically acceptable polymers selected from povidone, copovidone, polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0098] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of one or more pharmaceutically acceptable polymers selected from povidone, copovidone, polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0099] According to a particular embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of one or more pharmaceutically acceptable polymers selected from povidone, copovidone, polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, and mixtures thereof, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable polymers.

[0100] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of povidone, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and povidone.

[0101] According to a specific embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of povidone, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and povidone.

[0102] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of copovidone, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and copovidone.

[0103] According to a specific embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of copovidone, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and copovidone.

[0104] According to a specific embodiment, the ASD according to the present invention comprises 30% to 40% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 60% to 70% by weight of polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol.

[0105] According to a specific embodiment, the ASD according to the present invention comprises 33% to 37% by weight of ABX464 or a pharmaceutically acceptable salt thereof and 63% to 67% by weight of polyvinylcaprolactam-polyvinylacetate-polyethylene glycol, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol.

[0106] It must be understood that for the calculation of all these weight percentages relative to the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof as defined in the present invention and the one or more pharmaceutically acceptable carriers, only the amount of ABX464 forming the ASD according to the present invention and the one or more pharmaceutically acceptable carriers as defined in the present invention is taken into account. In other words, the calculation of these weight percentages does not take into account the amount of excipients that may be added later to obtain a pharmaceutical composition according to the present invention.

[0107] The pharmaceutically acceptable carrier suitable for the present invention can be a combination of two, three, four, five or more compounds selected from the group consisting of polymers, sugars, acids, surfactants, cyclodextrins, pentaerythritol, pentaerythrityl tetraacetate, urea, urethane, and hydroxyalkylxanthines.

[0108] According to a particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined herein and one or more acids as defined herein, in particular citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof.

[0109] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and one or more sugars as defined in the present invention.

[0110] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and one or more surfactants as defined in the present invention.

[0111] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined herein and one or more cyclodextrins as defined herein.

[0112] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and pentaerythritol.

[0113] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and pentaerythrityl tetraacetate.

[0114] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and urea.

[0115] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and a urethane.

[0116] According to another particular embodiment, the pharmaceutically acceptable carrier is a combination of one or more polymers as defined in the present invention and a hydroxyalkylxanthine.

[0117] As indicated above, three different types (or categories) of ASD can be observed depending on the properties of the pharmaceutical carrier. Indeed, pharmaceutical carriers suitable for use in ASD according to the present invention may have either or both of the following characteristics: strong intermolecular interactions and low molecular mobility.

[0118] The strong intermolecular interactions between the one or more carrier molecules and the ABX464 molecules make it possible to stabilize ABX464 and keep it in an amorphous form, preventing the molecules from clumping together.

[0119] The ASD of the present invention is thermally stable and remains amorphous, forming a homogeneous, monophasic system, even under the stress conditions detailed below (see, e.g., Examples 2.2, 2.3, and 2.4 below). As described above, the amorphous form of ABX464 in the ASD can be maintained after administration to a subject (patient) in need of the product. It has also been demonstrated in the experimental section using fasted and fed human in vitro models that the ASD of the present invention exhibits significantly greater solubility than the inherent crystalline form of ABX464 (see Example 3). Furthermore, as shown in Example 4, the inventors have demonstrated that the ASD of the present invention is chemically and physically stable after two weeks under stress conditions (25°C and 60% relative humidity; and 40°C and 75% relative humidity).

[0120] Methods for preparing ASD according to the present invention As mentioned above, there is also provided herein a method for the preparation of the amorphous solid dispersion as defined in the present invention, comprising the steps of: aa) combining 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier as defined herein, optionally in a suitable solvent or a mixture of suitable solvents, to obtain a solution to provide the amorphous solid dispersion.

[0121] According to another embodiment, there is also provided herein a method for preparing the amorphous solid dispersion as defined in the present invention, comprising the steps of: aa) combining 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier as defined herein, optionally with one suitable solvent or a mixture of suitable solvents, to obtain a solution; bb) mixing the combination or solution obtained in step aa); and cc) optionally evaporating said one or more solvents to provide said amorphous solid dispersion.

[0122] According to another embodiment, there is also provided herein a method for preparing the amorphous solid dispersion as defined in the present invention, comprising the steps of: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of suitable solvents to obtain a solution; b) adding at least one pharmaceutically acceptable carrier as defined in the present invention to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); and d) evaporating said one or more solvents to provide said amorphous solid dispersion.

[0123] In step a), the suitable solvent can be any volatile solvent capable of dissolving both the pharmaceutically acceptable carrier and ABX464 or a salt thereof, particularly, the suitable solvent is selected from C1-C6 alcohols, dichloromethane, acetonitrile, acetone, THF (tetrahydrofuran), diethyl ether and mixtures thereof, more particularly, selected from C1-C4 monoalcohols, dichloromethane and mixtures thereof, even more particularly, selected from methanol, ethanol, dichloromethane and mixtures thereof, even more particularly, methanol.

[0124] Advantageously, since the glass solution according to the invention has a higher viscosity compared to liquid solutions, the distribution of the solute molecules (ABX 464 molecules) may be irregular in the pharmaceutically acceptable carrier, and a uniform distribution in the glass solution can be ensured by mixing (step c), which can be carried out by any conventional means known in the art.

[0125] The evaporation step d) can be carried out by spray-drying or solvent evaporation methods, in particular spray-drying, which are well known in the art (see, for example, Prashant et al., Amorphous Solid Dispersions: A Promising Technology for Improving the Oral Bioavailability of Poorly Water-Soluble Drugs, S.Afr.Pharm.J., 2018, 85(1), 50-56).

[0126] If a spray-drying evaporation process is used, the ASD according to the present invention may also be termed a spray dried dispersion (SDD) herein.

[0127] Spray-drying involves three well-known steps: atomization of powder, drying, and recovery. Typically, the atomization is carried out through a nozzle to obtain the ASD. Some parameters are generally as follows: The nozzle may be 0.4 mm to 1 mm, in particular 0.6 mm; The inlet temperature can be between 85°C and 100°C, in particular 90°C; The outlet temperature can be 56℃-57℃ (this temperature is the result of a combination of parameters); The flow rate can be between 2 mL / min and 5 mL / min, and is particularly 3 mL / min; The nozzle flow rate can be between 6 L / hr and 10 L / hr, particularly 8 L / hr.

[0128] As an alternative to the method involving evaporation, hot melt extrusion can be carried out.

[0129] In hot-melt extrusion, ABX464 or a salt thereof is melted and mixed in a pharmaceutically acceptable carrier, as defined herein, to produce and stabilize the amorphous form of ABX464 or a salt thereof. The melt is then extruded and rapidly cooled to obtain a stable, solid, single-phase, glassy, ​​amorphous matrix. If necessary, the product thus obtained can then be advantageously milled to reduce particle size and then incorporated into oral solid dosage forms, as defined herein, such as tablets or capsules.

[0130] According to another embodiment, there is also provided herein a method for preparing the amorphous solid dispersion as defined in the present invention, said method comprising the steps of: a) mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier as defined in the present invention to obtain a powder mixture; b) introducing the powder mixture obtained in step a) into a hot melt extruder to obtain a non-powder amorphous solid dispersion material; c) The non-powdered amorphous solid dispersion material thus obtained is then milled to obtain an amorphous solid dispersion powder.

[0131] In the solvent evaporation method, the ABX 464 or its salt as defined in the present invention and the pharmaceutically acceptable carrier are solubilized in a volatile solvent. Advantageously, mixing at a molecular level can be performed (to optimize the dissolution characteristics of the final product). When this method is used, care should be taken to avoid phase separation when mixing both ABX 464 and the carrier into one solution.

[0132] According to a particular embodiment, the method for preparing the amorphous solid dispersion defined in the present invention comprises the following steps: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in methanol, ethanol or dichloromethane to obtain a solution; b) adding povidone, copovidone or polyvinylcaprolactam-polyvinylacetate-polyethylene glycol to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); and d) evaporating the methanol to provide the amorphous solid dispersion.

[0133] According to another particular embodiment, the method for preparing the amorphous solid dispersion as defined in the present invention comprises the following steps: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in methanol to obtain a solution; b) adding povidone, copovidone or polyvinylcaprolactam-polyvinylacetate-polyethylene glycol to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); and d) evaporating the methanol to provide the amorphous solid dispersion.

[0134] The method of preparation according to the invention presents many advantages.

[0135] First, the method includes several (three) essential steps.

[0136] This also allows the ASD to be obtained in significantly higher yields (at least about 80%).

[0137] Moreover, as shown in the experimental part (XRPD and mDSC characterization, see Example 2.2), this makes it possible to prepare homogeneous ASD according to the invention that is thermally stable up to 100°C (i.e. the ASD remains in amorphous form).

[0138] Furthermore, the UV-HPLC assay described in the experimental part (see Example 2.1) demonstrates that the method makes it possible to maintain the load of ABX464 in the ASD after the evaporation step d), more particularly after the spray-drying step.

[0139] Pharmaceutical compositions according to the present invention Also provided herein is a pharmaceutical composition comprising the amorphous solid dispersion as defined in the present invention and at least one pharmaceutically acceptable excipient.

[0140] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), or bucally as an oral or nasal spray, depending on the severity of the infection being treated. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, nasal, and intracranial injection or infusion techniques. In some embodiments, the ASD of the present invention can be administered orally or parenterally, once or more times daily, to achieve the desired therapeutic effect, at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day of the active ingredient ABX464.

[0141] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, such as aqueous solutions, suspensions, such as aqueous suspensions, syrups, and elixirs. In addition to the ASD of the present invention, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluents, the oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavorings, coloring agents, and fragrances. When an aqueous suspension is required for oral use, the ASD according to the present invention may be combined with emulsifying and suspending agents.

[0142] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

[0143] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter before use, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium.

[0144] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the ASD described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ABX464.

[0145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, lozenges, chewing gum, and granules. In such solid dosage forms, the ASD according to the present invention comprises at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) a filler or extender, such as starch, e.g., corn starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) a humectant, such as glycerol; d) a disintegrant, such as agar. , calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) adsorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffering agent. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0146] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release one or more active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight octavalent polyethylene glycols.

[0147] The ASD of the present invention can also be in microencapsulated form with one or more excipients, as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the ASD of the present invention can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.

[0148] Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, for example, magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release one or more of the active ingredients only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0149] Pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0150] Topical application for the lower intestinal tract can be effected in the form of a rectal suppository (see above) or a suitable enema. Topical transdermal patches may also be used.

[0151] For topical administration, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the ASD of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0152] Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0153] Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be prepared by dissolving or dispensing an ASD according to the present invention in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing an ASD according to the present invention in a polymer matrix or gel.

[0154] Dosage forms for topical or transdermal administration of an ASD of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.

[0155] The ASD according to the invention is admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers which may be required.

[0156] Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.

[0157] Indeed, for ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0158] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food.

[0159] Thus, according to a particular embodiment, the pharmaceutical composition comprising the amorphous solid dispersion as defined in the present invention and at least one pharmaceutically acceptable excipient is in the form of, inter alia, tablets, capsules, pills, lozenges, chewing gum, powders, granules, suppositories, emulsions, microemulsions, solutions, e.g. aqueous solutions, suspensions, e.g. aqueous suspensions, syrups, elixirs, ointments, drops, pastes, creams, lotions, gels, sprays, inhalants or patches.

[0160] In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0161] The amount of the ASD of the present invention that may be combined with the excipient or carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0162] According to a particular embodiment, the pharmaceutical composition according to the invention is an oral pharmaceutical composition.

[0163] Oral pharmaceutical compositions of the invention can be in the form of capsules, tablets, or sachets containing a powdered composition. Therapeutically effective oral doses for the formulations of the invention are determined by standard clinical techniques according to the judgment of a healthcare professional.

[0164] Due to the fact that the ASDs according to the invention are obtained in powder form, it is advantageous to protect them from relative humidity.

[0165] Thus, according to one embodiment, when the ASD of the present invention is formulated into capsules, tablets, suspensions, solutions, or syrups using conventional methods, they are protected in blisters. Another advantage provided by the use of blisters is that the capsules or tablets are also protected from oxygen and other contaminants.

[0166] The capsules may be soft gel or hard gel capsules. When the capsules are soft gel or hard gel capsules, they may advantageously contain liquid excipients, in particular a lipophilic liquid vehicle, Viscosity modifier for semi-solid lipophilic vehicles / lipophilic liquid vehicles, Solubilizers, surfactants, emulsifiers and adsorption promoters may include:

[0167] Among these excipients, mention may be made of the following: Refined specialty oils, such as: Peanut oil Castor oil cottonseed oil Corn (maize) oil olive oil Sesame oil soybean oil sunflower oil Medium chain triglycerides and their related esters, such as: Caprylic / capric triglyceride (Akomed E, Akomed R, Miglyol 810, and Captex 355) Medium-chain triglycerides (Labrafac CC) Propylene glycol diester of caprylic / capric acid (Labrafac PG) Propylene glycol monolaurate (Lauroglycol FCC) Fractionated coconut oil (Miglyol 812) Caprylic / Capric / Diglyceryl Succinate (Miglyol 829) Medium-chain diester of propylene glycol (Miglyol 840) Partial ester of diglycerides with natural fatty acids (Softisan 645). Solubilizers, surfactants, emulsifiers, and adsorption promoters, e.g. Propylene glycol monocaprylate (Capryol 90) Polyglycolic acid glycerides (Gelucire 44 / 14 and 50 / 13) Polyoxyl-40 hydrogenated castor oil (Cremophor RH 40) Glycerol Monostearate / Ditriglyceride + Glycerin (Imwitor 191) Glyceryl monocaprylate (Imwitor 308*) Glyceryl Cocoate / Citrate / Lactate (Imwitor 380) Glyceryl Mono-Di-Caprylate / Caprate (Imwitor 742) Isosteryl diglyceryl succinate (Imwitor 780K) Glyceryl Cocoate (Imwitor 928) Glyceryl Caprylate (Imwitor 988) Oleoyl macrogol-8 glycerides (Labrafil M 1944 CS) Linoleoyl macrogolglycerides (Labrafil M 2125 CS) PEG-8 Caprylic / Capric Glyceride (Labrasol) lauric acid Propylene glycol laurate (Lauroglycol 90) oleic acid Polyethylene glycol Propylene glycol Polyglycerol dioleate (Plurol Oleique CC 497) Polyoxyethylene-polyoxypropylene copolymers (Poloxamer 124 and 188) Partial glycerides of hydroxylated unsaturated fatty acids (Softigen 701) PEG-6 Caprylic / Capric Glycerides (Softigen 767) Polyoxyethylene glyceryl trioleate (Tagat TO) Polyoxyethylene (20) sorbitan monooleate (Tween 80).

[0168] In some embodiments, the present invention provides a tablet or capsule comprising the amorphous solid dispersion of the present invention and at least one pharmaceutically acceptable excipient.

[0169] In some particular embodiments, the present invention provides a capsule comprising the amorphous solid dispersion of the present invention and at least one pharmaceutically acceptable excipient, or provides a tablet comprising granules formed by the amorphous solid dispersion as defined herein and by at least one intragranular excipient, wherein the granules are compressed together with at least one extragranular excipient.

[0170] When the pharmaceutical composition according to the present invention is a tablet, the tablet may be coated or uncoated. Preferably, the tablet is coated by using any suitable film coating agent well known in the art.

[0171] The excipient can be any conventionally used excipient, such as those excipients described above, including intragranular and / or extragranular excipients.

[0172] The excipients may be selected from fillers, binders, antioxidants, disintegrants, lubricants, glidants, film coating agents, surfactants (different from the surfactants used as pharmaceutically acceptable carriers in the ASD), and mixtures thereof.

[0173] Fillers that can be used in accordance with the present invention include, but are not limited to, lactose (anhydrous), lactose monohydrate, spray-dried lactose; compressible sugars, dextrose, dextrates; starch (from any source, e.g., corn, potato, rice, wheat, which can be fully pregelatinized and partially gelatinized); cellulose; microcrystalline cellulose; inorganic salts, such as calcium phosphate, calcium tribasic, and calcium sulfate; and polyols, such as mannitol, sorbitol, and xylitol.

[0174] In some embodiments, the filler can be in an amount of 10% to 85% by weight, based on the total weight of the composition.

[0175] Lubricants that can be used according to the present invention include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, talc, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, and magnesium lauryl sulfate.

[0176] In some embodiments, the lubricant may be present in an amount of 0.3% to 4% by weight, preferably 0.3% to 2% by weight, based on the total weight of the composition.

[0177] Disintegrants that can be used in accordance with the present invention include, but are not limited to, croscarmellose sodium, sodium starch glycolate, starch (including starch from any source, e.g., corn, potato, rice, wheat, which can be fully pregelatinized and partially gelatinized), crospovidone, alginates such as calcium alginate and sodium alginate, alginic acid, and magnesium aluminum silicate.

[0178] In some embodiments, the disintegrant can be in an amount of 30% to 60% by weight, based on the total weight of the composition.

[0179] In other embodiments, the disintegrant may be present in an amount of 1% to 15% by weight, preferably 3% to 10% by weight, based on the total weight of the composition.

[0180] The surfactants that can be used as additives in the present invention include, but are not limited to, tocopherol, lecithin, egg yolk phospholipids, docusate sodium, capryol, labrafil, labrasol, lauroglycol, and mixtures thereof.

[0181] In some embodiments, the surfactant can be in an amount of 1% to 3% by weight, based on the total weight of the composition.

[0182] Glidants that can be used in accordance with the present invention include, but are not limited to, colloidal silicon dioxide.

[0183] In some embodiments, the fluidizing agent can be in an amount of 0.3% to 2% by weight, based on the total weight of the composition.

[0184] In some embodiments, the binder can be in an amount of 5% to 20% by weight, based on the total weight of the composition.

[0185] According to a particular embodiment, the pharmaceutical composition according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof as the only pharmaceutically active ingredient.

[0186] According to a particular embodiment, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is present in an amount ranging from 5% to 95% by weight relative to the total weight of the pharmaceutical composition.

[0187] According to a particular embodiment, the one or more pharmaceutically acceptable carriers are present in an amount of 5% to 95% by weight relative to the total weight of the pharmaceutical composition.

[0188] In some embodiments, the pharmaceutically acceptable excipient can include one or more of the one or more pharmaceutically acceptable carriers defined above.

[0189] According to a particular embodiment, the pharmaceutical composition according to the invention comprises ABX464:VA64 ASD, ABX464:K30 ASD, ABX464:Eudragit L100-55 ASD, ABX464:HPMCAS-MF ASD, ABX464:VA64:K30 ASD, ABX464:VA64:citric acid ASD, ABX464:K30:citric acid ASD, ABX464:VA64:Tween 80 ASD or ABX464:VA64:HPMCAS-MF ASD as defined in the present invention, and one or more further excipients, such as one or more pharmaceutically acceptable polymers, in particular copovidone and / or povidone. In these cases, it must be understood that the amount of polymer (e.g., copovidone and / or povidone) considered as an excipient does not need to be taken into account in calculating the weight ratio ABX464 / one or more pharmaceutically acceptable carriers defined in the present invention for the ASD in accordance with the present invention, and does not need to be taken into account in determining said amount by weight relative to the total weight of ABX464 and the one or more pharmaceutically acceptable carriers defined in accordance with the present invention for the ASD.

[0190] According to one embodiment, the pharmaceutical composition according to the invention is administered to a subject in need thereof at a dose of 1 mg to 1 g per day, in particular 10 mg to 150 mg per day, of the active ingredient ABX464, one or more times per day.

[0191] Pharmaceutical compositions according to the present invention may be in modified, sustained, controlled, delayed, or immediate release form.

[0192] Methods for preparing pharmaceutical compositions according to the present invention As mentioned above, there is also provided herein a method for preparing the pharmaceutical composition defined in the present invention, which comprises the steps of: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of suitable solvents to obtain a solution; b) adding at least one pharmaceutically acceptable carrier as defined in the present invention to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); d) evaporating said one or more solvents to provide said amorphous solid dispersion; e) mixing the amorphous solid dispersion of step d) with one or more excipients to obtain the pharmaceutical composition; and f) optionally coating the pharmaceutical composition thus obtained, if a coated pharmaceutical composition is required.

[0193] Steps a), b), c) and d) are the same as defined above for the method of preparing ASD according to the present invention.

[0194] The mixing step e) can be carried out by any conventional means known in the art.

[0195] Said step f) of coating may be carried out using one or more conventional coating agents known in the art.

[0196] If the pharmaceutical composition of the present invention is in the form of a tablet, a step of compressing the mixture as obtained in step e) must be carried out between step e) and the optional step f).

[0197] Therapeutic Uses and Methods of Administration As mentioned above, also provided herein is an amorphous solid dispersion as defined in the present invention or a pharmaceutical composition as defined in the present invention for use as a medicament and for use in the treatment and / or prevention of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0198] Further provided herein is a method of administering ABX464 or a salt thereof to a subject in need thereof, the method comprising: providing an oral pharmaceutical composition comprising ABX464 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier formulated as an ASD, and at least one pharmaceutically acceptable excipient; and orally administering the pharmaceutical composition in a therapeutically effective amount to a subject in need thereof. Includes.

[0199] ABX464 or a salt thereof can be administered alone or in combination with other therapeutic agents that can act synergistically with ABX464 or a salt thereof.

[0200] In a further embodiment, the present invention includes a method of orally administering a pharmaceutical composition comprising the amorphous solid dispersion comprising ABX464 or a salt thereof, and an additional therapeutic agent.

[0201] "Subjects" (including patients) include mammals, such as humans, companion animals (e.g., dogs, cats, birds, etc.), farm animals (e.g., cows, sheep, pigs, horses, chickens, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, birds, etc.).

[0202] According to another aspect, the present invention also relates to the use of an amorphous solid dispersion as defined in the present invention or a pharmaceutical composition as defined in the present invention for said manufacture of a medicament.

[0203] According to another aspect, the present invention also relates to the use of an amorphous solid dispersion as defined in the present invention or a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for the prevention and / or treatment of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0204] In another aspect, the present invention also relates to a therapeutic method for treating and / or preventing inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia, which method comprises administering to a patient in need thereof a pharmaceutical composition comprising an ASD as defined in the present invention.

[0205] According to another aspect, the present invention also relates to a therapeutic method for treating and / or preventing inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia, which method comprises administering to a patient in need thereof a therapeutically effective amount of an ASD as defined in the present invention.

[0206] inflammatory diseases Therefore, the present invention also relates to an ASD as defined above or a pharmaceutical composition as defined in the present invention for use in the treatment and / or prevention of inflammatory diseases.

[0207] According to the present invention, "inflammation" is a defensive response by the immune system to tissue injury and infection. However, the inflammatory response can be damaging to the body in some circumstances. In the acute phase, inflammation is characterized by pain, heat, redness, swelling, and loss of function. Inflammation can result from infection, irritation, or injury. l

[0208] Thus, "inflammatory disease" refers to a group of diseases and / or disorders caused by excessive or uncontrolled inflammation.

[0209] Inflammatory diseases include, but are not limited to, inflammatory diseases associated with autoimmune diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin and other inflammatory diseases involving epithelial cells such as bronchitis, inflammation associated with cancer such as colon cancer, inflammation associated with irritants, and inflammation associated with injury.

[0210] According to the present invention, the inflammatory disease, disorder or condition is selected from: (a) an inflammatory disease, disorder, or condition of the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis; (b) an inflammatory disease, disorder, or condition of the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a kidney transplant; (c) an inflammatory disease, disorder, or condition of the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant; (d) an inflammatory disease, disorder, or condition in the lung or heart selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary arterial hypertension, sarcoidosis, myocarditis, pericarditis, and acute or chronic rejection of a lung or heart transplant; (e) an inflammatory disease, disorder, or condition of the skin selected from contact dermatitis, atopic dermatitis, urticaria, chronic dermatitis, psoriasis, eczema, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic diseases of the skin; (f) an inflammatory disease, disorder, or condition in the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, arteriosclerosis, proliferative vascular disease, and restenosis; (g) an inflammatory disease, disorder, or condition of the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis; (h) an inflammatory disease, disorder, or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, chronic pain, traumatic brain injury including stroke, Alzheimer's disease, Parkinson's disease, myelitis, Charcot-Marie-Tooth disease type 1 (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathy; (i) an autoimmune disease, disorder, or condition selected from lupus, including the skin and kidney, Guillain-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis; (j) an inflammatory disease, disorder, or condition of the intestine selected from intestinal disorders, ulcerative colitis (UC), and Crohn's disease; (k) an inflammatory disease, disorder, or condition of the reproductive system selected from endometriosis, uterine fibroids, prostate dysplasia or hyperplasia, and cervical dysplasia; and (l) An inflammatory disease, disorder, or condition of the bones and / or joints selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow, or spine.

[0211] In certain embodiments, the inflammatory disease can be selected from the list consisting of inflammatory diseases associated with autoimmune diseases, central nervous system (CNS) inflammatory diseases, joint inflammatory diseases, inflammatory gastrointestinal diseases, inflammatory skin and other inflammatory diseases involving epithelial cells, inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury.

[0212] In particular, the inflammatory disease is selected from the list consisting of inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's, osteoarthritis, arteriosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjogren's syndrome, bronchitis, asthma, pulmonary arterial hypertension, NASH and colon cancer.

[0213] More particularly, the inflammatory disease is selected from the list consisting of inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, bronchitis, pulmonary arterial hypertension, NASH and colon cancer.

[0214] More particularly, the inflammatory disease is selected in the list consisting of inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, pulmonary arterial hypertension, NASH and psoriasis.

[0215] Preferably, inflammatory diseases according to the present invention include inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis.

[0216] Even more preferably, inflammatory diseases according to the present invention include inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis.

[0217] Inflammatory diseases can also include Alzheimer's disease, Parkinson's disease, asthma, arteriosclerosis and dermatitis.

[0218] Dermatitis may include eczema.

[0219] In view of the above, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in the treatment and / or prevention of an inflammatory disease, such as an inflammatory disease including inflammation itself and inflammation associated with an inflammatory disease.

[0220] Therefore, the present invention also relates to the use of an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for treating and / or preventing an inflammatory disease, such as inflammation itself and inflammation associated with an inflammatory disease.

[0221] The present invention also relates to the use of an ASD as defined in the present invention for the preparation of a composition, such as a medicament, for treating and / or preventing inflammation, including inflammation itself and inflammation associated with inflammatory diseases.

[0222] The present invention also relates to a method for treating and / or preventing an inflammatory disease, such as an inflammatory disease including inflammation itself and inflammation associated with said inflammatory disease, said method comprising the step of administering an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention to a patient in need thereof.

[0223] In some embodiments, the method of the present invention for treating an inflammatory disease, disorder or condition, or the pharmaceutical composition defined in the present invention for treating an ASD defined in the present invention or the use defined above, further comprises measuring and / or monitoring the presence and / or level of a biomarker in a patient, for example, a blood, plasma, tissue, saliva, and / or serum sample. In some embodiments, the biomarker measured and / or monitored in the method of the present invention is miR-124.

[0224] In some embodiments, the method of the present invention or the pharmaceutical composition as defined in the present invention for treating an inflammatory disease, disorder or condition, or the ASD as defined in the present invention or the use as defined above, further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient, for example in blood, plasma, tissue, saliva, and / or serum samples, before administering the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention as described herein.

[0225] In some embodiments, the method of the present invention or the pharmaceutical composition as defined in the present invention for treating an inflammatory disease, disorder or condition, or the ASD as defined in the present invention or the use as defined above, further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient during the course of treatment with the ASD as defined in the present invention or the pharmaceutical composition thereof as described herein.

[0226] In some embodiments, the method of the present invention for treating an inflammatory disease, disorder or condition, or the pharmaceutical composition as defined in the present invention for an ASD as defined in the present invention or the use as defined above, further comprises selecting a patient for treatment with an ASD as defined in the present invention or a pharmaceutical composition thereof by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient as described herein.

[0227] The provided ASD can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies include fixed combinations, staggered or independent administration of the compound of the present invention and one or more other therapeutic compounds, or combined administration of a fixed combination with one or more other therapeutic compounds. The compounds of the present invention can also be administered in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor therapy. Long-term therapy can be equivalent to adjuvant therapy in the context of other treatment strategies, as described above. Other possible therapies include therapy to maintain the patient's condition after tumor regression, or chemopreventive therapy, for example, in at-risk patients.

[0228] The additional agents may be administered separately from the provided ASD as part of a multiple dose regimen. Alternatively, the agents may be part of a single dosage form mixed together with the provided ASD in a single composition. When administered as part of a multiple dose regimen, the two active agents may be administered simultaneously, sequentially, or within a period typically less than 5 hours of each other.

[0229] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a provided ASD can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a provided ASD, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0230] In some embodiments, the ASD as defined herein may be administered with one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azu), and the like. Antimalarials such as chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), and thiazolidine (Thiazolidine®). trademark), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava®), and etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®), "anti-TNF" agents such as "anakinra (Kineret®), "anti-IL-1" agents such as rilonacept (Arcalyst®), anti-T cell antibodies such as thymoglobulin, IV immunoglobulin (IVIg), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), tocilizumab (Actemra®), diclofenac,"Anti-IL-6" agents such as cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as difenoxate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, albuterol (Ventolin®), beta-2 agonists such as HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), beclomethasone dipropionate (Beclovent®, Qvar®), benzodiazepines (Benza ... Inhaled corticosteroids such as fluconazole (Fentanyl®), flucloxone ...Methylxanthines such as Theo-24® and aminophylline, IgE antibodies such as omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emcitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), (R), stavudine (Zerit®), and zalcitabine (Hivid®); non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®); nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®); amprenavir (Agenerase®), atazanavir ( protease inhibitors such as Reyataz), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), enfuvirtide (Fuzeon®), entry inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®); anti-IL36 agents such as BI655130; dihydroorotate dehydrogenase inhibitors such as IMU-838;Anti-OX40 drugs such as KHK-4083, microbiome agents such as RBX2660 and SER-287, narrow-spectrum kinase inhibitors such as TOP-1288, anti-CD40 agents such as BI-655064 and FFP-104, guanylate cyclase agonists such as dolucanatide, sphingosine kinase inhibitors such as opaganib, anti-IL-12 / IL-23 agents such as AK-101, and ubiquitin protein ligase complex inhibitors such as BBT-401 , sphingosine receptor modulators such as BMS-986166, P38MAPK / PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-1α stabilizers such as GB-004, MAP3K8 protein inhibitors such as GS-4875, LAG-3 antibodies such as GSK-283171, RIPs such as GSK-2983559 2 kinase inhibitors, farnesoid X receptor agonists such as MET-409, CCK2 antagonists such as PNB-001, IL-23 receptor antagonists such as PTG-200, purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibitors such as apremilast, ICAM-1 inhibitors such as alicaforsen sodium, anti-IL23 drugs such as guselkumab, brazikumab, and mirquizumab, anti-IL23 drugs such as AMG-714, etc. These include L15 drugs, TYK2 inhibitors such as BMS-986165, NK cell activators such as CNDO-201, RIP-1 kinase inhibitors such as GSK-2982772, anti-NKGD2 agents such as JNJ-4500, CXCL-10 antibodies such as JT-02, IL-22 receptor agonists such as RG-7880, GATA-3 antagonists such as SB-012, and colony-stimulating factor 1 receptor inhibitors such as edicotinib, or combinations of one or more thereof.

[0231] Diseases caused by viruses The ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention may be useful in the treatment and / or prevention of various diseases caused by viruses, in particular retroviruses, and more particularly HIV, more particularly for use in reducing viral load in patients infected by viruses, in particular HIV, or virus-related conditions with long-term efficacy and without resistance.

[0232] Examples of viruses contemplated by the present invention include enveloped and naked viruses, which include DNA viruses, RNA viruses, and retroviruses, which include dsDNA viruses, ssDNA viruses, dsRNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, and dsDNA-RT viruses.

[0233] More particularly considered viruses are RNA viruses and retroviruses, such as the above-mentioned RNA viruses and retroviruses, including lentiviruses, and preferably HIV. Thus, more particularly considered virus-associated conditions are associated with RNA viruses or retroviruses, preferably HIV. HIV can include HIV-I, HIV-2, and all subtypes thereof, including HIV-I strains belonging to HIV-I subtype B, HIV-I subtype C, and HIV-I recombinant types. Examples include HIV-I strains selected from Ad8, AdAm, Isolate B, Isolate C, CRF01, CRF02, and CRF06. According to a preferred embodiment, the virus-associated condition is AIDS.

[0234] Three subfamilies can be distinguished within the retrovirus family: the oncoviruses, the lentiviruses and the spumaviruses. HIV belongs to the lentiviruses.

[0235] According to a particular embodiment, the retrovirus is selected from the group consisting of HIV viruses (HIV1 and HIV2), visna / maedi viruses, i.e., MVV (MVV / visna), equine infectious anemia virus, i.e., EIAV (equine infectious anemia virus), caprine arthritis encephalitis virus, i.e., CAEV (caprine arthritis encephalitis virus), simian immunodeficiency virus, i.e., SIV (simian immunodeficiency virus), avian leukemia virus, i.e., ALV (avian leukemia virus), Moloney virus, i.e., murine leukemia virus, also called MULV (Moloney virus), Abelson leukemia virus, mouse mammary tumor virus, Mason-Pfizer monkey virus, i.e., MPMV (Mason-Pfizer monkey virus), feline leukemia virus, i.e., FELV (feline leukemia virus), human leukemia virus HTLV-I, human leukemia virus HTLV-II, simian leukemia virus, i.e., STLV (simian leukemia virus), leukemia virus), bovine leukemia virus (BLV), primate type D tumor virus, type B tumor virus, Rous sarcoma virus (RSV), simian foamy virus (SFV) or chimpanzee simian virus, human foamy virus, and feline immunodeficiency virus, the human foamy virus (HFV), bovine syncytial virus (BSV), feline syncytial virus (FSV), the feline immunodeficiency virus, avian leukosis virus, walleye cutaneous sarcoma virus, T-cell lymphoma, acute ATL, lymphomatous ATL, chronic ATL, smoldering ATL, neurological diseases, tropical spastic paraplegia (HTLV),paraparesis-related myelopathy, inflammatory and autoimmune diseases such as uveitis, dermatitis, pneumonia, rheumatoid arthritis, and polymyositis, blood and skin diseases, lung diseases, brain diseases, and / or immunodeficiency diseases.

[0236] As used herein, the term oncovirus can include alpharetroviruses (e.g., avian leukosis virus and Rous sarcoma virus); betaretroviruses (e.g., mouse mammary tumor virus); gammaretroviruses (e.g., murine leukemia virus and feline leukemia virus); deltaretroviruses (e.g., bovine leukemia virus and human T lymphotropic virus); and epsilonretroviruses (e.g., walleye cutaneous sarcoma virus).

[0237] More generally, the retroviruses described herein include, for example, Visna / Medivirus or MVV / Visna, Equine Infectious Anemia Virus, or EIAV, Caprine Arthritis Encephalitis Virus, or CAEV, Simian Immunodeficiency Virus, or SIV, Avian Leukosis Virus, or ALV, Murine Leukemia Virus, also called Moloney Virus, or MULV, Abelson Leukemia Virus, Mouse Mammary Tumor Virus, Mason-Pfizer Monkey Virus, or MPMV, Feline Leukemia Virus, or FELV, Human Leukemia Virus, or HTLV- The virus may be human leukemia virus I, human leukemia virus HTLV-II, simian leukemia virus, i.e., STLV, bovine leukemia virus, i.e., BLV, primate oncovirus D, oncovirus B, Rous sarcoma virus, i.e., RSV, and / or simian foamy virus, i.e., SFV or chimpanzee simian virus, human foamy virus, and feline immunodeficiency virus, the human foamy virus (i.e., HFV), bovine syncytial virus (i.e., BSV), feline syncytial virus (FSV), and the feline immunodeficiency virus.

[0238] More particularly, HTLV-I is responsible for T-cell lymphoma (e.g., ATL, for adult T-cell leukemia / lymphoma, including different forms of ATL, e.g., ATL for adult T-cell leukemia / lymphoma, such as acute ATL, lymphomatous ATL, chronic ATL, and smoldering ATL), neurological disorders, tropical spastic paraparesis (TSP) (also known as HTLV-associated myelopathy (HAM) or chronic progressive myelopathy), and various inflammatory and autoimmune diseases such as uveitis, dermatitis, pneumonia, and rheumatoid arthritis; HTLV-II can be responsible for certain neurological, hematological, and skin disorders; HIV (HIV1 and HIV2) causes AIDS; the Visna virus causes lung and brain disease in sheep, and the feline immunodeficiency virus causes immunodeficiency in cats; and the Rous sarcoma virus and mouse mammary tumor virus cause tumor growth and cancer.

[0239] The present invention also relates to a method for treating and / or preventing a disease caused by a virus, in particular a retrovirus and more particularly HIV, which method comprises the step of administering an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention to a patient in need thereof.

[0240] Additionally, the present invention has the object of reducing the viral load in patients infected by a virus, in particular HIV, or a virus-related condition with long-lasting effectiveness and without resistance by using an ASD as defined in the present invention or said pharmaceutical composition as defined in the present invention.

[0241] In one embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in treating or preventing a retroviral infection or a retroviral-related condition, in particular an HIV infection or an HIV-related disease, in a patient in whom ineffective or reduced efficacy of prior art antiretroviral treatments has been demonstrated.

[0242] In another embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use for treating or preventing a retroviral infection or a retroviral-associated condition, in particular an HIV infection or an HIV-related disease, in a patient, wherein the patient is infected with a drug-resistant viral strain, more in particular a drug-resistant HIV strain.

[0243] Moreover, the present invention further relates to new doses and regimens of said ASD as defined in the present invention, and to its use in the treatment or prevention of viral infections, and in particular HIV, or virus-related conditions, more particularly where said use results in maintaining a low viral load after treatment has ended. Thus, according to one embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in the treatment or prevention of a viral infection or a virus-related condition, in particular HIV infection or an HIV-related disease, in a patient, where after treatment has ended; a low or undetectable viral load is maintained; and / or the CD4+ cell count is stabilized or increased.

[0244] According to another embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in the treatment or prevention of a viral infection or a virus-related condition in a patient, in particular an HIV infection or an HIV-related disease for which inefficacy of prior art antiretroviral treatments or a reduced therapeutic effect of prior art antivirals or antiretrovirals has been demonstrated.

[0245] According to yet another embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in the treatment or prevention of a viral infection or a virus-related condition, in particular an HIV infection or an HIV-related disease, in a patient, wherein the patient is infected with a drug-resistant strain.

[0246] In the framework of the present invention, the ASD as defined in the present invention may be administered in combination with other antiretroviral agents. According to one embodiment, ART (antiretroviral therapy) or HAART (highly active antiretroviral therapy) may be carried out using one or more of the following antiretroviral compounds: (i) Nucleoside / nucleotide reverse transcriptase inhibitors, also known as nucleoside analogues, such as abacavir, emtricitabine, and tenofovir; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, etravirine, and nevirapine; (iii) protease inhibitors (PIs), such as atazanavir, darunavir, and ritonavir; (iv) entry inhibitors, such as enfuvirtide and maraviroc; (v) Integrase inhibitors, such as dolutegravir and raltegravir.

[0247] Other examples of antiretroviral agents include, in a non-limiting manner: Zidovudine, Lamivudine, Emtricitabine, Didanosine, Stavudine, Abacavir, Zalcitabine, Racivir, Amdoxovir, Apricitabine, Elvucitabine, Efavirenz, Nevirapine, Etravirine, Delavirdine, Rilpvirine, Tenofovir, Fosal These include Fosalvudine, Amprenavir, Tipranavir, Indinavir, Saquinavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Lopinavir, Raltegravir, Elvitegravir, Dolutegravir, Enfuvirtide, Maraviroc, Vicriviroc, and combinations thereof.

[0248] In some embodiments, the ASD according to the invention is selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®); non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®); nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®). It may be administered in combination with one or more additional therapeutic agents selected from nucleotide reverse transcriptase inhibitors, protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Presista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentres®), and combinations thereof.

[0249] An ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention may also be useful for the treatment and / or prevention of diseases or coronavirus infections and conditions associated therewith caused by viruses belonging to the Coronaviridae family, and in particular Severe Acute Respiratory Syndrome caused by infection with SARS-CoV or SARS-CoV-2, including the causative strain of COVID-19 (also referred to herein as Coronavirus Disease 2019) and its mutant strains.

[0250] More particularly, SARS-CoV-2, formerly known as 2019-nCoV, belongs to the Coronaviridae family and is part of group 4 of the Baltimore classification.

[0251] For reference, the content of the "Baltimore Classification" reported herein further references the virus taxonomy set forth in the International Committee on Taxonomy of Viruses (ICTV) database, available online at https: / / talk.ictvonline.org / taxonomy / on March 20, 2020 (Email ratification February 2019 & MSL #34), which is incorporated herein in its entirety.

[0252] This classification therefore clusters viruses into families (or "groups") according to their genome type. As of 2018, the virus classification includes seven different groups: Group 1: double-stranded DNA viruses (dsDNA); Group 2: single-stranded DNA viruses (ssDNA); Group 3: double-stranded RNA viruses (dsRNA); Group 4: (+)strand or sense RNA viruses ((+)ssRNA); Group 5: (-)strand or antisense RNA viruses ((-)ssRNA); Group 6: single-stranded RNA viruses with DNA intermediates (ssRNA-RT); Group 7: double-stranded DNA viruses with an RNA intermediate (dsDNA-RT).

[0253] Moreover, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention is further particularly useful for the treatment and / or prevention of severe forms of SARS-CoV-2 infection: anti-inflammatory effect to counter the cytokine storm, mucosal effect, promotion of tissue repair to avoid sequelae after prolonged ventilation.

[0254] According to a particular embodiment, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention may be used in the early stages of COVID-19.

[0255] Indeed, clinically, SARS-CoV-2 infection can lead to cytokine storm syndrome, acute respiratory distress syndrome (ARDS), and multiple organ failure. Notably, cytokine storm (i.e., hyperinflammatory syndrome) is associated with the severity of COVID-19 (including increased MCP1, IL-1β, TNFα, IL-17, G-CSF, and IL-6). Early treatment and actions on viral replication and various cytokine pathways can successfully reduce the cytokine storm syndrome and "hyperinflammation," preventing ARDS and multiple organ failure.

[0256] Thus, in one embodiment, the present invention relates to an ASD as defined herein or a pharmaceutical composition as defined herein for use in a method for treating a group of patients, who may or may not be hospitalized, prior to the onset of respiratory distress syndrome associated with a coronavirus infection.

[0257] Thus, in one embodiment, the present invention relates to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in a method for treating or preventing the occurrence of respiratory distress syndrome associated with a coronavirus infection.

[0258] According to a particular embodiment, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention is for use in a method for treating or preventing a coronavirus infection, for treating or preventing the occurrence of vascular, cardiovascular, neurological or gastrointestinal diseases associated with coronavirus infection.

[0259] Advantageously, the ASD as defined in the present invention may be considered for use in the prophylactic treatment of coronavirus infections, alone or in combination with any other active agent, in particular any dynamin inhibitor, in particular any dynamin-2 inhibitor.

[0260] As used herein, a "condition associated with a coronavirus infection", particularly a condition associated with a severe acute respiratory syndrome-associated coronavirus such as SARS-CoV2, may be selected from the list including or consisting of severe respiratory distress syndrome, a cardiovascular condition, a vascular condition, a gastrointestinal condition or a neurological condition.

[0261] Advantageously, such patients who have or are at risk of having a condition associated with coronavirus infection may also be considered.

[0262] According to exemplary embodiments, the conditions associated with coronavirus infection that are particularly contemplated include pulmonary fibrosis, vasculitis, Kawasaki disease, and tissue damage or destruction, particularly lung tissue damage and destruction.

[0263] Unless otherwise indicated, all ASDs and pharmaceutical compositions disclosed are specifically contemplated herein for the treatment or prevention of coronaviruses, and therefore, although they may refer trivially to any member of the coronavirus family within the meaning of the Baltimore Protocol, a particular selection of viruses will be considered hereinafter as a preferred embodiment.

[0264] As used herein, the term "coronavirus family" refers to the corresponding family of RNA viruses belonging to Group 4 of the Baltimore classification, which itself is part of the suborder Coronidovirnae and order Nidovirales. The coronavirus family encompasses both the subfamily Letovirinae and the subfamily Orthocoronavirus.

[0265] As used herein, the term "Retoviridae" refers to the corresponding family of the Baltimore classification, which includes the genus Alpharetovirus, subgenus Myrchovirus, which includes (non-exhaustively) one species, Microhilaretoviridae.

[0266] As used herein, the term "Orthocoronavirus family" refers to the corresponding family of the Baltimore classification, which includes the genera Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.

[0267] As used herein, the term "alphacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Coracovirus, Decacovirus, Dubinacovirus, Ruchacovirus, Minacovirus, Minunacovirus, Myotakovirus, Mictakovirus, Pedakovirus, Rhynacovirus, Setracovirus, and Tegacovirus. In a non-exhaustive manner, this includes the following species: bat coronavirus CDPHE15, bat coronavirus HKU10, horseshoe bat alphacoronavirus HuB-2013, human coronavirus 229E, Lushen Rn rat coronavirus, ferret coronavirus, mink coronavirus 1, miniopterus bat coronavirus 1, miniopterus bat coronavirus HKU8, Myotis rickettii alphacoronavirus Sax-2011, gecko shark alphacoronavirus SC-2013, porcine epidemic diarrhea virus, Scotophilum bat coronavirus 512, horseshoe bat coronavirus HKU2, human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, and alphacoronavirus 1.

[0268] As used herein, the term "betacoronavirus" refers to the corresponding family of the Baltimore classification, including the subgenera Enbecovirus, Hibecovirus, Marbecovirus, Novecovirus, and Cerbecovirus. In a non-exhaustive manner, this encompasses the following species: Betacoronavirus 1, Chinese rat coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-associated coronavirus, Pipistrelle's bat coronavirus HKU5, Lesser long-eared bat coronavirus HKU4, Hedgehog coronavirus 1, Middle East respiratory syndrome-associated coronavirus, Pipistrelle's bat coronavirus HKU5, Lesser long-eared bat coronavirus HKU4, Rouset's bat coronavirus GCCDC1, Rouset's bat coronavirus HKU9, and Severe acute respiratory syndrome-associated coronavirus.

[0269] As used herein, the term "severe acute respiratory syndrome-associated coronavirus", i.e., SARS virus, includes, in a non-exhaustive manner, the SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2; including the strain that causes COVID-19 and their variants.

[0270] As used herein, the term "deltacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Andechovirus, Buldechovirus, Herdechovirus, and Mualdecovirus, which in a non-exhaustive manner include Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU19, and Common moorhen coronavirus HKU21.

[0271] As used herein, the term "gammacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Segakovirus and Igakovirus. In a non-exhaustive manner, this includes the following species: Beluga coronavirus SW1 and avian coronaviruses.

[0272] According to a particular embodiment, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a coronavirus infection is for reducing inflammation associated with the coronavirus infection.

[0273] According to a particular embodiment, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a coronavirus infection is for reducing the Coronaviridae viral load.

[0274] According to a particular embodiment, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a coronavirus infection is in combination with: Dynamin inhibitors, such as dynasore; and / or Antibiotics, for example, one selected from the group consisting of β-lactams, fluoroquinolones, and macrolides, such as azithromycin; Remdesivir; Ribavirin; ritonavir; Lopanibil; chloroquine or hydroxychloroquine; beta-interferon; an anti-inflammatory compound, such as one selected from the group consisting of anti-TNF, Jak inhibitors, anti-IL6 antibodies, and IL6 receptor antagonists; and / or Calcium inhibitors, such as diltiazem.

[0275] According to some particular embodiments, the coronavirus family is selected from the families Retroviridae and Orthocoronavirus.

[0276] According to some particular embodiments, the coronavirus is an alphacoronavirus or a betacoronavirus or a deltacoronavirus or a gammacoronavirus.

[0277] According to some particular embodiments, the coronavirus is an Enbecovirus or a Hibecovirus or a Marbecovivirus or a Novecovirus or a Sarbecovirus.

[0278] According to some particular embodiments, the coronavirus is a sarbecovirus selected from severe acute respiratory syndrome-associated coronaviruses.

[0279] According to some specific embodiments, the Severe Acute Respiratory Syndrome (SARS) associated coronavirus is selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2.

[0280] According to some preferred embodiments, the severe acute respiratory syndrome (SARS)-associated coronavirus is selected from SARS-CoV and SARS-CoV-2, e.g., SARS-CoV and SARS-CoV-2, including the causative strain of COVID-19 and variants thereof.

[0281] According to some embodiments, the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention is used in a method for treating or preventing a Coronaviridae infection, wherein levels of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in a patient's blood, plasma, tissue, saliva, pharynx, trachea, bronchoalveolar, and / or serum sample are measured during said use.

[0282] cancer An ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention may be useful in the treatment and / or prevention of various cancers.

[0283] As used herein, the term "cancer," unless otherwise stated, may relate to any disorder associated with abnormal cell proliferation, and thus includes malignant and benign tumors, metastatic and non-metastatic tumors, solid and non-solid tumors, such as blood-related cancers, which may include leukemia, lymphoma, and myeloma; it may relate to central nervous system (CNS) and non-CNS cancers. Unless otherwise stated, the term "cancer" also includes juvenile cancers, non-juvenile cancers, recurrent and non-recurrent cancers, and recurrent cancers.

[0284] Among the cancers, the following may be mentioned: blood-related cancer, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, thyroid cancer, gallbladder cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, hemangiopericytoma, Kaposi's sarcoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, carcinoma of the adrenal cortex, or ACTH-producing tumors.

[0285] According to one embodiment, the following cancers may be mentioned: head and neck cancer, stomach cancer, breast cancer, basal and squamous cell carcinoma, liver cancer, kidney cancer, brain cancer, lung cancer, pancreatic cancer, eye cancer, digestive cancer, colorectal cancer, esophageal cancer, colon cancer, bladder cancer, gallbladder cancer, thyroid cancer, melanoma, uterine / cervical cancer, ovarian cancer, bone cancer and kidney cancer.

[0286] According to another embodiment, the cancer is head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, adult or pediatric acute lymphocytic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), Leukemia), acute lymphocytic leukemia, adrenal cancer, anal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3 or 4), B- or NK / T-cell lymphoma, basal and squamous cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, adult brain and spinal cord tumor, pediatric brain and spinal cord tumor, anaplastic astrocytoma, breast cancer, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary, Castleman's disease, cervical cancer, cervical intraepithelial neoplasia, bile duct cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML) Myelomonocytic leukemia, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal cancer, esophageal squamous cell carcinoma, Ewing's sarcoma, Ewing's family of tumors, lymphocytic leukemia (ALL), eye cancer such as ocular melanoma and lymphoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM)multiforme), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, childhood leukemia, liver cancer, lung cancer, pulmonary carcinoid tumor, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, melanoma skin cancer, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, recurrent and metastatic nasopharyngeal cancer, neuroblastoma, glioma, non- The cancer may be selected from Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral cavity and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, ovarian cancer, pancreatic cancer, thyroid cancer, papillary thyroid cancer, childhood spinal ependymoma, penile cancer, pituitary tumor, pituitary adenoma, proneural tumor, prostate tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, tongue squamous cell carcinoma, gastric cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, kidney cancer, retinoblastoma, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0287] According to another embodiment, the cancer is head and neck squamous cell carcinoma, cervical squamous cell carcinoma, adult or pediatric acute lymphoblastic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), acute lymphoblastic leukemia, adrenal gland cancer, anal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3, 4), B- or NK / T-cell lymphoma, basement membrane and squamous cell carcinoma, bile duct cancer, bone cancer, brain tumor, adult brain and spinal cord tumor, pediatric brain and spinal cord tumor, anaplastic astrocytoma, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer, hereditary breast cancer, HER2 positive Breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary site, Castleman's disease, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal squamous cell carcinoma, Ewing's sarcoma, Ewing's family of tumors, lymphocytic leukemia (ALL), eye cancers such as ocular melanoma and lymphoma, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor GIST, gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma of the breast, Hodgkin's lymphoma, Kaposi's sarcoma, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, childhood leukemia, pulmonary carcinoid tumor, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, recurrent and metastatic nasal The cancer may be selected from oropharyngeal carcinoma, neuroblastoma, glioma, non-Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral cavity and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, thyroid cancer, papillary thyroid cancer, childhood spinal cord ependymoma, penile cancer, pituitary tumor, pituitary adenoma, proneural tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, tongue squamous cell carcinoma, testicular cancer, thymic carcinoma, uterine sarcoma, vaginal cancer, vulvar cancer, renal cancer, retinoblastoma, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0288] According to a further embodiment, the cancer is head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, malignant melanoma, gastric cancer, breast cancer, female breast cancer, young female breast cancer, basal and squamous cell carcinoma, liver cancer, brain tumor, anaplastic astrocytoma, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, eye cancer, gastric cancer, gastrointestinal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3, or 4), Colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, bladder cancer, bone cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, renal cancer, cervical intraepithelial neoplasia, bile duct cancer, leiomyosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), adult or pediatric acute myeloid leukemia (AML), acute lymphocytic leukemia Hematologic malignancies, B- or NK / T-cell lymphoma, cervical cancer, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, renal carcinoma, endometrial carcinoma, ovarian cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal cancer, esophageal squamous cell carcinoma, Ewing's sarcoma, lymphoblastic leukemia (ALL), mantle cell lymphoma, medulloblastoma The cancer may be selected from lymphoma, myelodysplastic syndrome, meningioma, multiple myeloma (MM), multiple myeloma with osteonecrosis of the jaw, nasopharyngeal carcinoma, recurrent and metastatic nasopharyngeal carcinoma, neuroblastoma, glioma, papillary thyroid carcinoma, pediatric spinal ependymoma, osteosarcoma, pulmonary metastatic osteosarcoma, pancreatic cancer, thyroid cancer, sarcoma, pituitary tumor, pituitary adenoma, proneural tumor, tongue squamous cell carcinoma, mesothelioma, retinoblastoma, and prostate cancer.

[0289] According to further embodiments, the cancer may be selected from head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, malignant melanoma, astroglioma, glioma, gastric cancer, breast cancer, cholangiocarcinoma, recurrent or metastatic nasopharyngeal carcinoma, basal and squamous skin cell carcinoma, liver cancer, brain tumor, anaplastic astrocytoma, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, glioblastoma, osteosarcoma, pulmonary metastatic osteosarcoma, pancreatic cancer, eye cancer, gastrointestinal cancer, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, hepatocellular carcinoma, HER2-positive breast cancer, bladder cancer, bone cancer, prostate cancer, retinoblastoma, and kidney cancer.

[0290] According to further embodiments, the cancer may be selected from anaplastic astrocytoma, astrocytic glioma, bladder cancer, breast cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, gefitinib-resistant non-small cell lung cancer, glioblastoma, glioma, hepatocellular carcinoma, HER2-positive breast cancer, head and neck squamous cell carcinoma, malignant melanoma, nasopharyngeal carcinoma (recurrent or metastatic), neck squamous cell carcinoma, non-small cell lung cancer, oral cancer, osteosarcoma, osteosarcoma (lung metastasis), prostate cancer, and retinoblastoma.

[0291] According to further embodiments, the cancer may be selected from anal cancer, bile duct cancer, gastrointestinal cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, esophageal cancer, esophageal squamous cell carcinoma, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, lung cancer, pulmonary carcinoid tumor, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, pulmonary metastatic osteosarcoma, gastric cancer, pancreatic cancer, small cell lung cancer, and small intestine cancer.

[0292] According to one embodiment, the patient does not present with clinically detectable metastases, in particular the patient has a pre-cancerous condition, early stage cancer or non-metastatic cancer, or the patient presents with clinically detectable metastases and the ASD as defined in the present invention does not directly target metastatic invasion.

[0293] In view of the above, the present invention relates herein to an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use in the treatment and / or prevention of cancer, such as the cancers mentioned above, and of dysplasia.

[0294] Therefore, the present invention also relates to the use of an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for treating and / or preventing cancer, such as the cancers mentioned herein above, and dysplasia.

[0295] The present invention also relates to the use of an ASD as defined in the present invention for the preparation of a composition, such as a medicament, for the treatment and / or prevention of cancer, such as the cancers mentioned herein above, and dysplasia, etc.

[0296] The present invention also relates to a method for preventing, inhibiting or treating cancer or dysplasia, which method comprises at least one step consisting of administering to a patient suffering therefrom an effective amount of an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention.

[0297] In some embodiments, the present invention relates to a method of the present invention or an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use as defined above for treating and / or preventing cancer or dysplasia, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples of the patient is measured before and / or during said use.

[0298] In some embodiments, the present invention relates to a method of the present invention or an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein the presence and / or expression levels of miR-124 in blood and / or tissue samples are measured to guide the dose or monitor the response to said treatment.

[0299] In some embodiments, the present invention relates to the method of the present invention or the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in blood, plasma, tissue, saliva, and / or serum samples of the patient is measured during said use.

[0300] In some embodiments, the present invention relates to the method of the present invention or the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein they are used in combination with another anti-tumor agent.

[0301] In some embodiments, the present invention relates to the method of the present invention or the ASD as defined in the present invention or the pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein it is used in combination with another therapy selected from chemotherapy, immunotherapy, radiation therapy, surgery, ultrasound, monoclonal antibodies, and cancer vaccines.

[0302] Among other anticancer drugs, mention may be made of: androgen receptor inhibitors, such as enzalutamide (Xtandi®, Astellas / Medivation), abiraterone (Zytiga®, Centocor / Ortho), antagonists of the gonadotropin-releasing hormone (GnRH) receptor, such as degalarix, Firmagon®, Fering Pharmaceuticals; anti-apoptotic agents, such as venetoclax (Venclexta®, AbbVie / Genentech), blinatumomab (Blincyto®, Amgen), navitoclax (ABT-263, Abbott); Antiproliferative and anti-inflammatory agents, such as vinca alkaloids (which include vinblastine, vincristine); Antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; L-asparaginase; antiplatelet agents; Antiproliferative / antibacterial alkylating agents, such as the nitrogen mustard cyclophosphamide and analogs (which include melphalan, chlorambucil, hexamethylmelamine, and thiotepa), alkylnitrosoureas (which include carmustine) and analogs, streptozocin, and triazenes (which include dacarbazine); Antiproliferative / antimitotic antimetabolites, such as folic acid analogues (which include methotrexate), aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / decrease protein or lipid kinase activity, as well as anti-angiogenic compounds; compounds that target, decrease or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine amine peptide enzyme inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Conforma Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer; Anti-fatigue agent; angiogenesis inhibitors, such as TNP-470; Aromatase inhibitors such as letrozole and anastrozole, exemestane; angiotensin; antisense oligonucleotides, e.g., antisense nucleic acids directed against miR124; anticoagulants, such as heparin, synthetic heparin salts, and other thrombin inhibitors; arginine inhibitors, such as AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics) and CB-1158 (Calithera Biosciences); Bone resorption inhibitors, such as Denosumab (Xgeva®, Amgen), bisphosphonates, such as Zoledronic acid (Zometa®, Novartis); CC chemokine receptor 4 (CCR4) inhibitors, such as mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan); CDK inhibitors, such as palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and CDK4 / CDK6 inhibitors such as trilaciclib (G1T28, G1 Therapeutics); Cell cycle inhibitors and differentiation inducers, such as tretinoin; Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone; DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mercuroretamine, mitomycin, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophene phosphamide; Fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; folate antagonists; FLT3 receptor inhibitors, such as enzalutamide, abiraterone, apalutamide, erlotinib, crizotinib, niraparib, olaparib, osimertinib, regorafenib, sunitinib, lestaurtinib, midostaurin, gilteritinib, semaxinib, linifanib, fostamatinib, pexidartinib, sorafenib, cabozantinib, ponatinib, irolasteltib, pacritinib, famitinib, pexidartinib, and quizartinib; glutaminase inhibitors, such as CD-839 (Calithera Biosciences); growth factor signaling kinase inhibitors; Growth factor inhibitors, such as vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors, such as olaratumab (Lartruvo®; Eli Lilly), cetuximab (Erbitux®, Eli Lilly), necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); hedgehog pathway inhibitors, such as sonidegib (Odomzo®, Sun Pharmaceuticals), and vismodegib (Erivedge®, Genentech); Histone deacetylase (HDAC) inhibitors, such as vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); velinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China); Hormones and their analogues, such as estrogen, tamoxifen, goserelin, bicalutamide, nilutamide; Isocitrate dehydrogenase (IDH) inhibitors, such as AG120 (Celgene, NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010); Isoflavones such as genistein; immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate; inhibitors of p53 suppressor proteins, such as ALRN-6924 (Aileron); inhibitors of transforming growth factor β (TGF-β or TGFβ), such as NIS793 (Novartis), fresolimumab (GC1008; Sanofi-Genzyme), M7824 (Merck KgaA—formerly MSB0011459X); iNKT cell agonists, e.g., ABX196 (Abivax) mTOR inhibitors, such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer); Microtubule inhibitors, such as taxanes (which include paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotoxins (etoposide, teniposide); Nitric oxide donor; Nucleoside inhibitors, such as trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology); mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource) Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesacinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme for asparagine depletion, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based anti-atherogenic agent, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based anti-atherogenic agent, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based agent, Ixempra®, Bristol-Myers Squibb);Nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); chlorafavine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleic acid analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Pharmaceutical); PI3K inhibitors, such as idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pitilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics); Platinum coordination complexes (e.g., cisplatin, oxiloplatin, carboplatin, nedaplatin, picoplatin, procarbazine, mitotane, satraplatin, and aminoglutethimide); Poly(ADB) ribose polymerase (PARP) inhibitors, such as those selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); velivalib (ABT-888, AbbVie); and BGB-290 (BeyGene, Inc); Proteasome inhibitors, such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer), bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda); pyrimidine and purine analogues such as floxuridine, capecitabine, and cytarabine; Receptor antagonists, secretion inhibitors, such as breviridin; Selective estrogen receptor modulators (SERMs), such as raloxifene (Evista®, Eli Lilly); Therapeutic antibodies, for example selected from: anti-TNF antibodies, anti-VEGF antibodies, anti-EGFR antibodies, anti-PD-1 antibodies, anti-HER2 antibodies, anti-CD20 antibodies, anti-IL17 antibodies, and anti-CTLA4 antibodies, anti-PDL1, anti-CD25, anti-α4 integrin, anti-IL6R, anti-C5, anti-IL 1. Anti-TPO, anti-IL12 / 23, anti-EPCAM / CD3, anti-CD30, anti-CD80 / 86, anti-anthrax, anti-CCR4, anti-CD6, anti-CD19, anti-α4β7, anti-IL6, anti-VEGFR-2, anti-SLAMF7, anti-GD2, anti-IL17A, anti-PCSK9, anti-IL5, anti-CD 22, anti-IL4, anti-PDGFRα, anti-IL17RA and anti-TcdB, and for example those selected from the following: abagovomab, abatacept, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumab, aducanumab, aflibercept, afutuji Afutuzymab, Alacizumab, Alefacept, Alemtuzumab, Alirocumab, Altumomab, Amatixumab, Anatumomab, Anetumab, Anifromumab, Anrukinzumab, Apolizumab, Arcitumomab ab), Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Altizumab, Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Begelomab, Belatacept,Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bimekizumab, Bivatuzumab, Blinatumomab, Blosozumab, Bococizumab Bococizumab, Brentuximab, Briakimumab, Brodalumab, Brolucizumab, Bronticizumab, Canakinumab, Cantuzumab, Caplacizumab, Capromab, Carlumab, Catumaxomab, Cedelizumab zumab, certolizumab, cetixumab, sitatuzumab, cixutumumab, clazakizumab, clenoliximab, clivatuzumab, codrituzumab, coltuximab, conatumumab, concizumab, crenezumab zumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab, daratumumab, dectrekumab, demcizumab, denintuzumab, denosumab, derlotixumab, detumomab, dinutuximab,Diridavumab, Dorlinomab, Drozitumab, Dupilumab, Durvalumab, Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelu mab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emibetuzumab, Enavatuzumab, Enfortumab, Enlimomab, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab mab, epitumomab, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab b), Farletuzumab, Fasinumab, Felvizumab, Fezkimumab, Ficlatuzumab, Figitumumab, Filivumab, Flanvotumab, Fletikumab, Fontolizumab, Foralumab, Foravirumab,Fresolimumab, Fulramumab, Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumab, Gevokizumab, Girentuximab, Glembatumumab, Golim ... Omiliximab, Guselkumab, Ibalizumab, Ibritumomab, Icrucumab, Idarucizumab, Igovomab, Imalumab, Imciromab, Imgatuzumab, Inclacumab, Indatuximab, Indusatumab, Infu Infliximab, Intetumumab, Inolimomab, Inotuzumab, Ipilimumab, Iratumumab, Isatuximab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab, Lampalizumab izumab, lebrikizumab, lemaresomab, lenzilumab, lerdelimumab, lexatumumab, ribivirumab, rifastuzumab, ligelizumab, rilotomab, lintuzumab, lirilumab, rodelizumab,Lokivetmab, Lorvotuzumab, Lucatumumab, Lulizumab, Lumiliximab, Lumretuzumab, Mapatumumab, Margetuximab, Maslimomab, Mavrilimumab, Matuzumab, Mepolizumab, Metelim Metelimumab, Milatuzumab, Minetumomab, Mirvetuximab, Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, Moxetumomab, Muromonab-CD3, Nacolomab, Namilumab, Naptumomab Naptumomab, Narnatumab, Natalizumab, Nebacumab, Necitumumab, Nemolizumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab, Obiltoxaximab, Obinutuzumab umab), Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Opicinumab, Oportuzumab, Oregovomab,Orticumab, Otelixizumab, Oltertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Panitumumab, Pancomab, Panobacumab, Parsatuzumab, Pascoli Pascolizumab, Pasotuxizumab, Pateclizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab, Pintumomab, Po Polatuzumab, Ponezumab, Priliximab, Pritumumab, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab, Raxibacumab, Refanezumab Refanezumab, Regavirumab, Reslizumab, Rilonacept, Rilotumumab, Linucumab, Rituximab, Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovelizumab, Ruplizumab,Sacituzumab, Samalizumab, Sarilumab, Satumomab, Secukimumab, Seribantumab, Setoxaximab, Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Siplizumab, Sirukumab, Sofituzumab, Solanezumab ab), solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab, tadocizumab, talizumab, tanezumab, taplitumomab, tarextumab, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, tesidolumab, TGN 1412, Ticlimumab, Tildrakizumab, Tigatuzumab, TNX-650, Tocilizumab, Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab,Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekimumab, Vandortuzumab, Vantictumab, Vanucizumab, Vapaliximab, Varlilumab, Vulvoxamic acid globulin (VVU) Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volocixumab, Vorsetuzumab, Votumumab, Zalutumimab, Zanolimumab, Zatuximab, Zatuximab, Ziralimumab, Ziv-Aflibercept, and Zolimomab; Topoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, and irinotecan; Toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; Kinase or VEGF inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx; dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, Bristol-Myers Squibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals; Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigutinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors such as cabozantinib (Cometriq®, Exelexis); and multikinase inhibitors such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors such as crizotinib (Xalkori®, Pfizer);Ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis), tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lusitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang) Pharmaceuticals, Republic of Korea; ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda);

[0303] In a non-limiting manner, the ASD of the present invention may be combined, alone or in the form of a kit of parts, with one or more of the following anti-cancer drugs or compounds: ABVD, AC, ACE, Abiraterone (Zytiga®), Abraxane, Abstral, Actinomycin D D), Actiq, Adriamycin, Afatinib (Giotrif®), Afinitor, Aflibercept (Zaltrap®), Aldara, Aldesleukin (IL-2, Proleukin or Interleukin 2), Alemtuzumab (MabCampath), Alkeran, Amsacrine (Amsidine, m-AMSA), Amsidine, Anastrozole (Arimidex®), Ara C, Aredia, Arimidex, Aromasin, arsenic trioxide (Trisenox®, ATO), asparaginase (Crisantaspase®, Erwinase®), axitinib (Inlyta®), azacitidine (Vidaza®), BEACOPP, BEAM, bendamustine (Levact®), bevacizumab Bevacizumab (Avastin), Bexarotene (Targretin®), Bicalutamide (Casodex®), Bleomycin, Etoposide and Platinum (BEP), Bortezomib (Velcade®), Bosulif, Bosutinib (Bosulif),Brentuximab (Adcetris®), Brufen, Buserelin (Suprefact®), Busilvex, Busulfan (Myleran, Busilvex), CAPE-OX, CAPOX, CAV, CAVE, CCNU, CHOP, CMF, CMV, CVP, Cabazitaxel (Jevtana®), Cabozantinib (Cometriq®), Caelyx, Calpol, Campto, Capecitabine (Xeloda®), Caprelsa, CarboMV MV), CarboTaxol, Carboplatin, Carboplatin and etoposide, Carboplatin and paclitaxel paclitaxel, Carmustine (BCNU, Gliadel®), Casodex, Ceritinib (Zykadia®), Cerubidin, Cetuximab (Erbitux®), ChlVPP, Chlorambucil (Leukeran®), Cisplatin, Cisplatin and Teysuno, Cisplatin and capecitabine (CX), Cisplatin, etoposide and ifosfamide ifosfamide (PEI), cisplatin, fluorouracil (5-FU) and trastuzumab, cladribine (Leustat®, LITAK), Clasteon,Clofarabine (Evoltra®), Co-codamol (Kapake®, Solpadol®, Tylex®), Cometriq, Cosmegen, Crisantaspase, Crizotinib (Xalkori®), Cyclophosphamide, Thalidomide and Dexamethasone (CTD), Cyprostat, Cyproterone acetate (Cyprostat®), Cytarabine (Ara C, cytosine arabinoside), Cytarabine in the cerebrospinal fluid, Cytosine arabinoside arabinoside, DHAP, DTIC, Dabrafenib (Tafinlar®), Dacarbazine (DTIC), Dacogen, Dactinomycin (actinomycin D, Cosmegen®), Dasatinib (Sprycel), Daunorubicin, De Gramont, Decapeptyl SR SR), Decitabine (Dacogen®), Degarelix (Firmagon®), Denosumab (Prolia®, Xgeva®), Depocyte, Dexamethasone, Diamorphine, Disodium pamidronate, Disprol, Docetaxel (Taxotere®), Docetaxel, Cisplatin and Fluorouracil (TPF), Doxifos, Doxil,Doxorubicin (Adriamycin), Doxorubicin and Ifosfamide, Doxifos, Drogenil, Durogesic, EC, ECF, EOF, EOX, EP, ESHAP, Effentora, Efudix, Eldisine, Eloxatin, Enzalutamide mide), Epirubicin (Pharmorubicin®), Epirubicin, cisplatin and capecitabine (ECX), Epirubicin, carboplatin and capecitabine (ECarboX), Eposin, Erbitux, Eribulin (Halaven®), Erlotinib (Tarceva®), Erwinase, Est Estracyt, Etopophos, Etoposide (Eposin®, Etopophos®, Vepesid®), Everolimus (Afinitor®), Evoltra, Exemestane (Aromasin®), FAD, FEC, FEC-T chemotherapy, FMD, FOLFIRINOX, FOLFOX, Fenix Faslodex, Femara, Fentanyl, Firmagon, Fludara, Fludarabine (Fludara®), Fludarabine, cyclophosphamide and rituximab (FCR), Fluorouracil (5FU), Flutamide, Folinic acid,Fluorouracil and irinotecan (FOLFIRI), Fulvestrant (faslodex®), G-CSF, gefitinib (Iressa), GemCarbo (gemcitabine and carboplatin), GemTaxol, gemcitabine (Gemzar), gemcitabine and capecitabine (GemCap), gemcitabine (Gemcita bine and cisplatin (GC), gemcitabine and paclitaxel (GemTaxol®), Gemzar, Giotrif, Gliadel, Glivec, Gonapeptyl, Depot, goserelin (Zoladex®), goserelin (Zoladex®, Novgos®), granulocyte colony-stimulating factor (GNF) colony stimulating factor (G-CSF), Halaven, Herceptin, Hycamtin, Hydrea, Hydroxycarbamide (Hydrea®), Hydroxyurea, I-DEX, ICE, IL-2, IPE, Ibandronic acid, Ibritumomab (Zevalin®), Ibrutinib (Imbruvica®), Ibuprofen (Brufen®, Nurofen®), Iclusig, Idarubicin (Zavedos®),Idarubicin and dexamethasone, Idelalisib (Zydelig®), Ifosfamide (Mitoxana®), Imatinib (Glivec®), Imiquimod cream (Aldara®), Imnovid, Instanyl, Interferon (Intron A), Interleukin (Intron A), A), ipilimumab (Yervoy®), Iressa, irinotecan (Campto®), irinotecan and capecitabine (Xeliri®), irinotecan de Gramont, irinotecan modified degramont Gramont, Javlor, Jevtana, Kadcyla, Kapake, Keytruda, Lanreotide (Somatuline®), Lanvis, Lapatinib (Tyverb®), Lenalidomide (Revlimid®), Letrozole (Femara®), Leukeran, Leuprorelin (Prostap®, Lutrate®), Leustat, Levact, Liposomal doxorubicin doxorubicin, Litak, Lomustine (CCNU), Lynparza, Lysodren, MIC, MMM, MPT, MST Continus, MVAC, MVP, MabCampath,Mabthera, Maxtrex, Medroxyprogesterone acetate (Provera), Megace, Megestrol acetate (Megace®), Melphalan (Alkeran®), Mepact, Mercaptopurine (Xaluprine®), Methotrexate (Maxtrex), Methyl prednisolone, Mifamurtide (Mepact®), Mitomycin C C), Mitotane, Mitoxana, Mitoxantrone (Mitozantrone®), Morphgesic SR, Morphine, Myleran, Myocet, Nab-paclitaxel, Nab-paclitaxel (Abraxane®), Navelbine, Nelarabine (Atriance®), Nexavar, Nilotinib (Tasigna®), Nintedanib (Vargatef®), Nipent ( Nipent, Nivolumab (Opdivo®), Novgos, Nurofen, Obinutuzumab (Gazyvaro®), Octreotide, Ofatumumab (Arzerra®), Olaparib (Lynparza®), Oncovin, Onkotrone, Opdivo, Oramorph,Oxaliplatin (Eloxatin), Oxaliplatin and capecitabine (Xelox®), PAD, PC (paclitaxel and carboplatin, CarboTaxol), PCV, PE, PMitCEBO, POMB / ACE, Paclitaxel (Taxol®), Paclitaxel and CarboTaxol Carboplatin, Pamidronate, Panadol, Panitumumab (Vectibix®), Paracetamol, Pazopanib (Votrient®), Pembrolizumab (Keytruda), Pemetrexed (Alimta®), Pemetrexed, and Carboplatin (carboplatin), pemetrexed and cisplatin, pentostatin (Nipent®), Perjeta, pertuzumab (Perjeta®), pixantrone (Pixuvri®), (Registered Trademark), Pixuvri, Pomalidomide (Imnovid®), Ponatinib, Potactasol, Prednisolone, Procarbazine, Proleukin, Prolia, Prostap, Provera, Purinethol, R-CHOP, R-CVP, R-DHAP, R-ESHAP, R-GCVP, RICE, raloxifene, raltitrexed (Tomudex®), regorafenib (Stivarga®), Revlimid, rituximab (Mabthera®), Sevredol, sodium clodronate clodronate (Bonefos®, Clasteon®, Loron®), Solpadol, sorafenib (Nexavar®), steroids (dexamethasone, prednisolone, methylprednisolone), streptozocin zocin (Zanosar®), Sunitinib (Sutent®), Sutent, TAC, TIP, Tafinlar, Tamoxifen, Tarceva, Targretin, Tasigna, Taxol, Taxotere, Taxotere and cyclophosphamidecyclophosphamide (TC), Temodal, Temozolomide (Temodal®), Temsirolimus (Torisel®), Tepadina, Teysuno, Thalidomide, Thiotepa (Tepadina®), Thioguanine (R), 6-TG, 6-thioguanine, Tomudex, Topotecan (Hycamtin, Potactasol), Torisel, Trabectedin (Yondelis), Trastuzumab (Herceptin®), Trastuzumab emtansine (Kadcyla®), Treosulfan, Tretinoin (Vesanoid®, ATRA), Triptorelin (Decapeptyl SR®, Gonapeptyl Depot®), Trisenox, Tylex, Tyverb, VIDE, vandetanib (Caprelsa®), Vargatef, VeIP, Vectibix, Velbe, Velcade, vemurafenib (Zelboraf®), Vepesid, Vesanoid, Vidaza, vinblastine (Velbe®), vincristine, actinomycin DD) (dactinomycin®) and cyclophosphamide (VAC), vincristine, actinomycin and ifosfamide (VAI), vincristine, doxorubicin and dexamethasone (VAD), vindesine (Eldisine®), vinflunine (Javlor®), vinorelbine (Navelbine®), vismodegib (Erivedge®), Votrient, XELOX, Xalkori, Zero Xeloda, Xgeva, Xtandi, Yervoy, Yondelis, Z-DEX, Zaltrap, Zanosar, Zavedos, Zelboraf, Zevalin, Zoladex (breast cancer), Zoladex (prostate cancer), zoledronic acid (Zometa®), Zometa, Zomorph, Zydelig, Zytiga.

[0304] According to certain embodiments, ASD can be combined with various chemotherapy, immunotherapy (e.g., checkpoint inhibitors, monoclonal antibodies), anti-tumor vaccines, RNA vaccines, magnetic particles, intravascular microrobots, radiation therapy, surgery, ultrasound, or other anti-tumor treatments, as described herein.

[0305] Thus, the present invention further provides an ASD as defined in the present invention or a pharmaceutical composition as defined in the present invention for use as an antitumor agent intended for patients who are also treated with any of immunotherapy, antitumor vaccines, RNA vaccines, radiation therapy, surgery, ultrasound therapy or other antitumor therapies.

[0306] According to one embodiment, the present invention relates to the ASD for the use as defined above or the pharmaceutical composition for the use as defined above, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in a blood, plasma, tissue, saliva and / or serum sample of the patient is measured during the use.

[0307] According to another embodiment, the present invention also relates to said ASD or said pharmaceutical composition for use as defined above, wherein said use is intended for a patient in which the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in a blood, plasma, tissue, saliva, and / or serum sample of said patient is measured during said use.

[0308] According to yet another embodiment, the present invention also relates to said ASD for the use as defined above or said pharmaceutical composition for the use as defined above, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples of said patient is measured before and / or during said use, in particular to monitor the effectiveness of and / or response to said use.

[0309] The present invention will now be described in more detail with reference to the following examples, which are provided to illustrate the present invention and should not be construed as limiting the scope and spirit of the present invention.

[0310] Example As used herein, the symbol "~" means approximately.

[0311] raw material The materials and equipment used in this disclosure are listed in Table 1 below.

[0312] [Table 1]

[0313] Example 1: Preparation of ASD according to the present invention Two batches of amorphous solid dispersions were prepared by spray-drying using a 4M8 Trix spray dryer (ProCepT, Belgium) equipped with a two-fluid nozzle. The list of parameters applied to the spray dryer is summarized in Table 2 below.

[0314] [Table 2]

[0315] First, 1.4 g of ABX464 was dissolved in 50 mL of MeOH, followed by filtration through a 0.22 μm PVDF filter membrane (Stericup Quick Release, Durapore). Then, 2.6 g of polymer (Kollidon® VA64 or Kollidon® K30, BASF) was weighed and added to the ABX464 solution. The total solids content (ABX464 and polymer) in the spray-drying solution was maintained at approximately 8% w / w. The mixture was kept under stirring until a homogeneous solution was obtained. The solution was fed into the spray dryer at a flow rate of 3 mL / min using a peristaltic pump. The solution was then spray-dried. The spray-drying solution used for the preparation of the feasibility batch was prepared with an ABX464:polymer ratio of 35:65 w / w.

[0316] A fine white powder was obtained after spray-drying. Approximately 80% yield was obtained for the produced SDDs (78.5% ABX464:Kollidon® VA64 (also designated herein as ABX464:VA64) and 80.9% ABX464:Kollidon® K30 (also designated herein as ABX464:K30)).

[0317] Example 2: Characterization of ASD according to the present invention Example 2.1: UV-HPLC (Ultraviolet-High Performance Liquid Chromatography) The UV-HPLC method used for the analysis of ABX464 is detailed in Table 3a below. For each HPLC run, two standard solutions (A and B) were prepared at 0.1 mg / mL in diluent (ACN:HO (50:50)).

[0318] Approximately 2.5 mg of ABX464 (API) was accurately weighed into a 25 mL volumetric flask. The volume was adjusted with diluent, and the standard was sonicated at ambient temperature for 15 minutes to ensure complete dissolution of the API. The solution was then filtered through a 0.2 μm PTFE syringe filter (13 mm diameter) and transferred into an amber glass vial in preparation for HPLC analysis. Two blank samples (diluent) were injected first to ensure an acceptable baseline and no interfering peaks eluted. This was followed by five injections of Standard A and two injections of Standard B. (System Suitability Test (SST) results are given in Table 3b below.)

[0319] [Table 3a]

[0320] [Table 3b]

[0321] Standard repeatability The average main peak area and % relative standard deviation (%RSD) were calculated for both standards to assess the precision of the system. The %RSD of the main peak of API in Standard Solution A should be <2.0%.

[0322] Standard agreement The standard agreement ratio of the response factor between standard solution A and standard solution B must be between 0.98 and 1.02, and was calculated using the following formula:

[0323]

number

[0324] Here, Area A (area A ) and Area B (area B ) are the average areas under the API peaks of standard solution A and standard solution B, respectively, and Conc A (concentration A ) and Conc B (concentration B ) are the concentrations of API in standard solution A and standard solution B, respectively.

[0325] UV-HPLC results: As expected, the UV-HPLC assay confirmed that both SDDs maintained approximately 35 wt. % drug loading after spray-drying (t=0 h) (see Table 4 below), resulting in approximately 65 wt. % of the pharmaceutically acceptable carrier (here, povidone or copovidone) relative to the total weight of ABX464 and the pharmaceutically acceptable carrier.

[0326] [Table 4]

[0327] Example 2.2: X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC) analysis XRPD X-ray powder diffraction (XRPD) analysis of the supplied API materials and SDD was performed using a Bruker D8 Advance powder diffractometer equipped with a Lynx Eye detector. Samples (approximately 5 mg) were placed in the center of a silicon sample holder. The samples were scanned from 2° to 40° 2θ using a step size of 0.04° 2θ. Data were analyzed using DIFFRAC. plus It was processed using EVA software, and the detailed parameters are summarized in Table 5 below.

[0328] [Table 5]

[0329] mDSC analysis Modulated differential scanning calorimetry (mDSC) was used to study the thermal behavior of the supplied API and SDD using a Q200 calorimeter (TA Instruments, USA). An inert atmosphere was maintained in the chamber by purging nitrogen at 50 mL / min. Approximately 2-5 mg of the sample was weighed into a sealed aluminum pan, equilibrated at 0°C, and after 5 minutes of isothermal heating, heated to 160°C at 5°C / min. A 40-second modulation period with a temperature amplitude of 1°C was applied. Data were processed using Universal Analysis 2000 software.

[0330] XRPD and mDSC results Immediately after preparation (t=0 h), both SDDs were confirmed to be amorphous with physical form determination by XRPD (FIG. 3) and mDSC (FIGS. 4 and 5).

[0331] FIG. 3 also includes an XRPD diagram of ABX464 in its native crystalline form, with the aim of demonstrating the amorphous forms of both SDDs.

[0332] Furthermore, mDSC analysis of both SDDs revealed that the T g One T different from gOnly the melting peak of ABX464 (present at about 120°C for ABX464) was observed. These observations suggested the formation of a good homogeneous dispersion of the ABX464 in both polymer matrices (sign of phase separation, i.e., a single T g However, the T obtained with both SDDs g It is possible to observe a difference of about 92°C for ABX464:VA64 (Figure 5) and about 135°C for ABX464:K30 (Figure 4).

[0333] These results therefore demonstrate that the ASD according to the invention is in amorphous form and forms a homogeneous dispersion of ABX464 in the polymer matrix.

[0334] Example 2.3: Scanning Electron Microscopy (SEM) The particle shape and surface topography of the SDD were examined by scanning electron microscopy (SEM). Approximately 1-2 mg of sample was mounted on an aluminum stub using conductive double-sided carbon adhesive tape, sputter-coated with 10 nm of gold in a Quorum Q150ES sputter coater (Quorum Technologies Ltd, UK), and photographed using a Tescan Vega3 scanning electron microscope (Tescan Bruno, Czech Republic). Details of magnification and beam voltage are included with the scanning electron micrographs in this report.

[0335] SEM results Immediately after preparation (t = 0 h), ABX464:VA64 and ABX464:K30 SDDs were evaluated by SEM to observe the particle morphology after the spray-drying process. Figures 2a, 2b, 2c, and 2d show the slightly different morphologies of both SDDs. At the highest magnification used (10 kx, Figures 2a and 2c), it can be observed that ABX464:VA64 SDDs exhibit spherical particles, while ABX464:K30 SDDs consist of more irregularly shaped particles. In terms of particle size, it can be observed that both SDDs have similar sizes, although ABX464:VA64 particles appear slightly larger (compared to ABX464:K30 SDDs) due to the observed higher degree of aggregation of these particles.

[0336] The morphology of the particles was also evaluated by SEM (see Figures 1a and 1b) to compare with that of ABX464 with its inherent crystalline morphology. These figures show lamellar particles with large particle sizes in the range of 50-200 μm.

[0337] Example 2.4: Thermogravimetric Analysis (TGA) Thermogravimetric analysis was used to quantify residual water / solvent levels. A simultaneous derivative technique was used (SDT, Q500 TA Instrument), which is capable of simultaneously providing TGA and DSC signals. Approximately 5-10 mg of raw material was weighed into an alumina pan and introduced into the instrument at room temperature under nitrogen at a flow rate of 60 mL / min. The sample was then heated to 350°C at a rate of 10°C / min, and the sample weight was recorded. Data were processed using Universal Analysis 2000 software.

[0338] TGA results Immediately after preparation (t=0 h), the SDD was analyzed by TGA to determine solvent loss.

[0339] The TGA thermogram (Figure 6) shows higher solvent loss in ABX464:K30 SDD (2.3%) compared to ABX464:VA64 SDD (1.0%).

[0340] Example 3: Two-Step Dissolution / Precipitation Fasted and Fed Human In Vitro Models The unique crystalline forms of ABX464 and ABX464:VA64 ASD (prepared according to Example 1 above) were tested using both Fasted and Fed Human in vitro models (designated the FaSSIF and FeSSIF models, respectively), which simulate the fasted and fed gastrointestinal fluids, respectively, for dissolution testing.

[0341] For the fasted in vitro model, 11.4 mg of ABX464:VA64 ASD (equivalent to 4.0 mg of ABX464) was weighed into six separate vials. To each vial, 1 ml of FaSSGF pH 1.2 solution preheated to 37°C was added. The suspensions were then vortexed at 37°C. After vortexing for 15 minutes, the suspension from the first vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter, ref. SLCR0.13NK) for HPLC-UV analysis of the supernatant. After vortexing for 30 minutes, the suspension from the second vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter, ref. SLCR0.13NK) for HPLC-UV analysis of the supernatant.

[0342] After vortexing for 30 minutes, 1 ml of FaSSIF x2 pH 6.5 / sodium bicarbonate 90 / 10 v / v preheated to 37°C was added to the other four vials. The suspensions were then vortexed at 37°C. After vortexing for 15 minutes, the suspension in the third vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After vortexing for 30 minutes, the suspension in the fourth vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After 60 min of vortexing, the suspension from the fifth vial was centrifuged at 18000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After 120 min of vortexing, the suspension from the sixth vial was centrifuged at 18000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant.

[0343] For the in vitro fed model, 11.4 mg of ABX464:VA64 ASD (4.0 mg equivalent of ABX464) was weighed into seven separate vials. To each vial, 1 ml of FeSSGF pH 3.0 solution preheated to 37°C was added. The suspensions were then vortexed at 37°C. After vortexing for 15 min, the suspension in the first vial was centrifuged at 18,000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV analysis of the supernatant. After vortexing for 30 min, the suspension in the second vial was centrifuged at 18,000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV analysis of the supernatant. After vortexing for 60 min, the suspension of the third vial was centrifuged at 18000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant.

[0344] After vortexing for 60 minutes, 0.5 ml of FeSSIF x3 pH 5.0 preheated to 37°C was added to the other four vials. The suspensions were then vortexed at 37°C. After vortexing for 15 minutes, the suspension in the fourth vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After vortexing for 30 minutes, the suspension in the fifth vial was centrifuged at 18,000 rpm for 5 minutes and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After 60 min of vortexing, the suspension from the sixth vial was centrifuged at 18,000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant. After 120 min of vortexing, the suspension from the seventh vial was centrifuged at 18,000 rpm for 5 min and filtered through a 0.45 μm filter (Millex LCR filter ref. SLCR0.13NK) for HPLC-UV administration of the supernatant.

[0345] As shown in Figures 7 and 8, ABX464:VA64 ASD exhibits higher solubility than the native crystalline form of ABX464 in both models.

[0346] Indeed, for the FASSIF model (final pH=6.5), the results show 0.230 mg / ml vs. 0.070 mg / ml for the last measurement point (FaSSGF pH 1.2 for 30 min + FaSSIF x2 pH 6.5 for 120 min / sodium bicarbonate 90 / 10 v / v) and the FESSIF model (final pH 5.0), and the results suggest 1.234 mg / ml vs. 0.508 mg / ml for the last measurement point (FeSSGF pH 3.0 for 60 min + FeSSIF x3 pH 5.0 for 120 min).

[0347] Figure 9 shows the amorphous nature of the residual ABX464:VA64 ASD in suspension at the end of both the fasted and fed human in vitro models (times 30 min + 120 min for the fasted model and 60 min + 120 min for the fed model, respectively).

[0348] Fasted gastric medium - FaSSGF pH=1.2

[0349] [Table 6]

[0350] Fasted Intestinal Media - FaSSIF pH 6.5

[0351] Composition / preparation of FaSSIF x2 (medium concentrated twice to accommodate dilution in fasting models)

[0352] [Table 7]

[0353] A mixture of 90% FaSSIF X2 (pH 6.5) + 10% sodium bicarbonate 80 g / L was prepared with the aim of keeping the pH equal to 6.5 in the intestinal compartment after dilution.

[0354] Feeding gastric medium - FeSSGF pH=3.0

[0355] [Table 8]

[0356] Feeding intestinal medium - FeSSIF pH=5.0

[0357] [Table 9]

[0358] The fed intestinal medium - FeSSIF pH=5.0 was concentrated 3 times to allow for dilution in the fed model.

[0359] Example 4: Chemical and physical stability of ABX464:VA64 ASD and ABX464:K30 ASD according to the present invention 4.1 The physical and chemical stability of ABX464:VA64 ASD and ABX464:K30 ASD has been studied by XRPD and HPLC-UV after 2 weeks under the following stress conditions: ●25℃ / 60% relative humidity ●40℃ / 75% relative humidity

[0360] For stability studies, ∼100 mg of the ABX464:VA64 ASD formulation was placed in two sealed glass vials. In one vial, saturated NaCl solution was pre-applied to the bottom of the vial to create 60% relative humidity. In the second vial, saturated NaBr solution was pre-applied to the bottom of the vial to create 75% relative humidity. The first vial was then placed in an oven controlled at 25°C for two weeks. The second vial was then placed in an oven controlled at 40°C for two weeks.

[0361] Results for ABX464:VA64 ASD and ABX464:K30 ASD The results are summarized below in Table 10. The same observations were made for each of the two ASDs tested.

[0362] [Table 10]

[0363] FIG. 10 demonstrates the amorphous nature of the ABX464:VA64 ASD formulation after 2 weeks at 25° C. / 60% RH and 40° C. / 75% RH, respectively.

[0364] FIG. 11 demonstrates the amorphous nature of the ABX464:K30 ASD formulation after 2 weeks at 25° C. / 60% RH and 40° C. / 75% RH, respectively.

[0365] Accordingly, Table 10 reports that the results of HPLC-UV analysis reveal no chemical degradation of the ABX464:VA64 ASD formulation after 2 weeks at 25°C / 60% RH and 40°C / 75% RH, respectively, and of the ABX464:K30 ASD formulation after 2 weeks at 25°C / 60% RH and 40°C / 75% RH, respectively.

[0366] These two results for each of the ABX464:VA64 ASD and ABX464:K30 ASD demonstrate the physical and chemical stability of the ABX464:VA64 and ABX464:K30 formulations after 2 weeks at 25°C / 60% RH and 40°C / 75% RH, respectively.

[0367] 4.2 The physical stability of ABX464:VA64 36 / 65 w / w ASD and ABX464:K30 36 / 65 w / w ASD has been studied by TGA after 7 days of storage under the following stress conditions: ●25℃ / 60% relative humidity ●40℃ / 75% relative humidity ●50℃ ●80℃

[0368] Sample preparation ~20 mg of powdered raw material was placed into twelve open 5 ml glass vials. The glass vials were placed individually inside a larger glass bottle sealed with a silicone seal. Two glass bottles were then placed in an oven controlled at 50°C, two other bottles in a second oven controlled at 80°C, one other bottle in a third oven controlled at 25°C and the last bottle in a fourth oven controlled at 40°C. A saturated salt solution of KCl at 80% relative humidity was added before storage in one bottle in an oven controlled at 50°C and 80°C, respectively. A saturated NaCl salt solution at 60% relative humidity was added before storage in the bottle in the oven controlled at 25°C. A saturated NaBr salt solution at 75% relative humidity was added before storage in the bottle in a controlled oven at 40°C.

[0369] The TGA results for ABX464:K30 36 / 65 w / w ASD and ABX464:PVPVA64 36 / 65 w / w ASD exposed to these stress conditions are provided below in Table 10a.

[0370] [Table 10a]

[0371] The inventors have also performed XRPD analysis to confirm that the above-tested ASDs according to the present invention remain stable in the amorphous form.

[0372] These results show that even in the presence of water and / or solvents in the ASD, the ASD according to the invention remains stable after 7 days of storage under stress conditions.

[0373] Example 5: Pharmaceutical composition in the form of a capsule according to the invention containing ABX464:COPOVIDONE ASD according to the invention (ABX464:VA64 ASD) or ABX464:POVIDONE ASD according to the invention (ABX464:K30 ASD) The following capsules were prepared with the ingredients in the respective amounts specified in Table 11 below.

[0374] [Table 11]

[0375] Such capsules could be prepared by substituting any other ASD according to the present invention for the ABX464:COPOVIDONE ASD powder.

[0376] The pharmaceutical compositions according to the present invention are useful in the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH, and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0377] Example 6: Preparation of ASD according to the invention by fast evaporation method and analytical characterization after different treatments Materials and Methods Rotavapor Buchi Buchi Rotavapor R200 + Vacuum Controller V-800 Bath temperature: 40℃ Speed ​​rate: 150rpm Vacuum degree: 150mBar (0.015Mpa)

[0378] Details of the ingredients used are summarized in Table 12 below:

[0379] [Table 12]

[0380] For methanol, DCM, PVP K30 and Kollidon® VA 64, see Table 1 above.

[0381] 6.1. Preparation Table 13 below lists nine additional prepared ASDs according to the present invention.

[0382] More particularly, Table 13 shows two binary mixtures (Preparations 1-2) and five ternary mixtures (Preparations 4-6 and 8-9).

[0383] The table shows the weight percent and weight of each component used. As set forth in the table, these ASDs contain 35 wt. % ABX464, X wt. % of a first compound (designated Additive 1), and optionally Y wt. % of a second compound (designated Additive 2), based on the total weight of the ASD.

[0384] [Table 13]

[0385] The synthesis of the ASD was carried out according to the following protocol using a fast evaporation process of an ABX464 / additive solution prepared using a volatile organic solvent (or mixture of organic solvents).

[0386] For each ABX464 / additive mixture listed in Table 13: Approximately 200 mg of ABX464 crystalline form I (see Table 13 for mass details) was weighed into a 20 ml glass cup. 5 ml of methanol was added to the glass vial and ABX464 crystalline Form I was solubilized using magnetic stirring for 15 minutes. The ABX464 methanol solution was then filtered through a 0.45 μm mesh PTFE filter. Preparation of additive solutions When a single additive is considered in an ABX464 / additive mixture: The calculated amount of selected additive was weighed into a 50 ml glass cup (see Table 13 for mass details). 40 ml of methanol (80 ml of 50 / 50 v / v methanol / dichloromethane for HPMCAs-MF) was added to the glass cup and magnetic stirring was used for 15 minutes to solubilize the selected additives. When two additives are considered in the ABX464 / additive mixture: The calculated amount of each selected additive was weighed into separate 40 ml glass cups (see Table 13 for mass details). 20 ml of methanol was added to each glass vial to solubilize the selected additives using magnetic stirring for 15 minutes. The two additive solutions were pooled in a 50 ml glass cup, and the resulting solution was homogenized using magnetic stirring for 5 min. The ABX464 solution and one or more additive solutions were pooled in a 150 ml glass balloon, and the resulting final solution was homogenized using magnetic stirring at 15°C. The solvent was then removed by rapid evaporation using a Bucchi-Rotavapor R200. The solid was then recovered at -80°C.

[0387] 6.2. Analytical characteristics after different treatments Materials and Methods X-ray powder diffraction (XRPD) Apparatus: Bruker D8-Advance diffractometer, model: Bragg-Brentano Source: CuKα1, λ = 1.5406 Å and CuKα2, λ = 1.54439 Å Generator: 35kV -40mA Detector: Lynx Eye

[0388] Thermogravimetry (TGA) Equipment:TA INSTRUMENTS:TGA Q500 Standard pan: TA 901670-901 non-hermetic Standard lid: TA 901671-901 Temperature range for measuring the mass loss associated with the desorption of absorbed or adsorbed water and / or residual solvent: 30°C to 150°C

[0389] Immediately after fast evaporation, the solids obtained for preparations 4, 5 and 9 were analyzed by XRPD and TGA.

[0390] Immediately after fast evaporation, the solids obtained for preparations 1, 2, 4, 5, 6, 8 and 9 are stored under vacuum at 40° C. for 24 hours before XRPD analysis.

[0391] Finally, after this treatment, preparations 4, 5, and 9 were also stored for 24 hours at RT in a 75% relative humidity atmosphere (~100 mg samples were placed in a sealed bottle under saturated NaCl salt solution) before XRPD, TGA, and KF (Karl Fischer titration is a classical titration method for determining trace amounts of water in samples in chemical analysis) analysis.

[0392] The inventors have performed XRPD analysis, the results of which confirm that all the ASDs tested remain in amorphous form.

[0393] The analytical characterization results obtained by XRPD, and / or TGA and / or KF are summarized in Table 14 below.

[0394] [Table 14]

[0395] Conclusion: Immediately after fast evaporation, the solids obtained for preparations 4, 5, and 9 were found to be amorphous by XRPD and to have ∼5–8 wt % residual solvent and / or water as measured by TGA, as shown in Figures 14, 15, and 18, respectively (not shown).

[0396] After 24 hours of storage at 40°C under vacuum: The solids obtained for preparations 4, 5, and 9 were found to be amorphous by XRPD and to have ∼2-3 wt% residual solvent and / or water as measured by TGA, as shown in Figures 14, 15, and 18, respectively (not shown). The solids obtained for preparations 1, 2, 6 and 8 were found to be in amorphous form by XRPD as shown in Figures 12, 13, 16 and 17, respectively.

[0397] Storage under vacuum at 40°C for 24 hours, then storage at RT under 75% RH for 24 hours: The solids obtained for preparations 4, 5, and 9 were found to be amorphous by XRPD, have ∼3-9 wt% residual solvent and / or water as measured by TGA (not shown), and have 4-7 wt% water as measured by KF, as shown in Figures 14, 15, and 18.

[0398] These results support the synthesis of ABX464 amorphous solid dispersions of seven ABX464 / additive formulations produced by a fast evaporation process and their physical stability (>24 hours) in the presence of residual organic solvent and / or absorbed water.

[0399] Example 7: Pharmaceutical composition in the form of a tablet according to the invention containing ABX464:copovidone ASD (ABX464:VA64 ASD) according to the invention The following tablets were prepared with the ingredients in the amounts specified in Tables 15 and 16 below.

[0400] First, the ASD powder was blended with intragranular excipients.

[0401] Secondly, the mixture thus obtained was subjected to dry granulation to form granules (96% w / w).

[0402] Third, the thus obtained granules (96% w / w) were blended with extragranular excipients.

[0403] Fourth, the mixture thus obtained was compressed into tablets.

[0404] Finally, the tablets thus obtained were coated with a film coating agent.

[0405] [Table 15]

[0406] [Table 16]

[0407] Such tablets could be prepared by substituting any other ASD according to the present invention for the ABX464:copovidone ASD powder.

[0408] The pharmaceutical compositions according to the present invention are useful in the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH, multiple sclerosis, diseases caused by viruses, and / or cancer and dysplasia. The present invention may be configured as follows. [Section 1] An amorphous solid dispersion comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. [Section 2] Item 1. The amorphous solid dispersion according to Item 1, wherein the pharmaceutically acceptable carrier is selected from a polymer, a sugar, an acid, a surfactant, a cyclodextrin or a cyclodextrin derivative, pentaerythritol, pentaerythrityl tetraacetate, urea, a urethane, a hydroxyalkylxanthine, and a mixture thereof, particularly a polymer, an acid, a surfactant, urea, and a mixture thereof, more particularly a polymer, an acid, a surfactant, and a mixture thereof. [Section 3] The pharmaceutically acceptable carrier is a polymer selected from homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose succinate, polymethacrylates, and mixtures thereof, in particular a polymer selected from povidone, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, and mixtures thereof, more in particular a polymer selected from povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymers, and mixtures thereof, where even more in particular copovidone; or a surfactant selected from Tweens, in particular Tween 80, or an acid selected from a combination of citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof, wherein more particularly citric acid; Item 3. The amorphous solid dispersion according to Item 1 or 2, [Section 4] Item 4. The amorphous solid dispersion according to any one of Items 1 to 3, wherein the amorphous solid dispersion is a glass solution that forms a homogeneous one-phase system, and 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is in an amorphous form. [Section 5] Item 5. The amorphous solid dispersion according to any one of Items 1 to 4, wherein the weight ratio of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof to the one or more pharmaceutically acceptable carriers is in the range of 1:20 to 1:0.5, particularly 1:10 to 1:1, and more particularly 1:2 to 1:1.5. [Section 6] Item 6. The amorphous solid dispersion according to any one of Items 1 to 5, wherein the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is present in an amount of 5% by weight to 70% by weight, particularly 30% by weight to 40% by weight, and more particularly 33% by weight to 37% by weight, based on the total weight of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers. [Section 7] Item 7. The amorphous solid dispersion according to any one of Items 1 to 6, wherein the one or more pharmaceutically acceptable carriers are present in an amount of 30% to 95% by weight, particularly 60% to 70% by weight, and more particularly 63% to 67% by weight, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers. [Section 8] 8. The amorphous solid dispersion according to any one of items 1 to 7, wherein the pharmaceutically acceptable carrier is one or more polymers as defined in items 2 and 3, optionally mixed with one or more acids and / or one or more surfactants, wherein the acids are in particular citric acid, succinic acid, malic acid, fumaric acid, tartaric acid or mixtures thereof, more in particular citric acid, and the surfactant is in particular Tween, more in particular Tween 80. [Section 9] A method for producing the amorphous solid dispersion according to any one of items 1 to 8, a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of suitable solvents to obtain a solution; b) adding at least one pharmaceutically acceptable carrier as defined in any one of items 1 to 8 to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); and d) evaporating said one or more solvents to provide said amorphous solid dispersion. The method, comprising the steps of: [Section 10] Item 10. The method according to item 9, wherein the suitable solvent in step a) is any volatile solvent capable of dissolving both the pharmaceutically acceptable carrier and ABX464 or a salt thereof, particularly the suitable solvent is selected from C1-C6 alcohols, dichloromethane, acetonitrile, acetone, THF (tetrahydrofuran), diethyl ether and mixtures thereof, more particularly selected from C1-C4 monoalcohols, dichloromethane and mixtures thereof, even more particularly selected from methanol, ethanol, dichloromethane and mixtures thereof, even more particularly methanol. [Section 11] Item 11. The method according to item 9 or 10, wherein the evaporation step d) is carried out by spray-drying or solvent evaporation, in particular spray-drying. [Section 12] a) mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier according to any one of items 1 to 8 to obtain a powder mixture; b) introducing the powder mixture obtained in step a) into a hot melt extruder to obtain a non-powder amorphous solid dispersion material; c) The non-powdered amorphous solid dispersion material thus obtained is then pulverized to obtain an amorphous solid dispersion powder. Item 9. A method for preparing the amorphous solid dispersion according to any one of items 1 to 8, comprising the steps of: [Section 13] Item 13. An amorphous solid dispersion obtainable by the method according to any one of items 9 to 12, comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. [Section 14] 14. A pharmaceutical composition comprising the amorphous solid dispersion according to any one of items 1 to 8 and 13 and at least one pharmaceutically acceptable excipient, in particular in the form of a tablet, capsule, pill, lozenge, chewing gum, powder, granule, suppository, emulsion, microemulsion, solution, e.g., aqueous solution, suspension, e.g., aqueous suspension, syrup, elixir, ointment, drop, paste, cream, lotion, gel, spray, inhalant or patch. [Section 15] Item 14. The pharmaceutical composition according to Item 14, wherein the pharmaceutical composition is a capsule or a tablet containing granules formed by the amorphous solid dispersion according to any one of Items 1 to 8 and 13 and at least one intragranular excipient, wherein the granules are compressed together with at least one extragranular excipient. [Section 16] Item 16. A method for preparing the pharmaceutical composition according to Item 14 or 15, comprising: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a mixture of suitable solvents to obtain a solution; b) adding at least one pharmaceutically acceptable carrier as defined in any one of items 1 to 8 to the solution of step a) thus obtained; c) optionally mixing the mixture obtained in step b); d) evaporating said one or more solvents to provide said amorphous solid dispersion; e) mixing the amorphous solid dispersion of step d) with one or more excipients to obtain the pharmaceutical composition; and f) optionally coating the pharmaceutical composition thus obtained, if a coated pharmaceutical composition is required; The method, comprising the steps of: [Section 17] Item 16. The amorphous solid dispersion according to any one of Items 1 to 8 and 13, or the pharmaceutical composition according to Item 14 or 15, for use as a pharmaceutical. [Section 18] The amorphous solid dispersion according to any one of Items 1 to 8 and 13, or the pharmaceutical composition according to Item 14 or 15, for use in the treatment and / or prevention of an inflammatory disease. [Section 19] The amorphous solid dispersion according to any one of Items 1 to 8 and 13, or the pharmaceutical composition according to Item 14 or 15, for use in the treatment and / or prevention of cancer. [Section 20] 20. The amorphous solid dispersion or pharmaceutical composition for use according to any one of items 17 to 19, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples from a patient is measured before and / or during said use, in particular to monitor the efficacy of and / or response to said use. [Section 21] Item 16. The amorphous solid dispersion according to any one of Items 1 to 8 and 13 or the pharmaceutical composition according to Item 14 or 15, for use in the treatment and / or prevention of a disease caused by a virus, in particular a retrovirus, more in particular HIV, more in particular for use in reducing the viral load in a patient infected with a virus, in particular HIV, or a virus-related condition, with long-lasting effect and in the absence of resistance. [Section 22] Item 16. The amorphous solid dispersion according to any one of Items 1 to 8 and 13 or the pharmaceutical composition according to Item 14 or 15, for use in the treatment and / or prevention of diseases caused by viruses belonging to the Coronaviridae family or coronavirus infections and conditions associated therewith, and in particular severe acute respiratory syndrome caused by infection with SARS-CoV or SARS-CoV-2, including the COVID-19 causative strain and its mutant strains. [Section 23] 23. The amorphous solid dispersion or pharmaceutical composition for use according to any one of items 17 to 22, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in a patient's blood, plasma, tissue, saliva, and / or serum sample is measured during the use.

Claims

1. 1. An amorphous solid dispersion comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, The pharmaceutically acceptable carrier may be Copovidone, povidone, methacrylic acid / ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate, a mixture of copovidone and povidone, a mixture of copovidone and citric acid, a mixture of povidone and citric acid, a mixture of copovidone and Tween 80, and a mixture of copovidone and hydroxypropyl methylcellulose acetate succinate. is selected from 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is present in an amount of 30% to 40% by weight, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers, and the one or more pharmaceutically acceptable carriers are present in an amount of 60% to 70% by weight, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers. The amorphous solid dispersion.

2. 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is present in an amount of 35% by weight based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers, and the one or more pharmaceutically acceptable carriers are present in an amount of 65% by weight based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers.

2. The amorphous solid dispersion of claim 1.

3. When the one or more pharmaceutically acceptable carriers are a mixture of a first compound and a second compound, and the mixture is selected from a mixture of copovidone and povidone, a mixture of copovidone and citric acid, a mixture of povidone and citric acid, a mixture of copovidone and Tween 80, or a mixture of copovidone and hydroxypropyl methylcellulose acetate succinate, the first compound is present in an amount of 45% by weight, based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers; and the second compound is present in an amount of 20% by weight based on the total weight of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof and the one or more pharmaceutically acceptable carriers; 3. The amorphous solid dispersion according to claim 1 or 2.

4. 4. The amorphous solid dispersion of claim 1, wherein the pharmaceutically acceptable carrier is povidone or copovidone.

5. 5. The amorphous solid dispersion of claim 1, wherein the amorphous solid dispersion is a glassy solution forming a homogeneous one-phase system, and the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof is in an amorphous form.

6. A method for preparing the amorphous solid dispersion of any one of claims 1 to 5, comprising: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a suitable mixture of solvents to obtain a solution; b) adding to the solution of step a) thus obtained at least one pharmaceutically acceptable carrier as defined in any one of claims 1 to 5; c) optionally mixing the mixture obtained in step b); and d) evaporating the one or more solvents to provide the amorphous solid dispersion. The method, comprising the steps of:

7. a) mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier according to any one of claims 1 to 5 to obtain a powder mixture; b) introducing the powder mixture obtained in step a) into a hot melt extruder to obtain a non-powder amorphous solid dispersion material; c) The non-powdered amorphous solid dispersion material thus obtained is then pulverized to obtain an amorphous solid dispersion powder.

6. A method for preparing the amorphous solid dispersion of any one of claims 1 to 5, comprising the steps of:

8. A pharmaceutical composition comprising the amorphous solid dispersion of any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient.

9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is a capsule or a tablet comprising granules formed by the amorphous solid dispersion of any one of claims 1 to 5 and by at least one intragranular excipient, wherein the granules are compressed together with at least one extragranular excipient.

10. A method for preparing the pharmaceutical composition of claim 8 or 9, comprising: a) dissolving 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof in a suitable solvent or a suitable mixture of solvents to obtain a solution; b) adding to the solution of step a) thus obtained at least one pharmaceutically acceptable carrier as defined in any one of claims 1 to 5; c) optionally mixing the mixture obtained in step b); d) evaporating the one or more solvents to provide the amorphous solid dispersion; e) mixing the amorphous solid dispersion of step d) with one or more excipients to obtain the pharmaceutical composition; and f) optionally coating the pharmaceutical composition thus obtained, if a coated pharmaceutical composition is required; The method, comprising the steps of:

11. 10. The amorphous solid dispersion according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 8 or 9, for use as a pharmaceutical.

12. 10. The amorphous solid dispersion according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 8 or 9, for use in the treatment and / or prevention of inflammatory diseases.

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